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Annals of Oncology www.annonc.oxfordjournals.org www.esmo.org www.jsmo.umin.jp 1 ISSN 0923-7534 (print) ISSN 1569-8041 (online) Volume 23 Supplement 9 2012 Abstract Book of the 37th ESMO Congress Vienna, Austria 28 September – 2 October 2012 Guest Editors: ESMO Educational Committee Scan to view this journal on your mobile device
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Annals<br />
of Oncology<br />
www.annonc.oxfordjournals.org<br />
www.esmo.org<br />
www.jsmo.umin.jp<br />
1<br />
ISSN 0923-7534 (print)<br />
ISSN 1569-8041 (online)<br />
Volume 23 Supplement 9 <strong>2012</strong><br />
<strong>Abstract</strong> <strong>Book</strong><br />
of <strong>the</strong> 37th <strong>ESMO</strong><br />
Congress<br />
Vienna, Austria<br />
28 September – 2 October <strong>2012</strong><br />
Guest Editors:<br />
<strong>ESMO</strong> Educational Committee<br />
Scan to view this journal<br />
on your mobile device
Annals of Oncology<br />
Official Journal of <strong>the</strong> European Society for Medical Oncology and<br />
<strong>the</strong> Japanese Society of Medical Oncology<br />
editor-in-chief:<br />
J. B. Vermorken, Edegem, Belgium<br />
associate editors<br />
Supportive and palliative care<br />
M. S. Aapro, Genolier, Switzerland<br />
D. Schrijvers, Antwerp, Belgium<br />
Hematologic malignancies<br />
J. O. Armitage, Omaha, Nebraska, USA<br />
M. Pfreundschuh, Hamburg/Saar,<br />
Germany<br />
Geriatric oncology<br />
L. Balducci, Tampa, Florida, USA<br />
H. Wildiers, Leuven, Belgium<br />
Radiation oncology<br />
J. Bernier, Geneva, Switzerland<br />
editorial board<br />
editors emeriti<br />
F. Cavalli, Bellinzona, Switzerland<br />
D. J. Kerr, <strong>Oxford</strong>, UK<br />
Epidemiology<br />
C. La Vecchia, Milan, Italy<br />
Urogenital tumors<br />
K. Fizazi, Villejuif, France<br />
D. Raghavan, Cleveland, Ohio, USA<br />
Gastrointestinal tumors<br />
C. J. A. Punt, Amsterdam, The Ne<strong>the</strong>rlands<br />
R. Labianca, Bergamo, Italy<br />
Lung tumors<br />
E. Felip, Barcelona, Spain<br />
N. Saijo, Osakasayama, Japan<br />
Head and neck tumors<br />
L. Licitra, Milan, Italy<br />
E. E. Vokes, Chicago, Illinois, USA<br />
Breast tumors<br />
M. Castiglione-Gertsch, Geneva,<br />
Switzerland<br />
D. A. Vorobiof, Johannesburg,<br />
South Africa<br />
Gynecologic malignancies<br />
J. Ledermann, London, UK<br />
H. Yoshikawa, Tsukuba, Japan<br />
Surgical oncology<br />
L. Påhlman, Uppsala, Sweden<br />
Translational research<br />
H. McLeod, Chapel Hill,<br />
North Carolina, USA<br />
G. Tortora, Verona, Italy<br />
F. Andre, Villejuif, France W. Hiddemann, Munich, Germany E. A. Perez, Jacksonville, Florida, USA<br />
K. K. Antman, New York, New York, USA C. Ishioka, Sendai, Japan B. C. Pestalozzi, Zurich, Switzerland<br />
B. Arun, Houston, Texas, USA P. Jacobs, Cape Town, South Africa G. J. Peters, Amsterdam, The Ne<strong>the</strong>rlands<br />
J. Baselga, Boston, Massachusetts, USA Y. Kakehi, Kagawa, Japan M. Posner, New York, USA<br />
C. Bokemeyer, Hamburg, Germany N. Katsumata, Tokyo, Japan A. Poveda, Valencia, Spain<br />
F. Cabanillas, Houston, Texas, USA B. Kaufman, Tel Hashomer, Israel A. Psyrri, New Haven, Connecticut, USA<br />
K. Chi, Vancouver, Canada S. B. Kaye, Sutton, UK D. Quinn, Los Angeles, California, USA<br />
F. Ciardiello, Naples, Italy U. Keilholz, Berlin, Germany V. Raina, New Delhi, India<br />
A. S. Coates, Sydney, Australia H. M. Khaled, Cairo, Egypt M. Ranson, Manchester, UK<br />
J. M. Connors, Vancouver, Canada C.-H. Köhne, Dresden, Germany R. Rosell, Badalona, Spain<br />
H. Cortés-Funes, Madrid, Spain P. A. Kosmidis, A<strong>the</strong>ns, Greece A. Roth, Geneva, Switzerland<br />
D. Cunningham, Sutton, UK H. Kunitoh, Tokyo, Japan M. Saghatchian, Villejuif, France<br />
S. Daryanani, Caracas, Venezuela T. Le Chevalier, London, UK M. Sasako, Nishinomiya, Japan<br />
S. Delaloge, Villejuif, France J. S. Macdonald, New York, New York, USA W. Scheithauer, Vienna, Austria<br />
A. Di Leo, Prato, Italy F. Mandelli, Rome, Italy J. H. M. Schellens, Amsterdam, The Ne<strong>the</strong>rlands<br />
C. Dittrich, Vienna, Austria P. Mauch, Boston, Masachusetts, USA H.-J. Schmoll, Halle, Germany<br />
J.-Y. Douillard, Saint-Herblain, France R. J. Mayer, Boston, Masachusetts, USA H. C. Schouten, Maastricht, The Ne<strong>the</strong>rlands<br />
L. H. Einhorn, Indianapolis, Indiana, USA M. Middleton, <strong>Oxford</strong>, UK K. C. Soo, Singapore<br />
E. A. Eisenhauer, Kingston, Canada H. Minami, Kobe, Japan C. N. Sternberg, Rome, Italy<br />
A. Eniu, Cluj-Napoca, Romania V. M. Moiseyenko, St Petersburg, S. T. Tagawa, New York, New York, USA<br />
B. Escudier, Villejuif, France Russian Federation M. Tahara, Chiba, Japan<br />
R. I. Fisher, Rochester, New York, USA F. M. Muggia, New York, New York, USA V. Tjan-Heijnen, Maastricht, The Ne<strong>the</strong>rlands<br />
G. Giaccone, Be<strong>the</strong>sda, Maryland, USA J. M. Nabholtz, Clermont-Ferrand, France S. Tjulandin, Moscow, Russian Federation<br />
A. J. Gelderblom, Leiden, The Ne<strong>the</strong>rlands Y. Nagata, Kyoto, Japan Y. Tokuda, Isehara, Japan<br />
B. Glimelius, Uppsala, Sweden T. Naoe, Nagoya, Japan M. Tonato, Perugia, Italy<br />
B. C. Goh, Singapore, Singapore T. Ngoma, Dar es Salaam, Tanzania T. Tursz, Villejuif, France<br />
A. Goldhirsch, Milan, Italy K. Nishio, Osaka, Japan C. Vallejos Sologuren, Lima, Peru<br />
M. D. Green, Melbourne, Australia K. Öberg, Uppsala, Sweden C. Verschraegen, Albuquerque,<br />
K. J. Harrington, London, UK A. Ohtsu, Kashiwa, Japan New Mexico, USA<br />
K. Hatake, Tokyo, Japan M. Peeters, Edegem, Belgium A. D. Zelenetz, New York, New York, USA<br />
executive editor: Lewis Rowett<br />
editorial office: Paola Minotti Bernasconi, Giovannella Porcu, Annals of Oncology, Via Luigi Taddei 4, CH-6962 Viganello-Lugano,<br />
Switzerland<br />
Annals of Oncology is covered in C.A.B. International, Current Clinical Cancer, Current Contents/Clinical Medicine®, Current Contents/<br />
Life Sciences, Elsevier BIOBASE/Current Awareness in Biological Sciences, EMBASE/Excerpta Medica, IBIDS, Index Medicus/MEDLINE,<br />
The International Monitor in Oncology, Medical Documentation Service, Science Citation Index® and Science Citation Index Expanded.
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drug disclaimer<br />
All reasonable precautions have been taken by <strong>the</strong> authors, editors and publisher<br />
to verify drug names and doses, <strong>the</strong> results of experimental work and <strong>the</strong> clinical<br />
findings published in this journal. The opinions expressed are those of <strong>the</strong><br />
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The editors and publisher can accept no liability whatsoever in respect of any<br />
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© The European Society for Medical Oncology <strong>2012</strong><br />
All rights reserved; no part of this publication may be reproduced, stored in a<br />
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photocopying, recording, or o<strong>the</strong>rwise without prior written permission<br />
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Notice:<br />
The content of <strong>the</strong> abstracts contained in this <strong>Abstract</strong> <strong>Book</strong> is subject to an<br />
embargo. <strong>Abstract</strong>s accepted for presentation at <strong>ESMO</strong> <strong>2012</strong> (Proffered Paper<br />
(oral presentation), Poster Discussion and Poster) and for publication in <strong>the</strong><br />
Congress <strong>Abstract</strong> <strong>Book</strong>, will be published online on <strong>the</strong> <strong>ESMO</strong> website on<br />
Monday, 17 September <strong>2012</strong>. Late-breaking abstracts will be made public at <strong>the</strong><br />
beginning of <strong>the</strong> official Congress session during which <strong>the</strong>y are presented.<br />
<strong>Abstract</strong>s selected for <strong>the</strong> official <strong>ESMO</strong> Press Program will be made public at<br />
<strong>the</strong> beginning of <strong>the</strong> official Press Conference or Congress session during which<br />
<strong>the</strong>y are presented, whichever comes first.<br />
Disclaimer:<br />
No responsibility is assumed by <strong>the</strong> organizers for any injury and/or damage to<br />
persons or property as a matter of products liability, negligence or o<strong>the</strong>rwise, or<br />
from any use or operation of any methods, products, instructions or ideas contained<br />
in <strong>the</strong> material herein. Because of <strong>the</strong> rapid advances in medical sciences,<br />
we recommend that independent verification of diagnoses and drug dosages<br />
should be made. Every effort has been made to faithfully reproduce <strong>the</strong><br />
abstracts as submitted. However, no responsibility is assumed by <strong>the</strong> organizers<br />
for any omissions or misprints.
Annals of<br />
Oncology<br />
Official Journal of <strong>the</strong> European Society<br />
for Medical Oncology and <strong>the</strong> Japanese<br />
Society of Medical Oncology<br />
Volume 23, <strong>2012</strong> Supplement 9<br />
<strong>Abstract</strong> <strong>Book</strong> of <strong>the</strong> <strong>ESMO</strong> <strong>2012</strong> Congress<br />
Vienna, Austria, 28 September – 2 October <strong>2012</strong><br />
Guest Editors: Scientific Committee of <strong>the</strong> <strong>ESMO</strong> <strong>2012</strong> Congress
Annals of Oncology<br />
Official Journal of <strong>the</strong> European Society for<br />
Medical Oncology and <strong>the</strong> Japanese Society of Medical Oncology<br />
Volume 23, <strong>2012</strong> Supplement 9<br />
<strong>Abstract</strong> <strong>Book</strong> of <strong>the</strong> <strong>ESMO</strong> <strong>2012</strong> Congress, Vienna, Austria<br />
28 September – 2 October <strong>2012</strong><br />
About <strong>ESMO</strong> ix7<br />
<strong>ESMO</strong> Committees ix8<br />
<strong>ESMO</strong> <strong>2012</strong> Congress Officers ix10<br />
<strong>ESMO</strong> <strong>2012</strong> Congress Organization ix12<br />
<strong>ESMO</strong> Congress Travel Grants ix13<br />
Acknowledgements ix14<br />
Exhibitors ix15<br />
<strong>ESMO</strong> Fellowships ix17<br />
Invited abstracts<br />
Hamilton Fairley Award ix21<br />
Keynote sessions<br />
PI 3-kinase and cancer metabolism ix21<br />
HPV biology and implications in gynecological<br />
malignancies ix22<br />
The hallmarks of cancer revisited ix23<br />
The characterization of lung cancer in multiple different<br />
diseases ix24<br />
Special Symposia<br />
The impact of <strong>the</strong> cancer genome project and high-throughput<br />
analyses on personalised oncology: today and tomorrow ix25<br />
Optimizing treatment in luminal breast cancer ix27<br />
How to integrate new drugs in <strong>the</strong> current <strong>the</strong>rapeutic<br />
landscape of metastatic triple negative breast cancer ix29<br />
Molecular neuro-oncology: new avenues in diagnosis and<br />
treatment ix31<br />
A paradigm shift in early drug development:<br />
individualizing to more patient benefit ix32<br />
How can medical oncologists deal with <strong>the</strong> new wave<br />
of genetic information about <strong>the</strong>ir patients? ix34<br />
Pursuing <strong>the</strong> NED condition in stage IV colorectal cancer ix35<br />
From biology to treatment in advanced pancreatic and<br />
gastroesophageal cancer ix37<br />
Re-inventing <strong>the</strong> medical treatment of advanced<br />
prostate cancer ix38<br />
Molecular answers and targets on <strong>the</strong> horizon for <strong>the</strong><br />
treatment of genitourinary malignancies ix39<br />
Emerging diagnostic and <strong>the</strong>rapeutic targets in<br />
gynecological cancers: from science to clinical practice ix40<br />
Biologically based treatment in head and neck squamous<br />
cell carcinoma (HNSCC) ix42<br />
Molecular targets in malignant lymphomas: from<br />
basic science to clinical practice ix44<br />
Volume 23 | Supplement 9 | September <strong>2012</strong><br />
Melanoma <strong>the</strong>rapy: from frustration to enthusiasm ix46<br />
Integrating targeted treatments with tumor biology and<br />
molecular imaging in <strong>the</strong> current and future management of<br />
neuroendocrine gastrointestinal tumors ix47<br />
Hot topics in early stage NSCLC ix49<br />
Latest innovations in NSCLC management ix51<br />
Evidence based answers to critical questions on cancer<br />
screening and prevention ix53<br />
Subtyping soft tissue sarcomas for treatment approaches ix54<br />
Key topics in supportive care ix56<br />
Joint Symposia<br />
<strong>ESMO</strong>-ASCO - Genomics in breast cancer: Opening new<br />
doors ix57<br />
<strong>ESMO</strong>/CSCO - Building <strong>the</strong> clinical trials of <strong>the</strong> future ix58<br />
<strong>ESMO</strong>-EACR - Targeted <strong>the</strong>rapies: Promises, successes<br />
and failures ix59<br />
<strong>ESMO</strong>-EANM-ESR - Imaging biomarkers in <strong>the</strong> era of<br />
targeted <strong>the</strong>rapies ix60<br />
<strong>ESMO</strong>-ESP - Molecular diagnostics for personalized<br />
cancer treatment ix61<br />
<strong>ESMO</strong>-ESTRO - Innovative approaches to <strong>the</strong> treatment<br />
of brain metastases ix62<br />
<strong>ESMO</strong>-JSMO - Recent advances in <strong>the</strong> treatment of<br />
GI tract and liver cancer in <strong>the</strong> EU and Japan ix63<br />
<strong>ESMO</strong>-MASCC - Integration between medical oncology<br />
and supportive care: Two sides of <strong>the</strong> same coin ix64<br />
<strong>ESMO</strong> DCTF-AORTIC-SLACOM-UICC-WHO - Independent<br />
and publicly funded research: A new global model ix65<br />
Society Symposium<br />
ESO – Celebrating 30 years of ESO and 50 issues of<br />
Cancer World. Cancer 2020: The road to personalized<br />
cancer care ix66<br />
Submitted abstracts<br />
Basic science ix67<br />
Biomarkers ix73<br />
Breast cancer, early stage ix95<br />
Breast cancer, locally advanced and metastatic ix116<br />
CNS tumors ix144<br />
Developmental <strong>the</strong>rapeutics ix152<br />
Familial cancer and genetic syndromes ix175<br />
Gastrointestinal tumors, colorectal ix178<br />
Gastrointestinal tumors, non-colorectal ix224<br />
Genitourinary tumors, non-prostate ix258<br />
Genitourinary tumors, prostate ix294
Gynecological cancers ix319<br />
Head and neck cancer ix334<br />
Hematological malignancies ix348<br />
Melanoma and o<strong>the</strong>r skin tumors ix361<br />
Neuroendocrine tumors and CUP ix376<br />
New diagnostics ix383<br />
Non-small cell lung cancer, early stage ix385<br />
Non-small cell lung cancer, locally advanced ix389<br />
Non-small cell lung cancer, metastatic ix400<br />
Oncology and public health ix447<br />
Palliative care ix462<br />
Prevention and screening ix469<br />
Psycho-oncology ix474<br />
Sarcoma ix478<br />
Small cell lung cancer and o<strong>the</strong>r thoracic malignancies ix492<br />
Supportive care ix499<br />
Translational research ix528<br />
Tumor biology and pathology ix541<br />
Author index ix546<br />
Subject index ix586<br />
Drug index ix601<br />
Translational research index ix604<br />
Note: <strong>Abstract</strong> suffixes<br />
“IN” indicates an invited abstract<br />
"O" indicates a submitted abstract accepted for oral presentation<br />
"PD" indicates a submitted abstract accepted for poster discussion<br />
"P" indicates a submitted abstract accepted for poster presentation<br />
abstracts with no suffix have not been accepted for presentation at <strong>the</strong> Congress but are published in <strong>the</strong> <strong>Abstract</strong> <strong>Book</strong>.<br />
“TiP” indicates a submitted abstract accepted for poster presentation, trial in progress<br />
__PR indicates a submitted abstract selected for press coverage<br />
Volume 23 | Supplement 9 | September <strong>2012</strong>
The European Society for Medical Oncology (<strong>ESMO</strong>)<br />
The European Society for Medical Oncology (<strong>ESMO</strong>) is <strong>the</strong> leading European professional organization, committed to<br />
advancing <strong>the</strong> specialty of medical oncology and promoting a multidisciplinary approach to cancer treatment and care.<br />
Since its founding in 1975 as a non-profit organization, <strong>ESMO</strong>’s mission has been to advance cancer care and cure. We<br />
achieve this through fostering and disseminating good science that leads to better medicine and determines best practice. In<br />
this way <strong>ESMO</strong> fulfils its goal to support oncology professionals in providing people with cancer with <strong>the</strong> most effective<br />
treatments available and <strong>the</strong> high-quality care <strong>the</strong>y deserve.<br />
The <strong>ESMO</strong> community is a powerful alliance of more than 7,000 committed oncology professionals from over 120<br />
countries. As a trusted organization with 35 years of experience and over 500 expert committee members, <strong>ESMO</strong> serves its<br />
members and <strong>the</strong> oncology community through:<br />
• Excellence in post-graduate oncology education and training<br />
• Leadership in transforming evidence-based research into standards of cancer care in Europe<br />
• Dedicated efforts to foster a more favorable environment for scientific research<br />
• Innovative international platforms to share expertise, best practices and disseminate <strong>the</strong> most up-to-date scientific<br />
research to as wide an audience as possible.<br />
<strong>ESMO</strong> has expanded its membership offering through OncologyPRO, an exclusive scientific and educational website: http:\<br />
\oncologypro.esmo.org. <strong>ESMO</strong>’s scientific journal, Annals of Oncology, ranks among <strong>the</strong> top clinical oncology journals<br />
worldwide. <strong>ESMO</strong> events are <strong>the</strong> meeting place in Europe for medical oncologists to update <strong>the</strong>ir knowledge, network and<br />
exchange ideas. <strong>ESMO</strong> also unites key oncology stakeholders and forges strategic partnerships to address critical issues<br />
related to <strong>the</strong> profession and practice of medical oncology. Recognized as an authoritative voice in <strong>the</strong> fight against cancer,<br />
<strong>ESMO</strong> is pleased to offer consultative expertise to oncology organizations and European authorities on important issues<br />
related to cancer research, prevention, diagnosis, treatment and care.<br />
Join <strong>the</strong> <strong>ESMO</strong> community today! Please visit www.esmo.org to learn more.<br />
European Society for Medical Oncology (<strong>ESMO</strong>)<br />
Via Luigi Taddei, 4, 6962 Viganello – Lugano, Switzerland<br />
T +41 (0)91 973 19 00<br />
F +41 (0)91 973 19 02<br />
W www.esmo.org<br />
E esmo@esmo.org
European Society for Medical Oncology Committees<br />
Executive Board<br />
President Martine Piccart, Belgium<br />
President-Elect Rolf A. Stahel, Switzerland<br />
Treasurer Fortunato Ciardiello, Italy<br />
Educational Committee Chair Jean-Yves Douillard, France<br />
National Representatives & Membership Committee Chair Razvan Popescu, Switzerland<br />
Public Policy Committee Chair Paolo Casali, Italy<br />
Guidelines Working Group Chair Andres Cervantes, Spain<br />
Member Elisabeth de Vries, Ne<strong>the</strong>rlands<br />
Member Cristiana Sessa, Switzerland<br />
Member Eric Van Cutsem, Belgium<br />
Chief Executive Officer Alan J. Howard, Switzerland<br />
Educational Committee Chair: Jean-Yves Douillard, France<br />
Cancer Patient Working Group Chair: Lorenz Jost, Switzerland<br />
Community Oncology Working Group Chair: Robert Eckert, Germany<br />
E-Learning and CME Working Group Chair: Claus-Henning Koehne, Germany<br />
Examination Working Group Chair: Richard Herrmann, Switzerland<br />
Global Curriculum Task Force Chair: Nicholas Pavlidis, Greece<br />
Palliative Care Working Group Chair: Nathan Cherny, Israel<br />
Publishing Working Group Chair: Michele Ghielmini, Switzerland<br />
Translational Research Working Group Chair: Giampaolo Tortora, Italy<br />
*Guidelines Working Group<br />
*The Guidelines WG reports directly to <strong>the</strong> EXC Board, <strong>the</strong> chair is sitting in <strong>the</strong><br />
Educational Committee for informative purposes only.<br />
Chair: Andrés Cervantes, Spain<br />
<strong>ESMO</strong> Faculty Coordinators<br />
Head and neck cancer Marco Merlano, Italy<br />
Chest tumors Enriqueta Felip, Spain<br />
Gastrointestinal tumors Alberto Sobrero, Italy<br />
Breast cancer Fabrice André, France<br />
Gynecologic cancer Jonathan Ledermann, UK<br />
Genitourinary cancer Bernard Escudier, France<br />
Sarcoma Jean-Yves Blay, France<br />
Hematologic malignancy Martin Dreyling, Germany<br />
Principles of clinical trials and systemic <strong>the</strong>rapy Christian Dittrich, Austria<br />
Cancer research Marco A. Pierotti, Italy<br />
Cancer prevention Hans-Joerg Senn, Switzerland<br />
Elderly Gilbert B. Zulian, Switzerland<br />
Supportive and palliative care Jorn Herrstedt, Denmark<br />
Cancer genetics Pierre Laurent-Puig, France<br />
CNS tumors Michael Weller, Switzerland<br />
CUP, endocrine tumors and o<strong>the</strong>rs George Pen<strong>the</strong>roudakis, Greece<br />
Melanoma Richard Dummer, Switzerland
Audit Committee Chair: Fortunato Ciardiello, Italy<br />
Young Oncologists Committee Chair: Michalis Karamouzis, Greece<br />
Fellowship and Award Committee Chair: Josep Tabernero, Spain<br />
Press and Media Affairs Chair: Fortunato Ciardiello, Italy<br />
Nominating Committee Chair: Jean-Pierre Armand, France<br />
Developing Countries Task Force Chair: Adamos Adamou, Cyprus<br />
Annals of Oncology Editorial Board Editor-in-Chief: Jan B. Vermorken, Belgium<br />
<strong>ESMO</strong> National Representatives<br />
Country Name Country Name<br />
Chair Razvan Popescu<br />
Albania Alketa Ymeri Latvia Alinta Hegmane<br />
Austria Gabriela Kornek Lithuania Rasa Janciauskiene<br />
Belarus Yauheni Baranau Luxembourg Stefan Rauh<br />
Belgium Ahmad Awada Macedonia Petar Stefanovski<br />
Bosnia Herzegovina Timur Ceric Moldova Vasile Musteata<br />
Bulgaria Zhasmina Mihaylova Montenegro Vladimir Todorovic<br />
Croatia Borislav Belev Ne<strong>the</strong>rlands A.N.M. Wymenga<br />
Cyprus George Marcoullis Norway Eva Hofsli<br />
Czech Republic Tomas Svoboda Poland Renata Zaucha<br />
Denmark Ulrik Lassen Portugal Paolo Cortes<br />
Estonia Peeter Padrik Romania Alexandru Eniu<br />
Finland Maarit Barlund Russian Federation Vladimir Moiseyenko<br />
France Michel Ducreux Serbia Zorica Tomasevic<br />
Georgia Tamari Rukhadze Slovakia Jozef Mardiak<br />
Germany Ulrich Keilholz Slovenia Erika Matos<br />
Greece Gerasimos Aravantinos Spain Ramon Colomer<br />
Hungary Istvan Lang Sweden Roger K. Henriksson<br />
Iceland Helgi Hafsteinn Helgason Switzerland Giannicola D’Addario<br />
Ireland Michael J. Martin Turkey Ahmet Demirkazik<br />
Israel Ron Epelbaum Ukraine Iryna Kryachok<br />
Italy Marina Garassino UK Robert Coleman<br />
<strong>ESMO</strong> Regional representatives<br />
Region Name Region Name<br />
Central America and <strong>the</strong> Caribbean Jean-René Clemenceau North Africa Gaafar Rabab<br />
China Jun Ma Oceania Gary Richardson<br />
Far East Sumitra Thongprasert Sub-Saharan Africa Verna Vanderpuye<br />
India, Pakistan, Bangladesh Maheboob Mahamud Basade South America Ignacio Muse<br />
Japan Kazuo Tamura USA, North America Everett E. Volkes<br />
Middle East Ashraf Awad Elkarim
<strong>ESMO</strong> <strong>2012</strong> Congress Officers<br />
<strong>ESMO</strong> <strong>2012</strong> Congress President<br />
Martine Piccart, Brussels, Belgium<br />
<strong>ESMO</strong> <strong>2012</strong> Scientific Committee Chair<br />
Josep Tabernero, Barcelona, Spain<br />
<strong>ESMO</strong> <strong>2012</strong> Educational Chair<br />
Rolf A. Stahel, Zurich, Switzerland<br />
<strong>ESMO</strong> <strong>2012</strong> Press Officer<br />
Fortunato Ciardiello, Naples, Italy<br />
<strong>ESMO</strong> <strong>2012</strong> Local Officer<br />
Christoph Zielinski, Vienna, Austria<br />
Scientific Sub-Committees<br />
Basic science and translational research<br />
Yosef Yarden, Rehovat, Israel, Chair<br />
Alan Ashworth, London, UK<br />
Carlos Caldas, Cambridge, UK<br />
Maria Grazia Daidone, Milan, Italy<br />
Caroline Dive, Manchester, UK<br />
Sabine Tejpar, Leuven, Belgium<br />
Giampaolo Tortora, Verona, Italy<br />
Breast cancer, early stage<br />
Ian Smith, London, UK, Chair<br />
Fatima Cardoso, Lisbon, Portugal<br />
Angelo di Leo, Prato, Italy<br />
Paul Ellis, London, UK<br />
Christos Sotiriou, Brussels, Belgium<br />
Christoph Zielinski, Vienna, Austria<br />
Breast cancer, metastatic<br />
Fabrice André, Villejuif, France, Chair<br />
Javier Cortes, Barcelona, Spain<br />
Giuseppe Curigliano, Milan, Italy<br />
Wolfgang Eiermann, Munich, Germany<br />
Luca Gianni, Milan, Italy<br />
Nick Turner, London, UK<br />
CNS tumors<br />
Michael Weller, Zurich, Switzerland, Chair<br />
Michael Brada, London, UK<br />
Christine Marosi, Vienna, Austria<br />
Roger Stupp, Lausanne, Switzerland<br />
Martin Van den Bent, Rotterdam, Ne<strong>the</strong>rlands<br />
Wolfgang Wick, Heidelberg, Germany<br />
Developmental <strong>the</strong>rapeutics<br />
Ahmad Awada, Brussels, Belgium, Chair<br />
José Baselga, Boston, USA<br />
Fiona Blackhall, Manchester, UK<br />
Christian Dittrich, Vienna, Austria<br />
Elisabeth Eisenhauer, Kingston, ON, Canada<br />
Tetsuya Mitsudomi, Aichi, Japan<br />
Jan Schellens, Amsterdam, Ne<strong>the</strong>rlands<br />
Gynecological cancers<br />
Nicoletta Colombo, Milan, Italy, Chair<br />
Stan Kaye, Sutton, UK<br />
Jonathan Ledermann, London, UK<br />
Andres Poveda, Valencia, Spain<br />
Cristiana Sessa, Bellinzona, Switzerland<br />
Ate van der Zee, Groningen, Ne<strong>the</strong>rlands<br />
Head and neck cancer<br />
Luis Paz-Ares, Seville, Spain, Chair<br />
Sandrine Faivre, Clichy, France<br />
Antonio Jimeno, Denver, Colorado, USA<br />
Jean Louis Lefebvre, Lille, France<br />
Lisa Licitra, Milan, Italy<br />
Amanda Psyrri, A<strong>the</strong>ns, Greece<br />
Hematological malignancies<br />
Martin Dreyling, Munich, Germany, Chair<br />
Meletios Dimopoulos, A<strong>the</strong>ns, Greece<br />
Michele Ghielmini, Bellinzona, Switzerland<br />
Håkan Mellstedt, Stockholm, Sweden<br />
Vincent Ribrag, Villejuif, France<br />
Lena Specht, Copenhagen, Denmark<br />
Melanoma and o<strong>the</strong>r skin tumors<br />
Alexander M.M. Eggermont, Villejuif, France, Chair<br />
Lars Bastholt, Odense, Denmark<br />
Reinhard Dummer, Zurich, Switzerland<br />
Ulrich Keilholz, Berlin, Germany<br />
David Khayat, Paris, France<br />
NETs and endocrine tumors<br />
Kjell Öberg, Uppsala, Sweden, Chair<br />
Dik Kwekkeboom, Rotterdam, Ne<strong>the</strong>rlands<br />
Eric Raymond, Paris, France<br />
Guido Rindi, Rome, Italy<br />
Ramon Salazar, Barcelona, Spain<br />
James Yao, Houston, USA
Familial cancer<br />
Judith Balmaña, Barcelona, Spain, Chair<br />
Elena Castro, London, UK<br />
Raphael Catane, Tel-Hashomer, Israel<br />
Isabel Chirivella Valencia, Spain<br />
Andrew Tutt, London, UK<br />
Eduardo Vilar, Ann Arbor, Michigan, USA<br />
Gastrointestinal tumors, colorectal<br />
Alberto Sobrero, Genoa, Italy, Chair<br />
Dirk Arnold, Hamburg, Germany<br />
Jean-Yves Douillard, Nantes, France<br />
Claus-Henning Koehne, Oldenburg, Germany<br />
Matt Seymour, London, UK<br />
Eric Van Cutsem, Leuven, Belgium<br />
Gastrointestinal tumors, non-colorectal<br />
Roberto Labianca, Bergamo, Italy, Chair<br />
Stefano Cascinu, Ancona, Italy<br />
Andres Cervantes, Valencia, Spain<br />
Manfred Lutz, Saarbrücken, Germany<br />
Emmanuel Mitry, Paris, France<br />
Arnaud Roth, Geneva, Switzerland<br />
Genitourinary tumors, prostate<br />
Johann S. de Bono, Sutton, UK, Chair<br />
Joan Carles, Barcelona, Spain<br />
Karim Fizazi, Villejuif, France<br />
Vesa Kataja, Kuopio, Finland<br />
Ian Tannock, Toronto, Canada<br />
Bertrand Tombal, Brussels, Belgium<br />
Genitourinary tumors, non-prostate<br />
Maria de Santis, Vienna, Austria, Chair<br />
Joaquim Bellmunt, Barcelona, Spain<br />
Carsten Bokemeyer, Hamburg, Germany<br />
Tim Eisen, Sutton, UK<br />
Christian Kollmannsberger, Vancouver, Canada<br />
Cora Sternberg, Rome, Italy<br />
NSCLC, early stage, SCLC and o<strong>the</strong>r thoracic malignancies<br />
Rafal Dziadziuszko, Gdansk, Poland, Chair<br />
Paul Baas, Amsterdam, Ne<strong>the</strong>rlands<br />
Benjamin Besse, Paris, France<br />
Giuseppe Giaccone, Be<strong>the</strong>sda, USA<br />
Rafael Rosell, Barcelona, Spain<br />
Suresh Senan, Amsterdam, Ne<strong>the</strong>rlands<br />
Walter Weder, Zurich, Switzerland<br />
NSCLC, metastatic<br />
Enriqueta Felip, Barcelona, Spain, Chair<br />
Federico Cappuzzo, Livorno, Italy<br />
Cesare Gridelli, Avellino, Italy<br />
Pasi Jånne, Houston, USA<br />
Tony Mok, Hong Kong, China<br />
Martin Reck, Grosshansdorf, Germany<br />
Oncology and public health<br />
Xavier Bosch, Barcelona, Spain, Chair<br />
Jan Willem Coebergh, Rotterdam, Ne<strong>the</strong>rlands<br />
Jack Cuzick London, UK<br />
Heinz Ludwig, Vienna, Austria<br />
Hans H. Storm, Copenhagen, Denmark<br />
Sarcoma<br />
Jaap Verweij, Rotterdam, Ne<strong>the</strong>rlands, Chair<br />
Jean-Yves Blay, Lyon, France<br />
Paolo Casali, Milan, Italy<br />
Alessandro Gronchi, Milan, Italy<br />
Ian Judson, London, UK<br />
Winette van der Graaf, Nijmegen, Ne<strong>the</strong>rlands<br />
Supportive and palliative care<br />
Fausto Roila, Perugia, Italy, Chair<br />
Matti Aapro, Genolier, Switzerland<br />
Mario Dicato, Luxembourg, Luxembourg<br />
Jørn Herrstedt, Copenhagen, Denmark<br />
Dorothy Keefe, Adelaide, Australia<br />
Dirk Schrijvers, Antwerp, Belgium<br />
The European Society for Medical Oncology wishes to express its appreciation and gratitude to all of <strong>the</strong> above persons for<br />
<strong>the</strong>ir major effort to select <strong>the</strong> content of this <strong>Abstract</strong> <strong>Book</strong>.
<strong>ESMO</strong> <strong>2012</strong> Congress Organization<br />
Congress coordination<br />
Scientific program<br />
<strong>Abstract</strong>s<br />
Travel grants<br />
Patient seminar<br />
Registration<br />
<strong>ESMO</strong> Head Office<br />
Via Luigi Taddei 4<br />
6962 Viganello-Lugano, Switzerland<br />
Congress Department<br />
Alessia Mora<br />
Program unit<br />
Kate Kronig, Sara Fontanella Chiarani, Jinger Rizzi<br />
Operations unit<br />
Chantal Cornu, Francesca Longo, Valentina Allevato<br />
Registration unit<br />
Letizia Scarfò, Nicole Bullo, Kristine Navarro<br />
Tel. +41 (0)91 973 19 16<br />
Fax +41 (0)91 973 19 18<br />
E-mail congress@esmo.org<br />
Sponsorship and industry relations Marketing Department<br />
Nikolaj Tomma<br />
Tel. +41 (0)91 973 19 90<br />
Fax +41 (0)91 973 19 05<br />
E-mail marketing@esmo.org<br />
Media relations Communication Department<br />
Vanessa Pavinato<br />
Tel. +41 (0)91 973 19 45<br />
Fax +41 (0)91 973 19 93<br />
E-mail media@esmo.org<br />
Exhibition management MAW - Medizinische Ausstellungs- u.<br />
Werbegesellschaft International Exhibitions<br />
and Advertising<br />
Freyung 6<br />
AT-1010 Vienna, Austria<br />
Tel. +43 1 536 63 42<br />
Fax +43 1 535 60 16<br />
E-mail esmo<strong>2012</strong>@media.co.at<br />
Hotel accommodation Mondial Congress & Events<br />
Operngasse 20b<br />
AT-1040 Vienna<br />
Tel. +43 1 588 04-0<br />
Fax +43 1 588 04 185<br />
Email esmo<strong>2012</strong>@mondial-congress.com
<strong>ESMO</strong> <strong>2012</strong> Congress Travel Grants<br />
47 travel grants have been awarded by <strong>the</strong> <strong>ESMO</strong> <strong>2012</strong> Scientific Committee on a competitive basis from among <strong>the</strong><br />
accepted abstracts.<br />
Travel grant recipients are:<br />
Ahmed, Soha, Egypt Marín-Aguilera, Mercedes, Spain<br />
Alfaar, Ahmad, Egypt Mohamed, Zameer, UK<br />
Bariani, Giovanni, Brazil Nappi, Lucia, Italy<br />
Berardi, Rossana, Italy Necchi, Andrea, Italy<br />
Bianchini, Diletta, UK Olmos, David, UK<br />
Bria, Emilio, Italy Omlin, Aurelius, UK<br />
Chatterjee, Koushik, India Ostwal, Vikas, India<br />
Chen, Xiaosong, China Pan, LI, China<br />
Criscitiello, Carmen, Italy Parlak, Cem, Turkey<br />
Custodio, Ana, Spain Pereira, Allan, Brazil<br />
Das, Priyabrata, India Rodriguez-Vida, Alejo, Spain<br />
De Graan, Anne-Joy, Ne<strong>the</strong>rlands Samoylenko, Igor, Russia<br />
De Mattos-Arruda, Leticia, Spain Seligmann, Jenny, UK<br />
Diaz-Padilla, Ivan, Canada Sharawat, Surender, India<br />
Elkhouly, Enas, Egypt Supernat, Anna, Poland<br />
George, Angela, UK Tao, Jessica, USA<br />
Iwamoto, Takayuki, Japan Vaccaro, Vanja, Italy<br />
Jang, Raymond, Canada van Gaal, J Carlijn, Ne<strong>the</strong>rlands<br />
Janjigian, Yelena, USA Waddell, Tom, UK<br />
Jo, Jae-Cheol, Korea Weiss, Glenn, USA<br />
Ju, Lixia, China Yakout, Tarek, Egypt<br />
Kelly, Zoe, UK Yousif, Nasser, USA<br />
Kumar, Aalok, Canada<br />
Manji, Arif, Canada<br />
Zakharova, Natalia, Russia<br />
Thanks<br />
<strong>ESMO</strong> expresses its gratitude to:<br />
The official carrier of <strong>the</strong> <strong>ESMO</strong> <strong>2012</strong> Congress for having offered preferential delegate fares.<br />
Advertising of a specific product does not mean acceptance by <strong>ESMO</strong> and it is <strong>the</strong> full responsibility of <strong>the</strong> corporation that<br />
it is in accordance with Swiss, Austrian and European law, where applicable.<br />
Without responsibility for any misprints.
<strong>ESMO</strong> wishes to thank <strong>the</strong> following companies for<br />
<strong>the</strong>ir support of <strong>the</strong> <strong>ESMO</strong> Congress <strong>2012</strong> activities.<br />
www.esmo<strong>2012</strong>.org<br />
The <strong>ESMO</strong> Congress <strong>2012</strong> <strong>Abstract</strong> USB<br />
keys are made possible by an unrestricted<br />
educational grant from Novartis<br />
The <strong>ESMO</strong> Congress <strong>2012</strong> Educational <strong>Book</strong><br />
CDs are made possible by an unrestricted<br />
educational grant from Pfi zer Oncology<br />
The <strong>ESMO</strong> Congress <strong>2012</strong> Poster CDs<br />
are made possible by an unrestricted<br />
educational grant from Amgen<br />
Educational Session Grant Providers<br />
Support, through an unrestricted educational<br />
grant, for <strong>the</strong> On-line Program at <strong>the</strong> <strong>ESMO</strong><br />
Congress <strong>2012</strong> has been provided by<br />
Bayer HealthCare<br />
The <strong>ESMO</strong> Congress <strong>2012</strong> Internet Access<br />
is made possible by an unrestricted<br />
educational grant from Roche<br />
The <strong>ESMO</strong> Congress <strong>2012</strong> Note Pads<br />
are made possible by an unrestricted<br />
educational grant from Merk Serono<br />
A portion of <strong>the</strong> <strong>ESMO</strong> Congress <strong>2012</strong><br />
Travel grants are provided by GSK<br />
Support, through an unrestricted educational<br />
grant, for <strong>the</strong> Educational Sessions at <strong>the</strong><br />
<strong>ESMO</strong> Congress <strong>2012</strong> on Melanoma has been<br />
provided by BMS<br />
Satellite Symposia Organizers<br />
<strong>ESMO</strong> wishes to thank <strong>the</strong> following companies for organizing satellite symposia at <strong>the</strong> <strong>ESMO</strong> Congress <strong>2012</strong>:<br />
9th Patient Seminar Supporters<br />
The 9th <strong>ESMO</strong> Patient Seminar is supported by an unrestricted educational grant by <strong>the</strong> following donors:<br />
Support, through an unrestricted educational<br />
grant, for <strong>the</strong> Educational Sessions at <strong>the</strong><br />
<strong>ESMO</strong> Congress <strong>2012</strong> on Pain Management<br />
has been provided by TEVA<br />
Thank you
Exhibitors<br />
The following companies are exhibiting at <strong>the</strong> <strong>ESMO</strong> <strong>2012</strong> Congress (data correct at time of going to print).<br />
Almac Janssen<br />
Altos Solutions, Inc. KPS Molecular Diagnostic Centre<br />
Amgen Labceutics<br />
ARIAD Pharmaceuticals, Inc. Lilly Oncology<br />
Aspen Pharma Trading Ltd. MEDIAN Technologies<br />
Astellas Pharma Europe Medscape Oncology<br />
BN ImmunoTherapeutics Merck Serono<br />
Baxter Deutschland GmbH MSD<br />
Bayer HealthCare Myriad Genetics GmbH<br />
Boehringer Ingelheim GmbH Nordic Pharma<br />
Bristol-Myers Squibb Novartis Oncology<br />
Caris Life Sciences Panagene Inc.<br />
Cato Software Solutions GmbH Pfizer Oncology<br />
Celgene PharmaMar<br />
Celltrion Healthcare Co., Ltd. Pharmadab d.o.o.<br />
CROMSOURCE Srl PharmaNet / i3<br />
Daiichi Sankyo Europe Pierre Fabre Medicament<br />
Delcath Systems, Inc. prIME Oncology<br />
Dendreon Corporation PRMA Consulting<br />
Effe Emme S.p.A. QIAGEN<br />
Eisai Europe Limited SANDOZ, a Novartis Company<br />
Elekta Ltd Sanofi Oncology<br />
Exelixis SSIF (Serono Symposia International Foundation)<br />
F. Hoffmann-La Roche Ltd Sigma-Tau S.p.A.<br />
Fresenius Kabi Sintesi Research<br />
GE Healthcare Sirtex Medical Europe GmbH<br />
Genomic Health Source BioScience<br />
GlaxoSmithKline Oncology SPECTROPATH, Inc.<br />
Helsinn Healthcare SA Taiho Pharmaceutical Co., Ltd.<br />
Hospira Takeda Pharmaceuticals Europe, Ltd.<br />
Imedex Teva Europe<br />
Ipsen Pharma Varian Medical Systems<br />
Ipsos Healthcare Veridex, Part of <strong>the</strong> Johnson & Johnson family of companies
Publishers/ <strong>Book</strong>sellers Societies<br />
AlphaMed Press AIOM - Associazione Italiana di Oncologia Medica<br />
Elsevier AOG - Association of Oncologist of Georgia<br />
Informa Healthcare ASCO - American Society of Clinical Oncology<br />
<strong>Oxford</strong> University Press BDA - Bio<strong>the</strong>rapy Development Association<br />
Wisepress Medical <strong>Book</strong>shop BIG - Breast International Group<br />
COS - Czech Oncology Society<br />
DGHO - Deutsche Gesellschaft für Hämatologie und Onkologie e. V.<br />
E-CANCER<br />
ECCO - European CanCer Organization<br />
EORTC - Eurepean Organisation for Research and Treatment of Cancer<br />
ESO - European School of Oncology<br />
ETOP - European Thoracic Oncology Platform<br />
JSMO - Japanese Society of Medical Oncology<br />
MAGYOT - Hungary<br />
MASCC - Multinational Association of Supportive Care in Cancer<br />
MOGA - Medical Oncology Group of Australia<br />
MOT - Hungary<br />
NDDO Education Foundation<br />
NGO - Brazilian Non-Governmental Organization (clinical oncology)<br />
RSRMO - Romanian Society for Radio<strong>the</strong>rapy and Medical Oncology<br />
RUSSCO - Russian Society<br />
SIOG - International Society of Geriatric Oncology<br />
St. Gallen Oncology Conferences (SONK)<br />
TOD - Turkish Medical Oncology Society<br />
UNICANCER<br />
Vienna School of Clinical Research<br />
WIN Consortium
<strong>ESMO</strong> Fellowships, 1989–2011<br />
The European Society for Medical Oncology is thankful to <strong>the</strong> following companies for <strong>the</strong>ir generous support:<br />
Fellow Year Sponsored by<br />
Stephan Bodis, Switzerland 1989–1991 Boehringer Ingelheim<br />
Jean Gérain, Belgium 1989–1991 Amgen<br />
Paul Kiefer, Germany 1989–1991 Glaxo<br />
C. Rafael Lopez, Spain 1989–1991 Hoffman–La Roche<br />
Emanuele Zucca, Italy 1989–1991 Sterling Winthrop<br />
Pierre–Yves Dietrich, Switzerland 1990–1992 Schering–Plough<br />
Manuel Domin Gomez, Spain 1990–1992 Medgenix<br />
Albert von Rohr, Switzerland 1990–1992 Ciba–Geigy<br />
Miguel Izquierdo Delso, Spain 1991–1993 EuroCetus<br />
Panayiotis Panayiotidis, Greece 1991–1993 Bristol–Myers Squibb<br />
Anna Russo, Italy 1991–1993 Farmitalia Carlo Erba<br />
Ekaterini Boleti, Greece 1993–1995 SmithKline Beecham<br />
Christos A. Papadimitriou, Greece 1993–1995 Pharmacia<br />
Luis Paz–Ares, Spain 1993–1995 Hoffman–La Roche<br />
Konstantinos N. Syrigos, Greece 1994–1996 Rhône–Poulenc Rorer / <strong>ESMO</strong><br />
Francesco Caponigro, Italy 1995–1996 Ciba–Geigy<br />
Vito Spataro, Switzerland 1995–1997 Bristol–Myers Squibb / <strong>ESMO</strong><br />
Ignacio Garcia–Ribas, Spain 1995–1997 Lilly Deutschland / <strong>ESMO</strong><br />
Jan Dürig, Germany 1997–1998 Eli Lilly / Lilly Deutschland<br />
Astrid Mayer, Austria 1996–1997 <strong>ESMO</strong><br />
Adam Pawinski, Poland 1996–1998 Rhône–Poulenc Rorer<br />
Patricia A. Ribeiro, Portugal 1997–1998 Ciba Geigy<br />
Federico Cappuzzo, Italy 1997–1999 Glaxo Wellcome<br />
José M. Trigo Perez, Spain 1997–1999 Hoechst Marion Roussel<br />
Christos Tolis, Greece 1997–1998 SmithKline Beecham<br />
Eleni Tsiompanou, Greece 1998–2000 <strong>ESMO</strong><br />
Ira I. Skvortsova, Russia 1998–2000 <strong>ESMO</strong><br />
Linda C. Pronk, Ne<strong>the</strong>rlands 1998–2000 <strong>ESMO</strong><br />
Ramon Salazar, Spain 1999–2001 Searle<br />
Francisca Vasquez, Spain 1999–2001 SmithKline Beecham<br />
Francesco Zappa, Switzerland 1999–2001 Rhône–Poulenc Rorer<br />
Michael Görn, Germany 1999–2001 Pharmacia & Upjohn / <strong>ESMO</strong><br />
Mauricio Riofrio, Ecuador 1999–2001 <strong>ESMO</strong><br />
Annarita Conconi, Italy 1999–2001 <strong>ESMO</strong><br />
Anna Llado, Spain 2000–2002 <strong>ESMO</strong><br />
Frank Mayer, Germany 2000–2002 <strong>ESMO</strong><br />
Mohamed Saad Ismail, Egypt 2000–2002 <strong>ESMO</strong><br />
Eleni Andreopoulou, Greece 2001–2003 <strong>ESMO</strong>
Martin Bard, France 2001–2002 <strong>ESMO</strong><br />
Niklas Zojer, Austria 2001–2002 <strong>ESMO</strong><br />
Emma Kulimova, Russia 2001–2003 <strong>ESMO</strong><br />
Sylvie Rottey, Belgium 2001–2002 <strong>ESMO</strong><br />
Fabrina Bologna, Argentina 2001–2003 <strong>ESMO</strong><br />
Zhasmina Mihaylova, Bulgaria 2001–2002 <strong>ESMO</strong><br />
Eleni Galani, Greece 2002–2003 <strong>ESMO</strong><br />
Barbara Viscioni, Italy 2002–2004 <strong>ESMO</strong><br />
Luciano Nicola de Wanneson, Argentina 2002–2003 <strong>ESMO</strong><br />
Veronika Ballova, Slovak Republic 2002–2003 <strong>ESMO</strong><br />
Vasiliki Michalaki, Greece 2002–2003 <strong>ESMO</strong><br />
Alexei Teterin, Russia 2002–2003 <strong>ESMO</strong><br />
Karina Vera, Argentina 2002–2003 <strong>ESMO</strong><br />
Robert Godal, Slovak Republic 2003–2004 <strong>ESMO</strong><br />
Joerger Markus, Switzerland 2003–2004 <strong>ESMO</strong><br />
Benjamin Besse, France 2003–2004 <strong>ESMO</strong><br />
Marzia Palma, Italy 2003–2004 <strong>ESMO</strong><br />
Erika Martinelli, Italy 2004–2005 Ortho Biotech<br />
Robert Godal, Slovakia 2004–2005 Amgen<br />
Mikhail Akimov, Russia 2004–2005 Merck<br />
Silvia Neciosup Delgado, Peru 2004–2005 AstraZeneca<br />
Rosa Conforti, Italy 2004–2005 <strong>ESMO</strong><br />
Maja Bradic, Serbia Montenegro 2005–2006 Amgen<br />
Semra Aydin, Germany 2005–2006 AstraZeneca<br />
Marzia Palma, Italy 2005–2006 Ortho Biotech<br />
Ioannis Mountzios, Greece 2005–2006 <strong>ESMO</strong><br />
Francesco Atzori, Italy 2006–2007 Amgen<br />
Daniel Koychev, Bulgaria 2006–2007 Amgen<br />
Hendrik Wermann, Germany 2006–2007 Novartis<br />
Orestis Lyros, Greece 2006–2007 AstraZeneca<br />
David Olmos Hidalgo, Spain 2006–2007 Bayer Oncology<br />
Rodrigo Ruiz Soto, Mexico 2006–2007 Wyeth Pharmaceuticals<br />
Aleksandar Celebic, Serbia 2007–2008 Amgen<br />
Isabelle Opitz, Germany 2007–2008 Bayer Oncology<br />
Nicola Cresti, Italy 2007–2008 Amgen<br />
Sherene Loi, Australia 2007–2008 Novartis<br />
Ben Markman, Australia 2007–2008 Wyeth Pharmaceuticals<br />
Mustapha Zoubir, Algeria 2007–2008 GE Healthcare<br />
Andrea Alimonti, Italy 2008–2009 Amgen<br />
Ekaterina Chigrinova, Russia 2008–2009 Roche<br />
Armelle Dufresne, France 2008–2009 Merk Serono<br />
Roberta Ferraldeschi, Italy 2008–2009 <strong>ESMO</strong><br />
Vassilios Golfinopoulos, Greece 2008–2009 <strong>ESMO</strong>
Ondrej Gojis, Czech Republic 2008–2009 GSK<br />
Viviane Hess, Switzerland 2008–2009 Novartis<br />
Christophe Massard, France 2008–2009 Amgen<br />
Floriana Morgillo, Italy 2008–2009 Roche<br />
Mahasti Saghatchian, France 2008–2009 <strong>ESMO</strong><br />
Balazs Dome, Hungary 2009–2010 Roche<br />
Laurent Quero, France 2009–2010 Pfizer Oncology<br />
Yoko Yanagisawa, Japan 2009–2010 Novartis<br />
Giorgi Dzagnidze, Georgia 2009–2010 MSD<br />
Eleni Karapanagiotou, Greece 2009–2010 Roche<br />
Giannis Mountzios, Greece 2009–2010 Roche<br />
Hatem Azim, Egypt 2010–2011 Roche<br />
Giulia Pasello, Italy 2010–2011 Roche<br />
Teresa Troiani, Italy 2010–2011 Amgen<br />
Michalis Karamouzis, Greece 2010–2011 Amgen<br />
Konstantinos Kamposioras, Greece 2010–2011 Roche<br />
Karin Tamas, Hungary 2010–2011 Roche<br />
Leticia De Mattos Arruda, Brazil 2010–2011 Amgen<br />
Michael Baumann, Switzerland 2010–2011 MSD<br />
Elena Castro Marcos, Spain 2010–2011 Novartis<br />
Daniela Kolarevic, Serbia 2011–<strong>2012</strong> Roche<br />
Sophie Postel–Vinay, France 2011–<strong>2012</strong> Roche<br />
Alejandra Armengol Alonso, Mexico 2011–<strong>2012</strong> Novartis<br />
Claudette Falato, Italy <strong>2012</strong>–2013 Roche<br />
Jennifer Gibbons Marsico, Uruguay <strong>2012</strong>–2013 Roche<br />
Angela Lamarca, Spain <strong>2012</strong>–2013 Amgen<br />
Elisabetta Pietri, Italy <strong>2012</strong>–2013 Amgen<br />
Loredana Vecchione, Italy <strong>2012</strong>–2013 Roche<br />
Jean–Sebastien Frenel, France <strong>2012</strong>–2013 Debiopharm, Ipsen<br />
Silvia Mihaela Ilie, Romania <strong>2012</strong>–2013 Novartis
hamilton fairley award<br />
1IN FROM EMPIRICAL TO RATIONAL TREATMENT OF HUMAN<br />
CANCERS CELLS AND THEIR STROMA<br />
J-Y Blay<br />
Department of Medicine, University Claude Bernard Lyon I, Centre Léon Bérard,<br />
Lyon, FRANCE<br />
In <strong>the</strong> last 5 years, <strong>the</strong>re has been a major acceleration of <strong>the</strong> understanding of <strong>the</strong><br />
molecular alterations responsible for cancer cells development. Large variety of<br />
genomic and epigenetic alterations, resulting in abnormal gene expression patterns,<br />
and cellular behavior can now be uncovered for each individual tumor. New<br />
nosological classifications, across and within histological subtypes, are emerging as a<br />
consequence of this knowledge resulting in a fragmentations of previous disease<br />
types mainly organ-based in a myriad of rare tumors. This complexity is<br />
multidimensional, and only starts to be understood, with <strong>the</strong> additional challenge<br />
that it evolves over time within subclones of tumor cells in each individual patients.<br />
Despite <strong>the</strong>se challenges, <strong>the</strong> partial understanding of this complexity we have<br />
reached has led to tremendous progresses for <strong>the</strong> treatment of patients with cancer<br />
recently, e.g. in CML, HER2+ breast cancer, GIST BRAF mutated melanomas, Alk<br />
mutated tumors. In each example, <strong>the</strong> targeting of a “key node”, a driver alteration in<br />
<strong>the</strong> process of neoplastic transformation, or tumor progression was often sufficient to<br />
achieve a major improvement. The identification of <strong>the</strong>se driver mutations has<br />
sometimes been stochastic, emerging from translational research programs aiming to<br />
find predictive factors, but is now more often coming from a rationale systematic<br />
approach to identify subgroups of cancers with similar genomic alterations. Novel<br />
nosological classifications must be built with <strong>the</strong>se tools, and our treatment<br />
paradigms will be based on <strong>the</strong>se. However, obvious obstacles are already visible:<br />
clonal heterogeneity of cancer, frequent emergence of resistance, integration of<br />
treatment targeting <strong>the</strong> immune stroma, but also compliance for long term<br />
treatment, and economical considerations. In this presentation, we will show some<br />
successful and non successful examples of development of targeted treatment to<br />
which we have contributed, and <strong>the</strong> lessons which should be drawn from <strong>the</strong>se<br />
examples for <strong>the</strong> future development of anticancer <strong>the</strong>rapies.<br />
Disclosure: The author has declared no conflicts of interest.<br />
PI 3-Kinase and cancer metabolism<br />
2IN PI 3-KINASE AND CANCER METABOLISM<br />
Annals of Oncology 23 (Supplement 9): ix21, <strong>2012</strong><br />
doi:10.1093/annonc/mds365/mds366<br />
L.C. Cantley<br />
Division of Signal Transduction, Beth Israel Deaconess Medical Center and<br />
Department of Systems Biology, Harvard Medical School, Boston, MA,<br />
UNITED STATES OF AMERICA<br />
Phosphoinositide 3-kinase (PI 3-Kinase) generates<br />
phosphatidylinositol-3,4,5-trisphosphate (PIP3) at <strong>the</strong> plasma membrane in response<br />
to stimulation of cells with growth factors and hormones. This lipid recruits certain<br />
signal transduction proteins to <strong>the</strong> membrane, initializing cellular signaling cascades<br />
that control glucose uptake, cell metabolism, protein syn<strong>the</strong>sis and cell growth. A<br />
central mediator of PI 3-Kinase signaling is <strong>the</strong> protein-Ser/Thr kinase, AKT. Over<br />
<strong>the</strong> past six years signaling networks downstream of AKT have been elucidated that<br />
regulate protein syn<strong>the</strong>sis and glucose metabolism, in part via activation of mTOR.<br />
Importantly, we have found that while growth factor receptors enhance glucose<br />
uptake and glucose metabolism, <strong>the</strong>y decrease <strong>the</strong> activity of pyruvate kinase, <strong>the</strong> last<br />
step in <strong>the</strong> pathway. Our studies indicate that <strong>the</strong> inhibition of pyruvate kinase allows<br />
cells to divert intermediates in glycolysis into pathways for syn<strong>the</strong>sis of DNA, RNA,<br />
proteins and lipids that are needed for cell growth.<br />
Disclosure: Dr. Cantley is a founder and member of <strong>the</strong> BOD of Agios<br />
Pharmaceuticals, a company that targets metabolic enzymes for treating cancer.<br />
Dr. Cantley consults for Novartis and GSK, companies developing drugs that target PI3K.<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com<br />
abstracts
abstracts<br />
hpv biology and implications in<br />
gynecological malignancies<br />
3IN FROM HYPOTHESIS TO PREVENTION IN 40 YEARS<br />
S.K. Kjaer<br />
Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center,<br />
Copenhagen, DENMARK<br />
Indications of a relationship between cervical cancer and sexual activity have been<br />
available for over a century. Early studies described sexual variables mainly in terms of<br />
marital status, age at first marriage and reproductive life, whereas more recent<br />
epidemiological studies have assessed <strong>the</strong> role of sexual habits and specifically<br />
identified <strong>the</strong> number of sexual partners and age at first intercourse as <strong>the</strong> most<br />
important risk factors. The finding of an independent effect of <strong>the</strong> number of sexual<br />
partners, and <strong>the</strong> increased risk for women whose husbands reported multiple sexual<br />
partners strongly pointed to <strong>the</strong> importance of a sexually transmitted infectious agent,<br />
although o<strong>the</strong>r factors such as smoking, parity and oral contraceptive use were also<br />
suggested to be important. For more than two decades, attention focused on herpes<br />
simplex virus type 2 as an etiological agent. However, subsequently it was suggested by<br />
Professor zur Hausen that certain types of human papillomavirus (HPV) might play a<br />
key etiological role. Although <strong>the</strong>re at that time was laboratory evidence supporting<br />
this hypo<strong>the</strong>sis, it was initially difficult to test it epidemiologically. With <strong>the</strong><br />
technological development and <strong>the</strong> collaboration between epidemiologists, virologists<br />
and clinicians it became increasingly clear that HPV is a necessary factor in <strong>the</strong><br />
development of cervical cancer and also is causing a proportion of o<strong>the</strong>r anogenital<br />
cancers in both women and men such as cancer of <strong>the</strong> vagina, vulva, penis and anus.<br />
In addition, it is associated with certain types of head and neck cancer. Based on <strong>the</strong><br />
research within this area, vaccines against certain types of HPV have now been<br />
developed and we have moved from hypo<strong>the</strong>sis to prevention in some 40 years.<br />
Disclosure: S.K. Kjaer: Received lecture fees, advisory board fees, and research grants<br />
through her institution from Merck and Sanofi Pasteur MSD.<br />
Annals of Oncology 23 (Supplement 9): ix22, <strong>2012</strong><br />
doi:10.1093/annonc/mds367<br />
4IN IMMUNE BIOLOGY OF HUMAN PAPILLOMAVIRUSES:<br />
IMPLICATIONS FOR VACCINE DEVELOPMENT<br />
L. Gissmann<br />
Division of Genome Modifications and Carcinogenesis, Gerrman Cancer<br />
Research Center, Heidelberg, GERMANY<br />
The “high-risk” types of human papillomaviruses (HPV), in particular PV 16 and 18<br />
are responsible for <strong>the</strong> development of almost all cases of cervical cancer, for a<br />
substantial fraction of o<strong>the</strong>r malignant anogenital tumors (penis, vulva and<br />
perianum) and for a proportion of head and neck cancer. The natural history of<br />
HPV infections and immunization experiments in animals with <strong>the</strong>ir respective<br />
papillomaviruses (e.g. <strong>the</strong> canine oral papillomavirus) clearly revealed <strong>the</strong><br />
involvement of <strong>the</strong> immune system in controlling <strong>the</strong> viral infections and <strong>the</strong><br />
diseases associated <strong>the</strong>rewith. Antibodies appear to be <strong>the</strong> key molecules in<br />
preventing of an infection whereas mostly T cells and cytokines are involved in<br />
controlling virus persistence and progression towards malignancy.<br />
During <strong>the</strong> natural course of infection human papillomaviruses are not particularly<br />
immunogenic since <strong>the</strong>ir biology makes <strong>the</strong>m barely “visible” by <strong>the</strong> immune system<br />
(infection is confined to <strong>the</strong> epi<strong>the</strong>lium) but also since it has acquired <strong>the</strong> ability to<br />
actively suppress certain immune functions. This is in remarkable contrast to <strong>the</strong><br />
strong immune response induced by i.m. immunization with virus particles when<br />
<strong>the</strong>y become exposed to and interact directly with circulating antigen presenting cells.<br />
There is mounting awareness about <strong>the</strong> mechanisms of <strong>the</strong>se interactions.<br />
Disclosure: Lutz Gissmann is a consultant to GlaxoSmithKline and Sanofi Pasteur<br />
MSD and, due to existing intellectual property, receives royalties from sales of<br />
Gardasil® and Cervarix®<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
<strong>the</strong> hallmarks of cancer revisited<br />
5IN HALLMARKS OF CANCER: A <strong>2012</strong> PERSPECTIVE<br />
D. Hanahan<br />
The Swiss Institute for Experimental Cancer Research (ISREC) School of Life<br />
Sciences, The Swiss Federal Institute of Technology Lausanne (EPFL) Lausanne,<br />
SWITZERLAND<br />
The Hallmarks of Cancer perspective (Hanahan & Weinberg, 2000; 2011)<br />
presents an organizing principle with which to distill <strong>the</strong> daunting complexity of<br />
human cancers into a rational commonality of <strong>the</strong>ir aberrant basis as<br />
proliferative disease, despite <strong>the</strong> disparate manifestations reflected in that<br />
complexity. A series of (now eight) acquired hallmark capabilities, each with<br />
distinctive properties, are arguably necessary for malignant progression,<br />
capabilities whose acquisition underlay <strong>the</strong> multistep nature of carcinogenesis.<br />
The mechanisms governing <strong>the</strong>se acquired capabilities involve not only genetic<br />
and epigenetic changes in <strong>the</strong> cancer cells that form <strong>the</strong> basis of chronic<br />
proliferation and persistence. Ostensibly normal cells recruited to compose <strong>the</strong><br />
neoplastic stroma of <strong>the</strong> tumor microenvironment – notably endo<strong>the</strong>lial cells<br />
and pericytes, infiltrating immune cells, and activated cancer associated<br />
fibroblasts –are also instrumental, functionally contributing to most of <strong>the</strong><br />
hallmark capabilities (Hanahan & Coussens <strong>2012</strong>). The hallmarks<br />
conceptualization, of discrete and quasi-independent capabilities necessary for<br />
progression, suggests new <strong>the</strong>rapeutic approaches involving targeting multiple<br />
hallmark functions, which are beginning to be tested in pre-clinical and<br />
clinical trials. Hanahan D, & Weinberg RA. (2000). The hallmarks of cancer.<br />
Cell.100: 57-70. Hanahan D, & Weinberg RA. (2011). Hallmarks of cancer: <strong>the</strong><br />
next generation. (2011). Cell.144: 646-674. Hanahan D, & Coussens LM.<br />
(<strong>2012</strong>). Accessories to <strong>the</strong> crime: functions of cells recruited to <strong>the</strong> tumor<br />
microenvironment. Cancer Cell. 21: 309-322.<br />
Disclosure: D. Hanahan: Member, Scientific Advisory Panel for Oncology,<br />
PfizerMember,SAB,&stockoptions,JennerexBio<strong>the</strong>rapeuticsunpaid<br />
consultant & stockholder, Onyx Pharma unpaid consultant & stockholder,<br />
Aveo Pharma.<br />
Annals Of Oncology 23 (Supplement 9): ix23, <strong>2012</strong><br />
doi:10.1093/annonc/mds368<br />
6IN FROM LANDMARKS OF CANCER TO TARGETED THERAPIES:<br />
LESSONS LEARNT AND PERSPECTIVES<br />
A. Awada<br />
Department of Medical Oncology, Institute Jules Bordet, Brussels, BELGIUM<br />
TKIs and antibodies (trastuzumab, imatinib,..) emerged as “revolutionary” drugs.<br />
Never<strong>the</strong>less, testing different agents in studies turned to be negative or “marginally”<br />
positive. Negative trials highlighted important issues: 1) The genetic complexity of<br />
carcinogenesis 2) Defining <strong>the</strong> implication of a target to oncogenesis is essential.<br />
3) Due to <strong>the</strong> “plasticity” of signaling pathways, combination agents or multitargeted<br />
kinase may be needed but “cumulative” toxicities emerged. 4) A well performed early<br />
study is a prerequisite for <strong>the</strong> succes of a new agent. Marginally positive studies lead<br />
in limited circumstances to retrospective identification of subpopulations likely to<br />
benefit (e.g., WT KRAS and sensitivity to EGFR MoAbs in CRC). The<br />
sensibilisation towards tumor selection has demonstrated better results. NSCLC<br />
with ALK gene rearrangements are senstitive to ALK inhibitors. Melanoma with<br />
BRAF mutation responded to vemurafenib. A drawback would be <strong>the</strong><br />
heterogeneity of <strong>the</strong> tumor. Moreover, modern techonologies allows <strong>the</strong><br />
development of agents with a higher selectivity. Although advances have been<br />
achieved fur<strong>the</strong>r, efforts are needed: Biomarkers of sensitivity have been evaluated<br />
but not optimaly validated. Mechanisms of resistance have been described, but a<br />
proper assessment is lacking. So it is fundamental to prioritize “powered” clinical<br />
trials. Prospective collection of biospecimens during disease evolution and<br />
<strong>the</strong>rapies must become a standard approach. A comprehensive drug development<br />
plan (in advanced or neoadjuvant setting) has <strong>the</strong> potential to identify drugs to be<br />
tested in <strong>the</strong> adjuvant setting in subgroups where cure will be much higher. The<br />
lessons learnt so far should bring <strong>the</strong> concept of “personalized treatment” closer to<br />
<strong>the</strong> reality. A close collaboration of scientists, chemists, investigators and<br />
statisticians is needed to reach this goal.<br />
Disclosure: The author has declared no conflicts of interest.<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.<br />
abstracts
abstracts<br />
<strong>the</strong> characterization of lung cancer<br />
in multiple different diseases<br />
7IN THE CHARACTERIZATION OF LUNG CANCER<br />
J. Soria<br />
Medicine Department, Institut Gustave Roussy, Villejuif, FRANCE<br />
The characterization of lung cancer Lung cancer is <strong>the</strong> leading cause of<br />
cancer-related deaths worldwide. Non-small cell lung cancer is currently being<br />
revisited on <strong>the</strong> basis of modern molecular portraits that allow <strong>the</strong> identification of<br />
new molecular subtypes. Larges scale studies have identified frequent mutations<br />
mainly in TP53, RB1, CDKN2A, and STK11 tumor suppressor and in EGFR,<br />
KRAS and NRAS oncogenes. Many o<strong>the</strong>r molecular abnormalities have been<br />
reported in o<strong>the</strong>r genes such as PI3K, PTEN, AKT1, MDM2, APC, HER2, KDR,<br />
MET, CTNNB1, ATM, BRAF, AKT1 and more recently ALK, RET, ROS as well as<br />
FGFR1. Beyond <strong>the</strong> now classical oncogene-drivers represented by EGFR mutation<br />
and ALK translocation, many o<strong>the</strong>r molecular abnormalities could be used for<br />
selection of specific <strong>the</strong>rapy such as amplification of HER2 and FGFR1,<br />
translocation of RET or ROS, or activating mutations of HER2, HER3, HER4,<br />
FGFR2 … Never<strong>the</strong>less <strong>the</strong> correlation between <strong>the</strong> presence of such abnormalities<br />
and clinical response are not definitively documented, although some interesting<br />
small series or case reports have been reported. The table below provides a<br />
summary of specific alterations, <strong>the</strong>ir frequencies and <strong>the</strong>ir potential corresponding<br />
molecular targeted interventions. DNA repair players are also potential predictors of<br />
standard anti-cancer <strong>the</strong>rapies (ERCC1, MSH2, BRCA1, PARP). In summary,<br />
characterization of <strong>the</strong> genomic changes that drive an individual patient’s disease is<br />
now critical to inform rationally targeted <strong>the</strong>rapies and treatment planning for<br />
patients with NSCLC.<br />
Disclosure: The author has declared no conflicts of interest.<br />
Table: 71N<br />
Molecular alteration<br />
Frequency in<br />
Adenocarcinoma<br />
8IN THE EVOLUTION OF CANCERS UPON TREATMENT WITH<br />
TARGETED THERAPIES<br />
No abstract submitted at time of going to press.<br />
Frequency in Squamous<br />
cell carcinoma Potential Drugs<br />
Annals of Oncology 23 (Supplement 9): ix24, <strong>2012</strong><br />
doi:10.1093/annonc/mds369<br />
EGFR mutation 10-40% 2-5% Gefitinib Erlotinib Afatinib PF-00299804<br />
EML4-ALK translocation 5-7% Rare Crizotinib, ASP3026, AP26113, CH5424802 LDK-378 HSP90 inhibitors<br />
ROS translocation 2% Rare Crizotinib, ASP3026, AP26113, CH5424802 LDK-378 HSP90 inhibitors<br />
RET translocation 6% Rare Vandetanib<br />
HER2 mutation or amplification 2% 6% Rare 2% Trastuzumab PF-00299804 Afatinib<br />
PI3K mutation or amplification 5% < 10% 5% < 10% GDC-0941 GDC 0980<br />
XL-147<br />
XL-765<br />
BEZ-235<br />
BKM120 BYL 719 PF-05212384<br />
MET amplification < 10% < 10% XL184 ARQ917 MetMab<br />
RAS mutation RAF mutation 10-30% 3% 5% 2% Sorafenib AZD6244; GSK1120212; AS703026, RO4987655 MEK162<br />
FGFR1 amplification 5% 20% BJG398, AZD4547, TKI258 EOS 3810<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
<strong>the</strong> impact of <strong>the</strong> cancer genome<br />
project and high-throughput analyses<br />
on personalised oncology: today and<br />
tomorrow<br />
9IN THE MOLECULAR HETEROGENEITY OF BREAST TUMORS<br />
A. Børresen-Dale<br />
Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo<br />
University Hospital, Oslo, and <strong>the</strong> K.G. Jebsen Center for BC Research,<br />
University of Oslo, Norway, Oslo, NORWAY<br />
Breast Cancer (BC) is a complex disease caused by accumulation of genetic<br />
alterations leading to a disturbed balance between proliferation and apoptosis,<br />
genetic instability and acquisition of an invasive and resistant phenotype. The<br />
inherent heterogeneity, including <strong>the</strong> microenvironment, contributes to each<br />
tumors phenotype and dictate tumors molecular portraits. We have generated<br />
high-throughput data of tumors from mRNA and miRNA expression, SNP-CGH<br />
and DNA-methylation, paired-end sequencing, protein expression by RPPA, and<br />
metabolic profiles from HR-MAS MR analyses. We have explored to which extent<br />
combining <strong>the</strong> various profiles derived from each level, can fur<strong>the</strong>r subdivide <strong>the</strong><br />
initially discovered expression subclasses and improve prognostic potential.<br />
Patterns of genomic aberrations that underlie specific expression subgroups may<br />
infer paths of tumor progression and shed light on mechanisms involved. We<br />
recently developed two platform-independent algorithms to explore genomic<br />
architectural distortion using aCGH data to measure whole-arm gains and losses<br />
(WAAI) and complex rearrangements (CAAI), and were able to separate <strong>the</strong> cases<br />
into eight subgroups. Within each subgroup data from expression analyses,<br />
sequencing and ploidy indicated that progression occurs along separate paths into<br />
more complex genotypes. The results emphasized <strong>the</strong> relation among structural<br />
genomic alterations, molecular subtype, and clinical behavior and showed that<br />
objective score of genomic complexity (CAAI) is an independent prognostic<br />
marker. By integrating data from <strong>the</strong> patient’s own genotype with multiple layers<br />
of data derived from <strong>the</strong> primary tumor, <strong>the</strong> different subclones within <strong>the</strong> tumor,<br />
as well as <strong>the</strong> metastases, we seek to reach a more fundamental understanding of<br />
<strong>the</strong> biological dynamics of breast cancer. This will facilitate identification of risk<br />
factors, search for novel cancer diagnostics, prediction of <strong>the</strong>rapeutic effects and<br />
prognosis and identification of new targets for <strong>the</strong>rapy, that may lead to a more<br />
personalized treatment of BC. Ref: Stephens P et al. Nature. 2009, Russnes HG<br />
et al. STM, 2010, Van LP et al. PNAS 2010, Kristensen VN et al, PNAS 2011,<br />
Russnes et al JCI, 2011, Curtis et al, Nature, <strong>2012</strong><br />
Disclosure: The author has declared no conflicts of interest.<br />
10IN INITIAL SEQUENCING OF BREAST CANCER GENOMES<br />
M. Stratton<br />
Cancer Genome Projects, The Wellcome Trust Sanger Institute, Hinxton,<br />
UNITED KINGDOM<br />
Over <strong>the</strong> last decade since <strong>the</strong> provision of <strong>the</strong> reference human genome DNA<br />
sequence, increasingly extensive sequence analyses of cancer genomes have led to <strong>the</strong><br />
discovery of new mutated cancer genes and have explored <strong>the</strong> extant patterns of<br />
somatic mutation. The scope of <strong>the</strong>se investigations has been constrained by<br />
sequence throughout and cost. However, <strong>the</strong> recent advent of novel sequencing<br />
technologies has ushered in a new era of cancer genome characterisation leading to<br />
partial or complete catalogues of somatic mutations in individual cancers. The<br />
combinations of mutated cancer genes and <strong>the</strong> mutational processes that are<br />
operative in <strong>the</strong> subclasses of breast cancer are becoming apparent. These studies are<br />
bringing new insights into <strong>the</strong> etiology, pathogenesis and classification of <strong>the</strong><br />
genetically heterogeneous set of diseases that are collectively termed breast cancer.<br />
Disclosure: The author has declared no conflicts of interest.<br />
Annals Of Oncology 23 (Supplement 9): ix25, <strong>2012</strong><br />
doi:10.1093/annonc/mds370<br />
11IN TOWARDS DECIPHERING THE GENETIC LANDSCAPE IN<br />
MELANOMA<br />
Y. Samuels 1 , T.D. Prickett 1 ,X.Wei 1 , J.C. Lin 2 , J.K. Teer 1 , S.A. Rosenberg 3<br />
1 National Institutes of Health, NHGRI, Be<strong>the</strong>sda, MD, UNITED STATES OF<br />
AMERICA, 2 Washington University School of Medicine, St Louis, MO, UNITED<br />
STATES OF AMERICA, 3 National Institutes of Health, NCI, Be<strong>the</strong>sda, MD,<br />
UNITED STATES OF AMERICA<br />
Melanoma is <strong>the</strong> deadliest form of human skin cancer, accounting for 70% of<br />
skin-cancer related deaths although it comprises only 4% of skin cancer cases. As<br />
opposed to <strong>the</strong> steady decrease in overall rate of o<strong>the</strong>r cancers, <strong>the</strong> incidence of<br />
melanoma continues to rise worldwide. The median patient survival is six months<br />
following diagnosis. There is a clear need to develop improved <strong>the</strong>rapy for this<br />
disease. Melanoma develops through acquired mutations in cancer genes. Cancer<br />
genome sequencing can identify recurring genetic alterations that will generate<br />
new approaches to <strong>the</strong> treatment of melanoma, enabling a more personalized<br />
approach, based on gene mutation profiles of each patient’s tumor. To<br />
systematically survey mutations in melanoma, we performed whole-exome<br />
sequencing of 14 matched normal and metastatic tumor DNAs. This allowed us to<br />
discover GRIN2A, a member of <strong>the</strong> ionotropic glutamate receptor family (iGluR),<br />
to be a significantly mutated gene that had not previously been identified as<br />
playing a role in melanoma. The comprehensive nature of <strong>the</strong> acquired data in<br />
this study allowed <strong>the</strong> identification of <strong>the</strong> glutamate signaling pathway to be<br />
significantly mutated, which includes GRIN2A, GRM3 and ERBB4, found to be<br />
mutated at 25, 16 and 19 percent of melanomas, respectively GRIN2A and GRM3,<br />
a metabotropic glutamate receptor (mGluR) are regulated by glutamate. GRIN2A,<br />
which is a ligand-gated ion channel, allows cations such as calcium to pass<br />
through <strong>the</strong> plasma membrane of <strong>the</strong> cell after <strong>the</strong> binding of glutamate to <strong>the</strong><br />
receptor. GRM3 activates pathways such as <strong>the</strong> MEK pathway upon glutamate<br />
binding. The functional interplay between GRIN2A, GRM3 and ERBB4 in<br />
melanoma will be discussed and preliminary data presented. Our findings have<br />
potential <strong>the</strong>rapeutic implications, as glutamate pathway modification has<br />
previously been shown to limit tumor growth. Fur<strong>the</strong>r investigation of <strong>the</strong><br />
glutamate pathway in melanoma a development of glutamate pathway inhibitors is<br />
<strong>the</strong>refore warranted.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
12IN MUTATIONAL AND CHROMOSOMAL SURVEYS<br />
OF PANCREATIC TUMORS<br />
A. Scarpa<br />
ARC-NET Research Centre and Department of Pathology and Diagnostic,<br />
University of Verona, Verona, ITALY<br />
Mirroring <strong>the</strong> cellular diversity within <strong>the</strong> pancreas, <strong>the</strong> spectrum of distinct<br />
pancreatic neoplasms shows histological and molecular features partially recalling<br />
<strong>the</strong> characteristics of <strong>the</strong> cell of origin. Pancreatic ductal adenocarcinoma (PDAC)<br />
is <strong>the</strong> most common neoplasm and bears <strong>the</strong> worst prognosis. Pancreatic<br />
neuroendocrine tumors (pNETs) are <strong>the</strong> second most common neoplasm with an<br />
incidence that is considerably increasing over <strong>the</strong> last 30-years. Our limited<br />
knowledge of <strong>the</strong> genetic basis of <strong>the</strong>se diseases based on candidate gene<br />
approaches has now been expanded by <strong>the</strong> use of massive parallel sequencing<br />
(MPS). These have helped to uncover <strong>the</strong> genomic landscape of cancers showing<br />
that, beyond high frequency mutations (Table 1), a plethora of different molecular<br />
features are identified at low frequency and define potential cancer subgroups of<br />
clinical interest. This is particularly true for PDAC that represents <strong>the</strong> real “social<br />
problem” among pancreatic neoplasms. Recent works exploring <strong>the</strong> structural<br />
variations’ landscape of PDAC have also highlighted a high degree of genetic<br />
heterogeneity in metastatic deposits, which substantially reflects <strong>the</strong> presence of<br />
different subclones within <strong>the</strong> primitive disease. When ignored, molecular<br />
heterogeneity can lead to failure in <strong>the</strong>rapeutic treatments, as drugs that may have<br />
efficacy in subgroups of patients with specific molecular phenotypes may show<br />
marginal response when tested in a large group of unselected patients. This calls<br />
for <strong>the</strong> revisitation of <strong>the</strong> classical pathological diagnosis of cancer where <strong>the</strong><br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com<br />
abstracts
abstracts<br />
description of intra-tumor heterogeneity at both morphological and molecular<br />
level are taken into account for a diagnoistic report to be clinically useful to<br />
devise first, second and additional <strong>the</strong>rapeutic choices.<br />
Table: 12IN Commonly mutated genes in different pancreatic neoplasms.<br />
Tumor Type a<br />
Genes b<br />
PDAC KRAS (100%), TP53 (85%), SMAD4 (38%), CDKN2A (25%)<br />
pNET MEN1 (44%), DAXX (25%), ATRX (17%), PTEN (7%), TSC2 (9%)<br />
IPMN KRAS (62%), GNAS (62%), RNF43 (75%)<br />
MCN KRAS (75%), RNF43 (37%)<br />
SPN CTNNB1 (100%)<br />
§ PDAC, pancreatic ductal adenocarcinoma; pNET, pancreatic neuroendocrine<br />
tumors; IPMN, intraductal papillary mucinous neoplasm; MCN, mucinous cystic<br />
neoplasm; SPN, solid pseudopapillary neoplasm.<br />
b Percentages within brackets refer to mutation frequencies assessed in specific<br />
clinical cohorts<br />
Disclosure: The author has declared no conflicts of interest.<br />
Annals Of Oncology
optimizing treatment in luminal breast<br />
cancer<br />
13IN INTRODUCTION: LUMINAL A AND B: HOW CURABLE ARE<br />
THEY?<br />
A. Di Leo 1 , N.H. Turner 1 , L. Malorni 1 , C. Guarducci 2<br />
1 Oncology- Istituto Toscano Tumori, Ospedale di Prato Sandro Pitigliani Med.<br />
Oncology Unit, Prato, ITALY, 2 Ospedale di Prato, Translational Research Unit,<br />
Prato, ITALY<br />
Hormone receptor positive (HR+) breast cancers can be separated by molecular<br />
subtyping into luminal A breast cancer (LUM A), which is more prevalent though<br />
less aggressive, and luminal B breast cancer (LUM B), which is associated with<br />
higher grade, increased proliferation rates, and an overall poorer prognosis. O<strong>the</strong>r<br />
than genetic molecular subtyping, which can be expensive and not readily available,<br />
it may be possible to differentiate between <strong>the</strong>se two subgroups using<br />
immunohistochemical assessment of <strong>the</strong> proliferative marker Ki67, as reported by<br />
Cheang et al, where a cut off of Ki67 14% was used. This method of assessment<br />
demonstrated utility in providing prognostic information, however <strong>the</strong> false positive<br />
and false negative rates were around 25%, suggesting <strong>the</strong>re is significant room for<br />
improvement within such a method, and thus highlighting an area for ongoing<br />
research. Methodology aside, differentiation of HR+ breast cancers by molecular<br />
subgroups is critical, in order to identify appropriate treatment options for patients.<br />
Generally, endocrine <strong>the</strong>rapy alone would be recommended for LUM A, which<br />
carries an excellent ten year breast cancer specific survival rate of approximately 90%.<br />
However, tumor dormancy and late recurrences beyond 10 years are characteristic of<br />
LUM A. There is a significant lack of knowledge of <strong>the</strong> mechanisms behind tumor<br />
dormancy, highlighting a crucial area for fur<strong>the</strong>r research. Additionally, <strong>the</strong> optimal<br />
manner and duration of endocrine <strong>the</strong>rapy in ei<strong>the</strong>r pre- or postmenopausal women<br />
is, as yet, unknown; extension of endocrine treatment beyond 5 or even 10 years, as<br />
well as <strong>the</strong> most effective endocrine <strong>the</strong>rapy agent, requires ongoing study to better<br />
define treatment algorithms for LUM A. LUM B, which is inherently more<br />
aggressive, requires more aggressive <strong>the</strong>rapy and thus is generally treated with both<br />
endocrine <strong>the</strong>rapy and chemo<strong>the</strong>rapy, though this approach is not always effective.<br />
Potential alternate or additional treatment options may include targeting of o<strong>the</strong>r<br />
pathways of importance in this subgroup. This <strong>the</strong>refore requires firstly identification<br />
of pathways active in LUM B, and secondly, development and assessment of targeted<br />
agents against <strong>the</strong>se pathways. The utility of inhibitors against mTOR, PI3K or<br />
IGFR-1 is of particular interest.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
14IN HOW TO OPTIMISE ENDOCRINE THERAPY<br />
S.R.D. Johnston<br />
Medicine, Royal Marsden Hospital NHS Foundation Trust, London, UNITED<br />
KINGDOM<br />
For post-menopausal women with early stage ER+ breast cancer, aromatase<br />
inhibitors are recommended to be part of adjuvant endocrine <strong>the</strong>rapy ei<strong>the</strong>r as<br />
up-front <strong>the</strong>rapy or as a switch strategy following initial tamoxifen <strong>the</strong>rapy. Both<br />
approaches are equally effective, and both are superior to tamoxifen alone for 5<br />
years. The current duration for aromatase inhibitors given as adjuvant <strong>the</strong>rapy is 5<br />
years based on current safety and efficacy data. However, <strong>the</strong> optimal duration of<br />
adjuvant endocrine <strong>the</strong>rapy is currently unknown, and extended adjuvant <strong>the</strong>rapy<br />
with aromatase inhibitors after tamoxifen is an increasingly utilised strategy for<br />
reducing ongoing risk of recurrence, especially for those deemed to be at greater<br />
risk such as those with node-positive disease or o<strong>the</strong>r indicators for late relapse. In<br />
pre-menopausal women with ER+ early breast cancer <strong>the</strong> added benefit of ovarian<br />
suppression over and above tamoxifen remains unknown. In women aged 10% <strong>the</strong> tumor is very unlikely to fall into <strong>the</strong><br />
lowest relapse risk category at post neoadjuvant endocrine <strong>the</strong>rapy surgery<br />
(preoperative endocrine prognostic index zero or PEPI-0 (defined as ER+ Stage 1 or<br />
2A, Ki67 < 2.7%) and <strong>the</strong>refore not suitable for continued neoadjuvant endocrine<br />
<strong>the</strong>rapy (since one of <strong>the</strong> objectives of our studies is to avoid chemo<strong>the</strong>rapy in AI<br />
sensitive tumors). We have recently completed a successful pilot of triaging 35<br />
patients with an early on treatment high Ki67 values to chemo<strong>the</strong>rapy with <strong>the</strong><br />
efficacy results to be reported at <strong>the</strong> San Antonio Breast Cancer Symposium. The<br />
ALTERNATE trial is based on <strong>the</strong>se principles (ALTernate approaches for clinical<br />
stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment) and<br />
will screen over 2000 patients to identify up to 400 cases of ER+ HER2- AI resistant<br />
breast cancer who will be suitable candidates for investigational neoadjuvant<br />
approaches to improve outcomes in this understudied group of high risk patients.<br />
Patients with PEPI-0 disease will be managed without adjuvant chemo<strong>the</strong>rapy with a<br />
prospective plan to demonstrate that <strong>the</strong> 5 year relapse rate is 5% or less.<br />
Disclosure: The author has declared no conflicts of interest.<br />
16IN NEW TARGETED AGENTS IN LUMINAL BC<br />
J. Baselga<br />
Massachusetts General Hospital Cancer Center and Harvard Medical School,<br />
Boston, MA, UNITED STATES OF AMERICA<br />
In recent years <strong>the</strong> description of well-defined molecular subtypes of breast cancer,<br />
toge<strong>the</strong>r with <strong>the</strong> identification of driving genetic alterations and signaling<br />
pathways, has led to <strong>the</strong> clinical development of a number of successful molecular<br />
targeted agents. Among <strong>the</strong>m, luminal B breast cancer is emerging as an important<br />
subset of ER+ tumors that are less responsive to hormonal <strong>the</strong>rapy. Novel targets<br />
under exploration in this group of patients include inhibitors of <strong>the</strong><br />
PI3K-AKT-mTOR. In this regard, a recently reported phase III study <strong>the</strong> mTOR<br />
inhibitor everolimus and exemestane to exemestane and placebo in 724 patients<br />
with HR+ breast cancer refractory to nonsteroidal aromatase inhibitors showed that<br />
<strong>the</strong> combination of everolimus and exemestane resulted in marked improvement in<br />
progression-free survival as determined by local investigator assessment (6.9 vs. 2.8<br />
months; hazard ratio [HR], 0.43; P = 1.4 × 10 −15 ) 1 .The clinical benefit observed in<br />
<strong>the</strong> combination arm also far exceeds <strong>the</strong> clinical benefit of single-agent everolimus<br />
in a similar population of patients. In addition novel PI3K inhibitors are being<br />
tested in patients with breast cancer including PI3K alpha specific agents that have<br />
shown activity in patients with breast cancer harboring PI3K mutations. O<strong>the</strong>r<br />
approaches include inhibitors against <strong>the</strong> MEK pathways, as well as receptor<br />
tyrosine kinase inhibitors such as <strong>the</strong> Insulin-like growth factor receptor (IGF-1R)<br />
and <strong>the</strong> fibroblast growth factor receptor (FGFR). The clinical development of <strong>the</strong>se<br />
agents will require a change from <strong>the</strong> current large randomized trials in unselected<br />
patient populations to smaller trials in molecular defined tumor types that<br />
incorporate tumor biomarker endpoints as well as functional imaging. New<br />
challenges include <strong>the</strong> appearance of resistance ei<strong>the</strong>r by acquired secondary<br />
mutations, or via induction of adaptive activation of compensatory pathways that<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com<br />
abstracts
prevent cell death. It is anticipated that combinatorial approaches, acting on <strong>the</strong><br />
secondary mutations and/or compensatory pathways, may markedly improve on <strong>the</strong><br />
effects of targeted agents used alone. 1. Baselga J, Campone M, Piccart M, et al.<br />
Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.<br />
N Engl J Med <strong>2012</strong>;366:520-9.<br />
Disclosure: J. Baselga: Consulting activity with Novartis and Genentech<br />
17IN PHARMACOGENETICS /GENOMICS (PGX) TO OPTIMIZE<br />
ENDOCRINE THERAPY<br />
J. Ingle<br />
Oncology, Mayo Clinic, Rochester, MN, UNITED STATES OF AMERICA<br />
Endocrine <strong>the</strong>rapy of breast cancer is associated with substantial variability between<br />
patients in terms of efficacy, adverse events and end organ effects indicating genetic<br />
variability. This discussion will consider <strong>the</strong> host (germline) genome and consider<br />
SERMs and 3 rd generation AIs. In of terms of single gene studies, most of <strong>the</strong> work<br />
has been done with CYP2D6 and tamoxifen efficacy (first reported by our group in<br />
2005) but <strong>the</strong> results have been mixed, related (in this author’s opinion) to a series of<br />
flawed retrospective studies. Additional studies focusing on tamoxifen have examined<br />
polymorphisms in phase II (conjugating) enzymes (UGTs, SULTs), ESR1 and ESR2,<br />
Annals of Oncology<br />
but results remain preliminary. Our group conducted <strong>the</strong> largest PGx GWAS to date<br />
in women receiving tamoxifen or raloxifene on NSABP P-1 and P-2 and identified<br />
SNPs associated with development of breast cancer and SNP-dependent mechanisms<br />
underlying SERM and estrogen-dependent regulation of BRCA1 expression.<br />
Considering AIs, substantial research has occurred relating to <strong>the</strong> aromatase gene<br />
CYP19. Our group has conducted GWAS in postmenopausal women with baseline<br />
hormone levels as <strong>the</strong> phenotype and identified SNPs related to estradiol levels, that<br />
achieved genome-wide significance, with one SNP creating an estrogen response<br />
element (ERE), and regulation by <strong>the</strong>se SNPs of estrogen-dependent TSPYL5<br />
induction and CYP19 adipose promotors induction. We also identified a<br />
genome-wide significant non-synonymous SNP in SLCO1B1 associated with<br />
estrone-conjugate levels. We have completed a GWAS in women receiving AIs with<br />
musculoskeletal adverse events (MS-AE) as <strong>the</strong> phenotype and identified a SNP that<br />
created an ERE, was associated with estrogen-dependent TCL1A expression, which in<br />
turn altered interleukin (IL) 17 receptor (R) A expression, IL-17, IL-12, IL-RB2, and<br />
IL-1R2 expression, as well as NF-κB transcriptional activity. These finding provide a<br />
pharmacological explanation for MS-AE in women treated with AIs. To date, PGx<br />
studies have not produced changes in clinical practice of endocrine <strong>the</strong>rapy for breast<br />
cancer. In several instances <strong>the</strong>y have served as discovery tools that provided<br />
direction for research that has led to new knowledge of <strong>the</strong> biology underlying<br />
endocrine <strong>the</strong>rapy.<br />
Disclosure: The author has declared no conflicts of interest.<br />
ix28 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
how to integrate new drugs in <strong>the</strong><br />
current <strong>the</strong>rapeutic landscape of<br />
metastatic triple negative breast<br />
cancer<br />
18IN INTRODUCTION: RECENT FAILURES IN DRUG DEVELOPMENT<br />
FOR TN MBC<br />
F. André<br />
Breast Cancer Unit, Department of Medical Oncology, Institut de Cancérologie<br />
Gustave Roussy, Villejuif Cedex, FRANCE<br />
Several compounds have been developed in <strong>the</strong> recent years in triple negative BC.<br />
Although associated with promising initial results, <strong>the</strong>y all failed to be fully<br />
implemented. Iniparib failed because <strong>the</strong> compound was not fully characterized, and<br />
because phase II trials amplified <strong>the</strong> effect of <strong>the</strong> drug. Olaparib failed because it<br />
targeted a rare population, and partially because its position in <strong>the</strong> <strong>the</strong>rapeutic<br />
sequence was unclear. Finally, bevacizumab, although registered, was not fully<br />
optimized in <strong>the</strong> practice. Overall, <strong>the</strong>se failures are illustrative of current questions<br />
in drug development. The first relates to <strong>the</strong> amount of information needed before<br />
moving to registration trials: is <strong>the</strong> compound characterized in preclinical models?<br />
Do we have evidence for bioactivity in early trials? Are phase II randomized trials<br />
optimal for decision to phase III? The second relates to <strong>the</strong> difficulties to develop<br />
drug in small populations defined by a biomarker: how to develop a predictive test?<br />
How to organize clinical research when less than 1 out of 10 patients screened will<br />
enter <strong>the</strong> trial? What is <strong>the</strong> path to registration for a drug targeting a rare<br />
population?<br />
Disclosure: F. André: advisory board : SANOFI, Roche, Astrazeneca, novartis<br />
speaker bureau: Novartis<br />
19IN DOES MOLECULAR TRIAGE HELP TO IDENTIFY HIGHLY<br />
SENSITIVE DISEASE?<br />
L. Pusztai<br />
Medical Oncology, Yale University, New Haven, CT, UNITED STATES OF<br />
AMERICA<br />
It is helpful to consider predictive biomarkers within three distinct categories that<br />
also represent different degrees of difficulty in terms of <strong>the</strong> predictor discovery<br />
process. (1) There are broad treatment response markers that are based on detecting<br />
a fundamental biological process that is relevant for <strong>the</strong> action of a class of drugs.<br />
Such markers have a large transcriptional (or o<strong>the</strong>r molecular) footprint and hence<br />
represent relatively low hanging fruits in <strong>the</strong> discovery process. For example, high<br />
tumor proliferation is such a marker for general chemo<strong>the</strong>rapy sensitivity or for<br />
worse baseline prognosis. It may be possible in <strong>the</strong> future to discover similar broad<br />
markers for metabolism-targeted agents or for immuno<strong>the</strong>rapies. (2) There are drug<br />
class-specific predictors such as estrogen receptor (ER) expression or human<br />
epidermal growth factor 2-receptor (HER2) amplification or activating mutations in<br />
critical signaling genes (e.g EGFR, bRAF, c-KIT, etc..) that represent singular driver<br />
events in tumors. These alterations reflect partial dependence on a given molecular<br />
pathway and can predict sensitivity to a variety of agents that target <strong>the</strong> involved<br />
pathway. Similar driver events for distinct small subsets of cancers are likely to be<br />
discovered in <strong>the</strong> next decade and could yield predictors with clinically useful<br />
negative predictive value. (3) Single drug-specific response markers that could be<br />
used to select one agent over ano<strong>the</strong>r have remained elusive despite extensive<br />
research efforts. This may be due to <strong>the</strong> case-to-case heterogeneity of molecular<br />
mechanisms that can converge to cause sensitivity or resistance to a particular<br />
molecule. Molecular markers under points (2) and (3) and <strong>the</strong>ir combinations exist<br />
and are useful to select adjuvant <strong>the</strong>rapies in breast cancer (e.g. Ki67, OncotypeDX,<br />
MammaPrint, ER, HER2, PAM50) or triage patients to clinical trials who are<br />
unlikely to do well with existing treatment modalities. Prospectively designed<br />
molecular triaging studies that directly test <strong>the</strong> positive predictive value of candidate<br />
response markers also remain an important research strategy to rapidly assess <strong>the</strong><br />
clinical utility of predictive markers.<br />
Disclosure: The author has declared no conflicts of interest.<br />
Annals of Oncology 23 (Supplement 9): ix29–ix30, <strong>2012</strong><br />
doi:10.1093/annonc/mds372<br />
20IN DEVELOPMENT OF NEW TARGETED AGENTS FOR TNBC<br />
N. Turner<br />
Breakthrough Breast Cancer, Institute of Cancer Research, London, UNITED<br />
KINGDOM<br />
Triple negative breast cancers are a highly diverse and heterogenous group of<br />
tumours. A number of different approaches to tackling this heterogeneity are<br />
emerging for <strong>the</strong> targeted treatment of TNBC. Targeting common genetic events<br />
of TNBCs. TNBCs have a high frequency of TP53 mutations in ∼60% of TNBC,<br />
a rate substantially higher than o<strong>the</strong>r breast cancer subtypes. Targeting TP53<br />
inactivation has historically been challenging, although preclinical data suggests<br />
that combinations of DNA damaging chemo<strong>the</strong>rapy with CHK1 or WEE1<br />
inhibitors has <strong>the</strong> potential to target TP53 deficiency. O<strong>the</strong>r common targetable<br />
events include genetic activation of <strong>the</strong> PI3 kinase pathway in ∼15-20% cancers,<br />
through PTEN deletions/ inactivating mutations and PIK3CA activating mutations,<br />
and loss of HR based DNA repair, though mutation of BRCA1/2 and BRCA1<br />
promoter methylation, that could be targeted with PARP inhibitors. A fur<strong>the</strong>r<br />
potentially targetable common event includes loss of <strong>the</strong> phosphatase PTPN12 and<br />
upregulation of specific receptor tyrosine kinases. Targeting TNBC subtype specific<br />
features. Gene expression studies have revealed multiple different gene expression<br />
subtypes in TNBC. The luminal AR subtype expresses <strong>the</strong> androgen receptor (AR)<br />
and now both preclinical and tentative clinical data to support AR as a<br />
<strong>the</strong>rapeutic target. Mesenchymal-like basal TNBC express autocrine FGF2 ligand<br />
that is important for <strong>the</strong>ir biology.<br />
Targeting individual rare events. A diverse set of potentially targetable oncogenic<br />
mutations and amplifications occur in TNBC that are likely important<br />
<strong>the</strong>rapeutic targets for individual cancers, but <strong>the</strong>se present a substantial<br />
challenge to drug development due to <strong>the</strong>ir individual rarity. Through such<br />
strategies to sub-segment TNBC progress will be made in delivering targeted<br />
<strong>the</strong>rapies for TNBC.<br />
Disclosure: N. Turner: Dr Nicholas Turner has received honoraria from Novartis,<br />
Astra Zeneca, Roche, Clovis, EOS<br />
21IN IS THERE A ROLE FOR NEW CYTOTOXIC AGENTS IN TNBC?<br />
J. Cortes<br />
Medical Oncology Department, Vall d’Hebron Institute of Oncology, Vall<br />
d’Hebron University Hospital, Barcelona, SPAIN<br />
Triple-negative breast cancer (TNBC), which accounts for 15% to 20% of all<br />
cases of breast cancer, is characterized by having estrogen-receptor<br />
(ER)-negative and progesterone-receptor (PR)-negative and has no<br />
overexpression of human epidermal growth factor receptor 2 (HER2). It is an<br />
aggressive subtype of breast cancer marked by higher rates of visceral and<br />
central nervous system metastases and poor disease-free survival compared with<br />
hormone receptor-positive sybtypes. In recent years, an increasing appreciation<br />
and identification of somatic mutations and o<strong>the</strong>r genetic aberrations that drive<br />
human malignancies have led us within reach of personalized cancer medicine.<br />
However, after a high expectation with iniparib, a non optimal PARP inhibitor,<br />
final data from a randomized phase III trial did not demonstrate this drug to<br />
improve outcomes in combination with chemo<strong>the</strong>rapy in patients with advanced<br />
TNBC and bevacizumab is <strong>the</strong> only “targeted” agent which has shown to<br />
improve outcomes in combination with chemo<strong>the</strong>rapy in patients with<br />
metastatic TNBC. Thus, chemo<strong>the</strong>rapy continues to be <strong>the</strong> standard of care in<br />
<strong>the</strong>se patients. Although taxanes and anthracyclines are still <strong>the</strong> most important<br />
compounds for patients with metastatic TNBC, <strong>the</strong> majority of <strong>the</strong>m will<br />
progress and patients will need new chemo<strong>the</strong>rapeutic drugs. Thus, new<br />
cytotoxic drugs are being studied in patients with TNBC in late-line. Among<br />
<strong>the</strong>m, new antimicrotubule agents such as eribulin mesylate have shown to<br />
increase survival versus <strong>the</strong> treatment of physiciańs choiceandseemstobe<br />
active also in this tumor type. O<strong>the</strong>r agents which seem to play a role are<br />
vinflunine and KNTR-102, a new polymeric conjugate of irinotecan, both in<br />
phase III trials. NKTR-102 has shown an impressive response rate in patients<br />
with very heavily pretreated TNBC, including taxanes, anthacyclines and<br />
capecitabine.<br />
Disclosure: J. Cortes: Consultant: Roche, Novartis, Celgene Honoraria: Roche,<br />
Celgene, Novartis, Cephalon/Teva<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com<br />
abstracts
22IN TARGETING THE HOST IN TNBC<br />
G. Curigliano<br />
Medicine, Istituto Europeo di Oncologia, Milano, ITALY<br />
Cancer medicine is increasingly moving toward a new era of personalized<br />
<strong>the</strong>rapeutics that embraces integrative approaches. Combinatorial strategies will target<br />
not only cancer cell-intrinsic pathways, but also cancer cell-extrinsic cells, pathways,<br />
and mediators of <strong>the</strong> tumor microenvironment. As <strong>the</strong> strategic goal of defining <strong>the</strong><br />
roles of <strong>the</strong> tumor microenvironment in primary and metastatic tumor progression,<br />
new discoveries can be envisioned to produce innovative multitargeting strategies that<br />
will be able to more thoroughly extinguish primary and metastatic disease,<br />
overcoming adaptive resistance mechanisms to such <strong>the</strong>rapies. The cancer<br />
microenvironment is constituted of non-transformed host stromal cells such as<br />
endo<strong>the</strong>lial cells,fibroblasts, various immune cells, and a complex extracellular matrix<br />
secreted by both <strong>the</strong> normal and neoplastic cells embedded in it. The importance of<br />
<strong>the</strong> microenvironment and its potential in cancer <strong>the</strong>rapy is just being established.<br />
Among modalities that target <strong>the</strong> microenvironment, harnessing immune responses<br />
Annals of Oncology<br />
has long been pursued. Efforts to turn on <strong>the</strong> immune system against cancers with<br />
inactivated tumor vaccines or intratumor injections of bacterial products to induce<br />
local inflammation and recruit an antitumor immune response have led to anecdotal<br />
successes. A major limitation of <strong>the</strong> various approaches to turning on an immune<br />
response to cancer is that <strong>the</strong> immune system exerts a major effort to avoid<br />
immune over-activation, which could harm healthy tissues. Cancer takes<br />
advantage of this ability to hide from <strong>the</strong> immune system by exploiting a series of<br />
immune escape mechanisms that were developed to avoid autoimmunity<br />
(mechanisms of tolerance). Among <strong>the</strong>se mechanisms are <strong>the</strong> hijacking of<br />
immune-cell–intrinsic checkpoints that are induced on T-cell activation. Blockade<br />
of one of <strong>the</strong>se checkpoints, cytotoxic T-lymphocyte–associated antigen 4<br />
(CTLA-4) or <strong>the</strong> programmed death 1 (PD-1) receptor, provided <strong>the</strong> first evidence<br />
of activity of an immune-modulation approach in <strong>the</strong> treatment of a solid tumor.<br />
The future frontier in <strong>the</strong> treatment of cancer requires identification of potential<br />
targets in order to personalize <strong>the</strong>rapies. The immune system remembers what it<br />
targets, so once <strong>the</strong> system is correctly activated, it may mediate a durable tumor<br />
response.<br />
Disclosure: The author has declared no conflicts of interest.<br />
ix30 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
molecular neuro-oncology: new<br />
avenues in diagnosis and treatment<br />
23IN ANAPLASTIC GLIOMA: WILL MOLECULAR PROFILING<br />
OVERRIDE HISTOLOGY?<br />
M.J. van den Bent<br />
Neuro-Oncology, ErasmusMC - Daniel den Hoed Cancer Center, Rotterdam,<br />
NETHERLANDS<br />
The histopathological diagnosis of anaplastic glioma is complicated by a disturbing<br />
interobserver variation. Several molecular assays are now of demonstrated value in<br />
anaplastic glioma. Recent randomized trials have shown that 1p/19q co-deletion is<br />
not only prognostic, but also predictive for improved outcome to RT with adjuvant<br />
PCV. Also, testing for IDH mutations is helpful for <strong>the</strong> in diagnosis of grade II and<br />
grade III, and has significant prognostic implications. MGMT promoter methylation<br />
in anaplastic gliomas seems to be <strong>the</strong> result of alter cell metabolism induced by IDH<br />
mutations which leads to <strong>the</strong> CpG island hypermethylation. Therefore, in anaplastic<br />
glioma MGMT promoter methylation appears to reflect IDH status.<br />
Conclusion: over <strong>the</strong> past two years, <strong>the</strong> role of molecular testing has greatly<br />
increased in <strong>the</strong> management of anaplastic gliomas.<br />
Disclosure: The author has declared no conflicts of interest.<br />
24IN MANAGEMENT OF GLIOBLASTOMA: THE ROAD TOWARDS<br />
STRATIFIED CANCER CARE<br />
M. Weller<br />
Department of Neurology, University Hospital Zurich, Zurich, SWITZERLAND<br />
Glioblastomas are highly malignant primary brain tumors presumably originating<br />
from neuroglial progenitor cells. Median survival is less than one year. Cytoreductive<br />
surgery, focal radio<strong>the</strong>rapy, and alkylating agent chemo<strong>the</strong>rapy are standard of care<br />
for favourable prognosis patients. These tumors can be classified by morphology,<br />
imaging parameters, clinical characteristics, single biomarkers or complex molecular<br />
signatures, Some of <strong>the</strong>se characteristics, including age and Karnofsky performance<br />
score, provide important prognostic information. In contrast, nei<strong>the</strong>r histological<br />
subtyping of glioblastoma nor specific imaging features have assumed prognostic<br />
relevance. Among multiple candidate biomarkers, only one, that is, promoter<br />
methylation of <strong>the</strong> O 6 -methylguanine methyltransferase (MGMT) gene, helps for<br />
clinical decision making. Patients with glioblastomas with MGMT promoter<br />
methylation derive more benefit from alkylating agent chemo<strong>the</strong>rapy. In <strong>the</strong> growing<br />
population of elderly patients with glioblastoma, combination radiochemo<strong>the</strong>rapy has<br />
not been shown to be superior to mono<strong>the</strong>rapy and may be mess well tolerated than<br />
ei<strong>the</strong>r radio<strong>the</strong>rapy or chemo<strong>the</strong>rapy alone. Here, MGMT promoter methylation may<br />
assume a major role as a predictive biomarker. Results from registration trials for two<br />
anti-angiogenic compounds, bevacizumab and cilengitide, are awaited. Biomarkers<br />
for benefit from anti-vascular endo<strong>the</strong>lial growth factor <strong>the</strong>rapies have not been<br />
introduced into <strong>the</strong> clinic. Positron emission tomography for <strong>the</strong> detection of avb3/5<br />
integrins might be used to select patients for treatment with anti-integrin<br />
anti-angiogenic approaches. Screening for a specific type of epidermal growth factor<br />
receptor mutation, EGFRvIII, is currently being explored as a biomarker for selecting<br />
patients for vaccination in two randomized clinical trials. Despite extensive efforts at<br />
defining biological markers as a basis for selecting <strong>the</strong>rapies, most treatment<br />
decisions for glioblastoma patients are still based on age and performance status<br />
today. However, several ongoing clinical trials may enrich <strong>the</strong> repertoire of criteria<br />
for clinical decision making in <strong>the</strong> very near future.<br />
Disclosure: M. Weller: The author has received honoraria for advisory<br />
boards and lectures from Antisense Pharma, Magforce, MSD, Merck Serono<br />
and Roche, as well as research support from Merck Serono, Roche and<br />
Antisense Pharma.<br />
Annals of Oncology 23 (Supplement 9): ix31, <strong>2012</strong><br />
doi:10.1093/annonc/mds373<br />
25IN THE MOLECULAR DISSECTION OF MEDULLOBLASTOMA<br />
S.M. Pfister<br />
Pediatric Neurooncology, German Cancer Research Center Heidelberg,<br />
Heidelberg, GERMANY<br />
Medulloblastoma is <strong>the</strong> most common malignant brain tumor in childhood,<br />
displaying tremendous biological and clinical heterogeneity. Four biological<br />
subgroups are consistently revealed in various studies based on gene expression<br />
profiling, but details of <strong>the</strong> genetic events driving each of <strong>the</strong>se subgroups remain<br />
elusive. We have performed an integrative deep-sequencing analysis to identify<br />
genetic alterations in 200 tumor-normal pairs. Strikingly, tetraploidy was found to<br />
be a common early event in clinically challenging Group 3 & 4 tumours. For<br />
SHH tumors in contrast, we have identified a subgroup of tumors in older<br />
children that show striking patterns of chromothripsis, all of which have<br />
underlying TP53 mutations, ei<strong>the</strong>r early somatic or germline. SHH tumors in<br />
adults, which are <strong>the</strong> predominant subgroup in this age group, in turn show a<br />
largely different mutation spectrum from <strong>the</strong>ir pediatric counterparts. Overall,<br />
beside known alterations (CTNNB1, PTCH1, MLL2, SMARCA4), several genes not<br />
previously implicated in medulloblastoma (DDX3X, CTDNEP1, KDM6A) were<br />
recurrently mutated, often in subgroup-specific patterns and many of <strong>the</strong>m<br />
involved in chromatin-remodelling. These findings provide a detailed insight into<br />
medulloblastoma tumorigenesis, and disclose novel targets for <strong>the</strong>rapeutic<br />
approaches, especially for Group 3 and 4 patients in children, and SHH tumors in<br />
adults.<br />
Disclosure: The author has declared no conflicts of interest.<br />
26IN BRAIN METASTASIS: CHALLENGES IN UNDERSTANDING<br />
PATHOGENESIS AND IN DESIGNING CLINICAL TRIALS<br />
M. Brada<br />
Clinical Oncology, UCLH & Leaders in Oncology Care, London,<br />
UNITED KINGDOM<br />
The presence of brain metastases (BM) remains a <strong>the</strong>rapeutic challenge as most<br />
trials with <strong>the</strong> exception of local treatment with surgery and radiosurgery in<br />
patients with solitary BM have failed. The negative trials suggest that <strong>the</strong> disease<br />
in <strong>the</strong> brain is not <strong>the</strong> principal determinant of life expectancy in patients with<br />
disseminated disease. Large trials without enrichment of <strong>the</strong> study population by a<br />
predictive biomarker are also unlikely to be successful. The blanket use of whole<br />
brain radio<strong>the</strong>rapy for multiple BMs is also no longer tenable. The concept of<br />
blood brain barrier, unlikely to be of significance in patients with enhancing brain<br />
metastases, should not be a bar to <strong>the</strong> use of chemo<strong>the</strong>rapy, where <strong>the</strong> principal<br />
determinant of efficacy is likely to be chemoresponsiveness of systemic disease.<br />
Successful use of prophylactic brain treatment is predicated on <strong>the</strong> assumption<br />
that brain dissemination is a late metastatic event. Metastases suppressors, with<br />
mode of action spanning <strong>the</strong> metastatic cascade, have prophylactic efficacy in vivo,<br />
although <strong>the</strong> studies are mostly based on non-spontaneous models, which are<br />
unlikely to reflect <strong>the</strong> true clinical situation. Never<strong>the</strong>less some agents are<br />
approaching <strong>the</strong> time of clinical application. The successful development of new<br />
<strong>the</strong>rapies for BMs needs refinement of <strong>the</strong> current trial design. Phase I/II studies<br />
of new agents should not exclude patients with BM to provide “proof of<br />
principle” of <strong>the</strong>rapeutic efficacy in <strong>the</strong> brain. Subsequent trials, with survival as<br />
<strong>the</strong> primary endpoint, should focus on patient population where BM are likely to<br />
be <strong>the</strong> determinants of outcome (i.e. with inactive systemic disease) and enriched<br />
for a predictive biomarker. Large trials, even in a single tumour type, testing a<br />
single agent or a combination, ei<strong>the</strong>r alone or in addition to standard treatment<br />
without appropriate patient selection are likely to continue to fail.<br />
Disclosure: The author has declared no conflicts of interest.<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com<br />
abstracts
abstracts<br />
a paradigm shift in early drug<br />
development: individualizing<br />
to more patient benefit<br />
27IN THE IMPORTANCE OF PATIENT SELECTION IN TREATMENT<br />
EFFICACY<br />
S. Aamdal<br />
Dept of Oncology, Oslo University Hospital, Oslo, NORWAY<br />
The importance of patient selection in treatment efficacy Cohorts of patients selected<br />
according to biomarkers are shifting <strong>the</strong> cancer treatment paradigm from population<br />
based to personalized medicine introducing a new area termed <strong>the</strong>ragnostics in<br />
which <strong>the</strong> combination of diagnostics and <strong>the</strong>rapeutics identifies patients most likely<br />
to benefit or not from a treatment regimen. Apart from safety and toxicity<br />
assessment phase I trials now also test hypo<strong>the</strong>sis, determine target engagement,<br />
biologic response, identify <strong>the</strong> appropriate patient population, proof-of-concept, and<br />
identify potential predictive biomarkers in Phase II and Phase III trials. There are<br />
several strategies to select patients on molecular bases for early drug development. 1)<br />
The molecular alterations are sufficient frequent in a tumor type that without<br />
pre-selection retrospective analysis of <strong>the</strong> mutation can be carried out. A<br />
retrospective analysis on fixed tissue can confirm <strong>the</strong> drug activity in presence of <strong>the</strong><br />
molecular alteration. Selection is <strong>the</strong>n based on tumor type, not on molecular<br />
analysis. Such selection would put a number of patients at risk of exposure to a study<br />
drug despite not presenting <strong>the</strong> target of interest. 2) Prescreening patients by sending<br />
tumor tissue to a central laboratory for analysis just before inclusion in a trial. This<br />
ensures state-of <strong>the</strong> art central laboratory analyses. Amount of tumor tissue may<br />
become an issue if several labs are involved. Turnaround time between molecular<br />
analyses and trial initiation may become too lengthy for patients with advanced<br />
disease. 3) Local prescreening of patients while still on standard treatment. Less<br />
tumor material is needed and no delay from progression on standard <strong>the</strong>rapy to<br />
recruitment in a clinical trial. Multiple patient consent forms are not necessary.<br />
However patients will be screened for participating, but never will enter trial due to<br />
early disease progression. Intra-tumor heterogeneity, presence of more than one<br />
clone in <strong>the</strong> tumor and inter-tumor heterogeneity, <strong>the</strong> presence of different genetic<br />
alterations in different metastases from a single patient is a major challenge to patient<br />
selection. Single cor biopsy may lead to underestimation of <strong>the</strong> mutations in <strong>the</strong><br />
tumor and could influence <strong>the</strong> efficacy of molecular targeted <strong>the</strong>rapies even in<br />
carefully selected patients.<br />
Disclosure: The author has declared no conflicts of interest.<br />
28IN THE ROLE OF TUMOR/MOLECULAR TARGET SELECTION<br />
IN THE SUCCESS OF A NEW AGENT<br />
C. Dittrich<br />
3rd Med. Dept.-Centre for Oncology and Haematology, Kaiser Franz<br />
Josef-spital, Vienna, Austria, LBI-ACR VIEnna & ACR-ITR Vienna, Vienna,<br />
AUSTRIA<br />
Rational drug discovery/development is targeted at structures and pathways, which<br />
cause, permit, or maintain malignancy. This let restrain from <strong>the</strong> histopathologically<br />
characterized organ entities and substitute <strong>the</strong>m for merely molecularly characterized<br />
entities, such as EGFR, HER2, KRAS, BRAF driven entities. The presence of a target<br />
and its <strong>the</strong>rapeutic consequence in one organ cannot be extrapolated to ano<strong>the</strong>r. As<br />
an example, a BRAF mutation positive (m+) status in melanoma, which is highly<br />
predictive for response to <strong>the</strong> anti-BRAF directed TKI vemurafenib (Fla<strong>the</strong>ry 2010),<br />
cannot be extrapolated to <strong>the</strong> situation in BRAFm+ CRC (Kopetz 2010). A fur<strong>the</strong>r<br />
difficulty in switching from tumor entity to target entity lies in <strong>the</strong> experience that<br />
clinical effectiveness does not only depend on whe<strong>the</strong>r a functional axis is hit by a<br />
drug or a class of drugs anyhow and anywhere, but moreover in a much more<br />
defined context; TKIs like erlotinib (Zhou 2011; Rosell <strong>2012</strong>) yielded increased OS<br />
and PFS, respectively, in EGFRm+ tumors. But, <strong>the</strong> interference of <strong>the</strong> same axis at a<br />
different site and via <strong>the</strong> anti-EGFR MoAb cetuximab (in combination with standard<br />
<strong>the</strong>rapy) led to an OS advantage independent of <strong>the</strong> EGFR mutational status of<br />
NSCLC (O’Byrne 2011). This touches upon <strong>the</strong> necessity to discover, identify,<br />
develop, and finally validate <strong>the</strong> most relevant biomarker(s) for <strong>the</strong> purpose of drug<br />
development, notably with high predictive accuracy early in <strong>the</strong> developmental<br />
process. In NSCLC, it took almost a decade of trial and error to better define <strong>the</strong><br />
position/clinical usefulness of various biomarkers and methodologies, respectively, to<br />
Annals of Oncology 23 (Supplement 9): ix32–ix33, <strong>2012</strong><br />
doi:10.1093/annonc/mds374<br />
characterize/measure <strong>the</strong> probability to benefit clinically in form of EGFR expression/<br />
gene amplification/copy number and mutations on <strong>the</strong> one side, and ORR, PFS, and<br />
OS, respectively, on <strong>the</strong> o<strong>the</strong>r side. A shortcoming derived from <strong>the</strong> earlier<br />
developmental process is <strong>the</strong> lack of fixing <strong>the</strong> right time point to preselect/enrich <strong>the</strong><br />
relevant patient population. This is of utmost importance, especially if patient<br />
segments are small. In addition, it has to be found out whe<strong>the</strong>r a new targeting<br />
substance is not only reaching /modulating <strong>the</strong> target, but has also enough impact on<br />
<strong>the</strong> relevant biology of <strong>the</strong> tumor to gain clinical effectiveness.<br />
Disclosure: C. Dittrich: Unrestricted research grants to <strong>the</strong> research institutes<br />
Honoraria for consulting services by several companies<br />
29IN WHAT IS THE FEATURE OF AN OPTIMAL NEW AGENT:<br />
SELECTIVE TARGET VERSUS MULTI-TARGETED VERSUS<br />
COMBINATION DRUGS<br />
J.H.M. Schellens, S. Marchetti<br />
Department of Clinical Pharmacology, The Ne<strong>the</strong>rlands Cancer Institute,<br />
Amsterdam, NETHERLANDS<br />
There are in principle two pharmacological ways to address <strong>the</strong> question whe<strong>the</strong>r<br />
selective targeted or multitargeted drugs are to be preferred as single agent and/or in<br />
combination. One approach is to focus on benefit and <strong>the</strong> o<strong>the</strong>r is to focus on safety.<br />
The modern era of development of targeted agents started with <strong>the</strong> launch of two<br />
key molecules: one monoclonal antibody (MoAb) rituxumab and one so-called small<br />
molecule imatinib. Rituximab was registered in <strong>the</strong> EU in 1998 and since <strong>the</strong>n about<br />
seven o<strong>the</strong>r MoAbs have been registered. All MoAbs tend to have a selective<br />
mechanism of action and target on average one key protein, for example CD-20<br />
(rituximab), or Her2 (trastuzumab). The benefit of <strong>the</strong>se drugs has been clearly<br />
demonstrated and <strong>the</strong> safety of <strong>the</strong>se MoAbs is on average good. Possible exception is<br />
where <strong>the</strong>y target <strong>the</strong> same proteins in normal tissues such as <strong>the</strong> skin (cetuximab,<br />
panitumumab), or <strong>the</strong> heart (trastuzumab) resulting in sometimes poorly predictable<br />
but on average manageable side-effects. The small molecule imatinib was registered<br />
in <strong>the</strong> EU in 2001 and since <strong>the</strong>n more than 13 o<strong>the</strong>r targeted small molecules have<br />
been registered. Some of <strong>the</strong>se drugs are ra<strong>the</strong>r selective, such as erlotinib (mainly<br />
EGFR) and vemurafenib (mainly BRAF V600) whereas o<strong>the</strong>rs are less selective and<br />
certainly less selective than <strong>the</strong> MoAbs, for example sorafenib, pazopanib and<br />
sunitinib. This translates into sometimes significant normal tissue toxicity (sunitinib).<br />
From <strong>the</strong> safety perspective one would prefer selective drugs targeting unique tumor<br />
expressed proteins or deranged pathways, which would result in a wide <strong>the</strong>rapeutic<br />
window. From a benefit perspective at first glance one might prefer multi targeted<br />
drugs as tumors show a multitude of mutations and amplifications and a double- or<br />
even multi-barreled shotgun approach might hit one or more of <strong>the</strong>se targets at <strong>the</strong><br />
same time. The disadvantage however is that <strong>the</strong> mutational profile may not fit to<br />
<strong>the</strong> activity spectrum of <strong>the</strong> “targeted” drug and that this approach will probably<br />
increase normal tissue toxicity. In view of increasing insight in <strong>the</strong> molecular<br />
derangements of tumors one would prefer to have many selective anticancer drugs<br />
that can safely be combined on <strong>the</strong> basis of a patient’s individual tumor genetic<br />
profile. This would fit into <strong>the</strong> concept of a “personalized treatment”.<br />
Disclosure: J.H.M. Schellens: Research grants have been received from: Roche, Eisai,<br />
GSK and Astrazeneca.S. Marchetti: No conflicts of interest to declare<br />
30IN BIOMARKERS OF RESISTANCE TO TARGETED AGENTS<br />
R. Bernards, S. Huang<br />
Molecular Carinogenesis, The Ne<strong>the</strong>rlands Cancer Institute, Amsterdam,<br />
NETHERLANDS<br />
Unresponsiveness to <strong>the</strong>rapy remains a significant problem in <strong>the</strong> treatment of<br />
cancer, also with <strong>the</strong> new classes of cancer drugs. In my laboratory, we use functional<br />
genetic approaches to identify biomarkers that can predict responsiveness to targeted<br />
cancer <strong>the</strong>rapeutics; drugs that specifically inhibit molecules or pathways that are<br />
often activated in cancer. Never<strong>the</strong>less, it remains poorly explained why a significant<br />
number of tumors do not respond to <strong>the</strong>se <strong>the</strong>rapies. We aim to elucidate <strong>the</strong><br />
molecular pathways that contribute to unresponsiveness to targeted cancer<br />
<strong>the</strong>rapeutics using a functional genetic approach. This will yield biomarkers that may<br />
be useful to predict how individual patients will respond to <strong>the</strong>se drugs.<br />
Fur<strong>the</strong>rmore, this work may allow <strong>the</strong> development of drugs that act in synergy with<br />
<strong>the</strong> established drug to prevent or overcome drug resistance. To identify biomarkers<br />
that control tumor cell responsiveness to cancer <strong>the</strong>rapeutics, we use multiple<br />
complementary approaches. First, we use genome wide loss-of-function genetic<br />
screens (with shRNA interference libraries) in cancer cells that are sensitive to <strong>the</strong><br />
drug-of-interest to search for genes whose down-regulation confers resistance to <strong>the</strong><br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
Annals of Oncology<br />
drug-of-interest (resistance screens). In addition, we use shRNA screens with a low<br />
dose of <strong>the</strong> drug to screen for genes whose inhibition enhances <strong>the</strong> toxicity of <strong>the</strong><br />
cancer drug (sensitizer screens). As a third approach, we use gain of function genetic<br />
screens in which we search for genes whose over-expression modulates drug<br />
responsiveness. Once we have identified candidate drug response biomarkers in relevant<br />
cell line models, we ask if <strong>the</strong> expression of <strong>the</strong>se genes is correlated with clinical<br />
response to <strong>the</strong> drug-of-interest. For this, we use tumor samples of cancer patients<br />
treated with <strong>the</strong> drug in question and whose response to <strong>the</strong>rapy is documented. In a<br />
fourth and distinct approach we perform high throughput sequencing of <strong>the</strong> “kinome”<br />
(some 600 genes) of tumor samples to identify connections between cancer genotype<br />
and drug responses Examples of <strong>the</strong>se approaches to identify biomarkers of response to<br />
different cancer drugs will be presented.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
31IN THE ROLE OF MOLECULAR IMAGING IN EARLY DRUG<br />
DEVELOPMENT<br />
K. Muylle<br />
Nuclear Medicine, Institut Jules Bordet, ULB, Brussels, BELGIUM<br />
Molecular cancer biology revealed an ever-increasing number of disease regulating<br />
intracellular and extracellular tumour targets. These new insights in <strong>the</strong> pathogenesis<br />
of tumor cells have lead to <strong>the</strong> development of a broad range of targeted <strong>the</strong>rapeutic<br />
agents. In cancer, few targets have been identified that cover all types of cancer from<br />
a given site of origin. Hence, patient selection by molecular characterization of<br />
disease subtype in an individual patient becomes increasingly important in order to<br />
avoid unnecessary toxicity, improve patient outcome and reduce <strong>the</strong> costs for clinical<br />
trials. Biomarkers are objectively measured indicators of biological and pathogenic<br />
processes and can be used to predict patient outcome (regardless of <strong>the</strong>rapy), to<br />
predict response to specific <strong>the</strong>rapies and for response assessment (monitoring). The<br />
advantages of imaging biomarkers over those that require a biopsy sample include<br />
non-invasiveness, <strong>the</strong> ability to quantify cellular targets for <strong>the</strong> entire disease burden,<br />
and <strong>the</strong>reby to avoid <strong>the</strong> sampling error that can occur with heterogeneous receptor<br />
expression and <strong>the</strong> potential for serial studies of <strong>the</strong> in vivo effects of a drug on <strong>the</strong><br />
target. In terms of drug development, predictive imaging biomarkers have a high<br />
potential for reducing costs of clinical trials, as <strong>the</strong>y can be used for enriching patient<br />
selection by assessing drug targeting and/or early-on response prediction. The scope<br />
of this presentation is to highlight <strong>the</strong> potential of molecular imaging in drug<br />
development, illustrated by examples where molecular imaging has been<br />
implemented in clinical trials.<br />
Disclosure: The author has declared no conflicts of interest.<br />
32IN CONCLUSIONS AND PERSPECTIVES<br />
A. Awada<br />
Department of Medical Oncology, Institute Jules Bordet, Brussels, BELGIUM<br />
Early clinical drug development in cancer included mainly <strong>the</strong> phase I program<br />
(aims: DLTs and recommended doses) and early phase II studies (aim: antitumor<br />
activity). In <strong>the</strong> era of molecular biology and <strong>the</strong> development of targeted agents, <strong>the</strong><br />
frontier between <strong>the</strong>se phases became less visible. Individualizing <strong>the</strong> early drug<br />
development process (from study design to patient/tumor selection) has lead to more<br />
patient benefit as recently illustrated in several commom and orphan solid tumors.<br />
This paradigm shift will be intensified in <strong>the</strong> near future by better patient selection,<br />
molecular target discovery, anticancer drugs selectivity, deeper understanding of <strong>the</strong><br />
biology of <strong>the</strong> tumors and mechanisms of sensitivity/resistance and <strong>the</strong> emerging role<br />
of molecular imaging to “map” <strong>the</strong> tumor and to document as early as possible <strong>the</strong><br />
tumor progression to <strong>the</strong> costly new anticancer agents. All <strong>the</strong>se issues will be<br />
developed by colleagues in this special symposium. My task will be to conclude and<br />
to present some perspectives. These will be based among o<strong>the</strong>rs on <strong>the</strong> development<br />
of new technologies, <strong>the</strong> understanding of <strong>the</strong> behaviour of primiray tumors and<br />
metastases and <strong>the</strong> integration of biological and technological advances into early<br />
clinical research investigation of new targeted agents.<br />
Disclosure: The author has declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds374 | ix33
abstracts<br />
how can medical oncologists deal with<br />
<strong>the</strong> new wave of genetic information<br />
about <strong>the</strong>ir patients?<br />
33IN CHALLENGES OF DEALING WITH NEXT GENERATION<br />
SEQUENCING FOR HEREDITARY CANCER IN CLINICAL<br />
PRACTICE<br />
K. Claes<br />
Center for Medical Genetics, Ghent University Hospital, Ghent, BELGIUM<br />
Next generation sequencing is one of <strong>the</strong> most significant technological advances in<br />
<strong>the</strong> biological sciences of <strong>the</strong> last 20-30 years. These recent advances have brought a<br />
paradigm shift in how medical researchers investigate both rare and common<br />
disorders. The ability to generate enormous amount of sequence data in a short time<br />
at an affordable cost makes this approach ideal for a wide range of applications from<br />
1) sequencing a panel of genes associated with a particular disease, 2) all coding<br />
regions (« exome sequencing ») to 3) <strong>the</strong> entire human genome. However, while <strong>the</strong><br />
technology promises to reduce <strong>the</strong> cost of sequencing an entire human genome to<br />
less than US$1000, one must question <strong>the</strong> diagnostic utility of complete genome<br />
sequencing for routine clinical testing, given <strong>the</strong> many interpretive challenges posed<br />
by this approach. Knowing that in 5-6% of <strong>the</strong> breast cancer patients analysed for <strong>the</strong><br />
coding regions of BRCA1/2 variants of unknown clinical significance (VUS) are<br />
identified, several thousands of VUS are being found by whole exome sequencing<br />
whereby <strong>the</strong> coding region of more than 20,000 genes are investigated. These,<br />
individually rare, VUS potentially have a negative impact on <strong>the</strong> individual<br />
concerned as <strong>the</strong>y create greater uncertainty. Currently, large scale implementation of<br />
functional assays is not a realistic option in diagnostic settings. Therefore, at present,<br />
to our opinion, for familial cancer syndromes, it appears that next-generation DNA<br />
sequencing may provide <strong>the</strong> greatest benefit to routine clinical testing by enabling<br />
comprehensive multigene panel sequencing. This should provide an advantage over<br />
traditional Sanger-based sequencing strategies while limiting <strong>the</strong> total test output to<br />
sets of genes with known diagnostic value. The finding of a deleterious mutation in<br />
such genes guarantees <strong>the</strong> patient <strong>the</strong> possibility of adequate clinical management<br />
and follow up according to (international) established guidelines.<br />
During <strong>the</strong> presentation we will discuss <strong>the</strong> current and near future state of clinical<br />
testing approaches for <strong>the</strong> best known and most frequent familial cancer syndromes<br />
and explore what (bioinformatic, quality control metrics and o<strong>the</strong>r) challenges must<br />
be addressed in order to extract diagnostic value from whole-exome and<br />
whole-genome sequencing for hereditary cancers.<br />
Disclosure: The author has declared no conflicts of interest.<br />
34IN IS IT NECESSARY TO SCREEN EVERYBODY FOR INHERITED<br />
CANCER? WHEN, WHY AND HOW<br />
E. Levy-Lahad<br />
Shaare Zedek Medical Center, Hebrew University Medical School, Medical<br />
Genetics Institute, Jerusalem, ISRAEL<br />
Individuals who inherited mutations conferring high cancer risks should ideally be<br />
identified before <strong>the</strong>y ever develop cancer. Such mutation carriers stand to reap <strong>the</strong><br />
greatest benefit from surveillance and prevention measures. This begs <strong>the</strong> question of<br />
<strong>the</strong> optimal means of identifying such carriers. Currently, carriers are usually<br />
identified after <strong>the</strong>y have already been diagnosed with cancer, representing a lost<br />
opportunity for prevention, or through a family history of cancer. Identification of<br />
carriers based on family history is limited by sufficient family size, sufficient<br />
information on family history of cancer, and familial communication about cancer<br />
diagnoses, and especially about results of genetic testing. We will present data on<br />
BRCA1/BRCA2 testing in <strong>the</strong> general Ashkenazi (European) Jewish population,<br />
which has common BRCA1/BRCA2 mutations, as a model for comprehensive<br />
genetic screening. In particular, we will discuss our findings that approximately half<br />
of BRCA1/BRCA2 families do not have significant family history, so that many<br />
carriers would not be identified without a general screening program. There are both<br />
technical and ethical challenges to such an approach, and <strong>the</strong>se will be discussed.<br />
Disclosure: The author has declared no conflicts of interest.<br />
35IN HOW CAN CANCER RISK AND GENETIC PREDICTION<br />
MODELS HELP ONCOLOGISTS IN THE CLINICS?<br />
D.G.R. Evans<br />
Regional Genetic Service, St Mary’s Hospital, Manchester, UNITED KINGDOM<br />
There are two forms main outputs of risk prediction models. These are <strong>the</strong> likelihood<br />
of a patient harbouring a mutation in a cancer predisposition gene and <strong>the</strong> likelihood<br />
of developing specific cancers. Whilst <strong>the</strong>re are a number of <strong>the</strong>se models for<br />
different cancer types, <strong>the</strong> most well developed area is that of breast cancer. An<br />
oncologist treating a breast cancer patient may be influenced in discussing treatment<br />
options by future risks of contralateral breast cancer and ovarian cancer. Entry into<br />
treatment trials such as those of targeted treatments with PARP inhibitors may also<br />
be influenced by genetic testing for BRCA1 and BRCA2. Finding a mutation in<br />
BRCA1/2 may also influence treatment choices including risk reducing surgery.<br />
Outputs of genetic risk for BRCA1/2 will usually drive <strong>the</strong> offer of mutation<br />
screening if <strong>the</strong> likelihood exceeds 10% although this is currently 20% in <strong>the</strong> UK.<br />
Models include computer based: BRCAPRO, BOADICEA, Tyrer-Cuzick and paper<br />
scoring systems such as <strong>the</strong> Manchester system. There have been numerous<br />
validations of <strong>the</strong> models which show that <strong>the</strong>y all perform reasonably well. The<br />
breast cancer risk element is most used for unaffected women and in <strong>the</strong> context of<br />
family history have only really been validated through one study where <strong>the</strong><br />
Tyrer-Cuzick model was <strong>the</strong> best performer. Incorporation of genetic testing<br />
information from Single Nucleotide Polymorphisms (SNPs) and mammographic<br />
density is likely to improve <strong>the</strong> precision of <strong>the</strong>se models in <strong>the</strong> near future.<br />
Disclosure: The author has declared no conflicts of interest.<br />
36IN NEW TREATMENT APPROACHES IN HEREDITARY CANCER:<br />
THE ROUTE TOWARDS PERSONALIZED CARE<br />
E. Vilar<br />
Department of Clinical Cancer Prevention, U.T. - M.D. Anderson Cancer Center,<br />
Houston, TX, UNITED STATES OF AMERICA<br />
Patients diagnosed with tumors arising on <strong>the</strong> basis of hereditary cancer syndromes<br />
represent a relatively small fraction from <strong>the</strong> total of cancer cases. However, <strong>the</strong><br />
risks to develop different types of tumors among carriers highlight <strong>the</strong> need to<br />
develop surveillance strategies and preventive interventions to decrease <strong>the</strong> burden<br />
of cancer in this population. The specific molecular characteristics displayed by<br />
<strong>the</strong>se tumors make <strong>the</strong>m ideal candidates to identify new targets and implement<br />
not only personalized cancer treatments but also targeted chemoprevention<br />
strategies. In addition, hereditary tumors have served as a model to gain fur<strong>the</strong>r<br />
knowledge in <strong>the</strong> molecular biology of cancer and to develop targeted drugs.<br />
The best example in this context is <strong>the</strong> case of PARP inhibitors and breast and<br />
ovarian tumors arising in families diagnosed with Hereditary Breast and Ovarian<br />
Cancer Syndrome (BRCA 1 and 2 mutations). In this presentation we will review<br />
<strong>the</strong> most recent research advances on target identification and drug development<br />
for hereditary cancer syndromes with a special emphasis in hereditary<br />
gastrointestinal cancers.<br />
Disclosure: The author has declared no conflicts of interest.<br />
37IN CONCLUSIONS AND PERSPECTIVES<br />
Annals of Oncology 23 (Supplement 9): ix34, <strong>2012</strong><br />
doi:10.1093/annonc/mds375<br />
R. Catane<br />
Division of Oncology, Chaim Sheba Medical Center, Ramat Gan, ISRAEL<br />
The aim of this session was to familiarize practicing oncologists with <strong>the</strong> concept of<br />
modern genetics and its implication for <strong>the</strong> daily practice. As busy oncologists, we<br />
are inundated with information, and unfortunately <strong>the</strong> important new genetic facts<br />
related to oncology are frequently presented with code words and acronyms, that<br />
make <strong>the</strong> information unusable. It is hoped that such regular session, in which expert<br />
geneticist would give us <strong>the</strong> needed genetic knowledge, coupled with “user’s manual”,<br />
will make us better medical oncologists. Moreover, we will be able to pass on <strong>the</strong><br />
required information to our patients, and be in a vantage position to present <strong>the</strong>m<br />
<strong>the</strong> oncology guidelines.<br />
Disclosure: The author has declared no conflicts of interest.<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
pursuing <strong>the</strong> ned condition in stage iv<br />
colorectal cancer<br />
38IN WHEN TO THINK OF SURGERY PLUS OR MINUS HIPEC<br />
FOR PERITONEAL CARCINOMATOSIS<br />
D. Elias<br />
Department of Surgical Oncology, Institut Gustave Roussy, Villejuif, FRANCE<br />
The occurrence of PC considerably worsens <strong>the</strong> prognosis of cancers. The classic<br />
treatment yields an overall survival of below 5% at 5years. However, in 20% of <strong>the</strong><br />
cases, <strong>the</strong> disease is exclusively peritoneal, and a treatment combining complete<br />
cytoreductive surgery (CCRS) plus hyper<strong>the</strong>rmic intraperitoneal chemo<strong>the</strong>rapy<br />
(HIPEC) has made it possible to achieve a major increase in 5-year overall survival.<br />
HIPEC is only proposed for treating residual infra-millimetric,PC and <strong>the</strong>refore, is<br />
logical and useful exclusively after CCRS. The current appropriate indications are as<br />
follows: For peritoneal pseudomyxomas (5-year OSR is above 80%). For colorectal<br />
PC (5-year OSR exceed 40%, with 18% of patients definitively cured). For<br />
meso<strong>the</strong>liomas (<strong>the</strong> 5-year OSR is close to 58%) Current doubtful indications are as<br />
follows: For gastric tumours (<strong>the</strong> 5-year OSR is close to 15%). For ovarian cancers<br />
(OSR are very low when CCRS + HIPEC is used as a salvage treatment). For few rare<br />
PC (not detailed).<br />
Conclusion: CCRS + HIPEC are <strong>the</strong> current gold standard <strong>the</strong>rapy for peritoneal<br />
extension of pseudomyxoma, meso<strong>the</strong>liomas and colorectal PC, for selected patients.<br />
Disclosure: The author has declared no conflicts of interest.<br />
39IN PRIORITIZING LIVER DIRECTED THERAPIES: SURGERY PLUS<br />
MINUS ABLATIVE TECHNIQUES<br />
T.J.M. Ruers<br />
Surgical Oncology, The Ne<strong>the</strong>rlands Cancer Institute, Amsterdam,<br />
NETHERLANDS<br />
Background: In patients with unresectable CRC LM <strong>the</strong>re is an increasing tendency<br />
to combine systemic chemo<strong>the</strong>rapy (CT) with local tumour destruction by RFA.<br />
Many retrospective studies indicate a possible benefit of this approach but definite<br />
proof was only obtained recently.<br />
Methods: In a randomised phase II intergroup study conducted by <strong>the</strong> EORTC<br />
<strong>the</strong> benefits of adding RFA to systemic CT was evaluated in patients with ≤9<br />
unresectable CRC LM and no extrahepatic disease. Between 2002 and 2007,<br />
119 pts were randomised between CT alone (59) or RFA plus CT (60) In<br />
both arms, CT consisted of 6 months FOLFOX (oxaliplatin 85mg/m2 and<br />
LV5FU2) plus, since October 2005, bevacizumab. The primary objective was to<br />
exclude a 30-months overall survival (OS) rate ≤38% with RFA + CT<br />
(Fleming Design). Safety and progression free survival (PFS) were secondary<br />
endpoints.<br />
Results: Baseline characteristics were similar between arms: 60% had ≥ 4 LM. 51<br />
patients (85%) received CT in <strong>the</strong> RFA + CT arm and 59 (all) in <strong>the</strong> CT arm. The<br />
median number of CT cycles for patients who started CT was 10 in both arms.<br />
Toxicity profiles for CT were comparable between both arms. At a median follow up<br />
of 4.4 years, <strong>the</strong> 30-month OS rate was 61.7% (95% CI, 48.21-73.93) in <strong>the</strong> RFA +CT<br />
arm and 57.6% (44.07 – 70.39) in <strong>the</strong> CT arm. In eligible patients (RFA + CT; 57 pts,<br />
CT; 58 pts) <strong>the</strong>se figures were 64.9% (95% CI, 51.13 – 77.09) and 56.9% (43.23<br />
-69.84), respectively. The median PFS was 16.8 months in <strong>the</strong> RFA + CT arm (95%<br />
CI, 11.7-22.1) and 9.9 months (9.3-13.7) in <strong>the</strong> CT arm (p = 0.025). The number of<br />
patients with first recurrence at <strong>the</strong> RFA site only was 5 (9%). 4 more patients (7%)<br />
had a first recurrence at a RFA site in combination with a recurrence elsewhere in<br />
<strong>the</strong> liver. In total 11 lesions (in 9 pt) out of 170 lesions treated by RFA recurred<br />
locally at first progression (6.5%).<br />
Conclusion: The EORTC CLOCC study is <strong>the</strong> first study that prospectively<br />
investigates <strong>the</strong> efficacy of RFA in combination with CT. The primary endpoint<br />
(30-months OS > 38%) was met, although also 30 months OS in <strong>the</strong> CT arm<br />
was much higher than 38%. RFA in combination with systemic <strong>the</strong>rapy resulted<br />
in a significant prolongation of PFS of nearly 7 months. Local control of <strong>the</strong><br />
lesions treated by RFA was high (93.5%). The study was not powered for OS.<br />
Annals of Oncology 23 (Supplement 9): ix35–ix36, <strong>2012</strong><br />
doi:10.1093/annonc/mds376<br />
Longer follow-will have to be awaited to eventually assess <strong>the</strong> effect of RFA<br />
on OS.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
40IN INTEGRATING LIVER DIRECTED THERAPIES SUCH AS<br />
EMBOLIZATION AND IMRT INTO SYSTEMIC TREATMENT<br />
D. Arnold, A. Stein<br />
Medical Oncology, Hubertus Wald Tumor Center, University Cancer Center<br />
Hamburg (UCCH), Hamburg, GERMANY<br />
Metastatic colorectal cancer confined to <strong>the</strong> liver is a distinct entity characterized by<br />
different prognosis and a broad variety of available local treatment approaches.<br />
Beneath <strong>the</strong> classical, albeit continuously developed approaches like surgery, radio<br />
frequency ablation (RFA) and transarterial chemoembolization (TACE), local<br />
radio<strong>the</strong>rapy (delivered ei<strong>the</strong>r by conventional, intensity modulated (IMRT) or<br />
stereotactic techniques (SBRT)) or selective intraarterial radio<strong>the</strong>rapy (SIRT) have<br />
been established in <strong>the</strong> last years. However, spread to <strong>the</strong> liver - even without<br />
extrahepatic manifestation - is <strong>the</strong> expression of systemic disease and thus urges for<br />
systemic control besides local ablation of existing metastases. For example, in liver<br />
metastases of mCRC, combination of systemic <strong>the</strong>rapy and surgery or RFA has<br />
demonstrated beneficial impact. The sequence of systemic and local treatment is not<br />
well defined yet. Although individual patients tumour characteristics will strongly<br />
impact <strong>the</strong> choice of upfront treatment approach (e.g. single small metastases after a<br />
long disease free interval versus “upfront” large manifestations with high tumour<br />
burden), upfront systemic treatment followed by local treatment and postprocedural<br />
systemic treatment if feasible may generally bear several benefits: beside prompt<br />
control of systemic disease and potential extrahepatic spread, an interval with<br />
systemic chemo<strong>the</strong>rapy will provide information about biology of metastatic cancer<br />
(e.g. rapid progression during chemo<strong>the</strong>rapy) and will fur<strong>the</strong>rmore enable a more<br />
tailored approach for remaining lesions after treatment induced tumour shrinkage.<br />
Therefore, current treatment approaches for localized liver metastases are using<br />
sequential ei<strong>the</strong>r neoadjuvant or periprocedural systemic and local treatment (e.g.<br />
RFA or surgery) or a concomitant approach with systemic treatment and local<br />
ablation in given intervals (e.g. TACE). Some local treatment approaches (e.g. SIRT<br />
or TACE) have demonstrated efficacy in malignant disease refractory to<br />
chemo<strong>the</strong>rapy, but <strong>the</strong> possibly greater impact in earlier disease settings combined<br />
with or after systemic treatment have not been elucidated yet. Fur<strong>the</strong>r research will<br />
need to determine <strong>the</strong> optimal combination and timing of local and systemic<br />
treatment approaches.<br />
Disclosure: D. Arnold: has received honoraria from Roche, sanofi-aventis, Merck<br />
Serono and Amgen, and research support from Roche and sanofi-aventis. A. Stein:<br />
received honoraria from Roche and Merck Serono<br />
41IN PURSUING THE NED CONDITION IN ADVANCED COLORECTAL<br />
CANCER: IMPLICATIONS FOR CLINICAL PRACTICE AND<br />
TRIAL DESIGN<br />
A. Sobrero 1 , A.A. Cogoni 2<br />
1 Oncologia Medica, IRCCS AOU San Martino - IST-Istituto Nazionale per la<br />
Ricerca sul Cancro, Genova, ITALY, 2 Medical Oncology, “SS. Annunziata”<br />
Hospital, Sassari, ITALY<br />
Cure is <strong>the</strong> most relevant endpoint in cancer treatment. Next comes OS followed<br />
by DFS. Cure actually transits through DFS of sufficiently long duration to assure<br />
no relapse. Hence <strong>the</strong> value of DFS and its link to cure. The appeal of getting a<br />
NED state is so strong just because of this link. However its clinical value is<br />
dependent upon two factors: <strong>the</strong> toxicity of <strong>the</strong> multimodal intervention and <strong>the</strong><br />
duration of <strong>the</strong> NED state. If <strong>the</strong> absence of disease lasts 12 months, giving <strong>the</strong><br />
patient <strong>the</strong> hope for cure during this period, anybody may consider this a<br />
meaningful result; but if RFS lasts only 4 months and <strong>the</strong> “toll” paid by <strong>the</strong><br />
patient has been substantial, this is clearly an irrelevant benefit. The heart of <strong>the</strong><br />
issue is that whenever a treatment has <strong>the</strong> potential of rendering <strong>the</strong> patient<br />
NED, we should consider it, but at <strong>the</strong> same time we should not be deceived by<br />
this perspective if <strong>the</strong> chances of benefit are too remote, as it is in <strong>the</strong> great<br />
majority of cases. Therefore our strategic choice towards aggressive programs<br />
should not be guided by eradicating all visible tumor deposits (technical<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com<br />
abstracts
feasibility), but by how high <strong>the</strong> chances are of obtaining a DFS of at least 6-12<br />
months. There are a series of concepts and data guiding us between what is<br />
technically feasible and what is oncologically sound. First, curability of stage IV<br />
may be as high as 50% in very selected case series, but in unselected cases<br />
curability is extremely low, 1 to 4% in non-dedicated randomized trials. Second,<br />
whenever we “push” for very extensive surgery, <strong>the</strong> median RFS is < 12 and<br />
sometimes < 6 months. Third <strong>the</strong> disease might accelerate its course under <strong>the</strong><br />
“shower” of wounds–related growth factors. Fourth, toxicity and costs of <strong>the</strong>se<br />
approaches are very high. The contrast between <strong>the</strong> appeal (and sometimes<br />
Annals of Oncology<br />
strong benefit) of <strong>the</strong> NED state and <strong>the</strong> questionable clinical value of this<br />
condition, when short lived, has implications on both clinical practice and <strong>the</strong><br />
design of clinical trials. Wrong deviations from <strong>the</strong> classical palliative systemic<br />
treatment, pursuing miraculous results, but actually promoting clinical<br />
deterioration, are <strong>the</strong> most common consequences of <strong>the</strong>se approaches in<br />
practice. Very high originality and relevance, but low intrinsic and external<br />
validity of <strong>the</strong> results are <strong>the</strong> classical features and limits of <strong>the</strong> trials designed<br />
andconductedinthisfield.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix36 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
from biology to treatment in advanced<br />
pancreatic and gastroesophageal<br />
cancer<br />
42IN TUMOR MARKERS AND BIOLOGY IN PANCREATIC CANCER<br />
M.A. Tempero<br />
Hematology / Oncology, University of California, San Francisco, CA, UNITED<br />
STATES OF AMERICA<br />
As we move forward into precision medicine, biomarkers will be required to define<br />
critical targets or to distinguish <strong>the</strong> diverse components of all cancers. Using<br />
biomarkers in <strong>the</strong>rapeutic strategies has been very successful for many malignancies,<br />
especially breast cancer, lung cancer, and hematologic malignancies. Many barriers<br />
exist for similar applications in pancreatic ductal adenocarcinoma. First, <strong>the</strong> unusual<br />
aggressiveness of this malignancy overall, suggests that <strong>the</strong> diversity in this disease is<br />
constrained within a more narrow spectrum. Second, until recently, drug <strong>the</strong>rapy has<br />
been only minimally effective in this disease. Finally, because so few patients proceed<br />
to resection and diagnosis is often made on scant fine-needle aspirates, access to<br />
tissue has been limited. However, this landscape is changing. Studies show that <strong>the</strong>re<br />
are distinct metastatic patterns which may be governed by early genetic aberrations.<br />
In addition, genetic subclasses exist which, when evaluated in available human cell<br />
lines, also track with varying sensitivity to available chemo<strong>the</strong>rapy. New<br />
chemo<strong>the</strong>rapy combinations, albeit with more traditional cytotoxic drugs, are<br />
producing striking improvements in survival, even in <strong>the</strong> setting of metastatic<br />
disease. New and more successful treatments, such as FOLFIRINOX and selected<br />
gemcitabine combinations, provide more options and enlarge <strong>the</strong> playing field for <strong>the</strong><br />
introduction of targeted <strong>the</strong>rapeutics. This also brings <strong>the</strong> importance of clinically<br />
actionable biomarkers to <strong>the</strong> foreground. As this story unfolds, attention must be<br />
given to <strong>the</strong> importance of building biorepositories from primary and secondary<br />
tumor sites, with associated germline DNA and providing clinical annotation for <strong>the</strong><br />
specimens. As technology improves and <strong>the</strong> cost of genomic sequencing decreases,<br />
we can expect a dramatic escalation in our understanding of <strong>the</strong> critical biologic<br />
pathways amenable to <strong>the</strong>rapeutic intervention<br />
Disclosure: The author has declared no conflicts of interest.<br />
43IN POTENTIAL CLINICAL APPLICATION AND TRIALS<br />
S. Cascinu<br />
Clinica di Oncologia Medica, AOU Ospedali Riuniti Ancona Università Politecnica<br />
delle Marche, Ancona, ITALY<br />
Ductal pancreatic adenocarcinoma remains a disease with dismal prognosis and<br />
several treatment approaches resulted in disappointing results. A better knowledge of<br />
molecular pathways involved in its development are mandatory in order to improve<br />
<strong>the</strong>rapeutic results. Infact, though a model for <strong>the</strong> development of pancreatic<br />
adenocarcinoma has been proposed some years ago, this is not able to explain <strong>the</strong><br />
role of stroma as well as which pathways could be effectively druggable. Fur<strong>the</strong>rmore,<br />
<strong>the</strong> results of clinical trials with biological agents (tipifarnib, cetuximab,<br />
bevacizumab, axitinib, sorafenib) are really disappointing. Therefore, biological<br />
characterization of ductal pancreatic adenocarcinoma may help to identify new<br />
pathways in order to select <strong>the</strong> best treatment for each patient. We should consider<br />
Annals of Oncology 23 (Supplement 9): ix37, <strong>2012</strong><br />
doi:10.1093/annonc/mds377<br />
ductal adenocarcinoma as an heterogeneous disease probably due to <strong>the</strong> different<br />
pathogenesis: chronic inflammatory disease, mucinous tumors, hereditary tumors,<br />
resulting in different specific genetic alterations. The knowledge of <strong>the</strong>se alterations<br />
may allow <strong>the</strong> identification of subgroups as well as <strong>the</strong> definition of specific<br />
treatment approaches. An assessment of potentially relevant pathways and how to<br />
inhibit <strong>the</strong>m will be presented.<br />
Disclosure: The author has declared no conflicts of interest.<br />
44IN TUMOR MARKERS AND BIOLOGY IN GASTROESOPHAGEAL<br />
CANCER<br />
M. Ebert<br />
Medicine II, Universitätsklinikum Mannheim, Mannheim, GERMANY<br />
Most patients with gastric cancer present with advanced disease. In <strong>the</strong>se cases ei<strong>the</strong>r<br />
multimodal <strong>the</strong>rapy or palliative treatment is required. In most cases patients with<br />
locally advanced gastric cancer undergo neoadjuvant <strong>the</strong>rapy and resection. In cases<br />
with distant metastasis palliative chemo<strong>the</strong>rapy is given. While many patients show<br />
treatment response, in most patients cancers progress and change of treatment lines<br />
is required. Therefore, predicting treatment response in neoadjuvant and palliative<br />
chemo<strong>the</strong>rapy is of special interest. While different molecular markers of treatment<br />
response have been described in various cancer, so far for esophageal and gastric<br />
cancer molecular response predictors are not well established. In some cases HER2/<br />
neu testing has shown additional value in combining chemo<strong>the</strong>rapy with<br />
trastuzumab. However, molecular response predictors in Her2/neu positive cases are<br />
also lacking. Interestingly, recent data from breast cancers have shown that activation<br />
of src may mediate resistance to trastuzumab. Inasmuch as targeting of active src<br />
could be option to resensitize breast cancers to trastuzumab <strong>the</strong>se studies need to be<br />
conducted in gastric cancers. Our own studies indicate that <strong>the</strong> inhibition of histone<br />
deacetylases may sensitize gastric cancers cells to epirubicine, which may also help to<br />
fur<strong>the</strong>r individualize chemo<strong>the</strong>rapy in gastric cancer.<br />
Disclosure: The author has declared no conflicts of interest.<br />
45IN CLINICAL TRIALS WITH BIOLOGICAL ENDPOINTS<br />
A.D. Roth<br />
Oncology, University Hospitals of Geneva, Geneva, SWITZERLAND<br />
Neoadjuvant chemo<strong>the</strong>rapy or radiochemo<strong>the</strong>rapy is a modality increasingly applied<br />
in <strong>the</strong> curative treatment of cancers of <strong>the</strong> esophagus and of <strong>the</strong> stomach. Complete<br />
pathological response (pCR) obtained after neoadjuvant <strong>the</strong>rapy of esophageal cancer<br />
is an indicator of good prognosis (up to 70% at 5 years). However, a mean for earlier<br />
assessment of <strong>the</strong> efficacy of neoadjuvant <strong>the</strong>rapy allowing to change regimen in case<br />
of no response or to go directly to surgery would be extremely welcome. Based on<br />
early reports of early extinction of PET-CT scan uptake in case of good response to<br />
chemo<strong>the</strong>rapy in several tumor type, <strong>the</strong> MUNICON trial investigated this biological<br />
endpoint in esophageal cancer showing a fairly good correlation between PET-CT<br />
extinction and pathological response. Several trials aiming at <strong>the</strong> validation of <strong>the</strong>se<br />
data have been started or are in preparation both in Europe and in <strong>the</strong> US. The<br />
strength and <strong>the</strong> weaknesses of this approach shall be discussed during this<br />
presentation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com<br />
abstracts
abstracts<br />
re-inventing <strong>the</strong> medical treatment<br />
of advanced prostate cancer<br />
46IN IMMUNOTHERAPY FOR ADVANCED PROSTATE CANCER<br />
P.W. Kantoff<br />
Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, UNITED STATES<br />
OF AMERICA<br />
While <strong>the</strong> concept of immuno<strong>the</strong>rapy for cancer has been proposed for many years, proof<br />
of principle did not exist. In <strong>the</strong> context of prostate cancer, <strong>the</strong> allogeneic cell based agent,<br />
GVAX has been tested. GVAX consists of a platform of irradiated hormone sensitive<br />
(LNCaP) and hormone resistant (PC-3) prostate cancer cell lines transduced with a<br />
replication-defective retrovirus bearing GM-CSF. Unfortunately, two phase III studies in<br />
men with metastatic castration resistant prostate cancer (CRPC) failed to demonstrate a<br />
survival advantage. More recently, <strong>the</strong> improved survival observed with sipuleucel-T, an<br />
autologous antigen presenting cell (APC)-based agent, for <strong>the</strong> treatment of patients with<br />
metastatic CRPC supports immuno<strong>the</strong>rapy as a valid approach for this disease.<br />
Sipuleucel-T uses a fusion antigen of prostatic acid phosphatase and GM-CSF. Evidence<br />
exists to support activation of APCs and T cells in an antigen specific fashion and that <strong>the</strong><br />
degree of activation correlates with overall survival. PROSTVAC-VF TRICOM, a poxvirus<br />
vector based PSA antigen targeted vaccine showed promising results in a randomized<br />
Phase II study and is now being tested in a international Phase III study. The CTLA-4<br />
inhibiting human monoclonal antibody, ipilimumab, has extended survival in advanced<br />
melanoma. Early phase I clinical trials of ipilimumab have yielded clinical and PSA<br />
responses in advanced CRPC. A Phase I/II trial was conducted using ipilimumab 10 mg/<br />
kg every 3 weeks x 4 with or without prior priming by single fraction of radiation to a<br />
metastatic bony site. Results were promising enough to launch 2 phase III clinical trials in<br />
men with metastatic CRPC who were ei<strong>the</strong>r chemo-naive or following prior<br />
chemo<strong>the</strong>rapy. The outcomes of <strong>the</strong>se 2 studies are pending.<br />
Disclosure: P.W. Kantoff: Amgen USA consultant (con), Bayer con, Bellicum con,<br />
BIND Biosciences SAB, BN Immuno<strong>the</strong>rapeutics con, Celgene DSMB, Dendreon<br />
con, Genetech con, Progenics Pharmaceuticals con, Janssen con, Takeda/Millenium<br />
DSMB, Oncogenex DSMB, Tokai con<br />
47IN HOW SHOULD WE USE CYTOTOXIC CHEMOTHERAPY IN THE<br />
TREATMENT OF CASTRATION-RESISTANT PROSTATE<br />
CANCER?<br />
O. Sartor<br />
Department of Medicine: Section of Hematology & Medical Oncology and<br />
Department of Urology, Tulane Cancer Center, New Orleans, LA, UNITED<br />
STATES OF AMERICA<br />
The recent incremental advances in metastatic castrate-resistant prostate cancer<br />
(mCRPC) may one day translate into more meaningful change. Today mCRPC<br />
<strong>the</strong>rapeutic choices are a sequential series of affairs with several ei<strong>the</strong>r/or decisions.<br />
Optimal sequencing is unstudied and endless speculation abound as to which drug is<br />
best best for which patient. Combination <strong>the</strong>rapies are in <strong>the</strong>ir infancy. In <strong>the</strong> past,<br />
<strong>the</strong> world of mCRPC was conveniently divided into <strong>the</strong> pre- and post-docetaxel<br />
space. That being said, <strong>the</strong> biologic basis for this was lacking and now we have new<br />
spaces such as <strong>the</strong> post-abiraterone/MDV3100 space that might in fact be more<br />
biologically meaningful. What do we do with patients progressing post-abiraterone or<br />
MDV3100? The data are sparse to date and so we gear up with new studies and read<br />
tea leaves in <strong>the</strong> interim. What is <strong>the</strong> role for cytotoxic chemo<strong>the</strong>rapies today’s<br />
mCRPC <strong>the</strong>rapeutic armamentarium? The new hormonal <strong>the</strong>rapies are now<br />
marching forward with provovative data in <strong>the</strong> “pre-chemo<strong>the</strong>rapy” space. Novel<br />
immuno<strong>the</strong>rapies have seized imaginations. The new world of truly active<br />
bone-targeted radiopharmaceuticals has arrived. Several facts seem clear. 1) <strong>the</strong><br />
newer hormonal <strong>the</strong>rapies are not effective for very long in mCRPC and after <strong>the</strong>y<br />
fail, <strong>the</strong> progression rate can be very rapid. Exotic new molecular mechanisms of<br />
resistance are discovered with regularity; <strong>the</strong> CRPC cells are truly devious little<br />
Darwinian machines. 2) Today, death from prostate cancer is a foregone conclusion<br />
for mCRPC patient. So does this help us answer how we use cytotoxic chemo<strong>the</strong>rapy<br />
today? Perhaps it si reasonable to point out that both docetaxel and cabazitaxel are<br />
clearly active agents and that some but not all patients will tolerate <strong>the</strong>m well.<br />
Currently many men die from prostate cancer without having had <strong>the</strong> opportunity to<br />
benefit from known active agents. The best responses to chemo<strong>the</strong>rapy, as with any<br />
agent, occur in patients with <strong>the</strong> best performance status. The concept that <strong>the</strong>rapies<br />
of lesser toxicity should be administered first is appropriate but <strong>the</strong> concept that<br />
Annals of Oncology 23 (Supplement 9): ix38, <strong>2012</strong><br />
doi:10.1093/annonc/mds378<br />
active <strong>the</strong>rapies should be on <strong>the</strong> shelf when treating an incurable disease is not.<br />
Striving for patients to receive as many active <strong>the</strong>rapies as feasible seems reasonable<br />
in an era when predicting <strong>the</strong>rapeutic response is more art than science.<br />
Disclosure: O. Sartor: Investigator and consultant for Algeta, Bayer, JNJ, Sanofi, and<br />
Dendreon. Consultant for Medivation and Astellas.<br />
48IN INTEGRATING NOVEL ENDOCRINE THERAPIES: SEQUENTIAL<br />
OR CONCOMITANT TREATMENT?<br />
J.S. de Bono<br />
Division of Cancer Therapeutics, Institute of Cancer Research Royal Marsden<br />
Hospital, Sutton, UNITED KINGDOM<br />
Prostate cancer progression is associated with continued androgen receptor (AR)<br />
activation despite treatment with castration and/or currently available anti-androgens.<br />
Abiraterone, a rationally- designed inhibitor of CYP17A1 has been recently approved<br />
for <strong>the</strong> treatment of docetaxel-treated castration-resistant prostate cancer (CRPC), is<br />
often effective, but requires co-administration with glucocorticoids to curtail side<br />
effects. Enzalutamide (MDV3100) is a novel AR antagonist that effectively blocks AR<br />
signaling when currently available AR antagonists are unable to do this and has shown<br />
impressive antitumor activity and a similar impact on overall survival as abiraterone.<br />
We now report that <strong>the</strong>se two drugs in combination may be superior to ei<strong>the</strong>r drug<br />
alone. We have hypo<strong>the</strong>sized that progressive disease on abiraterone may occur<br />
secondary to glucocorticoid-induced activation of mutated AR. We also found that<br />
prednisolone plasma levels in CRPC patients were sufficiently high to activate mutant<br />
AR. Mineralocorticoid receptor antagonists, such as spironoloactone and eplerenone<br />
that are used to treat side-effects related to mineralocorticoid excess, also bound to and<br />
activated signaling through both wild-type and mutant AR. Activation of mutant AR<br />
was inhibited by MDV3100, bicalutamide or greater concentrations of abiraterone.<br />
Moreover, higher androgenic steroid concentrations resulted in decreased enzalutamide<br />
antitumour activity. Toge<strong>the</strong>r, our findings provide a strong rationale for <strong>the</strong> clinical<br />
evaluation of combined CYP17A1 inhibition and AR antagonism by enzalutamide.<br />
Disclosure: J.S. de Bono: I am an employee of The Institute of Cancer Research that<br />
has a commercial interest in abiraterone. I have served as an advisor for J&J,<br />
Medivation, Astellas and Takeda.<br />
49IN HOW SHOULD WE UTILIZE BONE TREATMENTS:<br />
BISPHOSPHONATES, DENOSUMAB AND RADIUM-223<br />
C. Parker<br />
Academic Urology, Royal Marsden Hospital NHS Foundation Trust, Sutton,<br />
UNITED KINGDOM<br />
How should we utilize bone treatments: Bisphosphonates, denosumab and<br />
radium-223? Bone metastases are a prominent feature of CRPC, and can lead to<br />
significant skeletal-related events (SREs) such as spinal cord compression,<br />
pathological fracture, and <strong>the</strong> need for surgery or external-beam radio<strong>the</strong>rapy.<br />
Zoledronate, a bisphosphonate, reduces <strong>the</strong> risk of SREs (1) and has been widely,<br />
although not universally, regarded as a standard treatment for metastatic CRPC.<br />
More recently, denosumab, an antibody targeted at <strong>the</strong> RANK-ligand, has shown<br />
greater efficacy for SRE prevention with an acceptable toxicity profile (2), and has<br />
also been licensed for use. Radium-223, a bone-targetted alpha emitter, has been<br />
reported not only to reduce <strong>the</strong> risk of SREs, but also to improve overall survival.<br />
Although radium-223 is <strong>the</strong> first bone-targetted agent to improve overall survival in<br />
CRPC, it is not yet licensed for clinical use. I will review <strong>the</strong> clinical trial data<br />
concerning <strong>the</strong>se bone-targetted agents in CRPC, and give my personal view as to<br />
how <strong>the</strong>y should be used.<br />
References 1. A randomized, placebo-controlled trial of zoledronic acid in patients<br />
with hormone-refractory metastatic prostate carcinoma. Saad F, Gleason DM, Murray<br />
R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Chen B;<br />
Zoledronic Acid Prostate Cancer Study Group. J Natl Cancer Inst. 2002 Oct 2;94<br />
(19):1458-68. 2. Denosumab versus zoledronic acid for treatment of bone metastases<br />
in men with castration-resistant prostate cancer: a randomised, double-blind study.<br />
Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, Milecki P, Shore N,<br />
Rader M, Wang H, Jiang Q, Tadros S, Dansey R, Goessl C. Lancet. 2011 Mar 5;377<br />
(9768):813-22. 3. Overall survival benefit of radium-223 chloride (Alpharadin) in<br />
<strong>the</strong> treatment of patients with symptomatic bone metastases in castration-resistant<br />
prostate cancer (CRPC): A phase III randomized trial (ALSYMPCA). C. Parker,<br />
D. Heinrich, J.M. O’Sullivan, S. Fosså, A. Chodacki, T. Demkow, A. Cross, B. Bolstad,<br />
J. Garcia-Vargas, and O. Sartor. Eur J Cancer 47:Supp 2, Sept 2011 p3<br />
Disclosure: C. Parker: Advisory board membership for Amgen, BMS, Bayer,<br />
Dendreon, Janssen and Takeda<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
molecular answers and targets<br />
on <strong>the</strong> horizon for <strong>the</strong> treatment<br />
of genitourinary malignancies<br />
50IN GENES, CHROMOSOMES AND THE TREATMENT<br />
OF BLADDER CANCER<br />
J.E. Rosenberg<br />
Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center,<br />
New York, NY, UNITED STATES OF AMERICA<br />
Molecular analysis of bladder cancer is transforming our understanding of this<br />
disease. The relative abundance of bladder tumor tissue from <strong>the</strong>se patients due to<br />
frequent resections provides a major opportunity to understand <strong>the</strong> molecular<br />
pathogenesis. Non-muscle invasive bladder cancer tends to be characterized by<br />
oncogenic activation events (FGFR3 mutation, PIK3CA mutation), while muscle<br />
invasive bladder cancer is more associated with tumor suppressor gene inactivation<br />
(p53, Rb). DNA copy number analysis identifies multiple regions of recurrent<br />
chromosomal gains and losses, many of which delineate known oncogenes and<br />
tumor suppressor genes. High-throughput analysis of bladder cancer specimens is<br />
identifying multiple new targets that may be <strong>the</strong>rapeutically tractable in subsets of<br />
patients, including Her2 overexpression and amplification, b-raf mutation, and TSC1<br />
mutation. The clinical implications of <strong>the</strong> molecular events in bladder cancer have<br />
yet to be identified. Large-scale genomic efforts linking clinical data to outcome<br />
should lead to an improved understand of <strong>the</strong> molecular landscape of bladder cancer.<br />
Next-generation sequencing technologies are allowing <strong>the</strong> rapid assessment of<br />
molecular alterations, which may lead to clinical trials enriched for patients whose<br />
tumors contain druggable alterations. To capitalize on <strong>the</strong> genomic knowledge<br />
gained in bladder cancer, reliable molecular tests that are accepted by regulatory<br />
authorities, along with targeted agents aimed at actionable alterations are, need to<br />
break out of <strong>the</strong> current <strong>the</strong>rapeutic stalemate. Trials targeting some of <strong>the</strong>se novel<br />
alterations are beginning to enroll patients.<br />
Disclosure: J.E. Rosenberg: 1. Imclone- research funding 2. Oncogenex- consulting<br />
3. Boehringer-Ingelheim- consulting 4. GSK- research funding 5. Novartis- research<br />
funding<br />
51IN GENOMICS IN RENAL CANCER: FROM SCIENCE<br />
TO CLINICAL PRACTICE<br />
B.T. Teh<br />
Director and Principal Investigator, Nccs-vari Translational Research Laboratory,<br />
National Cancer Centre Singapore, Singapore, SINGAPORE<br />
Approximately 290,000 new cases of renal cell carcinoma (RCC) are diagnosed each<br />
year worldwide and 102,000 deaths. It is a morphologically, and genetically<br />
heterogenous disease with distinct underlying molecular mechanisms in each<br />
subtype. In this lecture, <strong>the</strong> evidence of this molecular heterogeneity with more<br />
recent discoveries will be presented and discussed. For example, we have recently<br />
identified <strong>the</strong> frequent mutations of PBRM1, a member of <strong>the</strong> SWI-SNF complex, in<br />
clear cell RCC (<strong>the</strong> most common type of RCC) and a lesser degree of mutations in<br />
a group of histone modifiers. This has opened up a new field of investigations, from<br />
basic biology to clinical implications. In addition, we also demonstrated <strong>the</strong><br />
involvement of LRRK2, a gene associated with early-onset Parkinson’s disease, in<br />
papillary type 1 RCC (second most common type of RCC) and its interaction with<br />
c-MET, a gene that has been previously implied in this subtype of tumors. We have<br />
also recently discovered a novel metabolic pathway that is integral to <strong>the</strong><br />
tumorigenesis of papillary type II (an aggressive type of papillary tumor). All <strong>the</strong>se<br />
present new opportunities for fur<strong>the</strong>r investigations to establish <strong>the</strong>ir biological and<br />
<strong>the</strong>rapeutic roles in RCC.<br />
Disclosure: The author has declared no conflicts of interest.<br />
Annals of Oncology 23 (Supplement 9): ix39, <strong>2012</strong><br />
doi:10.1093/annonc/mds379<br />
52IN SIGNALING PATHWAYS, MECHANISMS OF RESISTANCE<br />
AND TREATMENT DECISIONS IN RENAL CELL CANCER<br />
G. Tortora<br />
Medical Oncology, University of Verona Policlinico Borgo Roma, Verona, ITALY<br />
Renal cell cancer (RCC) is a highly vascularised disease and angiogenesis plays a<br />
critical role in tumor growth and spreading. For this reason, <strong>the</strong> main angiogenic<br />
pathways, involving <strong>the</strong> Vascular endo<strong>the</strong>lial growth factors (VEGFs), <strong>the</strong> VEGF<br />
receptors (VEGF-Rs), and <strong>the</strong> mammalian target of rapamycin (mTOR) are <strong>the</strong><br />
targets of drugs that have dramatically improved <strong>the</strong> outcome of patients affected by<br />
this disease. An increasing number of active agents directed against <strong>the</strong> above targets<br />
and o<strong>the</strong>r angiogenesis-related proteins, including <strong>the</strong> Fibroblast growth factors<br />
(FGFs) and <strong>the</strong>ir receptors (FGF-Rs), is now available. However, a biologically-based<br />
<strong>the</strong>rapeutic algorithm is still missing and <strong>the</strong> onset of drug resistance and <strong>the</strong> lack of<br />
validated biomarkers predictive of response to single agents and, more in general, to<br />
antiangiogenic drugs, do not allow to take full advantage of <strong>the</strong> <strong>the</strong>rapeutic options<br />
available. Interlukin 8 (IL-8) and FGF seem to play a role in <strong>the</strong> induction of<br />
resistance to TKIs. IL-8 overexpression is associated to resistance to sunitinib and<br />
IL-8 gene polymorphisms correlate with survival in patients treated with pazopanib.<br />
Increases in <strong>the</strong> FGF/FGF-Rs signalling is observed as escape to inhibition of <strong>the</strong><br />
VEGF-Rs by TKIs. On <strong>the</strong> o<strong>the</strong>r hand, activation of <strong>the</strong> PI3K/Akt pathway is<br />
responsible for <strong>the</strong> onset of resistance to mTOR inhibitors. Several studies are now<br />
extensively analyzing <strong>the</strong> predictive value of a variety of angiogenesis-related<br />
biomarkers, including soluble VEGF and VEGF-Rs, IL-8 expression and secretion,<br />
polymorphisms of VEGF and IL-8 genes, and VHL mutations. In addition imaging<br />
techniques are also under evaluation as promising dynamic biomarkers of<br />
antiangiogenic drugs activity or resistance in RCC. A better understanding of <strong>the</strong><br />
mechanisms of resistance and <strong>the</strong> validation of reliable biomarkers predictive of drug<br />
activity or resistance will help to select patients who can benefit from current and<br />
future treatments.<br />
Disclosure: The author has declared no conflicts of interest.<br />
53IN MOLECULAR INSIGHTS AND TREATMENT OUTLOOK<br />
FOR GU MALIGNANCIES<br />
J. Bellmunt<br />
Medical Oncology, University Hospital del Mar-IMIM, Barcelona, SPAIN<br />
The use of targeted <strong>the</strong>rapies has significantly improved outcomes for patients with<br />
mRCC. At present, in Europe and/or <strong>the</strong> USA, six/seven targeted agents are<br />
approved for first- and second-line treatment of clear cell mRCC: sunitinib,<br />
sorafenib, temsirolimus, everolimus, bevacizumab (in combination with interferon)<br />
pazopanib and axitinib (in <strong>the</strong> US). In addition, several new targeted agents, such as<br />
axitinib (in EU) and tivozanib, are also currently being filed for <strong>the</strong> treatment of<br />
mRCC after successful results of <strong>the</strong> phase III trials .New treatment options include<br />
targeting new pathways like c-MET or <strong>the</strong> use of novel more selective<br />
inmuno<strong>the</strong>rapies such as <strong>the</strong> anti-PD1 agent. The novel chemo<strong>the</strong>rapeutic agent<br />
Cabazitaxel with activity for CRPC in patients failing docetaxel is now available<br />
filling an unmet medical need for <strong>the</strong>se patients.In addition immuno<strong>the</strong>rapy with<br />
sipuleucel-T, <strong>the</strong> androgen biosyn<strong>the</strong>sis inhibitor abiraterone acetate, <strong>the</strong> radioisotope<br />
alpharadin and <strong>the</strong> anti-androgen MDV3100 have all shown to improve overall<br />
survival in randomized phase III studies for patients with mCRPC. Agents such as<br />
<strong>the</strong> dual VEGFr/MET inhibitor cabozantinib, <strong>the</strong> clusterin inhibitor custirsen and <strong>the</strong><br />
Src inhibitor dasatinib have shown encouraging results in phase II studies, and phase<br />
III results with <strong>the</strong>ses agents are eagerly awaited.Novel immuno<strong>the</strong>rapeutics such as<br />
prostate-specific membrane antigen-directed <strong>the</strong>rapy and <strong>the</strong> anti-cytotoxic T<br />
lymphocyte-associated receptor 4 (CTLA4) antibody ipilimumab are also under<br />
investigation. Targeted <strong>the</strong>rapy with novel drugs directed at specific molecular<br />
pathways opens promising new avenues in uro<strong>the</strong>lial tumors to improve patient<br />
outcome. Several phase II/III trials, with focus on bevacizumab, aflibercept, sunitinib,<br />
sorafenib, gefitinib, lapatinib and trastuzumab have not clarified any specific role for<br />
<strong>the</strong>se <strong>the</strong>rapies. However, <strong>the</strong> presently accruing trial comparing CG +/bevazicumab<br />
is in its half way to shed light on <strong>the</strong> role of antiangiogenics in<br />
uro<strong>the</strong>lial tumors. O<strong>the</strong>r novel, promising targeted agents, including pazopanib,<br />
cetuximab and everolimus has shown limited benefit. Identifying pathways critical<br />
for tumorigenesis can provide potential strategies for <strong>the</strong>rapeutic intervention in<br />
specific tumor types.<br />
Disclosure: The author has declared no conflicts of interest.<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com<br />
abstracts
abstracts<br />
emerging diagnostic and <strong>the</strong>rapeutic<br />
targets in gynecological cancers: from<br />
science to clinical practice<br />
54IN ANTIANGIOGENICS IN OVARIAN CANCER: WHERE ARE WE<br />
NOW?<br />
E.A. Eisenhauer<br />
Clinical Trials, Queen’s University NCIC Clinical Trials Group, Kingston, CANADA<br />
Vascular endo<strong>the</strong>lial growth factor (VEGF) is often over expressed in ovarian cancer<br />
(OVCA), promoting ascites and effusions. Preclinical studies of inhibition of VEGF<br />
and its receptors (VEGFR) show activity in OVCA xenografts. Clinical interest in<br />
evaluating VEGF (R) inhibition was triggered when <strong>the</strong> Gynecologic Oncology<br />
Group demonstrated single agent activity of <strong>the</strong> VEGF targeted antibody,<br />
bevacizumab (BEV) in recurrent OVCA. Since that time, BEV and small molecular<br />
VEGFR inhibitors have been studied in numerous phase II and III trials in OVCA.<br />
Randomized BEV trials are <strong>the</strong> most mature with results reported in first line<br />
(GOG218, ICON7), platinum sensitive recurrent disease (OCEANS trial) and<br />
platinum resistant recurrent disease (AURELIA trial) settings. All trials gave<br />
concurrent chemo<strong>the</strong>rapy + BEV with some providing maintenance BEV after<br />
chemo<strong>the</strong>rapy. All have shown a biological effect of <strong>the</strong> addition of BEV with higher<br />
response rates and longer progression free survival (PFS) in BEV arms. To date, no<br />
trial has shown overall survival (OS) improvement, although mature analyses for OS<br />
are awaited. Quality of life data have not suggested a benefit with BEV and toxicity is<br />
greater. Results of phase III trials of VEGFR inhibitors cedarinib, pazopanib and<br />
nintedanib are awaited. The BEV results lead to several important questions: 1) in<br />
<strong>the</strong> absence of significant OS improvement to date, is <strong>the</strong>re sufficient patient benefit<br />
from PFS increases to warrant incorporation of BEV into ovarian cancer treatment?<br />
And when over <strong>the</strong> course of <strong>the</strong> disease should <strong>the</strong> agent be given? 2) Is <strong>the</strong> use of<br />
BEV cost effective and affordable? 3) Which patient subset is benefiting most?<br />
Subgroup analysis of <strong>the</strong> ICON7 study, suggests that patients with greater bulk<br />
disease (Stage III> 1 cm residual and Stage IV) seem to derive more PFS benefit.<br />
Indeed in this subgroup, overall survival also was improved. However, in <strong>the</strong><br />
GOG0218 trial, <strong>the</strong> hazard ratio for PFS was observed to be better in patients with <<br />
1 cm residual. Some have suggested VEGF A plasma levels may be predictive of BEV<br />
benefit, but no results from <strong>the</strong> BEV OVCA trials are yet published. In summary,<br />
clinical results to date show significant PFS improvements from BEV in 4 trials, but<br />
it is unclear if this will translate into improved OS and how best and in whom BEV<br />
should be used in OVCA management.<br />
Disclosure: The author has declared no conflicts of interest.<br />
55IN TARGETING DNA REPAIR DEFICIENCY IN OVARIAN AND<br />
ENDOMETRIAL CANCERS<br />
S.B. Kaye<br />
Royal Marsden Hospital and Institute of Cancer Research, Sutton, UNITED<br />
KINGDOM<br />
The key repair deficiency in cancer cells which has led to recent <strong>the</strong>rapeutic<br />
innovation is homologous recombination deficiency (HRD), which is a defining<br />
feature of those cancers, particularly ovarian and breast, arising in patients with germ<br />
line BRCA mutations. Poly ADP ribose polymerase (PARP) inhibitors take advantage<br />
of HRD, through tumour specific syn<strong>the</strong>tic lethality to provide clear clinical efficacy<br />
as single agents with an excellent toxicity profile in patients with <strong>the</strong>se diseases.<br />
Response rates of 30%-60% have been documented according to prior platinum<br />
sensitivity. Their application has subsequently been broadened into patient with<br />
recurrent high grade serous ovarian cancer and platinum-sensitive disease, but who<br />
are not know to have germ line BRCA mutations. In <strong>the</strong>se cases a clear benefit was<br />
seen with <strong>the</strong> PARP inhibitor olaparib in a randomised maintenance <strong>the</strong>rapy trial in<br />
terms of progression-free survival (but not overall survival). A similar benefit in PFS<br />
was seen in a second maintenance trial in which olaparib was also combined with<br />
carboplatin - paclitaxel in <strong>the</strong> chemo<strong>the</strong>rapy phase of treatment. Several PARP<br />
inhibitors are now in active development in ovarian cancer and <strong>the</strong> focus is<br />
increasingly moving to <strong>the</strong>ir application in germ line BRCA associated disease where<br />
<strong>the</strong> extent of benefit of <strong>the</strong>se agents may after all be <strong>the</strong> greatest. As regards<br />
gynaecological cancers in general, <strong>the</strong> o<strong>the</strong>r disease of interest is endometrial cancer,<br />
in which in vitro data have also indicated substantial potential for PARP inhibitors.<br />
In endometrial cancer cell lines, HRD has also been noted and thought likely to<br />
relate to <strong>the</strong> characteristic PTEN loss seen in this disease (particularly Type I) ra<strong>the</strong>r<br />
Annals of Oncology 23 (Supplement 9): ix40–ix41, <strong>2012</strong><br />
doi:10.1093/annonc/mds380<br />
than BRCA dysfunction. Clinical trials with PARP inhibitors are <strong>the</strong>refore awaited<br />
with interest.<br />
References Banerjee S & Kaye SB; PARP inhibitors in BRCA gene-mutated ovarian<br />
cancer and beyond. Current Oncology Reports - 13: 442-449, 2011.<br />
Disclosure: The author has declared no conflicts of interest.<br />
56IN PI3K/AKT PATHWAYS IN OVARIAN AND ENDOMETRIAL<br />
CANCERS<br />
C. Sessa<br />
Oncology, IOSI Istituto Oncologico Svizzera Italiana Ospedale Regionale<br />
Bellinzona e Valli, Bellinzona, SWITZERLAND<br />
The PI3K pathway is frequently activated in many human tumors, including ovarian<br />
(OC) and endometrial cancer (EC). Mutations of <strong>the</strong> gene PIK3CA, which codes for<br />
<strong>the</strong> p110α subunit, have been reported in 6% of OC, with a higher incidence in<br />
endometrioid and clear cell type; a 24% incidence of amplification has been reported,<br />
with no difference among subtypes, with an overall incidence of 30% PIK3CA<br />
alterations regardless histotypes, and of 45% in endometrioid and clear cell. In a<br />
retrospective study in patients with gynaecologic malignancies receiving<br />
combinations with PI3K/AKT/mTOR inhibitors in Phase I studies, <strong>the</strong> objective<br />
response in patients with PIK3CA mutations, including OC, was higher (30%) than<br />
in patients with wild type PIK3CA (10%). The presence of many confounding factors<br />
(retrospective analysis, treatment with mTOR inhibitors, combinations with<br />
cytotoxics) did not allow to determine whe<strong>the</strong>r a relationship existed between<br />
PIK3CA mutations and sensitivity to PI3K or mTOR inhibitors. Loss of PTEN has<br />
been reported in 35%-50% of patients with EC; PIK3CA mutations have been<br />
reported in 39% of patients with EC with both PIK3CA and PTEN mutations in<br />
44%. The most recent data in EC in 243 patients samples indicate >80% PI3K<br />
pathway alterations including mutations of PIK3R1 and PIK3R2, <strong>the</strong> genes encoding<br />
p85α and p85β. KRAS mutation has been reported in 20% of EC with divergent<br />
results on <strong>the</strong> mutual exclusiveness of PI3K and KRAS mutations. The significance<br />
of a crosstalk between <strong>the</strong> two pathways is unknown and <strong>the</strong> role of a combinatorial<br />
approach is under investigations. The PI3K oncogene is a promising target for <strong>the</strong><br />
treatment of EC and clinical studies with pan PI3K, isoform specific PI3K or dual<br />
PI3K/mTOR inhibitors are ongoing in advanced EC. The general strategy in targeted<br />
<strong>the</strong>rapy is to switch from an empirical approach to a more personalized treatment,<br />
based on genetic alterations and mechanistic studies. So far, <strong>the</strong> available data with<br />
PI3K inhibitors don’t justify <strong>the</strong> selection of patients according to PI3K mutations.<br />
Treatment of patients with both wild type or mutant tumors, toge<strong>the</strong>r with <strong>the</strong><br />
availability of representative tumor samples, could lead to <strong>the</strong> identification, through<br />
genetic analysis in responders, of <strong>the</strong> alteration(s) of <strong>the</strong> target genes indicative of<br />
sensitivity to <strong>the</strong> agents administered.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
57IN MOLECULAR IMAGING OF GYNECOLOGICAL CANCERS:<br />
OVARIAN CANCER AS ROLE MODEL<br />
E.G.E. De Vries 1 , G.M. van Dam 2 , A.W.J.M. Glaudemans 3 , A.K.L. Reyners 1 ,<br />
A.G.J. van der Zee 4 , G.A.P. Hospers 1 , M.N. Lub-De Hooge 5<br />
1 Department of Medical Oncology, University Medical Center Groningen,<br />
Groningen, NETHERLANDS, 2 Department of Surgery, University Medical Center<br />
Groningen, Groningen, NETHERLANDS, 3 Department of Nuclear Medicine and<br />
Molecular Imaging, University Medical Center Groningen, Groningen,<br />
NETHERLANDS, 4 Department of Obstetrics and Gynaecology Department,<br />
University Medical Center Groningen, Groningen, NETHERLANDS, 5 Department<br />
of Hospital and Clinical Pharmacy and Nuclear Medicine and Molecular Imaging,<br />
University Medical Center Groningen, Groningen, NETHERLANDS<br />
Standard imaging work-up in ovarian cancer comprises chest imaging, ultrasound<br />
and abdominal/pelvic CT. To determine <strong>the</strong> extent of disease however, <strong>the</strong>se<br />
modalities have poor sensitivity. In addition, <strong>the</strong>y do not provide information about<br />
tumor characteristics such as tumor aggressiveness or presence of possible drug<br />
targets. Molecular imaging can provide serial non-invasive information about tumor<br />
characteristics and can be performed with various imaging techniques such as PET,<br />
SPECT and optical imaging. For this purpose, tumor-directed agents can be<br />
labeled with a radioactive nuclide, or a fluorescent dye. The PET-tracer<br />
18 F-fluorodeoxyglucose (FDG), visualizes glucose metabolism, which is often<br />
increased in tumors. Increasingly, it is possible to image specific drug-targets of<br />
tumors, such as hormone receptors, growth factors and growth factor receptors.<br />
Molecular imaging in metastatic breast cancer patients is feasible for <strong>the</strong> estrogen<br />
receptor with <strong>the</strong> 18 F-fluoroestradiol PET tracer and for HER2 with 111 In- and<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
Annals of Oncology<br />
89 Zr-trastuzumab for SPECT and PET respectively. A trial with 18 F-fluoroestradiol<br />
in ovarian cancer is ongoing. Imaging of vascular endo<strong>the</strong>lial growth factor<br />
(VEGF) with 89 Zr-bevacizumab has been performed by us in various tumor types.<br />
In addition, modulation of drug targets can be visualized by molecular imaging.<br />
Down-regulation of HER2 and VEGF tumor expression by HSP90 inhibition and<br />
of VEGF by mTOR inhibition was visualized in a human ovarian cancer bearing<br />
mice. Finally, optical imaging can provide real-time visualization of small lesions<br />
during surgery, allowing intra-operative staging and image-guided surgery. Folate<br />
receptors are often over-expressed in ovarian cancer and in a pilot-study we<br />
demonstrated, that ovarian cancer can be imaged intraoperatively by<br />
folate-fluorescein-isothiocyanate (folate-FITC). We are currently performing a<br />
feasibility fluorescence imaging study with <strong>the</strong> NIFR 800CW-bevacizumab tracer<br />
in primary breast cancer. Molecular imaging is still in its infancy and not part of<br />
current standards. However, <strong>the</strong> emerging possibilities of molecular imaging for<br />
staging, treatment decision-making, monitoring of treatment effects and<br />
image-guided surgery, justifies fur<strong>the</strong>r validation of molecular imaging in ovarian<br />
cancer.<br />
Disclosure: E.G.E. De Vries: Research grant Roche and Novartis. All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds380 | ix41
abstracts<br />
biologically based treatment in head<br />
and neck squamous cell carcinoma<br />
(hnscc)<br />
58IN THE IMPORTANCE OF WINDOW OF OPPORTUNITY STUDIES<br />
J.P. Machiels 1 , S. Schmitz 2<br />
1 Medical Oncology, Cliniques Universitaires St. Luc, Brussels, BELGIUM, 2 Head<br />
and Neck Surgery, Cliniques Universitaires Saint-Luc, Brussels, BELGIUM<br />
One way to better understand <strong>the</strong> molecular activity of a particular treatment is to<br />
perform trials with collection of pre- and post-treatment tumor biopsies. Squamous<br />
cell carcinoma of <strong>the</strong> head and neck (SCCHN) represents an attractive disease for<br />
this approach because <strong>the</strong>se tumors are generally easily accessible to iterative<br />
biopsies. We performed trials investigating figitumumab and sunitinib in recurrent<br />
and/or metastatic SCCHN after platinum failure. Pre-and post- treatment biopsies<br />
could be obtained in some patients. However, this trial design has some major<br />
limitations in regard of translational research. First, most patients have received<br />
radiation and/or chemo<strong>the</strong>rapy and/or surgery, and so have developed multifactorial<br />
resistance and are less likely to respond to new agents and, second, feasibility of<br />
conducting translational research is hampered by ethical considerations in obtaining<br />
iterative tumor biopsies in palliative patients. One way to resolve some of <strong>the</strong>se issues<br />
is to perform “window” studies where a targeted agent is given during <strong>the</strong><br />
incompressible period of time between <strong>the</strong> diagnosis and surgery in patients selected<br />
for a primary surgical treatment. Evaluation of compounds in <strong>the</strong> pre-operative<br />
window setting could maximize <strong>the</strong> chance of observing tumor response. In addition,<br />
<strong>the</strong> collection of biopsies before treatment and after treatment may provide insights<br />
into <strong>the</strong> pharmacodynamic effects of novel agents as well as <strong>the</strong>ir mechanisms of<br />
action and also help to identify some hypo<strong>the</strong>ses regarding treatment resistance. In<br />
SCCHN, <strong>the</strong> EGFR and its downstream molecular pathways are crucial and EGFR<br />
overexpression is linked with poor prognosis. Cetuximab combined with RT or CT<br />
improves survival. However, only a minority of patients benefits from anti-EGFR<br />
mAbs. We designed trials to investigate <strong>the</strong> safety, molecular and imaging response<br />
of anti-EGFR treatments in <strong>the</strong> window pre-operative study in SCCHN. Briefly, <strong>the</strong><br />
anti-EGFR drug was given during two weeks before surgery. 18FDG-PET, CT-scan<br />
or MRI, tumor biopsies, and plasma collection were taken before and after treatment.<br />
We demonstrated <strong>the</strong> safety and feasibility of this approach. Biological samples are<br />
currently analyzed to better understand <strong>the</strong> molecular mechanisms involved.<br />
Disclosure: J.P. Machiels: Advisory role for Boerhinger Research grant from Sanofi<br />
All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
59IN STRATEGIES TO OPTIMIZE EGFR THERAPIES<br />
B. Burtness<br />
Department of Medical Oncology Fox Chase Cancer Center, Philadelphia, PA,<br />
UNITED STATES OF AMERICA<br />
The epidermal growth factor receptor remains <strong>the</strong> best validated target for systemic<br />
<strong>the</strong>rapy of squamous cell carcinoma of <strong>the</strong> head and neck (SCCHN), with <strong>the</strong><br />
EGFR-directed monoclonal antibody cetuximab <strong>the</strong> only targeted <strong>the</strong>rapy to impact<br />
overall survival in this disease. However, <strong>the</strong> augmentation of response when<br />
cetuximab is added to conventional chemo<strong>the</strong>rapy for recurrent/metastatic disease is<br />
modest, as is <strong>the</strong> delay in time to progression; thus, de novo and acquired resistance<br />
to EGFR inhibition are significant problems. De novo resistance may result when<br />
downstream signaling intermediaries are altered, as with H-ras mutation or PTEN<br />
loss. To date, no signature of abnormality in <strong>the</strong> signaling stream has been shown to<br />
predict cetuximab resistance in SCCHN in a manner analogous to K-ras mutation as<br />
a predictor of cetuximab resistance in colorectal cancer. Combinations of cetuximab<br />
with PI3K, mTOR or Aurora kinase inhibitors are in clinical trial currently. Nuclear<br />
translocation of phosphorylated EGFR is documented in SCCHN and associated<br />
with worsened outcome. Once present in <strong>the</strong> nucleus, EGFR interacts with<br />
transcription factors and phosphorylates and stabilizes PCNA. Gefinitib and lapatinib<br />
appear to inhibit nuclear translocation. Nuclear translocation of EGFR and its<br />
intranuclear functions may represent targets more amenable to tyrosine kinase<br />
inhibitors than to cetuximab, and we are currently studying <strong>the</strong> combination of<br />
cetuximab and erlotinib toge<strong>the</strong>r with standard chemo<strong>the</strong>rapy for recurrent/<br />
metastatic disease. Acquired resistance may result from <strong>the</strong> upregulation of alternate<br />
HER family member receptor tyrosine kinases, and dual EGFR/HER2 or pan-HER<br />
inhibitors such as lapatinib and afatinib are under study. Afatinib is <strong>the</strong> first kinase<br />
inhibitor to show activity comparable to that of cetuximab. As an oral agent, it is<br />
Annals of Oncology 23 (Supplement 9): ix42–ix43, <strong>2012</strong><br />
doi:10.1093/annonc/mds381<br />
more suited to prolonged administration than is cetuximab, and an international<br />
phase III trial of afatinib vs. placebo for patients with poor risk locally advanced<br />
head and neck cancer who have completed chemoradiation. MET is ano<strong>the</strong>r receptor<br />
tyrosine kinase overexpressed in head and neck cancer, and associated with<br />
cetuximab resistance. Novel agents targeting MET include monoclonal antibodies<br />
and tyrosine kinase inhibitors.<br />
Disclosure: Paid consultant to Bristol Myers Squibb in <strong>2012</strong>. Unpaid Steering<br />
Committee member Boehringer Ingelheim, unpaid consultant Millenium<br />
Pharmaceuticals.<br />
60IN PREDICTORS OF SENSITIVITY AND RESISTANCE<br />
MECHANISMS<br />
A. Psyrri<br />
Internal Medicine, Attikon University Hospital, A<strong>the</strong>ns, GREECE<br />
The epidermal growth factor receptor (EGFR) is a validated molecular target in<br />
squamous cell carcinoma of <strong>the</strong> head and neck (HNSCC). However, despite high<br />
expression levels of EGFR protein in <strong>the</strong>se cancers, EGFR-targeted agents have only<br />
had modest single-agent activity. Therefore, major research aims are to better<br />
understand <strong>the</strong> underlying causes of intrinsic or acquired resistance, and to develop<br />
novel treatment strategies that potentiate <strong>the</strong> impact of EGFR inhibitors. At this<br />
point, <strong>the</strong> mechanisms of resistance to EGFR-targeted <strong>the</strong>rapies in patients with head<br />
and neck cancer are largely unknown. Potential mechanisms of resistance include <strong>the</strong><br />
following: (i) constitutive up-regulation of downstream targets of EGFR (i.e. <strong>the</strong><br />
downstream target is no longer regulated by EGFR), (ii) compensatory up-regulation<br />
of redundant receptor tyrosine kinases (RTKs) that signal through common effectors<br />
(pAKT is one such effector), (iii) Ligand-independent signaling (i.e. EGFRvIII):<br />
EGFRvIII is a mutant receptor with an in-frame deletion of <strong>the</strong> extracellular domain<br />
that renders <strong>the</strong> receptor constitutively active despite its inability to bind EGF, (iv)<br />
Transcriptional regulatory mechanisms that control EGFR expression:<br />
single-nucleotide polymorphisms (SNPs) in EGFR promoter region [i.e. GC<br />
(EGFR*1)] or common CA dinucleotide repeat in intron 1 of EGFR affects EGFR<br />
mRNA levels; (v) Inhibition of <strong>the</strong> ubiquitin-mediated degradation of EGFR: <strong>the</strong><br />
chromosome 11q13 region is frequently amplified in HNSCC (36%) and results in an<br />
increased expression of cortactin; (vi) Epi<strong>the</strong>lial to mesechymal transition. Strategies<br />
to optimize EGFR-targeted <strong>the</strong>rapy in head and neck cancer include not only <strong>the</strong><br />
selection for patients most likely to derive benefit but also <strong>the</strong> use of combination<br />
strategies to override resistance.<br />
Disclosure: The author has declared no conflicts of interest.<br />
61IN PARP INHIBITORS AND OTHER STRATEGIES IN<br />
CHEMORADIATION<br />
K.J. Harrington<br />
Targeted Therapy Laboratory, Institute of Cancer Reserach, London, UNITED<br />
KINGDOM<br />
Chemoradio<strong>the</strong>rapy (CRT) is <strong>the</strong> treatment of choice for many locally-advanced<br />
tumour types. In particular, platin-based CRT is <strong>the</strong> gold-standard for stage III/IV<br />
squamous cell cancers of <strong>the</strong> head and neck (SCCHN). Most SCCHN have defects in<br />
<strong>the</strong> DNA damage response. For example, p53 pathway signalling is frequently<br />
defective, ei<strong>the</strong>r through mutation or post-translational silencing by viral<br />
oncoproteins. Therefore, HNC are reliant on <strong>the</strong> G2/M cell cycle checkpoint – and<br />
this represents a potential point of attack for strategies combining RT and novel<br />
targeted radiosensitisers. In this presentation, approaches involving PARP, HSP90<br />
and Chk1 inhibition will be discussed. Poly (ADP-ribose) polymerase (PARP)<br />
inhibitors are potent radiosensitisers and should be <strong>the</strong> subject of careful clinical<br />
evaluation in combination regimens with RT or CRT. Data relating to <strong>the</strong>ir<br />
development will be reviewed. HSP90 maintains <strong>the</strong> stability and activity of a<br />
number of proteins key in cell cycle arrest, DNA damage repair and apoptosis linked<br />
to cellular response to radiation. NVP-AUY922 potently radiosensitized a selection<br />
of cell lines in in vitro clonogenic assays corresponding to depletion of<br />
radioresistance markers at equivalent concentrations. Radiosensitization was verified<br />
in vivo by delayed tumour growth and increased survival. Mechanistic analysis at<br />
clinically achievable concentrations show NVP-AUY922 in combination with RT<br />
exhibits multi-target interference in both cell cycle progression and DNA damage<br />
repair. In addition, we have explored <strong>the</strong> effect of Chk1 inhibition (SAR-020106) in<br />
combination with RT in vitro and in vivo. Colony and caspase activity assays in cell<br />
lines with non-functional p53 revealed significant radiosensitization by Chk1<br />
inhibition, in direct contrast to cell lines with functional p53. In vivo<br />
radiosensitization was confirmed by delayed tumour growth and increased survival<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
Annals of Oncology<br />
utilizing a fractionated drug and radiation schedule. Abrogation of RT-induced G2<br />
phase arrest using <strong>the</strong> Chk1 inhibitor was compensated by an increase in G1 phase<br />
population for cell lines with functional p53 (normal and malignant), in contrast to<br />
tumour cell lines with non-functional p53 (p53 mutant or HPV + ). In addition,<br />
Chk1 inhibition combined with RT caused inhibition of homologous recombinationmediated<br />
DDR.<br />
Disclosure: The author has declared no conflicts of interest.<br />
62IN NOVEL AGENTS AND PARADIGMS IN DEVELOPMENT IN<br />
HNSCC<br />
A. Jimeno<br />
Medicine/Oncology, University of Colorado School of Medicine, Aurora, CO,<br />
UNITED STATES OF AMERICA<br />
HNSCC is a particularly challenging disease due to <strong>the</strong> rarity of activating oncogene<br />
mutations and prevalence of mutations in tumor suppressor genes such as P53 and<br />
NOTCH1 with 47% and 19% mutation rates, respectively. The epidermal growth<br />
factor receptor (EGFR) inhibitor cetuximab is <strong>the</strong> only targeted drug for HNSCC,<br />
but to date, and despite its relatively low clinical efficacy, <strong>the</strong>re are no validated<br />
patient selection strategies. HPV types 16 and 18 through integration and replication<br />
of <strong>the</strong> E6/E7 proteins are <strong>the</strong> etiologic cause of an increasing percentage of HNSCC,<br />
which is becoming an epidemic among younger patients in Western countries. There<br />
is growing evidence that HPV+ and HPV- HNSCC have a different biology, and we<br />
can expect it will require different <strong>the</strong>rapy. In addition to embellishments to<br />
anti-EGFR <strong>the</strong>rapy new areas of research in HNSCC include PI3K inhibition (with<br />
<strong>the</strong> role of genetic selection still to be determined), novel anti-angiogenesis and<br />
anti-lymphangiogenesis such as ALK1 modulators, multikinase inhibitors,<br />
multi-targeted monoclonal antibodies aimed at more efficiently abrogating EGFR<br />
signaling and co-activated pathways, and agents aiming at inhibiting <strong>the</strong> HNSCC<br />
stem cell compartment such as Hedgehog pathway inhibitors.<br />
Disclosure: A. Jimeno: Research laboratory funding: - Infinity - Oncothyreon -<br />
Onconova Patent ownership: - Oncothyreon - Onconova<br />
63IN IMPLICATIONS FOR CLINICAL PRACTICE AND TRIAL DESIGN<br />
A. Psyrri<br />
Internal Medicine, Attikon University Hospital, A<strong>the</strong>ns, GREECE<br />
Targeted strategies have been developed in head and neck squamous cancer<br />
(HNSCC) in order to increase effectiveness and decrease toxicity. Epidermal growth<br />
factor receptor (EGFR) inhibitors are firmly established in HNSCC but <strong>the</strong> critical<br />
issue has been patient selection. O<strong>the</strong>r recently developed novel pathway inhibitors<br />
hold significant promise and are being tested in phase 1, 2 and 3 trials ei<strong>the</strong>r alone<br />
or concomitantly with radio<strong>the</strong>rapy or chemoradio<strong>the</strong>rapy. One such class of<br />
agents, <strong>the</strong> poly(ADP-ribose) polymerase (PARP) inhibitors, has shown activity in<br />
conjunction with radio<strong>the</strong>rapy in head and neck cancer cell lines. Pre-clinical data<br />
suggest that PARP inhibitors may potentiate <strong>the</strong> effects of radio<strong>the</strong>rapy in head and<br />
neck cancer cell lines and xenograft models. Sonic hedgehog (Shh) pathway plays<br />
an important role in HNSCC progression and should be considered a potential<br />
<strong>the</strong>rapeutic target. One clinical arena where targeted <strong>the</strong>rapies may also find place<br />
is in <strong>the</strong> adjuvant or prevention setting where minimal disease or precancerous<br />
lesions can be affected by shutdown of a single or few targets. Future directions lie<br />
in understanding <strong>the</strong> molecular basis of <strong>the</strong> mechanism of action of <strong>the</strong> drugs<br />
currently undergoing clinical evaluation. Increased understanding of <strong>the</strong> cell<br />
signaling processes involved might aid patient selection. Advances in genomics are<br />
revolutionizing <strong>the</strong> discovery of biomarkers and should improve <strong>the</strong> tumor<br />
selectivity of novel agents. There is also a need for <strong>the</strong> development of methods<br />
that can be used in pharmacodynamic studies in humans. A better understanding<br />
of <strong>the</strong> signaling pathways will not only inform our knowledge of cancer<br />
development but also help to refine <strong>the</strong> classification as well as <strong>the</strong> treatment of <strong>the</strong><br />
disease.<br />
Disclosure: The author has declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds381 | ix43
abstracts<br />
molecular targets in malignant<br />
lymphomas: from basic science<br />
to clinical practice<br />
64IN NEW ANTIBODIES IN THE POST-RITUXIMAB-ERA: ANOTHER<br />
BREAKTHROUGH?<br />
P. Johnson<br />
Cancer Research UK Centre, University of Southampton, Southampton,<br />
UNITED KINGDOM<br />
Monoclonal antibodies (mAb) are one of <strong>the</strong> successes of modern cancer medicine,<br />
with rituximab <strong>the</strong> first to enter widespread clinical application following <strong>the</strong><br />
demonstration of significant activity as a single agent, and superior results when<br />
combined with chemo<strong>the</strong>rapy for a variety of CD20+ lymphoma types. In parallel to<br />
extensive clinical studies, we continue to uncover novel aspects of biology of <strong>the</strong><br />
lymphoid cell surface. The molecules to which mAb have been targeted were<br />
identified several decades ago and few new ones have emerged recently, but <strong>the</strong>re is<br />
now increasing interest in effector mechanisms, selective delivery of radionuclides or<br />
toxins, and bispecific molecules to target T- or NK- cells. Once thought of as a<br />
comparatively inert component of <strong>the</strong> cell membrane, CD20 is in fact a dynamic<br />
molecule. It can undergo rapid redistribution, and different mAb cause different<br />
effects: those like Rituximab (“type I”) elicit redistribution into lipid-rich rafts,<br />
mediate complement fixation and antibody-directed cell-mediated cytotoxicity<br />
(ADCC). In contrast, those like <strong>the</strong> first anti-B-cell mAb characterised, B1 (“type II”)<br />
do not cause redistribution into rafts but mediate homotypic cell adhesion and<br />
programmed cell death. These differences have important <strong>the</strong>rapeutic results, and we<br />
have found that in lymphomas expressing <strong>the</strong> CD32 antigen (Fcgamma-R2b), type<br />
ImAb mediate rapid internalization of CD20 with lysosomal consumption, while<br />
type II do not. This has potential consequences for <strong>the</strong> <strong>the</strong>rapeutic effect, as does <strong>the</strong><br />
avidity with which mAb with different sugar groups bind to various Fc receptors. As<br />
well as radioconjugates, we are also returning to previously discarded approaches<br />
such as immunotxins, which have benefitted from advances in linker chemistry to<br />
improve <strong>the</strong>ir <strong>the</strong>rapeutic ratio. Problems of toxin liberation and systemic toxicity<br />
have been largely overcome, and a new generation of conjugates is finding<br />
application in lymphoma <strong>the</strong>rapy. Finally, <strong>the</strong> capacity to generate bispecific<br />
constructs that allow targeting of T-cells to <strong>the</strong> malignant cell surface holds <strong>the</strong><br />
promise of harnessing cellular as well as humoral immunity. The initial promise of<br />
antibody <strong>the</strong>rapy for lymphoma is already being fulfilled, and <strong>the</strong> next generation of<br />
compounds holds exciting challenges and great potential.<br />
Disclosure: P. Johnson: Advisory Boards for Pfizer, Millenium Takeda, Roche,<br />
Boehringer Ingelheim. Research funding from Janssen-Cilag.<br />
65IN MTOR INHIBITORS AND BEYOND: TARGETING A CRITICAL<br />
PATHWAY<br />
M.H. Dreyling<br />
Department of Medicine Iii, University of Munich, Munich, GERMANY<br />
Upregulation of <strong>the</strong> PI3K/AKT/mTOR signal pathway has been detected in<br />
numerous lymphoma subtypes including mantle cell lymphoma (MCL). Accordingly,<br />
<strong>the</strong> mTOR inhibitor Temsirolimus has been registered in EU based on a prospective<br />
randomized trial in 162 patients with relapsed MCL. In comparison to<br />
monochemo<strong>the</strong>rapy, Temsirolimus achieved significantly higher response rates (22%<br />
vs 2%) and longer progression-free survival (4.8 vs. 1.9 months). Moreover, <strong>the</strong><br />
efficacy of <strong>the</strong> mTOR inhibitor was confirmed not only in MCL, but also follicular<br />
and diffuse large B-cell lymphoma in numerous phase II studies. Based on in vitro<br />
studies current trials investigate <strong>the</strong> combination with chemo<strong>the</strong>rapy. Thus, all 12<br />
initial patients with relapsed MCL responded to a<br />
Bendamustin-Rituximab-Temsirolimus combination (BeRT). Recent research has<br />
confirmed <strong>the</strong> critical role of <strong>the</strong> B-cell receptor pathway upstream of mTOR in <strong>the</strong><br />
molecular pathogenesis of malignant lymphoma. This pathway represents <strong>the</strong><br />
physiological survival signal for maturating lymphocytes in <strong>the</strong> germinal center.<br />
Accordingly, small molecules attacking this pathway displayed high efficacy in<br />
various lymphoma subtypes even in mono<strong>the</strong>rapy. Thus, a SYK inhibitor has been<br />
shown to be effective in patients with relapsed diffuse large cell lymphoma. Especially<br />
both, an inhibitor of <strong>the</strong> PI3K delta isoform (GS-1101, formally Cal-101) only<br />
expressed in lymphoid cells and <strong>the</strong> BTK inhibitor ibrutinib showed high efficacy in<br />
relapsed mantle cell lymphoma (response rate about 70%) as well as CLL (response<br />
Annals of Oncology 23 (Supplement 9): ix44–ix45, <strong>2012</strong><br />
doi:10.1093/annonc/mds382<br />
rate between 70–90% in relapsed or previously untreated disease). In contrast,<br />
response rates were lower in follicular lymphoma presumely indicating <strong>the</strong> different<br />
survival signal of <strong>the</strong> constitutive BCL-2 overexpression in this lymphoma subtype.<br />
These data also confirm <strong>the</strong> crucial role of <strong>the</strong> micromilieu in lymphoid diseases<br />
which are hampered by <strong>the</strong> inhibition of <strong>the</strong> B-cell receptor pathway. Finally, recent<br />
in vitro data suggest some synergism of different members of <strong>the</strong> B-cell receptor<br />
pathway in combination with mTOR inhibition. Such molecular targeted strategies<br />
have <strong>the</strong>refore <strong>the</strong> potential to become part of <strong>the</strong> new treatment strategies in a broad<br />
spectrum of lymphoid neoplasias.<br />
Disclosure: M.H. Dreyling: Pfizer (Temsirolimus): scientific advisory board, speaker\<br />
\\’s honoraria Janssen (Ibrutinib): scientific advisory board, support of IITs, speaker\\<br />
\’s honoraria<br />
66IN PROTEASOME INHIBITORS: REALLY A TARGETED THERAPY?<br />
D. Colomer 1 , P. Perez-Galan 2 , G. Roué 2<br />
1 Hematopathology Unit, Hospital Clínic, Institut d’ Investigacions Biomèdiques<br />
August Pi i Sunyer (IDIBAPS), Barcelona, SPAIN, 2 Hematology-oncology. Cek,<br />
Institut d’ Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona,<br />
SPAIN<br />
Bortezomib is <strong>the</strong> first-in-class proteasome inhibitor that targets <strong>the</strong> critical process<br />
of intracellular protein modification and degradation. In 2006, bortezomib was<br />
approved for <strong>the</strong> treatment of relapsed or refractory MCL. The mechanisms of<br />
proteasome inhibition are very complex as <strong>the</strong>y affect many pathways. The Initial<br />
rationale for bortezomib use was inhibition of NF-kB activity. However, bortezomib<br />
does not block constitutive NF-kB activity in MCL and induces oxidative and<br />
endoplasmic reticulum (ER) stress. This cellular stress leads to <strong>the</strong> activation of a<br />
cytoprotective response called Unfolded Protein Response (UPR), that tries to aliviate<br />
ER stress and rescue <strong>the</strong> cell by different adaptive mechanisms. However under<br />
conditions of prolonged stress, apoptosis is activated. Apoptosis commitment starts<br />
with <strong>the</strong> transcriptional activation of <strong>the</strong> propapoptotic BH3-only protein Noxa,<br />
leading to mitochondrial apoptosis. However, half of MCL cases fail to respond, and<br />
resistance often appears after initial treatment. By gene expression analysis it has<br />
been reported that MCL bortezomib-resistant cell lines showed partial plasmacytic<br />
differentiation, including increased expression of IRF4 and its target genes, and of <strong>the</strong><br />
cell-surface markers CD38 and CD138. Tumors from patients with inferior clinical<br />
responses to bortezomib also had high IRF4 and CD38 expression, identifying<br />
possible clinical markers of bortezomib resistance. Also, a correlation between loss of<br />
sensitivity to bortezomib and up-regulation of <strong>the</strong> prosurvival chaperone BiP/Grp78<br />
controlling ER homeostasis has been observed. BiP/Grp78 forms a large multiprotein<br />
complex with o<strong>the</strong>r ER molecular chaperones, including HSP90. Combination of<br />
bortezomib with IPI-504, a HSP90 inhibitor that displace <strong>the</strong> client proteins and<br />
target <strong>the</strong>m for destruction by <strong>the</strong> proteasome system, prevented BiP/Grp78<br />
accumulation, <strong>the</strong>reby promoting apoptosis and inhibiting <strong>the</strong> growth of<br />
bortezomib-resistant tumor xenotransplants. In summary, targeting <strong>the</strong><br />
ubiquitin-proteasome pathway with bortezomib represents a potent arsenal in <strong>the</strong><br />
treatment of MCL, although we need to find new combinations and specific<br />
biomarkers that may help us to recognize which cases will be benefit from each<br />
specific treatment.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
67IN IMIDS: MULTIPLE PATHWAYS BUT DOES IT REALLY WORK?<br />
G. Morgan, C. Pawlyn, F. Davies<br />
Division of Molecular Pathology, The Institute of Cancer Research, London,<br />
UNITED KINGDOM<br />
The mechanism of action of IMiD® compounds has been <strong>the</strong> subject of much recent<br />
research which has highlighted <strong>the</strong> dual effects of <strong>the</strong>se drugs, with both direct<br />
tumoricidal effects and immunomodulatory activity. Lenalidomide exerts its<br />
tumoricidal effects through a number of mechanisms, including decreased<br />
production of cytokine and growth factors causing disruption of stromal support,<br />
induction of tumor suppressor genes leading to cell cycle arrest and activation of<br />
caspases triggering tumor cell apoptosis. A recent study showed that IMiD®<br />
compounds increase p21 expression by a novel epigenetic mechanism. Lenalidomide<br />
also provides sustained disease control by improving immune function, resulting in<br />
continued tumour killing. Lenalidomide exerts immunomodulatory effects via<br />
enhanced antigen-specific CD8+ T-cell cytolysis and by increasing natural killer<br />
(NK)-cell expression of death effector molecules. Lenalidomide and pomalidomide<br />
have greater tumoricidal effects than thalidomide. Lenalidomide also has a more<br />
potent effect on <strong>the</strong> immune system. Both thalidomide and pomalidomide have<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
Annals of Oncology<br />
potent anti-angiogenic properties. Evidence now indicates that clinical benefit can be<br />
gained in thalidomide-treated and refractory patients. In this respect cereblon has<br />
been identified as an intracellular imid binding moiety which is responsible for <strong>the</strong><br />
teratogenic effects of <strong>the</strong>se agents loss of which can mediate resistance to imids.It is<br />
possible to build combinations which improve <strong>the</strong> activity of Imid drugs.<br />
Co-administration of dexamethasone may synergistically improve <strong>the</strong> tumoricidal<br />
effects of lenalidomide but during maintenance <strong>the</strong> inhibition of <strong>the</strong><br />
immune-enhancing effect of lenalidomide may impair its activity. There are a number<br />
of antibodies, including elotuzomab, which may be combined with lenalidomide. In<br />
view of <strong>the</strong> effects of lenalidomide on <strong>the</strong> epigenetic upregulation of tumour suppressor<br />
genes combination with o<strong>the</strong>r epigenetic agents such as HDAC inhibitors and<br />
demethylating agents may be useful. As research continues, additional insights into <strong>the</strong><br />
mechanism of action of Imid drugs which may help to fur<strong>the</strong>r maximize <strong>the</strong> use of<br />
lenalidomide and subsequently pomalidomide in <strong>the</strong> treatment of MM.<br />
Disclosures: All authors have declared no conflicts of interest.<br />
68IN TARGETED THERAPY IN MALIGNANT LYMPHOMA: CLINICAL<br />
IMPLICATIONS AND PERSPECTIVES<br />
M. Ghielmini<br />
Medical Oncology, IOSI Istituto Oncologico Svizzera Italiana Ospedale Regionale<br />
Bellinzona e Valli, Bellinzona, SWITZERLAND<br />
With a whole range of new drugs showing activity in different types of<br />
lymphoma, we question if any of <strong>the</strong>se will make <strong>the</strong> new step forward as it has<br />
been <strong>the</strong> case with <strong>the</strong> introduction of doxorubicin, high-dose chemo<strong>the</strong>rapy or<br />
rituximab. If we look at some most significant diseases, we can hope that for<br />
Hodgkin’s lymphoma (HL) <strong>the</strong> advent of active drugs as brentixumab vedotin<br />
and panobinostat could make chemo<strong>the</strong>rapy more effective, reducing <strong>the</strong> number<br />
of cycles needed or allowing <strong>the</strong> avoidance of drugs with long-term side effects.<br />
In <strong>the</strong> treatment of diffuse large B-cell lymphoma (DLBCL) what is needed is a<br />
drug improving on <strong>the</strong> cure rate. The new available substances have not yet<br />
shown to be so promising but not all of <strong>the</strong>m have yet been combined with<br />
classical chemo<strong>the</strong>rapy. Follicular lymphoma (FL) is a well controllable disease<br />
but we want a drug which will render this disease curable; in <strong>the</strong> meanwhile we<br />
hope that patient-friendly treatments will allow long-term maintenance and<br />
disease control. The combination of lenalidomide with rituximab, but also <strong>the</strong><br />
new CAL 101, BTK inhibitors or inotuzumab ozogamicin could increase <strong>the</strong><br />
possibility of prolonging <strong>the</strong> time without symptoms of disease or treatment. The<br />
impact of <strong>the</strong>se drugs on survival though will be long to ascertain in such an<br />
indolent disease. Mantle cell lymphoma (MCL) remains rapidly progressing and<br />
difficult to treat. It is considered not curable and it will <strong>the</strong>refore be important<br />
ascertain <strong>the</strong> impact of bortezomib, temsirolimus, BTK and PI3K inhibitors or<br />
blinotumumab combined with standard treatment on survival or cure. Finally,<br />
peripheral T-cell lymphoma (PTCL) is an orphan disease compared to <strong>the</strong> B-cell<br />
lymphomas as it could not take advantage of <strong>the</strong> introduction of rituximab. In<br />
anaplastic large cell lymphoma (ALCL) brentuximab vedotin has shown very<br />
important activity and might make <strong>the</strong> difference, while <strong>the</strong> addition of<br />
pralatrexate, romidepsin or vorinostat could change <strong>the</strong> prognosis of <strong>the</strong> o<strong>the</strong>r<br />
entities. Despite many of <strong>the</strong>se drugs having shown promising data, <strong>the</strong> challenge<br />
is now to combine <strong>the</strong>m with standard treatment in order to obtain regimens<br />
which are more active but not more toxic. Phase II trials are ongoing to develop<br />
<strong>the</strong> optimal combination schedules.<br />
Disclosure: M. Ghielmini: Member of advisory board for Roche, Lilly, BMS, Celgene,<br />
Pfizer, Jansen<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds382 | ix45
abstracts<br />
melanoma <strong>the</strong>rapy: from frustration to<br />
enthusiasm<br />
69IN NEW MOLECULAR TARGETS IN MELANOMA<br />
R. Marais<br />
Chester Beatty Laboratories, The Institute of Cancer Research, London,<br />
UNITED KINGDOM<br />
Recent years have seen dramatic advances in <strong>the</strong> development of targeted and<br />
immunological <strong>the</strong>rapeutics for melanoma. In <strong>the</strong> area of targeted <strong>the</strong>rapy, <strong>the</strong><br />
development of BRAF inhibitors has led to new paradigms of melanoma treatment,<br />
because BRAF drugs such as vemurafenib and dabrafinib can achieve objective<br />
responses in BRAF mutant melanoma patients. However, <strong>the</strong>se responses are<br />
generally short-lived, and relapse may be inevitable. Notably, BRAF inhibitors drive<br />
an unexpected paradox: while <strong>the</strong>y inhibit RAF signalling in cells expressing mutant<br />
BRAF, <strong>the</strong>y activate RAF signalling in cells expressing oncogenic or activated RAS.<br />
This is because <strong>the</strong>se inhibitors drive <strong>the</strong> formation of homo and hetero-dimers<br />
between BRAF and <strong>the</strong> closely related protein CRAF. The activation of this paradox<br />
appear, at least in some instances to underlie <strong>the</strong> mechanisms of resistance, and <strong>the</strong>y<br />
also drive one of <strong>the</strong> curious side-effects of <strong>the</strong>se drugs, <strong>the</strong> induction of<br />
non-melanoma neoplasms in <strong>the</strong> skin. Critically, it appears that upon activation of<br />
<strong>the</strong> paradox, <strong>the</strong> tumour cells can switch from being sensitive to <strong>the</strong> drug to being<br />
addicted to it. This creates an unexpected complication when managing <strong>the</strong>se<br />
patients, but shows how improving our knowledge of <strong>the</strong> processes that drive<br />
tumourigenesis is critical to developing novel <strong>the</strong>rapeutic strategies for cancer<br />
patients.<br />
Disclosure: I have received an honourarium from Roche. I have consulted (unpaid)<br />
for novartis; I have consulted (unpaid) for Genentec.<br />
70IN HOW TO OVERCOME RESISTANCE IN MUTATION DRIVEN<br />
THERAPIES COMBINATION TARGETED THERAPY REGIMENS<br />
K.T. Flaherty<br />
Developmental Therapeutics, Cancer Center, Massachusetts General Hospital,<br />
Boston, MA, UNITED STATES OF AMERICA<br />
The identification of BRAF mutations in 2002 was <strong>the</strong> watershed event that turned<br />
<strong>the</strong> attention of <strong>the</strong> melanoma field to this concept. Seven years passed between <strong>the</strong><br />
identification of BRAF mutations and <strong>the</strong> validation of this target in melanoma<br />
patients with a potent and specific BRAF inhibitor, PLX4032. As phase II and phase<br />
III single-agent trials have established BRAF inhibition as a new standard of care for<br />
<strong>the</strong> BRAF mutated subpopulation, attention now turns to understanding mechanisms<br />
of resistance and rational combination approaches. The available evidence regarding<br />
acquired resistance mechanisms does not point to an obvious approach for<br />
developing second line or salvage <strong>the</strong>rapy for <strong>the</strong>se patients. Current efforts are<br />
focused on combining o<strong>the</strong>r targeted <strong>the</strong>rapies with BRAF inhibitors in <strong>the</strong> subgroup<br />
of patient who have BRAF mutations to overcome de novo resistance. The spectrum<br />
of potential combination <strong>the</strong>rapy regimens is broad. It has been known for several<br />
years that BRAF mutations are accompanied by genetic alterations that activate <strong>the</strong><br />
PI3K pathway and CDK4. Characterizing more than one genetic alteration before<br />
selecting such combinations is feasible and an appropriate way to stratify patients for<br />
next-generation combination <strong>the</strong>rapy clinical trials. Recent evidence suggests that<br />
stromal secreted by <strong>the</strong> tumor microenvironment confers resistance to BRAF<br />
inhibitor <strong>the</strong>rapy and HGF antibodies o small molecule c-met inhibitors represent<br />
available investigational agents to combined. Additionally, emerging evidence<br />
suggests that BRAF inhibitors induce a secondary immune response and<br />
combinations with various active immuno<strong>the</strong>rapies is being pursued. However, <strong>the</strong><br />
current inability to predict which patients are most likely to benefit from<br />
immuno<strong>the</strong>rapy represents a persistent challenge in arriving at a personalized<br />
approach with such combinations. Similarly, combination <strong>the</strong>rapy with BRAF<br />
inhibitors and anti-apoptotic drugs and agents that target developmental pathways in<br />
melanoma show promise but do not have an associated predictive biomarker.<br />
Disclosure: K.T. Flaherty: Consultant - Roche/Genentech, GlaxoSmithKline<br />
71IN ANTI CTLA4 AND PREDICTIVE BIOMARKERS<br />
J.S. Weber<br />
Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research<br />
Institute, Tampa, FL, UNITED STATES OF AMERICA<br />
The recent US FDA and EU EMA regulatory approval of ipilimumab, a CTLA-4<br />
antibody, has highlighted <strong>the</strong> need for pharmacodynamic and predictive markers of<br />
its clinical benefit. Ipilimumab’s RECIST response rate is in <strong>the</strong> realm of 10%, with<br />
ano<strong>the</strong>r 10-20% of patients having clinical benefit with stable disease past 6 months.<br />
Response and overall survival are related pharmacokinetically to its Cminns levels,<br />
although <strong>the</strong> rate of immune related adverse events also rises with increased dose.<br />
Several studies in <strong>the</strong> metastatic and adjuvant settings have defined<br />
pharmacodynamics and predictive markers for ipilimumab and determine if <strong>the</strong>y are<br />
associated with clinical benefit. HLA-DR, as well as <strong>the</strong> activation marker ICOS are<br />
increased on CD4 and CD8 T cells after ipilimumab treatment. An increase in <strong>the</strong><br />
early total lymphocyte count may be associated with outcome. Microarray analyses<br />
suggest that expression of a large number of genes are altered in CD4 T cells by<br />
ipilimumab, but fewer genes are impacted in CD8 T cells. Central memory cells are<br />
increased, with a corresponding decrease in naïve T cells. Gata3, a Th2 polarizing<br />
molecule was increased, yet TH17 cell induction and IL-17 levels were increased.<br />
Examination of tumors in patients treated with ipilimumab revealed a significant<br />
influx of CD8 T cells, which may be primarily PD-1 positive. In an adjuvant trial,<br />
pre-treatment CD8/EOMES/Ki67 positive T cells were significantly associated with<br />
relapse-free survival, and CD4/EOMES/Ki67 T cells were associated with low levels<br />
of irAEs, <strong>the</strong> mechanism-based side effects of ipilimumab. Analysis of tumor gene<br />
expression by microarrays suggest that an immune signature may also be predictive<br />
of benefit. The newly developed checkpoint inhibitor antibodies against PD-1 have<br />
been associated with excellent responses of long duration in melanoma, renal cell<br />
cancer and non-small cell lung cancer. Increases in circulating T regulatory cells and<br />
CD4/CTLA-4 expressing T cells was associated with response in one study. In<br />
tumors, PD-1 expression assessed by immunohistochemical staining was associated<br />
with outcome, and no patient with absent PD-L1 expression responded. These data<br />
provide a rationale for fur<strong>the</strong>r marker testing and novel trials of sequenced<br />
antibodies.<br />
Disclosure: J.S. Weber: I have received honraria of less than 10,000 USD from BMS,<br />
have sat on advisory boards for BMS, and my institution has received research<br />
money from BMS<br />
72IN THE COMBINATION OF CHEMO AND IMMUNOTHERAPY: HOW<br />
FOES BECOME FRIENDS<br />
No abstract submitted at time of going to press.<br />
Annals of Oncology 23 (Supplement 9): ix46, <strong>2012</strong><br />
doi:10.1093/annonc/mds383<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
integrating targeted treatments with<br />
tumor biology and molecular imaging in<br />
<strong>the</strong> current and future management of<br />
neuroendocrine gastrointestinal tumors<br />
73IN CLASSIFICATION AND TUMOR BIOLOGY OF NETS<br />
G. Rindi<br />
Università Cattolica - Policlinico A. Gemelli, Instituto di Anatomia Patologica,<br />
Rome, ITALY<br />
First recognized as “carcinoids” in <strong>the</strong> gastroenteropancreatic (GEP) tract,<br />
neuroendocrine tumors (NET) are a variety of neoplastic lesions distributed in most<br />
organs and apparata. The current World Health Organization (WHO 2010) define<br />
low and high grade neuroendocrine cancer types with <strong>the</strong> broad definition of<br />
neuroendocrine neoplasms and introduces grading (G1-G3) and Tumour Node<br />
Metastasis (TNM) staging for class definition. The proposed WHO 2010 grading<br />
system defines three classes (G1-G3) according to both mitotic count and Ki67<br />
index. Three classes are defined as WHO class 1, neuroendocrine tumor (NET), G1;<br />
WHO class 2, NET G2 and WHO class 3, neuroendocrine carcinoma (NEC), by<br />
definition G3. The definition of NET equalizes <strong>the</strong> previous definition of carcinoid<br />
(typical and atypical as variably utilized in <strong>the</strong> pathology literature) and of<br />
well-differentiated endocrine tumor/carcinoma as from <strong>the</strong> previous WHO<br />
classification. The WHO 2010 TNM substantially endorsed <strong>the</strong> classification<br />
originally proposed by <strong>the</strong> European Neuroendocrine Tumour Society (ENETS) with<br />
two exceptions in that i) it limits its application to NET G1-G2 (carcinoids) and ii) it<br />
shows significant differences for pancreas and appendix TNM definitions. In general<br />
a common staging system frame was defined with stage I tumors with limited<br />
growth, stage II larger or more invasive tumors, in absence of metastases, stage III<br />
tumors invading <strong>the</strong> surrounding structures or with loco-regional metastases and<br />
stage IV implying distant metastases. This classification system was first adopted by<br />
<strong>the</strong> International Union Against Cancer (UICC) and subsequently endorsed by both<br />
<strong>the</strong> American joint Cancer Committee (AJCC) and <strong>the</strong> WHO. Current oncology<br />
guidelines for Neuroendocrine neoplasms are largely based on proliferation fraction<br />
and stage to define specific <strong>the</strong>rapeutic options.<br />
Disclosure: G. Rindi: In <strong>the</strong> last three years I acted as consultant for Ipsen pharma<br />
and received speaker’s fee/honoraria from Novartis pharma, Ipsen pharma and<br />
Pfizer.<br />
74IN MOLECULAR IMAGING OF NETS<br />
A. Kjaer<br />
Clinical Physiology, Nuclear Medicine & Pet, Rigshospitalet,<br />
University of Copenahgen, Copenhagen, DENMARK<br />
The change in paradigm towards individualized, tailored <strong>the</strong>rapy has led to a<br />
need for diagnosing at <strong>the</strong> molecular level. Most of <strong>the</strong> molecular biology<br />
methods used today need tissue sampling for in vitro analysis. In contrast,<br />
molecular imaging allows for non-invasive studies at <strong>the</strong> molecular level in living,<br />
intact organisms. With PET it is possible to label bio-molecules with radioactive<br />
isotopes. This method can be used for non-invasive visualization of tumor<br />
specific receptors and tissue characteristics such as receptor expression,<br />
angiogenesis and ability to metastasize. Especially within cancer biology <strong>the</strong><br />
technique is expected to lead to a break-through in diagnosing and treatment.<br />
Among <strong>the</strong> different techniques for molecular imaging, <strong>the</strong> nuclear medicine<br />
based technologies have <strong>the</strong> greatest potential for translational use since methods<br />
developed in animal models may directly be transferred and used in humans.<br />
Fur<strong>the</strong>rmore, PET has a high sensitivity and allows for quantification. The lecture<br />
will review <strong>the</strong> current state of molecular imaging of NET with focus on <strong>the</strong> use<br />
of PET. Areas of recent developments include several new somatostatin receptor<br />
PET ligands that has improved diagnostic accuracy compared with previous<br />
methods using SPECT. In addition, FDG has been shown as a valuable<br />
prognostic tool and recent data from our institution will be shown. Finally,<br />
several new PET tracers seem valuable for tailoring and monitoring effect of new<br />
targeted <strong>the</strong>rapies. Examples of such tailoring and monitoring of <strong>the</strong>rapy will be<br />
reviewed and it will be discussed what <strong>the</strong> future clinical role in NET of such<br />
PET tracers may be.<br />
Disclosure: The author has declared no conflicts of interest.<br />
75IN PEPTIDE RECEPTOR RADIONUCLIDE THERAPY OF<br />
NEUROENDOCRINE TUMOURS<br />
L. Bodei 1 , C.M. Grana 2 , M. Cremonesi 2 , G. Paganelli 2<br />
1 Nuclear Medicine Division, European Institute of Oncology, Milan, ITALY,<br />
2 Nuclear Medicine, European Institute of Oncology, Milano, ITALY<br />
In <strong>the</strong> past two decades a new approach to neuroendocrine tumors based on specific<br />
receptor targeting was introduced in <strong>the</strong> clinical practice. Peptide receptor<br />
radionuclide <strong>the</strong>rapy (PRRT) consists in <strong>the</strong> systemic administration of a syn<strong>the</strong>tic<br />
analogue, radiolabelled with a suitable beta-emitting radionuclide. These compounds<br />
are able to irradiate tumors and <strong>the</strong>ir metastases via <strong>the</strong> internalization through a<br />
specific receptor subtype, generally over-expressed on <strong>the</strong> cell membrane. Pre-clinical<br />
studies have indicated many potential receptor candidates for PRRT. To date, <strong>the</strong><br />
mostly exploited system is <strong>the</strong> somatostatin-somatostatin receptor. PRRT can deliver<br />
high absorbed doses to tumors, adequate to achieve significant volume reduction.<br />
Treatment with radiolabeled somatostatin analogues, such as [ 90 Y-DOTA 0 ,<br />
Tyr 3 ]-octreotide (or 90 Y-DOTATOC) and [ 177 Lu-DOTA 0 ,Tyr 3 ]-octreotate (or<br />
177 Lu-DOTATATE), is an efficient new tool in <strong>the</strong> management of patients with<br />
inoperable or metastasized gastro-entero-pancreatic (GEP) neuroendocrine tumors.<br />
Clinical trials performed in several countries, despite different phase I-II protocols,<br />
showed complete and partial responses in 10 to 30% of patients for 90 Y-DOTATOC.<br />
In <strong>the</strong> clinical trial with 177 Lu-DOTATATE, 47% overall response rate was observed,<br />
with a median time to progression of >36 months and a significant impact on<br />
survival. FDG PET evaluation is useful to predict progression free survival to PRRT<br />
in G1/G2 neuroendocrine tumors. Significant biochemical and symptomatic<br />
responses in functioning tumors were encountered for both radiopeptides. Toxicity,<br />
requiring renal-protective agents, is generally mild and may involve kidneys and<br />
bone marrow. These data indicate that PRRT is a convincing <strong>the</strong>rapeutic tool in <strong>the</strong><br />
treatment scenario of GEP tumors. Newer strategies to increase <strong>the</strong> <strong>the</strong>rapeutic<br />
potential of PRRT, such as <strong>the</strong> combination with radiosensitizing chemo<strong>the</strong>rapy, are<br />
presently under investigation. Incoming phase III protocols comparing PRRT with<br />
177 Lu-DOTATATE versus conventional <strong>the</strong>rapies will help clarifying <strong>the</strong> position of<br />
PRRT in <strong>the</strong> <strong>the</strong>rapeutic algorithm of neuroendocrine tumors.<br />
Disclosure: The author has declared no conflicts of interest.<br />
76IN TARGETED TREATMENT OF NETS<br />
Annals of Oncology 23 (Supplement 9): ix47–ix48, <strong>2012</strong><br />
doi:10.1093/annonc/mds384<br />
J.C. Yao<br />
Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX,<br />
UNITED STATES OF AMERICA<br />
Low to intermediate grade neuroendocrine tumor (NET) constitutes a group of<br />
malignancies that share <strong>the</strong> capacity for secreting hormones and causing distinctive<br />
clinical syndromes. Until recently, <strong>the</strong>re were few evidence-based treatment options.<br />
Recent advances in targeted <strong>the</strong>rapy and completion of pivotal phase III studies have<br />
brought <strong>the</strong> approval of both everolimus and sunitinib for pancreatic NET. These<br />
large randomized studies demonstrated improvement of progression-free survival<br />
validating <strong>the</strong> PI3K/Akt/mTOR pathway and angiogenesis as important targets for<br />
fur<strong>the</strong>r advances. These studies also showed some of <strong>the</strong> challenges of NET including<br />
patient accrual and disease heterogeneity. Ongoing phase III studies comparing<br />
bevacizumab versus interferon and everolimus versus placebo among patients with<br />
o<strong>the</strong>r NET subtypes may bring much needed advances in areas of unmet need.<br />
Development of rational combinations is also ongoing. These ongoing studies as well<br />
as our improved understanding of <strong>the</strong> underlying molecular biology will bring<br />
needed advances.<br />
Disclosure: J.C. Yao: Consultant relationship with Ipsen, Lexicon, Novartis, Pfizer.<br />
1703IN IMPLICATIONS FOR CLINICAL PRACTICE AND TRIAL<br />
DESIGN<br />
K. Oeberg<br />
Endocrine Oncology, University Hospital Uppsala Akademiska Sjukhuset,<br />
Uppsala, SWEDEN<br />
Neuroendocrine GI tumors have demonstrated increase in incidence and prevalence<br />
during <strong>the</strong> last decades, reaching an incidence of 6/100,000 population recently. One<br />
of <strong>the</strong> reasons for <strong>the</strong> increasing incidence and prevalence is greater awareness<br />
among physicians about <strong>the</strong>se conditions but also a better diagnosis and treatment.<br />
Development of specific biomarkers, such as chromogranin A both for<br />
histopathology and marker in <strong>the</strong> circulation, facilitate <strong>the</strong> establishment of correct<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com<br />
abstracts
diagnosis and can also be used for follow-up of <strong>the</strong> patient. Molecular imaging is<br />
ano<strong>the</strong>r important step forward including somatostatin receptor scintigraphy,<br />
Gallium-68 DOTATATE, PET/CT as well as more specific PET-tracers such as<br />
C11-5HTP and GLP1 binding tracers. Molecular images are not only for localisation<br />
of <strong>the</strong> disease, but also for staging and of course also give information about <strong>the</strong><br />
metabolism and tumor biology. For several decades bio<strong>the</strong>rapy has been applied in<br />
patients with slow-growing NETs including somatostatin analogs and alpha<br />
interferon. The tumor cells express specific receptors for somatostatin as well as<br />
interferon. In recent days targeted treatment has been instituted with tyrosine kinase<br />
and mTOR inhibitors. These treatments have been particular useful for pancreatic<br />
NETs where preclinical evaluation of a single transduction pathways, such as IGF1<br />
receptor signalling as well as <strong>the</strong> mTOR signalling pathway has been explored and<br />
Annals of Oncology<br />
demonstrated to be activated in many of <strong>the</strong>se tumors. In recent years peptide<br />
receptor radio<strong>the</strong>rapy based on somatostatin analogs, such as 177 Lutetium<br />
DOTATATE and 90 Yttrium DOTATOC has been applied in NETs with significant<br />
antitumor effect and prolongation of survival. In <strong>the</strong> future <strong>the</strong> treatment will be<br />
based on tumor biology, molecular genetics and <strong>the</strong>reby aiming at personalized<br />
medicine. It will include combinations of new cytotoxic <strong>the</strong>rapies (temozolomide,<br />
capecitabine) toge<strong>the</strong>r with targeted agents such as sunitinib and everolimus, but also<br />
combined with PRRT.<br />
Disclosure: K. Oeberg: Advisory Board: Ipsen, Novartis. Speakers Buerau: Ipsen,<br />
Novartis, Pfizer<br />
ix48 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
hot topics in early stage nsclc<br />
77IN CUSTOMIZED ADJUVANT CHEMOTHERAPY: PROGNOSTIC<br />
AND PREDICTIVE FACTORS<br />
G. Bepler 1 , J. Moon 2 , R. Zinner 3 , R. Calhoun 4 , K. Kernstine 5 , C. Williams 6 ,<br />
P. Mack 7 , V. Oliveira 4 , D. Gandara 8<br />
1 Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute,<br />
Detroit, MI, UNITED STATES OF AMERICA, 2 Research, SWOG Statistical Center,<br />
Seattle, WA, UNITED STATES OF AMERICA, 3 Research, MD Anderson Cancer<br />
Center, Houston, TX, UNITED STATES OF AMERICA, 4 Cardiovascular, University<br />
of California Davis, Sacramento, CA, UNITED STATES OF AMERICA, 5 Thoracic<br />
Surgery, City of Hope, Duarte, CA, UNITED STATES OF AMERICA, 6 Research,<br />
Moffitt Cancer Center, Tampa, FL, UNITED STATES OF AMERICA, 7 Research,<br />
University of California Davis, Sacramento, CA, UNITED STATES OF AMERICA,<br />
8 Thoracic Oncolology Program, UC Davis Cancer Center, Sacramento, CA,<br />
UNITED STATES OF AMERICA<br />
Background: Adjuvant chemo<strong>the</strong>rapy provides a small, but significant, survival<br />
advantage for patients (pts) with completely resected stage II and III non-small-cell<br />
lung cancer (NSCLC). Prior data suggest that benefit from platinum-based adjuvant<br />
<strong>the</strong>rapy is limited to pts with low levels of ERCC1 (E1) expression. RRM1 (R1) is <strong>the</strong><br />
molecular target and key efficacy determinant for gemcitabine. We conducted a<br />
prospective clinical trial (SWOG-0720, NCT00792701) to determine if treatment<br />
selection based on in situ tumoral levels of E1 and R1 is feasible in a mixed<br />
environment of academic and community practices.<br />
Methods: Eligibility was confined to pts with a complete resection of stage I disease<br />
and a tumor diameter of 2 cm or larger. Biomarker levels were determined at <strong>the</strong><br />
protein level using automated quantitative analysis (AQUA, range of expression 1 -<br />
255), and classified as high or low based on a priori cut-off values (E1 >65.0; R1<br />
>40.0). Treatment consisted of four three-weekly cycles of cisplatin/gemcitabine (80<br />
mg/m 2 on day 1 and 1 g/m 2 on days 1 & 8) for those with low E1 and/or R1 levels.<br />
Pts with high levels of both markers were observed. Feasibility was defined as<br />
treatment assignment within 12 weeks from surgery in at least 75% of eligible pts.<br />
Results: 85 pts accrued between March 2009 and April 2011. Two pts were ineligible<br />
because of inadequate mediastinal lymph node sampling. E1 and R1 levels were<br />
successfully determined in all 83 eligible pts, and 72 pts (87%) were successfully<br />
assigned within <strong>the</strong> allotted time period. 64 pts (77%) were assigned to<br />
chemo<strong>the</strong>rapy and 19 (23%) to observation. E1 levels ranged from 4.3 – 211.2<br />
(median 44.7), and R1 levels ranged from 2.5 – 234.4 (median 39.3). Pts<br />
demographics: median age 64 y, age range 41-84 y, ♂/♀ = 48/52%, adeno/squam/<br />
o<strong>the</strong>r = 59/28/13, stage IA/IB = 38/62%, PS 0/1 = 52/48%.<br />
Conclusions: Adjuvant treatment assignment is feasible in pts with completely<br />
resected NSCLC in <strong>the</strong> cooperative group environment, and treatment assignment to<br />
chemo<strong>the</strong>rapy vs observation was not significantly different from prior experience.<br />
Support: NCI grants U10-CA014028, U10-CA032102, U10-CA038926,<br />
U10-CA046368, U10-CA046441, U10-CA105409, P30-CA022453, R01-CA129343<br />
Disclosure: All authors have declared no conflicts of interest.<br />
78IN IS THERE A ROLE FOR TARGETED AGENTS OR BIOLOGICALS<br />
IN STAGE I–III NSCLC?<br />
O. Gautschi<br />
Medizinische Onkologie, Luzerner Kantonsspital, Luzern, SWITZERLAND<br />
More than half of <strong>the</strong> patients with non-small cell lung cancer (NSCLC), including<br />
different tumor stages and histology subtypes, have actionable driver mutations. In<br />
patients with advanced NSCLC and activating EGFR mutations, randomized phase<br />
III trials with EGFR inhibitors (gefitinib, erlotinib and afatinib) demonstrated<br />
superior response rates and progression free survival compared with chemo<strong>the</strong>rapy.<br />
Phase II trials showed high response rates for crizotinib in advanced NSCLC with<br />
ALK-translocation and <strong>the</strong> results of two randomized phase III trials are awaited.<br />
Preliminary data from phase I-II trials and retrospective series suggest fur<strong>the</strong>r targets<br />
for tumor-specific <strong>the</strong>rapies, including MET, ROS1, HER2, BRAF, KRAS, PI3K and<br />
o<strong>the</strong>rs. Moreover, bevacizumab and cetuximab have shown clinical activity in phase<br />
III trials in combination with chemo<strong>the</strong>rapy in patients with advanced NSCLC<br />
selected by histology and EGFR expression, respectively. Rapid molecular testing is<br />
now available at many institutions, and <strong>the</strong> translation of <strong>the</strong>se novel <strong>the</strong>rapies from<br />
stage IV to earlier stages has begun. Caution is warranted, because cure – not tumor<br />
response – is <strong>the</strong> ultimate goal of <strong>the</strong>rapy, and <strong>the</strong> use of new drugs outside of a<br />
Annals of Oncology 23 (Supplement 9): ix49–ix50, <strong>2012</strong><br />
doi:10.1093/annonc/mds385<br />
clinical trial in patients with stage I-III NSCLC may be risky. Of note, S0023 and<br />
BR.19 showed no benefit with <strong>the</strong> addition of gefitinib to a radical treatment in<br />
patients with localized NSCLC, irrespective of EGFR mutation status. Fur<strong>the</strong>rmore,<br />
phase III trials suggested a possible antagonism when EGFR-TKIs were combined<br />
with chemo<strong>the</strong>rapy in patients with stage IV NSCLC. More recent studies indicate<br />
that such negative interaction may be avoided by pharmacodynamic separation (or<br />
"intercalation"), and that EGFR-TKIs as single agents could be used safely and<br />
effectively as induction <strong>the</strong>rapy before surgery in carefully selected patients with stage<br />
I-III NSCLC. At <strong>the</strong> meeting, <strong>the</strong>se data will be reviewed, and ongoing trials in this<br />
field will be discussed, including RADIANT (erlotinib), ADJUVANT (gefitinib), and<br />
ECOG 1505 (bevacizumab). Clinical cases will be presented to highlight problems<br />
and pitfalls of treating patients outside of controlled trials, and new avenues for<br />
clinical and translational research will be elucidated.<br />
Disclosure: The author has declared no conflicts of interest.<br />
79IN WHO SHOULD BE CONSIDERED FOR SURGERY FOR STAGE III<br />
DISEASE AND WHY?<br />
G. Stamatis<br />
Thoracic Surgery and Endoscopy, Ruhrlandklinik/University Essen, Essen,<br />
GERMANY<br />
For <strong>the</strong> treatment of patients with locally advanced NSCLC is important to recognize<br />
<strong>the</strong> variety of manifestations of <strong>the</strong> disease and <strong>the</strong> heterogeneity in <strong>the</strong> subgroups,<br />
so that surgery, multidisciplinary care or non-surgical approach can be tailored to<br />
<strong>the</strong> individual patient. For stage T3N1 and T1-3 N2A1/2 disease primary complete<br />
resection and systematic lymphadenectomy is beneficial for patients with functional<br />
and medical operability. Adjuvant chemo<strong>the</strong>rapy is recommended. After incomplete<br />
resection reoperation is indicated, o<strong>the</strong>rwise radiation is necessary. Patients with<br />
functional and/or medical inoperability are best treated by simultaneous or sequential<br />
chemo-/ radio<strong>the</strong>rapy or radio<strong>the</strong>rapy alone. For stageT1-3 N2A3 disease by<br />
technically resectabel patients, induction treatment (CTx or CTx/RTx) followed by<br />
resection results <strong>the</strong> best long term results. For patients with surgery and R0<br />
resection after induction CTx alone, postoperative RTx is recommended. For patients<br />
with single LNstation involved, primary surgery followed by CTx/RTx is possible. For<br />
patients with StageT1-3 N2A4 bulky disease and acceptable performance status,<br />
combination of chemo<strong>the</strong>rapy and radiation is <strong>the</strong> choice of treatment. For selected<br />
cases after induction chemo<strong>the</strong>rapy and good response <strong>the</strong> integration of surgery<br />
could be followed (if possible inside of studies). For stage T4N0-1 disease primary<br />
surgery or integration of surgery in a multimodality treatment is recommended for<br />
patients with functional and medical operability and involvement of carina, trachea,<br />
atrium, vena cava, pulmonary artery, vertebral body or metastasis in o<strong>the</strong>r lobe<br />
ipsilateral. Treatment strategies for IIIB disease are reduction of tumor associated<br />
symptoms and increasing of survival. For stageT4 N2, T1-3N3 disease combination<br />
of chemo<strong>the</strong>rapy and radiation is <strong>the</strong> choice of treatment. For selected cases after<br />
induction CTx/RTx and good response <strong>the</strong> integration of surgery could be followed<br />
(if possible inside of studies). For sulcus superior tumors stage II-IIIB induction<br />
CTx/RTx followed by surgery is recommended. Technical or functional inoperable<br />
patients should receive a definitive CTx/RTx. The multidisciplinary approach<br />
maximizes <strong>the</strong> chance of long term survival and minimizes <strong>the</strong> treatment related<br />
morbidity and mortality.<br />
Disclosure: The author has declared no conflicts of interest.<br />
80IN WHAT IS THE OPTIMAL RADIOTHERAPY COMBINED<br />
WITH CHEMOTHERAPY FOR STAGE III DISEASE?<br />
D. De Ruysscher<br />
Department of Radiation Oncology (Maastro), Grow, Maastricht University<br />
Medical Centre, Maastricht, NETHERLANDS<br />
For most stage III (T4, N2/3) NSCLC concurrent chemo-radio<strong>the</strong>rapy is <strong>the</strong> first<br />
choice treatment. Many series used a “standard” radio<strong>the</strong>rapy schedule of 60-66 Gy<br />
in 2 Gy QD fractions, combined with cisplatin and etoposide or vinorelbin or<br />
carboplatin-paclitaxel (CP). However, local recurrences (LR) occur in 30-50 % of <strong>the</strong><br />
patients. The observation that an improvement of local control (LC) leads to higher<br />
overall survival (OS) rates even at 5 years, has fuelled research aiming at increasing<br />
LC. Based on a phase II trial suggesting OS with 74 Gy/ 35 QD fractions over 60 Gy/<br />
30 QD fractions given concurrently with CP followed by two cycles adjuvant CP, and<br />
<strong>the</strong> possible beneficial effect of cetuximab as well, <strong>the</strong> RTOG embarked with <strong>the</strong><br />
randomised phase III trial RTOG 0617. Patients were treated with weekly CP and<br />
ei<strong>the</strong>r 60 Gy or 74 Gy in 2 Gy QD fractions, ei<strong>the</strong>r with or without cetuximab,<br />
followed by two cycles of consolidation CP ± cetuximab. At a planned interim<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com<br />
abstracts
analysis at 11 months median follow-up and including 213 patients in <strong>the</strong> 60 Gy arm<br />
and 204 having received 74 Gy, <strong>the</strong> high-dose arm had a worse OS (20.7 months vs.<br />
21.7 months, p = 0.02) and was closed. However, dose escalation can also be achieved<br />
by increasing biological intensification, ra<strong>the</strong>r than by adding fractions and thus<br />
increasing <strong>the</strong> overall treatment time. Most ongoing clinical trials on radiation dose<br />
intensification thus use individualised, accelerated iso-toxic radio<strong>the</strong>rapy (INDAR),<br />
based on organ at risk (OAR) constraints as <strong>the</strong>ir backbone. Obviously, much more<br />
knowledge needs to be obtained on <strong>the</strong> complex interactions between systemic<br />
treatments and radio<strong>the</strong>rapy and <strong>the</strong>ir effects on malignant tissues and OARs. RTOG<br />
0617 never<strong>the</strong>less illustrates that with current standard radio<strong>the</strong>rapy doses and<br />
Annals of Oncology<br />
fractionation, when delivered in well selected patients and when <strong>the</strong> whole treatment<br />
chain is of high quality, much better long-term survival can be achieved than in<br />
historical series. In view of <strong>the</strong> preliminary data of RTOG 0617 and ongoing dose<br />
intensification trials, radiation dose intensification is certainly not obsolete. For<br />
standard practice, current protocols and guidelines should not be changed but<br />
emphasis on quality assessment and if needed adjustment of <strong>the</strong> entire diagnostic,<br />
treatment and supportive care process should be <strong>the</strong> main goal.<br />
Disclosure: The author has declared no conflicts of interest.<br />
ix50 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
latest innovations in nsclc management<br />
81IN PERSONALIZED THERAPY AND BIO-MOLECULAR DRIVEN<br />
TREATMENT IN LUNG CANCER<br />
T. Mitsudomi<br />
Department of Thoracic Surgery, Kinki University Faculty of Medicine,<br />
Osaka-Sayama, JAPAN<br />
Discovery of activating mutation of <strong>the</strong> EGFR gene in 2004 opened <strong>the</strong> era of<br />
personalized <strong>the</strong>rapy in thoracic oncology. These tumors are highly dependent on<br />
<strong>the</strong> EGFR pathway and inhibition of this pathway results in dramatic induction of<br />
apoptosis in vitro, even though cancer cells may have various genetic alterations<br />
(oncogene addiction). These observations were soon translated into clinical trials.<br />
Recent 4 phase III clinical trials for patients with EGFR mutation (NEJ 002,<br />
WJTOG3405, OPTIMAL, EURTAC) reproducibly showed significantly longer<br />
progression free survival for those treated with EGFR-tyrosine kinase inhibitors<br />
(TKI) than those treated with platinum doublet chemo<strong>the</strong>rapy. Although <strong>the</strong>re was<br />
no difference in overall survival probably due to high crossover rate, it was<br />
noteworthy that 40% of patients in EGFR-TKI arm were able to go without<br />
platinum doublet and yet had similar survival outcome in WJTOG3405 In 2007, it<br />
was found that ∼5% of adenocarcinoma of <strong>the</strong> lung harbors EML4-ALK<br />
translocation and that <strong>the</strong>se tumors are also addicted to <strong>the</strong> ALK pathway. Clinical<br />
development of <strong>the</strong> first ALK-TKI, crizotinib, focusing on tumors with ALK<br />
translocation was quick in spite of its rarity. Just 4 years after discovery of<br />
EML4-ALK, crizotinib was approved by FDA for lung cancer with ALK<br />
translocation in 2011 We have learned how effective <strong>the</strong> targeted <strong>the</strong>rapy is, when<br />
“addicted oncogene” was pharmacologically inhibited. List of addicted oncogenes is<br />
expanding continuously and now it includes HER2, ROS1 or RET in<br />
adenocarcinoma of <strong>the</strong> lung. Efforts are also being made to identify addicted<br />
oncogenes in squamous cell carcinoma. Variant III of <strong>the</strong> EGFR gene, mutations of<br />
<strong>the</strong> DDR2 gene, amplification of <strong>the</strong> FGFR1 gene seem to be attractive targets of<br />
<strong>the</strong>rapy. However, even in patients with dramatic initial response in <strong>the</strong>se addicted<br />
tumors, resistance almost inevitably develops typically after less than 1 year.<br />
Mechanisms of <strong>the</strong> resistance include secondary mutation of <strong>the</strong> targeted gene and<br />
activation of alternative pathways. The future clinical trials should be based on<br />
individual mechanism found in re-biopsy specimens. It is also a challenge how<br />
efficaciously <strong>the</strong>se oncogene alterations are identified in each clinical specimen.<br />
Disclosure: T. Mitsudomi: I received honorarium from AstraZeneca, Chugai,<br />
Elo-Lilly, Pfizer, Daiichi-Sankyo and Taiho. I also served as an advisory board for<br />
Boehringer-Ingelheim, Pfizer, AstraZeneca, Chugai, Eli-Lilly, Merck-Serono.<br />
82IN MOLECULAR MECHANISMS OF ACQUIRED RESISTANCE<br />
TO KINASE INHIBITORS<br />
L.V. Sequist<br />
Cancer Center, Massachusetts General Hospital, Boston, MA, UNITED STATES<br />
OF AMERICA<br />
The discovery of mutations in <strong>the</strong> epidermal growth factor receptor (EGFR) gene was<br />
been a turning point in clinical lung cancer care. We now know from multiple phase 3<br />
randomized clinical trials that patients with advanced lung cancer should be screened<br />
for EGFR mutations at <strong>the</strong> time of diagnosis and that first-line genotype-specific<br />
<strong>the</strong>rapy with EGFR tyrosine kinase inhibitors (TKIs) can improve progression-free<br />
survival and quality of life compared to standard chemo<strong>the</strong>rapy. In <strong>the</strong> last few years<br />
we have seen o<strong>the</strong>r examples of successful genotype-directed <strong>the</strong>rapy for lung cancers<br />
with ALK and ROS translocations. However, one significant obstacle that we face in<br />
<strong>the</strong> clinic today is <strong>the</strong> development of acquired resistance to <strong>the</strong>rapy. In this lecture, we<br />
will review what is known about acquired resistance to TKI <strong>the</strong>rapies and discuss<br />
possible strategies for treating and/or preventing acquired resistance.<br />
Disclosure: L.V. Sequist: I have done paid consulting for Clovis Oncology and GSK.<br />
I have done pro-bono consulting for Merrimack Pharmaceuticals,<br />
Boehringer-Ingelheim and Daiichi-Sankyo<br />
Annals of Oncology 23 (Supplement 9): ix51–ix52, <strong>2012</strong><br />
doi:10.1093/annonc/mds386<br />
83IN NEW STRATEGIES ON THE HORIZON<br />
T.S.K. Mok<br />
Department of Clinical Oncology, Chinese University of Hong Kong Prince of<br />
Wales Hospital, Shatin, Hong Kong, CHINA<br />
Since <strong>the</strong> discovery of activating epidermal growth factor receptor (EGFR) mutation<br />
in 2004, personalized <strong>the</strong>rapy for patient with advanced non-small lung cancer<br />
(NSCLC) has become a reality. EGFR TKI and ALK inhibitor are standard treatment<br />
for pt with <strong>the</strong> target. Mutational status of signalling genes is key to management of<br />
lung cancer. Base on this principles, <strong>the</strong>re are a number of new treatment strategy on<br />
horizon. Clinical application of genome profiling is a strategy that may improve <strong>the</strong><br />
outcome of personalized <strong>the</strong>rapy. Population genome profiling has provided<br />
important information on patients with adenocarcinoma. A number of population<br />
based genome profile from patients with adenocarcinoma in USA, France, China and<br />
Japan have been reported. EGFR mutation is more common in Asian population<br />
while KRAS mutation is much less common. O<strong>the</strong>r mutations on ALK, BRAF,<br />
HER-2, PI3K, or MET are less frequent and similar across population. Future<br />
strategy will be personal genome profiling. With <strong>the</strong> improvement in efficiency and<br />
reduction in cost of second-generation sequencer, it will be feasible and practical to<br />
formulate treatment strategy according to genome profile. However, genome profile<br />
may vary over time and between tumors. Genomic heterogeneity must be addressed<br />
if attempt is comprehensive control of all tumor sites by a single targeted <strong>the</strong>rapy.<br />
Gerlinger et al (NEJM 366:883, <strong>2012</strong>) performed extensive exome sequencing from<br />
multiple site of renal cells tumor and its metastasis, and found 63 to 69% of somatic<br />
mutations are not consistently present in all tumor regions. Intra-tumor<br />
heterogeneity included <strong>the</strong> mTOR gene which is <strong>the</strong> primary target for approved<br />
<strong>the</strong>rapy such as everolimus. Thus authors concluded that single site needle biopsy<br />
may not be representative of <strong>the</strong> genomic status of <strong>the</strong> tumor. O<strong>the</strong>r examples<br />
including pancreatic cancer and breast cancer also review similar heterogeneity.<br />
There is no reason to believe lung cancer to be different. New strategy must be form<br />
to address tumor heterogeneity. In summary, new treatment strategies included<br />
individualized genome profiling and study of tumor heterogeneity. More specifically<br />
<strong>the</strong>re should be upcoming treatment strategy for KRAS mutation and squamous cell<br />
carcinoma.<br />
Disclosure: T.S.K. Mok: Consultancy with Astrazeneca, Roche, Pfizer, Eli Lilly,<br />
Merck Serono, Beigene, Eisai, Jannsen, Taiho Speaker engagment with Astrazeneca,<br />
Roche, Pfizer, Eli Lilly, Merck Serono<br />
84IN BREAKTHROUGHS IN BASIC RESEARCH<br />
P.A. Janne<br />
Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, MA,<br />
UNITED STATES OF AMERICA<br />
Over <strong>the</strong> last few years several basic research studies have led to new <strong>the</strong>rapeutic<br />
insights into <strong>the</strong> treatment of patients with advanced non-small cell lung cancer<br />
(NSCLC). These include genomic studies of lung cancers which have revealed<br />
novel potential <strong>the</strong>rapeutic targets. One such target is fibroblast growth factor<br />
receptor (FGFR) 1 which has been found to be amplified in a subset of<br />
squamous cell lung cancers. Preclinical studies have fur<strong>the</strong>r demonstrated that<br />
inhibition of FGFR1 kinase activity using FGFR tyrosine kinase inhibitors (TKIs)<br />
may be clinically effective in this subset of NSCLC. Clinical trials are now<br />
underway using FGFR TKIs in this subset of NSCLC. A second example is <strong>the</strong><br />
identification of novel genomic rearrangements of <strong>the</strong> RET oncogene in NSCLC.<br />
These rearrangements lead to a fusion gene (KIF5B-RET) which is transforming<br />
in vitro and in vivo. Several already approved kinase inhibitors, including<br />
vandetinib, sorafenib and sunitinib, also inhibit RET and may be effective as<br />
clinical <strong>the</strong>rapies in this subset of NSCLC. In addition, several more potent RET<br />
TKIs are under preclinical development and undergoing validation in model<br />
systems. A second recent basic science advance is <strong>the</strong> use of mouse models of<br />
lung cancer to mirror ongoing or planned clinical trials. These “co-clinical” trials<br />
aim to use <strong>the</strong> murine models to determine if <strong>the</strong>y can predict <strong>the</strong> outcome of<br />
human trials and/or be used to fur<strong>the</strong>r understand <strong>the</strong> success and limitations of<br />
<strong>the</strong> <strong>the</strong>rapeutic approach. A recent example evaluated docetaxel and <strong>the</strong> MEK<br />
inhibitor selumetinib compared to docetaxel alone in a genetically engineered<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com<br />
abstracts
mouse model of Kras mutant NSCLC. In this mouse model <strong>the</strong> combination led<br />
to a greater response rate and progression free survival compared to docetaxel<br />
alone. The result was similar in a recent clinical trial of <strong>the</strong> same <strong>the</strong>rapeutic<br />
design in KRAS mutant NSCLC. Interestingly, in <strong>the</strong> mouse model, those tumors<br />
with concurrent Lkb1 loss (occurs in about 30% of KRAS mutant NSCLC in<br />
humans), <strong>the</strong> combination of docetaxel/selumetinib was significantly less effective.<br />
These findings open <strong>the</strong> possibility of evaluating <strong>the</strong> impact of LKB1 loss in<br />
KRAS mutant NSCLC patients treated with selumentib/docetaxel and more<br />
broadly underscore <strong>the</strong> potential utility of animal models in informing <strong>the</strong> design<br />
of human clinical trials.<br />
Disclosure: P.A. Janne: I have acted as a consultant to Pfizer, Boehringer Ingelheim,<br />
Astra-Zeneca, Roche, Genentech and Sanofi<br />
85IN IMPLICATIONS FOR CLINICAL PRACTICE<br />
M. Reck<br />
Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, GERMANY<br />
Treatment of advanced non-small cell lung cancer (NSCLC) has become quite<br />
complex and differentiated according to a variety of clinical, histological and<br />
molecular markers. This development does have several implications on diagnosis<br />
and treatment of patients in clinical practice: • Molecular screening for activating<br />
EGFR mutations should be routinely performed in patients with advanced non<br />
squamous NSCLC. In clinical practice intensification of cooperation between<br />
oncologist and pathologist will be crucial in order to optimize <strong>the</strong> exchange of<br />
Annals of Oncology<br />
information and in order to minimize <strong>the</strong> time to <strong>the</strong> receipt of <strong>the</strong> test results.<br />
For <strong>the</strong> future sequential biopsies for <strong>the</strong> identification of resistance mediating<br />
mechanisms will be of increasing importance and should be integrated in <strong>the</strong><br />
diagnostic algorithm. • In <strong>the</strong> future a variety of highly specific drugs will be<br />
available or investigated in patients with molecular oncogenic alterations which do<br />
occur in NSCLC with frequency of less than 5%. In clinical practice it will be<br />
essential to create interregional diagnostic and <strong>the</strong>rapeutic networks to be able to<br />
identify and to treat most of <strong>the</strong>se patients adequately. • By introducing new<br />
targeted <strong>the</strong>rapies in treatment of Lung Cancer also a variety of specific side<br />
effects has been established. In clinical practice awareness as well as sufficient<br />
management strategies will be crucial to facilitate <strong>the</strong>se <strong>the</strong>rapies. • Maintenance<br />
<strong>the</strong>rapies ei<strong>the</strong>r by targeted agents of by cytotoxic chemo<strong>the</strong>rapy will be of<br />
growing importance in <strong>the</strong> future. Unlike classical cytotoxic chemo<strong>the</strong>rapy <strong>the</strong>se<br />
treatments are not characterized by a clear and defined number of cycles but by<br />
duration of treatment according to tumor response and tolerability. This new<br />
paradigm of treatment does have relevant implication on <strong>the</strong> interaction and<br />
communication between patient and physician. • Most of <strong>the</strong> efficacy information<br />
does come from highly selected trial populations in good Performance status.<br />
Unfortunately very few data are available for patients in restricted PS which<br />
represents a substantial subgroup of patients in daily life. In summary <strong>the</strong><br />
integration of new agents and new strategies offers a great chance to improve<br />
outcomes of lung cancer patients but changes in diagnosis and treatment<br />
schedules will have great implications in clinical practice.<br />
Disclosure: M. Reck: Member of Advisory Board (compensated): Hoffmann-La<br />
Roche, Lilly, AstraZeneca, Daiichi-Sankyo, BMS Honoraria for lectures: Hoffmann-La<br />
Roche, Lilly, AstraZeneca, Daiichi-Sankyo<br />
ix52 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
evidence based answers to critical<br />
questions on cancer screening<br />
and prevention<br />
86IN HPV ELIMINATION OF CERVICAL CANCER: THE NOVEL<br />
OPTIONS IN VACCINATION AND SCREENING<br />
J. Cuzick<br />
Centre for Cancer Prevention, Queen Mary University of London, London,<br />
UNITED KINGDOM<br />
The recognition that infection with certain human papillomavirus (HPV) types<br />
is a necessary cause of cervical cancer has opened new fronts for <strong>the</strong> prevention<br />
of this disease. Primary prevention is now possible via immunization and<br />
secondary prevention has gained impetus with <strong>the</strong> availability of HPV DNA<br />
testing. Although universal vaccination of teenagers and young women is a<br />
desirable policy, even with high uptake a substantial reduction in <strong>the</strong> burden of<br />
cervical cancer is unlikely for at least 10–15 years. To achieve cost-effective<br />
reductions, screening and immunization must be considered as integrated<br />
approaches. Several novel options are possible. If <strong>the</strong> nonavalent vaccine proves<br />
to be effective, a screen and vaccine strategy in older women is attractive, and<br />
raises <strong>the</strong> possibility of virtually eliminating cervix cancer in 5-10 years. New<br />
approaches for triage following primary HPV-based screening are also being<br />
developed and promise to substantially reduce referrals for non-progressive<br />
infections. These include HPV typing, p16 and methylation of viral and human<br />
genes. Lastly, <strong>the</strong> use of self sampling is likely to increase in vaccinated women<br />
with less frequent HPV-based tests. New collection devices and transport media<br />
will be needed to facilitate this.<br />
Disclosure: J. Cuzick: Advisory boards for Abbott, Becton-Dickinson, Roche,<br />
GenProbe, Qiagen, Glaxo Smith Kline, Merck.<br />
87IN PROSTATE CANCER: WHAT ARE THE PROSPECTS AND<br />
GUIDELINES FOR SCREENING AND PREVENTION?<br />
H. De Koning<br />
Public Health, Erasmus MC, Rotterdam, NETHERLANDS<br />
The European Randomized Study of Screening for Prostate Cancer (ERSPC)<br />
showed a significant prostate cancer mortality reduction in <strong>the</strong> screening group of<br />
21% after a median follow-up of 11 years, and of 29% in screened men when<br />
adjusted for selection bias. However, PSA screening is associated with considerable<br />
unfavorable effects. In <strong>the</strong> ERSPC screening group, cumulative incidence of<br />
prostate cancer was 7.4%, versus 5.1% in <strong>the</strong> control group. A proportion of <strong>the</strong><br />
screen-detected tumors (10-56%) would never have led to clinical symptoms but<br />
<strong>the</strong>se over-diagnosed cancers are frequently treated with associated risks of adverse<br />
effects. Fur<strong>the</strong>rmore, because of a long lead-time, estimated 5-12 years, men have<br />
to live longer with those effects. Two specific studies on quality of life after<br />
prostate cancer treatment have been performed for men participating in<br />
Rotterdam and Sweden. Pre-operatively 1-2% of <strong>the</strong> men were incontinent and<br />
31-40% impotent. After 18-52 months 6-16% of <strong>the</strong> radical prostatectomy patients<br />
and 3% of <strong>the</strong> radiation <strong>the</strong>rapy patients were incontinent. Six to 52 months after<br />
radical prostatectomy, 83-88% of pre-operatively potent men became impotent,<br />
compared with 42-66% of <strong>the</strong> men receiving radiation <strong>the</strong>rapy. In this lecture <strong>the</strong><br />
effects of screening strategies on prostate cancer mortality and quality of life will<br />
be quantified, using <strong>the</strong> well-validated MISCAN-model, developed by our institute,<br />
and hereby using results from <strong>the</strong> ERSPC. The implications of our results are that<br />
<strong>the</strong> benefit of PSA screening is diminished by loss of QALYs, that is dependent<br />
primarily on post-diagnosis long-term utility assumptions. Longer follow-up data<br />
from both <strong>the</strong> ERSPC and quality of life and cost-effectiveness analyses are<br />
essential for making universal recommendations regarding screening, but it is<br />
possible that limited testing of middle-aged men with relatively long intervals is a<br />
cost-effective public health policy.<br />
Disclosure: The author has declared no conflicts of interest.<br />
Annals of Oncology 23 (Supplement 9): ix53, <strong>2012</strong><br />
doi:10.1093/annonc/mds387<br />
88IN SCREENING FOR COLORECTAL CANCER: EUROPEAN<br />
GUIDELINES<br />
N. Segnan 1 , J. Patnick 2 , L. von Karsa 3<br />
1 Head, Department of Cancer Screening and Unit of Cancer Epidemiology, CPO<br />
Piemonte and S.Giovanni University Hospital, Turin, ITALY, 2 Nhs Breast<br />
Screening Programme, <strong>Oxford</strong> University, Sheffield, UNITED KINGDOM, 3 Quality<br />
Assurance Group, International Agency for Research on Cancer, Lyon Cedex,<br />
FRANCE<br />
Screening for colorectal cancer: European guidelines for quality assurance According<br />
to <strong>the</strong> most recent estimates by <strong>the</strong> International Agency for Research on Cancer<br />
(IARC) colorectal cancer (CRC) is <strong>the</strong> most common cancer in Europe and it is one<br />
of <strong>the</strong> most causes of cancer death in Europe. Worldwide CRC ranks third in<br />
incidence and fourth in mortality with an estimated 1.2 million cases and 0.6 million<br />
deaths annually. In <strong>the</strong> 27 Member States of <strong>the</strong> European Union (EU), CRC ranks<br />
first in incidence and second in mortality in both sexes, with approximately 334 000<br />
new cases and 149 000 deaths estimated for men and women combined in 2008.<br />
Even in those Member States in <strong>the</strong> lower range of age-standardised rates of CRC,<br />
<strong>the</strong> burden of disease is significant compared to o<strong>the</strong>r regions of <strong>the</strong> world. CRC is<br />
<strong>the</strong>refore an important health problem across <strong>the</strong> EU. Screening is an important tool<br />
in cancer control in countries with a significant burden of CRC, provided <strong>the</strong><br />
screening services are of high quality. The EU recommends population-based<br />
screening for breast, cervical and colorectal cancer using evidence-based tests with<br />
quality assurance of <strong>the</strong> entire screening process including diagnosis and<br />
management of patients with screen-detected lesions. In this context,<br />
multidisciplinary evidence-based guidelines for quality assurance in colorectal cancer<br />
screening and diagnosis have been developed by experts in a project coordinated by<br />
<strong>the</strong> IARC. The full guideline document covers <strong>the</strong> entire process of population-based<br />
screening. It consists of 10 chapters and over 250 recommendations, graded<br />
according to <strong>the</strong> strength of <strong>the</strong> recommendation and <strong>the</strong> supporting evidence. The<br />
450-page guidelines and <strong>the</strong> extensive evidence base have been published by <strong>the</strong><br />
European Commission. The content of <strong>the</strong> executive summary is presented here to<br />
promote international discussion and collaboration by making <strong>the</strong> principles and<br />
standards recommended in <strong>the</strong> new EU Guidelines known to a wider professional<br />
and scientific community. Following <strong>the</strong>se recommendations has <strong>the</strong> potential to<br />
enhance <strong>the</strong> control of colorectal cancer through improvement in <strong>the</strong> quality and<br />
effectiveness of screening programmes and services.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
89IN CANCER REGISTRIES IN SUPPORT OF PLANNING AND<br />
ASSESSING POPULATION BASED ONCOLOGY OUTCOMES<br />
J.W. Coebergh<br />
Department of Public Health, Erasmus MC, Rotterdam AND Comprehensive<br />
Cancer South (IKZ) Eindhoven, NETHERLANDS<br />
The about 200 population-based cancer registries in Europe are currently in an<br />
upswing thanks to an ERA-net FP7 project named EUROCOURSE www.eurocourse.<br />
org that aims to streng<strong>the</strong>n <strong>the</strong>ir infrastructure in order to better serve <strong>the</strong> clinical<br />
oncology and public health communities and policymakers to solidify & improve<br />
prevention (primary and through mass screening), cure (including quality of care)<br />
and care (both survivorship and palliative) in various ways: - clarifying widely<br />
diverging governance and budgets, despite uniform operational methodology and<br />
training needs of both data collectors and data analysts, which warrants valid,<br />
neutral, safe and integer data ga<strong>the</strong>ring and timely information ‘production’ on all<br />
aspects of incidence and prognosis of <strong>the</strong> cancers ‘that be’ both through on-line and<br />
peer-reviewed reporting and with a new European dataportal at IARC - promoting<br />
enrichment by linkages with o<strong>the</strong>r data sources, e.g. vital statistics and research, e.g.<br />
EPIC-study, and occupational, screening and clinical cohorts, with due attention to,<br />
traditionally very well kept, data protection (alas hampered by unwarranted obstacles<br />
in certain memberstates (a sequel from an unfortunate dictatorial past + incorrect<br />
interpretation of EU directive 95/46). - allowing registries to be sampling frame for<br />
in-depth studies of quality of care (adherence to guidelines/best practice?) both<br />
process and outcome carried out with more speed/urgency than usual because also<br />
needed in areas/parts of Europe without registry coverage, i.e. in or within more than<br />
50% of <strong>the</strong> EU, especially in larger memberstates) not only of first line treatments<br />
due to increasing application of targeted drugs and survivorship in <strong>the</strong> various<br />
phases of <strong>the</strong> disease - allowing depth via strategic collaborations with clinical,<br />
etiological, screening databases (stakeholders), promoting <strong>the</strong> cost-effectiveness of a<br />
rich infrastructure serving many users (Nordic ‘model’) versus <strong>the</strong> current threat of<br />
fragmentation by tumourspecific clinical databases (at risk for becoming data<br />
cemetaries) With <strong>the</strong> tree as metaphor a landscape of registries is shown, remaining<br />
close to its clinical roots. Major European references Comment: Lancet Oncology<br />
2005;6:193-5 Trends: Eur J Cancer 2008;44:1345-89 Recent data: Eur J Cancer<br />
2010;46:765-81.<br />
Disclosure: The author has declared no conflicts of interest.<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.<br />
abstracts
abstracts<br />
subtyping soft tissue sarcomas for<br />
treatment approaches<br />
90IN WHY WERE IGF-1R INHIBITORS DISAPPOINTING? CAN WE<br />
IMPROVE ACTIVITY BY BETTER PATIENT SELECTION OR USE<br />
OF COMBINATIONS?<br />
I. Judson<br />
Sarcoma Unit, Royal Marsden Hospital, London, UNITED KINGDOM<br />
It is been known for many years that <strong>the</strong> insulin-like growth factor (IGF) signalling<br />
pathway is important in human cancer. The IGF-1 receptor (IGF-1R) is upregulated<br />
in colorectal, breast, prostate and lung cancers. It was also known to be a potential<br />
target in Ewing’s sarcoma. The advent of specific monoclonal antibodies and small<br />
molecule tyrosine kinase inhibitors of IGF-1R led to many clinical trials. A<br />
combination of figitumumab with platinum doublet chemo<strong>the</strong>rapy resulted in a<br />
higher response rate and improved progression-free survival (PFS) in phase II, but a<br />
phase III trial was negative. In Ewing’s sarcoma activity was seen with R-1507,<br />
figitumumab and o<strong>the</strong>r agents. However, response rates in phase II studies were<br />
generally low, 14.2% with figitumumab, and duration generally short, e.g. with<br />
figitumumab median PFS 1.9 months, median survival 8.9 months. Occasionally,<br />
durable responses have been seen lasting for several years. Could better selection by<br />
<strong>the</strong> use of circulating biomarkers, e.g. IGF-1, or IGF binding proteins, be useful or<br />
does <strong>the</strong> answer lie with combinations? Laboratory studies suggest that combining<br />
IGF-1R inhibitors with inhibitors of AKT/mTOR, EGFR or MEK, could help to<br />
overcome resistance. Given <strong>the</strong> dearth of new agents for Ewing’s sarcoma it is to be<br />
hoped that continued access to <strong>the</strong>se agents will enable fur<strong>the</strong>r work on mechanisms<br />
of resistance and appropriate combination phase I/II studies to be performed. The<br />
book is not yet closed on IGF-1R as a target.<br />
Disclosure: The author has declared no conflicts of interest.<br />
91IN SUCCESSFUL TARGETING OF VEGFR IN SOFT TISSUE<br />
SARCOMAS<br />
W.T.A. van der Graaf<br />
Medical Oncology, Radboud University Nijmegen Medical Center, Nijmegen,<br />
NETHERLANDS<br />
Successful targeting of VEGFR in soft tissue sarcomas Increasing evidence suggests<br />
that angiogenesis plays an important role in <strong>the</strong> biology of <strong>the</strong> heterogeneous group<br />
of soft tissue sarcomas (STS). During <strong>the</strong> last years clinical studies have shown <strong>the</strong><br />
importance of targeting angiogenesis in STS. Most attention has been paid to<br />
pazopanib, a tyrosine kinase inhibitor, known for its activity in renal cell cancer.<br />
Pazopanib targets multiple kinases, including vascular endo<strong>the</strong>lial growth factors<br />
(VEGFR1-3), and platelet derived growth factors. In a previous phase 2 study in<br />
relapsed or metastatic STS (EORTC study 62043) <strong>the</strong> progression free rate at 12<br />
weeks was promising in <strong>the</strong> strata of leiomyosarcoma, synovial sarcoma, and o<strong>the</strong>r<br />
types of STS, but was disappointing in liposarcoma patients. In <strong>the</strong> subsequent phase<br />
3 study which consisted of 372 metastatic STS patients, pazopanib was compared<br />
with placebo in a 2:1 fashion in patients with progressive non-adipocytic STS, who<br />
had had anthracyclines and all locally available systemic treatment options. The<br />
results of this so-called PALETTE trial (EORTC study 62072), which allowed no<br />
crossover, showed a statistically significant improvement in PFS of 3 months: 4.6<br />
months with pazopanib compared to 1.6 month with placebo. The final overall<br />
survival did not show a significant improvement, being 12.5 months with pazopanib<br />
and 10.7 months with placebo. Pazopanib was generally well tolerated. Most<br />
common adverse events were fatigue, diarrhea, nausea, weight loss and hypertension.<br />
The effect of pazopanib was observed in all subgroups of STS, which suggests a<br />
universal important role of VEGFR, but whe<strong>the</strong>r this is <strong>the</strong> driving force in <strong>the</strong><br />
pathogenesis of all STS is unknown. Based on <strong>the</strong> positive results of <strong>the</strong> PALETTE<br />
study pazopanib has recently been approved by FDA and EMA for <strong>the</strong> treatment of<br />
patients with advanced STS who have received prior chemo<strong>the</strong>rapy. GIST and<br />
liposarcoma were not part of this registration. Apart from VEGFR also VEGF has<br />
been <strong>the</strong> target of a couple of clinical studies in STS, ei<strong>the</strong>r as single agent or as<br />
combination <strong>the</strong>rapy. With <strong>the</strong> success of pazopanib in STS <strong>the</strong> pathogenic role of<br />
<strong>the</strong> VEGF-VEGFR pathway in STS becomes even more of interest than has been<br />
before and <strong>the</strong> challenge will be to fur<strong>the</strong>r explore <strong>the</strong> success of targeting this<br />
pathway in future clinical studies.<br />
Disclosure: The author has declared no conflicts of interest.<br />
Annals of Oncology 23 (Supplement 9): ix54–ix55, <strong>2012</strong><br />
doi:10.1093/annonc/mds388<br />
92IN TREATING SARCOMA (INCLUDING GIST) SUBTYPES BASED<br />
ON MOLECULAR CHARACTERISTICS<br />
J-Y. Blay<br />
University Claude Bernard Lyon I, Centre Léon Bérard, Lyon, FRANCE<br />
Recent progress in <strong>the</strong> understanding of <strong>the</strong> biology of soft tissue sarcomas and<br />
locally aggressive connective tissue tumors have enabled <strong>the</strong> identification of distinct<br />
molecular and pathological entities: six molecular subgroups of connective tissue<br />
tumors may be distinguished: 1) sarcoma with specific translocations generating<br />
fusion gene whose protein products modulate transcription or may act as growth<br />
factors (e.g. EWS/Fli1 in Ewing sarcomas, PDGF-col1a1 in DFSP); 2) sarcomas with<br />
mutated activated kinases (KIT in GIST); 3) sarcomas with deletion of tumor<br />
suppressor genes such as NF1 sarcomas, or rhabdoid tumors (INI1); 4) Sarcomas<br />
with simple genetic alterations (mdm2/cdk4 amplification in WD/DD liposarcomas;<br />
5) Sarcomas with gross genetic alterations (e.g. leiomyosarcomas); 6) Tumors with<br />
alterations of <strong>the</strong> intercellular adhesion pathways (aggressive fibromatosis with APC<br />
deletion or b catenin mutations). These classifications are rapidly evolving. The<br />
identification of <strong>the</strong> “driver” mutation in some of <strong>the</strong>se diseases paved <strong>the</strong> way for<br />
<strong>the</strong> selection of efficient targeted <strong>the</strong>rapies in sarcomas and locally aggressive<br />
connective tissue tumors such as GIST, DFSP, PEComas, PVNS … Even though <strong>the</strong><br />
driving molecular event is not known, giant cell tumors of <strong>the</strong> bone fit in this<br />
category. Interestingly, with <strong>the</strong> refinement of molecular typing, even rare nosological<br />
entities evolve towards fur<strong>the</strong>r fragmentation: <strong>the</strong> identification of KIT and PDGFRA<br />
mutations, <strong>the</strong>n Raf, NF1, SDH mitated in GIST led to a rapid development of<br />
imatinib, sunitinib, and regorafenib, but with <strong>the</strong> more recent characterization of Raf,<br />
NF1, SDH gene muations, it is now recognized that GIST ga<strong>the</strong>rs probably 10<br />
different molecular entities with different <strong>the</strong>rapeutic rules and prognosis in localized<br />
and advanced phase. Recently, it was shown that targeting MdM2/p53 interaction in<br />
sarcomas with MDM2 amplification can lead to an efficient reactivation of p53 and<br />
biological response in tumor cell. Targeting CDK4 may also be worth exploring in<br />
similar context. Targeting a pathway downstream of <strong>the</strong> driver mutation can however<br />
be more challenging: in Ewing sarcoma, whose fusion gene product regulates<br />
IGFBP3, anti–IGF1R Ab yielded responses in now several phase I and II trials but<br />
only in a small proportion of patents for reasons yet unknown. In addition to <strong>the</strong>se<br />
examples, more empiric approaches have been successfully developed, with<br />
anti-angiogenics (pazopanib) and mTOR inhibitors (ridaforolimus) showing efficacy<br />
in phase III trials, in a broader group of sarcoma subtypes. Treating sarcoma<br />
subtypes according to <strong>the</strong>ir molecular characteristics is critical for <strong>the</strong> development<br />
of new treatments, and will also be essential to understand <strong>the</strong> biological<br />
mechanisms of response and resistance.<br />
Disclosure: J. Blay: Suppoted by grants from Novartis, GSK, Roche, Pharmamar<br />
93IN TARGETING HDM2 (HUMAN MDM2) IN SARCOMAS<br />
R.G. Maki<br />
Pediatrics, Medicine and Orthopaedics, Mount Sinai School of Medicine, NEW<br />
YORK, NY, UNITED STATES OF AMERICA<br />
Liposarcomas represent three families of genetically distinct cancers. The most<br />
common of <strong>the</strong>se is well-differentiated / dedifferentiated liposarcoma (WD-DD LS),<br />
which represents half of <strong>the</strong> liposarcomas with an incidence of 4–5 per million<br />
people. The well differentiated version of <strong>the</strong> tumor appears somewhat like fat, while<br />
dedifferentiated liposarcomas have typically lost most or all ability to store lipids.<br />
WD-DD LS is a unique entity with high copy number amplification of chromosome<br />
12q, followed by loss of portions of o<strong>the</strong>r chromosomes, such as 19q13, in more<br />
aggressive tumors, which notably is <strong>the</strong> locus for CEBPA, a key main adipocytic<br />
differentation gene. On chromosome 12q are located important genes in maintaining<br />
cell survival, such as CDK4 and HDM2 (<strong>the</strong> human version of MDM2) and<br />
YEATS4. Recent data also show epigentic effects to turn off adiopocytic<br />
differentiation genes. The presence of <strong>the</strong> amplified genes such as those above as well<br />
as AURKA nearby suggests inhibitors of <strong>the</strong>se proteins may be useful to trigger<br />
dysregulation and cell death of <strong>the</strong>se tumors cells with highl abnormal genomes.<br />
CDK4 inhibitors and HDM2 inhibitors are now being examined in phase I-II clinical<br />
trials in WD DD LS patients. In this talk, <strong>the</strong> biological background for examining<br />
HDM2 inhibitors in WD DD LS patients is discussed, as well as <strong>the</strong> potential role<br />
for <strong>the</strong>se inhibitors both in cancers with wild type p53 as well as those with<br />
genetically altered p53. There may not be <strong>the</strong> need to limit <strong>the</strong> examination of<br />
HDM2 inhibitors to WD DD LS, although issues remain regarding <strong>the</strong> toxicity<br />
observed with <strong>the</strong>se compounds to date.<br />
Disclosure: R.G. Maki: Consulting fees: GlaxoSmithKline, Bayer, Sanofi, Lilly,<br />
Morphotek, Eisai, Pfizer Research Support: Eisai, Ziopharm, Roche Honoraria:<br />
Ziopharm, Novartis Unpaid consulting: n-of-one, 23 & Me<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
Annals of Oncology<br />
94IN PERSPECTIVES OF SUBTYPING IN SOFT TISSUE SARCOMAS:<br />
THE RELEVANCE FOR CLINICAL TRIAL DESIGN<br />
J. Verweij<br />
Department of Medical Oncology, Erasmus University Medical Center – Daniel<br />
den Hoed Cancer Center, Rotterdam, NETHERLANDS<br />
In <strong>the</strong> relatively recent past soft tissue sarcomas were lumped toge<strong>the</strong>r for <strong>the</strong><br />
purpose of studying treatment effects in clinical trials. This has clearly served a<br />
purpose in <strong>the</strong> development of non-specific cytotoxic agents. But even for<br />
cytotoxic agents more recently hints of selective sensitivity of sarcoma subtypes<br />
emerged. So one can state in general that using unselected populations in soft<br />
tissue sarcoma trials increases <strong>the</strong> ease of patient accrual, but at <strong>the</strong> same time<br />
diminishes <strong>the</strong> chance of achieving a statistically significant clinical benefit. The<br />
identification of KIT as a single tumor growth driver in Gastrointestinal stromal<br />
tumor (GIST), and its subsequent effective inhibition with imatinib, have fur<strong>the</strong>r<br />
streng<strong>the</strong>ned <strong>the</strong> realization that <strong>the</strong> various subtypes of soft tissue sarcomas<br />
should each be considered as unique diseases. Because of <strong>the</strong> rarity of soft tissue<br />
sarcomas in general and <strong>the</strong> linked limited number of patients for each individual<br />
sarcoma subtype, <strong>the</strong> now required fur<strong>the</strong>r subsetting creates a challenge for<br />
current and future trial design. Evidence from recent trials suggests that, if <strong>the</strong>y<br />
are based on well-characterized preclinical data and/or clinical observations,<br />
performance of trials in select histologic subtypes should be pursued and is<br />
feasible; at least for tumor cell related targeted <strong>the</strong>rapeutic approaches. For targets<br />
in <strong>the</strong> tumor environment <strong>the</strong>re are also signals that subsets may be more<br />
sensitive, although this does not ensure that <strong>the</strong> o<strong>the</strong>r subsets are totally<br />
insensitive. There seems to be a gradual differentiation of sensitivity. For several<br />
agents <strong>the</strong> sensitivity of subsets could be predicted with predictive biomarkers, but<br />
biomarkers were of more limited value of biomarkers in assessing individual<br />
clinical benefit. This yields yet ano<strong>the</strong>r challenge, certainly for agents<br />
where growth inhibition ra<strong>the</strong>r than tumor regression is expected. All of <strong>the</strong>se<br />
aspects are guiding us towards new trial approaches that will shortly<br />
be discussed.<br />
Disclosure: The author has declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds388 | ix55
abstracts<br />
key topics in supportive care<br />
95IN PREVENTION AND TREATMENT OF OSTEONECROSIS<br />
C.A. Migliorati<br />
Diagnostic Sciences and Oral Medicine, University of Tennessee Health Science<br />
Center College of Dentistry, Memphis, TN, UNITED STATES OF AMERICA<br />
Jaw osteonecrosis associated with medications (JOM) is a significant oral<br />
complication of antiresorptive drugs (intravenous bisphosphonates and denosumab)<br />
used in <strong>the</strong> treatment of cancer patients with metastatic bone disease and multiple<br />
myeloma. This complication also develops in individuals with advanced cancers such<br />
as metastatic colorectal cancer, advanced nonsquamous non-small cell lung cancer,<br />
metastatic kidney cancer, glioblastoma, GIST, and advanced renal cell carcinoma<br />
treated with antiangiogenics (bevacizumab and sunitinib). There is also evidence that<br />
<strong>the</strong> use of <strong>the</strong>se medications in combined protocols can increase <strong>the</strong> risk of JOM.<br />
The management of JOM is difficult and patient’s quality of life can be<br />
compromised. Literature has suggested that <strong>the</strong> diagnosis and stabilization of dental<br />
disease aiming risk minimization prior to starting antiresorptive or antiangiogenic<br />
<strong>the</strong>rapy can prevent or reduce <strong>the</strong> incidence of JOM. Thus, referring patients for<br />
dental exam prior to initiating <strong>the</strong>rapy with <strong>the</strong>se drugs is recommended.<br />
Conservative dental <strong>the</strong>rapy was <strong>the</strong> standard of care for JOM. The clinical progress<br />
of invasive dental <strong>the</strong>rapy to eliminate necrotic bone was unfavorable with observed<br />
aggravation of <strong>the</strong> clinical defect and with <strong>the</strong> development of additional necrosis.<br />
Recently, more aggressive surgical protocols have been successful when using wide<br />
resection of necrotic bone, primary closure of <strong>the</strong> extraction site and a combination<br />
of topical and systemic antibiotics. The objective of this presentation is to update<br />
professionals who treat patients with solid tumors with bone metastasis such as<br />
breast, prostate and lung cancer, and bone malignancy like multiple myeloma, on <strong>the</strong><br />
new definition of JOM, clinical characteristics of <strong>the</strong> lesion, prevention and patient<br />
management. Good communication between oncologists and dental professionals is<br />
critical for <strong>the</strong> success of patient management. We expect to demonstrate that this<br />
new oral complication could be used as an example to alert health care professionals<br />
working in oncology of <strong>the</strong> importance of maintaining strict surveillance of possible<br />
new complications that can develop with <strong>the</strong> use of new oncologic treatment, a fast<br />
developing field.<br />
Disclosure: The author has declared no conflicts of interest.<br />
96IN HOW TO DEAL WITH PATIENTS WITH ACTIVE<br />
HEPATITIS B & C<br />
J. Lubel<br />
Gastroenterology, Eastern Health, Melbourne, VIC, AUSTRALIA<br />
Chronic viral hepatitis is a global problem with approximately 350 million people<br />
infected with hepatitis B virus (HBV) and 170 million people infected with<br />
hepatitis C virus (HCV) worldwide. It is estimated that one-third of <strong>the</strong> worlds<br />
population (over 2 billion people) have been infected with HBV. In Europe <strong>the</strong><br />
prevalence of HBV ranges between 0.1% and 7% whereas <strong>the</strong> prevalence of HCV<br />
ranges between 0.4% and 22%. These two viruses account for <strong>the</strong> majority of cases<br />
of chronic viral hepatitis and contribute to <strong>the</strong> development of cirrhosis and<br />
hepatocellular carcinoma, yet differ markedly in virology, natural history and<br />
management. In chronic viral hepatitis, equilibrium exists between <strong>the</strong> host’s<br />
immunity and viral replication. Immunosuppression allows viral replication to<br />
continue unchecked. In non-cirrhotic patients with HCV infection this rarely<br />
results in significant clinical sequelae and patients embarking on<br />
immunosuppressive <strong>the</strong>rapy can generally be monitored. In contrast, patients<br />
infected with hepatitis B may have significant hepatitis ‘flares’ following periods of<br />
immunosuppression which can result in hepatic failure, need for liver transplant<br />
and occasionally death. The hepatitis B virus itself is not cytopathic; hepatic<br />
inflammation occurs as a result of immune-mediated injury and <strong>the</strong>refore generally<br />
occurs after maximal immunosuppression. The cornerstone to management of<br />
HBV in patients receiving chemo<strong>the</strong>rapy is identification of currently or previously<br />
infected patients with appropriate requesting and interpretation of hepatitis B<br />
serology. In order to prevent HBV reactivation, all patients with chronic hepatitis<br />
B (CHB) should be started on antiviral prophylaxis before commencing<br />
immunosuppressive chemo<strong>the</strong>rapy and for a period of 12 months after<br />
chemo<strong>the</strong>rapy has been completed. In patients with high viral loads <strong>the</strong> use of<br />
antiviral agents with a high genetic barrier to resistance should be considered (eg<br />
entecavir and tenofovir). In those with low or undetectable viral loads lamivudine<br />
is an acceptable alternative. In patients who have apparently cleared hepatitis B<br />
(surface antigen negative, core antibody positive), HBV can reactivate with<br />
subsequent reappearance of surface antigen (seroreversion). This can be followed<br />
by clinically significant HBV flares. The risk of this occurring seems particularly<br />
high for regimens containing Rituximab. Patients unable to be monitored closely<br />
for reactivation with monthly HBV DNA quantification and liver function tests<br />
should receive antiviral prophylaxis.<br />
Disclosure: The author has declared no conflicts of interest.<br />
97IN INFLUENZA VACCINATION IN CANCER PATIENTS<br />
F. Menichetti<br />
Cisanello Hospital, Infectious Diseases Unit, Pisa, ITALY<br />
Seasonal influenza virus infections are an important cause of respiratory disease and<br />
cancer patients are at increased risk of complications. The CDC recommends annual<br />
vaccination with inactivated viral vaccine for immunosuppressed hosts including<br />
cancer patients. Limited data are available on <strong>the</strong> safety and immunogenicity of<br />
vaccination programs in this setting, especially for <strong>the</strong> optimal timing of vaccination<br />
during ongoing chemo<strong>the</strong>rapy and <strong>the</strong> overall rate of influenza vaccination in cancer<br />
patients is quite low (30%). Mulder et al. (2001) reported similar seroprotection rate<br />
after seasonal flu vaccine for patients treated with tyrosyne kinase inhibitors and<br />
control group. Eggink et al. (2011) reported a lower response rate to flu vaccine in<br />
breast cancer patients compared to healthy controls; a trend toward better resoponse<br />
was documented in patients receiving vaccine early during chemo<strong>the</strong>raspy (day 4)<br />
compared to those vaccinated during <strong>the</strong> last week (day 16). In <strong>the</strong> VACANCE study,<br />
cancer patients receiving 2 doses of an adjuvated H1N1 vaccine developed an higher<br />
seroconversion rate with respect <strong>the</strong> single dose (73% vs. 44%). Mackay et al.<br />
reported a lower rate of seroconversion and seroprotection after H1N1 vaccination in<br />
hematological patients with respect to solid tumors patient; rituximab combined to<br />
chemo<strong>the</strong>rapy was associated with <strong>the</strong> lower response rate to <strong>the</strong> flu vaccine. In<br />
summary, <strong>the</strong>re is <strong>the</strong> need for fur<strong>the</strong>r studies to optimize flu vaccine programs<br />
(patients selection, timing related to chemo<strong>the</strong>rapy, dose schedule) in cancer<br />
patients.<br />
Disclosure: The author has declared no conflicts of interest.<br />
98IN THROMBOSIS IN CANCER PATIENTS<br />
Annals of Oncology 23 (Supplement 9): ix56, <strong>2012</strong><br />
doi:10.1093/annonc/mds389<br />
M.A. Dicato<br />
Hematology- Oncology, Centre Hospitalier de Luxembourg, Luxembourg,<br />
LUXEMBOURG<br />
Arterial thrombosis is not a specific cancer related disorder except in some patients<br />
on some antiangiogenic drugs, but remains an infrequent event compared to venous<br />
thromboembolism (VTE). VTE is <strong>the</strong> second most frequent cause of death in cancer<br />
patients and is a predictor of mortality in hospitalized cancer patients. The death rate<br />
is about 30% in cancer patients when VTE occurs within 3 months of diagnosis.<br />
About 15% of patients suffering from cancer will have a VTE during <strong>the</strong> course of<br />
<strong>the</strong>ir disease and about 10% of patients with an idiopathic (?) VTE develop a cancer<br />
in <strong>the</strong> following two years. Risk factors for VTE in oncology are patient dependent,<br />
treatment dependent, type of cancer and stage dependent, The pathophysiology of<br />
VTE is complex. In addition to <strong>the</strong> standard causes, biomarkers and a clinical risk<br />
assessment score can be useful in deciding on time and duration of VTE prophylaxis<br />
and treatment. Prophylactic treatment in <strong>the</strong> ambulatory cancer patient needs to be<br />
discussed as newer anticoagulants like ultra low molecular weight heparin have been<br />
used recently in clinical trials and o<strong>the</strong>r novel agents (dabigatran, rivaroxaban and<br />
apixaban) marketed for orthopedic surgery and atrial fibrillation have become<br />
routine. The latter drugs are given orally, have negligeable interference with o<strong>the</strong>r<br />
medications or with foodstuffs and do not need laboratory surveillance. Approval for<br />
market release in VTE <strong>the</strong>rapy in <strong>the</strong> general medical situation is pending and will<br />
certainly be used in <strong>the</strong> oncological setting if cost compatible. Various guidelines<br />
(<strong>ESMO</strong>, ASCO, NCCN …) are concurrent in <strong>the</strong>ir recommendations depending on<br />
disease activity, anti-cancer treatments (surgery, chemo<strong>the</strong>rapy …) and <strong>the</strong> patient’s<br />
clinical situation. These will be discussed in regards to <strong>the</strong> ambulatory and<br />
hospitalized patient, for first episode and for recurrent VTE. Some data are available<br />
though not presently recommended, for anticoagulant <strong>the</strong>rapy in oncology for<br />
improving survival.<br />
Disclosure: The author has declared no conflicts of interest.<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
<strong>ESMO</strong>-ASCO Joint Symposium:<br />
Genomics in breast cancer: Opening<br />
new doors<br />
99IN NEXT GENERATION DNA SEQUENCING: FIRST RESULTS IN<br />
BREAST CANCER<br />
P. Campbell<br />
Cancer Genome Project, Wellcome Trust Sanger Institute, Cambridge, UNITED<br />
KINGDOM<br />
Cancer is driven by mutation. Using massively parallel sequencing technology, we<br />
can now sequence <strong>the</strong> entire genome of cancer samples, allowing <strong>the</strong> generation of<br />
comprehensive catalogues of somatic mutations of all classes. Bespoke algorithms<br />
have been developed to identify somatically acquired point mutations, copy number<br />
changes and genomic rearrangements, which require extensive validation by<br />
confirmatory testing. The findings from our first handful of breast cancer genomes<br />
illustrate <strong>the</strong> potential for next-generation sequencing to provide unprecedented<br />
insights into mutational processes, cellular repair pathways and gene networks<br />
associated with cancer development. I will also review possible applications of <strong>the</strong>se<br />
technologies in a diagnostic and clinical setting, and <strong>the</strong> potential routes for<br />
translation.<br />
Disclosure: The author has declared no conflicts of interest.<br />
100IN GENE EXPRESSION PROFILING OF BREAST CANCER: PAST<br />
AND FUTURE<br />
C. Sotiriou, D. Fumagalli<br />
Breast Cancer Translational Research Laboratory, Institute Jules Bordet,<br />
Brussels, BELGIUM<br />
It is intuitive that a high-throughput technology able to define <strong>the</strong> expression<br />
level of thousands of genes at once is more suited to investigate <strong>the</strong> complexity<br />
of cancer compared to <strong>the</strong> evaluation of single genes’ expression. This explains<br />
why <strong>the</strong> advent of microarray technology has had a profound impact on <strong>the</strong> way<br />
<strong>the</strong> nature and <strong>the</strong> clinical evolution of breast cancer (BC) are now perceived<br />
and investigated. Several studies have demonstrated that BC consists of different<br />
diseases with specific molecular profiles and clinical behaviors that can help<br />
selecting patients for enrollment in clinical trials and orienting <strong>the</strong>rapeutic<br />
approaches. Microarrays have also been used to identify gene expression<br />
signatures (GS) with a prognostic and/or predictive value. After a wave of “first<br />
generation signatures” mostly based on <strong>the</strong> ability of proliferation to discriminate<br />
which patients can be spared aggressive treatments, signatures of “second<br />
generation” have explored <strong>the</strong> prognostic value of gene related to immune<br />
response and stromal compartment. Multigene classifiers have also been<br />
developed to predict response to ei<strong>the</strong>r generic or specific endocrino- or<br />
chemo<strong>the</strong>rapies. Despite <strong>the</strong> reliability of microarray technology has been<br />
demonstrated, <strong>the</strong> clinical implementation of GS is still limited mostly in relation<br />
to <strong>the</strong> uncertainty of <strong>the</strong>ir added value compared to standard<br />
clinical-pathological factors. While <strong>the</strong> results of two big randomized trials will<br />
help establishing <strong>the</strong> clinical role of <strong>the</strong>se GS, <strong>the</strong> evolution of molecular<br />
technologies is setting <strong>the</strong> stage for a new interpreter. Next generation<br />
sequencing technologies are in fact providing an incredible amount of data that<br />
is revealing new insight in <strong>the</strong> complexity of BC nature and evolution. When<br />
compared to microarrays, <strong>the</strong> ability of RNA sequencing to quantify <strong>the</strong> level of<br />
expression of genes seems to be highly correlated for both single genes and gene<br />
signatures. Moreover, RNA sequencing has <strong>the</strong> advantage of identifying<br />
additional molecular events such as editing, which can have a major impact on<br />
cancer evolution. Even if more data are needed to set <strong>the</strong> role of this technology,<br />
RNA sequencing holds <strong>the</strong> potential to complement and increase <strong>the</strong> knowledge<br />
acquired so far with microarrays.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology 23 (Supplement 9): ix57, <strong>2012</strong><br />
doi:10.1093/annonc/mds481<br />
101IN PUTTING GENOMICS INTO CLINICAL PRACTICE<br />
A.M. Gonzalez-Angulo<br />
Department of Breast Medical Oncology and Dept. of System Biology, The<br />
University of Texas, Houston, TX, UNITED STATES OF AMERICA<br />
Over <strong>the</strong> last decade we have seen advances in breast cancer including <strong>the</strong> realization<br />
that breast cancer is not a homogenous disease but ra<strong>the</strong>r a conglomeration of a<br />
number of subtypes including luminal A, luminal B, HER2 enriched and basal like<br />
subtypes; each associated with a different prognostic outcome. The development of<br />
high-throughput techniques such as gene expression profiling platforms that are able<br />
to not only predict prognostic outcome but also, as <strong>the</strong> data indicate, predict for<br />
responsiveness to chemo<strong>the</strong>rapy and thus being able to identify groups who may not<br />
require chemo<strong>the</strong>rapy. Such data led to <strong>the</strong> endorsement for <strong>the</strong> use of Oncotype DX<br />
RS by ASCO and NCCN as both a prediction and prognostic tool among women with<br />
estrogen receptor-positive node negative breast cancer. The two prototypes that have<br />
<strong>the</strong> most clinical data reported and are being evaluated in prospective clinical trials are<br />
MammaPrint (Agendia, Inc., Amsterdam, The Ne<strong>the</strong>rlands) and Oncotype DX<br />
(Genomic Health, Inc., Santa Clara, CA). However <strong>the</strong> question remains as to whe<strong>the</strong>r<br />
such tools would be useful among women with node-positive disease. Women with<br />
node-positive disease have traditionally been considered to be at highest risk of<br />
recurrence. However, multigene assays may be able to identify a group of women with<br />
endocrine responsive, node positive disease that may not require chemo<strong>the</strong>rapy thus<br />
avoiding <strong>the</strong> associated toxicities. Prospective trials will be essential to accurately<br />
identify <strong>the</strong> groups that will and will not benefit from chemo<strong>the</strong>rapy. Until results of<br />
such studies are available <strong>the</strong> current guidelines still endorse <strong>the</strong> use of adjuvant<br />
chemo<strong>the</strong>rapy among all women with node positive disease.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
102IN WHOLE GENOME SEQUENCING FOR LUMINAL-TYPE<br />
BREAST CANCER<br />
M.J. Ellis<br />
Siteman Cancer Center Breast Cancer Program, Washington University School<br />
of Medicine, St Louis, MO, UNITED STATES OF AMERICA<br />
Whole genome sequencing is an unbiased approach to detect all classes of somatic<br />
mutation in a cancer. To correlate <strong>the</strong> variable clinical features of<br />
oestrogen-receptor-positive breast cancer with somatic alterations, we applied this<br />
technique to pre-treatment tumour biopsies accrued from patients in two studies of<br />
neoadjuvant aromatase inhibitor <strong>the</strong>rapy. Eighteen significantly mutated genes were<br />
identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously<br />
linked to haematopoietic disorders. These findings suggest that breast cancer, like<br />
leukaemia, can be viewed as a stem-cell disorder that produces indolent or aggressive<br />
tumours that display varying phenotypes depending on differentiation blocks<br />
generated by different mutation repertoires. Mutant MAP3K1 was associated with<br />
luminal A status, low grade histology and low proliferation rates, whereas mutant<br />
TP53 associated with <strong>the</strong> opposite pattern. Moreover, mutant GATA3 correlated with<br />
suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis<br />
demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar<br />
perturbations as MAP3K1 loss. These analyses also identified transcriptional<br />
associations to Ki67 response reside in a connected network under <strong>the</strong> control of<br />
several key ‘hub’ genes including MYC, FYN and MAP kinases, among o<strong>the</strong>rs.<br />
Targeting <strong>the</strong>se hubs in resistant tumours could produce <strong>the</strong>rapeutic advances. Aside<br />
from <strong>the</strong> common PIK3CA mutations, druggable mutations were relatively<br />
uncommon, but were observed in HER2, KIT, PDGFA, DDR1/2, MET, JAK1,<br />
CSFR1, LTK, BRAF and AKT1/2. If <strong>the</strong>se mutations are activating and drug sensitive<br />
<strong>the</strong>se are significant findings since breast cancer is so common that drug sensitizing<br />
mutations with a 1% prevalence represents a population with a similar magnitude to<br />
CML and PML, diseases in which a randomized trials are feasible. Distinct<br />
phenotypes in oestrogen-receptor-positive breast cancer are associated with specific<br />
patterns of somatic mutations that map into cellular pathways linked to tumour<br />
biology, but most recurrent mutations are relatively infrequent. Prospective clinical<br />
trials based on <strong>the</strong>se findings will require comprehensive genome sequencing and<br />
large mutation screening programs.<br />
Disclosure: The author has declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds481 | ix57
<strong>ESMO</strong>-CSCO Joint Symposium:<br />
Building <strong>the</strong> clinical trials of <strong>the</strong> future<br />
103IN IS THE NEOADJUVANT MODEL AN ACCELERATED PATH<br />
TOWARDS BREAST CANCER TREATMENT TAILORING?<br />
EXPERIENCE OF THE NEOALTTO TRIAL<br />
M. Piccart 1 , H.A. Azim, Jr 2<br />
1 Head of The Chemo<strong>the</strong>rapy Department, Jules Bordet Institute, Brussels,<br />
BELGIUM, 2 Breast Cancer Translational Research Laboratory, Institute Jules<br />
Bordet, Brussels, BELGIUM<br />
Around 5% of oncology agents in <strong>the</strong> development pipeline receive regulatory<br />
approval. This procedure is very long and expensive, which results in delaying <strong>the</strong><br />
availability of effective <strong>the</strong>rapies to patients. Fur<strong>the</strong>rmore, one available, <strong>the</strong>y are<br />
provided at a considerably high cost to compensate for <strong>the</strong> exhaustive development<br />
process. What is more frustrating is that after such a process we still have a crude<br />
idea on <strong>the</strong> subsets of patients who will “truly” benefit a given agent. Hence, <strong>the</strong>re is<br />
a need to adopt innovative strategies to accelerate drug development in a more<br />
efficient and targeted way. In breast cancer (BC), <strong>the</strong> neoadjuvant setting emerge as<br />
an excellent opportunity to incorporate biomarkers within <strong>the</strong> drug development<br />
process, taking <strong>the</strong> advent of <strong>the</strong> presence of a robust short term surrogate endpoint,<br />
like pathological complete response (pCR). It also allows interrogating <strong>the</strong> effect of<br />
novel <strong>the</strong>rapies on BC biology, via <strong>the</strong> collection of samples pre and post <strong>the</strong>rapy.<br />
These advantages would help in accelerating drug and biomarker development via<br />
<strong>the</strong> conduction of trials that are relatively small in size and short in duration. This<br />
would possibly have a positive impact on <strong>the</strong> health-care economics dimension as<br />
well. NeoALTTO is a phase 3 trial, which included 455 patients with HER2-positive<br />
non-metastatic BC. Patients randomized to lapatinib and trastuzumab in<br />
combination with paclitaxel had nearly double <strong>the</strong> pCR rate compared to those<br />
randomized to paclitaxel with ei<strong>the</strong>r drug alone. A similar trial but in <strong>the</strong> adjuvant<br />
setting (ALTTO) including nearly 8,000 patients has recently completed accrual. If<br />
<strong>the</strong> higher pCR rate in <strong>the</strong> NeoALLTO trial translated into improved long term<br />
outcome and this was confirmed in ALTTO, this could represent an important<br />
milestone in <strong>the</strong> way we develop targeted agents in BC, and hence conducting huge<br />
trials like ALTTO might not be needed in <strong>the</strong> future. The NeoALTTO trial also had<br />
an extensive translational research and molecular imaging programs with <strong>the</strong>ir results<br />
expected to be available very soon. It is fascinating to see <strong>the</strong> tremendous amount of<br />
information that can be generated and <strong>the</strong> possible impact this might have on patient<br />
care, with a study that included less than 500 patients. Hence, this model encourages<br />
<strong>the</strong> adoption of <strong>the</strong> neoadjuvant setting in investigating novel agents/treatment<br />
strategies, which could represent a smart, fast and cheap way in obtaining regulatory<br />
approval of effective agents.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
104IN CHINA’S EXPERIENCE IN JOINING THE LARGE ADJUVANT<br />
ALTTO TRIAL<br />
Z.F. Jiang<br />
307 Hospital Amms China, Beijing, CHINA<br />
The ALTTO study is a randomized, open label multi-center phase III study<br />
comparing <strong>the</strong> activity of lapatinib alone versus trastuzumab alone versus<br />
trastuzumab followed by lapatinib versus lapatinib concomitantly with trastuzumab<br />
in <strong>the</strong> adjuvant treatment of patients with ErbB2 overexpressing and/or amplified<br />
breast cancer. Patients will be enrolled according to one of two design schemas and<br />
will be randomized to one of four treatment regimens within each design schema.<br />
The primary objective of this study is to compare disease-free survival (DFS) in each<br />
treatment regimen. There were 5 sites in China which participated in <strong>the</strong> ALTTO<br />
study. From March 2008 to April 2010, a total of 441 patients were randomized to<br />
one of four treatment regimens within two design schemas (Design 2B was not<br />
applicable in China). The table shows 100 patients from our cancer center.<br />
Disclosure: The author has declared no conflicts of interest.<br />
Group Number Withdraw* Recurrence<br />
Trastuzumab alone 26 1 3<br />
Lapatinib alone ** 23 2 0<br />
Lapatinib + Trastuzumab ** * 25 2 0<br />
Trastuzumab → Lapatinib 26 0 0<br />
• * 3 subjects due to AE, 2 subject due to Personal reason • ** 2 subjects transfer to<br />
Trastuzumab alone <strong>the</strong>rapy due to AE • ** * 1subjects transfer to Trastuzumab alone<br />
<strong>the</strong>rapy due to AE All <strong>the</strong> subjects in China have finished study treatment and are<br />
now in follow up.<br />
105IN LUNG CANCER: THE EUROPEAN THORACIC ONCOLOGY<br />
PLATFORM<br />
R.A. Stahel<br />
Labor für Molekulare Onkologie, Universitätsspital, Zurich, SWITZERLAND<br />
The European Thoracic Oncology Platform (ETOP) is a foundation with <strong>the</strong> purpose to<br />
promote exchange and research in <strong>the</strong> field of thoracic malignancies. It was founded in<br />
2009 and continuous to enlarged its membership to now comprise more than 40 members,<br />
including groups and institutions from most parts of Europe, as well as one large cancer<br />
center in <strong>the</strong> USA and China, respectively (www.etop-eu.org). ETOP promotes exchange of<br />
information and research. This is done be an active web-site, a yearly ETOP meeting for<br />
associated members and <strong>the</strong>ir investigators, and by a residential workshop aimed at<br />
fostering <strong>the</strong> research activity of younger investigators. Lungscape is a large translational<br />
research project designed by ETOP. It aims to coordinating <strong>the</strong> research of a group of lung<br />
cancer specialists working in translational research across Europe. This initiative has <strong>the</strong><br />
potential to facilitate more rapid translation of biomarker knowledge to <strong>the</strong> clinic.<br />
Lungscape is evolving in step-wise fashion, starting with a retrospective analysis of up to<br />
2400 completely resected NSCLC from 16 institutions. The fundamental approach of<br />
Lungscape was to build a decentralized iBiobank of samples from lung cancer patients with<br />
annotated clinical and pathological data and at least three years of documented follow-up.<br />
The virtual nature of iBiobank and <strong>the</strong> introduction of standardized biomolecular<br />
assessments - in which samples are tested using identical protocols across local<br />
laboratories- removes <strong>the</strong> need of transferring samples to a central location for evaluation.<br />
ETOP has also initiated two clinical trials with biomarker components. BELIEF is phase II<br />
trial with erlotinib and bevacizumab for patients with non-squamous cell lung cancer and<br />
activating EGFR mutation stratified by <strong>the</strong> presence of T790M mutation as determined<br />
centrally by a very sensitive methodology. This is done on preclinical evidence suggestion<br />
synergy between EGFR TKI and antiangiogenetic <strong>the</strong>rapy for tumors in case of activating<br />
mutation and <strong>the</strong> presence of T790M. The EMPHASIS lung is a phase III trial comparing<br />
erlotinib and docetaxel in second line for squamous cell lung cancer. The study will allow<br />
determining <strong>the</strong> predictive role of a serum proteomic classifier called VeriStrat for a<br />
beneficial effect of erlotinib. O<strong>the</strong>r trials are in preparation.<br />
Disclosure: The author has declared no conflicts of interest.<br />
106IN LUNG CANCER ASIA STUDY GROUP EAST<br />
Y. Wu<br />
Guangdong Lung Cancer Institute, Guangdong General Hospital (GGH) &<br />
Guangdong Academy of Medical Sciences, Guangzhou, CHINA<br />
Over <strong>the</strong> past 10 years, <strong>the</strong>re have been significant advances in clinical trials and<br />
translation research on lung cancer in China. The significant event was <strong>the</strong> discovery of<br />
EGFR mutation in 2004. The first international clinical trial involved in Chinese<br />
investigators was INTERESTIN that compared gefitinib with docetacel in second lint<br />
treatment for advanced NSCLC. The most important international trial in China was<br />
IPASS. Sixteen centers from China contributed 31% cases (372/1217). On <strong>the</strong> above basis<br />
<strong>the</strong> Chinese Thoracic Oncology Group (CTONG) was found in 2007. CTONG’s mission<br />
is to design and develop multicenter clinical trials and provide a high level of evidence<br />
for clinical practice. Now <strong>the</strong> CTONG has 23 active centers. There are more 10 thousand<br />
new lung cancer cases per year in CTONG centers.<br />
As <strong>the</strong> first national cooperative group CTONG has led some important trials that had<br />
changed clinical practice. CTONG 0802 (OPTIMAL) established <strong>the</strong> role of erlotinib in<br />
first line setting for patients with advanced NSCLC and EGFR mutation. Its results have<br />
helped to register erlotinib as first-line <strong>the</strong>rapy in China and Europe. The CTONG 0804<br />
(INFORM) is <strong>the</strong> first maintenance study on gefitinib, and published on Lancet Oncology.<br />
The table lists <strong>the</strong> ongoing CTONG studies that focus on biomarker driven clinical trials.<br />
CTONG trials focusing on biomarkers.<br />
Annals of Oncology 23 (Supplement 9): ix58, <strong>2012</strong><br />
doi:10.1093/annonc/mds482<br />
Study number<br />
NCT<br />
number Title Status<br />
CTONG 0806 00891579 Pemetrexed versus Gefitinib in Patients with<br />
EGFR wild type and metastatic NSCLC who<br />
failure to platinum-based chemo<strong>the</strong>rapy<br />
Recruiting<br />
CTONG 0901 01024413 Erlotinib versus Gefitinib in Advanced NSCLC<br />
with Exon 19 or 21 Mutations<br />
Recruiting<br />
CTONG 1002 01236716 Nab-Paclitaxel Treatment in Advanced Recruiting<br />
Squamous Cell Carcinoma of <strong>the</strong> Lung<br />
CTONG 1103 01407822 Erlotinib versus chemo<strong>the</strong>rapy as neoadjuvants<br />
in IIIA-N2 NSCLC with EGFR mutations in<br />
Exon 19 or 21 (EMERGING)<br />
CTONG 1104 01405079 Gefitinib versus Vinorelbine/Platinum as<br />
adjuvant treatments in Stage II-IIIA<br />
(N1-N2) NSCLC with EGFR Mutations<br />
(ADJUVANT)<br />
Recruiting<br />
Recruiting<br />
Chinese investigators are also very active in molecular biomarker researches. The<br />
tumor bank of lung cancer with more 4000 sample was set up. Extensive translational<br />
works on EGFR mutations including EGFR heterogeneity and mutation profile on<br />
lung adenocarcinoma were investigated. More high-quality translational research is<br />
expected in <strong>the</strong> future.<br />
Disclosure: The author has declared no conflicts of interest.<br />
ix58 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
<strong>ESMO</strong>-EACR Joint Symposium:<br />
Targeted <strong>the</strong>rapies: Promises,<br />
successes and failures<br />
107IN HARNESSING CELLULAR SENESCENCE FOR CANCER<br />
PREVENTION AND THERAPY<br />
P.P. Pandolfi<br />
Medicine, BIDMC/Harvard Medical School, Boston, MA, UNITED STATES OF<br />
AMERICA<br />
We will present exciting new progress at developing what we regard as a new<br />
concept, which we refer to as “pro-senescence <strong>the</strong>rapy”, that aims at utilizing cellular<br />
senescence, a built-in failsafe mechanism in mammalian cell evoked by oncogenic<br />
stress, for cancer prevention and treatment.<br />
We will discuss how this analysis allowed us to identify novel and <strong>the</strong>rapeutically<br />
relevant molecular and biological types of cellular senescence that can be evoked and<br />
potentiated pharmacologically, in turn allowing <strong>the</strong> targeting of cancer stem cells as<br />
well as <strong>the</strong> “quiescent” cancer stem cell pool for <strong>the</strong>rapy.<br />
We will analyze how <strong>the</strong>se new concepts emerged from our analysis and systematic<br />
deconstruction of <strong>the</strong> molecular genetics of human cancer as studied in vivo in<br />
faithful mouse models, with particular emphasis on <strong>the</strong> role of aberrant PTEN/PI3K/<br />
AKT/mTOR signaling in tumorigenesis.<br />
Disclosure: The author has declared no conflicts of interest.<br />
108IN PI3K AND/OR MTOR INHIBITORS: CURRENT STATUS,<br />
FUTURE DIRECTIONS<br />
S. Loi<br />
Breast International Group (BIG), Institute Jules Bordet, Brussels, BELGIUM<br />
The high incidence of molecular aberrations that target <strong>the</strong> phosphatidylinositol-3<br />
kinase (PI3K) pathway in cancer, as well as <strong>the</strong> demonstration that many resistance<br />
mechanisms to drugs also involve this pathway, has unsurprisingly led to high<br />
interest in <strong>the</strong> development of agents to inhibit PI3K signaling. Currently, many<br />
PI3K targeted agents are in phase I/II testing, alone and in combination with<br />
agents that are usual standard of care as well as those that target potential<br />
resistance pathways such as MEK/ERK. Some agents are about to commence phase<br />
III evaluation. Thus far in phase I, <strong>the</strong>re have been signs of activity in <strong>the</strong> advanced<br />
setting for multiple tumor types but surprisingly yet no strong association with<br />
PI3K pathway aberrations such as PIK3CA mutations have been seen. Toxicities<br />
have been reasonably predictable and on-target, including hyperglycaemia,<br />
diarrhea, skin rash, nausea, fatigue and transaminitis Issues that are currently<br />
critical for optimal development in this field are: 1. understanding of who will<br />
benefit- thus far <strong>the</strong> relationship between PIK3CA, AKT1 mutations, PTEN loss<br />
and response to PI3K inhibitors has been not as clear as o<strong>the</strong>r targets such as<br />
BRAF mutants, EML4-ALK rearrangements and HER2 amplification. Activity has<br />
also been observed in genetically unselected cancer populations, though toxicity<br />
may preclude its acceptance in unselected populations if large and meaningful<br />
benefit cannot be shown; 2. Understanding <strong>the</strong> role of dual versus single versus<br />
isotype specific compounds- this may also depend on <strong>the</strong> genetic aberration and<br />
clinical setting; 3. prospective upfront stratification and power to look at mutated<br />
(as well as wild-type) subsets, particularly in early phase clinical trials;<br />
4. Determining rationale combinations with PI3K targeted <strong>the</strong>rapy, which will<br />
undoubtedly depend on <strong>the</strong> setting and cancer type. Addressing <strong>the</strong>se issues, along<br />
with adequate genotyping of <strong>the</strong> tumor, will ensure that we get a clear picture of<br />
<strong>the</strong> molecular background of which patients, tumor types and clinical setting<br />
benefits.<br />
Disclosure: The author has declared no conflicts of interest.<br />
109IN CANCER: AN ANGIOGENIC DISEASE?<br />
Annals of Oncology 23 (Supplement 9): ix59, <strong>2012</strong><br />
doi:10.1093/annonc/mds483<br />
M. Neeman<br />
Faculty of Biology, Weizmann Institute of Science, Rehovot, ISRAEL<br />
The angiogenic switch proposed by Folkman provided a compelling <strong>the</strong>ory for <strong>the</strong> well<br />
recognized phenomenon of tumor dormancy, where tumors show prolonged growth<br />
arrest and remain as microscopic nodules, sometimes for decades before converting into<br />
rapidly progressing cancer. At <strong>the</strong> basis of this <strong>the</strong>ory is <strong>the</strong> idea that diffusion of<br />
nutrients limits growth to a few cell layers, and perfusion, via sprouting of new blood<br />
vessels is required for sustained progression. Hypoxia was recognized as a potent<br />
microenvironmental stimulator of angiogenesis. Hypoxia stabilizes HIF1 alpha resulting<br />
in induced expression of VEGF, a potent vascular permeability factor and <strong>the</strong> central<br />
inducer of angiogenesis. Hypoxia, which affects genetic instability and selection for cells<br />
resistant to apoptosis, is thus also tightly linked with angiogenesis. Angiogenesis,<br />
induced by VEGF is accompanied by rapid elevation of vascular permeability. This<br />
acute effect of VEGF affects tumors in many ways. Extravasated plasma proteins result in<br />
extensive ECM remodeling to form a reactive stroma which supports Inflammation and<br />
tumor cell invasion. Elevated permeability enhances interstitial fluid pressure, limiting<br />
drug delivery. On <strong>the</strong> o<strong>the</strong>r hand, elevated vascular permeability provides thus far one of<br />
<strong>the</strong> most sensitive means for rapid detection and non invasive monitoring of cancer, as<br />
it results in accumulation and retention of contrast media and tumor enhancement on<br />
MRI and CT scans. Angiogenesis provides tumor cells with routes for metastatic spread<br />
to <strong>the</strong> blood circulation, and provide also <strong>the</strong> pressure gradient which drives interstitial<br />
fluid pressure and lymphatic drain and <strong>the</strong>reby facilitates colonization of sentinel lymph<br />
nodes. Despite <strong>the</strong> very strong support for <strong>the</strong> tight association of tumor progression<br />
with induction of angiogenesis, <strong>the</strong> experience with targeting angiogenesis in cancer<br />
<strong>the</strong>rapy has been relatively disappointing, and antiangiogenic <strong>the</strong>rapy is so far nor <strong>the</strong><br />
magic bullet as hoped. Thus clearly it is important to study <strong>the</strong> mechanisms by which<br />
tumors escape from antiangiogenic <strong>the</strong>rapy.<br />
Disclosure: The author has declared no conflicts of interest.<br />
110IN ANTIANGIOGENIC THERAPIES IN THE CLINIC: A<br />
DOUBLE-EDGED SWORD?<br />
D. Miles<br />
Medical Oncology, Mount Vernon Cancer Center, Northwood, UNITED<br />
KINGDOM<br />
Despite <strong>the</strong> initial promise originally proposed by Judah Folkman and o<strong>the</strong>rs,<br />
strategies aimed at tumour vasculature have met with variable success in <strong>the</strong> clinic.<br />
Antibodies and tyrosine kinase inhibitors targeting Vascular Endo<strong>the</strong>lial Growth<br />
Factor (VEGF) are among <strong>the</strong> most highly developed agents targeting angiogenesis.<br />
In indications such as renal cell cancer, where alterations in VEGF are regarded as<br />
<strong>the</strong> principle oncogenic driver, VEGF inhibition has lead to clinically meaningful<br />
improvements in progression-free and overall survival. In more common epi<strong>the</strong>lial<br />
malignancies, <strong>the</strong> efficacy VEGF inhibition has been more modest, possibly as a<br />
consequence of redundancy in <strong>the</strong> angiogenic process. The inherent complexity of<br />
<strong>the</strong> angiogenic response has also made it difficult to identify markers of efficacy, with<br />
a myriad of DNA, serological and dynamic (imaging) metrics being implicated in<br />
prognosis as well as prediction of treatment efficacy and toxicity, e.g., a<br />
second-generation assay of plasma VEGF appears to be of predictive benefit in a<br />
retrospective analysis of two studies in metastatic breast cancer and its use is being<br />
tested prospectively. The controversy surrounding <strong>the</strong> use of anti-angiogenic<br />
approaches in terms of efficacy and regulatory considerations, underscores <strong>the</strong><br />
challenges in <strong>the</strong>ir development: e.g., simple clinical observations that in<br />
malignancies with a relatively long natural history, attributable alterations in<br />
progression-free survival are unlikely to be a surrogate for overall survival. Similarly,<br />
while <strong>the</strong> available data for <strong>the</strong> use of anti-angiogenic agents in <strong>the</strong> adjuvant<br />
treatment of cancer is clearly disappointing it is not perhaps surprising, given <strong>the</strong><br />
likely lack of VEGF dependency of what we understand to be micro-metastatic<br />
disease. A clearer understanding of angiogenesis and its modulation will enable<br />
fur<strong>the</strong>r rational development of this important modality.<br />
Disclosure: The author has declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds483 | ix59
<strong>ESMO</strong>-EANM-ESR Joint Symposium:<br />
Imaging biomarkers in <strong>the</strong> era of<br />
targeted <strong>the</strong>rapies<br />
111IN STATISTICIAN – THE BASIS OF RECIST1.1<br />
J. Bogaerts<br />
Statistics Dept, EORTC, Brussels, BELGIUM<br />
Since its first publication in 2000 (Therasse et al., JNCI 2000) RECIST has become a<br />
widely applied method to assess solid tumor response and tumor progression.<br />
Advantages include its relative simplicity, <strong>the</strong> assurance that comparisons between trials<br />
can be reasonably applied, and <strong>the</strong> acceptance of its use in submitted data by regulators.<br />
Disadvantages include <strong>the</strong> difficulty to apply it in several tumor types and <strong>the</strong> generality<br />
of <strong>the</strong> method which does not have tumor type dependent adjustments.<br />
In 2009 (Eisenhauer et al, EJC 2009) version 1.1 of RECIST was published, with as key<br />
updates <strong>the</strong> restriction of <strong>the</strong> number of targets to a maximum of five, special<br />
considerations for lymph nodes, a minimum increase in <strong>the</strong> sum of target diameters by<br />
5 mm as an added requirement for progressive disease and a host of fur<strong>the</strong>r<br />
specifications and clarifications. A first limited inclusion of FDG-PET data was also<br />
made, but still requiring CT scan confirmation.<br />
Today work on RECIST continues, with extensive statistical analysis ongoing on <strong>the</strong> existing<br />
EORTC RECIST database, as well as efforts to collect FDG-PET data for evaluation of<br />
FDG-PET into <strong>the</strong> methodology. An overview of this work will be presented. Also, many<br />
questions exist in <strong>the</strong> community that may all have an impact on how RECIST should be<br />
modified: 3D imaging, <strong>the</strong> relatively new phenomenon of flare progression caused by some<br />
drugs, <strong>the</strong> extensive use of (RECIST based) progression free survival as a Phase III primary<br />
endpoint, <strong>the</strong> use of some new drugs beyond progression and <strong>the</strong> multitude of various<br />
imaging techniques in various stages of development.<br />
We will also report on <strong>the</strong> outcomes of an ongoing survey that queries <strong>the</strong> community for<br />
what are seen as <strong>the</strong> most important items to be addressed by future versions of RECIST.<br />
Disclosure: The author has declared no conflicts of interest.<br />
112IN RADIOLOGIST - HOW TO PERFORM CORRECT RECIST<br />
ASSESSMENT (CLINICAL TALK)<br />
Y. Menu<br />
Department of Radiology, Saint Antoine Hospital, Paris, FRANCE<br />
RECIST is a universal standard in tumour response evaluation. Therefore, it is of utmost<br />
importance that imaging technique and radiological reports are compliant with <strong>the</strong><br />
recommendation. Advantages of standardization comprise <strong>the</strong> comparability of different<br />
examinations in <strong>the</strong> same patient, and responses in a cohort. Precise definition of<br />
response or progression makes possible to evaluate <strong>the</strong> accuracy of a specific treatment.<br />
Ano<strong>the</strong>r advantage is that structured reporting is easier to perform, improving efficiency<br />
and communication. Technical requirements are important though easily achievable:<br />
slice thickness of 5 mm or less reconstructed in <strong>the</strong> axial plane, contiguous slices (on CT,<br />
minimal gap on MRI), robust and reproducible contrast injection with similar delay and<br />
injection rate, similar coverage ensure proper comparison of images and clear basis for<br />
decision making. Thinner slices, alternative planes, specific contrast media and/or<br />
customized MRI sequences are optional, and should not replace basic techniques.<br />
Interpretation of baseline images requires a perfect knowledge of <strong>the</strong> method for<br />
measurement of <strong>the</strong> largest diameter, identification of targets and non targets.<br />
Interpretation of evaluation examinations needs iterative comparison with Baseline and<br />
Nadir examinations, and identification of unequivocal new lesions. Obviously, a universal<br />
standard does not fit all oncology cases. It appears that some tumours like GIST or HCC<br />
may need adapted criteria in addition to RECIST. PET is only mildly included among<br />
<strong>the</strong> criteria, although it proves to be an important method for evaluation. Finally,<br />
morphology does not summarize tumour biology. Besides RECIST, <strong>the</strong> addition of<br />
structural, metabolic and/or functional information would be desirable.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
113IN ONCOLOGIC IMAGING <strong>2012</strong>: FROM MORPHOLOGY TO<br />
FUNCTION<br />
A. Graser<br />
Head of Oncologic Imaging, University of Munich, Munich, GERMANY<br />
Purpose: To demonstrate new trends and developments in oncologic imaging in <strong>2012</strong>.<br />
To show how functional imaging influences treatment decisions in patients with<br />
malignancy.<br />
Summary: In oncologic patients, imaging is <strong>the</strong> most important biomarker determining<br />
<strong>the</strong> stage and spread of disease as well as treatment success. Novel targeted <strong>the</strong>rapies lead<br />
to delayed or absent changes in size of tumors and metastatic lesions. New strategies in<br />
imaging are needed to depict treatment effects with respect to lesion vascularity and<br />
vessel density. Functional imaging tests aim at <strong>the</strong> determination of <strong>the</strong>se changes ra<strong>the</strong>r<br />
than at <strong>the</strong> depiction of morphologic alterations of lesions. Modalities used for<br />
functional imaging include time-resolved perfusion CT, dual energy CT, diffusion<br />
weighted MRI and perfusion MRI. To date, only few studies investigate <strong>the</strong> usefulness of<br />
Annals of Oncology 23 (Supplement 9): ix60, <strong>2012</strong><br />
doi:10.1093/annonc/mds484<br />
<strong>the</strong>se tests in patients on targeted <strong>the</strong>rapies. This presentation will feature information on<br />
<strong>the</strong> technical background of functional CT and MRI and assess <strong>the</strong>ir use in patients that<br />
are treated with antiangiogenic drugs. Both animal and human studies will be presented<br />
and <strong>the</strong> importance of early response imaging will be highlighted. The role of radiology<br />
as essential link between different medical fields becomes more and more important in<br />
<strong>the</strong> era of personalized medicine, and radiologists, nuclear medicine physicians, and<br />
oncologists have to be aware of specific imaging characteristics of findings in functional<br />
imaging tests.This presentation will include methodological and educational content as<br />
well as interesting case studies highlighting <strong>the</strong> importance of <strong>the</strong> most advanced<br />
imaging strategies to aid treatment decisions.<br />
Disclosure: A. Graser: Disclosures: Speaker’s Bureau, Siemens Healthcare and Bayer<br />
Healthcare<br />
114IN MOLECULAR IMAGING WITH PET/CT: FDG AND BEYOND<br />
S. Fanti<br />
Department of Nuclear Medicine, University of Bologna, Bologna, ITALY<br />
Molecular imaging has rapidly acquired importance for <strong>the</strong> evaluation of cancer patients,<br />
being complementary to conventional imaging methods as CT, MR and US. Among<br />
molecular imaging procedures, Positron Emission Tomography (PET) is <strong>the</strong> most diffuse<br />
and rapidly growing, and at present it is routinely used in patients affected by a large<br />
variety of malignant neoplastic diseases. Many papers in <strong>the</strong> literature have already<br />
demonstrated <strong>the</strong> utility of this imaging technique whose capabilities have been<br />
fur<strong>the</strong>rmore developed by <strong>the</strong> introduction of hybrid scanners, particularly PET-CT. The<br />
combination of functional data (given by PET) and anatomic details (provided by CT)<br />
allows to significantly increase diagnostic accuracy, essentially due to a better specificity.<br />
The usefulness of PET relies on its capability of investigating molecular processes by<br />
means of specific radiotracers, with <strong>the</strong> most employed being 18F-DeoxyGlucose (FDG).<br />
FDG PET scans give important information about tissues glucose consumption, usually<br />
very increased in <strong>the</strong> great majority of solid malignancies. A number of indications for<br />
PET use in clinical oncology have already been validated. Main indications are:<br />
characterization of uncertain lesions; staging; early evaluation of response to <strong>the</strong>rapy;<br />
evaluation of residual disease at <strong>the</strong>rapy completion and identification of relapse during<br />
follow-up.<br />
Despite FDG scans represent more than 90% of all PET scans, o<strong>the</strong>r positron emitter<br />
tracers are available and each one may be specific for different neoplastic diseases. In fact<br />
some malignancies do not show increase in glucose consumption and are almost<br />
invisible with FDG: <strong>the</strong>refore o<strong>the</strong>r tracers have been developed to study o<strong>the</strong>r metabolic<br />
pathways. Tracers already in clinical use include Choline (labeled with 11C or 18F), a<br />
marker of cell membrane metabolism particularly useful for prostate cancer detection;<br />
18F-Tyrosine and 11C-Methionine, which enable to study proteic metabolism and are<br />
successfully employed for CNS neoplastic diseases; 18F-DOPA and 68Ga-DOTA-NOC,<br />
useful in neuroendocrine tumors.<br />
Disclosure: The author has declared no conflicts of interest.<br />
115IN ADDRESSING CLINICAL CHALLENGES IN TARGETED<br />
THERAPIES WITH ADVANCED IMAGING<br />
W.J.G. Oyen<br />
Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre,<br />
Nijmegen, NETHERLANDS<br />
Advanced imaging techniques are being developed to provide information relevant for<br />
patient management beyond changes in tumor size. Treatment with novel targeted<br />
<strong>the</strong>rapies showed that conventional RECIST measurements are insufficient to assess<br />
response as changes in tumor size occur relatively late, if at all. It has been shown that<br />
molecular imaging techniques provide predictive and prognostic information at baseline<br />
or by comparing baseline scans to scans obtained very early after <strong>the</strong> start of treatment.<br />
It aims at <strong>the</strong> (very) early identification of responders before tumor shrinkage occurs, but<br />
also indicating a high likelihood of relapse even before tumor growth is apparent.<br />
Fur<strong>the</strong>rmore, molecular imaging with radiopharmaceuticals may aid in identifying<br />
receptor overexpression or pathway activation in tumors before treatment with targeted<br />
<strong>the</strong>rapies is initiated. The ability of FDG-PET to predict response of metastatic GIST to<br />
imatinib became <strong>the</strong> role model for <strong>the</strong> potential of molecular imaging to provide<br />
clinically relevant answers within days after <strong>the</strong> start of treatment. Since <strong>the</strong> introduction<br />
of integrated PET/CT <strong>the</strong> acceptance of <strong>the</strong> technology enormously increased. A large<br />
number of PET/CT studies was performed in patients treated with various targeted<br />
<strong>the</strong>rapies (both antibodies and TKIs) in a wide variety of tumor types with both FDG<br />
and o<strong>the</strong>r radiopharmaceuticals such as FLT, a marker of proliferation. Similary,<br />
advanced CT (perfusion) and MRI (dynamic MRI, DWI, MRS) techniques have taken<br />
advantage of <strong>the</strong> development of technology. Following <strong>the</strong> introduction of <strong>the</strong>rapeutic<br />
monoclonal antibodies such as bevacuzimab and trastuzumab, studies with <strong>the</strong><br />
radiolabeled derivatives have been used to image <strong>the</strong> tumor-associated factors and<br />
receptors, targeted by <strong>the</strong>se antibodies (immunoPET and immunoSPECT). It has been<br />
shown that this approach could successful visualize <strong>the</strong> antibody targets. More recently,<br />
small molecules (e.g. paclitaxel, lapatinib) have been radiolabeled and used in clinical<br />
studies. Following <strong>the</strong> numerous proof of principle and translational research studies, <strong>the</strong><br />
time has come time to develop <strong>the</strong> role of <strong>the</strong> advances towards evidence-based imaging<br />
in clinical practice by systematically positioning advanced imaging for treatment<br />
selection in clinical trials.<br />
Disclosure: The author has declared no conflicts of interest.<br />
ix60 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
<strong>ESMO</strong>-ESP Joint Symposium:<br />
Molecular diagnostics for personalized<br />
cancer treatment<br />
116IN NEXT GENERATION SEQUENCING IN THE CONTEXT OF<br />
CURRENT CLINICAL PRACTICE: IMPLEMENTATION AND<br />
CHALLENGES<br />
H. Morreau<br />
Leiden University Medical Center, Leiden, NETHERLANDS<br />
In <strong>the</strong> era of personalized medicine next generation sequencing (NGS) of normal<br />
and/or tumor DNA has already proven its value in <strong>the</strong> discovery phase of novel<br />
molecular defects associated with human disease. Different levels of information can<br />
be obtained from transcriptome sequencing, whole genome sequencing, exome<br />
sequencing, and sequencing of DNA enriched for methylated DNA. It is expected by<br />
many that soon <strong>the</strong> NGS sequencing will take its place in current clinical practice<br />
giving diagnostic, prognostic or predictive information. The complex biology<br />
underlying human disease is however now more and more surfacing. Already from<br />
<strong>the</strong> relatively simple tests using single biomarker sets, but now also from <strong>the</strong><br />
discovery phase NGS reports, it became clear that tumor heterogeneity is a major<br />
issue in clinical practice. Although some advocate that <strong>the</strong> solution should be to<br />
screen all metastasized lesions, obtaining those will be burdensome for patients. How<br />
to use such knowledge on heterogeneous DNA alterations in metastatic lesions for<br />
clinical decision making is also not so easily answered. In current clinical practice we<br />
see that with <strong>the</strong> success of neo-adjuvant <strong>the</strong>rapies for rectum-, esophagus-, stomach<br />
and breast cancers much of <strong>the</strong> molecular analyses should be done on limited<br />
material. With innovative methods, such as ultrasound guided trans-bronchial or<br />
trans- esophageal needle aspiration for staging of lung cancer combined with<br />
molecular analysis on very limited amounts of cancer cells, a similar trend can be<br />
seen. Although technical advances coming from e.g. single cell sequencing efforts can<br />
be applied it should be realized that such approaches can lead to diagnostic errors in<br />
true clinical practice. Therefore major quality assurance programs should be initiated<br />
before NGS can truly take its predicted role.<br />
Disclosure: The author has declared no conflicts of interest.<br />
117IN BIOMARKER DEVELOPMENT NEEDS TISSUE<br />
REPOSITORIES: NO HONEY WITHOUT BEES<br />
H. Lehr<br />
IUP Institut Universitaire de Pathologie de Lausanne, Lausanne, SWITZERLAND<br />
Pathologists have traditionally archived <strong>the</strong> tissues on which <strong>the</strong>y have established <strong>the</strong><br />
diagnoses for <strong>the</strong>ir patients. Like many o<strong>the</strong>r professional societies, <strong>the</strong> Swiss Society<br />
for Pathology has recommended that paraffin blocks be retained for a minimum of<br />
20 years (40 years for pediatric tumors). In addition to paraffin blocks, fresh tumor<br />
and non-tumorous tissues can be frozen rapidly and kept for many years in freezers<br />
at -80°C or in nitrogen tanks. The research value of <strong>the</strong>se archived tissues depends<br />
largely on <strong>the</strong> disposition of clinical information, on patient survival, and – ideally –<br />
on data concerning tumor response to treatment (chemo<strong>the</strong>rapy, targeted<br />
treatments). With this information, combined with <strong>the</strong> modern tools of molecular<br />
pathology, notably deep sequencing, novel cancer markers with prognostic and/or<br />
predicitve values can be detected in historic cohorts and verified in independent<br />
historic cohorts, before ultimately being tested prospectively in “new” cancer patients<br />
(<strong>the</strong> “honey”). Certainly, this can only be successful, (i) if <strong>the</strong> material is adequately<br />
stored and quality-controlled (is <strong>the</strong>re truely invasive carcinoma in <strong>the</strong> tissue block<br />
?), (ii) if <strong>the</strong> logistics for clinical data management is professionally organized, and<br />
(iii) if <strong>the</strong>re exists an understanding and a consent of <strong>the</strong> patients whose tissues are<br />
to be used for research. The first two tasks lay in <strong>the</strong> hands of professionals who run<br />
<strong>the</strong> bank (pathologists, technicians, data managers), and have to be compensated for<br />
<strong>the</strong>ir work (<strong>the</strong> “bees”). The third task needs to be solved at <strong>the</strong> level of <strong>the</strong> general<br />
population. The last few years have seen many fruitful discussions and conferences<br />
dedicated to establishing a consensus between <strong>the</strong> general population (patients) and<br />
<strong>the</strong> scientific community (researchers). A recent survey among 1600 French- and<br />
German-speaking Swiss citizens has shown that <strong>the</strong> population is highly- and quite<br />
unconditionally - in favor of biobanking for research, provided that patients are<br />
properly informed and that <strong>the</strong>ir (written) consent is asked.<br />
Disclosure: The author has declared no conflicts of interest.<br />
118IN KRAS AND COLORECTAL CANCER: WHAT’S NEXT?<br />
No abstract submitted at time of going to press.<br />
Annals of Oncology 23 (Supplement 9): ix61, <strong>2012</strong><br />
doi:10.1093/annonc/mds485<br />
119IN MOLECULAR TYPING OF LUNG CANCER: MORE PIECES TO<br />
THE PUZZLE<br />
S. Peters<br />
Oncology, Centre Hospitalier Universitaire Vaudois - CHUV, Lausanne,<br />
SWITZERLAND<br />
Distinct subtypes of NSCLC, so-called “oncogene addicted”, are driven by a specific<br />
genetic alteration sustaining tumor proliferation and survival – and are thus sensitive<br />
to inhibition of <strong>the</strong> corresponding activated pathway. This new paradigm has<br />
substantially impacted treatment from standard chemo<strong>the</strong>rapy customized patient<br />
characteristics, expected toxicity and histological subtype to molecularly driven<br />
approaches in advanced NSCLC. Nowadays, adenocarcinoma - but also squamous<br />
carcinoma in recent reports - can be fur<strong>the</strong>r subdivided into numerous clinically<br />
relevant molecular subsets. EGFR activating mutations or EML4-ALK translocation<br />
have been shown to be associated with better outcome when targeted by dedicated<br />
molecules. Treatment of patients with EGFR activating and sensitizing<br />
mutations-driven NSCLC with EGFR tyrosine kinase inhibitors (TKIs) results in an<br />
unprecedented response rate (RR) of 60-80%, a median progression free survival<br />
(PFS) of approximately 8-13 months, as well as an improved quality of life (QoL)<br />
compared to chemo<strong>the</strong>rapy. This was <strong>the</strong> first and a strong illustration of <strong>the</strong><br />
<strong>the</strong>rapeutic relevance of molecular classification of NSCLC. In NSCLC, ALK<br />
rearrangement has at least 3 reported fusion partners: EML4, KLC1, and KIF5B. In<br />
<strong>the</strong>se tumors, ALK is <strong>the</strong> sole determinant of critical growth pathways, resulting in<br />
activation of downstream canonical PI3K/AKT as well as MAPK/ERK pathways.<br />
Within <strong>the</strong> pivotal phase 1/2 clinical trial, treatment of 82 EML4-ALK positive<br />
patients with crizotinib resulted in a 57% RR and median PFS was 10 months. The<br />
kinetics of clinical response were comparable to previous experiences with EGFR<br />
TKIs in EGFR-mutated NSCLC. O<strong>the</strong>r transforming genetic alterations have been<br />
identified such as MET, Her2 and FGFR1 amplification, KRAS, NRAS, BRAF, MEK1,<br />
AKT1, PIK3CA, AKT, FGFR2, DDR2, PTEN and HER2 mutations, RET, ROS1 and<br />
ALK rearrangements. While every distinct alteration remains a rare event per se in<br />
our NSCLC population, <strong>the</strong>ir frequency was shown to vary according to histological<br />
subtype, and defined clinical characteristics including smoking history, gender and<br />
ethnicity. All of <strong>the</strong>m have to be subject of future epidemiological, fundamental,<br />
translational as well as clinical research in order to propose more active treatments to<br />
patients in <strong>the</strong> future.<br />
Disclosure: The author has declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds485 | ix61
<strong>ESMO</strong>-ESTRO Joint Symposium:<br />
Innovative approaches to <strong>the</strong> treatment<br />
of brain metastases<br />
120IN HOW NEW INSIGHTS IN THE BIOLOGY OF BRAIN<br />
METASTASES MAY LEAD TO THE IDENTIFICATION OF NEW<br />
EFFECTIVE MEDICAL THERAPIES<br />
B. Gril<br />
Women’s Cancer Section, Laboratory of Molecular Pharmacology, National<br />
Cancer Institute, National Institutes of Health, Be<strong>the</strong>sda, MD, UNITED STATES<br />
OF AMERICA<br />
Brain metastases are a devastating event in <strong>the</strong> progression of cancer and are<br />
expected to increase in incidence as chemo<strong>the</strong>rapies improve and lead to better<br />
systemic disease control. The brain offers unique environment as it is protected by<br />
<strong>the</strong> blood–brain barrier, which strongly limits <strong>the</strong> penetration of drugs. Using a<br />
quantitative model system for experimental breast cancer brain metastasis, vascular<br />
permeability was heterogeneous in brain metastases, with only 10% of lesions<br />
exhibiting sufficient permeability to mount an apoptotic response to taxol, suggesting<br />
that inadequate chemo<strong>the</strong>rapeutic drug distribution accounts for a lack of efficacy.<br />
We have tested 18 compounds, both traditional chemo<strong>the</strong>rapeutics and small<br />
molecule inhibitors, for efficacy in an experimental brain metastasis model.<br />
Prevention of <strong>the</strong> development of brain metastases was observed using vorinostat,<br />
lapatinib, pazopanib, TPI-287, gemcitabine and irinotecan. No drug effectively<br />
shrunk already established metastases. Our work strongly suggests that preventive<br />
approaches for <strong>the</strong> development of brain metastases constitutes a feasible clinical<br />
goal. We advocate <strong>the</strong> use of “secondary brain metastasis prevention” trials, in which<br />
patients with limited, treated brain metastases (without whole brain radio<strong>the</strong>rapy) are<br />
randomized to a preventive or placebo, with time to <strong>the</strong> development of a new<br />
metastasis as an endpoint. Close collaboration between researchers and medical<br />
oncologists will be needed to address <strong>the</strong>se challenges brought on by this growing<br />
and incurable disease.<br />
Disclosure: B. Gril: Dr. Patricia Steeg received research founding from Glaxo Smith<br />
Kline (for lapatinib, pazopanib and PLK inhibitor) and from Millennium<br />
Pharmaceuticals (for TAK-285).<br />
121IN PUTTING DRUGS AT WORK AGAINST BRAIN METASTASES<br />
IN HER2 POSITIVE BC: RESULTS OF THE LANDSCAPE TRIAL<br />
T. Bachelot 1 , G. Romieu 2 , C. Cropet 3 , M. Campone 4 , V. Diéras 5 , M. Jimenez 6 ,<br />
F. Dalenc 7 , E. Le Rhun 8 , C. Labbe-Devilliers 4<br />
1 Département De Cancérologie Médicale, Centre Léon Bérard, Lyon, FRANCE,<br />
2 Oncologie Médicale, Centre Val d’Aurelle, Montpellier, FRANCE, 3 Unité De<br />
Biostatistique Et D’evaluation Des Thérapeutiques, Centre Léon Bérard, Lyon,<br />
FRANCE, 4 Medical Oncology, Centre René Gauducheau (ICO) Institut de<br />
Cancerologie de l’Ouest, St Herblain, FRANCE, 5 Department of Medical<br />
Oncology, Clinical Trial Unit, Institut Curie, Paris, FRANCE, 6 R&d, Unicancer,<br />
Paris, FRANCE, 7 Oncologie Médicale, Centre Claudius Regaud, Toulouse,<br />
FRANCE, 8 Département De Sénologie, Centre Oscar LAMBRET, Lille, FRANCE<br />
Background: Brain metastases (BM) occur in 30 to 50% of metastatic breast cancers<br />
(MBC) overexpressing HER2. In case of diffuse BM, current treatment is primarily<br />
based on whole brain radio<strong>the</strong>rapy (WBRT). Few systemic options are available.<br />
Lapatinib (L) has shown some activity in association with capecitabine (C) after<br />
previous WBRT. The LANDSCAPE study assessed <strong>the</strong> efficacy of <strong>the</strong> association<br />
before any local treatment.<br />
Methods: Eligible pts had HER2+ MBC with BM not previously treated with WBRT,<br />
C or L. They received lapatinib 1,250 mg once daily and oral capecitabine 2,000 mg/<br />
m 2 from day 1 to day 14, every 21 days. The primary endpoint was <strong>the</strong> rate of central<br />
nervous system objective responses (CNS-OR) defined as a ≥50% volumetric<br />
reduction of CNS lesions in <strong>the</strong> absence of all <strong>the</strong> following: increasing steroid use,<br />
progressive neurologic symptoms, or progressive extra-CNS disease. Secondary<br />
endpoints included time to progression (TTP), time to WBRT, and toxicity.<br />
Findings: From April 2009 to August 2010, forty-five patients were included in <strong>the</strong><br />
study. 44 patients were evaluable for efficacy, with a median follow-up of 21.2<br />
months (range 2.2-27.6).The CNS-OR rate was 67.4% (95% CI: 51.5%-80.9%).<br />
Thirty-seven patients (86%) exhibited a reduction in tumor volume. Median time to<br />
progression was 5.5 months (95% CI: 4.3-6). At <strong>the</strong> time of analysis, 81.8% of<br />
patients had received brain radio<strong>the</strong>rapy, median time to radio<strong>the</strong>rapy was 8.3<br />
months (95% CI: 5.4-9.1). Most adverse events (AE) were grade 1-2 as already<br />
reported for this association, 22 patients (49%) experienced grade 3 or 4 treatment<br />
related toxicity and 14 patients presented at least one SAE; treatment was<br />
discontinued due to toxicity in 4 pts<br />
Interpretation: The association of L and C is effective in <strong>the</strong> treatment of BM of<br />
HER2 positive BC. Our data suggest that this regimen might be used right away at<br />
diagnosis of BM. This approach might change <strong>the</strong> management of selected patients<br />
with BM, allowing a delayed WBRT. This strategy deserves fur<strong>the</strong>r evaluation to<br />
confirm <strong>the</strong> clinical benefits for patients in terms of survival, cognitive functions and<br />
quality of life. We are currently planning such a randomized clinical trial.<br />
Disclosure: T. Bachelot: GSK: Board member Travel accommodation Reaserch grant,<br />
M. Campone: GSK: Board Member, V. Diéras: GSK: Board Member. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
122IN DOES IMRT, IMAT, TOMOTHERAPY REDUCE THE<br />
NEUROTOXICITY OF WHOLE BRAIN RADIOTHERAPY?<br />
No abstract submitted at time of going to press.<br />
Annals of Oncology 23 (Supplement 9): ix62, <strong>2012</strong><br />
doi:10.1093/annonc/mds486<br />
123IN THE BIOLOGICAL RATIONALE AND POTENTIAL ROLE OF<br />
RADIATION DOSE ESCALATION IN PATIENTS WITH BRAIN<br />
METASTASES<br />
F.J. Lagerwaard<br />
Radiation Oncology, Vrije University Medical Centre (VUMC), Amsterdam,<br />
NETHERLANDS<br />
The majority of patients with BM from solid tumors have a prognosis of only a few<br />
months based on extracranial tumor activity and performance status. The standard of<br />
care for <strong>the</strong>se patients consists of palliative treatment with steroids, and, if<br />
appropriate, a short course of whole brain radio<strong>the</strong>rapy (WBRT). Several prognostic<br />
classification systems such as <strong>the</strong> RPA classification [Gaspar 1997] or <strong>the</strong> DS-GPA<br />
[Sperduto 2008] enable identifying a subset of patients that may have long-term<br />
survival, provided that <strong>the</strong> BM are treated aggressively.<br />
Although neurosurgery is <strong>the</strong> traditional treatment for single BM at an accessible<br />
location, radiosurgery (RS) has been established as a non-invasive alternative. RS<br />
involves high-precision delivery of a single fraction of approximately 20 Gy directed<br />
to <strong>the</strong> lesion, resulting in local control rates of 60-90%, dependent on <strong>the</strong> size and<br />
aspect (poorer control for necrotic lesions). The survival benefit of RS has only been<br />
confirmed for a single BM in a randomized study [Andrews 2004], but improved<br />
functional autonomy was observed in all groups with 1-3 BM. The question whe<strong>the</strong>r<br />
WBRT should be added to RS has been a long-standing unresolved issue with<br />
proponents highlighting <strong>the</strong> better intracranial control, and opponents pointing out<br />
<strong>the</strong> neurocognitive toxicity of WBRT and available salvage options. As <strong>the</strong> risk of<br />
developing new BM following RS alone is not only dependent on extracranial tumor<br />
activity (reseeding) but also on <strong>the</strong> number of initially treated BM (misdiagnosis of<br />
occult BM), a more differentiated approach may be better suited.<br />
A well selected patient group with multiple BM in good performance status and<br />
absent progressive extracranial disease may be candidates for recently developed<br />
advanced radiation planning and delivery. Techniques such as volumetric<br />
intensity-modulated arc <strong>the</strong>rapy (VMAT, RapidArc) or Tomo<strong>the</strong>rapy have enabled<br />
fast and accurate delivery of fractionated stereotactic integrated boosts to multiple BM<br />
in combination with WBRT. The integrated approach of this technique allows steep<br />
dose gradients outside <strong>the</strong> BM, <strong>the</strong>reby minimizing toxicity. Early experiences with<br />
this technique have reported relatively high intracranial control rates.<br />
Disclosure: F.J. Lagerwaard: The Department of Radiation Oncology has research<br />
agreements with Varian medical systems and BrainLAB AG. The author has received<br />
honoraria for presentations from Varian medical systems and BrainLAB AG<br />
ix62 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
<strong>ESMO</strong>-JSMO Joint Symposium:<br />
Recent advances in <strong>the</strong> treatment of GI<br />
tract and liver cancer in <strong>the</strong> EU and<br />
Japan<br />
124IN HEPATOCELLULAR CARCINOMA: PRESENT TREATMENT<br />
STRATEGY IN JAPAN<br />
J. Furuse<br />
Department of Medical Oncology, Kyorin University School of Medicine, Tokyo,<br />
JAPAN<br />
Hepatocellular carcinoma (HCC) develops mainly from liver cirrhosis due to<br />
hepatitis B or C virus infection. A screening system in patients with cirrhosis is<br />
important to diagnose HCC at as earlier a stage as possible. As a result, in Japan,<br />
approximately 90% of HCC patients successfully undergo local <strong>the</strong>rapies including<br />
hepatectomy, local ablation, and transca<strong>the</strong>ter arterial chemoembolization (TACE).<br />
However, many patients develop recurrences or progression after <strong>the</strong>se treatments,<br />
and an effective systemic <strong>the</strong>rapy is needed to improve <strong>the</strong> survival.<br />
Sorafenib is <strong>the</strong> first agent which demonstrated survival benefits in patients with<br />
unresectable advanced HCC that was approved for HCC in Japan in May, 2009, and<br />
more than 13,000 patients have received systemic <strong>the</strong>rapy using sorafenib. In a survey<br />
by <strong>the</strong> Study Group on New Liver Cancer under <strong>the</strong> auspices of <strong>the</strong> Health and<br />
Labour Sciences Research Grant in Japan, 264 patients treated with sorafenib were<br />
analyzed and 90% of <strong>the</strong>se patients treated with sorafenib received prior treatments<br />
including hepatectomy, local ablation and/or TACE. Common adverse events were<br />
hand-foot skin reaction, rash and diarrhea. The median overall survival was 11.0<br />
months. These results were comparable with those of a large phase III trial of<br />
sorafenib, <strong>the</strong> SHARP trial.<br />
Following sorafenib, several targeted agents are currently under investigation in <strong>the</strong><br />
treatment of HCC at various stages. Large randomized control trials are needed to<br />
establish new standard treatments, and most trials have been conducted in<br />
international collaboration including Japan. On <strong>the</strong> o<strong>the</strong>r hand, some trials are<br />
conducted only in Japan, for example combination of hepatic arterial infusion<br />
chemo<strong>the</strong>rapy with sorafenib.<br />
In this presentation, <strong>the</strong> outcomes of sorafenib treatment in Japan and recent clinical<br />
trials in chemo<strong>the</strong>rapy are summarized and discussed.<br />
Disclosure: J. Furuse: I received honoraria and consulting fee from Bayer, Eli Lilly,<br />
Taiho, Chugai and Eisai.<br />
125IN HEPATOCELLULAR CARCINOMA IN THE EU<br />
J. Bruix<br />
Liver Unit, Hospital Clinic y Provincial de Barcelona, University of Barcelona,<br />
Barcelona, SPAIN<br />
The incidence of liver cancer varies across Europe. However, while figures have<br />
stabilised in Italy and Spain, Nor<strong>the</strong>rn countries present a slight increase in recent<br />
years. In most cases, liver cancer appears in <strong>the</strong> background of chronic liver disease<br />
related to hepatitis C or B, infection and alcoholism, among o<strong>the</strong>r risk factors.<br />
Current data show that hepatocellular carcinoma is <strong>the</strong> leading cause of death in<br />
patients with cirrhosis and that <strong>the</strong> incidence of intrahepatic cholangiocarcinoma is<br />
on <strong>the</strong> rise. Because of its clinical relevance all scientific associations have developed<br />
practice guidelines to inform patients, physicians and regulatory agents about <strong>the</strong><br />
established diagnostic and <strong>the</strong>rapeutic procedures. Non-invassive diagnostic criteria<br />
have been accepted and in almost all documents <strong>the</strong> recommended strategy for<br />
staging and treatment indication is <strong>the</strong> BCLC model. Following it, patients diagnosed<br />
with HCC are stratified into stages for which different treatment options are to be<br />
considered.<br />
References<br />
1. Jelic S, Sotiropoulos GC; <strong>ESMO</strong> Guidelines Working GroupHepatocellular<br />
carcinoma: <strong>ESMO</strong> Clinical Practice Guidelines for diagnosis, treatment and followup.<br />
Ann Oncol. 2010 ;21 Suppl 5:v59–64<br />
2. Bruix J, Sherman M. Management of hepatocellular carcinoma: An update.<br />
Hepatology. 2011 Mar 1;53 (3):1020–2.<br />
3. EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular<br />
carcinoma. J Hepatol. <strong>2012</strong> Apr;56 (4):908–43.<br />
4. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. <strong>2012</strong>;379<br />
(9822):1245–55.<br />
Disclosure: The author has declared no conflicts of interest.<br />
Annals of Oncology 23 (Supplement 9): ix63, <strong>2012</strong><br />
doi:10.1093/annonc/mds487<br />
126IN COLORECTAL CANCER: A NEW ORAL CYTOTOXIC AGENT<br />
REAPPEARS<br />
T. Yoshino<br />
Department of Gastroenterology & Gi Oncology, National Cancer Center Hospital<br />
East, Kashiwa, JAPAN<br />
Cytotoxic agents, such as fluoropyrimidine, irinotecan, and oxaliplatin and antibodies<br />
such as bevacizumab, and cetuximab and panitumumab have been shown to<br />
significantly improve <strong>the</strong> survival of patients with unresectable metastatic colorectal<br />
cancer (mCRC). Although many patients have a good long-term performance status,<br />
a standard <strong>the</strong>rapy for patients refractory to or unable to tolerate <strong>the</strong>se agents does<br />
not currently exist. TAS-102 is a novel oral nucleoside antitumor agent consisting of<br />
trifluorothymidine (FTD) and 5-chloro-6-(2-iminopyrrolidin-1-yl) methyl-2,4<br />
(1H,3H)-pyrimidinedione hydrochloride (TPI) at a molar ratio of 1 to 0.5. TAS-102<br />
possesses a mechanism of action different from that of o<strong>the</strong>r antitumor agents,<br />
including fluoropyrimidine, irinotecan and oxaliplatin. Based on a phase I clinical<br />
trial in Japan, <strong>the</strong> recommended dose of TAS-102 (35 mg/m 2 /b.i.d) twice daily<br />
administered orally in days 1-5 and 8-12 of a 28-day cycle was determined. These<br />
results indicated that TAS-102 was expected to fur<strong>the</strong>r improve <strong>the</strong> outcomes of<br />
patients with unresectable mCRC. We conducted randomized, double-blind phase II<br />
trial as a placebo-controlled study to evaluate <strong>the</strong> efficacy of TAS-102. A total of 172<br />
colorectal cancer patients who were refractory or intolerable to 2 or more regimens of<br />
standard chemo<strong>the</strong>rapy with a fluoropyrimidine, irinotecan, and oxaliplatin<br />
underwent ei<strong>the</strong>r TAS-102 plus best supportive care (BSC) (114 patients) or placebo<br />
plus BSC (58 patients) with <strong>the</strong> primary endpoint of overall survival. TAS-102<br />
significantly decreased death risk compared to placebo (hazard ratio, 0.56; 95%<br />
confidential interval [CI], 0.39-0.81; P = 0.0011). The median overall survival was 9.0<br />
months in <strong>the</strong> TAS-102 group and 6.6 months in <strong>the</strong> placebo group. TAS-102<br />
significantly improved progression-free survival (median, 2.0 months vs 1.0 month;<br />
hazard ratio, 0.41; 95% CI, 0.28-0.59; P < 0.0001). TAS-102 was effective regardless of<br />
KRAS mutational status. Grade 3 or higher adverse events observed in <strong>the</strong> TAS-102<br />
group were neutropenia (50.4%), leucopenia (28.3%), and anemia (16.8%). There<br />
were no treatment-related deaths. An international phase III trial is ongoing to<br />
confirm <strong>the</strong> clinical benefits of TAS-102 worldwide.<br />
Disclosure: T. Yoshino: I have honoraria with Chugai, Takeda, Bristol-Myers Squibb,<br />
Yakult and Merck Serono. I have research funding from Bayer, Taiho, Daiichi-sankyo<br />
and Quintiles. I have received consulting fee from Takeda.<br />
127IN CAN PET IMAGING HELP INDIVIDUALIZE THE TREATMENT<br />
OF COLORECTAL CANCER PATIENTS?<br />
A. Hendlisz<br />
Medicine Department, Institut Jules Bordet, Brussels, BELGIUM<br />
While <strong>the</strong> science of medicine tries to understand <strong>the</strong> rules and hidden laws behind<br />
diseases and <strong>the</strong>ir management, <strong>the</strong> art of medicine aims to treat individual patients<br />
by matching clinical observations and existing knowledge. The ambiguity between <strong>the</strong><br />
art and <strong>the</strong> science of medicine has never been so obvious than in our attempts to<br />
tailor cancer treatment to individual patients: <strong>the</strong> growing evidence of tumor<br />
heterogeneity makes understanding a patient’s disease increasingly complex, especially<br />
when one considers <strong>the</strong> inadequacy of current assessment tools, which is becoming<br />
more apparent each day. In <strong>the</strong> setting of advanced colorectal cancer (aCRC), three<br />
main clinical situations coexist: metastasis that is immediately resectable with curative<br />
intent, borderline resectable disease and definitively non-resectable disease. Despite<br />
broad parameters within which to treat disease, clinicians lack tools that can rapidly<br />
and reliably point out treatment inefficiency in order to allow a <strong>the</strong>rapeutic strategy to<br />
be quickly stopped or adapted. The usual endpoints of prospective randomized trials,<br />
which form <strong>the</strong> basis of <strong>the</strong> science of medicine, are seldom usable at <strong>the</strong> bedside to<br />
exercise <strong>the</strong> art of medicine. Death (overall survival) and progression (progression-free<br />
survival) both occur too long after <strong>the</strong> beginning of a treatment, and quality of life is<br />
much too subjective. The RECIST-based response rate is more readily available and<br />
relatively well standardized, but careful analysis reveals a definite but only small<br />
correlation with survival outcome in <strong>the</strong> aCRC setting. Several alternates for tumor<br />
response assessment have been studied: plasma tumor markers, circulating tumor cells,<br />
and functional imaging, notably <strong>the</strong> FDG-PET scan. However, few data from<br />
well-structured studies are available, and <strong>the</strong>y are sometimes discordant. Among <strong>the</strong>se<br />
alternatives, metabolic imaging by FDG-PET appears to be <strong>the</strong> most promising,<br />
bearing <strong>the</strong> highest and <strong>the</strong> most reproducible negative predictive value. This means<br />
that it could become useful both in <strong>the</strong> daily clinic and to develop new concepts for<br />
clinical trials. The aim of this review is to present <strong>the</strong> available evidence, point out<br />
areas of weakness, and consider how current findings might shape <strong>the</strong> future<br />
development of both FDG-PET techniques and study designs.<br />
Disclosure: The author has declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds487 | ix63
<strong>ESMO</strong>-MASCC Joint Symposium:<br />
Integration between medical oncology<br />
and supportive care: Two sides of <strong>the</strong><br />
same coin<br />
128IN SUPPORTIVE AND PALLIATIVE CARE: CORE ELEMENTS OF<br />
QUALITY CANCER CARE<br />
N.I. Cherny<br />
Dept Medical Oncology, Shaare Zedek Medical Centre Oncology Institute,<br />
Jerusalem, ISRAEL<br />
There has been much confusion regarding <strong>the</strong> definitions of supportive care (SC)<br />
and palliative care (PC) and many authorities use <strong>the</strong> terms interchangeably. Both<br />
MASCC and <strong>ESMO</strong> are among <strong>the</strong> minority of professional organizations that<br />
distinguish between <strong>the</strong> two. SC is defined as care that facilitate safe and effective anti<br />
cancer care, minimizing toxicity and optimizing physical, psychological and social<br />
function of patients undergoing disease management strategies. SC facilitates <strong>the</strong><br />
ability to deliver optimal anti cancer care and it has a particular focus on side effect<br />
prevention and management. All cancer patients undergoing treatment need SC and<br />
this is equally true for those undergoing curative treatments as it is for those<br />
undergoing treatment to mitigate <strong>the</strong> trajectory and consequences of advanced and<br />
incurable cancer. PC optimizes <strong>the</strong> comfort, function and social support of <strong>the</strong><br />
patient and <strong>the</strong>ir family when cure is not possible. The context of incurability, with<br />
all of its implications for <strong>the</strong> patent and family, that grounds palliative care as a<br />
special entity. “End of life care” or “terminal care” is defined as PC when death is<br />
imminent. End-of-life care acknowledges that <strong>the</strong> intensity of physical, psychological,<br />
existential, spiritual and family issues may be magnified by <strong>the</strong> patient’s approaching<br />
death. Patients with incurable cancer receiving antitumor <strong>the</strong>rapies will often need<br />
both S + PC.<br />
Conclusion: The delivery of high quality S + PC are core elements of quality<br />
oncological service and it is incumbent upon clinicians to be adequately skilled, to<br />
tend to <strong>the</strong>se needs with due diligence and to promote <strong>the</strong> development of effective<br />
service delivery frameworks to ensure that patients receive <strong>the</strong>se vita elements of<br />
quality care.<br />
Disclosure: The author has declared no conflicts of interest.<br />
129IN ANTIEMETICS: A WINDOW TO TRANSLATIONAL MEDICINE<br />
S. Grunberg<br />
Hematology/Oncology, University of Vermont, Burlington, VT, UNITED STATES<br />
OF AMERICA<br />
The concepts of targeted <strong>the</strong>rapy, molecular pharmacology, and population genetics<br />
are not new to <strong>the</strong> field of clinical antiemetic care. The most basic principle of<br />
antiemetic care is to identify and target neurotransmitter/neurotransmitter receptor<br />
pairs within <strong>the</strong> emetic reflex arc that can be suppressed without causing severe<br />
disruption of physiologic function. Early research focused on dopamine (D2)<br />
receptors led to effective antiemetics but also resulted in significant antidopaminergic<br />
toxicity. Identification of serotonin (5HT3) receptor pathways with similar<br />
emetogenic activity provided a target that could be effectively suppressed without<br />
antidopaminergic toxicity. Appreciation of <strong>the</strong> role of neurokinin (NK-1) receptors<br />
in delayed emesis complements previous knowledge and allows for more effective<br />
suppression of emesis throughout <strong>the</strong> period of emetic risk. More recently genetic<br />
mutations that alter <strong>the</strong>se neural pathways as well as <strong>the</strong> metabolic pathways of<br />
antiemetic agents have been appreciated. Over-expression of <strong>the</strong> CYP 2D6 pathway<br />
increases metabolism of some serotonin antagonist antiemetics and has been shown<br />
to decrease <strong>the</strong> efficacy of <strong>the</strong>se agents. A mutation in <strong>the</strong> 5-HT3B subunit of <strong>the</strong><br />
serotonin (5HT3) receptor itself can also alter sensitivity to emetogenic<br />
chemo<strong>the</strong>rapy and to antiemetic agents. Appreciation of <strong>the</strong> role of genotype and<br />
phenotype in <strong>the</strong> response of different ethnic groups to <strong>the</strong>rapy has now allowed<br />
correlation of lessons from population science with clinical treatment. A study from<br />
Malaysia comparing Chinese, Malay, and Indian populations receiving similar<br />
chemo<strong>the</strong>rapy and similar antiemetics has demonstrated an increased emetic<br />
response in <strong>the</strong> Chinese population. A study from <strong>the</strong> United States similarly<br />
demonstrated increased emetic response in a Chines population compared to a<br />
Caucasian population. Whole genome analysis to identify differences between <strong>the</strong>se<br />
ethnic groups may <strong>the</strong>refore lead back to genetic foci of interest that will in turn<br />
affect <strong>the</strong> clinical science of antiemetic protection. Such translational and<br />
multidisciplinary efforts increase knowledge of <strong>the</strong> basic mechanisms of disease and<br />
treatment while simultaneously improving patient quality of life.<br />
Disclosure: S. Grunberg: I have served as a consultant to Helsinn, Merck, Tesaro, AP<br />
Pharma, and Prostrakan. I also am a stockholder in and have received honoraria<br />
from Merck.<br />
Annals of Oncology 23 (Supplement 9): ix64, <strong>2012</strong><br />
doi:10.1093/annonc/mds488<br />
130IN GASTROINTESTINAL TOXICITY IN ONCOLOGY:<br />
EVOLUTIONARY SCIENCE<br />
D. Keefe<br />
Medicine, University of Adelaide, Adelaide, SA, AUSTRALIA<br />
Proper practice of Medical Oncology requires an understanding of <strong>the</strong> science of<br />
regimen-related toxicity (RRT); and as treatment regimens evolve, so too does that<br />
science. Mouth ulcers, pain, diarrhea and constipation are among <strong>the</strong> common side<br />
effects of chemo<strong>the</strong>rapy and hinder our ability to give adequate, perhaps curative,<br />
doses. As we increase our understanding of toxicity mechanism, so we slowly<br />
improve its prevention and treatment. However, this must not come at <strong>the</strong> cost of<br />
tumour-response, thus requiring understanding of <strong>the</strong> interaction between<br />
mechanism of action and of toxicity. Animal models have become increasingly<br />
sophisticated, and are used to screen for interventions that reduce toxicity without<br />
affecting tumour response. The introduction of <strong>the</strong> targeted anti-cancer (TAT) agents<br />
has fur<strong>the</strong>r complicated <strong>the</strong> picture, with GI toxicity being a major, and not always<br />
predicted effect. The mechanism of toxicity is often <strong>the</strong> same as <strong>the</strong> mechanism of<br />
action, making successful management difficult. Each new class of TAT has a new<br />
mechanism, epidemiology and presentation of toxicity, so we constantly need to<br />
update our understanding of <strong>the</strong> science. A mouth ulcer caused by methotrexate is<br />
not <strong>the</strong> same as one caused by an mTOR inhibitor. There has been a corresponding<br />
evolution in <strong>the</strong> doctor-patient relationship surrounding toxicity, as we have moved<br />
from <strong>the</strong> paternalistic relationship to a partnership, with Patient Reported Outcomes<br />
(PROs) increasingly important. Clinicians will usually rate a given toxicity less<br />
severely than will <strong>the</strong> patient; <strong>the</strong> message being that we need to listen to <strong>the</strong> patient.<br />
Risk prediction is receiving more attention, with Oncologists now talking about<br />
response prediction and risk prediction as two sides of <strong>the</strong> same coin, aiming to offer<br />
treatment to non-toxic responders, treatment with toxicity interventions to toxic<br />
responders, and completely avoid ineffective treatment for non-responders. We have<br />
moved from <strong>the</strong> simplistic risk prediction of age, sex, comorbidity and drugs, to<br />
complex gene and SNP analysis using modern bioinformatics. However, given <strong>the</strong><br />
common lag between drug development and successful toxicity interventions, toxicity<br />
specialists should be involved earlier in drug development. The science will continue<br />
to evolve as long as cancer treatment evolves.<br />
Disclosure: D. Keefe: Prof Keefe works with many companies in <strong>the</strong> development of<br />
agents in <strong>the</strong> field of GI toxicity. These include: Helsinn, Entera Health, Pfizer, GSK<br />
and Merck.<br />
131IN DEVELOPMENT OF RATIONAL THERAPEUTIC STRATEGIES<br />
FOR PATIENTS WITH PRE-CACHEXIA AND CACHEXIA<br />
THROUGH THE INTEGRATION OF ONCOLOGY AND<br />
PALLIATIVE CARE AND COLLABORATIVE CLINICAL TRIALS<br />
(EAPC-RESEARCH NETWORK)<br />
F. Strasser<br />
Oncological Palliative Medicine, Cantonal Hospital, St.Gallen, SWITZERLAND<br />
Nutritional issues are frequent but underestimated in advanced, incurable cancer<br />
patients (pts), impacting patients’ tolerability of anticancer treatment, quality of<br />
life, physical (and social) function, effective health services use and family<br />
members. The new cancer cachexia framework (Fearon & Strasser, Lancet<br />
Oncology 2011) separating simple starvation from cachexia, facilitates <strong>the</strong><br />
development of both effective nutritional, multimodal and tailored treatments.<br />
Collaborative, international efforts and EU-funding made this framework possible.<br />
Cachexia is defined by muscle loss relevantly impacting physical function, which is<br />
not reversible by nutrition only, and is caused by a combination of dysregulated<br />
eating ability and a dysbalanced catabolic and anabolic metabolism. To identify<br />
such pts in clinical practice, monitoring of % weight loss in <strong>the</strong> last 6 months and<br />
asking pts about appetite and eating shall become a standard procedure. The<br />
clinical assessment will diagnose cachexia, <strong>the</strong>n classify pts for <strong>the</strong> phase<br />
(pre-cachexia, cachexia, refractory cachexia), main domains (stores, intake,<br />
potential, performance), and severity. Currently a consensual cachexia assessment is<br />
developed involving various professional groups. For pre-cachexia and cachexia<br />
<strong>the</strong>re is currently no established <strong>the</strong>rapeutic intervention. Clinical trials<br />
investigating increase of nutritional intake (oral, enteral, parenteral) focus on<br />
patient populations having simple starvation. For cachexia treatment a multimodal<br />
approach is mandatory, tackling in a combined strategy its main causes of<br />
decreased eating ability, catabolism, decreased anabolism, and impaired<br />
neuro-muscular function. Preclinical studies and several clinical trials document <strong>the</strong><br />
potential of such interventions. A sentinel next step however, is <strong>the</strong> conduct of well<br />
powered, multimodal phase III trials in pre-cachexia and cachexia. For refractory<br />
cachexia, efforts concentrate to characterize <strong>the</strong>se pts and develop psychosocial and<br />
o<strong>the</strong>r symptom alleviating interventions. Currently guidelines on treatment are<br />
updated, applying <strong>the</strong> procedures of ESPEN. Educational initiatives emerge. All<br />
<strong>the</strong>se efforts mandate collaboration of professionals and working groups of involved<br />
societies (e.g., EAPC-RN, ESPEN, MASCC, <strong>ESMO</strong> PCWG, SCWD).<br />
Disclosure: F. Strasser: Unrestricted grants: Celgene (NCT01127386), Fresenius<br />
(http://www.surveymonkey.com/s/XBT6HQW.). Participation BYM338 trial<br />
(NCT01433263). Occasional Advisor: Baxter, Danone, Fresenius, Helsinn, Novartis,<br />
X-Biotech.<br />
ix64 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
<strong>ESMO</strong> DCTF-AORTIC-SLACOM-UICC-<br />
WHO Joint Symposium:<br />
Independent and publicly funded<br />
research: A new global model<br />
132IN GLOBAL CANCER RESEARCH; CURRENT SITUATION AND<br />
CHALLENGES<br />
E.L. Cazap<br />
Latinamerican & Caribbean Society for Medical Oncology (SLACOM), Buenos<br />
Aires, ARGENTINA<br />
Clinical research is vital to <strong>the</strong> development and improvement of methods to prevent,<br />
detect and treat cancer. The majority of clinical trials take place in <strong>the</strong> developed world<br />
through sponsored pharmaceutical company research. The corresponding lack of<br />
research in developing countries results in two unmet needs related to cancer<br />
treatment in <strong>the</strong> developing world. First, recommended treatments do not reflect<br />
ethnic (genetic), cultural and resource differences between developed countries and<br />
developing countries that are not subject to clinical research. Second, <strong>the</strong>re is little<br />
research conducted on those cancers that are primarily found in developing countries.<br />
Thus <strong>the</strong> ability to diagnose and treat <strong>the</strong>se diseases is impaired. This general picture<br />
reflects today’s situation globally, <strong>the</strong>n it is critical to promote clinical research in<br />
developing countries mainly with training of all levels of research professionals (data<br />
managers, research nurses, etc.) in a local context, and training on identifying<br />
resources to fund research outside of pharmaceutical company sponsorship.<br />
Disclosure: E.L. Cazap: Leadership Position SLACOM, ASCO, UICC Consultant:<br />
Bayer; Schering Pharma Honoraria: Bayer; Bristol-Myers Squibb; Fresenius Research<br />
Funding: Poniard Pharmaceuticals; Daiichi Sankyo Pharma; Breast Cancer Research<br />
Foundation (BCRF).<br />
133IN INDEPENDENT CANCER RESEARCH IN LATIN AMERICA: A<br />
NEW MODEL<br />
C. Vallejos-Sologuren<br />
Division of Research, Oncosalud SAC, Lima, PERU<br />
It is well known that pharmaceutical Industry leads <strong>the</strong> cancer research in Latin America,<br />
but also is well known that <strong>the</strong>re is a large pool of well-trained oncologists and basic<br />
scientists able to lead successfully scientific research of complex designs. A recent survey<br />
by Gomez et al (presented in <strong>the</strong> extended educational session at ASCO Annual Meeting<br />
2011), that involved <strong>the</strong> perception of oncologist from low income countries; reveals <strong>the</strong><br />
desires of Latin American medical oncologists to participate in clinical research from <strong>the</strong><br />
international cooperative groups. We - <strong>the</strong> Latin-American researchers- have learned that<br />
<strong>the</strong> academical investigation and <strong>the</strong> participation in <strong>the</strong> concept of study and research<br />
design is <strong>the</strong> best way to achieve academicals status. We have bet in <strong>the</strong> formation of local<br />
and regional cooperative groups, and we are doing efforts to implement research sites of<br />
excellence, improve our quality of data and seeking for collaboration of scientist from<br />
more developed countries to perform research involving complex procedures (eg.<br />
molecular analysis). Nowadays, <strong>the</strong> goal for our young researchers is get trained in<br />
renamed international institutions and establish strong links with o<strong>the</strong>r worldwide<br />
scientists. The future of research in our region reveal a landscape where we work toge<strong>the</strong>r<br />
to fight <strong>the</strong> cancer in benefit of our patients.<br />
Disclosure: The author has declared no conflicts of interest.<br />
134IN WHO AND CANCER RESEARCH<br />
No abstract submitted at time of going to press.<br />
135IN CANCER RESEARCH IN AFRICA<br />
I. Adewole<br />
Obstetrics and Gynaecology, College of Medicine, University of Ibadan, Ibadan,<br />
NIGERIA<br />
Cancer remains a public health challenge worldwide, and its fast rising nature in<br />
Africa is occasioned by <strong>the</strong> changing demographic and environmental characteristics.<br />
The epidemic is fur<strong>the</strong>r propelled by HIV/AIDS, poverty and ignorance within <strong>the</strong><br />
continent. At <strong>the</strong> moment, cancer is currently responsible for more than 7 million<br />
deaths per year. By 2030, it is projected that cancer alone will account for about 1.27<br />
million new cases and about a million deaths per annum.<br />
Disease prioritization is often a product of cutting edge research, and it is also a driver<br />
for follow-up implementations. The differential opportunity for sound translational<br />
research between developed countries and Africa is one of <strong>the</strong> key causal factors<br />
responsible for disease outcome between <strong>the</strong> two settings. At moment, <strong>the</strong> quality of<br />
cancer research is yet to offer <strong>the</strong> much-needed platform to generate a momentum for<br />
cancer prioritization in Africa. Cancer research from Africa is mostly donor funded,<br />
lacks depth of contextual framework - sociocultural, minimal multi-national outlook,<br />
lean basic science component, and low translational potential. O<strong>the</strong>r challenges<br />
include poor research friendly environment (laboratory, incentives and recognition);<br />
lack of mentoring programs, public funding comparable to NIH is non-existence, lack<br />
of robust cancer registry with necessary resources, and poor political support. The<br />
African Organisation for Research and Training in Cancer (AORTIC) has <strong>the</strong> vision of<br />
transforming <strong>the</strong> orientation of cancer researchers within <strong>the</strong> continent through<br />
provision of research capacity building opportunities, generation of a critical mass of<br />
cancer researchers that will form <strong>the</strong> core of <strong>the</strong> network, leading advocacy for local<br />
funding of cancer research in Africa, and promotion of center of excellence in cancer<br />
research at national and sub-regional level. It is imperative that cancer research in<br />
Africa charts a course that is visionary, pragmatic, multidisciplinary and sustainable as<br />
well as avoiding a “one perch approach”. A holistic approach to cancer research that<br />
will use both inductive and deductive reasoning philosophy is hereby advocated.<br />
Disclosure: The author has declared no conflicts of interest.<br />
136IN INTERNATIONAL RESEARCH<br />
Annals of Oncology 23 (Supplement 9): ix65, <strong>2012</strong><br />
doi:10.1093/annonc/mds489<br />
T. Cufer<br />
Department of Medical Oncology, University Clinic Golnik, Golnik, SLOVENIA<br />
Substantial increase in international clinical cancer research (CCR) observed during<br />
<strong>the</strong> last decade is due to fragmentation of major cancer types in biological subtypes<br />
with plethora of new treatment agents, both requiring a larger number of CCR<br />
participants, as well as to improved infrastructure and skills needed to perform CCR<br />
in developing countries. Based on ClinicalTrials.gov registry approx. one third of both<br />
academia- and industry-driven CCR is running on international basis nowadays: and<br />
<strong>the</strong> number of countries serving as trial sites in CCR reports published in prestigious<br />
journals doubled during <strong>the</strong> last decade. The scientific and logistical imperative for<br />
international CCR is clear, it shortens <strong>the</strong> time for clinical testing, offers an early<br />
access to new treatment strategies worldwide and lowers costs by establishing<br />
international networks of CCR. Clinical trials cooperative groups, already established<br />
as regional international groups (e.g. NCI-CTG, RTOG, NCIC, EORTC, CECOG,<br />
BIG, etc.), offer an excellent platform for exchange of scientific ideas, avoid<br />
unnecessary duplication of trials and represent a solid base for expanding international<br />
collaboration. But, <strong>the</strong>re are still a lot of regulatory, logistical, financial and scientific<br />
issues to be solved to fur<strong>the</strong>r improve international CCR and maximize its outcome.<br />
Regulatory requirements and oversight of <strong>the</strong> CTs need to be harmonized with data<br />
and tissue handling representing one of <strong>the</strong> main issues. Protection of publication<br />
rights and access to trial data is of upmost importance for transparency of CCR in<br />
developing countries. The drugs being evaluated in CCR must be available in<br />
participating countries, when approved. Formal training programs in CCR and ethics<br />
intended to future CCR leaders in developing countries, such as ICTW courses<br />
organized by ASCO and o<strong>the</strong>r academia organized GCP courses, need to be<br />
promoted. Effective collaboration between industry and cooperative groups has to be<br />
established. Our ability to establish international collaboration in CCR will results in<br />
maximization of our resources and patients, thus permitting international community<br />
to fur<strong>the</strong>r improve cancer control globally through effective CCR.<br />
Disclosure: The author has declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds489 | ix65
ESO Society Symposium:<br />
Celebrating 30 years of ESO and 50<br />
issues of Cancer World. Cancer 2020:<br />
The road to personalized cancer care<br />
137IN CAN WE WIN THE WAR ON CANCER GLOBALLY?<br />
F. Cavalli<br />
Oncology Institute of Sou<strong>the</strong>rn Switzerland, Bellinzona, SWITZERLAND<br />
In <strong>the</strong> last 15 years our understanding of <strong>the</strong> biology of cancer has increased tremendously<br />
and <strong>the</strong> speed, with which we acquire new knowledge about <strong>the</strong> basic biology of neoplastic<br />
diseases is currently increasing even fur<strong>the</strong>r. Thanks to <strong>the</strong> development in <strong>the</strong> field of<br />
translational research, some of this knowledge has been transferred into new and more<br />
efficacious treatments. Toge<strong>the</strong>r with intensified preventive efforts and some improvements as<br />
regards early detection, <strong>the</strong>se new treatments have contributed to <strong>the</strong> relative decline of <strong>the</strong><br />
overall cancer mortality, which we are currently witnessing at least in <strong>the</strong> most developed<br />
countries. Even here, however, costs of new treatments have reached a level which is no longer<br />
sustainable for most of <strong>the</strong> health care systems. Moreover, on a global scale, <strong>the</strong> situation<br />
looks quite worrysome. Mainly because of an explosion of new cancer cases in low- and<br />
middle income countries we are witnessing a rapid increase of <strong>the</strong> worldwide burden as<br />
demonstrated by following numbers: in <strong>the</strong> year 2000 <strong>the</strong>re were 11 millions new cancer<br />
diagnosed and 7 millions cancer deaths. If current trends will continue, in 2030 we will have<br />
27-28 millions new cancer diagnosed and 16-17 millions cancer deaths. Reasons for this<br />
evolution and possibilities to tackle this looming disaster will be presented. This situation will<br />
be at <strong>the</strong> centre of <strong>the</strong> discussions, which will take place in Lugano (26-27 October <strong>2012</strong>) at<br />
<strong>the</strong> World Oncology Forum (WOF), which will be organized by ESO with <strong>the</strong> title “Are we<br />
winning <strong>the</strong> war on cancer?”. Our current hypo<strong>the</strong>sis is that, although we are about to win <strong>the</strong><br />
battle from a medical and scientific point of view, we might lose <strong>the</strong> war on a global scale, if<br />
we will not be able to implement radical changes in <strong>the</strong> social/political environment.<br />
Disclosure: The author has declared no conflicts of interest.<br />
138IN PERSONALIZED THERAPY IN LUNG CANCER: THE PROMISE<br />
FOR THE FUTURE<br />
R.A. Stahel<br />
Labor für Molekulare Onkologie, Universitätsspital, Zurich, SWITZERLAND<br />
Chemo<strong>the</strong>rapy has improved <strong>the</strong> outcome of patients with non-small cell lung cancer with<br />
prolonged survival rates in advanced disease and higher cure rates in combination with<br />
surgery or radio<strong>the</strong>rapy for earlier stages of disease. With <strong>the</strong> exception of maintenance<br />
<strong>the</strong>rapy, <strong>the</strong> most recent advances have been achieved in patients with selected molecularly<br />
defined subgroups of non-small cell lung cancer. The area of personalized <strong>the</strong>rapy for lung<br />
cancer started in <strong>the</strong> year 2004 with <strong>the</strong> identification of activating EGFR mutations in lung<br />
adenocarcinoma being associated with striking clinical responses to EGFR tyrosine kinase<br />
inhibitors. Subsequent clinical studies lead to <strong>the</strong> approval of EGFR tyrosine kinase inhibitors<br />
gefitinib and erlotinib as fist line <strong>the</strong>rapy for this group of patients. These developments were<br />
followed by <strong>the</strong> discovery of ALK rearrangements as oncogenic driver for ano<strong>the</strong>r subgroup<br />
of lung adenocarcinoma and <strong>the</strong> demonstration of selective activity of <strong>the</strong> tyrosine kinase<br />
inhibitor crizotinib. Since, <strong>the</strong> field has developed rapidly with <strong>the</strong> detection of o<strong>the</strong>r<br />
potentially actionable mutations and genetic rearrangements in lung adenocarcinoma and<br />
lung squamous cell carcinoma. The consequence – at present restricted to patients with<br />
advanced disease – it a transition from empiric clinical trials based on patient characteristics<br />
to molecularly-driven clinical trials and - in clinical practice - a transition from a<br />
standardized <strong>the</strong>rapeutic approach to a personalized approach based on molecular tumor<br />
characteristics. There is evidence that <strong>the</strong> integration of EGFR tyrosine kinase inhibitors into<br />
<strong>the</strong> treatment of patients with tumors harboring an activating EGFR mutation is associated<br />
with more than a doubling of <strong>the</strong> time of survival as compared to treatment with<br />
chemo<strong>the</strong>rapy alone – no doubt a significant clinical improvement. However, <strong>the</strong> fact<br />
remains, that eventually tumors become resistant also to targeted <strong>the</strong>rapy. In consequence<br />
chemo<strong>the</strong>rapy is likely to stay as a treatment option for <strong>the</strong> future and research into how to<br />
counteract resistance will gain in importance. The major challenge however will be on how to<br />
optimally deal with new <strong>the</strong> opportunities. How to move from standardized medicine to<br />
personalized medicine will become a priority issue in health care delivery.<br />
Disclosure: The author has declared no conflicts of interest.<br />
139IN MELANOMA AS A PARADIGM MODEL TO DISCUSS THE<br />
OPPORTUNITIES AND LIMITATIONS OF REALIZING<br />
PERSONALIZED CANCER MEDICINE<br />
No abstract submitted at time of going to press.<br />
140IN DEVELOPING PATIENT-CENTRIC CANCER SERVICES FOR<br />
THE 21ST CENTURY<br />
A. Buzyn<br />
Institut National du Cancer, Boulogne Billancourt, FRANCE<br />
The future of cancer control may well involve personalized approach, although considering<br />
both <strong>the</strong> patient and <strong>the</strong> tumour uniqueness remains challenging. The wealth of<br />
Annals of Oncology 23 (Supplement 9): ix66, <strong>2012</strong><br />
doi:10.1093/annonc/mds490<br />
technological progress, improved research coordination and political willingness through<br />
cancer control plans are never<strong>the</strong>less convergent towards tailoring patient care. Nationwide<br />
access to innovation for better care is among INCa’s priorities. Researchers are mobilised to<br />
reduce health inequalities and to decipher <strong>the</strong> links between environment, behaviour and<br />
cancer occurrence. INCa’s actions towards personalised medicine include funding 28<br />
molecular genetics platforms since 2006. They perform predictive tests on tumour samples<br />
for targeted <strong>the</strong>rapies nationwide. In 2010, molecular testing was performed for 17,000 lung<br />
and 19,000 colon cancer patients. Collaboration with <strong>the</strong> pharmaceutical industry allows<br />
anticipating <strong>the</strong> release of new targeted <strong>the</strong>rapies. This organisation has proved to be cost<br />
effective for <strong>the</strong> health insurance. Its impact on <strong>the</strong>rapeutic decision is currently being<br />
assessed. Regarding <strong>the</strong> organisation of care, INCa helps structuring a care pathway that<br />
guides patients through a unique path from diagnosis stage to survivorship (including social<br />
or psychological conditions, return to employment), through 35 pilot projects. INCa also<br />
contributes to <strong>the</strong> implementation of specialised care networks: 17 networks of national<br />
expert centres combine expertise and proximity for adults with rare cancer, 15 coordination<br />
units specialised in geriatric oncology link geriatricians and oncologists, 8 experimental<br />
interregional appeal organisations promote integrated care for teenagers and young adults.<br />
Personalised medicine applied to cancers prevention and early detection is also considered.<br />
Personalized medicine in <strong>the</strong> 21th century is in progress, taking into account tumour or<br />
genetic specificities while placing individuals in <strong>the</strong> centre of <strong>the</strong> health care system.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
141INIS PERSONALISED CANCER CARE AFFORDABLE?<br />
R. Sullivan<br />
Institute of Cancer Policy, Kings Health Partners Integrated Cancer Centre,<br />
London, UNITED KINGDOM<br />
Is Cancer Care and Research Becoming a Luxury Good? Affording Cancer in <strong>the</strong> 21 st<br />
Century Cancer has become one of <strong>the</strong> most intractable global diseases in both high income<br />
and increasingly in emerging economies. This complex and complicated disease has been a<br />
major focus for R&D since <strong>the</strong> 1970’s. Global public sector spend on cancer R&D has<br />
reached over 16.5 billion euros and disease specific R&D activity in cancer dominates all<br />
o<strong>the</strong>r areas with over 14% of total global activity. Within this research activity translational<br />
cancer medicine has expanded in only 20 years to account for nearly 40% of research<br />
outputs. In parallel <strong>the</strong> direct healthcare costs of cancer now consume between 5 and 10%<br />
of high income healthcare budgets, with particular areas such as imaging and<br />
pharmaceutical costs growing at an average annual rate of over 10%. The costs of both care<br />
and research are growing beyond <strong>the</strong> ability of countries to manage and deliver cost effective<br />
R&D and national cancer plans. The vast expansion in new technologies in cancer (NME,<br />
procedures, biomarkers, etc) coupled to rapid macro-economic (especially pricing) and<br />
socio-demographic measures is overwhelming <strong>the</strong> ability of national and trans-national<br />
systems to, a) effectively translate research through appropriately powered clinical trials, and<br />
b) deliver sufficient improvements in outcomes to merit <strong>the</strong> prices now being demanded.<br />
Cancer has reached both a crossroads and is on an apparent trajectory that could see <strong>the</strong><br />
best care and fruits of research only available to affluent sectors of society. In this lecture we<br />
will explore <strong>the</strong> roots, trajectory and solutions to this convergent crisis and ask whe<strong>the</strong>r<br />
cancer care will become a luxury good; and whe<strong>the</strong>r <strong>the</strong> p-medicine agenda really can<br />
deliver tomorrows solutions or whe<strong>the</strong>r this is rapidly becoming a morally bankrupt<br />
paradigm that no-one will be able to afford.<br />
Disclosure: The author has declared no conflicts of interest.<br />
142IN PERSONALIZED CANCER CARE: EMPOWERING THE<br />
PATIENT<br />
K. Redmond<br />
Cancer World Magazine, European School of Oncology, Montagnola,<br />
SWITZERLAND<br />
The shift from <strong>the</strong> traditional “one size fits all” approach to treating cancer to a more<br />
“personalised” model where treatment is customised to <strong>the</strong> individual is good news for<br />
cancer patients. Potentially personalised cancer care will result in more optimal use of<br />
available treatments and less treatment-related side effects. Consequently patient outcomes<br />
should be improved. Cash-strapped health services are also set to benefit because resources<br />
should be used more efficiently to deliver more effective care. However, given that <strong>the</strong>re are<br />
many different cancers and cancer subtypes, and <strong>the</strong> fact that scientific advances cannot be<br />
applied equally across all cancers, it is unrealistic to think that every cancer patient will<br />
benefit from personalised cancer care over <strong>the</strong> coming decade. Moreover, <strong>the</strong>re is no<br />
guarantee that even those patients with cancers where <strong>the</strong>re is strong evidence that<br />
treatment should be customised according to tumour characteristics will gain access to more<br />
personalised treatments. This is because cancer patients’ right to receive care that is<br />
appropriate to <strong>the</strong>ir needs is not always upheld. Although numerous factors contribute to<br />
this situation; empowerment represents a key means for patients to realise <strong>the</strong>ir rights.<br />
Empowering cancer patients to be more involved in decision making can be challenging<br />
because of entrenched attitudes and beliefs, unrealistic expectations, cultural norms and<br />
literacy levels. Innovative communication technologies offer a novel way to empower<br />
patients but care is required to ensure that those who are less “technology savvy” are not<br />
discriminated by <strong>the</strong>ir lack of skills in using this media. The cancer community needs to<br />
engage closely with <strong>the</strong> media to ensure that coverage on <strong>the</strong> potential of personalised<br />
cancer care is balanced and does not generate unrealistic expectations. The media also has<br />
an important role to play to counteract negative attitudes about cancer.<br />
Disclosure: The author has declared no conflicts of interest.<br />
ix66 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
asic science<br />
143PD MET ACTIVATION BY AUTOCRINE LOOP RESCUES COLON<br />
CANCER CELLS FROM SENSITIVITY TO EGFR INHIBITION<br />
T. Troiani, D. Vitagliano, S. Napolitano, F. Morgillo, A. Capasso, V. Sforza,<br />
A. Nappi, L. Berrino, F. Ciardiello, E. Martinelli<br />
Division of Medical Oncology, Department of Experimental and Clinical Medicine<br />
and Surgery “F. Magrassi and A. Lanzara”, Second University of Naples, Naples,<br />
ITALY<br />
Background: Cetuximab, a monoclonal antibody targeting <strong>the</strong> epidermal growth<br />
factor receptor (EGFR), is active in K-RAS wild type colorectal cancer (CRC).<br />
However, initially in responding patients cancer cells would become resistant to<br />
EGFR inhibition by <strong>the</strong> activation of alternative growth controlling pathways<br />
including <strong>the</strong> hepatocyte growth factor (HGF)/MET-dependent signal.<br />
Methods: mRNA expression profiles of cetuximab-sensitive human GEO colon<br />
cancer cells and of <strong>the</strong>ir cetuximab-resistant derived GEO-CR cells were analyzed by<br />
microarrays. Protein expression levels were evaluated by western blot (WB). Growth<br />
factors were measure in <strong>the</strong> culture medium by Luminex technology. The in vitro<br />
antitumor activity of MET inhibitor (METi), was tested in a panel of ten human<br />
colon cancer cell lines by MTT assay.<br />
Results: Evaluation of gene expression profile identified a series of genes that were<br />
up-regulated in GEO-CR cells possibly involved in acquired resistance to EGFR<br />
inhibition. Among <strong>the</strong>se we found several genes involved in <strong>the</strong> MET pathway. WB<br />
analysis detected activated, phosphorylated MET in GEO-CR but not in GEO and in<br />
<strong>the</strong> o<strong>the</strong>r colon cancer cell lines tested. We also found in GEO-CR cells up-regulation<br />
of EGFR ligands such as transforming growth factor – α (TGFa) and Heparin<br />
Binding- Epidermal Growth Factor (HB-EGF). We fur<strong>the</strong>r observed expression of<br />
HGF in GEO-CR cells, supporting HGF/MET autocrine activation following acquired<br />
resistance to cetuximab treatment. In fact, <strong>the</strong> RAS/RAF/MEK/MAPK pathway was<br />
constitutively active despite of EGFR inhibition by cetuximab in GEO-CR cells<br />
possibly due to HGF-induced MET activation. Treatment with a potent and selective<br />
METi was able to overcome cetuximab resistance in GEO-CR cells and causes cell<br />
growth inhibition.<br />
Conclusion: These results suggest that autocrine activation of HGF/MET could be a<br />
relevant <strong>the</strong>rapeutic target in colorectal cancer patients that become resistant to<br />
anti-EGFR treatment.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
144PD OPTIMIZING GEMCITABINE EFFICACY THROUGH<br />
DEGRADATION OF RRM1<br />
G. Bepler, Y. Zhang, X. Li<br />
Karmanos Cancer Institute and Wayne State University, Detroit, MI, UNITED<br />
STATES OF AMERICA<br />
Objectives: RRM1 (ribonucleotide reductase M1) is <strong>the</strong> molecular target and key<br />
efficacy determinant of gemcitabine. Gemcitabine binds directly to active sites<br />
resulting in irreversible inactivation. Mechanisms that control RRM1 abundance are<br />
largely unknown, but may provide an opportunity for optimization of gemcitabine<br />
efficacy.<br />
Methods and results: We have identified that <strong>the</strong> E3 ubiquitin-protein ligases RNF2<br />
(RING finger protein 2, Ring1B) and Bmi1 (B cell-specific moloney murine leukemia<br />
virus insertion site 1) interact with RRM1 using yeast two-hybrid screening. We<br />
confirmed that RNF2and Bmi1 interact with RRM1 in vivo by immunoprecipitation.<br />
Confocal immunofluorescence microscopy revealed that RNF2 and Bmi1 completely<br />
co-localized with RRM1 in nucleus. RRM1 undergoes proteasome-mediated<br />
polyubiquitination and degradation. The proteasome inhibitor MG132 blocked <strong>the</strong><br />
turnover of RRM1. We found that RNF2 and Bmi1 can induce polyubiquitination of<br />
RRM1 in vitro and in vivo. Lysine (K) 548 and 224 are major polyubiquitination<br />
sites of RRM1. Substitution of <strong>the</strong> lysine residues 548 and 224, ei<strong>the</strong>r alone or<br />
toge<strong>the</strong>r, significantly reduced RRM1 polyubiquitination. Depletion of RNF2 and<br />
Bmi1 by siRNA increased RRM1 protein level and promoted chemoresistance to<br />
gemcitabine in vitro.<br />
Conclusions: These results establish that RNF2 and Bmi1 are E3 ubiquitin ligases of<br />
RRM1 that regulate RRM1 ubiquitination, degradation, and cellular response to<br />
Annals of Oncology 23 (Supplement 9): ix67–ix72, <strong>2012</strong><br />
doi:10.1093/annonc/mds390<br />
gemcitabine. This suggests that RNF2 and Bmi1 might be attractive <strong>the</strong>rapeutic<br />
targets to overcome gemcitabine resistance in malignancies.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
145P ZEB1 AND ZEB2 MEDIATE PANCREATIC FIBROBLAST<br />
INDUCED EPITHELIAL-TO MESENCHYMAL TRANSITION<br />
(EMT) IN PANCREATIC CANCER<br />
L. Visa 1 , E. Samper 2 , M. Rickmann 2 , A. Postigo 3 , E. Sanchez-Tilo 3 ,<br />
L. Fernandez-Cruz 4 , J. Maurel 5 , X. Molero 6 , E.C. Vaquero 2<br />
1 Department Medical Oncology, Hospital Clinic Barcelona, Barcelona, SPAIN,<br />
2 Gastroenterology Department, Hospital Clinic, Barcelona, SPAIN, 3 Oncology<br />
and Hematology, IDIBAPS, Barcelona, SPAIN, 4 Surgical Department, Hospital<br />
Clinic, Barcelona, SPAIN, 5 Medical Oncology, Hospital Clinic i Provincial,<br />
Barcelona, SPAIN, 6 Gastroenterologist, Hospital Vall Hebron, Barcelona, SPAIN<br />
EMT renders neoplastic cancer cells <strong>the</strong> ability to migrate and to invade distant<br />
organs. The hallmark of EMT is <strong>the</strong> loss of E-cadherin, which is a prerequisite for<br />
epi<strong>the</strong>lial tumor cell invasion. In pancreatic cancer, loss of tumor E-cadherin is an<br />
independent predictor of poor outcome.AIMS: To analyze <strong>the</strong> effect of pancreatic<br />
fibroblasts (PF) on inducing EMT in pancreatic cancer cells and to identify <strong>the</strong><br />
transcription factors (Snail, Slug, ZEB1, ZEB2) that mediate EMT process.<br />
Methods: Human PFs were isolated from human pancreatic specimens obtained<br />
from chronic pancreatitis and from unaffected margins of pancreatic adenocarcinoma<br />
and serous cistoadenoma. PF were cultured until complete cellular activation, as<br />
assessed by expression of a-smooth muscle actin, vimentin and fibronectin.<br />
Human pancreatic cancer cells Panc-1 were exposed to PF conditioned medium<br />
(PF-CM) and EMT analyzed by cell morphology, migration, and E-cadherin<br />
expression (quantitative RT-PCR and immunoblot). Gene expression of Snail, Slug,<br />
ZEB1, and ZEB2 was analyzed by quantitative RT-PCR, and <strong>the</strong>ir activity modulated<br />
by siRNA.<br />
Results: Conditioned media from all types of activated PFs induced EMT changes in<br />
Panc-1 cells, as shown by 1) morphological transition from cobblestone shaped to<br />
fibroblast-like cells, 2) stimulation of cell migration, and 3) E-cadherin down–<br />
regulation; mRNA expression of Snail transiently increased at 30 min after exposure<br />
to PF returning to basal levels afterwards; mRNA levels of ZEB1 were not<br />
up-regulated upon exposure to PF-CM. However, ZEB1 protein greatly accumulated<br />
after 48h incubation with PF-CM, suggesting that PF prevent ZEB1 degradation in<br />
Panc-1 cells. Combined RNA downregulation of ZEB1 and ZEB2, but not of Snail<br />
and/or Slug, suppressed E-cadherin repression induced by PF.<br />
Conclusion: Activated PFs promote <strong>the</strong> invasive phenotype of pancreatic cancer cells<br />
through ZEB1 and ZEB2 activation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
146P THE PROGNOSTIC VALUE OF MMP-9, MMP-2, TIMP-1 AND<br />
TIMP-2 IN BREAST CANCER AFTER TWELVE YEARS OF<br />
INITIAL INVESTIGATION<br />
D.C. Jinga 1 , A. Blidaru 2 , I. Condrea 3 , C. Ardeleanu 4 , D. Median 5 ,<br />
M. Stefanescu 6 , C. Matache 6<br />
1 Medical Oncology, University Bucharest Hospital, Bucharest, ROMANIA,<br />
2 Surgical, “Al.Trestioreanu” National Institute Of Oncology, Bucharest, ROMANIA,<br />
3 Pathology, “Al.Trestioreanu” National Institute of Oncology, Bucharest,<br />
ROMANIA, 4 Pathology, Victor Babes National Institute, Bucharest, ROMANIA,<br />
5 Medical Oncology, Institute of Oncology Bucharest, Fundeni Clinical Hospital<br />
Alexandru Treistoreanu, Bucharest, ROMANIA, 6 Immunology, Cantacuzino<br />
National Research for Microbiology and Immunology, Bucharest, ROMANIA<br />
Background: The aim of this study was to investigate <strong>the</strong> prognostic power of<br />
matrixmetalloproteinases (MMP-9, MMP-2) expression and activity as well as <strong>the</strong>ir<br />
natural inhibitors (TIMP-1, TIMP-2) expression in breast cancer tumours.<br />
Patients and methods: All of <strong>the</strong> experimental parameters were evaluated in fresh<br />
tumour tissue samples from thirty-two consecutive patients with primary invasive<br />
breast carcinomas collected between 2001-2002. Gelatinase activity (MMP-9 and<br />
MMP-2) was analysed by zymography while <strong>the</strong> expression level of MMP-9, MMP-2,<br />
TIMP-1 and TIMP-2 was quantified by commercial ELISA kits in 1% Triton-X 100<br />
tumour extracts. The Mann-Whitney U test and Spearman’s coefficient where<br />
calculated in order to establish <strong>the</strong> correlation of <strong>the</strong> experimentally determined<br />
parameters with relapse free survival (RFS), overall survival (OS) and <strong>the</strong> presence of<br />
metastasis and death (D) at <strong>the</strong> end of study.<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com<br />
abstracts
Results: TIMP-1 expression was increased in <strong>the</strong> groups of patients with RSF < 104<br />
months, with OS < 113 months and in those who died by comparison with <strong>the</strong>ir<br />
counterparts. These patients, especially <strong>the</strong> group with OS < 113 months, have also<br />
<strong>the</strong> lowest levels of TIMP-2 (p = 0.058). Therefore, MMP-2/TIMP-2 ratio<br />
distinguished statistically significant <strong>the</strong> groups of patients with OS greater and lower<br />
than 113 months (p = 0.051). On <strong>the</strong> o<strong>the</strong>r hand, TIMP-1/TIMP-2 ratio<br />
distinguished statistically significant groups of patients with RFS more than 104<br />
months (p = 0.057), with OS more than 113 months (p = 0.068) or alive (p = 0.038)<br />
of <strong>the</strong>ir counterparts. TIMP-1/TIMP-2 ratio directly correlated with <strong>the</strong> death of<br />
patients (r = 0.381, p = 0.034), being significantly higher in <strong>the</strong> group of patients who<br />
died.<br />
Conclusions: Our data suggested that as TIMP-1 expression is lower and TIMP-2<br />
expression is higher, both relapse free survival and overall survival are higher.<br />
TIMP-1/TIMP-2 and MMP-2/TIMP-2 ratios seemed to be long term prognostic<br />
markers. These results are consistent with our previous observation that showed a<br />
direct correlation between MMP-2/TIMP-2 ratio and <strong>the</strong> value of Nottingham<br />
Prognostic Index.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
147P HOX GENE EXPRESSION IN OVARIAN CANCER<br />
Z. Kelly 1 , H. Pandha 1 , K. Madhuri 2 , R. Morgan 2 , A. Michael 3<br />
1 Department of Microbial and Cellular Science, University of Surrey, Guildford,<br />
UNITED KINGDOM, 2 Gynaecology and Surgery, Royal Surrey County Hospital,<br />
Guildford, UNITED KINGDOM, 3 Oncology, University of Surrey PGMS,<br />
Oncology, Guildford, UNITED KINGDOM<br />
Background: Ovarian cancer is <strong>the</strong> leading cause of cancer death among all<br />
gynaecological cancers. The aggressive nature of ovarian cancer is partly due to its<br />
heterogeneity and lack of effective treatment strategies o<strong>the</strong>r than surgery and<br />
standard chemo<strong>the</strong>rapy. Fur<strong>the</strong>r work to understand <strong>the</strong> molecular changes and<br />
design more effective drugs is essential. We have studied <strong>the</strong> expression of HOX<br />
genes-a family of homeodomain-containing transcription factors that determine cell<br />
and tissue identity in <strong>the</strong> early embryo and have been found to be dysregulated in<br />
cancer. We looked at <strong>the</strong> HOX gene expression profile of all 39 HOX genes in<br />
primary ovarian and peritoneal tumours of different histotypes.<br />
Methods: HOX gene expression profiles were analysed in ovarian tumour samples<br />
and compared to normal ovarian tissue. RNA was isolated from tumour samples<br />
using <strong>the</strong> RNeasy® Plus Mini Kit (Qiagen Ltd) and <strong>the</strong> relative expression of all<br />
39HOX genes were determined by quantitative real-time polymerase chain reaction.<br />
The 2-tailed student’s t-test was applied to determine significant differences between<br />
tumours and normal ovary.<br />
Results: We have analysed a cohort of 72 patients with epi<strong>the</strong>lial ovarian cancer-59<br />
serous, 5 endometrioid, 5 clear cell, 3 MMMT and one mucinous. Dysregulation of<br />
certain HOX genes expression was found in <strong>the</strong> majority of ovarian tumour samples<br />
with little to no expression in normal ovarian epi<strong>the</strong>lium. By comparing HOX genes<br />
from all histotypes with normal ovarian tissue, 28 HOX genes were found to be<br />
upregulated in <strong>the</strong> tumours with P-values < 0.0001 for 20 genes. Expression of<br />
HOXB1, B2, B3, B7, B13, C11 and D12 were only seen in cancer tissue. HOXA9 and<br />
HOXB5 were found to be most highly expressed. The expression of HOXB5 was seen<br />
in 98% of <strong>the</strong> cancers analysed as compared with <strong>the</strong> normal ovarian tissue. The<br />
expression did not correlate with <strong>the</strong> clinical stage or CA-125 levels at presentation.<br />
The median follow up of <strong>the</strong> cohort was 26 months and median survival has not<br />
been reached.<br />
Conclusion: HOX genes were shown to be dysregulated in ovarian tumours, with a<br />
number of genes showing significant upregulation compared to normal ovarian<br />
epi<strong>the</strong>lium. HOXB5 and HOXA9 are <strong>the</strong> most highly up-regulated. This suggests<br />
that HOX genes may have a role in ovarian cancer oncogenesis.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
148P TARGETING NFKB IN CISPLATIN RESISTANT NSCLC<br />
K.A. Gately 1 , S. Heavey 1 , P. Godwin 1 , M. Barr 2 , K.J. O’Byrne 3<br />
1 Clinical Medicine, Trinity College Dublin/St James Hospital, Dublin, IRELAND,<br />
2 Clinical Medicine, Trinity College Dublin, Dublin, IRELAND, 3 Hope Directorate, St<br />
James’s Hospital, Dublin, IRELAND<br />
The most effective systemic chemo<strong>the</strong>rapy for Non Small Cell Lung Cancer (NSCLC)<br />
is cisplatin-based combination treatment. However, chemoresistance is a major<br />
<strong>the</strong>rapeutic problem with <strong>the</strong> patients’ tumours ei<strong>the</strong>r de novo resistant to <strong>the</strong>rapy or<br />
ultimately developing resistance to cisplatin. Understanding <strong>the</strong> mechanisms<br />
underpinning cisplatin resistance (CR) may lead to <strong>the</strong> development of predictive<br />
biomarkers and novel <strong>the</strong>rapies for NSCLC and o<strong>the</strong>r platinum treated tumours in<br />
<strong>the</strong> future. The NF-κB pathway has been implicated in tumour initiation,<br />
progression, and resistance to chemo<strong>the</strong>rapy. Although small-molecule inhibitors of<br />
NF-κB have been proposed as single-agent <strong>the</strong>rapies for cancers with aberrant<br />
NF-κB activity, most classic NF-κB inhibitors are poorly selective and result in<br />
off-target effects. Dehydroxymethyl-epoxyquinomicin (DHMEQ) is an inhibitor of<br />
Annals of Oncology<br />
low molecular weight designed from <strong>the</strong> structure of <strong>the</strong> antibiotic epoxyquinomicin<br />
C. The aim of this study is to investigate <strong>the</strong> role of <strong>the</strong> PI3K-NFκB pathway in<br />
resistance to cisplatin in NSCLC and assess <strong>the</strong> effect of NF-κB inhibition by<br />
DHMEQ in cisplatin sensitive and resistant cell lines. A panel of cisplatin resistant<br />
NSCLC cell lines (H460, SKMES1, A549) were developed in our laboratory. H460<br />
parent & resistant cell lines were screened for changes in mRNA expression using <strong>the</strong><br />
PI3K Profiler array (SABiosciences). Changes in gene expression were validated by<br />
QPCR and protein expression by Western blot and HCA. IkBa exons 3-5 were<br />
screened for mutations by sequencing. The effect of DHMEQ (inhibitor of NF-κB<br />
translocation) was assessed by HCA assays. An 11.99 fold increase in IkBa mRNA<br />
expression was identified in <strong>the</strong> cisplatin resistant H460 cells compared to parent<br />
cells. QPCR, Western blot and HCA confirmed this overexpression of IkBa. No<br />
mutations were identified in exons 3-5 of <strong>the</strong> IkBa gene. Inhibition of NF-kB by<br />
DHMEQ led to increased apoptosis and decreased proliferation in cisplatin resistant<br />
cells versus parent cells implying NF-kB plays a significant role in cisplatin<br />
resistance. We are evaluating <strong>the</strong> synergistic effects of DHMEQ and cisplatin both in<br />
vitro and in vivo on tumour growth and spontaneous lung metastasis in athymic<br />
nude mice. DHMEQ may provide a beneficial treatment strategy for NSCLC patients<br />
who progress on cisplatin.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
149P MICRORNA PROFILING AND CDDP-GPG DNA ADDUCT<br />
FORMATION ANALYSIS IN A PANEL OF CISPLATIN<br />
RESISTANT NON-SMALL CELL LUNG CANCER CELL LINES<br />
M. Barr 1 , S.G. Gray 2 , D.A. Fennell 3 , J.J. O’Leary 4 , D. Richard 5 , J. Thomale 6 ,<br />
A.C. Hoffmann 7 , K.J. O’Byrne 1<br />
1 Clinical Medicine, St James’s Hospital, Dublin, IRELAND, 2 Clinical Medicine,<br />
Trinity College Dublin, Dublin, IRELAND, 3 Centre for Cancer Research and Cell<br />
Biology, Queen’s University Belfast, Belfast, UNITED KINGDOM,<br />
4 Histopathology, St James’s Hospital, Dublin, IRELAND, 5 Queensland University<br />
of Technology, Institute of Health and Biomedical Innovation, Brisbane,<br />
AUSTRALIA, 6 Cancer Research, Institute for Cell Biology, University Hospital<br />
Essen, Germany, Essen, GERMANY, 7 Internal Medicine (Cancer Research),<br />
Molecular Oncology Risk-Profile Evaluation (M.O.R.E) University Hospital Essen,<br />
Germany, Essen, GERMANY<br />
Introduction: The outcome of cisplatin <strong>the</strong>rapy in NSCLC has reached a plateau,<br />
with <strong>the</strong> development of resistance being a major obstacle in <strong>the</strong> use of this drug.<br />
Understanding <strong>the</strong> molecular mechanisms underlying this resistance phenotype may<br />
aid in <strong>the</strong> development of novel agents that enhance <strong>the</strong> sensitivity of cisplatin. In<br />
this study, we examined <strong>the</strong> microRNA profile and levels of cisplatin-DNA adduct<br />
formation in a panel of cisplatin resistant NSCLC cell lines.<br />
Methods: We have previously generated a panel of cisplatin resistant (CisR) cell lines<br />
(MOR, H460, A549, SKMES-1, H1299) from original, age-matched parent (PT) cells<br />
and extensively characterised <strong>the</strong>se based on a number of functional assays including<br />
proliferation (MTT), apoptosis (FACS), cell cycle arrest (PI staining), survival ability<br />
(clonogenic assay), DNA copy number gains and losses (CGH arrays) and cancer<br />
stem cell marker expression (CD44, CD133, ALDH1, Nanog, Sox-2 and Oct-4) by<br />
FACS and Western blot analysis. MicroRNA profiling was carried out using <strong>the</strong><br />
nCounter miRNA Expression Assay consisting of 749 target miRNA’s.<br />
Immunofluorescence staining and measurement of specific DNA platination<br />
products (CDDP-GpG DNA adducts) was performed at 0, 4, 12 and 24h using<br />
immunofluorescence microscopy and quantitative digital image analysis using <strong>the</strong><br />
ACAS 6.0 CytometryAnalysis System, respectively.<br />
Results: In a panel of five NSCLC cell lines exhibiting a cisplatin resistant phenotype,<br />
a 3- and 13-miRNA signature was deduced, based on differential expression of 3<br />
miRNA’s (5/5 cell lines) and 13 miRNA’s (4/5 cell lines) in <strong>the</strong> CisR cell lines<br />
relative to <strong>the</strong>ir parent counterparts. Levels of CDDP-GpG adducts were greatly<br />
reduced in resistant cells up to 24h in response to cisplatin compared to that<br />
observed in corresponding parent cells.<br />
Conclusion: We have identified a distinct miRNA fingerprint in a clinically relevant,<br />
isogenic model of cisplatin resistance that may predict resistance to cisplatin in lung<br />
cancer. Fur<strong>the</strong>rmore, as cisplatin-DNA adducts correlate with cisplatin resistance in<br />
vitro, <strong>the</strong>se may be used as a potential predictive marker in patient response to<br />
platinum <strong>the</strong>rapy in NSCLC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
150P IL-23 IS EPIGENETICALLY REGULATED AND INDUCED BY<br />
CHEMOTHERAPY IN NSCLC<br />
A. Baird, J. Leonard, L. Kilmartin, É. Dockry, K.J. O’Byrne, S.G. Gray<br />
Clinical Medicine, Trinity College Dublin/St. James’s Hospital, Dublin, IRELAND<br />
Introduction: Inflammation plays a role in many malignant states including lung<br />
carcinogenesis. IL-23A is one such inflammatory mediator which may have a role in<br />
lung cancer. It is a hetero-dimeric cytokine composed of two covalently linked<br />
subunits consisting of p19 and p40. IL-23A plays a key role in chronic inflammation<br />
and angiogenesis through <strong>the</strong> promotion of IL-17 production by T helper 17 cells via<br />
ix68 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
<strong>the</strong> STAT signalling pathway and NF-κB. This study sought to determine <strong>the</strong><br />
expression and regulation of IL-23A in NSCLC.<br />
Methods: IL-23A expression levels were determined in a series of 34 tumour<br />
specimens with matched normal tissue taken from patients presenting with NSCLC.<br />
Basal expression levels were also examined in a panel of normal and NSCLC cell<br />
lines at <strong>the</strong> mRNA level. Using histone deacetylase (HDi), DNA methyltransferase<br />
(DNMTi) inhibitors and a ChIP assay it was determined if IL-23A was subject to<br />
epigenetic regulation in NSCLC cell lines (adenocarcinoma and squamous cell<br />
carcinoma). The effect of Gemcitabine on IL-23A expression was also studied. In<br />
addition, <strong>the</strong> effect of recombinant IL-23 treatment on NSCLC cell line proliferation<br />
was examined.<br />
Results: In a cohort of NSCLC patients, IL-23A expression levels were significantly<br />
elevated in tumour tissue compared with normal (p < 0.05). This elevation was also<br />
evident within <strong>the</strong> NSCLC sub types. Treatment with TSA (p < 0.05) and SAHA<br />
(p < 0.05) induced <strong>the</strong> expression of IL-23A in <strong>the</strong> A549 and SK-MES-1 cell lines. A<br />
ChIP assay confirmed dynamic remodelling of <strong>the</strong> IL-23A promoter region.<br />
Significant induction of IL-23A was also evident post treatment with a DNMTi<br />
(5-Aza-2’-Deoxycytidine) and Gemcitabine. Fur<strong>the</strong>rmore, treatment with<br />
recombinant IL-23 increased cellular proliferation in NSCLC cell lines that express<br />
functional IL-23R receptors.<br />
Conclusion: IL-23A was significantly elevated in a cohort of NSCLC patient tissues<br />
and is epigenetically regulated through histone post-translational modifications and<br />
DNA CpG residue methylation. The chemo<strong>the</strong>rapy agent, Gemcitabine, also induced<br />
IL-23A expression. Additionally, IL-23 promoted NSCLC cell line proliferation.<br />
These results may have important implications for treating NSCLC patients with<br />
epigenetic targeted <strong>the</strong>rapies or Gemcitabine.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
151P INTRATUMOR HETEROGENEITY OF ER STATUS IS A<br />
FEATURE OF INTERACTION BETWEEN MAMMARY<br />
CARCINOMA CELLS AND MICROENVIRONMENT<br />
I. Boichuk 1 , D. Burlaka 2<br />
1 Department of Cancer Experimental Therapeutics, R.E. Kavetsky Institute of<br />
Experimental Pathology, Oncology and Radiobiology, Kyiv, UKRAINE,<br />
2 Biotechnical Problems of Diagnostic, Institute Problems of Cryobiology and<br />
Cryomedicine of <strong>the</strong> National Academy of Sciences (IPCC), Kiev, UKRAINE<br />
The growth and survival of mammary carcinoma cells often depend on <strong>the</strong>ir<br />
estrogen sensitivity proving a rationale for targeted <strong>the</strong>rapy. The relationship between<br />
tumor growth and changing hormonal environment is demonstrated both in<br />
experiment and in clinical setting (age-related difference in breast cancer prognosis,<br />
changing estrogen and progesterone receptor patterns in breast carcinoma during <strong>the</strong><br />
menstrual cycle and menopause, etc.). The aim of this study was to analyze <strong>the</strong><br />
effects of <strong>the</strong> changing hormonal environment in <strong>the</strong> setting of <strong>the</strong> oestrus cycles on<br />
tumor growth and levels of estrogen receptors (ER) in murine mammary tumors.<br />
Methods: The dextran-coated charcoal radioactive ligand-binding ER assay method<br />
was used followed by Scatchard analysis.<br />
Results: The increment of tumor volume in mouse with mammary carcinoma is not<br />
a linear one but followed <strong>the</strong> pattern of changing hormonal levels within 4-day<br />
oestrus cycle in a wave-shaped manner. Upon <strong>the</strong> plateau of tumor growth, receptors<br />
are lost in half of cells. Thus, <strong>the</strong> population becomes heterogeneous in ER content.<br />
The widely accepted hypo<strong>the</strong>sis that <strong>the</strong> interaction of estrogen with cellular ER<br />
determines <strong>the</strong> hormone dependency of mammary tumors should now be challenged<br />
on <strong>the</strong> basis of <strong>the</strong> following observations: a) tumors arising in experimental animals<br />
with permanent high estrogen levels are receptor-positive and that with low estrogen<br />
levels are receptor-negative; b) tumors regrowing after complete or partial regression<br />
as a result of endocrine ablation or hormone administration are considered to be<br />
environment dependent ra<strong>the</strong>r than autonomous or hormone dependent; c)<br />
mammary tumors growing in <strong>the</strong> setting of cyclically changing hormonal level<br />
become heterogeneous.<br />
Conclusion: Tumor cells are highly sensitive to alterations in hormonal background.<br />
The adaptation to <strong>the</strong> altered microenvironment could promote metastases, tumor<br />
heterogeneity, and, oddly enough, transform <strong>the</strong> tumors into a nonmalignant state.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
152P BONE MARROW TRANSPLANTATION RESCUES INTESTINAL<br />
MUCOSA AFTER WHOLE BODY RADIATION VIA PARACRINE<br />
MECHANISMS<br />
H. Chang 1 , Y.H. Chang 1 , L. Lin 1 , C. Lou 1 , C. Chou 2<br />
1 National Institute of Cancer Research, National Health Research Institutes,<br />
Tainan, TAIWAN, 2 National Laboratory Animal Center, National Applied Research<br />
Laboratories, Taipei, TAIWAN<br />
Background: Our previous study reveals BM transplantation (BMT) triggers<br />
trafficking of host CD11b(+) myelomonocytic cells from <strong>the</strong> host marrow to <strong>the</strong><br />
radiation-injured intestinal mucosa, enhancing <strong>the</strong> proliferation of intestinal stroma<br />
cells, leading secondarily to epi<strong>the</strong>lial regeneration. In this study, we propose that<br />
BMT ameliorates intestinal damage via paracrine mechanisms.<br />
Materials and methods: Mouse survival, intestine microcolony assay, angiogenic<br />
cytokine array, immunonhistochemical studies of both intestine and BM were<br />
evaluated in mice after WBI and BMT. Epi<strong>the</strong>lial and stromal components within<br />
intestine mucosa were measured by immunoblotting and flowcytometry. BM<br />
conditioned medium (BMCM) with or without treatment with neutralizing<br />
antibodies to angiogenic cytokines were continuously infused to mice after WBI or<br />
whole abdomen irradiation. Carrageenan was used to deplete myelomonocytic cells<br />
of recipient mice.<br />
Results: BMT increases VEGF, bFGF and o<strong>the</strong>r angiogenic cytokines within intestine<br />
mucosa within 24 hrs after WBI. Continuous infusion of BMCM alone ameliorated<br />
radiation-induced intestine damage and improved survival of mice. Proliferation<br />
index, endo<strong>the</strong>lial cells, myofibroblasts as well as myelomonocytic cells within<br />
intestine were increased by BMCM within one week after radiation. Neutralization of<br />
bFGF, PDGF and o<strong>the</strong>r angiogenic cytokines within BMCM abolished <strong>the</strong> mitigating<br />
effect to intestine. Pretreatment of carrageenan to recipient mice depleted CD11b(+)<br />
myelomonocytic cells and reversed some of <strong>the</strong> angiogenic cytokine levels, including<br />
VEGF, within intestine mucosa after BMT from healthy donors.<br />
Conclusions: Our results suggest that BMT recruits host CD11b(+) myelomonocytic<br />
cells and enhances intestine stroma proliferation by secreting angiogenic cytokines<br />
including PDGF, bFGF. Host CD11b(+) myelomonocytic cells fur<strong>the</strong>r uplift <strong>the</strong><br />
angiogenic effect via cytokines including VEGF.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
153P TOCILIZUMAB CAN ENHANCE THE ANTI-TUMOR EFFECT OF<br />
IFN-α IN RENAL CELL CARCINOMA<br />
T. Oguro 1 , K. Ishibashi 1 , T. Sugino 2 , S. Kumagai 1 , N. Takahashi 1 , N. Haga 1 ,<br />
T. Yanagida 1 , K. Aikawa 1 , O. Yamaguchi 3 , Y. Kojima 1<br />
1 Urology, Fukushima Medical University, Fukushima, JAPAN, 2 Pathology,<br />
Fukushima Medical University, Fukushima, JAPAN, 3 Bioenginnering, Nihon<br />
University, Koriyama, JAPAN<br />
Background: Interleukin 6 (IL-6), one of <strong>the</strong> proinflammatory cytokines, contributes<br />
to <strong>the</strong> onset and maintenance of various types of cancer. IL-6 signaling induces<br />
up-regulation of SOCS3, which leads to interferon (IFN) –α resistance in renal cell<br />
carcinoma (RCC) cells. To propose a new treatment for mRCC, we investigated <strong>the</strong><br />
effect of combination <strong>the</strong>rapy with IFN-α and humanized antihuman IL-6R<br />
antibody, tocilizumab.<br />
Material and methods: Real time PCR (RT-PCR) was used to analyze gene<br />
expression of IL-6 and SOCS3 after IFN stimulation and ELISA were used for IL-6<br />
secretion in RCC cell lines. These expression levels were compared among <strong>the</strong> RCC<br />
cell lines, i.e., ACHN, Caki-1, TUHR3TKB, TUHR4TKB and 786-O.<br />
Phosphorylation of STAT-1, STAT-3 and ERK were investigated by Western blotting<br />
(WB) analysis. We investigated alteration of IL-6 signaling by tocilizumab, and<br />
analyzed its impacts on <strong>the</strong> susceptibility to IFN-α in RCC cells by MTT assay. The<br />
effects of tocilizumab on in vivo growth on 786-O xenografts were determined by<br />
SOCS3 expression, morphological observation and tumor volume.<br />
Results: Among <strong>the</strong> RCC cell lines, <strong>the</strong> expression levels of IL-6, SOCS3 in RT-PCR<br />
and <strong>the</strong> production level of IL-6 were highest in 786-O. These results revealed a<br />
correlation between <strong>the</strong> expression levels IL-6 and SOCS3 (P = 0.0001, r = 0.99974).<br />
Although <strong>the</strong> 786-O cells had IFN-α resistance, MTT assay showed that <strong>the</strong><br />
tocilizumab induced a growth inhibitory effect of IFN-α. WB analysis showed that<br />
phosphorylation level of STAT-1 was increased and <strong>the</strong> levels of STAT-3 and ERK<br />
were decreased with <strong>the</strong> simultaneous use of tocilizumab in 786-O cells. An in vivo<br />
study demonstrated that tocilizumab promoted IFN-α-induced cell death and growth<br />
suppression in 786-O cell xenograft in nude mice.<br />
Conclusions: IL-6 could be a key component in <strong>the</strong> resistance to IFN-α treatment of<br />
renal cell carcinoma. Antihuman IL-6R antibody can be an effective strategy to<br />
enhance <strong>the</strong> anti-tumor effect of IFN-α, and probably, <strong>the</strong> effect of angiogenic<br />
inhibitors, in human RCC cells.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
154P CO-TARGETING THE PI3K-MTOR & MEK PATHWAYS IN<br />
NSCLC<br />
S. Heavey, M. Barr, A. Ahmad, A. Davies, K.J. O’Byrne, K.A. Gately<br />
Clinical Medicine, Trinity College Dublin, Dublin, IRELAND<br />
The PI3K/Akt/mTOR and MAP/ERK kinase (MEK) pathways regulate cell growth<br />
and proliferation and are often dysregulated in cancer due to mutation, amplification,<br />
deletion, methylation and post-translational modifications. We and o<strong>the</strong>rs have<br />
shown that activation of <strong>the</strong> PI3K pathway in Non Small Cell Lung Cancer (NSCLC)<br />
leads to a more aggressive, drug-resistant disease which correlates to poor prognosis<br />
for patients. Combinations of PI3K and MEK and inhibitors have shown promise in<br />
preclinical cancer models, leading to <strong>the</strong> initiation of clinical trials cotargeting <strong>the</strong>se<br />
two key cancer signalling pathways. The selection of appropriate patient cohorts who<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds390 | ix69
will benefit from this targeted <strong>the</strong>rapy, using biomarkers, is key to <strong>the</strong> success of<br />
<strong>the</strong>se inhibitors. GDC-0941 is a PI3K targeted inhibitor which is currently in phase<br />
II trials for combination treatment with carboplatin, paclitaxel and bevacizumab in<br />
patients with previously untreated advanced or recurrent NSCLC. GDC-0980 is a<br />
selective dual inhibitor of PI3K and mTOR, which is currently in phase I trials for<br />
combination treatment with bevacizumab, trastuzumab and capecitabine in solid<br />
tumours. GDC-0973 is a MEK targeted inhibitor which is currently in Phase I<br />
clinical trials for treatment of patients with solid tumours in combination with<br />
GDC-0941. The aim of this study is to investigate <strong>the</strong> effects of GDC-0941,<br />
GDC-0980 and GDC-0973 alone and in combination on a panel of NSCLC cell lines<br />
and to develop cell line models resistant to dual inhibitor GDC-0980 which will <strong>the</strong>n<br />
be characterised to elucidate mechanisms involved in acquired resistance. The effects<br />
of GDC-0941 and GDC-0980 on pAkt, pS6 and cPARP levels, and <strong>the</strong> effects of<br />
GDC-0973 on MAPK and Bim levels were analysed by Western blot. The effects of<br />
<strong>the</strong>se inhibitors alone and in combination on cell proliferation and apoptosis were<br />
analysed by BrdU assay and by multiparameter apoptosis assays (using High Content<br />
Analysis) respectively. The results varied across <strong>the</strong> panel of cell lines, however <strong>the</strong><br />
dual inhibitor GDC-0980 demonstrated more significant anti-proliferative and<br />
pro-apoptotic effects than PI3K inhibitor GDC-0941. IC50 values for GDC-0980 are<br />
currently being used to treat <strong>the</strong> panel of cell lines in order to develop cell line<br />
models of resistance.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
155P EFFECT OF BEVACIZUMAB ON TUMOUR 5-FLUOROURACIL<br />
CONCENTRATION AND MICROCIRCULATORY PARAMETERS<br />
OBTAINED BY DYNAMIC CONTRAST-ENHANCED MRI IN A<br />
HEPATOCELLULAR CARCINOMA XENOGRAFT MODEL<br />
S. Mikulski 1 , L. Wang 2 , S. Hartono 3 , L. Martarello 4 , T.S. Koh 5 , B.C. Goh 2 ,<br />
C.H. Thng 5 , Q.S. Ng 6<br />
1 Graduate Medical School, Duke-NUS, Singapore, SINGAPORE, 2 Cancer<br />
Science Institute of Singapore, National University of Singapore, Singapore,<br />
SINGAPORE, 3 School of Electronic & Electrical Engineering, Nanyang<br />
Technological University, Singapore, SINGAPORE, 4 Roche Translational Medicine<br />
Hub, SingHealth, Singapore, SINGAPORE, 5 Department of Oncologic Imaging,<br />
National Cancer Centre, Singapore, SINGAPORE, 6 Department of Medical<br />
Oncology, National Cancer Centre, Singapore, SINGAPORE<br />
Introduction: Vascular endo<strong>the</strong>lial growth factor (VEGF) is expressed by tumours to<br />
promote angiogenesis. Clinical trials of anti-VEGF <strong>the</strong>rapy combined with<br />
chemo<strong>the</strong>rapy demonstrate improvement in survival. We investigate <strong>the</strong> effect of<br />
bevacizumab (bev), a humanized monoclonal antibody that inhibits VEGF-A, on<br />
tumour 5-fluorouracil (5FU) concentration in a hepatocellular carcinoma (HCC)<br />
xenograft model, toge<strong>the</strong>r with changes in tumour microcirculatory parameters<br />
obtained by dynamic contrast-enhanced (DCE) MRI.<br />
Methods: 48 immunodeficient mice implanted with subcutaneous HCC xenografts<br />
were first injected with bev (1mg/kg or 10mg/kg) or omalizumab (control). 1 day<br />
later, <strong>the</strong>y received 5FU and were sacrificed. Tumour and plasma 5FU concentration<br />
was measured by liquid chromatography-mass spectrometry. A subset of 17 mice<br />
underwent DCE MRI with gadolinium contrast at baseline and one day after bev/<br />
omalizumab injection. Scans employed a three-dimensional spoiled gradient recalled<br />
sequence with tracer concentration estimated using variable flip-angle technique.<br />
Data analysis employed a conventional two-compartment tracer kinetic model.<br />
Results: Tumour 5FU concentration (µg/g) was significantly lower 1 day after bev<br />
(10mg/kg) compared to control (8.4 vs 21.6, p = 0.027). However, <strong>the</strong>re was no<br />
significant difference in plasma 5FU concentration between <strong>the</strong> bev and control<br />
groups. Following bev (10mg/kg), DCE MRI measurements of tumour intravascular<br />
blood volume reduced by 38.3% (p = 0.01); <strong>the</strong>re was no significant change in<br />
DCE-MRI parameters in <strong>the</strong> control group. Following bev (1mg/kg), tumour<br />
permeability-surface area product (ml/100ml/min) correlated with tumour 5FU<br />
concentration (r 2 = 0.84, p = 0.01).<br />
Conclusion: Bev causes vascular shutdown consistent with its anti-angiogenic mode<br />
of action. Reduced tumour 5FU concentration suggests that <strong>the</strong> reported synergism<br />
between anti-VEGF and chemo<strong>the</strong>rapy may not be attributable to improved drug<br />
delivery at this early time point. DCE-MRI may play a role as a biomarker for<br />
tumour drug concentration following anti-VEGF <strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
156P TARGETING HSP90 IN IRRADIATED CANCER CELLS BLOCKS<br />
DNA-REPARATIVE, ANTIAPOPTOTIC AND ANGIOGENIC<br />
PATHWAYS<br />
V. Kudryavtsev, A. Demidkina, A. Kabakov<br />
Department of Radio<strong>the</strong>rapy, Medical Radiology Research Center, Obninsk,<br />
RUSSIAN FEDERATION<br />
Introduction: Human tumors are often resistant to radio<strong>the</strong>rapy; <strong>the</strong>refore,<br />
radiosensitization of <strong>the</strong>m is of importance. We explored how<br />
17-N-allilamino-17-demethoxygeldanamycin (17AAG), an inhibitor of <strong>the</strong> heat<br />
shock protein 90 (Hsp90) chaperone activity, affects radiation response of breast<br />
cancer cells. In addition, we examined effects of 17AAG on <strong>the</strong> angiogenic signaling<br />
because tumor-stimulated angiogenesis is a factor decreasing <strong>the</strong> efficacy of<br />
radio<strong>the</strong>rapy.<br />
Methods: MCF-7 cells cultured from human breast carcinoma were exposed to<br />
clinically relevant doses (2-5 Gy) of gamma-radiation, while some samples were<br />
co-treated with 10-500 nM 17AAG. The cell death/survival was assessed in<br />
annexin-V staining and clonogenic assays. Certain cell death-, DNA repair- and<br />
angiogenesis-related proteins were probed by immunoblotting. The p53 and ATM<br />
patterns were visualized by immunofluorescence.<br />
Results: In <strong>the</strong> breast cancer cells, 40-150 nM 17AAG inhibited <strong>the</strong> Hsp90<br />
chaperone function and down-regulated <strong>the</strong> Akt, survivin, HIF-1alpha, VEGF and<br />
Bcl-2 levels. The phosphorylation of Akt and its down-stream targets such as Bad,<br />
XIAP, GSK-3 or MDM2 became impaired. Enhanced activation of p53 and its longer<br />
up-regulation toge<strong>the</strong>r with <strong>the</strong> inhibition of phosphorylation and nuclear<br />
translocation of ATM were found in <strong>the</strong> cells irradiated at 2-5 Gy after incubation<br />
with 40-150 nM 17AAG. The cells co-treated by such a way exhibited massive<br />
apoptosis and sharply decreased clonogenicity, whereas <strong>the</strong> same irradiation without<br />
17AAG induced <strong>the</strong> less cytotoxicity. This radiosensitization seems to be due to (i)<br />
down-regulation or inactivation of antiapoptotic proteins (Akt, Bcl-2, survivin,<br />
XIAP), (ii) activation of pro-apoptotic proteins (Bad, GSK-3) and (iii) switching <strong>the</strong><br />
MDM2/p53/ATM-mediated DNA damage response from DNA repair to apoptosis.<br />
Besides <strong>the</strong> enhancement of radiation-induced killing of <strong>the</strong> cancer cells, 40-150 nM<br />
17AAG impaired <strong>the</strong>ir angiogenic potential that was revealed on down-regulation of<br />
HIF-1alpha and VEGF.<br />
Conclusion: Clinically achievable concentrations of 17AAG allow to enhance <strong>the</strong><br />
radiation response of human breast tumors and to suppress <strong>the</strong> tumor-stimulated<br />
angiogenesis.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
157P RITUXIMAB INDUCED INTERNALISATION OF B-CELLS CD20<br />
RECEPTOR IS INDEPENDENT OF THE INHIBITORY FC<br />
RECEPTOR (CD32B) INTRACELLULAR CELL SIGNALLING<br />
V. Shah, A. McIntosh, C.H.T. Chan, S.H. Lim, A.T. Vaughan, M.J. Glennie,<br />
A. Roghanian, M.S. Cragg<br />
Antibody and Vaccine Group, Cancer Sciences Unit, Southampton University<br />
Faculty of Medicine, University of Southampton, Southampton, UNITED<br />
KINGDOM<br />
The anti-CD20 monoclonal antibody, rituximab, has improved treatment outcomes<br />
in B-cell malignancies. However, several B-cell lymphomas ei<strong>the</strong>r do not respond to<br />
rituximab or develop resistance. Internalisation of rituximab may be partly<br />
responsible for this resistance. We recently showed that <strong>the</strong> level of <strong>the</strong> inhibitory Fc<br />
receptor (CD32B) at <strong>the</strong> cell surface controls <strong>the</strong> rate of rituximab internalisation.<br />
However, <strong>the</strong> precise mechanism involved has not been elucidated. Different isoforms<br />
of CD32B exist (B1 and B2), only one of which (B2) has previously been associated<br />
with an ability to internalise after engagement of immune complexes. The B1 form<br />
in contrast contains an additional intracellular region that makes it more resistant to<br />
internalisation. We <strong>the</strong>refore investigated <strong>the</strong> role of <strong>the</strong> two different CD32B<br />
isoforms (B1 and B2) and <strong>the</strong> associated intracellular tail on rituximab<br />
internalisation. CD32B1 and CD32B2 isoforms were stably transfected into<br />
CD32B −ve mouse IIA1.6 and human Ramos lymphoma cells, and flow cytometry was<br />
<strong>the</strong>n used to determine <strong>the</strong> relative rates of CD32B and CD20 internalisation.<br />
Additionally, we generated mutant versions of <strong>the</strong> CD32B receptors, including those<br />
lacking <strong>the</strong> entire cytoplasmic domain to assess <strong>the</strong> importance of intracellular<br />
signalling. In contrast to expectations both B1 and B2 CD32B isoforms were<br />
downregulated upon engagement with CD32B mAb as a surrogate for immune<br />
complexes, although in agreement with earlier reports <strong>the</strong> CD32B2 isoform<br />
internalised more extensively. However, <strong>the</strong> rate of rituximab internalisation occurred<br />
equally with both isoforms and was dependent on relative expression of CD32B and<br />
<strong>the</strong> CD20:CD32B ratio at <strong>the</strong> cell surface ra<strong>the</strong>r than any specific activity imparted<br />
by <strong>the</strong> CD32 intracellular domain. These studies suggest that <strong>the</strong> intracellular part of<br />
CD32B is redundant for rituximab-induced CD20 internalisation and imply that<br />
internalisation is augmented by CD32B through its physical ability to bind <strong>the</strong> Fc<br />
region of rituximab at <strong>the</strong> cell surface.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
158P TARGETING EFFICIENCY AND BIODISTRIBUTION OF<br />
EGFR-CONJUGATED MESOPOROUS SILICA NANOPARTICLES<br />
FOR CISPLATIN DELIVERY IN NUDE MICE WITH LUNG<br />
CANCER<br />
S. Sundarraj<br />
Zoology, Bharathiar University, Coimbatore, INDIA<br />
Annals of Oncology<br />
Lung cancer is <strong>the</strong> most malignant cancer today; in order to develop an effective<br />
drug delivery system for lung cancer <strong>the</strong>rapy In this study, an efficient approach for<br />
ix70 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
tumor-targeted drug delivery was developed with non-small cell lung cancer as <strong>the</strong><br />
targeting vehicle and a mesoporous silica nanoparticle as <strong>the</strong> drug carrier. A<br />
mesoporous silica nanoparticle-cisplatin drug delivery system was efficiently<br />
anchored to non-small cell lung cancer by specific EGFR recognitions at <strong>the</strong><br />
cytomembrane interface without any cell preconditioning. By <strong>the</strong> in vitro cell culture<br />
test, EGFR-MSN-cisplatin resulted in higher entrance efficiency on adenocarcinoma<br />
cells (A549) than that on normal lung cells (L-132) because A549 possessed greater<br />
amounts of EGFR. High levels of nanoparticles were uptake to each MSCLC cell with<br />
high cell viability and tumor-tropic ability. The intracellular retention time of <strong>the</strong><br />
MSN was no less than 48 h, which is sufficient for cell-directed tumor-tropic<br />
delivery. In vivo experiments proved that <strong>the</strong> burdened NSCLC can track down <strong>the</strong><br />
more efficiently and deliver cisplatin with wider distribution and longer retention<br />
lifetime in tumor tissues compared with free cisplatin and EGFR-MSN-cisplatin. The<br />
increased and prolonged cisplatin intratumoral distribution fur<strong>the</strong>r contributed to<br />
significantly enhanced tumor-cell apoptosis. This strategy has potential to be<br />
developed as a robust and generalizable method for targeted tumor <strong>the</strong>rapy with high<br />
efficiency and low systematic toxicity.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
159P DEAD/H (ASP-GLU-ALA-ASP/HIS) BOX POLYPEPTIDE 3,<br />
X-LINKED PLAYS AN ONCOGENIC ROLES TO INDUCE<br />
CANCER STEM CELL-LIKE PROPERTIES<br />
K. Nozaki 1 , H. Kagamu 1 , K. Ichikawa 1 , J. Koshio 1 , Y. Saida 1 , T. Tanaka 1 ,<br />
S. Miura 1 , S. Watanabe 2 , H. Yoshizawa 2 , I. Narita 1<br />
1 Division of Respiratory Medicine, Graduate School of Medical and Dental<br />
Sciences, Niigata University, Niigata, JAPAN, 2 Bioscience Medical Research<br />
Center, Niigata University Medical and Dental Hospital, Niigata, JAPAN<br />
Background: DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 3, X-linked<br />
(DDX3X) is a member of <strong>the</strong> DEAD-box family of ATP dependent RNA helicase.<br />
DEAD-box helicases have multiple functions including RNA splicing, mRNA export,<br />
transcriptional and translational regulation, RNA decay, and ribosome biogenesis. In<br />
<strong>the</strong> last <strong>ESMO</strong> meeting, we demonstrated that DDX3X is one of 4 proteins that are<br />
specifically expressed in CD133+ B16 melanoma cells, which possess cancer stem cell<br />
(CSC) properties and that a DDX3X vaccination induced antitumor <strong>the</strong>rapeutic<br />
immunity against parental melanoma. DDX3X is evolutionarily well conserved from<br />
yeast to humans, suggesting that it is essential for cell survival. In humans, DDX3X<br />
deletion or dysfunction results in genetically related primary amenorrhea and<br />
impaired female fertility. Although DDX3X was originally reported to suppress<br />
growth by modulating p21waf/cip1 gene expression, it has been recently shown that<br />
DDX3X is directly correlated with oncogenesis. Fur<strong>the</strong>rmore, it has been shown that<br />
DDX3X over-expression in breast cancer cells facilitates β-catenin signal transduction<br />
and induces epi<strong>the</strong>lial mesenchymal transition (EMT), a known feature of CSC.<br />
However, a precise mechanism how DDX3X, a RNA helicase, plays an oncogenic<br />
role to induce CSC features is still uncertain.<br />
Results: Immunoblotting analyses revealed that all of <strong>the</strong> examined cancer cells,<br />
including lung cancer, colon cancer and breast cancer cells expressed DDX3X, while<br />
normal human epidermal keratinocytes (NHEK), human microvascular endo<strong>the</strong>lial<br />
cells (HMEC), and normal human bronchial epi<strong>the</strong>lial cells (NHBE) faintly expressed<br />
DDX3X. Moreover, putative CSC marker positive cancer cells, such as 87.5, HCT116,<br />
and MCF7, strongly expressed DDX3X. HCT116 cells, which have CD133 and strong<br />
DDX3X expression, exhibit CSC like properties, such as high tumorgenicity, growth<br />
as non-adherent spheres, and aggressive invasion ability. Knockdown of DDX3X<br />
resulted in loss of CSC-like features. We found that epigenetic regulation by DDX3X<br />
play a critical role in oncogenesis.<br />
Conclusion: DDX3X plays an important role in inducing CSC properties.<br />
Disclosure: H. Kagamu: I received research fund from Otsuka Phamaceutical Co.,<br />
Ltd. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
160P GLUCOSE AND NKG2D LIGAND EXPRESSION: A LINK<br />
BETWEEN CELLULAR IMMUNOGENICITY AND WARBURG<br />
METABOLISM<br />
M.T. McCarthy 1 , G.E. Moncayo 2 ,C.O’Callaghan 1<br />
1 Nuffield Department of Clinical Medicine, University of <strong>Oxford</strong>, <strong>Oxford</strong>, UNITED<br />
KINGDOM, 2 Institute for Biomedical Research, Friedrich Meischer Institute,<br />
Basel, SWITZERLAND<br />
Natural killer group 2D (NKG2D) is an activating receptor constitutively expressed<br />
on <strong>the</strong> surface of human natural killer cells and CD8+ T-lymphocytes. The ligands<br />
for NKG2D, including MICA, are up-regulated in several pathophysiological settings,<br />
including cancer, and viral infection. In <strong>the</strong>se contexts, glucose metabolism is often<br />
perturbed (<strong>the</strong> Warburg effect) and glucose levels can be low in <strong>the</strong> tumour<br />
microenvironment. We hypo<strong>the</strong>sized that low glucose availability would reduce cell<br />
surface NKG2D ligand expression and lower <strong>the</strong> immunogenicity of malignant cells.<br />
Cell lines cultured in different glucose concentrations displayed a direct correlation<br />
between glucose level and cell surface expression of MICA, a key activating ligand of<br />
NKG2D. Real-time RT-PCR demonstrated an increase in MICA mRNA transcript<br />
levels with increasing glucose concentration. Chromium-release cytotoxicity assays<br />
demonstrated an NKG2D-dependent change in NK cell-mediated killing of target<br />
cells, in response to changing glucose availability. This suggests that extracellular<br />
glucose concentration may alter <strong>the</strong> susceptibility of malignant cells to<br />
immune-mediated clearance.<br />
We demonstrate that <strong>the</strong> contribution of glucose to nucleotide syn<strong>the</strong>sis is necessary<br />
for <strong>the</strong> observed increase in MICA expression. In a primary cell-viral infection model<br />
of NKG2D ligand induction, we demonstrate that glucose availability determines <strong>the</strong><br />
level of NKG2D ligand expression in <strong>the</strong> transition from healthy to infected cells. As<br />
with cell line models, reduced glucose availability in this primary cell model limits<br />
<strong>the</strong> up-regulation of NKG2D ligands observed in virus-infected cells. These results<br />
suggest that Warburg metabolism is important to support NKG2D ligand expression<br />
in <strong>the</strong>se models. The reduction in NKG2D ligand expression in a low glucose<br />
environment may represent a novel immune-evasion mechanism in aberrantly<br />
vascularized tumour microenvironments. Fur<strong>the</strong>r understanding of <strong>the</strong> downstream<br />
signaling pathways could lead to <strong>the</strong> development of novel <strong>the</strong>rapeutic agents.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
161P UTILIZATION OF FORMALIN-FIXED, PARAFFIN-EMBEDDED<br />
ARCHIVAL TISSUE FOR CYTOGENETIC ANALYSIS OF<br />
MICROARRAY-COMPARATIVE GENOMIC HYBRIDIZATION<br />
M. Oikawa 1 ,J.Arai 1 , H. Kondo 2 , M. Nakashima 3 , T. Hayashi 4 , K. Yoshiura 5 ,<br />
H. Yano 1 , T. Nagayasu 1<br />
1 Surgical Oncology, Nagaski University Hospital, Nagasaki, JAPAN, 2 Biostatistics<br />
Section, Division of Scientific Data Registry, Nagasaki University Graduate School<br />
of Biomedical Sciences, Nagasaki, JAPAN, 3 Tumor and Diagnostic Pathology,<br />
Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JAPAN,<br />
4 Pathology, Nagasaki University Hospital, Nagasaki, JAPAN, 5 Human Genetics,<br />
Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JAPAN<br />
Background: Utilization of formalin-fixed, paraffin-embedded (FFPE) archival tissue,<br />
which is <strong>the</strong> most common form of tissue preservation in routine practice, for<br />
cytogenetic analysis of microarray comparative genomic hybridization (aCGH)<br />
remains challenging. We searched for predictive factors of FFPE DNA performance<br />
on aCGH analysis.<br />
Materials and methods: Tumor DNA was extracted from 63 various types of FFPE<br />
archival tissues (31 of breast cancer, 24 of lung cancer, and 8 of thyroid tumor)<br />
followed by aCGH analysis using high-density oligonucleotide microarray. In two<br />
cases, tumor DNA from a matched frozen sample and tumor DNA after<br />
whole-genome amplification (WGA) from an FFPE sample were also analyzed. The<br />
derivative log ratio spread (DLRSpread) was used as a metric to assess <strong>the</strong> overall<br />
quality of each aCGH result.<br />
Results: The DLRSpread was significantly correlated with <strong>the</strong> double-stranded DNA<br />
ratio of tumor DNA, storage time, and degree of Cy5 labeling (P < 0.0001; correlation<br />
coefficients = -0.796, 0.551, and -0.481, respectively). Stepwise multiple linear<br />
regression analysis revealed that <strong>the</strong> double-stranded DNA ratio of tumor DNA is <strong>the</strong><br />
most significant predictive factor of <strong>the</strong> DLRSpread (regression coefficient = -0.4798;<br />
P < 0.0001). Cytogenetic profiles of FFPE samples and matched frozen samples were<br />
well concordant. Although <strong>the</strong> double-stranded DNA ratios were increased after<br />
WGA, <strong>the</strong> DLRSpreads were not improved.<br />
Conclusions: The double-stranded DNA ratio of tumor DNA predicted <strong>the</strong><br />
performance of DNA from FFPE samples on aCGH analysis. Quality control by<br />
<strong>the</strong>se metrics can utilize valuable FFPE archival tissue on aCGH analysis.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
162P DETERMINATION OF FREQUENCY OF OCCURRENCE OF THE<br />
VIRUS ASSOCIATED NON-HODGKINS LYMPHOMA (NHL) IN<br />
DIFFERENT AGE ASPECTS<br />
S.R. Abdiganieva, D.A. Pulatov, J.M. Ibragimov, D.A. Abdurakhmanov,<br />
K.K. Tuydjanova<br />
Chemo<strong>the</strong>rapy, National Cancer Research Center, Thashkent, UZBEKISTAN<br />
NHL is often characterized by unpredictable clinical course, i.e. patients with <strong>the</strong><br />
same disease stage, morphology, and treatments for this disease can be dramatically<br />
different. As a consequence, one can remain latent for many years, and o<strong>the</strong>rs, on<br />
<strong>the</strong> contrary, rapidly progressing incurable with <strong>the</strong> spread of <strong>the</strong> disease. One<br />
possible reason for <strong>the</strong> unexpected course of <strong>the</strong> disease may be <strong>the</strong> viral infection. It<br />
should be noted that such information on <strong>the</strong> epidemiology of <strong>the</strong> virus infection in<br />
<strong>the</strong> NHL, both scientific and practical information is completely absent. Therefore,<br />
no evidence of a viral effect of various agents on <strong>the</strong> clinical course of <strong>the</strong> NHL, are<br />
likely to evaluate <strong>the</strong> contribution to <strong>the</strong> pathogenesis and in <strong>the</strong> future to develop<br />
new approaches to its treatment. The purpose of this research is to study <strong>the</strong> virus<br />
infection in patients with NHL using molecular-biological methods of determining<br />
<strong>the</strong> frequency depending on <strong>the</strong> age of <strong>the</strong> patients. The object of <strong>the</strong> study served<br />
<strong>the</strong> lymph nodes of 27 patients: 20men (65%) and 7 women (35%). To detect<br />
infection analysis used immunoglobulin genes by PCR diagnostic of human<br />
papillomavirus general (HPVG), herpes simplex virus I + II (HSV I + II),<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds390 | ix71
cytomegalovirus (CMV). Analysis of <strong>the</strong> frequency of common virus infection in<br />
different age groups showed <strong>the</strong> presence of two peaks in patients aged 18 to 35years<br />
(HPVG-37,7%, HSV I + II-19, 1%, CMV-13, 9) and 65-78 years(HPVG-30,7%, HSV<br />
I + II-29, 1%, CMV-17, 5). In <strong>the</strong> o<strong>the</strong>r age periods were detected less frequently:<br />
36-45 years (HPVG-23.4%, HSV I + II-12, 1%, CMV-11, 9), 46-55 (HPVG-30.1%,<br />
HSV I + II-171%, CMV-10, 9), with <strong>the</strong> lowest frequency in <strong>the</strong> age of 56-64 years<br />
(HPVG-17,7%, HSV I + II-11, 1%, CMV-11, 9). From <strong>the</strong>se, <strong>the</strong> total extent of<br />
infection by age of patients was as follows: a high degree of infection ranged in age<br />
from 18 to 35 years (97.2%) and over 65-78 years (86.7%), moderate - 46-55 years<br />
(71.7%), low infection rates, 36-45 years (53.5%) and 56-64 years(54.5%). Thus, in<br />
our study, <strong>the</strong> presence of a virus associated NHL revealed in all cases, with a<br />
statistically significant increase in <strong>the</strong> frequency of occurrence of 18 to 44 years and<br />
over 65 years. Our evidence suggests that virus infection may play an important role<br />
in <strong>the</strong> pathogenesis of NHL, and <strong>the</strong> choice of treatment effectiveness and prognosis.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
163P TESTING AND ANALYSIS OF FLUORESCENT MARKERS<br />
PANEL FOR T-CELLS’ MULTIFUNCTIONALITY IN<br />
GLIOBLASTOMA MULTIFORME PATIENTS<br />
I. Ben-Horin 1 , I. Volovitz 2 , Z. Ram 3<br />
1 Oncology Devision, Tel Aviv Sourasky Medical Center-(Ichilov), Tel Aviv, ISRAEL,<br />
2 Cancer Immuno<strong>the</strong>rapy Lab, Tel-Aviv Sourasky Medical Center, Tel-Aviv,<br />
ISRAEL, 3 Neurosurgery, Tel-Aviv Sourasky Medical Center, Tel-Aviv, ISRAEL<br />
Introduction: Immuno<strong>the</strong>rapy had only limited success in brain tumors as <strong>the</strong> brain<br />
is regarded as an immunologically privileged site. Recently published work on a rat<br />
model showed that when live, non-attenuated brain tumor cells are injected<br />
subcutaneously <strong>the</strong>y are first accepted but are later spontaneously rejected. This<br />
immunologically mediated rejection of <strong>the</strong> brain tumors cells in peripheral sites leads<br />
to a similar intra-cranial tumor rejection. Objective: to characterize <strong>the</strong> different<br />
immune cell populations found in human glioblastoma multiforme (GBM) and in<br />
peripheral blood of GBM patients and to develop means to follow immune responses<br />
in <strong>the</strong> CNS to anti-tumor <strong>the</strong>rapy.<br />
Methods: Tumors were broken down and tumor cells isolated. Cultures of tumor<br />
cells with or without <strong>the</strong> respective patient’s activated or non-activated lymphocytes<br />
were prepared, stained with a fluorescent markers panel for T-cells multifuncionality<br />
and analyzed using flow cytometry. The panel was constructed in our lab with<br />
markers for CD3 (total T-cells), CD4 (Th cells), CD8 (CTL), IFNγ, TNFα, IL-12 and<br />
ViViD – a viability marker.<br />
Results: Our panel succeeded in characterizing <strong>the</strong> different immune cell<br />
populations. It also demonstrated that activation of CD4 T-cells increased IFNγ and<br />
IL12 expression and not TNFα’s expression. CD8 T-cells demonstrated a smaller rise<br />
in IFNγ and IL12 expression and no expression of TNFα, before or after stimulation.<br />
Non-activated lymphocytes demonstrated no multifunctionality while activated cells<br />
exhibited low levels of IFNγ and IL12 joint expression. The extent of<br />
multifuncionality differed between CD4 and CD8 cells.<br />
Conclusion: Our panel characterized <strong>the</strong> different T-cell populations in tumors. It<br />
demonstrated that only a small percentage of cells exhibited multifuncionality. To <strong>the</strong><br />
best of our knowledge this is <strong>the</strong> first time T-cells multifunctionality in brain tumors<br />
has been described. This phenomenon is of importance as it correlates with vaccines’<br />
potency. Future work will characterize <strong>the</strong> difference between peripheral and<br />
intratumoral T-cells and <strong>the</strong>ir interaction with o<strong>the</strong>r immune cells populations as we<br />
aim to understand tumor induced immune system inhibition.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
164 ISOLATION, PROLIFERATION, AND PHENOTYPING OF CANCER<br />
STEM CELLS FROM PRIMARY BREAST CANCERS: A MODEL<br />
FOR EVALUATING THE RESPONSE TO ANTI-TUMOR DRUGS<br />
M.I. Salamoon 1 , M. Al Jamali 2 , L. Youcef 2 , I. Kasem 3 , M. Bachour 1<br />
1 Medical Oncology, Al Bairouni University Hospital, Damascus, SYRIA, 2 Clinical<br />
Pharmaceutics, Faculty of Pharmacy, Damascus, SYRIA, 3 Biotech, Technical<br />
Institution, Damascus, SYRIA<br />
Background: Recent years have witnessed an increasing interest in <strong>the</strong> role of cancer<br />
stem cells (CSCs) because of selfrenewal, promoting metastasis, and resisting radioand<br />
chemo<strong>the</strong>rapies. In addition, <strong>the</strong> high levels of CSCs in tumor mass were linked<br />
to a poor prognosis, relapse and metastasis. For <strong>the</strong> former reasons SCS is currently a<br />
main focus of cancer research.<br />
Objective: This study aims at establishing a CSC cellular model, which might enable<br />
<strong>the</strong> testing of new chemo<strong>the</strong>rapeutics and/or combinatorial <strong>the</strong>rapies for currently<br />
used agents.<br />
Material and methods: We culture tumor cells obtained from primary breast tumors<br />
of Syrian patients. This was followed by isolating stem cell population existing in <strong>the</strong><br />
primary tumor by means of serial dilution of cells, and <strong>the</strong> characterization of <strong>the</strong>se<br />
cells by flow cytometry based on <strong>the</strong>ir morphology, surface antigen profile (CD44<br />
+ /high/CD24-/low), and <strong>the</strong>ir growth and enrichment in both adherent and<br />
Annals of Oncology<br />
non-adherent conditions. Finally, <strong>the</strong> viability of CSCs was tested after freezing cells<br />
in liquid nitrogen.<br />
Results and discussion: In this study, we were able to isolate CSCs from primary<br />
breast tumor with high purity exceeding 90%, and we showed <strong>the</strong>ir CSC<br />
characteristics, which included: i) CD44high/CD24-/low profile, ii) <strong>the</strong>ir ability to<br />
form tumorspheres in non-adherent/suspension conditions, iii) and <strong>the</strong>ir ability of<br />
resisting chemo<strong>the</strong>rapeutic agents in comparison with non-purified/non-stem breast<br />
tumor cells.<br />
Conclusions: Our results confirm <strong>the</strong> establishment of a cellular model representing<br />
<strong>the</strong> characteristics of cancer stem cell population. This breast CSC model could be<br />
useful in conducting research enabling <strong>the</strong> identification of responsible mechanisms<br />
behind breast cancer resistance to chemo<strong>the</strong>rapeutics. In addition, this model might<br />
enable <strong>the</strong> examining of new combinatorial <strong>the</strong>rapeutics by evaluating <strong>the</strong> effects of<br />
drug combinations targeting <strong>the</strong> different and heterogeneous cell populations inside<br />
breast tumors, both tumor non-stem as well as tumor stem cells, thus, achieving <strong>the</strong><br />
desirable <strong>the</strong>rapy outcomes.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
165 EFFECTS OF IL6 ON STATIN INDUCED APOPTOSIS IN HUMAN<br />
MELANOMA CELLS<br />
C. Minichsdorfer 1 , C. Wasinger 2 , E. Sieczkowski 3 , B. Atil 2 , M. Hohenegger 2<br />
1 Department of Medicine I, Medical University of Vienna, Vienna, AUSTRIA,<br />
2 Pharmacology, Medical University of Vienna, Vienna, AUSTRIA, 3 Neurology,<br />
Medical University of Vienna, Vienna, AUSTRIA<br />
Statins trigger apoptosis in primary cells and tumour cells. In particular, melanoma<br />
cells have been found to be susceptible to statin-induced apoptosis, although only<br />
after longer incubation times. Cells derived from metastatic melanoma cell lines<br />
(A375, 518A2) secrete high amounts of IL-6 in contrast to WM 35 cells which derive<br />
from an early lesion. However, IL-6 did not ameliorate <strong>the</strong> statin induced apoptosis<br />
in A375 and 518A2 cells. Conversely, in WM35 cells IL-6 led to a marked decrease<br />
in Cyclin D1 levels and enhanced <strong>the</strong> simvastatin induced apoptosis. Melanoma cells<br />
from early growth stage are more resistant to simvastatin induced apoptosis than<br />
metastatic melanoma cells. IL-6 plays a major role in <strong>the</strong> progression of melanoma.<br />
Interestingly, IL-6 has no cytostatic effect on metastatic melanoma cells but primes<br />
WM 35 cells for statin induced apoptosis. These pro-apoptotic stimuli confirm<br />
possible <strong>the</strong>rapeutic potentials and may guide feasibility for more potent statins in<br />
anti-cancer strategies and help to understand <strong>the</strong> dualistic effect of IL-6 during<br />
melanoma tumorigenesis. This work was supported by Herzfeldeŕsche<br />
Familienstiftung and FWF (grant P22385).<br />
Disclosure: All authors have declared no conflicts of interest.<br />
166 EFFECT OF NEURAL CELL ADHESION MOLECULE<br />
EXPRESSION ON GLYCOLYTIC PATHWAY IN MELANOMA<br />
H.J. Cho1 , M. Choi2 , J.D. Lee2 , C.H. Kim1 1<br />
Brain Korea 21 Project for Medical Science, Yonsei University, Seoul, KOREA,<br />
2<br />
Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul,<br />
KOREA<br />
Background: Neural cell adhesion molecule (NCAM), a member of <strong>the</strong><br />
immunoglobulin superfamily, has been well characterized in cell-cell adhesion,<br />
neurite outgrowth, and synaptic plasticity. Recent studies have also shown that <strong>the</strong><br />
expression of NCAM affects tumor progression. Indeed, <strong>the</strong> expression of NCAM has<br />
been implicated in <strong>the</strong> cellular invasion and metastasis of melanoma. Like many<br />
o<strong>the</strong>r malignant tumors, melanomas are dependent on aerobic glycolysis for ATP<br />
production. Many studies have consistently correlated poor prognosis and increased<br />
tumor aggressiveness with increased glucose uptake. In this study, we tested whe<strong>the</strong>r<br />
<strong>the</strong> expression of NCAM influences glycolytic pathways in mouse melanoma cell<br />
line.<br />
Methods: We constructed a recombinant viral vector derived from adeno-associated<br />
virus serotype 2 (rAAV2) that expresses NCAM. Mouse melanoma cell line B16F10<br />
was transduced with rAAV2. We performed in vitro fluorine-18 fluorodeoxyglucose<br />
( 18 F-FDG) uptake assay in a gamma counter. In addition, western blot analysis was<br />
carried out for glucose transporters (GLUT) and hexokinases (HK).<br />
Results: Transduction of B16F10 cells with rAAV2 NCAM resulted in increased<br />
18 F-FDG uptake. Western blot analyses demonstrated that <strong>the</strong> 180-kDa isoform of<br />
NCAM (NCAM 180) was up-regulated. Expression levels of GLUT1, GLUT2 and<br />
HK II were elevated.<br />
Conclusions: Overexpression of NCAM was associated with elevated levels of<br />
GLUT1, GLUT2, and HK II, which contributes to increased glycolysis. We<br />
demonstrated that 18 F-FDG uptake might be used as a surrogate marker for assessing<br />
NCAM expression in melanoma. In terms of monitoring NCAM expression, <strong>the</strong><br />
utility of 18 F-FDG uptake as a prognostic indicator requires fur<strong>the</strong>r elucidation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix72 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
iomarkers<br />
167O PREVALENCE AND CLINICAL OUTCOMES FOR PATIENTS<br />
WITH ALK GENE REARRANGEMENT IN EUROPE:<br />
PRELIMINARY RESULTS FROM THE EUROPEAN THORACIC<br />
ONCOLOGY PLATFORM LUNGSCAPE PROJECT<br />
F. Blackhall 1 , S. Peters 2 , K.M. Kerr 3 ,K.O’Byrne 4 , H. Hager 5 , A. Sejda 6 ,<br />
A. Soltermann 7 , C. Dooms 8 , E. Felip 9 , A. Marchetti 10 , E-J.M. Speel 11 , N. Price 12 ,<br />
S. Savic 13 , J. de Jong 14 , M. Martorell 15 , E. Thunnissen 16 , L. Bubendorf 17 ,<br />
O. Dafni 18 , R. Rosell 19 , R.A. Stahel 20<br />
1 Medical Oncology, Christie Hospital NHS Foundation Trust, Manchester,<br />
UNITED KINGDOM, 2 Multidisciplinary Oncology Center, Lausanne Cancer<br />
Center, Centre Hospitalier Universitaire Vaudois, Lausanne, SWITZERLAND,<br />
3 Department of Pathology, Aberdeen Royal Infirmary, Aberdeen, UNITED<br />
KINGDOM, 4 HOPE Directorate, St James’s Hospital, Dublin, IRELAND,<br />
5 Department of Pathology, Aarhus University Hospital, Aarhus, DENMARK,<br />
6 Medical University of Gdansk, Gdansk, POLAND, 7 Institut für Klinische<br />
Pathologie, Universitätsspital Zürich, Zurich, SWITZERLAND, 8 Department of<br />
Pulmonology, University Hospital Leuven, Leuven, BELGIUM, 9 Medical<br />
Oncology, Vall d’Hebron University Hospital, Barcelona, SPAIN, 10 Center of<br />
Predictive Molecular Medicine, University-Foundation, Chieti, ITALY, 11 Molecular<br />
Diagnostics, Department of Pathology, Maastricht, NETHERLANDS, 12 Aberdeen<br />
Royal Infirmary, Aberdeen, UNITED KINGDOM, 13 Pathology, Institute for<br />
Pathology, University Hospital Basel, Basel, SWITZERLAND, 14 Pathology, The<br />
Ne<strong>the</strong>rlands Cancer Institute, Amsterdam, NETHLANDS, 15 Consorcio Hospital<br />
General Universitario de Valencia, Universitat de Valencia, Valencia, SPAIN,<br />
16 Pathology, Vrije Universiteit Medical Center, Amsterdam, NETHERLANDS,<br />
17 Division of Cytology, Institute for Pathology, University Hospital Basel, Basel,<br />
SWITZERLAND, 18 Frontier Science Foundation-Hellas, A<strong>the</strong>ns, GREECE,<br />
19 Oncology Research, Catalan Institute of Oncology, Hospital Germans Trias i<br />
Pujol, Badalona (Barcelona), SPAIN, 20 Clinic of Oncology, University Hospital<br />
Zurich, Zurich, SWITZERLAND<br />
Background: The prevalence of ALK gene rearrangement (ALK+) in European<br />
patients with non-small cell lung cancer (NSCLC) is unknown. The Lungscape<br />
project provides a platform to evaluate its expression and clinical significance in a<br />
large cohort of patients with resected NSCLC from 13 European sites in 11<br />
countries.<br />
Methods: Participating sites retrospectively identified cases of NSCLC with<br />
clinical demographic and outcome data, and available tissue for research<br />
according to predefined protocol criteria. Local ethical and regulatory approvals<br />
were adhered to. Clinical data were entered to a central, secure database.<br />
Accepted cases on <strong>the</strong> basis of completeness of clinical data were assessed for<br />
ALK expression using immunohistochemistry (IHC) using antibody clone 5A4<br />
(Novocastra) and an H-score modified after Ruschoff et al. All cases were<br />
analysed at participating clinical pathology laboratories using <strong>the</strong> same protocol,<br />
control tissue microarray and after passing an external quality assurance<br />
exercise.<br />
Results: To date 998 cases of adenocarcinoma have been accepted to <strong>the</strong><br />
database and ALK IHC results are available for 743 (74%). Positive IHC<br />
staining is present in 54 cases (7.3%) with IHC 3+ in 17 cases (2.3%), 2+ in 6<br />
cases and 1+ in 31 cases. The median H-score is 45 (range 1-300) with<br />
homogeneous staining in 30% of cases and heterogeneous staining in at least<br />
70% of cases. In total <strong>the</strong>re are 38% women and 62% men, <strong>the</strong> proportion of<br />
stage I, II and III is 55, 23 and 22 % respectively, 16% of cases are never<br />
smokers and 99% Caucasian ethnicity. The median age of all cases (n = 998) is<br />
65 years (range 23 - 86) and for IHC + 63.2 years. With respect to gender and<br />
smoking status 11% of women, 5.6% of men, 13% of never-smokers, 5.3% of<br />
former smokers and 9.3% of current smokers demonstrated positive IHC<br />
for ALK.<br />
Conclusions: The preliminary results for this large multicentre European cohort<br />
demonstrate a prevalence of ALK assessed by IHC of 7.3%, with IHC 3+<br />
expression in 2.3% of cases. Correlation of IHC scores with fluorescent in situ<br />
hybridisation, clinical demographics and outcomes is ongoing and will be<br />
presented.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology 23 (Supplement 9): ix73–ix94, <strong>2012</strong><br />
doi:10.1093/annonc/mds391<br />
168O QUANTIFICATION OF CELL FREE DNA AS A PROGNOSTIC<br />
FACTOR IN ADVANCED NSCLC<br />
A. Dowler Nygaard 1 , K. Spindler 1 , R. Andersen 2 , N. Pallisgaard 2 , A. Jakobsen 1<br />
1 Department of Oncology, Vejle Hospital, Vejle, DENMARK, 2 Department of<br />
Clinical Biochemistry, Vejle Hospital Sygehus Lillebaelt, Vejle Sygehus,<br />
Vejle, DENMARK<br />
Purpose: To investigate <strong>the</strong> prognostic importance of baseline circulating cell free<br />
DNA (cfDNA) in plasma from patients with advanced Non Small Cell Lung Cancer<br />
(NSCLC) prior to first-line chemo<strong>the</strong>rapy.<br />
Material and methods: The inclusion criteria were; histopathologically verified<br />
advanced NSCLC, indication for first-line chemo<strong>the</strong>rapy and performance status (PS)<br />
0-2. Treatment comprised carboplatin (area under <strong>the</strong> curve (AUC)5) iv day 1, and<br />
vinorelbine 30 mg/m 2 iv day 1 and 60mg/m 2 po day 8, q3w. A maximum of six<br />
courses was given. Plasma was obtained from a pre-treatment EDTA blood-sample.<br />
The number of cfDNA alleles at baseline was assessed by an in-house quantitative<br />
polymerase chain reaction (qPCR).<br />
Results: A total of 246 patients were included, all receiving at least 1 course (median:<br />
4). The overall response rate was 26%. The number of cfDNA alleles ranged from<br />
480 to 1048500 per ml with a median value of 3200 and a 75 th percentile of 6040<br />
alleles per ml. The progression free survival (PFS) by intention to treat (ITT) was 5.4<br />
months and <strong>the</strong> overall survival (OS) 8.9 months. The baseline level of cfDNA was<br />
strongly correlated to outcome. The median PFS was 2.9 months in patients with<br />
high levels (> <strong>the</strong> 75 th percentile) compared to 5.7 months in patients with low levels<br />
(< <strong>the</strong> 75 th percentile) (HR: 1.83; 95% CI 1.29-2.59; p < 0.0001). The median OS was<br />
4.9 and 10.3 months, respectively (HR: 2.11; 95% CI 1.47-3.0; p < 0.0001). High levels<br />
of cfDNA were significantly associated with poor performance status (PS = 2), but<br />
nei<strong>the</strong>r age, gender, stage, histology nor number of metastases showed any<br />
correlation to <strong>the</strong> cfDNA-level. A multivariate Cox regression analysis confirmed an<br />
independent prognostic value of cfDNA in both PFS (p = 0.0002) and OS (p <<br />
0.0001). PS also remained an independent prognostic marker (p = 0.0003 (PFS) and<br />
p = 0.002 (OS)).<br />
Conclusion: High levels of cfDNA seem to have a strong prognostic influence as<br />
estimated by both PFS and OS in patients with newly diagnosed advanced NSCLC.<br />
Combined with PS it outlines a group of patients with minimal or no benefit of<br />
chemo<strong>the</strong>rapy, though fur<strong>the</strong>r investigations are warranted.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
169O IDENTIFICATION OF ENDOGLIN (CD105) AS AN<br />
EPIGENETICALLY REGULATED CANDIDATE TUMOUR<br />
SUPPRESSOR GENE IN LUNG CANCER<br />
K. O’Leary 1 , A. Shia 1 , V. Haley 1 , F. Cavicchioli 1 , A. Comino 2 , P. Vanella 3 ,<br />
M. Wischnewsky 4 , T. Crook 5 , C. Lo Nigro 3 , P. Schmid 1<br />
1 Oncology, Brighton and Sussex Medical School, Brighton, UNITED KINGDOM,<br />
2 Pathology, S. Croce General Hospital, Cuneo, ITALY, 3 Oncology, S. Croce<br />
General Hospital, Cuneo, ITALY, 4 Escience Lab, University of Bremen, Bremen,<br />
GERMANY, 5 Dundee Cancer Centre, University of Dundee, Dundee, UNITED<br />
KINGDOM<br />
Background: The transforming growth factor-beta (TGF-β) pathway is implicated<br />
in proliferation, migration, invasion, and metastasis of various cancers. Endoglin,<br />
a TGF-β accessory receptor which modulates TGF-β signalling, was identified in<br />
a genome-wide methylation screen for candidate tumour suppressors as a novel<br />
gene subject to transcriptional silencing in lung cancer. The aim of this project<br />
was to investigate whe<strong>the</strong>r epigenetic mechanisms play a role in loss of Endoglin<br />
expression in lung cancer and secondly, whe<strong>the</strong>r this has an impact on clinical<br />
outcome.<br />
Methods: Genome-wide methylation analysis was performed using methylation<br />
microarrays (Human 450K Methylation BeadChip) and demethylation assays with<br />
5-aza-2-deoxycytidine treatment coupled with mRNA array (Illumina HumanHT12<br />
v4 Expression BeadChip Kit) in lung cancer cell lines. Methylation was validated in a<br />
panel of 21 lung cancer cell lines (16 NSCLC, 6 SCLC), a series of 134 surgically<br />
resected, stage I or II non-small cell lung cancers and 19 non-malignant lung tissue<br />
samples using pyrosequencing and methylation-specific PCR (MSP). To assess <strong>the</strong><br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
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abstracts
functional consequences of Endoglin methylation in cell lines, expression was<br />
silenced by transfection with Endoglin-specific siRNA.<br />
Results: Methylation-dependent transcriptional silencing of Endoglin is a<br />
frequent event in lung cancer. Pyrosequencing and MSP analyses<br />
demonstrated dense methylation in <strong>the</strong> CpG island located in <strong>the</strong> 5’<br />
regulatory sequences of <strong>the</strong> gene in 20/22 lung cancer cell lines. Methylation<br />
of Endoglin correlated with absent or down-regulated mRNA and protein<br />
expression which could be reactivated by demethylation treatment. Using<br />
pyrosequencing, methylation was detected in 54.5% of lung cancer tissues.<br />
There was a strong trend for reduced survival in patients with Endoglin<br />
methylation (HR 1.44, 95%CI 0.74-2.79).<br />
Conclusion: Our data show that Endoglin is a common target of epigenetic<br />
silencing in lung cancer and that <strong>the</strong> resulting loss of expression may be<br />
associated with shorter survival. Work is ongoing to elucidate <strong>the</strong> mechanistic<br />
basis for this and to expand our cohort of patients to explore <strong>the</strong> value of<br />
Endoglin as a potential biomarker in lung cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
170O PROGNOSTIC AND PREDICTIVE VALUES OF KRAS IN<br />
EGFR-BASED SUBGROUPS AND COMBINED WITH P53 IN<br />
COMPLETELY RESECTED NON-SMALL CELL LUNG CANCER<br />
(NSCLC): A LACE-BIO STUDY<br />
P.A. Janne 1 , F.A. Shepherd 2 , C. Domerg 3 , G. Le Teuff 3 , R. Kratzke 4 , P. Hainaut 5 ,<br />
J. Pignon 3 , R. Rosell 6 , J. Soria 7 , M. Tsao 8<br />
1 Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, MA,<br />
UNITED STATES OF AMERICA, 2 Department of Medicine, Princess Margaret<br />
Hospital, Toronto, CANADA, 3 Oncology, Institut de Cancerologie<br />
Gustave-Roussy, Villejuif, FRANCE, 4 Oncology, University of Minnesota,<br />
Minneapolis, MN, UNITED STATES OF AMERICA, 5 Research, International<br />
Prevention Research Institute, Lyon, FRANCE, 6 Medical Oncology Service,<br />
Catalan Institute of Oncology ICO Badalona Hospital Germans Trias i Pujol,<br />
Medical Oncology, Badalona, SPAIN, 7 Dept. of Medicine, Institut de<br />
Cancérologie Gustave Roussy, Villejuif Cedex, FRANCE, 8 Pathology Department,<br />
Princess Margaret Hospital, University Health Network, Toronto, CANADA<br />
Background: We reported previously that KRAS is nei<strong>the</strong>r significantly<br />
prognostic nor predictive of benefit from adjuvant chemo<strong>the</strong>rapy (ACT) in<br />
NSCLC (Shepherd et al. Proc ASCO <strong>2012</strong>). P53 and EGFR mutations are also<br />
detected in NSCLC and P53 mutations can occur concurrently with KRAS<br />
mutations. We undertook to evaluate <strong>the</strong> prognostic and predictive effect of (i)<br />
KRAS in EGFR Wild-Type (WT) Adenocarcinoma (ADC) patients (pts) and (ii)<br />
KRAS combined with P53.<br />
Methods: Analysis included IALT, JBR10, CALGB-9633 and ANITA trials. KRAS,<br />
P53 and EGFR mutations (exons 19 and 21) were determined in blinded fashion in 3<br />
laboratories by direct sequencing. KRAS (WT/Mut) and P53 (WT/Mut) were<br />
combined in 4 groups with WT/WT as reference group. Hazard ratios (HR) and<br />
95% confidence intervals (CI) were estimated using <strong>the</strong> multivariable Cox model<br />
stratified by trial and adjusted on covariates, for Overall (OS) and Disease-Free<br />
Survival (DFS).<br />
Results: Among 1543 pts (605 ADC, 938 non-ADC) with documented KRAS<br />
genotype, EGFR was available in 485/605 ADC (12% of mutations) and P53 in<br />
1181/1543 (36% of mutations). In EGFR-WT ADC pts (n = 426), KRAS<br />
mutation, detected in 40%, was nei<strong>the</strong>r predictive (p = 0.96) nor prognostic in<br />
<strong>the</strong> observation group (OBS) (p = 0.65). In pts with KRAS and P53 status, 16%<br />
had only KRAS Mut, 32% P53 Mut only and 4% had both. Among pts with<br />
KRAS/P53 mutations, OS was worse in <strong>the</strong> ACT group (HR ACT vs. OBS 2.49;<br />
95%CI 1.10-5.66, p = 0.03) but not in pts with ei<strong>the</strong>r mutation alone: KRASMut/<br />
P53WT HR = 0.73 (0.47-1.13) KRASWT/P53Mut HR = 0.97 (0.73-1.29) and WT/<br />
WT HR = 0.82 (0.64-1.06). No significant heterogeneity among <strong>the</strong>se 4 HRs (p =<br />
0.06) was observed but <strong>the</strong>re was a significant difference when comparing only<br />
WT/WT and Mut/Mut groups (p = 0.01). The prognostic value of this<br />
combination was not significant in <strong>the</strong> OBS group (p = 0.57). Results were<br />
similar for DFS.<br />
Conclusions: Patients with both KRAS and P53 mutations have significantly worse<br />
outcome with ACT compared to those with WT/WT tumors. Fur<strong>the</strong>r studies are<br />
needed to understand <strong>the</strong> biologic basis for this. Supported by unrestricted grants<br />
from Sanofi Aventis and LNCC.<br />
Disclosure: J. Pignon: unrestricted research grant from Roche for a meta-analysis on<br />
bevacizumab in advanced NSCLC. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
Annals of Oncology<br />
171O MONITORING OF METASTATIC BREAST CANCER USING<br />
CIRCULATING TUMOUR DNA: A COMPARISON WITH<br />
CIRCULATING TUMOUR CELLS<br />
S. Dawson 1 , D. Tsui 1 , M. Murtaza 1 , H. Biggs 2 , S. Chin 1 , D. Gale 1 , T. Forshew 1 ,<br />
M. Wallis 3 , N. Rosenfeld 1 , C. Caldas 1<br />
1 Department of Oncology, Li Ka Shing Centre, Cancer Research UK, Cambridge<br />
Research Institute Addenbrooke’s Hospital, Cambridge, UNITED KINGDOM,<br />
2 Oncology, Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge<br />
University Hospitals NHS Foundation Trust, Cambridge, UNITED KINGDOM,<br />
3 Department of Radiology, Addenbrooke’s Hospital, Cambridge University<br />
Hospitals NHS Foundation Trust, Cambridge, UNITED KINGDOM<br />
Background: Management of metastatic breast cancer (MBC) requires monitoring of<br />
tumour response to determine treatment efficacy. Imaging is routinely used, but is<br />
often a poor indicator of dynamic clinical response. Circulating tumour cells (CTCs)<br />
have been extensively studied but dynamics of cell-free DNA carrying<br />
tumour-specific alterations (circulating tumour DNA, ctDNA) has only recently been<br />
demonstrated. We performed <strong>the</strong> first direct comparison of CTCs and ctDNA in<br />
relation to medical imaging, to compare <strong>the</strong> performance of <strong>the</strong>se biomarkers for <strong>the</strong><br />
non-invasive monitoring of MBC.<br />
Methods: Clinical details, imaging and serial whole blood were collected<br />
prospectively from women undergoing <strong>the</strong>rapy for MBC. DNA from tumour tissues<br />
was analysed using targeted and/or whole genome sequencing to identify somatic<br />
genetic alterations. These were used to design personalised assays to quantify ctDNA<br />
in plasma using digital PCR. CTCs were quantified at identical time points using <strong>the</strong><br />
CellSearch® system. A blinded review of all imaging was performed according to<br />
RECIST criteria.<br />
Results: Concurrent CTC and ctDNA data was available from 16 women across 58<br />
samples. Elevated CTCs (≥5 cells / 7.5ml blood) and ctDNA were identified in 11<br />
(69%) and 15 (94%) cases respectively. ctDNA levels were a median of 234-fold<br />
higher than CTC numbers and showed greater sensitivity for monitoring tumour<br />
dynamics. In several cases, rising ctDNA was identified months before progressive<br />
disease was detected by CTCs or imaging. Changes in ctDNA levels were also<br />
observed in a subset of women with no measurable disease using <strong>the</strong> o<strong>the</strong>r<br />
modalities. Multiple somatic mutations and structural variants were measured in<br />
parallel in ctDNA, demonstrating <strong>the</strong> utility of this methodology to follow clonal<br />
evolution during treatment.<br />
Conclusions: ctDNA is a more sensitive biomarker than CTCs for <strong>the</strong> monitoring of<br />
MBC and often provides <strong>the</strong> earliest measure of treatment response. ctDNA has <strong>the</strong><br />
potential to be used as a ‘liquid biopsy’ to directly monitor responses to targeted<br />
<strong>the</strong>rapies and detect <strong>the</strong> emergence of resistant mutations. Future work should focus<br />
on <strong>the</strong> integration of ctDNA monitoring into multi-centre prospective clinical trials.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
172O ER + /HER2+ AND ER-/HER2+ BREAST CANCERS ARE<br />
MOLECULARLY DISTINCT BUT IMMUNE GENE SIGNATURES<br />
ARE PROGNOSTIC AND PREDICTIVE IN BOTH GROUPS<br />
T. Iwamoto 1 , L. Pusztai 2 , J. Matsuoka 1 , M. Callari 3 , C.M. Kelly 5 ,Y.Qi 6 ,<br />
T. Motoki 1 , N. Taira 1 , L. Santarpia 4 , H. Doihara 1 , L. Gianni 3 , G. Bianchini 3<br />
1 Breast and Endocrine Surgery, Okayama University Hospital, Okayama, JAPAN,<br />
2 Breast Medical Oncology, MD Anderson Cancer Center, Houston, TX, UNITED<br />
STATES OF AMERICA, 3 Breast Medical Oncology, Fondazione IRCCS Istituto<br />
Nazionale dei Tumori, Milan, ITALY, 4 Oncology, Translational Research Unit,<br />
Hospital of Prato and Istituto Toscano Tumori, Prato, ITALY, 5 Department of<br />
Medical Oncology, Mater Misericordiae University Hospital, Dublin, IRELAND,<br />
6 Department of Bioinformatics and Computational Biology, MD Anderson<br />
Cancer Center, Houston, TX, UNITED STATES OF AMERICA<br />
Objectives: We examined if gene expression patterns differ among HER2 positive<br />
breast cancers by estrogen receptor (ER) status. We also assessed <strong>the</strong> prognostic and<br />
chemo<strong>the</strong>rapy response predictive values of over 3000 gene sets separately in <strong>the</strong> ER<br />
subsets.<br />
Methods: Publically available, clinically annotated Affymetrix gene expression data<br />
of 537 HER+ (ER-/HER2+ n = 278, ER + /HER2+ n = 259) and 2985 HER2-<br />
(ER thinsp;+ /HER2- n = 1923, ER-/HER2- n = 1062) patients were studied including<br />
121 node-negative, HER2+ cases with no systemic adjuvant <strong>the</strong>rapy (ER+ n = 61,<br />
ER- n = 60) and 86 HER2+ patients treated with neoadjuvant taxane or<br />
anthracycicline chemo<strong>the</strong>rapy (ER+ n = 27 and ER- n = 59).<br />
Results: Genes that distinguished ER+ from ER- cases differed for HER2+ and<br />
HER2- cancers. HER2+ cancers showed less difference by ER status compared to<br />
HER2- cancers (differentially expressed genes by ER status: n = 194 and n = 6750, p <<br />
1.0E10-6, shared genes 84%). Significant differences were also observed when HER2+<br />
and HER2- cancers were compared stratified by ER status (HER2-related<br />
differentially expressed genes in ER+ n = 242, in ER- n = 1200, p < 1.0E10-6, shared<br />
genes 20%). In ER + /HER2+ tumors, 67 gene sets (GSs) were associated with good<br />
prognosis (e.g. B, T and NK cells and interferon-gamma production) and 2 GS with<br />
poor prognosis (PTEN dependent cell cycle arrest and apoptosis) (p ≤ .001). The<br />
same GSs were also prognostic in ER-/HER2+ cancers. In <strong>the</strong> neoadjuvant series, 11<br />
ix74 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
and 2 GSs were associated in both ER+ and ER-/HER2+ groups with pathologic<br />
complete response (pCR) (e.g. T-cell activation and differentiation) and residual<br />
disease (RD) (e.g. Cell-cell junction) respectively (combined p ≤ .001). We also noted<br />
ER specific associations with pCR or RD. For instance, 18 GSs were associated with<br />
pCR in ER-/HER2+ (p ≤ .001) but not in ER + /HER2+ tumors (e.g. chemochine<br />
C-C binding and activity, phospholipid catabolic process).<br />
Conclusions: Among HER2+ tumors, ER- and ER+ cancers represent distinct<br />
molecular subtypes. Immune signatures predict for good prognosis and higher<br />
chemo<strong>the</strong>rapy sensitivity in HER2+ cancers regardless of ER status.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
173O OPTIMIZING THERAPEUTIC COMBINATIONS OF A<br />
SELECTIVE MEK 1/2 INHIBITOR (PIMASERTIB) WITH PI3K/<br />
MTOR INHIBITORS OR WITH MULTI-TARGETED KINASE<br />
INHIBITORS IN PIMASERTIB-RESISTANT HUMAN LUNG<br />
AND COLORECTAL CANCER CELLS<br />
E. Martinelli 1 , T. Troiani 1 , F. Morgillo 1 ,E.D’Aiuto 2 , L. Ciuffrida 3 , S. Costantini 3 ,<br />
L. Vecchione 4 , V. De Vriendt 4 , S. Tejpar 4 , F. Ciardiello 1<br />
1 Division of Medical Oncology, Department of Experimental and Clinical Medicine<br />
and Surgery “F. Magrassi and A. Lanzara”, Second University of Naples, Naples,<br />
ITALY, 2 Immunology Department, Second University of Naples, Naples, ITALY,<br />
3 Pharmacology Department, Second University of Naples, Naples, ITALY,<br />
4 Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, BELGIUM<br />
Background: The RAS/RAF/MEK/MAPK and <strong>the</strong> PTEN/PI3K/AKT/mTOR<br />
pathways are key intracellular signal transduction pathways for <strong>the</strong> control of survival<br />
and proliferation in human cancer cells. Selective inhibitors of different transducer<br />
molecules in <strong>the</strong>se pathways have being developed as molecular targeted anti-cancer<br />
<strong>the</strong>rapies.<br />
Methods: The in vitro and in vivo antitumor activity of pimasertib, a selective MEK<br />
½ inhibitor, alone or in combination with a PI3K inhibitor (PI3Ki), a mTOR<br />
inhibitor (everolimus), or with multitargeted kinase inhibitors (sorafenib and<br />
regorafenib) were tested in a panel of eleven human lung and colon cancer cell lines.<br />
Results: Following pimasertib treatment, <strong>the</strong> cancer cell lines were classified as<br />
pimasertib-sensitive (IC 50 for cell growth inhibition of approximately 0.001 µM) or<br />
pimasertib-resistant (IC 50 for cell growth inhibition above 3 µM). Evaluation of basal<br />
gene expression profiles by microarrays identified a series of genes that were<br />
up-regulated in pimasertib-resistant cancer cells and that were involved in both RAS/<br />
RAF/MEK/MAPK and PTEN/PI3K/AKT/mTOR pathways. Therefore, a series of<br />
combination experiments with pimasertib and ei<strong>the</strong>r PI3Ki, everolimus, sorafenib or<br />
regorafenib were conducted, demonstrating a synergistic effect in cell growth<br />
inhibition, G1 phase arrest and induction of apoptosis with a sustained blockade in<br />
MAPK- and AKT-dependent signaling pathways in pimasertib-resistant human<br />
colon carcinoma (HCT15) and lung adenocarcinoma (H1975) cells. Finally, in nude<br />
mice bearing established HCT15 and H1975 subcutaneous tumor xenografts, <strong>the</strong><br />
combination treatment with pimasertib and BEZ235 (a dual PI3K/mTOR inhibitor)<br />
or with sorafenib caused significant tumor growth delays and increase in mice<br />
survival as compared to single agent treatment.<br />
Conclusion: These results suggest that it is possible to overcome intrinsic resistance<br />
to MEK inhibition by <strong>the</strong> dual blockade of MAPK and PI3K pathways.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
174O VEGF-A-INDUCED TREG PROLIFERATION, A NOVEL<br />
MECHANISM OF TUMOR IMMUNE ESCAPE IN COLORECTAL<br />
CANCER: EFFECTS OF ANTI-VEGF/VEGFR THERAPIES<br />
M. Terme, S. Pernot, E. Marcheteau, O. Colussi, F. Sandoval, N. Benhamouda,<br />
E. Tartour, J. Taieb<br />
Parcc-european Georges Pompidou Hospital, INSERM U970, Paris, FRANCE<br />
Background: Regulatory T cells (Treg) are suspected of hindering an effective<br />
antitumor immune response in cancer. Multi-target anti-angiogenic tyrosine kinase<br />
inhibitors (TKI) that are routinely used as first or second line treatment of cancer<br />
patients, have been shown to decrease Treg proportion in tumor-bearing mice and<br />
metastatic renal cancer patients. However, <strong>the</strong> role of VEGF/VEGFR blockade in this<br />
effect is still debatable, and <strong>the</strong> direct impact of VEGF-A on Treg has not been studied.<br />
Methods: Treg proportion, number were analyzed by flow cytometry in peripheral<br />
blood of metastatic colorectal cancer (mCRC) patients treated with bevacizumab, and<br />
in CT26 tumor-bearing mice treated with drugs targeting <strong>the</strong> VEGF axis. The direct<br />
impact of VEGF on Treg increase in cancer was also studied.<br />
Results: Sunitinib (a TKI targeting VEGFR, PDGFR, c-kit), and anti-VEGF-A<br />
antibody both decreased Treg in CT26 tumor-bearing mice. Masitinib, a TKI that does<br />
not target VEGFR, did not reduce Treg proportion in CT26 bearing mice.<br />
Bevacizumab, an anti-VEGF-A monoclonal antibody, reduced Treg proportion in<br />
peripheral blood of mCRC patients. Proliferation of Treg was enhanced in CT26<br />
tumor-bearing mice compared to tumor-free mice and was decreased after<br />
anti-VEGF-A treatment. Fur<strong>the</strong>rmore, in vitro experiments have shown that VEGF-A<br />
could directly induce Treg proliferation. VEGFR1 and 2 were expressed on Treg in <strong>the</strong><br />
presence of a tumor. Anti-VEGFR2 antibody administration reduces Treg proportion<br />
and also proliferation in CT26 bearing mice, but anti-VEGFR1 antibody did not,<br />
suggesting that VEGF-A-induced Treg proliferation was dependent on VEGFR2<br />
expression. In metastatic CRC patients, Treg proliferation was also enhanced<br />
compared to healthy volunteers and was blocked by bevacizumab treatment.<br />
Conclusions: We identified a new mechanism by which VEGF-A induced by <strong>the</strong><br />
tumor could stimulate Treg proliferation. VEGF-A/VEGFR2 blockade reduced Treg<br />
proportion and proliferation in tumor-bearing mice and metastatic CRC patients<br />
suggesting that combination of anti-VEGF-A/VEGFR2 <strong>the</strong>rapies with immuno<strong>the</strong>rapeutic<br />
approaches in <strong>the</strong> future might be particularly relevant in CRC patients.<br />
Disclosure: J. Taieb: advisory role, Roche; research grant, Roche. All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
175PD EFFECTS OF CHEMOTHERAPY ON IPILIMUMAB-MEDIATED<br />
INCREASES IN ABSOLUTE LYMPHOCYTE COUNT AND<br />
ACTIVATION OF T CELLS<br />
S.D. Chasalow 1 , J.D. Wolchok 2 , M. Reck 3 , S. Maier 4 , V. Shahabi 5<br />
1 Bioinformatics, Bristol-Myers Squibb, Princeton, NJ, UNITED STATES OF<br />
AMERICA, 2 Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY,<br />
UNITED STATES OF AMERICA, 3 Thoracic Oncology, Hospital Grosshansdorf,<br />
Grosshansdorf, GERMANY, 4 Global Clinical Research, Bristol-Myers Squibb,<br />
Lawrenceville, NJ, UNITED STATES OF AMERICA, 5 Oncology Biomarkers,<br />
Bristol-Myers Squibb, Princeton, NJ, UNITED STATES OF AMERICA<br />
Background: Ipilimumab (IPI) is a fully human monoclonal antibody that binds<br />
CTLA-4 to augment an antitumor T-cell response. Consistent with <strong>the</strong> expected<br />
immune-stimulating effect, increases in absolute lymphocyte count (ALC) and<br />
activation of peripheral-blood T cells frequently have been observed in patients (pts)<br />
treated with IPI as mono<strong>the</strong>rapy. Such changes thus appear to be indicators of <strong>the</strong><br />
biological activity of IPI. Combining IPI with o<strong>the</strong>r treatments, such as<br />
chemo<strong>the</strong>rapy (CT), may have <strong>the</strong> potential to enhance efficacy. However, CT may<br />
also interfere with <strong>the</strong> immune-stimulating effects of IPI. The current analysis<br />
investigated <strong>the</strong> effect of IPI on ALC and T cell activation in <strong>the</strong> presence of CT.<br />
Methods: ALC was measured in 3 trials of IPI + CT (n = 887). In CA184024, IPI or<br />
placebo (PLB) was combined with dacarbazine (DTIC) in metastatic melanoma<br />
(MM) pts. In CA184041, IPI in 2 different dosing schedules or PLB was combined<br />
with carboplatin/paclitaxel (CP) in lung cancer (NSCLC and SCLC) pts. In<br />
CA184078, IPI was combined with PLB, CP, or DTIC in MM pts. ALC assessments<br />
from baseline through <strong>the</strong> end of a 12- or 18-week dosing period were included. In<br />
CA184078, frequency of peripheral-blood activated (HLA-DR + ) T cells at 0, 3, and<br />
11 weeks from first treatment was assessed by flow cytometry. Extended linear<br />
models were used to estimate mean ALC and T cell frequencies as a function of time<br />
and treatment group.<br />
Results: In all 3 studies, mean ALC increased significantly (p < 0.0001 to p = 0.027)<br />
over time after initiation of treatment in <strong>the</strong> IPI-containing arms, with or without<br />
CT, but not in <strong>the</strong> PLB arms. In <strong>the</strong> IPI arms, mean ALC changes from baseline to<br />
<strong>the</strong> end of IPI dosing ranged from 0.45 to 0.75 x 10 9 cells/L. ALC increases were<br />
temporally associated with IPI, but not CT, dosing. In CA184078, mean relative and<br />
absolute frequencies of activated CD4 + and CD8 + T cells increased significantly after<br />
start of IPI treatment similarly in <strong>the</strong> 3 arms.<br />
Conclusions: Mean increases in ALC and activated T cells, similar to those seen with<br />
IPI mono<strong>the</strong>rapy, were observed after treatment with IPI combined with CP or<br />
DTIC. This suggests that IPI maintains biological activity when administered with<br />
CT, thus supporting continued clinical evaluation of IPI/CT combination <strong>the</strong>rapy.<br />
Disclosure: S.D. Chasalow: Employment by Bristol-Myers Squibb, Bristol-Myers<br />
Squibb stock ownership. J.D. Wolchok: I am a consultant to Bristol-Myers Squibb,<br />
Merck and Glaxo Smith Kline. I have research support from Bristol-Myers Squibb.<br />
M. Reck: Consultant/advisor to Bristol-Myers Squibb, Hoffmann-La Roche, Eli Lilly,<br />
Pfizer, AstraZeneca, and Daiichi Sankyo; compensated, self. S. Maier: Employment<br />
by Bristol-Myers Squibb, Bristol-Myers Squibb stock ownership. V. Shahabi:<br />
Employment by Bristol-Myers Squibb, Bristol-Myers Squibb stock ownership.<br />
176PD PREDICTION OF LATE BREAST CANCER RECURRENCE BY<br />
THE ROR (PAM50) SCORE IN POSTMENOPAUSAL WOMEN<br />
IN THE TRANSATAC COHORT<br />
J. Cuzick 1 , I. Sestak 1 , S. Ferree 2 , J.W. Cowens 2 , M. Dowsett 3<br />
1 Centre for Epidemiology Ma<strong>the</strong>matics and Statistics, Queen Mary University of<br />
London, London, UNITED KINGDOM, 2 Nanostring Technologies, NanoString<br />
Technologies, Seattle, WA, UNITED STATES OF AMERICA, 3 Academic<br />
Department of Biochemistry, Breakthrough Research Centre, London, UNITED<br />
KINGDOM<br />
Background: Adjuvant endocrine <strong>the</strong>rapy beyond 5 years is known to be of benefit<br />
to some oestrogen receptor (ER) positive breast cancer patients. We have shown<br />
previously that <strong>the</strong> IHC4 score and <strong>the</strong> ROR score are significantly correlated with<br />
distant recurrence in <strong>the</strong> cohort from <strong>the</strong> TransATAC study. Here we assess <strong>the</strong><br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds391 | ix75
elationship between <strong>the</strong> ROR score, RS (Oncotype Dx) and <strong>the</strong> IHC4 score in<br />
predicting distant recurrence beyond 5 years.<br />
Methods: We determined <strong>the</strong> univariate and multivariate prognostic value of ROR<br />
score, RS, and IHC4 score for distant recurrence separately in years 0-5 and 5-10 of<br />
follow up for all patients (N = 940), and for node-negative (N = 683) and<br />
node-positive (N = 257) patients separately using proportional hazard models for<br />
time to distant recurrence.<br />
Results: In years 0-5, all three scores add significant prognostic information on<br />
distant recurrence in a univariate model (ROR: ΔLR-χ 2 = 41.50, P < 0.0001; RS:<br />
ΔLR-χ 2 = 23.23, P < 0.0001; IHC4: ΔLR-χ 2 = 36.18, P < 0.0001). When <strong>the</strong> Clinical<br />
Treatment Score (CTS) was added to <strong>the</strong> model, IHC4 added <strong>the</strong> most prognostic<br />
information in years 0-5 (ΔLR-χ 2 = 25.22, P < 0.0001). In years 5-10, ROR provided<br />
<strong>the</strong> most prognostic information in a univariate analysis although all scores were still<br />
significant in this time period (ROR: ΔLR-χ 2 = 46.31, P < 0.0001; RS: ΔLR-χ 2 = 10.95,<br />
P = 0.0009; IHC4: ΔLR-χ 2 = 12.42, P = 0.0004). In <strong>the</strong> multivariate model, ROR added<br />
<strong>the</strong> most prognostic information both overall (ΔLR-χ 2 = 16.66, P < 0.0001) and in<br />
node-negative patients (ΔLR-χ 2 = 8.82, P = 0.003). For all patients, smaller<br />
contributions were seen for RS (ΔLR-χ 2 = 5.42, P = 0.02) and IHC4 (ΔLR-χ 2 = 7.12, P<br />
= 0.008) and nei<strong>the</strong>r added significant information in node-negative patients. For<br />
node-positive patients, ROR added most information in years 5-10 in both <strong>the</strong><br />
univariate and multivariate model.<br />
Conclusion: Overall, all three scores provided significant additional prognostic<br />
information in <strong>the</strong> 5-10 year period, but ROR added most prognostic information in<br />
both <strong>the</strong> univariate and multivariate analysis and in node-negative patients. These<br />
results may be used to select patients who could benefit from hormonal <strong>the</strong>rapy<br />
beyond 5 years.<br />
Disclosure: J. Cuzick: Dr. Cuzick disclosed that he received grant support from and<br />
is a consultant for AstraZeneca. S. Ferree: Dr. Ferree disclosed that he is an employee<br />
of and shareholder in NanoString Technologies. J.W. Cowens: Dr. Cowens disclosed<br />
that he is an employees of and shareholder in NanoString Technologies. M. Dowsett:<br />
Dr. Dowsett disclosed that he received grant support from and is on <strong>the</strong> speaker’s<br />
bureau, has received grant support and provided legal advice for AstraZeneca and<br />
has sponsored IHC4 in a NICE assessment. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
177PD EXOSOMAL LONG NON-CODING RNA (LNCRNA) IN LUNG<br />
CANCER<br />
G. Kloecker 1 , C. Taylor 2 , N. Vinayek 1 , D. Taylor 2<br />
1 Dept. Medical Oncology & Hematology, Brown Cancer Center University of<br />
Louisville, Louisville, KY, UNITED STATES OF AMERICA, 2 Department of Ob/gyn,<br />
University of Louisville, Louisville, KY, UNITED STATES OF AMERICA<br />
Background: Long noncoding RNAs (lncRNAs) are master regulators of<br />
pluripotency, differentiation, body axis patterning and promoting developmental<br />
transitions. Dysregulation of lncRNA expression has been shown to be associated<br />
with a wide range of pathologies.<br />
Study Design: lncRNA within exosomes of lung cancer cell line (H838) and derived<br />
from patients with NSCLC were analyzed. After 10,000xg centifugation, microvesicles<br />
were isolated by chromatography (CT). Trizol isolated total RNA, which was<br />
analyzed for specific lncRNAs using <strong>the</strong> LncRNA profiler qPCR array (Systems<br />
Biosciences). RNA and ln RNA from tumor cells and <strong>the</strong> vesicles from NSCLC<br />
patient (n = 8) sera were analyzed <strong>the</strong> same way.<br />
Results: Microvesicles’ size, 50-200nm, was consistent with exosomes (CD63<br />
confirmed). Exosomes contained RNA and lncRNA. Comparison of lncRNA<br />
between tumor cells and <strong>the</strong>ir released exosomes revealed selectivity on <strong>the</strong> lncRNAs<br />
appearing in <strong>the</strong> exosomes. Three of 90 examined lncRNAs had a 10-fold increase<br />
within exosomes. Representative lncRNAs were compared between <strong>the</strong> cells and <strong>the</strong>ir<br />
released exosomes. For lncRNAs exhibiting epigenetic silencing, splicing regulation,<br />
regulating apoptosis and translational control <strong>the</strong> CT values of lncRNA within cells<br />
and <strong>the</strong> lncRNA within exosomes were <strong>the</strong> same (ANRIL cells 23.80 vs. 26.44<br />
exosomes. MALAT-1 cells 31.84 vs. 32.85 exosomes. BACE1AS cells 34.14 vs 34.86<br />
exosomes). The lncRNA profiles of cancer patients were distinct from normal.An<br />
increase of greater than 20-fold was observed in 58 lncRNAs in cancer<br />
patient-derived exosomes. In contrast, a decrease of 10-fold or greater was observed<br />
in 20 lncRNAs in cancer patients. LncRNAs exhibiting epigenetic silencing, In<br />
lncRNAs exhibiting splicing regulation and lncRNAs regulating apoptosis,were<br />
elevated 20-40 fold in cancer patient-derived exosomes versus controls. Conclusions:<br />
Misexpression of lncRNAs contributes to cancer development and progression.<br />
Cancer patients’ exosomes contain lncRNA distinct from non-cancer controls.Some<br />
lncRNAs, such as MALAT-1 (metastasis-associated in lung adenocarcinoma<br />
transcript) were identified in serum of NSCLC patients. The stability of exosomes in<br />
<strong>the</strong> peripheral circulation and <strong>the</strong> unique profile of lncRNAs suggest <strong>the</strong>ir ideal<br />
utility as a diagnostic biomarker.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
178P TUMOR ENDOTHELIAL MARKERS (TEMS) AS PROGNOSTIC<br />
AND PREDICTIVE MARKERS IN NON-SMALL CELL LUNG<br />
CANCER (NSCLC)<br />
A. Pircher 1 , G. Untergasser 1 , I.M. Heidegger 2 , J. Kern 1 , E. Gunsilius 1 , M. Fiegl 1 ,<br />
W. Hilbe 1<br />
1 Hematology and Oncology, Internal Medicine V, Medical University Innsbruck,<br />
Innsbruck, AUSTRIA, 2 Department of Urology, Medical University Innsbruck,<br />
Innsbruck, AUSTRIA<br />
Background: Tumor angiogenesis plays a crucial role in tumor development and<br />
progression. Genome analyses of endo<strong>the</strong>lial cells identified genes specifically<br />
expressed by tumor endo<strong>the</strong>lial cells. These so called tumor endo<strong>the</strong>lial markers<br />
(TEMs) are discussed as potential new <strong>the</strong>rapeutic targets or as biomarkers for<br />
monitoring anti-angiogenic <strong>the</strong>rapies. In non-small cell lung cancer (NSCLC) <strong>the</strong><br />
role of TEMs is not yet investigated. Therefore, <strong>the</strong> present study aims to define <strong>the</strong><br />
expression of TEMs in NSCLC cancer cell lines and tumor samples of NSCLC<br />
patients.<br />
Patients and methods: The expression of different TEMs (Robo4, Clec14 and<br />
ECSCR) was evaluated by qPCR and Western blot analyses in several NSCLC cancer<br />
cell lines (A549, Calu1, Colo699) compared to human umbilical vein endo<strong>the</strong>lial<br />
cells (HUVEC) and human bronchial epi<strong>the</strong>lial cells (HBEpC). The expression of<br />
TEMs in resected tumor tissue of NSCLC patients (n = 64) was measured by<br />
qPCR and compared to adjacent lung tissue (n = 52). Fur<strong>the</strong>r correlation analyses of<br />
patient samples with clinical course were performed using <strong>the</strong> data from <strong>the</strong> TYROL<br />
register.<br />
Results: NSCLC cancer cell lines and HBEpC do not express TEMs nei<strong>the</strong>r on<br />
mRNA or on protein level compared to HUVECs (p = 0.001). Quantitative analyses<br />
of Robo4, ECSCR and Clec14 mRNA expression showed a significant up-regulation<br />
of CLEC14 in tumor samples (p = 0.01). Evaluating paired tissue samples from<br />
cancerous and corresponding non-cancerous tissues (n = 31) also Robo4 showed a<br />
significant upregulation in cancer specimens (p = 0.04). ECSCR showed a statistical<br />
trend towards an overexpression in tumor tissue (p = 0.09). Immunohistochemichal<br />
analyses of Robo4 revealed a higher expression in tumor tissue in comparison to <strong>the</strong><br />
adjacent tissue (tumor vs. adjacent tissue; n = 20). Correlation with clinical data<br />
showed that increased TEM expression correlated with prolonged overall survival of<br />
NSCLC patients.<br />
Conclusion: TEMs are overexpressed in NSCLC tissue specimens but not in cancer<br />
cells suggesting that TEMs are upregulated in stromal tissue including tumor vessels.<br />
Therefore, TEMs provide a potential new target structure for anti-angiogenic<br />
<strong>the</strong>rapies. Increased TEM expression levels correlated with prolonged OS possibly<br />
due to vascular stabilization.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
179P INTEGRIN BETA1 MEDIATES EGFR TKI RESISTANCE<br />
THROUGH C-MET SIGNALING PATHWAY IN NON-SMALL<br />
CELL LUNG CANCER<br />
L. Ju 1 , C. Zhou 2<br />
1 Traditional Chinese Medicine, Shanghai Pulmonary Hospital, Tongji University,<br />
Shanghai, CHINA, 2 Oncology, Shanghai Pulmonary Hospital, Shanghai, CHINA<br />
Introduction: Although some patients are initially sensitive to epidermal growth<br />
factor receptor tyrosine kinase inhibitors (EGFR TKIs), resistance invariably<br />
develops. Therefore, it’s very important to study <strong>the</strong> molecular mechanism of this<br />
resistance. For <strong>the</strong> first time, we found that integrin β1 associates with EGFR TKIs<br />
resistance. We also investigated <strong>the</strong> crosstalk between integrin β1 and c-MET that is<br />
a recognized mechanism of EGFR TKIs resistance in non-small cell lung cancer<br />
(NSCLC) to explore <strong>the</strong> mechanism.<br />
Materials and methods: We study <strong>the</strong> <strong>the</strong> crosstalk between integrin β1 and c-MET<br />
using MTT, Western blot, TUNEL, xenograft model and immunohistochemical.<br />
Results: We found that integrin β1 and c-MET co-expressed in PC9 and PC9/AB2<br />
cell lines and <strong>the</strong> ligands of integrin β1 and c-MET could synergistically promote cell<br />
proliferation and <strong>the</strong>ir inhibitors could synergistically improve <strong>the</strong> sensitivity to<br />
gefitinib, increase apoptosis, and inhibit <strong>the</strong> phosphoralation of <strong>the</strong>ir downstream<br />
signal transduction: FAK and AKT. Ligand-dependent activation of integrin β1 could<br />
induce EGFR TKIs resistance and decreased gefitinib-induced apoptosis through<br />
activating c-MET and its downstream signals: FAK and AKT. On <strong>the</strong> o<strong>the</strong>r hand, in<br />
integrin β1 overexpressed xenograft tumor models, gefitinib couldn’t inhibit <strong>the</strong><br />
tumors growth effectively and reduce phosphorylation of AKT, FAK and c-MET<br />
effectively.<br />
Conclusions: Herein, it can be concluded that <strong>the</strong>re is crosstalk between integrin β1<br />
and c-MET and integrinβ1 mediates EGFR TKI resistance through c-MET signaling<br />
pathway in non-small cell lung cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix76 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
180P PREDICTIVE VALUE OF LKB1 IN PATIENTS WITH RESECTED<br />
NON SMALL CELL LUNG CANCER<br />
E. Fabre 1 , N. Pécuchet 1 , P. Laurent-Puig 2 , K. Pallier 2 , F. Le Pimpec-Bar<strong>the</strong>s 3 ,<br />
M. Riquet 3 , A. Cazes 4 , H. Blons 2<br />
1 Medical Oncology, Hopital Européen Georges Pompidou, Paris, FRANCE,<br />
2 UMR-S775, Université Paris Descartes, Paris, FRANCE, 3 Thoracic Surgery,<br />
Hopital Européen Georges Pompidou, Paris, FRANCE, 4 Pathology, Hopital<br />
Européen Georges Pompidou, Paris, FRANCE<br />
Background: LKB1/STK11 is a serine threonine kinase involved in signal<br />
transduction, energy sensing and cell polarity. We tested <strong>the</strong> predictive value of<br />
STK11 inactivating mutations in a series of resected non-small cell lung cancer<br />
(NSCLC) patients (pts).<br />
Methods: STK11 mutations were determined in a surgical series prospectively<br />
collected, No pts had received prior induction chemo<strong>the</strong>rapy. The entire coding<br />
region (exons 1-9) of STK11 including intron/exon boundaries was screened by<br />
direct sequencing. These tumors had previously been characterized for EGFR, TP53,<br />
KRAS, BRAF, PI3KCA, ERBB2 and AKT1 mutations for CDKN2A homozygous<br />
deletions and for CCND1, CCND3, CCNE1 amplifications. Prognostic factors were<br />
determined using univariate and multivariate log-rank analysis on disease-free<br />
survival (DFS) and cancer-specific survival (C-SS).<br />
Results: Clinical genotyping was performed in 69 pts including 29 females and 41<br />
males, histological diagnosis was adenocarcinoma in 54 cases. Tumor stage was IA<br />
(n =16), IB (n =25), IIA (n =6), IIB (n =8), or IIIA (n =14). Somatic mutations were<br />
observed: 27 (39%) TP53, 17 (24%) KRAS, 11 (16%) EGFR, 8 (11%) STK11, 1 (1%)<br />
PIK3CA, 1 (1%) ERBB2, and 0 (0%) BRAF. Cyclin amplifications were indentified in:<br />
10 (14%) CCND1, 8 (11%) CCNE1, 9 (13%) CCND3. In 9 cases (13%) CDKN2A<br />
were homozygously deleted. STK11 and EGFR mutations were mutually exclusive.<br />
CCND3 amplifications tended to be more frequent in STK11 mutated (3/8, 38%)<br />
relative to STK11 wild type (6/61, 10%) (p = 0.06). KRAS mutations had similar rate<br />
in STK11 mutated (3/8, 38%) and STK11 wild type (14/61, 23%) (p = 0.40). STK11<br />
mutations were more frequent in men (n= 5/8), adenocarcinoma (n = 6/8) and<br />
smokers (n= 7/8). In univariate analysis, STK11 was <strong>the</strong> only prognostic factor<br />
associated with a lower DFS (HR = 4.78 (95%CI: 0.08-0.65); p = 0.01). C-SS was lower<br />
in pts with: STK11 mutation, CCND3 amplification, stage II-III and no radiation<br />
<strong>the</strong>rapy. Multivariate analysis identified STK11 mutation to be an independent<br />
negative prognostic biomarker of C-SSl [hazard ratio (HR) =4.36 (95%CI 1.18-14.78);<br />
p =0.03).<br />
Conclusions: STK11 mutations appear as a useful biomarker that can be regarded as<br />
an independent factor for predicting <strong>the</strong> recurrence of resected NSCLC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
181P PROGNOSTIC RELEVANCE OF FIBROBLAST GROWTH<br />
FACTOR RECEPTOR 1 (FGFR1) GENE COPY NUMBER IN<br />
PURE LUNG SQUAMOUS-CELL CARCINOMA<br />
L. Terracciano 1 , E. Rossi 2 , L. Landi 2 , M. Roncalli 3 ,A.D’Incecco 2 ,<br />
M. D’Arcangelo 2 , A. Destro 3 , M. Incarbone 4 , M. Andreozzi 1 , F. Cappuzzo 2<br />
1 Pathology, University Hospital Basel, Basel, SWITZERLAND, 2 Oncology, Istituto<br />
Toscano Tumori, Livorno, ITALY, 3 Pathology, Milan University-Istituto Clinico<br />
Humanitas Cancer center, Rozzano, ITALY, 4 Surgery, Thoracic Surgery,<br />
Ospedale S.Giuseppe-Multimedica, Milan, ITALY<br />
Background: FGFR1 belongs to a family of five different receptors often dysregulated<br />
in human malignancies, including lung cancer. Recent studies showed that gene<br />
amplification is one of <strong>the</strong> mechanisms potentially responsible for FGFR<br />
dysregulation. Although FGFR1 gene amplification has been reported in up to 20%<br />
of lung cancer patients with squamous-cell carcinoma (SCC), prognostic effect is<br />
unknown. Aim of <strong>the</strong> present study was to assess <strong>the</strong> prognostic role of FGFR1 gene<br />
copy number (GCN) in pure lung SCC.<br />
Methods: A total of 378 patients were included in <strong>the</strong> present study. Pure SCC was<br />
defined as a tumor positive for P40 and negative for TTF1 using<br />
immunohistochemistry. FGFR1 was evaluated by fluorescence in situ hybridization<br />
(FISH) in tissue microarray sections from primary lung tumors. All cases with an<br />
FGFR1/centromere ratio ≥ 2 were considered as amplified (FGFR1 FISH+).<br />
Results: Among patients included onto <strong>the</strong> study, FGFR1 FISH analysis was<br />
successfully performed in 304 and 32 (10.5%) were FGFR1 FISH+. FGFR1<br />
amplification was significantly associated with P40 positive status (p = 0.002) and<br />
with lack of TTF1 expression (p = 0.005). In <strong>the</strong> whole population, no difference in<br />
disease-free survival (DFS) and overall survival (OS) was detected between FGFR1<br />
FISH positive and negative patients (DFS: 17.2 versus 17.0 months, p = 0.98; OS: not<br />
reached in both groups, p = 0.2). In <strong>the</strong> group of patients p40 + /TTF1 negative (N =<br />
66), 14 (21.2%) displayed FGFR1 gene amplification. No difference in survival was<br />
detected between FGFR1 FISH+ and negative patients in p40+ versus p40 negative<br />
(OS not reached versus 46.2 months, p = 0.41 in FGFR1 FISH + /p40+ versus any<br />
negative), nor in TTF1 negative versus TTF1+ (OS not reached versus 41.8 months<br />
in FGFR1 FISH + /TTF1 negative versus o<strong>the</strong>r subgroups) nor in FGFR FISH + /p40<br />
+ /TTF1 negative versus FGFR negative/p40 + /TTF1 negative (37.3 months versus<br />
not reached, p = 0.77).<br />
Conclusions: FGFR1 is amplified in 21% of pure lung SCC with no prognostic effect.<br />
The high percentage of gene amplification detected fur<strong>the</strong>r support anti-FGFR1<br />
strategies in individuals with pure SCC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
182P A PROSPECTIVE, MOLECULAR EPIDEMIOLOGICAL STUDY<br />
OF EGFR MUTATIONS IN ASIAN PATIENTS (PTS) WITH<br />
ADVANCED NON-SMALL-CELL LUNG CANCER WITH<br />
ADENOCARCINOMA HISTOLOGY (PIONEER) – CHINA<br />
SUBSET ANALYSIS<br />
Y. Shi 1 , S. Zhang 2 , M. Wang 3 , S. Yang 4 ,N.Li 5 ,G.Wu 6 , W. Liu 7 , G. Liao 8 ,<br />
K. Cai 9 , L. Chen 10<br />
1 Medical Oncology Department, Cancer Institute & Hospitall, Chinese Academy<br />
of Medical Sciences and Peking Union Medical College, Beijing, CHINA,<br />
2 Department of Medical Oncology, Beijing Chest Hospital, Capital Medical<br />
University, Beijing, CHINA, 3 Department of Respiratory Medicine, Peking Union<br />
Medical College Hospital, Beijing, CHINA, 4 Department of Medical Oncology,<br />
Henan Cancer Hospital, Zhengzhou, CHINA, 5 Department of Medical Oncology,<br />
Guangzhou Chest Hospital, Guangzhou, CHINA, 6 Cancer Centre of Union<br />
Hospital, Tongji Medical College, Huazhong University of Science and<br />
Technology, Hubei, CHINA, 7 Department of Medical Oncology, Fourth Hospital,<br />
Hebei Medical University, Hebei, CHINA, 8 Department of Medical Oncology, 309<br />
Hospital, Beijing, CHINA, 9 Department of Medical Oncology, South Hospital,<br />
Guangzhou, CHINA, 10 Department of Medical Oncology, 301 Hospital, Beijing,<br />
CHINA<br />
Background: The presence of EGFR mutations has been demonstrated to be<br />
associated with sensitivity to EGFR-TKIs by several phase III studies, but <strong>the</strong>re’s<br />
limited information of prospective EGFR mutation data in real-life setting in Asian<br />
population. The epidemiological prospective study (NCT01185314; PIONEER)<br />
investigated EGFR mutation (M) frequency in pts from Asia with newly diagnosed<br />
advanced lung adenocarcinoma (ADC) and <strong>the</strong> influence of demographic and<br />
clinical factors on EGFR M frequency. Here we report analysis results for <strong>the</strong> subset<br />
of pts from China.<br />
Methods: Pts were aged ≥20 years, with treatment naïve stage IIIB/IV lung ADC.<br />
Tumor sample (biopsy, surgical specimen, cytology) EGFR M status (primary<br />
endpoint; positive [M + ], negative [M-], undetermined [MU]) was determined using<br />
<strong>the</strong> Therascreen EGFR RGQ kit. EGFR M frequency was calculated and compared<br />
between demographic/clinical factor subgroups.<br />
Results: Of 747 pts in China (50.4% of <strong>the</strong> overall study population), 46.9% were<br />
female, mean age was 57 years (range 17-83), and 56% were never-smokers. EGFR M<br />
status was evaluated in 741 patients (6 [0.8%] were MU): 372 (50.2%) were M + , 369<br />
(49.8%) were M-. Gender, smoking status, pack years, metastasis, (all p < 0.001) and<br />
disease stage (p = 0.002) were significantly associated with presence of EGFR M. EGFR<br />
M+ frequency was 60.6% in females, 41.0% in males, 59.6% in never smokers, and<br />
35.3% in regular smokers. When combine gender and smoking status on overall<br />
judgment, <strong>the</strong> EGFR M+ frequency was 52.7% in male non-smokers, 61.5% in female<br />
non-smokers, 35.8% in male regular smokers, and 27.3% in female regular smokers.<br />
Summary of individual mutation types<br />
Number of patients<br />
with EGFR<br />
mutation test<br />
success<br />
Number (%) of pts<br />
741 (100.0)<br />
Exon 18<br />
G719X 4 (0.5)<br />
Exon 19<br />
Deletion 182 (24.6)<br />
Exon 20<br />
T790M 3 (0.4)<br />
S768I 8 (1.1)<br />
Insertion 15 (2.0)<br />
Exon 21<br />
L858R 169 (22.8)<br />
L861Q 6 (0.8)<br />
Conclusions: The overall EGFR mutation frequency in clinically unselected ADC<br />
was 50.2%. Smoking status and pack years had a statistically significant association<br />
with presence of EGFR mutation, but even in regular smokers, <strong>the</strong> mutation<br />
frequency was 35.3%.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds391 | ix77
183P EPIDERMAL GROWTH FACTOR RECEPTOR MUTATIONS IN<br />
ITALIAN NON-SMALL-CELL LUNG CANCER PATIENTS<br />
ENROLLED IN THE EGFR FASTNET PROGRAM<br />
N. Normanno 1 , C. Pinto 2 , G.L. Taddei 3 , G. Troncone 4 , P. Graziano 5 ,G.De<br />
Maglio 6 , M. Mottolese 7 , M. Di Maio 8 , C. Clemente 9 , A. Marchetti 10<br />
1 Dept. Biologia Cellulare e Bioterapie, Istituto Nazionale Tumori di Napoli, Napoli,<br />
ITALY, 2 Medical Oncology, Policlinico S.Orsola Malpighi, Bologna, ITALY,<br />
3 Surgical Pathology, Università degli Studi di Firenze, Firenze, ITALY, 4 Surgical<br />
Pathology, Università Federico II, Napoli, ITALY, 5 Surgical Pathology, Az.Osp. S.<br />
Camillo Forlanini, Rome, ITALY, 6 Surgical Pathology, Az. Osp. Universitaria, S.<br />
Maria della Misericordia, Udine, ITALY, 7 Surgical Pathology, Istituto Nazionale<br />
Tumori Regina Elena, Roma, ITALY, 8 Clinical Trials Unit, Istituto Nazionale Tumori<br />
di Napoli, Napoli, ITALY, 9 Surgical Pathology, IRCCS Policlinico S.Donato e Casa<br />
di Cura S. Pio X, Milano, ITALY, 10 Surgical Pathology, Università G.d’Annunzio,<br />
Chieti, ITALY<br />
Background: Assessment of epidermal growth factor receptor (EGFR) mutations is<br />
mandatory for appropriate selection of treatment for patients (pts) with advanced<br />
non-small-cell lung cancer (NSCLC).<br />
Methods: The EGFR FASTnet program was designed to facilitate <strong>the</strong> exchange of<br />
biological material, clinico-pathological data and reports between medical<br />
oncologists, pathologists and referral laboratories. EGFR mutational analysis was<br />
carried by Sanger sequencing, Real Time (RT)-PCR, Pyrosequencing, and o<strong>the</strong>r<br />
techniques. The Italian Association of Medical Oncology (AIOM) and <strong>the</strong> Italian<br />
Society of Pathology and Cytopathology - Italian division of International Academy<br />
of Pathology (SIAPeC-IAP) have full access to <strong>the</strong> anonymous EGFR FASTnet<br />
database.<br />
Results: As of December 31, 2011, 503 oncologists, 135 pathologists and 38 referral<br />
laboratories joined <strong>the</strong> EGFR FASTnet program. The enrolled cohort of 3819 pts<br />
with advanced NSCLC was significantly enriched for adenocarcinoma histology<br />
(3172 [83%]), female sex (1361 [36%]) and smoking history (never smoker 911<br />
[24%], former smoker > 15 yrs 880 [23%], light smoker 194 [5%]). Mutational<br />
analysis was feasible in 3567 pts (93%), and was carried by Sanger sequencing in<br />
2021 cases (57%), RT-PCR in 174 (5%), Pyrosequencing in 636 (18%) and o<strong>the</strong>r<br />
techniques in 736 (21%). EGFR mutations were found in 520 cases (14.6%): 334 in<br />
exon 19 (9.4%), 163 in exon 21 (4.6%), 7 in exon 18 (0.2%) and 16 in exon 20<br />
(0.4%). Proportion of mutated cases was slightly higher with RT-PCR (p = 0.049). A<br />
higher mutation rate was found in never smokers (32.0%), light smokers (18.7%) and<br />
former smokers >15 yrs (12.4%), as well as in adenocarcinoma (15.7%) and females<br />
(25.2%). EGFR mutations were also reported in 17/227 (7.5%) squamous carcinomas.<br />
However, 16/17 EGFR mutation positive patients with squamous carcinoma were<br />
never- or former-smokers.<br />
Conclusions: The pts for EGFR mutational screening are spontaneously selected by<br />
medical oncologists according to known predictive factors. The results of <strong>the</strong><br />
mutational analysis from clinical practice in Italy are consistent with data from<br />
literature. Never- and former-smoker NSCLC pts with squamous carcinoma should<br />
be tested for EGFR mutations.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
184P CLINICAL SIGNIFICANCE OF ANGIOPOIETIN-2 SERUM<br />
LEVELS IN NON-SMALL CELL LUNG CANCER<br />
A. Coelho 1 , A.M.F. Araujo 1 , R. Catarino 1 , M. Gomes 1 , A. Marques 2<br />
,R. Medeiros 1<br />
1 Molecular Oncology Unit, Portuguese Intitute of Oncology, Porto, PORTUGAL,<br />
2 Faculty of Medicine, University of Porto, Porto, PORTUGAL<br />
Introduction: Tumor vasculature is a very promising target in NSCLC, with VEGF<br />
inhibitors as part of standard care in some patients. Angiopoietin-2 (Ang-2) plays<br />
critical roles in angiogenesis in concert with VEGF. High tumor Ang-2 expression<br />
has negative prognostic implications in lung cancer patients, especially when VEGF<br />
expression is high. The aim of this study was <strong>the</strong> evaluation of Ang-2 and VEGF<br />
serum levels in NSCLC and tumor stages and its comparison with healthy controls.<br />
Patients and methods: The study included 30 controls, 145 NSCLC patients, (48<br />
epidermoid, 73 adenocarcinomas, 19 undiferenciated NSCLC, 4 large cells and 1<br />
mixed carcinoma), divided in 13 early and 132 advanced stages). Ang-2 and VEGF<br />
levels were evaluated in subject samples with R&D Quantikine ELISA Kit, according<br />
to manufacturer’s instructions.<br />
Results: Ang-2 levels were significantly different in <strong>the</strong> control and case groups<br />
(Mann-Whitney test, p = 0.003). Mean concentration values were 2855.50 pmol/ml<br />
(SE 268.64) vs 4164.90 pmol/ml (SE 200.56), respectively. Regarding stage analysis,<br />
Ang-2 levels were also statistically different according to tumor stage (Mann-Whitney<br />
test, p = 0.016): mean 2824.64 pmol/ml (standard error 472.82) and 4202.57 pmol/ml<br />
(203.05) for early and advanced stages, respectively. VEGF levels were significantly<br />
different in <strong>the</strong> control and case groups (Mann-Whitney test, p = 0.001). Mean<br />
concentration values were 312.63 pmol/ml (standard error 59.62) vs 675.51 pmol/ml<br />
(standard error 55.30), respectively. Regarding stage analysis, <strong>the</strong>re were no<br />
statistically significant differences between VEGF levels and tumor stage<br />
(Man-Whitney test, p = 0.197).<br />
Annals of Oncology<br />
Conclusions: Angiogenesis inhibitors have obvious, yet modest, antitumor activity in<br />
NSCLC. Ang-2 seems to be a promising target of such inhibitors and its serum levels<br />
may be useful to predict which patients will benefit more with this type of treatment,<br />
surpassing <strong>the</strong> need to obtain tumor tissue samples to assess its levels of expression.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
185P ACTIVATION OF AKT BY HYPOXIA PREDICTS POOR<br />
OUTCOME IN MALIGNANT PLEURAL MESOTHELIOMA (MPM)<br />
K.A. Gately 1 , D. Stewart 2 , S. Heavey 3 , A. Davies 3 , K.J. O’Byrne 3<br />
1 Clinical Medicine, St James’s Hospital, Dublin, IRELAND, 2 Thoracic Oncology,<br />
Glenfield Hospital, Leicester, UNITED KINGDOM, 3 Clinical Medicine, Trinity<br />
College Dublin/St. James’s Hospital, Dublin, IRELAND<br />
Introduction: The Phosphatidylinositol-3 kinase (PI3K)/Akt (PKB) pathway is<br />
activated in a wide range of tumour types, and plays a central role in cell survival.<br />
Recent evidence indicates that hypoxia induces upregulation of Akt and activation of<br />
<strong>the</strong> Akt/PKB pathway. Once activated, Akt phosphorylates a variety of downstream<br />
substrates, including FOXO3a, which decreases transcription of <strong>the</strong> pro-apoptotic<br />
factor Bim, facilitating cell survival. We have shown that nuclear phospho-Akt<br />
(pAkt) expression is associated with more advanced disease or poor prognosis in<br />
Non-Small Cell Lung Cancer and MPM. Carbonic Anhydrase (CA)-IX, a<br />
tumour-specific member of <strong>the</strong> carbonic anhydrase family, is a surrogate marker of<br />
hypoxia overexpressed in solid tumours. This study examines <strong>the</strong> expression of<br />
CA-IX and phosphorylated Akt (pAkt) in tumour samples from patients with MPM,<br />
correlating expression with established prognostic factors. The role of pAkt in <strong>the</strong><br />
survival of MPM cell lines exposed to both normoxia and hypoxia was also<br />
examined with both PI3K and PI3k-mTOR inhibitors.<br />
Methods: Tumour sections were stained using pAkt and CA-IX specific antibodies. The<br />
effect of hypoxia on pAkt, Akt and Bim expression in 4 MPM cell lines in <strong>the</strong> presence<br />
or absence of LY294002 (phosphatidylinositol-3-kinase inhibitor) was examined by<br />
Western blot. The percentage of apoptotic cells was also quantified in <strong>the</strong>se cells using<br />
FACs and High-Content Analysis (HCA). Changes in subcellular localisation of pAkt<br />
and FOXO3a were quantified using HCA. The cells were also transfected with siRNAs to<br />
PDK1or DNA-PKcs (two kinases known to catalyse <strong>the</strong> phosphorylation of Akt) and<br />
<strong>the</strong> effect on pAkt expression was determined by Western blot.<br />
Results: A positive association between CA-IX and pAkt staining implies<br />
intra-tumoural hypoxia may stimulate Akt phosphorylation. Multivariate analysis<br />
showed increased expression of nuclear pAkt was associated with poor survival.<br />
Hypoxia induced <strong>the</strong> activation of Akt in MPM cell lines resulting in changes in <strong>the</strong><br />
subcellular localisation of pAkt and FOXO3a. A greater increase in <strong>the</strong> level of<br />
apoptosis was seen in cells treated with PI3K inhibitors under hypoxia.<br />
Conclusion: pAkt plays an anti-apoptotic role in MPM and represents a potential<br />
<strong>the</strong>rapeutic target particularly in hypoxic tumours.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
186P ASSOCIATION OF TWO BRM PROMOTER VARIANTS WITH<br />
SURVIVAL OUTCOMES OF STAGE IV NON SMALL CELL LUNG<br />
CANCER (NSCLC) PATIENTS<br />
S. Cuffe 1 , A.K. Azad 2 , Y. Brhane 3 , D. Cheng 2 , Z. Chen 2 ,W.Xu 3 , F.A. Shepherd 1 ,<br />
M. Tsao 4 , D. Reisman 5 , G. Liu 1<br />
1 Department of Medical Oncology, Princess Margaret Hospital, University Health<br />
Network, Toronto, ON, CANADA, 2 Applied Molecular Oncology, Princess<br />
Margaret Hospital, Ontario Cancer Institute, Toronto, ON, CANADA,<br />
3 Department of Biostatistics, Princess Margaret Hospital, Ontario Cancer<br />
Institute, Toronto, ON, CANADA, 4 Pathology Department, Princess Margaret<br />
Hospital, University Health Network, Toronto, ON, CANADA, 5 Division of<br />
Hematology/Oncology, University of Florida, Florida, FL, UNITED STATES OF<br />
AMERICA<br />
Background: BRM, an ATPase subunit of <strong>the</strong> SWI/SNF chromatin remodeling<br />
complex, is a putative tumor susceptibility gene that is silenced in 15% of lung<br />
cancers. Two BRM promoter insertion variants (BRM-741 and BRM-1321) result in<br />
epigenetic silencing of BRM through recruitment of histone deacetylases. The<br />
presence of double homozygous BRM variants is associated with loss of BRM<br />
expression, and double <strong>the</strong> risk of lung cancer. Recently, pharmacological reversal of<br />
<strong>the</strong> epigenetic changes of BRM has been shown to be a potentially viable <strong>the</strong>rapeutic<br />
strategy. We investigated <strong>the</strong> association between BRM promoter variants and<br />
survival outcomes in advanced NSCLC patients.<br />
Methods: 313 stage IV NSCLC patients treated in Princess Margaret Hospital from<br />
2006-2010 were genotyped for <strong>the</strong> BRM promoter variants using TaqMan.<br />
Association of BRM variants and overall (OS) and progression free survival (PFS)<br />
were assessed using multivariate Cox proportional hazards models.<br />
Results: 71% were Caucasian; 71%, adenoca; median age, 63 yrs; Median OS, 1.1 yrs;<br />
median follow up, 1.8 yrs. The frequency of homozygosity was: BRM-741 25%;<br />
BRM-1321 21%; both 12%. Homozygous variants of BRM-741 were strongly<br />
associated with worse OS (adjusted HR [aHR] 3.5 [95% CI: 2.4-5.0; p = 1x10E-11])<br />
ix78 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
and PFS (aHR 2.3 [95% CI: 1.6-3.1; p = 8x10E-7]), compared to <strong>the</strong> wildtypes.<br />
Similar findings were observed for <strong>the</strong> BRM-1321 homozygous variants (aHR for OS<br />
of 2.5 [95% CI: 1.7-3.5; p = 1.1x10E-6]; aHR for PFS of 1.9 [95% CI: 1.3-2.6;<br />
p = .0004]). Finally, <strong>the</strong> presence of double homozygous BRM-741 and BRM-1321<br />
variants was strongly associated with substantially worse OS (aHR 4.4 [95% CI:<br />
2.7-7.1, p = 1x10E-9]) and PFS (aHR 3.6 [95% CI: 2.3-5.6, p = 2x10E-8]).<br />
Conclusion: The same two homozygous BRM promoter variants that are associated<br />
with increased risk of lung cancer are also strongly associated with adverse OS and<br />
PFS in this cohort of stage IV NSCLC patients. Validation of <strong>the</strong> results in<br />
prospective clinical trials is underway and will better elucidate whe<strong>the</strong>r <strong>the</strong>se BRM<br />
promoter variants are prognostic or predictive.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
187P RIBONUCLEOTIDE REDUCTASE SUBUNIT 2 (RRM2)<br />
PREDICTS SHORTER SURVIVAL IN RESECTED STAGE I-III<br />
NON-SMALL CELL LUNG CANCER (NSCLC) PATIENTS<br />
F. Grossi 1 , G. Barletta 1 , C. Sini 1 , E. Rijavec 1 , C. Genova 1 , M.G. Dal Bello 1 ,<br />
G. Savarino 2 , M. Truini 3 , F. Merlo 2 , P. Pronzato 4<br />
1 Lung Cancer Unit, National Institute for Cancer Research, Genoa, ITALY,<br />
2 Epidemiology, National Institute for Cancer Research, Genoa, ITALY,<br />
3 Department of Pathology, IRCCS AOU San Martino-IST, Genoa, ITALY,<br />
4 Oncologia Medica A, IRCCS AOU San Martino - IST-Istituto Nazionale per la<br />
Ricerca sul Cancro, Genova, ITALY<br />
Background: Biomarkers can help in identifying patients (pts) with early-stage<br />
NSCLC with high risk of relapse and poor prognosis. The aim of this study was to<br />
investigate <strong>the</strong> relationship between <strong>the</strong> levels of expression of 7 biomarkers, various<br />
clinicopathological characteristics and <strong>the</strong>ir prognostic significance.<br />
Methods: Tumor tissue from 82 radically resected stage I-III NSCLC pts were<br />
consecutively collected to investigate <strong>the</strong> mRNA expression and protein levels of <strong>the</strong><br />
following biomarkers using quantitative reverse transcriptase real-time PCR<br />
(qRT-PCR) and immunohistochemistry (IHC) with a tissue microarray technique:<br />
excision repair cross-complementation group 1 (ERCC1), breast cancer 1 (BRCA1),<br />
ribonucleotide reductase subunit 1 (RRM1), RRM2, p53R2, thymidylate synthase<br />
(TS) and class III beta-tubulin (β-Tub-III).<br />
Results: On a univariate analysis, p53R2 expression was significantly higher in<br />
adenocarcinoma (ADK) compared to squamous cell carcinoma (SSC) samples (p =<br />
0.002) and in stage I compared to stage II-III (p ≤ 0.001). ERCC1 expression was<br />
significantly higher in females compared to males (p = 0.03), and β-Tub-III<br />
expression was significantly higher in ADK than in SSC (p = 0.03). Pts with lower<br />
RRM2 expression survived longer than pts with higher RRM2 expression (p = 0.069).<br />
The multivariate analysis confirmed RRM2 as an independent prognostic marker of<br />
shorter survival (p= 0.031). The comparison between survival curves with qRT-PCR<br />
and IHC showed similar results with a trend towards longer survival among ERCC1<br />
negative pts, BRCA1 negative pts, p53R2 positive pts and among pts with low levels<br />
of RRM1 and RRM2, although <strong>the</strong> difference was not statistically significant with<br />
both methods. qRT-PCR and IHC have shown that β-Tub-III and TS had no<br />
significant impact on survival.<br />
Conclusions: This is <strong>the</strong> first study that identifies RRM2 expression as a negative<br />
prognostic factor in resected stage I-III NSCLC. Moreover, we have demonstrated <strong>the</strong><br />
differential expression of p53R2 and β-Tub-III in ADK compared to SSC and higher<br />
expression of p53R2 in pts with stage I compared to stage II-III NSCLC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
188P TROPOMYOSIN-RELATED KINASE B IS A THERAPEUTIC<br />
TARGET AND PROGNOSTIC FACTOR FOR AGGRESSIVE LUNG<br />
CANCER INCLUDING LCNEC<br />
S. Odate 1 , K. Nakamura 2 , H. Onishi 1 , A. Uchiyama 3 ,M.Kato 4 , M. Tanaka 2 ,<br />
M. Katano 1<br />
1 Cancer Therapy and Research, Kyushu University, Fukuoka, JAPAN, 2 Surgery<br />
and Oncology, Kyushu University, Fukuoka, JAPAN, 3 Surgery, Kyushu Kosei<br />
Nenkin Hospital, Fukuoka, JAPAN, 4 Surgery, Hamanomachi Hospital, Fukuoka,<br />
JAPAN<br />
Background: Lung cancer is one of <strong>the</strong> most common types of cancer, accounting<br />
for more deaths than any o<strong>the</strong>r types of cancer. Tropomyosin-related kinase B<br />
(TrkB) has previously been shown to be important in tumor progression in<br />
neuroblastoma, pancreatic cancer, and prostate cancer. However, little is known<br />
about biological significance of TrkB in human lung cancer. Here we investigate if<br />
TrkB may be a <strong>the</strong>rapeutic target and prognostic factor for lung cancer.<br />
Methods: Surgically resected specimen; The expression of TrkB and its ligand BDNF<br />
(Brain-derived neurotrophic factor) were investigated in 104 patients with primary<br />
lung cancers (8 small cell carcinomas, 11 large cell neuroendocrine carcinomas, 10<br />
large cell carcinomas, 20 adenocarcinomas, 55 squamous cell carcinomas) by<br />
immunohistochemical staining. In vitro assay; Large cell neuroendocrine carcinoma<br />
(LCNEC) cell lines (NCI-H460 and NCI-H810) expressing TrkB were used.<br />
TrkB-siRNA and TrkB tyrosine kinase inhibitor (K252a) were used to inhibit TrkB.<br />
BDNF-siRNA was used to inhibit BDNF. Cell proliferation and invasion were<br />
evaluated by MTT and Transwell assays, respectively.<br />
Results: 1) There were significantly higher TrkB and BDNF expressions in LCNEC<br />
cases than any o<strong>the</strong>r histological types. LCNEC cases also had poorer prognosis than<br />
any o<strong>the</strong>r histological types. 2) Higher expression of TrkB positively correlated with<br />
disease free survival (p < 0.001) and overall survival (p < 0.05) in all histological types.<br />
3) BDNF upregulated <strong>the</strong> invasion of LCNEC cell lines. 4) Knockdown of TrkB or<br />
BDNF mRNA expression using siRNA significantly decreased <strong>the</strong> invasion of LCNEC<br />
cell lines. K252a also significantly decreased <strong>the</strong> invasion of LCNEC cell lines.<br />
Conclusions: These data suggests that BDNF/TrkB signal is important in LCNEC<br />
and TrkB is a potential <strong>the</strong>rapeutic target and prognostic factor for aggressive lung<br />
cancer including LCNEC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
189P REDUCED CYP2D6 FUNCTION POTENTIATES THE<br />
GEFITINIB-INDUCED RASH IN PATIENTS WITH NON-SMALL<br />
CELL LUNG CANCER<br />
T. Suzumura 1 , T. Kimura 1 , S. Kudoh 1 , K. Umekawa 1 , M. Nagata 1 , Y. Kira 2 ,<br />
T. Nakai 1 , K. Matsuura 1 , N. Yoshimura 1 , K. Hirata 1<br />
1 Respiratory Medicine, Osaka City University, Osaka, JAPAN, 2 Department of<br />
Central Laboratory, Osaka City University, Osaka, JAPAN<br />
Background: Rash, liver dysfunction, and diarrhea are known as adverse events of<br />
erlotinib and gefitinib. However, clinical trials with gefitinib have reported different<br />
proportion of adverse events compared to those with erlotinib. In an in vitro study,<br />
cytochrome P450 (CYP) 2D6 was shown to be involved in <strong>the</strong> metabolism of gefitinib<br />
and not of erlotinib. It has been hypo<strong>the</strong>sized that CYP2D6 phenotypes may be<br />
implicated in different adverse events between in <strong>the</strong> gefitinib and erlotinib <strong>the</strong>rapies.<br />
Methods: The frequency of each adverse event was evaluated during <strong>the</strong> period that<br />
<strong>the</strong> patients received EGFR-TKI <strong>the</strong>rapy. CYP2D6 phenotypes were determined from<br />
<strong>the</strong> CYP2D6 genotype using real-time polymerase chain reaction methods, which are<br />
able to determine single nucleotide polymorphisms. The CYP2D6 phenotypes were<br />
categorized into 2 groups according to functional or reduced metabolic levels. In<br />
addition, we evaluated <strong>the</strong> odds ratio (OR) of adverse events with each factor,<br />
including CYP2D6 activities as well as treatment types.<br />
Results: Patients were identified through a query of patient information for subjects<br />
prospectively enrolled in <strong>the</strong> Medical Information System within Osaka City<br />
University Hospital between January 1999 and February <strong>2012</strong> that tracks all of <strong>the</strong><br />
patients referred for CYP2D6 sequencing from our hospital. A total of 232 patients<br />
received gefitinib <strong>the</strong>rapy, and 86 patients received erlotinib <strong>the</strong>rapy. Reduced<br />
function of CYP2D6 was associated with an increased risk of rash of grade 2 or more<br />
(OR 0.44, 95% confidence interval [CI] 0.21-0.94, p = 0.03), and not of diarrhea ≥<br />
grade 2 (OR 0.49, 95%CI 0.17-1.51, p = 0.20) and liver dysfunction ≥ grade 2 (OR<br />
1.08, 95%CI 0.52-2.34, p = 0.84) in gefitinib cohort. No associations were observed<br />
between any adverse events in erlotinib cohorts and CYP2D6 phenotypes (rash: OR<br />
1.77, 95%CI 0.54-6.41, p = 0.35; diarrhea: OR 1.08, 95%CI 0.21-7.43, p = 0.93; and<br />
liver dysfunction: OR 0.93, 95%CI 0.20-5.07, p = 0.93).<br />
Conclusions: CYP2D6 may relate to <strong>the</strong> metabolism of gefitinib and not of erlotinib.<br />
CYP2D6 phenotypes are one of promising factors for <strong>the</strong> development of rash in<br />
gefitinib <strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
190P INCREASE OF PLASMA ADIPONECTIN LEVELS AND<br />
DECREASE OF PRO-INFLAMMATORY CYTOKINES IN<br />
NON-SMALL CELL LUNG CANCER PATIENTS TREATED<br />
WITH EGFR-TKIS<br />
K. Umekawa 1 , T. Kimura 1 , T. Suzumura 2 , S. Kudoh 1 , T. Nakai 1 , M. Nagata 1 ,<br />
K. Matsuura 1 , S. Mitsuoka 1 , N. Yoshimura 1 , K. Hirata 1<br />
1 Respiratory Medicine, Osaka City University, Osaka, JAPAN, 2 Department of<br />
Respiratory Medicine, Graduate School of Medicine, Osaka City University,<br />
Osaka, JAPAN<br />
Background: Malnutrition in non-small cell lung cancer (NSCLC) is associated with<br />
advanced stage of disease and is needed for careful choice of treatment. The<br />
epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are<br />
routinely used for <strong>the</strong> treatment of advanced NSCLC with EGFR active mutations,<br />
which are promising <strong>the</strong> excellent responses. Recently, pro-inflammatory cytokines<br />
have been proposed as mediators of cancer cachexia. Adipose tissue produces and<br />
release substances called adipokines which include tumor necrosis factor-alpha<br />
(TNF-α), leptin, adiponectin, and resistin. Adiponectin suppresses <strong>the</strong> secretion of<br />
inflammatory cytokines such as IL-8, TNF-α, and induces <strong>the</strong> secretion of<br />
anti-inflammatory cytokines such as IL-10. It has been hypo<strong>the</strong>sized that EFGR-TKI<br />
<strong>the</strong>rapy may affect this adipokine network.<br />
Methods: The prospective study which evaluated correlations between <strong>the</strong> pre and<br />
post-treatment point of days 30 plasma adipokines and cytokines after EGFR-TKIs<br />
administration and clinical outcomes in advanced NSCLC was conducted at Osaka<br />
City University Hospital. Plasma adipokines and cytokines were analyzed by<br />
Luminex 200 PONENT system (Milliplex MAP kits; Millipore).<br />
Results: A total of 33 patients were enrolled. We obtained plasma samples for<br />
analyses 33 patients on pre-treatment point, and 23 patients on days 30 point.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds391 | ix79
Plasma adiponectin level on <strong>the</strong> pre-treatment point (40.34 ± 32.00ng/ml) was<br />
significantly lower than those on days 30 point (45.07 ± 26.38ng/ml, p = 0.01). On<br />
<strong>the</strong> pre-treatment point of plasma IL-8 (16.70 ± 16.01pg/ml), IL-10 (13.06 ±<br />
29.69pg/ml), insulin (656.9 ± 514.6pg/ml) levels were significantly higher than those<br />
on days 30 point (7.154 ± 5.674 pg/ml p = 0.02; 11.53 ± 30.92pg/ml, p = 0.04; and<br />
551.4 ± 520.2pg/ml, p = 0.02, respectively). The levels of leptin and resistin had no<br />
significant changes between pre and on days 30 points.<br />
Conclusions: The EGFR-TKIs treatment for NSCLC increased <strong>the</strong> plasma<br />
adiponectin levels and decreased <strong>the</strong> plasma insulin, IL-8 and IL-10 levels. Increase<br />
of adiponectin levels by EGFR-TKIs may resolve <strong>the</strong> inflammation and increase<br />
insulin sensitivity with reduced output of insulin.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
191P PROGNOSTIC AND PREDICTIVE IMPACT OF KI-67 INDEX IN<br />
NEO-ADJUVANT CHEMOTHERAPY BEFORE SURGERY IN<br />
NON-SMALL CELL LUNG CANCER<br />
J.N. Jakobsen 1 , E. Santoni-Rugiu 2 , J.B. Sorensen 1<br />
1 Oncology, National University Hospital, Copenhagen, DENMARK, 2 Pathology,<br />
National University Hospital, Copenhagen, DENMARK<br />
Background: Immunohistochemical assessment of <strong>the</strong> proportion of<br />
Ki-67-expressing cells is a method for evaluating proliferation rates in malignant<br />
tumors. Ki-67 index is <strong>the</strong>refore a proliferation marker and may potentially be used<br />
as a prognostic or predictive marker during chemo<strong>the</strong>rapy. In this study we<br />
correlated Ki-67 index to prognosis and chemo-sensitivity in non-small cell lung<br />
cancer (NSCLC) patients treated with neoadjuvant chemo<strong>the</strong>rapy before surgery.<br />
Materials and methods: Immunohistochemical assessment of Ki-67 index was<br />
performed on diagnostic biopsies from patients with histologically verified NSCLC<br />
stages T1-3N2M0 treated with neo-adjuvant chemo<strong>the</strong>rapy (paclitaxel 225 mg/m2<br />
and carboplatin AUC 6) followed by attempt of tumor resection and radio<strong>the</strong>rapy (2<br />
Gy x 30Fr/ 5F/W). Ki-67 index was defined as <strong>the</strong> percentage of stained tumor cells<br />
in biopsies containing at least 100 tumor cells.<br />
Results: A total of 64 biopsies (26 biopsies from primary tumors and 38 from lymph<br />
node metastases) from 51 consecutive patients were suitable for analysis. No<br />
significant differences in Ki-67 index between primary tumor (median ki-67 index<br />
40%) and lymph nodes (median Ki-67 index 50%) were observed (p = 0.871). The<br />
5-year-survival was 30% (Ki-67 index
Annals of Oncology<br />
were analyzed by cobas KRAS Mutation Test (Roche) from DNA purified from<br />
diagnostic samples.<br />
Results: 30 patients were enrolled in <strong>the</strong> BVZ group: 24 male, 6 female; median age: 62<br />
years; ECOG 1/2: 22/8; 27 adenocarcinoma and 3 undifferentiated large cell carcinoma.<br />
From <strong>the</strong>m, 7 (23.3%) patients were KRAS mutated. 16 patients were enrolled in <strong>the</strong><br />
control group: 14 male, 2 female; median age 58; ECOG 1/2: 9/7; 13 adenocarcinomas<br />
and 3 undifferentiated large cell carcinoma. From control group, 3 (18.8%) were KRAS<br />
mutated. BVZ <strong>the</strong>rapy showed a significant improved efficacy in KRAS wild-type<br />
compared to mutated patients (RR: 88.9% vs 14.3%, p = 0.045; and TTP: 9.4 months vs<br />
7.5 months, p = 0.033), but did not impact on overall survival (12.4 months vs 11.1<br />
months, p= 0.780). These differences were not observed in control group. Moreover, in<br />
KRAS wild-type patients, <strong>the</strong> BVZ addition to <strong>the</strong>rapy showed a significant improved<br />
efficacy compared to control group (RR: 88.9% vs 20%; p = 0.001).<br />
Conclusions: KRAS wild-type status in wild-type EGFR stage IV non-squamous<br />
NSCLC might be associated with enhanced RR and TTP in BVZ-platin-docetaxel<br />
treated patients, suggesting a potential role as a predictive biomarker in this<br />
population.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
195P THE PREVALENCE AND CLINICAL CHARACTERISTICS OF<br />
ALK AND ROS1 FUSIONS IN EAST ASIAN PATIENTS WITH<br />
NON-SMALL CELL LUNG CANCER<br />
W. Cai 1 , C. Zhou 2 ,S.Ren 1 , X. Chen 1 ,X.Li 2<br />
1 Oncology Department, Shanghai Pulmonary Hospital, Shanghai, CHINA, 2 Lung<br />
Cancer Institute, Shanghai Pulmonary Hospital, Shanghai, CHINA<br />
Background: ALK and ROS1 fusions have been proven to be oncogenic drivers in<br />
some subsets of lung cancer. The prevalence of ALK and ROS1 fusions in East Asian<br />
patients with non-small cell lung cancer (NSCLC) remains unclear.<br />
Objective: To determine <strong>the</strong> prevalence and clinical characteristics of ALK and ROS1<br />
fusions in East Asian patients with NSCLC.<br />
Patients and Methods: We screened 304 biopsied or surgically resected specimens<br />
from patients with histologically confirmed NSCLC for EML4-ALK and ROS1<br />
fusions using multiplex RT-PCR and validated all positive samples by Sanger<br />
sequencing. The patterns of ROS1 fusions involved in this study contained<br />
CD74-ROS1 and SLC34A2-ROS1.<br />
Results: Of <strong>the</strong>se 304 patients with NSCLC screened, 246 had adenocarcinoma, 21<br />
had adenosquamous and 35 had squamous cell lung cancer, with <strong>the</strong> male to female<br />
ratio of about 1:3 and median age of about 59 years. 89.8% of patients were never or<br />
light smokers. Patients with stage I, II, III or IV disease at diagnosis accounted for<br />
47.2%, 11.3%, 33.3% and 8.2%, respectively. The data of EML4-ALK fusion test were<br />
available on all <strong>the</strong> 304 patients, with an incidence of about 8.2%. The data of ROS1<br />
fusion test were available on 195 patients so far, with overall incidence of 3.0%. The<br />
relationship between EML4-ALK and ROS1 fusions and clinical characteristics will<br />
be presented at <strong>the</strong> conference.<br />
Conclusion: The EML4-ALK and ROS1 fusions are quite rare events, with <strong>the</strong><br />
prevalence of about 8.2% and 3.0% in East Asian patients with NSCLC, respectively.<br />
The data of clinical characteristics will be presented at <strong>the</strong> congress.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
196P PHARMACOGENETICS OF TAMOXIFEN ADJUVANT THERAPY<br />
AND ITS EFFICIACY: MDR1 POLYMORPHISMS IN CYP2D6<br />
EXTENSIVE METABOLIZERS WITH BREAST CANCER<br />
S. Argal csov 1,2,4 , O. Slanarˇ 2,3 , H. Bakhouche 2 ,M.Draždˇ áková 3 ,<br />
O. Matoušková 2 , T. Zima 3 , L. Pertuželka 1<br />
1 Department of Oncology, First Faculty of Medicine, Charles University and<br />
General Teaching Hospital, Prague, CZECH REPUBLIC, 2 Institute of<br />
Pharmacology, First Faculty of Medicine, Charles University and General<br />
Teaching Hospital, Prague, CZECH REPUBLIC, 3 Institute of Clinical Biochemistry<br />
and Laboratory Diagnostics, First Faculty of Medicine, Charles University and<br />
General Teaching Hospital, Prague, CZECH REPUBLIC, 4 Institute of<br />
Radio<strong>the</strong>rapy, First Faculty of Medicine, Charles University and Hospital Na<br />
Bulovce, Prague, CZECH REPUBLIC<br />
Background: The role of CYP2D6 polymorphisms in adjuvant breast cancer <strong>the</strong>rapy<br />
has not been standardised until now. Recent pre-clinical evidence suggests that <strong>the</strong><br />
active metabolite of tamoxifen, endoxifen, is a substrate for efflux pump<br />
P-glycoprotein (P-gp). The polymorphic MDR1 gene encoding <strong>the</strong> P-gp may thus<br />
represent a prognostic factor for <strong>the</strong> treatment outcome in addition to <strong>the</strong> previously<br />
studied pharmacogenetic factors. The aim of our study was to evaluate, if <strong>the</strong><br />
polymorphisms within MDR1 gene and CYP2D6 gene alter tamoxifen adjuvant<br />
treatment efficacy in breast cancer.<br />
Methods: Totally 252 women signed informed consent and participated in <strong>the</strong> study.<br />
After exclusion of poor metabolizers for CYP2D6, 227 women with estrogen receptor<br />
positive breast cancer were followed retrospectively for median period of 79 months.<br />
The primary analysis was conducted on time-to-event.<br />
Results: The cumulative observed recurrence rate was approximately 26.5%. The<br />
Cox-proportional hazard regression model revealed C3435T polymorphism, age and<br />
clinical tumor size at <strong>the</strong> time of diagnosis as significant covariates affecting <strong>the</strong> event free<br />
survival. The patients carrying at least one variant allele 3435T in MDR1 gene had<br />
significantly longer time to event survival resulting in hazard ratio of 0.44 (95%CI<br />
0.21-0.92) as compared with CC3435 patients. For <strong>the</strong> G2677T/A polymorphism, a<br />
non-significant trend suggesting that <strong>the</strong> wt homozygous may had worse treatment<br />
outcome as compared with <strong>the</strong> heterozygous or homozygous subjects for <strong>the</strong> variant alleles<br />
was noted. The respective median event free survival times were 93, 103, and 126 months.<br />
Conclusions: Wild type homozygous genotype in MDR1 polymorphism C3435T<br />
predicts for worse treatment outcome of tamoxifen adjuvant <strong>the</strong>rapy. This should be<br />
taken into account as a potential pharmacogenetic biomarker for <strong>the</strong> drug efficacy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
197P BREAST CANCER PATIENTS RESISTANT TO ENDOCRINE<br />
THERAPY ARE IMMUNODEFICIENT AND SHOW ENHANCED<br />
TRANSFORMING GROWTH FACTOR - BETA AND VASCULAR<br />
ENDOTHELIAL GROWTH FACTOR IN PLASMA<br />
E. Zavadova 1 , B. Konopasek 1 , M. Vocka 1 , T. Fucikova 2 , L. Petruzelka 3<br />
1 Oncology, General Hospital and Charles University, Prague, CZECH REPUBLIC,<br />
2 Immunology, Genreral Hospital and Charles University, Prague, CZECH<br />
REPUBLIC, 3 Oncology, General Faculty Hospital-Charles University, Prague,<br />
CZECH REPUBLIC<br />
Although more than 2/3 of treated patients respond to endocrine <strong>the</strong>rapy, most patients<br />
with metastatic breast cancer will develop resistance. It appears that ano<strong>the</strong>r factor<br />
contributing to <strong>the</strong> resistance may be transforming factor-beta (TGF-beta). It is a highly<br />
immunosuppressive factor that inhibits <strong>the</strong> natural and specific immunity against tumors<br />
and stimulates production of vascular endo<strong>the</strong>lial growth factor /VEGF. The purpose of<br />
<strong>the</strong> study was to monitor immune responses in patients with hormone receptor positive<br />
breast cancer resistant to hormone <strong>the</strong>rapy, particularly <strong>the</strong> examination of cellular (CD4,<br />
CD8, HLA-DR) as well as humoral immunity. TGF-beta, and VEGF production was<br />
monitored and we analyzed <strong>the</strong> changes during hormonal treatment.<br />
Methods: 80 patients included in <strong>the</strong> research project were receiving routine cancer<br />
treatment with endocrine <strong>the</strong>rapy. Basic parameters (histological type and grade, <strong>the</strong><br />
degree of expression of ER and PR, HER2,and <strong>the</strong> proliferative markers) were<br />
established. Patients were evaluated by a cancer clinical immunologist to exclude<br />
immune disorders, allergic or autoimmune origin. TGF-beta, VEGF were measured<br />
by ELISA and anti-tumor cellular immunity (CD4, CD8,) were measured by flow<br />
cytometry.<br />
Results: In patients with resistance to endocrine <strong>the</strong>rapy mainly depression in<br />
cellular immunity was found. Immunglobulin plasma level was decreased as well<br />
(mainly IgG4 subtype). Most patients have shown clinical symptoms of<br />
immunodeficiency (frequent infections of respiratory or urinary tract, herpetic<br />
infections); TGF-beta as well as VEGF plasma levels were increased.<br />
Conclusion: Correlation of <strong>the</strong>se factors with resistance to hormonal <strong>the</strong>rapy, and<br />
<strong>the</strong> state of anticancer immunity could help in <strong>the</strong> future with <strong>the</strong> prediction of<br />
resistance to hormonal <strong>the</strong>rapy and contribute to <strong>the</strong> selection of targeted immune<br />
<strong>the</strong>rapy in cancer patients.<br />
Dedication: This project was supported by grant IGA NT11168-3/2010.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
198P BIOMARKER (BM) RESULTS FROM GOG-0218, A PHASE 3<br />
TRIAL OF FRONT-LINE BEVACIZUMAB (BV) +<br />
CHEMOTHERAPY (CT) FOR OVARIAN CANCER (OC)<br />
M.J. Birrer 1 , H. Lankes 2 , R.A. Burger 3 , R. Mannel 4 , H. Homesley 5 , V. Henschel 6 ,<br />
M. Sovak 7 , S.J. Scherer 7 , S. de Haas 8 , C. Pallaud 9<br />
1 Hematology/Oncology, Massachusetts General Hospital, Cancer Center,<br />
Boston, MA, UNITED STATES OF AMERICA, 2 Gynecologic Oncology Group,<br />
Statistical & Data Center, Roswell Park Cancer Institute, Buffalo, NY, UNITED<br />
STATES OF AMERICA, 3 Department of Surgical Oncology, Fox Chase Cancer<br />
Center, Philadelphia, PA, UNITED STATES OF AMERICA, 4 Department of<br />
Obstetrics and Gynecology, University of Oklahoma Health Sciences Center,<br />
Oklahoma City, OK, UNITED STATES OF AMERICA, 5 Department of Obstetrics<br />
and Gynecology, Wake Forest University School of Medicine, Winston-Salem,<br />
NC, UNITED STATES OF AMERICA, 6 Biostatistics, F Hoffmann-La Roche Ltd,<br />
Basel, SWITZERLAND, 7 Pharma Development, Genentech, Inc., South<br />
San Francisco, CA, UNITED STATES OF AMERICA, 8 Pharma Development,<br />
F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, 9 Pdo Department,<br />
F. Hoffmann-La Roche Ltd., Basel, SWITZERLAND<br />
Background: GOG-0218 showed significantly improved progression-free survival<br />
(PFS) in patients (pts) receiving BV 15 mg/kg q3w concurrently with CT and<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds391 | ix81
Table: 198P<br />
PFS OS<br />
Median, mo HR Median, mo HR<br />
Subgroup<br />
VEGF-A<br />
PL BV PL BV<br />
≤ median 12.3 18.6 0.52 43.0 48.5 0.87<br />
> median 11.0 17.5 0.70 33.9 41.8 0.78<br />
≤ Q3 12.3 18.6 0.59 45.1 48.5 0.89<br />
> Q3<br />
VEGFR-2<br />
9.7 13.8 0.67 28.6 37.7 0.72<br />
≤ median 12.0 18.0 0.68 35.1 40.6 0.90<br />
> median 10.4 18.2 0.53 38.4 48.5 0.69<br />
≤ Q3 11.0 17.3 0.63 38.2 41.8 0.87<br />
> Q3 12.5 22.1 0.46 38.6 − 0.59<br />
Q = quartile<br />
continued alone until progression or for up to 15 mo. GOG-0218 includes extensive<br />
BM evaluation to identify pts benefitting most from BV. Analysis of plasma VEGF-A<br />
and VEGFR-2 was prioritised based on encouraging findings in BV trials in several<br />
tumour types.<br />
Methods: Pts with newly diagnosed stage IV or macroscopic optimal stage III OC<br />
were randomised to 6 cycles (c) of CT with: placebo (PL) c2−22 (arm A); BV c2<br />
−6 → PL c7−22 (arm B); or BV c2−22 (arm C). Post-surgery pre-CT plasma<br />
samples were analysed using a multiplex ELISA. Baseline (BL) BM levels were used<br />
to dichotomise pts. Potential interactions between BM levels and PFS (1° endpoint)<br />
and overall survival (OS; 2° endpoint) were tested using log-rank testing and Cox<br />
regression approaches.<br />
Results: Post-surgery samples were available from 582 of 1248 pts in arms A and<br />
C. Median BL VEGF-A and VEGFR-2 levels were 144.3 pg/mL and 14.7 ng/mL,<br />
respectively. No significant interaction was seen at α = 0.05. Exploratory analyses with<br />
o<strong>the</strong>r cut-offs are hypo<strong>the</strong>sis generating for potential predictive (VEGF-A and<br />
VEGFR-2) or prognostic (VEGF-A: OS) value. Exploratory analyses revealed no<br />
correlation between plasma VEGF-A and time since surgery.<br />
Conclusions: The potential prognostic (VEGF-A) and predictive (VEGF-A,<br />
VEGFR-2) value seen in breast, pancreatic and gastric cancers was not apparent in<br />
post-surgery samples from GOG-0218 using a median cut-off. Results with o<strong>the</strong>r<br />
cut-offs provide a rationale for fur<strong>the</strong>r investigation of potential prognostic and<br />
predictive value. Findings may reflect differing biology and interplay between<br />
VEGF-A isoforms across tumour types. The possible impact of pre- vs post-surgery<br />
samples is also being investigated.<br />
Disclosure: R.A. Burger: RB has served on Advisory Boards for Roche/Genentech. R.<br />
Mannel: RM has served on Advisory Boards for Genentech. V. Henschel: VH is<br />
employed by and holds shares in Roche. M. Sovak: MS is an employee of Genentech.<br />
S.J. Scherer: SS is an employee of Genentech Inc. S. De Haas: SdH is an empoloyee<br />
of F Hoffmann-La Roche Ltd. C. Pallaud: CP is an employee of F Hoffmann-La<br />
Roche Ltd. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
199P CHANGE IN HER2 STATUS AFTER NEOADJUVANT<br />
CHEMOTHERAPY AND THE SURVIVAL IMPACT<br />
A. Yoshida 1 , N. Hayashi 1 , O. Sachiko 2 , Y. Kajiura 1 , H. Yagata 1 , S. Nakamura 3 ,<br />
H. Yamauchi 1<br />
1 Breast Surgical Oncology, St. Luke’s International Hospital, Tokyo, JAPAN,<br />
2 Researcher, Center For Clinical Epidemiology St. Luke’s Life Science Institute,<br />
St. Luke’s International Hospital, Tokyp, JAPAN, 3 Department of Breast Surgical<br />
Oncology, Showa University School of Medicine, Tokyo, JAPAN<br />
Background: The incidence of change in HER2 status in primary breast cancer after<br />
neoadjuvant chemo<strong>the</strong>rapy (NAC) and whe<strong>the</strong>r <strong>the</strong> change affect prognosis is not<br />
well known.<br />
Patients and methods: One hundred eighty-four patients who were treated with<br />
anthracycline- and/or taxane-based NAC and had non-pathologic complete<br />
response between 2003 and 2005 in our hospital were enrolled. Human<br />
epidermal growth factor receptor 2 (HER2) status was assessed in specimen by<br />
core needle biopsy before NAC and in residual tumor of surgical specimen. We<br />
determine <strong>the</strong> impact of change in HER2 status on recurrence-free survival<br />
(RFS). All patients had not received HER2-targeting agents during study period.<br />
HER2-positive was defined as 3+ by immunohistochemistry and/or amplification<br />
by fluorescent in situ hybridization. Association between clinicopathologic<br />
factors, including clinical T stage, estrogen receptor (ER), progesterone receptor<br />
(PR), Nuclear grade (NG), and clinical response, and change in HER2 status<br />
after NAC were determined.<br />
Result: A median follow-up term was 74.1 months (range, 6.0 to 120.9 months).<br />
One hundred forty-nine of <strong>the</strong> 184 patients (80.9%) had HER2-negative tumors<br />
Annals of Oncology<br />
and 35 patients (19.0%) had HER2-positive tumor before NAC. HER2-negative<br />
tumors in 5 of <strong>the</strong> 149 patients (3.3%) changed to HER2-positive tumor.<br />
HER2-positive tumors in 7 of <strong>the</strong> 35 patients (20%) changed to HER2-negative<br />
tumor. In terms of RFS, <strong>the</strong>re was no difference between patients with and<br />
without change in HER2 status in both of <strong>the</strong> 149 patients with HER2-negative<br />
tumors and 35 patients with HER2-positive tumors before NAC (p = 0.56, p =<br />
0.96, respectively). Any clinicopathologic factors were not associated with change<br />
in HER2 status after NAC.<br />
Conclusion: We herein reported <strong>the</strong> incidence of change in HER2 status after NAC<br />
with <strong>the</strong> large sample size. However, change in HER2 status did not seems to affect<br />
prognosis due to <strong>the</strong> small events in this study. Fur<strong>the</strong>r well-powered study in<br />
needed to confirm <strong>the</strong> prognostic impact of change in HER2 status and needs<br />
of HER2-targeting agents for <strong>the</strong>se populations.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
200P NEW IMAGING AND MOLECULAR BIOMARKERS TO PREDICT<br />
PATHOLOGICAL RESPONSE TO BEVACIZUMAB-BASED<br />
TREATMENT IN NEOADJUVANT BREAST CANCER<br />
J. Garcia-Foncillas 1 , A. Plazaola 2 , B. Hernando 3 , R. Sanchez 4 , I. Alvarez 5 ,<br />
A. Antón 6 , P. Martinez Del Prado 7 , A. Llombart 8 , S. Sherer 9 , J.M. Lopez-Vega 10<br />
1 Oncology, Hospital Universitario. Fundacion Jimenez Diaz. Universidad<br />
Autónoma de Madrid, Madrid, SPAIN, 2 Oncology, Onkologikoa, Donosti, SPAIN,<br />
3 Oncology, Hospital de Burgos, Burgos, SPAIN, 4 Oncology, Hospital San Pedro,<br />
Logroño, SPAIN, 5 Medical Oncology Dept., Hospital Donostia, San Sebastian,<br />
SPAIN, 6 Oncology, H U Miguel Servet, Zaragoza, SPAIN, 7 Medical Oncology,<br />
University Hospital of Basurto, Bilbao, SPAIN, 8 Medical Oncology Service,<br />
Hospital Arnau de Vilanova, Valencia, SPAIN, 9 Research, Roche A.G. Basel,<br />
Basel, SWAZILAND, 10 Servicio de Oncologia Medica, Hospital Universitario<br />
Marques de Valdecilla, Santander, SPAIN<br />
Background: Early and robust prediction of pathological response in neoadjuvant<br />
breast cancer may help to identify which patients may benefit from<br />
bevacizumab-based <strong>the</strong>rapy. Different imaging and molecular approaches have been<br />
0evaluated in a multicenter clinical trial.<br />
Methods: 73 chemo<strong>the</strong>rapy naïve, stage II and III breast cancer (BC) patients<br />
(pts) were enrolled in a phase II, single-arm, multicenter, open-label and<br />
prospective clinical trial. Pts received single infusion of bevacizumab (15 mg/<br />
kg)(C1)3weekspriorto<strong>the</strong>beginningof neoadjuvant chemo<strong>the</strong>rapy (NAC)<br />
consisting of 4 cycles of docetaxel (60 mg/mq), doxorubicin (50 mg/mq) and<br />
bevacizumab (15 mg/ kg) every 21 days (C2-C5), followed by surgery. Tumor<br />
proliferation, hypoxia and perfusion were evaluated respectively using<br />
18F-Fluorothymidine (FLT) and 18F-Misonidazole (FMISO) positron emission<br />
tomography (PET/CT) and dynamic contrast enhancement magnetic resonance<br />
(DCE-MR). Serial imaging studies were performed in parallel at several time<br />
points including baseline (BL) and 14-21 days after bevacizumab alone (C1).<br />
Biomarker expression was assessed by immunohistochemistry (Ki67, CD31,<br />
CD31/Ki67, VEGFR2, pVEGFR2 [Y951]) before and after bevacizumab<br />
infusion (C1). Gene expression was analyzed using Affimetrix Human Gene<br />
ST 1.0.<br />
Results: Decrease in FMISO uptake >10% yielded a ROC curve area of 0.7 (95% CI:<br />
0.56 - 0.85) with high specificity (94%). Decrease in <strong>the</strong> phosphorilation status of<br />
VEGFR2 (Y951) >70% yielded a receiver operating characteristic (ROC) curve area of<br />
0.681 (95% CI: 0.536 - 0.825) with 84% sensitivity and 95% specificity. The change<br />
in phosphorilation status of VEGFR2p remains a significant predictor biomarker of<br />
response in multivariate analysis (OR = 0.9, IC%95 0.96-0.99, p = 0.04) after adjusting<br />
for clinical-pathological characteristics.<br />
ix82 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Conclusion: Our findings suggest that early changes on both biomarkers, FMISO<br />
and pVEGFR, with one cycle of bevacizumab alone predict pathological response in<br />
bevacizumab-based neoadjuvant <strong>the</strong>rapy in breast cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
201P PROGNOSTIC VALUE OF KI-67 LABELING INDEX IN<br />
PATIENTS WITH DUCTAL INTRAEPITHELIAL NEOPLASIA OF<br />
THE BREAST. POSTSURGICAL OUTCOME FOR 1171 WOMEN<br />
CARED FOR IN ONE SINGLE INSTITUTION OVER 10 YEARS<br />
M. Lazzeroni 1 , E. Botteri 2 , A. Guerrieri Gonzaga 1 , M.C. Leonardi 3 , D. Serrano 1 ,<br />
A. De Censi 4 , N. Rotmensz 2 , C. Varricchio 1 , B. Bonanni 1 , G. Puneri 5<br />
1 Division of Cancer Prevention and Genetics, European Institute of Oncology,<br />
Milan, ITALY, 2 Division of Epidemiology and Biostatistics, European Institute of<br />
Oncology, Milan, ITALY, 3 Division of Radio<strong>the</strong>rapy, European Institute of<br />
Oncology, Milan, ITALY, 4 Medical Oncology, E.O. Ospedali Galliera, Genoa,<br />
ITALY, 5 Division of Pathology, European Institute of Oncology, Milan, ITALY<br />
The aim of this analysis was to investigate <strong>the</strong> prognostic relevance of Ki-67 labeling<br />
index (LI) in patients with Ductal Intraepi<strong>the</strong>lial Neoplasia (DIN) of <strong>the</strong> breast. From<br />
January 1997 to December 2007, histopathologic and clinical data on 1,171<br />
consecutive patients operated for DIN in a single institution were collected through<br />
<strong>the</strong> institutional clinical database. The study was performed in accordance with<br />
REMARK criteria. The independent prognostic role of Ki-67 LI was evaluated with a<br />
multivariable Cox regression model. Median age was 52 years, median Ki-67 LI 15%<br />
(range 1-80) and median follow-up was 86 months (range 1-192). A total of 872<br />
(74.5%) patients underwent breast conservative surgery. Whole breast radio<strong>the</strong>rapy<br />
was administered to 356 patients, and 506 patients received endocrine treatment.<br />
Overall, 549 (46.9%) women were premenopausal at <strong>the</strong> time of diagnosis. In regard<br />
to histology, most DINs were solid or cribriform (75%), moderately-low differentiated<br />
(80%), with a low proliferating index (Ki-67 LI < 14%, 46%), and with estrogen<br />
receptor positive immunostaining (80%). Overall, ipsilateral recurrence of both<br />
invasive and in situ disease (5-year cumulative incidence) was 163 (10.7%). When<br />
dividing patients into three subgroups on <strong>the</strong> basis of Ki-67 LI (< 14%, 14-20% and<br />
>20%), <strong>the</strong> 5-year cumulative incidence of breast recurrences were 9.4%, 10.3%, and<br />
13.0% respectively [Hazard Ratio (HR) 14-20 vs 20 vs 40 pg/ml had improved TTP (328 D; p =<br />
0.01), compared to those with PlGF levels 66.3 pg/ml at D8-56 had improved PFS (p = 0.029) and OS (p =<br />
0.02). In RCC, 5 pts with ΔPlGF below this threshold had median PFS of 100 D<br />
vs 207 D in <strong>the</strong> remaining pts (p = NS). Across <strong>the</strong> P2 studies, toxicity<br />
thresholds were determined using PlGF levels at D8 and toxicity events resulting<br />
in dose reductions or interruptions. The efficacy and toxicity thresholds were<br />
used to identify optimal ΔPlGF levels associated with improved OS in HCC (p<br />
= 0.01) and RCC pts (p = 0.001).<br />
Conclusions: Optimal ΔPlGF plasma levels were identified and associated with<br />
improved outcome in HCC and RCC pts receiving linifanib. Monitoring of PlGF<br />
levels may allow clinicians to identify pts with increased sensitivity or toxicity risk on<br />
linifanib. Fur<strong>the</strong>r evaluation in randomized linifanib studies is warranted, including<br />
dose adjustments based on ΔPlGF levels.<br />
Disclosure: E.M. Mc Keegan: Full time Abbott employee who owns stock. A.<br />
Chakravartty: Full time Abbott employee who owns stock. P.J. Ansell: Full time<br />
Abbott employee who owns stock. S. Datwyler: Full time Abbott employee who owns<br />
stock. M.D. McKee: Full time Abbott employee who owns stock. J.L. Ricker: Full time<br />
Abbott employee who owns stock. D.M. Carlson: Full time Abbott employee who<br />
owns stock. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds391 | ix83
204P EVALUATION OF PTEN AND PIK3CA STATUS IN BREAST<br />
CANCER FOR PATIENT SELECTION<br />
V. Serra 1 , J. Rodon 2 , C.M. Aura 3 , A. Vivancos 4 , K. Stemke-Hale 5 ,<br />
H. Hibshoosh 6 , Y. Wang 7 , S. Ramon Y Cajal 3 , J. Tabernero 8 , J. Baselga 9<br />
1 Experimental Therapeutics Laboratory, Vall d’Hebron Institute of Oncology,<br />
Barcelona, SPAIN, 2 Phase I Unit, Medical Oncology Service, VHIO, Barcelona,<br />
SPAIN, 3 Molecular Pathology Laboratory, VHIO, Barcelona, SPAIN, 4 Cancer<br />
Genomics Group, VHIO, Barcelona, SPAIN, 5 Systems Biology, MD Anderson<br />
Cancer Center, Houston, TX, UNITED STATES OF AMERICA, 6 Department of<br />
Pathology and Cell Biology, Columbia University, New York, NY, UNITED STATES<br />
OF AMERICA, 7 Assay Application & Product Development, Mip, Affymetrix,<br />
Santa Clara, CA, UNITED STATES OF AMERICA, 8 Medical Oncology /<br />
Gastrointestinal Tumors Group, Vall d’Hebron University Hospital / VHIO,<br />
Barcelona, SPAIN, 9 Hematology/Oncology, MGH Cancer Center, Massachusetts<br />
General Hospital, Boston, MA, UNITED STATES OF AMERICA<br />
PTEN and PIK3CA status are potential predictors of response to PI3K-pathway<br />
inhibitors. Therefore, we searched <strong>the</strong> most reliable platform to assess both PTEN<br />
expression and PIK3CA mutations in primary and metastatic breast cancer (BC).<br />
We cross-validated <strong>the</strong> assays between different institutions. Studies were<br />
performed using four different sample sets of formalin-fixed paraffin-embedded<br />
(FFPE) breast cancers from VHUH/VHIO and from Columbia University. PTEN<br />
alterations were genotyped in 14 TNBCs by Oncoscan TM platform (Affymetrix)<br />
and were correlated to immunohistochemistry (IHC). PTEN loss of heterozygosity<br />
(LOH, n = 4) with or without overlapping PTEN mutation (n = 5) was concordant<br />
to PTEN protein loss (H-Score < 60) by IHC in 7 samples (7/8, 88%<br />
concordance). PTEN protein loss by IHC was also cross-validated between two<br />
institutions. In a cohort of 12 TNBCs containing eight PTEN low samples, only<br />
two samples were discordant (2/12, 17% discordance). Paired primary versus<br />
metastatic tumors were identified to transit ei<strong>the</strong>r way, in <strong>the</strong> PTEN assessment<br />
by IHC (2/8 paired samples, 25% transition). PIK3CA mutations by Oncoscan TM<br />
were concordant to MassARRAY (Sequenom) in 4 out of 5 mutated samples<br />
within <strong>the</strong> panel of 17 BCs. The discrepancy (1/17, 6%) was likely due to<br />
differences in <strong>the</strong> sensitivity of <strong>the</strong> two assays. In ano<strong>the</strong>r cohort of 21 BC<br />
samples, PIK3CA mutational status was cross-validated by MassARRAY at two<br />
institutions (MDACC and VHIO). Using identical, customized panels we found<br />
that only two samples were discordant because of mutant allele frequency close to<br />
<strong>the</strong> sensitivity of <strong>the</strong> assay (10%). Among 14 paired primary vs metastatic breast<br />
cancers we detected two transitions from wild type (WT) to H1047R mutation<br />
and one transition from E545K to WT (3/14, 21% transition), underscoring <strong>the</strong><br />
need to determine PIK3CA status in metastatic lesions. The divergence evaluating<br />
PTEN and PIK3CA status between institutions was due to different scoring<br />
methodologies and to sensitivity of <strong>the</strong> assays respectively. For patient<br />
pre-screening purposes, MassARRAY and IHC can be performed at each<br />
institution both in primary and metastatic breast cancer lesions. Oncoscan TM is a<br />
valid, centralized platform for evaluation of PTEN and PIK3CA genomic<br />
alterations in BC.<br />
Disclosure: Y. Wang: Yuker Wang is employee of Affymetrix Inc. All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
205P SIGNIFICANCE OF C-MET AS A THERAPEUTIC TARGET<br />
IN TRIPLE-NEGATIVE BREAST CANCER<br />
S. Kashiwagi, M. Yashiro, N. Aomatsu, H. Kawajiri, T. Takashima, N. Onoda,<br />
T. Ishikawa, K. Hirakawa<br />
Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka,<br />
JAPAN<br />
Background: The molecular and biological mechanisms of cancer proliferation and<br />
metastasis are being elucidated. Therapies targeting <strong>the</strong> biological characteristics of<br />
various cancers have been adopted. Hormone <strong>the</strong>rapy, molecular target <strong>the</strong>rapy, etc.,<br />
are chosen depending on against estrogen receptor (ER), progesterone receptor (PR)<br />
and human epidermal growth factor receptor 2 (HER2) expressions in breast cancer.<br />
However, no effective <strong>the</strong>rapy is available for ER-, PR-, and HER2-negative<br />
triple-negative breast cancer (TNBC) because <strong>the</strong>ir targets are unknown. c-met<br />
tyrosine kinase receptor for Hepatocyte growth factor (HGF) has attracted attention<br />
as a novel molecular target of cancer <strong>the</strong>rapy. The c-met receptor for HGF is<br />
involved in <strong>the</strong> migration, invasion, and proliferation of cancer cells. The activation<br />
mechanisms of c-met include <strong>the</strong> overexpression, amplification, and mutation of <strong>the</strong><br />
met gene, as well as ligand binding. Increased c-met protein expression, including<br />
coexpression with its ligand HGF, is observed in various cancers. Reportedly, <strong>the</strong><br />
prognosis of breast cancer is correlated with HGF/c-met coexpression and c-met<br />
overexpression. c-met signaling plays an important role in <strong>the</strong> proliferation of breast<br />
cancer cells. However, few reports have been published regarding <strong>the</strong>ir correlation<br />
with TNBC.<br />
Material and methods: A total of 1,036 patients who had undergone resection of a<br />
primary breast cancer at our institute were enrolled. ER / PR / HER2 status and<br />
c-met expression were assessed by immunohistochemistry. In vitro study, TNBC cell<br />
lines, MDA-MB 231 and OCUB-2, and non-TNBC cell lines, MCF-7 and OCUB-1,<br />
were used. c-met mRNA expression was examined by RT-PCR. Then, <strong>the</strong> effects of<br />
Annals of Oncology<br />
HGF, c-met siRNA, and c-met inhibitors on <strong>the</strong> proliferation of breast cancer cell<br />
lines were examined.<br />
Results: The 1,036 patients included 190 TNBC patients, whose prognoses were<br />
poorer than those of non-TNBC patients. In <strong>the</strong> TNBC patients, <strong>the</strong> c-met<br />
expression-positive group showed a poorer prognosis than <strong>the</strong> control group. c-met<br />
was expressed in <strong>the</strong> TNBC cell lines, whose proliferation was enhanced by HGF.<br />
c-met kinase inhibitors and c-met siRNA inhibited <strong>the</strong> proliferation of TNBC cell<br />
lines.<br />
Conclusion: c-met expression is a potential molecular target and useful in classifying<br />
TNBC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
206P PREDICTION OF DISEASE OUTCOME WITH QUANTITATIVE<br />
MEASUREMENT OF HER-2 RECEPTOR EXPRESSION AND<br />
DIMERIZATION IN PATIENTS WITH BREAST CANCER<br />
H. Bazin 1 , F. Andre 2 , M. Mathieu 3 , A. Ho-Pun-Cheung 4 , E. Lopez-Crapez 4 ,<br />
G. Mathis 1 , P. Garnero 1<br />
1 Research, Cisbio Bioassays, Codolet, FRANCE, 2 Department of Medical<br />
Oncology, Institut Gustave Roussy, Villejuif, FRANCE, 3 Department of Pathology,<br />
Institut Gustave Roussy, Villejuif, FRANCE, 4 Translational Research Unit, CRLC<br />
Val d’Aurelle Paul Lamarque, Montpellier, FRANCE<br />
Introduction: Expression of HER2 is commonly assessed by immunohistochemistry<br />
(IHC) and IHC-HER2 positive patients with breast cancer are candidate for<br />
anti-HER2 <strong>the</strong>rapy. However IHC is not quantitative, does not allow to detect subtle<br />
changes in HER2 expression and cannot assess HER2 dimerization which is critical<br />
for its activation. The aim of this study was to quantify <strong>the</strong> expression and<br />
dimerization of HER2 in patients with breast cancer and to relate <strong>the</strong>se<br />
measurements to disease outcome.<br />
Methods: Using a novel microtiter plate based Time Resolved Fluorescence<br />
(TR-FRET) assay we quantify HER2 receptor expression and dimerization on frozen<br />
tumor samples from 100 patients with breast cancer. Normalized fluorescence signals<br />
allowed a quantitative measure of <strong>the</strong> overall receptors/dimers expression. Disease<br />
free (DFS) and overall survival (OS) was assessed in each subject.<br />
Results: Among <strong>the</strong> 100 patients, 82 were IHC-HER2 negative, including 60 subjects<br />
who were ER+ and treated with hormonal <strong>the</strong>rapy. Using Cox proportional hazard<br />
analyses we showed that in IHC-HER2 negative, ER+ subjects, <strong>the</strong> presence of HER2<br />
dimer was significantly associated with both reduced DFS (p = 0.0001) and OS<br />
(p = 0.00237). Quantitative measure of HER2 expression was also associated with<br />
DFS (p = 0.0005) and OS (p = 0.03).<br />
Conclusion: Quantitative measurement of expression and dimerization of HER2 by<br />
<strong>the</strong> novel TR-FRET assay predicts disease outcome in IHC-HER2 negative, ER+<br />
breast cancer patients. These new biomarkers may be useful to identify failure<br />
patients to hormonal treatment who may benefit from adjuvant <strong>the</strong>rapy with<br />
anti-HER <strong>the</strong>rapy. Validation series is ongoing in 200 FFPE-samples and will be<br />
presented.<br />
Disclosure: F. Andre: research funding. M. Mathieu: research funding. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
207P KRAS MUTATIONAL STATUS AND OXALIPLATIN SENSITIVITY:<br />
THE OTHER SIDE OF THE MOON?<br />
A. Orlandi, M. Di Salvatore, M. Basso, C. Bagalà, A. Strippoli, A. Calegari,<br />
A. Astone, C. Pozzo, A. Cassano, C. Barone<br />
Unit of Medical Oncology, Catholic University of Sacred Heart, Rome, ITALY<br />
Background: Oxaliplatin is a milestone of colorectal cancer <strong>the</strong>rapy, but it is still<br />
lacking of a validated predictive biomarker of response. In a recent retrospective<br />
study we found a greater efficacy of oxaliplatin in KRAS mutated patients with<br />
metastatic colorectal cancer. Aim of <strong>the</strong> present study is to investigate “in vitro” <strong>the</strong><br />
molecular basis of this finding and <strong>the</strong> possible role of ERCC1, <strong>the</strong> main mechanism<br />
of oxaliplatin resistance.<br />
Methods: We selected four colorectal cancer cell lines, two KRAS wild type (wt)<br />
(HCT-8, HT-29) and two KRAS mutated (mt)(SW620, SW480). The sensitivity of<br />
<strong>the</strong>se cell lines to oxaliplatin was evaluated by MTT-test. ERCC1 levels before and<br />
after exposure to oxaliplatin were determined by RT-PCR. KRAS was silenced in a<br />
KRAS mt cell line (SW620) in order to evaluate <strong>the</strong> effect on oxaliplatin sensitivity<br />
and on ERCC1 levels. ERCC1 was also silenced in all cell lines to confirm his role in<br />
<strong>the</strong> KRAS-mediated oxaliplatin resistance pathway.<br />
Results: KRAS mt cell lines were more sensitive to oxaliplatin (OR 2,68; IC 95%<br />
1.511-4.757 p < 0.001). KRAS mt and wt cell lines did not show significant<br />
differences in ERCC1 basal levels, however, after 24h exposure to oxaliplatin, only<br />
resistant KRAS wt cell lines showed a statistically significant upregulation of ERCC1<br />
compared to KRAS mt cell lines (OR 42.9; IC 95% 17.260-106.972 p < 0.0005).<br />
Silencing of KRAS demonstrated to reduce Oxaliplatin sensitivity and to restore <strong>the</strong><br />
ability to induce ERCC1 in KRAS mt cell lines. Finally, silencing of ERCC1 increased<br />
Oxaliplatin citotoxicity only in those cells able to upregulate ERCC1 after exposure to<br />
ix84 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Oxaliplatin, that is KRAS wt and KRAS mt/KRAS silenced colorectal cancer cell<br />
lines.<br />
Conclusions: KRAS mt cell lines were more sensitive to oxaliplatin probably due to<br />
<strong>the</strong>ir inability to upregulate ERCC1 after exposure to this drug. Therefore, KRAS<br />
mutational status could represent a predictor of response to Oxaliplatin in colorectal<br />
cancer patients, as a surrogate for ERCC1 modulation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
208P EZH2 EXPRESSION IN COLORECTAL (CRC) CANCER: SINGLE<br />
NUCLEOTIDE POLYMORPHISM (SNP) CHARACTERIZATION<br />
AND CORRELATION WITH CLINICO-PATHOLOGICAL AND<br />
MOLECULAR PARAMETERS<br />
L. Fornaro 1 , F. Crea 2 , P. Faviana 3 , G. Masi 1 , C. Vivaldi 1 , V. De Gregorio 1 ,<br />
E. Paolicchi 2 , G. Fontanini 3 , R. Danesi 2 , A. Falcone 1<br />
1 U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria<br />
Pisana, Pisa, ITALY, 2 Dept of Internal Medicine, Dept of Oncology, Transplants<br />
and New Technologies, Pisa, ITALY, 3 Pathology, Azienda<br />
Ospedaliero-Universitaria Pisana, Pisa, ITALY<br />
Background: EZH2 is an epigenetic factor, essential for stem cell self-renewal. EZH2<br />
rs3757441 SNP is associated with outcome in metastatic CRC patients treated with<br />
FOLFIRI + /-bevacizumab.<br />
Material and methods: We are investigating <strong>the</strong> correlation between EZH2<br />
expression and o<strong>the</strong>r clinico-pathological and molecular parameters in 129 primary<br />
CRC samples. EZH2 expression was evaluated by immunohistochemistry, KRAS<br />
codon 12-13 and BRAF V600E mutations were screened by pyrosequencing analysis,<br />
and EZH2 SNP variants were identified by real-time PCR. Studied parameters were<br />
correlated with <strong>the</strong> percentage of EZH2-positive cells by T test and ANOVA.<br />
Results: Characteristics of <strong>the</strong> specimens so far evaluated are: stage I/II/III/IV, 5/47/<br />
54/23; grading 1/2/3, 0/81/48; right colon/left colon/rectum, 56/49/24; mucinous<br />
histology, 40; KRAS wt/mut, 74/55; BRAF wt/mut, 115/14; rs3757441 genotype CC/<br />
CT/TT, 5/36/59. The percentage of EZH2-positive cells does not correlate with tumor<br />
stage and grading, nor with KRAS and BRAF status. There is a trend toward higher<br />
EZH2 expression with rs3757441-CC genotype (p = 0.1). The percentage of<br />
EZH2-positive cells is significantly higher in mucinous than in non-mucinous<br />
tumors (p = 0.022).<br />
Conclusions: CRC tumors with mucinous features show higher EZH2 expression,<br />
which may represent one of <strong>the</strong> mechanisms behind a more aggressive tumor<br />
behavior. EZH2 could <strong>the</strong>refore represent a putative prognostic indicator and a<br />
candidate <strong>the</strong>rapeutic target in CRC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
209P PREDICTIVE VALUE OF CIRCULATING ENDOTHELIAL CELL<br />
(CEC) LEVELS IN METASTATIC OR LOCALLY ADVANCED<br />
NEUROENDOCRINE DIGESTIVE TUMOR PATIENTS TREATED<br />
WITH CHEMOTHERAPY AND BEVACIZUMAB<br />
F.F. Farace 1 , C. Lombard-Bohas 2 , E. Mitry 3 , M. Ychou 4 , L. Bengrine-Lefevre 5 ,<br />
T. Lecomte 6 , K. Joly 7 , M. Ducreux 8 , E. Baudin 9<br />
1 Laboratory of Translational Research, Institut Gustave Roussy, Villejuif, FRANCE,<br />
2 Medical Oncology, Hôpital Edouard Herriot Hospices Civils de Lyon, Lyon<br />
Cedex, FRANCE, 3 Oncologie Médicale, Institut Curie, Paris, FRANCE,<br />
4 Oncologie Médicale Digestive, Centre Val d’Aurelle, Montpellier, FRANCE,<br />
5 Oncologie Médicale, Hôpital Saint-Antoine, Paris, FRANCE,<br />
6 Hepato-gastro-enterologie, Hopital Trousseau, Tours, FRANCE, 7 Statistique,<br />
Laboratoires Roche, Boulogne Billancourt, FRANCE, 8 Oncologie Digestive,<br />
Institut de Cancérologie Gustave Roussy, Villejuif, FRANCE, 9 Oncologie, Institut<br />
Gustave Roussy, Villejuif, FRANCE<br />
Background: The efficacy/safety of bevacizumab in combination with chemo<strong>the</strong>rapy<br />
was investigated in patients (pts) with advanced progressive digestive neuroendocrine<br />
tumors (DigNET) (phase II BETTER study (ML20383)). Circulating endo<strong>the</strong>lial cell<br />
levels were explored as potential prognostic or predictive marker.<br />
Methods: Pts were enrolled in two arms depending on tumor primary localisation. Pts<br />
with duodeno-pancreatic NET were treated with 5-FU/streptozocin combined to<br />
bevacizumab (arm 1, n = 34). Patients with o<strong>the</strong>r digNET received capecitabine<br />
combined to bevacizumab (arm 2, n = 49). In 50 dig NET patients, CEC levels were<br />
monitored at several time points: -before treatment (baseline, BL), -on day 2 (d2) of<br />
cycle 1 (C1), -on day 22 (d22) of cycle 1 (C1) for arm 1 and day 1 (d1) of cycle 2 (C2)<br />
for arm 2, -at day 1 of each of <strong>the</strong> subsequent cycles and at <strong>the</strong> end of treatment. CECs<br />
were measured in 1ml erythocyte lysed whole blood by four color flow cytometry (FCM)<br />
and identified by a CD45 − CD31 + CD1467-amino-actinomycin (7AAD) − phenotype.<br />
Relation between CEC levels and clinico-biological characteristics, response to treatment<br />
and progression/death at 1 or 2 years (1 yr-, 2 yr-PFS) was examined. Non parametric<br />
Wilcoxon tests were used to analyze change from baseline and to evaluate <strong>the</strong><br />
association beteween CEC values and efficacy parameters.<br />
Results: Median CEC values were low at BL (4 CEC/mL) and similar for <strong>the</strong> 2 arms.<br />
CEC levels significantly increased on C1d2 onlv (media value: 7CEC/mL for <strong>the</strong> 2<br />
pooled arms, p = 0.019). A trend towards an association between changes in CEC<br />
levels between BL and C1d2, and progression/death during <strong>the</strong> first two years of<br />
treatment was observed (p = 0.078).<br />
Conclusions: Increased CECs at baseline could be an indicator of shorter PFS in<br />
digNET treated with <strong>the</strong> combination of bevacizumab and chemo<strong>the</strong>rapy. The<br />
mechanism of increased CECs at day 2 of treatment remains to be understood.<br />
Disclosure: E. Mitry: Honoraries: Roche. K. Joly: Employment: Roche. M. Ducreux:<br />
Consultant: Roche, Merck Serono Honoraries: Roche, Merck Serono, Amgen, Bayer,<br />
Fresenus, Pfizer, Sanofi Clinical research project: Pfizer, Chugai, Merck Serono. E.<br />
Baudin: Honoraries : Scientific committee of BETTER Trial. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
210P REVIEW OF THE CURRENT STATUS OF KRAS MUTATION<br />
TESTING IN FRANCE IN 2011: THE FLASH-KRAS STUDY<br />
M. Ducreux 1 , A. Lièvre 2 , P. Artru 3 , M. Guiu 4 , J. Merlin 5 , J.C. Sabourin 6 ,<br />
J. Viguier 7 , A. Bastie 8 , A. Seronde 8 , P. Laurent-Puig 9<br />
1 Oncologie Digestive, Institut Gustave Roussy, Villejuif, FRANCE, 2 Service<br />
d’Hépato-Gastroentérologie, Hopital Ambroise Paré, Boulogne-Billancourt,<br />
FRANCE, 3 Service d’Hépato-Gastroentérologie et d’Oncologie Digestive, Hopital<br />
Privé Jean Mermoz, Lyon, FRANCE, 4 Anatomie-Pathologie, Cabinet, Perpignan,<br />
FRANCE, 5 Unité de Biologie des Tumeurs, Centre Alexis Vautrin, Nancy,<br />
FRANCE, 6 Department of Pathology, INSERM U614, Rouen University Hospital,<br />
Rouen, FRANCE, 7 Centre De Coordination Des Dépistages des Cancers, CHRU<br />
Trousseau, Tours Cedex, FRANCE, 8 Medical Affairs, Merck Serono, Lyon,<br />
FRANCE, 9 UMR-S775, Université Paris Descartes, Paris, FRANCE<br />
Background: KRAS testing is required before treatment initiation of cetuximab in<br />
<strong>the</strong> management of metastatic colorectal cancer (mCRC). The objective of <strong>the</strong> study<br />
was to examine <strong>the</strong> current situation in 2011 regarding KRAS testing in <strong>the</strong> initial<br />
management of mCRC.<br />
Methods: This observational, retrospective, national study was carried out between<br />
March 28th and April 8th 2011. During this period 538 patients with mCRC were<br />
included across 160 french hospitals. The main objective was to assess <strong>the</strong> rate of<br />
KRAS testing in patients who had started first line (L1) treatment for mCRC. The<br />
secondary objectives were to describe <strong>the</strong> time taken and techniques used for KRAS<br />
testing, <strong>the</strong> possible reasons this test was not requested, to describe and analyse <strong>the</strong><br />
clinical characteristics of <strong>the</strong> patients and <strong>the</strong> planned L1 treatments and those finally<br />
received.<br />
Results: KRAS testing was carried out for 433 patients (81.1%) and not carried out<br />
for 101 patients (18.9%). The main reasons for not requesting <strong>the</strong> KRAS status were<br />
(several answers possible): anti-EGFR not prescribed (n = 58), candidate for surgery<br />
(n = 8), samples not useable (n = 5), age of <strong>the</strong> patient (n = 3), o<strong>the</strong>r (n = 24), data<br />
missing (n = 13). The genotyping results were available after a mean delay of 23.6 ±<br />
28.2 days. The KRAS testing was requested by an oncologist (45.5%), a<br />
gastroenterologist (31%), a surgeon (11.2%), a pathologist (7.2%) or a<br />
multidisciplinary group (5.1%) approximately 15 days (-66.5;33.6) median (min;<br />
max) after <strong>the</strong> diagnosis of metastases, and 15 days (-66.9;3.7) median (min; max)<br />
before <strong>the</strong> start of L1 treatment. Result of KRAS status had not been received before<br />
<strong>the</strong> L1 treatment was chosen in 56.6% of <strong>the</strong> patients. For patients with wild-type<br />
KRAS status whose <strong>the</strong>rapeutic management was modified after <strong>the</strong> result of KRAS<br />
testing (n = 108), this change was a prescription of an anti-EGFR in 77.8% of <strong>the</strong><br />
cases.<br />
Conclusion: The Flash-KRAS study is <strong>the</strong> first one to assess <strong>the</strong> current modalities of<br />
KRAS genotyping in France. It shows that in 2011 <strong>the</strong> KRAS test is an integral part<br />
of <strong>the</strong> management of patients with mCRC. None<strong>the</strong>less, it shows disparities<br />
between regions in terms of time to obtain results, which need to be improved to be<br />
compatible with <strong>the</strong> <strong>the</strong>rapeutic management.<br />
Disclosure: M. Ducreux: Merck Serono. A. Lièvre: Merck Serono. P. Artru: Merck<br />
Serono. M. Guiu: Merck Serono. J. Merlin: Merck Serono. J.C. Sabourin: Merck<br />
Serono. J. Viguier: Merck Serono. A. Seronde: Merck Serono. P. Laurent-Puig: Merck<br />
Serono. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
211P SOMATIC KRAS MUTATIONS AND RESISTANCE TO<br />
EGFR-TARGETED THERAPIES: IS KRAS READY TO INCLUDE<br />
AS A REFLEX TEST WITH EGFR IN NSCLC? AN EVIDENCE<br />
SYNTHESIS BASED APPROACH<br />
S. Murray 1 , F. Siannis 2 , D. Bafaloukos 3 , P. Kosmidis 4 , H. Linardou 5<br />
1 Oncology, GeneKor SA, A<strong>the</strong>ns, GREECE, 2 Department of Ma<strong>the</strong>matics,<br />
University of A<strong>the</strong>ns, A<strong>the</strong>ns, GREECE, 3 31st Department of Medical Oncology,<br />
Metropolitan Hospital, A<strong>the</strong>ns, GREECE, 4 Data Office, Hellenic Cooperative<br />
Oncology Group (HECOG), A<strong>the</strong>ns, GREECE, 5 Medical Oncology, Metropolitan<br />
Hospital, A<strong>the</strong>ns, GREECE<br />
Background: The intrinsic nature of <strong>the</strong> constitutive KRAS mutational activation in<br />
predicting an absence of response to anti-EGFR tyrosine kinase inhibitors (TKIs:<br />
gefitinib and erlotinib) in non-small-cell lung cancer (NSCLC) has recently been<br />
demonstrated. We questioned <strong>the</strong> validity of <strong>the</strong> inclusion of KRAS in reflex<br />
stratification of NSCLC patients.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds391 | ix85
Material and methods: We searched PubMed and MEDLINE for publications to<br />
31st August 2011 (last search 17/09/2011) pertaining to KRAS mutational status in<br />
patients with NSCLC receiving TKIs. Eligible studies reported complete (CR) and<br />
partial responses (PR), stratified by KRAS. Potential between-study heterogeneity was<br />
accommodated by use of random-effects models for bivariate meta-analysis of<br />
sensitivity and specificity. Positive and negative likelihood ratios (+LR and –LR) of<br />
KRAS and EGFR for predicting an absence (or presence) of response were calculated<br />
by use of pooled estimates for sensitivity and specificity.<br />
Results: For non-response, 26 studies (n = 1957; KRAS = 335, 17.1%) demonstrated a<br />
+LR = 40.65, and -LR = 0.82 (specificity = 0.99 [95% CI: 0.95-1.00]; sensitivity = 0.19<br />
[0.15-0.23]). For EGFR, 70 studies (n = 5346; EGFR = 1919, 35.9%) demonstrated a<br />
+LR = 5.6 and –LR = 0.25 (specificity = 0.86 [0.82-0.89]; sensitivity = 0.78 [0.74-0.82])<br />
for response. In a three way analysis <strong>the</strong> apparent difference in <strong>the</strong> likelihood of a<br />
patient with an EGFR mutation responding compared to KRAS is summarized in LR<br />
of +422.46 [95%CI: 56.98-3132.43, p < 0.001]; and LR +32.91 fold compared to WT<br />
patients [18.51-55.01, p < 0.001]. The likelihood of a ‘no-detectable’ mutation (WT)<br />
patient responding compared to a KRAS is LR +13.24 [1.76-99.65, p = 0.012].<br />
Conclusions: Although several studies examined KRAS and EGFR, insufficient data<br />
addresses <strong>the</strong> effect of KRAS on outcomes. The three-way stratification suggests<br />
significant differences in survival outcomes due to <strong>the</strong> high specificity of<br />
non-response to KRAS, and response to EGFR. It appears that reflex stratification<br />
incorporating KRAS with EGFR treatment decisions in NSCLC is ready for clinical<br />
implementation, prospective data on survival outcomes are still however welcome.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
212P BRAF V600E: PROGNOSTIC MARKER IN COLORECTAL<br />
CANCER<br />
S. Plestina 1 , I. Rako 2 , J. Jakic-Razumovic 3 , D. Katalinic 1 , J. Sertic 2<br />
1 Department of Oncology, University Hospital Center Zagreb, Zagreb, CROATIA,<br />
2 Department of Laboratory Diagnostics, University Hospital Center Zagreb,<br />
Zagreb, CROATIA, 3 Department of Pathology and Cytology, University Hospital<br />
Center Zagreb, Zagreb, CROATIA<br />
Activation of BRAF oncogene has been implicated in colorectal carcinogenesis. BRAF<br />
protein is a serin/threonine kinase, component of a conserved signaling pathway that<br />
regulates cellular responses to exstracellular signals. In human cancer, it is commonly<br />
activated by somatic hotspot mutation at nucleotide 1799 of <strong>the</strong> BRAF gene which<br />
leads to a single aminoacid substitution Val600Glu (V600E). The aim of this study<br />
was to compare clinical and pathological phenotype of colorectal cancers with<br />
incidence of BRAF gene mutation. Clinical and pathological characteristics such as<br />
age, sex, tumor size, histologic grade, Dukes’ stage, angioinvasion and tumor position<br />
were collected for each patient. Sections from 113 formalin-fixed paraffin-embedded<br />
(FFPE) tumor samples were evaluated for <strong>the</strong> BRAF V600E mutation using<br />
LightCycler PCR with allele-specific fluorescent probe melting curve analysis.<br />
Differences in clinical and pathological variables between <strong>the</strong> groups of patients with<br />
and without BRAF mutation were analyzed using Fisher exact test. Our results show<br />
that BRAF gene mutation was detected in 8.8% (10/113) samples. Statistical analysis<br />
revealed a significant association between <strong>the</strong> BRAF mutation and Dukes’ stage (p =<br />
0.04) where all mutations were found in tumors classified as Dukes’C (10/10).<br />
Incidence of mutation was higher in males, patients older than 60 years, tumors<br />
bigger than 5 cm, tumors with angioinvasion and poor differentiated tumors, but no<br />
significant association was found. All BRAF gene mutations were detected in colon<br />
cancers (p = 0.01). We can conclude that incidence of BRAF gene mutation was<br />
higher in tumors with poor prognostic markers which have been associated with<br />
poor tumor prognosis and progression of disease.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
213P RESULTS OF THE SECOND PILOT EXTERNAL QUALITY<br />
ASSURANCE SCHEME FOR SOMATIC EGFR MUTATION<br />
TESTING IN NON-SMALL-CELL LUNG CANCER (NSCLC)<br />
N. Normanno 1 , S. Patton 2 , F.H. Blackhall 3 , S. Murray 4 , K. Kerr 5 , M. Dietel 6 ,<br />
M. Filipits 7 , S. Benlloch 8 , R.A. Stahel 9 , E. Thunnissen 10<br />
1 Dept. Biologia Cellulare e Bioterapie, Istituto Nazionale Tumori di Napoli, Napoli,<br />
ITALY, 2 Genetic Medicine, St Mary’s Hospital, Manchester, UNITED KINGDOM,<br />
3 Medical Oncology Department, Christie Hospital NHS Trust, Manchester,<br />
UNITED KINGDOM, 4 Genetics, GeneKOR, A<strong>the</strong>ns, GREECE, 5 Department of<br />
Pathology, Aberdeen Royal Infirmary, Aberdeen, UNITED KINGDOM, 6 Surgical<br />
Pathology, Charité, Humboldt-Universität zu Berlin, Berlin, GERMANY,<br />
7 Medicine, Medical University of Vienna, Vienna, AUSTRIA, 8 Pangaea Biotech,<br />
USP Dexeus University Institute, Barcelona, SPAIN, 9 Oncology, University<br />
Hospital Zurich, Zurich, SWITZERLAND, 10 Pathology, VU University Medical<br />
Center, Amsterdam, NETHERLANDS<br />
Background: The External Quality Assurance (EQA) process aims at establishing<br />
performance levels and may identify systematic errors in methodology that may not<br />
be revealed by internal QA processes. The European Molecular Genetics Quality<br />
Network (EMQN), <strong>the</strong> European Society for Pathology (ESP), <strong>the</strong> European Thoracic<br />
Oncology Platform (ETOP) and <strong>the</strong> European Society of Medical Oncology (<strong>ESMO</strong>)<br />
Annals of Oncology<br />
with o<strong>the</strong>r leading European groups collaborated in a pilot EQA scheme for somatic<br />
EGFR gene mutational analysis in NSCLC.<br />
Material and methods: Samples generated from cell lines mimicking clinical<br />
fractions of neoplastic cell content were validated by 5 laboratories and <strong>the</strong>n provided<br />
to participating laboratories. Each sample was supplied with a mock clinical case.<br />
Participating laboratories registered with <strong>the</strong> EMQN, performed <strong>the</strong> analysis using<br />
<strong>the</strong>ir usual method(s), and submitted <strong>the</strong>ir results within a 6 week timeframe.<br />
Anonymous results were assessed and made available to all participants.<br />
Results: Of a total of 117 labs from 30 countries registered, 91 labs returned results.<br />
Sequencing and <strong>the</strong> DxS Therascreen kit were <strong>the</strong> main methodologies used by <strong>the</strong><br />
participants. The standard of genotyping was worrying, with a significant number of<br />
genotyping errors made. Only 42 (46.1%) participants reported <strong>the</strong> correct result for<br />
all 10 samples. The majority of errors were false-negative results (82.2%); however,<br />
15.1% of errors were due to false-positive results and 2.7% to a combination of both<br />
errors. There were 42 (4.8%) analytical failures of which 88.1% were distributed<br />
across 6 laboratories. The performance of 18 (19.8%) labs fell below <strong>the</strong> criteria for<br />
acceptable performance (score A,<br />
rs2293649, A > G) and beta-4 (rs743554, C > T, rs8669, C > G, rs871443, T > C,<br />
rs9367, T > C) integrins was performed by real-time PCR. Among 128 K-RAS wild<br />
type metastatic colorectal cancer patients treated with third-line irinotecan cetuximab<br />
62 (48%) were HER-3 negative and were included in <strong>the</strong> present study. At univariate<br />
analysis <strong>the</strong> beta-4 rs8669, rs871443 and rs9367 polymorphisms correlated with both<br />
median progression free survival and overall survival, whereas only <strong>the</strong> beta-4 rs8669<br />
genotype showed a trend for a statistically significant correlation with response<br />
(partial remission rate for genotype G vs. C-G/C = 20% vs. 48%, p = 0.059). At<br />
multivariate analysis only <strong>the</strong> same allelic variant of beta-4 (rs8669 G vs. C-G/C)<br />
maintained an independent role in negatively influencing median PFS (HR = 0.13,<br />
95%CI 0.051-0.35, p < 0.0001) and OS (HR = 0.29, 95%CI 0.10-0.81, p < 0.0001). We<br />
believe that beta-4 rs8669 genotyping may help identifying a sub-group of HER-3<br />
negative, K-RAS wild type colorectal cancer patients less likely to benefit from<br />
anti-EGFR treatment. Our findings could be also relevant in planning future trials<br />
testing treatment strategies against <strong>the</strong> integrins-activated molecular pathway.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
215P CANCER STEM CELL GENETIC PROFILE AS PREDICTOR OF<br />
RELAPSE IN RADICALLY RESECTED COLORECTAL CANCER<br />
R. Giampieri 1 , M. Scartozzi 1 , F. Piva 2 , C. Loretelli 1 , A. Mandolesi 3 , L. Faloppi 1 ,<br />
M. Bianconi 1 , A. Bittoni 1 , I. Bearzi 3 , S. Cascinu 1<br />
1 Clinica di Oncologia Medica, AOU Ospedali Riuniti Ancona Università<br />
Politecnica delle Marche, Ancona, ITALY, 2 Department of Specialized Clinical<br />
Sciences and Odontostomatology, Università Politecnica delle Marche, Ancona,<br />
ITALY, 3 Anatomia Patologica, AOU Ospedali Riuniti Ancona Università Politecnica<br />
delle Marche, Ancona, ITALY<br />
Although disease stage is <strong>the</strong> most relevant factor influencing treatment choice in locally<br />
advanced radically resected colorectal cancer, it is not uncommon to observe disease<br />
relapse in patients with apparent low risk stage that are usually excluded from an<br />
adjuvant <strong>the</strong>rapy. On <strong>the</strong> contrary we also know that some patients with high risk stage<br />
are not likely to relapse independently from medical treatment received. Preclinical data<br />
ix86 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
suggested that cancer stem cells may influence <strong>the</strong> biological behaviour of many solid<br />
tumours including colorectal cancer. We tested a panel of genetic markers of stemness in<br />
resected Dukes stage B and C colorectal cancer and <strong>the</strong>ir impact on prognosis. We<br />
performed k-means unsupervised clustering (K = 2) using <strong>the</strong> mRNA expression data of<br />
66 genes. The algorithm divided <strong>the</strong> patients into two groups (A and B) and most of <strong>the</strong><br />
patients clustered in a manner consistent with relapse free survival, defined as <strong>the</strong> time<br />
between primary surgery and first radiological sign of metastatic involvement or patients<br />
death, whichever came first. A total of 62 patients were analysed (46, 74% stage II and 16,<br />
26% stage III), 36 (58%) patients relapsed during <strong>the</strong> follow-up period (range 1.63-86.5<br />
months). Respectively 12 (19%) and 50 (81%) patients were allocated into group A and<br />
B. A significantly different median relapse-free survival was observed between <strong>the</strong> 2<br />
groups (22.18 vs 42.85 months, p = 0.0296). Interestingly enough, even if group A had a<br />
worse outcome in terms of risk of relapse, an higher percentage of stage II patients could<br />
be found in this group (83%) when compared with <strong>the</strong> group B (52%). Among of all<br />
genes tested, those with <strong>the</strong> higher “weight” in determining allocation into one of <strong>the</strong> two<br />
groups were CD44, ALCAM, DTX2, HSPA9, CCNA2, PDX1, MYST1, COL1A1 and<br />
ABCG2. This analysis supports <strong>the</strong> idea that, o<strong>the</strong>r than (or maybe more than) stage,<br />
biological variables, such as expression levels of colon cancer stem cell genes, may be<br />
relevant in determining an increased risk of relapse in resected colorectal cancer patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
216P GENE EXPRESSION PROFILING IN ESTOROGEN RECEPTOR<br />
POSITIVE BREAST CANCER WITH CANCER STEM-LIKE<br />
CELLS<br />
Y. Tsunoda 1 , M. Sakamoto 1 , E. Fukma 1 ,T.Sawada 2 , A. Sasaki 3 ,<br />
G. Yamamoto 3 , T. Tachikawa 3<br />
1 Breast Center, Kameda Medical Center, Kamogawa City, JAPAN, 2 Breast<br />
Surgery, Showa University School of Medicine, Tokyo, JAPAN, 3 Dental<br />
Pathology, Showa University School of Medicine, Tokyo, JAPAN<br />
Objective: Breast cancer cells with CD44 + CD24-/low gene expression signature have<br />
been suggested to have stem cell-like tumor-initiating properties. The purpose of this<br />
study is to clarify <strong>the</strong> gene expression profiling of cells with CD44 + CD24-/low gene<br />
expression signature in <strong>the</strong> estrogen receptor (ER) positive tumors.<br />
Methods: Laser-captured microdissection was used to select <strong>the</strong> isolation of cancer<br />
cells in 32 frozen tissues of breast cancer, and RNA extracted from <strong>the</strong>se cells was<br />
examined by real-time RT-PCR to quantify CD44 and CD24 expressions. Human<br />
stem cell RT 2 Profiler PCR Array was used for gene expression analysis in <strong>the</strong> groups<br />
of CD44 + CD24-/low and CD44 + CD24+ gene expression signature.<br />
Results: Thirty-two tumors were divided into 2 groups. Group A was composed of<br />
<strong>the</strong> CD44 + CD24-/low type, in which <strong>the</strong> ratio of CD44/CD24 was >10.0. Group B<br />
was composed of <strong>the</strong> CD44 + CD24+ type, in which <strong>the</strong> ratio was >0.1 and ≦ 10.0.<br />
The number of tumors in group A and B were 4 and28, respectively. Regarding <strong>the</strong><br />
correlation of CD44/CD24 status with tumor characteristics, <strong>the</strong> tumors of group A<br />
were significantly associated with axillary lymph node metastasis compared with<br />
those of group B (P = 0.009). There were no significant differences in tumor size,<br />
nuclear grade between <strong>the</strong> two groups. HER2 status in <strong>the</strong> tumors of group B was<br />
significantly higher than group A (P = 0.028). According to signaling pathways, <strong>the</strong><br />
number of expression genes for <strong>the</strong> Notch pathway in group A was significantly<br />
greater than in group B (P = 0.028). Overexpressed genes for ALDH1 (P = 0.021) and<br />
SOX2 (P = 0.018) were noted in group A compared to group B.<br />
Conclusion: This study suggests that <strong>the</strong> Notch pathway may be an important<br />
signaling pathway in luminal subtype with CD44 + CD24-/low gene expression<br />
signature. In addition, ei<strong>the</strong>r ALDH1or SOX2 may be a candidate marker for cancer<br />
stem cells in <strong>the</strong> ER positive breast cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
217P CARBON NANOTUBE DEVICES FOR THE DETECTION OF<br />
CIRCULATING TUMOR CELLS<br />
G. Kloecker 1 , B. King 2 , B. Panchapakesan 2<br />
1 Department of Medical Oncology & Hematology, Brown Cancer Center<br />
University of Louisville, Louisville, KY, UNITED STATES OF AMERICA,<br />
2 Department of Mechanical Engineering, University of Louisville, Louisville, KY,<br />
UNITED STATES OF AMERICA<br />
Introduction: Combining clinical and imaging tools with <strong>the</strong> presence and level of<br />
circulating cancer cells (CTC) has great potential. Carbon nanotube electrical devices<br />
are a promising technique to detect CTCs in small samples of blood. This study tests,<br />
if free energy change for specific interactions is higher than for non-specific<br />
interactions. Cell surface receptors found on breast cancer cells are targeted by<br />
functionalizing <strong>the</strong> carbon nanotube electronic devices with cancer-specific<br />
antibodies. The study also tested, if <strong>the</strong> concentration of CTCs correlates with <strong>the</strong><br />
change in <strong>the</strong> electronic properties of <strong>the</strong> nanotube device.<br />
Methods: Antibodies, specific for IGF1R, EPCAM, Her2, and a nonspecific antibody<br />
(EMD Biosciences, San Diego CA) in PBS are adsorbed on to <strong>the</strong> individual<br />
nanodevices. One ml drops of fresh human donor blood is mixed with 1 micro-liter<br />
of cancer cells (1000 cells). This mixture is applied to <strong>the</strong> device using a<br />
micro-pipette and <strong>the</strong> change in conductivity is measured. Negative control cell lines<br />
that do not overexpress IGF1R, EPCAM, or Her2, such as human Jurkat cells,<br />
human nontumorigenic MCF10A cells, and nontumorigenic R- mouse embryonic<br />
fibroblast cells with targeted disruption of <strong>the</strong> IGF1R gene are used as negative<br />
controls to test <strong>the</strong> device efficacy.<br />
Results: Functionalized nanotubes with specific antibodies elicited significant changes<br />
in conductivity (10 times change per 100 cells, r∧2 0.95) while non-specific interaction<br />
caused negligible conductivity changes. Larger conductivity drops were seen in blood<br />
containing cancer cells than blood alone or isolated white blood cells (change in<br />
resistance from 2-6 kW for 200 cells in blood, r∧2 0.95). Changes in conductance were<br />
linear with an increasing number of cells in <strong>the</strong> range of 10-300 cells/5 ml. (5 kW per<br />
100 cells, 20 kW per 200 cells and 30 kW per 300 cells, r∧20.95).<br />
Conclusion: The specific and proportional changes in conductivity suggest that this<br />
approach could be useful in sensing cancer cells in a small volume of blood.<br />
Monitors based on nano-technology may be of clinical utility in <strong>the</strong> detection of a<br />
wide variety of cancer types. This non-invasive test would give clinicians immediate<br />
results (similar to a glucometer), which can improve screening, response assessment<br />
and surveillance.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
218P CIRCULATING TUMOR CELLS AS A PROGNOSTIC MARKER<br />
IN ADVANCE COLORECTAL CANCER PATIENTS TREATED<br />
WITH CETUXIMAB-CONTAINING SALVAGE CHEMOTHERAPY<br />
S. Matsusaka 1 , Y. Kuboki 1 , M. Suenaga 1 , E. Shinozaki 1 , N. Mizunuma 1 ,<br />
K. Hatake 2<br />
1 Gastroenterology, Cancer Institute Hospital, Tokyo, JAPAN, 2 Medical Oncology,<br />
Cancer Institute Hospital of JFCR, Tokyo, JAPAN<br />
Background: Circulating tumor cells (CTC) can be a predictive, or a prognosis<br />
marker in advance colorectal cancer (ACC) patients treated with chemo<strong>the</strong>rapy plus<br />
targeted agents as front-line <strong>the</strong>rapy. We assessed assessed <strong>the</strong> prognostic and<br />
predictive role of CTC in ACC patients treated with cetuximab (with or without<br />
irinotecan) who had been previously treated with a fluoropyrimidine, irinotecan, and<br />
oxaliplatin.<br />
Material and methods: Between October 2008 and March 2011, 63 patients with<br />
KRAS wild-type ACC were treated with cetuximab as a third-line <strong>the</strong>rapy at <strong>the</strong><br />
Cancer Institute Hospital, providing written informed consent for CTC collection.<br />
We used CellSearch system for detection and EGFR expression for CTC. Patients<br />
were stratified into low (less than three CTC per 7.5ml of blood) or high (three or<br />
more CTC per 7.5ml of blood).<br />
Results: A total of 63 patients were assessable for CTC analysis. Of <strong>the</strong> 63 patients with<br />
evaluable baseline CTC results, 19 patients (30%) had high CTC. The median number of<br />
CTC was one (range 0- 220, mean 7.28) at baseline. Patients with high CTCs had a<br />
shorter median overall survival (8.9 months) than those with low CTCs (15.3 months)<br />
[P < 0.005; HR 2.2 (95% CI 1.2–3.9)]. There was no significant difference in PFS between<br />
<strong>the</strong> two groups (PFS; HR 1.2). Of <strong>the</strong> 33 patients with positive CTC, 7 patients (21%)<br />
had EGFR-positive CTC, and 26 patients (79%) had EGFR-negative CTC. The<br />
concordance rate for EGFR between tumor and CTC was 30.5%.<br />
Conclusion: High CTC count at baseline is a poor prognostic factor for OS in ACC<br />
patients treated with cetuximab-containing chemo<strong>the</strong>rapy as salvage.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
219P ASSESSMENT OF CIRCULATING FREE DNA (CFDNA) AND<br />
CIRCULATING MELANOMA CELLS (CMCS) AS PROGNOSTIC<br />
BIOMARKERS IN METASTATIC CUTANEOUS MELANOMA<br />
K. Aung 1 , L.T. Khoja 1 , C. Zhou 1 , M. Lancashire 1 , R. Sloane 1 , G. Brady 1 ,<br />
G. Clack 2 , A. Hughes 2 , P. Lorigan 3 , C. Dive 1<br />
1 Clinical and Experimental Pharmacology, The Paterson Institute for Cancer<br />
Research, Manchester, UNITED KINGDOM, 2 Early Phase Oncology,<br />
AstraZeneca Pharmaceuticals, Macclesfield, UNITED KINGDOM, 3 Medical<br />
Oncology, The Christie NHS Foundation Trust, Manchester, UNITED KINGDOM<br />
Background: cfDNA is detectable in patients with metastatic cutaneous melanoma and<br />
its plasma concentration could potentially predict <strong>the</strong>ir clinical outcomes. We assessed<br />
<strong>the</strong> correlation between cfDNA concentration and patients’ overall survival and clinical<br />
characteristics including known poor prognostic factors in melanoma. Prognostic value<br />
of CMCs number and its association with cfDNA level was also explored.<br />
Methods: Pre-treatment blood samples from 50 patients with metastatic cutaneous<br />
melanoma were collected prospectively. cfDNA was extracted from 1 ml of plasma using<br />
QIAamp Circulating Nucleic Acids Kit (Qiagen, Hilden, Germany) and quantified by<br />
RNase P qPCR (ABI Life Technologies, Foster City, NJ, USA). CMC enumeration per<br />
7.5 ml whole blood was performed within 96 hours of sample collection using <strong>the</strong><br />
CellSearch Melanoma Kit (Veridex, NJ, USA). Correlation between cfDNA<br />
concentration and clinical characteristics and CMC number was performed using<br />
χ 2 -test and Fisher’s exact test where appropriate. Survival curves were produced and<br />
compared by <strong>the</strong> Kaplan-Meier method and log-rank test respectively.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds391 | ix87
Results: The median concentration of cfDNA was 6.8 ng/ml (range 0-205.8) and<br />
median CMC number was 0/7.5ml (range 0-16). Patients with cfDNA concentration<br />
of >75% percentile had significantly shorter overall survival compared to those with<br />
cfDNA level
Annals of Oncology<br />
223P THE ANALYTICAL VALIDATION OF PROSTATE SPECIFIC<br />
MRNA DETECTION IN WHOLE BLOOD BY REVERSE<br />
TRANSCRIPTION-POLYMERASE CHAIN REACTION (RT-PCR)<br />
AS A PROGNOSTIC BIOMARKER FOR PATIENTS WITH<br />
CASTRATION-RESISTANT PROSTATE CANCER (CRPC)<br />
D. Danila 1 , A. Anand 1 , G. Heller 2 ,M.Wan 1 , M. Zehnder 1 , R. Khanin 3 ,<br />
N. Schultz 3 , M. Fleisher 4 , H. Lilja 5 , H.I. Scher 1<br />
1 Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center,<br />
New York, NY, UNITED STATES OF AMERICA, 2 Department of Epidemiology<br />
and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY,<br />
UNITED STATES OF AMERICA, 3 Department of Computational Biology,<br />
Memorial Sloan Kettering Cancer Center, New York, NY, UNITED STATES<br />
OF AMERICA, 4 Department of Laboratory Medicine, Memorial Sloan Kettering<br />
Cancer Center, New York, NY, UNITED STATES OF AMERICA, 5 Urology Service,<br />
Memorial Sloan Kettering Cancer Center, New York, NY, UNITED STATES OF<br />
AMERICA<br />
Background: To estimate <strong>the</strong> association between molecular biomarkers and<br />
outcomes, robust assays are needed before qualification in prospective trials.<br />
Although tumor specific transcripts detected in blood by PCR have been associated<br />
with clinical outcome, an analytically validated PCR platform enabling detection of<br />
CTC-associated transcripts in clinical settings remains to be identified. Here we<br />
explore <strong>the</strong> efficacy of detecting a panel of prostate specific transcripts in conjunction<br />
with conventional markers in CRPC.<br />
Method: Blood was collected from 97 patients with progressive CRPC in PAXgene<br />
tubes (2.5 ml) for total RNA extraction using PAXgene Blood RNA Kit. Five genes<br />
expressed in prostate but not in nucleated blood cells were analyzed by<br />
primer-specific RT-PCR. We used a Fluidigm Dynamic Array platform to<br />
analytically validate RT-PCR assays for KLK3, KLK2, HOXB13, GHRL2 and FOXA1<br />
transcripts. Each PCR-reaction was run in 6 replicates, detection thresholds for each<br />
gene were chosen by ROC analysis of an independent set of 56 CRPC patients versus<br />
51 healthy volunteers, and results were reported as transcripts present or absent.<br />
CellSearch reported CTC number/7.5 ml of blood drawn into CellSave tube.<br />
Result: Prostate specific transcripts were detected in 70/97 (72%, 95% CI 62-80%) of<br />
patients with progressive CRPC studied with a median survival time of 17 months<br />
(95% CI: 13.8, 23.5). 42/45 CRPC-patients with ≥5 CTC and 28/52 CRPC patients<br />
with
Table: 226P<br />
Methods: Pts were randomized 1:1 to T-DM1 3.6 mg/kg q3w or H 6 mg/kg q3w (8<br />
kg/mg in cycle 1) + T 75 or 100 mg/m 2 q3w and treated until disease progression.<br />
HER2 expression was measured by qRT-PCR in archival tissue samples from all<br />
randomized pts. Efficacy outcomes included investigator-assessed PFS and ORR. The<br />
analysis results presented here are based on <strong>the</strong> clinical data with a median follow-up<br />
of ∼14 mo in each arm.<br />
Results: In total, 122 tumor samples from 137 randomized pts were available for<br />
analysis of pre-treatment HER2 by qRT-PCR, resulting in a valid result for 116 pts (6<br />
samples were below <strong>the</strong> limit of quantification). Efficacy outcomes by low (
Annals of Oncology<br />
229P RELATIONSHIP BETWEEN INTESTINAL FUNCTION AND<br />
EXPOSURE TO SORAFENIB AND SUNITINIB IN CANCER<br />
PATIENTS<br />
J. Durand 1 , B. Blanchet 2 , M. Buyse 3 , N. Neveux 4 , P. Boudou-Rouquette 1 ,<br />
O. Mir 1 , M. Vidal 2 , L. Cynober 5 , F. Goldwasser 1<br />
1 Medical Oncology, Cochin Teaching Hospital, Paris, FRANCE,<br />
2 Pharmacology-Toxicology, Cochin Teaching Hospital, Paris, FRANCE,<br />
3 Pharmacy, St Antoine Teaching Hospital, Paris, FRANCE, 4 Clinical Chemistry<br />
Laboratory, Cochin Teaching Hospital, Paris, FRENCH GUYANA, 5 Laboratory of<br />
Biological Nutrition Ea 4466, Université Paris Descartes, Paris, FRANCE<br />
Background: Variability in exposure to sorafenib (SO) and sunitinib (SU), two oral<br />
tyrosine kinase inhibitors (TKI) approved for <strong>the</strong> treatment of various solid tumours,<br />
is large. Plasma citrulline (CIT) levels reflect <strong>the</strong> functional small bowel cell mass.<br />
We studied <strong>the</strong> relationship between TKI exposure and intestinal function in adult<br />
cancer patients (pts).<br />
Methods: CIT concentration and drug exposure were determined in 56 pts under SO<br />
(n = 38) or SU (n = 18) on day (D) 0 (baseline), <strong>the</strong>n D8 and D22 after treatment<br />
initiation. The clinical results led to in vitro studies. In vitro concentration<br />
dependent-cytotoxicity of SO and SU was evaluated in Caco-2 cell lines using<br />
mitochondrial toxicity test (MTT) assay. Under clinically relevant concentrations of<br />
SO (2-10 µg/mL) or SU (0.05-0.10 µg/mL), transepi<strong>the</strong>lial electrical resistance<br />
(TEER) and CIT levels at <strong>the</strong> basolateral side of Caco-2 cells were determined.<br />
Results: In SO-treated pts, mean citrullinemia on D8 was lower than at D0 (26.2 ±<br />
10.9 mmol/L vs 35.2 ± 13.4, p < 0.0001). Baseline citrullinemia correlated with SO<br />
Area Under Curve (AUC) (r = 0.59, p =0.0001). Median SO AUC on D22 was<br />
1.23-fold lower than SO AUC on D8 (67.0 vs 82.4 mg/L.h respectively, p = 0.033).<br />
Magnitude of decrease in citrullinemia between D0 and D8 correlated with<br />
subsequent decrease in SO AUC (r = 0.61, p < 0.001). In SU-treated pts, baseline<br />
citrullinemia was not correlated with drug exposure (r = -0.29, p = 0.26). Nei<strong>the</strong>r<br />
citrullinemia nor SU AUC varied over <strong>the</strong> study period (p = 0.55 and p = 0.23<br />
respectively). In vitro lethal concentration 50 (LC50) of SO (9.64 + 0.44 µg/mL) was<br />
close to <strong>the</strong>rapeutic concentration unlike SU LC 50 (2.07 + 0.11 µg/mL) which was<br />
40-fold higher. In SO-treated Caco-2 cells, TEER and CIT levels decreased compared<br />
to those of control group (p < 0.0001 and p = 0.017 respectively). SU did not cause<br />
any change of <strong>the</strong>se 2 parameters.<br />
Conclusions: Contrary to SU, SO caused in vitro a cytotoxic effect on Caco-2 cells at<br />
<strong>the</strong>rapeutic concentrations. This likely explains <strong>the</strong> different kinetics of CIT<br />
concentrations between SO- and SU-treated pts. Correlation between SO AUC and<br />
citrullinemia suggests strongly that functional enterocytic mass contributes to <strong>the</strong><br />
intra- and inter-individual variability in sorafenib exposure in cancer pts.<br />
Disclosure: O. Mir: BAYER, PFIZER, ROCHE. F. Goldwasser: BAYER, PFIZER,<br />
ROCHE. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
230P FEASIBILITY OF GENETIC ABERRATIONS ANALYSIS IN THE<br />
CIRCULATING TUMOR CELLS (CTCS)<br />
J. Antonello 1 , E. Rossi 2 , U. Basso 3 , A. Facchinetti 2 , V. Zagonel 3 ,J.<br />
F. Swennenhuis 4 , L.W. Terstappen 4 , A. Amadori 1 , R. Zamarchi 1<br />
1 Immunology and Molecular Oncology, IOV-IRCCS, Padova, ITALY, 2 Department<br />
of Surgery, Oncology and Gastroenterology, University of Padova, Padova,<br />
ITALY, 3 Medical Oncology, IOV-IRCCS, Padova, ITALY, 4 Medical Cell Biophysics,<br />
University of Twente, Twente, NETHERLANDS<br />
Background: In current practice cancer tissue is taken at diagnosis to assess <strong>the</strong><br />
presence of treatment targets. This however is suboptimal since tumor cells evolve<br />
due to genomic instability. Assessment of <strong>the</strong> genotype and phenotype of <strong>the</strong> CTCs<br />
will provide insights into which treatments would be most beneficial for <strong>the</strong><br />
individual patient. Feasibility to detect treatment targets in CTCs has been<br />
demonstrated (Meng, Tripathy et al. 2004; de Bono, Attard et al. 2007; Rossi, Basso<br />
et al. 2010; Wang, Pfister et al. 2010). In this context, <strong>the</strong> development of a<br />
cytogenetic assay for CTCs will be crucial for successful molecular targeted <strong>the</strong>rapy<br />
in cancer patients. Genetic characterization of CTCs is expected to ga<strong>the</strong>r new<br />
knowledge on <strong>the</strong> mechanism of metastasis and on potential targets of novel<br />
<strong>the</strong>rapeutic strategies.<br />
Patients and methods: Assay optimization for analysis of genetic aberrations of<br />
CTCs was performed with cells from tumor cell lines. Tumor cell lines with known<br />
chromosomal aberrations and mosaicism were spiked into 7.5mL whole blood<br />
samples, at numbers similar to those observed in-vivo in cancer patients. Tumor cells<br />
were enriched by CellSearch System and off-line purified and individually analyzed<br />
for chromosomal alterations. The procedure was next validated by using blood<br />
samples collected from cancer patients.<br />
Results/Conclusions: A robust protocol for <strong>the</strong> isolation of individual CTCs followed<br />
by DNA extraction and amplification after CellSearch enrichment was established.<br />
The number and <strong>the</strong> quality of CTCs needed to obtain an informative analysis of<br />
chromosomal aberrations were set up. Accrual of cancer patients for individual CTC<br />
isolation and molecular characterization is ongoing. Updated data including<br />
evaluations on prognostic value of <strong>the</strong> genetic aberrations analysis of <strong>the</strong> CTCs and<br />
correlation with clinical stage, tumor burden, metastatic sites and survival will be<br />
available and presented at <strong>the</strong> meeting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
231P META-ANALYSIS OF HER3 EXPRESSION AND PROGNOSIS<br />
IN SOLID TUMORS<br />
A. Ocana 1 , F. Vera Badillo 2 , B. Seruga 3 , A. Pandiella 4 ,E.Amir 2<br />
1 Medical Oncology, Albacete University Hospital, Albacete, SPAIN, 2 Medical<br />
Oncology, Princess Margaret Hospital, Toronto, CANADA, 3 Sector of Medical<br />
Oncology, Institute of Oncology, Ljubljana, SLOVENIA, 4 Salamanca Cancer<br />
Research Center, CIC-CSIC, Salamanca, SPAIN<br />
Introduction: Aberrant activation of various ErbB receptors has been linked with<br />
malignant transformation. HER3 is an ErbB family member that can dimerize with<br />
o<strong>the</strong>r ErbB receptors such as HER2 and can modulate <strong>the</strong> transmission of oncogenic<br />
stimuli. The prognostic role of HER3 is not clear, but numerous agents against HER3<br />
are currently in clinical development. Here we present a meta-analysis of studies<br />
evaluating <strong>the</strong> prognostic impact of HER3 expression.<br />
Material and methods: Pubmed was searched for studies evaluating expression of<br />
HER3 (as measured by immunohistochemistry-IHC) and overall survival (OS) in<br />
solid tumors. Published data were extracted and computed into odds ratios (ORs) for<br />
death at 3 and 5 years. Subgroup analyses were performed to evaluate <strong>the</strong> association<br />
of HER3 with overall survival in different tumor types. Data were pooled using<br />
generic inverse variance and random-effect modeling.<br />
Results: Eleven studies were eligible for analysis. Median sample size was 126.<br />
Colorectal cancers were evaluated in three studies and gastric in two, while breast,<br />
melanoma, pancreas, ovary, head and neck and cervix cancers were assessed in one<br />
study respectively. The median percentage of cases with HER3 expression was 43%.<br />
HER3 expression was associated with worse OS at both 3 and 5 years (OR: 2.23; 95%<br />
confidence interval [CI], 1.74 to 2.86, p < 0.001 and OR: 2.25; 95% CI, 1.77 to 2.86,<br />
p < 0.001, respectively). Among studies with known HER2 over-expression (breast,<br />
gastric and ovary cancers), <strong>the</strong> magnitude of effect of HER3 on OS was significantly<br />
greater (3-years OS OR: 3.33, 95% CI, 2.30 to 4.83, p < 0.001 and 5-year OS OR:<br />
3.17, 95% CI, 2.23 to 4.49, p < 0.001).<br />
Conclusion: Expression of HER3 is associated with worse survival in solid tumors.<br />
The effect of HER3 may be greater in those tumors where HER2 is also<br />
over-expressed. A validated method for HER3 assessment is required, but <strong>the</strong><br />
potential clinical benefit from targeting HER3 appears favorable.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
232 NESTED CASE CONTROL STUDY OF PROTEOMIC<br />
BIOMARKERS FOR INTERSTITIAL LUNG DISEASE IN<br />
JAPANESE PATIENTS WITH NON-SMALL CELL LUNG CANCER<br />
TREATED WITH ERLOTINIB<br />
N. Katakami 1 , S. Atagi 2 , H. Yoshioka 3 , M. Fukuoka 4 , A. Ogiwara 5 , M. Imai 6 ,<br />
M. Ueda 7 , S. Matsui 8<br />
1 Division of Integrated Oncology, Institute of Biomedical Research & Innovation<br />
Hospital, Kobe, JAPAN, 2 Internal Medicine, National Hospital Organization<br />
Kinki-Chuo Chest Medical Center, Sakai, JAPAN, 3 Respiratory Internal Medicine,<br />
Kurashiki Central Hospital, Kurashiki, JAPAN, 4 Medical Oncology, Izumi<br />
Municipal HospitalCancer Center, Izumi City, JAPAN, 5 Research and<br />
Development, Medical ProteoScope Co., Ltd, Yokohama, JAPAN, 6 Primary<br />
Lifecycle Management, Chugai Pharmaceutical Co., Ltd, Tokyo, JAPAN, 7 Clinical<br />
Research Planning, Chugai Pharmaceutical Co., Ltd, Tokyo, JAPAN, 8 Data<br />
Science, The Institute of Statistical Ma<strong>the</strong>matics, Tachikawa, JAPAN<br />
Background: Interstitial lung disease (ILD) is a serious adverse drug reaction<br />
associated with EGFR tyrosine kinase inhibitors, but its risk factors are yet to be<br />
elucidated. We sought to identify <strong>the</strong> proteomic biomarkers associated with ILD in<br />
Japanese patients with non-small cell lung cancer treated with erlotinib, and to build<br />
predictive models for development of ILD using <strong>the</strong> proteomic biomarkers.<br />
Methods: We conducted a nested case control study. The cases were subjects in<br />
whom ILD developed within 120 days after <strong>the</strong> administration of erlotinib following<br />
enrolment in <strong>the</strong> cohort, and <strong>the</strong> controls were randomly selected from patients<br />
without ILD who were treated with erlotinib. For <strong>the</strong> proteomics analysis, albumin<br />
and IgG were removed from serum samples obtained before <strong>the</strong> first administration<br />
of erlotinib, <strong>the</strong>n <strong>the</strong> samples were digested with protease and <strong>the</strong> resultant peptide<br />
fragments were separated, identified and assayed by LC–MS/MS. Logistic regression<br />
analysis was used for <strong>the</strong> identification and examination of predictability for ILD.<br />
Results: A total of 645 patients were enrolled in <strong>the</strong> cohort, 15 cases and 64 controls<br />
were analysed. Logistic regression analysis was performed to identify <strong>the</strong> peptide<br />
peaks and proteins assossiated with ILD. When multiplicity was taken into account,<br />
we were unable to statistically verify any genuine association between individual<br />
markers and ILD. Investigation of <strong>the</strong> predictive power based on leave-one-out<br />
cross-validation showed that <strong>the</strong> area under <strong>the</strong> ROC curve was 0.73 at a maximum.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds391 | ix91
However, additional analysis suggested that three proteins (C3, C4A/C4B and<br />
APOA1) have a stronger association with ILD than <strong>the</strong> o<strong>the</strong>r proteins tested.<br />
Conclusions: We were unable to conclude from <strong>the</strong> results of this study that any<br />
promising serum protein markers for predicting ILD had been identified. However,<br />
C3, C4A/C4B and APOA1 were suggested to be worth fur<strong>the</strong>r investigation.<br />
Disclosure: N. Katakami: corporate-sponsored research (Chugai Pharmaceutical<br />
Company). S. Atagi: corporate-sponsored research (Chugai Pharmaceutical Company).<br />
H. Yoshioka: corporate-sponsored research (Chugai Pharmaceutical Company). M.<br />
Fukuoka: o<strong>the</strong>r substantive relationships (Chugai, Astra Zeneca). A. Ogiwara:<br />
corporate-sponsored research (Chugai, Astra Zeneka). M. Imai: M Imai is employee of<br />
Chugai Pharmaceutical Co., Ltd. M. Ueda: M Ueda is employee of Chugai<br />
Pharmaceutical Co., Ltd. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
233 PSF3 IS A NOVEL PROGNOSTIC BIOMARKER IN LUNG<br />
ADENOCARCINOMA<br />
D. Hokka, Y. Maniwa, S. Tane, S. Tauchi, W. Nishio, M. Yoshimura<br />
Divisions of Thoracic Surgery, Department of Surgery, Kobe University Graduate<br />
School of Medicine, Kobe, JAPAN<br />
Background: PSF3 is a member of <strong>the</strong> highly evolutionarily conserved tetrameric<br />
complex termed GINS, composed of SLD5, PSF1, PSF2, and PSF3. Previous studies<br />
suggested that some GINS complex members are upregulated in cancer, but PSF3<br />
expression in lung adenocarcinoma has not been investigated. The objective of <strong>the</strong><br />
current study was to elucidate <strong>the</strong> role of PSF3 in lung adenocarcinoma by<br />
investigating clinical samples.<br />
Methods: We investigated <strong>the</strong> expression of PSF3 in cancer epi<strong>the</strong>lial cells<br />
immunohistochemically in 125 consecutive resected cases of lung adenocarcinoma.<br />
Results: Increased PSF3 expression was observed in 27 (21.6%) of <strong>the</strong> 125 cases.<br />
PSF3 expression was found to be correlated significantly with some<br />
clinicopathological factors. A univariate analysis and log–rank test indicated a<br />
significant association between PSF3 expression and lower overall survival rate (P =<br />
0.0001 and P < 0.0001, respectively). A multivariate analysis also indicated a<br />
statistically significant association between increased PSF3 expression and lower<br />
overall survival rate (hazard ratio, 5.2; P = 0.0027). In a subgroup analysis of only<br />
stage I patients, increased PSF3 expression was also significantly associated with a<br />
lower overall survival rate (P = 0.0008, log–rank test). Moreover, <strong>the</strong> Ki67 index level<br />
was higher in <strong>the</strong> PSF3- positive group than in <strong>the</strong> negative group (P < 0.0001,<br />
Mann–Whitney U-test).<br />
Conclusion: The current results indicated that PSF3 is a novel prognostic biomarker<br />
in lung adenocarcinoma.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
234 MUTATIONS IN THE EPIDERMAL GROWTH FACTOR<br />
RECEPTOR GENE IN NON-SMALL-CELL LUNG CANCER<br />
PATIENTS AND EGFR SERUM LEVELS<br />
E.Y. Romero-Ventosa 1 , M. Rodríguez Rodríguez 1 , S. Gonzalez Costas 1 ,<br />
A. GonzÁlez-PiÑeiro 2 , S. Blanco-Prieto 3 , M. Páez de La Cadena 3 ,I.<br />
Arias Santos 1 , B. Leboreiro Enriquez 1 , B. Bernardez Ferran 4 , E. Brozos 5<br />
1 Farmacia Hospitalaria, Complejo Hospitalario Universitario de Vigo<br />
(CHUVI)-Hospital Xeral-Cíes, Vigo, SPAIN, 2 Pathological Anatomy, Complejo<br />
Hospitalario Universitario de Vigo (CHUVI)-Hospital Xeral-Cíes, Vigo, SPAIN,<br />
3 Bioquímica, Genética E Inmunología, Universidad de Vigo, Vigo, SPAIN,<br />
4 Farmacia Hospitalaria, Complejo Hospitalario Universitario de Santiago (CHUS),<br />
Santiago, SPAIN, 5 Dept. of Medical Oncology, Complejo Hospitalario<br />
Universitario de Santiagode Compostela Sergas, Santiago de Compostela,<br />
SPAIN<br />
Background: Determine <strong>the</strong> existing mutations in <strong>the</strong> epidermal growth factor<br />
receptor (EGFR) gene in non-small-cell lung cancer (NSCLC) patients and correlate<br />
with survival. Also pretreatment EGFR serum levels were quantified and analyzed if<br />
<strong>the</strong>re were differences between patients with or without mutations.<br />
Methods: From July 09 and July 11 serum samples were collected before starting<br />
erlotinib. Serum levels of EGFR were quantified using an ELISA. Patients were<br />
examined for mutations in tissue by EGFR Mutation Test Kit cobas. SPSS was used<br />
to calculate overall survival (OS) and progression-free survival (PFS). Mann-Whitney<br />
U test was used for comparison of EGFR serum level.<br />
Results: 58 patients were studied but we obtained information of mutations in 34<br />
patients. All variants were found in exons 18, 19 and 21 of EGFR. No mutation<br />
was found in exon 20, only two polymorphisms. Of 32 patients analyzed, we<br />
detected a total of 11 mutations (34.4%). In exon 19 we found 8 mutations<br />
(del19) and affected 8 patients (72.7% mutations). In exon 21 we found two<br />
mutations (L858R and L861Q), each in 1 patient (18.2% mutations). In exon 18,<br />
G719X mutation was found in 1 patient (9.1% mutations). The remaining patients<br />
(65.6%) were wild type. Patients wild type have a median OS of 5.4 months (95%<br />
CI, 4.2 - 6.6) and mutated patients 12.6 months (95% CI, 4.7- 21.1); p = 0.033. In<br />
terms of PFS, wild type patients have a median PFS of 2.8 months (95% CI: 2.0 -<br />
3.6) and mutated 8.6 months (95% CI 2.0 - 15.1); p = 0.012. We determined<br />
Annals of Oncology<br />
serum levels of EGFR in 44 patients with a mean of 57.5 ng/mL. Of <strong>the</strong>se<br />
patients, 21 were wild type, 7 were mutated and 16 showed an unknown<br />
mutational status. In wild type patients, <strong>the</strong> mean serum levels of EGFR was 57.8<br />
ng/mL and in <strong>the</strong> mutant was 62.3 ng/mL.<br />
Conclusion: Patients with EGFR gene mutation have a higher OS and PFS. No<br />
differences were found in EGFR serum levels prior to erlotinib treatment between<br />
wild type and mutated patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
235 CORRELATION OF C609T POLYMORPHISM OF NADPH<br />
QUINONE OXIDOREDUCTASE 1 AND HEMATOLOGICAL<br />
TOXICITIES IN LUNG CANCER PATIENTS TREATED WITH<br />
AMRUBICIN<br />
M. Nagata 1 , T. Kimura 1 , T. Suzumura 1 , S. Kudoh 1 , K. Umekawa 1 , Y. Kira 2 ,<br />
K. Matsuura 1 , T. Nakai 1 , S. Mitsuoka 1 , K. Hirata 1<br />
1 Respiratory Medicine, Osaka City University, Osaka, JAPAN, 2 Department of<br />
Central Laboratory, Osaka City University, Osaka, JAPAN<br />
Background: Amrubicin hydrochloride (AMR) is a novel syn<strong>the</strong>tic<br />
aminoanthracycline derivative, that is metabolically activated to amrubicinol<br />
(AMR-OH) by carbonyl reductase. The cytotoxic activity of AMR-OH is promising<br />
for small cell lung cancer and considered as a key agent. NADPH Quinone<br />
Oxidoreductase 1 (NQO1) is a cytosolic flavoprotein that metabolizes <strong>the</strong> quinone<br />
structures contained in both AMR and AMR-OH. NQO1 expression genotyped<br />
homozygous for minor alleles (T/T) was low compared with homozygous for major<br />
alleles (C/C) or heterozygous (C/T). We hypo<strong>the</strong>sized that NQO1 C609T<br />
polymorphisms may relate to <strong>the</strong> AMR pharmacokinetics and clinical outcomes.<br />
Methods: The patients with lung cancer received AMR at a dose of 30 or 40mg/m 2 /<br />
day on day 1-3 at Osaka City University Hospital were enrolled. Plasma sampling<br />
was performed at <strong>the</strong> time points of 24h after <strong>the</strong> third AMR injection. The<br />
concentrations of AMR and AMR-OH were determined by HPLC method. NQO1<br />
C609T polymorphism was assayed using real-time polymerase chain reaction<br />
methods.<br />
Results: A total of 35 patients were enrolled. The C/C, C/T, and T/T were observed<br />
in 12 (34.3%), 16 (45.7%), and 7 (20%) patients, respectively. A dose of 30 mg/m 2<br />
was administered to 19 patients, and 40mg/m 2 was administered to 16 patients. The<br />
mean plasma concentrations of AMR-OH on day4 at a dose of 30mg/m 2 and 40mg/<br />
m 2 were 11.02 ± 3.83 and 16.18 ± 6.17 ng/ml, respectively (p = 0.005). In patients<br />
with AMR at a dose of 40mg/m 2 , <strong>the</strong> plasma concentrations of AMR-OH on day4<br />
exhibited a tendency toward a relationship with NQO1 genotypes with values of C/C<br />
20.5 ± 5.89, C/T 15.9 ± 5.43, and T/T 11.2 ± 4.47ng/ml (p = 0.066). The C/C was<br />
related to decrease changes in WBC, hemoglobin, and platelet counts (p = 0.01, p =<br />
0.03, and p = 0.0005, respectively). No significant correlations were observed between<br />
NQO1 genotypes and clinical outcomes at a dose of 30mg/m 2 .<br />
Conclusions: NQO1 C609T polymorphism had a tendency of correlation with <strong>the</strong><br />
plasma concentrations of AMR-OH, and <strong>the</strong>reby had significant correlations with<br />
hematologic toxicities. NQO1 genotype appears to be <strong>the</strong> candidate biomarker of<br />
hematological toxicities of AMR treatment at a dose of 40mg/m 2 .<br />
Disclosure: All authors have declared no conflicts of interest.<br />
236 POLYCYSTINS 1 AND 2 AS NOVEL PROGNOSTIC MARKERS<br />
IN COLORECTAL CANCER<br />
A.N. Gargalionis 1 , G. Dalagiorgou 1 , P. Korkolopoulou 2 , C. Piperi 1 , G. Levidou 2 ,<br />
C. Adamopoulos 1 , A. Zizi-Sermpetzoglou 3 , N. Tsavaris 4 , E.K. Basdra 1 ,A.<br />
G. Papavassiliou 1<br />
1 Department of Biological Chemistry, University of A<strong>the</strong>ns, School of Medicine,<br />
A<strong>the</strong>ns, GREECE, 2 First Department of Pathology, Laikon General Hospital,<br />
University of A<strong>the</strong>ns, School of Medicine, A<strong>the</strong>ns, GREECE, 3 Department of<br />
Pathology, Tzaneio General Hospital, Piraeus, GREECE, 4 Oncology Unit,<br />
Department of Pathophysiology, Laikon General Hospital, University of A<strong>the</strong>ns,<br />
School of Medicine, A<strong>the</strong>ns, GREECE<br />
Background/purpose: Polycystins 1 and 2 (PC-1 and PC-2) constitute a family of<br />
cellular proteins detected in a variety of epi<strong>the</strong>lial cells throughout human tissues.<br />
They function as mechanosensors and contribute to cellular homeostasis through<br />
proliferation, differentiation and apoptotic processes. Never<strong>the</strong>less, <strong>the</strong>ir fundamental<br />
role in cell-to-cell mechanical interactions, cell–matrix communication, tissue<br />
morphogenesis and planar cell polarity connote <strong>the</strong>ir engagement in processes of<br />
oncogenesis, including invasion and metastasis. The aim of <strong>the</strong> study was to<br />
investigate <strong>the</strong> expression of PC-1 and PC-2 in colorectal cancer (CRC), identify<br />
possible correlations with histopathological characteristics and explore <strong>the</strong><br />
underpinning signal transduction mechanisms.<br />
Methods: The immunohistochemical expression of PC-1 and PC-2 was evaluated in<br />
paraffin sections of 144 CRC patients and <strong>the</strong> results were statistically correlated with<br />
clinical and pathologic parameters. Molecular mechanisms were explored by Western<br />
blot, immunofluorescence and flow cytometry in SW480 CRC cell line expressing<br />
PC-1 and PC-2.<br />
ix92 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Results: Significantly elevated cytoplasmic expression was observed for PC-1 and PC-2<br />
in mucinous carcinomas (p = 0.0035 and p = 0.0001, respectively). High expression<br />
levels of PC-2 were correlated with advanced TNM stage (p = 0.0324) and depth of<br />
tumour invasion (p = 0.0311). High expression levels of PC-1 (p = 0.0078) and altered<br />
expression levels of PC-2 in <strong>the</strong> transition zone from normal to cancerous tissue (p =<br />
0.0198) were associated with reduced five-year survival rate. Altered expression of PC-1<br />
in <strong>the</strong> transition zone was correlated with higher chance of relapse for <strong>the</strong> patients (p =<br />
0.0019). Experiments in SW480 cells revealed funneling of PC-1 and PC-2 function via<br />
mammalian target of rapamycin (mTOR) and p70S6 kinases.<br />
Conclusions: Our findings suggest that PC-1 and PC-2 are implicated in <strong>the</strong><br />
development of an aggressive phenotype in CRC, as well as in reduced five-year<br />
survival rate and cancer-free survival, thus constituting potential prognostic markers.<br />
Their function seems to be partially mediated by key molecules of <strong>the</strong> mTOR<br />
signaling pathway.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
237 IMPACT OF FCGR2A AND FCGR3A POLYMORPHISMS ON THE<br />
CLINICAL OUTCOME OF PATIENTS WITH METASTATIC<br />
COLORECTAL CANCER TREATED WITH CETUXIMAB AND<br />
FOLFIRI AS 2ND-LINE THERAPY<br />
I. Yuka 1 , S. Hazama 1 , N. Okayama 2 , Y. Hinoda 2 , H. Mishima 3 , J. Sakamoto 4 ,<br />
Y. Miyake 5 , S. Iwamoto 6 , F. Goda 7 , M. Oka 1<br />
1 Department of Digestive Surgery and Surgical Oncol, Yamaguchi University<br />
Graduate School of Medicine, Ube, JAPAN, 2 Department of Oncology and<br />
Laboratory Medicine, Yamaguchi of University Graduate School of Medicine,<br />
Ube, JAPAN, 3 Surgery, National Osaka Medical Center, Osaka, JAPAN, 4 Young<br />
Leaders Program, Nagoya University, Nagoya, JAPAN, 5 Department of Surgery,<br />
Minoh City Hospital, Minoh, JAPAN, 6 Department of Surgery, Hirakata Hospital,<br />
Kansai Medical University, Hirakata, JAPAN, 7 Department of Gastroenterological<br />
Surgery, Kagawa University, Kida, JAPAN<br />
Background: Cetuximab, a chimeric IgG1 anti- EGFR monoclonal antibody shows<br />
activity in mCRC, mainly in wild-type KRAS tumors. Recent studies demonstrate<br />
antibody-dependent cell-mediated cytotoxicity (ADCC) is one of <strong>the</strong> modes of action<br />
for cetuximab. Fragment c gamma receptors (FcGR) play an important role in<br />
initiating ADCC. We investigated <strong>the</strong> association of FcGR polymorphisms with <strong>the</strong><br />
outcome of KRAS-wild type mCRC pts treated with cetuximab and FOLFIRI as 2 nd<br />
line <strong>the</strong>rapy (FLIER study).<br />
Patients and methods: 60 mCRC pts were enrolled onto <strong>the</strong> FLIER study, and 56<br />
pts were finally analyzed. Tumor tissues from 56 pts were screened, BRAF and PI3K<br />
mutations using direct sequencing and were screened genotype for FcGR2a (H131R)<br />
and FcGR3a (V158F) polymorphisms by Taqman assay. The association of each<br />
FcGR polymorphism with response rate (RR) and progression free survival (PFS)<br />
were analyzed.<br />
Results: The RR of 56 pts was 33.9%. No patient was response to <strong>the</strong> regimen with<br />
mutated BRAF and PI3K. A statistically significant difference was observed for PFS for F<br />
carriers to 158V/V pts (286 vs 154 days; P = 0.047, Kaplan-Meier curves). The difference<br />
was more significant among pts without mutation of BRAF or PI3K (301 vs 185 days; P<br />
= 0.016). The relationship between RR and polymorphisms was as follows, FcGR2a<br />
(HH: 10/35, HR: 6/15, RR: 3/6), FcGR3a (FF: 15/37, FV3/14, VV1/5). There was no<br />
relationship between each polymorphisms and RR (Chi-square test).<br />
Conclusion: In our analysis, mutations such as BRAF and PI3K were also important<br />
biomarkers of cetuximab. Fur<strong>the</strong>rmore, our date suggest that <strong>the</strong> FcGR3a<br />
polymorphisms may be also useful molecular markers to predict clinical outcome in<br />
mCRC pts treated with cetuximab. We will be able to select super-responders to<br />
cetuximab in combination with <strong>the</strong>se mutations and FcGR3a polymorphisms.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
238 TUMOR RESPONSE AND SURVIVAL IN PATIENTS WITH<br />
ADVANCED GASTRIC CANCER: THE PREDICTIVE VALUE OF<br />
CHEMOTHERAPY-INDUCED CHANGES IN FIBRINOGEN<br />
X. Qu, S. Zheng, Y. Teng, J. Zhang, Y. Luo, J. Wang, L. Zhao, X. Li, Y. Chen,<br />
Y. Liu<br />
Medical Oncology, The First Hospital of China Medical University, Shenyang,<br />
CHINA<br />
Purposes: Hyperfibrinogenemia in various carcinomas has previously been<br />
described. But, in advanced gastric cancer, whe<strong>the</strong>r or not chemo<strong>the</strong>rapy-induced<br />
changes in fibrinogen level relate to chemo<strong>the</strong>rapeutic response and prognosis<br />
remains unclear. The purposes of this study were: 1) to analyze <strong>the</strong> correlation<br />
between <strong>the</strong> chemo<strong>the</strong>rapy-induced changes of plasma fibrinogen level and <strong>the</strong><br />
chemo<strong>the</strong>rapeutic response after <strong>the</strong> first two courses of standard first-line<br />
chemo<strong>the</strong>rapy; and 2) to evaluate <strong>the</strong> prognostic significance of <strong>the</strong> change of plasma<br />
fibrinogen level in patients with advanced gastric cancer.<br />
Methods: In this retrospective study, <strong>the</strong> data of 84 patients with advanced gastric<br />
cancer were collected. After a median follow-up time of 280 days<br />
(range,58-1992days) 65patients had died by <strong>the</strong> cutoff day.The association between<br />
<strong>the</strong> pre-and post-chemo<strong>the</strong>rapy fibrinogen levels and patient clinic characteristics, or<br />
<strong>the</strong> association between <strong>the</strong> changes in fibrinogen and <strong>the</strong> response to chemo<strong>the</strong>rapy,<br />
were analyzed using SPSS software. Fur<strong>the</strong>rmore, <strong>the</strong> prognostic value of <strong>the</strong> change<br />
of fibrinogen levels was assessed.<br />
Results: The median pre-chemo<strong>the</strong>rapy plasma fibrinogen levels were 4.55g/L.<br />
Pre-chemo<strong>the</strong>rapy plasma fibrinogen levels correlated significantly with <strong>the</strong> age(p =<br />
0.017).There is a significant link between <strong>the</strong> decrease in fibrinogen level and partial<br />
response (PR; p = 0.000) and stable disease (SD; p = 0.015). But <strong>the</strong>re is not similar<br />
decrease in progressive disease (PD; p = 0.851). If <strong>the</strong> decrease is more than10%, we<br />
get longer overall survival (OS; p = 0.03).<br />
Conclusions: This study showed that <strong>the</strong> reduction in plasma fibrinogen levels<br />
induced by chemo<strong>the</strong>rapy might be a promising biomarker for evaluating <strong>the</strong> efficacy<br />
of chemo<strong>the</strong>rapy in advance gastric cancer. In addition, <strong>the</strong> change of plasma<br />
fibrinogen levels could be used as a prognostic parameter for <strong>the</strong> overall survival of<br />
patients with advanced gastric cancer. Relationship between <strong>the</strong> decrease fibrinogen<br />
level and chemo<strong>the</strong>rapeutic response.<br />
group N pre-chemo<strong>the</strong>rapy post-chemo<strong>the</strong>rapy P value<br />
Total 84 4.55 ± 1.25 4.02 ± 1.38 0.001<br />
DCR 72 4.45 ± 1.27 3.90 ± 1.14 0.000<br />
PR 14 4.88 ± 1.29 3.37 ± 0.71 0.000<br />
SD 58 4.41 ± 1.25 4.03 ± 1.19 0.015<br />
PD 12 4.83 ± 1.18 4.72 ± 2.32 0.851<br />
Disclosure: All authors have declared no conflicts of interest.<br />
239 IMMUNODIAGNOSTIC ASSAY FOR DETECTING URINARY<br />
NUCLEAR MATRIX PROTEIN 52 IN PATIENTS WITH BLADDER<br />
CANCER<br />
H.A. Abdel Latif 1 , H. El-Hadaad 2<br />
1 Histolooy and Cell Biology, Mansoura University, Faculty of Medicine, Mansoura,<br />
EGYPT, 2 Clinical Oncology, Mansoura University Hospital School of Medicine,<br />
Mansoura, EGYPT<br />
Objective: To report <strong>the</strong> rapid and simple detection of a nuclear matrix protein<br />
(NMP) in <strong>the</strong> urine of patients with bladder cancer using dot-enzyme-linked<br />
immunosorbent assay (ELISA).<br />
Patients and methods: Urine sample from 120 patients with bladder cancer and 60<br />
controls were evaluated using western blot and specific immunoglobulin G antibody<br />
to identify <strong>the</strong> urinary NMP marker using <strong>the</strong> developed dot-ELISA. The initial<br />
response and follow up of 82 patients treated by irradiation were followed using<br />
<strong>the</strong> assay.<br />
Results: The NMP marker was identified in <strong>the</strong> urine of patients with cancer<br />
bladder at 52 KDa (NMP-52) by Western blot. The dot-ELISA detected <strong>the</strong><br />
urinary NMP-52 marker in 85% of patients with squamous cell carcinoma and<br />
92% with transitional cell carcinoma. The positive and negative predictive values<br />
(95% and 91% respectively) and efficiency (92%) of <strong>the</strong> dot-ELISA were high.<br />
NMP-52 tumor marker detection was correlated with <strong>the</strong> response to<br />
radio<strong>the</strong>rapy.<br />
Conclusion: Detection of <strong>the</strong> urinary NMP-52 marker using dot-ELISA would be<br />
helpful in rapid diagnosis and follow up patients with bladder cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
240 MCM AS A USEFUL BIOMARKER FOR GRADED<br />
DIFFERENTIATION IN UROTHELIAL CANCER<br />
N. Narine 1 , D.N. Rana 1 , G. Stewart 2 , B.M. Thottakam 3 , A. Donnini 3 , A. Wilson 4 ,<br />
B. Turner 5 , W. Burrill 6 , K. Saeb-Parsy 7 , D. Harrison 8<br />
1 Cytology Department, Central Manchester Hospitals NHS Foundation,<br />
Manchester, UNITED KINGDOM, 2 Department of Urology and Edinburgh<br />
Urological Cancer Group, Western General Hospital, Edinburgh, UNITED<br />
KINGDOM, 3 Research and Development, Cytosystems Ltd, Aberdeen, UNITED<br />
KINGDOM, 4 Department of Computing, Robert Gordon University, Aberdeen,<br />
UNITED KINGDOM, 5 Department of Urology, Homerton University Hospital NHS<br />
Foundation Trust, London, UNITED KINGDOM, 6 University of Bradford, Ethical<br />
Tissue, Bradford, UNITED KINGDOM, 7 Department of Urology, Addenbrooke’s<br />
Hospital, Cambridge, UNITED KINGDOM, 8 Director of Laboratory Medicine, Nhs<br />
Lothian, Royal Infirmary of Edinburgh, Edinburgh, UNITED KINGDOM<br />
Introduction: Urine cytology has been used in <strong>the</strong> diagnosis of uro<strong>the</strong>lial cancer<br />
(UC) for high grade and in-situ lesions. Sensitivity for low grade carcinoma is<br />
problematic leading to both over and under diagnoses. To reduce this dilemma a<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds391 | ix93
number of biomarkers have been tried with varying results. Minichromsome<br />
Maintenance Proteins (MCMs) play a regulatory role in eukaryotic DNA<br />
replication and are expressed as normal cells progress from G0 into G1/S phase<br />
of <strong>the</strong> cell cycle. Over expression has been demonstrated in neoplasia in many<br />
sites including uro<strong>the</strong>lium. The aim of <strong>the</strong> study was to evaluate use of MCM2<br />
in urine cytology and tissue specimens to differentiate high grade from low<br />
grade UC.<br />
Methods: epi<strong>the</strong>lial cells retrieved from urine samples of 114 patients were stained<br />
with MCM2 using an immunocytochemical technique. MCM2 was similarly applied<br />
to 13 archived uro<strong>the</strong>lial tumour specimens. MCM positive cell counts were<br />
performed on all cytology specimens and results correlated to <strong>the</strong> different grades of<br />
UC. Tumor specimens were evaluated for MCM2 staining intensity, distribution and<br />
percentage of positive cells.<br />
Results: 26 of 114 patients were found to have UC. In cytology specimens <strong>the</strong><br />
MCM mean and median cell counts increased with grade of cancer (Table 1).<br />
Non cancerous urines had mean and median MCMs of 232 and 14<br />
respectively. In uro<strong>the</strong>lial solid tissue tumour specimens, MCM2 showed<br />
strong nuclear staining characteristics where <strong>the</strong> percentage of positive cells<br />
was related to tumor grade. The lowest percentage MCM stained cells was<br />
noted in grade 1 tumours, <strong>the</strong> highest percentage in grade 3. Staining<br />
distribution was predominantly in <strong>the</strong> basal zone of <strong>the</strong> uro<strong>the</strong>lium in grade 1<br />
tumours, basal and middle epi<strong>the</strong>lial zones in grade 2, and more diffusely<br />
distributed in grade 3 tumours. Table 1: MCM cell count with increasing grade<br />
of uro<strong>the</strong>lial cancer.<br />
Grade<br />
Number<br />
of cases Mean<br />
Standard<br />
Deviation Median<br />
G1 3 3207 5026 600<br />
G2 9 8177 15975 3000<br />
G3 13 14795 14167 10000<br />
CIS 1 40000 - 40000<br />
Total 26<br />
Conclusion: MCM2 could be a useful biomarker in differentiating low grade from<br />
high grade UC both in cytology and biopsy tissue specimens.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
242 GENERATION OF A SOMATIC MUTATIONS BRAF<br />
IN MELANOMA DATABASE (WWW.<br />
SOMATICMUTATIONS-BRAFMELANOMA.NET)<br />
H. Linardou 1 , S. Murray 2 , F. Siannis 3 , D. Bafaloukos 1<br />
1 1st Department of Medical Oncology, Metropolitan Hospital, A<strong>the</strong>ns, GREECE,<br />
2 Oncology, GeneKor SA, A<strong>the</strong>ns, GREECE, 3 Department of Ma<strong>the</strong>matics,<br />
University of A<strong>the</strong>ns, A<strong>the</strong>ns, GREECE<br />
Background: Somatic mutations of BRAF are correlated with improved outcomes in<br />
patients with melanoma treated with <strong>the</strong> anti-BRAF tyrosine kinase inhibitor<br />
Vemurafenib. The frequency and spectrum of <strong>the</strong>se mutations is currently not well<br />
classified within melanoma or amongst melanocytic lesions. A systematic<br />
compendium of BRAF mutations in human tumors may better clarify issues related<br />
to incidence and spectrum.<br />
Methods: Using a broad search string including “BRAF”, “RAS”, “Melanoma”,<br />
“Cancer” and associated synonyms we identified 3,879 abstracts from inception<br />
through to 23/12/2011 in MEDLINE (PubMed). Sub-searches for Melanoma or<br />
melanocytic lesions (naevi) identified 175 articles. Data extraction was conducted<br />
by two investigators. Fields included: incidence, melanoma subtype, AJCC stage,<br />
gender, sun exposure, site, Breslow status amongst o<strong>the</strong>rs split by mutational<br />
status.<br />
Results: With a total of 14,019 screened patients, 5,606 were identified to harbor<br />
a mutation (40.0%). Cumulative data indicated that <strong>the</strong>re were no significant<br />
differences according to gender (55.2% male, 57.8% female), ulceration (46.4%<br />
with, 44.6% without), stage (46.6% I, 52.7% IV), metastatic and primary<br />
cutaneous melanoma (39.7% vs 41.1%). Differences in incidence were seen<br />
between sun exposure (36.2% exposed, 44.8% non-), site [except ocular/ uveal]<br />
(10.5% mucosal, 44.6% o<strong>the</strong>r) and between benign and Spitz nevi (52.5%<br />
versus 5.5%).<br />
Conclusions: This compendium of datasets allows <strong>the</strong> investigation of several trends<br />
in melanoma and melanocytic lesions. Technical and intra-inter-tumor<br />
dis-concordance issues were highlighted. A comprehensive analysis of<br />
clinicopathological correlations will be presented.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
243 IMPACT OF PIK3CA MUTATIONS AND P95HER2 EXPRESSION<br />
ON THE OUTCOME OF HER2-POSITIVE METASTATIC BREAST<br />
CANCER PATIENTS TREATED WITH A TRASTUZUMAB-BASED<br />
THERAPY<br />
I. Stasi 1 , A. Fontana 2 , G. Allegrini 3 , C. Mazzanti 4 , S. Lucchesi 5 , E. Bona 2 ,<br />
I. Ferrarini 2 , B. Salvadori 2 , A. Falcone 6 , K. Zavaglia 4<br />
1 Medical Oncology, Azienda Ospedaliero Universitaria S.Chiara, Pisa, ITALY,<br />
2 Oncologia Medica Ii, Polo Oncologico, Ospedale S. Chiara, AOUP, Pisa, ITALY,<br />
3 Medical Oncology Unit, Pontedera Hospital, Pontedera, ITALY, 4 University of<br />
Pisa and Pisa University Hospital, Section of Molecular Pathology, Division of<br />
Surgical, Molecular, and Ultrastructural Pathology, pisa, ITALY, 5 Oncologia<br />
Medica, Ospedale "F. Lotti", Pontedera, ITALY, 6 Oncologia, Trapianti E Nuove<br />
Tecnologie In Medicina, Polo Oncologico - Azienda Ospedaliero-Universitaria<br />
Pisana - Istituto Toscano Tumori, Pisa, ITALY<br />
Background: Currently, no biomarkers of Trastuzumab (T) clinical resistance have<br />
been validated. The aim of this pilot study was to evaluate <strong>the</strong> impact of PIK3CA<br />
mutations and p95HER2 (pHER2 truncated form) expression on <strong>the</strong> efficacy of a<br />
T based-<strong>the</strong>rapy in a HER2-positive metastatic breast cancer (MBC) patients (pts).<br />
Methods: 107 HER2-positive MBC pts, treated in <strong>the</strong> last 10 years, were evaluated.<br />
Median age was 54 years (25-79); ECOG performance status was 0 in 56% of pts; all<br />
pts received several lines of treatment including T; biomarkers molecular analysis was<br />
performed in 70 tumor specimens. The IHC expression of p95HER2 was evaluated<br />
by a monoclonal antibody that specifically recognizes only <strong>the</strong> HER2 external<br />
domain; <strong>the</strong> HER2 integrity was defined by <strong>the</strong> presence of a homogeneous<br />
membrane staining (moderate or intense) in at least 30% of <strong>the</strong> cells, o<strong>the</strong>rwise <strong>the</strong><br />
HER2 was defined as p95HER2 positive. PIK3CA mutations in exons 9 and 20 were<br />
detected by automated sequencing. The molecular data were correlated to Time to<br />
progression (TTP) of <strong>the</strong> first line treatment including T and <strong>the</strong> Overall Survival<br />
(OS) by using <strong>the</strong> Kaplan-Meir method and <strong>the</strong> log-rank-test.<br />
Results: p95HER2 positive pts and PIK3CA mutations in exon 9 or 20 were detected<br />
in 42% and 22% of tumor specimens, respectively. p95HER2 positive tumors showed<br />
a shorter TTP and OS that did not reach statistical significance; PIK3CA mutations<br />
correlated with a worse TTP (median 7,6 vs 11,3 months) and OS (median 20,1 vs<br />
41,0 months, p= 0,046).<br />
Conclusions: These preliminary results suggest a possible role of PIK3CA mutational<br />
status in predicting <strong>the</strong> outcome of MBC pts treated with T.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
244 DETECTION OF CIRCULATING TUMOUR CELLS IN<br />
PERIPHERAL BLOOD OF PATIENTS WITH MALIGNANT<br />
PLEURAL MESOTHELIOMA<br />
J. Raphael 1 , C. Massard 2 ,F.Farace 3 , G. Le Teuff 4 , J. Margery 5 , F. Billiot 3 ,<br />
B. Besse 1 , A. Hollebecque 2 , J. Soria 1 , D. Planchard 1<br />
1 Thoracic Group, Inserm U981, Institut Gustave Roussy, Villejuif, FRANCE,<br />
2 Department of Medical Oncology, Institute Gustave Roussy, Villejuif, FRANCE,<br />
3 Laboratory of Translational Research, Institut Gustave Roussy, Villejuif, FRANCE,<br />
4 Department of Statistics and Epidemiology, Institut Gustave Roussy, Villejuif,<br />
FRANCE, 5 Pulmonary Department, Percy Hospital, Paris, FRANCE<br />
Background: The independent prognostic value of Circulating Tumour Cells (CTC)<br />
level has been demonstrated in patients with advanced breast, prostate and colorectal<br />
cancers. There is currently few data on Malignant Pleural Meso<strong>the</strong>lioma (MPM) and<br />
CTC. We investigated whe<strong>the</strong>r <strong>the</strong> presence of CTC was correlated with prognosis<br />
factors and treatment efficacy in MPM patients.<br />
Methods: Patients (pts) with MPM in progression were enrolled before any new line of<br />
treatment in a prospective monocentric study. CTC detection was made on peripheral<br />
blood samples (7.5ml) using <strong>the</strong> “CellSearch” assay according to <strong>the</strong> manufacturer’s<br />
protocol. The correlation between <strong>the</strong> presence of CTC and known worse prognosis<br />
factors was assessed using <strong>the</strong> X2 test. Progression Free Survival (PFS) was defined as <strong>the</strong><br />
time from diagnosis until first progression (PFS1) and as <strong>the</strong> time from CTC measure<br />
until progression or death (PFS2). Comparison of PFS according to CTC detection was<br />
performed using <strong>the</strong> log-rank test. The cut-off date of <strong>the</strong> analysis was May <strong>2012</strong>.<br />
Results: Twenty-five MPM pts with a median follow-up of 4.2 months were included.<br />
The median age and sex ratio (M/F) were 65 years old and 2.1 respectively. Eighty-four<br />
percent of pts had an epi<strong>the</strong>lioid MPM, 64% had a stage 4 disease, 60% had an anemia,<br />
a thrombocytosis or a leucocytosis at <strong>the</strong> time of inclusion. All pts except one had an<br />
Eastern Cooperative Oncology Group performance status (ECOG) < 2 and 64% received<br />
more than one line of chemo<strong>the</strong>rapy. CTC were detected in 48% of pts (n = 12) with a<br />
median level of 1.5 (0-36). No significant correlation was observed between <strong>the</strong> presence<br />
of CTC and a metastatic disease, an ECOG ≥ 1, <strong>the</strong> presence of anaemia, leucocytosis, or<br />
thrombocytosis and <strong>the</strong> non-epi<strong>the</strong>lioid type. The median PFS (1 and 2) were 17.9 (95%<br />
CI= [10.1-24.0]) and 2.5 (95%CI= [1.3-3.5]) months respectively. CTC detection was<br />
not a significant predictor of PFS 2 (p = 0.27).<br />
Conclusion: Detection of CTC has been done in a small cohort of MPM patients. It<br />
could be an important tool though we were not able to demonstrate a significant<br />
prognostic value or a difference in PFS between CTC levels. The "Cellsearch" assay<br />
might not be <strong>the</strong> best technique to use in this setting. Fur<strong>the</strong>r analyzes are in<br />
progress, and updated results will be presented in September.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix94 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
east cancer, early stage<br />
246O DOSE-DENSE SEQUENTIAL ADJUVANT CHEMOTHERAPY<br />
WITH EPIRUBICIN, PACLITAXEL AND CMF VERSUS<br />
EPIRUBICIN, CMF AND WEEKLY DOCETAXEL OR<br />
PACLITAXEL FOLLOWED BY TRASTUZUMAB FOR ONE YEAR<br />
IN PATIENTS WITH EARLY BREAST CANCER<br />
G. Fountzilas, H. Gogas, N. Pavlidis, A. Elef<strong>the</strong>raki, D. Skarlos, A. Koutras,<br />
E. Timo<strong>the</strong>adou, C. Papandreou, D. Pectasides, M. Dimopoulos<br />
Data Office, Hellenic Cooperative Oncology Group (HeCOG), A<strong>the</strong>ns, GREECE<br />
Background: Dose-dense sequential chemo<strong>the</strong>rapy including anthracyclines and<br />
taxanes has been well established in <strong>the</strong> adjuvant setting of high-risk operable breast<br />
cancer. However, <strong>the</strong> preferable taxane and optimal schedule of administration have<br />
not been defined, as yet.<br />
Patients and methods: From July 2005 until November 2008, 1,001 patients (990<br />
eligible) were randomized to receive 3 cycles of epirubicin 110 mg/m 2 followed by 3<br />
cycles of paclitaxel 200 mg/m 2 followed by 3 cycles of CMF (cyclophosphamide 840<br />
mg/m 2 ; methotrexate 57 mg/m 2 ; fluorouracil 840 mg/m 2 ) with G-CSF support<br />
(Group A; 333 patients) or to 3 cycles of epirubicin followed by 3 cycles of CMF, as<br />
in Group A, followed 3 weeks later by 9 weekly cycles of docetaxel 35 mg/m 2 (Group<br />
B; 331 patients) or 9 weekly cycles of paclitaxel 80 mg/m 2 (Group C; 328 patients).<br />
Radiation and hormonal <strong>the</strong>rapy were given after <strong>the</strong> completion of chemo<strong>the</strong>rapy.<br />
Trastuzumab was administered for 1 year to all HER2-positive patients post<br />
radiation.<br />
Results: At a median follow-up of 60 months, 123 patients had documented disease<br />
relapse (51 in Group A, 37 in Group B and 35 in Group C) and 81 deaths (30 in<br />
group A, 22 in group B and 29 in group C) had been observed. The 3-year<br />
disease-free survival (DFS) rate was 86%, 91% and 89%, with overall survival (OS)<br />
rates of 96%, 97% and 96%, respectively. No differences were found in DFS or OS<br />
between <strong>the</strong> three treatment groups (log-rank, p = 0.38 and p = 0.48, respectively).<br />
The most frequently reported severe adverse events were neutropenia (29% vs 27% vs<br />
24%, p = 0.31) and leucopenia (12% vs 13% vs 10%, p = 0.66). Febrile neutropenia<br />
occurred in fifty patients (6%, vs 5% vs 5%, p = 0.81). Severe mucositis was more<br />
frequent in Group B (3% vs 6% vs 1%, p = 0.001), while severe neuropathy was more<br />
frequent in Group A (4% vs 0% vs 1%, p < 0.001).<br />
Conclusions: No significant differences in DFS and OS between <strong>the</strong> three regimens<br />
were identified. Taxane regimen and schedule of administration preferentially<br />
influenced <strong>the</strong> type of severe toxicities. HER2-positive patients demonstrated<br />
comparable 3-year DFS and OS rates with those reported in o<strong>the</strong>r similar studies.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
247O PR THE DISCREPANCY BETWEEN HIGH PATHOLOGICAL<br />
COMPLETE RESPONSE (PCR) RATE AND LOW BREAST<br />
CONSERVING SURGERY (BCS) FOLLOWING<br />
NEOADJUVANT THERAPY: ANALYSIS FROM THE<br />
NEOALTTO TRIAL (BIG 1-06)<br />
C. Criscitiello1 , H.A. Azim, Jr2 , D. Agbor-Tarh3 , E. De Azambuja4 , M. Piccart5 ,<br />
J. Baselga6 , H. Eidtmann7 , S. Di Cosimo8 , I. Bradbury3 , I.T. Rubio9 1 2<br />
Department of Medicine, European Institute of Oncology, Milan, ITALY, Breast<br />
Cancer Translational Research Laboratory, Institute Jules Bordet, Brussels,<br />
BELGIUM, 3 Frontier Science, Frontier Science, Kincraig, UNITED KINGDOM,<br />
4 5<br />
Breast Data Centre, Institute Jules Bordet, Brussels, BELGIUM, Institut Jules<br />
Bordet, Institut Jules Bordet, Brussels, BELGIUM, 6 Hematology/Oncology, MGH<br />
Cancer Center, Massachusetts General Hospital, Boston, MA, UNITED STATES<br />
OF AMERICA, 7 Klinik für Gynäkologie und Geburtshilfe, Universitäts Frauenklinik<br />
Kiel, Kiel, GERMANY, 8 Medical Oncology, Istituto Nazionale Tumori, Milan, ITALY,<br />
9<br />
Department of Gynecology, Hospital Universitario Vall d’Hebron, Barcelona,<br />
SPAIN<br />
Background: The NeoALTTO trial showed that paclitaxel plus lapatinib and<br />
trastuzumab nearly doubles <strong>the</strong> rate of pCR compared to paclitaxel combined with<br />
ei<strong>the</strong>r drug alone (51.3% vs 29.5% vs 24.7%). However, this high pCR rate did not<br />
translate into a higher rate of BCS, which was around 40% across <strong>the</strong> 3 arms. We<br />
investigated different factors that may have affected <strong>the</strong> choice of surgery.<br />
Annals of Oncology 23 (Supplement 9): ix95–ix115, <strong>2012</strong><br />
doi:10.1093/annonc/mds392<br />
Patients and methods: In <strong>the</strong> NeoALTTO trial, patients (pts) with HER2+ breast<br />
cancer were randomized to ei<strong>the</strong>r trastuzumab, lapatinib or <strong>the</strong>ir combination<br />
concomitantly with paclitaxel prior to surgery. The 1 ry endpoint was pCR, defined as<br />
<strong>the</strong> absence of invasive cancer in <strong>the</strong> breast at <strong>the</strong> time of surgery. Here, we<br />
investigated <strong>the</strong> association between achieving pCR, and type of surgery, age,<br />
histology, grade, tumor size, ER status, multicentricity, response to <strong>the</strong>rapy and <strong>the</strong><br />
country where <strong>the</strong> treatment was given.<br />
Results: 429 pts were eligible for <strong>the</strong> analysis (26 have been excluded as <strong>the</strong>y did<br />
not undergo breast surgery), of whom 160 (37%) achieved a pCR. 242 (57%)<br />
and 187 (43%) pts had mastectomy and BCS, respectively. Mastectomy was more<br />
frequent if <strong>the</strong> patient was < 50, if treated in developing country, if <strong>the</strong> tumor<br />
was multicentric, >5 cm, or ER-. All pts diagnosed with lobular cancer (n = 17)<br />
underwent mastectomy regardless of pCR. 68 pts had a radiological complete<br />
response, yet 36 of those (53%) were subjected to mastectomy (25 pts (70%)<br />
achieved a pCR). Of <strong>the</strong> 128 pts considered for BCS at screening, only 95 (74%)<br />
had a conservative surgery and rates were similar according to pCR status (79%<br />
in pCR vs. 72% in no pCR). Conversely, 30% of pts initially evaluated as<br />
inoperable or requiring mastectomy had a BCS.<br />
Conclusion: Tumor characteristics prior to neoadjuvant <strong>the</strong>rapy appeared to play<br />
a main role in deciding <strong>the</strong> type of surgery irrespective of response. This may<br />
deny a large fraction of women <strong>the</strong> chance of preserving <strong>the</strong>ir breast. These<br />
results should be taken into account in addressing <strong>the</strong> criteria for BCS after<br />
neoadjuvant <strong>the</strong>rapy. GSK distributed <strong>the</strong> study drugs and provided financial<br />
support to <strong>the</strong> NeoALTTO trial, but imposed no restriction to <strong>the</strong> current<br />
analysis.<br />
Disclosure: E. De Azambuja: advisory board from GSK; honoraria from Roche.<br />
M. Piccart: Consulting/advisory role/honoraria from SanofiAventis, Amgen,<br />
Bayer, Bristol Myers Squibb, Roche, Glaxo Smith Kline, Boehringer, PharMar. S.<br />
Di Cosimo: Speaker for GSK. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
248O ANALYSIS OF CORRELATION BETWEEN WEIGHT AT<br />
DIAGNOSIS, WEIGHT GAIN AFTER BREAST CANCER<br />
TREATMENT AND RECURRENCE IN WOMEN WITH EARLY<br />
STAGE BREAST CANCER (EBC)<br />
P. Fedele 1 , A. Nacci 2 , A.M. Lapolla 1 , L. Orlando 1 , P. Schiavone 1 , A. Marino 1 ,<br />
M. Cinefra 1 , A. Ardizzone 1 , M. De Pasquale 1 , S. Cinieri 1<br />
1 Ospedale Perrino, Oncologia Brindisi, Brindisi, ITALY, 2 U.O.C. Oncologia,<br />
Ospedale A. Perrino, Brindisi, ITALY<br />
Background: Overweight at <strong>the</strong> time of EBC diagnosis has been linked frequently to<br />
poorer survival in most studies and some evidence suggests that women who gain<br />
weight after breast cancer diagnosis are at increased risk of cancer recurrence and<br />
death. Most previous studies on this topic have relied on retrospective chart reviews.<br />
The aim of this prospective, observational, single-center study is to determine<br />
whe<strong>the</strong>r weight at diagnosis and weight gain after EBC treatment are predictive of<br />
BC recurrence.<br />
Methods: From August 1997 to March <strong>2012</strong>, <strong>the</strong> study included a total of 520 EBC<br />
patients (stage I-IIIa). We assessed weight and body mass index (BMI = kg/m 2 )at<br />
baseline (≤ 1 month after surgery) and 24 months after completion of treatment<br />
(chemo<strong>the</strong>rapy ± radio<strong>the</strong>rapy). The chi square test (X 2 ) was conducted to determine<br />
if a significant correlation exists between BC recurrence and 3 categories of BMI at<br />
diagnosis (lean weight: BMI 25) and BC<br />
recurrence and weight changes after EBC treatment (loss of
Table: 248O<br />
249PD PROTEOMIC PREDICTORS OF OUTCOME AFTER ADJUVANT<br />
ANTI-HORMONAL THERAPY FOR HORMONE<br />
RECEPTOR-POSITIVE BREAST CANCER<br />
B. Hennessy1 , D. Faratian2 ,Z.Ju3 , A. Lluch-Hernandez4 , S. Myhre5 ,A.<br />
M. Gonzalez-Angulo6 , J. Overgaard7 , J. Alsner7 , A. Borresen-Dale5 , G.B. Mills8 1 2<br />
Medical Oncology, Beaumont Hospital, Dublin, IRELAND, Division of Pathology<br />
& Edinburgh Breakthrough Research Unit, University of Edinburgh, Edinburgh,<br />
UNITED KINGDOM, 3 Biostatistics and Applied Ma<strong>the</strong>matics, MD Anderson<br />
Cancer Center, Houston, TX, UNITED STATES OF AMERICA,<br />
4<br />
Serv. Hematologia Y Oncologia Medica, Hospital Clinico Universitario de<br />
Valencia, Valencia, SPAIN, 5 Department of Genetics, Institute for Cancer<br />
Research, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo,<br />
Norway, Oslo, NORWAY, 6 Breast Medical Oncology, MD Anderson Cancer<br />
Center, Houston, TX, UNITED STATES OF AMERICA, 7 Department of<br />
Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, DENMARK,<br />
8<br />
Systems Biology, MD Anderson Cancer Center, Houston, TX, UNITED STATES<br />
OF AMERICA<br />
Purpose: This study aimed to identify predictive proteomic biomarkers of outcome<br />
in women with estrogen and/or progesterone receptor-positive (ER/PR-positive)<br />
breast cancer after adjuvant tamoxifen, with sufficient power to alter patient<br />
management.<br />
Methods: Using reverse phase protein arrays (RPPA), 140 antibodies were applied to<br />
a training set of 197 ER/PR-positive breast cancers to identify predictors. An<br />
algorithm was developed that predicted patient outcomes using a subset of<br />
antibodies. Since RPPA is a useful exploratory tool but does not lend itself as a<br />
practical clinical tool to assay validated biomarkers, quantitative immunofluorescence<br />
for selected proteins was applied to 313 ER/PR-positive breast cancers (test set) for<br />
validation. Seventy-seven o<strong>the</strong>r ER/PR-positive cancers with transcriptional profiling<br />
data were used to compare <strong>the</strong> performance of <strong>the</strong> proteomic biomarkers and<br />
established genomic predictors. All patients were treated with adjuvant tamoxifen<br />
after loco-regional <strong>the</strong>rapy.<br />
Results: Two different combinations (4-protein/3-protein models) of four proteins<br />
(CCNB1/PAI1/PR/BCL2), subdivided lymph node-negative breast cancer patients<br />
into low-, medium- and high-risk groups with significantly different 10-year<br />
recurrence-free survival. The proteomic markers predicted 10-year distant<br />
metastasis-free survival in lymph node-negative patients in <strong>the</strong> test set in <strong>the</strong> low-,<br />
medium- and high-risk groups as follows: 0.9, 0.8, 0.7 (4-protein model (p = 0.05)),<br />
0.91, 0.8, 0.74 (3-protein model (p = 0.004)), with 74%/64% patients in <strong>the</strong> low-risk<br />
groups, respectively. The proteomic models outperformed clinical variables and<br />
genomic predictors in multivariate analyses.<br />
Conclusion: This study validates proteomic biomarkers that can be assayed in a<br />
practical inexpensive manner using immunofluorescence to identify lymph<br />
node-negative ER/PR-positive patients with excellent outcomes after adjuvant<br />
tamoxifen.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
250PD CLINICAL SIGNIFICANCE OF MICRORNA EXPRESSION AS A<br />
PROGNOSTIC FACTOR IN EARLY N+ BREAST CANCER (BC)<br />
E. Ciruelos 1 , G.A. De Velasco 1 , A. Gamez 2 , C. Castañeda 3 , J. Sepúlveda 1 ,<br />
I. Ghanem 1 , H. Cortes-Funes 1 , J.A. Fresno 4<br />
1 Medical Oncology, University Hospital 12 de Octubre, Madrid, SPAIN,<br />
2 Medicine, Autonoma University, Madrid, SPAIN, 3 Medical Oncology, Instituto de<br />
Enfermedades Neoplasicas, Lima, PERU, 4 Medical Oncology, University Hospital<br />
LaPaz, Madrid, SPAIN<br />
Background: MicroRNAs (miRNAs) are small noncoding RNA molecules that<br />
post-transcriptionally regulate gene expression. In <strong>the</strong> present study, we describe<br />
miRNA expression in early node-positive BC and identify a 8-miRNA score that<br />
could contribute to prognosis assessment.<br />
Methods: First, microarray analysis was performed using RNA samples extracted<br />
from primary breast cancer. The expression of miRNAs was analyzed by RT-qPCR<br />
using <strong>the</strong> TaqMan Arrays from Applied Biosystems. After a suitable normalization of<br />
<strong>the</strong> 677 miRNAs analyzed, 96 presented a good correlation between <strong>the</strong>ir expression<br />
Annals of Oncology<br />
Body Mass Index<br />
At diagnosis Changes after BC treatment<br />
30 kg/m 2<br />
Loss >1 kg/m 2<br />
Loss
Annals of Oncology<br />
252PD META-ANALYSIS OF PROSPECTIVE EUROPEAN STUDIES<br />
ASSESSING THE IMPACT OF USING THE 21-GENE<br />
RECURRENCE SCORE ASSAY ON CLINICAL DECISION<br />
MAKING IN WOMEN WITH ER-POSITIVE, HER2-NEGATIVE<br />
EARLY STAGE BREAST CANCER<br />
J. Albanell 1 , S. Holt 2 , J. Gligorov 3 , W. Eiermann 4 , C. Svedman 5<br />
1 Medical Oncology, University Hospital del Mar, Barcelona, SPAIN, 2 Surgical<br />
Department, Prince Philip Hospital, Llanelli, UNITED KINGDOM, 3 Medical<br />
Oncology Department, Tenon Hospital, Paris, FRANCE, 4 Medical,<br />
Interdisciplinary Oncology Center, Munich, GERMANY, 5 Medical, Genomic<br />
Health Inc, Redwood City, CA, UNITED STATES OF AMERICA<br />
Background: The Oncotype DX® Recurrence Score is a validated assay to help<br />
inform <strong>the</strong> appropriate treatment of estrogen receptor-positive (ER+), early stage<br />
breast cancer. Adjuvant treatment traditions vary significantly among different<br />
countries. Prospective studies assessing <strong>the</strong> impact of <strong>the</strong> Oncotype DX test on<br />
adjuvant treatment decisions have been performed in several European countries.<br />
This is a meta-analysis of <strong>the</strong>se studies.<br />
Methods: Four prospective studies assessing <strong>the</strong> impact of using <strong>the</strong> Recurrence<br />
Score result on clinical decision making in patients with node negative and pN1 (mi)<br />
disease were identified. Node positive patients were excluded. The identified studies<br />
had a similar study design with consecutive patients and treatment recommendations<br />
before and after having <strong>the</strong> Recurrence Score results were recorded. In three of <strong>the</strong><br />
studies, medical oncologists completed questionnaires regarding <strong>the</strong>ir confidence in<br />
<strong>the</strong>ir recommendation before and after knowing <strong>the</strong> patient’s Recurrence Score result.<br />
The final results of <strong>the</strong> studies in Germany, Spain and <strong>the</strong> UK have been presented<br />
and final data from <strong>the</strong> French study will be presented at ASCO <strong>2012</strong>.<br />
Results: A total of 589 patients with node negative or pN1 (mi) ER pos HER2<br />
negative early breast cancer were included in <strong>the</strong> four identified studies. Overall, 45%<br />
(range 36-52%) of patients in <strong>the</strong>se studies were recommended chemo-endocrine and<br />
55% endocrine treatment alone. After having <strong>the</strong> Recurrence Score result, 47% (range<br />
38-60%) of patients recommended chemo<strong>the</strong>rapy were changed to endocrine<br />
treatment alone and 17% (range 11-22%) of those recommended endocrine<br />
treatment alone were recommended chemo-endocrine treatment. There was a<br />
significant improvement in physician confidence in treatment recommendations<br />
when using <strong>the</strong> assay.<br />
Conclusion: Using Oncotype DX® is associated with a significant change in<br />
treatment decisions and a reduction in chemo<strong>the</strong>rapy use in studied European<br />
countries despite differences in <strong>the</strong>rapeutic traditions. The consistency of <strong>the</strong> results<br />
from different countries underlines <strong>the</strong> tests utility.<br />
Disclosure: J. Albanell: Participated advisory board (Genomic Health). S. Holt:<br />
Participated as a speaker, and in advisory board for Genomic Health. J. Gligorov:<br />
Has participated as speaker for Genomic Health. W. Eiermann: Participated as<br />
speaker and in advisory board for Genomic Health. C. Svedman: Employee and<br />
stocks in Genomic Health.<br />
253PD SECRAB (SEQUENCING OF CHEMOTHERAPY AND<br />
RADIOTHERAPY IN ADJUVANT BREAST CANCER)<br />
COSMESIS RESULTS<br />
I.N. Fernando 1 , S.J. Bowden 2 , C. Brookes 2 , A.M. Brunt 3 , M. Churn 4 ,<br />
J.H. Steven 1 , R.K. Agrawal 5 ,D.Rea 2<br />
1 Cancer Centre, University Hospitals Birmingham NHS Foundation Trust,<br />
Birmingham, UNITED KINGDOM, 2 CRCTU, School of Cancer Sciences,<br />
University of Birmigham, Birmingham, UNITED KINGDOM, 3 The Cancer Centre,<br />
University Hospital North Staffs, Stoke-on-Trent, UNITED KINGDOM, 4 Deansley<br />
Centre, New Cross Hospital, Wolverhampton, UNITED KINGDOM, 5 Department<br />
of Oncology, Shrewsbury and Telford Hospital NHS Trust, Shrewsbury, UNITED<br />
KINGDOM<br />
Background: SECRAB, a randomised trial comparing sequential (Seq) to<br />
synchronous (Syn) chemo-radiation using a CMF or Anthracycline-CMF regimen,<br />
demonstrates reduces local recurrence rates after Syn treatment for early breast<br />
cancer (EBC) (Fernando 2011 EJC:47 S2). Cosmesis study results are presented.<br />
Table: 253PD<br />
Cosmesis, n<br />
(%)<br />
Telangiectasia,<br />
n (%)<br />
Methods: 2296 women were randomised and cosmesis was assessed in 382. Cosmesis<br />
and telangiectasia were assessed as excellent, good, moderate and poor for patients<br />
having wide local excision (WLE) while telangiectasia alone was assessed for those<br />
having mastectomy. Photographs were taken for 301 patients for blinded<br />
independent review using a consensus method (Haviland 2008 Clin Oncol 20:497).<br />
Patient perception was assessed using EORTC BR23 quality of life questionnaire<br />
(Q 39-42). Assessments were made at baseline, 1, 2 and 5 years post surgery.<br />
Results: The results of clinician assessed cosmesis and telangiectasia are shown<br />
below. There was no statistically significant difference between <strong>the</strong> arms. Data on<br />
independent assessment of change in breast appearance after WLE was available for<br />
145 (98%) patients. Minimal, mild and marked changes were observed in 70, 29 and<br />
1% of patients respectively for <strong>the</strong> Syn arm and 72, 28 and 0% for <strong>the</strong> Seq arm.<br />
There was no difference between treatment arms (OR, mild/marked vs minimal, 1.10,<br />
95% CI 0.54-2.26, p = 0.8). There was no change in patient’s perception of <strong>the</strong>ir<br />
breast appearance (baseline vs. final assessment questionnaire).<br />
Conclusions: There was no significant difference in cosmesis or telangiectasia<br />
between <strong>the</strong> two arms as assessed by <strong>the</strong> clinician or by independent photographic<br />
review. There was no difference in patient perception of breast appearance. Contrary<br />
to <strong>the</strong> result of <strong>the</strong> main study, which showed a borderline significant worsening of<br />
telangiectasia in <strong>the</strong> Syn arm, no such difference was seen in <strong>the</strong> cosmesis study. Syn<br />
chemo-radiation reduces local recurrence in EBC without affecting cosmesis.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
254PD PATHOLOGICAL COMPLETE RESPONSE TO TRASTUZUMAB<br />
SUBCUTANEOUS FIXED-DOSE FORMULATION IN THE<br />
HANNAH STUDY: SUBGROUP ANALYSIS OF PATIENT<br />
DEMOGRAPHICS AND TUMOR CHARACTERISTICS AND<br />
INFLUENCE OF BODY WEIGHT (BW) AND SERUM TROUGH<br />
CONCENTRATION (CTROUGH) OF TRASTUZUMAB<br />
B. Melichar 1 , D. Stroyakovskiy 2 , J.S. Ahn 3 , M.V. Kopp 4 , V. Srimuninnimit 5 ,<br />
G. Kunz 6 ,J.Li 7 , T. van der Horst 8 , S. Muehlbauer 8 , C. Jackisch 9<br />
1 Oncology, University Hospital Olomouc Palacky University, Faculty of Medicine,<br />
Olomouc, CZECH REPUBLIC, 2 Chemo<strong>the</strong>rapy, Moscow City Oncology Hospital<br />
62, Moscow, RUSSIAN FEDERATION, 3 Haematology/Oncology, Samsung<br />
Medical Centre, Seoul, KOREA, 4 Chemo<strong>the</strong>rapy, Samara Regional Clinical<br />
Cancer Center, Samara, RUSSIAN FEDERATION, 5 Department of Medicine,<br />
Siriraj Hospital, Bangkok, THAILAND, 6 Oncology, St Johannes Hospital,<br />
Dortmund, GERMANY, 7 Clinical Pharmacology, Genentech Inc, South<br />
San Francisco, CA, UNITED STATES OF AMERICA, 8 Clinical Science,<br />
F. Hoffmann La-Roche Ltd, Basel, SWITZERLAND, 9 Oncology, Klinikum<br />
Offenbach GmbH, Offenbach, GERMANY<br />
Background: Intravenous (IV) trastuzumab (H) is <strong>the</strong> standard of care for<br />
HER2-positive breast cancer. The Phase III, neoadjuvant-adjuvant HannaH study<br />
(Jackisch et al. EBCC <strong>2012</strong>) demonstrated <strong>the</strong> non-inferiority of H subcutaneous<br />
(SC) vs. H-IV with respect to serum C trough of H and pathological complete response<br />
(pCR), with comparable safety profiles for <strong>the</strong> two formulations. The aim of <strong>the</strong><br />
presented analyses was to determine whe<strong>the</strong>r pCR rates (H-SC vs. H-IV) were<br />
consistent across subgroups, and to investigate <strong>the</strong> relationship of pCR with BW and<br />
serum Ctrough of H.<br />
Methods: Subgroup analyses of pCR were performed in <strong>the</strong> per-protocol population<br />
(PPP) based on patient demographics (race, age [< 65 and ≥ 65 years]) and disease<br />
characteristics (breast cancer type/subtype/histological grade, hormone receptor<br />
status). Fur<strong>the</strong>r analyses, including multiple logistic regression (MLR), investigated<br />
<strong>the</strong> relationship of pCR rate with BW and serum C trough of H. Covariates in <strong>the</strong> MLR<br />
model included treatment arm, serum Ctrough, BW, and all interactions between<br />
covariates, in order to account for <strong>the</strong> different dosing schemes (BW-based vs. fixed<br />
dosing).<br />
Results: pCR subgroup analyses showed that <strong>the</strong> numerically higher pCR rate point<br />
estimate in H-SC vs. H-IV was reflected in <strong>the</strong> majority of subgroups, with all<br />
confidence intervals for <strong>the</strong> rate difference (SC-IV) containing ‘0‘. The findings of <strong>the</strong><br />
PPP analysis were supported by results obtained in <strong>the</strong> ITT population. Fur<strong>the</strong>r<br />
analyses, including MLR, showed that nei<strong>the</strong>r BW nor serum Ctrough of H correlated<br />
with pCR rates in ei<strong>the</strong>r treatment arm.<br />
Category Odds Ratio (OR)<br />
Excellent Good Moderate/Poor (95% CI)<br />
Excellent/good vs<br />
Seq Syn Seq Syn Seq Syn<br />
moderate/poor<br />
14 (23) 15 (21) 37 (60) 37 (51) 11 (18) 21 (29) 1.87, (0.82,4.27) p = 0.1<br />
79 (68) 99 (62) 33 (28) 54 (34) 4 (4) 7 (4) 1.28, (0.37,4.48) p = 0.7<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds392 | ix97
Conclusions: BW and serum Ctrough of H did not impact on efficacy (pCR). The<br />
600 mg fixed dose of H-SC is efficacious irrespective of BW. This finding supports<br />
H-SC as a treatment alternative to <strong>the</strong> registered IV formulation.<br />
Disclosure: B. Melichar: Prof. Melichar has participated in advisory board<br />
meetings and received honoraria from F. Hoffmann-La Roche Ltd. J. Li: Jing Li<br />
is an employee of F. Hoffmann La-Roche Ltd, and owns stock in Roche<br />
Holdings. T. van der Horst: Tina van der Horst is an employee of<br />
F. Hoffmann-La Roche Ltd. S. Muehlbauer: Susanne Muehlbauer is an employee<br />
of F. Hoffmann-La Roche Ltd and owns stock in Roche Holdings. C. Jackisch:<br />
Christian Jackisch has participated in advisory board meetings for<br />
F. Hoffmann-La Roche Ltd. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
255PD CORRELATION BETWEEN CIRCULATING TUMOR CELLS<br />
(CTCS), PET/CT RESPONSE AND PATHOLOGICAL<br />
COMPLETE RESPONSE (PCR) IN PRIMARY HER2-POSITIVE<br />
(HER2+) BREAST CANCER PATIENTS: A SUB-STUDY FROM<br />
THE NEOALTTO TRIAL<br />
H.A. Azim, Jr 1 , F. Ro<strong>the</strong> 1 , C.M. Aura 2 , M. Bavington 3 , M. Maetens 1 , G. Rouas 1 ,<br />
E. De Azambuja 4 , C. Sotiriou 1 , S. Di Cosimo 5 , M. Ignatiadis 1<br />
1 Breast Cancer Translational Research Laboratory, Institute Jules Bordet,<br />
Brussels, BELGIUM, 2 Molecular Pathology Laboratory, VHIO, Barcelona, SPAIN,<br />
3 Programming, Frontier Science, Kincraig, UNITED KINGDOM, 4 Breast Data<br />
Centre, Institute Jules Bordet, Brussels, BELGIUM, 5 Medical Oncology, Istituto<br />
Nazionale Tumori, Milan, ITALY<br />
Background: Although CTC detection has been studied in patients receiving<br />
preoperative chemo<strong>the</strong>rapy, fewer data exist for preoperative chemo<strong>the</strong>rapy combined<br />
with anti-HER2 agents. Here, we report a sub-study of CTC detection within <strong>the</strong><br />
NeoALTTO trial.<br />
Methods: NeoALTTO is a randomized phase III trial in which patients with<br />
primary HER2+ breast cancer were randomized to trastuzumab, lapatinib or<br />
<strong>the</strong>ir combination for 6 weeks followed by <strong>the</strong> addition of paclitaxel for 12<br />
weeks prior to surgery. Participation in <strong>the</strong> CTC sub-study was optional. Blood<br />
samples were prospectively collected at baseline, after 2 weeks of anti-HER2<br />
treatment alone and prior to surgery. A total of 22.5mL of blood was reduced to<br />
7.5mL using a modified ficoll procedure that was <strong>the</strong>n processed using<br />
CellSearch®. Evaluation of HER2 expression in CTCs was performed using <strong>the</strong><br />
CellSearch® HER2 profiling kit. CTCs with HER2 staining intensity of 2 + /3+<br />
were considered as HER2+. Associations between CTC detection and primary<br />
tumor characteristics, pCR and PET/CT response (at week 2 & 6) were assessed<br />
using <strong>the</strong> chi-square test.<br />
Results: Out of 455 patients randomized, samples for CTC analysis were<br />
available for 51 (11%) patients from 16 sites, of whom 11 (21%) had ≥ 1 CTC/<br />
22.5ml in at least one time point (Table 1). At baseline, week 2 and surgery,<br />
we detected ≥1 CTC/22.5ml in 5/46 (11%), 4/41 (10%), and 5/31 (16%)<br />
patients with evaluable samples respectively. HER2+ CTCs were still detectable<br />
after 18 weeks of preoperative treatment with anti-HER2 agents plus paclitaxel<br />
in 3/31 (10%) patients. No significant association was observed between CTC<br />
detection (ei<strong>the</strong>r at baseline or week 2 or surgery), and clinicopathologic<br />
characteristics, pCR (p = 0.36) or PET/CT response at week 2 (p = 0.34) or week<br />
6 (p = 0.90).<br />
Conclusion: CTC detection does not appear to be associated with pCR in patients<br />
receiving preoperative anti-HER2 agents plus paclitaxel, acknowledging <strong>the</strong> lack of<br />
power within our study.<br />
Patient Treatment arm<br />
CTC / HER2+ CTC<br />
(number per 22.5mL) pCR<br />
Baseline Week 2 Prior to Surgery<br />
1 L 0 0 2 /2 NO<br />
2 L NA 2 /2 2 /2 NO<br />
3 L 1 /1 0 0 NO<br />
4 L NA 4 /3 NA NO<br />
5 T 0 1 /0 0 NO<br />
6 T 65 /52 0 2 /1 NO<br />
7 L+T 0 0 1 /0 NO<br />
8 L + T 1 /0 0 NA NO<br />
9 L + T 1 /0 0 0 YES<br />
10 L + T 1 /0 0 NA YES<br />
11 L + T 0 1 /0 1 /0 YES<br />
L: lapatinib; T: trastuzumab; NA: not applicable.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
256P FIVE YEARS FOLLOW UP OF PROSPECTIVE RANDOMIZED<br />
STUDY TO ASSESS THE EFFECT OF PROPHYLACTIC<br />
CRANIAL IRRADIATION IN HIGH RISK BREAST CANCER<br />
PATIENTS<br />
E.A. Elkhouly, H.M. Metwally, T.A. Hashem, K.K. Abdalaziz<br />
Clinical Oncology Dep., Menoufia University Hospital, Menoufia, EGYPT<br />
Aim: To assess <strong>the</strong> effect of Prophylactic cranial irradiation (PCI) in patients with<br />
high risk early breast cancer with primary end point CNS relapse where <strong>the</strong><br />
secondary end point is to assess <strong>the</strong> toxicity and QOL. At 5 years <strong>the</strong> aim is to assess<br />
CNS relapse, Overall Survival, NCF and QOL re-evaluation.<br />
Methods: It is 5 years re-evaluation of 62 patients with high risk invasive breast<br />
cancer. After adjuvant treatment, patients were randomized into: arm I who didn’t<br />
receive PCI, arm II who received PCI. Patients were collected from Jan. 2005 and<br />
followed up till Dec. 2007 with re-evaluationone on April <strong>2012</strong>. After a signed<br />
informed consent, <strong>the</strong> whole brain received 240 cGy per fraction, once daily, five<br />
times per week to a total dose of 2400cGy. Brain assessment by MRI studies as a<br />
baseline before PCI, at 6 months in <strong>the</strong> first year, and <strong>the</strong>n annually for at least<br />
5 years, and Assessment of Neuro-cognitive Function (NCF): basically before PCI,<br />
6 months, 1 year after PCI using Mini-Mental State Exam (MMSE). Health related<br />
quality of life was assessed for all patients with <strong>the</strong> Functional Assessment of Cancer<br />
Therapy-Brain (FACT-Br) Questionnaire Version 4, before PCI and 3 weeks, three<br />
months after PCI. Patients were followed up till April <strong>2012</strong>.<br />
Results: At <strong>the</strong> end of <strong>the</strong> study, <strong>the</strong>re is no incidence of CNS metastasis in PCI arm<br />
compared to 3.2% in control arm. In PCI arm, <strong>the</strong>re is no statistical difference in<br />
MMSE (before and after PCI, p = 0.619 ) and QOL assessment. At 5 years, in PCI<br />
arm, <strong>the</strong> incidence of CNS metastasis is 3.2 (only one case) while in Control arm it is<br />
12.9 (four cases). In PCI arm,<strong>the</strong>re was no statistically significant change in NCF and<br />
QOL in all items of FACT-Br questionnaire except in additional concerns (p 0.05, Log rank of 5 years survival = 0.59<br />
Conclusion: The rationale behind PCI is to control or eradicate undetectable<br />
micro-metastases before <strong>the</strong>y become clinically significant without inducing severe<br />
adverse effects .PCI associated with decreased incidence of CNS metastases with<br />
tolerated toxicities and did not negatively affect patient survival. This may be<br />
translated into <strong>the</strong>rapeutic gain at least for this short follow up period which<br />
warrants fur<strong>the</strong>r evaluation after a longer follow up period.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
257P EGFR AND P53 EXPRESSION IN ANDROGEN RECEPTOR<br />
(AR)-POSITIVE, TRIPLE NEGATIVE BREAST CANCER (TNBC)<br />
A. Gucalp 1 , G. Gupta 2 , S. Patil 3 , Y.H. Wen 4 , M. Akram 4 , E. Brogi 4 , S. Powell 2 ,<br />
A. Ho 2 , C.A. Hudis 1 , T.A. Traina 1<br />
1 Dept of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY,<br />
UNITED STATES OF AMERICA, 2 Radiation Oncology, Memorial Sloan-Kettering<br />
Cancer Center, New York, NY, UNITED STATES OF AMERICA, 3 Biostatistics and<br />
Epidemiology, Memorial Sloan-Kettering Cancer Center, New York, NY, UNITED<br />
STATES OF AMERICA, 4 Dept of Pathology, Memorial Sloan-Kettering Cancer<br />
Center, New York, NY, UNITED STATES OF AMERICA<br />
Background: TNBCs are a heterogeneous group characterized by lack of ER/PR/<br />
HER2 expression. Doane et al described a subgroup of TNBC associated with<br />
AR-dependent growth. While expression of EGFR and p53 are common in TNBC,<br />
<strong>the</strong>ir role in AR+ TNBC is less clear. We report <strong>the</strong> rates of EGFR and p53<br />
expression and clinicopathologic features of AR+ TNBC from a retrospective cohort<br />
at MSKCC.<br />
Methods: We identified 1,032 patients (pts) with resectable, TNBC (ER/PR < 1%;<br />
HER2 < 2 + /FISH < 2) who had surgery at MSKCC (1998-2006). Exclusions:<br />
neoadjuvant chemo<strong>the</strong>rapy, prior XRT, inflammatory/metastatic BC. TMAs were<br />
constructed from 210 readily available primary tumors (> 1 cm) with each tumor<br />
represented by 3 cores. AR was tested with DAKO Clone AR441, dilution (dil) 1:500;<br />
ratio of DAB nuclear staining to hematoxylin signal >1 SD above mean was defined<br />
as AR+. EGFR and p53 were tested with Thermo-Scientific Clone EP38Y, dil 1:50<br />
and DAKO Clone D07, dil 1:50 respectively. Scoring: 0-1+ negative, 2-3+ positive.<br />
Fisher’s exact test used to evaluate correlation between AR with EGFR and p53. RFS<br />
and OS evaluated using Kaplan-Meier methods. Clinicopathologic variables by AR<br />
status were compared using Chi-square/t-tests.<br />
Results: 166 pts had adequate cores for AR testing. 10% were AR+ (17/166). 160 pts<br />
were evaluable for EGFR and 164 pts for p53. Median (med) followup: AR + =6 years<br />
(y), AR- = 5.6y. Adjuvant chemo<strong>the</strong>rapy received: AR+ 82%, AR- 87%, P = 0.40.<br />
EGFR was expressed more frequently in AR- than AR+ TNBCs (111/143 (78%) vs 9/<br />
17 (53%); P =0.04). p53 expression was similar in AR- and AR+ TNBC (82/147<br />
(56%) vs 7/17 (41%); P =0.30). Clinicopathologic variables based on AR and EGFR<br />
status appeared similar. 3y RFS and OS data are below.<br />
Conclusion: Consistent with published reports, loss of AR expression correlates with<br />
EGFR expression. In contrast, no association was observed with p53 and AR. These<br />
ix98 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
data are hypo<strong>the</strong>sis generating regarding <strong>the</strong> mechanism of interaction of AR and<br />
EGFR in TNBC.<br />
-3 year RFS (95% CI) -3 year OS (95% CI)<br />
AR+ 76% (47-90) 88% (59-97)<br />
AR- 81% (74-87) 93% (87-96)<br />
AR+ EGFR+ (n = 9) 67% (39-98) 78% (36-94)<br />
AR+ EGFR- (n = 8) 88% (39-98) 100%<br />
AR- EGFR+ (n = 111) 82% (73-88) 91% (84-95)<br />
AR_ EGFR- (n = 32) 81% (61-92) 97% (80-100)<br />
Disclosure: All authors have declared no conflicts of interest.<br />
258P PROGNOSTIC FACTORS IN EARLY-STAGE TRIPLE NEGATIVE<br />
BREAST CANCER (TNBC): THE LIMITS OF CLINICAL AND<br />
PATHOLOGICAL FEATURES<br />
N. Pécuchet 1 , M. Le Frère Belda 2 , T. Popovski 3 , S. Haouas 1 , F. Chamming’S 4 ,<br />
F. Lécuru 5 , S. Oudard 1 , J. Medioni 1<br />
1 Dept. Medical Oncology, Hopital European George Pompidou, Paris, FRANCE,<br />
2 Dept. Pathology, Hopital European George Pompidou, Paris, FRANCE,<br />
3 Gynecology, Necker University Hospital, Paris, FRANCE, 4 Dept. Radiology,<br />
Hopital European George Pompidou, Paris, FRANCE, 5 Dept. Gynecologic<br />
Surgery, Hopital European George Pompidou, Paris, FRANCE<br />
Background: Triple negative breast cancer (TNBC) patients (pts) is an<br />
heterogeneous population regarding prognostic. Therefore, clinical and histological<br />
features were evaluated in a large monocenter cohort of patients treated for localized<br />
TNBC to identify good-prognostic TNBC.<br />
Methods: All consecutive early-stage TNBC (ER 0%, PR 0%, HER2 neg) patients treated<br />
at European Georges Pompidou Hospital, Paris, France, between 2000 and 2011 were<br />
included. Records were reviewed for demographic, clinical and pathological data.<br />
Prognostic factors were determined using univariate and multivariate stepwise log-rank<br />
analysis on disease-free survival (DFS) and overall survival (OS).<br />
Results: This analysis included 128 women with early-stage TNBC. Clinical and<br />
histological characteristics are summarized below. After a median follow-up of 37<br />
months 36 relapses and 19 deaths were observed. The 3-years recurrence rate was<br />
30% (95%CI 22-40) in <strong>the</strong> whole population. For DFS, bad prognostic factors in<br />
univariate analysis were: large tumor size (T3-4), node involvement (N1-3), node<br />
capsular effraction, lymphovascular invasion (LVI) and high grade (SBR 2-3).<br />
Multivariate analysis identified tumor size (T3-4) (HR 3.70, 95%CI 1.61-8.52) and<br />
LVI (HR 2.87, 95%CI 1.39-5.93) as independent factors. The 3-years recurrence rate<br />
remained high (20%, 95%CI 10-34) in patients with two good prognostic factors<br />
(T0-2 and no LVI). For OS, bad prognostic factors significant in univariate and<br />
multivariate analysis were: node capsular effraction (HR 3.57, 95%CI 1.17-10.92) and<br />
LVI (HR 3.43, 95%CI 1.18-9.92).<br />
Conclusions: In this early-stage TNBC series, LVI was a bad prognostic factor of<br />
relapse and death. However, <strong>the</strong> 3-years recurrence rate remained high in patients<br />
with good prognostic features. Therefore, new biomarkers are mandatory for a better<br />
stratification of this heterogeneous population.<br />
Clinical and histological characteristics<br />
N (128pts) %<br />
Median age (yrs)<br />
Histological type<br />
56 range 22-88<br />
Invasive ductal carcinoma 123 96<br />
Invasive lobular carcinoma<br />
Tumor stage<br />
5 4<br />
T0-T2 105 82<br />
T3-T4<br />
Node stage<br />
23 18<br />
N0 97 76<br />
N1-3<br />
Node capsular effraction<br />
31 24<br />
pos 14 11<br />
neg 111 87<br />
NE<br />
Tumor grade (SBR)<br />
3 2<br />
1 8 6<br />
2-3 107 84<br />
NE*<br />
Lymphovascular invasion (LVI)<br />
13 10<br />
pos 34 27<br />
neg 74 58<br />
NE** 20 16<br />
*Due to neoaduvant chemo<strong>the</strong>rapy **Due to small biopsies.<br />
Disclosure: S. Haouas: Grant from Association pour la Recherche en Thérapeutiques<br />
Innovantes en Cancérologie (ARTIC). All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
259P CLINICAL BEHAVIOR AND PROGNOSIS OF DIFFERENT<br />
IMMUNOHISTOCHEMISTRY-DETECTED SUBTYPES OF<br />
INVASIVE BREAST CANCER: A MONOINSTITUTIONAL SERIES<br />
A. Ferro 1 , C. Eccher 2 , R. Triolo 1 , A. Caldara 1 , M.C. Di Pasquale 1 , S. Moroso 1 ,<br />
L. Russo 1 , M. Barbareschi 3 , E. Galligioni 1<br />
1 Medical Oncology, Santa Chiara Hospital, Trento, ITALY, 2 E-health, FBK, Trento,<br />
ITALY, 3 Pathology, Santa Chiara Hospital, Trento, ITALY<br />
Background: Invasive breast cancer (IBC) is a heterogeneous disease. Gene<br />
expression profiling has identified several biologically distinct subtypes of IBCs. As<br />
proposed by Cheang et al, immunohistochemical (IHC) markers can be used as a<br />
surrogate for <strong>the</strong> molecular classification of IBC.<br />
Purpose: To evaluate different clinical behavior, relationship with o<strong>the</strong>r<br />
clinical-pathological features and survival outcomes of patients (pts) with different<br />
subtypes of IBC as classified using IHC markers.<br />
Methods: We evaluated 3461 IBC pts treated from 1995 to 2008 classified as: luminal<br />
A (ER and PR + , HER2- and Ki67< 14%), luminal B (ER and/or PR + , HER2- and<br />
Ki67 ≥ 14%), luminal C (ER and/or PR + , HER2 + , any Ki67), HER2+ (ER and PR,<br />
HER2 + , any Ki67), triple negative-TN (ER and PR-, HER2-, any Ki67). Log-rank<br />
test and Cox regression model were performed to evaluate <strong>the</strong> impact of IHC<br />
subtypes on overall survival (OS), Event Free Survival (EFS) and <strong>the</strong>ir correlation<br />
with o<strong>the</strong>r known prognostic factors.<br />
Results: We identified 909 (26.4%) luminal A, 1722 (49.9%) luminal B, 325<br />
luminal C (9.4%), 209 (5.7%) HER2+ and 296 (8.6%) TN. Median age was 61<br />
years. Luminal A was more frequently associated with older age, smaller size,<br />
negative axilla involvement, low grade (p < 0.001). There were 644 (18,6%) events<br />
(local and distant relapses, contralateral and second tumors): 100 in luminal A<br />
(11%), 334 in luminal B (19.4%), 62 in luminal C (19%), 66 in HER2+ (31%)<br />
and 84 in TN (28%). Different subtypes showed preferential sites of first local or<br />
distant relapses: luminal A had more bone and loco-regional and less visceral<br />
relapses than o<strong>the</strong>r subtypes. Median disease free interval (DFI) was longer in<br />
luminal A (60.3 months) than in luminal B (39.1 m), C (27.8 m), HER2 (30.8<br />
m) and TN (23.3 m). At median follow up of 77 months, EFS and OS were 94.0<br />
and 92.1% in luminal A, 86.2 and 82.7% in luminal B, 86.2 and 86.8% in<br />
luminal C, 72.7 and 72.7% in HER2 + , 78.0% and 73.9% in TN (p < 0.001).<br />
Luminal A presented <strong>the</strong> best prognosis among o<strong>the</strong>r luminal subtypes.<br />
IHC-based subtypes prognosis (EFS and OS) was independent of nodal status,<br />
grading, tumor size and age.<br />
Conclusions: In our experience IHC-based classification appared to be useful to<br />
divide IBCs in different biological entities. Its application could help <strong>the</strong> tailoring of<br />
adjuvant <strong>the</strong>rapies improving patient outcomes.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
260P PERITUMORAL VASCULAR INVASION AS PRINCIPAL<br />
ISTOLOGICAL PROGNOSTIC FACTOR IN TNBC<br />
G. Rizzo, V. Fregoni, G. Daprada, L. Pavesi, G. Gallizzi, I.T. Lorenzetti,<br />
R. Tancredi, E. Ferraris, A. Pagani<br />
Oncology Division, Fondazione Salvatore Maugeri, Pavia, ITALY<br />
Purpose: Triple-negative breast cancers (TNBC) is a specific histological subclass<br />
of breast cancer that has gained attention in recent years for its clinical and<br />
molecular heterogeneity with still no evidence of an optimal <strong>the</strong>rapeutic strategy.<br />
Aim of this study is to identify clinical and pathological features of TNBC<br />
reviewed in our center and try to figure out prognostic factors that can drive<br />
<strong>the</strong>rapeutic approach.<br />
Methods: In this retrospective study we reviewed 127 cases of TNBC (median<br />
Age 59) that underwent surgical treatment from 2003 to 2008 analyzing <strong>the</strong><br />
outcome (in terms of Disease Free Survival) in relation to clinical and<br />
pathologic features.<br />
Results: Univariate analysis performed on <strong>the</strong> entire cohort revealed that <strong>the</strong> cha<br />
Staging (P
261P BREAST CANCER SUBTYPES AND OUTCOME IN ELDERLY<br />
BREAST CANCER PATIENTS AGED 70 YEARS AND OLDER<br />
R. Königsberg 1 , G. Pfeiler 2 , N. Hammerschmid 2 , T. Klement 2 , A. Brunner 3 ,<br />
C. Dittrich 1<br />
1 Ludwig Boltzmann Institute for Applied Cancer Research (lbi-acr Vienna) – LB<br />
Cluster Translational Oncology, 3rd Medical Department – Centre for Oncology<br />
and Haematology, Kaiser Franz Josef-Spital, Vienna, AUSTRIA, 2 Department of<br />
Obstetrics and Gynaecology, Medical University of Vienna, Vienna, AUSTRIA,<br />
3 Department of Obstetrics and Gynaecology, Landesklinikum Thermenregion<br />
Moedling, Mödling, AUSTRIA<br />
Background: Tumor characteristics and patterns of recurrence in luminal A, luminal<br />
B, Her2 pos and triple negative breast cancer (bc) patients (pts) 70 years and older<br />
are still an area of uncertainty. In this investigation clinical pathological<br />
characteristics, disease recurrence and death were analysed according to <strong>the</strong> 4 bc<br />
subcategories and age in pts ≥70 years.<br />
Methods: Data of 274 elderly bc pts (≥70 years of age) diagnosed between 1998 and<br />
2004 were retrospectively analyzed by computer based chart information. Baseline<br />
tumor characteristics, patient demographics and patterns of recurrence were<br />
compared between luminal A, luminal B, Her2 pos and triple negative bc pts and 3<br />
age categories (70-75, 76 -80, ≥ 81 years).<br />
Results: Mean age was 76.95 years and mean time of follow-up was 52.23 months<br />
(range 0-144 months). Overall, recurrences were detected in 18.4% of pts. At <strong>the</strong> end<br />
of follow-up 69.0% of pts were alive, 15.0% and 16.1% died from bc and from o<strong>the</strong>r<br />
causes, respectively (p = 0.745). Median overall survival (OS) was 114.1 months (95%<br />
confidence interval 100.3 -181.7 months). 41.1%, 20.4%, 16.1% and 12.5% of patients<br />
had luminal A, luminal B, Her2 pos and triple negative bc, respectively. No<br />
significant differences were found regarding recurrences according to bc subtypes (p<br />
= 0.241). Triple negative bc had a significant shorter OS compared to lumianl A,<br />
luminal B and Her2 pos bc (72.7 months vs 124.1, 119.4 and 105.0 months,<br />
respectively (p < 0.001)). Overall, 21.5% of pts received no <strong>the</strong>rapy. Pts aged ≥81<br />
years (15.8%) received significantly less (p < 0.01) chemo-/antihormonal <strong>the</strong>rapy<br />
compared to pts ≤80 years. Pts aged 70-75 years (42.7%) had significantly (p =<br />
0.032) more recurrences compared to pts 76 years or older. Pts aged 70 - 75, 76 - 80<br />
and ≥ 81 years had median OS of 116.9, 115.4 and 73.1 months.<br />
Conclusions: Pts aged 70-75 years had significantly more recurrences; perhaps due<br />
to <strong>the</strong>ir lower risk of death from o<strong>the</strong>r causes. These data emphasize <strong>the</strong> necessity to<br />
foresee all bc subgroups of <strong>the</strong> elderly for adjuvant treatment irrespective of age but<br />
carefully considering co-morbidities, performance status and life-expectancy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
262P OUTCOMES OF ETHNIC MINORITY GROUPS WITH<br />
NODE-POSITIVE, NON-METASTATIC BREAST CANCER IN A<br />
TERTIARY REFERRAL CENTRE IN SYDNEY<br />
S.H. Lim 1 , J. Descallar 2 , P. Sayaloune 3 , G. Papadatos 4 , P. De Souza 1 ,<br />
G. Delaney 4<br />
1 Medical Oncology, Liverpool Hospital, Liverpool, NSW, AUSTRALIA, 2 Statistics,<br />
Ingham Institute for Applied Medical Research, Liverpool, NSW, AUSTRALIA,<br />
3 Data Management, Liverpool Hospital, Liverpool, NSW, AUSTRALIA, 4 Radiation<br />
Oncology, Liverpool Hospital, Liverpool, NSW, AUSTRALIA<br />
Background: South-Asian women in Europe are significantly younger than<br />
non-Asian at diagnosis, present with larger tumours, and have higher mastectomy<br />
rates. In Australia, <strong>the</strong>re is a paucity of data on early breast cancer in ethnic minority<br />
groups. The aim of this study is to examine racial differences in tumour<br />
characteristics and outcome in early node-positive breast cancer patients at Liverpool<br />
and Macarthur Cancer Therapy Centres in New South Wales (NSW), Australia.<br />
These tertiary centres service 20% of <strong>the</strong> NSW population, with 40% from a<br />
non-English speaking background.<br />
Methods: A retrospective review of patients referred to Liverpool and Macarthur<br />
with node-positive non-metastatic breast cancer diagnosed before November 2006.<br />
Variables included tumour size, number of positive nodes, histological grade,<br />
hormone receptor status, age at diagnosis, country of birth and treatment. Outcome<br />
was disease-free survival. Women of Australian/New Zealand or European<br />
backgrounds were classed as Caucasian; women from Indian sub-continent, East<br />
Asia, South-east Asia, Middle East and Polynesia were classed as Asian. The study<br />
was approved by ethics.<br />
Results: There were 644 patients, with median follow up of 6.1 years. The proportion<br />
of Australian/New Zealand, European, South/East/South-east Asian, Middle-Eastern<br />
and Polynesian populations comprised 48%, 20%, 12%, 6% and 2% respectively.<br />
Women with Asian backgrounds were significantly younger at presentation (48 vs 55<br />
years), and more likely to undergo mastectomy (46% vs 34%) and chemo<strong>the</strong>rapy<br />
(82% vs 68%) than non-Asians. Tumour grade, stage and receptor status were not<br />
statistically different between <strong>the</strong> two groups. Median age, tumour size, number of<br />
nodes involved, disease-free survival and overall survival, respectively, was 52.5 years,<br />
22mm, 2/19, 148 months and 177 months. Multivariate analysis identified risk<br />
factors of tumour size > 2cm (hazard ratio HR = 1.51, confidence interval CI<br />
Annals of Oncology<br />
1.06-2.41, p value 0.02), > 10 lymph nodes involved (HR = 2.64, CI 1.75-3.98, p-value<br />
Annals of Oncology<br />
Results: Of <strong>the</strong> 400 patients, 139 (34.8%) were under 35 years old and 261 (65.2%)<br />
were 35-39 years old with a median follow-up of 72.5 months (range,1-211months).<br />
Postoperative radiation <strong>the</strong>rapy was associated with longer DFS (HR, 0.130;<br />
p = 0.007) and OS (HR, 0.017; p = 0.001) in multivariate analysis of <strong>the</strong> 400 patients.<br />
However, <strong>the</strong>re were no significant differences in clinicopathological factors, DFS and<br />
OS between under 35 years and those 35-39 years of age.<br />
Conclusion: Our results suggested that postoperative radiation <strong>the</strong>rapy improved <strong>the</strong><br />
prognosis in young breast cancer patients. However, age at diagnosis was not<br />
associated with DFS or OS in patients under 40 years. Therefore, we recommend<br />
patients under 40 years to receive unified <strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
265P BREAST CANCER IN YOUNG WOMEN IN INDIA<br />
S.P. Deshmukh 1 , A.D. Mane 1 , B.P. Zade 2 , S.P. Sane 3<br />
1 Surgical Oncology, Ruby Hall Clinic, Pune, INDIA, 2 Radiation Oncology, Ruby<br />
Hall Clinic, Pune, INDIA, 3 Statistics, Ruby Hall Clinic, Pune, INDIA<br />
Background: The incidence of breast cancer is rising in India. It presents at a<br />
younger age in Indian population as compared to <strong>the</strong> western countries. Aims and<br />
objectives: This is a retrospective study of all breast cancer patients less than 40 years<br />
of age treated in single tertiary care center from June 2006 to June 2011. The aim<br />
was to assess <strong>the</strong> factors that may influence clinical outcome and prognosis including<br />
demographics, clinical characteristics and pathological findings and treatment.<br />
Materials and methods: Clinical data was collected from medical records. Variables<br />
like age, stage at presentation, surgery type, chemo<strong>the</strong>rapy, radiation, tumour size,<br />
grade, nodal status, perinodal extension, lymphovascular emboli, ER, PR and Her2<br />
neu status were analyzed in relation to outcome.<br />
Results: Out of 613 breast cancer patients, 91 were under 40 years of age<br />
corresponding to an incidence of 14.8%. Median tumour size was 3 cm and lymph<br />
node positivity was 56.9%. Lymphovascular emboli was positive in 42 patients<br />
(48.8%) and perinodal extension was positive in 36 patients (41.8%). Thirty patients<br />
(34.8%) were ER positive, while 39 patients (45.3%) were PR positive. Her 2 neu<br />
receptors were positive in 20 patients (23.2%). Thirty nine patients were triple<br />
negative (45.3%). The median follow up period was 27 months with <strong>the</strong> DFS being<br />
73.2% and OS being 87.2%. In univariate analysis, factors significantly associated<br />
with survival were stage at presentation, presence of lymhovascular emboli, presence<br />
of perinodal extension and grade of <strong>the</strong> tumour.<br />
Conclusions: Breast cancer in India is seen in younger patients and most of <strong>the</strong>se are<br />
triple negative breast cancers. Patients with breast cancer below 30 years of age are<br />
surviving more than <strong>the</strong> age group of 30 to 40 years. Survival of young breast cancer<br />
patients in India is comparable to western studies.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
266P TUMOR CHARACTERISTICS, TREATMENT AND OVERALL<br />
SURVIVAL (OS) IN BREAST CANCER PATIENTS (PTS) OVER 80<br />
YEARS: A COHORT FROM A SINGLE INSTITUTION<br />
C. Baldini 1 , A. Donnadieu 1 , A. Kramar 2 , V. Servent 1 , J. Bonneterre 3<br />
1 Breast Cancer, Centre Oscar Lambret, Lille, FRANCE, 2 Biostatistics, Centre<br />
Oscar Lambret, Lille, FRANCE, 3 Breast Cancer, Centre Oscar Lambret,<br />
Université Lille Nord de France, Lille, FRANCE<br />
The incidence rate of breast cancer in elderly women over 75 years old is 220 per<br />
100000 in France and is likely to increase in <strong>the</strong> future. We studied <strong>the</strong> impact of<br />
tumor and treatment characteristics on overall survival.<br />
Patients and methods: Data were collected for 208 non metastatic breast cancer pts<br />
over 80 years (213 tumors), treated from January 2000 to December 2009.<br />
Pathological data were obtained on a biopsy or on mastectomy specimens if patients<br />
had not received presurgical treatment.<br />
Statistical methods: Survival rates were estimated by Kaplan-Meier method. Tests<br />
were performed with <strong>the</strong> logrank test. Five year relative survival rates were estimated<br />
by Ederer2 method.<br />
Results: Median age at diagnosis was 83 years (80-95). 29% tumors were T1, 58% T2<br />
and 15% T3, 141 (66%) were ductular, 34 (16%) lobular and 38 (18%) had ano<strong>the</strong>r<br />
histological type. SBR grade (I/II/III) was 22%/49%/29% and unspecified in 42<br />
(20%). 167 pts (80%) were ER + , 129 (62%) PR + ; 40 (19%) ER–PgR–, and 171<br />
(81%) ER + PgR+. HER2 status, known in 126 pts, was positive in 18 (14%), and<br />
negative in 108 (86%). Ten pts were strictly triple negative (5%)(ER = 0, PgR = 0,<br />
HER2 = 0). Ki 67 among 59 tumors was over 15% in 43 pts (73%). Forty-nine pts<br />
(23%) had conservative surgery, 80 mastectomy (38%), 72 axillary dissection (34%)<br />
and 30 sentinel lymph node biopsy (14%). Axillary lymph node metastasis were<br />
observed in 52 pts (38%). 195 pts received hormono<strong>the</strong>rapy (68 as adjuvant <strong>the</strong>rapy,<br />
89 before surgery or alone), 72 patients radio<strong>the</strong>rapy (37%), 5 chemo<strong>the</strong>rapy (3%)<br />
and 1 had trastuzumab (0.5%). Median overall survival was 59 months. Median<br />
follow up was 76 months. The only significant prognostic factors on overall survival<br />
were age (48 months over 83 years, 79 before), ER and PgR status. ER positive and<br />
negative pts had a median survival of 60 months and 32 months respectively. Five<br />
year relative survival rate was 63%.<br />
Conclusion: Even if most pts had a ER+ tumor, <strong>the</strong> rate of poor prognosis factors is<br />
high: 29% SBR III, 14% HER2 positive, 5% triple negative and 73% had a KI67 index<br />
over 15%. Despite <strong>the</strong>se poor prognostic factors, survival was ra<strong>the</strong>r long with a<br />
median OS of 5 years.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
267P DISEASE-FREE SURVIVAL ACCORDING TO PATHOLOGIC<br />
RESPONSE AND P95-HER2 IN THE CHER-LOB<br />
NEOADJUVANT STUDY OF CHEMOTHERAPY PLUS<br />
TRASTUZUMAB, LAPATINIB OR COMBINED TRASTUZUMAB<br />
AND LAPATINIB IN HER2+ OPERABLE BREAST CANCER<br />
V. Guarneri 1 , G. Bisagni 2 , A. Bottini 3 , K. Cagossi 4 , A. Frassoldati 5 , F. Piacentini 1 ,<br />
C. Holford 6 , J. Bruey 7 ,R.D’Amico 1 , P.F. Conte 1<br />
1 Dept. of Hematology/Oncology, Modena University Hospital, Modena, ITALY,<br />
2 Department of Oncology, Arcispedale S Maria Nuova, Reggio Emilia, ITALY,<br />
3 Unit, Istituti Ospitalieri di Cremona, Cremona, ITALY, 4 Medical Oncology,<br />
Ospedale Ramazzini, Carpi, ITALY, 5 Dept of Clinical Oncology, Azienda<br />
Ospedaliera di Ferrara St. Anna, Ferrara, ITALY, 6 Research & Development,<br />
GlaxoSmithKline, Stockley Park, Uxbridge, UNITED KINGDOM, 7 Biomarker<br />
Research & Development, BioTheranostics, Inc, San Diego, CA, UNITED<br />
STATES OF AMERICA<br />
Introduction: This is a randomized phase II trial of preoperative sequential<br />
taxanes-anthracyclines in combination with trastuzumab, lapatinib, or combined<br />
trastuzumab and lapatinib in HER2 positve operable breast cancer. We previously<br />
reported that dual HER2 blockade with trastuzumab and lapatinib significantly<br />
increased <strong>the</strong> pathologic complete response (pCR) rate. The aim of <strong>the</strong> present<br />
post-hoc analysis is <strong>the</strong> evaluation of disease free survival (DFS) according to pCR,<br />
p95-HER2 expression, and treatment arm.<br />
Methods: 121 patients were randomly assigned to weekly paclitaxel followed by<br />
FE75C combined with trastuzumab (arm A, n= 36), lapatinib (arm B, n= 39), or<br />
trastuzumab and lapatinib (arm C, n= 46). P95-HER2 expression was measured by<br />
IHC (bioTheranostics, Inc. San Diego, CA). Patients were classified as having a<br />
p95-HER2 positive tumor in case of strong immunostaining in ≥80% of cells. pCR<br />
was defined as disappearance of infiltrating disease in breast and axillary nodes. DFS<br />
was calculated from <strong>the</strong> date of surgery to <strong>the</strong> date of recurrence (local or distant) or<br />
death.<br />
Results: Overall, pCR was observed in 32% of patients. The pCR rates per treatment<br />
arm were 25% in arm A, 26.3% in arm B, and 46.7% in arm C (Arm C vs combined<br />
Arms A + B: p = 0.018). Thirty-five patients (29%) resulted p95-HER2 positive. At<br />
<strong>the</strong> time of <strong>the</strong> present analysis, 17 DFS events have been reported. The expression of<br />
p95-HER2 was not significantly correlated with <strong>the</strong> probability of relapse, overall and<br />
per treatment arm. The risk of relapse was significantly lower for patients achieving a<br />
pCR (hazard ratio 0.09, p = 0.019). The 3-yr DFS rate was 88% in arm C vs 72% in<br />
arms A + B.<br />
Conclusions: The achievement of a pCR in breast and axillary nodes is predictive of<br />
outcome in HER2 positive breast cancer patients treated with neoadjuvant <strong>the</strong>rapy.<br />
This is consistent with o<strong>the</strong>r neoadjuvant studies. p95-HER2 appears to be nei<strong>the</strong>r<br />
predictive nor prognostic in this patient population. The combination arm resulted<br />
in a trend for a better DFS, probably reflecting <strong>the</strong> higher pCR rate observed.<br />
Sponsored by GlaxoSmithKline.<br />
Disclosure: C. Holford: Employer GlaxoSmithKline. J. Bruey: Employee at<br />
bioTheranostics, Inc. P.F. Conte: GlaxoSmithkline: research funds, speaker’s bureau,<br />
advisor. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
268P PROLIFERATION DETERMINED BY KI67 MARKER DEFINES<br />
PATHOLOGICAL COMPLETE RESPONSE IN A DOSE-DENSE<br />
NEOADJUVANT CHEMOTHERAPY SCHEDULE IN LOCALLY<br />
ADVANCED BREAST CANCER PATIENTS<br />
M.Y. Plata Fernandez 1 , A. Sanchez-Muñoz 2 , A. Jaén-Morago 1 ,<br />
M. Lomas-Garrido 1 , M. Fernández 1 , C. Llacer 2 , M. Fernández 1 , N. Ribelles 2 ,<br />
E. Alba-Conejo 2 , P. Sánchez-Rovira 1<br />
1 Oncología Médica, Complejo Hospitalario de Jaén, Jaén, SPAIN, 2 Oncology,<br />
Hospital Universitario Virgen de la Victoria, Malaga, SPAIN<br />
Background: The value of Ki67 proliferation biomarker during neoadjuvant<br />
chemo<strong>the</strong>rapy (NC) is less clear than with neoadjuvant endocrine <strong>the</strong>rapy. We study<br />
<strong>the</strong> role of proliferation according to Ki67 marker measured by<br />
immunohistochemistry (IHC) as a predictive factor of pathological complete<br />
response to NC.<br />
Methods: From May 2002 to June 2005, 127 pts diagnosed as stage II-III, including<br />
inflammatory tumors, breast cancer patients (pts) received one of <strong>the</strong> 2 NC regimens<br />
every 2 weeks with prophylactic growth factor support. Study A: adriamicin 40mg/<br />
m2 d1 plus P 150mg/m2-G 2000 mg/m2 d2 for 6 cycles (n = 54); study B: epirubicin<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds392 | ix101
90 mg/m2-cyclophophamide 600 mg/m2 d1 for 3 cycles, followed by a second<br />
sequence with paclitaxel (P) 150 mg/m2- gemcitabine (G) 2500 mg/m2 d1 +/trastuzumab<br />
2mg/kg/wk according to status Her2 (n= 73). In study A pts did not<br />
receive trastuzumab regardless of Her2 status. Ki67 was centrally assessed by IHC<br />
(Master Diagnostica clon SP6). Tumors were considered to have high proliferation<br />
rates (Ki67) if ≥ 20% of cell nuclei stained positive. Median age was 48 years. Her2+<br />
was observed in 31%, HR negative 34%, grade III 46% and high Ki67 47%.<br />
Pathological complete response (pCR) defined as absence of invasive cells in breast<br />
and lymph node was achieved in 35 pts (28%). Univariate and multivariate logistic<br />
regression models were used to study <strong>the</strong> association of each clinical-pathological<br />
variable with pCR.<br />
Results: High Ki67 was <strong>the</strong> main predictive factor of pCR to NC. In <strong>the</strong> univariate<br />
analysis histological grade (p = 0.001), HR (p < 0.001), Ki67 (p = 0.001) and p53 (p<br />
< 0.001) were statistically associated with pCR. A multivariate logistic regression<br />
showed than only high Ki67 (p = 0.02; OR = 5.5 CI95% 1.2- 18) and HR (p = 0.045;<br />
OR = 0.25 CI95% 0.05-0.97) were predictive for pCR.<br />
Conclusion: High proliferation determined by ki67 marker is an independent<br />
predictive factor for pCR in locally advanced breast cancer patients treated in two<br />
dose-dense NC schedules.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
269P NEOADJUVANT CHEMOTHERAPY IN OPERABLE BREAST<br />
CANCER: DATA FROM THE ASTER STUDY (AT FOR 3 CYCLES<br />
FOLLOWED BY CMF FOR 3 CYCLES)<br />
E. Puma1 , P. Mariani1 , S. Damian1 , M.C. Dazzani1 , E. De Benedictis1 , M. Parati2 ,<br />
L. Sica2 , A. Tessari1 , F.G.M. De Braud1 , A. Moliterni1 1<br />
Medical Oncology, Istituto Nazionale dei Tumori di Milano, Milan, ITALY,<br />
2<br />
Oncologia Medica, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano,<br />
ITALY<br />
Background: The ECTO-1 study demonstrated <strong>the</strong> efficacy of concurrent<br />
doxorubicin and paclitaxel (AT) for 4 cycles followed by cyclophosphamyde/<br />
methotrexate/fluorouracil (CMF) for 4 cycles in <strong>the</strong> neoadjuvant treatment of<br />
operable breast cancer (Gianni L. et al. Clin Cancer Res 2005). With <strong>the</strong> purpose of<br />
ameliorating <strong>the</strong> tolerability of <strong>the</strong> regimen, we designed <strong>the</strong> ASTER study to reduce<br />
both <strong>the</strong> duration and <strong>the</strong> total dose of neo-/adjuvant treatment with AT followed by<br />
CMF. Herein we report on <strong>the</strong> efficacy of <strong>the</strong> neoadjuvant portion of <strong>the</strong> trial.<br />
Methods: A total of 70 patients with operable breast cancer were enrolled between<br />
September 2008 and November 2011. Median age was 51 years (range 32-73); 74% of<br />
patients presented with hormone receptor positive (HR +) and 26% of patients with<br />
hormone receptor negative (HR -); 8% of patients presented HER2 overexpression/<br />
amplification; most of <strong>the</strong> patients had cT2 (96%); half presented with node<br />
involvement cN1 (54%). Patients were treated with neoadjuvant Adriamycin (60 mg/<br />
mq) + Paclitaxel (200 mg/mq) q21 for 3 cycles followed by CMF i.v. 1, 8q28 for 3<br />
cycles.<br />
Results: The pathological complete response (pCR), defined as <strong>the</strong> absence of<br />
neoplastic cells in <strong>the</strong> primary tumor was obtained in 11.5% of cases; tnpCR, defined<br />
as <strong>the</strong> absence of neoplastic cells in <strong>the</strong> primary tumor and in nodes, was obtained in<br />
10% of cases. Overall, 29% of patients with triple negative breast cancer achieved a<br />
pCR, while only 6% of HR positive breast cancer achieved a pCR.<br />
Conclusions: Neoadjuvant treatment with three cycles of AT followed by three cycles<br />
of CMF is effective in patients with operable breast cancer. The rate of pCR matched<br />
perfectly with <strong>the</strong> data obtained with <strong>the</strong> original schema AT x 4 followed by CMF x<br />
4 in 69 patients treated with primary chemo<strong>the</strong>rapy at our institute, within <strong>the</strong><br />
ECTO-1 study. The ASTER study sets <strong>the</strong> base for developing a less toxic<br />
chemo<strong>the</strong>rapy regimen sequential and non-cross resistant containing anthracycline<br />
and taxane for <strong>the</strong> treatment of operable breast cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
270P LONG-TERM OVERALL SURVIVAL (OS) AND DISEASE-FREE<br />
SURVIVAL (DFS) ACCORDING TO PCR IN BREAST CANCERS<br />
SUBTYPES: LUMINAL A AND B, TRIPLE NEGATIVE AND<br />
HER2 + , TREATED BY NEAODJUVANT CHEMOTHERAPY<br />
(NCT)<br />
C. Abrial 1 , Q. Wang-Lopez 1 , M. Mouret-Reynier 2 , P. Dubray-Longeras 2 , I. van<br />
Praagh-Doreau 2 , X. Durando 2 , P. Gimbergues 3 , J. Nabholtz 2 , F. Penault-Llorca 4 ,<br />
P. Chollet 2<br />
1 Clinical Research, Centre Jean Perrin, Clermont-Ferrand, FRANCE, 2 Oncology<br />
Department, Centre Jean Perrin, Clermont-Ferrand, FRANCE, 3 Surgery<br />
Department, Centre Jean Perrin, Clermont-Ferrand, FRANCE, 4 Dept. de<br />
Pathologie, Centre Jean Perrin, Clermont-Ferrand Cedex, FRANCE<br />
Background: In breast cancer, positive Hormone Receptors (HR) constitute a<br />
favourable prognostic factor whereas HER-2 overexpression is an adverse prognostic<br />
factor associated with a more aggressive tumor. In a retrospective database of 282<br />
Annals of Oncology<br />
breast cancer patients diagnosed from 1991 to 2006, we analysed <strong>the</strong> overall survival<br />
(OS) and <strong>the</strong> disease-free survival (DFS) of 4 phenotypes: HR-/HER-2- (triple<br />
negative, TN); HR + /Ki-67 < 20% (luminal A), HR + /Ki-67 > 20% or Her2+ (luminal<br />
B) and HER-2 overexpression (HER-2 + /HR-).<br />
Patients and methods: Median diameter of <strong>the</strong> invasive tumour was 40 mm<br />
[10-130]. 231 (82%) patients had a canalar carcinoma. 33% of <strong>the</strong> tumours were<br />
grade III SBR. Patients received ei<strong>the</strong>r an anthracycline-based chemo<strong>the</strong>rapy (47%), a<br />
taxane-based chemo<strong>the</strong>rapy (21%) or a combination of both (32%). The median<br />
number of NCT courses was 6 [1-8] followed by a surgery for 97.6%, a radio<strong>the</strong>rapy<br />
for 93%, an adjuvant chemo<strong>the</strong>rapy for 20% and/or an hormono<strong>the</strong>rapy for 56%.<br />
Only 5 patients received adjuvant herceptin for 1 year. In <strong>the</strong> different subgroups, we<br />
had 123 luminal A tumors (44%), 67 luminal B tumours (24%), 21 Her2+ tumours<br />
(7%) and 71 TN tumours (25% of patients).<br />
Results: According to tumour’s phenotype, <strong>the</strong> pCR (Chevallier’s classes1+2)<br />
was: 3.3% for luminal A, 16.6%, for luminal B, 33.3% for Her2+ HR- and 26%<br />
for triple negative tumours. On 2 April <strong>2012</strong>, <strong>the</strong> median follow-up was 148<br />
months (range, 63- 252). We evaluated <strong>the</strong> OS and <strong>the</strong> DFS in <strong>the</strong> four<br />
subgroups, at 10 years. -For TN: OS and DFS were 58.5% and 56.2%. -For<br />
luminal A: OS and DFS were 76.1% and 64.7%. -For luminal B: OS and DFS<br />
were 81.7% and 72.4%. -For Her2 + HR- subgroup: OS and DFS were 64.5% and<br />
56.4%. pCR is an objective method improvement after NCT, but it is variable<br />
among subsets, and may constitute an acquired prognostic factor. However, it<br />
was much smaller in hormonal-positive tumors subsets and may <strong>the</strong>re not be an<br />
endpoint per se. We observed a significant improvement of DFS and OS for<br />
patients who reached a pCR only in TN breast cancer. However Her2 subset<br />
may be too small to reach significance here.<br />
Conclusion: OS and DFS were better in luminal A and B subgroups. Conversely OS<br />
and DFS decreased for TN and Her2+ subtypes. When TN breast cancer patients<br />
reached a pCR, OS and DFS were significantly improved.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
271P ADDITIONAL SAFETY RESULTS OF HANNAH: A PHASE III<br />
RANDOMISED, OPEN-LABEL, INTERNATIONAL STUDY OF<br />
THE SUBCUTANEOUS FORMULATION OF TRASTUZUMAB (H)<br />
IN HER2-POSITIVE EARLY BREAST CANCER PATIENTS<br />
C. Jackisch 1 , M. Dank 2 , G. Frasci 3 , K.H. Park 4 , R.I. Lopez 5 , M. Johnston 6 ,<br />
D. Heinzmann 7 , H. Weber 7 , G. Ismael 8<br />
1 Department of Obstrics and Gynecology, Klinikum Offenbach GmbH,<br />
Offenbach, GERMANY, 2 Semmelweis Egyetem, Radiológiai és Onkoterápiás<br />
Klinika, Budapest, HUNGARY, 3 Division of Medical Oncology A, National Tumor<br />
Institute, Naples, ITALY, 4 Department of Internal Medicine, Korea University<br />
Anam Hospital, Seoul, KOREA, 5 Medical Oncology Department, National<br />
Oncology Institute, Panama, PANAMA, 6 Genentech Inc, South San Francisco,<br />
CA, UNITED STATES OF AMERICA, 7 Clinical Science, F. Hoffmann-La Roche<br />
Ltd, Basel, SWITZERLAND, 8 Medical Oncology, Fundation Amaral<br />
CarvalhoHospital of Jau, Jau, BRAZIL<br />
Background: HannaH demonstrated non-inferiority of <strong>the</strong> fixed-dose subcutaneous<br />
(SC) formulation of H compared with <strong>the</strong> intravenous (IV) formulation, based on<br />
co-primary endpoints of pharmacokinetics (C trough) and efficacy (pCR) (Jackisch<br />
et al, EBCC <strong>2012</strong>).<br />
Methods: Pts with HER2-positive, operable, locally advanced or inflammatory BC<br />
were randomised to receive 8 cycles of chemo<strong>the</strong>rapy (4x docetaxel 75 mg/m 2<br />
followed by 4x FEC 600/75/600 mg/m 2 ) concurrently with 3-wkly H, ei<strong>the</strong>r SC (600<br />
mg/5 mL) or IV (8 mg/kg to 6 mg/kg). After surgery, pts continued H-SC or IV to<br />
complete 1 year of treatment. Safety has been monitored until 24 mths after last dose<br />
of H, including cardiac monitoring.<br />
Results: Safety data from 298 (IV) /297 (SC) HannaH pts were analysed. At a<br />
median F/U of 12.3 months, 116 pts had completed adjuvant treatment and<br />
received a median of 17.5 (IV) and 17.0 (SC) H cycles. Pt characteristics were<br />
balanced at baseline. Overall, safety was comparable between arms. Most<br />
common AEs (>25% in ei<strong>the</strong>r arm) were alopecia, nausea, neutropenia,<br />
diarrhoea, as<strong>the</strong>nia, and fatigue, with similar incidence in <strong>the</strong> two arms.<br />
Incidence of severe AEs (≥ grade 3) was comparable between arms (both 52%);<br />
<strong>the</strong> most common of which were haematologic (36.9 [IV] v 35.4% [SC]), GI (6.4<br />
v 5.7%) and infections (5.0 v 6.7%). Serious AEs (SAEs) were reported in 12.4%<br />
(IV) v 20.9% (SC) of pts. The imbalance was largely driven by increased<br />
reporting of SAEs in <strong>the</strong> “infections” disease category in <strong>the</strong> SC v <strong>the</strong> IV arm<br />
(38.7 v 35.1%). Multiple logistic regression analyses did not reveal interactions<br />
between route of H treatment, body weight, and exposure (AUC) for SAEs or<br />
grade 3–5 AEs. AEs led to <strong>the</strong> withdrawal of 2.3% (IV) and 5.7% (SC) pts, with<br />
a contribution from cardiac AEs (3.0% [SC] v 1.3% [(IV]). Grade 1/2 AEs were<br />
reasons for withdrawal in 43% (IV) v 61% (SC) of pts. Grade 1/2 cardiac AEs<br />
led to withdrawal in 1.0% (IV) v 2.0% (SC) of pts. Incidence of cardiac AEs was<br />
similar in both arms: 12.1% % (IV) v 11.4% (SC).<br />
Conclusions: The safety profile of H-SC was comparable to that of H-IV.<br />
Detailed analyses of observed imbalances in SAEs and withdrawals will be<br />
provided.<br />
ix102 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Disclosure: C. Jackisch: I have participated in an advisory board for Roche.<br />
M. Johnston: I am currently an employee of Genentech Inc. D. Heinzmann: I<br />
am currently an employee of F. Hoffmann-La Roche. H. Weber: I am<br />
currently an employee of F. Hoffmann-La Roche. G. Ismael: I declare that my<br />
institute has received research funding from Roche and honoraria for<br />
attendance at conferences. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
272P SUBCUTANEOUS INJECTION OF TRASTUZUMAB – ANALYSIS<br />
OF ADMINISTRATION TIME AND INJECTION SITE<br />
REACTIONS<br />
X. Pivot 1 , V. Semiglazov 2 , S. Chen 3 , S.D. Moodley 4 , A. Manihkas 5 ,M.<br />
A. Coccia-Portugal 6 , M. Johnston 7 , T. van der Horst 8 , A. Bouhlel 8 , C. Jackisch 9<br />
1 Service Oncologie Medicale, C.H.U. Jean Minjoz, Besancon Cedex, FRANCE,<br />
2 Breast Cancer Department, N.N.Petrov Research Inst. of Oncology,<br />
St. Petersburg, RUSSIAN FEDERATION, 3 Division of Breast Surgery, Chang<br />
Gung Memorial Hospital, Taipei, TAIWAN, 4 Department of Oncology, Wits<br />
Oncology Donald Gordon Medical Centre, Johannesburg, SOUTH AFRICA,<br />
5 St Petersburg City Oncology Centre, St.Petersburg, RUSSIAN FEDERATION,<br />
6 Eastleigh Breast Cancer Care Centre, Pretoria, SOUTH AFRICA, 7 Genentech<br />
Inc, South San Francisco, CA, UNITED STATES OF AMERICA, 8 F. Hoffman-La<br />
Roche Ltd, Basel, SWITZERLAND, 9 Department of Obstrics and Gynecology,<br />
Klinikum Offenbach GmbH, Offenbach, GERMANY<br />
Background: Intravenous (IV) trastuzumab (H) is <strong>the</strong> standard of care for<br />
HER2-positive breast cancer (BC). A subcutaneous (SC) formulation of H has been<br />
developed. H SC formulation contains recombinant human hyaluronidase, which<br />
transiently hydrolyzes hyaluronan to facilitate delivery of H to <strong>the</strong> circulation. The<br />
HannaH study (Jackisch, et al. EBCC <strong>2012</strong>) demonstrated <strong>the</strong> non-inferiority of H<br />
SC (vs. H IV) in terms of pharmacokinetics and efficacy in patients with<br />
HER2-positive early BC. Safety observations for <strong>the</strong> two routes of administration<br />
were also similar.<br />
Methods: H SC injection was via handheld syringe, and an injection time of about<br />
5 minutes was recommended by <strong>the</strong> study protocol. The actual time taken was<br />
measured in <strong>the</strong> safety population at each administration. Injection site reactions<br />
(ISRs) associated with H SC were identified using a predefined basket of preferred<br />
terms from <strong>the</strong> medical dictionary for drug regulatory activities.<br />
Results: Duration of SC injections was generally between 1–5 minutes, with an<br />
average duration of 3.3 minutes (Table 1) compared with 60–90 minutes taken<br />
for IV administration. A low incidence of ISRs were seen with SC injections<br />
(Table 1), with all but two cases (grade 2) being grade 1; every case was<br />
reversible.<br />
Injection duration (minutes) Number of injections n (%) Incidence of ISRs n (%)<br />
< 2 51 (1.1) 0 (0)<br />
≥ 2 to < 3 2231 (49.2) 27 (1.2)<br />
≥ 3 to < 4 961 (21.2) 15 (1.6)<br />
≥ 4 to < 5 200 (4.4) 6 (3.0)<br />
≥ 5 to < 6 1024 (22.6) 27 (2.6)<br />
≥ 6 45 (1.0) 9 (20.0)<br />
Missing 25 (0.5) 0 (0)<br />
Total 4537 (100) 84 (1.9)<br />
Summary of injection duration and ISRs (injection site pain) in <strong>the</strong> H SC arm<br />
of <strong>the</strong> HannaH study (safety population) (N = 297) Incidence of ISRs was<br />
highest for injection durations of >6 minutes with 6 pts reporting 9 ISRs over<br />
<strong>the</strong> course of <strong>the</strong>ir treatment. In 3 pts (6 ISRs) injection time was prolonged<br />
due to injection pain. The remaining three ISRs constituted transient tissue<br />
tenderness at injection site.<br />
Conclusion: In <strong>the</strong> HannaH study, injection of H SC was generally well tolerated<br />
with a low incidence of ISRs (grades 1 and 2). These findings support <strong>the</strong> potential<br />
of H SC to provide improved convenience for patients compared to <strong>the</strong> existing IV<br />
formulation.<br />
Disclosure: X. Pivot: X. Pivot has served as a consultant or advisor for Hoffmann-La<br />
Roche, Novartis, GlaxoSmithKline and has received honoraria from sanofi-aventis.<br />
S.D. Moodley: SD Moodly has served as a member of an advisory board for La<br />
Roche Hoffman, sanofi-aventis, Britol Meyers Squibb, Nayer Schering, and has<br />
received corporate-sponsored research funding from sanfoi-aventis. M. Johnston: M<br />
Johnston is an employee of Genentech, a member of <strong>the</strong> Roche Group. T. van der<br />
Horst: T Horst is an employee of F. Hoffman-La Roche Inc. A. Bouhlel: A Bouchel is<br />
an employee of F. Hoffmann-La Roche Inc. C. Jackisch: C. Jackisch has served on<br />
advisory boards for Hoffmann-La Roche Inc. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
273P IMMUNOGENICITY OF TRASTUZUMAB INTRAVENOUS AND<br />
SUBCUTANEOUS FORMULATIONS IN THE PHASE III HANNAH<br />
STUDY<br />
R. Hegg1 , T. Pienkowski2 , S. Chen3 , E. Staroslawska4 , S. Falcon5 ,<br />
N. Kovalenko6 , N. Al-Sakaff7 , D. Heinzmann7 , G. Kolaitis8 , G. Ismael9 1 2<br />
Oncology, Hospital Pérola Byington and FMUSP, Sao Paulo, BRAZIL, MSC<br />
Memorial Cancer Centre, MSC Memorial Cancer Centre and Institute Maria<br />
Sklodowska-Curie, Warsaw, POLAND, 3 Changhua Christian Hospital, Taipei,<br />
TAIWAN, 4 St. John’s Cancer Center, Lublin, POLAND, 5 Hospital Nacional<br />
Edgardo Rebagliati Martins, Lima, PERU, 6 Stavropol Regional Clinical Oncology<br />
Dispensary, Stavropol, RUSSIAN FEDERATION, 7 Roche, Basel, SWITZERLAND,<br />
8 9<br />
Roche, Nutley, NJ, UNITED STATES OF AMERICA, Hospital Amaral Carvalho,<br />
Jau, BRAZIL<br />
Background: HannaH demonstrated non-inferiority of <strong>the</strong> fixed-dose subcutaneous<br />
(SC) formulation of trastuzumab (H) to <strong>the</strong> intravenous (IV) formulation, based on<br />
pharmacokinetics (Ctrough) and efficacy (pathological complete response [pCR])<br />
(Jackisch et al, EBCC <strong>2012</strong>). We report on efficacy and safety in relation to<br />
immunogenicity (anti-drug antibodies [ADAs]).<br />
Methods: Blood samples for ADA testing were drawn at baseline (BL), <strong>the</strong>n day 1 of<br />
cycles 2, 5 (pre-surgery), 13 and 18 (post-surgery) and at months 3, 6, 12, 18 and 24<br />
following last H dose. Screening for ADAs to H and rHuPH20 was by bridging<br />
immunoassays. Positive (pos) samples were re-tested, with confirmed pos patients<br />
(pts) <strong>the</strong>n tested for neutralizing antibodies (abs). Relationship between ADAs<br />
(against H and/or rHuPH20) with respect to, efficacy (pCR) and safety<br />
(infusion-related reactions, IRRs) was investigated.<br />
Results: The median follow-up (FU) (including ADA testing) was ∼12.3 months. At<br />
BL, 5.9% of pts (17/290) in <strong>the</strong> IV arm and 4.2% of pts (12/287) in <strong>the</strong> SC arm were<br />
pos for ADAs to H. Post-BL (treatment and FU), 3.4% (10/295) and 6.8% (20/295)<br />
pts in IV and SC, respectively were pos for ADAs to H. One pt was confirmed pos<br />
twice (non-consecutive time points). At BL, 7.6% of pts (22/290) in <strong>the</strong> SC arm were<br />
pos for ADAs to rHuPH20. Post-BL, <strong>the</strong> rate was 11.5% (34/295). Titer ranges<br />
post-BL were similar to those observed pre-BL. One pt was pos for ADAs to both H<br />
and rHuPH20. No neutralizing ADAs to H or rHuPH20 were seen. The pCR rate<br />
did not differ significantly between Anti-H ab (AHA)-pos (30% [IV n = 10], 55% [SC<br />
n = 20]) and AHA-neg (36.5% [IV n = 10], 41.6% [SC n = 20]) pts. Anti-rHuPH20<br />
status did not correlate with pCR rates (41.2% [pos n = 34] vs 41.7% [neg n = 254])<br />
in <strong>the</strong> SC arm. In pts given H SC or H IV, occurrences of IRRs were similar in<br />
AHA-neg (46.3% [SC n = 255] 37.6% [IV n = 263]) and -pos (40% [SC n = 20] 25%<br />
[IV n = 10]) pts. The incidence of pts with an IRR was similar in both anti-rHuPH20<br />
status groups (SC arm only; neg 44.5% [n = 254], pos 41.2% [n = 34]).<br />
Conclusion: Using a highly sensitive assay, ADAs against both H (IV/SC) and<br />
rHuPH20 (SC only) were observed transiently and were of no relevance in terms of<br />
efficacy or safety. Immunogenicity monitoring in <strong>the</strong> study is ongoing.<br />
Disclosure: T. Pienkowski: Dr Pienkowski has carried out research sponsored by F<br />
Hoffmann La Roche. N. Al-Sakaff: I have an interest in relation of one or more<br />
organistations that could be perceived as a conflict of interest in <strong>the</strong> context of <strong>the</strong><br />
subjuect of this abstract. Interest - o<strong>the</strong>r substantive relationship. Employee of F.<br />
Hoffman-La Roche Ltd. D. Heinzmann: I have an interest in relation of one or more<br />
organistations that could be perceived as a conflict of interest in <strong>the</strong> context of <strong>the</strong><br />
subjuect of this abstract. O<strong>the</strong>r substantive relationship: Employee of F Hoffman-La<br />
Roche and stockholder. G. Kolaitis: Dr Kolaitis is an employee and stockholder of F<br />
Hoffmann La Roche. G. Ismael: I have an interest that could be perceived as a<br />
conflict of interest in <strong>the</strong> context of <strong>the</strong> subjuect of this abstract. Corporate sponsored<br />
research - Roche O<strong>the</strong>r substantive relationships - honoraria for conferences (Roche).<br />
All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
274P A PHASE I DOSE ESCALATION AND BIOEQUIVALENCE STUDY<br />
OF A TRASTUZUMAB BIOSIMILAR (FTMB) IN HEALTHY MALE<br />
VOLUNTEERS<br />
L. Wisman 1 , E. De Cock 1 , J. Reijers 2 , I. De Visser 2 , M. De Kam 2 , S. van Os 1 ,<br />
G. Voortman 1 , L. Hooftman 1 , K. Burggraaf 2<br />
1 Clinical Operations, Synthon BV, Nijmegen, NETHERLANDS, 2 Cardiovascular<br />
Research, Center for Human Drug Research, Leiden, NETHERLANDS<br />
FTMB is a biosimilar of trastuzumab (Herceptin®), a humanized monoclonal<br />
antibody targeting <strong>the</strong> human epidermal growth factor receptor 2 (HER2).<br />
Herceptin® is registered for treatment of HER2-positive breast cancer and metastatic<br />
gastric cancer. Pharmacokinetic profiles of FTMB were compared to Herceptin® in<br />
this combined dose escalation and bioequivalence study. In <strong>the</strong> dose escalation part<br />
healthy male volunteers received single doses of 0.5, 1.5, 3.0 or 6.0 mg/kg FTMB in<br />
consecutive cohorts to assess <strong>the</strong> safety profile. At each dose level, subjects were<br />
randomized to FTMB (n = 6) or placebo (n = 2), with <strong>the</strong> exception of <strong>the</strong> 6 mg/kg<br />
cohort, where subjects were randomized to FTMB (n = 9), Herceptin® (n = 9) or<br />
placebo (n = 2). Safety data were evaluated by an independent data safety monitoring<br />
board. To establish bioequivalence a total of 92 healthy male subjects, including<br />
those of <strong>the</strong> 6 mg/kg dose escalation cohort, were randomized equally to FTMB or<br />
Herceptin®. Blood samples were taken prior and at regular, predefined time points up<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds392 | ix103
to 9 weeks after dosing. Trastuzumab levels were determined in serum with a<br />
validated bridging ELISA method. The mean area under <strong>the</strong> concentration-time<br />
curve from time zero to infinity (AUC 0-inf), normalized to 1 mg/kg and corrected for<br />
content differences between FTMB (Test) and Herceptin® (Reference) was 221.4 µg.d/<br />
mL for Test and 245.6 µg.d/mL for Reference. The ln-transformed Test/Reference (T/<br />
R) ratio for AUC 0-inf was 89.6% (90% confidence interval (CI): 85.1-94.4%),<br />
demonstrating bioequivalence based on <strong>the</strong> acceptance interval of 80.0-125.0%. For<br />
<strong>the</strong> secondary endpoint, maximum concentration observed (Cmax), <strong>the</strong> T/R ratio was<br />
89.4% (90% CI: 83.4-95.9%). Interestingly, <strong>the</strong> elimination of both FTMB and<br />
Herceptin® was shown to be non-linear. Adverse events o<strong>the</strong>r than <strong>the</strong> documented<br />
side effects of trastuzumab (fever, influenza-like illness, and fatigue) did not occur,<br />
and signs of cardiotoxicity were not observed. In conclusion, in this first<br />
bioequivalence study with a trastuzumab biosimilar in healthy male volunteers, single<br />
administration of FTMB was considered well tolerated in doses up to 6 mg/kg, and<br />
FTMB was demonstrated to be bioequivalent to Herceptin®.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
275P EFFICACY AND SAFETY OF TRASTUZUMAB IN SMALL HER2<br />
POSITIVE TUMORS. A SINGLE INSTITUTION EXPERIENCE<br />
M.V. Sano, E. Taibi, M. Alì, M. Chiarenza, S. Clementi, M. Caruso, R.A. Aiello<br />
Medical Oncology, Humanitas Centro Catanese di Oncologia, Catania, ITALY<br />
Background: Patients affected by breast cancer with negative lymph-node are<br />
considered at high risk if at least one of <strong>the</strong> following factors is present: tumor size ><br />
2 cm, HR negative, histological and/or nuclear grade 2-3 or age < 35 years. However<br />
some patients with HER2 positive cancers develop a recurrence despite small tumor<br />
size (< 2 cm) and none of <strong>the</strong>se factors. Four large trials confirmed <strong>the</strong> potential<br />
benefit of incorporating trastuzumab in adjuvant regimens as a standard treatment.<br />
The effectiveness of adjuvant trastuzumab has been demonstrated ei<strong>the</strong>r for node<br />
negative pT1c patients and for diseases at a higher risk. However <strong>the</strong>se trial were not<br />
able to provide any information regarding <strong>the</strong> outcome of patients with node<br />
negative tumours 0.05), respectively.<br />
Conclusions: Our data suggest that infra-centimetric HER2+ tumors are associated<br />
with a general poor outcome and Trastuzumab-based <strong>the</strong>rapies are justified. Future<br />
evaluation of dual anti-HER2 blockade in combination with chemo<strong>the</strong>rapy seems<br />
warranted in this setting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
277P SERUM CONCENTRATION OF ESTRONE (E1), NOT<br />
ESTRADIOL (E2), IS THE INDEPENDENT PREDICTIVE<br />
FACTOR OF RESPONSE TO NEO-ADJUVANT EXEMESTANE<br />
TREATMENT IN POSTMENOPAUSAL BREAST CANCER<br />
PATIENTS: JFMC 34-0601 TR<br />
S. Saji 1 , M. Takada 2 , N. Honma 3 , N. Masuda 4 , Y. Yamamoto 5 , K. Kuroi 6 ,<br />
H. Yamashita 7 , S. Ohno 8 , T. Ueno 9 ,M.Toi 9<br />
1 Target Therapy Oncology, Kyoto University Graduate School of Medicine, Kyoto,<br />
JAPAN, 2 Breast Surgery, Kyoto University, Kyoto, JAPAN, 3 Research Team For<br />
Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, JAPAN,<br />
4 Surgery and Breast Oncology, NHO Osaka National Hospital, Osaka, JAPAN,<br />
5 Breast and Endocrine Surgery, Kumamoto University, Kumamoto, JAPAN,<br />
6 Breast Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, JAPAN,<br />
7 Breast and Endocrine Surgery, Hokkaido University Hospital, Hokkaido, JAPAN,<br />
8 Breast Oncology, National Kyushu Cancer Center, Fukuoka, JAPAN, 9 Breast<br />
Surgery, Kyoto University Graduate School of Medicine, Kyoto, JAPAN<br />
Background: Local production of estrogen using aromatase at tumor site was thought to<br />
be <strong>the</strong> direct target of aromatase inhibitor (AI). However recent our works (Honma N,<br />
Can Sci 2011, Takada M, Breast <strong>2012</strong>) and o<strong>the</strong>rs (Lonning PE, Clin Can Res 2011)<br />
postulated that not local aromatase but whole body aromatase (possibly correlates to<br />
serum estrone (E1) level) would be <strong>the</strong> critical target of this drug.<br />
Patients and methods: Among <strong>the</strong> 116 postmenopausal patients who enrolled to <strong>the</strong><br />
JFMC 34-0601 phase II clinical trial of neo-adjuvant 24 weeks (wks) treatment with<br />
AI, exemestane, serums from 60 patients at pre-treatment, at 4wks and at <strong>the</strong> end of<br />
treatment (24wks) were subjected to this study. Estradiol (E2), E1,<br />
dehydroepiandrosterone (DHEA) and androstenedione (A) were measured using<br />
LC-MS/MS analysis for precise measurement, and E1- sulfate (E1S) was by RIA.<br />
Results: Mean pre-treatment serum levels of E2, E1 and E1S were 2.29, 12.86 and<br />
198.87 pg/ml, respectively. All <strong>the</strong>se estrogens decreased to under-detection level (0.5 pg/<br />
assay for E1 and E2, 5 pg/assay for E1S) at 4wks of treatment, and it maintained to <strong>the</strong><br />
end of <strong>the</strong> treatment in almost all patients irrespective of clinical response. Patients with<br />
higher concentration of pre-treatment E2 and E1 (cutoff = mean value) had more chance<br />
to obtain clinical objective response (p = 0.0245 and p = 0.0448, respectively). However<br />
in multivariate analysis, only E1 is <strong>the</strong> independent predictive factor for objective<br />
response (Odds 5.97, p = 0.0113), probably due to positive correlation of E2 to BMI,<br />
which is also predictive factor for AI response. When comparing pre-treatment level and<br />
those at 24wks (or at termination of treatment), patients with progressive disease showed<br />
significant increase of DHEA and A (p = 0.0313 for both), although patients with<br />
objective response maintained those at <strong>the</strong> same level.<br />
Conclusion: Pretreatment serum concentration of E1, not E2, is <strong>the</strong> independent<br />
predictive factor of clinical response to neo-adjuvant exemestane. Patients with<br />
disease progression showed significant increase of androgens during <strong>the</strong> treatment.<br />
Serum steroid concentrations using precise LC-MS/MS analysis may have <strong>the</strong><br />
informative value for <strong>the</strong> AI treatment, and <strong>the</strong> increased androgens would be <strong>the</strong><br />
important subject to be studied fur<strong>the</strong>r. (UMIN trial ID; C000000345)<br />
Disclosure: S. Saji: S.S. has a honorarium for lecture from Pfizer. M. Toi: M.T. has a<br />
research grant and honorarium for lecture from Pfizer. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
278P THE IMPACT OF PROGESTERONE RECEPTOR ON<br />
NODE-NEGATIVE BREAST CANCER SURVIVAL<br />
Annals of Oncology<br />
M. Solak 1 , F. Paksoy 2 , O. Keskin 1 , N. Kertmen 1 , M.K. Altundag 1<br />
1 Medical Oncology, Hacettepe University Oncology Institute, Ankara, TURKEY,<br />
2 Medical Oncology, Ankara Onkoloji Hastanesi, Ankara, TURKEY<br />
Background: The aim of this study was to evaluate tumor characteristics and survival rates<br />
of node-negative breast cancer patients according to progesterone receptor (PR) status.<br />
Methods: Of 2,218 breast cancer cases diagnosed between 1995 and 2011 in<br />
Hacettepe University, Institute of Oncology; 864 node-negative patients with known<br />
hormone receptor status were analyzed for age, tumor size, grade, lymphovascular<br />
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Annals of Oncology<br />
invasion and HER-2/neu status. Estrogen receptor (ER), PR and HER-2 status were<br />
determined using immunohistochemistry. Patients were classified into four groups;<br />
ER + /PR + , ER + /PR-, ER-/PR+ and ER-/PR-. Pearson Chi-Square test and<br />
Kaplan-Meier with log-rank test were performed for statistical analysis.<br />
Results: 575 (66.6%) patients had ER + PR + , 64 (7.4%) had ER + PR-, 43 (5.0%) had<br />
ER-PR+ and 182 (21.1%) had ER-PR- tumor. The median age of patients were 48 years<br />
(20-83) and were similar in all groups (p = 0.18). Majority of patients with PR- tumors<br />
were postmenopausal at <strong>the</strong> time of diagnosis (p = 0.021). The follow-up period was<br />
39.5 (1-273) months.<br />
Conclusions: Patients in PR- groups are more likely to have large-size and HER-2<br />
positive breast cancer. ER- groups are associated with high grade disease. Patients<br />
with PR+ breast cancer have significantly longer overall survival, compared to<br />
patients with ER+ tumors. Our data suggest that PR status is an important<br />
prognostic factor for node-negative breast cancer survival.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
279P PROGESTERON RECEPTOR STATUS IN DETERMINING THE<br />
PROGNOSIS OF ESTROGEN RECEPTOR POSITIVE /<br />
HER2-NEGATIVE BREAST CARCINOMA<br />
U. Yalcintas Arslan, O. Bal, T. Ozatli, K. Helvaci, O. Esbah, B. Budakoglu,<br />
U. Uyeturk, O.U. Sonmez, I. Turker, O.B. Oksuzoglu<br />
Department of Medical Oncology, Ankara Dr. A.Y.Oncology Research and<br />
Education Hospital, Ankara, TURKEY<br />
Background: The aim of this retrospective study was to determine whe<strong>the</strong>r<br />
progesteron receptor (PgR) status have an influence on <strong>the</strong> prognosis of estrogen<br />
receptor positive (ER+)/HER2-negative breast carcinoma (BC).<br />
Methods: We retrospectively reviewed <strong>the</strong> medical files of 1680 operable BC patients<br />
(pts) diagnosed between 1996 and 2011 and 456 of whom ER,PgR and HER2 status<br />
known were included in this study. Patients were categorized into 2 groups; as group<br />
A (ER + /PgR-/HER2-negative) and group B (ER + /PgR + /HER2-negative). Twenty<br />
one percent (97 pts) of <strong>the</strong> pts were in group A.<br />
Results: Median follow up was 33.5 (0-177) months. Median age was 54 (21-90) years.<br />
Sixty-one percent (278) of <strong>the</strong> pts had node-positive BC. Sixty percent (276) of <strong>the</strong> pts<br />
were postmenopausal. Eighty percent (365) of <strong>the</strong> pts received adjuvant chemo<strong>the</strong>rapy<br />
(ACT). Adjuvant hormono<strong>the</strong>rapy (AHT) was recommended to nearly all patients<br />
(mostly tamoxifen). Pts in group A had significantly higher lymph node positive disease<br />
as compared to group B (%70 vs 59%, p = .046). Although <strong>the</strong>re was no statistically<br />
significant difference between two groups for <strong>the</strong> first site of recurrence (mostly bone<br />
and soft tissue, p = .51), <strong>the</strong> number of recurrence and mortality events in group B were<br />
proportionally less than group A [27.8% and 21.2% for group B and 42.7% and 32.2%<br />
for group A;p = .005 and p = .004, respectively). In <strong>the</strong> node-positive subgroup, an<br />
important difference for relative risk RR of BC recurrence between groups A and B was<br />
found (34/68 vs 75/207, RR 1.3, CI:1.02-1.86, p = .034). But, <strong>the</strong> mortality risk was<br />
similar for lymph node-positive pts in groups A and B (16/63 vs 50/201,RR 1.0,<br />
CI:0.62-1.66,p = 0.93). Although DFS for group B was shorter, it was not statistically<br />
significant (5-year DFS rate 45% vs 35% p = .24). However, 5-year overall survival (OS)<br />
was significantly longer for pts in group B than group A (78% vs 67%,p = .043).<br />
Conclusions: PgR status has a great influence on <strong>the</strong> prognosis of BC pts especially<br />
negative PgR may have a significant negative influence on <strong>the</strong> prognosis of<br />
node-positive ER + /HER2- BC pts.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
280P ADJUVANT AROMATHASE INHIBITORS (AIS) HORMONE<br />
THERAPY (HT): WHICH REASONS LEAD PATIENTS (PTS) TO<br />
DISCONTINUE TREATMENT? A MONO INSTITUTIONAL<br />
ANALYSIS<br />
L. Moscetti 1 , M.A. Fabbri 1 , I. Sperduti 2 , P. Frittelli 3 , F. Nelli 1 , A. Massari 4 ,<br />
G. D’Auria 1 , L. Pompei 5 , E.M. Ruggeri 1<br />
1 Divisione di Oncologia, Ospedale Belcolle, ASL di Viterbo Oncology Unit,<br />
Viterbo, ITALY, 2 Biostatistics, Regina Elena Institute, Roma, ITALY, 3 Surgery,<br />
Breast Surgery, Ospedale Belcolle, ASL di Viterbo Oncology Unit, Viterbo, ITALY,<br />
4 Oncologia ed Ematologia, Anatomia Patologica, Ospedale Belcolle, ASL di<br />
Viterbo Oncology Unit, Viterbo, ITALY, 5 Oncologia ed Ematologia, Radioterapia,<br />
Ospedale Belcolle, ASL di Viterbo Oncology Unit, Viterbo, ITALY<br />
Background: AIs represents <strong>the</strong> standard HT for <strong>the</strong> adjuvant treatment of post<br />
menopausal endocrine sensitive early breast cancer. A percentage of pts interrupt<br />
treatment because of toxicity. In this setting <strong>the</strong> switch to o<strong>the</strong>r AIs or tamoxifen<br />
(TAM) may represent an option to allow <strong>the</strong> prosecution of HT. We reviewed <strong>the</strong><br />
main reasons for interruption of <strong>the</strong> AIs in our institution from 2006 to <strong>the</strong> present.<br />
Methods: 236 pts with a minimum treatment time up of 6 months were considered<br />
eligible for analysis. Pts characteristics: median age 64 yrs (35-89), median follow up<br />
24 months (6-28). Prior adjuvant CT: taxanes based: 47 pts, anthracyclines based: 43<br />
pts. 118 pts (49%) had received letrozole (L), 101 (43%) anastrozole (A), 18 (8%)<br />
exemestane (E). An alternative HT (AIs or tamoxifen [T]) was offered to pts who<br />
wanted or needed to interrupt permanently <strong>the</strong> ongoing drug.<br />
Results: According to <strong>the</strong> CTC NCI, arthralgia was <strong>the</strong> main toxicity observed (G1<br />
19.4%, G2/3 5.5%/1.7%. Overall 24 out of 236 pts (10%) needed discontinuation of<br />
AIs as a result of toxicity. Grade 2 and 3 arthralgia was <strong>the</strong> main reason for<br />
discontinuation in 13/24 pts (54%). No differences in <strong>the</strong> incidence of arthralgia were<br />
noted in pts who had received taxanes or anthracyclines. Headache (n = 2), alopecia<br />
(n = 2), G3 itching (n = 2), diffuse skin reaction (n = 1) allergic reaction with<br />
hypertensive crisis (n = 1), xerostomia and xerophthalmia (n = 1), insomnia (n = 1)<br />
and somnolence (n = 1) were <strong>the</strong> o<strong>the</strong>r reasons for discontinuance. In <strong>the</strong><br />
multivariate logistic regression analysis, age (65 yrs) and HT represent independent<br />
factors associated with <strong>the</strong> onset of arthralgia (respectively p = 0.006 and 0.008, OR<br />
2.65, CI95: 1.32-5.31). 17/24 pts were switched to E, 5 to T and 1 each to L and<br />
A. In pts who switched to ano<strong>the</strong>r AI we observed a reduction in <strong>the</strong> severity of <strong>the</strong><br />
arthralgia but not its complete resolution. A complete resolution of symptoms was<br />
observed for <strong>the</strong> o<strong>the</strong>r toxicities except for allergic reactions that recurred after<br />
switching from L to A. Moreover, <strong>the</strong> patient with <strong>the</strong> diffuse skin reaction, chose<br />
discontinuation of HT.<br />
Conclusions: In our analysis, 10% of pts discontinued AIs due to toxicity. Switching<br />
to alternative HT, and monitoring <strong>the</strong> toxicity, represent an option to offer to pts in<br />
order to avoid a premature and permanent interruption of an effective treatment.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
281P FOR WHICH PT1A, BN0M0 HORMONE RESPONSIVE INVASIVE<br />
BREAST CARCINOMAS COULD ENDOCRINE THERAPY BE<br />
AVOIDED?<br />
C. Perrin 1 , J. Edeline 1 , J. Leseur 2 , V. Lavoué 3 ,P.Tas 4 , H. Mesbah 5 ,<br />
C. Lefeuvre-Plesse 6 , D. Gedouin 6 , F. Penault-Llorca 7 , P. Kerbrat 1<br />
1 Medical Oncology Department, Eugène Marquis Center, Rennes, FRANCE,<br />
2 Radiation Department, Eugène Marquis Center, Rennes, FRANCE, 3 Surgical<br />
Oncology, University Hospital, Rennes, FRANCE, 4 Pathology Department,<br />
Eugène Marquis Center, Rennes, FRANCE, 5 Informations and Statistics, Eugène<br />
Marquis Center, Rennes, FRANCE, 6 Medical Oncology, Eugène Marquis Center,<br />
Rennes, FRANCE, 7 Dept. de Pathologie, Centre Jean Perrin, Clermont-Ferrand<br />
Cedex, FRANCE<br />
Background: Overtreatment is a daily concern in adjuvant setting for invasive breast<br />
carcinoma. Although chemo<strong>the</strong>rapy is <strong>the</strong> most controversial issue, endocrine<br />
<strong>the</strong>rapies must also be discussed.<br />
Methods: In this monocentric retrospective study, we analysed results of patients<br />
treated for hormone responsive invasive pT1a,bN0M0 breast cancer, focusing on <strong>the</strong><br />
population without adjuvant endocrine treatment. Women with previous history of<br />
invasive carcinoma were excluded.<br />
Results: In our institution, 382 patients with hormone responsive breast invasive<br />
pT1a,bN0M0 carcinoma were treated between 1997 and 2007. Local treatment<br />
involved ei<strong>the</strong>r mastectomy or partial breast surgery followed by breast<br />
radio<strong>the</strong>rapy. After multidisciplinary discussion, among <strong>the</strong> 382 patients, 162<br />
patients (42 %) did not receive any adjuvant endocrine treatment. Comparatively<br />
to <strong>the</strong> group treated with endocrine <strong>the</strong>rapy, <strong>the</strong>se patients had significantly<br />
more grade I tumors (81.4 % versus 47.2 %, p< 0.0001) and Ki67 < 14% (89.6%<br />
versus 72.4%, p < 0.0001). In patients not treated with endocrine <strong>the</strong>rapy, after a<br />
mean follow-up of 7.1 years, 5 years-disease free survival (DFS) was 93% and 5<br />
years-distant disease free survival was 98.7%. Remarkably, 5 years-DFS was<br />
particularly favourable for patients older than 50 years old (97.1% versus 82.1%<br />
for age < 50 years old, p = 0.0002) and for grade I carcinomas (97.3% versus<br />
76.7% for grade II-III, p= 0.0005). Only one metastatic recurrence occurred after<br />
10 years in <strong>the</strong> grade I group.<br />
Conclusion: This series of patients treated without adjuvant endocrine <strong>the</strong>rapies<br />
raises <strong>the</strong> issue of avoiding anti tumor endocrine <strong>the</strong>rapy in patients with hormone<br />
responsive pT1a,bN0M0, age> 50 years and grade I tumors.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
282P EVALUATION OF BONE MINERAL DENSITY (BMD) IN EARLY<br />
BREAST CANCER (EBC) PATIENTS TREATED WITH<br />
UP-FRONT OR SWITCH SCHEDULES OF AROMATASE<br />
INHIBITORS (AIS): RESULTS OF A SINGLE CENTRE<br />
RETROSPECTIVE STUDY<br />
P. Seminara 1 , A. Iannace 2 , G. Manna 2 , T. Losanno 2 , A. Emiliani 2 , E. Franzese 1 ,<br />
L. Frati 2<br />
1 Internal Medicine, Sapienza University, Rome, ITALY, 2 Department of<br />
Experimental Medicine, Sapienza University, Rome, ITALY<br />
Background: Aromatase inhibitors (AIs) are <strong>the</strong> standard adjuvant treatment of<br />
hormone responsive early breast cancer (EBC) in postmenopausal women. AIs are<br />
well tolerated but are associated with specific toxicities, including effect on bone<br />
(accelerated bone loss, bone fracture, osteoporosis) and musculoskeletal symptoms<br />
(ostealgia, arthralgia, myalgia) Aim: The present observational study investigated <strong>the</strong><br />
effect of BMD in postmenopausal women with EBC scheduled to receive AIs<br />
up-front or switch treatment after standard 2-3 years of adjuvant Tamoxifen<br />
(TAM-AIs).<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds392 | ix105
Patients and methods: We reviewed data for 89 patients with hormone<br />
receptor-positive EBC: 64 postmenopausal women received up-front AIs for 5 years;<br />
25 patients received TAM-AIs. BMD were assessed at baseline and during hormonal<br />
treatment once a year. Osteopenic patients received Calcium and vitamin D;<br />
osteoporotic patients received also oral biphosphonates.<br />
Results: No patient with a normal baseline BMD (T-score >-1) became osteoporotic<br />
during 5 years of follow-up. However, it was noted that more women receiving AIs<br />
up-front became osteopenic, as compared with TAMàAI treated women (AIs = 58%<br />
vs. TAM-AIs = 26%, p= 10% 86 124<br />
Unknown 10 25<br />
Results: SLN metastasis were found in 45 patientes in <strong>the</strong> OSNA group and in 49 in<br />
<strong>the</strong> historical group. There were no differences in rates of macrometastases (27 by<br />
OSNA, 41 by HE) and we found differences in micrometastasis rate (18 by OSNA<br />
and 8 by HE p =0.007). Axillary node dissection (ALND) was performed in 45<br />
patients in <strong>the</strong> OSNA group and in 49 in <strong>the</strong> historical group. All <strong>the</strong> patients<br />
diagnosed by OSNA had a complete ALND during <strong>the</strong> initial surgical procedure. In<br />
<strong>the</strong> historical cohort <strong>the</strong> ALND was performed during <strong>the</strong> initial surgical procedure<br />
in 41 patients, and ALND was performed in a second surgical procedure in 8<br />
patients.<br />
Conclusions: The OSNA assay can detect SLN metastasis as accurately as<br />
conventional pathology with increased detection of micrometastasis. The second<br />
surgery can be reduced with <strong>the</strong> OSNA assay.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
285P WHAT DO CLINICIANS DO WITH THE RESULTS OF THE<br />
SYSTEMATIC STAGING IMAGING AT THE TIME OF BREAST<br />
CANCER DIAGNOSIS?<br />
A. Turpin 1 , A. Mailliez 1 , P. Vennin 1 , J. Bonneterre 2<br />
1 Breast Cancer, Centre Oscar Lambret, Lille, FRANCE, 2 Breast Cancer, Centre<br />
Oscar Lambret, Université Lille Nord de France, Lille, FRANCE<br />
Introduction: Asymptomatic distant metastases are often looked for at <strong>the</strong> time of<br />
initial diagnosis of early breast cancer. However, <strong>the</strong>re is no consensus on when to<br />
perform it and on <strong>the</strong> consequences on <strong>the</strong> treatment.<br />
Patients and methods: 125 asymptomatic women receiving systemic neoadjuvant<br />
(33 patients (pts)) or adjuvant treatment (92 pts) for breast cancer at <strong>the</strong> Oscar<br />
Lambret Center in 09/2011 were considered. The staging imaging was a PET scan: 59<br />
pts, a CT scan + a bone scan: 61 pts and both: 5 pts. Results for each procedure were<br />
considered normal, abnormal but typically benign or potentially malignant. In this<br />
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Annals of Oncology<br />
case, ano<strong>the</strong>r imaging technique was carried out to confirm <strong>the</strong> suspected diagnosis.<br />
The patient was considered metastatic if <strong>the</strong> results of two different procedures were<br />
concordant and eventually in case of response to chemo<strong>the</strong>rapy. 1 patient had a<br />
biopsy (liver). 22 pts were Stage 1, 58 Stage 2, 44 Stage 3. 1 o<strong>the</strong>r patient had an<br />
excision of a recurrence on mastectomy scar.<br />
Bone scan + CT<br />
scan<br />
PET<br />
scan Both Total<br />
Pts 61 59 5 125<br />
Potentially<br />
malignant<br />
lesions<br />
13 8 2 23 (including<br />
confirmed<br />
malignant)<br />
Malignant lesions 5 2 2 9<br />
Benign lesions 33 15 1 49<br />
Confirmatory Procedures 19 19 2 40<br />
Results: 9 pts were considered metastatic (7%): 5 bone, 2 liver, 1 lung and 1 spleen.<br />
There was 1 Stage 1, 4 Stage 2, and 4 Stage 3. 3 of <strong>the</strong> 5 pts in <strong>the</strong> neoadjuvant<br />
setting were operated on (2 after <strong>the</strong> planned chemo<strong>the</strong>rapy: 1 complete response of<br />
lung metastasis and 1 sternal lesion treated by boost and 1 after modified protocol<br />
for unique liver lesion which will be treated by Cyberknife®). The 2 o<strong>the</strong>rs had bone<br />
lesions, received modified protocol and did not have surgery. For <strong>the</strong> pts in <strong>the</strong><br />
adjuvant setting, 2 received <strong>the</strong> full treatment (1 continued Trastuzumab beyond <strong>the</strong><br />
year planned), 1 received modified protocol of chemo<strong>the</strong>rapy <strong>the</strong>n radio<strong>the</strong>rapy and<br />
hormono<strong>the</strong>rapy and <strong>the</strong> last one received chemo<strong>the</strong>rapy alone.<br />
Conclusion: In this population of 125 pts selected for (neo) adjuvant chemo<strong>the</strong>rapy,<br />
40 imaging procedures were performed to check <strong>the</strong> lesions. 9 pts were considered as<br />
metastatic and only 5 had had a significant modification of <strong>the</strong>ir treatment. A<br />
systematic imaging staging in pts selected for adjuvant chemo<strong>the</strong>rapy should not be<br />
recommended.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
286P PROGNOSTIC AND PREDICTIVE VALUES OF BI-RADS<br />
CLASSIFICATION IN BREAST CANCER PATIENTS<br />
Y. Kuo 1 , L. Cheng 2 , T. Chang 1<br />
1 Surgery, National Cheng Kung University, Tainan, TAIWAN, 2 Radiology, National<br />
Cheng Kung University, Tainan, TAIWAN<br />
Objective: The goal of this study is to determine <strong>the</strong> prognostic and predictive values<br />
of <strong>the</strong> Breast Imaging Reporting and Data System (BI-RADS) classification in breast<br />
cancer patients.<br />
Patients and methods: 1045 patients with breast cancer were disgnosed between<br />
January 1, 1999, and December 31, 2007, and 512 (48.9%) of <strong>the</strong>m were classified as<br />
BI-RADS 5. Overall survival and disease-free survival were estimated with <strong>the</strong><br />
Kaplan-Meier method and compared across <strong>the</strong> two groups (BI-RADS 5 versus<br />
BI-RADS 0-4) using <strong>the</strong> log-rank test. Univariate and multivariate analyses were used<br />
to identify <strong>the</strong> prognostic factors.<br />
Results: The median follow-up time was 87.8 months. Laplan-Meier analysis showed<br />
a significant difference between <strong>the</strong> two subgroups in five-year overall survival (p <<br />
0.0001) and five-year disease-free survival (p < 0.0001). On multivariate analysis, <strong>the</strong><br />
BI-RADS mammographic findings, lymph node status, HER-2 status, and tumor<br />
grade were significant factors related to five-year overall survival and disease-free<br />
survival.<br />
Conclusion: The BI-RADS classification is a reliable prognostic and predictive factor.<br />
Taiwanese breast cancer patients with BI-RADS 5 mammographic finding showed a<br />
higher relapse rate than patients with BI-RADS 0-4 mammographic finding.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
287P STUDY OF STROMAL CD10 OVEREXPRESSION IN INVASIVE<br />
BRAEST CANCER AND ITS RELATIONSHIP WITH<br />
CLINCOPHATHOLOGIC FACTORS<br />
A. Taghizadeh Kermani 1 , A. Jafarian 2 , R. Ashabe Yamin 2 , M. Seilanian Toosi 1 ,<br />
L. Pourali 3 , A. Omidi Ashrafi 2<br />
1 Oncology, MUMS, Mashhad, IRAN, 2 Pathology, MUMS, Mashhad, IRAN,<br />
3 Gynecology, MUMS, Mashhad, IRAN<br />
Background: Carcinoma of <strong>the</strong> breast is <strong>the</strong> most common non-skin malignancy in<br />
women. Invasion and metastasis are considered as <strong>the</strong> major causes of cancer-related<br />
morbidity and mortality. It has long been proposed that secreted proteinases,<br />
including <strong>the</strong> matrix metalloproteinases, play an important role in tumor progression<br />
and mediating extracellular matrix remodeling. More recently, it has been suggested<br />
that extracellular proteinases also regulate growth factors and cytokines that may<br />
contribute to tumor progression. CD10 is a 90-110kd cell surface zinc-dependent<br />
metalloprotease. Since CD10 is structurally similar to matrix metalloproteinase and<br />
stromelysin it may facilitates cancer cell invasion and/or metastasis. The aim of this<br />
study was to investigat <strong>the</strong> rate of CD10 expression in <strong>the</strong> stromal cells of invasive<br />
ductal carcinomas of breast immunohistochemically and clarify its corelation with<br />
o<strong>the</strong>r clinicopathological factors of <strong>the</strong> disease.<br />
Methods: 100 patients with histopathologic diagnosis of IDC and 50 patients with<br />
fibroadenoma of breast (as <strong>the</strong> control group) were selected and 150 parafin blocks<br />
were obtained. The stained slides by IHC method for CD10 marker were examined<br />
separately by two pathologists and discrepancies were reviewed in a common session<br />
to get <strong>the</strong> final result.<br />
Results: Stromal CD10 was detected in 28% of <strong>the</strong> IDC. No immunoreactivity was<br />
identified in <strong>the</strong> stromal cells of normal breast. Stromal CD10 expression in IDC was<br />
significantly correlated with tumor size (P < 0.001), histologic grade (P < 0.001), <strong>the</strong><br />
presence of nodal metastases (P < 0.001) and estrogen receptor negative status (P =<br />
0.003).<br />
Conclusion: Stromal CD10 expression in IDC is closely correlated with invasion and<br />
metastasis and it may play an important role in <strong>the</strong> pathogenesis of IDC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
288P PROGNOSTIC TOOLS IN EARLY BREAST CANCER:<br />
PREDICTING BENEFIT OF ADJUVANT CHEMOTHERAPY<br />
E.E. Parkes 1 , C. Davidson 1 , A. Hussain 1 , C.R. James 1 , G.G. Hanna 2<br />
1 Medical Oncology, Nor<strong>the</strong>rn Ireland Cancer Centre, Belfast, UNITED<br />
KINGDOM, 2 Centre for Cancer Research and Cell Biology, Queens University<br />
Belfast, Belfast, UNITED KINGDOM<br />
Introduction: Adjuvant chemo<strong>the</strong>rapy (CT) in early breast cancer reduces <strong>the</strong> risk of<br />
mortality. However, absolute reductions in mortality can be small. For patient with<br />
low risk disease prognostic tools such as ‘Adjuvant! Online’ (AO) and ‘Predict’ (PD)<br />
can be used to estimate <strong>the</strong> benefit of adjuvant chemo<strong>the</strong>rapy. We compare <strong>the</strong><br />
survival gains estimated using AO and PD in routine clinical practice, assessing <strong>the</strong><br />
characteristics of patients in which AO and PD disagree.<br />
Methods: In a retrospective study using <strong>the</strong> hospital electronic database, <strong>the</strong><br />
clinical and pathological details of all patients with early breast cancer referred<br />
for adjuvant <strong>the</strong>rapy at <strong>the</strong> Nor<strong>the</strong>rn Ireland Cancer Centre in a 3 month period<br />
in 2011 were collected and were entered in to AO and PD to assess percentage<br />
benefit (absolute reduction in mortality at 10 years) from CT. We categorised<br />
patients into three prognostic groups: those where risk from CT outweighs<br />
benefit (5%) We excluded patients with metastatic disease at<br />
presentation, DCIS, a second primary breast cancer or receiving neo-adjuvant<br />
treatment.<br />
Results: Of <strong>the</strong> 200 patients identified, 43 (21.5%) fell in to different prognostic<br />
groups depending on whe<strong>the</strong>r AO or PD was used to calculate benefit from CT. In<br />
total, AO suggested marginal or significant benefit in 69.8% of patients, compared to<br />
60.4% using PD. Eight patients had “major” comorbidities, which is weighted only in<br />
AO, and were excluded in subsequent analysis. Of those without major<br />
comorbidities, AO offered at least 2% benefit in 80% of cases, and PD in only 57.1%.<br />
The majority (91.4%) of cases were ER positive, and node negative (82.9%). This<br />
difference was notable in women aged 65 or less, with 83.3% with >2% benefit using<br />
AO, and 61.1% using PD. AO estimates of benefit were on average 3.7% higher for<br />
this age group. HER2 status had little impact, with similar recommendations using<br />
ei<strong>the</strong>r AO or PD.<br />
Conclusions: This study highlights lack of concordance between two available online<br />
prognostic tools, notably in ER positive, node negative patients. For patients with a<br />
marginal benefit from CT, care must be used when making adjuvant treatment<br />
decisions.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
289P A STUDY OF THE IMPACT OF THE 21-GENE BREAST CANCER<br />
ASSAY ON THE USE OF ADJUVANT CHEMOTHERAPY IN<br />
WOMEN WITH BREAST CANCER IN A MEXICAN PUBLIC<br />
HOSPITAL<br />
J.E. Bargallo-Rocha 1 , F. Lara 1 , R.J. Shaw Dulin 1 , V. Perez-Sánchez 1 ,<br />
C. Villarreal-Garza 1 , H. Maldonado-Martinez 1 , A. Mohar-Betancourt 2 ,<br />
C. Yoshizawa 3 ,E.Burke 4 , C. Chao 4<br />
1 Breast Cancer Clinic, Instituto Nacional de Cancerología (INCan), Mexico City,<br />
MEXICO, 2 Biomedical Research, Instituto Nacional de Cancerología (INCan),<br />
Mexico City, MEXICO, 3 Biostatistics, Genomic Health, Inc., Redwood City, CA,<br />
UNITED STATES OF AMERICA, 4 Medical Affairs, Genomic Health, Inc.,<br />
Redwood City, CA, UNITED STATES OF AMERICA<br />
Background: The majority of early stage breast cancer patients in Mexico are treated<br />
through <strong>the</strong> public health system, and >80% are treated with chemo<strong>the</strong>rapy (CT).<br />
The 21-gene assay (Oncotype DX®) is available in Mexico but has been utilized<br />
primarily within <strong>the</strong> private health system. There are no data that describe <strong>the</strong><br />
potential impact of <strong>the</strong> assay on adjuvant treatment decision-making for public<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds392 | ix107
sector patients. The aim of this study is to characterize how assay results impact <strong>the</strong><br />
decision-making process and confidence of public sector physicians in Mexico to<br />
determine adjuvant <strong>the</strong>rapy. This is <strong>the</strong> first decision impact study of <strong>the</strong> Oncotype<br />
DX assay in Latin America.<br />
Methods: At total of 98 consecutive patients with ER + , HER2-, stage I-IIIa, N0/<br />
N1-3 breast cancer from <strong>the</strong> Instituto Nacional de Cancerologia in Mexico City,<br />
Mexico, were enrolled in <strong>the</strong> study. Via consensus discussion in multidisciplinary<br />
team meetings, physicians completed pre- and post-assay questionnaires<br />
regarding adjuvant treatment recommendations for each enrolled patient. The<br />
primary endpoint was <strong>the</strong> overall change in physician treatment<br />
recommendations resulting from <strong>the</strong> addition of <strong>the</strong> Recurrence Score® result in<br />
<strong>the</strong> decision-making process.<br />
Results: Pre- and post-assay results were available for 96 patients. Treatment<br />
decisions changed for 31/96 (32%: 95% CI 23%-43%) patients; 17/62 (27%; 95%<br />
CI 17%-40%) N0 and 14/34 (41%; 95% CI 25%-59%) N1-3 patients. Post-assay,<br />
8/50 (16%) of patients initially recommended hormonal <strong>the</strong>rapy (HT) were<br />
recommended chemohormonal <strong>the</strong>rapy (CHT) or CT, and 21/46 (46%) of<br />
patients initially recommended CHT/CT were recommended HT alone. The<br />
proportion of patients recommended CT decreased from 48% pre- to 34%<br />
post-assay (p = 0.024), a decrease of 14% overall, 6% in N0, and 26% in N1-3<br />
patients.<br />
Conclusions: These results suggest that use of <strong>the</strong> 21-gene assay in <strong>the</strong> Mexican<br />
public health system has an impact on adjuvant treatment recommendations and<br />
may reduce <strong>the</strong> use of chemo<strong>the</strong>rapy.<br />
Pre-Assay<br />
Post-Assay<br />
Adjuvant Therapy HT alone CT + HT CT alone Total<br />
HT alone 42 (44%) 7 (7%) 1 (1%) 50 (52%)<br />
CT + HT 21 (22%) 23 (24%) 2 (2%) 46 (48%)<br />
Total 63 (66%) 30 (31%) 3 (3%) 96<br />
Disclosure: C. Yoshizawa: Genomic Health- Employment and Stockholder. E. Burke:<br />
Genomic Health- Employment and Stockholder. C. Chao: Genomic Health-<br />
Employment and Stockholder. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
290P BROWN FAT SEEN ON FDG PET/CT IS INCREASED IN<br />
BREAST CANCER PATIENTS COMPARED TO THEIR AGE-<br />
AND WEIGHT-MATCHED CONTROLS WITH OTHER CANCERS<br />
K.H.R. Tkaczuk 1 , Q. Cao 2 , L. Jones 1 , M. Smith 2 , S. Chumsri 1 , J. Jenkins 2 ,<br />
V. Dilsizian 2 , W. Chen 2<br />
1 Medicine, University of Maryland Greenebaum Cancer Center, Baltimore, MD,<br />
UNITED STATES OF AMERICA, 2 Radiology, University of Maryland, Baltimore,<br />
MD, UNITED STATES OF AMERICA<br />
Purpose: We previously found increased brown fat deposits in mammary tissue of<br />
Rrca1 mutant breast cancer mouse models suggesting a potential role of brown fat<br />
environment in <strong>the</strong> early breast tumorigenesis. The goal of <strong>the</strong> current human study<br />
is to test <strong>the</strong> hypo<strong>the</strong>sis that <strong>the</strong> prevalence of brown fat activity seen on FDG PET/<br />
CT is increased in breast cancer (BC) patients.<br />
Methods: We conducted a retrospective study to assess <strong>the</strong> distribution and<br />
intensity of brown fat activity on FDG PET/CT in female BC patients compared to<br />
age- and weight-matched control subjects with o<strong>the</strong>r cancers mostly colon cancer.<br />
We analyzed 124 FDG PET/CT scans of BC patients done at <strong>the</strong> University of<br />
Maryland and 124 age- and weight-matched control subjects who had FDG PET/<br />
CT scan on <strong>the</strong> same day for staging of o<strong>the</strong>r cancers (<strong>the</strong> majority were colon<br />
cancer).<br />
Results: The prevalence of brown fat was higher in BC (12.9% or 16/124) than<br />
in <strong>the</strong>ir age- and weight-matched control subjects (5.6% or 7/124) (p < 0.05).<br />
When <strong>the</strong> data was stratified by age, among those who were ≤ 50 years old, <strong>the</strong><br />
prevalence of brown fat was 35.5% (11/31) in BC patients versus 9.1% (3/33) in<br />
<strong>the</strong> controls (p 50 years of age,<br />
<strong>the</strong>re was no difference in brown fat prevalence between BC patients and<br />
controls (5.4% or 5/93 vs 4.4% or 4/91; p = NS), respectively. Brown fat was<br />
more commonly identified in <strong>the</strong> bilateral supraclavicular regions in BC patients<br />
than controls (22 vs 6, p = 0.049). There was no difference in <strong>the</strong> intensity of<br />
brown fat between <strong>the</strong> 2 groups (mean SUV max = 3.5 ± 1.5 in BC vs 3.4 ± 0.7 in<br />
controls, p = NS).<br />
Conclusion: The prevalence of brown fat seen on FDG PET/CT is increased in BC<br />
patients compared to <strong>the</strong>ir age- and weight-matched controls with o<strong>the</strong>r cancers,<br />
particularly in patients aged 2 cm, number of positive LN<br />
(≥4), high tumor grade (G3), and negativity of hormone receptor in univariate<br />
analyses. However, in multivariate analyses, number of positive LN ≥4 (HR = 2.47;<br />
95% CI, 1.07-5.74; p = 0.035), high tumor grade (HR = 2.76; 95% CI, 1.08-7.09, p =<br />
0.034), and over-expression of p53 (HR = 6.55; 95% CI, 2.40-17.85, p < 0.001) were<br />
independent poor prognostic factors for RFS. And p53 over-expression was also<br />
related to poor OS (HR = 3.93; 95% CI, 1.04-14.81, p = 0.044). Patients with high p53<br />
expression (≥10% of positive cells) tended to have tumors with large size, higher<br />
grade and lower hormone receptor positivity compared to those of low p53<br />
expression.<br />
Conclusions: p53 over-expression along with number of positive LN and tumor<br />
grade was found to be useful biomarker to predict poor outcomes in patients with<br />
LN-positive breast cancer receiving docetaxel-based adjuvant chemo<strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
292P SERUM LEVELS OF VEGF PRE- AND POST-TREATMENT<br />
WITH BEVACIZUMAB (BEV) FOR EARLY STAGE BREAST<br />
CANCER (ESBC): ICORG 08-10<br />
A.M. Canonici 1 , I. Parker 2 ,T.O’Shea 2 , B. Moulton 2 , G. Gullo 3 , M.J. Kennedy 4 ,<br />
D. Tryfonopoulos 5 , N. Walsh 6 ,N.O’Donovan 6 , J.P. Crown 7<br />
1 NICB, Dublin City University, Dublin, IRELAND, 2 ICORG, Dublin, IRELAND,<br />
3 St Vincent’s University Hospital, Department of Medical Oncology, Dublin,<br />
IRELAND, 4 Dept Medical Oncology, St James’s Hospital, Dublin, IRELAND,<br />
5 Medical Oncology Unit, St Vincents University Hospital, Dublin, IRELAND,<br />
6 National Institute for Cellular Biotechnology, Molecular Therapeutics for Cancer<br />
Ireland, Dublin City University, Dublin, IRELAND, 7 Department of Medical<br />
Oncology, St Vincents University Hospital, Dublin, IRELAND<br />
Background: Angiogenesis, partly mediated by vascular endo<strong>the</strong>lial growth factor<br />
(VEGF), promotes metastases. BEV, an anti-VEGF monoclonal antibody which has<br />
some efficacy in metastatic BC is being studied as an adjuvant treatment for ESBC.<br />
However, <strong>the</strong>re are no validated biomarkers, and <strong>the</strong> effects of BEV on VEGF levels<br />
in pts with ESBC is unknown. We studied VEGF serum concentration in ESBC<br />
receiving BEV.<br />
Methods: 106 pts with HER-2 negative ESBC were included in this study. Patients<br />
received 4 cycles of docetaxel (75 mg/m2) + cyclophosphamide (600 mg/m2) with<br />
BEV (15 mg/kg) once every three weeks for one year. Serum samples were collected<br />
prior to commencement of treatment, at 6 months and 12 months. The VEGF levels<br />
in serum samples were determined, at each time point, using a VEGF enzyme-linked<br />
immunosorbent assay (ELISA).<br />
Results: VEGF concentration was determined in serum samples from 65 patients.<br />
Serum VEGF was detectable in 62 of 65 patients and <strong>the</strong> median level in untreated<br />
patients was 325.4 pg/ml (range 0.1 - 924.8 pg/ml). All of <strong>the</strong> 62 patients showed a<br />
significant decrease in VEGF concentration after 6 and 12 months of treatment<br />
(median 9 ± 42.1 pg/ml, p < 0.001 and 9 ± 43.9 pg/ml, p < 0.001 respectively). No<br />
significant change in median VEGF levels observed at 12 months compared to 6<br />
months (median 0 ± 60.3 pg/ml, p = 0.704). However, in 14 patients <strong>the</strong> levels of<br />
VEGF detected at 12 months were higher than at 6 months following treatment (p =<br />
0.045).<br />
Conclusion: Adjuvant <strong>the</strong>rapy with chemo<strong>the</strong>rapy and BEV is associated with a<br />
significant reduction in VEGF levels at 6 months.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix108 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
293P QUANTIFICATION OF TUMOR-SPECIFIC DNA IN BLOOD OF<br />
HEALTHY WOMEN AND BREAST CANCER PATIENTS<br />
S.N. Tamkovich 1 , V.A. Myleiko 1 , A.V. Starikov 2 , V.I. Permyakova 3 , V.V. Vlassov 1 ,<br />
P.P. Laktionov 1<br />
1 Cellular Biology Group, Institute of Chemical Biology and Fundamental<br />
Medicine, Novosibirsk, RUSSIAN FEDERATION, 2 Mammology Department,<br />
National Novosibirsk Regional Oncologic Dispensary, Novisibirsk, RUSSIAN<br />
FEDERATION, 3 Hematology Department, Central Clinical Hospital, Novisibirsk,<br />
RUSSIAN FEDERATION<br />
Despite of tumor location DNA from cancer cells was shown to got in circulating<br />
blood, thus DNA circulating in blood represent <strong>the</strong> valuable source of diagnostic<br />
material for non-invasive blood based tests for cancer.<br />
Material and methods: Blood from healthy female (n = 50) and breast cancer<br />
patients (n = 23, T1-2, N0-1, M0) were fractionated into plasma and cellular<br />
fractions, cell-surface-bound cirDNA (csbDNA) were eluted from cell surface with<br />
PBS/EDTA and trypsin solutions [1]. Total DNA was quantified with TaqMan PCR<br />
for LINE-1 repeats [2], methylated DNA of RARβ2 gene promoter was quantified<br />
with methylation-specific SYBR Green Real Time PCR [3].<br />
Results: Breast cancer patients had significantly higher mean concentration of<br />
methylated RARβ2 gene promoter in circulating DNA (cirDNA) and csbDNA<br />
fractions as compared to healthy controls: 192 vs. 132 pg/ml and 619 ng/ml vs. 413<br />
pg/ml, respectively; P < 0.005. No correlation was found between cirDNA levels and<br />
stage of tumor. ROC-curve analysis demonstrated sensitivity and specificity of<br />
cirDNA-based breast cancer detection as 52% and 65% respectively for cut-off value<br />
of 0.61 for plasma tumor cirDNA and 70% and 61% respectively for cut-off value of<br />
0.75 when cirDNA and csbDNA were analysed simultaneously. The data obtained<br />
demonstrate that along with cirDNA csbDNA provides a valuable source of material<br />
for breast cancer diagnostics. 1. Clin. Chem., 2005. V. 51. P. 1317-1319. 2. Anal.<br />
Biochem., 2011. V. 408. P. 354-356. 3. Eur. J. Cancer Prev., 2011. V. 20. P. 453-455.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
294P HIGH FREQUENCY OF BRCA 1/2 MUTATIONS AMONG<br />
ISRAELI NON ASHKENAZI BREAST CANCER PATIENTS<br />
F. Elyan 1 , O. Maimon 2 , A.F. Salah 3 , M. Sagi 1 , L. Kaduri 2 , I. Lerer 1 , Y. Goldberg 1 ,<br />
T. Hamburger 2 , D. Bercovich 4 , T. Peretz-Yablonski 5<br />
1 Department of Human Genetics, Hadassah-Hebrew University Medical Center,<br />
Jerusalem, ISRAEL, 2 Sharett Institute of Oncology, Hadassah-Hebrew University<br />
Medical Center, Jerusalem, ISRAEL, 3 Oncology and Radio<strong>the</strong>rapy, Hadassah<br />
University Hospital Hebrew University Medical Center, Jerusalem, ISRAEL, 4 Cga-<br />
Galil Genetic Analysis and Migal- Galilee Bio- Technology Center, CGA- Galil<br />
Genetic Analysis and Migal- Galilee Bio- Technology Center, Galil, ISRAEL,<br />
5 Sharett Institute of Oncology, Hadassah University Hospital Hebrew University<br />
Medical Center, Jerusalem, ISRAEL<br />
Background: Inherited mutations in <strong>the</strong> breast cancer susceptibility genes (BRCA1<br />
and BRCA2) are associated with a high risk of developing breast (BC) and ovarian<br />
cancers (OC) in females of different age and ethnic groups. The spectrum of<br />
mutations in <strong>the</strong>se genes varies between populations, with some showing a high<br />
frequency of unique mutations. Ashkenazi Jews have a high rate of founder<br />
mutations in BRCA1/2, in some o<strong>the</strong>r Jewish communities in Israel (Jews who<br />
immigrated to Israel from Iraq, Iran and Yemen), o<strong>the</strong>r founder mutations had been<br />
identified. Still high proportions of Israeli BC cases with strong family history have<br />
none of <strong>the</strong> known mutations at <strong>the</strong> BRCA1/2 genes.<br />
Methods and patients: Over 3000 breast cancer patients were evaluated in <strong>the</strong><br />
oncogentic clinic during 1997-2011. One hundred thirty seven of <strong>the</strong>m underwent<br />
full sequencing of <strong>the</strong> BRCA1/2 genes due to strong family history of breast and/or<br />
ovarian cancer or young age at presentation. Clinical and pathological characteristics<br />
of <strong>the</strong>se patients were evaluated.<br />
Result: Sixty seven percent were non Ashkenazi Jews, Mean age at BC onset was 44<br />
(22-77). In 20 patient (15%) BRCA 1(N = 8) or 2 (N = 12) mutations were identified.<br />
Three of <strong>the</strong> carriers had bilateral BC and 5 had OC as second primary .17 were of<br />
non Ashkenazi origin. Ninety five percent of <strong>the</strong> carriers had first degree family<br />
history of breast or ovarian cancer. The pathological information was available in half<br />
of <strong>the</strong> carriers. All had high grade (2-3) tumor, 90% of <strong>the</strong>m were HER2 negative<br />
and 60% ER positive. Age at presentation had no effect on BRCA1/2 status.<br />
BRCAPRO is a predictive model to assess BRCA status and has assessed in 9<br />
carriers, in 6 of <strong>the</strong>m, <strong>the</strong> probability was >80% and in one - 5%.<br />
Conclusions: A full sequence of <strong>the</strong> BRCA1/2 genes was performed in a selected<br />
group pf BC patient, who were negative for <strong>the</strong> common founder mutation in Israel.<br />
Fifteen percent were found to carry o<strong>the</strong>r BRCA1/2 mutations. We recommend that,<br />
patients with <strong>the</strong> following clinical features: Sephardic origin, first degree family<br />
history of BC or OC, high grade tumor, HER-2 negative, should be offered full<br />
BRCA1/2 testing. The role of BRCAPRO and o<strong>the</strong>r predictive model should be<br />
fur<strong>the</strong>r evaluated.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
295P CONCOMITANT USE OF ANTIDEPRESSANT DRUGS AND<br />
TAMOXIFEN<br />
L. Binkhorst 1 , R.H.J. Mathijssen 1 , M.P.P. van Herk-Sukel 2 , M. Bannink 3 , E.A.<br />
C. Wiemer 1 , T. van Gelder 4<br />
1 Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam,<br />
NETHERLANDS, 2 Oncology, PHARMO Institute, Utrecht, NETHERLANDS,<br />
3 Psychiatry, Erasmus MC, Rotterdam, NETHERLANDS, 4 Hospital Pharmacy,<br />
Erasmus MC, Rotterdam, NETHERLANDS<br />
The CYP2D6 enzyme is primarily involved in <strong>the</strong> metabolism of tamoxifen into its<br />
most important metabolite endoxifen. The efficacy of tamoxifen <strong>the</strong>rapy may be<br />
influenced by genetic polymorphisms of this enzyme and CYP2D6-inhibiting<br />
co-medication (e.g. antidepressant drugs). It is <strong>the</strong>refore generally recommended to<br />
avoid potent CYP2D6 inhibitors (e.g. paroxetine, fluoxetine) in tamoxifen patients.<br />
In this study, we examined whe<strong>the</strong>r women using tamoxifen still received strong<br />
CYP2D6-inhibiting antidepressants concomitantly during <strong>the</strong> period 2005-2010.<br />
Drug dispensing data for tamoxifen and seven antidepressants associated with<br />
CYP2D6 inhibition (paroxetine, fluoxetine, sertraline, fluvoxamine, (es)citalopram<br />
and venlafaxine), were obtained from <strong>the</strong> community pharmacy database of <strong>the</strong><br />
PHARMO Institute. This database contains dispensing data of > 3 million people<br />
in <strong>the</strong> Ne<strong>the</strong>rlands. Concomitant use of CYP2D6-inhibiting antidepressants in<br />
women using tamoxifen, as well as <strong>the</strong> use of antidepressants in <strong>the</strong> total<br />
population, were determined per year using PASW Statistics 17.0 (SPSS Inc.,<br />
Chicago, IL). Prevalence of <strong>the</strong> use of <strong>the</strong> four most common antidepressants<br />
among tamoxifen users, expressed as <strong>the</strong> number of women receiving an<br />
antidepressant concurrently with tamoxifen per 1000 tamoxifen users, is shown in<br />
<strong>the</strong> table. Although <strong>the</strong>re is a downwards trend for paroxetine, this drug is still<br />
one of <strong>the</strong> most frequently used antidepressants in tamoxifen patients. In addition,<br />
a similar trend was observed in <strong>the</strong> total population of <strong>the</strong> database. Venlafaxine<br />
and citalopram, associated with weak CYP2D6-inhibiting properties, are<br />
increasingly co-prescribed.<br />
2005 2006 2007 2008 2009 2010<br />
Paroxetine 47.1 44.3 46.6 41.7 36.9 28.8<br />
Fluoxetine 9.5 10.6 9.8 10.7 10.8 9.7<br />
Citalopram 17.0 23.5 22.4 26.2 25.2 28.5<br />
Venlafaxine 18.3 23.8 28.2 27.5 29.1 30.8<br />
Despite <strong>the</strong> strong biological rationale to avoid potent CYP2D6-inhibiting<br />
co-medication in tamoxifen treated patients, paroxetine is still often used along with<br />
tamoxifen. In clinical practice, one should be extremely alert to co-medication in<br />
<strong>the</strong>se patients. It is advised that strong CYP2D6 inhibitors are switched to weaker<br />
CYP2D6-inhibiting alternatives, if possible.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
296P ITEM RESPONSE THEORY AND FACTOR ANALYSIS AS MEAN<br />
TO CHARACTERIZE OCCURRENCE OF RESPONSE SHIFT FOR<br />
LONGITUDINAL QUALITY OF LIFE STUDY IN BREAST<br />
CANCER PATIENTS<br />
A. Anota 1 , C. Bascoul-Mollevi 2 , F. Guillemin 3 , T. Conroy 4 , M. Velten 5 , D. Jolly 6 ,<br />
M. Mercier 7 , S. Causeret 8 , T.S. Dabakuyo 9 , F. Bonnetain 9<br />
1 Plateform of Clinical Research "Quality of Life and Cancer", University hospital of<br />
Besançon, Besançon, FRANCE, 2 Biostatistic Unit, Centre Val-d’Aurelle - Paul<br />
Lamarque, Montpellier, FRANCE, 3 Clinical Epidemiology and Evaluation<br />
Department, CIC-EC, Nancy, FRANCE, 4 Oncology, Centre Alexis Vautrin,<br />
Vandoeuvre les Nancy Cedex, FRANCE, 5 Epidemiology and Public Health<br />
Laboratory, College of Medicine, Strasbourg, FRANCE, 6 Création Du Pôle<br />
Recherche Et Innovations, University Hospital, Reims, FRANCE, 7 Clinical<br />
Research Unit In Quality of Life, CHU Jean Minjoz, Besancon, FRANCE,<br />
8 Surgery, Centre Georges François Leclerc, Dijon, FRANCE, 9 Biostatistic and<br />
Epidemiological Unit(ea 4184), Centre Georges François Leclerc, Dijon, FRANCE<br />
Aims: Health-related quality of life (HRQoL) is a dynamic process which depends<br />
on <strong>the</strong> adaptation of <strong>the</strong> patient and reflected by a Response Shift (RS) effect. RS<br />
results in a recalibration, a reprioritization and a reconceptualization of key HRQoL<br />
domains. Longitudinal analyses of HRQoL have to take into account <strong>the</strong> possible<br />
occurrence of RS. However, <strong>the</strong>re is no standard of statistical analysis to characterize<br />
RS. Two complementary methods are investigated to characterize RS.<br />
Methods: This work builds on data of a prospective multicenter study including all<br />
primitive breast cancer patients or suspicion. HRQoL was evaluated using <strong>the</strong><br />
EORTC QLQ-C30 and QLQ-BR23 at baseline, after surgery, at 3 months and<br />
6 months, according to <strong>the</strong> « <strong>the</strong>n-test/post-test » design: <strong>the</strong> retrospective<br />
assessments done after surgery and at 3 months refer to baseline HRQoL; <strong>the</strong><br />
retrospective measurement done at 6 months refers to HRQoL at 3 months. The<br />
order <strong>the</strong>n-test and post-test of HRQoL questionnaires was randomized.<br />
Recalibration was explored by Multiple Correspondence Analyses (MCA) and <strong>the</strong><br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds392 | ix109
Linear Logistic Model with Relaxed Assumptions (LLRA) of Item Response Theory<br />
(IRT). LLRA gives trend of item easiness parameters. Reprioritization and<br />
reconceptualization were explored by Principal Component Analyses (PCA).<br />
Results: Between February 2006 and February 2008, 381 patients were included, 90%<br />
had a confirmed breast cancer. PCA show a secondary reprioritization of <strong>the</strong><br />
QLQ-C30’s dimensions. Fatigue and pain remain priority symptoms. Secondary<br />
symptoms are insomnia at baseline, diarrhea after surgery, nausea and vomiting at 3<br />
months and 6 months. A stronger and stronger link between functional scales reflects<br />
a reconceptualization. Main recalibration’s profiles reflected by MCA are from one<br />
modality to an adjacent one. A lower or upward recalibration of each dimension is<br />
reflected by <strong>the</strong> IRT model. Based on retrospective assessment at six months of<br />
HRQoL at three months, arm and breast symptoms were overestimated with trend<br />
parameters equal to -0.59 and -1.05 (p < 0.001).<br />
Conclusions: IRT models have mainly been used to validate HRQoL questionnaires.<br />
This work shows <strong>the</strong>ir interest to characterize occurrence of RS. Fur<strong>the</strong>r analyses<br />
should be lead to validate <strong>the</strong>ir abilities to characterize all RS components.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
297P PROFESSIONAL ATTITUDES TOWARDS TREATMENT OF<br />
RARE HISTOLOGICAL SUBTYPES OF CARCINOMAS OF THE<br />
BREAST: AN INTERNATIONAL PRACTICE SURVEY (PARIS<br />
STUDY)<br />
Z. Fadoukhair 1 , D. Lefeuvre 2 , K. Hofert 3 , E. Lanoy 2 , R. Rahhali 4 , M. Mathieu 5 ,<br />
C. Mazouni 6 , S. Delaloge 1<br />
1 Breast Cancer Unit, Department of Medical Oncology, Institut Gustave Roussy,<br />
Villejuif, FRANCE, 2 Biosatitistics, Gustave Roussy, villejuif, FRANCE, 3 Medical<br />
Oncology, University of liverpool, liverpool, UNITED KINGDOM, 4 Medical<br />
Oncology, National Institute of Oncology, Rabat, MOROCCO, 5 Department of<br />
Pathology, Institut Gustave Roussy, Villejuif, FRANCE, 6 Breast Cancer Unit,<br />
Department of Surgery, Institut Gustave Roussy, Villejuif, FRANCE<br />
Background: WHO classification has identified a dozen rare subtypes that account<br />
for less than 10% of all breast cancers (BC). They are generally not taken into<br />
account in international/national treatment (trt) guidelines. We evaluated<br />
professionals’ attitudes towards decision making regarding rare BC subtypes and<br />
<strong>the</strong>ir need for consensus guidelines.<br />
Methods: This international survey was conducted among 236 international BC<br />
experts including surgeons, pathologists, medical oncologists and radiation<br />
oncologists. Experts were chosen to be representative of all regions of <strong>the</strong> world.<br />
They were selected if part of regional, national or international BC guidelines<br />
committee(s), or active member of a BC-directed scientific society, or author > 50<br />
publications in <strong>the</strong> field of BC. They were contacted through email up to three times<br />
and were asked to fill an online questionnaire.<br />
Results: 86 experts from 32 countries responded (36%). A total of 50% were medical<br />
oncologists, 21% surgeons, 17% pathologists and 12% radiation oncologists. 77% of<br />
<strong>the</strong> experts declared <strong>the</strong>y based <strong>the</strong>ir general BC care decisions on regional, national<br />
or international guidelines. Up to 76% declared individual routine trt decisions for<br />
BC were taken by multi-disciplinary boards in <strong>the</strong>ir practice. However, only 10%<br />
strongly considered rare BC should be treated following national or international<br />
guidelines without specific individualisation. Interestingly, 50-80% described<br />
individualising treatment for rare breast cancers according to pathological subtype of<br />
<strong>the</strong> tumour in <strong>the</strong>ir practice. Three specific clinical situations of rare BC presented<br />
were associated with > 50% heterogeneity in trt decision among <strong>the</strong> 86 experts.<br />
Answers were associated with both region of residency and medical subspecialty.<br />
However, more than 90% of experts answered <strong>the</strong>y would welcome international<br />
recommendations for rare BC subtypes.<br />
Conclusion: Rare BC subtypes are diagnosed and managed very heterogeneously<br />
depending on geographical location, habits and specialist training of medical<br />
professionals. There is need for international consensus guidelines regarding <strong>the</strong>ir<br />
diagnosis and trt.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
298P PROFILE OF MALE BREAST CANCER: SINGLE INSTITUTION<br />
STUDY OF 76 PATIENTS FROM NORTHERN INDIA<br />
A. Gogia 1 , V. Raina 2 , S.V.S. Deo 3 , B.K. Mohanti 4 , N.K. Shukla 3<br />
1 Medical Oncology, All India Institute of Medical Sciences (AIIMS) Institute Rotary<br />
Cancer Hospital, New Delhi, INDIA, 2 Dept. of Medical Oncology, All India<br />
Institute of Medical Sciences (AIIMS) Institute Rotary Cancer Hospital, New Delhi,<br />
INDIA, 3 Surgical Oncology, AIIMS, New Delhi, INDIA, 4 Radiation Oncology, All<br />
India Institute of Medical Sciences (AIIMS) Institute Rotary Cancer Hospital, New<br />
Delhi, INDIA<br />
Background: Male breast cancer (MBC) is a rare disease and accounts for 1 % of all<br />
breast cancer. The aim of our study was to assess clinical, pathological parameters<br />
and outcome in MBC.<br />
Methods: This analysis was carried out in 76 male breast cancer patients with<br />
confirmed case of MBC who were registered in our breast cancer clinic between<br />
Annals of Oncology<br />
1996-2011 at Institute Rotary Cancer Hospital, All India Institute of Medical<br />
Sciences (AIIMS). Analysis was performed with descriptive statistics, <strong>the</strong> log rank test<br />
was used to compare outcome.<br />
Results: The median age was 56 years (range 28-80). The median duration of<br />
symptoms was 10 months (range 0.5-120). Breast lump was <strong>the</strong> commonest (93%)<br />
presenting symptom (right > left side). TNM Stage distribution was stage I -3 %,<br />
stage II- 20%, stage III- 55%, and stage IV- 22%. Positive family history was elicited<br />
in 8 (10.5%) patients. The median clinical tumour size was 3.9 cm. Modified Radical<br />
mastectomy was <strong>the</strong> commonest surgical procedure. IDC was <strong>the</strong> most common<br />
histology. Sixty percent of tumours were high grade and 55% had pathological node<br />
positive disease. ER/PR, her2neu status was available in 75% and 65% respectively.<br />
ER/PR and her2neu positivity was 90% and 30% respectively. Triple negative breast<br />
cancer (TNBC) constituted 20%. Median follow up was 36 months. Ten patients had<br />
relapsed of which 70% were distant, bone being <strong>the</strong> most common site followed by<br />
lung and liver. Five years disease free (DFS) and overall survival (OS) was 40% and<br />
60%. Higher nodal stage, tumour size (>5 c.m.), negative ER/PR status, positive<br />
her2neu status, and visceral metastasis at baseline predicted poor outcome.<br />
Conclusion: Our population had more advanced disease at presentation, higher<br />
her2neu positivity and higher triple negative status as compared to western<br />
population results in poorer outcome.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
299 ASSOCIATION OF ALPHA2A AND BETA2 ADRENOCEPTORS<br />
EXPRESSION WITH CLINICAL OUTCOME IN BREAST CANCER<br />
Y. Du, J. Lu<br />
Breast Surgery, Shanghai Cancer Center Fudan University, Shanghai, CHINA<br />
Previous studies have shown that alpha2-adrenoceptor antagonists can inhibit <strong>the</strong><br />
growth of breast cancer cells. The action of beta2 adrenoceptors on cell proliferation<br />
is still controversial. In this study, we investigated <strong>the</strong> association of alpha2a and<br />
beta2 adrenoceptors expression with tumor-relevant biological markers and clinical<br />
outcome. Immunohistochemistry assay was performed on paraffin-embedded tumors<br />
to detect alpha2a and beta2 adrenoceptor expression in 220 operable breast tumors.<br />
We initially demonstrated that alpha2a expression was associated with Her-2 status<br />
(P = 0.048) and a marginal significance was observed between alpha2a expression and<br />
ER (P = 0.061). We also find that beta2 expression was not associated with any<br />
tumor-relevant biological markers. Kaplan-Meier models trended to show<br />
associations between different beta2 expression and DFS (P = 0.092). Fur<strong>the</strong>r analysis<br />
was made and we found in hormone receptor positive breast cancer patients, strong<br />
beta2 expression correlated with better DFS than weak beta2 expression (P = 0.031).<br />
Multivariate analysis demonstrated that beta2 adrenoceptor (HR = 0.31, P = 0.039)<br />
and lymph node (HR = 2.85, P = 0.031) were independent predictors of DFS in<br />
hormone receptor positive breast cancer patients. In conclusion, this study showed<br />
that strong alpha2a expression occurred in ER positive and Her-2 negative breast<br />
cancers. In hormone receptor positive breast cancer patients, strong beta2 expression<br />
correlates with better DFS than weak beta2 expression. In hormone receptor positive<br />
breast cancer patients, beta2 ADR could be an independent predictors of DFS. Our<br />
results also suggest that <strong>the</strong> expression of beta2 adrenoceptor may be regulated by<br />
estrogen and progesterone or intercross may exist between <strong>the</strong> two pathways of beta2<br />
adrenoceptor and hormone receptor.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
300 THE PERCENTAGE OF CD44-/CD24-/LIN- CELLS IN PRIMARY<br />
BREAST TUMORS AND CORRELATION BETWEEN<br />
PROGNOSTIC FACTORS<br />
E. Yetimoglu1 , D. Cabuk2 , E. Karaoz3 ,S.Kaya2 , S. Temiz2 , O. Acikgoz2 ,<br />
K. Uygun2 , Z. Canturk4 , E. Yirmibesoglu5 , G. Aksu5 1<br />
Internal Medicine, Kocaeli University Medical School Hospital, Kocaeli, TURKEY,<br />
2<br />
Medical Oncology, Kocaeli University Medical School Hospital, Kocaeli,<br />
TURKEY, 3 Kocaeli University Center for Stem Cell and Gene Therapies Research<br />
and Practice, Kocaeli University Medical School Hospital, Kocaeli, TURKEY,<br />
4<br />
General Surgery, Kocaeli University Medical School Hospital, Kocaeli, TURKEY,<br />
5<br />
Radiation Oncology, Kocaeli University Medical School Hospital, Kocaeli,<br />
TURKEY<br />
Introduction: Breast cancer (BC) is associated with different molecular profiles and<br />
histological types. Different histological types contain cells with different phenotype<br />
and genotype. Many hypo<strong>the</strong>ses have been taken for understanding <strong>the</strong> causes of<br />
breast cancer’s heterogenecity. One of <strong>the</strong>se is breast cancer stem cell hypo<strong>the</strong>sis. The<br />
hypo<strong>the</strong>sis was proposed that cancers contain a subpopulation of cells similar to<br />
epi<strong>the</strong>lial stem cells. There are many methods used for identification of BC stem<br />
cells. One of <strong>the</strong>se methods is using cell surface markers. BC stem cells are defined<br />
by <strong>the</strong> phenotype CD44 + /CD24-/low/Lin-. The aim of this study is to investigate<br />
<strong>the</strong> percentages of CD44 + /CD24-/low/Lin- cells and <strong>the</strong> correlation between stem<br />
cells and prognostic factors in primary BC.<br />
Material and method: Twenty three women who underwent surgery for BC between<br />
May 2010 and January 2011 were enrolled in this study. Fresh tumor tissues were<br />
ix110 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
broken up enzymatically and CD44 + /CD24-/low/Lin- cell phenotype was idendified<br />
by using surface marker antibodies. The percentage of this phenotype was<br />
determined by surface marker expression of <strong>the</strong> cells by using flowcytometry.<br />
Results: The mean age of <strong>the</strong> patients (pts) was 47 and 52% had early stage BC.<br />
CD44 + /CD24-/low/Lin- cells were present in all tumor tissues and <strong>the</strong> mean<br />
percentage of <strong>the</strong>se cells was 1.43 ± 1.16%. The percentage of CD44 + /CD24-/low/<br />
Lin- cells was higher in postmenopausal women, early stage, Her-2 negative and low<br />
grade tumors, but it was not statistically significant. There was inverse correlation<br />
between involved lymph node numbers and <strong>the</strong> percentage of CD44 + /CD24-/low/<br />
Lin- cells but it was not statistically significant. There was no statistically significant<br />
correlation between <strong>the</strong> percentage of CD44 + /CD24-/low/Lin- cells and menopausal<br />
status, stage, grade, number of lymph nodes, hormone reseptors and HER-2 status.<br />
Conclusion: In our study CD44 + /CD24-/low/Lin- cells were present in all tumor<br />
tissues and <strong>the</strong> mean percentage of <strong>the</strong>se cells was 1.43 ± 1.16% as shown in previous<br />
studies. But <strong>the</strong>re was no statistically significant correlation between prognostic<br />
factors and <strong>the</strong> percentage of <strong>the</strong> CD44 + /CD24-/low/Lin- cells.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
301 EARLY BREAST CANCER AGRESSIVENESS DOES NOT DIFFER<br />
BETWEEN INSULIN-SENSITIVE AND INSULIN-RESISTANT<br />
POSTMENOPAUSAL NON-DIABETIC WOMEN<br />
H.K. van Halteren 1 , S.B. Bins 2 ,W.DeRoos 3 , A. Bosch 3 , J. Klein Gunnewiek 4 ,<br />
E. Ruijter 5 , J. Enserink 3<br />
1 Department of Internal Medicine, Ziekenhuis Gelderse Vallei, Ede,<br />
NETHERLANDS, 2 Internal Medicine, Gelderse Vallei Hospital, Ede,<br />
NETHERLANDS, 3 Surgery, Gelderse Vallei Hospital, Ede, NETHERLANDS,<br />
4 Clinical Chemistry, Gelderse Vallei Hospital, Ede, NETHERLANDS, 5 Pathology,<br />
Alysis Hospital, Arnhem, NETHERLANDS<br />
Background: The metabolic syndrome is known to negatively influence breast cancer<br />
outcome. One of <strong>the</strong> syndromès components is hyperinsulinism, which can exert<br />
tumor-promoting effects directly or through increased hepatic IGF1-production. A<br />
fasting insulin concentration > 10 µIU/ml and/or a HOMA score > 2.6 are considered<br />
diagnostic for <strong>the</strong> metabolic syndrome. We performed a pilot study to evaluate <strong>the</strong><br />
relation between insulin resistance and tumor characteristics.<br />
Study design: Prior to surgery we collected blood samples of 33 consecutive<br />
non-diabetic postmenopausal women with early breast cancer to measure fasting<br />
insulin and glucose concentration. Correlation analyses were performed for both<br />
fasting insulin and HOMA-score (insulin resistance index) and parameters tested<br />
were body mass index, mitotic activity index (MAI), Bloom Richardson score (BNR)<br />
and tumor diameter. We also compared nodal status, ER-status and Her2-status of<br />
insulin-resistant and insulin-sensitive breast cancer patients.<br />
Results: Median age was 66 (49- 86) years and median BMI was 25.8 (18.6- 45.4) kg/<br />
m2. Median MAI was 7 (1-52), median tumor diameter was 12 (3- 70) mm and 9<br />
patients had node-positive disease ( 2 N0itc, 5 N1, 2 N2). Insulin resistance was<br />
found in 5 (15 %) patients. BMI showed a strong positive correlation with insulin<br />
concentration and HOMA score (2-sided Pearson test; P= 0.000). Insulin resistant<br />
and insulin sensitive patients however did not differ in terms of MAI, BNR, tumor<br />
diameter, nodal status, ER-status and Her2-status.<br />
Conclusion: In postmenopausal non-diabetic women with early breast cancer insulin<br />
resistance is encountered quite often. It does however not appear to alter cancer<br />
biology.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
302 STUDY ON SERUM HER2 EXTRACELLULAR DOMAIN<br />
EXPRESSION IN EARLY STAGE BREAST CANCER PATIENTS<br />
L. Ma 1 , H. Yang 2 ,J.Li 3 ,F.Wang 2 , X. Han 3 ,Y.Shi 1<br />
1 Medical Oncology, Cancer Institute/Hospital, Beijing, CHINA, 2 Pathology,<br />
Cancer, Beijing, CHINA, 3 Clinical Laboratory, Cancer Institute/Hospital, Beijing,<br />
CHINA<br />
Background: The measurement of <strong>the</strong> human epidermal growth factor receptor 2<br />
(HER2) protein in <strong>the</strong> serum of metastatic breast cancer patients has now been<br />
reported, but <strong>the</strong>re are no consistent data to support <strong>the</strong> clinical utility of serum<br />
HER2 extracellular domain (ECD) for patients with early breast cancer. We aimed to<br />
evaluate <strong>the</strong> correlation between serum HER2 ECD levels and tumor HER2 status,<br />
and analyze <strong>the</strong>ir relationship with clinicopathological parameters in patients with<br />
early stage disease.<br />
Methods: A prospective study was conducted on 232 breast cancer patients with<br />
stage I-II diseases before treatment. Preoperative serum samples were measured by<br />
enzyme-linked immunosorbent assay (ELISA). Tissue HER2 status was analyzed by<br />
immunohistochemistry and fluorescence in situ hybridization assays.<br />
Results: The median serum HER2 ECD concentration was 6.8 ng/ml (range 1.3 -<br />
42.1 ng/ml). The best diagnostic cut-off value was 7.4 ng/ml (with 72.9% sensitivity<br />
and 85.3% specificity), which was lower than HER2 ECD cut-off value with<br />
metastasis breast cancer (15 ng/ml). High serum HER2 ECD levels were reported in<br />
89 patients (38.3%) and HER2 tissue positive expression was observed in 77 patients<br />
(33.2%) with a moderate concordance of 76.7%. Elevated serum HER2 ECD<br />
correlated with postmenopausal (p < 0.001), high tumor grade (p < 0.001), negativity<br />
of both estrogen (p = 0.007) and progesterone receptors (p < 0.001), high level of<br />
carbohydrate antigen 153 (CA153) (p = 0.039) and tissue polypeptide specific antigen<br />
(TPS) (p = 0.018).<br />
Conclusion: HER2 ECD, which is associated with poor prognosis, may provide more<br />
additional information compared with HER2 tissue alone. We support that it is<br />
necessary to decrease <strong>the</strong> cut-off value in evaluating serum HER2 ECD level for early<br />
stage breast cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
303 CLINICAL RELEVANCE OF HORMONE RECEPTORS, KI67 AND<br />
HER-2 STATUS AS BIOMARKERS SURROGATE FOR BREAST<br />
CANCER MOLECULAR SUBTYPES: A RETROSPECTIVE<br />
ANALYSIS OF DISEASE FREE SURVIVAL IN PATIENTS WITH T1<br />
N0/N+ BREAST CANCER<br />
A. Emiliani 1 , A. Iannace 1 , G. Nigita 2 , T. Losanno 1 , G. Manna 1 , E. Franzese 3 ,<br />
L. Frati 1<br />
1 Department Experimental Medicine, Sapienza University, Rome, ITALY, 2 Division<br />
of Surgery, Policlinico Casilino, Rome, ITALY, 3 Internal Medicine, Sapienza<br />
University, Rome, ITALY<br />
Background: Early breast cancer (EBC) is a heterogeneous disease with distinct<br />
clinical, pathological, and molecular features and different treatment responsiveness<br />
and outcomes. Aim of study was to evaluate outcomes according to molecular<br />
subtypes breast cancer classified by four biomarkers using immunohistochemistry<br />
(IHC).<br />
Patients and methods: We retrospectively reviewed 264 women with T1 N0/N+<br />
breast cancer, referred to a single centre (1986 - 2009) and treated according to<br />
European guidelines. The relationships between classical prognostic factors,<br />
molecular subtypes classified by IHC and Disease free survivals (DFS) were analyzed.<br />
Results: Univariate survival analysis showed a significantly different DFS at 5- and<br />
7-ys for N0 and N+ patient populations, with a better outcome for patients with<br />
node-negative tumors (5ys: N0 = 95.9% vs. N + =88.8, p = 0.03; 7ys: N0 = 94.8% vs.<br />
N + =86.0%, p = 0.02). Never<strong>the</strong>less, long-term outcome (15-ys) displayed an<br />
inversion of <strong>the</strong> survival curves with a lower DFS rate of 65% in N0 vs. 86% in N+<br />
patients (p < 0.0001). Regarding to Ki-67 tumor expression, patients with low Ki67<br />
values (Ki-67 < 14%) had a better 5-ys DFS compared to patients with high Ki-67<br />
(Ki-67 ≥ 14%). A significant difference in DFS has been observed also considering<br />
<strong>the</strong> tumor grading (G1 = 100%, G2 = 88%, G3 = 94.4%, p = 0.03). Based on molecular<br />
subtypes breast cancer classification by IHC, <strong>the</strong> 5-ys DFS rate was 98.4% for<br />
Luminal A (HR + , HER2-, Ki-67 < 14%), 96.3% for Luminal B HER2 negative (HR<br />
+ , HER2-, Ki-67 ≥ 14%), 83.3% for Luminal B HER2 positive (HR + , HER + , any<br />
Ki-67), 83.6% for HER2-like (HR-, HER2+) and 74.5% for Basal-like tumors (HR-,<br />
HER2-).<br />
Conclusions: At long-term follow-up, patients with T1N0 and patients with G2 EBC<br />
showed worst outcomes, probably because <strong>the</strong>y are considered to have a low<br />
recurrence risk and not received adjuvant chemo<strong>the</strong>rapy. Ki-67 expression is an<br />
important prognostic factor in hormone-receptors positive disease, allowing better<br />
definition of Luminal A and B molecular subtypes. Classic prognostic factors<br />
evaluated by IHC could be used as biomarkers surrogate for breast cancer molecular<br />
subtypes and might improve <strong>the</strong>rapeutic decision in EBC patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
304 PROGNOSTIC VALUE OF CIRCULATING TUMOR CELLS IN<br />
EARLY BREAST CANCER PATIENTS DETECTED BY RT-PCR<br />
OF MAMAGLOBIN<br />
A.M. Hilal 1 , H.M. Elzawahrey 1 , A.A. Abd Elwahab 2 , M.N. Abdelhafez 1 ,<br />
M.M. Moneer 3 , A.D. Darwish 1<br />
1 Medical Oncology, National Cancer Institute, Cairo, EGYPT, 2 Molecular Biology,<br />
National Cancer Institute, Cairo, EGYPT, 3 Epidemiology & Biostatistics, National<br />
Cancer Institute, Cairo, EGYPT<br />
Background: The identification of circulating tumor cells (CTC) could potentially<br />
become an important prognostic factor in breast cancer patient. The aim of this<br />
prospective study is to detect CTC in <strong>the</strong> blood of breast cancer patients and to<br />
correlate between detection of CTC and o<strong>the</strong>r prognostic factors, disease free survival<br />
and overall survival.<br />
Material and methods: The study was conducted at medical oncology department<br />
NCI, Cairo University during <strong>the</strong> period from August 2008 to August 2011. Forty<br />
two consecutive consenting female patients with non metastatic breast cancer who<br />
ended <strong>the</strong>ir adjuvant chemo<strong>the</strong>rapy and radio<strong>the</strong>rapy at least 2 years were recruited.<br />
Detection of CTC in <strong>the</strong> blood of our patients was done by measuring <strong>the</strong> gene<br />
expression for mammaglobin by RT-PCR, and <strong>the</strong>n <strong>the</strong> relative fold change was<br />
calculated relatively to normal samples.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds392 | ix111
Results: The median CTC fold changes were 9.3, ranging from 0 to 20.8 in <strong>the</strong> whole<br />
studied group while zero for <strong>the</strong> control group. There was a highly statistically<br />
significant difference (p = 0.001) between CTC fold changes for stage IIIA compared<br />
to stage II tumor, and a statistical significance (p = 0.070) in favor of higher CTC<br />
fold changes in those with Her2-neu receptor positivity. There was no significant<br />
correlation between higher CTCs and o<strong>the</strong>r factors related to <strong>the</strong> patients or disease<br />
characteristics. There was also no relation between CTC fold changes and overall<br />
survival or disease free survival.<br />
Conclusion: In this small study, mammaglobin is considered a sensitive marker for<br />
detection of CTC in breast cancer. CTC fold changes are correlated with tumor stage<br />
and Her2 status. Fur<strong>the</strong>r studies including larger number of patients and followed for<br />
longer period are recommended to evaluate this protocol more thoroughly.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
305 IMMUNOHISTOCHEMICAL KI67 LABELING INDEX HAS A<br />
SIMILAR PROLIFERATION PREDICTIVE POWER AS VARIOUS<br />
FIRST-GENERATION GENE SIGNATURES IN BREAST CANCER<br />
N. Niikura 1 , T. Iwamoto 2 , S. Masuda 3 , N. Kumaki 4 , M. Shirane 5 , K. Mori 5 ,<br />
T. Okamura 1 , Y. Saito 1 , Y. Suzuki 1 , Y. Tokuda 1<br />
1 Breast and Endocrine Surgery, Tokai University School of Medicine, Kanagawa,<br />
JAPAN, 2 Department of Breast and Endocrine Surgery, Okayama University<br />
Hospital, Okayama, JAPAN, 3 Department of Pathology, Nihon University School<br />
of Medicine, Tokyo, JAPAN, 4 Department of Pathology, Tokai University School<br />
of Medicine, Kanagawa, JAPAN, 5 Product Research, Chugai Pharmaceuticals<br />
Co. Ltd, Kanagawa, JAPAN<br />
Background: Immunohistochemical assessment of Ki67 labeling index (IHC Ki67)<br />
has been described as a prognostic and predictive marker for breast cancer. On <strong>the</strong><br />
o<strong>the</strong>r hand, several genetic prognostic markers have been described for breast cancer<br />
However, few clinical data sets provide information on correlations between genomic<br />
markers, mRNA Ki67, and IHC Ki67 in <strong>the</strong> same cohort of patients with survival<br />
data. The objective of this study is to examine <strong>the</strong> association between<br />
immunohistochemical Ki67 labeling index, Ki67 mRNA expression level, and<br />
first-generation gene signatures in a cohort of breast cancer patients.<br />
Patients and methods: We assessed associations between IHC Ki67 and<br />
first-generation gene signatures in a panel of 40 tumor samples, using an<br />
oligonucleotide microarray. Gene expression analyses included Ki67 alone (MKi67),<br />
21-gene signature, Mitosis Kinome score signature (MKS), and Genomic grade index<br />
(GGI). Correlation coefficients were calculated by Spearman’s rank correlation test.<br />
To assess <strong>the</strong> relationship between IHC Ki67 and survival outcomes, survival curves<br />
were calculated by <strong>the</strong> Kaplan–Meier method and compared with <strong>the</strong> log-rank test<br />
according to IHC Ki67.<br />
Results: Median age at diagnosis was 51 years. Treatments included adjuvant<br />
chemo<strong>the</strong>rapy (32 patients) and endocrine <strong>the</strong>rapy (21 patients). IHC Ki67, MKi67,<br />
and 3 genetic markers were highly correlated in all cases (Rho: 0.71–0.79). Estrogen<br />
receptor (ER)-positive cases exhibited strong correlations between IHC Ki67 and<br />
o<strong>the</strong>r signatures (Rho: 0.79–0.83). ER-negative cases displayed slightly lower<br />
correlations (Rho: 0.61–0.74). In ER-positive cases, <strong>the</strong> low IHC Ki67 group<br />
exhibited significantly longer relapse-free survival (RFS) than <strong>the</strong> high IHC Ki67<br />
group (p = 0.007). This difference was confirmed by multivariate analysis.<br />
Conclusions: Our data indicate that IHC Ki67 exhibits similar predictive power for<br />
proliferation in ER-positive cancers as genomic markers. Fur<strong>the</strong>r study of IHC Ki67<br />
is needed to define prognostic factors and predictive factors for chemo<strong>the</strong>rapy using<br />
central laboratory assessment.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
306 ONCOTYPE DX® - THE SíRIO-LIBANêS HOSPITAL CANCER<br />
CENTER EXPERIENCE<br />
A.A.L. Pereira 1 , A.K. Shimada 1 , F.C. Santini 1 , E.C. Nascimento 2 , K.B. Ribeiro 3 ,<br />
R.J. Marques 1 , M.S. Mano 1 , A. Katz 4<br />
1 Centro de Oncologia - 2° Andar, Sirio Libanes Hospital, Sao Paulo, BRAZIL,<br />
2 Imunohistoquímica e Biologia Molecular, Diagnostika, Sao Paulo, BRAZIL,<br />
3 Instituto de Ensino e Pesquisa, Sirio Libanes Hospital, Sao Paulo, BRAZIL,<br />
4 Centro de Oncologia, Sirio Libanes Hospital, Sao Paulo, BRAZIL<br />
Background: The Oncotype Dx® recurrence score (RS) assay quantifies <strong>the</strong> risk of<br />
distant recurrence (rDR) and its use has increased despite <strong>the</strong> lack of prospective<br />
studies.<br />
Methods: This is a cross-sectional study of consecutive patients (PTS) from our<br />
Institution with histologically confirmed invasive breast cancer (IBC) who underwent<br />
surgery with curative intent and in whom Oncotype Dx (ODx) was performed. The<br />
main objectives were to compare (1) <strong>the</strong> predicted rDR by RS and Adjuvant! (2) Risk<br />
allocation by RS and St Gallen Criteria and (3) <strong>the</strong> agreement between histological<br />
grading (HG) and RS.<br />
Annals of Oncology<br />
Results: From October/2006 to April/<strong>2012</strong>, 105 PTS with ER positive IBC were<br />
evaluated. Median age: 55y. Sixty-eight (64.8%) were EC IA; axillary lymph node<br />
involvement was seen in 25 PTS (14 micro and 11 macrometastasis). The rDR by RS<br />
was low in 64 PTS (60.9%), intermediate in 34 (32.4%) and high in 7 (6.7%).<br />
According to Saint Gallen, 12 (12%), 68 (68%) and 20 PTS (20%) were classified as<br />
low, intermediate and high risk, respectively, among 100 classifiable PTS. There was<br />
no statistically significant agreement between risk allocation by RS and Saint Gallen<br />
criteria (Kappa coefficient = -0.043; p = 0.401). Ki-67 data was available for 89 PTS:<br />
Annals of Oncology<br />
Aim: Retrospective analysis of relapse free (RFS) and overall survival (OS) in HER2+<br />
BC patients treated with adjuvant trastuzumab in years 2005-09.<br />
Results: Adjuvant T received 317 patients, median age 53 (min 23; max 78) years.<br />
Ninety five percent were invasive ductal carcinoma and 97% grade 2/3, 55% were ER<br />
positive. Tumor stage was T1 (29%), T2 (48%), T3 (11%), T4 (10%), unknown (2%).<br />
N stage was N0 (26%), N1 (50%), N2 (16%), N3 (7%), unknown (1%). All patients<br />
recieved adjuvant chemo<strong>the</strong>rapy, 41% anthracycline-based, 48% anthracycline and<br />
taxane- based. The median follow-up time was 4.5 (min 0.7; max 6.9) years. There<br />
were 66 relapses and 28 deaths. RFS was 98.1, 92.3, 84.2 and 80.8% at 1, 2, 3, 4 years,<br />
resp. OS was 99.7, 96.6, 93.4 and 92.5%, at 1, 2, 3, 4 years, resp. The independent<br />
prognostic factor for RFS were T stage (HR 1.2 95% CI1.0-1.4) and N stage (HR1.3<br />
(1.1-1.5). Chemo<strong>the</strong>rapy regimen was not found as a prognostic factor for RFS.<br />
Conclusions: This is one of <strong>the</strong> first reports of <strong>the</strong> population based results of <strong>the</strong><br />
adjuvant T treatment. Our results, based on adjuvant T treatment of real-life HER2<br />
+ BC patients, are fully comparable to <strong>the</strong> results obtained in HERA and Joint<br />
American study with 4-years RFS around 80%.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
309 DELAYED CARDIAC TOXICITY IN BREAST CANCER PATIENTS<br />
TREATED WITH ADJUVANT OR NEOADJUVANT<br />
CHEMOTHERAPY (INCLUDING ANTHRACYCLINES) AND<br />
TRASTUZUMAB<br />
A. Mailliez 1 , N. Kotecki 2 , C. Kouakam 3 , C. Fournier 4 , J. Bonneterre 5<br />
1 Breast Department, Centre Oscar Lambret, Lille, FRANCE, 2 Breast Cancer<br />
Departement, Centre Oscar Lambret, Lille, FRANCE, 3 Soins Externes, Centre<br />
Oscar Lambret, Lille, FRANCE, 4 Biostatistics, Centre Oscar Lambret, Lille,<br />
FRANCE, 5 Breast Cancer Department, Centre Oscar Lambret, Université Lille<br />
Nord de France, Lille Cedex, FRANCE<br />
New treatments in <strong>the</strong> (neo) adjuvant settings for HER2 positive breast cancer have<br />
recently changed <strong>the</strong>ir prognosis due to <strong>the</strong> systematic use of Trastuzumab (T).<br />
Progress however has been associated with a risk of cardiac toxicity. Since <strong>the</strong><br />
incidence of cardiotoxicity is low and inconsistent across <strong>the</strong> 5 major adjuvant trials,<br />
we undertook a study to determine <strong>the</strong> cardiotoxicity rate of adjuvant or neoadjuvant<br />
sequential chemo<strong>the</strong>rapy (3 FEC 100-3 Docetaxel) and T in non selected breast<br />
cancer pts treated at <strong>the</strong> Oscar Lambret Center between 2005-2007 and who did not<br />
relapse.<br />
Patients (pts) and methods: 121 pts met <strong>the</strong> inclusion criteria and were invited for a<br />
cardiac evaluation. 79 accepted and had a clinical examination, an Electrocardiogram<br />
(ECG) and an isotopic or echocardiographic measurement of Left Ventricular<br />
Ejection Fraction (LVEF). We also retrospectively collected, LVEF values at<br />
chemo<strong>the</strong>rapy initiation, at T initiation, and after 3, 6, 9 and 12 months of<br />
T. Cardiotoxicity was defined as a decrease in LVEF of more than 10% or a level of<br />
LVEF less than 55% or clinical or ECG symptoms. The 33 pts not responding to <strong>the</strong><br />
convocation had similar characteristics to those analysed.<br />
Results: 51 pts received 1 year T, 7 pts had 6 months T and 21 pts stopped T before<br />
1 year because of a decrease in LVEF. Median follow up was 5.1 years (3.2 to- 6.5).<br />
66 pts had at least 4 evaluations and were considered evaluable. No pts experienced<br />
clinical or ECG symptoms. 30 pts always had a normal LVEF. 36 pts (55%) had a<br />
normal initial LVEF but a decrease during follow up; 20% appeared more than 6<br />
months after initiation. 11 pts (16%) had previously experienced a decrease in LVEF<br />
with anthracyclines, eight of whom also had cardiotoxicity during T. No risk factor<br />
of cardiac disease was observed in pts with cardiotoxicity. No correlation was found<br />
with age, side of <strong>the</strong> tumor, previous radio<strong>the</strong>rapy. Cardiotoxicity was more<br />
frequently observed in pts with ER negative tumors (74% vs 39%). At <strong>the</strong> time of <strong>the</strong><br />
last evaluation, no abnormal LVEF was observed.<br />
Conclusion: The cardiotoxiciy rate was unexpectedly high in <strong>the</strong>se non selected pts.<br />
Never<strong>the</strong>less, LVEF remained normal after a median follow up of 5.1 year.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
310 EVALUATION OF AROMATASE INHIBITOR-RELATED<br />
ARTHRALGIA IN EARLY BREAST CANCER PATIENTS<br />
N. Romero Laorden, C. Olier, X. Mielgo, S. Falagán, A. Velástegui, S. Hernando,<br />
J.C. Cámara, A. Hurtado, J. Garcia-Donas, C. Jara<br />
Medical Oncology, Hospital Universitario Fundacion Alcorcon, Alcorcon, Madrid,<br />
SPAIN<br />
Introduction: Aromatase inhibitors (AI) have demonstrated a disease-free survival<br />
benefit compared with tamoxifen as adjuvant <strong>the</strong>rapy in <strong>the</strong> treatment of<br />
hormone-dependent early breast cancer in postmenopausal women. Although <strong>the</strong> AI<br />
are associated with fewer thromboembolic events and endometrial abnormalities than<br />
tamoxifen, an increase in arthralgia, skeletal, and muscle pain has been reported and<br />
cited as <strong>the</strong> primary reason for discontinuation of AI <strong>the</strong>rapy. The aim of our study<br />
was to evaluate <strong>the</strong> incidence and <strong>the</strong> impact of <strong>the</strong> arthralgia syndrome in our<br />
population.<br />
Methods: Postmenopausal patients with <strong>the</strong> diagnosis of early-stage<br />
hormone-sensitive breast cancer receiving AI <strong>the</strong>rapy at our institution were<br />
included prospectively between 2010-<strong>2012</strong>. We performed a specific survey to<br />
evaluate articular toxicity collecting presence of arthralgias, EVA scale, use of<br />
analgesic, start time and localization of <strong>the</strong> pain. Clinical data was collected<br />
from our department database. Univariate analysis was used to compare<br />
those with AI-related arthralgia and different demographic and clinical<br />
features.<br />
Results: A total of 83 women were included, with a mean age 63.2, BMI 28.4,<br />
menopause mean age 48.2. Regarding to <strong>the</strong> features of <strong>the</strong> primary tumor,<br />
81.9% had ductal carcinoma histology, 28.9% stage I, 54.2% stage II, 16.8% stage<br />
III. At <strong>the</strong> moment of <strong>the</strong> evaluation, 68.7% (57/83) were receiving treatment<br />
with anastrozole, 15.7% (13/83) letrozole, 15.7% (13/83) exemestane. 86.7% (72/<br />
83) had joint pain, of <strong>the</strong>m 68.1% (49/72) related <strong>the</strong>ir pain to <strong>the</strong> hormone<br />
<strong>the</strong>rapy, 31.9% (23/72) to previous diseases or ano<strong>the</strong>r treatments. The<br />
articulations more frequently affected were located in <strong>the</strong> back, knees and hands.<br />
Regarding to <strong>the</strong> pain intensity, mean maximum EVA was 6.03, minimum 1.06.<br />
Only 2 of <strong>the</strong> patients affected stopped <strong>the</strong>rapy, and it was changed for ano<strong>the</strong>r<br />
aromatase inhibitor. No differences were seen between <strong>the</strong> different aromatase<br />
inhibitors.<br />
Conclusions: The incidence of arthralgia associated with aromatase inhibitors<br />
was superior in our series compared with results previously published in<br />
clinical trials. Fur<strong>the</strong>r research in this field should be developed to clarify <strong>the</strong><br />
prevalence and severity of joint symptoms related to AI and to define factors<br />
that may be associated with an increased risk of this treatment-related adverse<br />
effect.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
311 ENDOMETRIAL EFFECTS OF TAMOXIFEN AND EXEMESTANE<br />
IN EARLY BREAST CANCER: FINAL RESULTS OF A<br />
RANDOMIZED PHASE III TRIAL<br />
O. Garrone 1 , E. Principe 2 , M. Monteverde 3 , M. Occelli 1 , G. Bertelli 4 , B. Favilla 2 ,<br />
T. Catzeddu 1 , P. Vanella 1 , E. Miraglio 1 , M. Merlano 1<br />
1 Clinical Oncology, Azienda Ospedaliera St. Croce e Carle, Cuneo, ITALY,<br />
2 Gynecology, Azienda Ospedaliera St. Croce e Carle, Cuneo, ITALY, 3 Oncology,<br />
S. Croce General Hospital, Cuneo, ITALY, 4 Oncology, South West Wales Cancer<br />
Instiute, Swansea, UNITED KINGDOM<br />
Background: Tamoxifen (T) has been for a long time <strong>the</strong> treatment of choice<br />
in hormonal receptor positive early breast cancer patients (EBCP). It is<br />
known that T has partial estrogen agonistic activity on uterus determining<br />
an increase in gynecological symptoms. Long-term T treatment can lead to<br />
an increased incidence of endometrial cancer. The availability of aromatase<br />
inhibitors (AI) has modified <strong>the</strong> prescription options in postmenopausal<br />
breast cancer patients while remaining <strong>the</strong> standard of care in<br />
premenopausal setting. AI do not mediate <strong>the</strong>ir effects through <strong>the</strong> estrogen<br />
receptor potentially conferring tolerability advantages to women particularly<br />
in relation to <strong>the</strong>ir effects on <strong>the</strong> endometrium. So far some studies<br />
including all <strong>the</strong> available AI have been published which confirmed <strong>the</strong> lack<br />
of estrogen effects of AI on endometrium compared to T. In 2001 we<br />
started a phase III study comparing T and Exemestane (E) in EBCP in<br />
order to evaluate <strong>the</strong> differences in <strong>the</strong> endometrial changes recorded by<br />
transvaginal ultrasound (TVUS).<br />
Material and methods: Postmenopausal hormonal receptor positive EBCP were<br />
randomly assigned to receive T or E. A baseline TVUS was performed and repeated<br />
after 6 and 12 months. The primary end-point, endometrial thickness (ET) was<br />
evaluated with T-test.<br />
Results: From 2001 to 2008 220 patients were enrolled in our department. Patients’<br />
characteristics were well balanced in each arm. Definitive results are summarized in<br />
<strong>the</strong> table:<br />
ET<br />
(median)<br />
Baseline<br />
ET (median)<br />
After 6 m<br />
p(ET<br />
baseline<br />
vs 6<br />
months)<br />
ET (median)<br />
After 12 m<br />
p (ET<br />
baseline<br />
vs 12<br />
months)<br />
E 3 (1.4-5) 3 (1.17-9.3) NS 2.8 (0.02-13.5) NS<br />
T 3 (0.14-5) 6.64 (1.9-19.7)
312: Table: Chemo<strong>the</strong>rapy uptake within MWRH<br />
Decision-making tools (DMT)<br />
Nottingham Prognostic Index (NPI) · Excellent (≤ 2.40) ·<br />
Good (2.41 – 3.40) · Moderate (3.41 – 5.40) · Poor (≥<br />
5.41)<br />
Adjuvant! Online (AO) – additional 10-year survival<br />
benefit of chemo<strong>the</strong>rapy and hormonal <strong>the</strong>rapy ·<br />
0.0 – 2.5% · 2.6 – 5.0% · 5.1 – 7.5% · ≥ 7.5%<br />
Oncotype Dx Recurrence Score (RS) Assay · Low (1–17) ·<br />
Intermediate (18 – 30) · High (>31)<br />
312 CORRELATION BETWEEN DECISION-MAKING TOOLS AND<br />
CHEMOTHERAPY UPTAKE IN NODE-NEGATIVE ENDOCRINE<br />
RECEPTOR EARLY-STAGE BREAST CANCER IN<br />
MID-WESTERN IRELAND<br />
K.I. Quintyne 1 , B. Woulfe 1 , J.C. Coffey 2 , R.K. Gupta 1<br />
1 Mid-Western Cancer Centre (MWCC), Mid-Western Regional Hospital (MWRH),<br />
Limerick, IRELAND, 2 Department of Surgery, Mid-Western Regional Hospital<br />
(MWRH), Limerick, IRELAND<br />
Background: Good clinical judgement remains <strong>the</strong> best tool in determining a<br />
<strong>the</strong>rapeutic plan; however this process has become easier, and more reproducible<br />
with <strong>the</strong> ongoing progression of decision-making adjuncts such as: Nottingham<br />
Prognostic Index (NPI), which incorporates pathological features; Adjuvant! Online<br />
(AO), which incorporates clinic-pathological features; and Oncotype Dx ® Recurrence<br />
Score (RS) assay, which incorporates genetic features. We herein report our<br />
experience with <strong>the</strong> use of <strong>the</strong>se tools, and <strong>the</strong>ir potential impact on chemo<strong>the</strong>rapy<br />
uptake for patients in MWRH, Limerick, Ireland.<br />
Methods: Study period: 01/09/2008 – 31/12/<strong>2012</strong>. Data was derived from (1) MWCC<br />
Oncology database (2) pathology reports (3) patient files (4) RS assay reports. Data<br />
was collated and entered into an Access database and exported into SPSS (v.18) for<br />
analysis. Results Seventy-seven (77) patients with early stage endocrine positive breast<br />
cancer were analysed. Median age: 55.9 years (range: 30.6 – 72.3 years). Median<br />
follow-up: 20.9 months. Findings are shown below in tabular form.<br />
Conclusions: Chemo<strong>the</strong>rapy uptake from <strong>the</strong> decision-making tools was varied<br />
within <strong>the</strong> cohort, but it was uniformly noted that patients were more likely to<br />
undertake chemo<strong>the</strong>rapy if <strong>the</strong>y had higher indices derived from <strong>the</strong>se DMT, except<br />
in cases where <strong>the</strong> patients declined <strong>the</strong>rapy, or if physicians’ preference differed on<br />
clinical grounds. This highlights that none of <strong>the</strong> available DMT are perfect in<br />
isolation, but when used in concert, <strong>the</strong>y can elucidate <strong>the</strong> best potential treatment<br />
pathway following consultation between patients and <strong>the</strong>ir healthcare providers; this<br />
is given by <strong>the</strong> fact that <strong>the</strong>y all rely on different subsets of information to predict<br />
potential outcome. Fur<strong>the</strong>r work is needed to find an algorithm that can<br />
appropriately incorporate <strong>the</strong>se DMT any potential patient’s best interest.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
313 DOCETAXEL IN THE TREATMENT OF BREAST CANCER: A<br />
MULTICENTER RETROSPECTIVE STUDY FROM CHINA<br />
B. Xu<br />
Medical Department, Cancer Hospital, Chinese Academy of Medical Sciences,<br />
Beijing, CHINA<br />
Background: Docetaxel is considered as a fundamental drug in <strong>the</strong> treatment of<br />
breast cancer. It has been extensively incorporated into <strong>the</strong> neoadjuvant, adjuvant<br />
and metastatic treatment. The aim of this study was to investigate how breast cancer<br />
patients are treated with docetaxel in China.<br />
Methods: A retrospective review of chemo<strong>the</strong>rapy with docetaxel performed from<br />
2009 to 2011 was carried out in China. Study included all patients diagnosed with<br />
invasive breast cancer and treated with docetaxel-containing regimens in forty-two<br />
cancer centers from 12 provinces in China. Regimens were compared in different<br />
subgroups based on stage, subtype, and lymph node (LN) status. Patterns of<br />
chemo<strong>the</strong>rapy were also compared to published guidelines.<br />
Results: Among 2188 breast cancer patients treated with docetaxel, 1881 (86.0%)<br />
were in adjuvant or/and neoadjuvant setting (including 91 in both settings). The<br />
mean age was 48.7 (range, 14-82). Compared with 288 patients using docetaxel as<br />
single agent <strong>the</strong>rapy, more patients (86.8%) used docetaxel-containing combination<br />
regimens. The mean cycle administered and dose for every cycle was 4.8 and 73.0<br />
mg/m2, respectively. Dose reduction and delay occurred in 409 (19.7%) patients<br />
mainly due to non-medical factors (10.9%) and hematologic toxicity (5.9%). TAC,<br />
TA, TC, TX, and AC-T regimens were given in 34.8%, 19.7%, 17.4%, 5.3%, and 2.2%<br />
of patients respectively. TAC was used more frequently in triple-negative breast<br />
cancer (TNBC) than o<strong>the</strong>r patients (43.0% vs. 32.7%, P = 0.004). In <strong>the</strong> (neo)<br />
adjuvant setting, TAC regimen was used more frequently in LN-positive patients<br />
Chemo<strong>the</strong>rapy Uptake<br />
Offered Undertaken Not offered<br />
2/7 16/41 21/29 0/0 1/7 13/41 21/29 0/0 5/7 25/41 8/29 0/0<br />
8/21 12/33 9/13 10/<br />
10<br />
Annals of Oncology<br />
6/21 10/33 9/13 10/10 13/21 21/33 4/13 0/10<br />
13/38 20/33 6/6 11/38 18/33 6/6 25/38 13/33 0/6<br />
than LN-negative group (44.2% vs. 30.0%, P < 0.001). Of 1682 patients in adjuvant<br />
setting, 729 (43.3%) were treated with triplet (TAC or AC-T). In 290 patients<br />
receiving neoadjuvant chemo<strong>the</strong>rapy, only 94 (32.4%) used TAC and none used<br />
AC-T (P = 0.013).<br />
Conclusions: Docetaxel was widely used in <strong>the</strong> treatment of breast cancer in China,<br />
especially in <strong>the</strong> (neo)adjuvant setting. TAC regimen was <strong>the</strong> most frequent option,<br />
especially in patients with TNBC or LN-positive BC. Although AC-T was also<br />
recommended in adjuvant setting by most guidelines, it was less commonly used<br />
compared to TAC regimen in China.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
314 MOVING FROM 2D TO 3D-CRT PLANNING OF CHEST WALL<br />
FOR POSTMASTECTOMY BREAST CANCER PATIENTS:<br />
MANSOURA UNIVERSITY EXPERIENCE<br />
I. Awad, D. Zayed, N. Abotouk, T. Dawood<br />
Clinical Oncology, Mansoura University Hospital School of Medicine, Mansoura,<br />
EGYPT<br />
Background: This study evaluates <strong>the</strong> dose distribution of <strong>the</strong> wedged tangential<br />
beam three-dimensionally planned conformal radio<strong>the</strong>rapy (3D-CRT) compared to<br />
<strong>the</strong> previously used (5 years ago) two-dimensionally(2D) planned radio<strong>the</strong>rapy of <strong>the</strong><br />
chest wall for postmastectomy breast cancer patients in Clinical Oncology and<br />
Nuclear Medicine Department - Mansoura University.<br />
Patients and methods: Thirty six breast cancer patients were randomized for<br />
planning by both <strong>the</strong> standard 3D-CRT and 2D-RT techniques for radio<strong>the</strong>rapy of<br />
<strong>the</strong> chest wall. Dose-volume histograms were carried out by <strong>the</strong> 3D treatment<br />
planning system. They were assessed for <strong>the</strong> PTV and organs at risk. The total dose<br />
was 50 Gy in 25 fractions.<br />
Results: The three–dimensionally planned conformal radio<strong>the</strong>rapy showed a<br />
significantly better homogeneity index of <strong>the</strong> PTV (chest wall). The ipsilateral mean lung<br />
dose was significantly reduced with <strong>the</strong> tangential beam 3D-CRT plans with an average<br />
of 24.6% (1217 cGy versus 1614 cGy). For <strong>the</strong> left sided breast cancer patients, <strong>the</strong> mean<br />
heart dose was also reduced by an average of 48.6% (718 cGy versus 1398 cGy).<br />
Conclusions: The tangential beam 3D-CRT planning demonstrated a significantly<br />
better homogeneity index for <strong>the</strong> PTV of <strong>the</strong> postmastectomy breast cancer patients<br />
with a statistically significant reduction in <strong>the</strong> mean doses of <strong>the</strong> ipsilateral lung and<br />
<strong>the</strong> heart for <strong>the</strong> left –sided breast cancer patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
315TiP SAFEHER: A STUDY OF ASSISTED- AND<br />
SELF-ADMINISTERED SUBCUTANEOUS TRASTUZUMAB<br />
(H-SC) AS ADJUVANT THERAPY IN PATIENTS WITH EARLY<br />
HER2-POSITIVE BREAST CANCER (EBC)<br />
J. Gligorov 1 , H.A. Azim 2 , B. Ataseven 3 , M. Delaurentiis 4 , K.H. Jung 5 , F. Herbst 6 ,<br />
A. Llombart 7 , A. Manikhas 8 , S. Osborne 9 , X. Pivot 10<br />
1 Medical Oncology Department, Tenon Hospital, Paris, FRANCE, 2 Clinical<br />
Oncology Department, Cairo University, Cairo, EGYPT, 3 Department of<br />
Obstetrics and Gynaecology, Rot-Kreuz-Klinikum, Munich, GERMANY, 4 Breast<br />
Oncology Department, National Cancer Institute “Fondazione Pascale”, Napoli,<br />
ITALY, 5 Department of Oncology, Asan Medical Center, University of Ulsan<br />
College of Medicine, Seoul, KOREA, 6 Oncology, F. Hoffmann-La Roche Ltd.,<br />
Basel, SWITZERLAND, 7 Medical Oncology Service, Hospital Arnau de Vilanova,<br />
Valencia, SPAIN, 8 Oncology, Oncology Hospital of St. Petersburg,<br />
St. Petersburg, RUSSIAN FEDERATION, 9 Statistics, F. Hoffmann-La Roche Ltd.,<br />
Basel, SWITZERLAND, 10 Chimiothérapie – Oncologie, CHU Jean Minjoz,<br />
Besançon, FRANCE<br />
Purpose: One year of H-based <strong>the</strong>rapy, consisting of 18 q3w cycles, is standard of<br />
care for <strong>the</strong> adjuvant treatment of HER2-positive EBC. H is administered<br />
ix114 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
intravenously (IV) over 30–90 mins. An SC formulation of H has been developed,<br />
which is rapidly administered (up to 5 mins), potentially improving convenience for<br />
patients and clinical staff, and reducing administration costs. The Phase III HannaH<br />
study (NCT00950300) demonstrated that <strong>the</strong> pharmacokinetics and efficacy of H-SC<br />
were non-inferior to that of H-IV, meeting <strong>the</strong> co-primary endpoints. The safety<br />
profile of H-SC was comparable and consistent with <strong>the</strong> known safety profile of<br />
H-IV. SafeHer is designed to fur<strong>the</strong>r evaluate <strong>the</strong> safety and tolerability of H-SC in a<br />
broader patient population; to allow greater understanding of a range of safety data.<br />
H-SC will be administered via one of two different routes (handheld syringe [vial<br />
formulation] or single-use injection device [SID]; which allows self-administration).<br />
Supportive data on SID safety and patient satisfaction with self-administration will be<br />
collected.<br />
Methods: SafeHer is a multicentre, international, Phase III open-label trial<br />
(NCT01566721). The primary objective is <strong>the</strong> safety and tolerability of H-SC.<br />
Secondary objectives include disease-free survival, overall survival and patient<br />
satisfaction with SID administration. Immunogenicity of H and recombinant human<br />
hyaluronidase in a subset of patients using <strong>the</strong> SID at select sites is an exploratory<br />
objective. Planned enrolment is 2500 patients, assigned to one of two cohorts at <strong>the</strong><br />
investigators’ discretion ± concurrent/sequential chemo<strong>the</strong>rapy. All patients will<br />
receive H-SC at a fixed dose of 600mg regardless of body weight, for a total of 18<br />
cycles (q3w) via injection into <strong>the</strong> thigh over a period of up to 5 minutes. Patients in<br />
cohort A (n = 1800) will receive H-SC using handheld syringes. Patients in cohort B<br />
(n = 700) will receive H-SC using an SID, first via assisted administration and <strong>the</strong>n<br />
self-administered (in select patients). Enrolment began in May <strong>2012</strong> and parallel<br />
substudies may be performed at selected centres to evaluate medical resource<br />
utilisation (“time and motion study”).<br />
Disclosure: J. Gligorov: I disclose potential conflict of interest : advisory boards and<br />
speaker honoraria for Roche laboratories. H.A. Azim: I serve on <strong>the</strong> advisory board<br />
of Roche in <strong>the</strong> middle east. B. Ataseven: I am a Roche International Steering<br />
Committee member for <strong>the</strong> SafeHer trial. I have received speaker honoraria from<br />
Roche for giveing lectures. I participated in and received a travel grant from Roche<br />
for SABCS 2011. M. Delaurentiis: I am a member of a Roche Advisory Board. F.<br />
Herbst: I am an employee of, and am a stockholder in, F. Hoffmann-La Roche. A.<br />
Llombart: I am a member of a Roche Advisory Board. S. Osborne: I am an employee<br />
of Roche. X. Pivot: I am a member of Roche and GSK Advisory Boards. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
316TiP DENOSUMAB VERSUS PLACEBO AS ADJUVANT<br />
TREATMENT FOR WOMEN WITH EARLY-STAGE BREAST<br />
CANCER AT HIGH RISK OF DISEASE RECURRENCE<br />
(D-CARE): AN IN PROGRESS, PHASE 3 CLINICAL TRIAL<br />
R.E. Coleman 1 , C. Barrios 2 , R. Bell 3 , D.M. Finkelstein 4 ,H.Iwata 5 , M. Martin 6 ,<br />
A. Braun 7 ,C.Ke 8 , T. Maniar 7 , P.E. Goss 9<br />
1 Academic Unit of Clinical Oncology, University of Sheffield, Sheffield Cancer<br />
Research Centre, Sheffield, UNITED KINGDOM, 2 Department of Medicine,<br />
PUCRS School of Medicine, Porto Alegre, BRAZIL, 3 The Andrew Love Cancer<br />
Centre, Geelong Hospital:Deakin University, Geelong, AUSTRALIA, 4 Biostatistics,<br />
Massachusetts General Hospital, Boston, MA, UNITED STATES OF AMERICA,<br />
5 Aichi Cancer Center, Breast Oncology, Nagoya University School of Medicine,<br />
Nagoya, JAPAN, 6 Medical Oncology Service, Hospital General Universitario<br />
Gregorio Marañón, Madrid, SPAIN, 7 Hematology/oncology, Amgen Inc.,<br />
Thousand Oaks, CA, UNITED STATES OF AMERICA, 8 Biostatistics, Amgen Inc.,<br />
Thousand Oaks, CA, UNITED STATES OF AMERICA, 9 Cancer Center,<br />
Massachusetts General Hospital, Boston, MA, UNITED STATES OF AMERICA<br />
Background: Bone represents approximately 40% of all first recurrences in<br />
women with early-stage breast cancer and is a common site of distant<br />
recurrence. In preclinical studies, RANKL inhibition significantly delays skeletal<br />
tumour formation, reduces skeletal tumour burden, and prolongs survival of<br />
tumour-bearing mice. Denosumab is approved for <strong>the</strong> prevention of<br />
skeletal-related events (SREs) in patients with established bone metastases from<br />
solid tumours.<br />
Purpose: The D-CARE trial is designed to assess if denosumab treatment<br />
prolongs bone metastasis-free survival (BMFS) and disease-free survival (DFS)<br />
in <strong>the</strong> adjuvant breast cancer setting. The primary endpoint of this<br />
event-driven trial is BMFS. Secondary endpoints include DFS and overall<br />
survival. Additional endpoints are safety, breast density, incidence of SREs<br />
(following <strong>the</strong> development of bone metastasis), patient reported outcomes, and<br />
biomarkers.<br />
Methods: In this international, randomized, double-blind, and placebo<br />
controlled phase 3 trial, approximately 4,500 women with stage II or III breast<br />
cancer, at high risk for recurrence and with known hormone and HER-2<br />
receptor status, are eligible. High risk is defined as biopsy evidence of breast<br />
cancer in regional lymph nodes, tumour size > 5 cm, (T3), or locally advanced<br />
disease (T4). Standard-of-care adjuvant or neoadjuvant chemo-, endocrine, or<br />
HER-2 targeted <strong>the</strong>rapy, alone or in combination, must be planned. Patients<br />
with a prior history of breast cancer (except DCIS or LCIS) or distant<br />
metastasis, oral bisphosphonate (BP) use within 1 year of randomization, or<br />
any intravenous BP use, are not eligible. Patients are randomized 1:1 to receive<br />
denosumab 120 mg or placebo subcutaneously monthly for 6 months, <strong>the</strong>n<br />
every 3 months for a total of 5 years of treatment. Supplemental vitamin D (≥<br />
400 IU) and calcium (≥ 500 mg) will be administered. The trial, sponsored by<br />
Amgen Inc. and registered with <strong>the</strong> ClinicalTrials.gov identifier NCT01077154,<br />
began enrolling patients in June 2010 and isexpectedtocompleteenrolmentin<br />
late <strong>2012</strong>.<br />
Disclosure: R.E. Coleman: O<strong>the</strong>r substantive relationships: Expert testimony -<br />
Novartis. R. Bell: Advisory Board Member : Amgen. M. Martin: Advisory Board<br />
Member amgen, roche, bayer, novartis, gsk, sanofi. A. Braun: Employee : Amgen<br />
Inc Stock : Amgen Inc. C. Ke: Employer : Amgen Inc. Stock ownership : Amgen Inc.<br />
T. Maniar: Employee :: Amgen Inc. Stock ownership :: Amgen Inc. P.E. Goss:<br />
Honoraria for Pfizer and Novartis. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds392 | ix115
abstracts<br />
breast cancer, locally advanced and<br />
metastatic<br />
317O FIRST EFFICACY RESULTS FROM THE TURANDOT PHASE III<br />
TRIAL COMPARING TWO BEVACIZUMAB (BEV)-CONTAINING<br />
REGIMENS AS FIRST-LINE THERAPY FOR HER2-NEGATIVE<br />
METASTATIC BREAST CANCER (MBC)<br />
C. Zielinski, 1 , I. Lang 2 , M. Inbar 3 , Z. Kahan 4 , R. Greil 5 , S. Beslija 6 ,<br />
S.M. Stemmer 7 , B. Kaufman 8 , Z. Zvirbule 9 , G. Steger 1 , B. Melichar 10 ,<br />
T. Pienkowski 11 , D. Sirbu 12 , L. Petruzelka 13 , A. Eniu 14 , B. Nisenbaum 15 ,<br />
M. Dank 16 , R. Anghel 17 , D. Messinger 18 , T. Brodowicz 1<br />
1 Medical University of Vienna, Vienna, AUSTRIA, 2 National Institute of Oncology,<br />
Budapest, HUNGARY, 3 Tel Aviv Sourasky Medical Centre, Tel Aviv, ISRAEL,<br />
4 University of Szeged, Szeged, HUNGARY, 5 University Hospital Salzburg,<br />
Salzburg, AUSTRIA, 6 Institute of Oncology, Sarajevo, BOSNIA AND<br />
HERZOGOVINA, 7 Rabin Medical Center, Petach Tikva, ISRAEL, 8 Sheba Medical<br />
Center, Tel Hashomer, ISRAEL, 9 Riga Eastern Clinical University Hospital, Riga,<br />
LATVIA, 10 Fakultni nemocnice Olomouc, Olomouc, CZECH REPUBLIC,<br />
11 Postgraduate Medical Center, Warsaw, POLAND, 12 Oncomed Oncology<br />
Practice, Timisoara, ROMANIA, 13 Charles University Prague, Prague, CZECH<br />
REPUBLIC, 14 Cancer Institute I Chiricuta, Cluj-Napoca, ROMANIA, 15 Meir<br />
Medical Center, Kfar Saba, ISRAEL, 16 Semmelweis University Radiology Clinic,<br />
Budapest, HUNGARY, 17 Institutul Oncologic Bucuresti, Bucarest, ROMANIA,<br />
18 IST GmbH, Mannheim, GERMANY<br />
Background: TURANDOT is <strong>the</strong> first prospective trial to compare BEV combined<br />
with ei<strong>the</strong>r paclitaxel (PAC) or capecitabine (CAP). We report <strong>the</strong> planned interim<br />
analysis (IA) of efficacy.<br />
Methods: Patients with HER2-negative mBC who had received no prior<br />
chemo<strong>the</strong>rapy for mBC were randomised to receive ei<strong>the</strong>r BEV–PAC (BEV 10 mg/<br />
kg d1 & 15 + PAC 90 mg/m d1, 8 & 15 q4w) or BEV–CAP (BEV 15 mg/kg d1 + CAP<br />
1000 mg/m bid d1–14 q3w) until disease progression or unacceptable toxicity. The<br />
primary objective is to demonstrate non-inferior overall survival (OS) with BEV–<br />
CAP vs BEV–PAC. Interim and final OS analyses were planned after 175 and 389<br />
deaths, respectively, in <strong>the</strong> per-protocol (PP) population to reject <strong>the</strong> null hypo<strong>the</strong>sis<br />
of inferiority (hazard ratio [HR] ≥1.33) with 80% power and overall α = 0.025.<br />
Secondary endpoints include response rate (RR), progression-free survival (PFS),<br />
safety and quality of life.<br />
Results: Median follow-up was 19 months at data cut-off for this IA (1 Sep 2011).<br />
Baseline characteristics were generally similar in <strong>the</strong> 2 treatment arms.<br />
BEV-PAC<br />
(n = 285)<br />
Median age, years 59 59<br />
Visceral metastases, % 65 73<br />
Prior (neo)adjuvant taxane, %<br />
OS<br />
20 18<br />
a<br />
Events, % 33 35<br />
1-year OS rate, % b<br />
81 79<br />
HR (97.5% RCI c )<br />
1.04 (−∞ to 1.69)<br />
for non-inferiority<br />
p = 0.0593 d<br />
RR<br />
Overall, % 44 27<br />
CMH test (superiority)<br />
PFS<br />
p < 0.0001<br />
Events, % 62 77<br />
Median, months 11.0 8.1<br />
HR (95% CI) 1.36 (1.09 to 1.68)<br />
Log-rank (superiority) p = 0.0052<br />
BEV–CAP<br />
(n = 279)<br />
RCI = repeated confidence interval<br />
a PP population (n = 533)<br />
b Kaplan–Meier estimate<br />
c Using O’Brien–Fleming boundaries<br />
d Non-inferiority not shown as p > 0.00105 (α at IA) AEs were consistent with <strong>the</strong><br />
known safety profiles of BEV, PAC and CAP. The most common grade ≥3 AEs were<br />
neutropenia (18%), peripheral neuropathy (14%) and leucopenia (7%) with BEV–<br />
PAC and hand-foot syndrome (16%), hypertension (6%) and diarrhoea (5%) with<br />
BEV–CAP.<br />
Annals of Oncology 23 (Supplement 9): ix116–ix143, <strong>2012</strong><br />
doi:10.1093/annonc/mds393<br />
Conclusion: In this planned IA, <strong>the</strong> non-inferiority criterion has not been met but<br />
OS results do not indicate relevant differences. Final results are expected in 2014. PFS<br />
and RR were better with BEV–PAC and very similar to previous data for BEV–PAC<br />
(E2100) and BEV–CAP (RIBBON-1).<br />
Disclosure: R. Greil: RG has received research support and honoraria from Roche. S.<br />
Beslija: SB has received research support and honoraria from Roche. D. Messinger:<br />
Employee of IST GmbH, CRO which is providing various services and consultancies<br />
for Hoffmann-La Roche and CECOG. T. Brodowicz: TB has received honoraria from<br />
Roche. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
318O PH IB/II STUDY OF BKM120 PLUS TRASTUZUMAB (T) IN<br />
PATIENTS WITH T-RESISTANT HER2+ ADVANCED BREAST<br />
CANCER (BC)<br />
B. Pistilli 1 , A. Urruticoechea 2 , S. Chan 3 , H.S. Han 4 , G. Jerusalem 5 , A. Kong 6 ,<br />
Q. Ru 7 , S. Ruquet 8 , D.W. Sternberg 7 , C. Saura 9<br />
1 Dipartimento di Oncologia, Ospedale di Macerata, Macerata, ITALY, 2 Oncology,<br />
Catalan Institute of Oncology, Barcelona, SPAIN, 3 Oncology and Radio<strong>the</strong>rapy,<br />
Nottingham University Hospital, Nottingham, UNITED KINGDOM, 4 Women’s<br />
Oncology, Moffitt Cancer Center, Tampa, FL, UNITED STATES OF AMERICA,<br />
5 Medical Oncology, Centre Hospitalier Universitaire du Sart-Tilman, Liege,<br />
BELGIUM, 6 Oncology, <strong>Oxford</strong> University Hospitals NHS Trust, <strong>Oxford</strong>, UNITED<br />
KINGDOM, 7 Oncology, Novartis Oncology, Florham Park, NJ, UNITED STATES<br />
OF AMERICA, 8 Oncology, Novartis Oncology, Paris, FRANCE, 9 Vall D’hebron<br />
Hospital, Vall d’Hebron Institute of Oncology, Barcelona, SPAIN<br />
Background: PI3K/AKT/mTOR pathway upregulation has been implicated in T<br />
resistance, and thus <strong>the</strong> impact of pathway inhibition on restoration of <strong>the</strong>rapeutic<br />
sensitivity is being investigated. The RP2D of BKM120, an oral pan-class I PI3K<br />
inhibitor, plus T is 100 mg/d. Here, we present Ph II results of BKM120 + T in pts<br />
with T-resistant advanced HER2+ BC.<br />
Methods: Pts with HER2+ locally adv/metastatic BC resistant to T (progression<br />
while on T, or within 4 wks [metastatic] or 12 mths [adjuvant] of last T dose)<br />
received daily BKM120 (100 mg) and <strong>the</strong> standard wkly dose of T. Ph II eligibility<br />
criteria: ≥1 measurable lesion, ≥1 but ≤4 prior anti-HER2 regimens (incl.<br />
trastuzumab [required], lapatinib, and/or T-DM1), and ≤3 lines of prior<br />
chemo<strong>the</strong>rapy for metastatic disease. Ph IB pts treated at <strong>the</strong> RP2D who met Ph II<br />
eligibility criteria were included in <strong>the</strong> analysis.<br />
Results: As of 23 March <strong>2012</strong>, 53 pts were included in <strong>the</strong> Ph II analysis (safety set;<br />
incl. 8 pts from Ph IB). 49 pts were evaluable for response (full analysis set); median<br />
age 52 yrs (28–75); median no. prior antineoplastic regimens 4 (1–10); 5 pts had a<br />
baseline CNS lesion (3 measurable target; 2 non-target). At data cut-off, 9 pts were<br />
still on study. Most pts discontinued treatment due to disease progression (55%); 8<br />
pts (16%) withdrew due to AEs. Mean duration of BKM120 exposure was 11 wks<br />
(0.1–41). Most common suspected study-drug related G3/4 AEs: ALT increased<br />
(5 pts); rash (5 pts); AST increased (4 pts); as<strong>the</strong>nia (3 pts); nausea, anxiety, skin<br />
photosensitivity, hyperglycemia (2 pts each). Partial responses (RECIST) were seen in<br />
4 pts (8%), and stable disease (SD) was noted in 20 pts (41%); <strong>the</strong> disease control<br />
rate (CR, PR, or SD) was 49%. Preliminary results indicate that, of <strong>the</strong> 5 pts with<br />
baseline brain mets (BM), 2 pts had SD in <strong>the</strong> CNS without evidence of progression<br />
at study withdrawal; 2 pts had overall SD (1 for 90 days and 1 for 106 days) before<br />
progression in <strong>the</strong> CNS; 1 pt was not evaluated in <strong>the</strong> CNS after study entry.<br />
Conclusion: BKM120 in combination with T has an acceptable safety profile, and<br />
has shown encouraging preliminary activity in heavily pretreated HER2+ metastatic<br />
BC pts with T resistance, including pts with BM.<br />
Disclosure: Q. Ru: Employee of Novartis. S. Ruquet: Employee of Novartis. D.W.<br />
Sternberg: Employee of Novartis. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
319O SIGNIFICANT ANTITUMOR ACTIVITY OF E-3810, A NOVEL<br />
FGFR AND VEGFR INHIBITOR, IN PATIENTS WITH FGFR1<br />
AMPLIFIED BREAST CANCER<br />
R. Dienstmann 1 , F. Andre 2 , J. Soria 3 , J. Tabernero 4 , F.G.M. De Braud 5 ,<br />
R. Cereda 6 , R. Bahleda 3 , A. Hollebecque 3 , A. Delmonte 7 , M.G. Camboni 6<br />
1 Molecular Therapeutics Research Unit, Vall d’Hebron University Hospital,<br />
Barcelona, SPAIN, 2 Department of Medical Oncology, Institut Gustave Roussy,<br />
Villejuif Cedex, FRANCE, 3 Dept. of Medicine, Sitep, Institut Gustave Roussy, Villejuif<br />
Cedex, FRANCE, 4 Medical Oncology Service, Vall d’Hebron University Hospital,<br />
Barcelona, SPAIN, 5 Division of Oncology, Fondazione IRCCS - Istituto Nazionale dei<br />
Tumori, Milano, ITALY, 6 R&d Dept., EOS SpA, Milano, ITALY, 7 Clinical Pharmacology<br />
- New Drugs Development, Istituto Europeo di Oncologia, Milano, ITALY<br />
Background: Amplification of <strong>the</strong> FGFR1 gene occurs in subsets of tumors, notably<br />
breast cancer (BC), where <strong>the</strong> altered FGF pathway may be clinically relevant.<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
Annals of Oncology<br />
Methods: E-3810 is a kinase inhibitor targeting FGFR1 and VEGFR1, 2, 3. Its safety<br />
and activity, at <strong>the</strong> daily oral dose of 20 or 15 mg on a continuous schedule, are<br />
being assessed in patients with solid tumors and FGFR1 amplification or potentially<br />
sensitive to antiangiogenic agents. The study is an open label non comparative<br />
extension of <strong>the</strong> first in man dose-escalation trial; <strong>the</strong> efficacy threshold, set for <strong>the</strong><br />
FGFR1+ cohort only, requires 3/14 confirmed objective RECIST responses or<br />
non-progressive disease ≥ 6 cycles (one-stage Fleming design: H0 5%, H1 30%, power<br />
80%).<br />
Results: 46 patients with various tumor types (including 13 FGFR1+) were recruited.<br />
8 patients (4/13 and 4/33 treated respectively at 20 and 15 mg; none in <strong>the</strong> FGFR1+<br />
cohort) were withdrawn for toxicity including: G3 proteinuria (5), headache and<br />
vomiting (2), pancreatic enzymes increase (1), recovered in all cases. Hypertension<br />
G2-3, proteinuria G2, GI intolerance, as<strong>the</strong>nia and weight loss led to dose reduction<br />
in 20 patients; frequent TSH increase required supplementation. Tolerability was<br />
better in <strong>the</strong> FGFR1+ cohort, in line with a limited prior exposure to antiangiogenic<br />
treatments. Antitumor activity is shown in <strong>the</strong> table:<br />
Antiangiogenic Sensitive FGF-amplified (1)<br />
Evaluable PR SD PD Evaluable PR SD PD<br />
Breast cancer 1 1 9 4 ** 3 2<br />
O<strong>the</strong>r 23 3 *** 13 7 2 1 * 1<br />
Total 24 3 14 7 11 4 4 3<br />
(1) incl. <strong>the</strong> two BC patients with 11q amplification; * SD ≥ 24 weeks; ** 1 PET<br />
response (bone lesions); ***2 thyroid; 1 thymic carcinoma. 12 women with BC were<br />
recruited (9 HR + , 1 HER2 + /HR + , 2 TN); 8 were FGFR1 + , 2 more had 11q<br />
amplification (CGH). They were treated with a median of 5 prior chemo<strong>the</strong>rapy<br />
lines; 9, 10 and 5 patients also received ≥ 1 endocrine, antiangiogenic and<br />
experimental <strong>the</strong>rapies, respectively. There were 4 PRs sustained over 4-6 courses (3<br />
FGFR1 and one FGF4 amplification), with 3 responders still on treatment.<br />
Conclusions: E-3810 has shown significant activity in heavily pretreated BC, with<br />
durable responses in patients with altered FGF pathway. Fur<strong>the</strong>r studies are planned<br />
in this population.<br />
Disclosure: R. Cereda: Currently an employee and stock holder at EOS SpA. M.G.<br />
Camboni: Currently an employee and stock holder at EOS SpA. All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
320PD SIGNIFICANTLY SUPERIOR OUTCOME AFTER<br />
NEOADJUVANT CHEMOTHERAPY WITH DOCETAXEL,<br />
ANTHRACYCLINE AND CYCLOPHOSPHOMIDE VERSUS<br />
DOCETAXEL PLUS CYCLOPHOSPHOMIDE: RESULTS FROM<br />
THE NATT TRIAL IN TRIPLE NEGATIVE OR HER2 POSITIVE<br />
BREAST CANCER<br />
X. Chen 1 ,G.Ye 2 , C. Zhang 3 ,X.Li 4 , K. Shen 1<br />
1 Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong<br />
University School of Medicine, Shanghai, CHINA, 2 Department of Breast<br />
Surgery, The First People’s Hospital of Foshan, Foshan, CHINA, 3 Department of<br />
Breast Surgery, Guangzhou General Hospital of Guangzhou Military Area,<br />
Guangzhou, CHINA, 4 Department of Breast Surgery, Shanxi Provincical Cancer<br />
Hospital, Taiyuan, CHINA<br />
Objective: To evaluate <strong>the</strong> activity and safety of docetaxel plus cyclophosphomide<br />
(TC) compared with docetaxel, anthracycline and cyclophosphomide (TAC) in<br />
neoadjuvant treatment of triple negative or HER2 positive breast cancer, which may<br />
help us to determine <strong>the</strong> role of anthracycline in breast cancer treatment.<br />
Methods: Clinical stage IIB or III breast cancer patients were treated with six cycles<br />
of TC (docetaxle 75 mg/m2 and cyclophosphomide 600 mg/m2) or TAC (docetaxle<br />
75 mg/m2, anthracycline, and cyclophosphomide 500 mg/m2). Ei<strong>the</strong>r epirubicin<br />
60mg/m2 or adimycin 50mg/m2 was allowed as an anthracycline regimen. The<br />
primary end point was pathological complete remission (pCR), defined as no<br />
residual invasive cancer in breast and axillary lymph node. Seconday end points<br />
included safety, clinical response rate, event free survival (EFS), disease free survival<br />
(DFS), and overall survival (OS).<br />
Results: 102 patients were randomized and 96 patients were available for analysis<br />
(TC: n = 45; TAC: n = 51). After surgery, pCR rate was 6.8% (3/45) and 17.6% (9/51)<br />
in TC and TAC group, respectively, P = 0.113. There was also no difference in clinical<br />
response rate. However, with mean follow up of 20 (3-36) months, TAC treatment,<br />
compared with TC, resulted in a significantly superior EFS (80.4% vs 60.0%,<br />
respectively; adjusted HR = 2.42 (95% CI: 1.11 to 5.30); P = 0.027), better DFS (84.3%<br />
vs 64.4%, respectively; adjusted HR = 2.85 (95% CI: 1.21 to 6.74); P = 0.017) and a<br />
trend towards less death (96.1% vs 86.7%, respectively; adjusted HR = 2.52 (95% CI:<br />
0.41-15.38); P = 0.315). Patients treated with TAC had relative high rates of grade 3-4<br />
neutropenia and leukopenia, and rates of o<strong>the</strong>r severe adverse events were similar<br />
and no patients died on treatment.<br />
Conclusions: pCR rate was not significantly different between TAC and TC in<br />
neodajuvant treatment of triple negative or HER2 positive breast cancer. Adding<br />
anthracycline to TC can significantly improve patients’ outcome, which deserves<br />
fur<strong>the</strong>r investigation. (Sponsored by Sanofi; ClinicalTrials.gov number,<br />
NCT00912444.)<br />
Disclosure: All authors have declared no conflicts of interest.<br />
321PD IMPACT OF MULTIFOCAL OR MULTICENTRIC DISEASE<br />
ON SURGICAL, LOCOREGIONAL, AND DISTANT SURVIVAL<br />
AFTER NEOADJUVANT CHEMOTHERAPY IN 3562 BREAST<br />
CANCER PATIENTS<br />
B. Ataseven 1 , J.U. Blohmer 2 , C. Denkert 3 , B. Gerber 4 , J. Heil 5 , T. Kühn 6 ,<br />
S. Kümmel 7 , M. Rezai 8 , S. Loibl 9 , G. von Minckwitz 10<br />
1 Frauenklinik, Rotkreuzklinikum München, München, GERMANY, 2 Gynäkologie<br />
und Geburtshilfe, Sankt Gertrauden-Krankenhaus, Berlin, GERMANY, 3 Institut für<br />
Pathologie, Charité Universitätsmedizin Berlin, Berlin, GERMANY, 4 Frauenklinik,<br />
Uniklinik Rostock, Rostock, GERMANY, 5 Universitäts-brustzentrum,<br />
Universitäts-Frauenklinik, Heidelberg, GERMANY, 6 Brustzentrum, Frauenklinik,<br />
Gifhorn, GERMANY, 7 Brustzentrum, Kliniken Essen Mitte, Essen, GERMANY,<br />
8 Brustzentrums, Luisenkrankenhaus, Düsseldorf, GERMANY, 9 Medicine and<br />
Research, German Breast Group, Neu-Isenburg, GERMANY, 10 Managing<br />
Director, GBG Forschungs GmbH, Neu-Isenburg, GERMANY<br />
Purpose: To evaluate patients outcome with multifocal or multicentric breast cancer<br />
after neoadjuvant chemo<strong>the</strong>rapy by type of surgery.<br />
Patients and methods: Participants of <strong>the</strong> GeparTrio and GeparQuattro trials with<br />
operable or locally advanced tumors received anthracycline-taxane (+/- anti-HER2-based<br />
neoadjuvant chemo<strong>the</strong>rapy and were classified as having unifocal (one lesion detected by<br />
physical examination, sonography, and mammography ± MRI), multifocal (≥2 lesions in<br />
one breast quadrant), or multicentric (≥ 1lesionin≥2 quadrants) disease. Breast<br />
conservation was allowed when tumor-free margins were achieved.<br />
Results: Tumors of 3,562 participants were classified as unifocal (N = 2793; 78.4%),<br />
multifocal (N = 429; 12.0%), and multicentric (N = 340; 9.5%). Breast conservation<br />
was performed in 71.7%, 56.2%, and 35.1%, respectively (P < 0.0001). At surgery<br />
pathological complete response (pCR) rates were 18.7%, 14.1%, and 14.9%,<br />
respectively (P = 0.047). After median follow up of 46.3 months locoregional and<br />
distant-relapse-free survival were worse in patients with multicentric disease versus<br />
uni- or multifocal disease treated with mastectomy (P = 0.007 and 0.061,<br />
respectively), but not when treated by breast conservation (P = 0.634 and 0.650,<br />
respectively). Patients with pCR showed a low locoregional relapse rate irrespective of<br />
focality (P = 0.713) but a higher distant relapse rate in case of multicentric disease (P<br />
= 0.003). Prognostic factors for locoregional recurrence in multivariable analysis were<br />
tumor and nodal status at surgery, grading, hormone-receptor status, and type of<br />
surgery, but not focality of <strong>the</strong> tumor. Overall survival was not statistically different<br />
through all focality groups.<br />
Conclusions: Breast conservation for multifocal or multicentric breast cancer after<br />
neoadjuvant chemo<strong>the</strong>rapy is feasible and seems not to impair outcome if tumor-free<br />
margins were achieved.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
322PD A TREATMENT-INTERACTION ANALYSIS BALANCING<br />
PATHOLOGICAL COMPLETE RESPONSES (PCR) AND<br />
CARDIOTOXICITY OF SINGLE-(S)/DUAL-(D) HER2<br />
INHIBITION AND NEOADJUVANT CHEMOTHERAPY (CT)<br />
BACKBONE IN OPERABLE/LOCALLY ADVANCED BREAST<br />
CANCER (O/LABC) PATIENTS<br />
E. Bria 1 , M. Bonomi 1 , J. Furlanetto 1 , S. Pilotto 1 , L. Carbognin 1 , F. Massari 1 ,<br />
E. Lucchini 1 , D. Melisi 1 , D. Giannarelli 2 , G. Tortora 1<br />
1 Medical Oncology, Azienda Ospedaliera Universitaria Integrata Verona-“Borgo<br />
Roma”, Verona, ITALY, 2 Medical Oncology, Regina Elena National Cancer<br />
Institute, Roma, ITALY<br />
Purpose: Given <strong>the</strong> toxicity drawbacks potentially related to <strong>the</strong> combination of<br />
anthracylines and a D-HER2 inhibition, a treatment interaction analysis of <strong>the</strong><br />
available randomized trials was accomplished.<br />
Methods: pCR (breast + axilla), breast conserving surgery (BCS), grade 3-4<br />
neutropenia/cardiotoxicity, and febrile neutropenia (FN), events were extracted from<br />
papers/presentation and cumulated according to a random-effect model; 95%<br />
confidence intervals (CI) were derived. A sensitivity analysis according to S/D HER2<br />
inhibition, hormonal receptors (HRs) and CT (anthracyclines-taxanes: anthra-TAX;<br />
TAX alone) was accomplished to test for interaction. Absolute differences (AD) with<br />
95% CIs, and <strong>the</strong> number of pts needed to treat/harm (NNT/NNH) for 1 to benefit<br />
were calculated to derive <strong>the</strong> Likelihood of being Helped or Harmed (LHH).<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds393 | ix117
Results: 8 trials (2092 pts) with 1955 pts treated with anti-HER2 <strong>the</strong>rapy<br />
(Trastuzumab, Lapatinib and Pertuzumab), were ga<strong>the</strong>red; pCR rates according to<br />
HER2 inhibition follow:<br />
CT HER2-Inhibition Rates (95% CI) Interaction (p) NNT<br />
Anthra-TAX S 37.0 [34.0, 40.0] 0.22 2.7<br />
D 44.3 [33.3, 55.2] 2.2<br />
TAX S 21.7 [18.1, 25.3]
Annals of Oncology<br />
325PD PHASE I/II TRIAL OF ABIRATERONE ACETATE (AA) IN<br />
ESTROGEN RECEPTOR (ERα) OR ANDROGEN RECEPTOR<br />
(AR) POSITIVE METASTATIC BREAST CANCER (MBC)<br />
C.H.M. Ng 1 , I. Macpherson 2 ,D.Rea 3 , J. Spicer 4 , A. Bowman 5 , A. Jones 6 ,<br />
M. Dowsett 7 , S.R.D. Johnston 8 , N. Dobbs 9 , J.S. de Bono 10<br />
1 Drug Development, Royal Marsden Hospital, Surrey, UNITED KINGDOM,<br />
2 Cancer Trial Research, Beatson West of Scotland Cancer CentreGartnavel<br />
General Hospital, Glasgow, UNITED KINGDOM, 3 Medical Oncology, The<br />
University of Birmingham Institute for Cancer Studies, Birmingham, UNITED<br />
KINGDOM, 4 Research Oncology, King’s Health Partners at Guy’s Hospital,<br />
London, UNITED KINGDOM, 5 Medical Oncology, Edinburgh Cancer Centre,<br />
Edinburgh, UNITED KINGDOM, 6 Medical Oncology, University College London<br />
Hospital, London, UNITED KINGDOM, 7 Academic Department of Biochemistry,<br />
Breakthrough Research Centre, London, UNITED KINGDOM, 8 Breast Oncology,<br />
Royal Marsden NHS Foundation Trust & Institute of Cancer Research, London,<br />
UNITED KINGDOM, 9 Drug Development Office, Cancer Research UK, London,<br />
UNITED KINGDOM, 10 Drug Development Unit, Royal Marsden Hospital NHS<br />
Foundation Trust, Surrey, UNITED KINGDOM<br />
Background: Abiraterone irreversibly inhibits 17-hydroxylase/c-17-20 lyase (CYP17),<br />
reducing androgen and estrogen levels and improves overall survival from castration<br />
resistant prostate cancer. We hypo<strong>the</strong>sized that: A) Postmenopausal ERα+ MBC<br />
continue to be ERα + /AR driven; and, B) Postmenopausal ERα- AR+ MBC can be<br />
driven by AR.<br />
Methods: This Phase I/II trial of AA with hydrocortisone evaluated tolerability,<br />
pharmacokinetic (PK)-pharmacodynamic (PD) profile and anti-tumor activity. Two<br />
parallel but non-randomized Phase II arms utilized a Gehan design (95% probability<br />
of detecting a 24wk clinical benefit rate (CBR, partial response [PR] + stable disease)<br />
of > 20%; 14 patients [pts] in <strong>the</strong> first stage; 11 in <strong>the</strong> second stage for each arm).<br />
Prior <strong>the</strong>rapy with ≥ 2 lines of endocrine <strong>the</strong>rapy (for ERα+ arm); ≥ 1 line of chemo<br />
(for AR + ERα- arm); and prior trastuzumab if HER2-positive was required. ERα and<br />
AR positivity was defined as immunoreactivity in ≥ 1% cells.<br />
Results: In <strong>the</strong> phase I study, daily dosing of AA was well tolerated with variable PK<br />
at all dose levels. PD studies of CYP17 blockade demonstrated suppression of<br />
circulating estradiol and androgen levels below <strong>the</strong> limit of assay detection with<br />
1000mg and 250-2000mg AA respectively; 1000mg was selected for Phase II<br />
evaluation. In <strong>the</strong> ERα+ arm, 6 pts (Phase I) and 25pts (Phase II) received 1000mg<br />
AA, of whom 4 were HER2-positive. The median age (range) was 60 (46-80), prior<br />
lines of hormonal and chemo<strong>the</strong>rapy were 3 (2-4) and 2 (0-5) respectively. There was<br />
1 partial response (PR) lasting 14m in a pt who had received 4 and 5 lines of<br />
hormonal and chemo<strong>the</strong>rapy respectively. Median progression-free survival was<br />
11wk. CBR at 24wk was 21%. In <strong>the</strong> AR + ERα- arm, recruitment is ongoing.<br />
Hypokalaemia easily managed by hydrocortisone administration, was <strong>the</strong> commonest<br />
drug related adverse event (AE).<br />
Conclusion: AA was well tolerated and merits fur<strong>the</strong>r evaluation in MBC. Cancer<br />
Research UK (Drug Development Office) Sponsored and funded <strong>the</strong> trial. Johnson &<br />
Johnson provided AA.<br />
Disclosure: M. Dowsett: The Institute of Cancer Research has a commercial interest<br />
in Abiraterone. Mitch Dowsett is an employee of <strong>the</strong> Institute of Cancer Research,<br />
which has a ‘Rewards to Inventors’ scheme and is a recipient of <strong>the</strong> scheme. J.S. de<br />
Bono: The Institute of Cancer Research has a commercial interest in Abiraterone.<br />
Prof de Bono is an employee of <strong>the</strong> Institute of Cancer Research, and recipient of a<br />
‘Rewards to Inventors’ scheme. He is also a consultant for Johnson and Johnson. All<br />
o<strong>the</strong>r authors have declared no conflicts of interest.<br />
326PD PACLITAXEL-BASED VERSUS DOCETAXEL-BASED<br />
REGIMENS IN METASTATIC BREAST CANCER: A<br />
SYSTEMATIC REVIEW AND META-ANALYSIS OF<br />
RANDOMIZED CONTROLLED TRIALS<br />
W. Qi, Y. Yao, Z. Shen, F. Lin, Y. Sun, D. Min, A. He, L. Tang<br />
Dept. of Oncology, The Sixth People’s Hospital Shanghai Jiaotong University,<br />
Shanghai, CHINA<br />
Background: Docetaxel and paclitaxel show significant clinical activity in metastatic<br />
breast cancer (MBC) and have been approved for MBC by U.S. Food and Drug<br />
Administration, but it is still unclear whe<strong>the</strong>r paclitaxel-based regimen improves<br />
outcome over docetaxel-based regimen in patients with MBC. We <strong>the</strong>refore<br />
performed a meta-analysis of randomized controlled trials that compared<br />
paclitaxel-based with docetaxel-based regimens in MBC.<br />
Method: We systematically searched for randomized controlled trials that<br />
comparing paclitaxel-based with docetaxel-based regimens in patients with<br />
metastatic breast cancer in PUBMED, EMBASE and Cochrane databases.<br />
<strong>Abstract</strong>s presented at <strong>the</strong> conference were also searched. The primary endpoint<br />
was overall survival (OS). Secondary endpoints were progression free survival<br />
(PFS), time to progression (TTP), overall response rate (ORR), and grade 3 or 4<br />
toxicity. Data were extracted from <strong>the</strong> studies by two independent reviewers. The<br />
meta-analysis was performed by Stata version 12.0 software (Stata Corporation,<br />
College Station, TX, USA).<br />
Results: Seven eligible trials involving 1694 patients with MBC were selected. Our<br />
meta-analysis results showed that paclitaxel-based regimen was comparable to<br />
docetaxel-based regimen in terms of OS (HR: 0.87, 95%CI: 0.60-1.27, p = 0.476),PFS<br />
(HR:0.76,95%CI:0.58-1.00, p = 0.052), TTP(HR: 1.13, 95%CI: 0.81-1.58, p = 0.459),<br />
and ORR(RR:1.01, 95%CI: 0.88-1.15, p = 0.915), but less grade 3 or 4 adverse events<br />
including anemia(RR:0.64,95%CI:0.44-0.94,p = 0.023), neutropenia (RR:0.74,95%<br />
CI:0.58-0.93, p = 0.011), febrile neutropenia (RR:0.38, 95%CI:0.15-0.96, p = 0.041),<br />
thrombopenia (RR:0.62, 95%CI: 0.41-0.96,p = 0.033),mucositis (RR:0.082, 95%<br />
CI:0.025-0.27,p = 0.000),diarrhea(RR:0.194,95%CI:0.081-0.47,p = 0.000) and fatigue<br />
(RR:0.434,95%CI:0.20-0.96,p = 0.039) were observed in paclitaxel-based regimen.<br />
Conclusion: The present systematic review and meta-analysis demonstrate that both<br />
taxanes-based regimens show comparable efficacy for patients with MBC, and<br />
paclitaxel-based regimen is associated with less toxicity and better tolerability,<br />
especially in older patients and when used in weekly regimens.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
327PD BODY MASS INDEX AND PROGNOSIS OF WOMEN WITH<br />
METASTATIC BREAST CANCER<br />
A. Gennari 1 , D. Amadori 2 , O. Nanni 2 , A. Decensi 1 , P.F. Conte 3 , M. Puntoni 1 ,<br />
P. Bruzzi 4<br />
1 EO Galliera, SC Oncologia, Genoa, ITALY, 2 Medical Oncology, IRST - Meldola,<br />
Meldola, ITALY, 3 Dept. of Hematology/Oncology, Ospedale Policlinico-Modena,<br />
Modena, ITALY, 4 Clinical Epidemiology, IST-San Martino, Genoa, ITALY<br />
Obesity is a well known risk factor for <strong>the</strong> development of breast cancer and an<br />
adverse prognostic factor in those women who have already been diagnosed with<br />
breast cancer. However, <strong>the</strong> effect of obesity on <strong>the</strong> prognosis of MBC women has<br />
not been explored so far. The aim of this study was to evaluate <strong>the</strong> influence of Body<br />
Mass Index (BMI) on <strong>the</strong> prognosis of MBC patients receiving first line<br />
chemo<strong>the</strong>rapy.<br />
Methods: The relationship between BMI (kg/m2), and progression free (PFS) or<br />
overall survival (OS) was assessed in 698 MBC patients enrolled in 3 clinical trials of<br />
first line chemo<strong>the</strong>rapy, conducted by <strong>the</strong> same collaborative group. Conventional<br />
WHO BMI definitions were applied: normal 18.5-24.9 kg/m2, overweight 25-30 kg/<br />
m2, obese >30 kg/m2. PFS and OS were calculated by Kaplan-Meier estimation;<br />
multivariate Cox analysis was performed adjusting for age, menopausal status, PS<br />
and study.<br />
Results: Information on BMI at <strong>the</strong> time of study entry, was available on 489<br />
women. All patients received first line chemo<strong>the</strong>rapy regimens including<br />
anthracyclines and taxanes, ei<strong>the</strong>r in sequence or combination. Median follow up was<br />
18 months (range 0.4 to 88.3). Overall, 40.3% of <strong>the</strong> patients were normal, 38.2%<br />
were overweight and 21.5% were obese. Median age was 57 years (range 25 to 73); PS<br />
was 0 in 93% of <strong>the</strong> patients. A non significant trend toward improved PFS was<br />
found in overweight women: median PFS was 13.1 months (95% CI 11.0-15.2) in<br />
BMI 25-30 versus 10.8 months (8.9-12.6) in BMI < 25 and 12.2 (95% CI 10.4-14.0)<br />
in BMI >30, p = 0.2. Median OS was 32.0 months (95% CI 24.9-39.1) in BMI < 25<br />
versus 32.9 (95% CI 27.7-38.1) in BMI 25-30 and 30.7 (95% CI 24.3-37.0) in BMI<br />
>30, p = 0.8. By multivariate analysis, none of <strong>the</strong> considered variables was<br />
significantly associated with differences in PFS and/or OS.<br />
Conclusions: In this study BMI at baseline was not significantly associated with <strong>the</strong><br />
outcome of MBC patients treated with first line chemo<strong>the</strong>rapy; however, a non<br />
significant trend for an improved PFS was observed in overweight women as<br />
compared to normal weight and obese patients. These data suggest that overweight<br />
should not be regarded as an adverse prognostic factor patients with MBC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
328PD PROGRESSION-FREE SURVIVAL AS A SURROGATE FOR<br />
OVERALL SURVIVAL IN METASTATIC BREAST CANCER<br />
C. Beauchemin 1 , D. Cooper 2 , M. Lapierre 1 , L. Yelle 3 , J. Lachaine 1<br />
1 Faculty of Pharmacy, University of Montreal, Montreal, QC, CANADA, 2 Direction<br />
Scientifique De L’inscription, Institut National d’Excellence en Santé et en<br />
Services Sociaux (INESSS), Quebec, QC, CANADA, 3 Oncology Department,<br />
Notre-Dame Hospital, Montreal, QC, CANADA<br />
Objectives: Progression-free survival (PFS) is frequently used to establish <strong>the</strong> clinical<br />
efficacy of anti-cancer drugs. However, <strong>the</strong> surrogacy of PFS for overall survival (OS)<br />
remains a matter of uncertainty in metastatic breast cancer (mBC). Therefore, <strong>the</strong><br />
aim of this study was to assess <strong>the</strong> relationship between PFS and OS in mBC using a<br />
trial-based approach.<br />
Methods: A systematic literature review was conducted using <strong>the</strong> PICO method:<br />
Population consisted of women with mBC; Interventions and Comparators were<br />
standard treatments for mBC or best supportive care; Outcomes of interest were<br />
median PFS or TTP and median OS. A correlation analysis between median PFS and<br />
OS was first performed and subgroup analyses were conducted to explore possible<br />
reasons for heterogeneity. Then, <strong>the</strong> relationship between <strong>the</strong> treatment effect on PFS<br />
and OS was assessed. The treatment effect on PFS and OS was quantified by <strong>the</strong><br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds393 | ix119
absolute difference of median values. Linear regression analysis was also conducted<br />
to predict <strong>the</strong> effects of a new anticancer drug on OS on <strong>the</strong> basis of its effects on<br />
PFS.<br />
Results: A total of 5041 studies were identified and 144 fulfilled <strong>the</strong> eligibility<br />
criteria. Selected studies included 315 treatment arms, which represents 43,459<br />
patients with mBC. There was a significant relationship between median PFS and<br />
median OS across included trials (r = 0.428; p < 0.01). The correlation between<br />
median PFS/TTP and median OS was higher for studies evaluating chemo<strong>the</strong>rapy<br />
alone (r = 0.575; p ≤ 0.01) or in combination (r = 0.632; p ≤ 0.01) compared with<br />
those evaluating hormone <strong>the</strong>rapy (non-significant r). The correlation coefficient for<br />
<strong>the</strong> treatment effect on PFS and OS was estimated at 0.427 (p < 0.01). The linear<br />
regression equation was: ΔOS = -0.088 (95% CI, -1.347 to 1.172) + 1.753 (95% CI,<br />
1.307 to 2.198) * ΔPFS, with a proportion of variation explained (R 2 ) of 0.86. Results<br />
of <strong>the</strong> regression analysis predict that a difference in median PFS/TTP of 5, 10, 15,<br />
and 20 months would translate into a difference in median OS of 8.7, 17.4, 26.2, and<br />
35.0 months respectively.<br />
Conclusion: The present findings point toward a statistically significant correlation<br />
between PFS and OS in <strong>the</strong> context of mBC and support <strong>the</strong> surrogacy of PFS for OS<br />
in this cancer setting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
329P PATIENT-REPORTED OUTCOMES (PROS) FROM EMILIA, A<br />
PHASE 3 STUDY OF TRASTUZUMAB EMTANSINE (T-DM1) VS<br />
CAPECITABINE AND LAPATINIB (XL) IN HER2-POSITIVE<br />
LOCALLY ADVANCED OR MBC<br />
M. Welslau, 1 , V. Diéras2 , J. Sohn3 , S. Hurvitz4 , D. Lalla5 , L. Fang6 , E. Guardino7 ,<br />
D. Miles8 1<br />
Medical Office Hematology, Praxis Dr. Klausmann / Dr. Welslau, Aschaffenburg,<br />
GERMANY, 2 Department of Medical Oncology, Clinical Trial Unit, Institut Curie,<br />
Paris, FRANCE, 3 Medical Oncology, Yonsei University College of Medicine,<br />
Seoul, KOREA, 4 Medical Oncology, UCLA Jonsson Comprehensive Cancer<br />
Center and Translational Oncology Research International, Los Angeles, CA,<br />
UNITED STATES OF AMERICA, 5 Health Outcomes, Genentech, South San<br />
Francisco, CA, UNITED STATES OF AMERICA, 6 Biostatistics, Genentech, South<br />
San Francisco, CA, UNITED STATES OF AMERICA, 7 Breast Medical Oncology,<br />
Genentech, Inc., South San Francisco, CA, UNITED STATES OF AMERICA,<br />
8<br />
Medical Oncology, Mount Vernon Cancer Center, Northwood, UNITED<br />
KINGDOM<br />
Background: The antibody-drug conjugate T-DM1 combines <strong>the</strong> antitumor activities<br />
of trastuzumab (T) with intracellular delivery of <strong>the</strong> cytotoxic agent DM1. In <strong>the</strong><br />
EMILIA study, <strong>the</strong> efficacy and safety of T-DM1 was compared to XL. Here we<br />
report <strong>the</strong> PRO results.<br />
Methods: Pts with centrally confirmed HER2-positive MBC and prior <strong>the</strong>rapy with<br />
T and a taxane were randomized to T-DM1 or XL administered in 21-day cycles. Pts<br />
completed <strong>the</strong> FACT-B, a 37-item questionnaire composed of 5 subscales at baseline<br />
and on day 1 every 2 cycles until disease progression (PD), 6 wks after PD and every<br />
3 mos <strong>the</strong>reafter. A 24-item subset of FACT-B, <strong>the</strong> Trial Outcome Index (TOI)<br />
provides a summary of physical and functional well-being and breast cancer-specific<br />
symptoms. Time to FACT-B TOI worsening (ie, ≥5 point decrease in TOI), <strong>the</strong> main<br />
PRO analysis, was assessed by Kaplan-Meier methods and a Cox model in female pts<br />
with baseline and ≥1 post-baseline TOI score. An exploratory PRO end point was<br />
<strong>the</strong> incidence of symptoms measured by <strong>the</strong> Diarrhea Assessment Scale (DAS), in<br />
which pts rated diarrhea symptoms in 4 domains (frequency, urgency, discomfort,<br />
stool consistency) on a 4-point scale at baseline and on day 1 of each cycle until PD.<br />
Results: Pts treated with T-DM1 had longer PFS (9.6 vs 6.4 months; HR=0.650;<br />
P1 stool per day<br />
(57% vs 30%); loose or watery stools (70% vs 37%); somewhat to very urgent stools<br />
(54% vs 26%) and mild-moderate to very severe abdominal discomfort with bowel<br />
movements (45% vs 25%).<br />
Conclusions: Improvements in efficacy and safety were accompanied by, clinically<br />
significant benefits in health-related quality of life in pts treated with T-DM1 vs XL.<br />
Keywords: diarrhea, T-DM1, patient-reported outcomes, HER2-positive.<br />
Disclosure: V. Diéras: *Compensated consultant/advisory relationship with<br />
Genentech/Roche, Novartis, Sanofi, Amgen, Clovis, Pfizer, GSK *Honoraria from<br />
Genentech/Roche, Novartis, Sanofi, Amgen, Clovis, Pfizer, GSK J. Sohn: Research<br />
funding from Roche, Amgen and GSKS. Hurvitz: *Support for study-related travel<br />
from Roche *Research funding for institution from Roche D. Lalla: Genentech<br />
employee, owns Roche stockL. Fang: Genentech employee, owns Roche stockE.<br />
Guardino: Genentech employee, owns Roche stock All o<strong>the</strong>r authors have declared<br />
no conflicts of interest.<br />
Annals of Oncology<br />
330P QUALITY OF LIFE (QOL) ASSESSMENT IN WOMEN WITH<br />
LOCALLY ADVANCED (LA) OR METASTATIC BREAST CANCER<br />
(MBC): RESULTS OF A PHASE II TRIAL WITH ERIBULIN<br />
W.R. Simons 1 , J. Cortes 2<br />
1 Global Health Technology Assessment, Eisai, Inc., Woodcliff Lake, NJ, UNITED<br />
STATES OF AMERICA, 2 Breast Cancer Program, Vall d’Hebron University<br />
Hospital, Barcelona, SPAIN<br />
Objective: Eribulin is a nontaxane microtubule dynamics inhibitor with a<br />
mechanism of action different from many o<strong>the</strong>r tubulin targeting agents and<br />
indicated for mono<strong>the</strong>rapy treatment of patients with LA or MBC who have<br />
progressed after at least an anthracycline and a taxane. While eribulin has shown<br />
overall survival and extended progression free periods benefits in <strong>the</strong>se women, QoL<br />
associated with those benefits need to be determined.<br />
Methods: We use a Phase II clinical trial where 291 women with LA or MBC were<br />
required to have received prior treatment with an anthracycline, a taxane, and<br />
capecitabine. Eribulin was administered at 1.23 mg/m 2 (equivalent to 1.4mg/m 2<br />
eribulin mesilate) i.v. over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle.<br />
EORTC-QLQ-BR32 was administered every second cycle, before drug administration<br />
and before patients were informed of <strong>the</strong>ir tumor assessment. As <strong>the</strong>se data are<br />
repeated observations, every second cycle, across <strong>the</strong> course of treatment, generalized<br />
estimating equations (GEE) were applied to individual QOL scores with response,<br />
complete or partial tumor response as well as progressive disease as independent<br />
indicators.<br />
Results: Two-hundred eighty three women provided a total of 1068 QOL<br />
assessments. Their general health status was 68.88 (P < 0.0001) on a 100 point scale,<br />
improving by 7.90 (P = 0.0153) when responding to eribulin. Indeed, women<br />
responding to eribulin improved in each of <strong>the</strong> subscale domains, including<br />
emotional functioning (10.54; P = 0.0004), physical functioning (12.95; P = 0.0008),<br />
role functioning (9.37; P =0.0005), pain (7.90; P = 0.0153) and breast symptoms<br />
(-12.42; P = 0.0004). Hair loss was a concern, (-9.18; P = 0.0001). Conversely,<br />
progressive disease significantly worsens <strong>the</strong>ir QOL, physical functioning by (-19.18;<br />
P < 0.0001), role functioning (-9.36; P < 0.0001) and emotional functioning (-10.459;<br />
P < 0.0001).<br />
Conclusion: LABC or MBC significantly impacts every aspect of <strong>the</strong>se women’s lives<br />
as measured by <strong>the</strong> EORTC-QLQ-BR32 questionnaire. While hair loss was a<br />
concern, eribulin provided <strong>the</strong>se women with significant relief and measureable and<br />
meaningful improvements in overall QOL, including emotional, social, role<br />
functioning subscales and pain and breast symptoms.<br />
Disclosure: W.R. Simons: W. Robert Simons is an Eisai Inc employee. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
331P IMPACT OF RESPONSE SHIFT ON TIME TO QUALITY OF LIFE<br />
SCORES DETERIORATION IN BREAST CANCER PATIENTS: IS<br />
IT TIME TO MOVE FOR QOL RECIST CRITERION?<br />
Z. Hamidou 1 , T.S. Dabakuyo 1 , F. Guillemin 2 , T. Conroy 3 , M. Velten 4 , D. Jolly 5 ,<br />
M. Mercier 6 , S. Causeret 7 , J. Cuisnier 7 , F. Bonnetain 1<br />
1 Biostatistic and Epidemiological Unit(ea 4184), Centre Georges François<br />
Leclerc, Dijon, FRANCE, 2 Clinical Epidemiology and Evaluation Department,<br />
CIC-EC, Nancy, FRANCE, 3 Oncology, Centre Alexis Vautrin, Vandoeuvre Les<br />
Nancy Cedex, FRANCE, 4 Epidemiology and Public Health Laboratory, College of<br />
Medicine, Strasbourg, FRANCE, 5 Création du Pôle Recherche et Innovations,<br />
University Hospital, Reims, FRANCE, 6 Cellular and Molecular Biology Laboratory<br />
EA 3181, University Hospital of Besançon, Besançon, FRANCE, 7 Surgery,<br />
Centre Georges François Leclerc, Dijon, FRANCE<br />
Background: Time to quality of life (QoL) score deterioration (TD) is a method of<br />
longitudinal QoL data analysis that has been proposed for breast cancer (BC)<br />
patients (Hamidou et al Oncologist 2011). As for RECIST criteria, <strong>the</strong> optimal<br />
definitions dealing with reference should be explored. This study aims to study <strong>the</strong><br />
impact of changes in internal standards (CIS) of response-shift (RS) and <strong>the</strong><br />
influence of baseline QoL expectancies on TD.<br />
Methods: A prospective multicenter study including all women hospitalized for a<br />
primary BC was conducted. The EORTC-QLQ-C30 and BR-23 questionnaires were<br />
used to assess <strong>the</strong> QoL at baseline, at <strong>the</strong> end of 1 st hospitalization, and 3 and 6<br />
months after. CIS was investigated by <strong>the</strong> <strong>the</strong>n-test method. QoL expectancy was<br />
assessed at baseline using Likert scale. Deterioration was defined as a decrease in<br />
QoL scores reaching at least <strong>the</strong> mean difference identified as minimal clinically<br />
important difference (MCID) using Jaeschke’s transition question. Sensitivity analyses<br />
were done using <strong>the</strong> <strong>the</strong>n-test score as reference score, and considering 5 and 10<br />
points as MCID. TD was estimated using Kaplan-Meier method. Cox regression<br />
analyses were used to identify factors influencing TD.<br />
Results: From February 2006 to February 2008, 381 women were included. For role<br />
functioning dimension, <strong>the</strong> median TD increased from 3.2 months [95% CI:<br />
3.1-3.36] to 4.76 months [3.3-6.2] when adjusting on CIS. For body image when<br />
ix120 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
adjusting on CIS, sentinel lymph node biopsy became significantly associated with<br />
longer TD (HR: 0.64[0.43-0.94]) as compared to axillary lymph node dissection,<br />
radio<strong>the</strong>rapy to a shorter TD (HR: 0.63[0.42-0.95] and <strong>the</strong> type of surgery had no<br />
effect on TD. For global health, cognitive and social functioning dimensions, patients<br />
expecting deterioration in <strong>the</strong>ir QoL had a significantly shorter TD. For fatigue and<br />
breast symptom scales, patients expecting no change had a significantly shorter TD,<br />
as compared to patients expecting an improvement. Sensitivity analyses using a<br />
MDCS of 5 or 10 confirmed <strong>the</strong>se results.<br />
Conclusions: Our results suggest that it would be more accurate to take into account<br />
CIS component of RS as well as QoL expectancies to estimate TD of QoL scores in<br />
patient with BC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
332P HEALTH STATE UTILITY DETERMINATION IN ADVANCED<br />
STAGE BREAST CANCER PATIENTS<br />
W.R. Simons<br />
Global Health Technology Assessment, Eisai, Inc., Woodcliff Lake, NJ, UNITED<br />
STATES OF AMERICA<br />
Background: Quality-adjusted Time Without Symptoms of disease and Toxicity<br />
(Q-TWiST) survival analysis where time without disease progression is rewarded<br />
while time without disease progression but with toxicities is penalized by applying a<br />
utility weight is increasingly common in health technology assessments of cancer<br />
treatments. AIM: We assess women’s preferences for health states specific to<br />
advanced stage breast cancer including a baseline diagnoses of ABC, treatment<br />
response, no treatment response but no disease progression, disease progression and<br />
hormonal <strong>the</strong>rapy specific toxicities.<br />
Method: Using FACT-B quality of life data from a randomized clinical trial in ABC<br />
univariate statistics were obtained for each item for each health state without regard<br />
to treatment. These item scores were paired to <strong>the</strong> actual narrative in <strong>the</strong> FACT-B to<br />
construct health state narratives consisting of physical, social, emotional, functional<br />
well-being and additional concerns content domains. The order of <strong>the</strong> content<br />
domains was varied to prevent order bias. One hundred and nine peri- or<br />
post-menopausal women were recruited and interviewed by a single woman in <strong>the</strong>ir<br />
age group using visual analogue and standard gamble techniques. Univariate and<br />
multivariate analyses were performed to control for age, marital status, menopausal<br />
status and whe<strong>the</strong>r <strong>the</strong> interviewee has had breast cancer or any o<strong>the</strong>r cancer.<br />
Results: Of <strong>the</strong> 109 recruited 100 women completed <strong>the</strong> interview, mean age was<br />
55.76 years, 64% were postmenopausal, 11% had breast cancer previously and 16%<br />
had ano<strong>the</strong>r type of cancer previously. Multiple regressions results for <strong>the</strong> VAS scores<br />
yielded values of 51.8 (p < 0.01) for baseline ABC diagnosis, 82.5 (p < 0.01) for<br />
treatment response, 57.5 (p < 0.01) for no response no progression and 38.4<br />
(p < 0.01) for disease progression. The SG results were 0.64 (p < 0.01), 0.76<br />
(p < 0.01), 0.67 (p < 0.01), and 0.50 (p < 0.01), respectively. Women who previously<br />
had breast cancer related <strong>the</strong> health states consistently higher (p < 0.05) in <strong>the</strong> VAS<br />
and SG analyses. The trade-off between a chance of treatment response yet <strong>the</strong><br />
possibility of toxicity yielded a utility score of 0.34 (p < 0.01).<br />
Conclusion: These VAS and SG scores can be used to better assess women’s<br />
preference for treatment options in ABC.<br />
Disclosure: W.R. Simons: This research was conducted independent of Eisai Inc.<br />
333P COST EFFECTIVENESS OF ADJUVANT CYCLOPHOSPHAMIDE<br />
CONTAINING REGIMES TO AT IN THE TREATMENT OF<br />
BREAST CANCER IN GERMANY<br />
E. Walter<br />
IPF, IPF Institute for Pharmaeconomic Research, Vienna, AUSTRIA<br />
Objectives: 58,000 women in Germany are diagnosed with breast cancer each year.<br />
Anthracycline-containing regimes - in addition to o<strong>the</strong>r treatment options - have<br />
been standard adjuvant breast cancer regimens. The purpose of this analysis was to<br />
estimate <strong>the</strong> cost-effectiveness of AT (doxorubicin, docetaxel) compared with AC<br />
(doxorubicin, cyclophosphamide), CMF (cyclophosphamide, methotrexat,<br />
5-fluoruracil) and FEC (5-fluoruracil, epirubicin, cyclophosphamide) administered as<br />
adjuvant <strong>the</strong>rapy to women with node-positive breast cancer in Germany.<br />
Methods: We developed a multi-country Cost-Utility-Model to simulate <strong>the</strong><br />
long-term consequences from initiation of adjuvant chemo<strong>the</strong>rapy over 10 years.<br />
Markov modelling techniques were used to estimate incidence of complications<br />
during chemo<strong>the</strong>rapy (febrile neutropenia, chemo<strong>the</strong>rapy induced nausea/vomiting,<br />
dose-reduction, dose-delay, o<strong>the</strong>r grade 3/4 adverse events) and long-term<br />
consequences like local or distant relapse, secondary acute myelogenous leukemia,<br />
chronic heart failure and death. Monte-Carlo-simulation accounted for uncertainty.<br />
Probabilities were derived from clinical and epidemiological studies; direct costs from<br />
published sources from <strong>the</strong> payer’s perspective. QALYs, life years and costs were<br />
discounted at 3% p.a.<br />
Results: Over a 10-year timeframe, costs and outcomes associated with AT amounts<br />
to 21,055.91 € and 6.3 QALYs (7 LYs). Costs associated with AC are 17,018.04 €,<br />
while outcomes are comparable to AT. The cost saving potential associated to AC vs.<br />
AT amounts to 4,037.87 € per patient. Costs and outcomes associated with CMF are<br />
17,790.42 € and 6.3 QALYs (6.94 LYs), leading to a cost saving potential of €<br />
3,265.49 with CMF vs AT. FEC associated total costs are 18,471.84 €.<br />
Quality-adjusted life expectancy increases to 6.5 years, which represents a QALY gain<br />
of 0.2 QALYs over 10 years vs. AT. The increase in life expectancy without quality<br />
adjustment amounts to 7.4 years and leads to 0.4 LYs gained with FEC versus AT.<br />
Accordingly, FEC dominates AT.<br />
Conclusion: Cyclophosphamide-based regimens (FEC, AC and CMF) demonstrate a<br />
better performance from cost-effectiveness perspective vs. AT (doxorubicin,<br />
docetaxel).<br />
Disclosure: All authors have declared no conflicts of interest.<br />
334P HEALTH-RELATED QUALITY OF LIFE (QOL) IN METASTATIC<br />
BREAST CANCER PATIENTS TREATED WITH EVEROLIMUS<br />
AND EXEMESTANE VERSUS EXEMESTANE MONOTHERAPY<br />
H. Burris 1 , J.T. Beck 2 ,H.Rugo 3 , J. Baselga 4 , F. Lebrun 5 , T. Taran 6 , L. Bennett 7 ,<br />
J. Ricci 8 , T. Sahmoud 9 , G.N. Hortobagyi 10<br />
1 Highlands Oncology Group, Highlands Oncology Group, Nashville, TN, UNITED<br />
STATES OF AMERICA, 2 Highlands Oncology Group, Highlands Oncology Group,<br />
Fayetteville, AR, UNITED STATES OF AMERICA, 3 Helen Diller Family<br />
Comprehensive Cancer Center, University of California, San Francisco, CA,<br />
UNITED STATES OF AMERICA, 4 Massachusetts General Hospital Cancer Center<br />
and Harvard Medical School, Massachusetts General Hospital Cancer Center<br />
and Harvard Medical School, Boston, MA, UNITED STATES OF AMERICA,<br />
5 Jules Bordet Institute, Institute Jules Bordet, Brussels, BELGIUM, 6 Sr Global<br />
Clinical Leader, Novartis Pharmaceuticals Corporation, East Hanover, NJ,<br />
UNITED STATES OF AMERICA, 7 Biometrics, RTI Health Solutions, Research<br />
Triangle Park, NC, UNITED STATES OF AMERICA, 8 Wellmera Ag, Wellmera AG,<br />
Basel, SWITZERLAND, 9 Gbl Clin Program Head, Novartis Pharmaceuticals<br />
Corporation, East Hanover, NJ, UNITED STATES OF AMERICA, 10 The University<br />
of Texas MD Anderson Cancer Center, The University of Texas MD Anderson<br />
Cancer Center, Houston, TX, UNITED STATES OF AMERICA<br />
Background: The phase 3 BOLERO-2 study randomized 724 patients with<br />
hormone-receptor–positive (HR + ) advanced breast cancer and recurrence or<br />
progression during/after nonsteroidal aromatase inhibitor <strong>the</strong>rapy to everolimus<br />
(EVE) plus exemestane (EXE) or EXE and placebo (PBO). Interim analysis after 12<br />
months’ median follow up demonstrated that EVE + EXE significantly improved<br />
progression-free survival (PFS) vs EXE + PBO, with a higher rate of grade 3/4 adverse<br />
events but no deterioration in QOL. We report here on additional post hoc analyses<br />
of patient-reported QOL.<br />
Methods: Using <strong>the</strong> EORTC QLQ-C30 questionnaire and QLQ-BR23 module,<br />
QOL was assessed at baseline and every 6 weeks <strong>the</strong>reafter until progression or<br />
discontinuation. The QLQ-C30 consists of 30 items combined into 15<br />
subscales, including Global Health Status (GHS). The BR23 consists of 23 items<br />
specific to breast cancer combined into symptom and functioning subscales,<br />
including breast symptom (BS) and arm symptom (AS) scales. Average<br />
difference in change from baseline between treatment groups was evaluated<br />
using linear mixed models with several adjustment covariates. Sensitivity<br />
analysis was conducted using pattern-mixture models to examine <strong>the</strong> effect of<br />
study dropout on or before week 24. Treatments were compared using<br />
differences of least squares mean (LSM) changes from baseline at each<br />
timepoint and overall.<br />
Results: Linear mixed models indicated no statistically significant overall difference<br />
between EVE + EXE and EXE + PBO for GHS (LSM difference = –2.0; 95% CI = –4.8,<br />
0.9), breast symptoms (LSM difference = 0.3; 95% CI = –2.8, 2.4), or arm symptoms<br />
(LSM difference = –0.2; 95% CI = –2.8, 2.4). Pattern-mixture models indicated that<br />
patients who dropped out early had worsening QOL over time in both treatment<br />
arms; EVE + EXE patients who did not drop out early had stable QOL, whereas EXE<br />
+ PBO was associated with worsening QOL over time.<br />
Conclusions: These additional analyses from <strong>the</strong> BOLERO-2 study confirm that<br />
compared with EXE alone, EVE + EXE improved PFS without adversely impacting<br />
QOL in patients with HR + advanced breast cancer progressing despite nonsteroidal<br />
aromatase inhibitors.<br />
Disclosure: J.T. Beck: Has received grant support from Pfizer and Novartis. H.<br />
Rugo: Has received grant support from Pfizer and Merck, and has received travel<br />
support from Novartis. J. Baselga: Is a consultant to Novartis, Roche, Merck,<br />
sanofi-aventis, Verastem, Bayer, Chugai, Exelixis, Onyx, and Constellation. T.<br />
Taran: Is an employee of Novartis with stock options. L. Bennett: Is an employee<br />
of RTI Health Solutions, which contracted with Novartis for data analysis<br />
services. J. Ricci: Is a consultant to Novartis. T. Sahmoud: Is an employee of<br />
Novartis with stock options. G.N. Hortobagyi: Member of <strong>the</strong> Sci Ad Board of<br />
Allergan; consultant to Allergan, Novartis, Genentech, and sanofi-aventis; has<br />
received grant support from Novartis; travel expense reimbursement from<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds393 | ix121
Novartis, Genentech, and sanofi-aventis. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
335P DYSPHONIA AS A PREVIOUSLY UNREPORTED SIDE EFFECT<br />
OF BEVACIZUMAB TREATMENT IN PATIENTS WITH<br />
METASTATIC BREAST CANCER<br />
S.A. Radema 1 , P. Souverein 2 , R. Meyboom 2 , F. Ahmadizar 2 , C. Onland-Moret 2 ,<br />
A. Maitland-Vd Zee 2<br />
1 Internal Medicine, Gelre Ziekenhuizen, Apeldoorn, NETHERLANDS,<br />
2 Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology<br />
and Clinical Pharmacology, Utrecht University, Utrecht, NETHERLANDS<br />
Introduction: Bevacizumab is a humanized monoclonal antibody directed against<br />
vascular endo<strong>the</strong>lial growth factor A and has been approved for <strong>the</strong> treatment of<br />
several metastatic tumours. There is considerable heterogeneity in <strong>the</strong> response to<br />
treatment with bevacizumab, both in effectiveness and in toxicity. Here we describe a<br />
previously unreported adverse drug reaction (adr) in pts with MBC treated with<br />
bevacizumab.<br />
Methods: In a teaching hospital in <strong>the</strong> Ne<strong>the</strong>rlands (from Sep 2009 to Jul 2011), 32<br />
consecutive pts with MBC treated with chemo<strong>the</strong>rapy and bevacizumab were<br />
registered in a retrospective database. TNM stage, comorbidities, concomitant<br />
medication, prior treatment for <strong>the</strong> primary tumour, date of metastatic disease, prior<br />
treatment for metastatic disease and toxicities were recorded. The WHO global<br />
individual case safety report database, VigiBase, contains summaries of suspected<br />
spontaneous case reports summated by health care professionals and pts to national<br />
pharmacovigilance centres . As of May 2010, VigiBase contained >5 million case<br />
reports. . We searched <strong>the</strong> VigiBase extraction of Dec 2011 for dysphonia. Reporting<br />
odds ratios (ROR) were calculated for <strong>the</strong> occurrence of dysphonia compared with<br />
o<strong>the</strong>r adr for bevacizumab and paclitaxel.<br />
Results: In total, 9/32 pts (28%) reported dysphonia during treatment with<br />
bevacizumab and 5/9 pts underwent ENT examination. In several pts marked<br />
oedema of <strong>the</strong> vocal cords and/or chronic laryngitis were found. As of Dec 2011,<br />
6,880,361 reports were available in VigiBase, of which16,239 were related to<br />
dysphonia. For bevacizumab <strong>the</strong>re were 51 reports for dysphonia and 46,041 reports<br />
for o<strong>the</strong>r adr. Corresponding figures for all o<strong>the</strong>r drugs were 22,108 reports for<br />
dysphonia and 25,151,628 reports for o<strong>the</strong>r adverse effects: ROR of 1.26 (95% CI:<br />
0.95-1.66). For paclitaxel <strong>the</strong>re were 45 reports for dysphonia and 85,988 reports for<br />
o<strong>the</strong>r adr. Corresponding figures for all o<strong>the</strong>r drugs were 22,114 reports for<br />
dysphonia and 25,111,681 reports for o<strong>the</strong>r adverse effects: ROR of 0.59 (95% CI:<br />
0.44-0.80)meaning that <strong>the</strong> risk of angiooedema is significantly higher in<br />
bevacizumab users compared to paclitaxel users.<br />
Conclusion: Dysphonia is a previously unreported side-effect in pts with MBC<br />
treated with bevacizumab and paclitaxel.<br />
Disclosure: S.A. Radema: I am member of an advisory board for Roche. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
336P PATTERNS OF CLINICAL MANAGEMENT AND RESOURCE<br />
UTILIZATION FOR POSTMENOPAUSAL<br />
HORMONE-RECEPTOR–POSITIVE HER2-NEGATIVE (HR+<br />
HER2–) ADVANCED BREAST CANCER (ABC) IN EUROPE<br />
G. Jerusalem 1 , N. Marinsek 2 , J. Ricci 3 , J. Etchberger 2 , R. Degun 2 , G. Benelli 4 ,<br />
S. Saletan 5 , F. André 6<br />
1 Centre Hospitalier Universitaire du Sart Tilman, Centre Hospitalier Universitaire<br />
du Sart Tilman, Liège, BELGIUM, 2 Navigant Consulting, Inc, Navigant<br />
Consulting, Inc, London, UNITED KINGDOM, 3 Wellmera AG, Wellmera AG,<br />
Basel, SWITZERLAND, 4 Novartis Farma S.p.a., Saronno, ITALY, 5 Onco Ex Dir<br />
Clinical Res Phys, Novartis Pharmaceuticals Corporation, East Hanover, NJ,<br />
UNITED STATES OF AMERICA, 6 Breast Cancer Unit, Institut Gustave Roussy,<br />
Villejuif, FRANCE<br />
Objective: To understand treatment patterns and quantify resource utilization of<br />
HR + HER2 − aBC, with <strong>the</strong> overall aim of comparing costs and disease burden as<br />
patients progress from hormonal <strong>the</strong>rapy (HT) to chemo<strong>the</strong>rapy (CT).<br />
Methods: We conducted a chart audit in France, Germany, The Ne<strong>the</strong>rlands,<br />
Belgium, and Sweden of 375 living and deceased postmenopausal female patients (75<br />
per country) diagnosed with ER + HER2 − aBC in <strong>the</strong> past 4 years. Patients were<br />
required to have progressed on ≥ 1 line of prior HT ei<strong>the</strong>r in <strong>the</strong> adjuvant or<br />
advanced setting and to have completed ≥ 1 line of CT treatment (minimum 2 full<br />
cycles) in <strong>the</strong> aBC setting. The chart audit was completed online using a<br />
standardized form developed with <strong>the</strong> assistance of European academic physicians,<br />
pharmacy directors, and hospital administrators. Participation was sought from 25<br />
oncologists per country, except in Germany (15 oncologists and 10 gynecologists to<br />
reflect local clinical practice). Data collection was compliant with European and<br />
country market research regulations.<br />
Results: Our report details <strong>the</strong> patient care pathway, CT side effects, and resource<br />
utilization in <strong>the</strong> inpatient and outpatient settings throughout <strong>the</strong> continuum of aBC<br />
Annals of Oncology<br />
care. Preliminary analyses indicate that 55% of HR + HER2 − aBC patients are first<br />
treated with HT and switch to CT after 1.5 lines of HT. This switch is primarily<br />
influenced by <strong>the</strong> extent (56%) and progression rate (36%) of metastases. The switch<br />
from HT to CT is associated with increased resource utilization and <strong>the</strong> associated<br />
costs of treating aBC. In addition to cost of drug <strong>the</strong>rapies, <strong>the</strong> main drivers of cost<br />
are treatment for CT side effects (chiefly febrile neutropenia and diarrhea) and<br />
related hospitalization events. CT side effects that have <strong>the</strong> greatest impact on <strong>the</strong><br />
overall disease burden of aBC include alopecia, nausea, vomiting, fatigue, and<br />
peripheral neuropathy.<br />
Conclusions: Our results highlight <strong>the</strong> increased costs and disease burden for<br />
postmenopausal ER + HER2 − aBC patients treated with CT versus HT.<br />
Disclosure: G. Jerusalem: Consultant, Novartis Pharmaceuticals Corporation. N.<br />
Marinsek: Consultant, Novartis Pharmaceuticals Corporation. J. Ricci: Advisor,<br />
consultant, Novartis Pharmaceuticals Corporation. J. Etchberger: Consultant,<br />
Novartis Pharmaceuticals Corporation. R. Degun: Consultant, Novartis<br />
Pharmaceuticals Corporation. G. Benelli: Employees of Novartis with stock/stock<br />
options. S. Saletan: Employee of Novartis with stock/stock options. F. André:<br />
Financial support from sanofi-aventis, Novartis, Roche, AstraZeneca<br />
337P EFFICIENCY FRONTIER ANALYSIS (EFA) OF METASTATIC<br />
BREAST CANCER (MBC) TREATMENTS: A UK PERSPECTIVE<br />
C. Burudpakdee 1 , D. Bertwistle 2<br />
1 Health Economics and Outcomes Research, IMS Health, Philadelphia, PA,<br />
UNITED STATES OF AMERICA, 2 Heor, IMS Health, London, UNITED KINGDOM<br />
Background: As newer <strong>the</strong>rapies for mBC become available, understanding <strong>the</strong><br />
efficiency of <strong>the</strong>se <strong>the</strong>rapies will be important for HTA recommendations and<br />
treatment decisions. EFA may be a useful method of assessing <strong>the</strong> efficiency of newer<br />
interventions. The EFA displays <strong>the</strong> outlay (cost) and gains with technologies, and<br />
displays <strong>the</strong> next most efficient option going forward. This study was designed to<br />
evaluate whe<strong>the</strong>r EFA could be useful in identifying <strong>the</strong> efficiency of mBC <strong>the</strong>rapies<br />
adopted by <strong>the</strong> NHS, and to identify <strong>the</strong> efficiency frontier for newer technologies.<br />
Methods: A literature search was performed to identify mBC treatments that<br />
underwent HTA in <strong>the</strong> UK. Reports were reviewed to identify treatment efficacy and<br />
HTA recommendations. Costs were determined for a course of treatment. The<br />
incremental costs per patient were plotted on <strong>the</strong> horizontal axis and incremental<br />
median overall survival (ΔOS) of each treatment was plotted on <strong>the</strong> vertical axis to<br />
construct <strong>the</strong> EFA line. Treatments below this line are considered inefficient options.<br />
Treatments above this line have better OS and may redefine <strong>the</strong> efficiency frontier.<br />
Treatments in <strong>the</strong> upper right quadrant beyond <strong>the</strong> frontier line are in an area where<br />
ceiling price has not been defined. Treatments in <strong>the</strong> lower right quadrant beyond<br />
<strong>the</strong> frontier line are inefficient due to higher cost for lower OS.<br />
Results: Ten reports that evaluated efficacy in terms of median OS were included in<br />
<strong>the</strong> EFA. The <strong>the</strong>rapies are paclitaxel albumin, gemcitabine, trastuzumab,<br />
bevacizumab, lapatinib, eribulin and fulvestrant. On <strong>the</strong> frontier line are paclitaxel<br />
albumin (ΔOS of 2.3 months at £2020), gemcitabine (ΔOS of 2.8 months at £6020),<br />
and trastuzumab (ΔOS of 4 months at £16939); all received positive<br />
recommendations. Lapatinib (ΔOS of 1.9 months at £10180), bevacizumab (ΔOS of<br />
1.7 months at £36560), eribulin (ΔOS of 2.5 months at £4834) and fulvestrant (ΔOS<br />
of 2.3 months at £2481) are all below <strong>the</strong> frontier line and received negative<br />
recommendations.<br />
Conclusion: EFA may be a useful method for assessing <strong>the</strong> efficiency of new mBC<br />
treatment options for clinical use. Fur<strong>the</strong>r studies are needed to better understand<br />
value in terms of efficiency of treatments in o<strong>the</strong>r tumor types and disease areas.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
338P A CONJOINT ANALYSIS OF WILLINGNESS TO PAY TO AVOID<br />
METASTATIC BREAST CANCER SIDE EFFECTS<br />
D. Lalla 1 , M. Brammer 1 , R. Carlton 2 , T. Bramley 2 ,A.D’Souza 3<br />
1 Health Outcomes, Genentech/Roche, South San Francisco, CA, UNITED<br />
STATES OF AMERICA, 2 Global Value Strategies, Xcenda, Palm Harbor, FL,<br />
UNITED STATES OF AMERICA, 3 Data Analytics, Xcenda, Palm Harbor, FL,<br />
UNITED STATES OF AMERICA<br />
Background: Patients with metastatic breast cancer (MBC) are treated with a variety<br />
of regimens with differing side effect profiles. In addition to efficacy, side effect<br />
profile can be an important consideration in <strong>the</strong>rapy choice. Conjoint analysis is a<br />
research method used to evaluate how trade-offs are made between different<br />
attributes. This study assessed <strong>the</strong> willingness to pay (WTP) to avoid side effects<br />
related to MBC treatment using conjoint analysis. The WTP thus informs clinicians<br />
of patients’ preferences and which side effects <strong>the</strong>y are most desirous of avoiding.<br />
Methods: An online, self-administered survey of MBC patients in <strong>the</strong> US was<br />
conducted. The survey was fielded with a sample of adult female patients with a<br />
diagnosis of MBC. Key variables (attributes) included in <strong>the</strong> analysis and with levels<br />
described in lay terms were: Alopecia, Diarrhea, Fatigue, Pain, Nausea, Neuropathy,<br />
Neutropenia and Out of pocket costs. 15 scenarios (choice-based conjoint questions)<br />
ix122 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Table: 340P<br />
Characteristics N 201 (%) Characteristics N 201 (%)<br />
T size Tis-T1-T2 T3-T4 T Unk 138(68,6) 40 (20) 23 (11,4) PgR Pos Neg Unk 142(70,6) 33 (16,4) 26 (13)<br />
Nodal Status N0 N+ Nx 54 (26,9) 120 (59,7) 27 (13,4) Adj CT Yes No Unk 105 (51,7) 94 (46,8) 3 (1,5)<br />
ER Pos Neg Unk 169 (84) 12 (6) 20 (10) Adj HT Yes No Unk 141 (70,1) 46 (22,9) 14 (7)<br />
were presented where patients selected <strong>the</strong> most preferred <strong>the</strong>rapy. Each <strong>the</strong>rapy was<br />
described with three distinct variables. The choices of variables for each <strong>the</strong>rapy<br />
included two side effects and an out of pocket price. The survey also collected<br />
information on prior treatment regimens, previous side effect history, and<br />
demographics.<br />
Results: There were 298 responses. Most respondents were white (84%), married<br />
(57%) over 40 years of age (86%), and had private insurance (57%). MBC patients<br />
were willing to pay $3,894 to avoid severe diarrhea, $3,479 to avoid being<br />
hospitalized due to infection, $3,211 to avoid severe nausea, $2,764 to avoid severe<br />
tingling in hands and feet, $2,652 to avoid severe fatigue, $1,853 to avoid obvious<br />
hair loss and $1,458 to avoid severe pain. The most important attributes when<br />
selecting a <strong>the</strong>rapy for MBC in terms of average utility were neutropenia, diarrhea<br />
and nausea.<br />
Conclusions: Patients most highly value <strong>the</strong> avoidance of diarrhea, neutropenia, and<br />
nausea with MBC treatment regimens. These are common side effects seen in many<br />
regimens used for treatment of MBC. This information can aid clinical decision<br />
making when selecting between MBC treatment options. Treatment regimens<br />
providing clinical efficacy while decreasing or eliminating key side effects would be<br />
an important choice to consider.<br />
Disclosure: D. Lalla: Dr. Lalla is an employee of Genentech, which funded this<br />
analysis. M. Brammer: Dr. Brammer is an employee of Genentech, which funded this<br />
analysis. R. Carlton: Dr. Carlton is an employee of Xcenda, which received funding<br />
from Genentech to conduct this analysis. T. Bramley: Dr. Bramley is an employee of<br />
Xcenda, which received funding from Genentech to conduct this analysis. A.<br />
D’Souza: Dr. D’Souza is an employee of Xcenda, which received funding from<br />
Genentech to conduct this anaysis.<br />
339P FULVESTRANT 500 MG AS FIRST-LINE TREATMENT IN<br />
HORMONE-POSITIVE (HR+) METASTATIC BREAST CANCER<br />
(MBC) PATIENTS (PTS): PROSPECTIVE EVALUATION OF<br />
ACTIVITY, SAFETY, QUALITY OF LIFE (QOL) AND TUMOUR<br />
MARKERS CHANGES<br />
R. Palumbo 1 , G. Bernardo 1 , A. Riccardi 2 , F. Sottotetti 1 , B. Tagliaferri 1 , E. Pozzi 1 ,<br />
C.M. Teragni 1 , A. Bernardo 1<br />
1 Oncologia Medica 2, Fondazione S. Maugeri IRCCS, Pavia, ITALY, 2 Medical<br />
Oncology, University of Pavia, Pavia, ITALY<br />
Background: Fulvestrant 500 mg has been shown to have a biologically greater effect<br />
and to produce a clinical meaningful benefit over Fulvestrant 250 mg. We carried out<br />
a prospective phase II trial to evaluate <strong>the</strong> activity and safety of such an option as 1 st<br />
line treatment of HR+ MBC; an analysis of QoL, patient compliance, and prognostic<br />
value of tumour markers monitoring was also performed.<br />
Patients and methods: Pts with HR+ MBC relapsing after Tamoxifen and/or<br />
Aromatase Inhibitors adjuvant <strong>the</strong>rapy received Fulvestrant 500 mg i.m. on day 0,<br />
<strong>the</strong>n 500 mg on days 14-28 and every 28 days <strong>the</strong>reafter, until disease progression or<br />
unacceptable toxicity or patient refusal. Changes in cancer antigen 15.3 (CA 15.3)<br />
and carcinoembryonic antigen (CEA) were monitored monthly over treatment; QoL<br />
and treatment tolerability were assessed every 2 cycles.<br />
Results: Forty-eight consecutive pts were enrolled and treated. The overall clinical<br />
benefit rate was 68%, with 3 (6%) complete (CR) and 12 (25%) partial responses<br />
(PR), and 18 (48%) stable diseases (SD ) lasting >24 weeks. The median PFS was 11<br />
months, median response duration was 9 months. Toxicity was manageable, also in<br />
pts given long-duration <strong>the</strong>rapy (>18 months). Analysis of QoL by QLQ-BR23<br />
showed no deterioration of <strong>the</strong> evaluated items over treatment, while <strong>the</strong> compliance<br />
assessment documented an improvement of tolerability of treatment compared with<br />
<strong>the</strong>ir previous adjuvant hormono<strong>the</strong>rapy. In pts achieving a CR or PR both CA 15.3<br />
and CEA serial levels decreased significantly over <strong>the</strong> first 4 months of treatment,<br />
while in long-lasting SD a statistically significant difference from baseline was<br />
reached within a median of 8 months.<br />
Conclusions: Our results confirm <strong>the</strong> known activity and tolerability of Fulvestrant<br />
500 mg as 1 st line <strong>the</strong>rapy for HR+ MBC, with good patient compliance over<br />
long-term treatment and preservation of QoL. Of interest, changes in tumour<br />
markers resulted significantly predictive of treatment activity in responding pts, in<br />
contrast with previously reported data with Fulvestrant 250 mg, reflecting and<br />
additional difference between <strong>the</strong> two drug dosages.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
340P FULVESTRANT AFTER FAILUR OF ADJUVANT HORMONAL<br />
THERAPY: MULTICENTER RETROSPECTIVE OBSERVATIONAL<br />
STUDY<br />
O. Garrone 1 , C. Bighin 2 , F. Vaira 3 , M. Donadio 4 , O. Alabiso 5 , M. Carapezza 6 ,<br />
E. Baldini 7 , M. Merlano 1 , N. Biglia 8 , P. Pronzato 9<br />
1 Clinical Oncology, Azienda Ospedaliera St. Croce e Carle, Cuneo, ITALY,<br />
2 Medical Oncology, Ist Naz Ric Cancro, Genova, ITALY, 3 Medical Oncology,<br />
Ospedale Felettino, LA Spezia, ITALY, 4 Oncoematology, Ospedale S. Giovanni<br />
Battista, Torino, ITALY, 5 Medical Oncology, AOU Maggiore della Carità, Novara,<br />
ITALY, 6 Medical Oncology, Ospedale degli Infermi, Biella, ITALY, 7 Medical<br />
Oncology, USL 2, Lucca, ITALY, 8 Gynecology, Ospedale Umberto I, Torino,<br />
ITALY, 9 Oncologia Medica A, IRCCS AOU San Martino - IST-Istituto Nazionale<br />
per la Ricerca sul Cancro, Genova, ITALY<br />
Background: Aromatase inhibitors (AI) are superior to TAM in <strong>the</strong> treatment of<br />
hormonal receptor positive metastatic breast cancer (MBC). Fulvestrant (F), an<br />
estrogen receptor antagonist demonstrated activity when used after failure of previous<br />
TAM or AI. Objective: To evaluate <strong>the</strong> position of F in <strong>the</strong> hormonal strategy<br />
sequence in hormonal responsive MBC related to <strong>the</strong> evolution of adjuvant<br />
hormonal <strong>the</strong>rapy (HT).<br />
Material and methods: MBC patients with disease progression after adjuvant HT or<br />
after treatment (CT or HT) for metastatic disease, candidate to receive F at <strong>the</strong> dose<br />
of 250 mg/ month (registered in AIFA database) from May 1st 2006 to July 31st<br />
2008. The study registered <strong>the</strong> HT sequence in clinical practice. Overall 201 patients<br />
were collected from 13 Italian Centers. Main patients’ characteristics are summarized<br />
in <strong>the</strong> table.<br />
Results: ORR were: CR 2%; PR 7%; SD 43%; PD 41%; NE 7%. Eighty-six patients<br />
(43%) had visceral metastases. Median duration of F was 7 months (1-42); 8<br />
patients are ongoing and for 1 patient <strong>the</strong> duration was unknown. 16, 39 and 56<br />
patients received F as 1st, 2nd and 3rd line <strong>the</strong>rapy respectively. For <strong>the</strong> remaining<br />
patients F was administered as more than <strong>the</strong> 4th line <strong>the</strong>rapy. The possibility to<br />
obtain a benefit from F did not seem to correlate with <strong>the</strong> line of treatment. One<br />
of <strong>the</strong> 2 CR occurred in a patient with visceral disease (lung). Among <strong>the</strong> patients<br />
who progressed under treatment 42% had visceral disease, that was almost <strong>the</strong><br />
same rate of <strong>the</strong> whole population. This data suggests that <strong>the</strong>re is lack of<br />
correlation between <strong>the</strong> sites of disease and <strong>the</strong> probability of benefit. Toxicity was<br />
negligible.<br />
Conclusions: More than 50% of <strong>the</strong> patients benefited from F notwithstanding 73%<br />
of <strong>the</strong>m received <strong>the</strong> treatment as third or more line of HT. This study does not<br />
show any correlation between <strong>the</strong> sites of <strong>the</strong> metastases and <strong>the</strong> treatment results.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
341P ADJUSTED INDIRECT COMPARISON ANALYSIS<br />
DEMONSTRATES SIGNIFICANT BENEFIT IN<br />
PROGRESSION-FREE SURVIVAL FOR FULVESTRANT 500MG<br />
COMPARED TO ANASTROZOLE IN ADVANCED BREAST<br />
CANCER<br />
P. Schmid 1 , P. Turner 2 , M. Howlett 3<br />
1 Clinical Investigation and Research Unit, Brighton and Sussex Medical School,<br />
Brighton, UNITED KINGDOM, 2 Payer Evidence, AstraZeneca Ltd, Luton,<br />
UNITED KINGDOM, 3 Medical Affairs, Astrazeneca Ltd, Luton, UNITED<br />
KINGDOM<br />
Objectives: Randomised controlled trials (RCTs) provide <strong>the</strong> highest level of<br />
evidence for comparing two treatments. However, with <strong>the</strong> increasing number of<br />
cancer drugs, direct comparison through RCTs is not feasible for all treatment<br />
indications and combinations. Bucher et al (1997) have developed a method for an<br />
adjusted indirect comparison analysis between RCTs. This method was used to<br />
compare <strong>the</strong> efficacy of fulvestrant 500mg and anastrozole 1mg in advanced breast<br />
cancer (ABC).<br />
Methods: A systematic literature search on RCTs of fulvestrant 500mg or anastrozole<br />
1mg in ABC was performed in June 2011, using CENTRAL, EMBASE and<br />
MEDLINE databases. Published data were used to perform a meta-analysis and an<br />
adjusted indirect comparison analysis (Bucher method). The primary endpoint was<br />
progression free survival (PFS).<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds393 | ix123
Results: Three RCTs with 1023 patients were identified comparing fulvestrant 500mg<br />
(F500) with fulvestrant 250mg (F250), and two RCTs with a total of 851 patients<br />
were identified comparing anastrozole 1mg (Ana) with fulvestrant 250mg.<br />
Meta-analysis demonstrated a significant benefit in PFS for F500 compared to F250<br />
(Hazard ratio (HR) 0.80 95% Confidence Interval (CI):0.69-0.93). There was no<br />
significant difference in PFS between Ana and F250 (HR 0.95, 95%CI 0.82-1.1).<br />
Using F250 as common comparator, <strong>the</strong> adjusted indirect comparison analysis<br />
demonstrated a significant benefit in PFS for F500 compared to Ana (HR 0.76, 95%<br />
CI 0.62-0.94).<br />
Conclusions: In <strong>the</strong> absence of a direct RCT comparison, this adjusted indirect<br />
comparison shows that fulvestrant 500mg significantly improves PFS in ABC<br />
compared to anastrozole 1mg. Bucher HC, Guyatt GH, Griffith LE, Walter SD<br />
(1997). The results of direct and indirect treatment comparisons in meta-analysis of<br />
randomized controlled trials. J Clin Epidemiol. 1997 Jun;50(6):683-91.<br />
Disclosure: P. Turner: Pauline Turner is a full-time employee of AstraZeneca and is<br />
a stockholder in Astra Zeneca. M. Howlett: Mat<strong>the</strong>w Howlett is a full time employee<br />
of Astrazeneca and is a stockholder in Astrazeneca. All o<strong>the</strong>r authors have declared<br />
no conflicts of interest.<br />
342P FULVESTRANT (FUL) PLUS ENZASTAURIN (ENZA) VS FUL<br />
PLUS PLACEBO (PBO) IN AROMATASE INHIBITOR<br />
(AI)-RESISTANT METASTATIC BREAST CANCER (MBC):<br />
A RANDOMIZED, DOUBLE-BLIND, PHASE 2 TRIAL<br />
R.S. De Jong 1 , G.S. Sonke 2 , N. Maass 3 , K. Mansouri 4 , L. Cirri 5 , P. Shi 6 ,<br />
O. Hamid 6 , G. Mariani 7<br />
1 Department of Internal Medicine, Martini Hospital, Groningen, NETHERLANDS,<br />
2 Department of Medical Oncology, Ne<strong>the</strong>rlands Cancer Institute - Antoni van<br />
Leeuwenhoek, Amsterdam, NETHERLANDS, 3 Department of Gynecology and<br />
Obstetrics, University Hospital Aachen, Aachen, GERMANY, 4 Oncology, Lilly<br />
Deutschland GmbH, Bad Homburg, GERMANY, 5 Oncology, Eli Lilly and<br />
Company Italia SPA, Florence, ITALY, 6 Clinical Oncology, Eli Lilly and Company,<br />
Indianapolis, IN, UNITED STATES OF AMERICA, 7 Department of Medical<br />
Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, ITALY<br />
AIs are used as first-line treatment for postmenopausal women with<br />
hormone-receptor-positive MBC. Overexpression of PKC α has been linked to AI<br />
resistance in several studies. We examined whe<strong>the</strong>r Enza, a serine/threonine kinase<br />
inhibitor that targets PKC, could improve <strong>the</strong> effect of Ful in pts who progressed<br />
following first-line AI treatment for MBC.<br />
Postmenopausal pts with hormone-receptor-positive, HER2-negative, locally<br />
advanced or MBC who progressed on prior AI received a loading dose of Ful 500 mg<br />
IM on Day (D) 1 and 250 mg on D 15 of Cycle (C) 1 and D 1 of each cycle<br />
<strong>the</strong>reafter. Enza 500 mg or PBO was administered orally once daily (QD) or 250 mg<br />
twice daily (BID). Primary endpoint was <strong>the</strong> clinical benefit rate (CBR). Secondary<br />
endpoints were response rate (RR), duration of CB, progression-free survival (PFS)<br />
and safety. A total of 156 pts was randomly assigned to <strong>the</strong>rapy; 152 received at least<br />
1 dose of study drug (39 BID; 55 QD; 58 PBO). Baseline disease characteristics were<br />
balanced across arms. There was no statistically significant difference in CBR between<br />
pts in Ful + Enza vs Ful + PBO. There was no statistically significant difference in<br />
CBRs, RRs and PFS between pts on QD and BID dosing schedules. Pts on BID<br />
dosing had numerically more TEAEs vs those on QD and PBO (61.5%, 43.6%, and<br />
46.6%, respectively) and numerically more Grade 3/4 TEAEs vs QD and PBO<br />
(17.9%, 9.1%, and 5.2%, respectively). Most frequent Grade 3/4 TEAEs in <strong>the</strong> BID<br />
arm were fatigue (n [%]) (4 [10.3%]), dyspnea (2 [5.1%]) and nausea (2 [5.1%]).<br />
8 pts died; 5 due to disease, 3 due to AEs: 1 drug-related hepatic dysfunction (Enza<br />
QD arm), 1 non-drug-related myocardial infarction and 1 non-drug-related<br />
respiratory failure (both in <strong>the</strong> Enza BID arm).<br />
CBR<br />
Number of responders,<br />
Ful + Enza<br />
[QD + BID]<br />
N=94<br />
Ful + PBO<br />
N = 58 P-value vs PBO<br />
0.62<br />
24 (44.8)<br />
n (%), (95% CI)<br />
41 (43.6)<br />
(33.4, 54.2) (31.7, 58.5)<br />
RR, % (95% CI) 5.3 (1.7, 12.0) 5.2 (1.1, 14.4) 0.64<br />
PFS, months (95% CI) 5.2 (3.5, 7.4) 5.5 (3.8, 7.4) 0.59<br />
Median duration of CB, months 9.6 9.7 0.86<br />
CBR = complete response + partial response + stable disease Addition of Enza to Ful<br />
does not improve disease outcome in pts with locally advanced or MBC after<br />
progression on AI.<br />
Disclosure: K. Mansouri: K. Mansouri is an employees of Eli Lilly and Co. L. Cirri:<br />
L. Cirri is an employees of Eli Lilly and Co. P. Shi: P. Shi is an employees of Eli Lilly<br />
and Co. O. Hamid: O. Hamid is an mployees of Eli Lilly and Co. All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
Annals of Oncology<br />
343P NEW IMMUNOHISTOCHEMICAL MARKERS PREDICTIVE<br />
OF RESPONSE TO NEOADJUVANT CHEMOTHERAPY PLUS<br />
TRASTUZUMAB IN HER2-POSITIVE LOCALLY ADVANCED<br />
BREAST CANCER: A SINGLE CENTER EXPERIENCE<br />
G. Faggioni 1 , C. Ghiotto 1 , E. Orvieto 2 , S. Valpione 1<br />
1 Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, ITALY,<br />
2 Anatomia Patologica, Azienda Ospedaliera di Padova, Padova, ITALY<br />
We present <strong>the</strong> results of a prospective pilot study aimed to investigate <strong>the</strong> value of<br />
new immunohistochemichal predictive markers of response to chemo<strong>the</strong>rapy in<br />
locally advanced HER-2 breast cancer. pTEN loss, pAKT and HER-3 overexpression<br />
cause PI3K activation and induce resistance to trastuzumab in vitro and in vivo, with<br />
poorer clinical responses in patients with advanced disease. We studied <strong>the</strong><br />
espression of EGFR, HER-3, pTEN and pAKT in 31 patients with locally advanced<br />
HER-2 positive breast cancer who received neoadjuvant chemo<strong>the</strong>rapy plus<br />
trastuzumab. Mean age of patients was 55.7 years (median 55, 95% CI 44,2-63,5<br />
years). Results of immunohistochemistral staining are reassumed in <strong>the</strong> table.<br />
Mean Median 25% C.I. 75% C.I.<br />
ER% 40,6 40,0 0,0 77,5<br />
PgR% 23,1 10,0 0,0 40,0<br />
Ki-67% 38,2 40,0 25,0 50,0<br />
EGFR Hscore 6,1 0,0 0,0 1,0<br />
HER3 (% positive cells) 50,0 50,0 32,5 70,0<br />
HER3 intensity 1,5 1,0 1,0 2,0<br />
HER3 H score 82,6 70,0 32,5 115,0<br />
PTEN (% positive cells) 48,9 70,0 2,5 70,0<br />
PTEN intensity 1,5 1,0 1,0 2,0<br />
AKT Hscore 56,7 20,0 0,0 70,0<br />
AKT IRS 2,5 2,0 0,0 3,0<br />
Patients were homogeneous for tumor burden at diagnosis and received<br />
anthraciclin-taxane and trastuzumab-based neoadjuvant treatment. 14 out of<br />
31patients achieved pathological complete remission. Ki-67 and HER3 H score were<br />
significatively higher in patients who achieved complete remission (medians were<br />
45.5% versus 25%, p = 0.022; 100% versus 50%, p = 0.045 respectively. We found a<br />
correlation between EGFR H score and HER3 Hscore (p = 0.02), and an inverse<br />
correlation between age and EGFR H score (p = 0.05) and between PgR and AKT<br />
intensity (p = 0.03). Ki-67 and HER3 H score maintained significatively different<br />
medians in <strong>the</strong> group of patients who experienced pathological complete response<br />
versus <strong>the</strong> group on incomplete responders with multivariate analysis (p < 0.01).<br />
Disclosure: All authors have declared no conflicts of interest.<br />
344P PHARMACOKINETICS (PK) OF PERTUZUMAB (P) WITH<br />
TRASTUZUMAB (T) AND DOCETAXEL (D) IN HER2-POSITIVE<br />
FIRST-LINE METASTATIC BREAST CANCER (MBC): RESULTS<br />
FROM THE PHASE III TRIAL CLEOPATRA<br />
J. Cortes 1 , S. Swain 2 , I. Kudaba 3 , M. Hauschild 4 , T. Patel 5 , E. Grincuka 6 ,<br />
N. Masuda 7 , V. McNally 8 , J. Visich 9 , J. Baselga 10<br />
1 Oncologia, Vall d’Hebron University Hospital Institut d’Oncologia, Barcelona,<br />
SPAIN, 2 Medstar Washington Hospital Center, Washinton Cancer Institute,<br />
Washington, WA, UNITED STATES OF AMERICA, 3 Oncology Center, Riga East<br />
University Hospital, Riga, LATVIA, 4 Spital Rheinfelden & Laufenburg,<br />
Gesundheitszentrum Fricktal, Rheinfelden, SWITZERLAND, 5 The Mark<br />
H. Zangmeister Center, Mid Ohio Oncology/Hematology, Inc., Columbus, OH,<br />
UNITED STATES OF AMERICA, 6 Department of Oncology, Daugavpils Regional<br />
Hospital, Daugavpils, LATVIA, 7 Surgery and Breast Oncology, NHO Osaka<br />
National Hospital, Osaka, JAPAN, 8 Products Limited, Roche, Welwyn, UNITED<br />
KINGDOM, 9 Genentech, Genentech, South San Francisco, CA, UNITED<br />
STATES OF AMERICA, 10 Hematology/oncology, MGH Cancer Center,<br />
Massachusetts General Hospital, Boston, MA, UNITED STATES OF AMERICA<br />
Introduction: P is a humanized mAb that inhibits heterodimerization of HER2. P<br />
and T bind distinct HER2 epitopes, and due to <strong>the</strong>ir complementary mechanisms of<br />
action <strong>the</strong>y provide a more comprehensive blockade of HER2 signaling. Based on<br />
preclinical efficacy models, a steady-state trough P concentration (Ctrough) of 20 ug/<br />
ml was selected as target in pts. CLEOPATRA is a Phase III study comparing P + T<br />
+ D vs placebo (Pla) + T + D in HER2-positive 1L MBC (Baselga NEJM <strong>2012</strong>). The<br />
objectives of <strong>the</strong> substudy reported here are to characterize <strong>the</strong> P PK in <strong>the</strong> presence<br />
of T and D, and to explore potential drug − drug interactions.<br />
Methods: P/Pla (840 mg loading, 420 mg maintenance) was administered on Day 1<br />
of each cycle; T (8 mg/kg loading, 6 mg/kg maintenance) was administered on Day 2<br />
of Cycle 1 and on Day 1 of each cycle onward following P; D (75 mg/m 2 , escalation<br />
to 100 mg/m 2 if tolerated) was administered on Day 2 of Cycle 1 following T and on<br />
Day 1 of each cycle onward following T. All drugs were given q3w iv. Blood samples<br />
ix124 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
for P were collected before and after infusion at Cycles 1, 3, 6, 9, 12, 15, 18, and at<br />
treatment discontinuation. Samples for T were collected before and after infusion at<br />
Cycles 1 and 3. Samples for D were collected at Cycle 1 at 8 serial time points during<br />
and following <strong>the</strong> infusion over a 24 h period to allow calculation of C max, CL, V ss,<br />
t 1/2, AUC 0–t, and AUC 0-inf.<br />
Results: 37 pts (17 Pla arm, 20 P arm) were available for PK evaluation. Serum P<br />
Ctrough exceeded <strong>the</strong> target of 20 ug/ml in >90% of pts and <strong>the</strong>re was no impact of T<br />
and D on P PK, compared with historical data. Mean serum T Cmax and Cmin at<br />
Cycles 1 and 3 were similar in both arms. Ratios of geometric LS means of P + T +<br />
D/Pla + T + D x100 for serum T were: Cycle 1 C max 90.3; Cycle 3 C min 95.9; Cycle 3<br />
C max 81.0. D PK parameters were similar in both arms. Ratios of geometric LS<br />
means of P + T + D/Pla + T + D x100 for plasma D were: AUC 0–t 104.9, AUC 0-inf<br />
101.4, C max 92.5.<br />
Conclusion: P PK parameters were consistent with previous studies, and<br />
co-administration of T and D appears not to influence P PK in HER2-positive MBC.<br />
There was no evidence of drug − drug interactions between P and T, or between P<br />
and D, which have different clearance pathways.<br />
Disclosure: J. Cortes: I am an advisory board member for Roche, Celgene and<br />
Novartis. I have received research funding from Roche, Celgene, Cephalon and<br />
Ferrer. S. Swain: Advisory Board for Genentech/Roche for EMILIA study and<br />
Avastin - uncompensated. Research funding: Genentech/Roche. T. Patel: I have<br />
an advisory board membership for Genentech/Roche to disclose and are a<br />
speaker for Genentech/Roche. I have received research funding from Genentech/<br />
Roche. N. Masuda: I have honoraria to disclose received from Chugai<br />
Pharmaceutical Co., Ltd. V. McNally: I am a Roche employee and hold Roche<br />
shares. J. Visich: I am an employee of Genentech. J. Baselga: Dr Baselga reports<br />
<strong>the</strong> following relationships with relation to <strong>the</strong> topic of this abstract: Roche,<br />
Sanofi Aventis, Consulting/Scientific Advisory Board. Roche, Sanofi Aventis,<br />
Honoraria for speaking engagements. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
345P PROGNOSTIC FACTORS INFLUENCING THE SELECTION<br />
OF BEVACIZUMAB COMBINED WITH CHEMOTHERAPY IN<br />
PATIENTS WITH HER2-NEGATIVE METASTATIC BREAST<br />
CANCER IN ROUTINE CLINICAL PRACTICE.<br />
ONCOSUR-AVALOX: OBSERVATIONAL CROSS-SECTIONAL<br />
STUDY<br />
L. Manso 1 , R. Perez-Carrion 2 , J.I. Chacon Lopez-Muniz 3 , A. García Palomo 4 ,<br />
E. Galve Calvo 5 , R.M. Llorente 6 , J. Casinello 7 , G. Catalán 8 , C. Llorca 9 ,<br />
C. Grávalos 10<br />
1 Medical Oncology, Hopital 12 de Octubre, Madrid, SPAIN, 2 Oncology, Hospital<br />
Universitario Quiron, Madrid, SPAIN, 3 Oncolog, Hospital Virgen de la Salud,<br />
Toledo, SPAIN, 4 Oncology, Hospital de León, Leon, SPAIN, 5 Oncology, Hospital<br />
de Basurto, Bilbao, SPAIN, 6 Oncology, Hospital Universitario Dr. Peset, Valencia,<br />
SPAIN, 7 Oncology, Hospital General Guadalajara, Guadalajara, SPAIN,<br />
8 Oncology, Hospital Son Llatzer, Palma de Mallorca, SPAIN, 9 Oncology, Hospital<br />
de Elda, Alicante, SPAIN, 10 Medical Oncology, Hospital Doce de Octubre,<br />
Madrid, SPAIN<br />
Background: Combining bevacizumab (BEV) with chemo<strong>the</strong>rapy (CT) improves<br />
survival in HER2-negative metastatic breast cancer (MBC). We investigated <strong>the</strong><br />
influence of age, ECOG, hormonal status, number of sites and location of metastases<br />
and patient decision on <strong>the</strong> selection of BEV combined with CT in MBC.<br />
Methods: Observational cross-sectional multicenter study in pts with HER2- negative<br />
MBC who have received first-line CT with BEV.<br />
Results: From November 2010 to November 2011, 124 pts were included:<br />
median age 51 (45-64) yr; ECOG: 0 = 50%; 60% pre-menopausic; 23%<br />
triple-negative (TN); 77% hormone receptorpositive (HR+). Metastatic disease:<br />
≥3 sites = 42% (TN: 32%; HR + : 45%); location: 44% bone, 35% lung, 30% liver.<br />
Most frequent BEV-based combinations were paclitaxel/BEV (53%) and<br />
docetaxel/BEV (14.5%); median no. of CT cycles: 6 (5-8). A disease-free survival<br />
(DFS) ≥12 months was achieved by 73%; TN: 68%; HR + : 76%. Overall<br />
response rate (ORR) was 58%: 51% partial response (PR), 7% complete response<br />
(CR); 28% stable disease (SD) and 10% disease progression. TN: ORR 44% (40%<br />
PR), clinical benefit 80% (36% SD); HR + : ORR 62% (54% PR), clinical benefit<br />
87% (25% SD). 58% presented at least one toxicity, mainly grade 1-2; 26%<br />
BEV-related: only 3 (2.4%) grade 3 toxicities; no grade 4. Receiving adjuvant<br />
hormonal <strong>the</strong>rapy was associated to DFS ≥12 months (p < 0.05). ER+ tumors<br />
(OR: 0.215; 95% CI: 0.08-0.56; p = 0.002) and one metastatic site, vs. ≥3 sites<br />
(OR: 0.309; 95% CI: 0.12-0.83; p = 0.020) were independent factors associated<br />
with <strong>the</strong> selection of paclitaxel-BEV <strong>the</strong>rapy in <strong>the</strong> overall population (TN or<br />
HR+). Metastases in <strong>the</strong> liver were significantly related to paclitaxel-BEV<br />
administration (p < 0.01).<br />
Conclusions: Our findings suggest that first-line CT with BEV is an active and<br />
tolerable treatment option for pts with TN and HR+ MBC. ER+ tumors and a single<br />
metastatic site were identified as independent factors for <strong>the</strong> selection of a<br />
paclitaxel-BEV <strong>the</strong>rapy. The presence of metastases in <strong>the</strong> liver was significantly<br />
associated to <strong>the</strong> administration of a paclitaxel-BEV regimen.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
346P CHARACTERISTICS OF PATIENTS WITH HER2-POSITIVE<br />
METASTATIC (MBC) OR LOCALLY ADVANCED BREAST<br />
CANCER (ABC), TREATED WITH TRASTUZUMAB (T) AS 1ST<br />
LINE-THERAPY AND PROGRESSION-FREE FOR AT LEAST<br />
3 YEARS: INTERIM ANALYSIS OF THE LORHA STUDY<br />
O. Tredan 1 ,B.You 2 , P. Beuzeboc 3 , D. Coeffic 4 , A. Lortholary 5 , M. Fellous 6 ,T.De<br />
La Motte Rouge 7 , F. Andre 8 , L. Arnould 9 , J. Ferrero 10<br />
1 Medical Oncology, Lyon Bérard Centre, Lyon, FRANCE, 2 Medical Oncology,<br />
Lyon-Sud Hospital, Lyon, FRANCE, 3 Medical Oncology Unit, Curie Institute,<br />
Paris, FRANCE, 4 Medical Oncology, Clinique Hartmann, Neuilly-sur-Seine,<br />
FRANCE, 5 Medical Oncology, Ca<strong>the</strong>rine de Sienne Institute, Nantes, FRANCE,<br />
6 Medical, Roche France, Boulogne Billancourt, FRANCE, 7 Medical Oncology,<br />
Salpétrière Hospital, Paris, FRANCE, 8 Department of Medical Oncology, Institut<br />
Gustave Roussy, Villejuif Cedex, FRANCE, 9 Biology & Pathology of The Tumor,<br />
Centre GF LECLERC, Dijon, FRANCE, 10 Oncologie Médicale, Centre Antoine<br />
Lacassagne, Nice Cedex, FRANCE<br />
Background: For more than ten years, treatment of HER2-positive mBC patients<br />
(Pts) is based on T plus taxane in 1 st line <strong>the</strong>rapy. So far, in numerous studies, we<br />
have observed few subsets of Pts (long-term responders) who have not experienced<br />
disease progression for several years after T-based regimen in 1 st line treatment. This<br />
study aims to characterise <strong>the</strong>se Pts in <strong>the</strong> daily practice from a clinical and<br />
biological perspective.<br />
Material and methods: This is an ambispective French multicentre non-interventional<br />
study. Eligible Pts were women aged ≥18 years with HER2-positive mBC or aBC<br />
treated with T as 1 st line and who were progression-free for at least 3 years after<br />
starting T. The primary objective was to describe <strong>the</strong> clinical and tumor characteristics<br />
of <strong>the</strong>se Pts. Progression Free Survival (PFS), Overall Survival (OS), data on treatment<br />
administration and safety were also collected. An exploratory biomarkers analysis is<br />
planned on tumor tissue samples. Here we present some preliminary results based on<br />
<strong>the</strong> interim analysis performed at <strong>the</strong> end of inclusions.<br />
Results: 159 Pts were enrolled in 2011 and 110 Pts were eligible for data analysis.<br />
Median age was 59 years [34-95]. Tumor characteristics were: invasive ductal<br />
carcinoma for 96 Pts (88%), positive hormonal receptors in 63 Pts (58%). At initial<br />
diagnosis, presenting stages were I-II for 52 Pts (50%). 36 Pts (33%) had a mBC de<br />
novo or an aBC. The main metastatic localisations were bone, liver and lung in 51<br />
(47%), 35 (32%) and 22 (20%) Pts respectively. Median T treatment duration was 4.1<br />
years [0.8 - 11.0] in 1 st line. T was associated with a taxane-based chemo<strong>the</strong>rapy in<br />
86 Pts (78%). Median PFS was 6.4 years [4.9; - ]. Median OS was not reached. 13<br />
retrospective adverse events related to T (cardiac or leading to discontinuation) were<br />
reported. None of <strong>the</strong>se was serious.<br />
Conclusions: In this long PFS population treated with a T-based treatment in first<br />
line for aBC or mBC Pts, no specific profile in terms of clinical or histological<br />
characteristics have been observed. Thus, <strong>the</strong> exploratory biomarkers analysis will be<br />
useful to identify such a profile.<br />
Disclosure: O. Tredan: Roche consultant. P. Beuzeboc: Roche consultant. D. Coeffic:<br />
Roche consultant. M. Fellous: Roche employee. L. Arnould: Roche Consultant. All<br />
o<strong>the</strong>r authors have declared no conflicts of interest.<br />
347P THE ENCHANTTM TRIAL: AN OPEN LABEL MULTICENTER<br />
PHASE 2 WINDOW OF OPPORTUNITY STUDY EVALUATING<br />
GANETESPIB (STA-9090) MONOTHERAPY IN WOMEN WITH<br />
PREVIOUSLY UNTREATED METASTATIC HER2 POSITIVE OR<br />
TRIPLE NEGATIVE BREAST CANCER (TNBC)<br />
D. Cameron 1 , M.S. Mano 2 , V. Vukovic 3 , F. Teofilovici 3 , R. Bradley 3 , A. Awada 4<br />
1 Oncology, Edinburgh Cancer CentreWestern General Hospital, Edinburgh,<br />
UNITED KINGDOM, 2 Medical Oncology, ICESP, Sao Paulo, BRAZIL, 3 Oncology,<br />
Synta pharmaceuticals, lexington, MA, UNITED STATES OF AMERICA,<br />
4 Department of Medical Oncology, Institute Jules Bordet, Brussels, BELGIUM<br />
Background: Hsp90 is a molecular chaperone required for proper folding and<br />
activation of many cancer-promoting proteins. Several Hsp90 clients are<br />
oncoproteins known to play a key role in <strong>the</strong> pathobiology of breast cancer, including<br />
HER2, p95- HER2 , EGFR, ER, PI3K, AKT, and VEGFR. The inactivation of <strong>the</strong>se<br />
oncoproteins by Hsp90 inhibition is a promising approach for breast cancer <strong>the</strong>rapy.<br />
Ganetespib is an Hsp90 inhibitor which has shown anti-tumor activity in heavily<br />
pretreated patients with lung, breast, and o<strong>the</strong>r cancers. Ganetespib is well tolerated<br />
without severe liver or common ocular toxicities. In a phase 2 trial, 22 breast cancer<br />
patients who had received up to 3 prior lines of chemo<strong>the</strong>rapy including trastuzumab<br />
were treated with ganetespib mono<strong>the</strong>rapy. In patients with HER2+ disease, <strong>the</strong><br />
objective response rate (ORR) was 15% (2/13) and <strong>the</strong> SD rate was 46% (6/13). Only<br />
3 patients presented with TNBC; one of those patients achieved SD with substantial<br />
tumor shrinkage on treatment.<br />
Methods: This is a single arm international open-label Phase 2 study in patients with<br />
HER2 amplified, or triple negative breast cancer. Patients must not have received any<br />
prior <strong>the</strong>rapy in <strong>the</strong> metastatic setting. Prior adjuvant <strong>the</strong>rapy is allowed.<br />
Primary endpoint: ORR. Main secondary endpoints include disease control rate, and<br />
progression free survival. Additionally, fresh biopsies and serum samples are<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds393 | ix125
collected from all patients for determination of predictors of response and<br />
mechanisms of resistance to treatment. Patients are treated with ganetespib<br />
150 mg/m 2 is given twice weekly of a 4-week cycle for up to 12 weeks. A total of<br />
70 patients are planned for accrual. At <strong>the</strong> time of submission, <strong>the</strong> study is receiving<br />
IRB approvals in several centers.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
348P HGFK1 INHIBITS BONE METASTASIS IN BREAST CANCER<br />
THROUGH THE TAK1/P38 MAPK SIGNALING PATHWAY<br />
Y-Z. Bu 1 , Z. Shen 2<br />
1 Department of Surgery, Lianshui People’s Hospital, Jiangsu Province, CHINA,<br />
2 Department of Oncology, Shanghai 6th People’s Hospital, Shanghai Jiao Tong<br />
University, Shanghai, CHINA<br />
Background: Breast cancer metastasis to bone represents a devastating complication<br />
of advanced breast cancer, frequently resulting in significant increases in morbidity<br />
and mortality. An understanding of <strong>the</strong> mechanisms that govern breast cancer<br />
metastasis at <strong>the</strong> molecular level should lead to more effective <strong>the</strong>rapies. Recently, <strong>the</strong><br />
kringle 1 domain of human hepatocyte growth factor (HGFK1) was identified as a<br />
candidate metastasis suppressor gene.<br />
Methods: Here, we investigated whe<strong>the</strong>r HGFK1 is a key regulator of breast cancer<br />
bone metastasis.<br />
Results: Of <strong>the</strong> 193 human breast carcinoma tissue samples examined, HGFK1<br />
expression was positive in 82 (42.4%). The positive expression of HGFK1 was<br />
significantly associated with a better prognostic value (P < 0.001) and inversely<br />
correlated with bone metastasis (P = 0.003). The efficacy of adeno-associated virus<br />
carrying HGFK1 (AAV-HGFK1) in osteolytic bone metastasis was <strong>the</strong>n evaluated<br />
using an in vivo bone metastasis model. AAV-HGFK1 significantly inhibited<br />
osteolytic bone metastasis and prolonged <strong>the</strong> survival of mice in this model (P <<br />
0.01). In vitro, HGFK1 expression resulted in significant anti-invasion effects,<br />
enhanced <strong>the</strong> phosphorylation of TAK1, p38 MAPK and MAPKAPK2, and<br />
decreased <strong>the</strong> expression of receptor activator of NF-κB (RANK), which was<br />
abrogated by <strong>the</strong> p38 MAPK inhibitor SB203580.<br />
Conclusions: This study shows for <strong>the</strong> first time that HGFK1 significantly inhibits<br />
<strong>the</strong> metastasis of breast cancer to bone by activating <strong>the</strong> TAK1/p38 MAPK signaling<br />
pathway and inhibiting RANK expression. Thus, AAV-HGFK1 treatment represents<br />
a potential <strong>the</strong>rapy for bone metastasis in breast cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
349P IMPACT OF DIABETES AND HYPERGLYCEMIA ON SURVIVAL<br />
IN ADVANCED BREAST CANCER PATIENTS<br />
R.J. Shaw Dulin 1 , C. Villarreal-Garza 1 , F. Lara 1 , L. Bacon 2 , D. Rivera 2 , A.D.<br />
Rivera Salceda 2 , L. Urzua 2 , L. Herrera 3 , C. Aguila 2 , J.E. Bargallo-Rocha 1<br />
1 Breast Tumor Department, Instituto Nacional de Cancerología Mexico, Mexico<br />
City, MEXICO, 2 Medical Oncology, Instituto Nacional de Cancerología Mexico,<br />
Mexico City, MEXICO, 3 Department of Biomedical Research In Cancer, Instituto<br />
Nacional de Cancerologia, Mexico City, MEXICO<br />
Background: Clinical experience and previous studies suggest that women with<br />
diabetes and breast cancer have worse outcomes than <strong>the</strong>ir non-diabetic counterparts.<br />
The purpose of this study was to examine <strong>the</strong> impact of diabetes and hyperglycemia<br />
on cancer-specific survival of patients with metastatic or recurrent breast cancer.<br />
Methods: We performed a retrospective analysis of patients with advanced breast<br />
cancer receiving palliative chemo<strong>the</strong>rapy from 2006 to 2011 at <strong>the</strong> National Cancer<br />
Institute in Mexico, and compared breast cancer-specific mortality in diabetic and<br />
non-diabetic patients, as well as in patients that presented hyperglycemia during<br />
palliative treatment.<br />
Results: A total of 265 patients receiving palliative <strong>the</strong>rapy were eligible for inclusion.<br />
Previous diagnosis or detection of diabetes at recurrence was recorded in 40 patients<br />
(15%). No difference was observed between diabetic and non-diabetic patients in<br />
terms of OS. A statistically significant difference in OS was observed between patients<br />
without diabetes and diabetic patients who had hyperglycemia (p = 0.003). OS in<br />
diabetic patients with proper metabolic control was shown to be superior compared<br />
to diabetics with hyperglycemia (p = 0.01) Hyperglycemia was identified in 14% of<br />
non-diabetics at some point while receiving palliative treatment. For patients that<br />
experienced hyperglycemia during treatment or who had a mean glucose level above<br />
130, ei<strong>the</strong>r in <strong>the</strong> diabetic or non-diabetic subgroups, a worse outcome was noted<br />
compared to normoglycemic patients, with a HR of 1.5 (p = 0.029) and HR of 2.04<br />
(p = 0.006) for death, respectively.<br />
Conclusions: Elevated glucose levels confer a poor outcome in diabetic and<br />
non-diabetic patients in contrast with patients with normoglycemic levels, conferring<br />
an elevated risk of death. According to <strong>the</strong>se results, clinicians must monitor glucose<br />
levels during treatment for advanced breast cancer disease, and should take action in<br />
order to maintain normal glucose levels.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
350P ANTITUMOR ACTIVITY OF DUAL PI3K AND ER BLOCKADE<br />
IN ER POSITIVE BREAST CANCER MODELS<br />
J. Tao 1 , M. Scaltriti 1 , S. Marlow 1 , M. Elkabets 1 , N. Morse 1 , D. Sgroi 2 , J. Baselga 1<br />
1 Cancer Center, Massachusetts General Hospital, Charlestown, MA, UNITED<br />
STATES OF AMERICA, 2 Molecular Pathology Unit, Massachusetts General<br />
Hospital, Charlestown, MA, UNITED STATES OF AMERICA<br />
Background: Activation of <strong>the</strong> phosphoinositide 3-kinase (PI3K) pathway, ei<strong>the</strong>r by<br />
receptor tyrosine kinase overexpression or PI3K/Akt/mTOR axis dysregulation, has<br />
been implicated in endocrine <strong>the</strong>rapy resistance, prompting combination of PI3K<br />
inhibitors and antiestrogen <strong>the</strong>rapy in <strong>the</strong> clinical setting such as in <strong>the</strong> recent<br />
BOLERO-2 study. We hypo<strong>the</strong>size that dissecting <strong>the</strong> molecular crosstalk between<br />
<strong>the</strong> PI3K and estrogen receptor (ER) pathways will help define <strong>the</strong> subset of patients<br />
most responsive to combined PI3K/antiestrogen <strong>the</strong>rapy.<br />
Methods: ER+ cell lines MCF7, MCF7-long term estrogen deprived (LTED),<br />
MCF7-fulvestrant resistant clones Fslx64 and Fslx70, T47D, ZR75-1, CAMA1,<br />
MDA361, KPL-1, BT474, EFM19, HCC1428, UACC812, were treated with <strong>the</strong> ER<br />
degrader, fulvestrant, and <strong>the</strong> p110α-specific PI3K inhibitor BYL719 in vitro. Cell<br />
viability was measured by CellTiter-Glo and Crystal Violet. MCF7 and ER+<br />
patient-derived xenografts were treated with fulvestrant, BYL719 or <strong>the</strong> combination<br />
in vivo. Protein expression was measured by Western blot and<br />
immunohistochemistry.<br />
Results: Fulvestrant or BYL719 treatment resulted in variable inhibition of cell<br />
viability in all ER+ cell lines. Combination treatment was significantly superior to<br />
mono<strong>the</strong>rapy in MCF7, MCF7-LTED, MCF7-Fslx64 and MCF7-Fslx70. While MCF7<br />
clones Fslx64 and Fslx70 were resistant to >1 µM of fulvestrant, <strong>the</strong>y were exquisitely<br />
sensitive to BYL719. Moreover, PI3K inhibition led to ER upregulation in ER+ cell<br />
lines, including those most sensitive to combination treatment. Total ER levels also<br />
increased in MCF7 xenografts treated with <strong>the</strong>rapeutic doses of BYL719.<br />
Conclusions: Combined treatment with BYL719 and fulvestrant in vitro was superior to<br />
single-agent treatment in 4 of 13 ER+ cell lines. Importantly, dual PI3K/ER blockade was<br />
effective in cells resistant to ER deprivation and/or degradation. Induced ER levels<br />
following PI3K suppression may represent a feedback mechanism by which ER+ cells<br />
escape PI3K inhibition. We are currently studying whe<strong>the</strong>r this phenomenon predicts<br />
sensitivity to dual PI3K/ER blockade in ER+ breast cancer models.<br />
Disclosure: J. Baselga: J. Baselga is a consultant/advisory board member for Aragon,<br />
AstraZeneca, Sanofi, Bayer, Onyx, Chugai, Constellation, Exelixis, Intellikine, Merck,<br />
Novartis, and Roche Genentech. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
351P SAFETY OF EVEROLIMUS FOR WOMEN OVER 65 YEARS OF<br />
AGE WITH ADVANCED BREAST CANCER: 18-MO FOLLOW-UP<br />
OF BOLERO-2<br />
M. Gnant 1 , S. Noguchi 2 ,Y.Ito 3 , M. Piccart 4 , J. Baselga 5 , A. Panneerselvam 6 ,<br />
T. Taran 6 , T. Sahmoud 6 , G.N. Hortobagyi 7 , K. Pritchard 8<br />
1 Deparment of Surgery, Medical University of Vienna, Vienna, AUSTRIA,<br />
2 Department of Breast and Endocrine Surgery, Osaka University, Osaka, JAPAN,<br />
3 Department of Medical Oncology, Cancer Institute Hospital, Japanese<br />
Foundation for Cancer Research, Tokyo, JAPAN, 4 Institut Jules Bordet, Institut<br />
Jules Bordet, Brussels, BELGIUM, 5 Massachusetts General Hospital Cancer<br />
Center and Harvard Medical School, Massachusetts General Hospital Cancer<br />
Center and Harvard Medical School, Boston, MA, UNITED STATES OF<br />
AMERICA, 6 Novartis Pharmaceuticals Corporation, East Hanover, NJ, UNITED<br />
STATES OF AMERICA, 7 The University of Texas Md Anderson Cancer Center,<br />
The University of Texas MD Anderson Cancer Center, Houston, TX, UNITED<br />
STATES OF AMERICA, 8 Medical Oncology, Sunnybrook Odette Cancer Center,<br />
Toronto, CANADA<br />
Background: Hormone-receptor–positive (HR + ) breast cancer (BC) refractory/<br />
resistant to nonsteroidal aromatase inhibitor (NSAI) may be treated with <strong>the</strong><br />
steroidal AI exemestane (EXE), although <strong>the</strong>re is no approved treatment standard.<br />
The BOLERO-2 trial showed that adding everolimus (EVE) to EXE significantly<br />
improved clinical benefit beyond that of EXE alone (Hortobagyi et al, SABCS 2011,<br />
<strong>Abstract</strong> S3-7). As many women with advanced BC are elderly (≥ 65 years), <strong>the</strong><br />
efficacy and tolerability of EVE + EXE in this population are of interest.<br />
Methods: BOLERO-2 is a phase 3, randomized trial comparing EVE (10 mg once<br />
daily) vs placebo (PBO), both plus EXE (25 mg once daily) in postmenopausal<br />
women with advanced HR + BC progressing or recurring after NSAIs.<br />
Results: Baseline disease and prior treatment characteristics were balanced between<br />
study arms (N = 724). At 18 months’ median follow-up, adding EVE to EXE<br />
significantly improved progression-free survival in patients < 65 (n = 449; 8.3 vs 2.9<br />
mo; HR = 0.38; 95% CI = 0.30, 0.47) and ≥ 65 years (n = 275; 6.8 vs 4.0 mo; HR =<br />
0.59; 95% CI = 0.43, 0.80). Overall incidence of adverse events (AEs) was marginally<br />
higher in patients ≥ 65 years (n = 272, safety population) compared with those < 65<br />
years. Grade 3/4 AEs occurred in 50% of patients ≥ 65 years compared with 42% of<br />
patients < 65 years. Incidences of grade 3/4 stomatitis, rash, pneumonitis, and<br />
hyperglycemia in EVE-treated patients ≥ 65 years and those < 65 years were similar.<br />
Additional analysis using an age cutoff of 70 years also showed no meaningful<br />
differences in <strong>the</strong> efficacy/safety profile of EVE. Grade 3/4 AEs in patients ≥ 65 years<br />
ix126 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
reported among patients receiving EVE (n = 192) but not in those receiving PBO<br />
included anemia (9%), hyperglycemia (7%), stomatitis (9%), dyspnea (8%),<br />
pneumonitis (5%), neutropenia (3%), and hypertension (2%). These AEs were also<br />
reported at similar frequency in EVE-treated patients < 65 years.<br />
Conclusions: Adding EVE to EXE was effective and well tolerated overall and, in<br />
elderly patients with advanced BC, grade 3/4 AEs were uncommon and manageable.<br />
Overall, AEs were consistent with <strong>the</strong> known safety profile of EVE.<br />
Disclosure: M. Gnant: Research support from GSK, Sanofi-Aventis, Novartis, and<br />
Roche, consultant to Merrion and Novartis, and received honoraria & travel support<br />
from Amgen, Pfizer, Novartis, GSK, Bayer, Sandoz, AstraZeneca, and<br />
GenomicHealth. S. Noguchi: S. Noguchi received grant support from AstraZeneca,<br />
BMS, Chugai, GSK, Novartis, Pfizer, Sanofi-Aventis, and Takeda, and honoraria<br />
(speaking, advisory boards, etc.) from AstraZeneca, Chugai, GSK, Novartis, Pfizer,<br />
Sanofi-Aventis, and Takeda. M. Piccart: Board for PharmaMar, consultant<br />
Sanofi-Aventis, Amgen, BMS, GSK, Boehringer, Roche, & Bayer, grant support<br />
Pfizer, Amgen, Bayer, Boehringer, BMS, GSK, Roche, & Sanofi-Aventis, honoraria<br />
Bayer, BMS, GSK, Boehringer, Roche, Amgen, & AstraZeneca. J. Baselga: J. Baselga is<br />
a consultant to Novartis, Roche, Merck, Sanofi-Aventis, Verastem, Bayer, Chugai,<br />
Exelixis, Onyx, and Constellation. A. Panneerselvam: Employee of Novartis with<br />
stock/stock options. T. Taran: Employee of Novartis with stock/stock options. T.<br />
Sahmoud: Employee of Novartis with stock/stock options. G.N. Hortobagyi: Member<br />
of <strong>the</strong> Scientific Advisory Board of Allergan, is a consultant to Allergan, Novartis,<br />
Genentech, and Sanofi-Aventis, has received grant support from Novartis, and has<br />
received travel expense reimbursement from Novartis, Genentech, and<br />
Sanofi-Aventis. K. Pritchard: Consult sanaven AZE Roche PFE NVR ABR AMG GSK<br />
res funding NCICCT Grp contracted AZE BMS SanAven AMG PFE NVR GSK &<br />
OrthoBio honoraria & Spkr B SanAven AZE PFE Roche NVR & AMG paid expert<br />
test SanAven AZE & GSK AdCom SanAven AZE Roche PFE NVR GSK & AMG. All<br />
o<strong>the</strong>r authors have declared no conflicts of interest.<br />
352P MTOR EXPRESSION IN BASAL-LIKE BREAST CANCER AND<br />
THE ABILITY OF EVEROLIMUS TO INHIBIT THE INVASION<br />
CANCER CELL CAPACITY<br />
D.F. Martins, B. Sousa, J. Paredes, F. Schmitt<br />
Cancer Genetics- Breast Pathology, Institute of Molecular Pathology and<br />
Immunology of <strong>the</strong> University of Porto, IPATIMUP, University of Porto, Porto,<br />
PORTUGAL<br />
The introduction of high-throughput technologies in breast cancer enabled <strong>the</strong><br />
recognition of groups with prognostic value, in which target-<strong>the</strong>rapies can be applied.<br />
However, a relevant percentage of patients show no clinical benefit or incur in <strong>the</strong><br />
development of acquired resistance. A possible solution could be <strong>the</strong> inhibition of<br />
pathways that are common in all tumor subtypes that have a proven role in<br />
carcinogenesis. Alterations of <strong>the</strong> serine-threonine kinase mammalian target of<br />
rapamycin (mTOR) signaling pathway are common in cancer and thus mTOR is being<br />
pursued as a <strong>the</strong>rapeutic agent. Everolimus, a rapamycin analog, has already an<br />
established activity in <strong>the</strong> treatment of renal cell carcinoma. In this study, we proposed<br />
to evaluate <strong>the</strong> expression of activated mTOR in a large series of invasive carcinoma<br />
samples and cell lines, and its association with <strong>the</strong> four main molecular subtypes<br />
(Luminal A, Luminal B, HER2-overexpressing and Basal-like). We also aimed to<br />
evaluate <strong>the</strong> ability of Everolimus to inhibit mTOR expression and function in breast<br />
cancer cells. p-mTOR expression was found in 66.7% (231/348) of <strong>the</strong> invasive breast<br />
carcinoma cases analysed. Considering <strong>the</strong> molecular subtypes of breast carcinomas,<br />
p-mTOR was more frequently observed in basal-like breast carcinomas (80.6%). All<br />
breast cancer cell lines, representative of distinct molecular subtypes, showed<br />
expression of total and activated mTOR. These cells have been treated with RAD001,<br />
in order to assess <strong>the</strong>ir sensitivity to this drug, and all cell lines showed a decrease of<br />
p-mTOR expression after everolimus treatment. Due to <strong>the</strong> higher prevalence of<br />
p-mTOR in basal-like tumors, we treated three basal-like cell lines with Everolimus to<br />
assess <strong>the</strong> effects on cell invasion and aggregation. Cell invasion was significantly<br />
inhibited in response to Everolimus. The results revealed that <strong>the</strong>re is a significant<br />
higher frequency of p-mTOR in basal-like tumors, compared with <strong>the</strong> o<strong>the</strong>r subtypes.<br />
In addition, Everolimus is able to significantly decrease mTOR expression and activity,<br />
inhibiting invasion capacity of basal-like breast cancer cells emphasizing <strong>the</strong><br />
antitumour activity of mTOR inhibitors in breast cancer models.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
353P THE PROGNOSTIC MEANING OF PROTEIN TYROSINE<br />
PHOSPHATASE NON-RECEPTOR TYPE 12 (PTPN 12)<br />
EXPRESSION LOSS IN BREAST CANCER PATIENTS<br />
M.H. Kim 1 , S. Lee 1 , J.S. Koo 2<br />
1 Department of Internal Medicine, Yonsei University College of Medicine, Seoul,<br />
KOREA, 2 Department of Pathology, Yonsei University College of Medicine, Seoul,<br />
KOREA<br />
Background: Recent preclinical studies showed that protein tyrosine phosphatase<br />
non-receptor type 12 (PTPN 12) appears to be an important tumor suppressor in<br />
breast cancer. However, <strong>the</strong> clinical and prognostic significance of PTPN 12<br />
expression in breast cancer patients has not been elucidated yet.<br />
Methods: PTPN 12 expression status was assessed for 183 patients who<br />
underwent curative surgery for operable breast cancer between May 2000 and<br />
August 2003, using immunohistochemical (IHC) assay of tissue microarray.<br />
Clinicopathologic characteristics, and expression status of ER, PR, EGFR, HER-2<br />
were compared according to PTPN 12 expression status. The prognostic<br />
significance of PTPN 12 expression on disease-free survival (DFS) and overall<br />
survival (OS) was analyzed and <strong>the</strong> prognosis was also assessed in subgroups<br />
defined on <strong>the</strong> basis of major prognostic factors and ER, PR, HER-2, EGFR<br />
expression status.<br />
Results: Loss of PTPN 12 expression was observed in 35.5% of <strong>the</strong> patients in this<br />
study. No significant differences were found in <strong>the</strong> clinicopathological characteristics<br />
and ER, PR, HER-2, EGFR expression status between PTPN 12 loss versus PTPN 12<br />
intact patients. At a median follow-up of 9.9 years (range, 0.7-11.1), patients with<br />
PTPN 12 loss showed worse 10-year DFS than those with intact PTPN 12 expression<br />
(74.8% vs. 83.1%), but without statistical significance (p = 0.220). Ten-year overall<br />
survival of patients was not different according to PTPN 12 expression status. In <strong>the</strong><br />
subgroup analysis performed in HER2 (-) and EGFR (-) patients (n = 128), <strong>the</strong> DFS<br />
was shorter in patients with PTPN 12 loss in univariate analysis (p = 0.057), and <strong>the</strong><br />
difference was independently significant in multivariate analysis (hazard ratio, 2.97;<br />
95% confidence interval, 1.05-8.37; p = 0.040). In <strong>the</strong> subgroup of patients who<br />
received hormone <strong>the</strong>rapy alone as adjuvant treatment (n = 28), all recurrences were<br />
occurred in patients with PTPN 12 loss (5 recurrence in 16 patients) whereas <strong>the</strong>re<br />
was no recurrence in patients with intact PTPN 12 expression.<br />
Conclusion: PTPN 12 expression loss was associated to poor disease free survival in<br />
HER2 negative and EGFR negative breast cancer patients in this study. Our finding<br />
suggests that PTPN 12 may have a prognostic meaning predicting recurrence in<br />
HER2 negative and EGFR negative breast cancer patients, and future validation is<br />
warranted.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
354P GENETIC INTERACTION PROFILE MAY PREDICT<br />
BEVACIZUMAB (BV) EFFICACY IN METASTATIC BREAST<br />
CANCER (MBC) PATIENTS (PTS): AN EXPLORATORY<br />
RETROSPECTIVE ANALYSIS<br />
G. Allegrini 1 , G. Bocci 2 , A. Fontana 3 , A. Camerini 4 , A. Ferro 5 , M.E. Cazzaniga 5 ,<br />
V. Casadei 6 , E. Bona 7 , M. Scalese 8 , A. Falcone 3<br />
1 Medical Oncology Unit, Pontedera Hospital, Pontedera, ITALY, 2 Universita’ di<br />
Pisa, Divisione Di Farmacologia e Chemioterapia - Dipartimento di Medicina<br />
Interna, Pisa, ITALY, 3 Oncologia Medica II, Polo Oncologico, Ospedale S. Chiara,<br />
AOUP, Pisa, ITALY, 4 Oncologia Medica, Ospedale Versilia, Lido di Camaiore,<br />
ITALY, 5 Struttura Complessa Di Oncologia Medica, Azienda ospedaliera San<br />
Gerardo, Monza, ITALY, 6 Oncologia Medica, AOR Marche NORD, Pesaro, ITALY,<br />
7 U.O. Oncologia Medica, Oncologia Universitaria Pisa, Pisa, ITALY, 8 Istituto<br />
Fisiologia Clinica, Centro Nazionale di Ricerca di Pisa, Pisa, ITALY<br />
Background: previous retrospective studies have attempted to identify a possible role<br />
of VEGF single nucleotide polymorphisms (SNPs) to predict BV efficacy in terms of<br />
OS and PFS in MBC pts with conflicting results (Schneider 2008, Grimaldi 2011,<br />
Lambrechts 2011).<br />
Methods: on <strong>the</strong> basis of <strong>the</strong>se preliminary data, we decided to assess in a MBC<br />
population if different VEGF, VEGFR-2, IL-8, IL-6, HIF-1alfa, EPAS-1 and TSP-1<br />
genotypes could predict first line BV + Paclitaxel (P) response in terms both of OS<br />
and PFS. Analyses were performed on germline DNA obtained from blood samples.<br />
Fourteen polymorphisms were investigated by real-time PCR technique. Both single<br />
and combinations of SNPs were investigated. The multifactor dimensionality<br />
reduction (MDR) methodology was applied to identify a genetic interaction profile<br />
for PFS (http://sourgeforge.net/projects/mdr/).<br />
Results: 102 pts have been enrolled from 8 Oncology Units. Main pts<br />
characteristics are: median age 59 years (range 32-81), ECOG-PS 0/1 in 78%/22%,<br />
hormone receptor positive 83%, previous adjuvant chemo<strong>the</strong>rapy 68%, disease free<br />
interval (DFI) < 12 months 27%. After a median follow up of 17.4 months<br />
(1.9-54.7), mPFS was 11.6 months (95% CI: 10.6-12.6) and mOS was 32.4 months<br />
(95% CI: 25.9-38.9). None of SNPs were individually associated with PFS.<br />
Conversely, a genetic interaction profile consisting of VEGFR-2 rs11133360 and<br />
IL-8 rs4073 was significantly associated with PFS. mPFS was 14 months (95% CI:<br />
11.7-16.3) and 10.9 months (95% CI: 9.3-12.4) for <strong>the</strong> favorable and unfavorable<br />
genetic profile, respectively (HR = 0.63, 95% CI: 0.4-0-99, p= 0.046). Fur<strong>the</strong>rmore,<br />
at <strong>the</strong> multivariate analysis hormone receptor positive (HR = 0.22, 95% CI:<br />
0.12-0-41, p < 0.0001), DFI >12 months (HR= 0.4, 95% CI: 0.2-0.82, p= 0.011) and<br />
BV maintenance (HR = 0.63, 95% CI: 0.25.0.71, p = 0.001) were significantly<br />
associated with a better PFS.<br />
Conclusions: genetic interaction between VEGFR-2 rs11133360 and IL-8 rs4073<br />
polymorphisms could predict BV response in terms of PFS. With a longer follow up<br />
correlations with OS will be investigated. Prospective study is planned. Study<br />
supported by <strong>the</strong> no-profit foundation F.A.R.O.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds393 | ix127
355P FIRST REPORT OF LONG-TERM RESPONDERS TO<br />
FIRST-LINE BEVACIZUMAB (BEV) COMBINED WITH<br />
CHEMOTHERAPY IN TWO INDEPENDENT COHORTS OF<br />
HER2-NEG METASTATIC BREAST CANCER PATIENTS (PTS)<br />
WITH HORMONE RECEPTOR –POSITIVE (HR+) AND<br />
TRIPLE-NEGATIVE (TN) TUMORS<br />
M. Saghatchian 1 , C. Levy 2 , C.B. Villanueva 3 , J. Fleury 4 , V. Diéras 5 ,<br />
A. Mercier-Blas 6 , H. Simon 7 , C. Le Maignan 8 , N. Mesnard 9 , E. Antoine 10<br />
1 Breast Cancer Unit, Department of Medical Oncology, Institut de Canc, Villejuif<br />
Cedex, FRANCE, 2 Sénologie, Centre François Baclesse, Caen, FRANCE,<br />
3 Service Oncologie Medicale, C.H.U. Jean Minjoz, Besancon Cedex, FRANCE,<br />
4 Oncologie, Pole Santé République, Clermont Ferrand, FRANCE, 5 Department of<br />
Medical Oncology, Clinical Trial Unit, Institut Curie, Paris, FRANCE, 6 Oncologie,<br />
Centre de Radiothérapie Saint-Vincent, Saint-Grégoire, FRANCE, 7 Oncologie<br />
Médicale, Hôpital Augustin Morvan, Brest, FRANCE, 8 Oncologie Médicale,<br />
Hôpital Saint-Louis, Paris, FRANCE, 9 Medical Affair, Roche SAS, Boulogne<br />
Billancourt, FRANCE, 10 Oncologie Médicale, Clinique Hartmann,<br />
Neuilly-Sur-Seine, FRANCE<br />
Background: First-line BEV combined with weekly paclitaxel, docetaxel or o<strong>the</strong>r<br />
chemo<strong>the</strong>rapy significantly improves progression-free survival (PFS) in<br />
HER2-negative metastatic breast cancer (mBC), as shown in E2100, AVADO and<br />
RIBBON-1 trials. In <strong>the</strong> ATHENA study, 21% of pts continued BEV for ≥1 year<br />
with no new safety outcome and a time to progression of 19.9 months (95% CI<br />
18.9-21.8 months). To fur<strong>the</strong>r understand and provide insight into <strong>the</strong> efficacy and<br />
safety of long-term responders to first-line BEV, we conducted a descriptive study of<br />
2 different cohorts of pts with mBC: HR+ and TN, treated in routine oncology<br />
practice with at least 1 year of first-line BEV.<br />
Methods: Pts who had received first-line BEV(≥1 year) associated to chemo<strong>the</strong>rapy<br />
were retrospectively included in <strong>the</strong> 2 independent cohorts and followed up, if <strong>the</strong>y<br />
were alive at inclusion, for 18 months. Clinico-pathological characteristics, treatment<br />
received, efficacy and safety data were collected.<br />
Results: The recruitment of <strong>the</strong> TNBC cohort was just completed (n = 80) and<br />
results will be presented at <strong>the</strong> meeting. In <strong>the</strong> HR+ cohort (n = 132), 28.1% of <strong>the</strong><br />
pts had a disease-free interval 3 metastatic sites at<br />
diagnosis, and more than 1/3 of <strong>the</strong> patient had lung and/or liver involvement. In<br />
association to 1 st line BEV, 93,2% had received a taxane as initial 1st line<br />
chemo<strong>the</strong>rapy, 76.2% had received maintenance endocrine <strong>the</strong>rapy and 4.2% had<br />
received maintenance chemo<strong>the</strong>rapy (capecitabine). Best response obtained in 1st<br />
line was a complete response or partial response for 84,6%. With a median follow-up<br />
of 33 months, median PFS was 27.4 months (95% CI [23.2-33.8]). Overall survival<br />
data were immature as 84.8% of <strong>the</strong> pts were alive at inclusion. The most common<br />
BEV related grade 3/4 adverse events were hypertension (7.5%), bleeding (1.9%),<br />
proteinuria (1.3%) and congestive heart failure (1.3%).<br />
Conclusion: Prolonged BEV-containing <strong>the</strong>rapy in this HR+ cohort is of interest and<br />
suggests that some pts achieve sustained disease control with limited side effects.<br />
Disclosure: V. Diéras: Advisory boards and Symposium participation. H. Simon:<br />
Member of an advisory board: Roche Mastology Group. N. Mesnard: Roche<br />
employee. E. Antoine: Membership of an advisory board. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
356P BEVACIZUMAB–CAPECITABINE (BEV–CAP) AFTER INITIAL<br />
1ST-LINE BEVACIZUMAB–DOCETAXEL (BEV–DOC) IN<br />
PATIENTS (PTS) WITH HER2-NEGATIVE METASTATIC<br />
BREAST CANCER (MBC): SAFETY ANALYSIS OF THE IMELDA<br />
TRIAL<br />
J. Gligorov 1 , E. Alba-Conejo 2 , J. Bines 3 , P.A. Cortes 4 , D.C. Doval 5 , Z. Jiang 6 ,<br />
U. Freudensprung 7 , G. Mustacchi 8<br />
1 Oncologie Medicale, APHP, CancerEst, Tenon Hospital, Paris, FRANCE,<br />
2 Oncology, Hospital Universitario Virgen de la Victoria, Malaga, SPAIN, 3 Medical<br />
Oncology, Instituto Nacional de Cancer, Rio de Janeiro, BRAZIL, 4 Medical<br />
Oncology, Centro Hospitalar Lisboa Norte - Hospital Sta Maria(HSM-CHLN),<br />
Lisbon, PORTUGAL, 5 Medical Oncology, Rajiv Gandhi Cancer Institute and<br />
Table: 356P<br />
Pts, n (%)<br />
Research Centre, New Delhi, INDIA, 6 Department of Breast Cancer, Affiliated<br />
Hospital of Academy of Military Medical Sciences, Beijing, CHINA, 7 Global<br />
Medical Affairs Biometrics, F Hoffmann-La Roche Ltd, Basel, SWITZERLAND,<br />
8<br />
Docente Di Oncologia Medica, Centro Oncologico ASS1 Triestina, Università di<br />
Trieste, Trieste, ITALY<br />
Background: Combining BEV with 1st-line chemo<strong>the</strong>rapy (CT) significantly<br />
improved progression-free survival (PFS) and response rate (RR) vs CT alone in 3<br />
randomised phase III trials (E2100, AVADO, RIBBON-1). In AVADO, DOC 100 mg/<br />
m 2 was given for a median of 5.5 months (maximum 9 cycles), after which BEV 15<br />
mg/kg was continued as a single agent. IMELDA was designed in <strong>the</strong> context of<br />
BEV–DOC approval to determine whe<strong>the</strong>r efficacy is improved by adding CAP to<br />
BEV maintenance <strong>the</strong>rapy after discontinuing DOC.<br />
Methods: Eligible pts had HER2-negative measurable mBC, ECOG PS 0/1, had<br />
received no prior CT for mBC and were eligible for taxane-based CT. After initial<br />
1st-line <strong>the</strong>rapy with 3–6 cycles of BEV–DOC, pts free of progressive disease (PD)<br />
were randomised to BEV alone or BEV–CAP (BEV 15 mg/kg q3w; CAP 1000 mg/m 2<br />
bid d1–14 q3w) until PD. The primary endpoint is PFS; secondary endpoints include<br />
safety, RR and overall survival.<br />
Results: Between June 2009 and March 2011 (when enrolment to <strong>the</strong> study was<br />
terminated prematurely after withdrawal of BEV–DOC regulatory approval), 284 pts<br />
began BEV–DOC. Median age was 52 y (range 24–80), 17% were aged ≥65 y, 53%<br />
had ECOG PS 0 and 30% had triple-negative mBC. Maintenance <strong>the</strong>rapy was<br />
administered in 183 pts (64%). Key safety results are below.<br />
Conclusions: Most grade ≥3 AEs during BEV–DOC were typical DOC-related AEs.<br />
Apart from hypertension and proteinuria, BEV AEs occurred predominantly in early<br />
cycles, suggesting that long-term BEV is well tolerated. Efficacy results are expected<br />
in 2013.<br />
Disclosure: J. Gligorov: JG has sat on Advisory Boards and received speaker<br />
honoraria from Roche. J. Bines: JB has served on Advisory Boards for Roche. P.A.<br />
Cortes: PC has served on Advisory Boards for Roche, BMS and Sanofi-Aventis. U.<br />
Freudensprung: UF works as a Contractor for F Hoffmann-La Roche Ltd. G.<br />
Mustacchi: GM has acted as a Consultant for Roche, Agendia, Celgene, Novartis,<br />
Merck, Glaxo, Eisai. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
357P NON PEGYLATED LIPOSOMAL DOXORUBICIN BEYOND THE<br />
FIRST LINE TREATMENT OF METASTATIC BREAST CANCER<br />
PATIENTS: A RETROSPECTIVE ANALYSIS<br />
S. Bernhard 1 , L. Mansi 1 , V. Nerich 2 , C.B. Villanueva 1 , E. Dobi 1 , H. Almotlak 1 ,<br />
F. Bazan 1 , L. Chaigneau 1 , L. Cals 1 , X. Pivot 1<br />
1 Department of Medical Oncology, University Hospital J. Minjoz, Besancon,<br />
FRANCE, 2 Pharmacy Department, University Hospital J. Minjoz, Besancon,<br />
FRANCE<br />
Background: The aim of this retrospective study was to access <strong>the</strong> benefit of a<br />
non-pegylated liposomal doxorubicin (NPLD) treatment beyond <strong>the</strong> first line <strong>the</strong>rapy<br />
in patients with metastatic breast cancer (MBC) after previous exposure to an<br />
anthracycline containing regimen.<br />
Patients and methods: A pharmacy prospectively collected database in <strong>the</strong><br />
Franche-Comte region, was used to identify a cohort of patients with MBC treated by<br />
NPLD regimen between 2003 and 2010.In total, 140 patients were included in <strong>the</strong><br />
analysis. Progression-free survival (PFS) was chosen as <strong>the</strong> primary efficacy endpoint.<br />
Cox proportional hazard models were fitted to identify factors that could influence<br />
both PFS and overall survival (OS) lenght. Survival data were computed according to<br />
Kaplan Meier method.<br />
Results: Primary tumours characteristics were oestrogen receptor-positive,<br />
progesterone receptor positive and HER2 positive in 77%, 63% and 20% respectively.<br />
Median PFS length was 4 months [95% CI: 2-5] and 33% of patients experienced a<br />
PFS longer than 6 months. Overall response (OR) was observed in 27 patients<br />
(19.3%, 95%CI [10.2-28.4]). Median OS after NPLD was 13 months [95% CI: 10-14].<br />
In multivariate analysis, prognostic factors significantly related to longer OS from<br />
NPLD first exposure were age younger than 50 years old (HR = 0.57 [0.35-0.93], p =<br />
0.02) and HER2 positive tumour (HR = 0.53 [0.30-0.95], p = 0.03). 17 patients<br />
Initial<br />
BEV–DOC phase (N = 284)<br />
Maintenance<br />
BEV ± CAP phase (N = 183)<br />
Discontinued <strong>the</strong>rapy 99 (35) 134 (73)<br />
PD AE O<strong>the</strong>r/unknown 41 (14) 31 (11) 27 (10) 101 (55) 15 (8) 18 (10)<br />
Grade ≥3 AEs, n (%) 138 (49) 63 (34)<br />
Neutropenia Febrile neutropenia Diarrhoea Mucosal inflammation 44 (15) 30 (11) 3 (1) 9 (3) 6 (2) 6 (2) 2 (1) 0 2 (1) 2 (1) 1 (1) 25 (14)<br />
Grade ≥3 BEV AEs of<br />
special interest<br />
As<strong>the</strong>nia Hand-foot syndrome<br />
AE = adverse event; TE = thromboembolic event<br />
Hypertension Proteinuria Bleeding Arterial TE Venous TE<br />
Wound-healing complication GI perforation<br />
Annals of Oncology<br />
5 (2) 1 (
Annals of Oncology<br />
(12.1%) discontinued NPLD treatment due to toxicity. In those, 9 (6.4%) patients<br />
experienced cardiac toxicity (grade 2 or 3) . There were 2 (1.4%) deaths related to<br />
cardiac toxicity.<br />
Conclusion: Re-challenge by an anthracycline-containing regimen should been<br />
considered in patients with MBC taking into account this encouraging ORR and <strong>the</strong><br />
length of PFS and response duration. However cardiac safety of patients must be<br />
carefully investigated during <strong>the</strong> treatment taking into account <strong>the</strong> number of<br />
treatment cessation due to cardiac damage. Of interest <strong>the</strong> subset of patients with<br />
HER2 positive tumour seemed to highly benefit from <strong>the</strong> NLPD. This finding<br />
emphasizes <strong>the</strong> sensitivity to anthracycline in this subset of HER2 positive tumours<br />
and oncologist should not forgot anthracycline containing regimen as a possible<br />
option in MBC after failure to numerous lines including chemo<strong>the</strong>rapy and HER2<br />
targeted agents.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
358P PHARMACOKINETICS OF ERIBULIN MESILATE IN<br />
COMBINATION WITH CAPECITABINE IN PATIENTS WITH<br />
ADVANCED/METASTATIC CANCER: RESULTS FROM A PHASE<br />
IB DOSE-ESCALATION STUDY<br />
C.J. Twelves 1 , M. Nasim 2 , A. Anthoney 1 ,N.Cresti 3 , C. Savulsky 4 , C. Johnston 4 ,<br />
L. Reyderman 5 , J. Wanders 4 , R. Plummer 3 , T.R.J. Evans 2<br />
1 Clinical Cancer Research Groups, Leeds Institute of Molecular Medicine and St<br />
James’s Institute of Oncology, Leeds, UNITED KINGDOM, 2 Medical Oncology,<br />
Beatson West of Scotland Cancer Centre, Glasgow, UNITED KINGDOM,<br />
3 Medical Oncology, Nor<strong>the</strong>rn Institute for Cancer Research, University of<br />
Newcastle upon Tyne, Newcastle, UNITED KINGDOM, 4 Medical Oncology, Eisai<br />
Ltd, Hatfield, UNITED KINGDOM, 5 Medical Oncology, Eisai Inc., Woodcliff Lake,<br />
NJ, UNITED STATES OF AMERICA<br />
Background: Eribulin is a microtubule dynamics inhibitor EMA approved for certain<br />
patients (pts) with locally advanced (LA)/metastatic breast cancer (MBC) who have<br />
received ≥2 prior chemo<strong>the</strong>rapeutic regimens for advanced disease. Prior <strong>the</strong>rapy<br />
should have included an anthracycline and taxane. This Phase Ib, open-label<br />
dose-escalation study assessed maximum tolerated dose (MTD), safety and<br />
pharmacokinetics (PK) of eribulin in combination with capecitabine in pts with<br />
advanced/metastatic cancer.<br />
Methods: Pts received eribulin mesilate (2–5-min IV) by Schedule 1 (1.2, 1.6 or 2.0<br />
mg/m 2 on Day [D] 1) or Schedule 2 (0.7, 1.1 or 1.4 mg/m 2 on D1 and D8) in<br />
combination with twice-daily oral capecitabine 1000 mg/m 2 on D1–14 every 21 days.<br />
To assess PK and drug-drug interaction of eribulin, capecitabine and capecitabine<br />
metabolites in Cycle 1 and 2, samples were taken on D1 (pre-, 0, 0.25, 0.5, 1–4, 6<br />
and 8 h post-dose), any time on D2–3 and D4–6, and D8 (Schedule 1: pre-, 0.5, 1–4<br />
and 6 h post-capecitabine; Schedule 2: pre-dose). PK was examined by<br />
non-compartmental analysis, and cardiac repolarization by 12-lead ECGs at<br />
screening, D1 (pre- and 4 h post-dose), D2–3, D8 and D15. Correlation of eribulin<br />
and capecitabine plasma concentrations with change from baseline (Δ) QTc was<br />
explored.<br />
Results: Schedule 1 (n = 19) and Schedule 2 (n = 15) MTDs were 1.6 and 1.4 mg/<br />
m 2 eribulin mesilate, respectively. Dose-limiting toxicities (all n = 1) were: Grade<br />
(G) 4 neutropenia, G3 febrile neutropenia, G3 fatigue, G3 lethargy (Schedule 1);<br />
G4 neutropenic sepsis, G3 neutropenia (Schedule 2). There were no unexpected<br />
toxicities. Eribulin PK was independent of schedule and had dose-related increases<br />
in exposure. No accumulation occurred upon multiple dosing; at each dose,<br />
eribulin PK was comparable in Cycles 1 and 2. Exposure to capecitabine and<br />
metabolites was variable and independent of schedule. Co-administration had no<br />
effect on ΔQTc.<br />
Conclusions: No drug-drug interaction of eribulin and capecitabine was observed.<br />
From <strong>the</strong>se results, <strong>the</strong> combination appears to be tolerated without effect on<br />
cardiac repolarization. A Phase II LA/MBC study evaluating Schedule 2 MTD is<br />
ongoing.<br />
Disclosure: C.J. Twelves: The author declares <strong>the</strong> following conflicts of interest:<br />
consultant/advisory role (Eisai) and honoraria/speakers bureau (Eisai). C.<br />
Savulsky: The author declares <strong>the</strong> following conflicts of interest: employee (Eisai<br />
Ltd). C. Johnston: The author declares <strong>the</strong> following conflicts of interest:<br />
employee (Eisai Ltd). L. Reyderman: The author declares <strong>the</strong> following conflicts<br />
of interest: employee (Eisai Inc.). J. Wanders: The author declares <strong>the</strong> following<br />
conflicts of interest: employee at <strong>the</strong> time of study (Eisai Ltd). R. Plummer:<br />
The author declares <strong>the</strong> following conflicts of interest: research funding (Eisai<br />
Ltd). T.R..J. Evans: The author declares <strong>the</strong> following conflicts of interest:<br />
research funding (Eisai Ltd). All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
359P ACTIVITY AND SAFETY OF A COMBINATION OF EPIRUBICIN,<br />
DOCETAXEL AND CISPLATIN AS NEOADJUVANT TREATMENT<br />
FOR LOCALLY ADVANCED BREAST CANCER (LABC): A<br />
PRELIMINARY REPORT<br />
N. Avci 1 , O. Kanat 1 , S. Gokgoz 2 , S. Tolunay 3 , U. Topal 4 , E. Cubukcu 1 , F. Olmez 1<br />
1 Medical Oncology, Uludag University Faculty of Medicine, Bursa, TURKEY,<br />
2 Surgery, Uludag University Faculty of Medicine, Bursa, TURKEY, 3 Pathology,<br />
Uludag University Faculty of Medicine, Bursa, TURKEY, 4 Radiology, Uludag<br />
University Faculty of Medicine, Bursa, TURKEY<br />
Aim and background: Efficacy of cisplatin-containing triplet chemo<strong>the</strong>rapy regimens<br />
for neoadjuvant <strong>the</strong>rapy of LABC has not been investigated extensively. The aim of<br />
this study was to evaluate activity and safety of a combination of epirubicin,<br />
docetaxel and cisplatin (ETC) in <strong>the</strong> neoadjuvant setting.<br />
Patients and methods: Forty-two patients with LABC (T2-T4, N0-N2, M0) were<br />
enrolled <strong>the</strong> study from March 2010 to April 2011. These patients received epirubicin<br />
(60 mg/m2 intravenously [I.V.] day 1), docetaxel (60 mg/m2 I.V. day 1) and cisplatin<br />
(60 mg/m2 I.V. day 1) every 21 days for at least 4 cycles, plus a final 2 additional<br />
cycles. Upon completion of <strong>the</strong>rapy, <strong>the</strong> primary tumor was resected when not<br />
contraindicated. The primary endpoint was <strong>the</strong> pathological complete response<br />
(pCR) rate; seconday endpoints included response rate and toxicity.<br />
Results: Median patients age was 48 years (range, 23-73 years). Median tumor size<br />
was 3.2 cm. Thirty-seven patients (88%) received 6 cycles of ETC. The overall clinical<br />
response rate was 78.6%. Twenty of 42 patients (47.6%) achieved a complete<br />
pathological response (CPR). All tumors became operable after neoadjuvant<br />
chemo<strong>the</strong>rapy. The most common side effect was myelotoxicity. WHO grade 4<br />
neutropenia developed in 30 (73%) patients. No recurrence was observed in any<br />
patient after a mean follow-up of 17 months (13-21 months).<br />
Conclusion: Although our study group was small and <strong>the</strong> follow-up period relatively<br />
short-term, <strong>the</strong> considerably high rates of CPR in this preliminary series suggest that<br />
ETC regimen may be a promising option in neoadjuvant treatment of LABC. ><br />
Disclosure: All authors have declared no conflicts of interest.<br />
360P SEQUENTIAL DOCETAXEL AS ADJUVANT CHEMOTHERAPY<br />
FOR NODE-POSITIVE OR/AND T3 OR T4 BREAST CANCER:<br />
CLINICAL OUTCOME (MANSOURA UNIVERSITY)<br />
H. Sakr 1 , R.H. Hamed 1 , A.H. Anter 1 , T. Yossef 2<br />
1 Clinical Oncology and Nuclear Medicine, Mansoura University, Egypt,<br />
Mansoura, EGYPT, 2 General Surgery, Faculty of Medicine, Mansoura University,<br />
Mansoura, EGYPT<br />
Purpose: This trial compared six cycles of fluorouracil, epirubicin, and<br />
cyclophosphamide (FEC) with a sequential regimen of three cycles of FEC followed<br />
by three cycles of docetaxel (FEC-D) as adjuvant treatment for women with<br />
node-positive or/and T3 or T4 breast cancer.<br />
Patients and methods: Between January 2006 and January 2010, 657 patients with<br />
operable breast cancer were randomly assigned to ei<strong>the</strong>r FEC every 21 days for six<br />
cycles, or three cycles of FEC followed by three cycles of docetaxel, both given every<br />
21 days. Radio<strong>the</strong>rapy was mandatory for all patients who had undergone breast<br />
conserving surgery. Radiation to <strong>the</strong> chest wall, supraclavicular area, was<br />
recommended following mastectomy. Hormone-receptor–positive patients received<br />
tamoxifen for 5 years after chemo<strong>the</strong>rapy. The primary end point was 5-year<br />
disease-free survival (DFS).<br />
Results: Median follow-up was 61 months. Five-year DFS rates were 74% with FEC<br />
and 78% with FEC-D (P= .013). Multivariate analysis adjusted for prognostic factors<br />
showed a 17% reduction in <strong>the</strong> relative risk of relapse with FEC-D. Five-year overall<br />
survival rates were 85% with FEC and 89.4% with FEC-D, demonstrating a 27%<br />
reduction in <strong>the</strong> relative risk of death (P= .014). The incidence of grade 3 to 4<br />
neutropenia, <strong>the</strong> need for hematopoietic growth factor and incidence of nausea<br />
/vomiting were higher with FEC. Docetaxel was associated with more febrile<br />
neutropenia, stomatitis, edema, and nail disorders. Though rare overall, <strong>the</strong>re were<br />
fewer cardiac events after FEC-D, attributable mainly to <strong>the</strong> lower anthracycline<br />
cumulative dose.<br />
Conclusion: Sequential adjuvant chemo<strong>the</strong>rapy with FEC followed by docetaxel<br />
significantly improves disease free and overall survival in node-positive or/and T3 or<br />
T4 breast cancer patients and. Although <strong>the</strong> magnitude of <strong>the</strong> benefit observed with<br />
FEC-D, differences in <strong>the</strong> toxicity profiles of FEC and FEC-D may influence <strong>the</strong><br />
choice of treatment for patients<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds393 | ix129
361P A RETROSPECTIVE ANALYSIS OF PLATINUM-BASED<br />
NEOADJUVANT CHEMOTHERAPY FOR LOCAL ADVANCED<br />
TRIPLE NEGATIVE BREAST CANCER<br />
F. Fei, Y. Du, X. Gu, C. Chen, J. Wu, Z. Shao<br />
Breast Surgery, Shanghai Cancer Center Fudan University, Shanghai, CHINA<br />
Purpose: We retrospectively analyzed platinum-based neoadjuvant chemo<strong>the</strong>rapy for<br />
LATNBC to compare survival outcomes between patients with PCR and with<br />
non-PCR. Fur<strong>the</strong>rmore, <strong>the</strong> disease free survival of LATNBC patients with PCR<br />
continuously receiving primary regimen as adjuvant setting had comparative<br />
advantage concerning that of “PCR” patients switching to o<strong>the</strong>r regimens as adjuvant<br />
setting as well as those without any chemo<strong>the</strong>rapy after sugery.<br />
Patients and methods: 124 women with stage II or III TNBCs experienced<br />
platinum-based regimens as neoadjuvant chemo<strong>the</strong>rapy from Nov 1, 2007 to Dec 31,<br />
2011. All patients were divided into <strong>the</strong> two groups, who were with and without PCR<br />
in <strong>the</strong> pathological reports after surgery. According to <strong>the</strong> adjuvant settings for<br />
LATNBC patients with PCR, <strong>the</strong> three arms were determined as continuous primary<br />
regimen (<strong>the</strong> same as neoadjuvant) arm, no more chemo<strong>the</strong>rapy arm and switching<br />
arm. Disease free survival was computed using <strong>the</strong> Kaplan-Meier product limit<br />
method.<br />
Result: We presented a retrospective chart review of 124 LATNBC patients who<br />
underwent platinum-based neoadjuvant chemo<strong>the</strong>rapy in our hospital. Fifty (40.32%)<br />
of those patients receiving neoadjuvant chemo<strong>the</strong>rapy had PCR when <strong>the</strong>y<br />
underwent surgery. After controlling for covariates associated with survival, patients<br />
undergoing neoadjuvant chemo<strong>the</strong>rapy with residual tumor had significantly worse<br />
survival than patients with PCR (HR = 0.37,P < 0.05). Of 50 patients with PCR<br />
confirmed by surgery, <strong>the</strong> disease free survival of 24 cases switching to o<strong>the</strong>r<br />
regimens in <strong>the</strong> adjuvant setting was significantly better than that of 24 cases<br />
continuously receving primary regimens in <strong>the</strong> adjuvant setting (HR= 0.51, P =<br />
0.025)and that of 2 cases with no more chemo<strong>the</strong>rapy(HR= 0.58, P = 0.017)<br />
Conclusion: Patients with PCR had statistically significantly better clinical survival<br />
than those with non-PCR after platinum-based neoadjuvant settings.So far, if<br />
LATNBC patients with PCR after platinum-based neoadjuvant chemo<strong>the</strong>rapy, <strong>the</strong>y<br />
might have better clinical survival if <strong>the</strong>y receive switching regimens than to receive<br />
primary regimens and to continue with no additional chemo<strong>the</strong>rapy after surgery. A<br />
randomized prospective study needs to be carried out to streng<strong>the</strong>n <strong>the</strong> results<br />
because of statistical bias.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
362P MIGHT EARLY METABOLIC RESPONSE BY 18F-FDG-PET/CT<br />
BE USEFUL TO SELECT PATIENTS (PTS) WITH BREAST<br />
CANCER (BC) WHO WILL NOT OPTIMALLY RESPOND TO<br />
PREOPERATIVE CHEMOTHERAPY (PCT)?<br />
G. Zucchini1 , S. Quercia1 , C. Zamagni1 , D. Santini2 , M. Taffurelli3 , S. Fanti4 ,A.<br />
A. Martoni1 1<br />
Medical Oncology Unit, S. Orsola-Malpighi University Hospital, Bologna, ITALY,<br />
2 3<br />
Pathology Unit, S. Orsola-Malpighi University Hospital, Bologna, ITALY, Breast<br />
Surgery Unit, S. Orsola-Malpighi University Hospital, Bologna, ITALY,<br />
4<br />
Department of Nuclear Medicine, S. Orsola-Malpighi University Hospital,<br />
Bologna, ITALY<br />
Purpose: To evaluate 18F-2-fluoro-2-deoxy-D-glucose positron emission<br />
tomography/computed tomography (18F-FDG PET/CT) changes between<br />
baseline and after 2 cycles of PCT in pts with early/locally advanced (E/LA) BC,<br />
with <strong>the</strong> aim to verify whe<strong>the</strong>r early metabolic assessment of response during<br />
PCT may have a role in clinical practice to enable early changes in <strong>the</strong><br />
<strong>the</strong>rapeutic strategy.<br />
Patients and methods: Sixty pts with newly diagnosed E/LA BC received 6-8 cycles<br />
of anthracycline and taxane-based PCT. Fifty-eight pts underwent surgery, which<br />
consisted in breast conserving surgery or radical mastectomy; axillary node dissection<br />
was performed in all cases. Optimal pathologic response (pR) to PCT was defined as<br />
absence of cancer cells in breast and ipsilateral axillary lymph nodes. All o<strong>the</strong>r<br />
conditions were defined as nonresponders (pNR). Maximum standardized uptake<br />
value (SUV max) with 18F-FDG PET/CT was measured for each pathologic lesion at<br />
baseline and after 2 cycles of PCT. SUV max percentage changes (Δ-SUV) were<br />
compared with pR rate according to immunohistochemical (IHC) BC characteristics.<br />
Δ-SUV >50% defined a metabolic response (MetR).<br />
Results: Thirteen (22%) of 60 pts achieved pR. According to IHC, pR rates where<br />
16% in ERpositive/HER2negative (ER + /HER2-) pts, 29% and 27% in<br />
HER2-positive (HER2+) and triple negative (TN) pts respectively. Sensitivity of<br />
metR to identify pR was 100% in all three subgroups, but <strong>the</strong> specificity was low:<br />
38% in ER + /HER2- pts (38%) was <strong>the</strong> highest value. In this subgroup of pts PET<br />
had a low positive predictive value (24%), while <strong>the</strong> negative predictive value was<br />
100%, showing, compared to HER2+ and TN pts, <strong>the</strong> highest ability to correctly<br />
predict pNR (32%). At a median follow-up of 36.6 months, recurrence rate was<br />
higher in metabolic non-responders, particularly in <strong>the</strong> ER + /HER2- subgroup, in<br />
which Kaplan-Meier analysis of disease-free survival confirmed a significant<br />
difference (p = 0.0490).<br />
Conclusions: PET assay after 2 cycles of PCT correctly predicted pNR in 32% of ER<br />
+ /HER2- pts, identifying a subgroup of BC pts with worse prognosis who might<br />
benefit from an early change of <strong>the</strong> <strong>the</strong>rapeutic strategy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
363P BREAST CANCER RECURRENCES AT THE CHEST WALL<br />
(BCRCW) WHEN STANDARD TREATMENTS (TX) HAVE FAILED:<br />
LYSO-THERMOSENSITIVE LIPOSOMAL DOXORUBICIN (LTLD)<br />
+ MILD LOCAL HYPERTHERMIA (MLH)<br />
H.S. Rugo 1 , S.C. Formenti 2 , R.J. Myerson 3 , C.J. Diederich 4 , B.M. O’Connor 5 ,<br />
A.J. Matzkowitz 6 , F. Muggia 7<br />
1 Department of Medicine, University of California, San Francisco, CA, UNITED<br />
STATES OF AMERICA, 2 Radiation Oncology, NYU Langone Medical Center, NY,<br />
UNITED STATES OF AMERICA, 3 Radiation Oncology, Washington University<br />
School of Medicine in St. Louis, MO, UNITED STATES OF AMERICA, 4 Radiation<br />
Oncology, University of California, San Francisco, CA, UNITED STATES OF<br />
AMERICA, 5 Radiation Oncology, Commonwealth Atrius Cancer Center, MA,<br />
UNITED STATES OF AMERICA, 6 Radiation Oncology, Florida Cancer Specialists,<br />
New Port Richey, FL, UNITED STATES OF AMERICA, 7 Cancer Institute, NYU<br />
Langone Medical Center, New York, NY, UNITED STATES OF AMERICA<br />
Background: BCRCW has a poor prognosis, with disfigurement, pain, and<br />
restriction of movement. Study treatment consisted of LTLD that releases high<br />
concentrations of doxorubicin (Dox) in areas treated with mild hyper<strong>the</strong>rmia at ><br />
39.5°C. MLH kills tumor cells, selectively increases liposomal permeability in tumor<br />
microvasculature, releases Dox from LTLD, and promotes Dox tumor uptake.<br />
Methods: We conducted a phase I study of LTLD + MLH in patients (pts) with<br />
BCRCW tumors < 3 cm deep who had failed all standard Tx including surgery,<br />
radiation, and chemo<strong>the</strong>rapy (CTx). Pts received up to 6 LTLD/MLH Txs every 21<br />
days. Dosing cohorts started at 40 mg/m 2 and stopped escalation at 50 mg/m 2 . LTLD<br />
was infused IV over 30 minutes (min); <strong>the</strong>n MLH was given by microwave or<br />
ultrasound. The <strong>the</strong>rmal dose goal was 40°C-42°C for 60 min. Pharmacokinetic<br />
samples for total plasma Dox and doxorubicinol (Doxol) were taken at 0.5, 5, 10 and<br />
24 hours after starting infusion.<br />
Results: Eleven pts with a median of 4 prior CTx (range 2 – 12) were enrolled; 10<br />
had recurred after prior anthracycline (AC). All pts received > 2 cycles. The within<br />
subject variability in Dox and Doxol exposure was small with mean Cycle 2 vs Cycle<br />
1 ratios ranging from 0.99 to 1.06.<br />
Cmax/dose (ng/ml)/(mg/m 2 Dox<br />
)<br />
Doxol<br />
AUClast/dose ((ng*hr/ml)/(mg/m 2 ) Dox<br />
Doxol<br />
Annals of Oncology<br />
Cycle 1<br />
499.82<br />
0.46<br />
1,338.18<br />
7.96<br />
Cycle 2<br />
512.00<br />
0.45<br />
1,381.82<br />
8.04<br />
Two types of grade 3/4 toxicity were seen in > 5% of 42 cycles given: reversible<br />
neutropenia in 17 (40.5%) and reversible leukopenia in 9 (21.4%). One case (each) of<br />
mucositis (grade 1), chest wall <strong>the</strong>rmal burn, and chest wall cellulitis (both grade 4)<br />
occurred, and no cases of cardiomyopathy or hand-foot toxicity were seen. The rate<br />
of clinically significant (> 6 point) QoL improvement on <strong>the</strong> FACT-B after 2 cycles<br />
was 54.5% (95% CI: 25.1% - 83.9%), including 1 lasting > 3 months. The local<br />
objective response rate was 45.5% (95% CI: 16.1% - 74.9%), with 1 complete and 4<br />
partial local responses.<br />
Conclusion: LTLD + MLH is safe and active in BCRCW pts with prior radiation and<br />
AC exposure. A phase II study is underway.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
364P IMMUNOHISTOCHEMICAL PREDICTORS OF THE CLINICAL<br />
AND PATHOLOGICAL RESPONSE TO NEOADJUVANT<br />
CHEMOTHERAPY IN LOCALLY ADVANCED BREAST CANCER<br />
M. Rodionova 1 , D. Ryabchikov 1 , S. Portnoy 2 , I. Vorotnikov 1 , N. Chkhikvadze 1<br />
1 Breast Cancer Department, N.N. Blokhin Russian Cancer Research Center,<br />
Moscow, RUSSIAN FEDERATION, 2 Department of Female Reproductive System<br />
Carcinomas, N.N.Blohkin Cancer Research Center, Moscow, RUSSIAN<br />
FEDERATION<br />
Purpose: To determine predictive immunohistochemical characteristics of <strong>the</strong> tumor<br />
correlated with <strong>the</strong> response to neoadjuvant chemo<strong>the</strong>rapy in patients with locally<br />
advanced breast cancer.<br />
Material and methods: A prospective study of 87 breast cancer patients<br />
(Т2-4N0-M0) treated in N.N.Blokhin Russian Cancer Research Center 1997 - 2009.<br />
Tumor samples were taken prior to neoadjuvant chemo<strong>the</strong>rapy (cor-biosy).<br />
Pathological criteria assessed were: histological variant, tumor grade, HR and Her-2/<br />
neu status, Ki67 expression and glycoprotein Pgp-170 status. After 4-6 cycles of<br />
chemo<strong>the</strong>rapy all <strong>the</strong> patients underwent radical surgery. We quantified <strong>the</strong> response<br />
ix130 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
clinically and pathologically (Lavnikova’s system of <strong>the</strong>rapeutic pathomorphism<br />
evaluation).<br />
Results: The experimental results showed <strong>the</strong> following response rates: complete<br />
response – 11 (12.6%), partial response – 54 (62.1%), stable disease – 21 (24.1%)<br />
patients. One patient had progression of <strong>the</strong> disease. Stable disease correlated<br />
significantly with positive Pgp-170 status (41.7% vs. 17.7%, р = 0.04), whilst negative<br />
Pgp-170 – with objective response (82.4% vs. 54.2%, р = 0.02). Pathomorphism was<br />
achieved as follows: lack of pathomorphism - 10(11.5%), first-degree pathomorphism<br />
17(19.5%), second-degree – 28(32.2%), third-degree – 18(20.7%), fourth-degree – 14<br />
(16.1%). Rare histological variants had more often third-degree pathomorphism than<br />
ductal carcinoma (р = 0.02); G1 had more often fourth-degree pathomorphism than<br />
G2 (p = 0.002); high-degree pathomorphism was more frequently observed in<br />
patients with N2 status than with N0 (p = 0.006) and N1 (p = 0.009). Her-2/neu +<br />
tumors showed lower degree of pathomorphism that those with HR status (23.7% vs.<br />
45.6%, р = 0.03). Pgp 170+ tumors had significantly more often no (p = 0.004) or<br />
first-degree pathomorphism (p = 0.004), and as a result – lower rate of high degree<br />
pathomorphism than in Pgp-170 negative tumors (12.5% and 47.1%, respectively).<br />
Conclusions: Some pathological and immunohistochemical characteristics of <strong>the</strong><br />
tumor can be assessed preoperatively and predict <strong>the</strong> likelihood of <strong>the</strong> clinical and<br />
pathological response to neoadjuvant chemo<strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
365P IS POSTMASTECTOMY RADIOTHERAPY FOR PATIENTS<br />
DIAGNOSED WITH BREAST CANCER WHO HAVE RECEIVED<br />
NEOADJUVANT THERAPY REALLY NECESSARY?<br />
R.M. Rodríguez 1 , M.T. Cano Osuna 1 , G. Pulido 2 , I. Porras 1 , P. Sánchez 1 ,<br />
A. Moreno 1 , J. Jiménez 1 , M.J. Ortiz-Morales 1 , E. Aranda Aguilar 3 ,J.De<br />
La Haba 3<br />
1 Medical Oncology, Universitay Hospital Reina Sofia, Córdoba, SPAIN, 2 Medical<br />
Oncology, University Reina Sofia Hospital, Cordoba, SPAIN, 3 Oncology<br />
Deparment, IMIBIC-Hospital Reina Sofía, Córdoba, SPAIN<br />
Introduction: The role of adjuvant radio<strong>the</strong>rapy (RTA) after mastectomy in patients<br />
who have received neoadjuvant treatment is controversial and it has not been shown<br />
benefit in ramdomized clinical trials (ref ASCO-Guide lines). On <strong>the</strong> o<strong>the</strong>r hand, <strong>the</strong><br />
low rates of local and distant recurrences after complete pathological response (RPc)<br />
question <strong>the</strong> value of local control disease.<br />
Objective: To analyze <strong>the</strong> rate and profile of recurrence in breast cancer patients who<br />
have received neoadjuvant chemo<strong>the</strong>rapy, mastectomy with and without radio<strong>the</strong>rapy.<br />
Patients and methods: From <strong>the</strong> Department of Medical Oncology, University<br />
Hospital Reina Sofia we have identified 171 patients between 1997 and 2010 who<br />
have received neoadjuvant treatment. 36 patients have not received radio<strong>the</strong>rapy<br />
treatment after mastectomy. We present clinical and biological features of patients<br />
and <strong>the</strong>ir evolution.<br />
Results: The mean age is 53 years, 100% are stage II and III (55.6% and 44.4%),<br />
infiltrating ductal histology (88.9%) and poorly differentiated tumors (44.4%).<br />
Regarding to hormonal status, 58.3% are hormone receptor positive and Her-2 33.3%<br />
and 21% are triple negative. The rate of pathological complete response (T and N) is<br />
22.2%. at T of 41.7%. With a follow-up mean of 19.92 months (SD: 13.9), we have<br />
found one recurrence of <strong>the</strong> disease localized in liver. At this moment we do not<br />
have any local recurrence.<br />
Conclusions: Based on our experience and <strong>the</strong> lack of data supporting radio<strong>the</strong>rapy<br />
in <strong>the</strong>se patients, we believe that radio<strong>the</strong>rapy should be assessed on individual basis,<br />
pending randomized studies provide direct benefit.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
366P THE IMPACT OF ADDITIONAL PROGNOSTIC INFORMATION<br />
OBTAINED FROM KI-67 CHANGES AFTER NEOADJUVANT<br />
CHEMOTHERAPY VARIES IN SUBTYPE OF BREAST CANCER<br />
N. Matsubara, H. Mukai, Y. Naito, M. Nezu, K. Itoh<br />
Oncology and Hematology, National Cancer Center Hospital East, Kashiwa,<br />
JAPAN<br />
Introduction: A reduction in <strong>the</strong> Ki-67 index after neoadjuvant chemo<strong>the</strong>rapy has<br />
been reported to be associated with a favorable prognosis. The present study<br />
investigates whe<strong>the</strong>r a reduction in Ki-67 may be a predictive surrogate marker of<br />
favorable prognosis in each subtype of breast cancer.<br />
Methods: A total of 385 patients who received neoadjuvant anthracycline followed<br />
by taxane chemo<strong>the</strong>rapy and subsequent surgery for invasive breast cancer were<br />
analyzed retrospectively. By immunohistochemistry (IHC), patients were divided into<br />
4 subtypes (Luminal A, Luminal B, Triple negative and HER2). Ki-67 was examined<br />
by IHC in pre-treatment core needle samples and post-treatment surgical excisional<br />
specimens. The relapse-free survival (RFS) rate was compared among each subtype.<br />
Results: The median follow-up period was 56 months. The rate of pathological<br />
complete response was higher for HER2 (34.8%) and Triple negative (24.3%)<br />
subtypes than for Luminal B (8.3%) and Luminal A (3.8%) subtypes (p < 0.0001). A<br />
reduction in Ki-67 was observed in 58.5%, 83.4%, 70.2% and 74.2% of patients in <strong>the</strong><br />
Luminal A, Luminal B, Triple negative and HER2 subtypes, respectively. The<br />
differences in RFS between patients whose Ki-67 was reduced and those not reduced<br />
were statistically significant for Luminal B (81.4% vs. 50.0%, p = 0.003), Triple<br />
negative (74.8% vs. 43.5%, p = 0.003) and HER2 (82.7% vs. 59.0%, p = 0.008).<br />
However, for Luminal A, <strong>the</strong> difference in RFS was not observed depend on <strong>the</strong><br />
changes of Ki-67 (78.8% vs. 75.3%, p = 0.78).<br />
Conclusions: The reduction in Ki-67 after neoadjuvant chemo<strong>the</strong>rapy is a predictive<br />
surrogate marker of a favorable RFS. However, this conclusion could not be applied<br />
to Luminal A subtype.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
367P ELECTROCHEMOTHERAPY FOR CHEST WALL RECURRENCE<br />
FROM BREAST CANCER IN OLDER WOMEN: ANALYSIS<br />
OF 55 PATIENTS<br />
L.G. Campana 1 , S. Galuppo 2 , S. Valpione 3 , C. Falci 4 , L. Corti 2 , A. Brunello 5 ,<br />
G. Zavagno 6 , C. Ghiotto 4 , C.R. Rossi 1<br />
1 Sarcoma and Melanoma Unit, Veneto Region Oncology Research Institute<br />
(IOV-IRCCS), Padova, ITALY, 2 Radio<strong>the</strong>rapy Unit, Veneto Region Oncology<br />
Research Institute (IOV-IRCCS), Padova, ITALY, 3 Medical Oncology School,<br />
University of Padova, Padova, ITALY, 4 Medical Oncology-ii, Veneto Region<br />
Oncology Research Institute (IOV-IRCCS), Padova, ITALY, 5 Medical Oncology<br />
Unit-I, Veneto Region Oncology Research Institute (IOV-IRCCS), Padova, ITALY,<br />
6 Dept. of Surgery and Gastroenterological Sciences, University of Padova,<br />
Surgery Branch, Padova, ITALY<br />
Background: The incidence of chest wall recurrence (CWR) after mastectomy for<br />
breast cancer (BC) ranges from 5 to 40%. It is a common finding that a number of<br />
patients are not suitable for radical resection or full-dose radio<strong>the</strong>rapy. When<br />
resistance to systemic <strong>the</strong>rapies occurs, electrochemo<strong>the</strong>rapy (ECT), an<br />
electroporation-based local drug delivery system, could represent a valuable treatment<br />
option for older women.<br />
Methods: We analyzed a prospectively maintained database of 55 BC patients (median<br />
70 years, range 38-88) with irresectable CWR who experienced disease progression<br />
after at least 2 lines of systemic <strong>the</strong>rapies. Tumor response, response duration and<br />
toxicity profile were analyzed according to patients’ age (70 years).<br />
Results: The patients received a median of 2 ECT courses (range, 1-5). Younger<br />
(n = 27) and elderly (n = 28) patients were comparable for clinico-pathological<br />
features, except for <strong>the</strong> number of CW metastases (median 15 vs 8, respectively, P<br />
= .040). Two-month objective response was: complete 22 patients (40.0%), partial 26<br />
(47.3%), no change 7 (12.7%). The complete response rate was significantly higher in<br />
<strong>the</strong> elderly group (57.7 vs 28%, P = .02). Pain and local toxicity scores were similar,<br />
but worsened with <strong>the</strong> increasing number of ECT applications. Median follow-up<br />
was 32 months (range, 6–53), 3-year local control rate was 70%. Thirty-three patients<br />
(60%) developed new lesions (NL) in non-electroporated areas (median, 6.6 months).<br />
Less than 10 metastases (P < .001), <strong>the</strong> narrower area of tumor spread on <strong>the</strong> CW (P<br />
= .022), endocrine- instead of chemo<strong>the</strong>rapy (P = .025) and complete response after<br />
ECT (P = .019) were associated to longer NL-free survival. Older women showed a<br />
trend to a lower local tumor control compared to younger patients (2-year local<br />
progression-free survival, 83 versus 88%, P = .120). On <strong>the</strong> contrary, elderly patients<br />
reported a better 2-year NL-free survival (45 versus 22%, P = .095).<br />
Conclusions: Older patients with CWR present fewer skin metastases and are more<br />
likely to achieve complete response after ECT. The satisfactory CW control without<br />
severe toxicity makes elderly women with refractory CWR suitable candidates for<br />
ECT application.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
368P IS SURGERY OF THE PRIMARY TUMOR CONVENIENT<br />
IN METASTATIC BREAST CANCER?<br />
F. Petrelli1 , M. Cabiddu2 , K.F. Borgonovo2 , M. Ghilardi2 , F. Maspero2 ,<br />
M. Cremonesi2 , S. Barni2 1<br />
UO Oncologia, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio, ITALY,<br />
2<br />
Medical Oncology Division, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio,<br />
ITALY<br />
Introduction: Stage IV breast cancer is treated primarily with systemic <strong>the</strong>rapies.<br />
Excision of <strong>the</strong> primary breast cancer tumor in presence of synchronous distant<br />
metastases is a controversial argument, and a standard recommendation is not<br />
proposed by current guidelines. We performed a meta-analysis with <strong>the</strong> aim of pooling<br />
<strong>the</strong> existing survival data of surgery of <strong>the</strong> breast primary tumor in stage IV disease.<br />
Materials and methods: We searched PubMed for publications including female,<br />
with histologically confirmed stage IV breast cancer at presentation and an intact<br />
primary tumor. Primary outcome was overall survival (OS) in patients treated with<br />
resection of primary breast cancer in presence of synchronous distant metastases.<br />
Secondary endpoints were PFS or TTP (and local and/or distant PFS or TTP,<br />
whichever reported). Hazard ratios (HRs) for survival when reported after<br />
multivariate analysis (with 95% confidence intervals) were obtained from<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds393 | ix131
publications and aggregated in a meta-analysis. A meta-regression weighted for<br />
extent of disease, ER/HER2 status, age, visceral or bone disease, rate of radio<strong>the</strong>rapy,<br />
and systemic <strong>the</strong>rapies offered was also performed.<br />
Results: 15 articles were included in this meta-analysis (all retrospective case series),<br />
for a total of 15.378 patients. Surgery of <strong>the</strong> primary breast cancer appeared to be an<br />
independent factor for an improved survival in <strong>the</strong> multivariate analyses from <strong>the</strong><br />
individual studies, with an HR of 0.69 (p < 0.00001). According to meta-regression, <strong>the</strong><br />
survival benefit was independent of age, extent, site of metastatic disease and HER2<br />
status, but was directly proportional to rate of patients exposed to systemic <strong>the</strong>rapies<br />
and radio<strong>the</strong>rapy and inversely correlated to ER+ status of <strong>the</strong> population included.<br />
Conclusions: Our pooled-analysis, reveals that surgery of an intact primary tumor,<br />
although associated with distant metastases, reduces <strong>the</strong> risk of death by 30%. This<br />
results are particular significant if local surgery is associated with systemic <strong>the</strong>rapy<br />
and radio<strong>the</strong>rapy into a multimodality strategy. The surgical excision of a primary<br />
breast cancer in patients with stage IV disease – if feasible - should be discussed with<br />
and proposed to patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
369P BEING THERE FOR WOMEN WITH METASTATIC BREAST<br />
CANCER. A PAN-EUROPEAN PATIENT SURVEY<br />
C.J. Twelves 1 , J. Stebbing 2<br />
1 Clinical Cancer Research Groups, Leeds Institute of Molecular Medicine and St<br />
James’s Institute of Oncology, Leeds, UNITED KINGDOM, 2 Oncology, Imperial<br />
College & Imperial College Healthcare NHS Trust, London, UNITED KINGDOM<br />
Background: This two-part European patient survey was designed to help identify<br />
needs of women with metastatic breast cancer (MBC), through understanding <strong>the</strong>ir<br />
experiences of diagnosis, treatment and care.<br />
Material and methods: The survey, initiated in March 2011, was conducted using a<br />
two-stage methodology. The first stage collected views on standards of MBC care and<br />
unmet needs of patients from 47 MBC-related patient groups in 8 European<br />
countries. This information was used to develop <strong>the</strong> second stage patient survey. The<br />
patient survey was designed to capture personal experiences of MBC diagnosis,<br />
treatment, information provision and to determine insights into <strong>the</strong> ‘trade-off’<br />
between extending overall survival and side effects associated with MBC treatment.<br />
This online survey was open to women with locally advanced or MBC or <strong>the</strong>ir carers.<br />
All data were collected using anonymised local language questionnaires with<br />
responders recruited through local patient groups.<br />
Results: A total of 230 responses were received from 17 identified European<br />
countries (94% of whom had locally advanced or MBC, and 6% of whom were adult<br />
carers). Although <strong>the</strong> overall experience of care was generally good to excellent<br />
(77%), <strong>the</strong>re were still gaps in terms of treatment choice and information provision.<br />
Specifically, findings indicate that 32% of patients perceived treatment choice to be<br />
lacking. Overall, results showed that 67% of women with locally advanced or MBC<br />
believed life-extending treatment to be important so that <strong>the</strong>y could spend more time<br />
with <strong>the</strong>ir family and friends; <strong>the</strong> same proportion judged <strong>the</strong>ir treatment worthwhile<br />
if it prolonged survival, irrespective of potential side effects. Additionally, 68% of<br />
responders would have liked more information about future medical treatments and<br />
research, with 57% wishing to receive this information from <strong>the</strong>ir oncologist.<br />
Conclusions: These new survey findings highlight <strong>the</strong> unmet needs of women with<br />
MBC in Europe with respect to treatment choice and provision of information.<br />
Prolonging survival is a priority for most women, even if associated with toxicity.<br />
Disclosure: C.J. Twelves: The Being There survey was supported by an educational<br />
grant from Eisai Europe Limited. J. Stebbing: The Being There survey was supported<br />
by an educational grant from Eisai Europe Limited.<br />
370P CNS METASTASES, SUBTYPES AND SURVIVAL IN BREAST<br />
CANCER: A POPULATION BASED STUDY IN EASTERN<br />
SWITZERLAND<br />
D. König 1 , B. Thürlimann 2 , F. Otto 3 , L. Plasswilm 4 , M. Hoefliger 5 ,I.<br />
K. Senn-Schönenberger 6 , U. Müller 7 , C. Öhlschlegel 8 , H. Senn 3 , S.M. Ess 1<br />
1 Krebsliga Ostschweiz, Cancer Registry St. Gallen-Appenzell, St. Gallen,<br />
SWITZERLAND, 2 Breast Center St. Gallen, Kantonsspital St. Gallen, St. Gallen,<br />
SWITZERLAND, 3 Zetup, Tumor-und Brustzentrum ZeTuP AG, St. Gallen,<br />
SWITZERLAND, 4 Department of Radiation Therapy, Kantonsspital St. Gallen,<br />
St. Gallen, SWITZERLAND, 5 Oncology Practice, Altstätten, SWITZERLAND,<br />
6 Oncology Practice, St. Gallen, SWITZERLAND, 7 Oncology Practice, Sargans,<br />
SWITZERLAND, 8 Institute of Pathology, Kantonsspital St. Gallen, St. Gallen,<br />
SWITZERLAND<br />
Purpose: To examine tumor characteristics and outcomes associated with central<br />
nervous system (CNS) metastases in patients with metastatic breast cancer (MBC).<br />
Methods: Patients listed in <strong>the</strong> regional cancer registry of St. Gallen-Appenzell<br />
with MBC between 2003-2009 were included. Estrogen- (ER), progesterone<br />
receptor (PR) and HER2 status were collected from pathology reports. Biologic<br />
subtypes were approximated using standard immunohistochemical markers.<br />
Survival status was assessed in January <strong>2012</strong>. Multivariate logistic regression<br />
models were used to identify factors associated with <strong>the</strong> risk of developing CNS<br />
metastases and with survival >12 months (mt) after <strong>the</strong> diagnosis of CNS<br />
involvement.<br />
Results: Overall, CNS metastases were observed in 170 (22%) of 773 patients<br />
with MBC included in <strong>the</strong> study. In <strong>the</strong> multivariate model, factors associated<br />
with CNS metastases were age
Annals of Oncology<br />
372P INCIDENCE OF BONE METASTASES AND SURVIVAL AFTER A<br />
DIAGNOSIS OF BONE METASTASES (BM) IN BREAST<br />
CANCER PATIENTS<br />
L. Holmberg 1 , M. Harries 2 , O. Agbaje 1 , H. Garmo 3 , S. Kabilan 3 , A. Taylor 4 ,<br />
A. Purushotham 5<br />
1 Division of Cancer Studies, Cancer Epidemiology Unit, Research Oncology,<br />
Kings College London School of Medicine, Guys Hospital, London, UNITED<br />
KINGDOM, 2 Department of Medical Oncology, Guys and St Thomas’s Hospitals<br />
NHS Foundation Trust, Guys Hospital, London, UNITED KINGDOM, 3 Division of<br />
Cancer Studies, Cancer Epidemiology Unit, Research Oncology, King’s College<br />
London School of Medicine, Guys Hospital, London, UNITED KINGDOM,<br />
4 Centre for Observational Research (Oncology), Amgen Ltd., Uxbridge, UNITED<br />
KINGDOM, 5 Division of Cancer Studies, Research Oncology, Kings College<br />
London School of Medicine, Guys Hospital, London, UNITED KINGDOM<br />
Objectives: To measure crude and cumulative incidence of BM and cumulative<br />
survival after diagnosis of BM. BM were grouped by (i) BM only (ii) BM followed by<br />
visceral metastases (iii) visceral metastases followed by BM.<br />
Methods: Kaplan-Meier and Cox regression database analysis of women with breast<br />
cancer diagnosed 1975-2006 and treated at Guys Hospital London, whose details<br />
were prospectively updated regularly till end 2010.<br />
Results: Of 7064 women, 1589 (22%) developed BM by end follow-up (mean 8.4<br />
years); 2254 (32%) were diagnosed with breast cancer < 50 years, and 4810 (68%)<br />
≥50 years; 735 (14.4%) were classified as grade I, 2303 (45.3%) grade II and 2049<br />
(40.3%) grade III; 1530 (27.8%) were estrogen receptor (ER) –ve and 3982 (72.2%)<br />
ER +ve. Of all BM, 535 (33.7%) patients were in group i; 871 (54.8%) in group ii and<br />
183 (11.5%) in group iii. Incidence of all BM within 0-3 years from breast cancer<br />
diagnosis was highest in 1980 (64/1000 person years) and lowest in 2006 (11/1000<br />
person years), with <strong>the</strong> decline most pronounced in 1985-1990. Cumulative incidence<br />
of BM after 5 years follow up was highest in 1976-1982 (0.25 [95% CI 0.23-0.27]),<br />
falling to 0.22 (0.20-0.24) in 1983-1989, 0.18 (0.10-0.14) in 1990-1997 and 0.095<br />
(0.08-0.12) in 1998-2006.Risk of BM was significantly influenced by: calendar period<br />
of breast cancer diagnosis, HR was 0.77 (0.68-0.86) 1983-1989, 0.46 (0.40-0.54)<br />
1990-1997 and 0.33 (0.28-0.40) 1998-2006, all vs 1975-1982; tumour grade, HR 1.23<br />
(1.08 - 1.40) grade 3 vs 1-2; nodal status, HR 1.88 (1.60-2.21) 1-3 nodes vs 0 nodes<br />
and 3.95 (3.36-4.64) 4+ nodes vs 0 nodes; and tumour size, HR 2.00 (1.75-2.29) 2-5<br />
cm vs
Thus <strong>the</strong> primary aim to target BCSCs to control metastasis and relapse of disease<br />
was somewhat obtained. We fur<strong>the</strong>r plan to correlate ratio of selected markers<br />
present in patients in pre- and post-chemo<strong>the</strong>rapeutic condition with time to<br />
recurrence, mortality, morbidity and progression-free survival.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
376 GENETIC POLYMORPHISM IN AURORA-A AS A RISK FACTOR<br />
IN EGYPTIAN WOMEN WITH BREAST CANCER<br />
M.M. Saber 1 , S.Y. Akel 2 , G.T. Ali 2 , N.H. Ibrahim 2<br />
1 Dept. Medical Oncology, National Cancer Institute, Cairo, EGYPT, 2 Clinical<br />
Pathology Department, National Cancer Institute, Cairo, EGYPT<br />
Introduction: Although many risk factors have been identified, <strong>the</strong> cause of any<br />
individual breast cancer (BC) is most often unknowable. Aurora A, <strong>the</strong> gene,<br />
encoding serine/threonine kinase, has been shown to be over expressed in many<br />
tumors, noticeably in BC. The aim is to study <strong>the</strong> single nucleotide polymorphism in<br />
Aurora-A, and compare <strong>the</strong> frequency distributions of different genotypes between<br />
patients with BC and those with fibroadenoma to define its tumorigenic contribution<br />
to BC development.<br />
Patients and methods: This study was conducted on 60 pathologically confirmed BC<br />
patients, 20 patients with fibroadenoma and 40 frequency matched controls. There<br />
were no age, stage or histology restrictions.Serum CA-15-3&estradiol were measured.<br />
DNA was isolated from peripheral blood lymphocytes for genotyping of Aurora A at<br />
<strong>the</strong> T91A (Phe31Ile) site and were analyzed by PCR–RFLP assay.<br />
Results: This study showed that women carrying <strong>the</strong> Ile/Ile genotype had an increased<br />
risk of developing BC (P = 0.04). Logistic regression analysis showed that subjects<br />
having IIe/IIe genotype had a 9.3fold increased risk of developing BC compared with<br />
those with <strong>the</strong> Phe/Phe genotype (OR 9.3;95% CI 1.12-77.69). The heterozygous Phe/<br />
IIe genotype was not significantly associated with <strong>the</strong> risk of cancer, suggesting a<br />
possible recessive effect of <strong>the</strong> polymorphism. No significant association was observed<br />
between <strong>the</strong> polymorphism and <strong>the</strong> risk of fibroadenoma. Patients with negative ER<br />
&PR were more likely to carry <strong>the</strong> IIe/IIe genotype compared with positive ER &PR<br />
positive patients (34.8% vs 5.4%). Serum estradiol showed significant increase in <strong>the</strong><br />
BC category (p= 0.016), while, no significant difference was observed between <strong>the</strong><br />
benign and <strong>the</strong> control categories (p = 0.41). The presence of +ve family history (FH)<br />
of BC and history of sex hormone intake showed significant increase in BC category<br />
when compared to control group and benign group. In BC group, patients with +ve<br />
FH had 7.5 times <strong>the</strong> chance of carrying IIe/IIe genotype compared to patients with –<br />
ve FH (OR7.5; 95% CI 1.53-36.71, P0.01).<br />
Conclusion: This study provides <strong>the</strong> evidence that <strong>the</strong> Aurora-A Ile/Ile genotype is<br />
associated with an increased risk for <strong>the</strong> occurrence but not progression of BC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
377 CLINICAL, MOLECULAR PROFILES AND RESPONSE TO<br />
NEOADJUVANT CHEMOTHERAPY IN PATIENTS WITH LOCALLY<br />
ADVANCED BREAST CANCER: AN INDIAN EXPERIENCE<br />
D. Arya, B. Parikh, P.M. Shah, S.N. Shukla, K.M. Patel, A.S. Anand, S.S. Talati,<br />
S.A. Shah, A.A. Patel, B.B. Parekh<br />
Medical Oncology, Action Cancer Hospital, Delhi, INDIA 2 Dept. of Medical and<br />
Pediatric Hemato Oncology, Gujarat Cancer and Research Institute Civil Hospital<br />
Campus, M.P. Shah Cancer Hospital, Ahmedabad, INDIA<br />
Background: Breast cancer is now <strong>the</strong> most common cancer in many parts of India<br />
and Locally advanced breast cancer (LABC) accounts for nearly one thirds of cases.<br />
Advanced stages at presentation are attributed to late diagnosis and biologically<br />
aggressive disease in Indian women.<br />
Materials and methods: Patients diagnosed with inoperable LABC at <strong>the</strong> Gujarat<br />
Cancer and Research Institute, Ahmedabad, India were included in <strong>the</strong> study.<br />
Baseline evaluation included clinical assessment, testing for Estrogen Receptor(ER),<br />
Progesterone Receptor (PgR), Her2Neu and serum Vascular Endo<strong>the</strong>lial Growth<br />
Factor (S. VEGF). First line NACT was FAC or FEC. Patients were assessed clinically<br />
and radiologically at <strong>the</strong> end of 3 cycles for response evaluation (mammography or<br />
ultrasonography of breast). S. VEGF levels were repeated at <strong>the</strong> end of 3 cycles of<br />
NACT or before surgery. All resectable patients underwent a Modified Radical<br />
Mastectomy. Unresectable patients were offered taxanes based chemo<strong>the</strong>rapy or<br />
supportive care.<br />
Results: Fifty seven patients with LABC were included. Fifty Four patients (95%)<br />
received NACT. Mean age at diagnosis was 49 years. ER was positive in 51%, PgR<br />
in 35% and Her2Neu in 47%. Mean baseline S. VEGF was 463.4pg/ml. Baseline<br />
S. VEGF was higher in patients who were hormone receptor or Her2Neu positive.<br />
The overall clinical response rate [complete response (cCR) + partial response<br />
(cPR)] to <strong>the</strong> initial anthracycline based chemo<strong>the</strong>rapy was 63%, cCR was 0%.<br />
Resectability rate after 1st line NACT was 77%. Pathological CR (pCR) rate was<br />
4%. There was no significant reduction in S. VEGF levels after NACT, irrespective<br />
of clinical or pathological responses. Nearly 17% of patients were lost to follow up<br />
at various stages of treatment including three patients who refused any kind of<br />
treatment.<br />
Conclusions: This study analyzes clinical and molecular profile of patients with<br />
LABC in India which differs from that seen in developed nations. High treatment<br />
drop-out rates may reflect treatment related toxicities, socio-cultural and logistical<br />
issues in a big developing country. Responses to anthracycline based NACT are<br />
comparable to <strong>the</strong> results reported from similar centers.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
378 RESPONSE TO NEOADJUVANT THERAPY AND DISEASE FREE<br />
SURVIVAL AND OVERALL SURVIVAL IN PATIENTS WITH<br />
TRIPLE-NEGATIVE BREAST CANCER (TNBC): SINGLE CENTER<br />
EXPERIENCE<br />
T. Pascual 1 , E. Ciruelos 1 , L. Manso 1 , I. Ghanem 1 , R.A. Manneh 1 , C. Mendiola 1 ,<br />
D. Lora 2 , H. Cortes-Funes 1<br />
1 Medical Oncology, Hopital 12 de Octubre, Madrid, SPAIN, 2 Clinical Investigation<br />
Unit, Imas12, University Hospital 12 de Octubre, Madrid, SPAIN<br />
Background: Triple negative breast cancer (TNBC) is a distinct subtype of BC wich<br />
is characterized by <strong>the</strong> absence of expression of estrogen receptor (ER), progesterone<br />
receptor (PR) or HER2/neu. TNBC is a very heterogeneous disease, that accounts for<br />
15 to 20% of breast cancers. Despite initial chemosensitivity, patients with TNBC<br />
had a poorer outcome in terms of disease-free and overall survival, compared to<br />
non-triple-negative breast cancers. Neoadjuvant chemo<strong>the</strong>rapy is commonly used for<br />
<strong>the</strong> initial treatment for TNBC, allowing for a higher rate of breast-conserving<br />
surgery and giving clues about <strong>the</strong> individual responsiveness of a particular cancer to<br />
chemo<strong>the</strong>rapy.<br />
Methods: We retrospectively reviewed 66 TNBC patients treated with neoadjuvant<br />
chemo<strong>the</strong>rapy diagnosed at our institution between 2001-2011. They were divided<br />
into three subgroups: complete pathological response after neoadjuvant<br />
chemo<strong>the</strong>rapy (group A), residual tumor smaller than 1 centimeter wide (group B),<br />
and residual tumor bigger than 1 centimeter wide or involving lymph nodes.<br />
Results: (One patient died before surgery and ano<strong>the</strong>r patient refused it. Twenty<br />
(31%) of <strong>the</strong> o<strong>the</strong>r 64 patients achieved a complete pathological response. Mean DFS<br />
was 2,15 years; recurrent disease was higher for C (20,64%) vs B (3pts, 23%) vs A (2<br />
pts, 10%) (p = 0,0003). Most common recurrent sites were local (18) and bone (9).<br />
Mean OS was 4,5 years (95% IC 3,6 – 5,4); 3 (15%) pts died in A, 3 (23%) in B vs 16<br />
(51%) in C (p = 0,03).<br />
Conclusions: The pathologic complete response rate seen in our series is consistent<br />
with <strong>the</strong> one reported in o<strong>the</strong>r studies involving neoadjuvant chemo<strong>the</strong>rapy for<br />
TNBC. The pathologic response after a neoadjuvant <strong>the</strong>rapy correlates with<br />
disease-free and overall survival rates.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
379 ULTRASOUND ESTIMATION OF THE BLOOD FLOW IN BREAST<br />
CARCINOMAS AS A PREDICTIVE FACTOR OF EFFICIENCY<br />
OF NEOADJUVANT POLYCHEMOTHERAPY (NPCT)<br />
J. Zaivelieva 1 , I. Schepotin 1 , O. Zotov 1 , L. Kireeva 2 , T. Kondratova 2<br />
1 Oncology Department, National Medical University O.O. Bogomolets, Oncology<br />
Department, Kyiv, UKRAINE, 2 Department of Diagnostic, Kyiv City Consultative<br />
and Diagnostic Centre, Kyiv, UKRAINE<br />
Objective: Using ultrasound (US) techniques to determine <strong>the</strong> role of <strong>the</strong> intensity of<br />
<strong>the</strong> blood flow (BF) of breast tumors as a criterion of efficiency ACnPCT.<br />
Methods: 30 patients aged 50-62 years with verified BC, who were candidates for 3<br />
courses of AC-nPCT, were carried out color-coded US in <strong>the</strong> triplex mode scanning<br />
and power doppler.<br />
Luminal A Luminal B HER2(+) Triple-negative<br />
T2N0M0 3 1 - 2<br />
T2N1M0 3 2 2 2<br />
T3N0M0 3 4 1 3<br />
T3N1M0 1 1 - 2<br />
Average systolic blood flow<br />
velocity, ACBFL (cm/sec)<br />
14,2 ± 2,6 15,9 ± 3,9 14,6 ± 2,5 16,2 ± 2,8<br />
Measurements were made of resistance index (IR), pulsating index (IP).<br />
Annals of Oncology<br />
Results: ACBFV is increased and corresponds to <strong>the</strong> malignancy process, while<br />
higher rates were in patients with <strong>the</strong> triple-negative breast cancer (16,2 ± 2,8 cm/sec)<br />
and luminal B type (15,9 ± 3,9 cm/sec). While luminal A type had ACBFL 14,2 ± 2,6<br />
cm/sec and HER2(+) had 14,6 ± 2,5 cm/sec. IR in all subgroups was 0,73 ± 0,12, that<br />
matches <strong>the</strong> sharply increased values, and shows an increase peripheral resistance in<br />
vessels. IP was 12,35 ± 1,75, that reflects <strong>the</strong> amplified elastic and flexible properties<br />
of <strong>the</strong> newly formed blood vessels. Effect of AC-nPCT was higher in patients with<br />
<strong>the</strong> luminal B type (CR – 5, PR – 3). In patients with triple-negative BC effect of<br />
nPCT was worse, despite <strong>the</strong> high rate of BF in <strong>the</strong> tumor (PR – 1, stabilization – 6,<br />
ix134 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
progression – 2). In patients with low rate of BF in <strong>the</strong> tumor (luminal A, HER2(+)<br />
type) effect was <strong>the</strong> worst (PR – 2, stabilization – 7, progression – 4 patients in both<br />
groups). The correlation coefficient was statistically significant for BF as increased<br />
ACBFV, IR, IP, and <strong>the</strong> frequency of CR + PR to nPCT of luminal B type.<br />
Conclusions: There is a correlation between <strong>the</strong> velocity of BF and degree of<br />
destruction of tumor by cytostatics. While <strong>the</strong> rate of BF depended on <strong>the</strong> molecular<br />
type of <strong>the</strong> tumor and did not depend on <strong>the</strong> size of <strong>the</strong> primary tumor.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
380 IMPACT OF BODY MASS INDEX (BMI) ON DISEASE FREE<br />
SURVIVAL AND LIKELIHOOD OF PATHOLOGIC COMPLETE<br />
RESPONSE IN PATIENTS WITH LOCALLY ADVANCED BREAST<br />
CANCER TREATED WITH NEOADJUVANT CHEMOTHERAPY<br />
A. Armengol-Alonso 1 , A. Arance 1 , M. Campayo 1 , X. González-Farré 1 ,<br />
A. García-Herrera 2 , P.L. Fernández 2 , X. Caparros 3 , I. Alonso 3 , B. Farrus 4 ,<br />
M. Muñoz 1<br />
1 Oncologia Medica, Hospital Clinic y Provincial de Barcelona, Barcelona, SPAIN,<br />
2 Pathology, Hospital Clinic y Pronvincial Barcelona, Barcelona, SPAIN,<br />
3 Gynecology and Obstetrics Department, Hospital Clinic Barcelona, Barcelona,<br />
SPAIN, 4 Department of Radiation Oncology, Hospital Clinic Barcelona,<br />
Barcelona, SPAIN<br />
Background: The BMI is a clinical parameter that although not perfect is often used<br />
to measure adiposity. In breast cancer <strong>the</strong>re are multiple studies indicating that<br />
overweight/obesity (O/O) is related with lower survival and increased risk of relapse.<br />
It has been also reported less likely to achieve a pathological complete response<br />
(pCR) after neoadjuvant chemo<strong>the</strong>rapy (NAC) in O/O patients.<br />
Methods: We retrospectively reviewed <strong>the</strong> records of 108 patients diagnosed with<br />
invasive locally advanced breast cancer (ILABC) who had been treated with NAC<br />
(anthracycline + taxane ± trastuzumab). The aim of our study was to review <strong>the</strong><br />
impact of BMI on <strong>the</strong> pCR and <strong>the</strong> possibility of recurrence. pCR was defined as <strong>the</strong><br />
criterion of strict pCR breast+nodes.<br />
Results: From 2004 to 2011, 108 patients received NAC. Based on <strong>the</strong>ir weight and<br />
height at baseline we divided into two groups; group 1: underweight/normal (BMI<br />
383 WHY DO WOMEN WITH BREAST CANCER IN SARAWAK,<br />
MALAYSIA PRESENT LATE?<br />
B.C. Devi<br />
Radio<strong>the</strong>rapy, Oncology & Palliative Care, Sarawak General Hospital, Sarawak,<br />
MALAYSIA<br />
Introduction: Breast cancer (BC) is <strong>the</strong> most common cancer in Sarawak. We<br />
explore <strong>the</strong> reasons of late stage presentation in this study.<br />
Methods: Based on a 175 questions questionnaire, information on barriers to late<br />
presentation were collected as a prospective study on 626 cases (2009 to 2011).<br />
Descriptive statistics and statistical tests were performed using <strong>the</strong> SPSS ver 17.0.<br />
Results: The stage at diagnosis differed significantly with 71% of <strong>the</strong> Chinese being<br />
diagnosed at early stage compared to only 50% in Malay and 45% in Natives (p <<br />
0.0004). The delay between first symptom and first medical consultation (DELAY 1)<br />
was more than one month in 57% of <strong>the</strong> patients and it differed significantly among<br />
ethnic groups (50% for Chinese, 64% for Malay and 65% for Natives, p < 0.002). The<br />
highest delay were: women aged 50 years (53%, p < 0.037); from<br />
rural area (65%) vs urban areas (55%, p < 0.04).The main variables affecting this<br />
delay were knowledge about BC (p < 0.004), lack of interest in one’s health ( p <<br />
0.0005) and choice of first professional consulted (doctor/nurse vs traditional healer,<br />
p < 0.03). The delay between first medical consultation and effective diagnosis<br />
(DELAY 2) for > 1 month was 14% of <strong>the</strong> patients and it differed significantly among<br />
ethnic groups (14% for Chinese, 23% for Malay and 13% for Natives, p < 0.0008).<br />
The main reasons: <strong>the</strong> number of doctors consulted before diagnosis (less <strong>the</strong> better,<br />
p < 0.0003); Malays (66.4%) and natives (64.4%) consulted more than two doctors<br />
when compared to Chinese (42.6%, p < 0.0001) and were less likely to follow <strong>the</strong><br />
recommendations given by <strong>the</strong> doctors (p < 0.06). The impact of teaching Breast<br />
self-examination (BSE) on DELAY 1 and 2: Seventy-eight percent of patients were<br />
taught BSE and by 80% of government nurses. The age group (30-40 years) had been<br />
taught BSE more than o<strong>the</strong>r age groups. For DELAY 1, 72% were not taught BSE,<br />
p < 0.0001. There was no difference for those with DELAY 2. However for both<br />
DELAY 1 and 2, 42% were not taught BSE, p < 0.0001.<br />
Conclusions: More than 50% of <strong>the</strong> patients had DELAY 1 and 14% for DELAY<br />
2. Learning BSE had an impact on DELAY 1 but not for DELAY2. Those in age<br />
groups (>40 to 60 years) had less BSE taught and this finding is crucial for public<br />
health education as most BC occur after 45 years.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
384 THE ROLE OF ANTIESTROGENS IN BREAST CANSER CELLS’<br />
INVASIVENESS<br />
D.V. Lymperatou<br />
Department of Medicine, Division of Oncology, University Hospital of Patras,<br />
Patras, GREECE<br />
Aim: The current study investigates <strong>the</strong> effect of two selective antagonists of <strong>the</strong><br />
estrogen receptor (ER), fulvestrant (FL) and tamoxifen (Tam), on <strong>the</strong> invasive ability<br />
of breast cancer cells. ER blockage using anti-estrogens is associated with a small<br />
induction of invasiveness. Moreover, matrix metalloproteinases (MMPs) contribute<br />
to this procedure by cleaving components of <strong>the</strong> extracellular matrix, forming a path<br />
for <strong>the</strong> migrating cells. In addition, <strong>the</strong> focal adhesion kinase (FAK) plays a central<br />
role in invasiveness.<br />
Methods: We used two ER+ breast cancer cell lines, MCF7 and T47D. Cells were<br />
stimulated by estradiol (E2) and <strong>the</strong>n treated with FL, Tam and <strong>the</strong> metabolites<br />
endoxifen (End) and 4OH-tamoxifen (4OHT). The invasiveness was evaluated using<br />
<strong>the</strong> matrigel assay and MMPs expression with gelatin zymography assay. Using<br />
immunofluoresence, we study <strong>the</strong> expression and localization of phospho FAK and<br />
its correlation with F-actin.<br />
Results: We found that E2 exerts a protective role in invasiveness. On <strong>the</strong> contrary,<br />
<strong>the</strong> anti-estrogens, as well as <strong>the</strong>ir metabolites reversed <strong>the</strong> effect of E2, a finding that<br />
was more obvious with Tam. The effect of <strong>the</strong> agents on MMPs expression was more<br />
pronounced at 48 h, when Tam and 4OHT were found to reduce <strong>the</strong> levels of both<br />
MMP-2 and MMP-9 compared to FL. Following E2 exposure, <strong>the</strong> maximum<br />
autophosphorylation of FAK (Y397) was observed at 10 min. At <strong>the</strong> same time point<br />
we assessed <strong>the</strong> effect of our agents, regarding <strong>the</strong> spatial organization of actin fibers.<br />
The concurrent administration of E2 with FL, Tam or End was associated with<br />
rearrangement of cytoskeleton, a finding that was not observed in untreated cells, as<br />
well as after <strong>the</strong> use of 4OHT and E2 or E2 alone.<br />
Conclusions: Our results indicate that <strong>the</strong> metabolite 4OHT is superior to <strong>the</strong><br />
pro-drug Tam as well as <strong>the</strong> pure anti-estrogen FL with respect to invasiveness,<br />
MMPs induction and actin rearrangement. Regarding <strong>the</strong> comparison of Tam with<br />
FL, <strong>the</strong> effect on MMPs and rearrangement was similar. However, FL was found to<br />
be slightly superior to Tam concerning invasiveness.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
385 CANCER STEM CELL-LIKE CELLS: A THERAPEUTIC MODEL IN<br />
BREAST CANCER PATIENTS, WHERE ANY OTHER<br />
RECOMMENDED THERAPY HAS FAILED<br />
I. Papasotiriou 1 , M. Chatziioannou 2 , M. Toloudi 2 , E. Ioannou 2 , R. Hammon 3 ,<br />
U. Jacob 4 , N. Hembry 5 , A. Kopic 4<br />
1 Research & Development-Clinical, Research Genetic Cancer Centre Ltd, Filotas,<br />
GREECE, 2 Research & Development, Research Genetic Cancer Centre Ltd,<br />
Filotas, GREECE, 3 Clinical, ATMC, Texas, TX, UNITED STATES OF AMERICA,<br />
4 Clinical, Privatklinik AMC, Dornstetten-Hallawangen, GERMANY, 5 Clinical, Litfield<br />
Medical House, Bristol, UNITED KINGDOM<br />
Introduction: Nowadays, <strong>the</strong> difficulty to treat metastatic breast cancers is high.<br />
Many clinical <strong>the</strong>rapeutic lines have failed and <strong>the</strong>re is no suggested <strong>the</strong>rapeutic<br />
approach (in literature) concerning this type of tumors. The last decades,<br />
circulating tumor cells (CTCs) are <strong>the</strong> state – of – <strong>the</strong> –art in cancer <strong>the</strong>rapy. In<br />
<strong>the</strong> present study, CTCs were isolated and identified. CSCs (cancer stem cells)<br />
were isolated from <strong>the</strong> above population of CTCs and <strong>the</strong>ir gene pattern was<br />
compared with those from <strong>the</strong> primary tumor as well as with those from <strong>the</strong><br />
metastatic tumor. This study attempts to find a correlation between <strong>the</strong> CTCs and<br />
<strong>the</strong> metastatic regions in comparison with <strong>the</strong> primary tumor as well as to find<br />
out if all <strong>the</strong> CSCs have <strong>the</strong> same hallmarks in <strong>the</strong> selected breast cancer stem<br />
cell populations.<br />
Materials and methods: In order <strong>the</strong> protocol to be performed, CTCs from<br />
patient’s blood samples were isolated and <strong>the</strong>n cultured in appropriate conditions.<br />
CSCs were identified and isolated from <strong>the</strong> population of CTCs. mRNA was<br />
extracted and was used for Microarray hybridization assays. The same procedure<br />
was repeated for primary tumor as well for metastatic tumor samples. The<br />
expression pattern of primary tumor cells was compared with those in <strong>the</strong><br />
metastatic tumor. Finally, <strong>the</strong> <strong>the</strong>rapeutic approach which was based on <strong>the</strong> above<br />
findings, was designed.<br />
Results: The results showed that <strong>the</strong> gene expression pattern of metastatic sites is<br />
similar to that of metastatic sites and less to that of <strong>the</strong> primary site. Then, <strong>the</strong><br />
patients followed a <strong>the</strong>rapeutic approach based on <strong>the</strong> data of <strong>the</strong> clinical results<br />
which were evaluated within a six- month period showing that <strong>the</strong> patients showed<br />
an objective response rate.<br />
Conclusion: The results showed that <strong>the</strong> entity that determines <strong>the</strong> clinical outcome<br />
in breast cancer, is <strong>the</strong> sub-population of CTCs, <strong>the</strong> circulating CSCs. Moreover,<br />
<strong>the</strong>re are various types of CSCs in one patient, and not only one, as <strong>the</strong>y have<br />
different growth mechanisms in primary and secondary tumors.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
386 BREAST CANCER PATIENTS WITH HER2NEU<br />
OVEREXPRESSION: RELATIONSHIP AMONG<br />
CLINICOPATHOLOGICAL CHARACTERISTICS AND LOCAL/<br />
DISTANT RECURRENCES AND SURVIVAL<br />
C. Bellido-Ribes 1 , S. Gonzalez 2 , A. Garcia 3 , V. Obadia 2 , R. Bastus 4 ,<br />
J. Fernández 4 , A. Aguilar 4 , L. Cirera 4<br />
1 Medical Oncology, Mutua Terrassa University Hospital, Terrassa, SPAIN,<br />
2 Medical Oncology, Hospital Mutua Terrassa, Terrassa, SPAIN, 3 Breast Unit,<br />
Departament of Gynecology, Hospital Mutua Terrassa, Terrassa, SPAIN,<br />
4 Hospital Mutua Terrassa, Terrassa, SPAIN<br />
Objectives: The aim of this study was to correlate <strong>the</strong> overexpression of HER2 with<br />
clinical pathologic characteristics and its influence on local/distant recurrence and<br />
survival.<br />
Methods: From 1998 to 2010, prospective data of 146 patients with invasive breast<br />
cancer with HER-2 overexpression was studied. The sample was divided into three<br />
groups: Negative hormonal receptors (NHR); Luminal B1 (Estrogen receptor +/-,<br />
Progesterone receptor +), Luminal B2 (Estrogen receptor +, Progesterone receptor -).<br />
Histological type (HT), size tumor (T), differentiation grade (DG), and nodal status<br />
were determined. Correlation with local and distant recurrence, and 5-year overall<br />
survival was done.<br />
Results: NHR: 33.5%, luminal B1: 47.5%; Luminal B2: 19% Clinical pathologic<br />
characteristics:<br />
Age (%) Size(%) HT (%)<br />
70 T1 T2 T3 T4 Ductal Lobular<br />
NHR 23 51 26 39 37 4 10 98 2<br />
Luminal B1 33 51 16 51 39 9 1 99 1<br />
Luminal B2 22 64 14 53 43 30 4 96 4<br />
ix136 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
DG (%) Nodal Status<br />
G1 G2 G3 Negative Positive<br />
NHR 0 21 79 59 41<br />
Luminal B1 11 37 52 48 52<br />
Luminal B 0 28 73 57 43<br />
Local and distant recurrence and overall survival at 5 years follow-up:<br />
Local Recurrence<br />
(%)<br />
Metastasis Recurrence<br />
(%)<br />
NHR 6 20 81.5<br />
Luminal B1 2 8 88.5<br />
Luminal B2 4 15 86.5<br />
Overall Survival<br />
(%)<br />
Conclusions: Patients with NHR and patients with PR- had more aggressive<br />
differentiation grade, less axillary infiltration and increased risk of distant metastasis.<br />
At 5-year follow-up, overall survival was better in <strong>the</strong> PR+ group.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
387 CRANIAL MAGNETIC RESONANCE IMAGING (MRI) IN THE<br />
STAGING OF HER2-POSITIVE BREAST CANCER PATIENTS<br />
M.A. Kaplan 1 , A. Inal 1 , M. Kucukoner 1 , Z. Urakci 1 , F. Ekici 1 , U. Firat 2 ,<br />
A. Isikdogan 1<br />
1 Medical Oncology, Dicle University, Diyarbakir, TURKEY, 2 Pathology,<br />
Dicle University, Diyarbakir, TURKEY<br />
Purpose: The aim of <strong>the</strong> current study was to evaluate whe<strong>the</strong>r early detection of brain<br />
metastases could improve survival outcomes in HER2-positive breast cancer patients.<br />
Patients and methods: HER2-positive breast cancer patients without neurological<br />
symptoms within 12 months from current stage of diagnosis were included in <strong>the</strong><br />
study. The factors affecting <strong>the</strong> development of brain metastasis in <strong>the</strong> entire group<br />
and <strong>the</strong> metastatic patients were investigated, respectively. Survival durations after<br />
first metastasis and brain metastasis were compared between <strong>the</strong> asymptomatic and<br />
symptomatic patients<br />
Results: Eleven of <strong>the</strong> 96 patients (11.5%) had occult brain metastasis. Of whom 9<br />
patients were in <strong>the</strong> metastatic group, only 2 patients were in <strong>the</strong> non-metastatic<br />
group, (22% vs 3.6%, respectively, p = 0.008). Although median survival durations<br />
from first metastasis (27.4 vs 20.2 months, respectively, p = 0.858) and brain<br />
metastasis (5.2 vs 4.4 months, respectively, p = 0.710) similar, cerebral death was<br />
numerically different (22% vs 46%, p = 0.271) in <strong>the</strong> asymptomatic and symptomatic<br />
patients.<br />
Conclusion: Present study suggests that routine cranial imaging do not bring any<br />
benefit to <strong>the</strong> non-metastatic HER2-positive breast cancer patients. Fur<strong>the</strong>rmore,<br />
although early detection of brain metastasis provides reduction in cerebral deaths, it<br />
does not prolong survival in metastatic patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
388 DIAGNOSIS OF BREAST CANCER METASTASES WITH PET/TC<br />
IN PATIENTS WITH ELEVATION OF TUMOR MARKERS: FINAL<br />
DATA<br />
A. Mafodda 1 , A. Prestifilippo 2 , R. Maisano 1 , D. Giuffrida 2 , D. Aricò 3 , D. Azzarello 1 ,<br />
M. Mare 2 , M. Nardi 1<br />
1 Oncologia Medica, A.O. B.M.M., Reggio Calabria, ITALY, 2 Oncologia Medica,<br />
Istituto Oncologico del Mediterraneo, Viagrande, ITALY, 3 Medicina Nucleare,<br />
Centro Catanese di Oncologia, Catania, ITALY<br />
Background: Breast cancer is one of <strong>the</strong> most common cancers worldwide. PET /<br />
CT is more accurate than traditional methods for <strong>the</strong> detection of distant metastases<br />
or local recurrence and enables for early assessment of treatment response in patients<br />
after surgery for breast cancer undergoing primary chemo<strong>the</strong>rapy. PET/CT is not<br />
considered a conventional examination during follow-up of patients with breast<br />
cancer, but recent data indicate its usefulness both in cases of asymptomatic increase<br />
of tumor markers that uncertain conventional imaging results. This study investigates<br />
<strong>the</strong> potential role of PET / CT to detect clinically occult metastases in patients with<br />
suspected recurrence of breast cancer during follow-up.<br />
Methods: The authors studied 67 patients in breast cancer follow-up after primary<br />
surgery and chemo<strong>the</strong>rapy and/or external radio<strong>the</strong>rapy. All patients were in<br />
remission without any o<strong>the</strong>r clinical or instrumental signs of relapses, except for <strong>the</strong><br />
progressive elevation of CA 15.3 and/or CEA, tested during <strong>the</strong> follow-up. In 47<br />
patients conventional imaging provided uncertain results and increase of CA 15.3<br />
that was not correlated to any evidence of metastatic disease. The final diagnosis was<br />
obtained by histopathology (n.13) or by combined follow-up (n.54), including<br />
imaging at least 6 months later.<br />
Results: Disease relapse was proven in 55 out of 67 patients and successfully PET/CT has<br />
identified clinically occult disease with an excellent sensitivity. In 21 cases <strong>the</strong> anatomical<br />
distribution of metastasis sites was in <strong>the</strong> bone, 16 in <strong>the</strong> lymphonode, 11 in <strong>the</strong> lung and<br />
7 in <strong>the</strong> liver. We found 2 false-negative, 4 false-positive and 6 true-negative.<br />
Conclusions: PET/TC may be more sensitive than <strong>the</strong> serum tumor markers in<br />
detecting relapse of breast cancer. This study demonstrated <strong>the</strong> clinical utility of<br />
tumor marker-guided PET in <strong>the</strong> follow-up of breast cancer patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
389 SURGICAL RESECTION OF LOCALLY ADVANCED PRIMARY<br />
TUMOR IN PATIENTS WITH DISTANT METASTATIC BREAST<br />
CANCER AT DIAGNOSIS: RESULTS OF A RETROSPECTIVE<br />
COMPARATIVE STUDY<br />
S. Arifi 1 , F.Z. Hijri 1 , Z. Benbrahim 2 , Y. Akasbi 1 , S. Elfakir 3 , N. Mellas 1 ,<br />
A. Melhouf 4 , A. Banani 4 , O. El Mesbahi 1<br />
1 Medical Oncology, Hassan II University Hospital, Fez, MOROCCO, 2 Medical<br />
Oncology, University Hospital of Hassan II, Fez, MOROCCO, 3 Epidemiology,<br />
Hassan II University Hospital, Fez, MOROCCO, 4 Gynecology, Hassan II<br />
University Hospital, Fez, MOROCCO<br />
Background: Women with metastatic breast cancer (MBC) with intact locally<br />
advanced primary tumors (LAT) present aggressive local symptoms that may warrant<br />
palliative surgery to <strong>the</strong> breast. However, it is unclear if such surgery o<strong>the</strong>rwise<br />
improves clinical outcome. The aim of this study is to demonstrate if surgery of <strong>the</strong><br />
breast may avoid uncontrolled chest wall disease and may improve survival.<br />
Methods: We reviewed <strong>the</strong> records of all MBC patients presented with intact LAT,<br />
treated at our institution between 2007 and 2011.We compared two groups of<br />
patients: surgical group versus nonsurgical group. Clinical outcome was assessed in<br />
<strong>the</strong> two groups. Prognostic factors affecting loco regional relapse, were evaluated.<br />
Results: 75 patients were identified. The mean patient age was 49 ± 12.15 years. 52%<br />
were pre menopausal women. 87.1 % of tumors were hormone receptors positive.<br />
Her2 was assessed in 59 cases and was positive in 33.9%. Inflammatory breast cancer<br />
presented 16 %. Clinical lymph node involvement was noted in 58.7% cases. 69.6%<br />
had visceral metastasis and 5.3 % had brain metastasis. 89.3% have good Performans<br />
Status ≤ 1. All women received systemic <strong>the</strong>rapy. First-line <strong>the</strong>rapy consisted of<br />
anthracycline-based regimen (95.6%) and Taxane (39.7%). Among patients with<br />
HER2 positive 36.4% received Trastuzumab. Only 14% of patients with bone<br />
metastasis received bisphosphonate. 49.3% underwent mastectomy while 50.7% had<br />
intact LAT. The two groups were well balanced regarding demographics, clinicals,<br />
and tumors, characteristics. Among women who underwent mastectomy 48.5% had<br />
axillary lymph node dissection, and excision margins were positive in 25% cases.<br />
Loco regional radio<strong>the</strong>rapy (LRRT) was given to 8 women. pCR occurred in 7<br />
patients among those who were operated. Local recurrence (LR) occurred in 9<br />
patients (28.1%). Median time to local relapse was 3 months (2-19). LR was related<br />
to excision margin (p = 0.0001) and LRRT (p = 0.04). Median PFS was 10 months in<br />
nonsurgical group patients versus 16.5 months in surgical group.<br />
Conclusions: MBC patients with locally advanced breast cancer who underwent<br />
mastectomy had improvement in local symptoms when <strong>the</strong> excision margin was in<br />
sano. However, <strong>the</strong> impact of this surgery in survival is not clear.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
390 CISPLATIN, CYCLOPHOSPHAMIDE, METHOTREXATE, AND<br />
5-FLUOROURACIL (PCMF) AS FIRST LINE THERAPY OF<br />
METASTATIC TRIPLE NEGATIVE BREAST CANCER (MTNBC)<br />
IN PATIENTS PREVIOUSLY TREATED WITH ADJUVANT<br />
ANTHRACYCLINES AND TAXANES: RETROSPECTIVE<br />
ANALYSIS<br />
D.A. Donat<br />
Internal Oncology, Institute of Oncology Vojvodina, Sremska Kamenica, SERBIA<br />
Background: The purpose of this study was to evaluate <strong>the</strong> efficacy and toxicity of<br />
applied PCMF chemo<strong>the</strong>rapy every four weeks (q4w) in <strong>the</strong> treatment of MTNBC<br />
patients (pts) previously treated with adjuvant anthracyclines and taxanes.<br />
Methods: We administered cisplatin 30 mg/m2 on day 1 to 3 with regular hydration,<br />
cyclophosphamide 400 mg/m 2 on day 1 to 5, 5-fluorouracil 500mg/m 2 on day 2 and<br />
4, and methotrexate 30mg/m 2 on day 1, 3, and 5.The evaluation was performed after<br />
4 cycles. We included 76 pts (median age 58 years, range: 32-71 years). PS medium<br />
was 1 (0-2); 21 pts (27.6%) were premenopausal and 55 (62.4%) postmenopausal.<br />
Adjuvant anthracyclines (AC or FAC x 4) and taxanes (paclitaxel/w x 12, or<br />
docetaxel/3w x 4) <strong>the</strong>rapy was applied in all patients. DFS 12 months in 29 pts (38.2%). Adjuvant radio<strong>the</strong>rapy was<br />
applied in 48 pts (63.2%). Visceral metastases were observed in 51 pts (67.1%), bone<br />
metastases in 34 (44.7%), and soft tissue metastases in 11 pts (14.5%). Only one<br />
organ was affected in 15 pts (19.7%), in 41 (53.9%) two organs, and in 5 pts (6.6%)<br />
three or more.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds393 | ix137
Results: We evaluated 76 pts with MTNBC after 4 cycles of PCMF chemo<strong>the</strong>rapy.<br />
CR was found in 3 pts (3.9%), PR in 16 pts (21.0%), SD in 11 pts (14.5%), and PD<br />
in 39 pts (51.3%); with ORR in 19 pts (24.9%) and TCR in 30 pts (39.5%).<br />
Hematological toxicity: grade 3 and 4 anemia was found in 4 pts (5.3%) and<br />
leukopenia in 9 pts (11.8%). Non-hematological toxicity: renal grade 3 awas observed<br />
in 2 pts (2.6%). Not a single <strong>the</strong>rapy was interrupted due to toxicity, but <strong>the</strong>rapy<br />
prolongation was present in 15% of applied cycles.<br />
Conclusions: The application of PCMF chemo<strong>the</strong>rapy q4w in <strong>the</strong> treatment of<br />
patients previously treated with anthracyclines and taxanes as adjuvant treatment<br />
appeared to be effective with ORR in 24.9% and TCR in 39.5% and can be<br />
administered with good tolerance.It is today our standard treatment in this pts<br />
population.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
391 TRASTUZUMAB-BASED CHEMOTHERAPY (CT) FOR<br />
HER2-POSITIVE METASTATIC BREAST CANCER (MBC): WHICH<br />
OPTIMAL PARTNER BEYOND THE FIRST LINE? A<br />
SINGLE-CENTRE RETROSPECTIVE STUDY<br />
R. Palumbo 1 , A. Bernardo 1 , A. Riccardi 2 , F. Sottotetti 1 , M. Azzarà 2 ,<br />
B. Tagliaferri 1 , E. Pozzi 1 , C.M. Teragni 1 , G. Bernardo 1<br />
1 Oncologia Medica 2, Fondazione S. Maugeri IRCCS, Pavia, ITALY, 2 Medical<br />
Oncology, University of Pavia, Pavia, ITALY<br />
Background: The activity of trastuzumab-based chemo<strong>the</strong>rapy (CT) in HER2+ MBC<br />
is well established, but <strong>the</strong> question of <strong>the</strong> optimal CT partner remains a relevant<br />
issue. We performed a retrospective comparison of <strong>the</strong> clinical outcomes associated<br />
with different trastuzumab-CT regimens.<br />
Patients and methods: Patients (pts) for this analysis were selected from a<br />
monoinstitutional database of HER2+ MBC pts receiving trastuzumab-based CT for<br />
<strong>the</strong> metastatic disease (February 2005-December 2008). Treatment activity and safety<br />
were assessed by <strong>the</strong> WHO criteria, time to progression (TTP) and overall survival<br />
(OS) were calculated by <strong>the</strong> Kaplan Meier method.<br />
Results: A total of 147 pts with measurable disease were evaluated: 57 received<br />
trastuzumab with weekly vinorelbine (T/VNR), 48 weekly or 3–weekly trastuzumab<br />
plus docetaxel (T/Doc), 42 a triple combination of 3-weekly trastuzumab plus oral<br />
vinorelbine and capecitabine (T/osVNR/Cape) as 1 st line <strong>the</strong>rapy. Objective RR was<br />
76% in <strong>the</strong> T/VNR group, 68% in <strong>the</strong> T/Doc regimen, and 72% in <strong>the</strong> T/osVNR/<br />
Cape combination. There was no significant difference in median TTP according to<br />
treatment type (14, 11 and 12 months, respectively, p = 0.62); median OS was 36<br />
months, 32 and 34 months, respectively (p = 0.48). More treatment-related grade 3-4<br />
toxicities were recorded in <strong>the</strong> T/Doc population. Following progression, pts received<br />
trastuzumab-based subsequent lines of treatment; according to our Institution police,<br />
shifting to a different CT partner: all had a 2 nd line, 86 a 3 rd line, 41 a 4 th line, 7 a<br />
5 th line. In univariate analysis no visceral involvement, T/Doc 1 st line CT, low<br />
primary tumor grading were correlated with better PFS and OS; in multivariate<br />
analysis <strong>the</strong> number of trastuzumab-based regimens was <strong>the</strong> only factor with<br />
statistically significant impact on OS (p = 0.02).<br />
Conclusions: These results confirm <strong>the</strong> high activity of <strong>the</strong> tested regimens as 1 st<br />
line <strong>the</strong>rapy of HER2+ MBC, without significant differences in clinical outcomes,<br />
also suggesting <strong>the</strong> benefit of multiple lines of trastuzumab-based CT in a<br />
significant subset of pts, since each subsequent line may contribute to a longer<br />
OS.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
392 PHASE II STUDY OF SINGLE AGENT ORAL VINORELBINE (OV)<br />
AS FIRST-LINE CHEMOTHERAPY (CT) IN PATIENTS (PTS) WITH<br />
HER-2 NEGATIVE METASTATIC BREAST CANCER (MBC): A<br />
SINGLE CENTER EXPERIENCE<br />
M. Mansour 1 , C. Mourad 2<br />
1 Oncology, Erfan Hospital, Jeddah, SAUDI ARABIA, 2 Medical Affairs, Pierre<br />
Fabre Medicament, Beirut, LEBANON<br />
Background: Quality of life and pts’ preferences play an important role in treatment<br />
decision-making in <strong>the</strong> metastatic setting. Previous studies indicated that Oral CT is<br />
convenient and a preferred option by many pts. We hereby report <strong>the</strong> efficacy and<br />
safety of OV as first-line CT for MBC.<br />
Patients and methods: 31 pts were enrolled between January 2007 and December<br />
2010. All pts had measurable disease, a majority (84%) relapsing after anthracyclines<br />
(ANT) and/or taxanes (TXN) adjuvant treatment, WHO PS ≤ 2, adequate bone<br />
marrow, hepatic and renal functions and no adjuvant CT within <strong>the</strong> last 6 months.<br />
Pts were treated every 3 weeks with OV 60 mg/m 2 D1 and D8 for <strong>the</strong> 1 st cycle and<br />
<strong>the</strong>reafter 80 mg/m 2 D1 and D8 every 3 weeks in <strong>the</strong> absence of G4 neutropenia<br />
and/or febrile neutropenia. Treatment was administered until disease progression or<br />
unexpected adverse event or pt refusal to continue. Primary endpoint (EP) was<br />
Objective Response Rate (ORR); secondary EPs were TTP, OS and safety. Follow-up<br />
results until April <strong>2012</strong> are reported.<br />
Results: Median age was 42 years (range, 33 -75); median WHO PS 1 (range, 0-2).<br />
Previous adjuvant <strong>the</strong>rapy: ANT-based alone: 29%, TXN-based alone: 19%, ANT plus<br />
TXN: 36%, o<strong>the</strong>r: 16%. Median disease-free interval from end of previous CT was 7<br />
months. 26 pts (84%) had 2 or more metastatic sites, liver (61%), bone (58%), lung<br />
(58%) being <strong>the</strong> most frequent sites. A median of 6 cycles were administered (range,<br />
2-20). ORR was achieved in 9 pts (29%), including 1 complete and 8 partial responses.<br />
12 pts (39%) had stable disease, resulting in a clinical benefit rate (CBR) of 68%. In pts<br />
pretreated by ANT, ORR was 35% and CBR was 70%. Median TTP was 3.7 months<br />
[95% CI: 2.2-5.2]. Median survival was 16 months [95% CI: 11.4-20.6]. 3 pts (10%)<br />
developed G 3-4 neutropenia. No events of febrile neutropenia, cardiac, renal toxicities<br />
or alopecia were recorded. G 3 thrombocytopenia was reported in 2 pts (6%). 5 pts<br />
(16%) developed G 3 nausea-vomiting.<br />
Conclusions: Results show a good efficacy and tolerance profile of OV as first line CT<br />
for HER-2 negative MBC pts. Similar activity was observed in <strong>the</strong> sub-group of pts<br />
pretreated by ANT.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
393 VINORELBINE WITH OR WITHOUT TRASTUZUMAB<br />
IN METASTATIC BREAST CANCER<br />
Annals of Oncology<br />
A. Stravodimou, K. Zaman, I.A. Voutsadakis<br />
Centre Pluridisciplinaire d’Oncologie, Centre Hospitalier Universitaire Vaudois -<br />
CHUV, Lausanne, SWITZERLAND<br />
Background: Vinorelbine is one of <strong>the</strong> most widely used drugs in metastatic breast<br />
cancer. We report a single center experience with vinorelbine with or without<br />
trastuzumab in patients with metastatic breast cancer.<br />
Patients and methods: All patients with metastatic breast cancer receiving<br />
vinorelbine with or without trastuzumab during a six years period were<br />
retrospectively reviewed. Demographic data and data on response, time to<br />
progression (TTP) and survival were collected. Patients received vinorelbine IV<br />
25-30 mg/m2or PO 60-80 mg/m2 in days 1 and 8 of a 21 days cycle. In patients who<br />
received concomitant trastuzumab a standard dosing schedule with 8 mg/kg loading<br />
dose followed by 6 mg/kg in subsequent administrations every three weeks was used.<br />
Results: Eighty seven women were included. The median age was 63 years (range 32<br />
to 85). Sixty two patients received vinorelbine alone and 25 patients received<br />
vinorelbine with trastuzumab. In 67 patients this was <strong>the</strong> first line treatment for<br />
metastatic disease and in 20 patients it was 2nd or later line of treatment. Seventy<br />
patients were evaluable for response while <strong>the</strong> remaining seventeen patients were not<br />
evaluable due to early progression (n = 6) or early termination of treatment for<br />
adversary effects (n = 11). The response rate of evaluable patients was 37.1% [1.4%<br />
Complete Response (CR) and 35.7% Partial Response (PR)]. Eighteen additional<br />
patients (25.7%) had Stable Disease (SD) for three or more months resulting in a<br />
Disease Control Rate of 62.8%. Twenty four of 54 (44.4%) patients receiving first line<br />
treatment had a response while in <strong>the</strong> second and subsequent lines setting two of 16<br />
(12.5%) patients responded (x2 = 9.66, p = 0.001). A response was obtained in 63.6%<br />
of patients receiving concomitant trastuzumab and in 25% of patients receiving<br />
vinorelbine alone (x2 = 13.63, p = 0.0002). The median TTP was six months (range<br />
1-45). Sixty six patients of <strong>the</strong> cohort have died and <strong>the</strong> median overall survival was<br />
11.5 months (range 1-83). Adverse effects necessitating interruption of treatment<br />
were observed in 18.5% of patients.<br />
Conclusion: This retrospective study of vinorelbine in metastatic breast cancer<br />
confirms a high disease control rate. Response rate is higher in first line treatment<br />
compared to subsequent lines and with <strong>the</strong> combination with trastuzumab.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
394 A RETROSPECTIVE STUDY OF CISPLATIN/VINORELBINE<br />
VERSUS CAPECITABINE/VINORELBINE AS SECOND-LINE OR<br />
THIRD-LINE TREATMENT IN ADVANCED BREAST CANCER<br />
Y. Liu 1 , S. Shi 1 ,X.Qu 1 , J. Shi 2 , L. Zhang 2 ,L.Xu 2 , Y. Teng 2<br />
1 Medical Oncology, The First Hospital of China Medical University, Shenyang,<br />
CHINA, 2 Department of Oncology, The First Affiliated Hospital of China Medical<br />
University, Shenyang, CHINA<br />
Purpose: To compare <strong>the</strong> efficacy and safety of cisplatin or capecitabine, both with<br />
vinorelbine, as second-line or third-line treatment in advanced breast cancer<br />
previously treated with anthracyclines and/or taxanes.<br />
Methods: From June 2004 to November 2011, 62 advanced breast cancer patients<br />
were eligible. Patients (38) enrolled in group NP received VIN 25mg/m 2 on day 1<br />
and 8 combined with Cisplatin 75mg/m 2 on day 1 of a 21-day cycle. Patients (24)<br />
enrolled in group NX received VIN 25mg/m 2 on day 1 and 8 of a 21-day cycle<br />
combined with CAP 1000mg/m 2 twice daily for 14 consecutive days followed by 7<br />
days of rest. Tumor assessment was performed every 2 cycles according to RESIST<br />
criteria. Toxicity was assessed according to National Cancer Institute Common<br />
Toxicity Criteria (version 3.0).<br />
Results: The overall response rate (ORR) in group NP was 47.4%, all were partial<br />
responses (PRs). In group NX, ORR was 33.3% (P = 0.275), with 4.2% CRs and<br />
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Annals of Oncology<br />
29.2% PRs. Median time to progression (TTP) was 6.1 months (range, 3.2-9.0<br />
months) in group NP and 6.3 months (range, 4.1-8.5 months) in group NX(P =<br />
0.783). COX regression showed no statistically significant difference (P = 0.782, OR =<br />
0.920). Median overall survival (OS) was 28.8 months (range, 21.6-36.0 months) in<br />
group NP and 15.1 months (9.6-20.6 months) in group NX(P = 0.027, OR = 0.495).<br />
COX regression showed a statistically significant difference(P = 0.045). Neutropenia<br />
was <strong>the</strong> most frequent hematologic toxicity, with 57.9% grade 3/4 neutropenia<br />
observed in group NP and 38.1% in group NX(P = 0.145). 13.2% grade 3/4 vomiting<br />
was seen in group NP and no grade 3/4 vomiting in group NX. No grade 3/4<br />
nephrotoxicity or hand-foot syndrome was noted in both groups.<br />
Conclusion: Better OS was seen in group NP than in group NX. Treatment-related<br />
toxicity in both groups was manageable.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
395 DOCETAXEL (D), GEMCITABINE (G) AND BEVACIZUMAB (BEV)<br />
AS SALVAGE CHEMOTHERAPY (CT) FOR HER-2 NEGATIVE<br />
METASTATIC BREAST CANCER (MBC)<br />
E. Kontopodis 1 , C. Christophylakis 1 , N. Kentepozidis 1 , I. Boukovinas 1 ,<br />
S. Giassas 1 , E. Saloustros 1 , A. Kalykaki 1 , V. Bozionelou 2 , V. Georgoulias 1 ,<br />
D. Mavroudis 1<br />
1 Medical Oncology, Hellenic Oncology Research Group (HORG), A<strong>the</strong>ns,<br />
GREECE, 2 Medical Oncology, University General Hospital of Heraklion, A<strong>the</strong>ns,<br />
GREECE<br />
Introduction: The combination of D and G is a valid salvage CT regimen for <strong>the</strong><br />
treatment of mBC. When combined with CT, Bev has increased <strong>the</strong> response rate and<br />
progression-free survival (PFS) in both first and second line treatment of mBC. In this<br />
multicenter study, we evaluated <strong>the</strong> combination of D, G, and Bev, administered<br />
biweekly, as second or fur<strong>the</strong>r line CT in patients (pts) with HER-2 negative mBC.<br />
Methods: Women with HER-2 negative mBC, who had received at least one prior<br />
line of CT, were treated with D 50 mg/m2, G 1500 mg/m2 and Bev 10 mg/Kg, in<br />
cycles every two weeks. Bev was continued until disease progression. This was a<br />
study with Simon’s optimal two step statistical design.<br />
Results: Forty-eight pts have been enrolled. Median age was 61 years, performance<br />
status was 0-1 in 95.8% and 2 in 4.2% of pts, 83.3% had hormone receptor positive<br />
disease, and 47.9% had received one prior line of CT. All pts were evaluable for<br />
toxicity and 43 for response. Objective response rate was 44.2% (95% confidence<br />
interval [CI], 29.3-59%), median PFS was 6.8 months (95% CI, 4.5-9.1 months), and<br />
median overall survival 20.1 months (95% CI, 9.9-30.3 months). Grade 3-4<br />
hematologic toxicity consisted of neutropenia (39.6%) and febrile neutropenia<br />
(4.2%). Most common grade 2-3 non-hematologic adverse events included nausea<br />
(10.4%), diarrhea (10.5%), neurotoxicity (12.5%), fatigue (31.3%), allergic reactions<br />
(6.3%), hemorrhage (4.2%), and hypertension (4.2%). No grade 4 non-hematologic<br />
toxicities or toxic deaths were recorded.<br />
Conclusion: The combination of D, G and Bev has promising activity and a<br />
manageable toxicity profile as salvage CT for HER-2 negative mBC. Updated results<br />
will be presented at <strong>the</strong> congress.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
396 EFFICACY OF TRASTUZUMAB CONTAINING RETREATMENT<br />
AFTER PROGRESSION ON LAPATINIB THERAPY IN JAPANESE<br />
PATIENTS WITH HER2-POSITIVE METASTATIC BREAST<br />
CANCER<br />
M. Hattori 1 ,H.Iwata 1 , T. Fujita 1 , M. Sawaki 1 , N. Kondo 1 , A. Horio 1 , K. Muro 2<br />
1 Breast Oncology, Aichi Cancer Center, Nagoya, JAPAN, 2 Clinical Oncology,<br />
Aichi Cancer Center Hospital, Nagoya, JAPAN<br />
Background: Lapatinib has been approved for HER2 positive metastatic breast cancer<br />
patients with refractory to trastuzumab (T) <strong>the</strong>rapy in Japan. Currently, it has been<br />
proposed that lapatinib can resensitize trastuzumab–mediated antibody-dependent<br />
cellular cytotoxicity (ADCC). Recent clinical data suggest <strong>the</strong> efficacy of T containing<br />
retreatment after progression on lapatinib <strong>the</strong>rapy in patients with HER2-positive<br />
metastatic breast cancer. Here, we present a retrospective review of data from 25<br />
patients who received T containing retreatment after progression on lapatinib <strong>the</strong>rapy.<br />
Methods: We reviewed <strong>the</strong> data of 50 patients with HER2-positive metastatic breast<br />
cancer who received lapatinib <strong>the</strong>rapy in our institution from August 2004 through<br />
March <strong>2012</strong>. Of <strong>the</strong>se, 25 patients received T containing retreatment after<br />
progression on lapatinib <strong>the</strong>rapy. We retrospectively assessed <strong>the</strong> clinical benefit of<br />
this treatment regimen in <strong>the</strong>se patients.<br />
Results: Luminal-HER2 and HER2-enriched subtypes were identified in 13 (52%)<br />
and 12 (48%) of <strong>the</strong>se cases, respectively. The median duration of lapatinib <strong>the</strong>rapy<br />
was 5.9 months (range, 1.8-20.2 months). The median number of preceding<br />
regimens was 3 (range, 2-8) in metastatic setting. Seven patients (31.8%) responded<br />
to T containing retreatment; all 7 patients achieved PR and none achieved CR. There<br />
were no significant differences in subtype, number of preceding regimens and brain<br />
metastases; however, responders achieved higher clinical response from lapatinib<br />
<strong>the</strong>rapy than non-responders (response rate of 84% versus 13%, respectively). The<br />
median time to progression of T containing retreatment was 3.0 months (95% CI,<br />
2.4-3.5 months). Among seven responders to T containing retreatment, one patient<br />
responded to refractory T containing regimen. All patients tolerated T containing<br />
retreatment with no occurrence of Grade 3/4 toxicities.<br />
Conclusion: T containing retreatment could be a favorable treatment regimen which<br />
can achieve clinical response in patients with HER2-positive metastatic breast cancer<br />
who experienced progression on prior trastuzumab and following lapatinib <strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
397 LOW DOSES OF GEMCITABINE (G) WITH CISPLATIN (C)<br />
IN TREATMENT OF METASTATIC BREAST CANCER (MBC)<br />
PROGRESSING AFTER ANTHRACYCLINES, TAXANES,<br />
CAPECITABINE AND OTHER ANTINEOPLASTIC AGENTS<br />
T.Y. Semiglazova 1 , M.L. Gershanovich 1 , D.H. Latipova 1 , L.V. Filatova 1 ,V.<br />
A. Chubenko 1 , V.F. Semiglazov 2 , V.V. Semiglazov 3 , P.V. Krivorotko 2 ,D.<br />
E. Matsko 4 , V.V. Klimenko 3<br />
1 Department of Chemo<strong>the</strong>rapy, N.N.Petrov Research Inst. of Oncology,<br />
St. Petersburg, RUSSIAN FEDERATION, 2 Breast Cancer Department, N.N.<br />
Petrov Research Inst. of Oncology, St. Petersburg, RUSSIAN FEDERATION,<br />
3 Department of Oncology, Pavlov Medical University, St. Petersburg, RUSSIAN<br />
FEDERATION, 4 Department of Pathology, N.N.Petrov Research Inst. of<br />
Oncology, St. Petersburg, RUSSIAN FEDERATION<br />
Background: The highest synergism of G was registered with C, as G suppresses DNA<br />
reparation after its damage from C, which leads to apoptosis of tumor cell. The study of<br />
optimal doses of G and C combination continues for intensive pretreated MBC.<br />
Purpose: Evaluate efficiency and tolerability of <strong>the</strong> low doses of G and C in 131<br />
patients with MBC progressing after anthracyclines, taxanes, capecitabine and o<strong>the</strong>r<br />
antineoplastic agents.<br />
Methods: G 600-750 mg/m 2 and C 30 mg/m 2 were administered on days 1 and 8<br />
every 3 weeks in <strong>the</strong> 2 nd line for 28 patients, in <strong>the</strong> 3 rd for 54 patients and in <strong>the</strong> 4 th<br />
for 49 patients. Groups were comparable in age, performance status (PS), ER/PgR<br />
and HER2 expressions, localization and number of metastatic sites prior to<br />
treatment.<br />
Results: Total amount of cycles: 549, median 4.2 per patient (range: 2-12). The<br />
overall response (OR) of all patients was 27%, clinical benefit (OR + stable disease) –<br />
71.7%, with median time to progression (TTP) 4.8 months (95% CI 3.9-5.7 months)<br />
and median overall survival (OS) 14.6 months (95% CI 12.1-17.1 months). The OR<br />
in <strong>the</strong> 2 nd line was observed in 39.3%, in <strong>the</strong> 3 rd – 27.8% and in <strong>the</strong> 4 th – 18.4% (р <<br />
0.05), clinical benefit – in 85.7, 59.3 and 77.6% (р > 0.05) respectively. Pain intensity<br />
reduction and improvement of PS were noted in patients in spite of <strong>the</strong> lines. Linear<br />
discriminant and regression analyses showed that OR, TTP and OS didn’t depend on<br />
<strong>the</strong> ER/PgR and HER2 expressions, but ECOG 2-3, pain syndrome, metastases in <strong>the</strong><br />
lymph nodes and liver were <strong>the</strong> factors of poor prognosis. The treatment-related<br />
adverse events were neutropenia, anemia, thrombocytopenia, alopecia, nausea,<br />
vomiting, peripheral neuropathy and fatigue. Toxicities with grade 3-4 intensity were<br />
neutropenia (31.6% of patients), vomiting (0.8%), anemia (2.3%), thrombocytopenia<br />
(3.1%). No febrile neutropenia and deaths related to <strong>the</strong> study treatment occurred.<br />
Conclusions: The low doses of G with C are effective and tolerable in treatment of<br />
MBC progressing after antracycline, taxanes, capecitabine, o<strong>the</strong>r antineoplastic agents not<br />
only in <strong>the</strong> 2 nd and 3 rd ,butalsoin<strong>the</strong>4 th lines and are suitable for outpatient <strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
398 LONG TERM USE OF CAPECITABINE IN PATIENTS WITH<br />
LOCALLY RECURRENT OR METASTATIC BREAST CANCER<br />
D.H. Josephs 1 , R. Mir 2 , T. Siow 1 , L.E. Dumas 1 , V. Michalarea 1 , E. Sawyer 2 ,J.<br />
L. Mansi 1<br />
1 Medical Oncology Offices, 4th Floor Bermondsey Wing, Guys Hospital, Guys<br />
and St Thomas’s NHS Trust, London, UNITED KINGDOM, 2 Clinical Oncology,<br />
Guy’s and St Thomas’ NHS Trust, London, UNITED KINGDOM<br />
Background: Capecitabine mono<strong>the</strong>rapy is considered standard treatment in<br />
anthracycline- and taxane-pretreated locally recurrent or metastatic breast cancer and<br />
has proven efficacy in this setting. Here we report <strong>the</strong> findings of a retrospective<br />
study to evaluate <strong>the</strong> impact of continuing capecitabine treatment beyond <strong>the</strong><br />
standard 6 cycles until disease progression, on efficacy and outcomes in patients with<br />
locally recurrent or metastatic breast cancer. In addition we sought to consolidate <strong>the</strong><br />
information known about capecitabine dose modification and efficacy outcomes in<br />
this patient population.<br />
Patients and methods: Clinical databases in two institutions were used to identify all<br />
patients with locally advanced or metastatic breast cancer treated with capecitabine<br />
over <strong>the</strong> period July 2006 – July 2011. Baseline characteristics, progression-free (PFS)<br />
and overall survival (OS) were recorded.<br />
Results: In total, 150 patients met <strong>the</strong> inclusion criteria. Of <strong>the</strong>se patients 67 (45%)<br />
received less than 6 cycles, 17 (11%) received 6 cycles only and 66 (44%) received<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds393 | ix139
more than 6 cycles of capecitabine. 65 (43%) patients commenced treatment at a<br />
dose less than 1250mg/m2 twice daily and 60 patients (40%) received a dose<br />
reduction during treatment. Median overall survival was longer in those patients who<br />
received more than 6 cycles of capecitabine treatment (20.9 months) compared to<br />
those who stopped at 6 cycles by clinical decision (16.3 months) although this did<br />
not reach significance (P = 0.088). PFS and OS were similar among patients who<br />
received lower vs. full-dose capecitabine (PFS P = 0.32, OS P = 0.71).<br />
Conclusions: In this retrospective analysis, patients receiving more than 6 cycles of<br />
treatment had a better OS than those who stopped at 6 cycles (by clinical decision).<br />
Continuing capecitabine mono<strong>the</strong>rapy beyond <strong>the</strong> standard 6 cycles if well tolerated,<br />
should be considered in patients with locally recurrent or metastatic breast cancer as<br />
this may prolong PFS. In addition, <strong>the</strong>se data support <strong>the</strong> practice of dose-reducing<br />
capecitabine, including <strong>the</strong> possibility of starting at a lower dose (
Annals of Oncology<br />
Table: 404<br />
Patient Sex Age Primary tumor Histology Previous treatment Survival (months)<br />
A F 41 breast IDC, HR- CT, S, RT, sT 1,6 +<br />
B F 44 breast IDC, HR+ CT, RT, HT, S, sT 23,7<br />
C F 31 breast IDC, HR+ S, RT, HT, sT 2,4<br />
D M 58 stomach ADC CT, S 1<br />
lymph-nodes (greater than 8). Discrete variables significantly associated with MC<br />
were: high tumor grade (p = 0,001), presence of vascular invasion (p = 0,038), greater<br />
tumor staging (pT3, pT4 p < 0,001) and axillar staging (pN3 p = 0,002), hormonal<br />
receptor negativity (p < 0,001) and Her-2 overexpression (p = 0,001). Multivariate<br />
analysis showed that only <strong>the</strong> presence of o<strong>the</strong>r distant metastases (p < 0,005) was<br />
significantly associated with high risk of develop MC with an odds ratio of 9.8.<br />
Conclusions: We identified breast cancer patients at high risk to develop MC. These<br />
patients may benefit from an early diagnosis of MC to obtain better results with<br />
current treatments and to improve quality of life.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
403 QUALITY OF LIFE AND SYMPTOMS IN BREAST CANCER<br />
PATIENTS UNDERGOING CONVENTIONAL CHEMOTHERAPY<br />
T.P. Nikitina 1 , K.A. Kurbatova 2 , I.V. Rykov 3 , N.A. Polyakova 4 , L.V. Kindyanova 5 ,<br />
A.M. Yermachenkova 5 , D.A. Fedorenko 6 , T.I. Ionova 7<br />
1 Oncology and Hematology Department, Multinational Center for Quality of Life<br />
Research, St-Petersburg, RUSSIAN FEDERATION, 2 Dpartment of Biostatistics,<br />
1Multinational Center for Quality of Life Research, St-Petersburg, RUSSIAN<br />
FEDERATION, 3 Department of Oncology, The L.G. Sokolov Memorial Hospital<br />
№122, St-Petersburg, RUSSIAN FEDERATION, 4 Department of Chemo<strong>the</strong>rapy,<br />
Regional Oncological Center, Ivanovo, RUSSIAN FEDERATION, 5 Department of<br />
Chemo<strong>the</strong>rapy, Regional Clinical Oncological Center, Khabarovsk, RUSSIAN<br />
FEDERATION, 6 Hematology and Cellular Therapy, National Pirogov Medical<br />
Surgical Center, Moscow, RUSSIAN FEDERATION, 7 Department of Oncology/<br />
hematology, Multinational Center for Quality of Life, St. Petersburg, RUSSIAN<br />
FEDERATION<br />
Quality of life (QoL) and symptom assessment are of increasing importance to<br />
evaluate treatment outcomes in breast cancer patients. We aimed to study feasibility<br />
of using standardized QoL and symptom assessment tools to determine benefits and<br />
risks of conventional chemo<strong>the</strong>rapy (CT) in breast cancer patients. One hundred and<br />
seven breast cancer patients (Stages I-IV) were included in <strong>the</strong> study (58% patients<br />
with metastatic breast cancer). Mean age/SD – 53/10 y.o. All <strong>the</strong> patients underwent<br />
taxane based CT with <strong>the</strong> previous treatment including CT (89%), surgery (69%),<br />
radio<strong>the</strong>rapy (39%), hormone <strong>the</strong>rapy (24%) or bio<strong>the</strong>rapy (9%). QoL was assessed<br />
using generic QoL questionnaires, <strong>the</strong> SF-36 and <strong>the</strong> EQ-5D; symptoms – by using<br />
Comprehensive Symptom Profile in Patients with Breast Cancer (CSP-Br). The<br />
CSP-Br is a self-reported tool which allows to assess <strong>the</strong> severity of 57 symptoms<br />
specific for breast cancer patients. Distribution of patients according to <strong>the</strong> grades of<br />
QoL impairment was analyzed using <strong>the</strong> SF-36. For comparison of means at different<br />
time-points Wilcoxon’s matched pairs test was used. The patients reported <strong>the</strong><br />
usefulness of PROs tools to facilitate patient-physician communication. The following<br />
distribution of patients receiving taxane based CT according to <strong>the</strong> grades of QoL<br />
impairment was observed: 23% of patients had no QoL impairment; 15% patients -<br />
mild QoL impairment, 33% - moderate or severe QoL impairment, and 19% - critical<br />
QoL impairment. Health index measured by <strong>the</strong> EQ-5D decreased during <strong>the</strong> CT<br />
cycle and improved by <strong>the</strong> next CT cycle. The most prevalent and disturbing<br />
symptoms were <strong>the</strong> following: hair loss (>90%), fatigue, feeling of constant tiredness<br />
(>80%) and psychological symptoms (>70%). Definite deterioration of symptom<br />
profile and severity was observed in a week after CT cycle completion: <strong>the</strong> severity of<br />
21 out of 47 symptoms increased significantly (p < 0.05). The usefulness of<br />
patient-reported outcome measures to distinguish patients in terms of QoL<br />
impairment as well as in terms of severity and number of symptoms experienced was<br />
demonstrated. The SF-36, EQ-5D and CSP-Br are robust and feasible tools to<br />
measure benefits and risks of breast cancer treatment from patient perspective.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
404 INTRATHECAL TRASTUZUMAB IN THE TREATMENT OF<br />
LEPTOMENINGEAL METASTASES FROM HER2-POSITIVE<br />
CANCER<br />
D. Machado 1 , M. Oliveira 2 , S. Esteves 3 , T. Marques 1 , A. Clara 1 , M. Brito 1 ,<br />
J. Freire 1 , J. Bravo Marques 4 , A. Moreira 1<br />
1 Medical Oncology, Portuguese Institute of Oncology, Lisbon, PORTUGAL,<br />
2 Breast Cancer Group, Vall d’Hebron Institut d’Oncologia, Barcelona, SPAIN,<br />
3 Clinical Investigation Unit, Portuguese Institute of Oncology, Lisbon, PORTUGAL,<br />
4 Neuro-oncology, Portuguese Oncology Insitute, Lisbon, PORTUGAL<br />
Introduction: Up to 8% of all cancer patients develop leptomeningeal metastases<br />
(LM). Median overall survival after diagnosis is approximately 1 month.<br />
Trastuzumab, a monoclonal antibody against <strong>the</strong> HER2 receptor, is used in <strong>the</strong><br />
treatment of HER2 positive cancer patients. It is still not clear if systemic<br />
trastuzumab can penetrate <strong>the</strong> intact blood brain barrier, because of its high<br />
molecular weight. Given intra<strong>the</strong>cally, trastuzumab could achieve higher<br />
concentrations in <strong>the</strong> cerebrospinal fluid (CSF).<br />
Purpose: Determine safety, response and overall survival of patients treated with<br />
intra<strong>the</strong>cal (IT) trastuzumab, in a single centre population.<br />
Patients and methods: Clinical data of patients treated with IT trastuzumab have<br />
been reviewed. Survival was defined as time since beginning of IT trastuzumab until<br />
death or last follow-up.<br />
Results: A total of 4 patients have been treated with IT trastuzumab (Table 1).<br />
Table 1. Patient characteristics, previous treatment and survival.. All HER2 positive,<br />
IDC invasive ductal carcinoma, ADC adenocarcinoma, S surgery, RT radio<strong>the</strong>rapy,<br />
HT hormonal treatment, sT systemic trastuzumab. LM were confirmed by lumbar<br />
puncture in patients B, C and D. In patient A LM were diagnosed by MRI (CSF<br />
cytology persistently negative). Patients A, B, and C received weekly IT<br />
trastuzumab 25 mg. Patient D received weekly IT (trastuzumab 25 mg +<br />
methotrexate 12 mg). Toxicity related to IT trastuzumab was not observed. The<br />
CSF cytology remained positive in patient D and became negative after 1 and 3<br />
weeks for patient C and B, respectively. Patient A was still receiving treatment at<br />
last follow-up.<br />
Conclusions: In our group of patients, IT trastuzumab was well tolerated and had<br />
encouraging results. Ours is a small and somewhat heterogeneous population and we<br />
can not extrapolate on <strong>the</strong> efficacy of trastuzumab in this setting, but a study with a<br />
larger number of patients is warranted and may help identify patients appropriate for<br />
this <strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
405TiP A PHASE II STUDY OF ALBUMIN-BOUND PACLITAXEL<br />
COMBINED WITH EPIRUBICIN AND CYCLOPHOSPHAMIDE<br />
AS NEO-ADJUVANT THERAPY IN BREAST CANCER WOMEN<br />
J. Zhang, S. Zhang, L. Liu, B.X. Zhang<br />
The Third Surgical Department of Breast Cancer, Tianjin Cancer Hospital, Tianjin,<br />
CHINA<br />
Purpose: To observe whe<strong>the</strong>r <strong>the</strong> efficacy and safety of Albumin-Bound Paclitaxel<br />
has advantage over Cremophor-Formulated Paclitaxel as neo-adjuvant <strong>the</strong>rapy in<br />
breast cancer<br />
Patients and methods: Twenty-six breast cancer patients were enrolled into<br />
Albumin-Bound Paclitaxel group. Albumin-Bound Paclitaxel 260mg/m 2 ,<br />
Epirubicin 60 mg/m 2 , Cyclophosphamide 500mg/m 2 was administrated as<br />
neo-adjuvant <strong>the</strong>rapy. Twenty-six patients who were treated with<br />
Cremophor-Formulated Paclitaxel 175mg/m 2 , Epirubicin 60 mg/m 2 ,<br />
Cyclophosphamide 500mg/m 2 as <strong>the</strong> control group. The objective observation<br />
include <strong>the</strong> pathologic complete response rates, clinical response rates, safety and<br />
toxicity. The PI3K, pAKT, mTOR, BAD protein were examined before and after<br />
chemo<strong>the</strong>rapy in two groups.<br />
Results: 34.6% patients (9/26) in Albumin-Bound Paclitaxel group achieved a<br />
clinical complete response, this rate was 11.5% higher than control group which<br />
rate was 23.1%(6/26). 15.4% patients (4/26) in Albumin-Bound Paclitaxel group<br />
achieved a pathologic complete response, this rate was 11.6% higher than control<br />
group which rate was 3.8%(1/26). None patients (0/26) in Albumin-Bound<br />
Paclitaxel group occurs neutropenia but 15.4% patients (4/26) in control group<br />
occurs neutropenia during chemo<strong>the</strong>rapy. All patients have normal left<br />
ventricular ejection fraction range (LVEF > 50%) before and after <strong>the</strong>rapy. The<br />
positive rate of PI3K, mTOR, pAKT expression decreased 45.6%,42.5%,41.1%<br />
respectively in Albumin-Bound Paclitaxel group after chemo<strong>the</strong>rapy and <strong>the</strong><br />
control group decreased 13.2%,14.1%,10.1%. The positive rate of BAD expression<br />
increased 21.6% in Albumin-Bound Paclitaxel group after chemo<strong>the</strong>rapy and <strong>the</strong><br />
control group only increased 6.2%.<br />
Conclusion: Albumin-Bound Paclitaxel has advantage in clinical response rate<br />
over Cremophor-Formulated Paclitaxel in breast cancer. Albumin-Bound<br />
Paclitaxel has no more additional adverse events than Cremophor-Formulated<br />
Paclitaxel. Albumin-Bound Paclitaxel has lower incidence of neutropenia than<br />
Cremophor-Formulated Paclitaxel. Albumin-Bound Paclitaxel decrease <strong>the</strong><br />
expression of PI3K, pAKT, mTOR protein and increase <strong>the</strong> expression of BAD<br />
protein more significantly than Cremophor-Formulated Paclitaxel after<br />
chemo<strong>the</strong>rapy<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds393 | ix141
406TiP PHASE II TRIAL OF PRIMARY SYSTEMIC THERAPY (PST)<br />
WITH DOCETAXEL (D) FOLLOWED BY HIGH-DOSE<br />
EPIRUBICIN IN COMBINATION WITH CYCLOPHOSPHAMIDE<br />
(EC) PLUS CONCURRENT TRASTUZUMAB (T) FOR STAGE<br />
II-III HER-2 POSITIVE BREAST CANCER PATIENTS (PTS)<br />
P. Vici 1 , L. Pizzuti 1 , M. Mottolese 2 , D. Sergi 1 , A. Di Benedetto 2 , C. Botti 3 ,<br />
L. Perracchio 4 , E. Pescarmona 4 , A. Carpino 5 , L. Di Lauro 1<br />
1 Division of Medical Oncology B, Regina Elena National Cancer Institute, Rome,<br />
ITALY, 2 Molecular Medicine Department, Regina Elena National Cancer Institute,<br />
Rome, ITALY, 3 A Surgery Division, Regina Elena National Cancer Institute, Rome,<br />
ITALY, 4 Pathology Department, Regina Elena National Cancer Institute, Rome,<br />
ITALY, 5 Cardiology Division, Regina Elena National Cancer Institute, Rome, ITALY<br />
Background: PST with taxanes, anthracycline-containing regimens and T showed a<br />
high percentage of pathologic complete response (pCR); T administered concurrently<br />
with chemo<strong>the</strong>rapy is more effective, but <strong>the</strong> combination with anthracyclines may be at<br />
risk of cardiotoxicity. The present study evaluates efficacy and toxicity of T administered<br />
concurrently with a sequential regimen of D followed by EC in neoadjuvant setting.<br />
Materials and methods: This phase II single stage trial is enrolling pts with cT2-T4,<br />
N0-2, M0, Her-2 positive (IHC 3+ or 2+ amplified) breast cancer. A core biopsy is<br />
required prior treatment start to evaluate hormonal receptors, Ki67, topoisomerase II,<br />
Her-2, with re-evaluation of <strong>the</strong>se parameters, whenever possible, at definite surgery.<br />
LVEF is evaluated before and during treatment. Blood samples are collected at<br />
baseline for evaluation of 9 genetic polymorphisms related to higher risk of<br />
developing cardiac toxicity. We are quantitatively evaluating gene copy number by<br />
multiple ligand probe amplification (MLPA), PTEN, p-Akt, p-MAPK, and PIK3CA<br />
mutations. Pts receive 4 cycles of D (100mg/m2) plus T (loading dose 8mg/kg<br />
followed by 6mg/kg), followed by 4 cycles of EC (120/600mg/m2) plus T, every 3<br />
weeks. Definite surgery is planned at <strong>the</strong> end of PST, and standard radio<strong>the</strong>rapy and<br />
hormonal adjuvant treatment in case of positive hormonal receptors are given;<br />
adjuvant T is given for 6 months. The primary objective of <strong>the</strong> trial is pCR (absence<br />
of invasive tumor cells in <strong>the</strong> breast and axilla); secondary objectives are cardiac<br />
safety, toxicity, disease-free survival. The planned sample size is 42 pts.<br />
Results: To date, 29 pts have been enrolled; median age is 45 years, pre/<br />
postmenopausal 22/7, ER and/or PgR positive in 16 pts. 27 pts are evaluable for<br />
pathological response: we observed 20 pCR (74%, 95%C.I, 57.5-90.6). Grade 3-4<br />
neutropenia was <strong>the</strong> most frequent toxicity, encountered in 75% of <strong>the</strong> pts, o<strong>the</strong>r<br />
toxicities were mild to moderate. No clinical cardiotoxicity was observed.<br />
Conclusions: At preliminary analysis, PST with sequential administration of D<br />
followed by EC, given concurrently with T, appears to be very active and safe in stage<br />
II-III breast cancer pts.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
407TiP TREATMENT OF PATIENTS WITH HORMONE RECEPTOR<br />
(HR)-POSITIVE AND HER2-POSITIVE LOCALLY ADVANCED<br />
OR METASTATIC BC WITH A COMBINATION OF<br />
PERTUZUMAB AND TRASTUZUMAB PLUS AN AROMATASE<br />
INHIBITOR (AI): AN OPEN-LABEL RANDOMISED PHASE II<br />
STUDY (PERTAIN)<br />
G. Arpino 1 , C. Poole 2 , J. Ferrero 3 , J.R. De La Haba 4 , L. Mitchell 5 , C. Pelizon 5 ,M.<br />
F. Rimawi 6<br />
1 Università Degli Studi Di Napoli Federico II, Dipartimento di Endocrinologia ed<br />
Oncologia Molecolare e Clinica, Naples, ITALY, 2 Arden Cancer Research Centre,<br />
University Hospitals Coventry and Warwickshire, Coventry, UNITED KINGDOM,<br />
3 Departement d’Oncologie Medicale, Centre Antoine Lacassagne, Nice,<br />
FRANCE, 4 Medical Oncology Department, Reina Sofía Hospital, Córdoba,<br />
SPAIN, 5 F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, 6 Lester & Sue Smith<br />
Breast Center, Baylor College of Medicine, Houston, TX, UNITED STATES OF<br />
AMERICA<br />
Background: Development of resistance to endocrine <strong>the</strong>rapy in patients (pts) with<br />
breast cancer (BC) is a major clinical concern. Preclinical studies suggest that<br />
blockade of HR with HER2 inhibition may be key to overcoming resistance and<br />
improving clinical outcomes. The combination of pertuzumab (P) and trastuzumab<br />
(H) with docetaxel significantly improves outcomes by a comprehensive blockade of<br />
HER2 signalling. However, initial results suggest that this benefit may be less<br />
apparent in HR-positive pts. PERTAIN is <strong>the</strong> first study to assess whe<strong>the</strong>r a fuller<br />
blockade of HER signalling with P and H in conjunction with an AI may resensitise<br />
HER2-positive tumours to endocrine <strong>the</strong>rapy and provide an effective first-line<br />
treatment option in pts with HR-positive and HER2-positive advanced BC.<br />
Methods: PERTAIN is a multicentre, open-label, Phase II trial for postmenopausal<br />
women with HER2-positive and HR-positive locally advanced/metastatic BC to assess<br />
<strong>the</strong> efficacy of P plus H with an AI as first-line <strong>the</strong>rapy. Pts will be randomised 1:1 to<br />
Arm 1 (P: 840 mg initial dose, 420 mg q3w iv; H: 8 mg/kg initial dose, 6 mg/kg q3w iv;<br />
AI [anastrozole 1 mg or letrozole 2.5 mg qd po]) or Arm 2 (H + AI at same dose as Arm<br />
1). Induction chemo<strong>the</strong>rapy (CT) (docetaxel or paclitaxel) may be given to pts for up to<br />
18 weeks at <strong>the</strong> investigator’s discretion. Administration of study medications will<br />
continue until disease progression or unacceptable toxicity. Pts must not have been<br />
treated with anti-HER2 agents, except H and/or lapatinib in <strong>the</strong> (neo)adjuvant setting,<br />
Annals of Oncology<br />
and must have no CNS involvement or clinically significant cardiovascular disease. The<br />
primary endpoint is progression free survival (PFS); secondary endpoints include overall<br />
survival, overall response rate, clinical benefit rate, duration of response, time to<br />
response, safety and tolerability, and QoL. The study opened in April <strong>2012</strong> and will<br />
recruit 250 pts. The main analysis for <strong>the</strong> primary endpoint (after 165 PFS events) will<br />
include a treatment group variable and be stratified by whe<strong>the</strong>r pts were chosen to<br />
receive induction CT (Yes/No) and time since adjuvant hormone <strong>the</strong>rapy (
Annals of Oncology<br />
P is distinct from that bound by trastuzumab (H) and <strong>the</strong>ir complementary<br />
mechanisms of action lead to a more comprehensive HER2 blockade when<br />
combined. Data from <strong>the</strong> phase III trial CLEOPATRA showed significantly improved<br />
PFS in pts with HER2-positive 1L MBC given P + H + docetaxel (D). As H was not<br />
widely available in <strong>the</strong> (neo)adjuvant setting prior to CLEOPATRA recruitment, a<br />
relatively low proportion of pts in CLEOPATRA had previously received H. PERUSE<br />
will assess <strong>the</strong> safety and tolerability of P + H + one of a choice of taxanes (T) as 1L<br />
<strong>the</strong>rapy for pts with HER2-positive metastatic or locally advanced BC. Efficacy<br />
endpoints will also be recorded in PERUSE, in a pt population likely to have<br />
experienced wider exposure to prior H <strong>the</strong>rapy.<br />
Methods: PERUSE is a phase IIIb, multicenter, open-label, single-arm study in pts<br />
with HER2-positive BC who have not been treated with systemic non-hormonal<br />
anticancer <strong>the</strong>rapy for MBC. The planned sample size is 1500. Pts will receive, P:<br />
840mg initial dose, 420mg q3w IV; H: 8mg/kg initial dose, 6mg/kg q3w IV, T: D,<br />
paclitaxel or nab-paclitaxel according to local guidelines. A planned protocol<br />
amendment will allow HR-positive pts to receive endocrine <strong>the</strong>rapy in conjunction<br />
with P + H following completion of T in line with clinical practice. Treatment will be<br />
administered until disease progression or unacceptable toxicity. At baseline, pts must<br />
have an LVEF of ≥50%, ECOG PS of 0, 1 or 2 and must not have received prior<br />
anti-HER2 agents for MBC. Prior H and/or lapatinib in <strong>the</strong> (neo)adjuvant setting is<br />
allowed, provided <strong>the</strong>re was no disease progression on-treatment. A disease-free<br />
interval of ≥6 months is required. The primary endpoint is safety and tolerability.<br />
Secondary endpoints include PFS, OS, ORR, CBR, duration of response, time to<br />
response and QoL. The final analysis will be carried out when pts have been followed<br />
up for ≥12 months. Interim analyses are planned after enrollment of ∼350, 700 and<br />
1000 pts. Regular interim safety assessments by a DSMB will take place.<br />
Disclosure: D. Miles: I have an interest in relation with one organisation that could<br />
be perceived as a possible conflict of interest in <strong>the</strong> context of <strong>the</strong> subject of this<br />
abstract. I have served on Advisory Board Meetings for Roche/Genentech. F. Puglisi:<br />
I have an interest in relation with one organisation that could be perceived as a<br />
possible conflict of interest in <strong>the</strong> context of <strong>the</strong> subject of this abstract. I participate<br />
in Advisory Board Meetings for Roche. A. Schneeweiss: I have an interest in relation<br />
with one organisation that could be perceived as a possible conflict of interest in <strong>the</strong><br />
context of <strong>the</strong> subject of this abstract. I serve on Roche Advisory Boards and am in<br />
volved with corporate-sponsored research with Roche. L. Mitchell: I am currently an<br />
employee of F. Hoffmann-La Roche. A. Dünne: I have an interest in relation with<br />
one organisation that could be perceived as a possible conflict of interest in <strong>the</strong><br />
context of <strong>the</strong> subject of this abstract. I am an employee of hoffmann-La Roche.<br />
T. Bachelot: I have an interest in relation with one organisation that could be<br />
perceived as a possible conflict of interest in <strong>the</strong> context of <strong>the</strong> subject of this<br />
abstract. I am involved with Roche sponsoredresearch and Roche advisory Board<br />
Meetings. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds393 | ix143
abstracts<br />
CNS tumors<br />
410O CONDITIONAL PROBABILITY OF SURVIVAL IN PATIENTS<br />
WITH GLIOBLASTOMA MULTIFORME IN THE<br />
TEMOZOLOMIDE TREATMENT ERA<br />
M. McNamara 1 , Z. Lwin 2 , H. Jiang 3 , C. Chung 4 , B. Millar 4 , N. Laperriere 4 ,<br />
W. Mason 1<br />
1 Medical Oncology, Princess Margaret Hospital, Toronto, CANADA, 2 Medical<br />
Oncology, Mater Adult Hospital, Brisbane, QLD, AUSTRALIA, 3 Biostatistics,<br />
Princess Margaret Hospital, Toronto, ON, CANADA, 4 Radiation Oncology,<br />
Princess Margaret Hospital, Toronto, ON, CANADA<br />
Introduction: Glioblastoma multiforme (GBM) is <strong>the</strong> most aggressive of gliomas.<br />
With standard treatment consisting of surgery followed by radio<strong>the</strong>rapy (RT) with<br />
concurrent and adjuvant temozolomide (TMZ), median survival is approximately<br />
14.6 mo. These estimates are not as informative to patients (pts) who have survived<br />
for some time after diagnosis. Aim: To retrospectively review outcomes and report<br />
conditional probability estimates in <strong>the</strong> TMZ treatment era of pts who presented to a<br />
multidisciplinary team at <strong>the</strong> tertiary referral center PrincessMargaretHospital,<br />
Toronto, with a diagnosis of GBM.<br />
Methods: 892 pts were followed from 01/04 – 08/10. Complete demographics,<br />
performance status (PS), GBM localization, extent of surgery, percent receiving RT<br />
+/− TMZ, overall survival (OS) and conditional probability were analyzed.<br />
Results: The cohort includes 548 (61%) males with median age 62 (5-93). Baseline<br />
PS was 0-1 in 600 (67%), 2-3 in 251 (28%) pts. 205 (23%) had frontal lobe tumors.<br />
Extent of surgery; 26% biopsy, 68% partial/subtotal resection, 6% unknown. 516<br />
(58%) received concurrent RT/TMZ +/− adjuvant TMZ. Survival was similar for<br />
those with frontal lobe tumors vs o<strong>the</strong>r locations (10.2 vs 9.7 mo, Logrank test p =<br />
0.28). OS for biopsy pts was 4.5 mo (3.5 – 6.2), and partial/subtotal resection pts;<br />
11.6 mo (10.3 – 12.5) (p < 0.001). OS for pts receiving standard RT/TMZ +/− TMZ<br />
was 14.2 mo (13.3 – 15.1). Age and PS were significant prognostic factors for OS<br />
(p < 0.001). The OS and conditional probability of survival for entire cohort of<br />
892 pts is detailed in Table. 43 (5%) are still alive, 727 (81%) deceased, status<br />
unknown in 122 (14%).<br />
Time Overall Survival (%) 95% CI<br />
Conditional<br />
Probability<br />
of Survival (%) 95% CI<br />
1 Year 43.1 39.8 – 46.4 41.4 35.9 – 47.0<br />
2 Year 17.9 15.2 – 20.7 57.4 47.5 – 67.4<br />
3 Year 10.3 8.0 – 12.8 80.6 68.4 – 92.8<br />
4 Year 8.3 6.1 – 10.9 85.6 71.1 – 100<br />
5 Year 7.1 5.0 – 9.7 81.5 60.9 – 100<br />
Conclusion: The conditional probability of surviving an additional yr after survival<br />
to 2 yrs post diagnosis exceeds <strong>the</strong> 1 yr survival rate, indicating that <strong>the</strong> future<br />
prognosis of a pt who has survived for 2 yrs may be as good as those recently<br />
diagnosed. Conditional probabilities of survival in this general disease population in<br />
<strong>the</strong> era of TMZ <strong>the</strong>rapy may provide more accurate life expectancy predictions for<br />
survivors of GBM.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
411O A PILOT STUDY CORRELATING IDH-1/2 GENE STATUS WITH<br />
2-HYDROXYGLUTARATE (2HG) CONCENTRATION IN PLASMA<br />
AND URINE FROM PATIENTS (PTS) WITH GLIOMA<br />
G. Lombardi 1 , G. Corona 2 , P. Farina 1 , F. Zustovich 1 , R. Bertorelle 3 , P. Fiduccia 1 ,<br />
A. Della Puppa 4 , M.P. Gardiman 5 , A. Salvalaggio 1 , G. Toffoli 2 , V. Zagonel 1<br />
1 Medical Oncology 1, Venetian Oncology Institute – IRCCS, Padua, ITALY,<br />
2 Molecular Oncology and Translational Medicine, Experimental and Clinical<br />
Pharmacology Unit, Aviano, ITALY, 3 Molecular Immunology and Oncology,<br />
Venetian Oncology Institute – IRCCS, Padua, ITALY, 4 Neurosurgery Department,<br />
Azienda Ospedaliera di Padova, Padua, ITALY, 5 Pathology Department, Azienda<br />
Ospedaliera di Padova, Padua, ITALY<br />
Background: IDH-1/2 mutations are a prognostic markers in gliomas. These<br />
mutations results in <strong>the</strong> production of 2HG. We investigated whe<strong>the</strong>r 2HG produced<br />
Annals of Oncology 23 (Supplement 9): ix144–ix151, <strong>2012</strong><br />
doi:10.1093/annonc/mds394<br />
by IDH-1/2 mutant gliomas accumulates in patient’s plasma and urine and whe<strong>the</strong>r<br />
this accumulation can be used to assess IDH-1/2 mutation status.<br />
Methods: we prospectively studied PTS with intracranial gliomas and measurable<br />
disease on brain-MRI. All PTS had a partial surgical resection or a recurrent disease.<br />
The resected tissues were analyzed for IDH-1/2 mutational status; subsequently, in<br />
absence of chemo<strong>the</strong>rapy and after 3 weeks from a prior surgery, a plasma and an<br />
overnight-urine samples collection were taken from consecutive PTS. 2HG<br />
concentrations were determinate by liquid chromatography tandem mass<br />
spectrometry. The statistical significance of <strong>the</strong> difference in <strong>the</strong> level of 2HG<br />
between <strong>the</strong> PTS with IDH-1/2 mutated and control group were evaluated by non<br />
parametric Mann- Whitney test.<br />
Results: we analyzed 13 PTS with IDH-1 mutated and 13 PTS with IDH-1/2<br />
wild-type; 2 PTS with low-grade glioma and 24 PTS with high-grade glioma; 10<br />
females and 16 males. In all PTS we analyzed <strong>the</strong> mean 2HG concentration in<br />
plasma (P_2HG) and urine samples normalized by creatinine concentration<br />
(U_2HG). The results are shown in Table 1. We found significant differences in<br />
mean U_2HG, and in mean P_2HG/U_2HG in patients with or without IDH<br />
mutated. No statistically significant associations of tumor volume and U_2HG, of<br />
tumor volume and P_2HG were found in all PTS and in PTS with IDH1 mutated.<br />
Conclusions: U_2HG and P_2HG/U_2HG might be used as markers to differentiate<br />
between gliomas with and without IDH mutated. No associations were found<br />
between tumor volume and U_2HG and P_2HG, indicating that 2HG might not be<br />
utilized as marker to monitor tumor growth. However, a larger number of samples<br />
need to be analyzed to draw final conclusions.<br />
IDH wt IDH mutated p<br />
U_2HG* 7.49 ± 3.87 5.00 ± 3.08 0.03<br />
P_2HG (ng/mL) 86.42 ± 38.74 112.74 ± 73.19 0.26<br />
P_2HG/U_2HG* 13.96 ± 7.54 23.83 ± 9.00 0.006<br />
*Concentration of 2HG (µg/mL) normalized by creatinine concentration (mg/mL)<br />
Disclosure: All authors have declared no conflicts of interest.<br />
412O TYROSINE KINASE INHIBITORS WITHOUT RADIATION<br />
THERAPY FOR BRAIN METASTASES FROM EGFR-MUTANT<br />
ADENOCARCINOMA OF LUNG<br />
T. Iuchi 1 , M. Shingyoji 2 , T. Sakaida 1 , S. Yokoi 3 , M. Itakura 2 , K. Kawasaki 1 ,<br />
Y. Hasegawa 1 , H. Kageyama 3 , T. Iizasa 2<br />
1 Neurological Surgery, Chiba Cancer Center, Chiba, JAPAN, 2 Thoracic Disease,<br />
Chiba Cancer Center, Chiba, JAPAN, 3 Cancer Diagnosis, Chiba Cancer Center<br />
Research Institute, Chiba, JAPAN<br />
Backgrounds: Whole-brain radiation <strong>the</strong>rapy (WBRT) and/or stereotactic<br />
radiosurgery (SRS) are standard treatments for brain metastases (BMs). However,<br />
patients (pts) treated by radiation <strong>the</strong>rapy (RT) have a risk of decline in learning and<br />
memory functions. The aim of this study is to clarify <strong>the</strong> efficacy and safety of<br />
chemo<strong>the</strong>rapy without RT for BMs.<br />
Materials and methods: BMs from lung adenocarcinomas (Ads) with<br />
EGFR-mutation were enrolled. As tyrosine kinase inhibitors (TKIs), gefitinib was<br />
used at first, and erlotinib was administrated at tumor progression. Erlotinib was also<br />
selected for pts in whom intracranial lesions appeared after gefitinib. The response to<br />
TKIs was evaluated on MRI. WBRT or SRS was performed only at tumor<br />
progression after TKIs. The primary endpoint was overall survival, and <strong>the</strong> secondary<br />
endpoints were maximum response to TKIs, progression-free survival and time to<br />
RT after diagnosis of BMs.<br />
Results: In this study, 37 pts were enrolled. The types of EGFR-mutations were as<br />
follows: Ex19 deletion (Ex19del) in 20, Ex21L858R in 14, and o<strong>the</strong>r types of<br />
mutations in 3 cases. The maximum response was PD in one, SD in 3, PR in 22 and<br />
CR in 9 pts (response rate: 83.8%). The progression-free and overall survival times<br />
were 8.9 and 28.3 months. The median time to RT (WBRT in 14 and SRS in 3 cases)<br />
from diagnosis of BMs was 14.3 months. During <strong>the</strong> follow-up period, 9 deaths were<br />
observed but none of <strong>the</strong>m were owing to <strong>the</strong> intracranial lesions. Among <strong>the</strong>se 9<br />
pts, no RT was required in 2. Pneumonitis was observed in one case after gefitinib,<br />
but no o<strong>the</strong>r severe adverse event was observed. When we divided <strong>the</strong> pts owing to<br />
<strong>the</strong> types of mutations (Ex19del vs. o<strong>the</strong>rs), response to TKI was superior in Ex19<br />
deleted cases (p = 0.031), and <strong>the</strong> progression-free survival time was significantly<br />
longer in cases with Ex19del (14.5 months) in compared with those with o<strong>the</strong>r types<br />
of mutations (8.0 months, p = 0.002). In Ex19 deleted cases, TKIs could delay RT for<br />
18.3 months.<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
Annals of Oncology<br />
Conclusions: TKIs showed favorable effect on control of EGFR-mutant BMs, and it<br />
delayed RT for more than one year. Ex19del was <strong>the</strong> significant predictor of response<br />
to TKIs in BMs. TKIs without RT was safe and acceptable treatment for BMs from<br />
EGFR-mutant lung Ads.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
413PD HYPOFRACTIONATED RADIOTHERAPY FOR PEDIATRIC<br />
DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): A<br />
PROSPECTIVE CONTROLLED RANDOMIZED TRIAL<br />
S.A. Ahmed 1 , E. Eldebaway 2 , N. Elkhateeb 2 , M.S. Zaghloul 2<br />
1 Radio<strong>the</strong>rapy Department, Children’s Cancer Hospital Egypt, Cairo, EGYPT,<br />
2 Radio<strong>the</strong>rapy Department, Children’s Cancer Hospital, Cairo, EGYPT<br />
Background: Pediatric Diffuse intrinsic pediatric glioma (DIPG) remained dismal<br />
regardless of <strong>the</strong> new <strong>the</strong>rapeutic and technical attempts.<br />
Purpose: To investigate <strong>the</strong> efficacy and toxicity of hypofractionated radio<strong>the</strong>rapy in<br />
pediatric DIPG compared to conventional radio<strong>the</strong>rapy and to determine <strong>the</strong><br />
prognostic factors for its overall (OS) and progression-free survival (PFS). Patients<br />
and methods: Sixty four children, below <strong>the</strong> age of 18 years, who presented to<br />
Children’s Cancer Hospital, Egypt (CCHE) during <strong>the</strong> period July 2007 and July<br />
2011 were randomized into 2 groups. The hypofractionated group received 39 Gy in<br />
13 fractions in 21/2 weeks and <strong>the</strong> conventional arm receiving 55.8 Gy in 31<br />
fractions in 6 weeks using conformal radio<strong>the</strong>rapy technique. The two arms were not<br />
different in age, gender, performance status and tumor volume.<br />
Results: Thirty two children were randomized in each arm. The median OS for<br />
<strong>the</strong> whole group was 9.5 ± 1.0 months: 7.4 ± 1.0 months for <strong>the</strong> hypofractionated<br />
arm and 9.9 ± 1.0 months for <strong>the</strong> conventional arm. The whole group has median<br />
PFS of 7.3 ± 0.8 months; 7.0 ± 1.4 months for <strong>the</strong> hypofractionated and 7.7 ± 1.1<br />
for <strong>the</strong> conventional arm. On <strong>the</strong> o<strong>the</strong>r hand, <strong>the</strong> 1-year and 2-year OS were 41.4<br />
± 9.2% and 28.4 ± 8,8% in <strong>the</strong> hypofractionated arm and 36.2 ± 8.7% and 32.3 ±<br />
7.8% in <strong>the</strong> conventional arm. None of <strong>the</strong>se differences was statistically<br />
significant. Fur<strong>the</strong>rmore, none of <strong>the</strong> tested factors (age, gender, performance<br />
status, tumor volume, radiation volume or tumor extension) proved to have<br />
statistically significant influence on OS or PFS. All patients showed marked degree<br />
of improvement in symptoms and signs with earlier response in <strong>the</strong><br />
hypofractionated arm. The immediate and delayed side effects were not different<br />
between <strong>the</strong> 2 arms.<br />
Conclusions: Hypofractionated radio<strong>the</strong>rapy had similar overall, progression-free<br />
survival and delayed effect (in <strong>the</strong> long survivors) to conventional fractionation. It<br />
offers less burden on <strong>the</strong> patients, <strong>the</strong>ir families and <strong>the</strong> treating machines and<br />
departments.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
414PD IS BRAIN-ONLY METASTATIC BREAST CANCER A DISTINCT<br />
ENTITY?<br />
A.S. Berghoff 1 , Z. Bago-Horvath 2 , G.G. Steger 3 , C. Zielinski 3 , R. Bartsch 3 ,<br />
M. Preusser 3<br />
1 Institute of Neurology, Medical University of Vienna, Vienna, AUSTRIA, 2 Institute<br />
of Pathology, Medical University of Vienna, Vienna, AUSTRIA, 3 Department of<br />
Medicine I, Clinical Division of Medical Oncology, Medical University of Vienna,<br />
Vienna, AUSTRIA<br />
Background: Up to 40% of metastatic breast cancer patients (pts) are diagnosed with<br />
brain metastases (BM) during <strong>the</strong>ir course of diseases. Some case reports and small<br />
patient series have indicated that breast cancer pts with <strong>the</strong> brain as only metastatic<br />
site (“brain-only”) may have a more favourable prognosis than BM pts with more<br />
widespread metastatic disease.<br />
Methods: We identified all breast cancer pts with BM treated at our institution<br />
between 1990 and 2011. For each patient, full information on follow up and<br />
administered <strong>the</strong>rapies was mandatory for inclusion. Estrogen-receptor (ER),<br />
progesterone-receptor and HER2 status were determined according to standard<br />
protocols. We performed statistical analyses including computation of survival<br />
probabilities.<br />
Results: Overall, 223 female pts (26.0% luminal subtype; 47.5% HER2 subtype;<br />
26.5% triple negative subtype) with BM of metastatic breast cancer were included in<br />
this study. In 60/223 pts (26.9%) <strong>the</strong> brain was <strong>the</strong> first metastatic site. Brain as first<br />
metastatic site was significantly less common in <strong>the</strong> HER2-positive subtype than in<br />
luminal and triple negative subtypes (p = 0.005). 38/223 (17%) of BM pts did not<br />
develop extracranial metastases (ECM) during <strong>the</strong>ir disease course and were classified<br />
as “brain-only” cases. Brain-only metastatic behaviour was not associated with breast<br />
cancer subtype or number of BM. The median OS of <strong>the</strong> brain-only pts was 11<br />
months (range 0-69) and was significantly longer than in pts with BM and ECM<br />
(5 months, range 0 to 104) (p = 0.007). High KPS (p = 0.02), single BM (p < 0.001)<br />
and ER expression (p = 0.014) were associated with favourable OS in <strong>the</strong> brain-only<br />
cohort. 7/38 (18.4%) brain-only pts had long-time survival of more than 3 years after<br />
diagnosis of BM.<br />
Conclusions: Among breast cancer pts with BM, brain-only metastatic behaviour is<br />
not associated with breast cancer subtype, but with favourable survival prognosis.<br />
Exploitation of all multimodal treatment options is warranted in breast cancer pts<br />
with brain-only metastatic disease, as long-term survival is not uncommon in this<br />
patient population.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
415PD THE CAREGIVERS PERSPECTIVE ON THE END-OF-LIFE<br />
PHASE OF GLIOBLASTOMA PATIENTS<br />
B. Flechl 1 , M. Ackerl 1 , C. Sax 1 , S. Oberndorfer 2 , B. Calabek 3 , E. Sizoo 4 ,<br />
J. Reijneveld 4 , R. Crevenna 5 , M. Preusser 1 , C. Marosi 1<br />
1 Internal Medicine, Medical University of Vienna, Vienna, AUSTRIA, 2 Neurology,<br />
Landesklinikum St. Pölten, St. Pölten, AUSTRIA, 3 Neurology, Kaiser Franz Josef<br />
Hospital, Vienna, AUSTRIA, 4 Neurology, VU University Medical Centre,<br />
Amsterdam, NETHERLANDS, 5 Physical Medicine and Rehabilitation, Medical<br />
University of Vienna, Vienna, AUSTRIA<br />
Objective: Glioblastoma multiforme (GBM) still harbours an inevitably fatal<br />
prognosis. The specially course of this disease poses unique challenges in care<br />
provision to <strong>the</strong> relatives. We lack data about <strong>the</strong> caregiverś perspective on <strong>the</strong><br />
end-of-life (EOL) phase of GBM patients to improve counseling and support.<br />
Methods: In this retrospective study we included 52 caregivers of deceased GBM<br />
patients treated in two hospitals in Vienna, Austria. We used a specially developed<br />
questionnaire by <strong>the</strong> Medical University of Amsterdam to explore and document <strong>the</strong><br />
last three months of living of GBM patients.<br />
Results: Most of <strong>the</strong> included caregivers were <strong>the</strong> partners of <strong>the</strong> patients (88%) and<br />
two thirds were female. The most common symptom in GBM patients was fatigue<br />
(87%), followed by reduced consciousness (81%) and aphasia (77%). 22% of <strong>the</strong><br />
patients were bedbound during <strong>the</strong>ir last three months increasing to 80% in <strong>the</strong> last<br />
week of life. 30% of <strong>the</strong> caregivers told that <strong>the</strong>y felt incompletely informed for <strong>the</strong>ir<br />
task and about <strong>the</strong> illness of <strong>the</strong>ir loved one. They stated <strong>the</strong> quality of life (QOL) of<br />
<strong>the</strong> patients with 2.2 and <strong>the</strong>ir own with 2.8 on a scale of 1 to 7 whereas 7 displays<br />
<strong>the</strong> best possible answer. The majority of <strong>the</strong> patients (46%) died in hospitals and<br />
38% at home, which was <strong>the</strong> most often expressed wish for place of death (45%) by<br />
patients. Regarding <strong>the</strong> caregiverś symptoms, sadness (90%), fear (69%), burnout<br />
(60%), less interest in o<strong>the</strong>rs (54%) and irritation (42%) were <strong>the</strong> leading ones and<br />
did not differ significantly in-between <strong>the</strong> places of death.<br />
Conclusion: The caregivers reported that <strong>the</strong>ir quality of life (QOL) was only slightly<br />
better than <strong>the</strong> QOL <strong>the</strong>y attributed to <strong>the</strong> patients. About two thirds of <strong>the</strong><br />
caregivers felt overstrained and stress <strong>the</strong>reby <strong>the</strong> urgent need for support and<br />
dedicated educational programs.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
416PD RE-SURGERY FOR RECURRENT GLIOBLASTOMA:<br />
OUTCOME ANALISYS AND CORRELTION WITH<br />
MGMT STATUS<br />
A. Brandes 1 , E. Franceschi 1 , R. Poggi 1 , R. Degli Esposti 1 , M. Di Battista 1 ,<br />
L. Lombardo 1 , F. Girardi 1 , D. Palleschi 1 , S. Bartolini 1 , M. Ermani 2<br />
1 Medical Oncology, Bellaria-Maggiore Hospital, Azienda USL, Bologna, ITALY,<br />
2 Department of Neurosciences, Statistic and Informatic Unit, Azienda<br />
Ospedale-Università, Padova, ITALY<br />
Introduction: treatment options for glioblastoma at recurrence are various despite<br />
<strong>the</strong> limited efficacy. Surgical resection have been used both for confirmation of<br />
recurrent disease as well as for debulking in order to provide relief of symptoms.<br />
Therefore, <strong>the</strong> role surgical resection for recurrent glioblastoma, has not been<br />
completely clarified.<br />
Methods: A retrospective analysis was made for glioblastoma patients followed<br />
between 01/2005 and 06/2010. Eligibility criteria for <strong>the</strong> study were: age ≥18 years;<br />
PS:0-2; chemo<strong>the</strong>rapy at disease progression after RT/TMZ, availability of data<br />
regarding second progression.<br />
Results: 232 patients with recurrent glioblastoma (mean age: 52 years, range: 18-77<br />
years, MGMT methylated/unmethylated: 62 [37.6%] / 103 [62.4%]) were evaluated.<br />
At progression after RT/TMZ, 102 patients (44%) were treated with re-surgery<br />
followed by chemo<strong>the</strong>rapy, and 130 patients (56%) with chemo<strong>the</strong>rapy alone. Overall<br />
survival from first surgery was 22.4 moths (95% CI: 20–24.7), being 25.8 months<br />
(95%CI:20.6–31) in patients who received second surgery at recurrence, and 18.6<br />
months (95%CI:17–20.1–p = 0.003) in patients treated without surgery. However, in<br />
multivariate analysis no significant effect of re-surgery was found (p = 0.11) being<br />
age (p = 0.001), MGMT methylation (p = 0.002) and PFS6 (p = 0.0001) <strong>the</strong> only<br />
significant prognostic factors. Moreover, median time between first and second<br />
surgery was 13.1 months, being significantly longer in patients with MGMT<br />
methylated than in patients MGMT unmethylated (19.3 vs 13 months, p = 0.001).<br />
Median survival time calculated from first recurrence was 8.6 months (95%<br />
CI:7.4–9.8), and 9.6 months (95%CI:7.5–11.6) and 7.5 months (95%CI:5.7–9.3) in<br />
patients that received second surgery or not, respectively (p = 0.3).<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds394 | ix145
Conclusions: Our data suggested that second surgery may have a limited impact in<br />
<strong>the</strong> clinical course of recurrent glioblastoma patients. MGMT methylation status, as<br />
well o<strong>the</strong>r clinical factors (i.e. age) remain <strong>the</strong> major prognostic determinants of <strong>the</strong><br />
outcome.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
417PD A PHASE 2 TRIAL OF THE MULTITARGETED KINASE<br />
INHIBITOR LENVATINIB (E7080) IN PATIENTS (PTS) WITH<br />
RECURRENT GLIOBLASTOMA (GBM) AND DISEASE<br />
PROGRESSION FOLLOWING PRIOR BEVACIZUMAB<br />
TREATMENT<br />
D.A. Reardon 1 ,E.Pan 2 ,J.Fan 3 , J. Mink 3 , D.P. Barboriak 4 , J.J. Vredenburgh 5 ,<br />
A. Desjardins 5 , K. Peters 5 , J.P. O’Brien 3 , P.Y. Wen 1<br />
1 Neuro-oncology Department, Dana-Farber Cancer Insitute, Boston, MA,<br />
UNITED STATES OF AMERICA, 2 Neuro-oncology, Moffitt Cancer Center, Tampa,<br />
FL, UNITED STATES OF AMERICA, 3 PCU, Eisai Inc., Woodcliff Lake, NJ,<br />
UNITED STATES OF AMERICA, 4 Radiology, Duke University Medical Center,<br />
Durham, NC, UNITED STATES OF AMERICA, 5 Medicine, The Preston Robert<br />
Tisch Brain Tumor Center at Duke, Durham, NC, UNITED STATES OF AMERICA<br />
Background: There is no effective <strong>the</strong>rapy for recurrent GBM pts following<br />
progression on <strong>the</strong> vascular endo<strong>the</strong>lial growth factor (VEGF)-targeting agent<br />
bevacizumab (BV), with historical series reporting progression-free survival at 6<br />
months (PFS-6) of only 2%. Several mechanisms of tumor adaptation following<br />
anti-VEGF <strong>the</strong>rapy have been proposed, including upregulation of alternative<br />
angiogenic cytokines. We <strong>the</strong>refore performed a single-arm phase 2 study to evaluate<br />
lenvatinib (L), an oral tyrosine kinase inhibitor targeting FGFR1-4, PDGFRβ,<br />
VEGFR1-3, RET, and KIT, in pts with recurrent GBM progressing on BV.<br />
Methods: 32 pts with recurrent GBM (≤2 prior progressions) and progression on<br />
BV received L 24 mg once daily in 28-day cycles until PD or unacceptable toxicity.<br />
Dynamic contrast-enhanced MRI was performed before and after 1 day of L on a<br />
subset of pts (n = 16). Response was assessed using Response Assessment in<br />
Neuro-Oncology criteria. Primary endpoint was PFS-6. This cohort has completed<br />
enrollment; 1 pt is still ongoing.<br />
Results: Median age was 52 y, 56% were male, and 19% had a KPS
Annals of Oncology<br />
420PD SYSTEMIC TEMSIROLIMUS ADMINISTRATION REDUCES<br />
TUMOR GROWTH IN AN ORTHOTOPIC MOUSE<br />
MENINGIOMA MODEL<br />
C. Mawrin, D. Pachow, E. Kirches<br />
Neuropathology, University of Magdeburg, Magdeburg, GERMANY<br />
Meningiomas represent <strong>the</strong> most frequent intracranial tumors. While most cases<br />
correspond to WHO grade I, about 5% belong to <strong>the</strong> aggressive atypical subtype, and<br />
1% are anaplastic meningiomas with poor clinical outcome. However, even <strong>the</strong><br />
treatment of benign subtypes might be challenging in recurrent tumors and if<br />
complete resection is impossible. So far, no chemo<strong>the</strong>rapy regime has been proven to<br />
be effective; radio<strong>the</strong>rapy is used to treat aggressive meningiomas. We have<br />
previously established that human meningiomas have activated mTORC-1 signalling,<br />
and that meningioma cells are responsive to mTORC-1 inhibitors. In <strong>the</strong> present<br />
study, we used an orthotopic mouse meningioma model established in our lab to<br />
monitore <strong>the</strong> effect of systemic temsirolimus treatment on meningioma cells grown<br />
in <strong>the</strong> subarachnoidal space. Following orthotopic injection of malignant IOMM-Lee<br />
meningioma cells, mice (n = 8) were treated daily with 20mg/kg temsirolimus<br />
intraperitoneally for nine days, beginning at day 3. Control animals (n = 8) were<br />
treated with diluent only. Tumor growth was monitored by magnetic resonance<br />
imaging (MRI). We observed that at day 9, mice treated with temsirolimus had a<br />
significantly (p < 0.01) reduced tumor volume in MRI measurements compared to<br />
controls. Western blot analysis of tumor tissue removed from <strong>the</strong> skull showed<br />
reduced phosphorylation of mTOR and p70S6K in treated mice, indicating successful<br />
orthotopic inihibition of mTORC-1 activity by intraperitoneal treatment. Thus, our<br />
study demonstrates <strong>the</strong> successful systemic inhibition of malignant meningioma cell<br />
growth by targeting <strong>the</strong> mTORC-1 pathway. These data might serve as a basis for<br />
starting a clinical trial using temsirolimus in patients with recurrent or aggressive<br />
meningiomas.<br />
Disclosure: C. Mawrin: Work was supported in part by Pfizer Inc. and <strong>the</strong> Deutsche<br />
Krebshilfe. D. Pachow: work was supported in part by Pfizer Inc. and <strong>the</strong> Deutsche<br />
Krebshilfe. E. Kirches: work was supported in part by Pfizer Inc. and <strong>the</strong> Deutsche<br />
Krebshilfe<br />
421P OUTCOME AND MOLECULAR CHARACTERISTICS OF YOUNG<br />
ADULT PATIENTS WITH NEWLY DIAGNOSED PRIMARY<br />
GLIOBLASTOMA: A STUDY OF THE SOCIETY OF AUSTRIAN<br />
NEUROONCOLOGY (SANO)<br />
C. Marosi 1 , A. Leibetseder 2 , M. Ackerl 3 , B. Flechl 3 , C. Sax 3 , A. Wöhrer 4 ,<br />
M. Preusser 5 , K. Dieckmann 6 , J. Pichler 7 , S. Spiegl Kreinecker 7<br />
1 Department of Oncology, Medical University of Vienna, Vienna, AUSTRIA,<br />
2 Oncology, Medizinische Universität Wien, Wien, AUSTRIA, 3 Internal Medicine,<br />
Medical University of Vienna, Vienna, AUSTRIA, 4 Institute for Neurology, Medical<br />
University of Vienna, Vienna, AUSTRIA, 5 Department of Medicine I, Medical<br />
University of Vienna, Wien, AUSTRIA, 6 Radio<strong>the</strong>rapy, Medical University Vienna,<br />
Vienna, AUSTRIA, 7 Neurooncology, Wagner Jauregg Spital, Linz, AUSTRIA<br />
Background: Young age is well-known as favorable prognostic factor for patients<br />
with glioblastoma multiforme (GBM). We reviewed <strong>the</strong> outcome and molecular<br />
tumor characteristics of “young” adult patients with newly diagnosed GBM treated in<br />
two Austrian Neurooncology centers.<br />
Patients and methods: Data of patients with histologically proven GBM diagnosed<br />
between age 18 and 40 were retrospectively analysed. All cases presented as newly<br />
diagnosed GBM without previous history of neurological disease. All were treated<br />
with standard first line <strong>the</strong>rapy. IDH1-R132H mutation status was analyzed by<br />
immunohistochemistry. Moreover, tumour samples were tested for MGMT<br />
promoter methylation using methylation-specific polymerase chain reaction<br />
(MS-PCR). The primary endpoint was overall survival (OS) and time to tumour<br />
progression (TTP).<br />
Results: We included 70 patients (36 men and 34 women; 47 from Vienna, 23 from<br />
Linz) with a median age of 33 (range 18 to 40 years) in our study. IDH1-R132H<br />
mutations were detected in 22/56 (39.3%) cases and MGMT promoter methylation in<br />
33/54 (61.1%) cases with available tissue samples. IDH1 mutation was highly<br />
significantly associated with MGMT promoter methylation (p < 0.0001, Chi-square<br />
test). In patients with wild type IDH median TTP was 12.6 months and median OS<br />
43.0 months, versus 22.2 months (TTP) and 50.6 months (OS) observed in patients<br />
with mutated IDH. Nei<strong>the</strong>r IDH1 nor MGMT status showed a statistically significant<br />
association with TTP or OS in our cohort. Of note, <strong>the</strong> social and economical situation<br />
of <strong>the</strong> young GBM patients was alarming, as only a minority of patients (17%)<br />
succeeded in staying employed after receiving <strong>the</strong> diagnosis.<br />
Conclusions: We found a high frequency of IDH1 mutations and MGMT promoter<br />
methylation among young adult patients with primary GBM that may contribute to<br />
<strong>the</strong> generally favourable outcome associated with young age in glioblastoma patients.<br />
The social and economic coverage of glioma patients remains an unsolved<br />
socio-ethical problem.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
423P THE IMPACT OF VALPROIC ACID IN OVERALL SURVIVAL<br />
OF PATIENTS WITH GLIOBLASTOMA MULTIFORME<br />
S.R. Meireles 1 , M.L. Salgado 1 , D. Almeida 1 , L. Castro 2 , P. Linhares 3 , L. Osório 4 ,<br />
A.S.A. Costa 1 , C. Caeiro 1 , M. Damasceno 1<br />
1 Medical Oncology Department, Hospital São João, Porto, PORTUGAL,<br />
2 Histopathology Department, Hospital São João, Porto, PORTUGAL,<br />
3 Neurosurgery Department, Hospital São João, Porto, PORTUGAL,<br />
4 Radio<strong>the</strong>rapy Department, Hospital São João, Porto, PORTUGAL<br />
Background: Seizures occur in up to 50% of patients with glioblastoma multiforme<br />
(GBM). Retrospective analysis of <strong>the</strong> pivotal European Organization for Research and<br />
Treatment of Cancer/National Cancer Institute of Canada clinical trial showed that<br />
<strong>the</strong> use of <strong>the</strong> antiepileptic (AED) valproic acid (VPA) may improve survival among<br />
patients with newly diagnosed glioblastoma receiving temozolamide compared to<br />
o<strong>the</strong>r AED or no treatment. We aimed to analyse <strong>the</strong> impact of VPA in overall<br />
survival (OS) of GBM patients submitted to Stupp’s protocol.<br />
Material and methods: Retrospective study of GBM patients who completed<br />
concomitant phase of Stupp’s protocol from March 2004 until December 2011.<br />
Patients needing two AED to seizure control were excluded.<br />
Results: One hundred thirty two patients were included. Median age at diagnosis was<br />
61 years-old [24;79] and 68,2% were male. Seizures were present at diagnosis in<br />
16,7% of cases. 55,3% were AED-free, 35,6% received VPA and 9,1% took ano<strong>the</strong>r<br />
AED. Median OS was 15 months (95%CI: 13,3-16,7) and 2-year OS was 31,8%.<br />
Patients submitted to VPA had better median OS versus o<strong>the</strong>r AED or no treatment<br />
at all, although <strong>the</strong> difference was not statistically meaningful (16 vs 15 vs 14 months,<br />
p = 0.74). In univariate and multivariate analysis, ECOG PS ≥ 1 (HR: 1.58, 95% CI<br />
1.01-2.47, p = 0.04), corticosteroid use (HR: 1.83, 95% CI 1.05-3.18, p = 0.03) and < 6<br />
cycles of temozolamide in maintenance phase (HR: 3.15, 95% CI 2.05-4.85,<br />
p < 0.001) were <strong>the</strong> only independent factors with negative impact on OS.<br />
VPA treatment was not significantly correlated with OS (HR: 0.96, 95%<br />
CI 0.47-1.96, p = 0.90).<br />
Conclusion: Opposite to <strong>the</strong> literature data, VPA didn’t show any survival advantage<br />
in GBM patients. ECOG PS ≥1, corticosteroid use and < 6 cycles of temozolamide in<br />
maintenance phase were correlated with worst prognosis. Future studies are needed<br />
to confirm and understand which mechanisms justify any potencial survival benefit<br />
of VPA.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
424P CAN TIME FROM LAST CHEMOTHERAPY TO RECURRENCE<br />
BE A PREDICTOR OF CHEMOSENSITIVITY IN RCURRENT<br />
GLOBLASTOMA?<br />
E. Franceschi 1 , R. Agati 2 , R. Poggi 3 , P. Dall’Occa 1 , M. Bartolotti 1 , M. Di Battista 1 ,<br />
G. Marucci 4 , F. Girardi 3 , M. Ermani 5 , A. Brandes 3<br />
1 Department of Medical Oncology, Bellaria and Maggiore Hospitals, Azienda<br />
USL Bologna, Bologna, ITALY, 2 Neuroradiology Department, Bellaria-Maggiore<br />
Hospital, Azienda USL, Bologna, ITALY, 3 Medical Oncology, Bellaria-Maggiore<br />
Hospital, Azienda USL, Bologna, ITALY, 4 Section of Pathology M. Malpighi,<br />
Department of Haematology and Oncological Sciences L. and A. Seragnoli,<br />
Bellaria Hospital, University of Bologna, Bologna, ITALY, 5 Department of<br />
Neurosciences, Statistic and Informatic Unit, Azienda Ospedale-Università,<br />
Padova, ITALY<br />
Purpose: Since temozolomide in combination with radio<strong>the</strong>rapy (RT/TMZ) became<br />
a new standard for newly diagnosed glioblastoma, <strong>the</strong> scenario at recurrence became<br />
less defined. Moreover, <strong>the</strong> role of prognostic and predictive factors for <strong>the</strong> second<br />
treatment has not been clarified.<br />
Methods: A retrospective analysis was made for glioblastoma patients followed<br />
between 01/2005 and 06/2010. Eligibility criteria for <strong>the</strong> study were: age ≥18 years;<br />
PS:0-2; chemo<strong>the</strong>rapy at disease progression after RT/TMZ, availability of data<br />
regarding second progression.<br />
Results: 232 patients with recurrent glioblastoma (mean age: 52 years, range:<br />
18-77years, MGMT methylated/unmethylated: 62 [37.6%] / 103 [62.4%]) were<br />
evaluated. At progression after RT/TMZ, 102 patients (44%) were treated with<br />
surgery followed by chemo<strong>the</strong>rapy, and 130 patients (56%) with chemo<strong>the</strong>rapy alone.<br />
Chemo<strong>the</strong>rapy consisted in TMZ rechallenge 5/28 in 80 patients (34%), nitrosoureas<br />
in 120 patients (52%), experimental treatments in 32 patients (14%). PFS-6<br />
calculated from 1st to 2nd PD was 22% (95%CI:16.3-26.9%). Time from <strong>the</strong> last<br />
adjuvant TMZ treatment to recurrence (TTR) was shorter in patients treated with<br />
nitrosoureas (2.6 months) than in patients treated with TMZ (9.8 months, p <<br />
0.00001). Univariate analysis showed that longer TTR (p = 0.007) and type of<br />
chemo<strong>the</strong>rapy (TMZ vs nitrosoureas p = 0.033) were both significantly correlated<br />
with PFS. Only TTR showed an effect on PFS (p = 0.07) in multivariate analysis.<br />
Median OS from recurrence was 8.6 months (95%CI:7.4-9.8), and 11.3 months (95%<br />
CI:9.5-13), 7.4 months (95%CI:6.3-8.5), and 7.1 months (95%CI:4.6-9.8), with TMZ,<br />
nitrosoureas, or o<strong>the</strong>r treatments, respectively. TTR and type of chemo<strong>the</strong>rapy at<br />
recurrence were significantly correlated with OS (p = 0.026 and p = 0.016) in<br />
univariate but not in multivariate analysis.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds394 | ix147
Conclusions: As in o<strong>the</strong>r cancer types (i.e. ovarian cancer), TTR seems to be<br />
promising as a predictive factor for PFS obtained with treatments for recurrence and<br />
could be useful in patients’ stratification. TMZ rechallenge seems more useful than<br />
nitrosoureas if TTR is longer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
425P CLINICAL IMPACT OF [11C]-METHIONINE POSITRON<br />
EMISSION TOMOGRAPHY ON THE TREATMENT OF PRIMARY<br />
AND RECURRENT GLIOMAS<br />
M. Santoni 1 , R. Berardi 2 , A. Bittoni 2 , A. Paccapelo 3 , C. Nanni 4 , S. Fanti 4 ,<br />
L. Burattini 2 , S. Cascinu 2<br />
1 Clinica Di Oncologia Medica, AO Ospedali Riuniti, Università Politecnica delle<br />
Marche, Ancona, ITALY, 2 Clinica di Oncologia Medica, AOU Ospedali Riuniti<br />
Ancona Università Politecnica delle Marche, Ancona, ITALY, 3 Medical Oncology,<br />
Ospedali Riuniti Torrette, Ancona, ITALY, 4 Department of Nuclear Medicine,<br />
University of Bologna, Bologna, ITALY<br />
Purpose: To assess whe<strong>the</strong>r 11C-methionine positron emission tomography<br />
( 11 C-MET PET) has a clinical significance in <strong>the</strong> management of glioma patients.<br />
Patients and methods: Fifty-three patients with histologically proven primary gliomas<br />
(16 grade II, 15 grade III, and 22 grade IV) were investigated repeatedly with 11C-MET<br />
PET. A total of 249 PET scans were performed, with a median of 4 scans for each<br />
patient. Functional imaging with PET was compared with concurrent MRI or CT.<br />
Results: We registered high sensibility and specificity in <strong>the</strong> management of glioma<br />
patients. The mean 11C-MET uptake index results significantly correlated with histological<br />
grade. The overall survival (OS) of GBM patients who underwent 11C-MET PET serial<br />
controls and parallel CT or MRI scans resulted to be 29.24 months, significantly higher<br />
compared to OS of GBM who underwent CT or MRI alone during follow up.<br />
Conclusion: 11C-MET PET allowed <strong>the</strong> detection of malignant progression in low<br />
grade glioma patients and <strong>the</strong> assessment of post-surgery status in both low and<br />
anaplastic gliomas with high sensibility and specificity. Thus, 11C-MET PET<br />
expresses its maximum potential in earlier disclosing recurrence during <strong>the</strong><br />
long-term follow-up of GBM patients, with a relevant impact on <strong>the</strong>rapeutic course<br />
and survival of <strong>the</strong>se patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
426P COMPARISON OF MICRORNA EXPRESSION LEVELS<br />
BETWEEN INITIAL AND RECURRENT GLIOBLASTOMA<br />
SPECIMENS<br />
A. Ilhan-Mutlu 1 , A. Wöhrer 2 , A.S. Berghoff 3 , G. Widhalm 4 , C. Marosi 1 ,<br />
L. Wagner 5 , M. Preusser 1<br />
1 Department of Oncology, Medical University of Vienna, Vienna, AUSTRIA,<br />
2 Institute for Neurology, Medical University of Vienna, Vienna, AUSTRIA, 3 Institute<br />
of Neurology, Medical University of Vienna, Vienna, AUSTRIA, 4 Department of<br />
Neurosurgery, Medical University of Vienna, Vienna, AUSTRIA, 5 Department of<br />
Nephrology, Medical University of Vienna, Vienna, AUSTRIA<br />
Background: Glioblastoma is <strong>the</strong> most frequent primary brain tumour in adults.<br />
Recent <strong>the</strong>rapeutic advances increased patient’s survival rates, but tumour recurrence<br />
inevitably occurs and is associated with dismal prognosis. The pathobiological<br />
mechanisms involved in glioblastoma recurrence are still mostly unclear. MicroRNAs<br />
are a recently identified class of small non protein encoding RNAs and tumour‐<br />
specific microRNA signatures have been proposed as novel indicators for tumour<br />
proliferation, aggressiveness, differentiation and metastases development for many<br />
cancer types. However, <strong>the</strong>re are only few data on <strong>the</strong> involvement of microRNAs in<br />
<strong>the</strong>rapy resistance and recurrence of glioblastoma.<br />
Methods: We selected <strong>the</strong> following 7 microRNAs with potential relevance for<br />
glioblastoma pathobiology by means of a comprehensive literature search:<br />
microRNA196b, microRNA21, microRNA10b, microRNA181b, microRNA181c,<br />
microRNA221, microRNA222 and microRNA195. We fur<strong>the</strong>r selected 17 primary<br />
glioblastoma patients, of whom formalin fixed and paraffin embedded tissue (FFPE)<br />
tumor tissue samples of <strong>the</strong> initial operation and a re-operation for tumor recurrence<br />
were available. Patients had received first line treatment consisting of postoperative<br />
combined radiochemo<strong>the</strong>rapy with temozolomide (n = 15) or fotemustine and<br />
dacarbazine (n = 2). We analysed <strong>the</strong> expression of <strong>the</strong> 7 microRNAs in all 34 tumor<br />
tissue samples by RT-qPCR. Expression levels were correlated with each o<strong>the</strong>r and<br />
with clinical parameters.<br />
Results: All microRNAs except microRNA196b showed detectable levels of expressions.<br />
Comparison of microRNA levels between first and second resections revealed no<br />
significant change. Cox regression analyses showed no significant association of<br />
microRNA expression levels in <strong>the</strong> tumor tissue with progression free survival times.<br />
Conclusion: Expression levels of microRNA21, microRNA10b, microRNA181b,<br />
microRNA181c, microRNA221, microRNA222 and microRNA195 do not to differ<br />
significantly between initial and recurrent tumors and seem not to influence time to<br />
recurrence in primary glioblastoma.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
427P ABLATIVE RADIOTHERAPY OF BRAIN METASTASES AND<br />
POSTOPERATIVE RADIOTHERAPY WITH OR WITHOUT<br />
“PROPHYLACTIC” CRANIAL IRRADIATION USING RAPIDARC<br />
AND SIMULTANEOUS INTEGRATED BOOST (SIB)<br />
P.A. Gut 1 , K.F. Kothbauer 2 , R. Seiler 1 , R. Greiner 1<br />
1 Radioonkologie, Luzerner Kantonsspital, Luzern, SWITZERLAND,<br />
2 Neurochirurgie, Luzerner Kantonsspital, Luzern, SWITZERLAND<br />
Annals of Oncology<br />
Objective: Patients with solitary or few brain metastases and good performance<br />
status should be treated with a local radical intention. It remains unclear, whe<strong>the</strong>r<br />
additional whole brain radio<strong>the</strong>rapy WBRT is necessary. We report about our<br />
alternative radio<strong>the</strong>rapy procedure with fractionated radical dose to metastases and<br />
"mild" dose to <strong>the</strong> remaining brain.<br />
Materials and methods: From 1/2010 until 12/2011 we treated 84 metastases in 46<br />
patients with radical intent. 25 patients had a solitary lesion and 12 were irradiated<br />
after resection. Using RapidArc technique with simultaneous integrated boost (SIB)<br />
most metastases were treated to 15 × 4 Gy = 60 Gy (PTV1) and <strong>the</strong> whole brain<br />
received - if indicated- a "prophylactic" dose of 15 × 1.8 Gy = 27 Gy (PTV2) . 13<br />
Patients received local treatment for <strong>the</strong>ir metastases without WBRT. Following<br />
resection of <strong>the</strong> metastasis <strong>the</strong> tumour bed was irradiated to 15 x 3.2 Gy = 48 Gy,<br />
residual/unresected macroscopic tumour to 15 x 4 Gy = 60 Gy. A 3-5 mm margin<br />
was used from GTV to PTV, with no additional margin for CTV. The minimum<br />
dose of PTV1 was 95% of <strong>the</strong> prescribed dose, wheras <strong>the</strong> median dose for PTV2<br />
was 27 Gy.<br />
Results: This treatment regime was tolerated very well without major toxicity and in<br />
general better than conventional WBRT (10 × 3 Gy). Median follow-up time after<br />
treatment was 7 months. 18 (39%) patients died and <strong>the</strong> median survival time is 12<br />
months. Local tumour control after treatment with15x4 Gy has been 100%, whereas<br />
one metastasis relapsed after resection and postoperative RT (15 × 3.2 Gy). 10<br />
patients (21%) were presented with new distant brain metastases.<br />
Conclusions: Ablative treatment of brain metastases can be performed efficiently<br />
with RapidArc and combined with prophylactic cranial irradiation using SIB. Local<br />
tumor control is nearly 100% and <strong>the</strong> toxicity is very low.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
428P PHASE 1 STUDY OF VELIPARIB WITH CONCURRENT WHOLE<br />
BRAIN RADIATION THERAPY (WBRT) IN PATIENTS (PTS)<br />
WITH BRAIN METASTASES (METS)<br />
M.P. Mehta 1 , W.J. Curran 2 , D. Wang 3 , F. Wang 4 , L. Kleinberg 5 , A. Brade 6 ,<br />
J. Qian 7 , T. Leahy, 8 , B. Desai 9 , V.L. Giranda 9<br />
1 Radiation Oncology, Northwestern University Feinberg School of Medicine,<br />
Chicago, IL, UNITED STATES OF AMERICA, 2 Department of Radiation<br />
Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, UNITED<br />
STATES OF AMERICA, 3 Department of Oncology/hematology, Henry Ford<br />
Hospital, Detroit, MI, UNITED STATES OF AMERICA, 4 Dept. of Radiation<br />
Oncology, Kansas University Medical Center, Kansas City, KS, UNITED STATES<br />
OF AMERICA, 5 Department of Radiation Oncology and Molecular Radiation<br />
Sciences, Johns Hopkins University, Baltimore, MD, UNITED STATES OF<br />
AMERICA, 6 Dept. of Radiation Oncology, Princess Margaret Hospital, University<br />
of Toronto, Toronto, ON, CANADA, 7 Global Statistics and Data Management,<br />
Abbott, Abbott Park, IL, UNITED STATES OF AMERICA, 8 Clinical Program<br />
Management-oncology, Abbott, Abbott Park, IL, UNITED STATES OF AMERICA,<br />
9 Global Pharmaceutical Research and Development, Abbott, Abbott Park, IL,<br />
UNITED STATES OF AMERICA<br />
Background: Veliparib, an oral PARP-1 and -2 inhibitor, potentiates <strong>the</strong> antitumor<br />
activity of DNA damaging agents including radiation <strong>the</strong>rapy in vivo, and is shown<br />
to cross <strong>the</strong> blood-brain barrier. Updated data on safety and antitumor activity from<br />
an ongoing phase 1, dose-escalation study of veliparib with concurrent WBRT in pts<br />
with brain mets are presented here.<br />
Methods: Pts with brain mets (including leptomeningeal) from primary non-CNS<br />
metastatic solid tumors (except germ cell cancer), adequate organ function, and<br />
Karnofsky performanace status (KPS) ≥70 were treated with WBRT (37.5 Gy in 15<br />
fractions or 30 Gy in 10 fractions daily) and veliparib BID in escalating doses of 10–<br />
300 mg; <strong>the</strong> final WBRT fraction was followed by 1 extra day of veliparib. Safety and<br />
exploratory efficacy were assessed. Safety was evaluated in pts who received at least 1<br />
dose of veliparib. Best brain tumor response (complete or partial per RECIST) rates<br />
were calculated for all pts who had at least 1 measureable lesion at baseline. Median<br />
survival time was estimated using Kaplan-Meier methodology for all dosed pts.<br />
Results: To date, 66 pts (M/F, 23/43; median age 58 y) have been treated. Baseline<br />
KPS was 70, 80, 90, and 100 in 7.6, 31.8, 37.9, and 22.7% pts, respectively; primary<br />
tumor types were breast (n = 21), NSCLC (n = 23), melanoma (n = 10), colorectal<br />
(n = 3), renal (n = 1), and o<strong>the</strong>rs (n = 8); 74.2% pts had multiple lesions, and 16.7%<br />
had prior brain stereotactic radiosurgery. Treatment-emergent dose-limiting toxicities<br />
were grade 3 hypokalemia and hyponatremia in 1 pt each at <strong>the</strong> 150 mg dose. Grade<br />
3/4 treatment-emergent adverse events (≥4%) were fatigue (6.1%), dehydration<br />
(6.1%), anemia (4.5%), thrombocytopenia (4.5%), hyperglycemia (4.5%), and<br />
ix148 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
hyponatremia (4.5%). Best tumor response rate and median survival time were 36.8%<br />
and 6.6 months (m) for NSCLC, and 50% and 8.3 m for breast cancer.<br />
Conclusion: Addition of veliparib up to 200 mg BID was well tolerated with<br />
concurrent standard WBRT and dose escalation is ongoing. These encouraging safety<br />
and preliminary efficacy data suggest that veliparib requires fur<strong>the</strong>r evaluation as a<br />
radiosensitizer with WBRT in pts with NSCLC and brain mets in a randomized trial.<br />
Disclosure: M.P. Mehta: Consultant: Abbott, BMS, Elekta, Merck, Novartis, Novocure,<br />
Tomo<strong>the</strong>rapy, Vertex; Stock Options: Accuray, Pharmacyclics; DSMB: Apogenix;<br />
Protocol Data Review: Adnexus; Board of Directors: Pharmacyclics. W.J. Curran: Dr.<br />
Curran had served on <strong>the</strong> advisory board of Lilly, BMS, and Plexxikon. There are no<br />
conflicts. D. Wang: As a clinical investigator, and <strong>the</strong> principle investigator at Henry<br />
Ford Health System, I have conducted this clinical trial that is financially supported by<br />
Abbott Oncology. I have no o<strong>the</strong>r conflict of interest to be disclosed, o<strong>the</strong>rwise. L.<br />
Kleinberg: I have received research funding from Abbott. J. Qian: Full-time Abbott<br />
employee and stockholder. T. Leahy: Full-time Abbott employee and stockholder. B.<br />
Desai: Full-time Abbott employee and stockholder. V.L. Giranda: Full-time Abbott<br />
employee and stockholder. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
429P NEUROLOGICAL (NEU) AND CYTOLOGICAL (CYT) RESPONSE<br />
(R) AS EARLY PREDICTORS OF TIME-TO-PROGRESSION<br />
(TTP) AND OVERALL SURVIVAL (OS) IN PATIENTS (PTS) WITH<br />
LEPTOMENINGEAL CARCINOMATOSIS (LMC) TREATED WITH<br />
INTRATHECAL (I.T) LIPOSOMAL CYTARABINE (LYC)<br />
J.P. Fusco, E. Castanon Alvarez, L. Zubiri, P. Martín, O.E. Carranza Rua,<br />
J. Espinos Jimenez, J. Rodriguez, M. Santisteban, J.M. Aramendia,<br />
I. Gil-BazoDepartment of Oncology, Clínica Universidad de Navarra, Pamplona,<br />
SPAIN<br />
Background: The palliative treatment of LMC involves i.t chemo<strong>the</strong>rapy or supportive<br />
care. Lcy is a slow-releasing cytarabine formulation approved for leptomeningeal<br />
involvement of hematological malignancies. In pts with LMC from solid tumors<br />
interesting Neu and Cyt R rates after i.t Lcy have been observed. However, <strong>the</strong> potential<br />
use of those responses as early predictors of TTP and OS has never been explored. Here<br />
we show how both Neu and Cyt R can precociously predict a longer TTP and OS.<br />
Patients and methods: Twenty-seven pts with LMC consecutively treated at our<br />
institution with i.t Lcy under compassionate use (17/27 female), were studied. All pts<br />
received i.t Lcy (50 mg) every 2 weeks (w) during induction and every 4 w during<br />
maintenance. Neu and Cyt responses were assessed before every Lcy cycle.<br />
Results: The predominant primary tumor origin was breast (15/27), followed by<br />
gastrointestinal (3), lung (3), brain (2), and 4 o<strong>the</strong>r organs. A complete Neu R<br />
(resolution of all Neu symptoms) was seen in 3/27 pts; partial R (improvement of<br />
>50% of Neu symptoms for >2 w) in 6/27 pts; stable disease (no change in Neu<br />
symptoms) in 8/27 pts and progressive disease (progression or appearance of new<br />
Neu symptoms) in 10/27 pts. The Cyt assessment was available in 9/27 pts with a<br />
Cyt complete R confirmed in 7/9 pts. The median time to Neu and Cyt R was 15<br />
days (d) and 14 d, respectively. The overall median TTP was 22 d and <strong>the</strong> median<br />
OS was 41 d. In a subgroup analysis regarding <strong>the</strong> type of R achieved with <strong>the</strong><br />
treatment, <strong>the</strong> median TTP and OS for pts showing a combined Neu and Cyt R were<br />
significantly longer compared to those in pts showing both, Neu and Cyt progression<br />
as shown in table 1. The most frequently reported adverse event was grade 2<br />
headache with no grade 4 toxicities.<br />
Conclusions: For <strong>the</strong> first time, Neu and Cyt R are shown to be early predictors of<br />
TTP and OS in pts receiving i.t Lcy for LMC. This result could help to early select<br />
patients most likely to benefit from i.t Lcy and to consider discontinuation when very<br />
poor prognosis is estimated.<br />
Neu R Cyt R TTP (d) OS (d) p<br />
Yes Yes 122 141 0.001<br />
Yes No 14 32 0.001<br />
No Yes 42 72 0.001<br />
No No 3 3 0.001<br />
Disclosure: All authors have declared no conflicts of interest.<br />
430P DEMOGRAPHIC DATA AND TREATMENT OUTCOME IN<br />
RETINOBLASTOMA: RETROSPECTIVE REVIEW FROM<br />
TERTIARY CENTRE IN INDIA<br />
F.A. Ansari 1 , P. Shukla 2 , V. Roshan 1 , B. Mohanti 1<br />
1 Radio<strong>the</strong>rapy, aiims, Delhi, INDIA, 2 Radiation Oncology, All India Institute of<br />
Medical Sciences (AIIMS) Institute Rotary Cancer Hospital, New Delhi, INDIA<br />
Purpose: To characterize <strong>the</strong> patient population and analyse treatment outcome in<br />
patients with retinoblastoma.<br />
Method and material: A retrospective study of 180 patients with retinoblastoma<br />
affecting a total of 297 eyes. Demographic data, tumor features and outcome were<br />
assessed.<br />
Results: The mean age of diagnosis was 32 months (range 2-204 months) for<br />
unilateral eyes and 26 months ( range 2-132months) for bilateral eyes. The male<br />
to female ratio was 1.4:1. The most common symptoms was leukokoria (74%),<br />
followed by proptosis of eye (11.5%), strabismus (8%) and poor vision (6.5%).<br />
Out of 297 eyes 39 were Group I-II, 17 were Group III, 198 were group IV-V<br />
and 43 had missing information. The mean basal diameter was 14mm (range<br />
2–37mm). The mean interval between initial diagnosis and treatment was<br />
7months ( range 1-36 months). Familial history was seen in eight patients (4.4%).<br />
Out of 180 patients 64 patients received radiation. 144 patients underwent<br />
enucleation. No children underwent bilateral enucleation. All patients were treated<br />
with 6–12 cycles of chemo<strong>the</strong>rapy vincristine, etoposide and carboplatin.<br />
Chemo<strong>the</strong>rapy offer satisfactory local control for Group I-III, with treatment<br />
failure necessitating additional radiation and or enucleation in only 14% of<br />
patients. The radiation doses were ei<strong>the</strong>r 39Gy in 13 fraction, three fraction per<br />
week or 40Gy in 20 fraction, five fraction per week. The mean duration of follow<br />
up was 28 months (0-64months). The overall local control or freedom from<br />
relapse was 55%. Local control in patients receiving radiation after enucleation<br />
was 84%. Distant metastases were seen in 13 patients (preauricular node (5),<br />
vertebrae (3), humerus (1), suprasellar (1), scalp (1), CSF(1), and meningeal<br />
dissemination (1)). No case of second malignant neoplasm has been reported.<br />
Conclusion: Lack of awareness leads to delay in diagnosis and treatment.<br />
Multimodality treatment is required for management of retinoblastoma.<br />
Chemoreduction offer satisfactory control retinoblastoma in group I-III, with<br />
preservation of vision. There is significant improvement in local control with<br />
radiation <strong>the</strong>rapy in locally advance cases.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
431 BLOOD VESSELS WITH DIFFERENT CHARACTERISTICS HAVE<br />
DISTINCT IMPACT ON SURVIVAL OF GLIOBLASTOMA<br />
MULTIFORME PATIENTS<br />
M. Kase 1 , A. Minajeva 2 , K. Niinepuu 2 , S. Kase 3 , A. Adamson 2 , M. Saretok 2 ,<br />
M. Vardja 4 , T. Asser 5 , J. Jaal 6<br />
1 Dept. of Radio<strong>the</strong>rapy, North Estonia Medical Centre, Oncology and<br />
Haematology Clinic, Tallinn, ESTONIA, 2 Faculty of Medicine, University of Tartu,<br />
Tartu, ESTONIA, 3 Nursing, Health Care College, Tartu, ESTONIA, 4 Dept of<br />
Radio<strong>the</strong>rapy and Oncological Therapy, Tartu University Hospital, Haematology<br />
and Oncology Clinic, Tartu, ESTONIA, 5 Dept of Neurosurgery, Tartu University<br />
Hospital, Tartu, ESTONIA, 6 Dept of Radio<strong>the</strong>rapy and Oncological Therapy, Tartu<br />
University Hospital, Tartu, ESTONIA<br />
Background: Glioblastoma multiforme (GBM) is <strong>the</strong> most aggressive type of brain<br />
tumor in adults. GBMs are highly angiogenic: next to capillaries and bigger blood<br />
vessels, microvascular proliferations (MP) forming glomeruloid structures can be<br />
found. The aim of our study was to evaluate <strong>the</strong> prognostic significance of different<br />
blood vessel types in GBM.<br />
Methods: Between Jan 2006 and Dec 2008, 42 patients (30–77 years) received<br />
postoperative radio<strong>the</strong>rapy and chemo<strong>the</strong>rapy. Surgically excised GBM tissues were<br />
histologically examined for overall proportion of MP (low, medium, high) and <strong>the</strong><br />
total number of blood vessels (per microscopic field). Also, immunohistochemical<br />
staining intensity of CD133 and ICAM-1 were determined in endo<strong>the</strong>lial cells<br />
(arbitrary score 0–3). Finally, blood vessel parameters were correlated with patients<br />
overall survival.<br />
Results: The overall proportion of MP was low-medium in 39% and high in 61%<br />
of GBM patients. The number of blood vessels per microscopic field was 2.5 ± 1.4<br />
(mean ± SD). A positive association was found between <strong>the</strong> number of blood<br />
vessels and endo<strong>the</strong>lial CD133 staining intensity (p = 0.03). However, between <strong>the</strong><br />
number of blood vessels and endo<strong>the</strong>lial ICAM-1 staining intensity, a negative<br />
correlation was detected (p = 0.04). Median survival time of <strong>the</strong> study group was<br />
10.0 months (95% CI 9.0–11.0). The proportion of MP did not significantly affect<br />
survival (log rank test, p = 0.07). However, <strong>the</strong> survival time clearly depended on<br />
<strong>the</strong> number of blood vessels in GBM tissue (log rank test, p = 0.03). Median<br />
survival times for patients with low (
432 GAMMA KNIFE RADIOSURGERY AS A MAIN MODALITY IN<br />
TREATING INTRACRANIAL LESIONS OF NF II PATIENTS<br />
K. Abdel Karim, 1 , N.M. Elmashad 2 ,W.Reda 1 , A. El Shehaby 1<br />
1 Gamma Knife Center, Nasser Institute, Cairo, EGYPT, 2 Clinical Oncology<br />
Department, Tanta University, Tanta, EGYPT<br />
Objective: Gamma knife radiosurgery GKS was used for <strong>the</strong> treatment of <strong>the</strong><br />
patients with Neurofibromatosis type II (NFII) for years to achieve better tumor<br />
control and to avoid <strong>the</strong> post operative neurological deficits. This study aimed at<br />
exploring <strong>the</strong> effect of GKS on <strong>the</strong> tumor control rate, <strong>the</strong> avoidance of new<br />
neurological deficits, and <strong>the</strong> associated morbidity.<br />
Methods: We revised <strong>the</strong> data of 50 intracranial NFII patients (ei<strong>the</strong>r vestibular<br />
schwannomas or meningiomas) who were treated consequently between July 2001<br />
and October 2009 in our center, <strong>the</strong> data of 43 patients were evaluable. The mean<br />
follow up period was 43.7 months (range 6 to 96). We treated 22 females (51.2%)<br />
and 21 males (48.8%) with a mean age of 27.6 years (range 9–53 years). Eight<br />
patients (18.6%) had a family history of NFII, 29 patients (67.4%) had previous<br />
surgeries. A hundred and seventy NFII lesions were treated in 169 treatment<br />
procedures, 83/170 were vestibular schwannomas and 87 were meningiomas. The<br />
mean number of treated lesions per patient was 3.97 (range 1–14). The mean<br />
marginal dose was 11.9 Gy (range 8 to 13 Gy), with a mean isodose of 52.5%, mean<br />
percent coverage was 95.7% (ranged 71-100%). The mean target volume was 11.1 cc<br />
(range 0.1 to 26.11 cc).<br />
Results: Regarding <strong>the</strong> overall radiological response, 16 lesions (9.4%) had<br />
regressed, 146 (85.9%) remained stable, and 8 (4.7%) had progressed. For 83<br />
schwannomas, 7 lesions (8.4%) had regression, 72 (86.7%) remained stable, and 4<br />
(4.8%) developed progression. For <strong>the</strong> 87 meningiomas, 9 (10.3%) had regressed,<br />
74 (85.1%) were stable, and 4 (4.6%) had progressed. The Overall survival rate<br />
(OS) for all patients was 95.3% (only 2 died), <strong>the</strong> mean tumor control rate of<br />
95.1%. The overall Freedom from neurological deficits was 97.7%. Only one patient<br />
complained of Grade III facial palsy which was temporary and resolved after<br />
medical treatment. Using a median dose of 12 Gy maintained serviceable hearing<br />
in 56.6% of ears.<br />
Conclusion: Gamma knife radiosurgery for NFII patients can achieve good tumor<br />
control and preserved function with low risk of morbidity.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
433 PEMETREXED AND WHOLE-BRAIN RADIATION THERAPY<br />
FOR TREATMENT OF BRAIN METASTASES FROM NON<br />
SMALL-CELL LUNG ADENOCARCINOMA: A SINGLE<br />
INSTITUTON ANALYSIS<br />
C. Chargari 1 , Y. Moussaid 2 , C. Helissey 1 , J. Jacob 1 , O. Bauduceau 1 ,<br />
B. Ceccaldi 1 , L. Védrine 1 , S. Le Moulec 1<br />
1 Oncology and Radiation Oncology, Hôpital d’Instruction des Armées du<br />
Val-de-Grâce, Paris, FRANCE, 2 Rabat, Hopital d’Instruction des Armées<br />
Mohamed V, Rabat, MOROCCO<br />
Background: Folate antimetabolite pemetrexed was approved for treatment of<br />
patients with metastatic non small-cell lung carcinoma (NSCLC). Its activity on brain<br />
metastases makes it attractive in combination with whole brain radiation <strong>the</strong>rapy<br />
(WBRT), but this regimen could also potentially increase toxicity.<br />
Patients and treatment: We retrospectively assessed <strong>the</strong> use of pemetrexed<br />
concurrently with WBRT in 12 consecutive patients with brain metastases from<br />
NSCLC. Patients received pemetrexed 500 mg/m2, ei<strong>the</strong>r alone (n = 4) or combined<br />
with cisplatin 75mg/m2 (n = 6) or carboplatin AUC5 (n = 2). Median total number of<br />
pemetrexed-based chemo<strong>the</strong>rapy cycles was 3.5 (range: 1–8). In <strong>the</strong> course of<br />
chemo<strong>the</strong>rapy, patients received WBRT delivering 30 Gy in 10 fractions (n = 8) or 20<br />
Gy in 5 fractions (n = 4).<br />
Results: Six patients improved neurologically with treatment (five complete and one<br />
partial responses). Four patients had <strong>the</strong>ir neurological symptoms stable. Best<br />
radiological response was complete response lasting until last follow-up in one<br />
patient. Five patients experienced partial response. One patient had stable disease.<br />
Progressions were identified in four patients, within a median time interval of 17<br />
weeks (range: 6–58 weeks). Three patients were not analyzable for tumor response<br />
because of rapid systemic progression leading to death. Two of <strong>the</strong>m had improved<br />
neurologically. No high-grade WBRT-toxicity was reported but one patient<br />
developed symptoms suggestive of a limbic encephalopathy five weeks after WBRT<br />
completion.<br />
Conclusion: The combination of pemetrexed with WBRT was associated with a<br />
substantial improvement of neurological deficits and tumor responses in most<br />
patients. However, survival remained disappointing and <strong>the</strong>re were concerns<br />
about toxicity in one patient. A clinical trial is required for better analyzing <strong>the</strong><br />
potential synergistic effects of drug with radiation and evaluating neurological<br />
toxicity.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
434 LIMITED PREDICTIVE VALUE OF SCORING SYSTEMS FOR<br />
METASTATIC SPINAL CORD COMPRESSION (MSCC):<br />
RESTROSPECTIVE MONOCENTRIC STUDY<br />
E. Tabouret 1 , C. Cauvin 2 , S. Fuentes 3 , B. Esterni 4 , T. Adetchessi 3 , N. Salem 5 ,<br />
A. Madroszyk 2 , A. Gonçalves 1 ,P.Viens 6 , G. Gravis-Mescam 1<br />
1 Medical Oncology, Paoli Calmettes, Marseille, FRANCE, 2 Medical Oncology,<br />
Institut Paoli Calmettes, Marseille, FRANCE, 3 Neuro-surgery, AP HM, Marseille,<br />
FRANCE, 4 Biostatistic, Paoli Calmette, Marseille, FRANCE, 5 Radio<strong>the</strong>rapy, Paoli<br />
Calmettes, Marseille, FRANCE, 6 Cancer Center, Institute Paoli Calmettes,<br />
Marseille Cedex, FRANCE<br />
Background: Incidence of MSCC is increasing, paralleling increasing life expectancy<br />
of patients (pts). We analyzed pts referred for surgery for MSCC to evaluate scoring<br />
system relevance, prognosis factors, efficiency and safety.<br />
Methods: From 2004 to 2010 148 pts (77 men) with oncologic (84%) and<br />
hematological (16 %) diseases had surgery for MSCC. Patients and tumoral<br />
characteristics were recorded. Prognostic value of Tomita, Tokuhashi scores, ASA<br />
score, Frankel score (FS) and pain was investigated.<br />
Results: Median age was 60 y (22–87). Lung (17%) and breast cancer (18%), were<br />
mainly represented. Multiple extra-bone metastases were observed in 39% of pts.<br />
Pain was present in 96% of pts and 66% were hyperalgic (pain score > 6). FS was<br />
decreased for 49% of pts and median Karnofsky Performance Scale (KPS) was 70%.<br />
Majority had laminectomy with spinal fixation: 73 %. Radio<strong>the</strong>rapy was done for<br />
68%. Median overall survival (OS) was 8.9 months (IC95: 4.4–13). Tokuhashi but not<br />
Tomita score was relevant. Survival predictive accuracy of TS was only 51%. By<br />
univariate analyses, moderate pain (p = 0.001), primary breast (p = 0.02) or<br />
hematological (p < 0.001) diseases are associated with higher OS than lung cancer<br />
(p = 0.004). Absence of extra-bone metastase (p < 0.001), KPS > 70 (p < 0.001), ASA<br />
score (p < 0.001), FS (p = 0.01), type of surgery (p = 0.03), post surgery<br />
chemo<strong>the</strong>rapy (p < 0.001) presented prognostic value. By multivariate analysis<br />
extra-bone metastases (p = 0.004), KPS (p = 0.001) and ASA score (p = 0.007)<br />
remained significant. Pain decrease was observed for 75% of pts. After surgery, 92%<br />
of pts were ambulatory and FS was improved for 31%. Surgery complications<br />
occurred in 16.8% and only 7% of pts died within 30 days.<br />
Conclusion: Surgery for MSCC is associated with limited morbidity, improvement of<br />
patients’ autonomy and remission of pain. In our study, usual scores seem not<br />
relevant, whereas ASA score, KPS and extra-bone metastases are significant survival<br />
prognostic factors.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
435TiP A DUAL PHASE I/II STUDY OF TH-302 AND BEVACIZUMAB<br />
IN RESECTABLE RECURRENT GLIOBLASTOMA FOLLOWING<br />
BEVACIZUMAB FAILURE<br />
R.M. Zuniga 1 , J. Sun 2 , J.R. Floyd 1 , S.R. Yerragudi 1 , C. Hart 2 , C. Eng 2 ,<br />
A.J. Brenner 1<br />
1 Cancer Therapy and Research Center, University of Texas Health Sceince<br />
Center at San Antonio, San Antonio, TX, UNITED STATES OF AMERICA,<br />
2 Clinical Operations, Threshold Pharmaceuticals, South San Francisco, CA,<br />
UNITED STATES OF AMERICA<br />
Introduction: Bevacizumab, a recombinant human monoclonal anti-VEGF antibody,<br />
exhibits anti-tumor activity in recurrent glioblastoma; however, <strong>the</strong> median progression<br />
free survival (PFS) of patients who progress on bevacizumab and are subsequently<br />
started on a non-bevacizumab containing regimen is only 1.6 months. Pre-clinical<br />
studies have shown that anti-angiogenic treatment leads to an increase in hypoxia in<br />
<strong>the</strong> tumor microenvironment leading to increased invasiveness. Hypoxia upregulates<br />
survival mechanisms, inhibits apoptosis, and stimulates invasiveness. TH-302 is a<br />
hypoxia-activated prodrug that once activated releases <strong>the</strong> alkylating agent Br-IPM.<br />
This drug has shown to potentiate, in vivo, <strong>the</strong> anti-tumor efficacy of o<strong>the</strong>r<br />
anti-angiogenic agents. This dual phase I/II study enrolled subjects with recurrent<br />
glioblastoma following bevacizumab failure that were planned for repeat craniotomy.<br />
Methods: Single center, dose-escalation, prospective study with TH-302 single dose at<br />
575 mg/m2 or placebo administered pre-operatively, followed by postoperative<br />
combination <strong>the</strong>rapy of bevacizumab at 10 mg/kg every 2 weeks and TH-302 dose<br />
escalated 240–480 mg/m2 every 2 weeks (4 week cycle) until disease progression.<br />
Resected tumor tissue was evaluated for hypoxia induced pimonidazole adducts,<br />
endogenous CAIX staining, double-strand DNA damage by gamma-H2AX and MGMT<br />
expression.<br />
Results: Five patients underwent craniotomy and initiated TH-302 plus bevacizumab.<br />
No dose limiting toxicity was reported. There were no grade 3 or 4 adverse events<br />
(AEs) observed at 240mg/m2, and one grade 3 (skin ulceration) and no grade 4 AEs<br />
observed thus far in <strong>the</strong> second cohort at 340mg/m2. Of <strong>the</strong> initial 5 patients treated,<br />
one patient had a partial response (PR) and 3 patients had stable disease (SD) per<br />
RANO criteria. Histological assessment of resected tumors demonstrated extensive<br />
areas of hypoxia as measured by pimonidazole and a heterogeneous distribution of<br />
gamma-H2AX staining.<br />
ix150 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Conclusions: TH-302 demonstrates good tolerability when combined with<br />
bevacizumab. The MTD has not been reached and only one grade 3/4 toxicity was<br />
observed. Dose escalation is ongoing, with planned expansion at <strong>the</strong> MTD.<br />
Disclosure: J. Sun: The author is an employee of pharmaceutical industry with a<br />
financial interest in <strong>the</strong> drug which is <strong>the</strong> subject of this abstract. C. Hart: The<br />
author is an employee of pharmaceutical industry with a financial interest in <strong>the</strong><br />
drug which is <strong>the</strong> subject of this abstract. C. Eng: The author is an employee of<br />
pharmaceutical industry with a financial interest in <strong>the</strong> drug which is <strong>the</strong> subject of<br />
this abstract. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
437TiP A RANDOMISED PHASE II STUDY OF CARBOPLATIN AND<br />
BEVACIZUMAB IN RECURRENT GLIOBLASTOMA<br />
MULTIFORME (CABARET STUDY). COOPERATIVE TRIALS<br />
GROUP FOR NEURO-ONCOLOGY (COGNO)<br />
K. Field1 , M.A. Rosenthal1 , H. Wheeler2 , L. Cher3 ,E.Hovey4 , A.K. Nowak5 ,<br />
C. Brown6 , A. Livingstone6 , K. Sawkins6 , R.J. Simes6 1<br />
Department of Medical Oncology, Royal Melbourne Hospital, Parkville, VIC,<br />
AUSTRALIA, 2 Medical Oncology, Royal North Shore Hospital, Sydney, NSW,<br />
AUSTRALIA, 3 Neuro-Oncology, Austin Hospital, Melbourne, VIC, AUSTRALIA,<br />
4<br />
Medical Oncology, Prince of Wales Hospital, Sydney, NSW, AUSTRALIA,<br />
5<br />
Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA, AUSTRALIA,<br />
6<br />
Clinical Trials, NH&MRC Clinical Trials Centre, University of Sydney, Sydney,<br />
NSW, AUSTRALIA<br />
Background: Glioblastoma (GBM) is <strong>the</strong> most aggressive malignant glial tumor.<br />
There is no accepted standard management after disease progression. Much remains<br />
unknown about <strong>the</strong> optimal use of bevacizumab (bev), including <strong>the</strong> role of<br />
continuing beyond progression, and patterns of radiological progression during and<br />
after use. In addition, <strong>the</strong> new Response Assessment in Neuro-Oncology (RANO)<br />
criteria have yet to be validated prospectively.<br />
Methods: This study is a multi-centre, stratified randomised phase II trial. Patients<br />
have recurrent GBM after radio<strong>the</strong>rapy and temozolomide, have had no o<strong>the</strong>r<br />
chemo<strong>the</strong>rapy for GBM, and have ECOG performance status 0–2. At least three<br />
months have elapsed since radio<strong>the</strong>rapy. In Part 1, patients are randomised 1:1 to<br />
intravenous bev 10 mg/kg 2-weekly and carboplatin AUC5 4-weekly or bev<br />
mono<strong>the</strong>rapy. On progression, eligible patients are randomised to continue or cease<br />
bev (Part 2). The primary objective is to determine <strong>the</strong> effect of bev plus carboplatin<br />
versus bev alone on progression-free survival according to modified RANO criteria.<br />
Secondary endpoints are response rates, cognitive function, quality of life, steroid<br />
dose, toxicity, and overall survival. CogState, a validated neurocognitive testing<br />
system, is being used prospectively for <strong>the</strong> first time in this population and compared<br />
with mini-mental state examination. Exploratory endpoints include biomarker<br />
analyses, comparison of modified RANO and modified MacDonald criteria,<br />
predictive value of early MRI after 2 doses of bev, steroid dosing, and location and<br />
type of radiological progression during and after <strong>the</strong>rapy.<br />
Results: Enrolment commenced in Nov 2010, completing Part 1 accrual in Mar <strong>2012</strong><br />
with 122 patients randomised from 17 Australian sites. Randomisation to Part 2<br />
continues. Feasibility and safety data will be presented; efficacy outcome results are<br />
not expected until 2013.<br />
Conclusions: The study results will significantly improve knowledge regarding <strong>the</strong><br />
use of bevacizumab in <strong>the</strong> setting of recurrent GBM, as well as providing for <strong>the</strong> first<br />
time a prospective analysis of CogState neurocognitive testing for patients with brain<br />
tumours.<br />
Disclosure: M.A. Rosenthal: Roche Advisory Board member. H. Wheeler: Roche<br />
Advisory Board member. E. Hovey: Roche Advisory Board member. A.K. Nowak:<br />
Roche Advisory Board member and has received research funding through Roche<br />
Australia. R.J. Simes: Roche Advisory Board Member. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds394 | ix151
abstracts<br />
developmental <strong>the</strong>rapeutics<br />
438O PHASE II ACTIVITY OF THE HSP90 INHIBITOR AUY922 IN<br />
PATIENTS WITH ALK-REARRANGED (ALK+) OR<br />
EGFR-MUTATED ADVANCED NON-SMALL CELL LUNG<br />
CANCER (NSCLC)<br />
E. Felip 1 , E. Carcereny 2 , F. Barlesi 3 , L. Gandhi 4 , L.V. Sequist 5 , S-W. Kim 6 , H.J.<br />
M. Groen 7 , B. Besse 8 , D-W. Kim 9 , E. Smit 10 , M. Akimov 11 , E. Avsar 12 ,<br />
S. Bailey 13 , W. Ofosu-Appiah 14 , E.B. Garon 15<br />
1 Medical Oncology, Vall d’Hebron University Hospital, Barcelona, SPAIN,<br />
2 Medical Oncology Service, Catalan Institute of Oncology, Hospital Germans<br />
Trias i Pujol, Badalona, SPAIN, 3 Multidisciplinary Oncology and Therapeutic<br />
Innovations Department & Centre Investigation Clinique, Aix Marseille University,<br />
Marseille, FRANCE, 4 Oncology, Dana-Faber Cancer Institute, Boston, UNITED<br />
STATES OF AMERICA, 5 Medicine, Massachusetts General Hospital, Boston,<br />
MA, UNITED STATES OF AMERICA, 6 Oncology, Asan Medical Center, Seoul,<br />
KOREA, 7 Pulmonary Diseases, University Hospital Groningen (UMCG),<br />
Groningen, NETHERLANDS, 8 Departement of Medicine, Institute Gustave<br />
Roussy, Villejuif, FRANCE, 9 Department of Internal Medicine, Seoul National<br />
University Hospital, Seoul, KOREA, 10 Department of Pulmonary Diseases, Vrije<br />
Universiteit Medical Centre, Amsterdam, NETHERLANDS, 11 Oncology<br />
Translational Medicine, Novartis Pharma AG, Basel, SWITZERLAND, 12 Oncology<br />
Translational Medicine, Novartis Pharmaceuticals, East Hanover, NJ, UNITED<br />
STATES OF AMERICA, 13 Biometrics and Data Management, Novartis Pharma<br />
AG, Basel, SWITZERLAND, 14 Oncology, Novartis Oncology, Florham Park, NJ,<br />
UNITED STATES OF AMERICA, 15 Translational Oncology Research, David Geffen<br />
School of Medicine at UCLA, Los Angeles, UNITED STATES OF AMERICA<br />
Background: AUY922 is a highly potent, non-geldanamycin, HSP90 inhibitor.<br />
HSP90 is a chaperone of client proteins relevant in NSCLC pathogenesis, including<br />
ALK and EGFR. Oncogenic fusion genes giving constitutive ALK activity (ALK+)<br />
occur in up to 6% of NSCLCs, and EGFR mutation (mut) occurs in 10–20% of cases.<br />
We report data from a Phase II study of AUY922 in patients (pts) with previously<br />
treated, advanced NSCLC, stratified by molecular status.<br />
Methods: Pts with advanced NSCLC who progressed following ≥1 prior line of<br />
chemo<strong>the</strong>rapy, received AUY922 (70 mg/m 2 )asaonce-weekly,1-hrinfusion.Ptswere<br />
assigned to 1 of 4 strata: ALK + , EGFR-mut, KRAS-mut, or EGFR/KRAS/ALK wild-type.<br />
A Bayesian partially exchangeable multinomial model was used in <strong>the</strong> statistical analysis<br />
of <strong>the</strong> study. Primary endpoint was confirmed objective response rate or stable disease at<br />
18 wks. Secondary endpoints included OS, PFS, and safety/tolerability.<br />
Results: On 6 April <strong>2012</strong> cutoff, 121 pts had been treated (ALK+ [n = 22; both<br />
crizotinib (CRZ) treated and naïve], EGFR-mut [n = 35], KRAS-mut [n = 28], EGFR/<br />
KRAS/ALK wild-type [n = 33], undetermined [n = 3]); pts were heavily pretreated<br />
(61% had received ≥3 prior regimens). Clinical activity of AUY922 was seen in pts<br />
with ALK+ and EGFR-mut NSCLC, with partial responses in 6/21 (29%) pts and 7/<br />
35 (20%) pts, respectively. 4/6 ALK+ responders were CRZ-naïve and 2/6 were<br />
pretreated. Estimated median PFS rates (FAS) were 42% and 34% at 18 wks in ALK+<br />
and EGFR mut pts, respectively. In EGFR-mut pts who had progressed just after<br />
EGFR tyrosine kinase inhibitor (TKI) <strong>the</strong>rapy, median PFS rate at 18 wks was 45%<br />
vs 21% in pts who had not received a TKI as <strong>the</strong>ir immediate pre-AUY922 <strong>the</strong>rapy.<br />
The most frequent adverse events (AEs) were eye disorders (77%), diarrhea (74%),<br />
and nausea (46%). Most AEs were grade (Gr) 1/2; Gr 3/4 AEs were rare (all 3 patients) were: fatigue (n = 4; 3 grade 1/2, 1<br />
grade 3), nausea (n = 4; grade 1). No treatment-related serious AEs were observed.<br />
No DLTs were observed; <strong>the</strong> 120 mg dose level remains under evaluation. At 90 mg<br />
(n = 3), Day 29 geometric mean Cmax, Ctrough, AUC(0-24hr), and t1/2 were: 402 ng/<br />
mL, 170 ng/mL, 6130 ng*hr/mL, 29 hr, respectively. At <strong>the</strong> time of analysis, 8 pts had<br />
≥1 set of tumor response measurements starting ≥8 weeks after first dose. Partial<br />
responses were observed in 4 of 4 ALK+ pts (60 mg n = 1; 90 mg n = 3, including <strong>the</strong><br />
crizotinib-naïve ACUP pt). Anti-tumor activity at 120 mg remains to be evaluated. In<br />
summary, AP26113 was well tolerated with preliminary anti-cancer activity in ALK+<br />
pts naïve to or failing prior crizotinib. The phase 2 expansion will include 4 cohorts:<br />
ALK+ NSCLC that is 1) naïve or 2) resistant to prior ALK-targeted <strong>the</strong>rapy; 3)<br />
EGFRm NSCLC that is resistant to EGFR-targeted <strong>the</strong>rapy; 4) o<strong>the</strong>r cancers with<br />
abnormalities in ALK or o<strong>the</strong>r AP26113 targets. ClinicalTrials.gov: NCT01449461.<br />
Disclosure: G.J. Weiss: GJW has received funds and o<strong>the</strong>r support related to<br />
participation in this clinical trial from ARIAD Pharmaceuticals, Inc. through his<br />
employer, Scottsdale Healthcare. GJW has served on Speakers Bureaus for<br />
Genentech, Pfizer, and Eli Lilly. N.I. Narasimhan: NIN is an employee of ARIAD<br />
Pharmaceuticals, Inc. D.J. Dorer: DJD is an employee of ARIAD Pharmaceuticals,<br />
Inc. V.M. Rivera: VMR is an employee of ARIAD Pharmaceuticals, Inc. J. Zhang: JZ<br />
is an employee of ARIAD Pharmaceuticals, Inc. T. Clackson: TC is an employee of<br />
ARIAD Pharmaceuticals, Inc. F. Haluska: FH is an employee of and owns stock/stock<br />
options in ARIAD Pharmaceuticals, Inc. A.T. Shaw: ATS has received consulting<br />
fees/honorarium from ARIAD, Pfizer, Chugai, and Daiichi. ATS has received support<br />
in <strong>the</strong> form of grants paid to her employer by Novartis and AstraZeneca. D.R.<br />
Camidge: DRC has received consulting fees/honorarium from ARIAD and has served<br />
on advisory boards for Pfizer, Chugai, Novartis, and ARIAD. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
Annals of Oncology<br />
440O RESULTS OF A FIRST-IN-HUMAN PHASE I STUDY OF THE<br />
ALK INHIBITOR LDK378 IN ADVANCED SOLID TUMORS<br />
A.T. Shaw 1 , D.R. Camidge 2 , E. Felip 3 , S. Sharma 4 , D.S.W. Tan 5 , D. Kim 6 ,<br />
T. De Pas 7 , J.F. Vansteenkiste 8 , A. Santoro 9 , G. Liu 10 , M. Goldwasser 11 ,<br />
D. Dai 12 , A.L. Boral 13 , R. Mehra 14<br />
1 Medicine, Harvard Medical School, Boston, MA, UNITED STATES OF<br />
AMERICA, 2 School of Medicine, University of Colorado, Denver, CO, UNITED<br />
STATES OF AMERICA, 3 Oncology, Vall d’Hebron University Hospital, Barcelona,<br />
SPAIN, 4 Center for Investigational Therapeutics, Huntsman Cancer Institute, Salt<br />
Lake City, UT, UNITED STATES OF AMERICA, 5 Department of Medical<br />
Oncology, National Cancer Center, Singapore, SINGAPORE, 6 Department of<br />
Internal Medicine, Seoul National University Hospital, Seoul, KOREA, 7 Medical<br />
Oncology Unit of Respiratory Tract and Sarcomas, Istituto Europeo di Oncologia,<br />
Milano, ITALY, 8 Respiratory Oncology Unit (pulmonology), University Hospital<br />
Gasthuisberg, Leuven, BELGIUM, 9 Department of Medical Oncology and<br />
Hematology, Istituto Clinico Humanitas, Rozzano, ITALY, 10 Ontario Cancer<br />
Institute, Princess Margeret Hospital, Toronto, ON, CANADA, 11 Novartis<br />
Institutes for BioMedical Research, Novartis Pharmaceuticals, Cambridge, MA,<br />
UNITED STATES OF AMERICA, 12 Oncology Clinical Pharmacology, Novartis<br />
Pharmaceuticals, East Hanover, NJ, UNITED STATES OF AMERICA, 13 Clinical<br />
Research, Novartis Institutes for Biomedical Research, Inc, Cambridge, MA,<br />
UNITED STATES OF AMERICA, 14 Department of Developmental Therapeutics,<br />
Fox Chase Cancer Center, Philadelphia, PA, UNITED STATES OF AMERICA<br />
Background: Translocations of <strong>the</strong> anaplastic lymphoma kinase (ALK) gene occur in<br />
3–8% of NSCLC. LDK378 is a novel, potent small molecule ALK inhibitor that produces<br />
tumor regressions in ALK-driven (ALK+) NSCLC xenografts. A Phase 1 study is being<br />
conducted with <strong>the</strong> primary objective of determining <strong>the</strong> MTD and safety profile in<br />
patients (pts) with ALK+ cancers. O<strong>the</strong>r objectives are to assess safety, PK, and<br />
antitumor activity in pts with ALK+ NSCLC, ei<strong>the</strong>r previously untreated with ALK<br />
inhibitors, or relapsed following ALK inhibitor treatment, and o<strong>the</strong>r ALK+ cancers.<br />
Methods: LDK378 was administered orally once-daily on a continuous 21-day<br />
schedule, in adult pts with advanced malignancies harboring a genetic alteration in<br />
ALK who progressed on standard <strong>the</strong>rapy or for whom <strong>the</strong>re was no effective<br />
<strong>the</strong>rapy. Dose escalation was guided by a Bayesian logistic regression model to<br />
determine <strong>the</strong> MTD, and started at 50 mg/day.<br />
Results: As of 25 April<strong>2012</strong>, 56 pts (primary site: lung 50 pts [37 with prior crizotinib];<br />
breast 4 pts; o<strong>the</strong>r 2 pts; median age 53 (22–76) years; 88% ECOG PS 0/1) had received<br />
LDK378 at doses of 50–750 mg/day. Of 47 pts evaluable for response (per investigator),<br />
<strong>the</strong>re were 24 (51%) responses. All responses were in ALK+ NSCLC (FISH positive in<br />
≥15% of tumor cells). In 26 pts with NSCLC who had progressed following crizotinib and<br />
were treated at ≥400 mg/day <strong>the</strong>re were 21 (81%) responses. Dose limiting toxicities (DLTs)<br />
have occurred in 2/14 pts at 400 mg/day, 2/9 pts at 600 mg/day, and 1/9 pts at 750 mg/day.<br />
DLTs included diarrhea, vomiting, nausea, dehydration, and ALT elevation. The MTD was<br />
750 mg/day. At <strong>the</strong> cutoff date, 36 (64%) pts remain on treatment. Discontinuations were<br />
due to adverse events (AEs) in 1 (2%), and disease progression in 19 (34%) pts. The most<br />
frequent AEs (all grades) were nausea 33 (59%), vomiting 30 (54%), and diarrhea 27 (48%)<br />
pts. The most frequent Grade 3/4 AE was diarrhea (5 [9%] pts). Oral absorption of<br />
LDK378 was rapid with a T max of 5–6 hours, and half-life was about 36 hours.<br />
Conclusions: Daily oral LDK378 is well tolerated and <strong>the</strong> MTD was 750 mg/day.<br />
Striking activity was seen in ALK+ NSCLC pts treated at doses ≥400mg, who had<br />
previously progressed following crizotinib.<br />
Disclosure: A.T. Shaw: I have a consultant/advisory role for Pfizer, Novartis, Chugar,<br />
Ariad, and Daiichi. D.R. Camidge: I have a compensated consultant/advisory role<br />
with Novartis Pharmacuticals Inc. S. Sharma: I have a compensated consultant/<br />
advisory role for Novartis (LEAD Summit). I have received honoraria for Novartis<br />
LEAD Summit. I have received research funding from Novartis (Phase Ib clinical<br />
trial). D.S.W. Tan: I have received research funding from Novartis. M. Goldwasser:<br />
Employment or leadership position to disclose: Associate Director Biostatistics:<br />
Novartis Pharmaceuticals. D. Dai: Employment or leadership position to disclose.<br />
Clinical Pharmacology Expert: Novartis Pharmaceuticals; Stock ownership: Myself;<br />
Novartis Pharmaceuticals. A.L. Boral: I am an employee of Novartis Institutes for<br />
Biomedical Sciences (Executive Director). I have stock ownership (Novartis). All<br />
o<strong>the</strong>r authors have declared no conflicts of interest.<br />
441O A PHASE I/II STUDY OF ALK INHIBITOR CH5424802 IN<br />
PATIENTS WITH ALK-POSITIVE NSCLC; SAFETY AND<br />
EFFICACY INTERIM RESULTS OF THE PHASE II PORTION<br />
M. Nishio1 , K. Kiura2 , K. Nakagawa3 , T. Seto4 , A. Inoue5 , M. Maemondo6 ,<br />
T. Hida7 , M. Harada8 , H. Yoshioka9 , T. Tamura10 1<br />
Thracic Oncology Center, Cancer Institute Hospital of JFCR, Tokyo, JAPAN,<br />
2<br />
Department of Respiratory Medicine, Okayama University Hospital, Okayama,<br />
JAPAN, 3 Medical Oncology, Kinki University School of Medicine, Osaka, JAPAN,<br />
4<br />
Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, JAPAN,<br />
5<br />
Department of Respiratory Medicine, Tohoku University, Sendai, JAPAN,<br />
6<br />
Department of Respiratory Medicine, Miyagi Cancer Center, Natori, JAPAN,<br />
7 8<br />
Thoracic Oncology, Aichi Cancer Center, Nagoya, JAPAN, Respiratory Medicine,<br />
National Hospital Organization Hokkaido Cancer Center, Sapporo, JAPAN,<br />
9 10<br />
Respiratory, Kurashiki Central Hospital, Kurashiki, JAPAN, Division of Internal<br />
Medicine and Thoracic Oncology, National Cancer Center Hospital, Tokyo, JAPAN<br />
Background: Anaplastic lymphoma kinase (ALK) is a tyrosine kinase constitutively<br />
activated following chromosomal gene translocation in a subset of non-small cell<br />
lung cancer (NSCLC). CH5424802, an oral ALK inhibitor, was well tolerated with<br />
promising efficacy in patients (pts) with ALK-positive NSCLC in <strong>the</strong> phase I portion<br />
(ASCO <strong>2012</strong>). Here we report <strong>the</strong> interim results of <strong>the</strong> ongoing phase II portion.<br />
Methods: The primary objective of <strong>the</strong> phase II portion was to investigate <strong>the</strong> efficacy<br />
and safety at <strong>the</strong> recommended dose (RD) determined in <strong>the</strong> phase I portion. Pts with<br />
ALK-positive NSCLC, measurable disease, and no prior ALK inhibitor <strong>the</strong>rapy were<br />
treated with CH5424802 at 300 mg bid until progressive disease or intolerable toxicity.<br />
Results: As of March 23, <strong>2012</strong>, 34 pts have been enrolled: median age; 46 years, M/F;<br />
16/18, ECOG PS 0/1; 17/17, never-smoker; 62%, number of prior chemo<strong>the</strong>rapy 1/2/<br />
3/ > 4; 18/6/0/10. Among <strong>the</strong> first 15 pts, <strong>the</strong> response rate was 73.3% with 1 CR and<br />
10 PRs. Main treatment-related adverse events (AEs) among <strong>the</strong> 34 pts were AST<br />
increased (7 pts), ALT increased (6), neutropenia (5), rash (4), nausea (4), myalgia<br />
(3), dysgeusia (3), constipation (3), blood CPK increased (3), blood bilirubin<br />
increased (3), and blood ALP increased (3), which were mostly Grade 1 except for<br />
neutropenia. Grade 3 treatment-related AEs were two cases of neutropenia. For<br />
treatment-related eye disorders which are frequent in crizotinib, only one Grade 1<br />
case (vision blurred) was observed. No treatment-related AEs led to dose reduction.<br />
At <strong>the</strong> time of submission, 30 pts are on study (range 1 - 8 months).<br />
Conclusion: CH5424802 demonstrated clinically meaningful antitumor activity with<br />
well tolerated toxicity profile. A phase I/II study in ALK-positive NSCLC pts<br />
previously treated with or without crizotinib is ongoing in <strong>the</strong> US.<br />
Disclosure: M. Nishio: Corporate-sponsored research:Chugai pharmaceutical Co.,<br />
Ltd., Pfizer. K. Kiura: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd.,<br />
Pfizer. K. Nakagawa: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd.,<br />
Pfizer. T. Seto: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., Pfizer.<br />
A. Inoue: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., Pfizer. M.<br />
Maemondo: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd. T. Hida:<br />
Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., Pfizer. M. Harada:<br />
Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., Pfizer. H. Yoshioka:<br />
Corporate-sponsored research:Chugai pharmaceutical Co., Ltd. T. Tamura:<br />
Corporate-sponsored research:Chugai pharmaceutical Co., Ltd.<br />
442O PI3K KINASE INHIBITOR GSK2126458 (GSK458): CLINICAL<br />
ACTIVITY IN SELECT PATIENT (PT) POPULATIONS DEFINED<br />
BY PREDICTIVE MARKERS (STUDY P3K112826)<br />
P. Munster 1 , R. van der Noll 2 , E. Voest 3 , J. Specht 4 , T.L. Werner 5 , E.C. Dees 6 ,<br />
A.R. Tan 7 , A. Daud 8 , J. Schellens 9 , M.P. Lolkema 3 , M. Griffin 4 , N. Agarwal 10 ,<br />
G.S. Falchook 11 , J.F. Kleha 12 , M. Durante 13 , D.A. Smith 12 , L. Adams 12 ,<br />
J. Greshock 12 , S.R. Morris 12 , R. Kurzrock 11<br />
1 Medicine, Division of Hem/Onc, University of California, San Francisco,<br />
San Francisco, CA, USA, 2 Department of Pharmacology, The Ne<strong>the</strong>rlands<br />
Cancer Institute, Amsterdam, NETHERLANDS, 3 Department of Medical<br />
Oncology, University Medical Center Utrecht, Utrecht, NETHERLANDS,<br />
4 University of Washington Division of Medical Oncology, Fred Hutchinson Cancer<br />
Research Center, Seattle, WA, UNITED STATES OF AMERICA, 5 Department of<br />
Internal Medicine, Oncology Division, University of Utah School of Medicine, Salt<br />
Lake City, UT, UNITED STATES OF AMERICA, 6 Developmental Therapeutics<br />
Working Group, UNC Lineberger Cancer Comprehensive Cancer Center, Chapel<br />
Hill, NC, UNITED STATES OF AMERICA, 7 Breast Medical Oncology and Phase I<br />
Program, The Cancer Institute of New Jersey, New Brunswick, NJ, UNITED<br />
STATES OF AMERICA, 8 Melanoma Program, University of California,<br />
San Francisco, San Francisco, CA, UNITED STATES OF AMERICA, 9 Department<br />
of Pharmacology, The Ne<strong>the</strong>rlands Cancer Institute, Amsterdam,<br />
NETHERLANDS, 10 Hunstman Cancer Institute, University of Utah, Salt Lake City,<br />
UT, UNITED STATES OF AMERICA, 11 Department of Investigational Cancer<br />
Therapeutics, UT MD Anderson Cancer Center, Houston, TX, UNITED STATES<br />
OF AMERICA, 12 Research and Development, Oncology, GlaxoSmithKline,<br />
Research Triangle Park, NC, UNITED STATES OF AMERICA, 13 Research and<br />
Development, Oncology, GlaxoSmithKline, Collegeville, PA, UNITED STATES OF<br />
AMERICA<br />
Background: GSK458 is an oral, potent inhibitor of PI3K (α, β, γ, δ), mTORC1, and<br />
mTORC2. Cell lines with activation of <strong>the</strong> PI3K pathway are more likely to be<br />
sensitive to GSK458.<br />
Methods: Pts with advanced solid tumors received GSK458 until disease progression<br />
or intolerable toxicity. Dose escalation with once (QD) and twice daily dosing (BID)<br />
was explored. Pharmacodynamics (PD) (tumor biopsies and FDG–PET) in unselected<br />
populations, and clinical activity in specific populations (PIK3CA-mutant and wild-type<br />
[WT]) bladder cancer, renal cell carcinoma, PIK3CA-mutant metastatic breast cancer,<br />
and KRAS-WT metastatic endometrial cancer) were evaluated.<br />
Results: 170 pts (49% female; mean age 57 [22-85] yrs) received doses ranging from<br />
0.1 to 3 mg, <strong>the</strong> MTD for both QD and BID was 2.5 mg. The median (range) time<br />
above <strong>the</strong> target plasma concentration (20 ng/mL) was longer in BID versus QD<br />
dosing: 21hour (h) (14.8-24; n = 6) versus 8h (0-23.9; n = 18), respectively. Dose<br />
limiting toxicities were Grade 3 diarrhea. Most frequent (≥ 20%) drug related adverse<br />
events were diarrhea (28%), fatigue (24%) and nausea (23%). A dose response<br />
relationship between GSK458 plasma concentrations and increases in serum insulin<br />
levels was observed. 13 paired pre/post-dose tumor biopsies showed inconsistent<br />
changes in pAKT/total AKT, Ki67 and phospho-histone-H3. 9 pts had pre/post-dose<br />
FDG-PET; one pt had a mean SUV value decrease by ≥30% post-dose although none<br />
had responses per RECIST. Objective responses were seen in bladder cancer (1/3<br />
PIK3CA mutant and 2/15 wild-type) and renal cell (2/23: 1 CR duration 25+ months,<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds395 | ix153
1PR), but no responses were seen in PIK3CA-mutant breast cancer (1/10: stable for >6<br />
months) or KRAS-WT endometrial cancer (1/12: stable disease for > 6 months).<br />
Conclusions: Based on its superior pharmacokinetic profile, BID is <strong>the</strong><br />
recommended schedule for GSK458 mono<strong>the</strong>rapy. Surrogate PD markers (insulin)<br />
indicate on target activity. GSK458 showed promising activity in PIK3CA mutant<br />
bladder cancer and RCC.<br />
Disclosure: P. Munster: Phase I Research: GSKJ. Specht: Corporate-sponsored<br />
research: Pfizer, BMS, Genentech, BiPar Sciences, Boehringer IngelheimE.C. Dees:<br />
Corporate-sponsored research: GSK, Novartis, Genentech/Roche, MillenniumA. Tan:<br />
Corporate-sponsored research: GSKA. Daud: Membership on an advisory board or<br />
board of directors: Oncosec; Corporate-sponsored research: GSK, Pfizer, Merck,<br />
Oncosec, Exelixis G. Falchook: Corporate-sponsored research: GSK; GSK Travel<br />
reimbursement for <strong>ESMO</strong> 2010J. F. Kleha: Stock ownership: GSK; GSK EmployeeM.<br />
Durante: Stock ownership: GSK; GSK EmployeeD.A. Smith: Stock ownership: GSK;<br />
GSK EmployeeL. Adams: Stock ownership: GSK; GSK EmployeeJ. Greshock: Stock<br />
ownership: GSK; GSK EmployeeS.R. Morris: Stock ownership: GSK; GSK<br />
EmployeeAll o<strong>the</strong>r authors have declared no conflicts of interest.<br />
443PD PHARMACODYNAMIC (PD) – PHARMACOKINETIC (PK)<br />
STUDY OF FICLATUZUMAB(F), A MONOCLONAL ANTIBODY<br />
(MAB) DIRECTED TO THE HEPATOCYTE GROWTH FACTOR<br />
(HGF), IN PATIENTS (PTS) WITH ADVANCED SOLID TUMORS<br />
WHO HAVE LIVER METASTASES (METS)<br />
E. Elez 1 , J. Tabernero 2 , L. Prudkin 3 , S. Agarwal 4 , M. Han 4 , M. Credi 4 ,W.Yin 4 ,<br />
N. Kuriyama 4 , J. Baselga 5<br />
1 Medical Oncology, Vall d’Hebron University Hospital, Barcelona, SPAIN,<br />
2 Oncology Department, Vall d’Hebron University HospitalMedical Oncology<br />
Service, Barcelona, SPAIN, 3 Pathology, Vall d’Hebron University Hospital,<br />
Barcelona, SPAIN, 4 Oncology, AVEO Pharmaceuticals, Inc, Cambridge, MA,<br />
UNITED STATES OF AMERICA, 5 Hematology/Oncology, MGH Cancer Center,<br />
Massachusetts General Hospital, Boston, MA, UNITED STATES OF AMERICA<br />
Background: F is a humanized IgG1 mAb directed to HGF that inhibits activation of<br />
<strong>the</strong> c-Met receptor, with potential anti-tumor activity. This study was to define <strong>the</strong><br />
optimal dose using PD and PK assessments.<br />
Methods: Pts with solid tumors and liver mets, with phospho (p)-Met expression<br />
were sequentially enrolled into 2, 10, or 20 mg/kg (RP2D, defined in a previous<br />
study), of F given IV every 2 wks and were evaluated every 8 wks for response<br />
using RECIST 1.1. Target pathway modulation was assessed by measuring <strong>the</strong><br />
following PD markers by IHC in biopsies of liver mets: p-Met, p-Akt, p-ERK,<br />
p-S6K, HGF, and c-Met; Ki67 and cleaved caspase-3; and CD31. PD-evaluable pts<br />
had measurable p-Met at Cycle 1 Day 1 pre-dose and at least one post-dose<br />
timepoint. Serum was collected to measure F, anti-drug antibody (ADA), s-Met,<br />
HGF, and HGF/F complex levels by ELISA.<br />
Results: Nineteen pts received F: 15 male/4 female; median age 60 years; ECOG PS 0/1<br />
(8/11 pts). The most frequent TEAEs, mostly Grade 1 to 3, were as<strong>the</strong>nia, edema, hepatic<br />
pain (32% each), cough (26%). There were no DLTs or ADA. Serum albumin decreased<br />
to below normal for most pts at EOT and recovered at <strong>the</strong> follow up visit. Best overall<br />
response was SD (5/18 pts) and disease progression (13/18 pts), and median duration of<br />
treatment was 6 wks (range 2-59). PK analysis revealed dose-proportional drug exposure<br />
with a low systemic clearance leading to a terminal half-life of 7.4 to 10.0 days, and a low<br />
volume of distribution approximating <strong>the</strong> plasma volume. F treatment increased <strong>the</strong> total<br />
serum HGF and HGF/F complex levels. Increasing dose of F resulted in progressive<br />
decreases in p-Met and p-AKT. At RP2D, <strong>the</strong> majority of pts experienced ≥ 25%<br />
decrease from baseline in p-Met, p-ERK, p-Akt, Ki67 and CD31.<br />
Conclusions: Ficlatuzumab(F) is well tolerated in this population. The PK of F in<br />
this study was consistent with that reported previously. Increase in post-dose serum<br />
HGF and HGF/F complex levels indicates target engagement. At RP2D, a majority of<br />
pts experienced decreases in key cell signaling PD markers. This study supports <strong>the</strong><br />
selection of 20 mg/kg F dose as RP2D.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
444PD PHASE I DOSE-ESCALATION STUDY OF ORAL SELECTIVE<br />
C-MET INHIBITOR EMD 1214063 IN PATIENTS WITH<br />
ADVANCED SOLID TUMORS<br />
G.S. Falchook 1 , D.S. Hong 1 , H.M. Amin 2 ,S.Fu 1 , S.A. Piha-Paul 1 ,<br />
M.B. Klevesath 3 , V. Jego 4 , A. Johne 5 , S. Stinchi 6 , R. Kurzrock 1<br />
1 Department of Investigational Cancer Therapeutics, UT MD Anderson Cancer<br />
Center, Houston, TX, UNITED STATES OF AMERICA, 2 Department of<br />
Hematopathology, UT MD Anderson Cancer Center, Houston, TX, UNITED<br />
STATES OF AMERICA, 3 Global Early Development Unit - Oncology, Merck<br />
KGaA, Darmstadt, GERMANY, 4 Biostatistics Geneva, Merck Serono, Geneva,<br />
SWITZERLAND, 5 Clinical Pharmacology, Merck KGaA, Darmstadt, GERMANY,<br />
6 Istituto Di Ricerche Biomediche, Merck Serono RBM, Colleretto Giacosa, ITALY<br />
Purpose: The cell surface receptor tyrosine kinase c-Met and its ligand, hepatocyte<br />
growth factor (HGF), mediate cell migration, survival and proliferation. EMD<br />
Annals of Oncology<br />
1214063 is a highly selective, reversible and ATP-competitive c-Met inhibitor that<br />
causes growth inhibition and regression of HGF-dependent and HGF-independent<br />
tumors in pre-clinical models.<br />
Methods: This is a first-in-man dose-escalation study to establish <strong>the</strong> MTD of EMD<br />
1214063. Eligible pts had advanced solid tumors not amenable to standard <strong>the</strong>rapy.<br />
Following a 3 + 3 dose escalation scheme, pts were treated with once-daily oral EMD<br />
1214063 according to two 21-day-cycle schedules, ei<strong>the</strong>r days 1-14 followed by a<br />
7-day rest (regimen 1, [R1]), or continuous 3 times weekly (regimen 2, [R2]). An<br />
optimised formulation was introduced in August 2011. Pd markers were evaluated in<br />
paired tumor biopsies using immunohistochemistry (IHC) and a Luminex based<br />
assay.<br />
Results: Until 3 November 2011, 50 pts had been treated; 27 in R1 and 23 in R2.<br />
The dose was escalated from 30 mg/day to 230 mg/day in R1 and to 115 mg/day in<br />
R2 with <strong>the</strong> initial formulation. For <strong>the</strong> optimised formulation, data are available for<br />
30 mg and 60 mg/day for R1, and for 60 mg/day in R2. Cmax and AUC increased<br />
with dose. The optimised formulation showed higher oral bioavailability. Two DLTs<br />
were reported, a G4 lipase and G3 amylase elevation in 1 pt in R1 at 115 mg/day,<br />
and a G3 lipase elevation in R2 at 115 mg/day. No treatment-related SAEs were<br />
observed. Treatment-related AEs of ≥G2 included nausea (n = 1), vomiting (n = 1),<br />
decreased appetite (n = 2), diarrhea (n = 1), and fatigue (n = 1) in R1, and<br />
neutropenia (n = 1) and fatigue (n = 1) in R2. Forty-four patients (88%) had no<br />
drug-related AE >G1. Analysis of pre- and on-treatment biopsies showed decreased<br />
phospho-c-Met staining intensity under treatment on IHC and >80% reduction in<br />
phospho-c-Met levels on <strong>the</strong> Luminex assay. Preliminary anti-tumor activity included<br />
an unconfirmed PR in 1 pt and SD ≥4 months in 7 pts. One pt with sarcomatoid<br />
bladder cancer and multiple MET copies due to polysomy of Chr 7 achieved SD for<br />
12+ months.<br />
Conclusion: The MTD has not yet been reached and dose escalation of EMD<br />
1214063 continues. Updated results will be presented.<br />
Disclosure: G.S. Falchook: Has a consultant/advisory relationship with EMS Serono,<br />
received research funding of EMD Serono, received travel reimbursement from EMD<br />
Serono. H.M. Amin: Received research funding of EMD SeronoM.B. Klevesath:<br />
Merck KGaA employeeV. Jego: Merck Serono employeeA. Johne: Merck Serono<br />
employeeS. Stinchi: Merck Serono employeeR. Kurzrock: Received research funding<br />
of EMD Serono and Merck KGaAAll o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
445PD CLINICAL ACTIVITY AND PHARMACOKINETICS (PK) OF<br />
CABOZANTINIB (XL184) IN PATIENTS WITH PROGRESSIVE<br />
MEDULLARY THYROID CARCINOMA (MTC)<br />
E.E.W. Cohen 1 , R. Elisei 2 , M.J. Schlumberger 3 , S.P. Müller 4 , P. Schöffski 5 ,<br />
M. Brose 6 , M. Shah 7 , D.R. Miles 8 , L.T. Nguyen 8 , S. Sherman 9<br />
1 Dept of Medicine, University of Chicago Medical Center, Chicago, IL, UNITED<br />
STATES OF AMERICA, 2 Department of Endocrinology, University of Pisa, Pisa,<br />
ITALY, 3 Medical Imaging, Institut de Canc, Villejuif Cedex, FRANCE, 4 Klinik und<br />
Poliklinik für Nuklearmedizin, Universitätsklinikum Essen, Essen, GERMANY,<br />
5 Department of General Medical Oncology, University Hospitals Leuven, Leuven,<br />
BELGIUM, 6 Dept of Medicine, University of Pennsylvania Health System,<br />
Philadelphia, PA, UNITED STATES OF AMERICA, 7 College of Medicine, Ohio<br />
State University, Columbus, OH, UNITED STATES OF AMERICA, 8 Nonclinical<br />
Development, Exelixis, Inc., South San Francisco, CA, UNITED STATES OF<br />
AMERICA, 9 Department of Endocrine Neoplasia and Hormonal Disorders,<br />
University of Texas MD Anderson Cancer Center, Houston, TX, UNITED STATES<br />
OF AMERICA<br />
Background: Cabozantinib (cabo) is a potent oral <strong>the</strong>rapy that inhibits MET,<br />
VEGFR2, and RET. In a phase 1 study, cabo demonstrated anti-tumor activity in<br />
patients with MTC, and a long terminal half-life of 120 hours. We report<br />
clinical activity and PK analyses from a Phase 3 study of cabo versus placebo<br />
(P) in patients with progressive, unresectable, locally advanced or metastatic<br />
MTC.<br />
Methods: Patients with MTC and documented RECIST progression within 14<br />
months (mo) of screening were randomized 2:1 to receive cabo (140 mg freebase qd,<br />
n = 219) or placebo (n = 111). Blood samples for PK were collected on days 1 and 29.<br />
Baseline tumor and blood samples were evaluated for RET mutation status. Tumor<br />
assessments occurred every 12 weeks, and <strong>the</strong> primary efficacy measure was<br />
progression-free survival (PFS), assessed by an independent radiology committee<br />
using RECIST.<br />
Results: Statistically significant PFS prolongation was observed, with median PFS for<br />
cabo of 11.2 mo versus 4.0 mo for P (HR 0.28, 95% CI 0.19-0.40, p < 0.0001). PFS<br />
results favored <strong>the</strong> cabo group across all RET mutation subgroups with hazard ratios<br />
0.24, 0.47, and 0.30 for RET mutation positive, negative, and unknown subgroups.<br />
The 12-mo progression-free landmark estimate is 47.3% for cabo and 7.2% for P;<br />
objective response rate was 28% for cabo vs 0% for P. Cabo demonstrated moderate<br />
accumulation, with plasma C max ∼3.6-fold increased at steady-state (Day 29) relative<br />
to Day 1. Plasma concentrations did not fluctuate markedly over <strong>the</strong> 24 hr dosing<br />
interval on Day 29. In a population-PK analysis, moderate inter-subject variability in<br />
clearance (CL/F) was observed (CV of ∼35%). No clinically significant covariates on<br />
PK were identified which would require dose adjustment, and PFS for cabo-treated<br />
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Annals of Oncology<br />
subjects did not correlate with individual subject steady-state AUC predicted for<br />
uninterrupted 140 mg qd dosing.<br />
Conclusions: Cabo significantly prolonged PFS compared to placebo in a patient<br />
population with progressive MTC. PK analysis supports administration of cabo as a<br />
fixed dose without adjustment for patient covariates.<br />
Disclosure: M.J. Schlumberger: MJ Schlumberger has been a compensated<br />
consultant for Exelixis. M. Brose: Dr. Brose has received research funding and<br />
honoraria from Exelixis. M. Shah: Dr. Shah has received research funding from<br />
Exelixis. D.R. Miles: D. Miles is an employee and stockholder of Exelixis. L.T.<br />
Nguyen: Linh Nguyen is an employee and stockholder in Exelixis. S. Sherman: Dr.<br />
Sherman is a compensated consultant to Exelixis. All o<strong>the</strong>r authors have declared<br />
no conflicts of interest.<br />
446PD PHASE I STUDY OF AFATINIB (BIBW 2992), AN ERBB<br />
FAMILY BLOCKER PLUS NINTEDANIB (BIBF 1120), A TRIPLE<br />
ANGIOKINASE INHIBITOR, IN PATIENTS (PTS) WITH<br />
ADVANCED SOLID TUMOURS<br />
J. Soria 1 , A. Hollebecque 1 , C. Massard 1 , E. Deutsch 1 , A. Varga 1 , N. Morsli 2 ,<br />
M. Ould Kaci 2 , H. Staines 2 , K. Marzin 3 , R. Bahleda 1<br />
1 Dept. of Medicine, Institut Gustave Roussy, Villejuif Cedex, FRANCE, 2 Medical<br />
Affairs, Boehringer Ingelheim, Paris, FRANCE, 3 Pharmacokinetics, Boehringer<br />
Ingelheim, Biberach, GERMANY<br />
Background: Inhibiting multiple signalling pathways with <strong>the</strong> combination of<br />
afatinib, an oral irreversible ErbB Family Blocker, and nintedanib, an oral triple<br />
angiokinase inhibitor of VEGFR, PDGFR and FGFR, may lead to better efficacy.<br />
Methods: This Phase I study used a modified 3 + 3 design to determine <strong>the</strong><br />
maximum tolerated dose (MTD) of afatinib, with dose escalating from 10 to 40 mg<br />
qd given in 2 schedules: continuous (C) or intermittent (I) (every o<strong>the</strong>r week), in<br />
combination with fixed-dose nintedanib (200 mg bid reduced to 150 mg bid after<br />
protocol amendment) in a 28-day cycle. Secondary endpoints were safety, efficacy,<br />
pharmacokinetics (PK), and circulating tumour cells (CTC) analysis. Treatment<br />
continued until disease progression or intolerability.<br />
Results: 45 pts with heavily pretreated advanced solid tumours were included: 26<br />
men; median age 56 years (range 37–73); main cancer types: lung (NSCLC),<br />
colorectal, breast, melanoma and ovary. Main adverse events were diarrhoea,<br />
as<strong>the</strong>nia, nausea, vomiting and transaminase elevation. Two MTDs were established:<br />
afatinib 40 mg qd (I) plus nintedanib 150 mg bid and afatinib 30 mg qd (C) plus<br />
nintedanib 150 mg bid (Table). Efficacy data showed evidence of antitumour activity<br />
with partial responses (RECIST) observed in 2 pts (HER2-negative breast cancer, and<br />
head & neck squamous cell carcinoma) and stable disease in 27 pts (lasting >3<br />
months in 8 pts). Preliminary PK data showed no drug–drug interaction. CTC<br />
analysis will be presented.<br />
Afatinib (C or I)<br />
(mg qd)<br />
Nintedanib<br />
(mg bid)<br />
Evaluable pts/<br />
dose-limiting<br />
toxicity (DLT) DLT/Grade (G)<br />
10 C 200 3/0<br />
20 C 200 3/0<br />
30 C 200 7/2 diarrhoea G3,<br />
transaminase elevation<br />
G3<br />
40 C 200 3/3 diarrhoea G3,<br />
transaminase elevation<br />
G3; creatinine increase<br />
G2<br />
30 I 200 6/2 diarrhoea G3,<br />
transaminase elevation<br />
G3, creatinine increase<br />
G2<br />
40 I 200 6/2 dehydration G3,<br />
transaminase elevation<br />
G4<br />
40 C 150 3/2 diarrhoea G3, renal<br />
failure G3<br />
40 I 150 6/0 MTD<br />
30 C 150 6/0 MTD<br />
Conclusion: At MTD, <strong>the</strong> combination of afatinib with nintedanib showed a<br />
manageable safety profile and evidence of activity in different heavily pretreated<br />
tumour types.<br />
Disclosure: J. Soria: Honoraria from Boehringer Ingelheim and Roche. N. Morsli:<br />
Employee of Boehringer Ingelheim. M. Ould Kaci: Employee of Boehringer<br />
Ingelheim. H. Staines: Employee of Boehringer Ingelheim. K. Marzin: Employee of<br />
Boehringer Ingelheim. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
447PD PRECLINICAL AND CLINICAL EVALUATION OF THE<br />
COMBINATION OF SORAFENIB AND EVEROLIMUS IN<br />
PATIENTS WITH ADVANCED SOLID TUMORS<br />
W.W. Ma1 , C. Weekes2 , D.K. Pawaskar3 , G. Fetterly1 , W.A. Messersmith2 ,<br />
G.K. Dy1 , R.M. Straubinger3 , W.J. Jusko3 , S.G. Eckhardt4 , A.A. Adjei5 1<br />
Medicine, Roswell Park Cancer Institute, Buffalo, NY, UNITED STATES OF<br />
AMERICA, 2 Medicine, Univ of Colorado Health Sci Ctr, Aurora, CO, UNITED<br />
STATES OF AMERICA, 3 Pharmaceutical Sciences, State University of New York<br />
at Buffalo, Buffalo, NY, UNITED STATES OF AMERICA, 4 Medical Oncology,<br />
University of Colorado Denver, Denver, CO, UNITED STATES OF AMERICA,<br />
5<br />
Medicine Oncology, Roswell Park Cancer Institute, Buffalo, NY, UNITED<br />
STATES OF AMERICA<br />
Background: Using a patient-derived primary pancreatic cancer (PanCa) xenograft<br />
SCID mouse model, we found synergistic anti-tumor effects of sorafenib (S) 20 mg/<br />
kg + everolimus (E) 1 mg/kg, and greater efficacy than ei<strong>the</strong>r drug alone. No<br />
significant mouse toxicity was observed (weight loss, fur quality, GI toxicity). Here, we<br />
conducted a phase I and pharmacokinetic (PK) study of S + E in patients with advanced<br />
solid tumors, intending to expand to a phase II PanCa trial. Methods: Patients with<br />
advanced solid tumors were treated at dose levels (DL): [DL1] S 400 mg bid + E 5 mg<br />
daily; [DL2] S 400 mg bid + E 10 mg daily every 28-day cycle using a 3 + 3 dose<br />
escalation design. Patients started treatment with ei<strong>the</strong>r S or E alone during a 1-week<br />
run-in, and <strong>the</strong> o<strong>the</strong>r agent added from Cycle 1 Day 1 onwards. Plasma samples were<br />
collected and analyzed for S and E, and PK was compared to preclinical studies.<br />
Results: Ten of 22 patients were evaluable for dose-limiting toxicity (DLT). Two of 6<br />
and 3 of 4 patients developed DLT at DL1 and 2 respectively, including grade (G) 3<br />
diarrhea, rash, hypophosphatemia, hand-foot syndrome and G4 fistula. Median<br />
cycles received were 1.5. Clinical E exposure (AUC profile) was significantly lower (1/<br />
100th) than in preclinical combination studies whereas S exposure was comparable.<br />
Best response was stable disease for 6 cycles (168 days) in a uterine carcinosarcoma<br />
patient at DL1 (prior <strong>the</strong>rapy PFS 114 days). Intention-to-treat analysis of 12<br />
advanced gemcitabine-refractory (GR) PanCa patients showed median survival of 2.7<br />
mo (95%CI 0, 6.8 mo). No PK interaction between S and E was observed.<br />
Conclusions: E at doses 5 mg and 10 mg daily combined with S 400 mg bid were not<br />
tolerable in patients. S toxicity appeared accentuated by E co- administration with no<br />
drug-drug PK interaction observed. Efficacy was observed in uterine carcinosarcoma but<br />
no significant efficacy in GR-PanCa. Although our preclinical model indicated efficacy<br />
of S + E in PanCa, it failed to predict <strong>the</strong> clinical toxicity profile.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
448PD A PHASE I STUDY OF THE COMBINATION OF RO4929097<br />
(RO) AND CEDIRANIB (CD) IN PATIENTS WITH ADVANCED<br />
SOLID TUMORS (PJC-004/NCI 8503)<br />
S. Sahebjam 1 , P. Bedard 2 , V. Castonguay 1 , H. Chen 3 , S.P. Ivy 3 , A.M. Oza 1 ,<br />
E.X. Chen 1 , H.W. Hirte 4 , L. Siu 1 , S.J. Hotte 4<br />
1 Drug Development Program, Medical Oncology, Princess Margaret Hospital,<br />
Toronto, ON, CANADA, 2 Dept of Medical Oncology, Princess Margaret Hospital,<br />
Toronto, ON, CANADA, 3 Cancer Therapy Evaluation Program, National Cancer<br />
Institute, Be<strong>the</strong>sda, MD, UNITED STATES OF AMERICA, 4 Medical Oncology,<br />
Juravinski Cancer Centre, Hamilton, ON, CANADA<br />
Background: The NOTCH signaling pathway has been implicated in <strong>the</strong><br />
tumorigenesis and resistance to anti-VEGF <strong>the</strong>rapy, providing a rationale for <strong>the</strong><br />
combination of RO, a gamma secretase inhibitor of NOTCH signaling, and Cd, a<br />
VEGFR-tyrosine multi-kinase inhibitor.<br />
Methods: The primary objectives of this study were to assess safety, tolerability, and<br />
recommended phase II dose (RP2D) of combination <strong>the</strong>rapy in patients (pts) with<br />
advanced solid tumors. Secondary objectives were to determine preliminary anti-tumor<br />
efficacy, as per RECIST v1.1 criteria, as well as pharmacokinetic (PK) and<br />
pharmacodynamic (PD) studies. A standard 3 + 3 design was used. Cycle 1 is 42 days (D),<br />
where RO is given orally once daily D1-3, 8-10, 15-17, 22-24, 29-31, 36-38 and Cd is<br />
given orally once daily D22-42. Cycles 2 + are 21 days, with RO given D1-3, 8-10, 15-17<br />
and Cd given D1-21. Dose-limiting toxicity (DLT) was evaluated during cycle 1 (42 days).<br />
Results: Twenty pts (median age of 54 [18-87]; ECOG 0-1) have been treated at 3<br />
dose levels (DL): 7 pts at DL1 (RO = 10 mg; Cd =20 mg), 7 pts at DL2 (RO = 20 mg;<br />
Cd = 20 mg), and 6 pts at DL3 (RO = 20 mg; Cd = 30 mg). Primary tumors included:<br />
colorectal carcinoma (6), uterine sarcoma (4), renal cell carcinoma (3), and o<strong>the</strong>rs<br />
(7). Pts received a median number of 3 cycles (range 1-20). The most common<br />
adverse events (AEs) of all grades possibly related to study drugs included (#pts):<br />
diarrhea (12), hypertension (HTN) (11), fatigue (11), and nausea (9). Grade 3+ AEs<br />
possibly related to study drugs included HTN, ALT and AST elevation, diarrhea, and<br />
hypophosphatemia. Two DLTs were observed: grade 4 HTN in DL1 which resolved<br />
after dose reduction and grade 4 AST elevation in DL2 which improved after<br />
discontinuing treatment. Of <strong>the</strong> 19 patients evaluable for response, <strong>the</strong> best response<br />
was stable disease (SD) in 12 pts and progressive disease in 7. Prolonged SD of ≥6<br />
cycles was observed in 4 pts, including 1 pt with low grade endometrial stromal<br />
sarcoma on DL1 who remains on study after 20 cycles.<br />
Conclusions: RO in combination with Cd is generally well tolerated at <strong>the</strong><br />
DLs tested. The RP2D was defined as 20mg RO and 30mg Cd. PK data for<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds395 | ix155
RO and Cd, as well as PD data for circulating angiogenic factors will be<br />
presented.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
449PD PHASE 1 DOSE-ESCALATION TRIAL OF THE<br />
INVESTIGATIONAL HEDGEHOG (HH) PATHWAY INHIBITOR<br />
TAK-441 IN PATIENTS WITH ADVANCED SOLID TUMORS<br />
J.W. Goldman 1 , S.G. Eckhardt 2 , M. Borad 3 , M. Hidalgo 4 , D.P. Ryan 5 , A. Parikh 6 ,<br />
S. Kuan 7 ,J.Yu 7 , S. Stewart 1 , L.S. Rosen 1<br />
1 Hematology / Oncology, UCLA Medical Center, Santa Monica, CA, UNITED<br />
STATES OF AMERICA, 2 Medical Oncology, University of Colorado School of<br />
Medicine, Aurora, CO, UNITED STATES OF AMERICA, 3 Hematology / Oncology,<br />
Mayo Clinic, Scottsdale, AZ, UNITED STATES OF AMERICA, 4 GIi Cancer Clinical<br />
Research Unit, CNIO- Spanish National Cancer Center, Madrid, SPAIN,<br />
5 Hematology / Oncology, Massachusetts General Hospital, Boston, MA, UNITED<br />
STATES OF AMERICA, 6 General Medicine, Takeda Pharmaceuticals<br />
International, Inc., Deerfield, IL, UNITED STATES OF AMERICA, 7 Clinical<br />
Pharmacology, Millennium Pharmaceuticals, Inc., Cambridge, MA, UNITED<br />
STATES OF AMERICA<br />
Background: Dysregulation of <strong>the</strong> Hh pathway is a principal event in <strong>the</strong><br />
carcinogenesis of multiple tumor types, including basal cell carcinoma. TAK-441 is<br />
an investigational, orally-available inhibitor of <strong>the</strong> G protein-coupled receptor<br />
Smoo<strong>the</strong>ned, a component of <strong>the</strong> Hh signalling cascade.<br />
Methods: This study (NCT01204073) was designed to determine safety, maximum<br />
tolerated dose (MTD) and maximum feasible dose (MFD) in patients with advanced<br />
solid tumors. Cycles consisted of 3 weeks continuous dosing, with a single-dose cycle<br />
1 lead-in, followed by 7 d pharmacokinetics (PK). Dose escalation (DE) proceeded in<br />
a modified 3 + 3 fashion. Radiographic tumor assessments were performed after<br />
cycles 2, 4, and every 4 cycles <strong>the</strong>reafter.<br />
Results: Thirty-two patients were enrolled in <strong>the</strong> DE phase, median age 59 y (range<br />
28–82), and treated with doses from 50–1600 mg daily. TAK-441 concentrations<br />
were quantifiable in plasma after <strong>the</strong> starting 50 mg dose, with total exposure<br />
increasing dose-proportionally to 800 mg. Maximum plasma concentration typically<br />
was reached 3 h post-dose. The median terminal disposition half-life was 15 h (range<br />
6–35 h). DLTs of Gr 3 fatigue and muscle spasms were observed in 1 pt at <strong>the</strong> 1600<br />
mg dose. Six subjects discontinued due to an adverse event (AE) including a patient<br />
who suffered a fatal cerebral hemorrhage in cycle 4 related to 50 mg TAK-441. Most<br />
common treatment-emergent AEs were muscle spasms (44%), dysguesia (41%),<br />
nausea (41%), fatigue (38%) and constipation (28%). The MFD is 1600 mg and <strong>the</strong><br />
MTD has not been reached. Four patients remained on trial for >10 cycles, and 3<br />
patients continue on treatment. Response and PK/PD data will be presented.<br />
Conclusions: TAK-441 was well-tolerated up to an MFD of 1600 mg taken once<br />
daily. A dose expansion cohort has been initiated at 800 mg in patients with<br />
untreated basal cell carcinoma.<br />
Disclosure: S.G. Eckhardt: Consultancy, Research funding and Speakers Bureau/<br />
Advisory Committee for Millennium/Takeda. S. Kuan: Employment with Millennium<br />
Pharmaceuticals, Inc. J. Yu: Employment and consultancy for Millennium. L.S. Rosen:<br />
Research support from Millennium. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
450PD A PHASE IB COMBINATION STUDY OF RO4929097 (RO), A<br />
GAMMA-SECRETASE INHIBITOR, AND TEMSIROLIMUS<br />
(TEM) IN PATIENTS (PTS) WITH ADVANCED SOLID TUMORS<br />
I. Diaz-Padilla 1 , S.J. Hotte 2 , S.P. Ivy 3 , A.M. Oza 1 , H.W. Hirte 2 , A.R.A. Razak 1 ,<br />
E.X. Chen 1 , I. Brana Garcia 1 , L. Siu 1 , P. Bedard 1<br />
1 Dept. of Medical Oncology and Hematology, Princess Margaret Hospital,<br />
Toronto, ON, CANADA, 2 Medical Oncology, Juravinski Cancer Centre, Hamilton,<br />
ON, CANADA, 3 Cancer Therapy Evaluation Program, National Cancer Institute,<br />
Be<strong>the</strong>sda, MD, UNITED STATES OF AMERICA<br />
Background: The notch signalling pathway has a critical role in regulating cellular<br />
differentiation, proliferation, and apoptosis. RO is a potent and selective gamma-secretase<br />
inhibitor with antitumor activity in animal models. Pre-clinical experiments indicate that<br />
<strong>the</strong> PI3K/AKT/mTOR pathway may mediate resistance to gamma secretase inhibitors,<br />
providing a rationale for combination <strong>the</strong>rapy with RO and TEM.<br />
Methods: A phase Ib dose-escalation study with a 3 + 3 design was conducted.<br />
Three dose levels (DLs) were planned. Objectives were to determine <strong>the</strong><br />
recommended phase II dose (RP2D), safety, pharmacokinetics (PK) and<br />
pharmacodynamics (PD) of <strong>the</strong> combination. Eligible pts received once daily oral<br />
RO on a 3 day on/4 day off schedule every week (QW), and intravenous QW<br />
TEM. Initial doses were 10 mg RO and 25 mg TEM. Cycles were every 21 days,<br />
except for cycle 1, which was 28 days. Treatment-related dose-limiting toxicities<br />
(DLTs) were evaluated during cycle 1.<br />
Results: 17 pts (data cut-off 26-Apr-<strong>2012</strong>) have been treated on three DLs. Number of<br />
pts, DLTs and schedule are shown in Table 1. Demographics: M:F 6:11; median age: 60<br />
yrs (range 28-84); ECOG 0/1:4/13. Pts received a median of 3 cycles (range 1-12). The<br />
most common adverse events (AEs) related to <strong>the</strong> study drug combination included:<br />
fatigue (82%; G3 6%), mucositis, (71%; G3 6%), neutropenia (59%; G3 12%), anemia<br />
(59%;G30%),andhypertriglyceridemia(59%,G30%).TwoDLTs(G3rash,G3<br />
mucositis) were observed in <strong>the</strong> same patient in DL1 prompting dose expansion. No<br />
additional DLTs were observed. Of 15 patients evaluable for response, no objective<br />
responses were observed. 11 pts (73%) had stable disease (SD) as <strong>the</strong>ir best response; with<br />
3 pts (sarcoma, neuroendocrine, non-small cell lung cancer) on <strong>the</strong>rapy for ≥6 cycles.<br />
Conclusions: RO can be safely combined with TEM. The RP2D was established as<br />
RO at 20 mg combined with 37.5 mg of TEM. PK and circulating angiogenic factors<br />
analyses will be presented.<br />
RO Dose<br />
(mg)<br />
TEM Dose<br />
(mg)<br />
No. of pts<br />
treated<br />
No. of pts<br />
with DLT DLT<br />
Dose Level<br />
1 †<br />
10 25 8 1 G3 rash, G3<br />
mucositis<br />
2 20 25 3 0<br />
3 ∧<br />
20 37.5 6 0<br />
† 2 pts were not evaluable for DLT ∧ DL3 (RP2D) was expanded to 6 pts<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
451P PHASE I AND PHARMACOKINETICS/PHARMACODYNAMICS<br />
(PK/PD) STUDY OF MEK INHIBITOR, RO4987655, IN<br />
JAPANESE PATIENTS WITH ADVANCED SOLID TUMORS<br />
S. Nakamichi 1 , H. Nokihara 1 , N. Yamamoto 1 , Y. Tamura 1 , K. Honda 1 , H. Wakui 1 ,<br />
Y. Yamada 2 , N. Yamazaki 3 , S. Suzuki 4 , T. Tamura 1<br />
1 Division of Thoracic Oncology, National Cancer Center Hospital, Tokyo, JAPAN,<br />
2 Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo,<br />
JAPAN, 3 Division of Dermatological Oncology, National Cancer Center Hospital,<br />
Tokyo, JAPAN, 4 Division of Ophthalmic Oncology, National Cancer Center<br />
Hospital, Tokyo, JAPAN<br />
Background: RO4987655, an oral and selective inhibitor of MEK, is a key enzyme of<br />
<strong>the</strong> MAPK signaling pathway. This was a phase I, non-randomized, open-label,<br />
dose-escalation study in Japanese patients with advanced solid tumors. Primary<br />
objectives were determination of maximum tolerated dose (MTD) based on<br />
dose-limiting toxicities (DLTs), safety evaluation and PK analysis. Secondary<br />
objectives were PD analysis and exploratory analysis of RO4987655’s anti-tumor<br />
activity according to <strong>the</strong> RECIST 1.0 criteria.<br />
Methods: Patients received an oral single dose of RO4987655 (1, 2, 4, 5, and 6.5 mg)<br />
(Cycle 0) followed by continuous once daily dosing (QD, 1, 2, and 4 mg/day) <strong>the</strong>n<br />
twice daily dosing (4, 5, and 6.5 mg BID, total daily dose: 8, 10, and 13 mg/day) in<br />
28-day cycles. A 3 + 3 dose-escalation design was used. Blood samples for PK analysis<br />
were collected in Cycle 0 (Day 1, 2, and 3) and in Cycle 1 (Day 1, 8, 15, and 22). PD<br />
was evaluated by pERK inhibition in peripheral blood mononuclear cells (PBMCs).<br />
Results: As of March <strong>2012</strong>, 25 patients were enrolled in 6 cohorts of 1, 2, 4, 8, 10,<br />
and 13 mg/day. Four DLTs were observed in <strong>the</strong> 13 mg/day (n = 2) and 10 mg/day<br />
(n = 2) cohorts, all of <strong>the</strong>m reversible Grade 3 creatine phosphokinase (CPK)<br />
elevation. MTD was defined as 8 mg/day. Most commonly related adverse events<br />
(AEs) included dermatitis acneiform, CPK elevation, and eye disorders. Plasma<br />
exposure of RO4987655 appeared to increase in a dose-proportional manner with a<br />
plasma half-life (t1/2) of 14.0 to 24.4 hours. After multiple dose administration,<br />
steady-state conditions were reached by Cycle 1 Day 8 (240 hours). The inhibitory<br />
effects of RO4987655 on pERK in PBMCs increased in a dose-dependent manner.<br />
Conclusions: The MTD of RO4987655 for Japanese patients was defined as 8 mg/<br />
day. RO4987655 has a manageable safety profile with a favorable PK/PD correlation<br />
in Japanese patients with advanced solid tumors.<br />
Disclosure: S. Nakamichi: This phase I clinical trial is sponsored by Chugai<br />
Pharmaceutical Co., Ltd. H. Nokihara: This phase I clinical trial is sponsored by<br />
Chugai Pharmaceutical Co., Ltd. N. Yamamoto: This phase I clinical trial is<br />
sponsored by Chugai Pharmaceutical Co., Ltd. Y. Tamura: This phase I clinical trial<br />
is sponsored by Chugai Pharmaceutical Co., Ltd. K. Honda: This phase I clinical trial<br />
is sponsored by Chugai Pharmaceutical Co., Ltd. H. Wakui: This phase I clinical trial<br />
is sponsored by Chugai Pharmaceutical Co., Ltd. Y. Yamada: This phase I clinical<br />
trial is sponsored by Chugai Pharmaceutical Co., Ltd. N. Yamazaki: This phase I<br />
clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd. S. Suzuki: This phase I<br />
clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd. T. Tamura: This phase<br />
I clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd.<br />
ix156 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
452P A PHASE 1B STUDY TO EVALUATE THE SAFETY AND<br />
PHARMACOLOGY OF THE DUAL PI3K-MTOR INHIBITOR<br />
GDC-0980 IN COMBINATION WITH A FLUOROPYRIMIDINE,<br />
OXALIPLATIN, AND BEVACIZUMAB (BEV) IN PATIENTS WITH<br />
ADVANCED SOLID TUMORS<br />
L.S. Rosen1 , J. Goldman1 , S. Stewart1 , J.M. Hubbard2 , M. Roos2 ,W.Lin3 ,<br />
G. Shankar4 , J. Capdevila5 , E. Freas6 , S. Leong6 1<br />
Division of Hematology Oncology, UCLA, Santa Monica, CA, UNITED STATES<br />
OF AMERICA, 2 Oncology, Mayo Clinic, Rochester, MN, UNITED STATES OF<br />
AMERICA, 3 Bioocology Early Clinical Development, Genentech Inc, South<br />
San Francisco, CA, UNITED STATES OF AMERICA, 4 Biooncology Early Clinical<br />
Development, Genentech Inc, South San Francisco, CA, UNITED STATES OF<br />
AMERICA, 5 Medical Oncology, Hospital Vall d’Hebrón, Barcelona, SPAIN,<br />
6<br />
Medicine/oncology, University of Colorado, Denver, CO, UNITED STATES OF<br />
AMERICA<br />
Background: PI3K signaling is altered in many cancer types. In colorectal cancer<br />
(CRC), ∼30% of <strong>the</strong> tumors harbor PIK3CA mutations, and ∼20% of tumors have<br />
PTEN loss. GDC-0980 has demonstrated synergy with fluoropyrimidines, a common<br />
<strong>the</strong>rapeutic agent in colorectal and advanced breast cancers.<br />
Methods: This was a standard 3 + 3 dose escalation design to determine <strong>the</strong><br />
recommended phase 2 dose (RP2D) of GDC-0980 with capecitabine (CPC) (Arm A) or<br />
with mFOLFOX6 + Bev (Arm B) in patients (pts) with advanced solid tumors. In Arm A,<br />
GDC-0980 and CPC are given daily for 14 consecutive days in each 21-day cycle. In Arm<br />
B, GDC-0980 is given for 7 consecutive days in a 14-day cycle with mFOLFOX6 given on<br />
<strong>the</strong> first day. Bev is given on Day 1 starting in Cycle 5 during <strong>the</strong> dose escalation stage.<br />
Results: In Arm A 6 pts received 25mg GDC-0980 and 1650mg/m2 bid of CPC<br />
(A1); 3 pts received 40mg GDC-0980 and 1650mg/m2 CPC (A2); and 9 pts received<br />
40mg GDC-0980 and 2000mg/m2 CPC (A3). Common adverse events (AEs) in<br />
>20% pts were nausea, fatigue, decreased appetite, hyperglycemia, vomiting, diarrhea,<br />
stomatitis, mucositis and rash. One dose limiting toxicity (DLT) of G3 AST/ALT was<br />
observed in A1. The RP2D in Arm A is 40mg GDC-0980 + 2000mg/m2 CPC. One pt<br />
in A2 with HNSCC experienced a confirmed partial response (cPR, ≥6mo). In Arm<br />
B, 4 pts received 25 mg (B1) and 6 pts received 40mg GDC-0980 (B2) in combination<br />
with mFOLFOX6 and Bev (10 mg/kg). The RP2D in Arm B is 40mg GDC-0980 +<br />
mFOLFOX6 + Bev. Common AEs in >20% pts were nausea, vomiting, decreased<br />
appetite, diarrhea, fatigue, peripheral neuropathy and thrombocytopenia. One DLT of<br />
G4 thrombocytopenia was observed in cohort B2. Cohort expansion with CRC pts in<br />
Arm B is ongoing. Two pts in cohort B1 (cholangiocarcinoma, anal cancer)<br />
experienced cPRs (≥6mo). The PK of GDC-0980 and CPC or 5-FU, oxaliplatin and<br />
leucovorin suggests minimal drug-drug interaction. Biomarker analysis is ongoing.<br />
Conclusions: GDC-0980 combined with fluoropyrimidine-based regimens is well<br />
tolerated, with confirmed antitumor activity. The RP2Ds are identified.<br />
Disclosure: L.S. Rosen: Research support received from Genentech, <strong>the</strong> study<br />
sponsor. J. Goldman: Research support received from Genentech, <strong>the</strong> study sponsor.<br />
W. Lin: Genentech Employee. G. Shankar: Genentech Employee. S. Leong: Presently<br />
receiving research support for clinical trials from: Genentech, Pfizer, Astra Zeneca<br />
Presently recieving laboratory research support from Pfizer. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
453P ANTI-PROGRAMMED DEATH-1 (PD-1) (BMS-936558/<br />
MDX-1106/ONO-4538) IN PATIENTS (PTS) WITH ADVANCED<br />
SOLID TUMORS: CLINICAL ACTIVITY, SAFETY, AND<br />
MOLECULAR MARKERS<br />
S.L. Topalian1 , J.R. Brahmer1 , F.S. Hodi2 , D.F. McDermott3 , D.C. Smith4 ,<br />
S. Gettinger5 , J.M. Taube1 , A. Gupta6 , J.M. Wigginton7 , M. Sznol8 1<br />
Melanoma Program, Sidney Kimmel Cancer Center at Johns Hopkins<br />
University, Baltimore, MD, UNITED STATES OF AMERICA, 2 Melanoma Center,<br />
Dana-Farber Cancer Institute, Boston, MA, UNITED STATES OF AMERICA,<br />
3<br />
Biology Therapy Program, Beth Israel Deaconess Medical Center, Boston, MA,<br />
UNITED STATES OF AMERICA, 4 Department of Internal Medicine, University of<br />
Michigan, Ann Arbor, MI, UNITED STATES OF AMERICA, 5 Section of Medical<br />
Oncology, Yale University School of Medicine, New Haven, CT, UNITED STATES<br />
OF AMERICA, 6 Discovery Medicine, Immuno-oncology, Bristol-Myers Squibb,<br />
Princeton, NJ, UNITED STATES OF AMERICA, 7 Discovery Medicine-clinical<br />
Oncology, Bristol-Myers Squibb, Princeton, NJ, UNITED STATES OF AMERICA,<br />
8<br />
Section of Medicine Oncology, Yale Cancer Center, New Haven, CT, UNITED<br />
STATES OF AMERICA<br />
Purpose: Blockade of PD-1, a co-inhibitory receptor expressed by activated T cells,<br />
can overcome immune resistance and mediate tumor regression. This study describes<br />
<strong>the</strong> activity and safety of BMS-936558, an anti-PD-1 monoclonal antibody, in pts<br />
with advanced cancers.<br />
Methods: Pts received BMS-936558 IV q2wk at 0.1 − 10 mg/kg during dose<br />
escalation and/or cohort expansion. Tumors were assessed by RECIST v1.0. Pts<br />
received up to 12 cycles (4 doses/cycle) or until unacceptable toxicity, confirmed<br />
progressive disease, or complete response.<br />
Results: As of Feb 24, <strong>2012</strong>, 296 pts with melanoma (MEL, n = 104), non-small<br />
cell lung (NSCLC, n = 122), renal cell (RCC, n = 34), colorectal (n = 19), and prostate<br />
(n = 17) cancer were treated. Median duration of <strong>the</strong>rapy was 16 wks (range 2.0 −<br />
121.7 wks). MTD was not reached. Grade ≥3 drug-related AEs occurred in 14% of<br />
pts. AEs of special interest included pneumonitis, vitiligo, colitis, hepatitis,<br />
hypophysitis, and thyroiditis. There were 3 deaths due to pneumonitis. In evaluable<br />
pts, objective responses (ORs) or prolonged stable disease was observed in MEL,<br />
RCC, and NSCLC (Table). Some had a persistent reduction in overall tumor burden<br />
in <strong>the</strong> presence of new lesions and were not categorized as responders. To assess<br />
PD-1 ligand (PD-L1) as a potential predictive molecular marker,<br />
immunohistochemistry was performed on pretreatment tumor biopsies from 42 pts.<br />
Of 25 pts with PD-L1(+) tumors, 9 (36%) achieved OR vs 0/17 with PD-L1(-).<br />
Conclusions: BMS-936558 produces durable activity in advanced NSCLC, MEL, and<br />
RCC, supporting fur<strong>the</strong>r clinical development. Preliminary data suggest a<br />
relationship between PD-L1 expression status on tumor cells and OR. Additional<br />
long-term follow-up data will be reported.<br />
Tumor<br />
type<br />
Dose,<br />
mg/kg<br />
No.<br />
pts a<br />
ORR, No. pts (%)<br />
[95% CI]<br />
SD ≥24 wks,<br />
No. pts (%)<br />
[95% CI]<br />
PFSR at 24<br />
wks, %<br />
[95% CI]<br />
MEL 0.1 − 10 94 26 (28)* [19 − 38] 6 (6) [2 − 13] 41 [30 − 51]<br />
NSCLC 1 − 10 76 14 (18) [11 − 29] 5 (7) [2 − 15] 26 [16 − 36]<br />
RCC 1 − 10 33 9 (27)* [13 − 46] 9 (27) [13 − 46] 56 [39 − 73]<br />
a<br />
Response-evaluable pts dosed by 07/01/2011 *1 CR ORR = objective response rate<br />
([{CR + PR} ÷ n] × 100); PFSR = progression-free survival rate; SD = stable disease<br />
Disclosure: S.L. Topalian: Consultant/Advisory Role: Bristol-Myers Squibb (myself,<br />
uncompensated); Amplimmune Inc (immediate family member, compensated).<br />
Research Funding: Bristol-Myers Squibb. F.S. Hodi: Consultant or Advisory Role:<br />
Bristol-Myers Squibb (myself, uncompensated). Research Funding: Bristol-Myers<br />
Squibb (myself). D.F. McDermott: Advisory Board Role: Bristol-Myers Squibb (Ad<br />
board participation). D.C. Smith: Research Funding: BMS Oncology (myself). J.M.<br />
Taube: Research Funding: Bristol-Myers Squibb (myself). A. Gupta: Employment or<br />
Leadership Role: Bristol-Myers Squibb (employment, myself, compensated). Stock<br />
Ownership: Bristol-Myers Squibb (myself). J.M. Wigginton: Employment or<br />
Leadership Role: Bristol-Myers Squibb (employment, myself, compensated). Stock<br />
Ownership: Bristol-Myers Squibb (myself). M. Sznol: Consultant or Advisory Role:<br />
Bristol-Myers Squibb (myself, compensated). Research Funding: Bristol-Myers Squibb<br />
(clinical trial funding, myself). All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
454P PHASE IB DOSE-ESCALATION STUDY OF BEZ235 OR<br />
BKM120 IN COMBINATION WITH PACLITAXEL (PTX) IN<br />
PATIENTS WITH ADVANCED SOLID TUMORS<br />
L. Dirix 1 , M. Schuler 2 , J. Machiels 3 , D. Hess 4 , A. Awada 5 , N. Steeghs 6 ,<br />
L. Paz-Ares 7 , R. von Moos 8 , B. Rabault 9 , J. Rodon 10<br />
1 Clinical Trials Oncology, Sint Augustinus Hospital, Antwerp, BELGIUM,<br />
2 Westdeutsches Tumorzentrum, Universitätsklinikum Essen, Essen, GERMANY,<br />
3 Department of Medical Oncology, Cliniques Universitaires Saint-Luc, Bruxelles,<br />
BELGIUM, 4 Medical Oncology, Kantonsspital St. Gallen, St. Gallen,<br />
SWITZERLAND, 5 Department of Medical Oncology, Institute Jules Bordet,<br />
Brussels, BELGIUM, 6 Medical Oncology, Ne<strong>the</strong>rlands Cancer Institute,<br />
Amsterdam, NETHERLANDS, 7 Medical Oncology, University Hospital Virgen del<br />
Rocio, Seville, SPAIN, 8 Medizinische Onkologie und Hämatologie, Kantonsspital<br />
Graubünden, Chur, SWITZERLAND, 9 Oncology, Novartis Pharma AG, Basel,<br />
SWITZERLAND, 10 Medical Oncology, Vall d’Hebron University Hospital,<br />
Barcelona, SPAIN<br />
Background: The pan-PI3K inhibitor BKM120 and <strong>the</strong> dual PI3K/mTOR inhibitor<br />
BEZ235 have demonstrated preclinical and clinical antitumor activity as single agents<br />
and in combination with o<strong>the</strong>r drugs. Here, we report interim results of BKM120 or<br />
BEZ235 + PTX in pts with advanced solid tumors.<br />
Methods: In <strong>the</strong> first 2 arms of this 4-arm Phase Ib dose-escalation study, pts with<br />
metastatic or locally advanced solid tumors received once-daily oral BKM120 or<br />
BEZ235 + wkly IV PTX. Dose-escalation was guided by a Bayesian logistic regression<br />
model with overdose control. The primary objective was to determine <strong>the</strong> MTD of<br />
BKM120 or BEZ235 + PTX.<br />
Results: 33 pts were treated with BKM120 (mg/d) + PTX (mg/m 2 ) at 6 dosing levels:<br />
40/70 (1 pt); 40/80 (5 pts); 60/80 (3 pts); 80/80 (4 pts); 100/80 (16 pts); and 120/80<br />
(4 pts). DLTs were observed in 4 pts (1/16 at 100/80 and 3/4 at 120/80), including<br />
as<strong>the</strong>nia, hyperglycemia, and depression. The MTD of BKM120/PTX was declared as<br />
100/80. Most common G3/4-suspected study treatment-related AEs (>5%) were<br />
neutropenia, hyperglycemia, and anemia. For <strong>the</strong> BEZ235 arm, 29 pts were treated<br />
with BEZ235 (mg/d) + PTX (mg/m 2 ) at 4 dosing levels: 400/70 (2 pts); 400/80 (3<br />
pts); 600/80 (4 pts); and 800/80 (20 pts). DLTs were observed in 4 pts (3/20 at 800/<br />
80 and 1/4 at 600/80), including GI events, peripheral neuropathy, and febrile<br />
neutropenia. The MTD of BEZ235/PTX was declared as 800/80. Most common G3/<br />
4-suspected study treatment-related AEs (>10%) were fatigue, diarrhea, and anemia.<br />
As of Feb 29, 29 pts were evaluable for response in each arm. In <strong>the</strong> BKM120/PTX<br />
arm, 1 CR (penile carcinoma [Ca]), 4 PRs (breast and ovarian Ca pts, each with<br />
multiple lines of prior <strong>the</strong>rapy [12 and 3] and progression on prior PTX; cervical<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds395 | ix157
and vulvar Ca), and 11 SDs were observed. In <strong>the</strong> BEZ235/PTX arm, 1 PR (large-cell<br />
Ca of <strong>the</strong> lung, taxane-naïve), and 9 SDs were observed.<br />
Conclusion: BKM120 or BEZ235 + PTX were generally well tolerated and showed<br />
preliminary signs of efficacy. The MTDs of both BKM120/PTX and BEZ235/PTX<br />
were reached. For BKM120, <strong>the</strong> MTD in combination with PTX was <strong>the</strong> same as <strong>the</strong><br />
single-agent MTD. Arms 3 and 4 will determine <strong>the</strong> MTD of BEZ235 or BKM120 +<br />
PTX and trastuzumab in pts with advanced HER2+ breast Ca.<br />
Disclosure: M. Schuler: Martin Schuler is an advisor for Novartis, and receives<br />
research funding from Novartis. J. Machiels: Jean-Pascal Machiels is on an advisory<br />
board for Boehringer, and receives a research grant from Sanofi. D. Hess: Dagmar<br />
Hess owns < 30,000 swiss francs of Novartis stocks. N. Steeghs: Neeltje Steeghs<br />
receives research funding from Novartis. L. Paz-Ares: Luis Paz-Ares has been an<br />
advisor for Lilly, Bayer, Roche and Pfizer. He has also received honoraria from all of<br />
<strong>the</strong> above. R. von Moos: Roger von Moos is a participant of advisory boards for<br />
Amgen, Novartis, Roche, BMS, and MSD, and receives unrestricted research grants<br />
and speaker honoraria from Amgen and Roche. B. Rabault: Bertrand Rabault is a<br />
employee of Novartis Pharma AG and owns stock in novartis pharma. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
455P EVOLUTION OF CLINICAL TRIAL DESIGN IN EARLY DRUG<br />
DEVELOPMENT: THE USE OF EXPANSION COHORTS (ECS) IN<br />
PHASE I CANCER TRIALS (PITS)<br />
A. Manji 1 , I. Brana Garcia 1 ,E.Amir 2 , I.F. Tannock 2 , P. Bedard 1 , A.M. Oza 1 ,<br />
L. Siu 1 , A.R.A. Razak 1<br />
1 Drug Development Program, Division of Medical Oncology and Hematology,<br />
Princess Margaret Hospital, Toronto, ON, CANADA, 2 Medical Oncology,<br />
Princess Margaret Hospital, Toronto, ON, CANADA<br />
Background: ECs are frequently used to optimize <strong>the</strong> yield of PITs. However, <strong>the</strong>ir<br />
rationale and value have yet to be evaluated. Here, we explore <strong>the</strong> prevalence,<br />
characteristics and objectives of ECs in single-agent PITs.<br />
Methods: We conducted a systematic review using MEDLINE and EMBASE to<br />
identify all adult single-agent PITs published after 2006. Eligibility assessment and<br />
data extraction were performed by 2 reviewers. The primary endpoint was <strong>the</strong><br />
proportion of PITs with ≥ 1 EC. Additional endpoints included factors associated<br />
with EC inclusion and whe<strong>the</strong>r <strong>the</strong> EC objectives were stated and achieved.<br />
Results: 4,557 articles were reviewed and 591 trials met eligibility criteria. 139 (24%)<br />
included ≥ 1 EC. Use of ECs in single-agent PITs increased between 2006 and 2011<br />
(12.2% to 35.7%, Spearman’s rho 0.20, p < 0.001). In PITs with ECs, a median of 22<br />
and 17 subjects were enrolled in <strong>the</strong> dose-escalation cohorts (DECs) and ECs<br />
respectively. In unadjusted analysis, PITs were more likely to include an EC if <strong>the</strong>y<br />
were multi-center (OR 2.41, 95% CI 1.52-3.82, p < 0.001), industry-sponsored (OR<br />
1.80, 95% CI 1.12-2.91, p = 0.02), and evaluating non-cytotoxic agents (OR 2.12, 95%<br />
CI 1.30-3.47, p = 0.003). In multivariable analysis, <strong>the</strong>se factors retained statistical<br />
significance except for industry sponsorship. Geographical location of study and<br />
tumor type were not significant. EC objectives were reported in 74% of trials and<br />
included safety (83%), efficacy (45%), pharmacokinetics (28%), pharmacodynamics<br />
(23%), and patient enrichment (14%). Among ECs assessing safety, <strong>the</strong> MTD was<br />
modified in 14% and new toxicities defined in 53%. Among ECs designed to assess<br />
efficacy, only 24 of 46 (52%) reported EC efficacy separately; of <strong>the</strong>se, only 3 (13%)<br />
reported tumor responses in EC subjects not previously observed in <strong>the</strong> DEC.<br />
Conclusions: The utilization of ECs in PITs has increased with time and is more<br />
common for multi-center trials of non-cytotoxic agents. Safety and efficacy are<br />
common objectives but 26% failed to report explicit aims. Although <strong>the</strong> majority of<br />
ECs supplement PITs with meaningful safety data, <strong>the</strong>ir role in assessing preliminary<br />
efficacy requires better definition.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
456P MULTICENTER, DOSE-ESCALATION STUDY OF THE<br />
INVESTIGATIONAL DRUG TAK-733, AN ORAL MEK<br />
INHIBITOR, IN PATIENTS (PTS) WITH ADVANCED SOLID<br />
TUMORS: PRELIMINARY PHASE 1 RESULTS<br />
A.A. Adjei 1 , P.M. LoRusso 2 , A. Ribas 3 , J.A. Sosman 4 , G.K. Dy 1 ,<br />
B. Chmielowski 5 , P. Lipman 6 , X. Zhou 7 , E. Gangolli 8 , V. Bozón 9<br />
1 Medicine Oncology, Roswell Park Cancer Institute, Buffalo, NY, UNITED<br />
STATES OF AMERICA, 2 Oncology, Karmanos Cancer Institute, Detroit, MI,<br />
UNITED STATES OF AMERICA, 3 Oncology, UCLA Jonsson Comprehensive<br />
Cancer Center, Los Angeles, CA, UNITED STATES OF AMERICA, 4 Hematology/<br />
Oncology, Vanderbilt University Medical Center, Nashville, TN, UNITED STATES<br />
OF AMERICA, 5 Medicine, University of California Los Angeles, Los Angeles, CA,<br />
UNITED STATES OF AMERICA, 6 Biostatistics, Millennium Pharmaceuticals, Inc.,<br />
Cambridge, MA, UNITED STATES OF AMERICA, 7 Clinical Pharmacology,<br />
Millennium Pharmaceuticals, Inc., Cambridge, MA, UNITED STATES OF<br />
AMERICA, 8 Translational Medicine, Millennium Pharmaceuticals, Inc., Cambridge,<br />
MA, UNITED STATES OF AMERICA, 9 Oncology, Clinical Research, Millennium<br />
Pharmaceuticals, Inc., Cambridge, MA, UNITED STATES OF AMERICA<br />
Background: TAK-733 is an investigational, orally available, selective,<br />
non-ATP-competitive, allosteric inhibitor of MEK1/2 shown to have anti-tumor<br />
Annals of Oncology<br />
activity in multiple xenograft models. In this first-in-human ph 1 study<br />
(NCT00948467), we evaluated safety, pharmacokinetics (PK), pharmacodynamics<br />
(PD), maximum tolerated dose (MTD) and efficacy of TAK-733 in pts with advanced<br />
solid tumors.<br />
Methods: Pts aged ≥18 y, with ECOG PS 0–2 and radiographically or clinically<br />
evaluable tumors were eligible. Pts received TAK-733 QD on d 1–21 in 28-d cycles;<br />
doses escalated in a modified 3 + 3 design based on dose-limiting toxicities (DLTs) in<br />
cycle 1 to determine MTD. Plasma and blood samples for PK and PD analysis were<br />
collected pre-dose on d 1, 8, 15 and 21 and post-dose d 1 and 21 in cycle 1.<br />
Results: As of March 16, <strong>2012</strong>, 44 pts median age 58 (range 24 − 75) and 50% male,<br />
received TAK-733 (dose mg, [n]: 0.2, [1]; 0.4, [1]; 0.8, [2]; 1.6, [2]; 3.2, [4]; 4.4, [4]; 6,<br />
[4]; 8.4, [9]; 11.8, [8]; 16, [9]). 2 pts had DLTs (11.8 and 16.0 mg; both Grade 3<br />
acneiform rash); MTD has not been reached. Pts received a median of 2 cycles<br />
(range 1-11, 6 pts ≥6 cycles). Safety and PK data are shown in <strong>the</strong> table. Maximum<br />
inhibition (Emax) of ERK phosphorylationin peripheral blood lymphocytes ranged<br />
from 21-95% (TAK-733; 0.2-16 mg QD), median E max were 63%, 78%, and 92% at<br />
8.4, 11.8, and 16 mg, respectively. In 32 evaluable pts, 1 pt (16 mg dose) with<br />
melanoma (BRAF L597R) had partial response confirmed at cycle 6 (RECIST v1.1)<br />
and is still on treatment at cycle 8; 12 pts had a best response of stable disease.<br />
Conclusions: These preliminary data indicate that TAK-733 is generally well<br />
tolerated and pharmacodynamically active with signs of anti-tumor activity in pts<br />
with advanced non-hematologic malignancies. Dose escalation is continuing to<br />
determine <strong>the</strong> MTD.<br />
AEs, NCI-CTCAE v4.0 N = 44<br />
Drug-related AE, n (%)<br />
≥15%<br />
37 (84)<br />
Dermatitis acneiform 19 (43)<br />
Diarrhoea 8 (18)<br />
Grade ≥3 drug-related AE, n (%)<br />
≥5%<br />
7 (16)<br />
Dermatitis acneiform 2 (5)<br />
Creatine phosphokinase evaluation 2 (5)<br />
PK data N = 41<br />
Tmax, h 3<br />
T1/2, h 53<br />
Disclosure: P.M. LoRusso: Consultancy or advisory board (Millennium<br />
Pharmaceuticals Inc.), Research Funding (Millennium Pharmaceuticals Inc.). A.<br />
Ribas: Consultancy or advisory board (Millennium Pharmaceuticals Inc.), Honoraria<br />
(Millennium Pharmaceuticals Inc.). J.A. Sosman: Consultancy or advisory board<br />
(Millennium Pharmaceuticals Inc.), Honoraria (Millennium Pharmaceuticals Inc.). B.<br />
Chmielowski: Consultancy within past 2 years (GSK, Genentech, Prome<strong>the</strong>us, CytRx,<br />
Morphotek). Membership on Board of Directors, Speakers Bureau, Advisory<br />
Committee (BMS, Genentech, Prome<strong>the</strong>us). P. Lipman: Employment (Millennium<br />
Pharmaceuticals Inc.). X. Zhou: Employment (Millennium Pharmaceuticals Inc.). V.<br />
Bozón: Employment (Millennium Pharmaceuticals Inc.). All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
457P A PHASE I DOSE ESCALATION AND EXPANSION TRIAL OF<br />
BKM120, AN ORAL PAN-PI3K INHIBITOR, IN PATIENTS WITH<br />
ADVANCED SOLID TUMORS: ANALYSIS OF<br />
PHARMACODYNAMIC BIOMARKER DATA<br />
J. Rodon 1 , J. Bendell 2 , A.R.A. Razak 3 , M.J.A. De Jonge 4 , F. Eskens 5 ,E.Di<br />
Tomaso 6 , D.W. Sternberg 7 , L. Wang 8 , C. Sarr 9 , J. Baselga 10<br />
1 Medical Oncology, Vall d’Hebron University Hospital, Barcelona, SPAIN, 2 GI<br />
Oncology Research/drug Development Unit, Sarah Cannon Research Institute,<br />
Nashville, TN, UNITED STATES OF AMERICA, 3 Dept. of Medical Oncology and<br />
Hematology, Princess Margaret Hospital, Toronto, ON, CANADA, 4 Department<br />
of Medical Oncology, Erasmus University Medical Center, Rotterdam,<br />
NETHERLANDS, 5 Dept. of Medical Oncology, Erasmus University Medical<br />
Center, Rotterdam, NETHERLANDS, 6 Institutes for Biomedical Research,<br />
Novartis, Cambridge, MA, UNITED STATES OF AMERICA, 7 Oncology, Novartis<br />
Oncology, Florham Park, NJ, UNITED STATES OF AMERICA, 8 Oncology BDM,<br />
Novartis Institutes for Biomedical Research, Cambridge, MA, UNITED STATES<br />
OF AMERICA, 9 Modeling & Simulation, Novartis Pharmaceuticals, East Hanover,<br />
NJ, UNITED STATES OF AMERICA, 10 Hematology/Oncology, MGH Cancer<br />
Center, Massachusetts General Hospital, Boston, MA, UNITED STATES OF<br />
AMERICA<br />
Background: The MTD of single-agent BKM120 was previously declared as 100 mg/<br />
day in a Phase I study in patients (pts) with advanced solid tumors (NCT01068483;<br />
Bendell et al. 2011). Here we report on <strong>the</strong> analysis of pharmacodynamic biomarkers<br />
from pts in <strong>the</strong> dose-escalation and dose-expansion arms of <strong>the</strong> Phase I study. The<br />
inhibitory effects of BKM120 were investigated (i) in <strong>the</strong> context of glucose<br />
metabolism regulation, a known PI3K-dependent process, and (ii) in <strong>the</strong> context of<br />
tumor biology, by surveying <strong>the</strong> phosphorylation of proteins downstream of PI3K.<br />
Methods: 83 pts received oral daily BKM120. Tumor samples were analyzed for<br />
PIK3CA mutation and PTEN expression. Blood C-peptide (glucose metabolism) was<br />
ix158 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
measured at Cmax (2–4 hrs post-dose) on Day 1 in 72 pts. Pathway phosphorylation<br />
in surrogate tissue was investigated in 51 paired skin samples by correlating changes<br />
in pS6 (baseline to Day 28) with <strong>the</strong> mean dose of BKM120 administered in each pt.<br />
In 8 pts where pre/post treatment biopsies could be obtained, pS6, pAKT, p4EBP1<br />
and Ki67 were quantified within limits of tissue availability.<br />
Results: Blood C-peptide at Cmax on Day 1 increased as a function of <strong>the</strong> 1st dose<br />
administered, with no change after 12.5 mg and mean increase of 72% (range: 56–<br />
84%) after 150 mg. Inhibition of pS6 on Day 28 (range: 20–60%) was observed in<br />
tumor tissue from 5 out of 8 pts. 4 of <strong>the</strong>se 5 pts also demonstrated a decrease in<br />
ei<strong>the</strong>r pAKT (range: 30–70%) or p4EBP1 (range: 27–35%) with 1 pt displaying a<br />
mean 30% decrease in all 3 markers. A decrease in proliferation as measured by<br />
Ki67 was observed in 4 pts (range: 13–60%) suggesting a potential biological<br />
impact in response to PI3K pathway inhibition. Inhibition of pS6 in skin increased<br />
moderately with <strong>the</strong> mean administered dose of BKM120 (mean inhibition of –28,<br />
–37, and –40%, for 12.5–60 mg, >60–90 mg, and >90 mg dose ranges, respectively)<br />
suggesting a relationship between treatment dose and <strong>the</strong> degree of PI3K pathway<br />
inhibition.<br />
Conclusion: This analysis supports <strong>the</strong> notion that daily BKM120 not only has <strong>the</strong><br />
ability to induce inhibition of <strong>the</strong> immediate effector of PI3K (pAKT) but also to<br />
downregulate <strong>the</strong> pathway fur<strong>the</strong>r downstream (pS6) at MTD.<br />
Disclosure: F. Eskens: Membership on an advisory board: Participant of LEAD<br />
summit meetings (Novartis). E. Di Tomaso: Employee of Novartis. D.W. Sternberg:<br />
Employee of Novartis. L. Wang: Employee of Novartis. C. Sarr: Employee of<br />
Novartis. Stock Ownership in Novartis Pharmaceuticals. J. Baselga: Novartis<br />
Scientific Ad Board (NVPBKM120); o<strong>the</strong>r pan‐PI3K inhibitors: Consulting for<br />
Exelixis; XL147; Roche‐Genentech Scientific Ad Board; GDC0941. All consulting<br />
relationships have CA’s in place which conform to <strong>the</strong> Partners/Harvard COI<br />
Policies. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
458P PHASE IB DOSE-ESCALATION STUDY OF THE AKT INHIBITOR<br />
GDC-0068 WITH DOCETAXEL (D) OR MODIFIED FOLFOX6 (F)<br />
IN PATIENTS (PTS) WITH ADVANCED SOLID TUMORS<br />
J. Bendell 1 , D. Roda 2 , J. Mateo 3 , A. Hollebecque 4 , L. De Mattos-Arruda 5 ,<br />
R. Meng 6 , S. Isakoff 7 , L.R. Molife 8 , J. Tabernero 9 , A. Cervantes Ruiperez 10<br />
1 GI Oncology Research/Drug Development Unit, Sarah Cannon Research<br />
Institute, Nashville, TN, UNITED STATES OF AMERICA, 2 Department of<br />
Hematology and Medical Oncology, Hospital Clinico, Valencia, SPAIN, 3 Drug<br />
Development Unit, The Royal Marsden NHS Trust, Sutton, Surrey, UNITED<br />
KINGDOM, 4 Dept. of Medicine, Institut Gustave Roussy, Villejuif Cedex,<br />
FRANCE, 5 Medical Oncology, Vall d’Hebron Hospital, Barcelona, SPAIN,<br />
6 Exploratory Clinical Development, Genentech, So San Francisco, CA, UNITED<br />
STATES OF AMERICA, 7 Department of Hematology and Medical Oncology,<br />
Massachusetts General Hospital, Boston, MA, UNITED STATES OF AMERICA,<br />
8 Drug Development Unit, Royal Marsden Hospital, London, UNITED KINGDOM,<br />
9 Medical Oncology Department, Vall d’Hebron University Hospital, Barcelona,<br />
SPAIN, 10 Serv. Hematologia y Oncologia Medica, Hospital Clinico Universitario<br />
de Valencia, Valencia, SPAIN<br />
Background: Aberrant activation of <strong>the</strong> phosphoinositide 3-kinase (PI3K)/Akt<br />
pathway occurs in cancers and may lead to chemoresistance. GDC-0068 is a potent<br />
ATP-competitive small molecule inhibitor of all Akt isoforms. In preclinical models,<br />
GDC-0068 synergistically combined with taxanes and 5FU/platinum. This study<br />
evaluated safety, pharmacokinetics (PK), and efficacy of GDC-0068 combined with<br />
DorF.<br />
Methods: Eligible pts with metastatic solid tumors, treated with up to 3 regimens,<br />
received ei<strong>the</strong>r D, 75 mg/m 2 Day1 and escalating GDC-0068 daily (QD) Days 2-15<br />
every 21 days (Arm A); or F, bolus 5FU 400 mg/m 2 , leucovorin 400 mg/m 2 ,<br />
oxaliplatin (OX) 85 mg/m 2 Day 1, infusional 5FU 2400 mg/m 2 for 46 hours and<br />
GDC-0068 QD Days 1-7 every 14 days (Arm B). GDC-0068 dose was capped at 600<br />
mg QD, <strong>the</strong> single-agent MTD. Secondary endpoints were PK and predictive<br />
biomarker assessment.<br />
Results: 47 pts enrolled as of May <strong>2012</strong>: Arm A (GDC-0068 in mg): 100 (n = 3), 200<br />
(n = 4), 400 (n = 7), 600 (n = 10, with expansion), and Arm B: 100 (n = 6), 200 (n =<br />
9), 400 (n = 6), 600 (n = 2, ongoing). Grade ≥ 2 adverse events (AEs) related to<br />
GDC-0068 in ≥ 10% of pts were nausea (17%), diarrhea (13%), fatigue (13%) in Arm<br />
A and nausea (17%) and diarrhea (13%) in Arm B. Fasting hyperglycemia due to<br />
GDC-0068 was only Grade 1 ( 6 months. Among 11 pts evaluable for IHC (immunohistochemistry)<br />
staining, 8 pts had high expression of PD-L1, a ligand of PD-1, on <strong>the</strong>ir tumor<br />
tissues, and 2 of <strong>the</strong>m achieved PR. No pts with low PD-L1 expression showed<br />
objective response.<br />
Conclusion: ONO-4538 was well tolerated up to <strong>the</strong> 20 mg/kg and antitumor activity<br />
was observed within 1-10 mg/kg.<br />
Disclosure: N. Yamamoto: Chugai pharmaceutical co., ltd. Pfizer Kyowa-Hakko<br />
Kirin co., ltd. Y. Yamada: Bayer Yakult AstraZeneca. H. Nokihara: TAIHO<br />
PHARMACEUTICAL CO., LTD Merck Serono Pfizer. T. Tamura: Chugai<br />
Pharmaceutical co., ltd. Daichi-Sankyo co., ltd. Boehringer Ingelheim ABBOTT<br />
JAPAN Co., LTD Eisai co., ltd. Bristol-Myers Squibb Kyowa-Hakko Kirin co., ltd. All<br />
o<strong>the</strong>r authors have declared no conflicts of interest.<br />
460P PHASE I AND II CLINICAL STUDY OF CANCER VACCINE<br />
CONSISTING OF 5 NOVEL EPITOPE PEPTIDES FOR PATIENTS<br />
WITH METASTATIC COLORECTAL CANCER (MCRC)<br />
S. Hazama 1 , Y. Nakamura 2 , K. Yoshida 3 , T. Tsunoda 3 , H. Tanaka 4 , K. Tahara 5 ,<br />
R. Shimizu 1 , K. Okuno 6 , K. Yoshimatsu 7 , M. Oka 1<br />
1 Department of Digestive Surgery and Surgical Oncol, Yamaguchi University<br />
Graduate School of Medicine, Ube, JAPAN, 2 Institute of Medical Science,<br />
University of Tokyo, Tokyo, JAPAN, 3 Cancer Immunology, OncoTherapy<br />
Science, Inc., Tokyo, JAPAN, 4 Digestive Surgery, Osaka City University, Osaka,<br />
JAPAN, 5 Surgery, Kure Kyosai Hospital, Kure, JAPAN, 6 Surgery, Kinki University,<br />
Osaka, JAPAN, 7 Surgery, Tokyo Womens Univercity, Tokyo, JAPAN<br />
Background: We have reported a phase I (PI) study for patients (pts) with mCRC<br />
using 5 novel HLA-A24-restricted peptides, which were derived from 3 oncoantigens<br />
(RNF43, TOMM34, KOC1), and from VEGFR1 and VEGFR2 at 2011 ASCO (oral<br />
paper). At <strong>2012</strong> <strong>ESMO</strong>, we will present <strong>the</strong> biomarkers for <strong>the</strong> efficacy of PI study,<br />
and an interim report about PII study of cancer vaccine consisting of 5 novel epitope<br />
peptides and FOLFOX for chemo naïve pts with mCRC.<br />
Methods: In a PI study conducted for mCRC, biomarkers were searched for <strong>the</strong><br />
efficacy of vaccination. Eighteen mCRC pts who failed to standard <strong>the</strong>rapy were<br />
enrolled in this study. Five peptides were injected to <strong>the</strong> inguinal or axillal region<br />
weekly at 0.5 mg to 3 pts, 1 mg to 3 pts, and 3 mg to 12 pts. Vaccinations were<br />
continuing until <strong>the</strong> pts refusal. Blood cell counts, CRP, and ELISPOT were<br />
performed before and after vaccinations. PII study was conducted to evaluate <strong>the</strong><br />
efficacy of vaccination added on <strong>the</strong> standard FOLFOX <strong>the</strong>rapy for chemo naïve pts<br />
with mCRC. All enrolled patients had received FOLFOX and vaccination without<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds395 | ix159
knowing HLA-A status double-blindly, and <strong>the</strong> HLA genotype will not key-opened<br />
until <strong>the</strong> final analysis point. The endpoints evaluate between HLA-A*2402 positive<br />
(24(+), n = 60) and HLA-A*2402 negative (24(-), n = 40) group, because <strong>the</strong><br />
frequency of A*2402 in Japanese pts forecast about 60%.<br />
Results: In PI study, <strong>the</strong> total numbers of peptide specific response were 2 in 3 pts at<br />
0.5mg, 6 in 3 pts at 1.0 mg, and 37 in 12 pts at 3.0 mg. We decided that <strong>the</strong> RD was<br />
3.0 mg. One patient experienced a CR and 6 pts revealed SD. The median OS was<br />
15.2 months. The lymphocyte% (above 15%: p < 0.022) and CRP (below 1.0 mg/dl: p<br />
< 0.008) were primitive but important biomarkers to predict OS. In <strong>the</strong> low CRP<br />
group, pts with 3 or more peptides specific responses at 8 weeks survived longer than<br />
o<strong>the</strong>rs(p = 0.032). In PII study, 86 pts were enrolled. The PFS of all pts without HLA<br />
key-open was seemed to be improved as compared to NO16966 study 9 month after<br />
<strong>the</strong> initial <strong>the</strong>rapy. This result indicated <strong>the</strong> delayed effect which is characteristic in<br />
vaccine <strong>the</strong>rapy.<br />
Conclusions: The PI study demonstrated that Lymphocyte%, CRP and CTL<br />
responses were predictive biomarkers for vaccination. The interim report about PII<br />
study will be presented at <strong>the</strong> meeting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
461P MLN8237 (ALISERTIB), AN INVESTIGATIONAL AURORA A<br />
KINASE INHIBITOR, IN PATIENTS (PTS) WITH NON-SMALL<br />
CELL LUNG CANCER (NSCLC), SMALL CELL LUNG CANCER<br />
(SCLC), BREAST CANCER (BRC), HEAD AND NECK<br />
SQUAMOUS CELL CARCINOMA (HNSCC), AND<br />
GASTROESOPHAGEAL CANCER (GE): EMERGING PHASE (PH)<br />
2 RESULTS<br />
B. Melichar 1 , P. Lee 2 , R.H. Alvarez 3 , M. Degardin 4 , J. Bennouna 5 ,<br />
C. Schusterbauer 6 , B. Zhang 7 , E. Benaim 8 , P. Rosen 9<br />
1 Oncology, University Fakultní Nemocnice Olomouc – Onkologická Klinika,<br />
Olomouc, CZECH REPUBLIC, 2 Oncology, Tower Cancer Research Foundation,<br />
Beverly Hills, CA, UNITED STATES OF AMERICA, 3 Division of Cancer Medicine,<br />
MD Anderson Cancer Center, Houston, TX, UNITED STATES OF AMERICA,<br />
4 Département de Cancérologie Cervico-faciale, Centre Oscar Lambret, Lille,<br />
FRANCE, 5 Pharmacology and Clinical Oncology, Institut de Cancérologie de<br />
l’Ouest, Nantes, FRANCE, 6 Clinical, Millennium Pharmaceuticals, Inc.,<br />
Cambridge, MA, UNITED STATES OF AMERICA, 7 Biostatistics, Millennium<br />
Pharmaceuticals, Inc., Cambridge, MA, UNITED STATES OF AMERICA, 8 Clinical<br />
Development, Millennium Pharmaceuticals, Inc., Cambridge, MA, UNITED<br />
STATES OF AMERICA, 9 Hematology and Medical Oncology, Providence Saint<br />
Joseph Medical Center, Burbank, CA, UNITED STATES OF AMERICA<br />
Background: Aurora A Kinase plays a key role in centrosome maturation and<br />
spindle formation in mitosis, and is frequently amplified or overexpressed in various<br />
human cancers. MLN8237 is an investigational, oral, selective AAK inhibitor being<br />
evaluated in pts with hematologic and non-hematologic malignancies. Here we<br />
report ph 2 results from an ongoing multicenter ph 1/2 trial of MLN8237 in pts with<br />
advanced solid tumors (NCT01045421).<br />
Methods: Pts aged ≥18 y with relapsed/refractory NSCLC, SCLC, BrC, HNSCC,<br />
or GE adenocarcinoma, ECOG PS 0–1, measurable disease by RECIST, and ≤2<br />
prior cytotoxic chemo<strong>the</strong>rapy regimens (≤4 in BrC) were eligible. Ph 2<br />
enrollment followed a two-stage Simon’s design; to proceed to <strong>the</strong> second stage,<br />
at least two responses were required in <strong>the</strong> first 20 response-evaluable pts<br />
enrolled in that tumor cohort. The primary and secondary ph 2 objectives were<br />
overall response rate and safety profile, respectively. Response was assessed by<br />
RECIST v1.1. MLN8237 was administered orally as an enteric-coated tablet at <strong>the</strong><br />
MTD of 50 mg BID for 7 d followed by 14-d rest in 21-d cycles (determined in<br />
ph 1).<br />
Results: As of March 29 <strong>2012</strong>, 226 pts have been treated in ph 2: HNSCC (n =<br />
54), BrC (n = 53), GE adenocarcinoma (n = 53); SCLC (n = 40), and NSCLC (n =<br />
26); median age was 61 y (range 30–88). Best responses achieved are: partial<br />
response in 17 pts (BrC, n = 6; SCLC, n = 4; H&N, n = 3; GE adenocarcinoma, n<br />
= 3; NSCLC, n = 1), and stable disease in 92 pts. Median cycles of treatment is 2<br />
(range: 1–15). 89% of pts reported drug-related adverse events (AEs); <strong>the</strong> most<br />
common included neutropenia (44%), fatigue (38%), alopecia (38%), diarrhea<br />
(30%), and anemia (27%). Grade ≥3 drug-related AEs were seen in 53% of pts<br />
and included neutropenia (36%), leukopenia (10%), and anemia (10%). 21 pts<br />
(9%) discontinued due to AEs; <strong>the</strong>re were 19 on-study deaths (none<br />
drug-related).<br />
Conclusions: These emerging ph 2 data suggest antitumor activity for MLN8237,<br />
and fur<strong>the</strong>r support a developing safety profile that is generally well tolerated across a<br />
range of solid tumors.<br />
Disclosure: B. Melichar: Honoraria Roche, Novartis, advisory board Roche. R.H.<br />
Alvarez: Consultancy (BMS, Roche), Honoraria (BMS), Research funding (GSK,<br />
Cylene Pharmaceuticals, Millennium Pharmaceuticals Inc., Novartis, Prome<strong>the</strong>us<br />
Annals of Oncology<br />
Therapeutics and Diagnostics, Eisai). J. Bennouna: Honoraria (AMGEN),<br />
Membership on Board of Directors, Speakers Bureau, Advisory Committee (Roche,<br />
AMGEN, Sanofi-Aventis). C. Schusterbauer: Employment (Millennium<br />
Pharmaceuticals, Inc.). B. Zhang: Employment (Millennium Pharmaceuticals, Inc.)<br />
and stock ownership (Takeda). E. Benaim: Employment (Millennium<br />
Pharmaceuticals, Inc.) and stock ownership (Takeda). P. Rosen: Research funding<br />
(Millennium Pharmaceuticals Inc.). All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
462P A PHASE IB CLINICAL STUDY WITH 18F-FDG-PET RESPONSE<br />
EVALUATION OF THE COMBINATION OF TEMSIROLIMUS (T)<br />
AND PEGYLATED LIPOSOMAL DOXORUBICIN (PLD) IN<br />
BREAST, ENDOMETRIAL AND OVARIAN CANCER<br />
M.J. Sonderen 1 , I.M.E. Desar 1 , L. De Geus-Oei 2 , W.T.A. van der Graaf 1 ,<br />
W.J.G. Oyen 2 , P.B. Ottevanger 1 , C.M.L. van Herpen 1<br />
1 Department of Medical Oncology/452, Radboud University Medical Centre<br />
Nijmegen, Nijmegen, NETHERLANDS, 2 Department of Nuclear Medicine,<br />
Radboud University Nijmegen Medical Centre, Nijmegen, NETHERLANDS<br />
Background: PLD is active in metastatic breast, endometrial and ovarian cancer.<br />
Preclinical data suggest that mTOR inhibitors can reverse resistance to doxorubicin.<br />
Therefore, <strong>the</strong> combination of T and PLD is promising.<br />
Methods: This phase I study assessed <strong>the</strong> MTD, safety and activity of <strong>the</strong><br />
combination of T and PLD in advanced or recurrent breast, endometrial or ovarian<br />
cancer. After a 2 wk run in period with T iv once weekly, PLD iv once every 4 wks<br />
was added. The MTD was defined as <strong>the</strong> highest dose at which ≤ 1 DLT had been<br />
observed among 6 pts. FDG PET scans were performed at baseline (B), after 2 and 6<br />
wks to assess <strong>the</strong> effect on tumor metabolism. A CT scan was performed for RECIST<br />
evaluation at B and after 10 wks. PET scans were evaluated by SUV analysis and<br />
total lesion glycolysis (TLG). The fractional change in SUV and TLG between <strong>the</strong><br />
first, second and third FDG-PET was calculated.<br />
Results: 20 pts were enrolled. On <strong>the</strong> 4 th dose level with 20 mg T and 40 mg/m 2 PLD<br />
2 DLTs occurred in 6 pts, a grade 3 thrombocytopenic bleeding and a grade 3 skin<br />
toxicity. Thus <strong>the</strong> MTD was assessed at 15 mg T and 40 mg/m 2 PLD. AEs occurring<br />
most frequently were (all grds/grd 3-4 (%)) fatigue (84/5), nausea (84/16) and<br />
mucositis (79/21). 3 pts showed PR and 9 SD (> 3 months). The mean PFS was 4.9<br />
months with 2 pts still on treatment. The fractional decrease in TLG from <strong>the</strong> first to<br />
<strong>the</strong> second FDG-PET for PR pts differed from those who had not (p= 0.018 for<br />
ΔTLG50). The fractional change in SUVmax from <strong>the</strong> second to <strong>the</strong> third FDG-PET<br />
differed between pts who had PD and those who had not (+14.0 versus -15.8, p =<br />
0.034). The degree of decrease in SUVmax between <strong>the</strong> FDG-PET made after 2 and<br />
6 wks was associated with better PFS (HR 1.068; p = 0.013).<br />
Conclusions: The combination of T and PLD is safe and tolerable. The MTD was<br />
assessed at PLD 40 mg/m 2 once every 4 wks and T 15 mg weekly. Early response<br />
evaluation with FDG-PET could predict PR and PD early after start of treatment.<br />
The activity of this combination in breast, endometrial and ovarian cancer pts is<br />
promising and warrants fur<strong>the</strong>r studies with FDG-PET evaluation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
463P DEVELOPMENT OF CANCER STEM CELLS THERAPEUTICS<br />
A.A. Epenetos 1 , C. Kousparou 2 , M. Deonarain 1 , S. Stylianou 2<br />
1 Life Sciences, Imperial College London, London, UNITED KINGDOM, 2 Cancer<br />
Research, Trojantec, Nicosia, CYPRUS<br />
Cancer Stem Cells, (CSCs), are responsible for <strong>the</strong> initiation, metastasis and<br />
recurrence of a variety of cancers and may be a key reason for <strong>the</strong> failure of current<br />
<strong>the</strong>rapies. Cancer Stem cells operate through similar signaling pathways as normal<br />
stem cells such as Notch, Hedgehog,Wnt and o<strong>the</strong>rs. Notch signaling is abnormal in<br />
many, if not all cancers as shown in cancer stem cell development. Fur<strong>the</strong>rmore, it<br />
may be that some cancers are ‘addicted’ to Notch signaling. This presents<br />
opportunities for tumour-specific intervention. As all <strong>the</strong> signaling cascades converge<br />
on <strong>the</strong> Notch transcriptional complex (NTC) in <strong>the</strong> nucleus, we have developed a<br />
novel syn<strong>the</strong>tic protein acting as a Notch inhibitor operating at nuclear level. This<br />
protein is based on <strong>the</strong> cell penetrating protein (CPP) antennapedia (Antp) produced<br />
toge<strong>the</strong>r with a dominant-negative truncated mastermind-like protein (DN-MAML)<br />
called TR4. TR4 has been shown in vitro and in vivo to have anti-Notch and<br />
anti-cancer activity with similar potency to many of <strong>the</strong> gamma-secretase inhibitors<br />
or monoclonal antibodies being developed by o<strong>the</strong>rs against this pathway, but it is<br />
completely specific for <strong>the</strong> NTC. In summary, a specific Notch inhibitor has shown<br />
anticancer activity and could now be considered for clinical development.<br />
Disclosure: A.A. Epenetos: Receive directors fees from Trojantec ltd. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
ix160 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
464P A PHASE I STUDY OF DAILY AFATINIB, AN IRREVERSIBLE<br />
ERBB FAMILY BLOCKER, COMBINED WITH WEEKLY<br />
PACLITAXEL AND 2-WEEKLY BEVACIZUMAB IN PATIENTS<br />
WITH ADVANCED SOLID TUMOURS<br />
D. Enting 1 , J.E. Ang 2 ,C.O’Hanlon-Brown 1 , R. Kristeleit 3 ,<br />
M. Uttenreu<strong>the</strong>r-Fischer 4 , K. Pemberton 5 , K. Pelling 6 , D. Schnell 7 , J.S. de Bono 8 ,<br />
J. Spicer 1<br />
1 Department of Oncology, King’s College School of Medicine and Guy’s<br />
Hospital, London, UNITED KINGDOM, 2 Drug Development Unit, Royal Marsden<br />
Hospital NHS Foundation Trust, Sutton, UNITED KINGDOM, 3 Drug Development<br />
Unit, Royal Marsden Hospital, Sutton, UNITED KINGDOM, 4 Clinical Development<br />
& Medical Affairs, Boehringer Ingelheim, Biberach, GERMANY, 5 Cinical Research<br />
/ Oncology, Boehringer Ingelheim, Bracknell, UNITED KINGDOM, 6 Statistics,<br />
Boehringer Ingelheim, Bracknell, UNITED KINGDOM, 7 Translational Medicine,<br />
Boehringer Ingelheim, Biberach, GERMANY, 8 Drug Development Unit, Royal<br />
Marsden Hospital NHS Foundation Trust, Surrey, UNITED KINGDOM<br />
Background: The clinical efficacy of cytotoxic agents can be enhanced both by ErbB<br />
inhibition and by bevacizumab (Bev). The primary objective of this study was to<br />
determine <strong>the</strong> maximum tolerated dose (MTD) of afatinib (A), an oral, irreversible<br />
ErbB Family Blocker, in combination with paclitaxel (P) and Bev.<br />
Afatinib<br />
(mg/day)<br />
Paclitaxel<br />
(mg/m 2<br />
Days 1, 8,<br />
15)<br />
Bevacizumab<br />
(mg/kg Days 1,<br />
15)<br />
All pts/<br />
Evaluable<br />
pts/Pts with<br />
DLT<br />
DLT (all<br />
Grade 3)<br />
40 80 5 7/6/2 Fatigue/diarrhoea;<br />
fatigue<br />
30 80 5 5/5/2 Diarrhoea;<br />
paronychia<br />
20 80 5 3/3/0<br />
20 80 7.5 6/6/1 Mucositis<br />
(recommended<br />
dose)<br />
20 80 10 8/6/1 Dysphonia (MTD)<br />
Overall, <strong>the</strong> most frequent (any grade) adverse events (AEs) included diarrhoea<br />
(86%), fatigue (86%), rash (69%), mucositis (59%), and nausea (59%). Partial<br />
responses were confirmed in pts with non-small cell lung (n = 2) and cervical (n = 1)<br />
cancer. Eleven pts completed at least 6 treatment cycles of combination <strong>the</strong>rapy.<br />
Methods: A Phase I open-label 3 + 3 design dose-escalation trial was undertaken to<br />
determine safety, pharmacokinetics (PK), and antitumour efficacy of A combined<br />
with P (fixed dose 80 mg/m 2 on Days 1, 8 and 15 of a 4-week cycle), and Bev (5 mg/<br />
kg starting dose to be escalated to 10 mg/kg) administered on Days 1 and 15 in<br />
patients (pts) with advanced solid tumours. After at least 6 cycles of triplet<br />
combination <strong>the</strong>rapy, pts benefiting and tolerating treatment were eligible to<br />
continue treatment with A and Bev. The PK data of P and Bev (± A), as well as <strong>the</strong><br />
steady state PK of A combined with P and Bev will be presented.<br />
Results: Twenty-nine pts were enrolled (12 male; median age: 58 years [range: 21–73];<br />
ECOG PS 0/1: 3/26). The MTD dose previously established for A (40 mg/day) in<br />
combination with P only (above schedule; Spicer et al. <strong>ESMO</strong> 2008) had to be<br />
de-escalated to 30 mg and <strong>the</strong>n to 20 mg after 2/6 pts developed dose-limiting toxicities<br />
(DLTs) at 40 mg A and 2/5 at 30 mg A when combined with P and Bev 5 mg/kg.<br />
Conclusions: Promising antitumour activity was seen with <strong>the</strong> combination of A at<br />
20 mg/day with weekly P 80 mg/m 2 and 2-weekly Bev 7.5 mg/kg, <strong>the</strong> recommended<br />
dose for a Phase II study. At this dose, AEs of A combined with P and Bev were<br />
generally mild to moderate and manageable.<br />
Disclosure: M. Uttenreu<strong>the</strong>r-Fischer: Employee of Boehringer-Ingelheim. K.<br />
Pemberton: Employee of Boehringer Ingelheim. K. Pelling: Employee of Boehringer<br />
Ingelheim. D. Schnell: Employee of SocraMetrics/Boehringer Ingelheim. J.S. de Bono: I<br />
have served as a paid consultant for Boehringer Ingelheim. J. Spicer: Honoraria from<br />
Boehringer Ingelheim. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
465P THE PRECLINICAL PHARMACOLOGICAL PROFILE OF<br />
ANAMORELIN/ONO-7643, A NEW GHRELIN RECEPTOR<br />
AGONIST FOR THE TREATMENT OF CANCER CACHEXIA<br />
C. Pietra 1 , Y. Takeda 2 , N. Tazawa-Ogata 2 , M. Minami 2 , X. Yuanfeng 3 , E. Duus 4 ,<br />
R. Northrup 4<br />
1 Research and Preclinical, Helsinn Healthcare SA, Pambio Noranco,<br />
SWITZERLAND, 2 Discovery Research Laboratories, ONO Pharmaceutical,<br />
Osaka, JAPAN, 3 In Vitro Assay, HDB Biosciences, Shanghai, CHINA, 4 RD,<br />
Helsinn Therapeutics Inc., Bridgewater, NJ, UNITED STATES OF AMERICA<br />
Introduction: Ghrelin is <strong>the</strong> only known circulating orexigenic hormone which acts<br />
as <strong>the</strong> endogenous ligand for <strong>the</strong> ghrelin receptor (GRLN), and is considered a<br />
potential agent to treat cancer cachexia/anorexia. The aim of this study was to<br />
evaluate <strong>the</strong> in vitro and in vivo pharmacological activities of Anamorelin/<br />
ONO-7643 (ANA), a new syn<strong>the</strong>tic ghrelin receptor agonist, on food intake (FI),<br />
body weight (BW) and GH in rats.<br />
Material and methods: HEK293 cells expressing human recombinant ghrelin<br />
receptor were utilized in a Fluorescent Imaging Plate Reader (FLIPR), along with<br />
Fluo-8 dye to signal intracellular calcium. Ghrelin and ANA were incubated<br />
(0.001-1000 nM) to generate a concentration-response increase of Ca ++ . Binding<br />
experiments were also performed by using [ 125 I]Ghrelin. In vivo experiments were<br />
performed on male SD rats after oral treatment of ANA or vehicle. FI and BW were<br />
measured daily from Day 1 up to Day 7 of once-daily treatment. In o<strong>the</strong>r<br />
experiments, blood samples were collected at different time interval up to 6 hours<br />
post single dose for GH measurements.<br />
Results: Ghrelin and ANA showed a significant agonist activity on <strong>the</strong> ghrelin<br />
receptor in <strong>the</strong> FLIPR assay, with EC50 values of 0.67 nM and 0.74 nM, respectively.<br />
No significant antagonist activity was observed with ANA up to 1000 nM. In binding<br />
experiments, <strong>the</strong> affinity of ghrelin and ANA for ghrelin receptors were evaluated<br />
and resulted in a K i of0.58 nM and 0.70 nM, respectively. In <strong>the</strong> in vivo experiments,<br />
ANA (3, 10, 30 mg/kg p.o.) significantly (p < 0.05 vs vehicle ) increased FI and BW<br />
gain.The effect on FI was stable from Day 2 to Day 7 of treatment. ANA at <strong>the</strong> same<br />
doses increased GH AUC 0-6h and induced an increase in plasma GH levels. The<br />
effect was dose-dependent, and GH AUC 0-6h at 10 and 30 mg/kg p.o. were<br />
significantly higher (p < 0.05) than vehicle-treated animals.<br />
Conclusions: Anamorelin is a potent ghrelin agonist endowed with significant<br />
orexigenic activity demonstrating both an increase of FI and BW after subchronic<br />
treatment in rats. Plasma GH levels were increased after a single administration of<br />
ANA. These results support <strong>the</strong> continued investigation of Anamorelin as a potential<br />
treatment of cancer cachexia/anorexia.<br />
Disclosure: C. Pietra: Employee of Helsinn SA. Y. Takeda: Ono employee. N.<br />
Tazawa-Ogata: ONO employee. M. Minami: ONO Employee. E. Duus: Helsinn<br />
Therapeutics employee. R. Northrup: Helsinn<strong>the</strong>raputics employee. All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
466P THE SAFETY AND EFFICACY OF SORAFENIB COMBINED<br />
WITH TRANSARTERIAL CHEMOEMBOLIZATION FOR<br />
PATIENTS WITH UNRESECTABLE HEPATOCELLULAR<br />
CARCINOMA<br />
W. Shao, N. Cong, J. Song<br />
Interventional Therapy, Shandong Cancer Hospital and Institute, Jinan, CHINA<br />
Background and aim: Transarterial chemoembolization(TACE) is widely used for<br />
unresectable hepatocellular carcinoma. However, <strong>the</strong> hypoxia caused by TACE in<br />
surviving tumor cell leads to release of angiogenic and growth factors contributing to<br />
poor outcome. Sorafenib can block tumor cell proliferation and angiogenesis. The<br />
hypo<strong>the</strong>sis is that patients with unresectable HCC may benefit from sorafenib in<br />
combination with TACE.<br />
Methods: This is a retrospective study involving patients with unresectable HCC who<br />
had received at least one TACE session. Patients received sorafenib 400 mg twice per day<br />
and were monitored monthly. Dose reduction from 400mg to 200mg of sorafenib bid<br />
was permitted. The primary outcome is safety. The second outcome is overall survival.<br />
Results: Twenty one patients (mean age, 58 years; Child-Pugh class A, 100%; ECOG<br />
PS 0, 100%; BCLC B, 36.8%; BCLC C, 63.2%) were included from April, 2009 to<br />
February, 2011. The mean TACE sessions prior to or after sorafenib administration<br />
were 4.3 ± 2.9 and 1.5 ± 0.4 respectively. All patients were treated with sorafenib<br />
despite radiographic progression until <strong>the</strong>re was deterioration in patient’s Child-Pugh<br />
class to C, ECOG PS score to 4, or had intolerant adverse events or death. Two<br />
patients quitted <strong>the</strong> study for intolerant diarrhea and withdrawn of consent,<br />
respectively. Of <strong>the</strong> o<strong>the</strong>r 19 patients, no grade 3 or 4 adverse events were observed.<br />
The most common toxicities were dermatology adverse effects (94.7%), diarrhea<br />
(63.2%) and alopecia (26.3%). Sorafenib dose was reduced temporarily in 14 patients<br />
(73.7%). Most of toxicities could be relieved after dose reductions and not aggravated<br />
again even <strong>the</strong> dose of sorafenib resumed to 400 mg bid. Five patients remained on<br />
sorafenib as of February 29, <strong>2012</strong>, and were censored at that time point. The median<br />
survival was 12 months (9.2-14.8 months.<br />
Conclusion: The combination of sorafenib and TACE for unresectable HCC is safe<br />
providing that dose adjustment is permitted. The survival benefit is promising.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
467P PHASE I STUDY OF U3-1287, A HUMAN MONOCLONAL<br />
ANTIBODY TARGETING HER3, IN JAPANESE PATIENTS WITH<br />
ADVANCED SOLID TUMORS<br />
H. Wakui1 , N. Yamamoto1 , S. Nakamichi1 , Y. Tamura1 , H. Nokihara1 ,<br />
Y. Yamada2 , T. Tamura1 1<br />
Division of Thoracic Oncology, National Cancer Center Hospital, Tokyo, JAPAN,<br />
2<br />
Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo,<br />
JAPAN<br />
Background: HER3 is a key dimerization partner for HER-family members that<br />
activates oncogenic signaling pathways lead to cell survival and proliferation.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds395 | ix161
Acquired-resistance to EGFR inhibitors may result from <strong>the</strong> activation of HER3 and/<br />
or HER2, which share overlapping <strong>the</strong> signaling pathways. U3-1287 is a fully human<br />
anti-HER3 monoclonal antibody that has demonstrated anticancer activity in<br />
preclinical models. In a preceding US phase I study, <strong>the</strong> tolerability of U3-1287 was<br />
evaluated up to <strong>the</strong> dose of 20 mg/kg without dose-limiting toxicities (DLTs). In this<br />
study, we evaluated <strong>the</strong> tolerability, pharmacokinetics (PK) and potential antitumor<br />
activities of U3-1287 in Japanese patients with solid tumors up to <strong>the</strong> dose of 18 mg/kg.<br />
Methods: Patients received U3-1287 at a dose of 9 mg/kg or 18 mg/kg intravenously<br />
every 3 weeks (q3w). Tumor response, incidence of anti-U3-1287 antibodies<br />
(HAHA), and level of soluble HER3 (sHER3) were also evaluated.<br />
Results: Nine patients, 3 at 9 mg/kg and 6 at 18 mg/kg, were enrolled. Five<br />
patients were male and median (range) age of 67 (50-69) years. Tumor types were<br />
lung (2), colorectal (2), esophageal (2), breast (1), cervical (1), and sarcoma (1). No<br />
DLTs were reported. U3-1287-related AEs were ALT increase (3 patients),<br />
thrombocytopenia, diarrhea, stomatitis, cheilitis, rash, and AST increase (2 each).<br />
Plasma disappearance was bi-phasic and terminal half-life at <strong>the</strong> dose of 18 mg/kg<br />
was approximately 9 days. PK profiles were similar to those in <strong>the</strong> US phase I<br />
study. Four patients had best responses of stable disease. All patients tested were<br />
negative for HAHA formation. Level of sHER3 unexpectedly increased about<br />
four times in all patients. Mean sHER3 concentrations at baseline and day 15 were<br />
3.8 ng/mL and 16.5 ng/mL, respectively. These changes did not correlate with<br />
clinical response (at day15 in SD and PD patients; 16.7 ng/mL and 16.9 ng/ml,<br />
respectively).<br />
Conclusions: U3-1287 was well tolerated up to 18 mg/kg in Japanese patients with<br />
solid tumors. These data support a dosing regimen of 18 mg/kg q3w in future<br />
studies.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
468P PHASE I STUDY TO COMPARE SAFETY AND<br />
PHARMACOKINETICS OF AFATINIB, AN ORAL IRREVERSIBLE<br />
ERBB FAMILY BLOCKER, IN NON-CANCER SUBJECTS WITH<br />
HEPATIC IMPAIRMENT TO MATCHED HEALTHY SUBJECTS<br />
D. Schnell 1 , S. Buschke 2 , H. Fuchs 3 , R. Göldner 4 , M. Uttenreu<strong>the</strong>r-Fischer 5 ,<br />
P. Stopfer 6 , S. Wind 2 , A. Halabi 7 , R. Koenen 1<br />
1 Translational Medicine, Boehringer Ingelheim, Biberach, GERMANY,<br />
2 Pharmacokinetics, Boehringer Ingelheim, Biberach, GERMANY, 3 Drug<br />
Metabolism & Pharmacokinetics, Boehringer Ingelheim, Biberach, GERMANY,<br />
4 Statistics, Boehringer Ingelheim, Biberach, GERMANY, 5 Clinical Development &<br />
Medical Affairs, Boehringer Ingelheim, Biberach, GERMANY, 6 Clinical<br />
Pharmacokinetics/pharmacodynamics, Boehringer Ingelheim, Biberach, GERMANY,<br />
7 Medical Director, CRS Clinical Research Services Kiel GmbH, Kiel, GERMANY<br />
Background: Afatinib (BIBW 2992) is an oral, irreversible ErbB Family Blocker. It<br />
was found to be mainly excreted via faeces and is highly protein bound. To define<br />
<strong>the</strong> impact of different degrees of hepatic impairment (HI) on <strong>the</strong> pharmacokinetics<br />
(PK) and safety of afatinib, a dedicated Phase I trial was conducted.<br />
Methods: This single-dose, open-label, dose-escalation study in a matched group<br />
design included male or female subjects with HI (mild: Child Pugh A, score 5 or 6;<br />
moderate: Child Pugh B, score 7 to 9) and healthy volunteers (HV) matched to <strong>the</strong><br />
HI subjects based on age, weight, sex and creatinine clearance. Dose escalation of<br />
afatinib from 30 to 50 mg was performed depending on tolerability and PK. Plasma<br />
and urine sampling was performed for up to 240 hours (h) and 72 h after afatinib<br />
administration, respectively. Primary endpoints were comparison of AUC 0-∞ and<br />
C max of afatinib between subjects with HI and matched healthy subjects. For all o<strong>the</strong>r<br />
parameters, descriptive statistics were calculated. Additionally, blood samples were<br />
drawn to determine in vitro plasma protein binding of afatinib.<br />
Results: Thirty-five subjects entered <strong>the</strong> trial: 3 subjects with mild HI received<br />
single-dose 30 mg afatinib and 32 subjects received single-dose 50 mg afatinib.<br />
Tolerability of afatinib was good, with 6/35 subjects showing AEs, which were related<br />
to afatinib in 3/35 subjects. Main PK parameters are given in Table 1. After a single<br />
dose of 50 mg, PK parameters were similar between patients with HI and <strong>the</strong>ir<br />
matched HV controls.<br />
Conclusions: Mild and moderate HI had no influence on <strong>the</strong> PK and tolerability of a<br />
single dose of 50 mg afatinib. Table 1: Comparison of main PK parameters after<br />
single-dose administration of 50 mg afatinib.<br />
Table: 468P<br />
50 mg afatinib,<br />
mild HI (N = 8)<br />
50 mg afatinib, HV<br />
matched to mild HI<br />
(N = 8)<br />
Disclosure: D. Schnell: Employee of SocraMetrics / Boehringer Ingelheim. S. Buschke:<br />
Employee of Boehringer Ingelheim. H. Fuchs: Employee of Boehringer Ingelheim. R.<br />
Göldner: Employee of Boehringer Ingelheim. M. Uttenreu<strong>the</strong>r-Fischer: Employee of<br />
Boehringer Ingelheim. P. Stopfer: Employee of Boehringer Ingelheim. S. Wind:<br />
Employee of Boehringer Ingelheim. A. Halabi: Employee of CRS Clinical Research<br />
Services / Boehringer Ingelheim. R. Koenen: Employee of Boehringer Ingelheim.<br />
469P THE CLINICAL UTILITY OF A CHANGE IN THE ROYAL<br />
MARSDEN HOSPITAL PROGNOSTIC SCORE (RMHPS) IN<br />
PATIENTS (PTS) PRIOR TO PHASE I CLINICAL TRIAL<br />
THERAPY<br />
C.O. Michie1 , M. Ong1 , J. Mateo1 , A.M. Young1 , D. Olmos2 , J.E. Ang1 ,<br />
L.R. Molife1 , U. Banerji1 , J.S. de Bono1 , S.B. Kaye1 1<br />
Drug Development Unit, Royal Marsden Hospital, Sutton, UNITED KINGDOM,<br />
2<br />
DDU/Prostate Unit, Royal Marsden HospitalNHS Foundation Trust, Sutton,<br />
UNITED KINGDOM<br />
Background: Previously we developed and validated <strong>the</strong> RMHPS to aid patient<br />
selection for phase I clinical trials 1 . However, its sensitivity in predicting short-term<br />
outcome is limited. Here we assessed whe<strong>the</strong>r, prior to trial entry, a worsening of<br />
RMHPS during screening improves specificity.<br />
Methods: Pts treated in phase I trials between Sep 09-11 at RMH Drug Development<br />
Unit were identified from a prospectively-collected database. RMHPS was calculated<br />
at 2 distinct timepoints; ≤1 wk prior to start of <strong>the</strong>rapy and at an earlier<br />
timepoint ≤ 8 wks previously. RMHPS of 0-1 and 2-3 were denoted low and high<br />
respectively. Pts were divided into 4 groups based on <strong>the</strong> sequential RMHPS:<br />
low-low; low-high; high-low; and high-high. Median overall survival (OS) and time<br />
to study withdrawal were estimated by Kaplan-Meier method and prognostic<br />
variables compared by multivariate Cox regression analysis.<br />
Results: One hundred and thirty one pts were identified. The most common<br />
tumours were colorectal, ovary and breast. Median age and lines of prior<br />
chemo<strong>the</strong>rapy was 57y and 2 respectively. 99% of pts had ECOG PS 0/1 at baseline<br />
while 89% had distant metastases. Pts were treated on study for a median of 70 days<br />
(d), with 74.8% discontinuing for progression, 8.4% for toxicity and 12.2% for o<strong>the</strong>r<br />
reasons. Study withdrawal
Annals of Oncology<br />
subcutaneous (SC) formulation of trastuzumab has shown non-inferiority vs.<br />
trastuzumab IV in a large Phase III study (Jackisch, et al. <strong>2012</strong>). A proprietary<br />
single-use injection device (SID) has been developed to enable automated injection<br />
of trastuzumab SC formulation, thus offering potential for self-administration. In<br />
previous studies, trastuzumab SC was injected manually.<br />
Methods: This randomized, open-label study assessed <strong>the</strong> pharmacokinetic (PK)<br />
comparability and safety of a single 600 mg dose of trastuzumab SC injected<br />
manually (N = 60) or using <strong>the</strong> SID (N = 59) in healthy male subjects. PK and safety<br />
were assessed before dosing and up to day 63 after dosing, with cardiac safety<br />
monitoring up to Week 21.<br />
Results: The primary analysis showed that <strong>the</strong> study met <strong>the</strong> pre-specified criteria for<br />
comparability between modes of administration, as demonstrated by AUC0–21 days<br />
and Cmax values. Sensitivity analyses to assess possible variability due to body weight<br />
and actual dose delivered supported <strong>the</strong> co-primary analysis findings. The incidence<br />
of adverse events (AEs) of any grade was similar between arms with no grade 4 AEs,<br />
deaths, or cardiac, serious or SID-related AEs. Two grade 3 AEs occurred: pyrexia<br />
and head injury, both in <strong>the</strong> manual administration arm. Pain assessments and<br />
infusion-related/injection site reactions were similar. SID attachment and wearing<br />
comfort received top scores in all cases, while SID removal received <strong>the</strong> top score in<br />
all but two cases (acceptable). There were no SID failures. The incidence of<br />
antibodies to trastuzumab and recombinant human hyaluronidase was similar<br />
between arms, with no neutralizing antibodies detected and no relevant effects on PK<br />
observed.<br />
Conclusion: This study demonstrated comparability of two modes of administration<br />
for trastuzumab SC based on standard PK parameters, with comparable safety for<br />
trastuzumab SC administered manually and using <strong>the</strong> single-use injection device,<br />
which demonstrated consistent performance and tolerability.<br />
Disclosure: M. Lehle: Michaela Lehle is an employee of F. Hoffmann-La Roche Ltd.<br />
D. Heinzmann: Dominik Heinzmann is an employee of F. Hoffmann-La Roche Ltd<br />
and a stockholder in Roche Holdings. R. Mangat: Ranvir Mangat is an employee of<br />
Genentech Inc, and a stockholder of Roche Holdings. C. Li: Chunze Li is an<br />
employee of Genentech Inc, and a stockholder of Roche Holdings. L.A.<br />
Herráez-Baranda: Luis Herráez-Baranda is an employee of F. Hoffmann La-Roche<br />
Ltd. B.L. Lum: Bertram Lum is an employee of Genentech Inc, and a stockholder of<br />
Roche Holdings. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
471P A PHASE I, DOSE-ESCALATION STUDY OF MGCD265, A<br />
MULTI-TARGETED ORAL TYROSINE KINASE RECEPTOR<br />
INHIBITOR, FOR TREATMENT OF ADVANCED SOLID TUMORS<br />
H.I. Hurwitz 1 , C.K. Kollmannsberger 2 , M. Juretic 3 , J. Wang 3 , M. Fournel 3 ,<br />
C. Bonfils 3 , C. Maroun 3 , R.W. Humphrey 3 , J. Besterman 3 , G. Shapiro 4<br />
1 Division of Hematology and Oncology, Duke University Medical Center, Durham,<br />
NC, UNITED STATES OF AMERICA, 2 BCCA Vancouver Cancer Centre,<br />
University of British Columbia Division of Medical Oncology, Vancouver, BC,<br />
CANADA, 3 Clinical Affairs, Methylgene, Inc, Montreal, QC, CANADA, 4 Oncology,<br />
Dana-Farber Cancer Institute, Boston, MA, UNITED STATES OF AMERICA<br />
Background: MGCD265 is a multikinase inhibitor with activity against Met, VEGFR<br />
1, 2 and 3, Tie-2 and Ron that has been shown in preclinical models to possess<br />
broad antitumor effects.<br />
Methods: Patients with advanced malignancies were enrolled in a phase I,<br />
open-label, dose-escalation study. Oral MGCD265 was administered daily over a<br />
3-wk cycle, at a starting dose of 24 mg/m2 once daily. QD and BID dosing were<br />
tested sequentially. The study’s primary aim was to determine <strong>the</strong> safety profile of<br />
MGCD265, including maximum tolerated dose (MTD) and dose-limiting toxicities<br />
(DLT). Pharmacokinetics, pharmacodynamics and antitumor activity were also<br />
evaluated.<br />
Results: To date, 61 patients have been enrolled, with dose escalation up to 313 mg/<br />
m2 BID. Increasing dose frequency to BID increased exposure of MGCD265 by<br />
approximately twofold. Drug exposure achieved to date is in <strong>the</strong> range where tumor<br />
growth inhibition was observed with Met-sensitive preclinical models.<br />
Dose-dependent inhibition of Met phosphorylation was demonstrated in an ex vivo<br />
model using patient plasma, with up to 55% inhibition observed at doses to date.<br />
MTD has not yet been reached, and dose escalation continues. MGCD265 was well<br />
tolerated. DLTs were observed in 5 patients (N = 1 each): fatigue, diarrhea, lipase<br />
elevation, pituitary hemorrhage (all grade 3) and hypertension (grade 2,<br />
protocol-defined), all occurring in cycle 1 at daily doses ≥ 250 mg/m2. Drug-related<br />
grade 3 adverse events beyond cycle 1 were diarrhea, fatigue, elevated lipase and<br />
elevated alkaline phosphatase (N = 1 each). Of 51 response-evaluable patients to date,<br />
22 achieved stable disease (SD) for ≥2 cycles, and 7 achieved SD for ≥6 cycles (1<br />
patient up to 12 cycles).<br />
Conclusions: This study supports <strong>the</strong> safety of MGCD265 in patients with advanced<br />
malignancies. There are encouraging early signs of efficacy, with prolonged stable<br />
disease noted in several heavily pretreated patients.<br />
Disclosure: H.I. Hurwitz: Research funding from Methylgene, Inc. C.K.<br />
Kollmannsberger: Research funding from Methylgene, Inc. M. Juretic: Employee of<br />
Methylgene, Inc. J. Wang: Employee of Methylgene, Inc. M. Fournel: Employee of<br />
Methylgene, Inc. C. Bonfils: Employee of Methylgene, Inc. C. Maroun: Employee of<br />
Methylgene, Inc. R.W. Humphrey: Employee of Methylgene, Inc. J. Besterman:<br />
Employee of Methylgene, Inc. G. Shapiro: Research funding from Methylgene, Inc.<br />
472P CATUMAXOMAB SHOWS COMPARABLE ANTI-TUMOR<br />
ACTIVITY IN VITRO WITH IMMUNE EFFECTOR CELLS FROM<br />
DIFFERENT ETHNICITIES WITH DIFFERENT FCγR GENE<br />
POLYMORPHISMS<br />
F. Marmé 1 , K. Hasegawa 2 , H. Martinius 3 , J. Atz 3 , K. Fujiwara 2<br />
1 INF 460, Universitätsfrauenklinik Heidelberg & Nationales Centrum für<br />
Tumorerkrankungen (NCT), Heidelberg, GERMANY, 2 Department of Gynecologic<br />
Oncology, Saitama International Medical Center, Saitama, JAPAN, 3 Munich,<br />
Fresenius Biotech GmbH, Munich, GERMANY<br />
Background: Catumaxomab, <strong>the</strong> approved <strong>the</strong>rapy for treatment of malignant<br />
ascites, exerts its anti-tumor effects via T-cell-mediated lysis, antibody-dependent<br />
cell-mediated cytotoxicity, and phagocytosis via activation of FcγR-positive accessory<br />
cells. It has been reported that FcγR-polymorphisms influence <strong>the</strong> IgG binding<br />
capacity of <strong>the</strong> receptor and that ethnic groups may differ with respect to<br />
responsiveness of immune effector cells to antibody-based <strong>the</strong>rapies. The present<br />
nonclinical study <strong>the</strong>refore investigated potential inter-ethnic differences (Caucasian<br />
vs. Japanese, Korean, Black African and Hispanic Donors) and FcγR-gene<br />
polymorphisms with regard to <strong>the</strong> potency of catumaxomab in vitro.<br />
Methods: Blood samples of healthy subjects of different ethnic background (25<br />
donors of Caucasian, Korean, Black African and Hispanic ethnicity and 15 Japanese<br />
donors) were collected for comparative analyses. PBMCs were purified from whole<br />
blood samples and used as effector cells evaluating catumaxomab-mediated<br />
cytotoxicity towards EpCAM+ tumor target cells (HCT-8; colon) in vitro.<br />
Fur<strong>the</strong>rmore, <strong>the</strong> samples were genotyped for FcγR IIa and FcγR IIIa gene<br />
polymorphisms by PCR.<br />
Results: The comparative analysis of catumaxomab-mediated cytotoxicity obtained<br />
for <strong>the</strong> individual ethnic subgroups did not reveal major inter-ethnic differences<br />
although genetic polymorphisms for FcγR IIa/IIIa had been identified among<br />
donors. Even though a wider variability was observed among Caucasians, <strong>the</strong><br />
potency range observed with immune effector cells of Japanese, Korean, Black<br />
African and Hispanic was found to be within <strong>the</strong> potency range observed for <strong>the</strong><br />
Caucasian ethnicity.<br />
Conclusions: No impact of ethnic background or FcγRIIa/IIIa polymorphism on <strong>the</strong><br />
immune cell-mediated pharmacological activity of <strong>the</strong> trifunctional antibody<br />
catumaxomab could be identified in vitro. Therefore, it can be assumed that patients<br />
with a different ethnic background may also benefit from catumaxomab <strong>the</strong>rapy as<br />
already demonstrated for Caucasian patients.<br />
Disclosure: F. Marmé: consultant for Fresenius Biotech GmbH. K. Hasegawa:<br />
financial support for clinical studies from Fresenius Biotech GmbH. H. Martinius:<br />
works for Fresenius Biotech GmbH. J. Atz: works for Fresenius Biotech GmbH. K.<br />
Fujiwara: financial support for clinical studies from Fresenius Biotech GmbH.<br />
473P TREATMENT OF CHEMOTHERAPY-INDUCED ORAL<br />
MUCOSITIS BY SILYMARIN<br />
T.S. Altaei<br />
Pharmacology and Toxicology, Hawler Medical University, Erbil, IRAQ<br />
Background: Oral mucositis is a common and severe complication of head and neck<br />
radiation <strong>the</strong>rapy. Silymarin is a polyphenolic flavonoid extracted from <strong>the</strong> milk<br />
thistle exhibits a strong antioxidant activity, and anti-inflammatory effects. The<br />
efficacy for <strong>the</strong> treatment was assessed in comparison with indomethacin.<br />
Patients and methods: A prospective, randomized, double blind; placebo controlled<br />
study was conducted in 65 of chemo<strong>the</strong>rapy-induced oral mucositis patients; plasma<br />
IL-1β, leptin, and Trolox equivalent antioxidant capacity (TEAC) were assessed for 3<br />
orally treated groups; Silymarin 140mg, or Indomethacin 25mg, or placebo, 3 times<br />
daily for 14 days, radiation technique and dose were similar. The oral mucositis was<br />
assessed weekly according to OMAS and WHO scale, pain related to oral mucositis<br />
was scored subjectively by visual analog scale.<br />
Results: Patients’ characteristics showed no significant differences between tested<br />
groups. Statistical significance showed in; lower OMAS value at <strong>the</strong> time of<br />
using Silymarin, and lower mean time to healing of oral mucositis in Silymarin<br />
treated group compared to Indomethacin treated and placebo groups. Ulcer<br />
healing and pain relief were seen in 100% of Silymarin treated group but only<br />
40% of Indomethacin treated group compared to placebo after 5 days of<br />
treatment. Serum IL-1β, leptin were reduced significantly, and TEAC showed<br />
significant elevation in Silymarin treated group compared to baseline and o<strong>the</strong>r<br />
tested drugs.<br />
Conclusion: Silymarin could interrupt or block <strong>the</strong> mucositis process at multiple targets<br />
that protect <strong>the</strong> mucosa and promote healing of chemo<strong>the</strong>rapy-induced mucositis by<br />
reducing <strong>the</strong> incidence, blocking <strong>the</strong> oxidative stress and anti-inflammatory actions. Key<br />
words: Silymarin, chemo<strong>the</strong>rapy-induced mucositis, IL-1β,leptin.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds395 | ix163
474P PHASE 1 STUDY OF THE SELECTIVE AKT INHIBITOR<br />
MK-2206 IN JAPANESE PATIENTS WITH ADVANCED SOLID<br />
TUMORS<br />
Y. Tanabe1 ,T.Doi2 , K. Tamura1 , K. Yonemori1 , M. Kodaira1 ,N.Fuse2 ,<br />
H. Bando2 , Y. Maeda3 , T. Shimamoto3 , A. Ohtsu4 1<br />
Breast and Medical Oncology Division, National Cancer Center Hospital, Tokyo,<br />
JAPAN, 2 Gastroenterology & GI Oncology Department, National Cancer Center<br />
Hospital East, Chiba, JAPAN, 3 Japan Development, MSD K.K., Tokyo, JAPAN,<br />
4<br />
Research Center for Innovative Oncology, National Cancer Center Hospital East,<br />
Chiba, JAPAN<br />
Background: The AKT pathway, which mediates cell proliferation, survival, and<br />
angiogenesis, is commonly dysregulated in cancer. MK-2206 is an orally active,<br />
allosteric AKT 1/2 inhibitor with wide preclinical activity. This open-label,<br />
nonrandomized study investigated <strong>the</strong> safety, pharmacokinetics (PK),<br />
pharmacodynamics (PD), and antitumor activity of MK-2206 in Japanese patients<br />
with solid tumors who were refractory to standard <strong>the</strong>rapy.<br />
Methods: Patients received once every o<strong>the</strong>r day (qod) or once-weekly (qw) doses of<br />
MK-2206 in 28-day treatment cycles, with a 1-week drug holiday following Cycle<br />
1. Dose-limiting toxicities (DLTs) were evaluated during Cycle 1, with cohorts of 3,<br />
6, or 9 patients, depending on <strong>the</strong> dose studied and adverse events (AEs) experienced<br />
by patients. Overall antitumor activity was assessed at designated time points every<br />
o<strong>the</strong>r treatment cycle after initial screening, following RECIST guidelines.<br />
Results: Treated patients (N = 24; male/female: 10/14; median age: 57 yrs; ECOG PS<br />
0/1: 16/8) received MK-2206 45 mg or 60 mg qod (n = 12) and 135 mg or 200 mg<br />
qw (n = 12). Grade 3 rash was <strong>the</strong> DLT at both 60 mg qod (1 of 9 patients) and 200<br />
mg qw (3 of 9 patients). Common reversible drug-related toxicities included rash<br />
(83.3%), stomatitis (58.3%), pyrexia (58.3%), and hyperglycemia (54.2%). MK-2206<br />
terminal half-life did not differ from non-Japanese patients (69–80 h vs 60–90 h), but<br />
Cmax, AUC, and Ctroughwere generally higher in Japanese patients (1.5- to 1.7-fold).<br />
ANOVA models that adjusted for body weight suggested that PK differences could be<br />
mostly attributed to between-study body weight differences. PD assays demonstrated<br />
inhibition of blood pAKT at Day 15 (27.6%–61.4%). Modest antitumor activity was<br />
observed with a best response of stable disease (SD) lasting longer than 42 weeks;<br />
patients who achieved SD had various diagnoses, including neuroendocrine<br />
carcinoma and esophageal cancer.<br />
Conclusion: MK-2206 at doses up to 60 mg or 200 mg has a long terminal half-life<br />
and can be safely administered on ei<strong>the</strong>r qod or qw dosing schedules. Higher<br />
exposures were observed in Japanese patients, but this could be explained by body<br />
weight differences.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
475P FINAL ANALYSIS OF PHASE I AND PHARMACOKINETICS/<br />
PHARMACODYNAMICS (PK/PD) STUDY OF RO5126766, A<br />
FIRST-IN-CLASS DUAL RAF/MEK INHIBITOR, IN JAPANESE<br />
PATIENTS WITH ADVANCED SOLID TUMORS<br />
K. Honda 1 , N. Yamamoto 1 , H. Nokihara 1 , Y. Tamura 1 , H. Asahina 1 , Y. Yamada 2 ,<br />
S. Suzuki 3 , N. Yamazaki 4 , T. Tamura 1<br />
1 Division of Thoracic Oncology, National Cancer Center Hospital, Tokyo, JAPAN,<br />
2 Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo,<br />
JAPAN, 3 Division of Ophthalmic Oncology, National Cancer Center Hospital,<br />
Tokyo, JAPAN, 4 Division of Dermatological Oncology, National Cancer Center<br />
Hospital, Tokyo, JAPAN<br />
Background: RO5126766 is a highly selective and orally active dual inhibitor of Raf<br />
and MEK, key enzymes in <strong>the</strong> MAPK signaling pathway. This was a phase I,<br />
dose-escalation study in Japanese patients with advanced solid tumors. This Phase I<br />
study was aimed to assess maximum tolerated dose (MTD) based on dose-limiting<br />
toxicities (DLTs), safety evaluation, PK/PD analysis and exploratory analysis of<br />
anti-tumor activity.<br />
Methods: Patients received an oral single dose administration of RO5126766 (0.8,<br />
1.2, 1.8, and 2.25 mg) followed by continuous once daily dosing in 28-day cycles. A<br />
3 + 3 dose-escalation design was used. PD was evaluated by pMEK and pERK<br />
inhibition in peripheral blood mononuclear cells (PBMCs). Archival tumor tissue or<br />
biopsy samples were collected to analyze <strong>the</strong> mutation status of K-Ras and B-Raf<br />
only from patients who had consented to provide samples.<br />
Results: Twelve patients were enrolled into 4 sequential cohorts at 0.8, 1.2, 1.8, and<br />
2.25 mg/day. As 2.25 mg/day had already been defined as <strong>the</strong> MTD of <strong>the</strong> QD oral<br />
dosing regimen in ano<strong>the</strong>r phase I study conducted in Europe, doses higher than<br />
2.25 mg/day were not administered. In <strong>the</strong> dose range tested, no DLTs were observed<br />
and <strong>the</strong> MTD was not defined. Frequent adverse events (AEs) included dermatitis<br />
acneiform, creatine phosphorkinase (CPK) elevation, and eye disorders. Plasma<br />
exposure of RO5126766 appeared to increase in a dose-proportional manner with a<br />
long plasma half-life (t 1/2) of 45.8 to 93.7 hours. Following multiple dose<br />
administration, steady-state conditions were reached by Cycle 1 Day 8 (240 hours).<br />
No clear associations between PK parameters and occurrence of skin disorders, CPK<br />
elevation, or eye disorder were found. The inhibitory effects of RO5126766 on both<br />
pMEK and pERK in PBMCs increased in a dose-dependent manner. These<br />
Annals of Oncology<br />
inhibitory effects were achieved at >80% over <strong>the</strong> dose level of 1.2 mg at steady state<br />
phase. Five out of 12 patients achieved stable disease including a melanoma case with<br />
over 20 % shrinkage.<br />
Conclusions: RO5126766 has a manageable safety profile up to 2.25 mg/day with a<br />
favorable PK/PD correlation in Japanese patients with advanced tumors.<br />
Disclosure: K. Honda: This phase I clinical trial is sponsored by Chugai<br />
Pharmaceutical Co., Ltd. N. Yamamoto: This phase I clinical trial is sponsored by<br />
Chugai Pharmaceutical Co., Ltd. H. Nokihara: This phase I clinical trial is sponsored<br />
by Chugai Pharmaceutical Co., Ltd. Y. Tamura: This phase I clinical trial is<br />
sponsored by Chugai Pharmaceutical Co., Ltd. H. Asahina: This phase I clinical trial<br />
is sponsored by Chugai Pharmaceutical Co., Ltd. Y. Yamada: This phase I clinical<br />
trial is sponsored by Chugai Pharmaceutical Co., Ltd. S. Suzuki: This phase I clinical<br />
trial is sponsored by Chugai Pharmaceutical Co., Ltd. N. Yamazaki: This phase I<br />
clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd. T. Tamura: This phase<br />
I clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd.<br />
476P TRASTUZUMAB-INDUCED EARLY CARDIAC DYSFUNCTION<br />
ASSESSED BY SPECKLE TRACKING ECHOCARDIOGRAPHY:<br />
CORRELATION WITH CHRONIC INFLAMMATION AND<br />
OXIDATIVE STRESS MARKERS<br />
M. Dessi’ 1 , G. Mantovani 1 , C. Madeddu 1 , L. Orgiano 1 , P. Alessandra 2 ,<br />
C. Cadeddu 2 , G. Antoni 2 , R. Serpe 1 , G. Mercuro 2<br />
1 Department of Medical Oncology, University of Cagliari, Cagliari, ITALY,<br />
2 Department of Cardiovascular Diseases, University of Cagliari, Cagliari, ITALY<br />
Background: Trastuzumab (TZM) was shown to be very effective in patients with<br />
breast cancer overexpressing HER-2 in <strong>the</strong> neoadjuvant, adjuvant and metastatic<br />
setting. It has a mild cardiac toxicity which may increase when administered in<br />
combination with anthracyclines. The “Speckle Tracking Echocardiography” (STE),<br />
able to assess cardiac mechanics [cardiac torsion movements and <strong>the</strong> global,<br />
circumferential, radial and longitudinal Strain (S) and Strain Rate (SR)], and identify<br />
at an early stage left ventricular dysfunction, was used for cardiac monitoring. The<br />
present study aimed to assess <strong>the</strong> STE changes induced by TZM and correlate <strong>the</strong>m<br />
with changes of chronic inflammation and oxidative stress markers.<br />
Methods: A phase IV, prospective, non-randomized study was designed: planned<br />
sample size 60 patients. Inclusion criteria: 18–70 yo women with HER-2 + ve breast<br />
cancer receiving TZM, LVEF ≥55%; ECOG PS score 0-2, no history of cardiac<br />
disease. The STE parameters (global, circumferential, radial and longitudinal S and<br />
SR) and chronic inflammation (IL-6 and TNF-α)/oxidative stress (reactive oxygen<br />
species and gluthatione peroxidase) markers were assessed at baseline, after each<br />
three-weekly TZM administration, up to <strong>the</strong> 8th TZM dose.<br />
Results: At September 2011, 30 patients (mean ± SD age 53 ± 10 y) were enrolled<br />
and completed <strong>the</strong> study. A significant reduction of <strong>the</strong> peak of radial and<br />
circumferential SR (p < 0.01 and p < 0.005) as first sign of systolic dysfunction was<br />
observed at <strong>the</strong> 3rd TZM dose. A significant reduction of <strong>the</strong> peak of longitudinal SR<br />
(p < 0.01) was observed at <strong>the</strong> 4th TZM dose. As for laboratory parameters, TNF-α<br />
increased significantly at <strong>the</strong> 2nd and 3rd TZM dose, whilst <strong>the</strong> remaining laboratory<br />
parameters did not change significantly.<br />
Conclusions: These preliminary results suggest that TZM treatment induces an early<br />
preclinical cardiac systolic dysfunction which correlates with an increase of TNF-α.<br />
The study is in progress to reach <strong>the</strong> planned sample size, monitor patients for an<br />
adequate follow-up time and eventually select patients candidates for an effective<br />
cardioprotective treatment. This study was Funded by AIRC - project number 8679.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
477P LIPOSOMAL PRODRUG OF MITOMYCIN C WITH THIOLYTIC<br />
ACTIVATION: IMPROVED THERAPEUTIC INDEX OVER<br />
MITOMYCIN C IN PRECLINICAL STUDIES<br />
A.A. Gabizon 1 , Y. Amitay 2 , H. Shmeeda 3 , S. Zalipsky 4<br />
1 Oncology, Shaare Zedek Medical Center, Jerusalem, ISRAEL, 2 Experimental<br />
Oncology, Lipomedix Pharmaceuticals Inc., Jerusalem, ISRAEL, 3 Experimental<br />
Oncology, Shaare Zedek Medical Center, Jerusalem, ISRAEL, 4 Consultant,<br />
Lipomedix Pharmaceuticals Inc., Jerusalem, ISRAEL<br />
We have developed a formulation of a mitomycin-C lipid-based prodrug (MLP) in<br />
pegylated liposomes (PL) in which MLP is activated by thiolytic cleavage to<br />
mitomycin C (MMC). PL-MLP (PROMITIL) was previously reported to have<br />
reduced toxicity and an improved <strong>the</strong>rapeutic index as compared to MMC in human<br />
and mouse tumor models. In <strong>the</strong> following studies, we examined <strong>the</strong><br />
pharmacokinetics, toxicity, and <strong>the</strong>rapeutic activity of scaled-up batches of PL-MLP<br />
(prepared under <strong>the</strong> same protocol design as for clinical batches) in rodent and<br />
miniswine species. PL-MLP is a liquid suspension of vesicles of ∼100 nm diameter<br />
with MLP entrapped in <strong>the</strong> lipid bilayer at 10% molar ratio. Pharmacokinetic studies<br />
revealed major (>100-fold) differences in Cmax, AUC, plasma clearance and volume<br />
of distribution between MMC (i.v. 3 mg/kg) and PL-MLP (i.v. 6 mg/kg in<br />
MMC-equivalents). While MMC is cleared from blood within minutes and<br />
extensively distributed to peripheral tissues, PL-MLP is cleared very slowly with a<br />
ix164 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
mono-exponential half-life of ∼15 hours in rats and has a limited volume<br />
distribution roughly equivalent to <strong>the</strong> blood volume. In rat toxicity studies in rats,<br />
<strong>the</strong> MTD of PL-MLP was two to three-fold higher than that of MMC in<br />
mg-equivalent doses. Therapeutic studies in BALB/c mice inoculated i.p. with C26<br />
tumor cells show a clear survival advantage for treatment with PL-MLP over free<br />
MMC at all dose levels tested, whe<strong>the</strong>r treatment was administered by <strong>the</strong> i.v. or by<br />
<strong>the</strong> i.p. route. In <strong>the</strong> porcine model, no acute infusion reaction to i.v. administration<br />
of PL-MLP was observed. PL-MLP appears to be a stable formulation with minimal<br />
prodrug activation and release of MMC in circulation, yet significant antitumor<br />
activity, indicating in vivo prodrug activation in tumors. PL-MLP may represent an<br />
effective <strong>the</strong>rapeutic tool in a broad spectrum of malignancies, including multi-drug<br />
resistant tumors, with improved safety over free MMC, and is due to be tested in a<br />
human phase I study in <strong>2012</strong>.<br />
Disclosure: A.A. Gabizon: I am <strong>the</strong> founder and Chief Scientist of Lipomedix Inc., a<br />
company with a vested interest in <strong>the</strong> product discussed in this presentation. Y.<br />
Amitay: Paid employee of Lipomedix, a product of which is discussed here. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
478P PHASE I SAFETY AND TOLERABILITY OF ONCE DAILY ORAL<br />
AFATINIB (A) (BIBW 2992) IN COMBINATION WITH<br />
GEMCITABINE (G) IN PATIENTS (PTS) WITH ADVANCED<br />
SOLID TUMOURS<br />
S. Zanetta 1 , J. Bennouna 2 , N. Isambert 3 , H. De Mont-Serrat 4 , I. Tschoepe 4 ,<br />
P. Squiban 4 , J. Delord 5<br />
1 Oncology Department, Centre Georges François Leclerc, Dijon, FRANCE,<br />
2 Oncology/ Pneumology, Institut de Cancerologie de l’Ouest-site René<br />
Gauducheau, Nantes, FRANCE, 3 Medical Oncology, Centre Georges François<br />
Leclerc, Dijon, FRANCE, 4 Medical Affairs, Boehringer Ingelheim, Reims,<br />
FRANCE, 5 Clinical Resarch Unit, Institut Claudius Regaud, Toulouse Cedex,<br />
FRANCE<br />
Background: A is an orally bioavailable, irreversible, ErbB Family Blocker. This open<br />
label, Phase I, dose escalation trial investigated <strong>the</strong> safety, tolerability and<br />
pharmacokinetics of A in two parallel dose cohort expansion parts, in combination<br />
with ei<strong>the</strong>r G (Part A) or docetaxel (Part B) in pts with relapsed or refractory solid<br />
tumours. Preliminary results from Part A are presented here.<br />
Methods: Eligible pts (confirmed diagnosis of advanced solid tumours, Eastern<br />
Cooperative Oncology Group Performance Status 0–1) received once-daily, oral<br />
dosing of A in combination with G, given intravenously at Day 1 and at Day 8 of<br />
every 3 week cycle. Dosing of A started on Day 2 of Cycle 1. The primary objective<br />
was to establish <strong>the</strong> maximum tolerated dose (MTD) based on <strong>the</strong> occurrence of<br />
dose limiting toxicities (DLTs) observed in Cycle 1. Dose escalation was performed<br />
with cohorts of 3–6 pts using a 3 + 3 design. Initial starting dose level was A 30 mg/<br />
day and G 1000mg /m 2 , escalating up to A 50 mg/day and G 1250 mg/m 2 , until <strong>the</strong><br />
MTD was reached, and followed by a pharmacokinetic expansion cohort of 12 pts at<br />
<strong>the</strong> MTD level.<br />
Results: Nineteen pts were treated in <strong>the</strong> escalation part of <strong>the</strong> study with <strong>the</strong><br />
following baseline characteristics: mean age (53.7 years), female (63.2%) and number<br />
of prior chemo<strong>the</strong>rapies (≤2: 26%; >2: 74%). In Cycle 1, DLTs were experienced by<br />
one pt out of six receiving A 30 mg and G 1250 mg/m 2 , and in two pts at a dose<br />
level of A 40 mg/day and G 1250 mg/m 2 . Adverse events (AEs) observed in most pts<br />
were diarrhoea (89.5%) and rash (63.2%). MTD was exceeded at a dose level of A 40<br />
mg/day and G 1250 mg/m 2 . An intermediate dose level of A 40 mg/day and G 1000<br />
mg/m 2 is currently under evaluation with two pts enrolled to date.<br />
Conclusions: In pts with relapsed or refractory advanced solid tumours, <strong>the</strong><br />
combination of A with G is well tolerated, with manageable AEs. Dose finding is<br />
ongoing and MTD, safety profile and preliminary evidence of activity are anticipated<br />
to be reported at time of presentation.<br />
Disclosure: J. Bennouna: I have received honoraria from roche, boehringer<br />
ingelheim, and amgen for advisory board. It is for myself. H. De Mont-Serrat:<br />
Employee of Boehringer Ingelheim. I. Tschoepe: Employee of Boehringer Ingelheim.<br />
P. Squiban: Employee of Boehringer Ingelheim. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
479P THE IMPACT OF PATIENT SOCIO-ECONONOMIC STATUS ON<br />
ACCESS TO EARLY PHASE CANCER TRIALS<br />
A. Mohd Noor 1 , S. Vizor 2 , B. McLennan 2 , D. Sarker 2 , H. Moller 1 , J. Spicer 1 ,<br />
S. Papa 1<br />
1 School of Medicine, Cancer Research Division, King’s College London, London,<br />
UNITED KINGDOM, 2 Medical Oncology, Guy’s and St Thomas NHS Foundation<br />
Trust, London, UNITED KINGDOM<br />
Background: Little is known about <strong>the</strong> influence of sociodemographic factors on<br />
patient access to early phase cancer trials. The toxicity and efficacy of cancer drugs<br />
can vary according to sociodemographic factors, and <strong>the</strong>se differences should be<br />
considered to ensure generalisability of results and equality of access.<br />
Method: We conducted a review of patients referred to <strong>the</strong> early phase trials unit at our<br />
centre in <strong>the</strong> five years to <strong>2012</strong>. Electronic records were studied for demographic and<br />
cancer-specific data. Socio-economic status was defined by <strong>the</strong> Index of Multiple<br />
Deprivation (IMD; 1 - least deprived, 5 - most deprived) recorded for <strong>the</strong> regional Cancer<br />
Registry population according to postal code. Multivariate analysis (adjusting for gender,<br />
age and tumour type) was performed comparing 10,784 incident cancer cases in south<br />
east London with <strong>the</strong> patients referred to our unit, and with those enrolled in a trial.<br />
Results: 430 patients (195 female) were referred for consideration of an early phase<br />
trial, with a median age of 62 years (range: 22-86). Ethnicity was 74% white.<br />
Univariate analysis of ethnicity suggested <strong>the</strong> non-white population was less likely to<br />
be recruited (OR 0.48, 95% CI 0.26-0.88), but this relationship was lost with<br />
adjustment for age, gender, cancer type and IMD. Multivariate analysis showed that<br />
referral was less likely for patients in <strong>the</strong> more deprived quintiles (IMD-5: OR 0.53,<br />
95% CI 0.38-0.74). However, once referred to <strong>the</strong> unit, enrollment in a trial was not<br />
affected by IMD (IMD-5: OR 0.81, 95% CI 0.40-1.63).<br />
Conclusion: We show for <strong>the</strong> first time that social deprivation affects referral to an early<br />
phase cancer trials unit. The least deprived patients are almost twice as likely to be referred<br />
to <strong>the</strong> trial unit compared with <strong>the</strong> most deprived. This may be because patients in <strong>the</strong><br />
higher deprivation quintiles are less suitable for a trial, for example due to comorbidities,<br />
or because of inequalities that could be addressed with patient or referrer education.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
480P SINGLE INSTITUTION PHASE I TRIAL OF THE NOVEL<br />
COMPOUND FIRST-IN-CLASS PDM08 IN REFRACTORY SOLID<br />
TUMORS (NCT01380249)<br />
J. Barriuso 1 , I. Soria 2 , V. Moreno 1 , M. Coronado 3 , I. Galicia 4 , M.A. Figueredo 2 ,<br />
J. Frias 5 , J. Feliu 6 , A. Carcas 5 , J.L. Subiza 2<br />
1 Oncology Phase I Unit, La Paz University Hospital, Madrid, SPAIN, 2 Inmunology<br />
Department, San Carlos Hospital, Madrid, SPAIN, 3 Nuclear Medicine, La Paz<br />
University Hospital, Madrid, SPAIN, 4 UCICEC, La Paz University Hospital,<br />
Madrid, SPAIN, 5 Pharmacology, La Paz University Hospital, Madrid, SPAIN,<br />
6 Medical Oncology, La Paz University Hospital, Madrid, SPAIN<br />
Background: PDM08 is a syn<strong>the</strong>tic derivative of <strong>the</strong> pyroglutamic acid with anti<br />
tumor effect in different murine cancer models. The absence of direct effect on<br />
tumour cells and <strong>the</strong> antitumor activity found in immunocompetent models<br />
indicates an immune response mediated mechanism. The aim was to assess <strong>the</strong><br />
tolerability and safety profile of PDM08.<br />
Methods: PDM08 was administered twice a week for four-week cycles. An accelerate<br />
escalation phase was chosen with cohorts of 2 patients (pts) that had <strong>the</strong> possibility<br />
of escalate once to <strong>the</strong> next dose level if no grade ≥2 toxicity and no progressive<br />
disease were observed. An expansion cohort was planned at <strong>the</strong> MTD or <strong>the</strong> optimal<br />
biological dose (OBD). Extensive pharmacokinetic and pharmacodynamic (PD) data<br />
were collected. Preliminary efficacy was evaluated by PET-CT.<br />
Results: Since July 2011, 17 patients (pts) were recruited into 8 different dose levels<br />
(4pts were escalated) ranged from 0.560 mg to 56 mg. Pt characteristics were: males<br />
52.9%. Median age: 68 (28-76). ECOG 0: 64.7%. Median of previous treatments was<br />
3 ranged 2 to 5. 3 pts presented G1 headache. No DLTs were found. The best<br />
outcome was stable disease (SD) for 5 pts (4 colorectal and 1 endometrial), one<br />
being stable for 12 weeks, one 14 weeks and one remains stable after 21 weeks. 12.9%<br />
of <strong>the</strong> lesions evaluated by PET-CT showed a reduction in <strong>the</strong> maximum Standard<br />
Uptake Value (SUV) of 18-FDG. A pooled analysis of PD data from patients with<br />
<strong>the</strong> best response showed a statistically significant increased in serum levels of<br />
IL-17A, IL-13, IL-4, IL-5, TNFα, IL-22 and IL-1β (p < 0.05) from baseline.<br />
Interestingly patients without benefit showed higher basal levels of <strong>the</strong>se cytokines.<br />
The analysis of blood cell populations in pts with SD found a trend to increase <strong>the</strong><br />
absolute numbers of NKT (CD56, CD4), neutrophils (CD45, CD15, CD16b) and<br />
some specific markers of Myeloid-derived suppressor cells (CD11b, CD33). The OBD<br />
derived from PD changes was 56 mg.<br />
Conclusions: PDM08 is <strong>the</strong> first compound of a new class of drugs that can be<br />
dose-escalated safely in an accelerated manner and has promising activity. PD results<br />
suggest that PDM08 is boosting <strong>the</strong> innate immune response against cancer cells<br />
confirming preclinical data.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
481P TESETAXEL: ANALYSIS OF TWO DOSING SCHEDULES (ONCE<br />
WEEKLY VS. EVERY 3 WEEKS) USING A NOVEL ORAL<br />
TAXANE<br />
M. Beeram 1 , K. Papadopoulos 1 , A.W. Tolcher 1 , D. Rasco 1 , T. Cousin 2 , L. Itri 2 ,<br />
A. Patnaik 1<br />
1 Developmental Therapeutics, The START Center for Cancer Care, San Antonio,<br />
TX, UNITED STATES OF AMERICA, 2 Developmental Therapeutics, Genta<br />
Incorporated, Berkeley Heights, NJ, UNITED STATES OF AMERICA<br />
Background: Tesetaxel (TST) is a novel oral taxane that is active in taxane-resistant<br />
models, is not a substrate for p-glycoprotein, and has limited preclinical neuropathy.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds395 | ix165
TST is active in breast and gastric cancers when administered orally once every 3<br />
weeks (Q3W). Taxanes may have schedule-related activity and adverse reactions. We<br />
conducted a dose-ranging study comparing <strong>the</strong> safety, efficacy, and pharmacokinetics<br />
(PK) using two schedules.<br />
Methods: Patients (pts) had solid tumors, ECOG PS ≤ 2, and adequate organ<br />
function. In Schedule 1, TST was given once every 3 weeks from 18 to 27 mg/m2,<br />
escalated in increments of 3 mg/m2 to determine <strong>the</strong> MTD. In Schedule 2, TST was<br />
given once weekly for 3 weeks every 28 days, beginning at a total flat dose of 25 mg/<br />
cycle with increases up to 75 mg/cycle. Dosing was <strong>the</strong>n converted to a weight-based<br />
regimen at weekly doses of 12.5, 15, and 17.5 mg/m2 (i.e. total per cycle dose up to<br />
52.5 mg/m2). 3 pts were treated at each dose level until <strong>the</strong> MTD.<br />
Results: 27 pts were treated on Schedule 1. The MTD was 27 mg/m2 and<br />
neutropenia was dose-limiting. One pt with nasopharyngeal carcinoma had a PR and<br />
11 pts had stable disease, including several with taxane-resistant breast cancer. Cmax<br />
and AUC increased with increasing dose; however, <strong>the</strong> differences across <strong>the</strong> dose<br />
range examined were modest. No dose-related differences were apparent for o<strong>the</strong>r PK<br />
parameters. On schedule 2, 26 pts were treated in 8 dose cohorts. The MTD was 15<br />
mg/m2 (total cycle dose, 45 mg/m2). Constitutional symptoms (fatigue and anorexia)<br />
proved dose-limiting at 17.5 mg/m2/wk. Only 1 pt had Grade 3 neutropenia. One pt<br />
with MBC (who had progressed after 2 prior taxane regimens) had a PR; 1 pt with<br />
prostate cancer had prolonged PSA reduction. PK analyses showed low but<br />
progressive increases in trough TST concentrations (0.4–4.6 nmol/mL) 7 days after<br />
each succeeding dose, consistent with <strong>the</strong> prolonged T½ of this drug (∼180 hrs).<br />
There was no substantial drug accumulation over multiple cycles.<br />
Conclusions: Tesetaxel administered once every 3 weeks is active in pts with<br />
advanced gastric, breast and o<strong>the</strong>r solid tumors, including pts who have received<br />
prior taxanes. The weekly regimen is currently being evaluated in Phase 2.<br />
Disclosure: A.W. Tolcher: Corporate sponsored research. T. Cousin: Employee of Genta<br />
Inc. L. Itri: Employee of Genta Inc. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
482P PHASE 1 STUDY OF BPM 31510 (UBIDECARANONE) IN<br />
ADVANCED SOLID TUMORS: UPDATED ANALYSIS OF A<br />
NOVEL TREATMENT WITH PROMISING ACTIVITY<br />
S.P. Chawla 1 , A. Hendifar 1 , V.S. Chua 1 , D. Quon 1 , V. Narasimhan 1 , Y. Lavinski 2 ,<br />
J. McCook 3 , R. Sarangarajan 3 , P. Song 3 , N. Narain 3<br />
1 Clinical Research, Sarcoma Oncology Center, Los Angeles, CA, UNITED<br />
STATES OF AMERICA, 2 Research, MutualHealth LLC, Newport Beach, CA,<br />
UNITED STATES OF AMERICA, 3 Clinical Research, Berg Pharma, Natick, CA,<br />
UNITED STATES OF AMERICA<br />
Background: BPM is a novel small molecule that targets aerobic glycolytic pathway,<br />
re-capitulates BCL-2 mediated apoptosis and disrupts tumor angiogenesis.<br />
Methods: A standard 3 + 3, dose-escalation study was designed with primary<br />
objectives of dose finding (MTD), toxicity and pharmacokinetic correlates (PK).<br />
Secondary objectives included response, response duration and clinical benefit.<br />
Results: 42 patients with advanced solid tumors (refractory to standard <strong>the</strong>rapy)<br />
were enrolled in 8 dose cohorts (5.6 mg/kg to 104.3 mg/kg). The trial is still<br />
ongoing as <strong>the</strong> MTD has yet to be reached. 31 (74%) patients completed at least<br />
one cycle and are considered evaluable for efficacy and toxicity. Median number of<br />
treatment cycles administered were 2 (range, 1-7) with median duration of 14<br />
weeks (4-52 weeks). Of <strong>the</strong> 31 evaluable patients, 23 had grade I and 14 patients<br />
grade II elevation of INR without any significant clinical bleeding. Normalization<br />
of INR was observed in all <strong>the</strong> patients with vitamin K supplementation. Nine<br />
patients (29.0%) experienced mild headache during <strong>the</strong> first week of <strong>the</strong>rapy,<br />
relieved with acetaminophen. There was no grade 3/4 treatment related toxicity.<br />
The pharmacokinetics of BPM was noted to be linear. The values for t1/2 ranged<br />
from 2.18 to 13.3 hr, with little or no dependence of t1/2 on dose. Objective<br />
tumor responses were noted at <strong>the</strong> dose of 58.6mg/kg with 1 complete response<br />
(myxoid liposarcoma) and 1 minor response (fibrosarcoma). With a median follow<br />
up of 14 weeks (4-52 weeks) clinical stabilization was observed in 61% of <strong>the</strong><br />
patients.<br />
Conclusions: Interim data from this phase I study indicate that BPM is well tolerated<br />
with no dose limiting toxicity to date. There was no grade III/IV toxicity. Grade I/II<br />
toxicity included elevation of INR (without significant clinical bleeding) and mild<br />
headache. One patient had partial and one patient had minor response with<br />
stabilization of <strong>the</strong> disease in <strong>the</strong> majority. The current trial is in progress and <strong>the</strong>re<br />
is strong rationale for fur<strong>the</strong>r development of this unique compound which lacks <strong>the</strong><br />
toxicity associated with chemo<strong>the</strong>rapy.<br />
Disclosure: S.P. Chawla: I am an adviser to Berg Pharma LLC, Natick, MA; USA. A.<br />
Hendifar: I am an adviser to Berg Pharma LLC, Natick, MA; USA. V.S. Chua: I am<br />
an adviser to Berg Pharma LLC, Natick, MA; USA. D. Quon: I am an adviser to Berg<br />
Pharma LLC, Natick, MA; USA. Y. Lavinski: I am an employee of Berg Pharma LLC,<br />
Natick, MA; USA. J. McCook: I am an employee of Berg Pharma LLC, Natick, MA;<br />
USA. R. Sarangarajan: I am an employee of Berg Pharma LLC, Natick, MA; USA. P.<br />
Song: I am an employee of Berg Pharma LLC, Natick, MA; USA. N. Narain: I am an<br />
employee of Berg Pharma LLC, Natick, MA; USA. All o<strong>the</strong>r authors have declared<br />
no conflicts of interest.<br />
Annals of Oncology<br />
483P DESIGNER PEPTIDE ANTAGONIST OF THE LEPTIN<br />
RECEPTOR WITH PERIPHERAL ANTINEOPLASTIC ACTIVITY<br />
S. Beccari1 , L.J. Otvos2 , G.L. Cetto3 , E. Surmacz2 1<br />
Medical Oncology, Azienda Ospedaliera Universitaria Integrata Verona-"Borgo<br />
Roma", Verona, ITALY, 2 Sbarro Institute for Cancer Research and Molecular<br />
Medicine, Temple University, Philadelphia, PA, UNITED STATES OF AMERICA,<br />
3<br />
Medicine, Azienda Ospedaliera Universitaria Integrata Verona-"Borgo Roma",<br />
Verona, ITALY<br />
Background: Obesity-related hormone leptin has been implicated in <strong>the</strong><br />
development and progression of different cancer types. Studies in vitro and animal<br />
models documented that leptin promotes cancer cell proliferation and<br />
neoangiogenesis. Targeting leptin signaling could become a new <strong>the</strong>rapeutic option<br />
for <strong>the</strong> treatment of cancer, especially in obese patients. In order to inhibit<br />
pro-neoplastic leptin activity, we developed peptidomimetics that are analogs of<br />
leptin/leptin receptor (ObR) interaction site, able to compete with leptin binding and<br />
capable of blocking leptin effects in vitro and in vivo. The lead compound (Allo-aca),<br />
however, crosses <strong>the</strong> blood-brain-barrier (BBB), inducing undesirable orexigenic<br />
effects and consequent weight gain. Redesign of Allo-aca to decouple its Central<br />
Nervous System (CNS) and peripheral activity should produce superior compound<br />
for cancer treatment.<br />
Objective: The aim of this study was to design and test Allo-aca derivatives for <strong>the</strong>ir<br />
biodistribution, BBB penetration and in vitro anti-neoplastic activity against breast<br />
and colorectal cancer cells.<br />
Results: Examination of several Allo-aca derivatives resulted in identification of <strong>the</strong><br />
peptidomimetic D-Ser. D-Ser did not distribute across BBB but was present in <strong>the</strong><br />
periphery of experimantal animals. D-Ser was shown to bind ObR, and inhibit<br />
leptin-dependent-proliferation of ObR-positive breast and colorectal cancer cells in<br />
vitro at <strong>the</strong> concentration of 1 nM. Its efficacy was demonstrated both in adhesion<br />
and in three-dimensional cultures, without showing any partial agonistic activity.<br />
Antiproliferative D-Ser action was associated with <strong>the</strong> inhibition of several<br />
leptin-induced pathways, including JAK/STAT3, MAPK/ERK1/2 and PI3K/AKT,<br />
Cyclin D1 and E-cadherin.<br />
Conclusions: D-Ser is <strong>the</strong> first novel leptin-based peptidomimetic featuring<br />
peripheral ObR antagonistic activity. D-Ser inhibits leptin-dependent growth of<br />
breast and colorectal cancer cells through downregulation of several key mitogenic/<br />
survival pathways. The novel peptide may serve as a prototype to develop new<br />
onco<strong>the</strong>rapeutics, useful for <strong>the</strong> management of obesity-related cancers.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
484P LURBINECTEDIN (PM01183) IN COMBINATION WITH<br />
GEMCITABINE (GEM). PRELIMINARY RESULTS OF AN<br />
ONGOING PHASE IB STUDY<br />
E. Calvo 1 ,L.Ares 2 , M. Foster 3 , I. López Calderero 2 , A. Cubillo 1 , A. Velasco 4 ,<br />
V. Boni 1 , D. Wilkins 3 , A. Soto-Matos 5 , S. Szyldergemajn 4<br />
1 Oncology, Hospital Sanchinarro/START, Madrid, SPAIN, 2 Oncology Service,<br />
Hospital Virgen del Rocio, Seville, SPAIN, 3 Oncology, University College of<br />
London Hospital, London, UNITED KINGDOM, 4 Clinical Operations, PharmaMar,<br />
Colmenat Viejo, Madrid, SPAIN, 5 Clinical, PharmaMar, Colmenat Viejo, Madrid,<br />
SPAIN<br />
Background: PM01183 is a new anticancer agent. It exerts a wide anti-tumour<br />
activity through minor groove DNA-binding. Pre-clinical evidence of synergism has<br />
been observed in combination with GEM. Single agent PM01183 has clinical activity<br />
in pancreatic and platinum-resistant ovarian cancer. Reversible neutropenia and high<br />
emetogenic potential are <strong>the</strong> main single agent toxicity.<br />
Methods: Informed and consented adult patients (pts) were included. The starting<br />
dose was PM01183 2.5 mg + GEM 800 mg/m 2 , on Days 1 and 8 q3wk. The dose was<br />
escalated in cohorts of 3-6 pts aiming to define <strong>the</strong> maximum tolerated dose (MTD).<br />
The highest dose reached with less than 1/3 of at least 9 pts having dose-limiting<br />
toxicities (DLTs) in Cycle 1 will be <strong>the</strong> recommended dose (RD). Age was restricted<br />
up to 75 years, PS-ECOG 0-1, have adequate major organ function and no more<br />
than 2 prior chemo<strong>the</strong>rapy lines. Prior adjuvant GEM was allowed if relapse<br />
occurred >6 months.<br />
Results: As of MAY <strong>2012</strong>, 23 pts were treated across 4 dose levels (DL), 8 (35%)<br />
were female, median age was 60 (37–72). NSCLC (n = 12; 52%), pancreatic/biliary<br />
tract (n = 5; 22%) and gynaecological (n = 4; 17%) were <strong>the</strong> most frequent tumour<br />
types. Dose escalation proceeded until <strong>the</strong> MTD was reached: DL 4 PM01183 3.5 mg<br />
+ GEM 1000 mg/m 2 . Three pts experienced DLTs: Day 8 omission (neutropenia),<br />
febrile neutropenia, neutropenic infection/sepsis and grade 4 thrombocytopenia. One<br />
fatal sepsis occurred at <strong>the</strong> MTD. DL 3 (PM01183 3.5 mg + GEM 800 mg/m 2 )<br />
expansion as possible RD is ongoing. PM01183/GEM seems well tolerated at doses<br />
below <strong>the</strong> MTD. O<strong>the</strong>r toxicities in addition to reversible myelosuppression were<br />
mild nausea/vomiting, asymptomatic LFTs increases, pneumonia, anaemia or fatigue.<br />
Evidence of activity includes: 2/12 partial (PR) + 1/12 complete response (CR) in<br />
NSCLC (2 pts are ongoing after 13+ and 10+ cycles) and 1/4 PR in gynecological.<br />
No pharmacokinetic interaction was observed.<br />
ix166 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Conclusions: The combination of PM01183 and GEM seems feasible with an<br />
acceptable safety profile below <strong>the</strong> MTD: PM01183 3.5 mg+ GEM 1000 mg/m 2 .RD<br />
cohort expansion is currently ongoing. The combination is showing promising<br />
anti-tumour activity. Updated results will be presented in <strong>the</strong> meeting.<br />
Disclosure: A. Velasco: membership PharmaMar. A. Soto-Matos: PharmaMar<br />
membership. S. Szyldergemajn: PharmaMar membership. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
485P CHALLENGE IN THE PHARMACOKINETIC EVALUATION OF<br />
DTS-108, A NEW TOPOISOMERASE I INHIBITOR, IN<br />
PATIENTS WITH ADVANCED CARCINOMAS<br />
O. Mir 1 , S. Faivre 2 ,C.Dreyer 3 , R. Coriat 4 , M. Bouattour 3 , F. Goldwasser 5 ,<br />
E. Raymond 3<br />
1 Oncology Department, Teaching Hospital Cochin, AP-HPUniversit, Paris Cedex,<br />
FRANCE, 2 Internal Medicine, Hopital Beaujon, Clichy, FRANCE, 3 Oncology<br />
Department, Beaujon University Hospital, Clichy, FRANCE, 4 Oncology<br />
Department, CHU Cochin, Paris, FRANCE, 5 Oncology, Cochin Hospital, Paris,<br />
FRANCE<br />
Background: DTS-108 is a soluble pro-drug of SN38, <strong>the</strong> active metabolite of<br />
irinotecan, where <strong>the</strong> SN38 moiety is covalently linked to a 20AA peptide through a<br />
specific cross-linker that releases SN38 by esterase bond cleavage. DTS-108 was<br />
designed to achieve <strong>the</strong>rapeutic levels of SN38, while reducing diarrhea.<br />
Methods: SN-38 and SN-38G levels were evaluate with fluorescence HPLC test and<br />
LC/MS/MS methods. The pharmacokinetics of DTS-108, <strong>the</strong> adverse event (AE)<br />
profile, <strong>the</strong> dose limiting toxicities (DLT) at cycle 1, <strong>the</strong> maximum tolerated dose<br />
(MTD), and <strong>the</strong> recommended phase II dose (RD) of intravenous DTS-108 (1-2<br />
hours) every two weeks (q2w) in patients (pts) with advanced/metastatic carcinomas<br />
was conducted.<br />
Results: Forty-Two pts received DTS-108 across 14 dosing cohorts (range: 3-416mg/<br />
m2). All grade AEs were as<strong>the</strong>nia (43%), nausea (43%), diarrhea (41%), vomiting<br />
(33%), anemia (31%), rash (21%), anorexia (21%), alopecia (19%), abdominal pain<br />
(19%), and neutropenia (19%). Neutropenia was <strong>the</strong> dose limiting toxicity of<br />
DTS-108. Neutropenia started to be observed at doses >56 mg/m2. At 416 mg/m2, 3/<br />
6 pts had grade 4 neutropenia. Fluorescence HPLC was initially used to quantify<br />
DTS-108 and its metabolites (SN-38 and SN-38G). Sample stability analysis of this<br />
method showed that SN38 values were inaccurate as DTS-108 degraded forming<br />
ex-vivo SN-38 during <strong>the</strong> blood collection, plasma storage, and/or sample extraction.<br />
New processes and analytical LC/MS/MS methods for testing SN-38 were<br />
implemented. At <strong>the</strong> dose of 313 mg/m2, mean DTS-108, SN38, and SN38G<br />
AUCINF (CV%) were 439293 (24%), 1992 (34%), and 4538 (46%) h*ng/mL. Tumor<br />
stabilization (RECIST) was observed in 9 pts and confirmed in 6 pts.<br />
Conclusions: SN-38 concentration using Fluorescence HPLC failed to monitor<br />
drug escalation in topoisomerase I inhibitor because of ex vivo degradation. SN-38<br />
exposures using LC/MS/MS methods are consistent with less variables values and<br />
allow drug monitoring. DTS-108 induced no dose-limiting diarrhea but<br />
neutropenia and infusion skin reactions. The dose level 313 mg/m2 was declared<br />
<strong>the</strong> MTD based on 5 of <strong>the</strong> 6 patients treated at this dose level having no<br />
dose-limiting neutropenia and <strong>the</strong> overall improvement in <strong>the</strong> management of<br />
infusion réactions.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
486P PHARMACOKINETICS (PK) AND SAFETY OF TESETAXEL, A<br />
NOVEL ORAL TAXANE, IN JAPANESE PATIENTS (PTS) WITH<br />
ADVANCED SOLID TUMORS<br />
K. Tanaka 1 , T. Kurata 1 , Y. Fujisaka 2 , H. Kawakami 1 , H. Hayashi 1 , T. Cousin 3 ,<br />
W. Okamoto 1 , T. Kudoh 1 ,T.Satoh 1 , K. Nakagawa 1<br />
1 Medical Oncology, Kinki University School of Medicine, Osaka, JAPAN,<br />
2 Medical Oncology, Kinki University Faculty of Medicine, Osaka, JAPAN, 3 Clinical<br />
Operations, Genta Incorporated, Berkeley Heights, NJ, UNITED STATES OF<br />
AMERICA<br />
Background: Tesetaxel is an orally administered taxane that, unlike IV analogs, is<br />
not a Pgp substrate (a primary mechanism of taxane resistance). This novel agent has<br />
a long plasma T½ (∼180 h), allowing administration once every 3 weeks (Q3W).<br />
Tesetaxel is particularly active in breast and gastric cancers, with response rates of<br />
50% and 20%, respectively, in 1st-line metastatic breast and 2nd-line gastric cancer.<br />
Among > 500 pts treated to date, no hypersensitivity reactions have occurred, and<br />
neurotoxicity has been distinctly uncommon. In Western pts, <strong>the</strong> maximally<br />
tolerated dose (MTD) of tesetaxel is 27 mg/m 2 Q3W, and neutropenia is dose<br />
limiting. We conducted a phase I intersubject dose-escalation study to evaluate safety<br />
and PK in Japanese pts.<br />
Methods: Eligibility criteria included age ≥ 20 years, advanced or metastatic solid<br />
tumors, ECOG PS ≤ 1, and adequate organ function. Tesetaxel 24 mg/m 2 was given<br />
on day 1 of a 21-day cycle to <strong>the</strong> first cohort. The dose was escalated to 27 mg/m 2<br />
and 31 mg/m 2 in successive cohorts absent dose-limiting toxicity (DLT). Serial blood<br />
samples were obtained for PK analysis and assayed by HPLC.<br />
Results: Twelve pts (9 men, 3 women; age 39-74 yr) were enrolled (3 each in <strong>the</strong> 24<br />
and 31 mg/m 2 cohorts and 6 in <strong>the</strong> 27 mg/m 2 cohort). Most pts were heavily<br />
pretreated; <strong>the</strong> median number of prior chemo<strong>the</strong>rapy regimens was<br />
4. Neutropenia ≥ grade 3 occurred in 1 pt in <strong>the</strong> 24 mg/m 2 and 27 mg/m 2 cohorts<br />
and 2 pts in <strong>the</strong> 31 mg/m 2 cohort. DLT (febrile neutropenia) was observed in 1 pt at<br />
<strong>the</strong> 31 mg/m 2 dose. Mean PK data (see table) were similar in Western and Japanese<br />
pts, with an expected dose-dependent increase in exposure.<br />
Dose level Patients (n) C max T max AUC 0-168 h<br />
24 mg/m 2<br />
27 mg/m 2<br />
*31 mg/m 2<br />
Western (11) 29.7 2.5 594<br />
Japanese (3) 29.0 2.7 658<br />
Western (7) 31.2 2.1 869<br />
Japanese (3) †<br />
46.6 4.7 818<br />
Japanese (3) 57.0 2.0 1036<br />
† Results of PK analyses for last 3 pts enrolled not yet available * Dose not studied in<br />
Western pts<br />
Conclusion: This study indicates that tolerability and PK of tesetaxel is similar in<br />
Western and Japanese pts. Final data will be presented.<br />
Disclosure: T. Cousin: I am an employee of Genta Incorporated, <strong>the</strong> company that is<br />
developing tesetaxel. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
487P CORRELATION OF INFUSION-RELATED REACTIONS (IRR)<br />
AND OUTCOME IN PATIENTS RECEIVING NGR-HTNF<br />
TREATMENT<br />
G. Rossoni1 , V. Gregorc1 , A. Bulotta1 , M.G. Viganò1 , G. Todisco1 , A. Lambiase2 ,<br />
C. Bordignon2 1 2<br />
Oncologia, IRCCS San Raffaele, Milano, ITALY, Clinical Development, MolMed,<br />
Milan, ITALY<br />
Background: NGR-hTNF (asn-gly-arg-human tumor necrosis factor) induces<br />
systemic release of cytokines and intratumoral infiltration of effector T cells.<br />
Intravenous infusion of NGR-hTNF is characterized by onset of IRR, mostly<br />
consisting of transient grade 1-2 chills. Incidence, predictors of development, and<br />
relationships with outcome of IRR were assessed across 5 phase 2 single-arm trials of<br />
NGR-hTNF.<br />
Methods: 205 patients (pts) with solid tumors received NGR-hTNF 0.8 µg/m 2 every<br />
3 weeks (q3w) given ei<strong>the</strong>r alone in colon cancer (n = 45), liver cancer (n = 40), and<br />
meso<strong>the</strong>lioma (n = 55), or with doxorubicin in small-cell lung cancer (n = 28) and<br />
ovarian cancer (n = 37). Tumor assessment by RECIST was done q6w until<br />
progressive disease (PD). Logistic and Cox proportional-hazards regression models<br />
were used to analyze associations between IRR and outcome, in terms of response<br />
rate (RR, complete and partial response), disease control rate (DCR, rate of pts<br />
without PD at 6 weeks), and progression-free survival (PFS).<br />
Results: Overall, 137/205 pts (67%) experienced IRR on treatment, while 68 pts<br />
(33%) did not report IRR. In <strong>the</strong> IRR group, 63% of pts had grade 1 and 37% grade<br />
2. By time of onset, 88% of pts developed IRRs within first 6 weeks and 12% later.<br />
Baseline characteristics in <strong>the</strong> IRR v non-IRR groups were: median age 66 v 64; male<br />
50% v 56%; PS 1-2 34% v 35%, range of prior lines 1-4 v 1-5. Among baseline<br />
factors, only a low number of prior regimens predicted for IRR (odds ratio, OR 1.4 p<br />
= .02). The RR was 12% (95% CI 7-18) in <strong>the</strong> IRR group and 3% (1-10) in <strong>the</strong><br />
non-IRR group (OR 4.4 p = .05), while DCR was 50% (42-59) in pts who had IRR<br />
and 34% (23-46) in pts who did not (OR 2.0 p = .02). On landmark analysis set at<br />
6-week time point, PFS was significantly improved in pts with IRR (hazard ratio, HR<br />
0.63 p = .007). Six-month PFS rates were 17% (11-23) for <strong>the</strong> IRR group and 6%<br />
(1-12) for <strong>the</strong> non-IRR group (log-rank p = .005). In multivariable analyses<br />
(adjusting for age, sex, PS, prior lines, and tumor types), <strong>the</strong> onset of IRR remained<br />
independent predictor of higher likelihood of response (OR 4.8 p = .05) and lower<br />
risk of progression or death (HR 0.62 p = .009).<br />
Conclusions: Occurrence of IRR may identify pts who are more likely to gain benefit<br />
from NGR-hTNF treatment.<br />
Disclosure: A. Lambiase: Employment- MolMed. C. Bordignon: Employment -<br />
MolMed. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
488P IMPACT OF SOLUBLE TUMOR NECROSIS<br />
FACTOR-RECEPTORS (STNF-RS) SHEDDING ON OUTCOME IN<br />
PATIENTS TREATED WITH NGR-HTNF<br />
P.A. Zucali 1 , M. Simonelli 1 , F. De Vincenzo 1 , E. Lorenzi 1 , A. Santoro 1 ,<br />
A. Lambiase 2 , C. Bordignon 2<br />
1 Department of Oncology, Humanitas Cancer Center IRCCS, Rozzano, ITALY,<br />
2 Clinical Development, MolMed, Milan, ITALY<br />
Background: NGR-hTNF (asn-gly-arg-human tumor necrosis factor) displays a<br />
biphasic dose-response curve with activity shown at very low or high doses.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds395 | ix167
Treatment-induced shedding of circulating sTNF-R1 or -R2 may block drug effects.<br />
The impact of this counterregulatory mechanism on NGR-hTNF activity was<br />
assessed in two phase I trials.<br />
Methods: Sixty patients (pts) with refractory solid tumors (median age, 60 years; M/<br />
F 44/16; PS 0/1-2 25/35; median prior treatment lines, 3) received NGR-hTNF every<br />
3 weeks (q3w) given at low doses (0.2 to 1.6 µg/m 2 n = 14) or high doses (60 to 325<br />
µg/m 2 n = 46). Tumor assessment by RECIST was done q6w until progressive disease<br />
(PD). We assessed <strong>the</strong> associations between baseline-normalized plasma levels of<br />
sTNF-R2 after 1st treatment cycle and clinical outcomes in terms of disease control<br />
rate (DCR, rate of pts without PD after 6 weeks) and progression-free survival (PFS)<br />
Results: The levels of sTNF-R2 peaked significantly higher than sTNF-R1 (p < .0001)<br />
and increased dose proportionally (p = .0003), with a median distribution value of<br />
8.6 ng/mL (interquartile range 4.5-10.7). Using <strong>the</strong> 25th percentile as cut-off value,<br />
<strong>the</strong> sTNF-R2 levels were dichotomized in low (≤ 4.5 ng/mL n = 15) or high (> 4.5<br />
ng/mL n = 45). Mean number of cycles was 5.5 (range 1-29) and 2.5 (1-6) in pts with<br />
low or high levels, respectively. By univariate analyses, low sTNF-R2 levels were<br />
significantly associated with increased DCR (odds ratio, OR 3.8 p = 0.04) and<br />
improved PFS (hazard ratio, HR 0.29 p = .002). DCR was 58% (95% CI 32-81) and<br />
26% (16-41) in pts with low or high levels, respectively. Six-month PFS rates were<br />
29% in pts with low levels and 0% in pts with high levels (log-rank p = 0.0008).<br />
Median duration of disease control was 7.5 months in pts with low levels and 2.9<br />
months in pts with high levels (log-rank p = .007). After adjusting for age, sex, PS,<br />
and prior lines, a low sTNF-R2 level remained independent predictor of higher DCR<br />
(OR 5.2 p = .03) and longer PFS (HR = 0.27 p = .002). The highest sTNF-R2 levels<br />
(75th percentile) were associated with <strong>the</strong> worst survival rates (HR 2.6 p = .01)<br />
Conclusions: Early treatment-induced changes in sTNF-R2 shedding may identify<br />
pts who have a greater likelihood of benefit from NGR-hTNF.<br />
Disclosure: A. Lambiase: Employment - MolMed. C. Bordignon: Employment -<br />
MolMed. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
489P FOOD EFFECT STUDY OF THE INVESTIGATIONAL AURORA A<br />
KINASE (AAK) INHIBITOR MLN8237 (ALISERTIB) IN PATIENTS<br />
WITH ADVANCED SOLID TUMORS<br />
G.S. Falchook 1 , X. Zhou 2 , L.S. Rosen 3 , K. Venkatakrishnan 2 , R. Kurzrock 1 ,<br />
D. Mahalingam 4 , J. Goldman 5 , J. Jung 6 , C. Milch 2 , J. Sarantopoulos 7<br />
1 Investigational Cancer Therapeutics, The University of Texas M. D. Anderson<br />
Cancer Center, Houston, TX, UNITED STATES OF AMERICA, 2 Clinical<br />
Pharmacology, Millennium Pharmaceuticals, Inc., Cambridge, MA, UNITED<br />
STATES OF AMERICA, 3 Oncology, Premiere Oncology, Santa Monica, CA,<br />
UNITED STATES OF AMERICA, 4 Oncology, Institute for Drug Development,<br />
Cancer Therapy and Research Center at University of Texas Health Science<br />
Center San Antonio, San Antonio, TX, UNITED STATES OF AMERICA, 5 Division<br />
of Hematology Oncology, David Geffen School of Medicine, UCLA Medical<br />
Center, Santa Monica, CA, UNITED STATES OF AMERICA, 6 Biostatistics,<br />
Millennium Pharmaceuticals, Inc., Cambridge, MA, UNITED STATES OF<br />
AMERICA, 7 Oncology, Institute for Drug Development, Cancer Therapy and<br />
Research Center at Universtiy of Texas Health Science Center San Antonio, San<br />
Antonio, TX, UNITED STATES OF AMERICA<br />
Background: MLN8237 (alisertib) is an investigational, orally available, selective<br />
AAK inhibitor currently in clinical development for multiple oncology indications.<br />
The recommended phase 2 dose is 50 mg twice daily for 7 d in a 21-d cycle. This<br />
study was conducted to characterize <strong>the</strong> effects of food on single-dose<br />
pharmacokinetics (PK) of MLN8237 in pts with advanced solid tumors.<br />
Methods: Eligible pts were aged ≥18 y and had ECOG PS 0–1. Following overnight<br />
fasting for at least 10 h, pts received a single 50 mg dose of MLN8237 (enteric-coated<br />
tablet) under ei<strong>the</strong>r fasted or fed conditions with a standard high-fat meal using a<br />
2-cycle, 2-way crossover design. PK samples were collected in Cycles 1 and 2<br />
pre-dose and following Day 1 dosing up to 48 h post-Day 1 dose. Ratio of geometric<br />
mean C max and AUC 0-last under fed conditions in reference to those under fasted<br />
conditions was calculated and <strong>the</strong> associated 90% CI were estimated using analysis of<br />
variances. Additional endpoints were safety and response.<br />
Results: 24 pts were enrolled: 33% male, 96% white, median age 58 y, and mean<br />
weight 64 kg. 14 pts were PK-evaluable (10 pts not PK-evaluable due to insufficient<br />
data). Following a single oral dose of MLN8237, median Tmax was 6 and 3 h for fed<br />
and fasted treatment, respectively. The geometric mean of AUC 0-last following single<br />
dose under fed conditions was 106% of that under fasted conditions (90% CI: 82%,<br />
137%). The geometric mean of C max under fed conditions was 83% of that under<br />
fasted conditions (90% CI: 66%, 106%). Following multiple dose administration, 23<br />
(96%) pts had a drug-related adverse event (AE). Most common drug-related grade<br />
3/4 AEs were neutropenia (50%), leukopenia (38%), and thrombocytopenia (21%). 3<br />
pts had drug-related serious AEs. One pt died (non-drug-related respiratory arrest).<br />
Stable disease was achieved in 12 pts, including 1 pt with melanoma who received<br />
∼11 cycles.<br />
Conclusions: Systemic exposures achieved following a single 50 mg dose of<br />
MLN8237 administered following a high-fat meal are similar to those observed in <strong>the</strong><br />
fasted state. These data support <strong>the</strong> conclusion that MLN8237 may be administered<br />
without regard for <strong>the</strong> timing of meals in future clinical studies.<br />
Annals of Oncology<br />
Disclosure: G.S. Falchook: Research funding: Millennium Pharmaceuticals, Inc. X.<br />
Zhou: Employment: Millennium Pharmaceuticals, Inc. L.S. Rosen: Research support:<br />
Millennium Pharmaceuticals, Inc. K. Venkatakrishnan: Employment: Millennium<br />
Pharmaceuticals, Inc. R. Kurzrock: Research funding: Millennium Pharmaceuticals,<br />
Inc. J. Jung: Employment: Millennium Pharmaceuticals, Inc. C. Milch: Employment:<br />
Millennium Pharmaceuticals, Inc. Ownership interest: Takeda. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
490P CLINICAL EVALUATION OF DENDRITIC CELL BASED<br />
VACCINES PULSED WITH WT1 AND/OR MUC1 FOR PATIENTS<br />
WITH ADVANCED OR RECURRENT CANCERS<br />
S. Tsujitani 1 , M. Tanii 2 , Y. Yonemitsu 3<br />
1 Department of Translational Medicine, National Center for Global Health and<br />
Medicine, Tokyo, JAPAN, 2 Department of Medical Oncology, Fukuoka Imax<br />
Clinic, Fukuoka, JAPAN, 3 R&D Laboratory for Innovative Bio<strong>the</strong>rapeutics, Kyushu<br />
University, Fukuoka, JAPAN<br />
Background: Dendritic cell (DC)-based vaccines have been expected as one of new<br />
<strong>the</strong>rapeutic approaches to treat cancer patients; however, <strong>the</strong>ir clinical outcome is not<br />
fully elucidated. We here report a single center retrospective study analyzing <strong>the</strong><br />
survival of patients with various cancers.<br />
Patients and methods: DC-based vaccines pulsed with WT1 and/or MUC1 peptides<br />
has been carried out in 180 patients with advanced or recurrent cancers between<br />
September 2009 and September 2011. Previous standard chemo<strong>the</strong>rapy failed in most<br />
patients and ano<strong>the</strong>r chemo<strong>the</strong>rapy was given with DC-based <strong>the</strong>rapy. Intradermal<br />
injection of 1 x 107 mature DCs was repeated biweekly. After 1 course of treatment<br />
(7 times of injection), clinical efficacy was evaluated with RECIST criteria or tumor<br />
markers.<br />
Results: In 180 patients, 119 patients completed 1 course treatment. Patient with 0-1<br />
levels of performance status occupied 93% of 119 patients. One-year survival rate of<br />
<strong>the</strong> 119 patients was 57.6% and did not reach to MST. One-year survival rates were<br />
54% in lung cancer (n = 14), 35% in pancreas cancer (n = 14), 100% in colon cancer<br />
(n = 9), 50% in ovarian cancer (n = 9), 83% in breast cancer (n = 7) and 86% in<br />
gastric cancer (n = 5). In 20 patients with more than 1-year follow-up period and<br />
definite assessment of clinical response, 4 (20%) CR, 4 (20%) PR, 9 (45%) SD and 3<br />
(15%) PD were obtained. One-year survival rates were 100% in CR cases, 100% in<br />
PR, 67% in SD and 33% in PD.<br />
Conclusions: In patients with 1 course DC-based <strong>the</strong>rapy, survival more than 1 year<br />
may be expected, particularly in those with definitive disease control after treatment.<br />
DC-based <strong>the</strong>rapy may be suitable to patients with better performance status.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
491P BODY COMPOSITION IS LINKED TO TOXICITY AND<br />
OUTCOME IN PATIENTS (PTS) INCLUDED IN PHASE I TRIALS<br />
S. Cousin 1 , A. Hollebecque 1 , S. Koscielny 2 , A. Varga 1 , V. Baracos 3 , J. Soria 1 ,<br />
S. Antoun 4<br />
1 Department of Medicine, Institut Gustave Roussy, Villejuif, FRANCE,<br />
2 Department of Biostatistics and Epidemiology, Institut Gustave Roussy, Villejuif,<br />
FRANCE, 3 Department of Oncology, University of Alberta, Edmonton, AB,<br />
CANADA, 4 Emergency Department, Institut Gustave Roussy, Villejuif, FRANCE<br />
Background: Phase I clinical trials are dose- and toxicity–finding studies designed to<br />
identify <strong>the</strong> recommended phase II dose of new drugs. Thus, it appears crucial to<br />
distinguish toxicity directly related to <strong>the</strong> tested drug or to pts characteristics.<br />
Because previous studies have shown that sarcopenia could be linked to drug toxicity,<br />
we have evaluated <strong>the</strong> effects of body composition parameters on <strong>the</strong> toxicities<br />
incidence among phase I included pts.<br />
Methods: We have carried out a prospective single institution study which included<br />
all pts consecutively treated from January 2011 to July 2011 in our phase I unit,<br />
irrespective of <strong>the</strong> tumor type and/or drug nature. Clinical and biological nutritional<br />
parameters were recorded. Analysis of <strong>the</strong> computerized tomography (CT) images<br />
realized within 30 days before inclusion was used to evaluate cross-sectional areas<br />
(cm 2 ) of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and<br />
muscle tissue (MT). The 3 rd lumbard vertebra (L3) was chosen as a landmark since<br />
L3 and whole-body measurements are linearly related. Images were analyzed using<br />
Slice-O-Matic software V4.3 (Tomovision). Tissue cross-sectional areas were<br />
computed. Analysis was stratified on sex. Comparisons used Chi-2 test,<br />
Kruskal-Wallis test and log rank test.<br />
Results: The study population consisted in 64 men and 49 women. The median age<br />
was 57.3 years. Drug interruption due to toxicity (DIT) occurred in 15% of <strong>the</strong> pts.<br />
The only factor associated with DIT was low MT: 117 cm 2 versus 138 cm 2 (p=<br />
0.039). Pts who did not experiment DIT were more likely to have MT > median (56%<br />
versus 15%, p = 0.007). None of <strong>the</strong> following parameters were found to be associated<br />
with DIT: weight change >5%, >10%, Albumin< 35g/l, lacticodeshydrogenase > 250<br />
IU/l, transthyretin 6mg/l. Additionally, VAT <<br />
ix168 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
median was associated with poorer overall survival (OS) (p = 0.01) and shorter<br />
progression free survival (PFS) (p = 0.02).<br />
Conclusion: In a heterogeneous population of pts enrolled in various phase I trials,<br />
low muscle tissue was associated with <strong>the</strong> drug interruption due to toxicity. OS and<br />
PFS were linked to <strong>the</strong> VAT. Body composition is linked to toxicities risk and<br />
outcome in phase I pts.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
492P CLINICAL EFFECTS OF MGCD265, AN ORAL TYROSINE<br />
KINASE INHIBITOR, IN COMBINATION WITH ERLOTINIB OR<br />
DOCETAXEL FOR TREATMENT OF ADVANCED<br />
GASTROESOPHAGEAL AND NSCLC TUMORS<br />
A. Patnaik 1 , K. Papadopoulos 1 , A.W. Tolcher 1 , M. Beeram 1 , M. Tawashi 2 ,<br />
M. Fournel 2 , C. Maroun 2 , R.W. Humphrey 2 , J. Besterman 2 , P.J. O’Dwyer 3<br />
1 Developmental Therapeutics, The START Center for Cancer Care, San Antonio,<br />
TX, UNITED STATES OF AMERICA, 2 Clinical Affairs, Methylgene, Inc, Montreal,<br />
QC, CANADA, 3 Abramson Cancer Center, University of Pennsylvania,<br />
Philadelphia, PA, UNITED STATES OF AMERICA<br />
Background: MGCD265, a multikinase inhibitor with nM IC50 against Met, VEGFR<br />
1, 2 and 3, Tie-2 and Ron, has been shown in preclinical models to possess broad<br />
antitumor effects. A phase I study was undertaken to assess <strong>the</strong>rapy with MGCD265<br />
and docetaxel or erlotinib for treatment of solid tumors.<br />
Methods: Patients (pts) with advanced solid tumors were enrolled in an open-label,<br />
dose-escalation study using <strong>the</strong> standard 3 + 3 design. All pts received 3-wk cycles of<br />
MGCD265 (p.o. QD or BID) with docetaxel or erlotinib per standard of care, as<br />
defined by investigators. Endpoints were safety, pharmacodynamics,<br />
pharmacokinetics and antitumor activity of <strong>the</strong> combination <strong>the</strong>rapy.<br />
Results: Of 89 pts enrolled, <strong>the</strong>re were 12 cases of NSCLC (docetaxel group) and 9 cases<br />
of gastroesophageal (GE) cancer (erlotinib group). Of 10 response-evaluable NSCLC pts,<br />
all met criteria for stable disease (SD) for ≥2 cycles (including 2 pts with partial<br />
response). Five pts achieved SD for 5-16 mos, with four exceeding time on prior <strong>the</strong>rapy.<br />
Two pts have not reached first evaluation. Treatment continues in 3 pts. Four of nine GE<br />
pts achieved SD. Three remained stable for 10-18 mos, exceeding time on prior <strong>the</strong>rapy.<br />
Treatment continues in 1 pt. A plasma-based assay of Met phosphorylation showed up<br />
to 30% inhibition at doses to date. PK analysis is pending. Dose escalation continues.<br />
Toxicities were mostly mild to moderate. Nonhematologic adverse event (AEs) ≥ grade<br />
3 were reported in 20% of pts in each treatment arm, and were primarily GI-related.<br />
Expected docetaxel–associated hematologic AEs were also observed.<br />
Conclusions: Preliminary findings from a phase I study suggest that MGCD265 and<br />
docetaxel or erlotinib may hold promise for treatment of NSCLC and GE tumors.<br />
Clinical response was seen in <strong>the</strong> majority of NSCLC pts, with almost 50% achieving<br />
SD for ≥5 mos. Select GE pts achieved SD for more than 10 mos. AE rates with<br />
combination <strong>the</strong>rapy were in <strong>the</strong> expected range.<br />
Disclosure: A. Patnaik: Research funding from Methylgene, Inc. K. Papadopoulos:<br />
Research funding from Methylgene, Inc. A.W. Tolcher: Research funding from<br />
Methylgene, Inc. M. Beeram: Research funding from Methylgene, Inc. M. Tawashi:<br />
Employee of Methylgene, Inc. M. Fournel: Employee of Methylgene, Inc. C. Maroun:<br />
Employee of Methylgene, Inc. R.W. Humphrey: Employee of Methylgene, Inc. J.<br />
Besterman: Employee of Methylgene, Inc. P.J. O’Dwyer: Research funding from<br />
Methylgene, Inc.<br />
493P PHARMACOKINETIC PROFILE OF MGCD265, AN ORAL<br />
TYROSINE KINASE INHIBITOR, WITH OR WITHOUT FOOD IN<br />
HEALTHY VOLUNTEERS<br />
E. Sicard 1 , M. Juretic 2 , M. Drouin 2 , G. Reid 2 , J. Wang 2 , W. Hunt 2 , C. Maroun 2 ,<br />
J. Besterman 2<br />
1 Clinical Research, Algorithme Pharma, Laval, QB, CANADA, 2 Clinical Affairs,<br />
Methylgene, Inc, Montreal, QB, CANADA<br />
Background: MGCD265 is a novel targeted cancer <strong>the</strong>rapeutic, currently in phase I/<br />
II clinical trials, that inhibits Met and VEGF receptor tyrosine kinases. The abnormal<br />
activation of Met is involved in tumor development and metastasis, and VEGF<br />
kinase is responsible for inappropriate angiogenesis that nourishes <strong>the</strong> tumor.<br />
MGCD265 has demonstrated a favorable safety profile in patients with advanced<br />
malignancies and can safely be combined with o<strong>the</strong>r cancer <strong>the</strong>rapeutics such as<br />
docetaxel and erlotinib. The objective of this Phase I study was to assess <strong>the</strong><br />
bioavailability of MGCD265 under fasting and fed conditions in healthy volunteers.<br />
Methods: This was a randomized, laboratory-blinded, 2-period, crossover study.<br />
MGCD265 was administered as a single dose (100 mg) after a 10-hr overnight fast. For<br />
<strong>the</strong> fasting condition, fasting was continued for at least 4 hrs following drug<br />
administration. For <strong>the</strong> fed condition, subjects received a standardized meal 30 mins<br />
before drug administration. Blood samplings for <strong>the</strong> pharmacokinetic (PK) evaluation<br />
were done from pre-dose to up to 96 hrs post-dose. Safety was evaluated through <strong>the</strong><br />
assessment of adverse events (AEs), laboratory tests, vital signs and 12-lead ECG.<br />
Results: Fourteen subjects were recruited [M/F: 8/6; median age: 51 years old (range<br />
41-65); median BMI: 25 kg/m2 (range: 19-29)]. One female subject discontinued<br />
early due to a fall (unrelated to MGCD265). Using nominal timepoints, on average,<br />
<strong>the</strong> fed condition was associated with an ∼3 fold increase in Cmax, AUCT, and<br />
AUCinf. The half-life of MGCD265 was found to be ∼34 hrs. Tmax was calculated<br />
to be 7 hrs and 10 hrs under fasting and fed conditions, respectively. MGCD265<br />
related AEs were mostly mild and included dry mouth in 3 subjects, somnolence in 1<br />
subject and moderate diarrhea in 1 subject. There were no clinically significant<br />
changes in vital signs, ECG or laboratory values.<br />
Conclusions: Exposure of MGCD265 increased significantly in <strong>the</strong> presence of a<br />
meal, with no added toxicity. The prolonged sampling time used in this study<br />
provided a more accurate estimation of MGCD265 half-life (∼34 hrs) compared to<br />
<strong>the</strong> estimate found in patients with advanced malignancies (∼23 hrs).<br />
Disclosure: E. Sicard: Research funding from Methylgene, Inc. M. Juretic: Employee<br />
of Methylgene, Inc. M. Drouin: Employee of Methylgene, Inc. G. Reid: Employee of<br />
Methylgene, Inc. J. Wang: Employee of Methylgene, Inc. W. Hunt: Employee of<br />
Methylgene, Inc. C. Maroun: Employee of Methylgene, Inc. J. Besterman: Employee<br />
of Methylgene, Inc.<br />
494P PHASE I SAFETY AND TOLERABILITY OF ONCE DAILY ORAL<br />
AFATINIB (A) IN COMBINATION WITH DOCETAXEL (D) IN<br />
PATIENTS (PTS) WITH RELAPSED OR REFRACTORY<br />
ADVANCED SOLID TUMOURS<br />
H. Senellart 1 , J. Bennouna 1 , N. Isambert 2 , H. De Mont-Serrat 3 , P. Squiban 3 ,<br />
I. Tschoepe 3 , J. Delord 4<br />
1 Department of Medical Oncology, Centre René Gauducheau, Saint-Herblain<br />
Cedex, FRANCE, 2 Medical Oncology, Centre Georges François Leclerc, Dijon,<br />
FRANCE, 3 Medical Affairs, Boehringer Ingelheim, Reims, FRANCE, 4 Clinical<br />
Resarch Unit, Institut Claudius Regaud, Toulouse Cedex, FRANCE<br />
Background: A is an orally bioavailable, irreversible, ErbB Family Blocker. This open<br />
label, Phase I, dose escalation trial investigated <strong>the</strong> safety, tolerability and<br />
pharmacokinetics (PK) of A, in two parallel dose cohort expansion parts, in<br />
combination with ei<strong>the</strong>r gemcitabine (Part A) or D (Part B) in pts with relapsed or<br />
refractory solid tumours. Preliminary results from Part B are presented here.<br />
Methods: Eligible pts (advanced solid tumours, Eastern Cooperative Oncology Group<br />
Performance Status 0–1) received once daily, oral dosing of A with D, given<br />
intravenously on Day 1 of every 3 week cycle. Primary objective was to establish <strong>the</strong><br />
maximum tolerated dose (MTD) based on <strong>the</strong> occurrence of dose limiting toxicities<br />
(DLT) observed in Cycle 1. Dose escalation was performed with cohorts of 3–6 pts<br />
using a 3 + 3 design. Initial starting dose level was A 30 mg/day and D 60 mg/m 2 ,<br />
escalating up to A 50 mg/day and D 75 mg/m 2 until <strong>the</strong> MTD was reached, and<br />
followed by a PK expansion cohort of 12 pts at <strong>the</strong> MTD level.<br />
Results: To date, 27 pts have been treated in Part B, 18 pts in <strong>the</strong> escalation phase<br />
with A (30–50 mg/day) and D (60–75 mg/m 2 ), and 9 pts in <strong>the</strong> expansion phase<br />
with A 40 mg/day and D 75 mg/m 2 . Baseline characteristics were mean age (56.4<br />
years), female (44.4%), and number of prior chemo<strong>the</strong>rapies (≤ 2: 48%; >2: 52%).<br />
Adverse events (AEs) were manageable and <strong>the</strong> MTD was not exceeded in <strong>the</strong> tested<br />
dose range up to A 50 mg/day and D 75 mg/m 2 . AEs were diarrhoea (92.6%) and<br />
as<strong>the</strong>nia (77.8%). Selected dose level for <strong>the</strong> expansion cohort (A 40 mg/d with D 75<br />
mg/m 2 ) was based on <strong>the</strong> potential for diarrhoea and rash during later cycles. At this<br />
dosage, events qualifying for DLT such as febrile neutropenia (2), diarrhoea Grade 3,<br />
hypokalaemia Grade 3, hyponatraemia Grade 3, increase of creatininaemia Grade 2<br />
and oral mucositis, were observed in 7 pts.<br />
Conclusions: Based on <strong>the</strong> rate of DLTs observed at 40 mg/day A + 75 mg/m 2 D, <strong>the</strong><br />
decision was made to evaluate fur<strong>the</strong>r <strong>the</strong> A 30 mg/day + D 75 mg/m 2 dose regimen<br />
in an additional cohort of 12 pts. Additional safety data and preliminary evidence of<br />
activity are anticipated to be available at <strong>the</strong> time of presentation.<br />
Disclosure: J. Bennouna: I have received honoraria from roche, boeringher, amgen<br />
for advisory board. It is for myself. H. De Mont-Serrat: Employee of Boehringer<br />
Ingelheim. P. Squiban: Employee of Boehringer Ingelheim. I. Tschoepe: Employee of<br />
Boehringer Ingelheim. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
495P CONTRIBUTION OF IMMUNOGENIC CELL DEATH (ICD) TO<br />
THE ANTI-TUMOR ACTIVITY OF CATUMAXOMAB<br />
(ANTI-EPCAM X ANTI-CD3)<br />
D. Goéré, C. Flament, N. Chaput-Gras, L. Zitvogel<br />
Surgical Oncology, Institut Gustave Roussy, Villejuif, FRANCE<br />
Background: The trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3) is<br />
approved (EU) for <strong>the</strong> intraperitoneal treatment of malignant ascites. Catumaxomab<br />
is a trifunctional antibody targeting EpCAM on tumor cells, CD3 on T lymphocytes<br />
and binding to FcγR positive accessory cells <strong>the</strong>reby leading to <strong>the</strong> elimination of<br />
EpCAM+ tumor cells by different immune-mediated mechanisms. It has been<br />
reported that tumor cell death triggered by some immunogenic compounds or drugs<br />
used in <strong>the</strong> oncological armamentarium participates in <strong>the</strong> long term protection of<br />
patients treated with chemo<strong>the</strong>rapy. The present nonclinical study investigated<br />
whe<strong>the</strong>r catumaxomab promotes immunogenic cell death (ICD) mechanisms which<br />
may contribute to its mode of action and its pharmacological activity in vivo.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds395 | ix169
Methods: Ei<strong>the</strong>r co-cultures of peripheral blood mononuclear cells from healthy<br />
volunteers and EpCAM+ tumor cells (allogeneic system) or ascites cells from patients<br />
with malignant ascites (autologous system) were incubated in <strong>the</strong> presence of<br />
catumaxomab for 24-48 hours. Analysis of T, NK, DC/monocyte cell activation and<br />
measurement of cytokine release in cell culture supernatants was performed.<br />
Subsequent analyses included investigation of cell death of EpCAM+ tumor cells and<br />
evaluation of ICD parameters (calreticulin, HMGB1, ATP).<br />
Results: The trifunctional antibody catumaxomab, in <strong>the</strong> presence of EpCAM+<br />
tumor cells, induces activation of T lymphocytes, both CD4, CD8, with induction of<br />
Th1 and Th17 polarization accompanied by a by-stander NK cell triggering. In <strong>the</strong><br />
absence of ICD chemo<strong>the</strong>rapy (oxaliplatin, doxorubicin), no ICD markers<br />
(calreticulin, HMGB1, ATP) can be detected on EpCAM+ tumor cells. However,<br />
following a pre-sensitization by suboptimal doses of oxaliplatin, catumaxomab could<br />
promote enhanced exposure of calreticulin, HMGB1 and ATP release from EpCAM+<br />
tumor cells (allogeneic system).<br />
Conclusions: Activation of T cells and induction of inflammatory lymphocytes mainly<br />
contributes to <strong>the</strong> catumaxomab-mediated elimination of EpCAM+ tumor target cells.<br />
ICD mechanisms including release of HMGB1 and ATP, exposure of calreticulin by<br />
targeted tumor cells may fur<strong>the</strong>r promote <strong>the</strong> anti-tumor activity of catumaxomab.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
496P A PHASE 1 STUDY OF MM-111; A BISPECIFIC HER2/HER3<br />
ANTIBODY FUSION PROTEIN, COMBINED WITH MULTIPLE<br />
TREATMENT REGIMENS IN PATIENTS WITH ADVANCED<br />
HER2 POSITIVE SOLID TUMORS<br />
D. Richards 1 , F. Braiteh 1 , S. Anthony 1 , W. Edenfield 1 , B. Hellerstedt 1 , R. Raju 2 ,<br />
P. Conkling 1 , C. McDonagh 3 , S. Frye 3 , V. Moyo 3<br />
1 Research, US Oncology, The Woodlands, TX, UNITED STATES OF AMERICA,<br />
2 Research, Alliance Oncology Research, Kettering, OH, UNITED STATES OF<br />
AMERICA, 3 Clinical Development, Merrimack Pharmaceuticals, Cambridge, MA,<br />
UNITED STATES OF AMERICA<br />
Background: Ligand-activated HER3 forms a potent signaling heterodimer with<br />
HER2 and is emerging as key tumorigenic node and mediator of drug resistance.<br />
MM-111 (111) is a novel molecule that inhibits ligand activated HER3 signaling in<br />
HER2+ tumors. Preclinically, MM-111 potentiates <strong>the</strong> anti-tumor activity of and<br />
mitigates resistance to trastuzumab, lapatinib and chemo<strong>the</strong>rapies. This study<br />
evaluates <strong>the</strong> safety of MM-111 combined with standard of care (SOC)<br />
HER2-targeting regimens (Rx), namely; capecitabine (X), cisplatin (C), and<br />
trastuzumab (T) (Arm 1); lapatinib (L) + /- trastuzumab (Arm 2); and paclitaxel (P)<br />
with trastuzumab (Arm 3).<br />
Methods: This was a multi-arm Phase 1, dose escalation study of MM-111 in<br />
combination with SOC regimens to evaluate safety, pharmacokinetics (PK), and<br />
anti-tumor activity. Patients were required to have documented advanced HER2+<br />
cancer, with adequate organ function. Each arm was designed to run as a separate<br />
Phase 1 study to address safety and tolerability and each arm utilized a "3 + 3" design<br />
with standard dosing of <strong>the</strong> SOC regimen. MM-111 was dosed weekly at 10mg/kg<br />
and escalated up to 20mg/kg where possible.<br />
Results: As of 30 March <strong>2012</strong>, thirty patients had been enrolled across three arms.<br />
Dose-limiting toxicities (DLTs) included myelosuppression, infection, vomiting,<br />
diarrhea, mucositis, hypokalemia, hyponatremia, hypophosphatemia, hyperuricemia<br />
and one report of congestive heart failure (CHF). Serious Adverse Events (SAEs)<br />
included pneumothorax, confusion, hemiparesis, seizure, sepsis, diarrhea, disease<br />
progression and CHF (also DLT). The table below summarizes patient outcomes.<br />
Cohort 1 Arm 1 Arm 2 Arm 3<br />
Rx (Dose) X (1000) C (80) T (4/2) L (1000 mg) T (4/2) P (80) T (4/2)<br />
Units<br />
111 & T<br />
(mg/kg)<br />
XC&P<br />
(mg/m<br />
111 (10) 111 (10) 111 (10)<br />
2 )<br />
N 6 3 8<br />
DLT 4 0 1<br />
SAE 4 1 2<br />
Cohort 2 XCT LT PT<br />
111 (5) 111 (20) 111 (20)<br />
N 3 7 3<br />
DLT 2 1 0<br />
SAE 0 4 0<br />
CR; PR; SD<br />
/N<br />
1 CR;2 PR;2 SD /9 2 PR/10 4 PR;5 SD /11<br />
MM-111 dosing required fur<strong>the</strong>r reduction to 5mg/kg in arm 1 but was safely<br />
escalated to 20mg/kg in arms 2 and 3.<br />
Conclusion: Overall, MM-111 could be safely combined with SOC HER2 regimens.<br />
Additional safety, PK and efficacy data will be provided.<br />
Annals of Oncology<br />
Disclosure: C. McDonagh: Employed by Merrimack. Stock Ownership. S. Frye:<br />
employed by Merrimack. Stock Ownership. V. Moyo: Employed by Merrimack. Stock<br />
Ownership. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
497P DOSE-ESCALATION PHASE I STUDY OF CABAZITAXEL (CBZ)<br />
+ GEMCITABINE (GEM) IN PATIENTS (PTS) WITH METASTATIC<br />
OR UNRESECTABLE ADVANCED SOLID MALIGNANCY<br />
O. Rixe 1 , I. Puzanov 2 , P.M. LoRusso 3 , J. Yin 4 , S. Doroumian 5 , X. Zhi 6 ,<br />
A.J. Olszanski 7<br />
1 Cancer Center, Georgia Health Sciences University, Augusta, GA, UNITED<br />
STATES OF AMERICA, 2 Division of Hematology-oncology, Vanderbilt University<br />
Medical Center, Nashville, TN, UNITED STATES OF AMERICA, 3 Department of<br />
Oncology, Karmanos Cancer Institute / Wayne State University, Detroit, MI,<br />
UNITED STATES OF AMERICA, 4 N/a, Sanofi, Bridgewater, NJ, UNITED STATES<br />
OF AMERICA, 5 Research and Development, Sanofi, Montpellier, FRANCE,<br />
6 Biostatistics, Sanofi, Bridgewater, NJ, UNITED STATES OF AMERICA, 7 Medical<br />
Oncology Department, Fox Chase Cancer Center, Philadelphia, PA, UNITED<br />
STATES OF AMERICA<br />
Rationale: Gem + taxane combinations have shown activity in some advanced<br />
cancers. Cbz (a novel taxane) + prednisone (P) improved overall survival vs<br />
mitoxantrone + P in pts with metastatic castration-resistant prostate cancer previously<br />
treated with docetaxel (de Bono 2010).<br />
Methods: A Phase I study (NCT01001221) was conducted to determine <strong>the</strong><br />
maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz + Gem<br />
(parts 1a and 1b) and to evaluate antitumour activity at <strong>the</strong> MTD (part 2). Pts with<br />
histologically or cytologically confirmed metastatic or unresectable solid tumours<br />
without existing standard treatment were eligible. Cohorts of 3–6 pts were treated<br />
with Cbz (15–20 mg/m 2 1-h infusion) followed by Gem (700–1000 mg/m 2 )ond1<br />
and Gem alone on d8 (part 1a). The administration sequence on d1 was <strong>the</strong>n<br />
reversed (part 1b), based on preliminary PK data.<br />
Results: Of <strong>the</strong> 12 pts in part 1a, 5 pts were treated at Cbz 20 mg/m 2 + Gem 1000<br />
mg/m 2 dose level (DL 20/1000), 5 pts at DL 15/900 and 2 pts at DL 15/700. In part<br />
1b, all 6 pts were treated at <strong>the</strong> lowest DL (700/15) allowed. At all DLs, ≥ 2 pts<br />
experienced a DLT, regardless of administration sequence. DLTs were febrile<br />
neutropenia (FN) (4 pts), Grade (Gr) 4 neutropenia (2 pts), Gr 4 thrombocytopenia<br />
(2 pts) and Gr 3 AST increase (1 pt). No MTD was established and part 2 was not<br />
performed. All pts experienced at least 1 treatment-emergent AE (TEAE); <strong>the</strong> most<br />
frequent all grade non-haematological TEAEs were fatigue 66.7%, decreased appetite<br />
50.0%, diarrhoea 44.4%, nausea 38.9% and weight decrease 33.3%. Gr 3–4<br />
haematological toxicities included neutropenia 66.7%, thrombocytopenia 33.3% and<br />
FN 22.2%. Nine pts continued study treatment and received 6–22 cycles; 3 pts had a<br />
partial response (melanoma, prostate small cell and appendiceal tumours), while 8<br />
pts experienced stable disease. PK analysis did not reveal a drug–drug interaction<br />
between Cbz and Gem.<br />
Conclusion: The MTD of Cbz + Gem could not be established due to DLTs.<br />
Antitumour activity was observed and drug administration sequence did not affect<br />
<strong>the</strong> toxicity profile. Fur<strong>the</strong>r investigation of alternative dosing regimens is warranted<br />
in an effort to establish a tolerable combination.<br />
Disclosure: P.M. LoRusso: Has received research funding from Sanofi. J. Yin: Is a<br />
Sanofi employee and owns Sanofi stocks and shares. S. Doroumian: Is a Sanofi<br />
employee (pharmacokineticist) and owns Sanofi stocks and shares. X. Zhi: Is a Sanofi<br />
employee (statistician) and owns Sanofi stocks and shares. A.J. Olszanski: Research<br />
funding - Sanofi supplies support for <strong>the</strong> conduct of <strong>the</strong> study. All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
498P FIRST-IN-HUMAN PHASE I ADMINISTRATION OF YS110, A<br />
HUMANIZED MONOCLONAL ANTIBODY DIRECTED AGAINST<br />
THE CD26 MOLECULE IN CANCER PATIENTS<br />
E. Angevin 1 , V. Trillet-Lenoir 2 , N. Isambert 3 , J. Alexandre 4 , F. Valleix 5 , T. Podoll 6 ,<br />
I. Miyashita 7 , T. Yamada 8 , Y. Kaneko 9 , C. Morimoto 10<br />
1 Sitep, Institut Gustave Roussy, Villejuif, FRANCE, 2 Service D’oncologie<br />
Médicale, Hopital Lyon Sud, Pierre Bénite, FRANCE, 3 Unité De Phase I, Centre<br />
Georges François Leclerc, Dijon, FRANCE, 4 Service D’oncologie Médicale,<br />
Hopital Cochin, paris, FRANCE, 5 Clinical Research, FV-Clinical subcontractor for<br />
Harrison Clinical Research, Pontoise, FRANCE, 6 Oncology Department, Y’s<br />
Therapeutics, Redwood City, CA, UNITED STATES OF AMERICA, 7 Clinical<br />
Development, Kissei Pharmaceuticals, Tokyo, JAPAN, 8 Department of<br />
Pathology, Keio university School of Medicine, Tokyo, JAPAN, 9 Clinical<br />
Development, Y’s AC, Tokyo, JAPAN, 10 Division of Clinical Immunology,<br />
University of Tokyo, Tokyo, JAPAN<br />
Background: YS110 is a recombinant humanized IgG1 monoclonal antibody that<br />
selectively binds with high affinity to <strong>the</strong> extracellular domain of <strong>the</strong> CD26 antigen.<br />
CD26, a widely distributed 110-kDa transmembrane glycoprotein with intrinsic<br />
DPPIV activity and its truncated soluble form (sCD26/DPPIV) also present in serum<br />
ix170 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
and fluids, is known to play an important role in tumor biology. CD26 is frequently<br />
highly expressed on multiple cancer cell types, especially meso<strong>the</strong>lioma and renal cell<br />
carcinoma (RCC). In addition to its role in proteolysis via <strong>the</strong> DPPIV activity, CD26<br />
also acts as a receptor involved in T-cell co-stimulation and immune regulation.<br />
Preclinical evaluations of YS110 have demonstrated anti-tumor effects in cancer cell<br />
lines and xenografts expressing <strong>the</strong> CD26 antigen without significant side effects in<br />
toxicology studies (up to 100 mg/kg as single dose or 30 mg/kg for 5 weekly doses in<br />
cynomolgus monkeys).<br />
Phase I design and endpoints: The ongoing YSCMA-EU-0001 trial is a Phase I/II<br />
study of YS110 escalating dose administered intravenously once every 2 weeks for 3<br />
doses (Days 1, 15, 29). Patients must have progressive locally advanced inoperable<br />
and/or metastatic histologically confirmed solid tumors, refractory to prior standard<br />
<strong>the</strong>rapies, with confirmed CD26 + tumor expression (≥ 20% of <strong>the</strong> tumor cells by<br />
central IHC evaluation). The primary endpoint is to determine <strong>the</strong> Maximum<br />
Tolerated Dose/Recommended Dose of YS110 and <strong>the</strong> pattern of DLTs. Secondary<br />
endpoints are <strong>the</strong> determination of <strong>the</strong> PK/PD parameters (i.e. analysis of cytokine<br />
release, immunophenotyping, circulating DPPIV activity and sCD26 antigen level).<br />
Preliminary antitumor efficacy is evaluated by RECIST1.1 criteria at Day 43. Patients<br />
demonstrating objective response or stable disease receive additional treatment cycles.<br />
Status of <strong>the</strong> study: As of May 1 st <strong>2012</strong>, 22 patients (13 meso<strong>the</strong>lioma, 9 RCC) have<br />
been treated with 3 bi-weekly infusions over 29 days at 0.1, 0.4, 1 and 2 mg/kg. Based<br />
on PK data for <strong>the</strong>m, <strong>the</strong> next cohort of 3 patients will be dosed at 2 mg/kg with<br />
weekly infusions over 29 days starting in May <strong>2012</strong>. Safety, PK/PD, and preliminary<br />
efficacy data will be presented.<br />
Disclosure: T. Podoll: Compensated employment position : President of Y\\’s<br />
Therapeutics Compensated Consultant role. I. Miyashita: Compensated Employment<br />
role: Director Kissei Pharmaceuticals Co, Ltd. Y. Kaneko: Compensated employment<br />
role : managing board of directors Y’s AC Stock ownership: Y’s AC. C. Morimoto:<br />
Compensated Consultant role : Kissei Pharmaceuticals Co, Ltd Stock ownership: Y’s<br />
Therapeutics Honororia: Kissei Pharmaceuticals Co, Ltd Research funding: Y’s<br />
Therapeutics. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
499P INCIDENCE AND RELEVANCE OF PROTEINURIA IN<br />
BEVACIZUMAB (BV)-TREATED PATIENTS (PTS): POOLED<br />
ANALYSIS FROM RANDOMIZED CONTROLLED TRIALS (RCTS)<br />
R. Lafayette 1 , B. McCall 2 , N.F. Li 3 , L. Chu 4 , P. Werner 5 , A. Das 6 , R.J. Glassock 7<br />
1 Nephrology, Stanford Glomerular Disease Center, Stanford, CA, UNITED<br />
STATES OF AMERICA, 2 Product Development, Oncology, Genentech, Inc.,<br />
South San Francisco, CA, UNITED STATES OF AMERICA, 3 Biostatistics,<br />
Genentech, Inc., South San Francisco, CA, UNITED STATES OF AMERICA,<br />
4 Global Product Development Biometrics, Genentech, Inc., South<br />
San Francisco, CA, UNITED STATES OF AMERICA, 5 Statistical Programming<br />
and Analysis (spa), F. Hoffmann-La Roche AG, Basel, SWITZERLAND, 6 PDCO,<br />
Genentech, Inc., South San Francisco, CA, UNITED STATES OF AMERICA, 7 The<br />
David Geffen School of Medicine, UCLA, Laguna Niguel, CA, UNITED STATES<br />
OF AMERICA<br />
Background: Proteinuria (PU) is a recognized adverse event with BV treatment (tx);<br />
however it is not known if BV-related PU is associated with clinical outcomes. This<br />
analysis was undertaken to define <strong>the</strong> relationship between PU with BV tx and<br />
sequelae, including changes in kidney function.<br />
Methods: A pooled safety database, comprising 22 phase 2/3 RCTs of BV across<br />
tumor types, was used to characterize PU events. Analysis pools were created based<br />
on data availability in individual studies. Raw and time-adjusted PU rates and data<br />
on <strong>the</strong> association between PU and arterial thromboembolic events (TEs), venous<br />
TEs, and infection were derived from Pool 1 (17 RCTs; n = 14,548). Data from Pool<br />
2 (8 RCTs; n = 9,158) were used to estimate <strong>the</strong> association between lab-reported PU<br />
and changes in kidney function based on serum creatinine (sCr) levels. Severity of<br />
kidney function change was categorized using <strong>the</strong> RIFLE classification for acute<br />
kidney injury (AKI). Potential predictors of PU were also assessed.<br />
Results: In Pool 1, <strong>the</strong> incidence rate of any-grade (gr) PU was 8.2% (733/8917) and<br />
4.6% (257/5631) in BV and control pts, respectively; gr ≥3 PU occurred in 1.4% and<br />
0.2%, respectively. Pts developing PU had a numerically increased rate of any-gr<br />
infection irrespective of tx (driven mostly by urinary tract infection); however, no<br />
association was found between PU and TEs (arterial or venous). In Pool 2, PU gr<br />
and tx appeared to slightly shift <strong>the</strong> rate of post-baseline AKI (Table). Evaluated risk<br />
factors (age, sex, history of hypertension or diabetes) were not found to be<br />
significantly predictive for gr ≥3 PU.<br />
Conclusions: The use of laboratory events and pooled data confirm a modest<br />
increase in PU with BV tx. The development of PU in BV-treated pts was associated<br />
with a modest increase in <strong>the</strong> risk of infection, but not TEs, and a trend toward a<br />
decrease in kidney function. Whe<strong>the</strong>r <strong>the</strong>se associations are causal cannot be<br />
determined by this analysis.<br />
Tx group<br />
BV (n =<br />
5098)<br />
No BV (n =<br />
3186)<br />
Worst<br />
post-BL gr<br />
of PU a<br />
Pts without<br />
PU at BL,<br />
n<br />
Worst post-BL kidney function (RIFLE<br />
classification), n (%)<br />
Normal Risk b<br />
Injury c<br />
Failure d<br />
0 2960 2277 (76.9) 585 (19.8) 66 (2.2) 25 (0.8)<br />
1 1381 1021 (73.9) 307 (22.2) 31 (2.2) 20 (1.4)<br />
2 562 391 (69.6) 137 (24.4) 18 (3.2) 14 (2.5)<br />
3 59 34 (57.6) 19 (32.2) 4 (6.8) 2 (3.4)<br />
0 2144 1736 (81.0) 349 (16.3) 39 (1.8) 18 (0.8)<br />
1 769 618 (80.4) 123 (16.0) 19 (2.5) 9 (1.2)<br />
2 166 124 (74.7) 32 (19.3) 7 (4.2) 3 (1.8)<br />
3 2 1 (50.0) 1 (50.0) — —<br />
a CTCAE grade. No patients had gr 4 PU.<br />
b Increased sCR ×1.5 or estimated creatinine clearance (eCrCl) decrease >25%.<br />
c Increased sCr ×2 or eCrCl decrease >50%.<br />
d Increased sCr ×3, eCrCl decrease >75% or sCr ≥4 mg/dL.<br />
Note: missing values for each row are not shown.<br />
BL, baseline.<br />
Disclosure: B. McCall: Dr. McCall is an employee of and holds stock options in<br />
Genentech, Inc. N.F. Li: Dr. Li is an employee of and holds stock options in<br />
Genentech, Inc. L. Chu: Ms. Chu is an employee of and holds stock options in<br />
Genentech, Inc. P. Werner: Dr. Werner is an employee of F. Hoffmann-La Roche<br />
Ltd. A. Das: Dr. Das is an employee of and holds stock options in Genentech, Inc. R.<br />
J. Glassock: Dr. Glassock is a consultant to Genentech. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
500P THE LEEDS FORMULA: A NEW, MORE ACCURATE AND<br />
WIDELY APPLICABLE FORMULA FOR ESTIMATING RENAL<br />
FUNCTION, ACCOUNTING FOR VARIABILITY IN CREATININE<br />
ASSAY MEASUREMENT<br />
F. Collinson 1 , W. Gregory 1 , C. Twelves 2 , C. Handforth 3 , M. Bosomworth 4 ,<br />
G. Hall 3<br />
1 Clinical Trials Research Unit, University of Leeds, Leeds, UNITED KINGDOM,<br />
2 Clinical Cancer Research Groups, Leeds Institute of Molecular Medicine & St<br />
James’s Institute of Oncology, Leeds, UNITED KINGDOM, 3 St James’s Institute<br />
of Oncology, St James’s University Hospital, Leeds, UNITED KINGDOM, 4 Blood<br />
Sciences, St James’s University Hospital, Leeds, UNITED KINGDOM<br />
Introduction: Many formulae are used to estimate renal function, but none account<br />
for <strong>the</strong> significant variation in creatinine (Cr) measurement between <strong>the</strong> 26 assays<br />
currently used in <strong>the</strong> UK. The UK National External Quality Assessment Service has<br />
published assay-specific Cr adjustors, but <strong>the</strong> calculated ’standardised Cr’ (SCr)<br />
dangerously overestimates GFR when used in formulae such as Cockroft and Gault<br />
(C&G) and Wright (W). We aimed to develop a simple formula to accurately<br />
estimate GFR in oncology patients, using easily available patient characteristics and<br />
<strong>the</strong> SCr, hence accounting for inter-assay variation.<br />
Methods: Isotopic GFR (iGFR) was measured using Tc 99m DTPA clearance. Serum<br />
Cr was measured using <strong>the</strong> O’Leary Jaffe assay and from this SCr derived. Clinical<br />
parameters (age, sex, height, weight, SCr, urea and albumin) were used in regression<br />
modelling (STATA) to investigate <strong>the</strong> relationship of individual parameters with<br />
iGFR. From this a novel formula was derived to estimate iGFR (<strong>the</strong> Leeds formula).<br />
This formula was <strong>the</strong>n prospectively validated on a second cohort of patients.<br />
Results: In <strong>the</strong> discovery set 423 oncology patients were included with a range of<br />
malignancies, a median age of 49 (range 18-91) years and serum Cr between 50-130<br />
µmol/l who underwent iGFR measurement between 1/4/06 and 31/3/09. A model<br />
incorporating SCr, age, sex, height, weight, urea and albumin predicted iGFR<br />
(median calculated GFR 92 ml/ min, range 25-217; r 2 of 0.74) more accurately than<br />
alternative established GFR formulae e.g. C&G and W formulae (r 2 0.4-0.6) .<br />
Prospective validation on a separate cohort of oncology patients (496 patients<br />
between 1/4/09 and 31/3/11) validated <strong>the</strong> Leeds formula with an r 2 of 0.71 for<br />
correlation with iGFR.<br />
Conclusions: The Leeds formula uses readily available clinical information to<br />
estimate GFR more precisely than existing formulae and has <strong>the</strong> advantage of being<br />
applicable to Cr results from any laboratory provided <strong>the</strong> assay type is known. Many<br />
oncologists do not appreciate <strong>the</strong> resultant effect of inter-Cr assay variability on<br />
estimated renal function (GFR) and hence chemo<strong>the</strong>rapy dosing.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds395 | ix171
501 PRECLINICAL DATA INVESTIGATING THE USE OF<br />
SARACATINIB IN RENAL CELL CARCINOMA<br />
K. Sharpe1 ,Y.Lu1 , D. Berney1 , C. Rofe1 , T. Powles2 1<br />
Molecular Oncology, Barts Cancer Institute, London, UNITED KINGDOM,<br />
2<br />
Barts Cancer Institute, St Bartholomew’s Hospital QMUL, London, UNITED<br />
KINGDOM<br />
Background: SRC, a non-receptor tyrosine kinase, has been shown to effect pathways<br />
implicated in anti-VEGF drug resistance. Anti-VEGF drugs provide standard of care<br />
in renal cell carcinoma (RCC) and <strong>the</strong>refore we investigated <strong>the</strong> potential of <strong>the</strong> SRC<br />
inhibitor saracatinib in preclinical models of RCC.<br />
Methods and results: In vitro MTS assays were performed on a panel of RCC cell<br />
lines which demonstrated saracatinib significantly reduced cell viability in all RCC<br />
cell lines tested in a dose-dependent manner. Follow-up experiments performed<br />
using two separate isogenic cell lines confirmed that mutation of <strong>the</strong> VHL gene<br />
impaired saracatinib’s ability to reduce cell viability. In vitro migration assays<br />
confirmed saracatinib’s ability to reduce motility and migration and this effect did<br />
not correlate with VHL status. Using <strong>the</strong> VHL-null 786-O xenograft model we<br />
investigated <strong>the</strong> impact of saracatinib in vivo. Saracatinib (25 mg/kg) significantly<br />
slowed tumour growth compared to vehicle-treated tumours. Fur<strong>the</strong>rmore, when<br />
combined with <strong>the</strong> anti-VEGF drug cediranib, combination <strong>the</strong>rapy (25 mg/kg +<br />
3mg/kg) significantly slowed tumour growth when compared to cediranib<br />
mono<strong>the</strong>rapy (3mg/kg). Combination <strong>the</strong>rapy significantly reduced vessel density (as<br />
measured by CD31 immunohistochemistry [IHC]) and increased <strong>the</strong> percentage of<br />
apoptotic cells (cleaved-caspase 3 IHC) compared to vehicle-treated tumours.<br />
Moreover, combination <strong>the</strong>rapy increased <strong>the</strong> percentage of apoptotic cells compared<br />
to cediranib mono<strong>the</strong>rapy but this result did not reach statistical significance. IHC<br />
analysis showed that saracatinib (25mg/kg) significantly reduced tumour<br />
phospho-STAT3 levels.<br />
Conclusions: These data demonstrate saracatinib’s potential to reduce RCC cell<br />
viability and motility in vitro and slow tumour growth in vivo both as mono<strong>the</strong>rapy<br />
and in combination with an anti-VEGF agent. A randomised phase II trial is<br />
ongoing to investigate <strong>the</strong> potential of combining saracatinib and cediranib in VEGF<br />
TKI refractory RCC.<br />
Disclosure: K. Sharpe: Kevin Sharpe receives an MRC CASE stipend which<br />
AstraZeneca contributes towards. T. Powles: Thomas Powles has participated in<br />
advisory boards for Pfizer and GSK and has received research funding from <strong>the</strong>se<br />
institutions. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
502 ASSOCIATION BETWEEN PERIPHERAL BLOOD LYMPHOCYTE<br />
COUNT (PBLC) AND OUTCOME IN PATIENTS WITH SOLID<br />
TUMORS TREATED WITH NGR-HTNF<br />
A. Bulotta1 , V. Gregorc1 , G. Rossoni1 , G. Todisco1 , M.G. Viganò1 , A. Lambiase2 ,<br />
C. Bordignon2 1 2<br />
Oncologia, IRCCS San Raffaele, Milano, ITALY, Clinical Development, MolMed,<br />
Milan, ITALY<br />
Background: NGR-hTNF (asn-gly-arg-human tumor necrosis factor) induces<br />
antitumor effects by selectively damaging tumor neovasculature and increasing<br />
intratumoral infiltration of effector T cells. We investigated whe<strong>the</strong>r pretreatment<br />
PBLC values were associated with treatment outcomes in 5 phase II single-arm trials<br />
on 205 patients (pts) who were refractory/resistant to standard <strong>the</strong>rapies.<br />
Methods: NGR-hTNF 0.8 µg/m 2 was given every 3 weeks (q3w) alone in pts with<br />
malignant pleural meso<strong>the</strong>lioma (MPM n = 55), hepatocellular carcinoma (HCC n =<br />
40), and colorectal cancer (CRC n = 45), or combined with doxorubicin in small-cell<br />
lung cancer (SCLC n = 28) and ovarian cancer (OC n = 37). Tumor assessment by<br />
RECIST was done q6w until progression. Kaplan-Meier methods and Cox models<br />
were used to determine univariate and multivariate associations between baseline<br />
PBLC and progression-free survival (PFS) and overall survival (OS).<br />
Results: Median baseline PBLC value was 1.4/mL (range 0.3-6.9; interquartile range<br />
1.0-1.8) in 198 pts with available pretreatment counts. The first distribution quartile<br />
was used as cut-off value to dichotomize PBLC into high (≥ 1.0; n = 144, 73%) or<br />
low (< 1.0; n = 54, 27%) levels. Baseline characteristics (high v low levels): median<br />
age 65 v 65; male 51% v 52%; PS 1-2 31% v 39%, range of prior treatment lines 1-5 v<br />
1-5. Mean number of cycles was 4.5 (range 1-24) in pts with high and 3.3 (1-13) in<br />
pts with low levels (p = .02). In univariate analyses, pts with high PBLC had<br />
significantly improved PFS (HR = 0.68 p = .02) and OS (HR = 0.51 p = .0001).<br />
Six-month PFS rates were 21% (95% CI 14-28) in <strong>the</strong> high and 9% (1-17) in <strong>the</strong> low<br />
PBLC groups (log-rank p = .02), while 1-year OS was 52% (44-60) in pts with high<br />
and 28% (16-40) in pts with low levels (p = .0001). After adjusting for major baseline<br />
factors (age, gender, PS, prior lines, and tumor type), a high PBLC remained<br />
independent predictor of longer PFS (HR = 0.60 p = .01) and OS (HR = 0.52 p<br />
= .0003). Median OS in pts stratified by PBLC < 1.0/mL, 1.0 to 1.8/mL, and > 1.8/mL<br />
were 7.7, 9.1, and 16.7 months, respectively (p < .0001 for trend).<br />
Conclusions: Pretreatment PBLC value may be used to identify which patients are<br />
likely to gain treatment benefit from NGR-hTNF.<br />
Annals of Oncology<br />
Disclosure: C. Bordignon: Employment - MolMed. All o<strong>the</strong>r authors have declared<br />
no conflicts of interest.<br />
503 A PHASE I,II TRIAL OF AUTOLOGOUS DENDRITIC CELL<br />
TUMOR VACCINE COMBINED WITH IRRADIATION PATIENTS<br />
WITH REFRACTORY METASTATIC COLORECTAL CANCER<br />
Y.J. Choi, Y.M. Seol, H.J. Kim, J.S. Chung, G.J. Cho<br />
Hemato- Oncology, Pusan National University Hospital, Busan, KOREA<br />
Purpose: A dendritic cell vaccine has been developed as a novel strategy for<br />
generating antitumor immunity in <strong>the</strong> treatment of cancer. The purpose of this study<br />
was to assess <strong>the</strong> maximal tolerated dose, safety, clinical efficacy and immunologic<br />
response of a new dendritic cell vaccine (DC-Vac) combined with irradiation in<br />
patients with metastatic colorectal cancer.<br />
Methods (Materials): 22 patients with metastatic colorectal cancer were assigned to<br />
study that received 3, 6, or 12 × 106 DC-Vac 3 times at 2 week intervals and<br />
additional 2 times at 4 weeks intervals. On <strong>the</strong> day before and on <strong>the</strong> day of each<br />
vaccination, each patient received a 4 Gy radiation dose to <strong>the</strong> target tumor. On <strong>the</strong><br />
day of vaccination, <strong>the</strong> indicated dose of autologus DCs was injected in to <strong>the</strong><br />
irradiated tumor using ultrasound-guided needle injection procrdure. We also<br />
evaluated immunologic and tumor responses.<br />
Results: The maximum dose of DC-Vac (12 × 106) was shown to be safe. In 5 of 9<br />
patients, <strong>the</strong> vaccine resulted in increased interferon (IFN)-_ production by CD8+<br />
cells after exposure to tumor lysate. The response evaluation was performed in 15 of<br />
<strong>the</strong> 17 patients who received at least 4 injections. Stable and progressive disease was<br />
found in 4 and 11 patients, respectively.<br />
Conclusions: The DC-based immuno<strong>the</strong>rapy and radio<strong>the</strong>rapy is <strong>the</strong>oretically<br />
synergistic for <strong>the</strong> local control and systemic control. The DCVac/IRⓡ<br />
immuno<strong>the</strong>rapy combined with irradiation was tolerable and safe in <strong>the</strong> evaluated<br />
cases of refractory metastatic colorectal cancer. Future work should include well<br />
designed a phase II clinical trials.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
504 SECOND CYCLE OF CATUMAXOMAB TREATMENT IN<br />
PATIENTS WITH MALIGNANT ASCITES: RESULTS FROM THE<br />
SECIMAS STUDY<br />
G. Oskay-Özcelik 1 , I.B. Vergote 2 , A. Santoro 3 , F. Marmé 4 , P. Rosenberg 5 ,<br />
J. Sehouli 6<br />
1 Gynäkologisch-Onkologische Schwerpunktpraxis, Praxis Hindenburg, Berlin,<br />
GERMANY, 2 Obstetrics & Gynaecology, University Hospital Gasthuisberg,<br />
Leuven, BELGIUM, 3 Oncology Hematology, Humanitas Cancer Center, Istituto<br />
Clinico Humanitas, Rozzano, ITALY, 4 Inf 460, Universitätsfrauenklinik Heidelberg<br />
& Nationales Centrum für Tumorerkrankungen (NCT), Heidelberg, GERMANY,<br />
5 Onkologiska Kliniken Universitetssjukhuset, University Hospital Linköping,<br />
Linköping, SWEDEN, 6 Department of Gynecology, Charite Medical University,<br />
Berlin, GERMANY<br />
Purpose: The SECIMAS study investigated <strong>the</strong> feasibility of a second cycle of 4<br />
intra-peritoneal (i.p.) infusions of catumaxomab in patients who responded to<br />
treatment with 4 i.p. catumaxomab infusions in <strong>the</strong> CASIMAS study.<br />
Patients and methods: Eligible patients had to have completed 4 i.p. prior infusions<br />
of catumaxomab in <strong>the</strong> CASIMAS study and required <strong>the</strong>ir first <strong>the</strong>rapeutic puncture<br />
after > 60 days. Primary endpoint was <strong>the</strong> proportion of patients who were able to<br />
receive at least 3 infusions. Secondary endpoints were safety including a composite<br />
safety score (CSS) summarizing <strong>the</strong> worst CTCAE grades for <strong>the</strong> main TEAEs<br />
(pyrexia, nausea, vomiting, and abdominal pain) and <strong>the</strong> development of anti-drug<br />
antibodies (ADA). Efficacy endpoints were puncture-free survival (PuFS), time to<br />
puncture (TTPu) and overall survival (OS).<br />
Results: Eight of 9 selected patients from <strong>the</strong> CASIMAS study were treated with a<br />
2nd of catumaxomab. Eight (100%) patients received all 4 infusions within 20<br />
days, thus <strong>the</strong> primary endpoint was met with a high compliance rate. The<br />
median CSS was comparable for <strong>the</strong>se 8 patients with 3.4 after <strong>the</strong> first cycle and<br />
3.0 after <strong>the</strong> second cycle. Less patients in <strong>the</strong> SECIMAS study had AEs with<br />
CTC >3 (25%) compared to CASIMAS (70.1%). All 8 (100%) patients were<br />
ADA-positive at study entry and remained ADA-positive throughout treatment.<br />
PuFS was 47.5 days (28;181) and TTPu 60 days (34;na) after <strong>the</strong> 2nd cycle, while<br />
it was 37 days (24;61) and 102 days (69;159), respectively after <strong>the</strong> first cycle. OS<br />
was 406.5 days (281;480) in <strong>the</strong> SECIMAS study and 201 days (169;241) in <strong>the</strong><br />
CASIMAS study.<br />
Conclusions: The study demonstrates that despite <strong>the</strong> advanced stage of disease and<br />
<strong>the</strong> presence of ADA, a second cycle of i.p. catumaxomab treatment is feasible and<br />
well tolerated in selected patients suffering from malignant ascites and requiring<br />
treatment for ascites after a first cycle of catumaxomab. These patients actually seem to<br />
benefit from <strong>the</strong> second cycle catumaxomab in <strong>the</strong> same range as after <strong>the</strong> first cycle.<br />
Disclosure: I.B. Vergote: consultant for Fresenius Biotech GmbH. A. Santoro:<br />
financial support for Fresenius Biotech GmbH. F. Marmé: financial support for<br />
ix172 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
clinical studies from Fresenius Biotech GmbH. P. Rosenberg: financial support for<br />
clinical studies from Fresenius Biotech GmbH. J. Sehouli: consultant for Fresenius<br />
Biotech GmbH and financial support for clinical studies. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
505 BASELINE PLASMA BIOMARKER SIGNATURE IS ASSOCIATED<br />
WITH IMPROVED SURVIVAL IN ADVANCED NSCLC PATIENTS<br />
ON LINIFANIB<br />
E.M. Mc Keegan 1 , P.J. Ansell 1 , G. Davis 2 , S. Chan 2 , R.K. Chandran 2 ,S.Gawel 2 ,<br />
M.D. McKee 1 , J.L. Ricker 3 , D.M. Carlson 1 , V. Devanarayan 3<br />
1 Global Pharmaceutical Research and Development, Abbott, Abbott Park, IL,<br />
UNITED STATES OF AMERICA, 2 Abbott Diagnostics Division, Abbott, Abbott<br />
Park, IL, UNITED STATES OF AMERICA, 3 GPRD, Abbott, Abbott Park, IL,<br />
UNITED STATES OF AMERICA<br />
Background: Linifanib is a potent and selective VEGF and PDGF receptor inhibitor<br />
that has activity in unselected, advanced NSCLC patients (pts) both as mono<strong>the</strong>rapy<br />
in <strong>the</strong> relapsed setting and with carboplatin (C) and paclitaxel (P) in <strong>the</strong> first-line<br />
setting. A baseline plasma biomarker signature identifying NSCLC pts most sensitive<br />
to linifanib is needed.<br />
Methods: An exploratory retrospective analysis of 4 randomized clinical trials<br />
(linifanib or o<strong>the</strong>r treatments: ABT-510 [thrombospondin mimetic], pemetrexed +/-<br />
ABT-751 [tubulin inhibitor], docetaxel +/- ABT-751) in relapsed NSCLC was<br />
conducted. Evaluable baseline plasma samples were obtained from 116 pts who<br />
received linifanib and 125 pts on o<strong>the</strong>r treatments. A signature combining<br />
established tumor markers (carcinoembryonic antigen [CEA] and fragments of<br />
cytokeratin 19 [CYFRA 21-1]) was derived using a sequential BATTing approach.<br />
The signature was <strong>the</strong>n tested across a randomized trial of CP + placebo, linifanib 7.5<br />
mg, or linifanib 12.5 mg in first-line advanced, non-squamous NSCLC.<br />
Results: In 2/3L NSCLC, <strong>the</strong> signature was associated with improvement in survival<br />
on linifanib mono<strong>the</strong>rapy (HR = 0.51 vs. signature negative; P = 0.0017), but no<br />
improvement in survival on o<strong>the</strong>r treatments (P = 0.72). In <strong>the</strong> first-line setting with<br />
CP, <strong>the</strong> signature was associated with significant PFS improvement with linifanib and<br />
a trend towards significant overall survival improvement at high dose (Table).<br />
Signature positive patients<br />
CP +<br />
Placebo<br />
N=19<br />
Median PFS, m<br />
[95% CI]<br />
Median OS, m<br />
[95% CI]<br />
CP + Linifanib<br />
7.5 mg<br />
N=24<br />
5.4 [1.5, 6.9] 10.2 [3.9, NR]<br />
HR = 0.49*,<br />
11.3 [9.2,<br />
17.4]<br />
P = 0.049**<br />
12.5 [6.2, NR]<br />
HR = 1.02*,<br />
P = 0.758**<br />
CP + Linifanib<br />
12.5 mg N = 26<br />
8.3 [4.8, NR]<br />
HR = 0.38*,<br />
P = 0.029**<br />
17.4 [12.9, NR]<br />
HR = 0.54*,<br />
P = 0.137**<br />
NR= not reached *Adjusted for ECOG PS and gender. **Stratified log-rank test;<br />
P-value compared with CP + placebo.<br />
Conclusion: A baseline plasma biomarker signature is associated with improved<br />
survival in advanced NSCLC patients on linifanib. Incorporation of this signature<br />
should be considered in any fur<strong>the</strong>r investigation of linifanib in NSCLC.<br />
Disclosure: E.M. Mc Keegan: Employee and shareholder of Abbott. P.J. Ansell:<br />
Employee and shareholder of Abbott. G. Davis: Employee and shareholder of Abbott.<br />
S. Chan: Employee and shareholder of Abbott. R.K. Chandran: Employee and<br />
shareholder of Abbott. S. Gawel: Employee and shareholder of Abbott. M.D. McKee:<br />
Employee and shareholder of Abbott. J.L. Ricker: Employee and shareholder of<br />
Abbott. D.M. Carlson: Employee and shareholder of Abbott. V. Devanarayan:<br />
Employee and shareholder of Abbott.<br />
507 PHASE I, OPEN-LABEL, RANDOMIZED, CROSSOVER STUDY<br />
EVALUATING THE EFFECTS OF LINIFANIB ON QTC INTERVALS<br />
IN PATIENTS WITH SOLID TUMORS<br />
Y. Chiu 1 , P.M. LoRusso 2 , J.L. Ricker 3 ,X.Li 1 , R. Pradhan 1 , D.M. Carlson 3<br />
1 Clinical Pharmacology and Pharmacometrics, Abbott, Abbott Park, IL, UNITED<br />
STATES OF AMERICA, 2 Eisenberg Center for Translational Therapeutics,<br />
Barbara Ann Karmanos Cancer Institute, Detroit, MI, UNITED STATES OF<br />
AMERICA, 3 GPRD, Abbott, Abbott Park, IL, UNITED STATES OF AMERICA<br />
Background: Linifanib (ABT-869) is a novel, orally active and selective inhibitor of<br />
VEGF and PDGF family of receptor tyrosine kinases that has shown antitumor<br />
activity in multiple types of solid tumors. This study was conducted to evaluate <strong>the</strong><br />
potential effects of linifanib on QTc prolongation in patients (pts) with advanced<br />
solid tumors.<br />
Methods: Enrolled pts (N = 24; ≥18 years) had measurable disease refractory to<br />
standard <strong>the</strong>rapies, ECOG PS 0-1, and adequate organ function. Pts received 2<br />
sequences of regimens of 0.25 mg/kg orally administered linifanib up to a<br />
maximum dose of 17.5 mg. Pts received a morning dose on Days 1 and 7 under<br />
fasting and fed conditions in a crossover fashion. Serial triplicate ECG recordings<br />
were obtained on Day –1, and over 24 hours on Day 1 and 7; single recordings<br />
were obtained at screening and study completion or discontinuation. Plasma<br />
samples were collected for 72 hours on Day 1 and 7 for pharmacokinetic<br />
analysis. Effects of linifanib on cardiac repolarization were analyzed using a<br />
linear mixed effects model on time-matched baseline adjusted QTcF intervals.<br />
The primary end point was <strong>the</strong> time-matched difference for on-treatment QTcF<br />
from baseline (ΔQTcF). An intersection-union test was performed within <strong>the</strong><br />
framework of <strong>the</strong> corresponding linear mixed effects model. The relationship<br />
between ΔQTcF and plasma linifanib concentration was explored using a linear<br />
mixed effects model.<br />
Results: In <strong>the</strong> 24 pts evaluated, baseline QTcF ranged from 360.9 ms to 468.6 ms.<br />
After linifanib administration, <strong>the</strong> mean ΔQTcF ranged from –4.04 ms to 0.73 ms for<br />
<strong>the</strong> fasting regimen, and from –5.94 ms to –1.37 ms for <strong>the</strong> fed regimen. The upper<br />
95% confidence bound was 4.30 ms (ie, 500 ms or change of >30<br />
ms from baseline.<br />
Conclusion: At <strong>the</strong> maximum tolerated dose of 0.25 mg/kg, linifanib had no effect<br />
on cardiac repolarization in pts with advanced solid tumors.<br />
Disclosure: Y. Chiu: Full-time Abbott employee and stockholder. P.M. LoRusso:<br />
Patricia LoRusso’s institution receives research funding from Abbott. J.L. Ricker:<br />
Full-time Abbott employee and stockholder. X. Li: Full-time Abbott employee and<br />
stockholder. R. Pradhan: Full-time Abbott employee and stockholder. D.M. Carlson:<br />
Full-time Abbott employee and stockholder.<br />
508 ELECTROPHYSIOLOGICAL INVESTIGATION OF THE EFFECTS<br />
OF METOPROLOL AND DILTIAZEM ON PAZOPANIB INDUCED<br />
PROLONGED CARDIAC REPOLARISATION AND<br />
PROARRYTHMIC EFFECTS: EXPERIMENTAL STUDY<br />
T. Akman1 , O. Erbas2 , L. Akman3 , A.U. Yilmaz1 1<br />
Medical Oncology, Dokuz Eylul University Faculty of Medicine, Izmir, TURKEY,<br />
2<br />
Department of Physiology, Ege University Medical School, Izmir, TURKEY,<br />
3<br />
Department of Obstetrics and Gynecology, Ege University Medical School,<br />
Izmir, TURKEY<br />
Objective: Pazopanib is a potent multi-targeted tyrosine kinase inhibitor which<br />
is approved for <strong>the</strong> treatment of advanced RCC patients. While exploring <strong>the</strong><br />
<strong>the</strong>rapeutic index of TKIs, oncology investigators are confronted with drug<br />
adverse effects such as cardiac toxicities. QT prolongation has taken attention<br />
because of <strong>the</strong> risk of serious cardiac arrhythmias such as torsade de pointes<br />
(TdP) and sudden cardiac death. In several studies QTc prolongation was<br />
observed with TKIs such as sunitinib, vandetanib, dasatinib, crizotinib.<br />
However <strong>the</strong>re are no data showing QTc prolongation with pazopanib<br />
treatment. In this study, we aimed to demonstrate <strong>the</strong> pazopanib induced<br />
proarrythmic electrophysiological effects and investigate <strong>the</strong> possible protective<br />
effects of metoprolol and diltiazem to ECG changes in an experimental<br />
model.<br />
Method: In this study 24 Sprague-Dawley adult male rats were used. Rats were<br />
randomly assigned to 4 groups (n = 6). To <strong>the</strong> first group (normal group),<br />
intraperitoneal injection of 6 ml/kg of saline were given and to <strong>the</strong> o<strong>the</strong>r groups 100<br />
mg/kg pazopanib were given via orogastric tubes. 3 hours after oral administration of<br />
pazopanib, to <strong>the</strong> second group (control group) saline, to <strong>the</strong> third group 1 mg/kg<br />
metoprolol and to <strong>the</strong> fourth group 1mg/kg diltiazem were applicated<br />
intraperitoneally. 1 hours after application of <strong>the</strong>se drugs, under anes<strong>the</strong>sia, QTc was<br />
calculated by taking ECG in derivation I.<br />
Results: The mean QTc interval was 126,2 ± 2.99 s in group 1, 159.66 ± 6.02 s in<br />
group 2, 106.66 ± 2.64 in group 3 and 123.33 ± 1.72 s in group 4. Groups 3 and 4<br />
had significantly shorter QTc intervals compared to group 2 (p < 0.001).<br />
Conclusion: This is <strong>the</strong> first experimental study evaluating <strong>the</strong> use of<br />
prophylactic <strong>the</strong>rapy with metoprolol and diltiazem in pazopanib induced QT<br />
prolongation. In this present experimental study we demonstrated <strong>the</strong><br />
beneficial prophylactic effects of metoprolol and diltiazem in pazopanib<br />
induced QT prolongation. More evidence is needed to evaluate <strong>the</strong><br />
effectiveness and safety of <strong>the</strong>se drugs. Future prospective and<br />
randomized studies will be needed to confirm recommendations for high risk<br />
patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds395 | ix173
509TiP LUX-LUNG 8: A RANDOMIZED, OPEN-LABEL, PHASE III<br />
TRIAL OF AFATINIB VS. ERLOTINIB IN PATIENTS WITH<br />
ADVANCED SQUAMOUS CELL CARCINOMA OF THE LUNG<br />
AS SECOND-LINE THERAPY FOLLOWING FIRST-LINE<br />
PLATINUM-BASED CHEMOTHERAPY<br />
G. Goss 1 ,S.Lu 2 , E. Felip 3 , A. Ardizzoni 4 , V. Georgoulias 5 , S. Gadgeel 6 ,<br />
V. Chand 7 ,Y.Gu 7 , Y.S. Olivo 8 , J. Soria 9<br />
1 Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, ON, CANADA,<br />
2 Shanghai Lung Tumor Clinical Center, Shanghai Chest Hospital, Shanghai,<br />
CHINA, 3 Oncology, Vall d’Hebron University Hospital, Barcelona, SPAIN,<br />
4 Onco-hematology Department of Internal Medicine, A.O. Universitaria di Parma,<br />
Parma, ITALY, 5 Medical Oncology, University Hospital of Heraklion, Heraklion,<br />
GREECE, 6 Medical Oncology, Karmanos Cancer Center, Detroit, MI, UNITED<br />
STATES OF AMERICA, 7 Clinical Development - Oncology, Boehringer Ingelheim<br />
Pharmaceuticals, Inc., Ridgefield, CT, UNITED STATES OF AMERICA, 8 Clinical<br />
Trial Management, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT,<br />
UNITED STATES OF AMERICA, 9 Dept. of Medicine, Institut de Cancérologie<br />
Gustave Roussy, Villejuif Cedex, FRANCE<br />
Background: Patients with advanced squamous cell carcinoma (SCC) of <strong>the</strong> lung<br />
have limited treatment options. Although treatment with <strong>the</strong> EGFR tyrosine kinase<br />
inhibitor erlotinib is indicated in <strong>the</strong> second- or third-line or maintenance setting,<br />
<strong>the</strong> benefit is limited. Afatinib is a novel, selective, orally bioavailable, ErbB family<br />
blocker, irreversibly blocking EGFR (ErbB1), HER2 (ErbB2) and HER4 (ErbB4).<br />
Based on its promising preclinical profile and clinical activity in trials of SCC of <strong>the</strong><br />
head and neck and lung, we seek to determine if <strong>the</strong> irreversible inhibition of <strong>the</strong><br />
ErbB family translates into clinical benefit for patients with SCC of <strong>the</strong> lung.<br />
Methods: This trial will compare <strong>the</strong> efficacy of afatinib versus erlotinib as<br />
second-line treatment for patients with SCC of <strong>the</strong> lung, as measured by<br />
progression-free survival. Key patient eligibility criteria include: advanced NSCLC<br />
squamous or mixed histology, completion of at least 4 cycles of platinum-based<br />
doublet chemo<strong>the</strong>rapy, eligible to receive EGFR-directed <strong>the</strong>rapy as second-line<br />
<strong>the</strong>rapy, ECOG PS 0–1, adequate organ function, availability of archived tumour<br />
tissue for correlative studies and no prior EGFR-directed <strong>the</strong>rapy. Secondary<br />
endpoints are comparison of overall survival, objective response rate, disease control<br />
rate, tumour shrinkage, assessment of health-related quality of life and safety in both<br />
treatment groups. Eligible patients will be randomized (1:1) to receive ei<strong>the</strong>r afatinib<br />
or erlotinib and stratified based on race (East Asian vs. o<strong>the</strong>r). Eight hundred<br />
patients are planned to be enrolled globally. Independent radiological assessment of<br />
<strong>the</strong> primary endpoint will be completed in a treatment-blinded manner. An<br />
independent data monitoring committee will monitor safety and efficacy of <strong>the</strong> trial.<br />
Disclosure: G. Goss: Consultant or advisory relationship to Boehringer Ingelheim,<br />
compensated prior to conduct of <strong>the</strong> study. S. Lu: Consultant or advisory<br />
relationship, compensated, AstraZeneca China for Iressa. A. Ardizzoni: O<strong>the</strong>r<br />
remuneration: GSK DSMC PRAME Study. V. Georgoulias: Consultant or advisory<br />
relationship, uncompensated for GSK, Novartis, Sanofi, Janssen-Cilag, Amgen.<br />
Honoraria and research funding from GSK, Novartis, Sanofi, Janssen-Cilag, Amgen.<br />
S. Gadgeel: Consultant or advisory relationship for Boehringer Ingelheim. V. Chand:<br />
Employee of Boehringer Ingelheim Pharmaceuticals, Inc. Y. Gu: Employee of<br />
Boehringer Ingelheim Pharmaceuticals, Inc. Y.S. Olivo: Employee of Boehringer<br />
Ingelheim Pharmaceuticals, Inc. J. Soria: Honoraria from Boehringer Ingelheim and<br />
Roche. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
510TiP DENDRITIC CELL THERAPY FOR PATIENTS WITH<br />
REFRACTORY SOLID TUMOURS<br />
P.P. Bapsy 1 , B. Sharan 2 , C. Kumar 2 , A. Mahmood 2 , B. Rangarajan 3 , S. Atilli 4 ,<br />
M. Jain 5 , S. Subramanian 6 , S. Rajappa 7 , M. Srivastava 8<br />
1 Oncology, Apollo Hospitals, Bangalore, INDIA, 2 Research and Development,<br />
APAC Biotech Pvt. Ltd, Gurgaon, INDIA, 3 Medical Oncology, Mazumdar Shaw<br />
Cancer Centre, Bangalore, INDIA, 4 Oncology, Bibi General Hospital, Hyderabad,<br />
INDIA, 5 Medical Oncology, Ruby Hall Clinic, Pune, INDIA, 6 Oncology, V S<br />
Hospital, Chennai, INDIA, 7 Medical Oncology, Basavatarakam Indo-American<br />
Cancer Centre, Hyderabad, INDIA, 8 Clinical Research, Nextvel Consulting LLP,<br />
Bangalore, INDIA<br />
Background: Dendritic Cell (DC) <strong>the</strong>rapy initiates immune response against tumor.<br />
Study ongoing in 7 sites in India has objective to assess toxicity and efficacy in<br />
refractory solid tumours.<br />
Materials: DC <strong>the</strong>rapy is prepared using Peripheral Blood Mononuclear Cells<br />
(PBMCs), cultured with cytokines (IL4 and GMCSF) and exposed to patient’s<br />
antigen retrieved from <strong>the</strong>ir own tumor tissue. Mature DCs are harvested on Day 8<br />
and checked for surface markers (CD 80 + (PE)CD 86+ (APC) and CD 83 + ( FITC)<br />
positive) and adequate counts (>1 million DCs) per dose. Patients with recurrent<br />
disease on symptomatic care were enrolled and 6 doses of DC were administered<br />
over 14 week’s period. Response criteria used are RECIST-version 1.1 (Response<br />
Evaluation Criteria for Solid Tumours) and irRC (Immune Related Response<br />
Criteria). Per protocol, Objective Response (OR) covers Stable Disease (SD), Partial<br />
Response (PR) and Complete Response (CR).<br />
Results and observations: 51 patients (ovary-9, colon and rectum- 7, head & neck -6,<br />
lung-5, Prostate- 5, sarcoma-4, breast-4, stomach-3, cervix-3, squamous cell carcinoma<br />
of heel-1, pancreas-1, melanoma-1, renal cell-1 and Cholangiocarcinoma-1) were<br />
enrolled and evaluated for safety. 220 infusions have been completed. All patients<br />
tolerated <strong>the</strong>rapy well except one who had single episode of rigors during one infusion.<br />
Annals of Oncology<br />
O<strong>the</strong>r adverse events reported were due to disease progression. Response assessment<br />
was done at Week 8 (before dose 4), Week 14 (before dose 6) and Week 26 from start<br />
of <strong>the</strong>rapy. 33 patients’ Week 8 assessment is 22/33 (67%) OR by irRC and 9/33 (27%)<br />
by RECIST. Among OR, 1 shows PR for 2 consecutive visits. 20 patients’ Week 14<br />
assessment is 9/20 (45%) continuing with OR by irRC and 6/20 (30%) are OR by<br />
RECIST. Trends suggest patients with chronic disease (average period of disease of 45<br />
months), less metastatic sites, fewer prior chemo<strong>the</strong>rapy failure and cancers like ovary,<br />
prostate and breast, have responded well. 19 patients are on trial, 6 are alive after<br />
withdrawal and are being followed up for survival and 26 died due to disease<br />
progression. Survival data is yet to mature.<br />
Conclusions: DC <strong>the</strong>rapy is safe and extremely well tolerated. The response data is<br />
encouraging. More survival data is needed to conclude survival benefit.<br />
Disclosure: P.P. Bapsy: I am medical monitor for <strong>the</strong> study (consultant), involved<br />
with <strong>the</strong> study design, scientific inputs and safety monitoring aspects of <strong>the</strong> study. I<br />
am being paid a monthly professional fee for this activity. B. Sharan: I work for<br />
APAC Biotech (sponsor) as Research Director in <strong>the</strong> R & D Department and am<br />
being paid my monthly salary. C. Kumar: I work as Asst Director R & D for <strong>the</strong><br />
sponsor APAC Biotech Pvt. Ltd. I get mothly salary for my job. A. Mahmood: I<br />
work as Senior Research Scientist in <strong>the</strong> R&D Department of APAC Biotech Pvt. Ltd<br />
and get my monthly salary. B. Rangarajan: I am Investigator for <strong>the</strong> trial and being<br />
compensated for my role as Clinical Research Investigator. S. Atilli: I am Investigator<br />
for <strong>the</strong> trial and being compensated for my role as Clinical Research Investigator.<br />
M. Jain: I am Investigator for <strong>the</strong> trial and being compensated for my role as Clinical<br />
Research Investigator. S. Subramanian: I am Investigator for <strong>the</strong> trial and being<br />
compensated for my role as Clinical Research Investigator. S. Rajappa: I am<br />
Investigator for <strong>the</strong> trial and being compensated for my role as Clinical Research<br />
Investigator. M. Srivastava: I am providing advisory consultancy to APAC Biotech<br />
Pvt. Ltd for study operations and being paid professional fees.<br />
1708PD MOLECULAR PROFILE AND ANTI-TUMOR ACTIVITY IN<br />
NON-SMALL CELL LUNG CANCER (NSCLC) PATIENTS (PTS)<br />
IN A PHASE 1 STUDY OF CABOZANTINIB (XL184) IN JAPAN<br />
H. Nokihara 1 , N. Yamamoto 1 , S. Nakamichi 1 , H. Wakui 1 , Y. Yamada 2 , J. Frye 3 ,<br />
A. Decillis 4 , T. Tamura 5<br />
1 Division of Thoracic Oncology, National Cancer Center Hospital, Tokyo, JAPAN,<br />
2 Medical Oncology, National Cancer Center Hospital, Tokyo, JAPAN, 3 Medical<br />
Affairs, Exelixis, Inc., South San Francisco, CA, UNITED STATES OF AMERICA,<br />
4 Clinical Development And Medical Affairs, Exelixis, Inc., South San Francisco,<br />
CA, UNITED STATES OF AMERICA, 5 Division of Internal Medicine and Thoracic<br />
Oncology, National Cancer Center Hospital, Tokyo, JAPAN<br />
Background: Cabozantinib is a potent targeted <strong>the</strong>rapy that inhibits MET, VEGFR2,<br />
and RET. Anti-tumor activity in patients (pts) has been observed in a broad range of<br />
tumors including NSCLC. The primary objective of this phase 1 study is to determine<br />
<strong>the</strong> maximum tolerated dose (MTD) / recommended phase 2 dose in Japanese pts.<br />
Methods: Pts with advanced solid malignancies are enrolled in successive cohorts to<br />
receive escalating doses of cabozantinib orally once daily in a 3 + 3 trial design. Dose<br />
limiting toxicities (DLTs) are determined using Cycle 1 data. Response is assessed<br />
using modified RECIST v1.0. Results: As of 1 June <strong>2012</strong>, 14 pts were enrolled<br />
including 5 pts with non-small cell lung adenocarcinoma. Pts have been treated at 3<br />
dose levels: 40, 60 and 80 mg. The NSCLC pts had a median of 4 prior regimens<br />
(range, 2 – 6). Four of <strong>the</strong> 5 NSCLC pts had a confirmed partial response (cPR)<br />
including a 51 yo female whose pre-treatment tumor sample lacked an EGFR<br />
activating mutation Analysis of tumor obtained pre-treatment and at progression<br />
demonstrated a KIF5B-RET fusion.<br />
Smoking Molecular<br />
Treatment Best<br />
Age Gender History Profile<br />
Duration (mos) Response<br />
64 Female Never EGFR mutation 15+ cPR<br />
51 Female Former EGFR wt, RET<br />
fusion positive<br />
9 cPR<br />
58 Female Never EGFR wt 10 cPR<br />
43 Male Former ALK fusion positive 4 cPR<br />
64 Female Never EGFR wt, ALK<br />
fusion negative<br />
6.5 SD<br />
DLT of Grade 3 hypertension was reported in 2 pts. The MTD using a capsule<br />
formulation is 60 mg. Adverse events were generally mild to moderate and include<br />
hypertension, palmar-plantar erythrodyses<strong>the</strong>sia, diarrhea, mucositis, rash, edema<br />
and headache. Laboratory abnormalities include elevated AST/ALT, lipase and TSH;<br />
and neutropenia and thrombocytopenia. Preliminary PK analysis showed that dosenormalized<br />
exposure in Japanese pts is approximately 2-fold higher than in non-<br />
Japanese pts. Despite relatively higher exposures, cabozantinib 60 mg daily appears to<br />
be a well tolerated dose. Conclusions: Cabozantinib appears well tolerated. Signs of<br />
antitumor activity include response and prolonged stable disease in NSCLC pts.<br />
Accrual and additional molecular characterization is ongoing.<br />
Disclosure: H. Nokihara: Taiho Pharmaceutical Co., Ltd, Merck Serono, Pfizer. N.<br />
Yamamoto: Chugai pharmaceutical co., ltd., Pfizer, Kyowa-Hakko Kirin co., ltd. Y.<br />
Yamada: Bayer, Yakult, AstraZeneca. J. Frye: Paid employee of Exelixis Exelixis stock<br />
ownership. A. Decillis: Paid Employee of Exelixis Exelixis Stock Ownership. T.<br />
Tamura: Chugai Pharmaceutical co., ltd., Daichi-Sankyo co., ltd., Boehringer<br />
Ingelheim, Abbott Japan Co., Ltd, Eisai co., ltd., Bristol-Myers Squibb, Kyowa-Hakko<br />
Kirin co., ltd. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
ix174 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
familial cancer and genetic syndromes<br />
511PD GERMLINE MUTATIONS IN CDH1 AND THE HEREDITARY<br />
DIFFUSE GASTRIC AND LOBULAR BREAST CANCER<br />
SYNDROME<br />
P.R. Benusiglio 1 , D. Malka 2 , A. De Pauw 3 , B. Buecher 3 , E. Rouleau 4 , C. Colas 5 ,<br />
S. Grandjouan 6 , M. Blayau 7 , S. Delaloge 8 , O. Caron 1<br />
1 Clinical Cancer Genetics, Department of Medical Oncology, Institut Gustave<br />
Roussy, Villejuif, FRANCE, 2 Gastrointestinal Oncology, Department of Medical<br />
Oncology., Institut Gustave Roussy, Villejuif, FRANCE, 3 Cancer Genetics, Institut<br />
Curie, Paris, FRANCE, 4 Cancer Genetics, Centre Rene Huguenin, Saint-Cloud,<br />
FRANCE, 5 Cancer Genetics, La Pitie Salpetriere, Paris, FRANCE,<br />
6 Gastroenterology, Hopital Cochin, Paris, FRANCE, 7 Molecular Genetics, CHU<br />
de Rennes - Hôpital Pontchaillou, Rennes, FRANCE, 8 Breast Cancer Unit,<br />
Department of Medical Oncology, Institut Gustave Roussy, Villejuif, FRANCE<br />
Background: Germline mutations in <strong>the</strong> E-cadherin gene (CDH1) are found in up to<br />
48% of families with hereditary diffuse gastric cancer (HDGC), a syndrome<br />
characterized by multiple cases of DGC in a family. In 2010, experts updated CDH1<br />
testing criteria and included individuals and families with diagnoses of both DGC<br />
and lobular breast cancer (LBC), as an excess of LBC had been observed in HDGC<br />
families. We describe <strong>the</strong> characteristics associated with CDH1 mutations in a group<br />
of French patients and show that individuals or families with multiple LBC but no<br />
DGC should be offered genetic testing.<br />
Methods: We studied all index cases in which a CDH1 mutation had been identified<br />
between 2006 and 2011 in <strong>the</strong> Paris region.<br />
Results: We found 17 index cases with a CDH1 mutation, ten males and seven<br />
females, age was 17–63. Eight had familial DGC, four had sporadic DGC at a young<br />
age, one was a healthy male with two relatives with DGC, and one was a female with<br />
LBC and two siblings with DGC. Additionally, three females (18%) with no personal<br />
or family history of DGC had suffered from bilateral LBC under age 50. Only one<br />
was tested at diagnosis. She was offered prophylactic gastrectomy, and foci of DGC<br />
were seen on <strong>the</strong> surgical specimen. She is now doing well. The two o<strong>the</strong>rs, who had<br />
initial negative BRCA1/2 screening, were only tested for CDH1 mutations years later<br />
after <strong>the</strong>y had developed symptomatic DGC.<br />
Discussion: Three of our cases were females with bilateral LBC but no personal<br />
or family history of DGC. Two of <strong>the</strong>m were only tested for CDH1 mutations<br />
once <strong>the</strong>y had developed symptomatic DGC. Prophylactic gastrectomy is now<br />
systematically offered to mutation carriers, and <strong>the</strong>se two cases would have been<br />
spared highly-lethal, symptomatic DGC, had <strong>the</strong>y benefited from preventive<br />
surgery. The 2010 CDH1 testing criteria should be expanded and include cases or<br />
families with multiple LBC but no DGC. More precisely, any patient or family<br />
with multiple LBC under age 50 should be tested for CDH1 mutations, as<br />
carriers are offered life-saving surgery and adapted breast surveillance. Finally, we<br />
propose for consideration <strong>the</strong> name “hereditary diffuse gastric and lobular breast<br />
cancer” to define <strong>the</strong> cancer susceptibility syndrome associated with mutations<br />
in CDH1.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
512PD PORTUGUESE HIGH-RISK BREAST/OVARIAN CANCER:<br />
SURVIVAL ANALYSIS<br />
P. Machado 1 , A. Clara 2 ,A.Mayer 3 , S. Fragoso 1 , S. Santos 1 , A. Luís 4 ,<br />
A. Opinião 4 , J. Parreira 5 , C. Simões 5 ,F.Vaz 4<br />
1 Molecular Biology Research Unit, Portuguese Institute of Oncology of Lisbon,<br />
Lisbon, PORTUGAL, 2 Medical Oncology, Portuguese Institute of Oncology,<br />
Lisbon, PORTUGAL, 3 Sou<strong>the</strong>rn Portuguese Cancer Registry (ROR-SUL),<br />
Table: 512PD<br />
Female breast cancer Ovarian cancer<br />
Annals of Oncology 23 (Supplement 9): ix175–ix177, <strong>2012</strong><br />
doi:10.1093/annonc/mds396<br />
Portuguese Institute of Oncology of Lisbon, Lisbon, PORTUGAL, 4 Medical<br />
Oncology, Breast Cancer Risk Evaluation Clinic, Instituto Português de Oncologia<br />
de Lisboa, Lisbon, PORTUGAL, 5 Breast Cancer Risk Evaluation Clinic, Instituto<br />
Português de Oncologia de Lisboa, Lisbon, PORTUGAL<br />
Introduction: Even if only 5–10% of breast cancer (BC) is due to genetic<br />
predisposition (mainly related to BRCA1/2 mutations), its incidence, <strong>the</strong> high risk of<br />
<strong>the</strong>se families and <strong>the</strong> possible prophylactic interventions make <strong>the</strong> study of <strong>the</strong>se<br />
cases relevant. Scarce data suggest different survival in BRCA1 and BRCA2 associated<br />
ovarian cancer (OC). We aimed to analyze <strong>the</strong> survival of our BRCA1/2 BC and OC<br />
survivors.<br />
Patients and methods: Review of all BRCA1/2 cancer survivors identified until<br />
September 2011. All patients underwent pre and post-test counselling and were<br />
pre-screened for <strong>the</strong> c.156_157insAlu BRCA2 Portuguese founder mutation<br />
[Machado et al, 2007]. Negative patients were fur<strong>the</strong>r analysed by CSCE and MLPA.<br />
Date of diagnosis and survival was obtained for 3 BRCA positive patients subgroups:<br />
BRCA1, BRCA2 (non c.156_157insAlu) and Alu (c.156_157insAlu). The control<br />
group (BRCAwt ) consisted on index patients screened during <strong>the</strong> same period, who<br />
were not BRCA1/2 positive and for whom we found information in <strong>the</strong> Sou<strong>the</strong>rn<br />
Portuguese Cancer Registry (ROR-Sul).<br />
Results: Nine hundred and eighty consecutive index patients were screened and<br />
139 BRCA1/2 positive families were identified: 44 BRCA1 and 95 BRCA2 (44<br />
c.156_157insAlu). A total of 99 BC (88 female + 11 male) and 18 OC were identified<br />
in <strong>the</strong>se families. Mean age at diagnosis and overall survival data for <strong>the</strong> 3 BRCA<br />
subgroups and control, regarding BC and OC are resumed in table1. Fur<strong>the</strong>r clinical<br />
characterization (stage, presence of multiple cancers, prophylactic surgeries) is under<br />
way. Table1. Overall survival in pts with BC and OC: BRCA1/2 carriers vs<br />
wtBRCA1/2.<br />
Conclusion: BC was <strong>the</strong> more frequent type of cancer in <strong>the</strong>se patients and<br />
BRCA1/2 carriers show a higher overall survival comparatively to BC pts with wt<br />
BRCA (P = 0,0197). The overall survival for OC is better for BRCA2 carriers<br />
((P = 0,0310). OC numbers are small and more follow up of <strong>the</strong>se and future<br />
identified carriers are needed.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
513PD BRCA STATUS, MOLECULAR PROFILE AND CLINICAL<br />
VARIABLES IN PRIMARY BILATERAL BREAST CANCERS: A<br />
POPULATION-BASED CANCER REGISTRY STUDY<br />
A. Musolino 1 , M.A. Bella 1 , M. Michiara 2 , P. Zanelli 3 , N. Naldi 1 , B. Bortesi 1 ,<br />
P. Sgargi 2 , R. Camisa 1 , T.M. Neri 3 , A. Ardizzoni 1<br />
1 Medical Oncology Unit, University Hospital of Parma, Parma, ITALY, 2 Medical<br />
Oncology Unit, University Hospital of Parma and Cancer Registry of Parma<br />
Province, Parma, ITALY, 3 Medical Genetics Unit, University Hospital of Parma,<br />
Parma, ITALY<br />
Introduction: Incidence of primary bilateral breast cancer (BBC) is rare and does<br />
not exceed 5%. BRCA1/2 mutation carriers diagnosed with breast cancer have a<br />
strong life time risk of developing contralateral breast cancer. Objectives To address<br />
both <strong>the</strong> proportion of BBC associated with BRCA1/2 germline mutations and <strong>the</strong><br />
contribution of germline mutations to <strong>the</strong> clinical features and outcome of <strong>the</strong>se<br />
tumors.<br />
Materials and methods: We identified 263 BBC patients (pts) from a cohort of 9585<br />
women with a first primary breast cancer systematically collected by <strong>the</strong> Cancer Registry<br />
of Parma Province from 1978 to 2006. Among <strong>the</strong>se, 55 women, unselected for family<br />
history, were subjected to BRCA1/2 testing. In addition, 55 unilateral breast cancer pts,<br />
which tested negative for BRCA1/2 mutations, were evaluated as control group.<br />
Results: BRCA mutations were detected in 13 (24%) of 55 BBC pts. Family history of<br />
breast cancer was identified in 8% of <strong>the</strong>se pts compared with 7% of non-carriers<br />
BRCA1 BRCA2 Alu BRCAwt BRCA1 BRCA2 Alu BRCAwt<br />
N 33 20 35 302 2 8 8 12<br />
Mean age at diagnosis (y) 43,5 40,1 45,9 68,3 47,2 55,8<br />
Mean OS (months) 107,59 145,23 144,70 78,47 40,45 57,92 86,48 64,14<br />
N of deaths 5 4 7 51 1 4 1 7<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com<br />
abstracts
(P = 0.64). Synchronous BBC was significantly rarer in BRCA carriers than in<br />
non-carriers. In addition, BRCA-positive pts were younger at diagnosis than<br />
BRCA-negative ones. The combination of high histologic grade, ER, PR, and HER2<br />
negativity in both bilateral tumors was more frequent among BRCA-1 positive<br />
tumors than BRCA-2 positive and non-BRCA tumors (P < 0.001). Taken collectively,<br />
BRCA-positive BBC correlated with triple negative status compared to non-BRCA<br />
BBC and unilateral breast cancer controls (P < 0.001). There were no survival<br />
differences between BRCA-positive and non-BRCA tumors.<br />
Conclusions: Our data show that <strong>the</strong> combination of BBC occurrence and breast<br />
tumor phenotype can provide an efficient model for identifying individuals with high<br />
risk for BRCA mutations and support <strong>the</strong> hypo<strong>the</strong>sis that BBC in BRCA carriers is<br />
qualitatively distinct from non-BRCA BBC and from sporadic, unilateral breast<br />
cancer. Fur<strong>the</strong>r studies of incident cases are needed to better define <strong>the</strong> prognostic<br />
value of BRCA mutations.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
514P GASTRIC CANCER IN PORTUGUESE FAMILIES WITH BRCA2<br />
GENE MUTATIONS<br />
M.T.A. Alexandre 1 , A. Luís 2 , A. Opinião 2 , S. Bento 3 , C. Simões 3 , J. Parreira 3 ,<br />
S. Fragoso 4 , P. Machado 4 , S. Santos 4 ,F.Vaz 2<br />
1 Medical Oncology, Instituto Português de Oncologia de Lisboa, Lisbon,<br />
PORTUGAL, 2 Medical Oncology, Breast Cancer Risk Evaluation Clinic, Instituto<br />
Português de Oncologia de Lisboa, Lisbon, PORTUGAL, 3 Breast Cancer Risk<br />
Evaluation Clinic, Instituto Português de Oncologia de Lisboa, Lisbon,<br />
PORTUGAL, 4 Molecular Biology Research Unit, Instituto Português de Oncologia<br />
de Lisboa, Lisbon, PORTUGAL<br />
Background and objective: BRCA 1/2 are tumor suppressor genes responsible for a<br />
high number of hereditary breast and ovarian cancers. BRCA 2 mutations are also<br />
associated with higher risk of o<strong>the</strong>r cancers: prostate, melanoma, pancreatic, gastric and<br />
bile duct cancer. BRCA2 mutations are more frequent than BRCA1 mutations in Portugal<br />
and GC has, historically, a high incidence in this country. Our objective was to analyze <strong>the</strong><br />
frequency and characteristics of GC in confirmed BRCA2 Portuguese families.<br />
Methods: Retrospective analysis of all BRCA2 families registered in our Clinic. All<br />
cases of GC, on <strong>the</strong> mutated side of <strong>the</strong> family, for 3 consecutive generations, were<br />
registered. The control group consisted of breast cancer families with standard risk of<br />
breast cancer (FSRBC) (with probability
Annals of Oncology<br />
compare <strong>the</strong> family history record and <strong>the</strong> hereditary cancer perception risk according<br />
to National Cancer Institute (NCI) criteria before and after <strong>the</strong> creation of a<br />
multidisciplinary heredofamilial cancer unit (HFCU) in our medical oncology service.<br />
Methods: We retrospectively analyze <strong>the</strong> clinical records from new incoming patients<br />
of our medical oncology service in two cohorts: Cohort 1, from January 2009 to<br />
December 2009 (616 patients, before HFCU creation); and cohort 2, from May 2010 to<br />
April 2011 (after HFCU creation, first 312 patients analyzed). Family history record<br />
(yes/no) and NCI general hereditary cancer criteria (unusually early age; one or more<br />
first-degree relatives affected with <strong>the</strong> same or a related tumor; synchronous, bilateral<br />
or metachronous cancer in <strong>the</strong> same patient; atypical presentations) were collected.<br />
Results were compared using chi- square test. p
abstracts<br />
gastrointestinal tumors, colorectal<br />
518O MAINTENANCE TREATMENT WITH IMMUNOMODULATOR<br />
MGN1703 FOLLOWING INDUCTION WITH STANDARD 1ST<br />
LINE THERAPY PROLONGS PROGRESSION-FREE SURVIVAL<br />
IN PATIENTS WITH METASTATIC COLORECTAL (MCRC):<br />
RESULTS OF THE PHASE II/III IMPACT TRIAL<br />
D. Arnold 1 , H.J. Schmoll 2 , J. Riera-Knorrenschild 3 , F. Mayer 4 , H. Kroening 5 ,<br />
W. Scheithauer 6 , D. Nitsche 7 , M. Tschaika 8 , M. Schmidt 8 , B. Wittig 9<br />
1 University Cancer Centre Hamburg, Hubertus Wald Tumour Centre KMTZ,<br />
Hamburg, GERMANY, 2 Dept. Hematology/ Oncology, University of Halle Martin<br />
Lu<strong>the</strong>r University Hospital, Halle, GERMANY, 3 Clinic for Hematology, Oncology<br />
and Immunology, Universitaetsklinikum Giessen und Marburg, Marburg,<br />
GERMANY, 4 Medizinische Klinik und Poliklinik II, Eberhard-Karls-Universität<br />
Tübingen, Tübingen, GERMANY, 5 Schwerpunktpraxis für Haematologie und<br />
Onkologie, Schwerpunktpraxis für Haematologie und Onkologie, Magdeburg,<br />
GERMANY, 6 Department of Medicine I, Medical University of Vienna, Vienna,<br />
AUSTRIA, 7 Innere Medizin I, Hämatologie und Onkologie, Barmherzige<br />
Schwestern Linz, Linz, AUSTRIA, 8 Clinical Development, Mologen AG, Berlin,<br />
GERMANY, 9 Foundation Institute Molecular Biology and Bioinformatics, Freie<br />
Universität Berlin, Berlin, GERMANY<br />
Introduction: Standard chemo<strong>the</strong>rapy is increasingly discontinued after successful<br />
“induction” in patients (pts) undergoing 1 st line treatment for mCRC. MGN1703<br />
is a syn<strong>the</strong>tic DNA-based immunomodulator acting as an agonist of TLR-9 that<br />
has shown preclinical activity in mCRC. This study has been conducted to assess<br />
clinical efficacy, immunogenicity, and safety of MGN1703 as maintenance vs.<br />
placebo.<br />
Methods: The IMPACT study is an international, multicenter, randomized<br />
double-blind placebo-controlled phase II/III study. Pts with mCRC showing disease<br />
control (CR, PR or SD) after 4.5 to 6 months of 1st-line standard <strong>the</strong>rapy with<br />
FOLFOX/XELOX or FOLFIRI +/- bevacizumab (investigatoŕs choice) were included.<br />
Results: Interim analysis of <strong>the</strong> unblinded data revealed a strong <strong>the</strong>rapeutic effect<br />
compared to anticipated PFS. Therefore, patients were withheld from fur<strong>the</strong>r<br />
randomization, according to a decision of <strong>the</strong> steering committee. In <strong>the</strong> ITT<br />
population (N = 55 pts), hazard ratio (HR) was 0.53 in favor of MGN1703 (p =<br />
0.062). In <strong>the</strong> per-protocol population (excluding screening failures; N = 50), HR was<br />
0.43 (p = 0.015). In <strong>the</strong> pre-defined target population (2 out of 3 factors: CEA
Annals of Oncology<br />
Conclusions: The analysis of this randomized phase III trial has not shown a benefit<br />
for adding cetuximab to FOLFOX4 in patients with resected stage III mKRAS CC<br />
with global results very close to those observed in KRAS wild type pts. Supported by<br />
Merck-Serono, Sanofi-Aventis.<br />
Disclosure: G. Folprecht: - Honoraries, for lectures and advisory boards from Merck<br />
KGaA and Bristol Mayers Squibb. -study grant from Merck KGaA -involved in clinical<br />
trials with Imclone and Merck KGaA J. Taieb: advisory board and consutancy for Sanofi<br />
Aventis and Merck Serono. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
521O DEFICIENT MISMATCH REPAIR (DMMR) AND BRAF<br />
MUTATION (MT) STATUS IN PATIENTS (PTS) WITH<br />
METASTATIC COLORECTAL CANCER (MCRC): A<br />
META-ANALYSIS OF THE CAIRO, CAIRO2, COIN AND FOCUS<br />
STUDIES<br />
S. Venderbosch 1 , T. De Haan 2 , D.A.M. Heideman 3 , T.S. Maughan 4 , C.G. Smith 5 ,<br />
P. Quirke 6 , S.D. Richman 6 , I.D. Nagtegaal 1 , C.J.A. Punt 7 , M. Koopman 8<br />
1 Pathology, Radboud University Nijmegen Medical Centre, Nijmegen,<br />
NETHERLANDS, 2 Epidemiology, Biostatistics and Health Technology<br />
Assessment, Radboud University Nijmegen Medical Centre, Nijmegen,<br />
NETHERLANDS, 3 Department of Pathology, VU University Medical Centre,<br />
Amsterdam, NETHERLANDS, 4 Oncology, Gray Institute for Radiation Oncology<br />
& Biology University of <strong>Oxford</strong>, <strong>Oxford</strong>, UNITED KINGDOM, 5 School of Medicine,<br />
Cardiff University, Cardiff, UNITED KINGDOM, 6 Pathology and Tumour Biology,<br />
Leeds Institute of Molecular Medicine, Leeds, UNITED KINGDOM, 7 Department<br />
of Medical Oncology, Academic Medical Center, Amsterdam, NETHERLANDS,<br />
8 Medical Oncology, University Hospital Utrecht, Utrecht, NETHERLANDS<br />
Introduction: In stage II-III CRC <strong>the</strong> overall incidence of BRAF mt and dMMR is<br />
8% and 10-20%, resp. The incidence of BRAF mt in sporadic dMMR is high (24%,<br />
Roth et al., JCO 2010), and BRAF mt, in contrast to dMMR, has a negative<br />
prognostic value. The incidence of dMMR and BRAF mt in mCRC is approx. 4%<br />
and 8%, resp. No data from large series of mCRC pts are available on <strong>the</strong> prognostic<br />
value of BRAF mt in combination with dMMR.<br />
Methods: We performed a meta-analysis of 4 mCRC trials: CAIRO, CAIRO2, COIN<br />
and FOCUS. The primary outcome measure was <strong>the</strong> hazard ratio (HR) for<br />
progression free survival (PFS) and overall survival (OS) in relation to BRAF and<br />
MMR status. For <strong>the</strong> meta-analysis a cox regression analysis was performed on<br />
individual pt data.<br />
Results: In total 3064 pts were analysed, of whom 151 (4.9%) exhibited dMMR, and<br />
263 (8.6%) BRAF mt. A BRAF mt was observed in 211 (7.2%), and 52 (34.4%) of <strong>the</strong><br />
pts with a proficient mismatch repair system (pMMR) and dMMR, resp. PFS was<br />
significantly worse for dMMR vs. pMMR pts (HR 1.22; 95% CI, 1.03-1.46), but not<br />
OS (HR 1.13; 95% CI, 0.94-1.36). PFS and OS were significantly worse for BRAF mt<br />
vs. BRAF wildtype (wt) pts (HR 1.28; 95% CI, 1.12-1.46 and HR 1.81; 95% CI,<br />
1.57-2.09, resp.). Within <strong>the</strong> pMMR group, BRAF mt pts had a significantly worse<br />
PFS and OS compared to BRAF wt pts (HR 1.32; 95% CI 1.09-1.61, and HR 1.88;<br />
95% CI 1.53-2.30, resp.). Within <strong>the</strong> dMMR group no significant differences were<br />
found for PFS and OS in BRAF mt pts vs. BRAF wt pts (HR 1.05; 95% CI 0.65-1.68,<br />
and HR 1.49; 95% CI 0.91-2.43, resp.). Within <strong>the</strong> BRAF mt group PFS and OS were<br />
not significantly different between pMMR and dMMR pts (HR 0.96; 95% CI<br />
0.63-1.47, and HR 1.03; 95% CI 0.67-1.59, resp.). Within <strong>the</strong> BRAF wt group, PFS<br />
and OS were not significantly different for pMMR vs. dMMR pts (HR 1.32; 95% CI<br />
0.99-1.75, and HR 1.22; 95% CI 0.90-1.65, resp.).<br />
Conclusion: In this meta-analysis of mCRC pts we observed a higher incidence of<br />
BRAF mt in dMMR than reported for early-stage CRC pts. In mCRC pts, dMMR is<br />
associated with a worse PFS compared to pMMR. The prognostic role of BRAF mt<br />
in mCRC is restricted to pMMR pts. Our data confirm <strong>the</strong> worse prognostic value of<br />
BRAF mt vs BRAF wt.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
522PD DEVELOPMENT AND VALIDATION OF A ROBUST<br />
MOLECULAR DIAGNOSTIC TEST (COLOPRINT) FOR<br />
PREDICTING OUTCOME IN STAGE II COLON CANCER<br />
PATIENTS<br />
T. Bachleitner-Hofmann 1 , I. Simon 2 , R. Salazar 3 , J. Tabernero 4 , R. Rosenberg 5 ,<br />
J. van der Akker 6 ,Y.Li 7 , B. Chan 7 , G. Lanza 8 , A. Glas 6<br />
1 Department of Surgery, Medical University of Vienna, Vienna, AUSTRIA,<br />
2 Research and Development, Agendia NV, Amsterdam, NETHERLANDS, 3 G-I<br />
Unit. Medical Oncology Dpt., Institut Catal, Barcelona, SPAIN, 4 Oncology<br />
Department, Vall d’Hebron University Hospital, Barcelona, SPAIN, 5 Department<br />
of Surgery, Klinikum Rechtas der Isar, Munich, GERMANY, 6 Product Support,<br />
Agendia NV, Amsterdam, NETHERLANDS, 7 Product Support, Agendia Inc,<br />
Irvine, CA, UNITED STATES OF AMERICA, 8 5istituto di Anatomia E Istologia<br />
Patologica, University di Ferrara, Ferrara, ITALY<br />
Background: Only between 25 to 35% of stage II and IIIA colon cancer patients will<br />
experience a relapse of <strong>the</strong>ir disease and may benefit from adjuvant chemo<strong>the</strong>rapy.<br />
ColoPrint is a gene expression classifier that can predict disease relapse in patients<br />
with early-stage colorectal cancer and helps to identify patients with higher risk of<br />
relapse.<br />
Methods: ColoPrint was developed using whole genome expression data and<br />
was validated in public datasets and an independent patient cohort of 206<br />
patients (Salazar et al., JCO 2011). The signature was translated to a<br />
customized 8-pack microarray. Positive and negative hybridization control genes<br />
monitor <strong>the</strong> quality of hybridization and a colon specific normalization gene<br />
set (n = 461) guarantee reliability of results. Reproducibility and precision<br />
studies with 20 times 6 samples were performed by multiple operators on<br />
multiple days. Additional independent patient cohorts were validated on <strong>the</strong><br />
customized arrays. Uni- and multi-variate analyses were performed on <strong>the</strong><br />
pooled stage II patient set (n = 320), <strong>the</strong> subset of T3/ MSS patients (n = 227)<br />
and stage IIIA (n = 16).<br />
Results: The prognostic classifier was evaluated in reproducibility and stability<br />
assays and stringent quality controls were established following <strong>the</strong> successful<br />
lead of <strong>the</strong> FDA-cleared MammaPrint assay. Results of all tests met <strong>the</strong> pre-set<br />
criteria. In <strong>the</strong> analysis of all stage II and IIIA patients, ColoPrint classified<br />
two-third of patients as being at low risk. The 3-year Relapse-Free-Survial (RFS)<br />
RFS was 92% and 77% for low and high risk patients respectively with a HR of<br />
2.9 (p = 0.001). Clinical and pathological risk parameters from <strong>the</strong> NCCN<br />
guidelines can be combined with ColoPrint for even more personalized risk<br />
assessment. ColoPrint is also able to distinguish risk groups in <strong>the</strong> subgroup of<br />
patients with T3 and MSS phenotype (HR= 2.7, p = 0.01) and IIIA (HR= 3.6,<br />
p=0.08).<br />
Conclusions: ColoPrint was technically and clinically validated and is now available<br />
for diagnostic use. ColoPrint significantly improves prognostic accuracy, <strong>the</strong>reby<br />
facilitating <strong>the</strong> identification of patients at higher risk who might be considered for<br />
additional treatment.<br />
Disclosure: I. Simon: Employee of Agendia (maker of ColoPrint). J. van der Akker:<br />
Employee of Agendia (maker of ColoPrint). Y. Li: Employee of Agendia (maker of<br />
ColoPrint). B. Chan: Employee of Agendia (maker of ColoPrint). A. Glas: Employee<br />
of Agendia (maker of ColoPrint). All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
523PD THE 12-GENE COLON CANCER RECURRENCE SCORE (RS)<br />
PREDICTS RECURRENCE IN STAGE II AND III COLON<br />
CANCER PATIENTS TREATED WITH 5FU/LV (FU) AND 5FU/<br />
LV + OXALIPLATIN (FU + OX): VALIDATION IN NSABP C07<br />
M.J. O’Connell 1 , M. Lee 2 , M. Lopatin 3 , G. Yo<strong>the</strong>rs 4 , K.M. Clark-Langone 5 ,<br />
C. Millward 6 , S. Paik 1 , S. Sharif 1 , S. Shak 2 , N. Wolmark 1<br />
1 NSABP, National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA,<br />
UNITED STATES OF AMERICA, 2 Oncology Development, Genomic Health, Inc.,<br />
Redwood City, CA, UNITED STATES OF AMERICA, 3 Biostatistics, Genomic<br />
Health, Inc., Redwood City, CA, UNITED STATES OF AMERICA, 4 Biostatistical<br />
Center, NSABP, Pittsburgh, PA, UNITED STATES OF AMERICA, 5 Development<br />
Laboratory, Genomic Health, Inc., Redwood City, CA, UNITED STATES OF<br />
AMERICA, 6 Pathology, Genomic Health, Inc., Redwood City, CA, UNITED<br />
STATES OF AMERICA<br />
Background: Standardized tools which accurately quantify recurrence risk are<br />
needed for optimal adjuvant treatment of colon cancer. The 12-gene RS has been<br />
validated in stage II colon cancer pts from QUASAR and CALGB 9581. We<br />
conducted a large prospectively-designed clinical validation study of RS, w/<br />
pre-specified endpoints, methods, and analysis plan, in stage II and III colon cancer<br />
pts randomized to FU or FU + Ox in C-07.<br />
Methods: 50% of C-07 pts w/ tissue were randomly selected, stratified on stage and<br />
recurrence. Gene expression was quantitated by RT-PCR on 25 µm manually<br />
microdissected fixed tumor tissue. Data were analyzed by Cox regression controlling<br />
for stage and treatment (TRT).<br />
Results: RT-PCR was successful in 892/921 pts (97%): 449 FU, 443 FU + Ox; 264 st II,<br />
409 st IIIA/B, 219 st IIIC. The primary endpoint was met: RS predicted recurrence<br />
(HR/25 units = 1.96, 95% CI 1.50-2.55 p < .001). RS also predicted DFS (p < .001) and<br />
OS (p < .001). RS predicted recurrence (p = .001) independent of T and N stage,<br />
MMR, nodes examined, grade, and TRT. Predefined high RS group (25% of pts) had<br />
higher recurrence risk than low RS group (39% of pts): HR = 2.11, p < .001. Cox model<br />
5 yr recurrence risk (95%CI) in FU treated pts by RS group (low, high): st II 9%<br />
(6-13%), 18% (12-25%); st IIIA/B 21% (16-26%), 38% (30-46%); st IIIC 40% (32-48%),<br />
64% (55-74%). RS did not have significant interaction w/ stage (p = 0.90) or age (p =<br />
0.76). Relative Ox benefit was similar across range of RS (interaction p = 0.48);<br />
accordingly, in Cox model and Kaplan-Meier analyses, absolute Ox benefit increased<br />
w/ higher RS. In an exploratory analysis of 735 genes, 16 genes were identified as<br />
associated with relative Ox benefit after controlling false discovery rate at 20%.<br />
Conclusions: RS predicts recurrence risk in stage II and III colon cancer, capturing<br />
underlying biology and providing risk information beyond conventional factors. RS is<br />
not predictive of relative Ox benefit but enables better discrimination of absolute Ox<br />
benefit as a function of risk. Incorporating RS into <strong>the</strong> clinical context may better<br />
inform adjuvant <strong>the</strong>rapy decisions for pts w/ stage III as well as stage II colon<br />
cancer.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds397 | ix179
Disclosure: M. Lee: I am an employee and stockholder of Genomic Health, Inc. M.<br />
Lopatin: I am an employee and stockholder of Genomic Health, Inc. K.M.<br />
Clark-Langone: I am an employee and stockholder of Genomic Health, Inc. C.<br />
Millward: I am an employee and stockholder of Genomic Health, Inc. S. Shak: I am<br />
Chief Medical Officer and a stockholder of Genomic Health, Inc. All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
524PD ERCC1, DEFECTIVE MISMATCH REPAIR STATUS AS<br />
PREDICTIVE BIOMARKER OF SURVIVAL FOR STAGE III<br />
COLON CANCER PATIENTS RECEIVING OXALIPLATIN<br />
BASED ADJUVANT CHEMOTHERAPY<br />
P. Li, G. Chen<br />
Colorectal Surgery, Cancer Center, Sun Yat-Sen Universtiy, Guangzhou, CHINA<br />
Background: Several trials showed excision repair cross-complementation group 1<br />
(ERCC1) expression status is a candidate marker for predicting efficacy of<br />
oxaliplatin (OX) treatment for metastatic colorectal cancer (CRC). Association<br />
between <strong>the</strong> expression of mismatch repair genes (MMR) and favorable<br />
postoperative survival in stage II CRC receiving 5-FU chemo<strong>the</strong>rapy has been<br />
identified. whe<strong>the</strong>r <strong>the</strong> expression of ERCC1 protein and MMR status are associated<br />
with survival of stage IIIB colon cancer receiving OX-based chemo<strong>the</strong>rapy is<br />
unclear.<br />
Patients and methods: We enrolled 255 patients with stage III colon cancer after<br />
radical surgery. There were 95 patients receiving full-course Mayo clinic<br />
chemo<strong>the</strong>rapy and 160 patients received mFOLFOX6 or XELOX chemo<strong>the</strong>rapy.<br />
Immunohistochemistry analysis of <strong>the</strong> expression of MMR and ERCC1 was<br />
performed in tumor tissue. A predictive model for 5-year disease-free survival (DFS)<br />
and overall survival (OS) was constructed by using Kaplan-Meier analysis, logistic<br />
and Cox regression.<br />
Results: The patients with positive ERCC1 tumors had lower 5-year DFS (54%)<br />
than those with negative ERCC1 tumors (72%) in combined <strong>the</strong>rapy group (HR:<br />
1.98 95%CI: 1.19-3.31 p = 0.009).The OS was also lower in combined <strong>the</strong>rapy<br />
group with positive ERCC1 tumors (60%) than those patients with negative<br />
ERCC1 tumors (78% HR: 2.44 95%CI: 1.37-4.34 p = 0.02). In multivariate analysis,<br />
ERCC1 expression remained an independent significant predictive factor for DFS<br />
and OS (DFS HR: 2.33 95%CI: 1.37-3.93 p < 0.001, OS HR: 2.87 95%CI: 1.59-5.16<br />
p < 0.001). The protein expression of ERCC1 showed no statistical significance of<br />
DFS or OS in fluorouracil group (DFS HR: 1.16 95%CI: 0.63-2.14 p = 0.62, OS<br />
HR: 1.16 95%CI: 0.63-2.14 p = 0.63). The MMR status had no statistical<br />
significance of DFS or OS between combined <strong>the</strong>rapy group and single-drug<br />
group.<br />
Conclusion: ERCC1 status was shown to be a highly predictive selection<br />
criterion in relation to <strong>the</strong> treatment decision regarding <strong>the</strong> addition of OX to<br />
5-FU for stage IIIB colon cancer. MMR status had no predictive value in this<br />
setting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
525PD HSA-MIR31-3P EXPRESSION AS A PREDICTOR OF<br />
ANTI-EGFR RESPONSE IN WILD-TYPE KRAS PATIENTS<br />
WITH METASTATIC COLORECTAL CANCER<br />
P. Laurent-Puig 1 , G. Manceau 1 , J. Bachet 2 , B. Chibaudel 3 , F. Liebaert 4 ,<br />
O. Bouché 5 , F. Penault-Llorca 6 , M.D. Diebold 5 , T. André 3 , S. Imbeaud 7<br />
1 UMR-S775, Université Paris Descartes, Paris, FRANCE, 2 Gastroenterology<br />
Hepatology, Hôpital Pitié-Salpêtrière, Paris, FRANCE, 3 Department of Medical<br />
Oncology, Hôpital Saint Antoine, Paris, FRANCE, 4 R&D, Integragen, Evry,<br />
FRANCE, 5 Hepatology-Gastroenterology, Hopital Robert Debré, Reims,<br />
FRANCE, 6 Recherche, CJP-ERTICA, Clermont-Ferrand, FRANCE, 7 UMR-S674,<br />
Inserm, Paris, FRANCE<br />
In colorectal cancer, KRAS mutations are associated with resistance to anti-EGFR<br />
antibodies. A major challenge is to identify, in wild-type KRAS patients, markers<br />
that predict response to this <strong>the</strong>rapy. We focused on miRNAs, which can play<br />
role in <strong>the</strong> resistance to anti-EGFR based chemo<strong>the</strong>rapy for metastatic colorectal<br />
cancer (mCRC). We first analysed 1145 miRNAs in 84 colorectal tumors and 5<br />
normal colon mucosae. We <strong>the</strong>n conducted a study with 3 subgroups of patients.<br />
Group 1 is a retrospective series of patients treated by cetuximab and irinotecan,<br />
group 2 is a prospective collection of patient treated by cetuximab or<br />
panitumumab based chemo<strong>the</strong>rapy and group 3 is a series of patients<br />
prospectively treated by panitumumab and irinotecan as third-line. Using a Cox<br />
proportional hazards model, fitted using principal components analysis of group<br />
1, we identified a predictive signature of 11 miRNA linked to disease free survival<br />
(p < 0.01). Validation by RT PCR showed that all <strong>the</strong> survival information is<br />
associated with miRNA hsa-mir-31-3p. We tested expression of this miRNA and<br />
Annals of Oncology<br />
<strong>the</strong> presence or absence of mutation BRAF on group 1 of 33 patients, in a Cox<br />
model, and found a hazard ratio (HR) of 1.9 CI95% [1.1-2.9]. In <strong>the</strong> two<br />
prospective series (38 patients) <strong>the</strong> prognostic impact of hsa-mir31-3p <strong>the</strong> HR is<br />
estimated to 1.9 CI95% [1.1-3.1]. We applied <strong>the</strong> multivariate model obtained<br />
from group 1 to group 2 and 3 in order to predict <strong>the</strong> disease free survival of <strong>the</strong><br />
patients. The accuracy of <strong>the</strong> prediction measured by <strong>the</strong> AUC is 0.77. The<br />
performance of <strong>the</strong> test remains stable from 10 weeks to 48 weeks. A Cox<br />
proportional hazards model based on <strong>the</strong> hsa-mir31-3p logged expression, fitted<br />
using principal components from group 1 and BRAF mutation status as a clinical<br />
covariate allowed us to classify group 2 and 3 according to a free progression<br />
survival risk score (P = 0.005) with a specificity of 62% [95% CI: 38%-82%] and a<br />
sensitivity of 82% [95% CI: 56%-96%] for <strong>the</strong> prediction model. We established a<br />
nomogram, taking into account mir-31-3p expression level, age, gender and BRAF<br />
mutation status, which predict <strong>the</strong> progression risk (P < 0.0001). It is <strong>the</strong> first tool<br />
for selecting individual patients with a wild-type KRAS tumor for anti-EGFR<br />
<strong>the</strong>rapy.<br />
Disclosure: P. Laurent-Puig: Received clinical research grant from Integragen.<br />
F. Liebaert: Integragen S.A Employee. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
526PD DEVELOPMENT OF A PREDICTIVE SCORE USING<br />
AMPHIREGULIN (AREG), EPIREGULIN (EREG) AND<br />
EGFR-FISH EXPRESSION LEVELS TO DETERMINE<br />
TREATMENT EFFICACY IN MCRC PATIENTS RECEIVING<br />
CETUXIMAB-BASED THERAPY. ANALYSIS OF THE GERMAN<br />
AIO CRC-0104 TRIAL<br />
V. Heinemann 1 , R. Laubender 2 , D.P. Modest 1 , A. Jung 3 , L. Fischer von<br />
Weikersthal 4 , U. Vehling-Kaiser 5 , C. Giessen 1 , T. Kirchner 3 , U. Mansmann 2 ,<br />
S. Stintzing 1<br />
1 Department of Medical Oncology and Comprehensive Cancer Center, University<br />
of Munich, Munich, GERMANY, 2 University of Munich, Institute of Medical<br />
Informatics, Biostatistics, and Epidemiology, München, GERMANY, 3 Institute of<br />
Pathology, Univsersity of Munich, Munich, GERMANY, 4 Oncological Practice,<br />
Gesundheitszentrum St. Marien, Amberg, GERMANY, 5 Onkologische<br />
Schwerpunktpraxis, Onkologisches und Palliativmedizinisches Netzwerk<br />
Landshut, Landshut, GERMANY<br />
Background: We investigated <strong>the</strong> expression of <strong>the</strong> EGFR ligands amphiregulin<br />
(AREG) and epiregulin (EREG) as well as <strong>the</strong> amplification of <strong>the</strong> EGFR-gene in<br />
tumor specimens of mCRC patients (pts) treated first-line with anti-EGFR targeted<br />
cetuximab toge<strong>the</strong>r with CAPOX or CAPIRI. All three factors have shown <strong>the</strong><br />
capability to separate patient groups of different prognosis. Here we used a composite<br />
score to calculate response probability.<br />
Methods: A total of 185 mCRC pts were randomized to cetuximab plus CAPIRI or<br />
plus CAPOX. The primary study endpoint was ORR. Age, gender, study arm, KRAS<br />
mutational status, BRAF mutational status, AREG, EREG and EGFR-FISH expression<br />
levels were used for multivariate logistic regression analysis.<br />
Results: AREG and EGFR-FISH significantly correlated with ORR. These factors<br />
were used to create a prediction model for ORR by using logistic regression<br />
model. The linear predictor of this model is given by LP = -7.63 + (0.35*log<br />
[AREG]) + (6.58*[EGFR-FISH]) which can be used to calculate <strong>the</strong> probability of<br />
ORR by exp(LP) / [1 + exp(LP)]. The discriminatory ability of this model was<br />
assessed by ROC analyses were <strong>the</strong> optimal cut-off of <strong>the</strong> linear predictor<br />
discriminating best between responders and non-responders with respect to ORR<br />
was identified by using <strong>the</strong> Youden index and is given by -0.095. The area under<br />
<strong>the</strong> ROC curve (AUC) is 0.79 (95% confidence interval: 0.63, 0.90). Using this<br />
formula, response and survival times with a cut-off of 50% of ORR probability<br />
were calculated. ORR was significantly higher in <strong>the</strong> positive cohort and reached<br />
81% vs. 42% in <strong>the</strong> negative cohort (p= 0.009). This led to significantly longer<br />
survival times in <strong>the</strong> positive cohort, with regard to PFS (8.6 mo vs 4.6 mo; HR<br />
0.44; p = 0.003) and OS (38.4 mo vs 17.2 mo; HR 0.37; p= 0.001).<br />
Conclusion: In this retrospective and exploratory analysis it was possible to predict<br />
ORR probability with <strong>the</strong> help of molecular markers. There is an acceptable<br />
discriminatory performance as measured by <strong>the</strong> AUC for predicting ORR by<br />
AREG and EGFR-FISH Hence, both molecular markers might be promising<br />
candidates for predicting ORR under cetuximab-based treatment regimens and<br />
prospective evaluation of <strong>the</strong>se markers is needed for replicating and validating our<br />
findings.<br />
Disclosure: V. Heinemann: Honoraria and travel support: Merck, Roche, Amgen. R.<br />
Laubender: Travel support: Merck. D.P. Modest: Honoraria and Travel Support:<br />
Amgen, Roche. A. Jung: Honoraria and travel Support: Amgen, Roche. C. Giessen:<br />
travel Support: Merck, Roche. T. Kirchner: Research Grant, Honoraria and Travel<br />
Support: Merck, Amgen, Roche. U. Mansmann: Honoraia and Travel support:<br />
Merck, Amgen. S. Stintzing: Honoraria and travel support: Merck, Amgen, Roche.<br />
All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
ix180 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
527PD PHARMACOGENETIC PREDICTORS OF SEVERE CHRONIC<br />
PERIPHERAL NEUROPATHY IN STAGE II-III COLON CANCER<br />
(CC) PATIENTS TREATED WITH OXALIPLATIN-BASED<br />
ADJUVANT CHEMOTHERAPY (CT). A GEMCAD STUDY<br />
A. Custodio 1 , J. Moreno 1 , J. Aparicio 2 , J. Gallego Plazas 3 ,C.<br />
Fernández Martos 4 , J. Maurel 5 , D. Ramos 6 , P. Cejas 1 , R. Madero 7 , J. Feliu 1<br />
1 Medical Oncology, La Paz University Hospital, Madrid, SPAIN, 2 Medical<br />
Oncology Department, La Fe University Hospital, Valencia, SPAIN, 3 Medical<br />
Oncology Department, Elche University Hospital, Elche, SPAIN, 4 Medical<br />
Oncology Department, Fundación Instituto Valenciano de Oncología, Valencia,<br />
SPAIN, 5 Medical Oncology, Hospital Clinic i Provincial, Barcelona, SPAIN,<br />
6 Pathology Department, La Fe University Hospital, Valencia, SPAIN, 7 Biostatistics<br />
Unit, La Paz University Hospital, Madrid, SPAIN<br />
Background: Oxaliplatin-based CT is now <strong>the</strong> standard adjuvant <strong>the</strong>rapy after<br />
resection of stage III and selected high-risk stage II CC. However, this treatment is<br />
often associated with cumulative peripheral neuropathy. Predicting individual patient<br />
risk for developing severe neuropathy could improve <strong>the</strong> quality of care by allowing<br />
<strong>the</strong> individualization of treatment. Our aim is to identify single nucleotide<br />
polymorphisms (SNPs) in genes involved in oxaliplatin sensitivity to predict severe<br />
(grade 2-3) oxaliplatin-induced chronic peripheral neuropathy (OXCPN) among<br />
stage II-III CC patients who received adjuvant CT.<br />
Methods: DNA was extracted from formalin-fixed-paraffin-embedded samples from<br />
202 surgically treated high-risk stage II (29.7%) and stage III (70.3%) CC patients<br />
receiving adjuvant oxaliplatin and fluoropyrimidines CT (25.24% FOLFOX, 74.75%<br />
CAPOX) from January 2004 to December 2008. Median follow-up was 51.4 months<br />
(7-96). Genotyping was performed for 35 SNPs in 18 genes involved in oxaliplatin<br />
metabolism (ERCC and XRCC groups), cell cycle and drug transport using<br />
MassARRAY (SEQUENOM) technology. A total of 177 stage II-III CC patients also<br />
treated with oxaliplatin-based CT were enrolled as a validation set.<br />
Results: Forty-eight (23.8%) patients experienced grade 2-3 OXCPN. The cyclin H<br />
(CCNH) (rs2230641) C/C genotype was associated with a higher risk of severe<br />
OXCPN (57.1% C/C, 24.2% C/T, 21.3% T/T; RR: 5.197, p = 0.041). In addition,<br />
patients harboring <strong>the</strong> CCNH (rs2230641) C/C and/or ATP-binding cassette<br />
subfamily G member (ABCG2) (rs3114018) A/A haplotype had a higher risk of<br />
grade 2-3 OXCPN compared to <strong>the</strong> CCNH (rs2230641) any T and ABCG2<br />
(rs3114018) any C haplotype (36.5% vs. 19.6%, respectively; RR:2.36; 95% CI,<br />
1.17-4.78; p = 0.022). The ability to predict severe OXCPN of this combined analysis<br />
was <strong>the</strong>n independently validated in <strong>the</strong> second cohort (RR: 2.82; 95% CI, 1.41-5.63;<br />
p = 0.003).<br />
Conclusions: Our data suggest that SNPs in CCNH and ABCG2 can predict <strong>the</strong><br />
development of severe OXCPN in stage II-III CC patients. The analysis of <strong>the</strong>se<br />
SNPs may be useful in personalized adjuvant CT.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
528PD THE EFFECT OF CHEMOTHERAPY HOLIDAY ON THE<br />
OVERALL SURVIVAL OF PATIENTS WITH ADVANCED<br />
COLORECTAL CANCER: A META-ANALYSIS OF<br />
RANDOMIZED TRIALS<br />
A.A.L. Pereira 1 , J.F.M. Rego 2 , P.M. Hoff 1 , A. Sasse 3 , R.P. Riechelmann 2<br />
1 Centro De Oncologia - 2° Andar, Sirio Libanes Hospital, Sao Paulo, BRAZIL,<br />
2 Clinical Oncology, Instituto do Cancer do estado de Sao Paulo, Sao Paulo,<br />
BRAZIL, 3 Cevon Centre for Evidences In Oncology, UNICAMP - Universidade<br />
Estadual de Campinas, Campinas, BRAZIL<br />
Background: The impact of <strong>the</strong> duration of chemo<strong>the</strong>rapy on <strong>the</strong> outcomes of<br />
patients with advanced colorectal cancer is controversial. Our objective was to<br />
perform a systematic review and meta-analysis of randomized controlled trials (RCT)<br />
that compared chemo<strong>the</strong>rapy continuously administered until disease progression<br />
versus chemo<strong>the</strong>rapy interruption in patients with metastatic colorectal cancer.<br />
Methods: We systematically searched for all RCT in which metastatic colorectal cancer<br />
patients were randomized to continuous <strong>the</strong>rapy until progression or chemo<strong>the</strong>rapy<br />
discontinuation after maximal response or fixed number of cycles. Trials were located<br />
through searches of PubMed, Cochrane Library and of ASCO/<strong>ESMO</strong> abstracts up to<br />
February <strong>2012</strong>. Two authors independently extracted <strong>the</strong> data, and consensus was<br />
achieved when <strong>the</strong>re was disagreement. Meta-analyses were performed using<br />
random-effects model. Hazard ratios (HR) were used for <strong>the</strong> meta-analysis and were<br />
expressed with 95% confidence intervals (CI). Statistical heterogeneity of data was<br />
evaluated with <strong>the</strong> chi-square test, and expressed using <strong>the</strong> I2 index.<br />
Results: Our search retrieved 42 RCT, of which five were eligible, with 1815 patients<br />
included. The analysis of progression-free survival (PFS) was not possible due to <strong>the</strong><br />
different definitions of PFS across trials. The median chemo<strong>the</strong>rapy free interval in<br />
<strong>the</strong> discontinuation group was 3.9 months. The pooled analysis of overall survival<br />
included 1776 patients (one trial was not included because it did not present<br />
extractable data). The metanalysis showed a statistically significant survival benefit<br />
with continuously given chemo<strong>the</strong>rapy (HR = 0.90, 95% CI = 0.82 to 0.99; p = 0.03; I2<br />
0%) in comparison to chemo<strong>the</strong>rapy holiday strategy. Quality of life was reported in<br />
one trial and no difference was found in it.<br />
Conclusions: Chemo<strong>the</strong>rapy delivered continuously until tumor progression appears<br />
to be associated with a modest but significantly better survival in patients with<br />
advanced colorectal cancer over chemo<strong>the</strong>rapy interruption. Continued <strong>the</strong>rapy may<br />
be available for selected patients with more aggressive disease.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
529PD RANDOMIZED PHASE III IN ELDERLY PATIENTS<br />
COMPARING LV5FU2 WITH OR WITHOUT IRINOTECAN FOR<br />
1ST-LINE TREATMENT OF METASTATIC COLORECTAL<br />
CANCER (FFCD 2001-02)<br />
E. Mitry 1 , L. Venat-Bouvet 2 , J. Phelip 3 , E. Maillard 4 , J. Jouve 5 , X. Adhoute 6 ,<br />
D. Gargot 7 , M. Gasmi 8 , L. Bedenne 9 , T. Aparicio 10<br />
1 Oncologie Médicale, Institut Curie, Paris, FRANCE, 2 Oncology, CHU de<br />
Limoges, Limoges, FRANCE, 3 Gastroenterology, CHU, St-Etienne, FRANCE,<br />
4 Biostatistiques, FFCD, Dijon, FRANCE, 5 Hepatogastrolentorology Department,<br />
CHU Le Bocage, Dijon, FRANCE, 6 Gastroenterology, Hôpital Haut-Leveque,<br />
Pessac, FRANCE, 7 Gastroenterology, Centre hospitalier, Blois, FRANCE,<br />
8 Hepatogastroenterology Department, Hôpital Nord, Marseille, FRANCE, 9 FFCD,<br />
Dijon, FRANCE, 10 Gastroenterology, CHU, Avicenne, FRANCE<br />
Background: Metastatic colorectal cancer (mCRC) most frequently occurs in elderly<br />
patients (pts), but <strong>the</strong>se are less frequently treated with chemo<strong>the</strong>rapy (CT) than<br />
younger ones. We report <strong>the</strong> final results of <strong>the</strong> first phase III study in elderly pts<br />
with mCRC receiving a 5FU-based CT with or without irinotecan.<br />
Methods: Elderly pts (75+) with previously untreated mCRC were randomly<br />
assigned to receive a 5FU-based CT, ei<strong>the</strong>r alone or in combination with<br />
irinotecan (FU arms: LV5FU2 or simplified LV5FU2, IRI arms: LV5FU2-CPT11<br />
or FOLFIRI, reduced dosage for cycles 1 and 2). Stratification criteria were: center,<br />
Charlson index, Karnofsky index, previous adjuvant CT, sex, age, alkaline<br />
phosphatases. Primary endpoint was progression free survival (PFS). 240 events<br />
(282 pts) were required to demonstrate an improvement of median PFS from 5.5<br />
to 7.9 months (m) in <strong>the</strong> IRI arm (bilateral α = 5%, β = 80%). Secondary<br />
endpoints were overall survival (OS), safety, objective response rate (ORR), QOL<br />
and geriatric evaluation. Kaplan-Meier estimation, log-rank tests and Cox model<br />
(HR with 95%CI) were used.<br />
Results: Between 06/2003-05/2010, 142 pts were randomly assigned to FU and 140<br />
to IRI. Median age was similar in both arms 80 years (range 74-92). Main<br />
characteristics were well-balanced. Median duration of treatment was 3.5 m in FU<br />
and 4.5 m in IRI. At least one CT dose reduction was observed for 30.9% pts in FU<br />
and 52.6% pts in IRI. No significant difference was observed for <strong>the</strong> median PFS: FU<br />
5.2 m vs IRI 7.3 m, HR = 0.84 (0.66-1.07), p = 0.15. ORR was superior in IRI arm (p<br />
= 0.002): FU 27.4% (95% CI: 20.1-35.8) vs IRI 46.3% (95% CI: 37.6-55.1). Median<br />
OS was 14.2 m in FU vs 13.3 m in IRI, HR = 0.96 (0.75-1.24). More patients<br />
presented grade 3-4 toxicities in IRI arm (76.3% vs 52.2%), mainly neutropenia<br />
(38.5% vs 5.2% of pts), diarrhea (22.2% vs 5.2% of pts) and febrile neutropenia (6.7%<br />
vs 0.7% of pts). Toxic deaths occurred in 2 pts in each arm.<br />
Conclusion: In this elderly population, adding irinotecan to an infusional 5FU-based<br />
CT seems to increase PFS but does not improve survival and was associated with an<br />
increased toxicity.<br />
Disclosure: E. Mitry: Aventis, Pfizer: sponsor of <strong>the</strong> trial. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
530PD CAPECITABINE (CAPE) +/- BEVACIZUMAB (BEV) IN THE<br />
ADJUVANT TREATMENT OF COLORECTAL CANCER (CRC) -<br />
FIRST AND FINAL TOXICITY RESULTS FROM THE<br />
INTERNATIONAL PHASE III QUASAR2 TRIAL<br />
R.S. Midgley 1 ,S.Love 1 , V. Potter 2 , E. Segelov 3 , D.R. Ferry 4 , A. Weaver 5 ,<br />
C. Scudder 1 , P. Julier 1 , S. Grumett 6 , D.J. Kerr 7<br />
1 Department of Oncology, University of <strong>Oxford</strong>, <strong>Oxford</strong>, UNITED KINGDOM,<br />
2 Department of Oncology, Nottingham University Hospitals NHS Trust,<br />
Nottingham, UNITED KINGDOM, 3 St Vincents Clinical School, University of New<br />
South Wales, Sydney, NSW, AUSTRALIA, 4 Medical Oncology, Russells Hall<br />
Hospital, Dudley, UNITED KINGDOM, 5 Department of Oncology, <strong>Oxford</strong><br />
University Hospitals Trust, <strong>Oxford</strong>, UNITED KINGDOM, 6 Department of<br />
Oncology, Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, UNITED<br />
KINGDOM, 7 Nuffield Department of Clinical Laboratory Sciences, University of<br />
<strong>Oxford</strong>, <strong>Oxford</strong>, UNITED KINGDOM<br />
Background: Bevacizumab is an anti-VEGF antibody approved for use in metastatic<br />
colorectal cancer (CRC). However 2 trials have suggested lack of efficacy in<br />
combination with dual agent chemo<strong>the</strong>rapy in <strong>the</strong> adjuvant setting and <strong>the</strong>re has<br />
been some indication that <strong>the</strong> spectrum of toxicity may be different compared to that<br />
observed in patients with advanced disease.<br />
Methods: The international phase III trial, QUASAR2, randomised stage III and<br />
high risk stage II CRC patients who had undergone potentially curative resection to<br />
receive oral Cape (1250mg/m 2 bd, days 1-14 q 21d) alone for 6/12 or Cape (6/12)<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds397 | ix181
plus intravenous Bev(7.5mg/kg q 21d) for 12/12. This abstract overviews <strong>the</strong> final<br />
toxicity data (15/12 minimum follow up per patient) from <strong>the</strong> Q2 trial.<br />
Results: 1952 patients were consented and randomised and, after excluding patients<br />
who did not receive at least one cycle of treatment, 963 patients receiving Cape alone<br />
and 959 patients receiving Cape plus Bev were analysed. Baseline characteristics<br />
(gender / age / stage of disease) were balanced across <strong>the</strong> 2 arms. See frequency of<br />
selected toxicities, as % patients, in table below.<br />
Discussion: As expected, <strong>the</strong> rates of hypertension (all grade or high grade) and<br />
proteinuria and wound healing (all grade) were significantly higher among patients<br />
receiving Bev. Although <strong>the</strong> addition of Bev did not increase diarrhoea rates, <strong>the</strong><br />
frequency and severity of HFS was increased. This is not well recognised. Although<br />
cardiac chest pain was not increased by <strong>the</strong> addition of Bev, both arterial and venous<br />
thrombo-embolism (ATE/VTE) rates were increased although <strong>the</strong> difference only<br />
reached significance for VTE in this study. This is in contrast to most results in <strong>the</strong><br />
advanced disease setting and may be a result of an interaction between post-operative<br />
risk of VTE and pro-thrombotic potential of Bev. Of note, an excess of ‘possibly<br />
treatment-related’ deaths was found in patients receiving Bev (1.9% vs 0.8%:RR2.3:CI<br />
1.0-5.2) and this just reached significance (p = 0.05). All results will be expanded in<br />
detail in <strong>the</strong> presentation / poster.<br />
Cape/ Bev Cape RR/CI/p<br />
Hypertension (all grades) 33.4 7.8 4.3/3.4-5.4/p < 0.001<br />
Hypertension (g3/4) 3.8 0.6 6.0/2.6-14.2/p < 0.001<br />
Proteinuria (all grades) 20.5 5.1 4.0/3.0-5.4/p < 0.001<br />
Poor wound healing (all grades) 3.1 1.8 1.8/1.0-3.2/p = 0.05<br />
Diarrhoea (g3/4) 10.8 10.6 1.0/0.8-1.3/p = 0.9<br />
Hand-foot syndrome (g3/4) 26.8 20.9 1.3/1.1-1.5/p = 0.002<br />
Cardiac chest pain SAE 2.7 2.6 1.0/0.6-1.8/p = 0.9<br />
Arterial Thromboembolism SAE 1.1 0.6 1.8/0.7-5.0/p = 0.2<br />
Venous Thromboembolism SAE 4.3 2.3 1.9/1.1-3.1/p = 0.01<br />
Disclosure: R.S. Midgley: Au<strong>the</strong>r has received no strings attached educational<br />
unrestricted grant for clinical research and has sat on advisory boards for Roche.<br />
V. Potter: Au<strong>the</strong>r has received a travel grant and has sat on an advisory board for<br />
ROche. E. Segelov: Author has sat on an advisory board for Roche Autralia.<br />
D.R. Ferry: Au<strong>the</strong>r has received travel grants, research grants and has sat on advisory<br />
boards for Roche. S. Grumett: Au<strong>the</strong>r has received traval grants and has sat on<br />
advisory boards for Roche. D.J. Kerr: Au<strong>the</strong>r has received no strings attached<br />
educational unrestricted grant for clinical research and has sat on Advisory Boards<br />
for ROche. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
531P SHOULD PALLIATIVE RESECTION OF PRIMARY TUMOR BE<br />
PERFORMED IN PATIENTS WITH ADVANCED COLORECTAL<br />
CANCER? A SYSTEMATIC REVIEW & META-ANALYSIS<br />
S. Ahmed 1 , R.K. Shahid 2 , A. Leis 3 , K. Haider 1 , P. Pahwa 3<br />
1 Medical Oncology, Saskatoon Cancer Centre University of Saskatchewan,<br />
Saskatoon, SK, CANADA, 2 Medicine, University of Saskatchewan, Saskatoon,<br />
SK, CANADA, 3 Community Health & Epidemiology, University of Saskatchewan,<br />
Saskatoon, SK, CANADA<br />
Background: Colorectal cancer (CRC) is a leading cause of cancer death. Surgical<br />
resection of <strong>the</strong> primary tumor in patients with advanced CRC remains controversial.<br />
Limited data is available regarding potential benefits and risk of primary tumor<br />
resection in such patients.<br />
Objectives: To compare survival of patients with advanced CRC who underwent<br />
surgical resection of primary tumor with patients without resection. The review also<br />
aims to determine post-operative mortality & non-fatal complications rates, primary<br />
tumor complications rate (PTCR), non-resection surgical procedures rate (NSPR)<br />
and quality of life (QOL).<br />
Methods: A literature search was conducted by using CENTRAL (<strong>2012</strong>), Medline<br />
(1946-<strong>2012</strong>), and EMBASE (1947-<strong>2012</strong>). Selection Criteria: Studies involving patients<br />
with advanced colorectal adenocarcinoma who underwent primary tumor resection<br />
were selected using pre-specified eligibility criteria with restriction to publication<br />
dates from 1980, English language and human studies. Data Collection and analysis:<br />
Screening, evaluation of relevant articles and data abstraction was done in<br />
duplication and agreement was assessed. Articles that met <strong>the</strong> inclusion criteria were<br />
assessed for quality by using Ottawa-Newcastle score. Data was collected and<br />
syn<strong>the</strong>sized as per protocol.<br />
Results: Of total of 3379 reports, 15 retrospective observational studies were selected<br />
with patients population of 12456. Among 12456 patients, 8620 (69%) underwent<br />
surgery with a median overall survival of <strong>the</strong> 15.2 months (range: 10-30.7) compared<br />
with 11.4 months (range: 3-22) of <strong>the</strong> non-resection group. Hazard ratio (HR) for<br />
survival was 1.44 (95% CI: 1.26-1.64) favoring surgical intervention. Mean 30 days<br />
post-operative mortality and non-fatal complications rates were 4.9% (95% CI: 0-9.7)<br />
& 25.9% (95%CI: 20.1-31.6) respectively. Mean PTCR & NSPR in <strong>the</strong> control group<br />
were 29.7% (95%CI: 18.5-41.0) and 27.6% (95 CI: 15.4-39.9) respectively. No study<br />
provided QOL data. Sub-group analysis that were defined a priori revealed HR of<br />
1.46 (95% CI: 1.20-1.78) favoring surgical intervention in patients treated with<br />
modern chemo<strong>the</strong>rapy.<br />
Conclusions: The retrospective data favors primary tumors resection in advanced<br />
CRC. Future prospective randomized trials are warranted to confirm <strong>the</strong> findings.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
532P PTEN AND ADVANCED COLORECTAL CANCER (CRC):<br />
ANALYSIS FROM THE PHASE III AGITG MAX TRIAL OF<br />
CAPECITABINE ALONE OR IN COMBINATION WITH<br />
BEVACIZUMAB +/- MITOMYCIN C<br />
T. Price 1 , J. Hardingham 1 , C. Lee 2 , A. Townsend 1 , J. Wrin 1 , K. Wilson 2 ,<br />
A. Weickhardt 3 , R.J. Simes 2 , C. Munroe 3 , N. Tebbutt 4<br />
1 Department of Medical Oncology, The Queen Elizabeth Hospital, Woodville<br />
South, SA, AUSTRALIA, 2 CTC, University of Sydney, Sydney, NSW,<br />
AUSTRALIA, 3 Oncology, Ludwig Institute, Melbourne, VIC, AUSTRALIA,<br />
4 Medical Oncology, Austin Hospital, Heidelberg, VIC, AUSTRALIA<br />
Background: The tumour suppressor gene PTEN may have a role as a biomarker for<br />
anti-EGFR <strong>the</strong>rapy in CRC. As PTEN expression also has a relationship with VEGF<br />
expression via HIF-1 alpha, and <strong>the</strong> PI3K/mTOR pathways, we have explored <strong>the</strong><br />
potential that PTEN loss may be predictive of outcome with an anti-VEGF agent. We<br />
also assess <strong>the</strong> prognostic value of PTEN as this remains controversial.<br />
Methods: Patients enrolled in <strong>the</strong> Phase III MAX trial of capecitabine (C) +/bevacizumab<br />
(B) (+/- mitomycin C (M)) with available tissues were analysed for<br />
PTEN expression (loss v no loss) as assessed using a Taqman® copy number assay to<br />
measure copy number variation at <strong>the</strong> PTEN locus. The predictive value of PTEN<br />
status for bevacizumab efficacy was examined. PTEN status was also correlated with<br />
progression-free survival (PFS) and overall survival (OS) outcomes, and a second sub<br />
analysis grouping PTEN by KRAS/BRAF status was also performed.<br />
Results: Of <strong>the</strong> original 471 patients enrolled in <strong>the</strong> trial, tissues from 302 (64.1%)<br />
patients were analysed. Baseline characteristics of those with and without tissues were<br />
comparable. PTEN loss was observed in 38.7% of patients. There was no relationship<br />
between PTEN loss and KRAS or BRAF mutation (KRAS/BRAF MT v WT with<br />
PTEN loss; 34%/37% v 41%/39% respectively). PTEN loss was associated with rectal<br />
primary (p = 0.01) and lower rates of lung metastasis (p = 0.03). By using <strong>the</strong><br />
comparison of C v CB + CBM, PTEN status was not significantly predictive of <strong>the</strong><br />
effectiveness of B for PFS or OS (Table). PTEN status is also not prognostic for PFS<br />
or OS in multivariate analyses adjusting for o<strong>the</strong>r baseline factors (Loss v No Loss<br />
PFS HR 0.9 (0.7-1.16), OS HR 1.04 (0.79-1.38)). PTEN was also not prognostic when<br />
assessed by KRAS and BRAF status.<br />
Conclusions: PTEN status did not significantly predict different benefit with<br />
anti-VEGF <strong>the</strong>rapy. PTEN status was not prognostic for survival in advanced<br />
colorectal cancer.<br />
C vs CB + CBM Loss No loss P value (for interaction)<br />
PFS HR 0.51 0.33 - 0.79 HR 0.72 0.52-0.98 P = .26<br />
OS HR 0.75 0.47-1.19 HR 1.00 0.70-1.43 P = .35<br />
Disclosure: T. Price: Uncompensated Advisory board Merck, AMGEN and Roche.<br />
Travel grants Merck and AMGEN. N. Tebbutt: Uncompensated Ad board Roche. All<br />
o<strong>the</strong>r authors have declared no conflicts of interest.<br />
533P SOMATIC K-RAS MUTATION IS PREDICTIVE IN COLORECTAL<br />
CANCER, BUT IS IT PROGNOSTIC? A SYSTEMATIC REVIEW<br />
AND META-ANALYSIS<br />
I.B. Tan, T. Seah, S.L. Koo, S. Choo, C.K. Tham, D. Chong<br />
Medical Oncology, National Cancer Centre, Singapore, SINGAPORE<br />
Annals of Oncology<br />
Background: Consistent data from retrospective molecular analysis performed in<br />
multiple phase 3 Randomized controlled trials (RCTs) have established that somatic<br />
KRAS mutation (K-RAS-mt) is a strong predictor of non-response to anti-epidermal<br />
growth factor receptor antibody (anti-EGFR) <strong>the</strong>rapy in colorectal cancer. However,<br />
K-RAS’s role as a prognostic marker remains undefined. We performed a systematic<br />
review and meta-analysis to determine <strong>the</strong> prognostic significance of somatic K-RAS<br />
mutation.<br />
Methods: We searched MEDLINE, EMBASE, and CENTRAL databases, <strong>ESMO</strong> and<br />
ASCO meeting proceedings for Phase 3 RCTs in colorectal cancer for which<br />
retrospective molecular analysis of K-RAS mutation was performed on archival<br />
patient samples. Studies were pooled according to setting of treatment (adjuvant, 1 st<br />
line metastatic, refractory). Meta-analysis was performed using random-effects model.<br />
The outcomes of interest were disease-free survival in <strong>the</strong> adjuvant setting and<br />
overall survival (OS) for advanced disease.<br />
Results: 14 Phase 3 trials which enrolled 18,991 patients were identified, of whom<br />
13,143 had K-RAS status ascertained (69.2% range: 48%-100%) In pooled data of<br />
ix182 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
patients who did not receive anti-EGFR <strong>the</strong>rapy and had K-RAS status ascertained,<br />
patients with K-RAS-wt patients had better survival outcomes compared to<br />
K-RAS-mt patients. In <strong>the</strong> adjuvant setting (Disease Free Survival HR 0.75 95% CI:<br />
0.66-0.87, p < 0.001), 1 st line metastatic (Overall Survival: HR 0.85 (95% CI:<br />
0.76-0.96), p < 0.01) and refractory disease (Overall Survival: HR 0.75 95% CI:<br />
0.64-0.89, p < 0.01).<br />
Conclusion: Beyond being a predictive marker of non-response to EGFR antibodies,<br />
among patients with early stage, 1 st line metastatic and refractory colorectal cancer<br />
who do not receive anti-EGFR <strong>the</strong>rapy, K-RAS is a negative prognostic marker.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
534P PROGNOSTIC IMPACT OF PHOSPHO-ER-ALPHA (PER-α) IN<br />
SURGICALLY RESECTED COLON CANCER<br />
I. López Calderero 1 , A.C. Moya 2 , A.A. Gonzalez 3 , A.C. Carranza 4 , M.C. Conde 1 ,<br />
S. Molina-Pinelo 2 , M.D.P. Herrera 2 , M.L.L. Miron 1 , P.E. Garcia 1 ,<br />
R. Garcia-Carbonero 1<br />
1 Oncology Service, Hospital Virgen del Rocio, Seville, SPAIN, 2 Laboratorio de<br />
Biologia Molecular del Cancer, Instituto de Biomedicina de Sevilla, Seville,<br />
SPAIN, 3 Departamento de Anatomía Patológica, Hospital central de Asturias,<br />
Oviedo, SPAIN, 4 Pathology Department, Hospitales Universitarios Virgen del<br />
Rocio, Seville, SPAIN<br />
Background: Preclinical models and randomized clinical trials suggest a protective<br />
role for estrogens against colorectal cancer (CRC). ER-β is <strong>the</strong> prevalent estrogen<br />
receptor in normal colonic mucosa, while its expression is significantly reduced in<br />
CRC. An increased ER-α/β ratio has been documented in colon carcinomas and this<br />
is associated with increased proliferation and decreased apoptosis. The aim of our<br />
study was to evaluate <strong>the</strong> expression of activated ER-α and its prognostic<br />
implications in a series of patients with surgically resected stage II-III CRC.<br />
Methods: Phosphorylated ER-α [Ser167] expression was evaluated by<br />
immunohistochemistry (IHC) in tissue microarrays (TMA) of 218 CRC<br />
paraffin-embedded tumor samples. A pER-α score was calculated for each sample<br />
according to staining intensity and proportion of stained cells assessed by two<br />
pathologists blinded to <strong>the</strong> clinical data. Univariate and multivariate analyses were<br />
performed to assess <strong>the</strong> correlation of pER-α score with clinicopathological features<br />
and survival.<br />
Results: pER-α staining was negative in 39 tumors (18%), 1+ in 164(75%), 2+ in<br />
11(5%), and unavailable in 4(2%). Half of <strong>the</strong> samples had positive staining in<br />
>10% of tumor cells. A high pER-α score was more common in women<br />
(female:56% vs male:45%; p = 0.07), older patients (>65years:56% vs 120mg/dl:66% vs<br />
A, overall response rate (partial reponse and stable disease) was 25%<br />
for <strong>the</strong> patients with <strong>the</strong> A/A genotype, 73% for <strong>the</strong> C/A genotype and 85% for C/C<br />
(p = 0.032). Progression free survival (PFS) was 2.5 months for patients harbouring<br />
<strong>the</strong> A/A genotype compare to 8 months for <strong>the</strong> patients with A/C and C/C<br />
genotypes (p = 0.0001); overall survival was also superior for patients containing <strong>the</strong><br />
allele C genotypes (5 months for AA and 18 months for C/A and C/C); p = 0.001.<br />
For <strong>the</strong> polymorphism g.75395312G > A, <strong>the</strong> G/G genotype overall response rate was<br />
100% compare to 69% for <strong>the</strong> A/G and A/A genotypes (p = 0.048). PFS did not<br />
reach statistical significance for this polymorphism. None of <strong>the</strong> two Tag SNPs for<br />
<strong>the</strong> EREG ligand were found to correlate with response.<br />
Conclusions: AREG polimorphisms may help to identify refractory mCRC patients<br />
who will benefit from irinotecan plus anti-EGFR treatment.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
537P DIFFERENCES IN KRAS AND BRAF MUTATION PREVALENCE<br />
IN METASTATIC COLORECTAL CARCINOMA USING<br />
HIGH-SENSITIVITY TAQMELT VS ARMS-SCORPION PCR<br />
ASSAYS<br />
S. Zazo 1 , T. Caldes 2 , N. Pérez González 1 , J. Madoz 1 ,J.Satre 2 , R. Manso 1 ,<br />
D. Ferrandez 3 , T. Ramos 4 , J. Garcia-Foncillas 5 , E. Diaz-Rubio 2<br />
1 Pathology Department, Fundacion Jimenez Diaz, Madrid, SPAIN, 2 Medical<br />
Oncology, Hospital Clinico San Carlos, Madrid, SPAIN, 3 Roche Farma, Roche<br />
Farma Spain, Madrid, SPAIN, 4 Roche Diagnostics, Roche Diagnostics,<br />
Barcelona, SPAIN, 5 Oncology, Fundación Jiménez Díaz, Madrid, SPAIN<br />
Background: Activating KRAS mutations are present in approximately 35-40% of<br />
patients with metastatic colorectal cancer (mCRC) and have been significantly<br />
associated with lack of response to anti-EGFR antibody <strong>the</strong>rapies. Although current<br />
guidelines recommend testing for frequent KRAS codons 12/13 mutations (G12D,<br />
G12A, G12V, G12S, G12R, G12C and G13D), emerging data indicate that additional<br />
KRAS and BRAF mutations might be also predictive of non-responsiveness to<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds397 | ix183
anti-EGFR treatment. The present study is aimed to analyze <strong>the</strong> prevalence of<br />
Iow-frequent KRAS and BRAF V600 mutations in caucasian mCRC population.<br />
Methods: A two institution retrospective cohort of 1238 consecutive KRAS wild<br />
type mCRC patients previously studied for frequent 7 mutations in codons 12/13<br />
by <strong>the</strong> CE-IVD marked ARMS-scorpion real-time polymerase chain reaction PCR<br />
(Therascreen, Qiagen) was assayed by <strong>the</strong> diagnostic TaqMelt PCR assay cobas<br />
KRAS Mutation and cobas BRAF V600 Mutation Tests (Roche), which are<br />
designed to detect 19 mutations in KRAS codons 12, 13 and 61 (including G12F,<br />
G13C, G13R, G13S, G13A, G13V, G131, Q61H, Q61K, Q61R, Q61L, Q61E and<br />
Q61P) and BRAF V600 (V600E, V600K and V600D) mutations. DNA was<br />
obtained by cobas DNA preparation kit from one single 5um formalin-fixed<br />
paraffin-embedded tissue section. Discrepances in data are planned to confirm by<br />
next-generation sequencing.<br />
Results: In all samples, sufficient DNA was obtained for KRAS and BRAF mutational<br />
studies. Among 1238 KRAS codons 12/13 wild-type patients by ARMS-scorpion<br />
PCR, 166 (13.4%) showed KRAS mutations, 117 (9.5%) in codons 12/13, and 49<br />
(4%) in codon 61. BRAF V600 mutations were detected in 9% cases. In<br />
ARMS-scorpion PCR KRAS mutated patients, mutations were confirmed by cobas in<br />
all cases.<br />
Conclusions: The cobas Mutation Tests are robust and reproducible assays that, 1)<br />
requires a very small amount of tissue; 2) detects up to 13.4% mutations in codons<br />
12, 13 and 61 of <strong>the</strong> KRAS gene in wild-type mCRC population; and, 3) 9% of<br />
patients showed BRAF mutations in same population.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
538P THE ROLE OF COX-2 AND KI-67 OVEREXPRESSION IN THE<br />
PREDICTION OF PATHOLOGIC RESPONSE OF RECTAL<br />
CANCER TO NEOADJUVANT CHEMORADIATION THERAPY<br />
A. Taghizadeh Kermani 1 , A. Jafarian 2 , J. Esmaeili 2 , N. Mohammadian Roshan 2 ,<br />
M. Seilanian Toosi 1 , A. Omidi Ashrafi 2 , M. Karimi Shahri 2<br />
1 Oncology, MUMS, Mashhad, IRAN, 2 Pathology, MUMS, Mashhad, IRAN<br />
Background: The response to neoadjuvant chemoradio<strong>the</strong>rapy (CRT) is not <strong>the</strong><br />
same among all cases with advanced rectal cancer. Aims: In this study, we<br />
investigated <strong>the</strong> association between overexpression of two molecular markers<br />
(COX-2 and Ki-67) and tumor response to neoadjuvant <strong>the</strong>rapy. Design: A<br />
retrospective cohort study.<br />
Materials and methods: Forty five patients with stage II-III rectal carcinoma were<br />
enrolled. All patients were treated with neoadjuvant <strong>the</strong>rapy (45-50.4 Gy plus<br />
Capecitabin) between 2002 and 2009 in our institute. The pretreatment specimens<br />
were IHC stained for COX-2 and Ki-67 markers. The tumor response to neoadjuvant<br />
treatment was evaluated using a 5 point tumor regression grade (TRG) system. The<br />
induced inflammation and necrosis after chemoradio<strong>the</strong>rapy were also investigated.<br />
Statistical analysis: Statistical analysis was performed using SPSS version 11.5 and<br />
statistical significance was determined at P < 0.05.<br />
Results: The pathologic response to neoadjuvant treatment from complete response<br />
as (TRG = 1) through no response as (TRG = 5) was found in 10 (22.2%), 8 (17%), 6<br />
(13.3%), 16 (35.6%), and 5 (11.1%) cases. In comparison with poor responders<br />
(TRG: 4,5), patients with good response to neoadjuvant treatment (TRG: 1,2) were<br />
associated with lower pretreatment mean COX-2 staining extent (72.9% vs. 22.8%,<br />
P < 0.001) as well as lower mean Ki-67 staining extent ( 70.7% vs. 28.5%, p < 0.001).<br />
High COX-2 staining and high Ki-67 index were significantly associated with more<br />
inflammation. Patients with high COX-2 expression showed also significantly more<br />
necrosis in <strong>the</strong>ir postsurgical specimens.<br />
Conclusions: Overexpression of COX-2 and high Ki-67 index were associated with a<br />
poorer response to neoadjuvant chemoradio<strong>the</strong>rapy. These markers might be helpful<br />
to define those patients with rectal carcinoma who benefit more from neoadjuvant<br />
treatments.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
539P PTK7 OVEREXPRESSION IS ASSOCIATED WITH REDUCED<br />
METASTASIS-FREE SURVIVAL (MFS) IN COLORECTAL<br />
CANCER<br />
A. Gonçalves 1 , A. Lhoumeau 2 , G. Monges 3 , J. Delpero 4 , J.L. Raoul 2 , J. Borg 2<br />
1 Medical Oncology, Institut Paoli-Calmettes, Marseille, FRANCE, 2 Molecular<br />
Pharmacology, Institut Paoli-Calmettes, Marseille, FRANCE, 3 Biopathology,<br />
Institut Paoli-Calmettes, Marseille, FRANCE, 4 Surgical Oncology, Institut<br />
Paoli-Calmettes, Marseille, FRANCE<br />
Background: Protein tyrosine kinase-7 (PTK7) is a receptor tyrosine kinase (TK),<br />
with no identified natural ligand and a catalytically inactive intracellular TK domain.<br />
PTK7 expression is up-regulated in many human cancers, including colorectal cancer<br />
(CRC), but little is known about its role in cancer biology. Here, we have examined<br />
PTK7 protein expression in tumor and matched normal tissues from CRC patients<br />
by immunohistochemistry (IHC) and addressed <strong>the</strong> phenotypic impact of PTK7<br />
down-regulation in CRC cell lines.<br />
Annals of Oncology<br />
Methods: A TMA containing both tumor and matched normal tissues was built<br />
from a cohort of 192 patients with CRC collected between 1990 and 1998 at <strong>the</strong><br />
Institut Paoli-Calmettes, Marseille, France. PTK7 expression was analyzed by IHC<br />
using polyclonal goat antibody anti-CC4 (R&D systems, USA). Percentage of stained<br />
cells was measured and staining intensity was scored as 0 (absent), 1 (weak), 2<br />
(moderate) and 3 (strong). PTK7-expressing CRC cell lines were transfected with<br />
PTK7- or control- shRNA and evaluated for cell proliferation, cytotoxic-induced<br />
apoptosis and cell migration.<br />
Results: Patient population had <strong>the</strong> following characteristics: median age, 63 ys<br />
(range 29-89); sex ratio = male (52%), female (48%); site = colon (90%), rectum<br />
(10%); stage = I-III (64%), IV (36%); median follow-up = 104 months. Staining<br />
intensity (0-1 = 65% of cases, 2 = 19% of cases, 3 =16% of cases, in tumor tissues<br />
versus 0-1 = 86% of cases, 2 = 11% of cases, 3= 3% of cases, in normal tissues; p =<br />
1,91.10-8) as well as average percentage of stained cells (30% in tumor tissues versus<br />
2% in normal tissues; p = 5.74.10-14) were higher in tumor compared to normal<br />
tissues. In stage I-III population (n = 122), 5-year MFS was lower in PTK7-positive<br />
(>10% of cells stained with intensity > 2) compared to PTK7-negative CRC (54%<br />
[95%CI: 38-75%] versus 75% [95%CI: 65-88%], p = 0.034, log-rank test). This impact<br />
was maintained in multivariate analysis and similar trends were observed in overall<br />
survival, while not reaching statistical significance. In vitro, PTK7 inhibition by<br />
shRNA significantly reduced cell migration.<br />
Conclusion: PTK7 protein is overexpressed in CRC and is associated with reduced<br />
MFS, possibly due to an impact on cell migration.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
540P THE INTRA-TUMOR STROMA MICROENVIRONMENT IN<br />
THERAPY MANAGEMENT FOR COLON CANCER PATIENTS<br />
W. Mesker 1 ,V.G.Pelt 1 , H. Gelderblom 2 , V. H. Krieken 3 , D.J. Kerr 4 , R. Tollenaar 1<br />
1 Surgery, Leiden University Medical Center (LUMC), Leiden, NETHERLANDS,<br />
2 Medical Oncology, Leiden University Medical Center (LUMC), Leiden,<br />
NETHERLANDS, 3 Pathology, University Medical Center St. Radboud, Nijmegen,<br />
NETHERLANDS, 4 Dept of Clinical Pharmacology, University of <strong>Oxford</strong>, <strong>Oxford</strong>,<br />
UNITED KINGDOM<br />
There is need to identify patients with colon cancer who benefit treatment. We<br />
previously have found that <strong>the</strong> stroma-tissue surrounding cancer cells plays an<br />
important role in tumor behavior and is reported as an independent prognostic<br />
parameter. Patients with a high stroma percentage within <strong>the</strong> primary tumor have a<br />
poor prognosis. Validation of <strong>the</strong> parameter was performed in <strong>the</strong> VICTOR trial.<br />
Recently <strong>the</strong> stroma percentage in lymph nodes and metastases was found a<br />
heterogenous process. Moreover <strong>the</strong> stroma groups respond differently to<br />
chemo<strong>the</strong>rapy regimens.<br />
Methods: Tissue samples consisting of 5 µm Haematoxylin and Eosin (H&E) stained<br />
sections from <strong>the</strong> most invasive part of <strong>the</strong> primary tumor were analyzed for <strong>the</strong>ir<br />
tumor-stroma percentage. Stroma-high (>50% stroma) and stroma-low (≤50%<br />
stroma) groups were evaluated with respect to survival time and response to <strong>the</strong>rapy.<br />
For patients with and without adjuvant <strong>the</strong>rapy (CT) (n = 150) <strong>the</strong> primary tumor<br />
(PT) lymph nodes (LN) and liver metastases were analyzed.<br />
Findings: What is <strong>the</strong> profit of additional LN analysis? The CT treated stroma-low<br />
patient group showed an improved survival (5-yr OS 75% vs 83%, DFS 76% vs 83%,<br />
TTR 84% vs 100%). In <strong>the</strong> stroma-high patient group we did not notice any<br />
improvement of survival (5-yr OS 77% vs. 72%, DFS 68% vs. 68%, TTR 81% vs.<br />
77%). Which stroma group responds better to <strong>the</strong>rapy? The stroma-high group<br />
showed a better response to <strong>the</strong>rapy compared to <strong>the</strong> stroma-low group (increase<br />
5-yr OS 22% vs. 8%, DFS 18% vs. 8%, TTR 21% vs. 13%).<br />
Interpretation: The intra-tumor stroma percentage has proven to be a prognostic<br />
factor. It supports selective treatment for stroma-high and stroma-low patients.<br />
Preliminary results show that adjuvant <strong>the</strong>rapy is more efficient for patients with a<br />
high stroma percentage.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
541P THE HISTOLOGICAL IMPORTANCE OF SIGNET RING CELL<br />
AND MUCINOUS ADENOCARCINOMA ON OUTCOMES IN<br />
PATIENTS WITH COLORECTAL CANCER<br />
S. Campos-Gomez 1 , V. Rosas Camargo 1 , R.A. Ramirez Fallas 1 , J.H.<br />
Flores Arredondo 2 , L. Morales Juarez 1 , S.I. Perez Alvarez 1 ,D.<br />
Valdez Bocanegra 1 , D. Huitzil Melendez 1<br />
1 Medical Oncology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador<br />
Zubiran, Mexico DF, MEXICO, 2 Research Department, The Methodist Hospital<br />
Research Institute, Houston, TX, UNITED STATES OF AMERICA<br />
The diagnosis of signet ring cell carcinoma (SRC) and mucinous<br />
adenocarcinoma (MC) represents approximately 1% and 15% of all colorectal<br />
cancers (CRC) respectively. Both entities have an aggressive biological behavior,<br />
but SRC tends to be <strong>the</strong> worst. A retrospective revision of cases was done in our<br />
institution to evaluate <strong>the</strong> clinical relevance, including metastasic patterns and<br />
ix184 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
overall outcome of patients with a SRC and MC component in patients with<br />
colorectal cancer.<br />
Methods: Clinical charts of all patients with a diagnosis of primary CRC were<br />
reviewed between 2001 and 2011 at our institution; those with a histological<br />
component of SRC and MC adenocarcinomas were registered. The analysis of<br />
primary tumor site, stage at presentation, tumor grade, metastasic sites, symptoms<br />
and survival for each group were performed and compared.<br />
Results: A total of 530 patients with primary CRC were identified. Signet cell was<br />
accounted for in 4% of patients with colorectal cancer, 14% had MC and <strong>the</strong> rest<br />
pure adenocarcinoma (72%). Median age of diagnosis for non-signet/non-mucinous<br />
adenocarcinomas was 61 years in comparison to 47 years for mucinous and signet<br />
cell carcinoma. SRC presented at more advanced stages III/IV at diagnosis (72%)<br />
more often than mucinous (46%) and highest tumor grade (SRC, 47%; MC 28%).<br />
There was no significant difference in location of primary cancer in both histologic<br />
types, presenting principally in ascending colon (28% vs 38%) and <strong>the</strong> rectum (28%<br />
vs 26%). Patients with a component of SRC and MC metastasized in a large<br />
proportion to <strong>the</strong> peritoneum and ovaries (80%) followed by ovary and lung. The<br />
most frequent symptom was abdominal pain (57%) in both groups. SCR carcinoma<br />
had significantly worse overall five-year relative survival than MC (25% vs 60%; p <<br />
0.002). Median survival of SRC compared to mucinous was 30 vs 88 months<br />
respectively.<br />
Conclusion: SRC in colorectal cancer has a very poor prognosis in comparison to<br />
o<strong>the</strong>r histologic types. The clinical and pathologic course is outright aggressive and<br />
presents in a younger population of patients with a higher tumor grade and in more<br />
advanced stages than MC. Both groups share patterns of metastasis predominantly to<br />
peritoneum and ovaries.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
542P DOWN-REGULATION OF γ-GLUTAMYL HYDROLASE GENE<br />
EXPRESSION IN TUMOR TISSUES IS ASSOCIATED WITH<br />
RESPONSE TO ORAL URACIL AND TEGAFUR/LEUCOVORIN<br />
CHEMOTHERAPY IN PATIENTS WITH COLORECTAL CANCER<br />
S. Sadahiro1 , T. Suzuki1 , A. Tanaka1 , K. Okada1 , A. Kamijo1 , H. Nagase2 ,<br />
J. Uchida2 1<br />
Gastrointestinal Surgery, Tokai University School of Medicine, Isehara, JAPAN,<br />
2<br />
Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima,<br />
JAPAN<br />
Background: 5-Flurouracil (5-FU)/leucovorin (LV) and oral uracil and tegafur<br />
(UFT)/LV are widely used as standard adjuvant chemo<strong>the</strong>rapy for colorectal cancer<br />
(CRC). We previously reported that right-sided tumors with high thymidine<br />
phosphorylase (TP) gene expression on pre-chemo<strong>the</strong>rapy tumor biopsy are<br />
associated with a response to UFT/LV chemo<strong>the</strong>rapy in patients with CRC. In <strong>the</strong><br />
present study, we examined <strong>the</strong> relation between chemo<strong>the</strong>rapy-induced gene<br />
expression changes (post-chemo<strong>the</strong>rapy/pre-chemo<strong>the</strong>rapy gene expression ratio) in<br />
CRC tissues and <strong>the</strong> efficacy of UFT/LV treatment.<br />
Material and methods: The subjects were 73 patients with CRC who were<br />
scheduled to undergo surgery. UFT (300 mg/m 2 /day) and LV (75 mg/day) were<br />
administered for 2 weeks before surgery. We assessed pathological response based<br />
on <strong>the</strong> extent of residual cancer cells and granulation tissue. The mRNA<br />
expressions of 6 pyrimidine-related enzymes and 8 reduced folate-related enzymes<br />
were quantitatively evaluated using a RT-PCR assay in paired samples of<br />
pre-chemo<strong>the</strong>rapy tumor-biopsy specimens and post-chemo<strong>the</strong>rapy resected-tumor<br />
specimens.<br />
Results: Pathological responses were observed in 19.2% (14/73) of <strong>the</strong> patients.<br />
Gene expression of γ-glutamyl hydrolase (GGH) was generally down-regulated<br />
after chemo<strong>the</strong>rapy, and <strong>the</strong> extent of GGH down-regulation among <strong>the</strong><br />
responders was significantly greater than that among <strong>the</strong> non-responders, with<br />
<strong>the</strong> least p value of 0.0009 among <strong>the</strong> genes studied. The extent of GGH<br />
down-regulation among right-sided tumors with high sensitivity to UFT/LV<br />
chemo<strong>the</strong>rapy was significantly greater than that among left-sided tumors (p =<br />
0.0135). Moreover, on combined analysis of tumor site and sex, <strong>the</strong> extent of<br />
GGH down-regulation among left-sided tumors in men that showed low<br />
sensitivity to UFT/LV chemo<strong>the</strong>rapy was significantly smaller than that among<br />
o<strong>the</strong>rtumors(p=0.0018).<br />
Conclusion: Down-regulation of GGH gene expression in primary CRC tissues after<br />
UFT/LV chemo<strong>the</strong>rapy is associated with a response to chemo<strong>the</strong>rapy in patients<br />
with CRC.<br />
Disclosure: H. Nagase: He is an employee of Taiho Pharmaceutical Co. J. Uchida:<br />
He is an employee of Taiho Pharmaceutical Co. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
543P P16(INK4A) GENE HYPERMETHYLATION AND KRAS<br />
MUTATION ARE INDEPENDENT PREDICTORS OF FOLFIRI<br />
AND CETUXIMAB CHEMOTHERAPY IN PATIENTS WITH<br />
METASTATIC COLORECTAL CANCER (MCRC)<br />
S.H. Kim 1 , K.H. Park 2 , S.J. Shin 1 , K.Y. Lee 3 , T.I. Kim 1 , N.K. Kim 3 , S.Y. Rha 1 ,<br />
J.K. Roh 1 , J.B. Ahn 1<br />
1 Internal Medicine, Yonsei University College of Medicine, Seoul, KOREA,<br />
2 Cancer Metastasis Research Center, Yonsei Cancer Center, Yonsei University<br />
College of Medicine, Seoul, KOREA, 3 Surgery, Yonsei University College of<br />
Medicine, Seoul, KOREA<br />
Background: P16 (INK4a) inhibits cyclin dependent kinases (CDKs) and plays various<br />
roles in cancer and senescence. P16 aberrancy is frequently detected in various<br />
cancers and may contribute to multidrug resistance. Hypermethylation of CpG island<br />
of p16 occurs in a significant proportion in colorectal cancer (CRC) and also is one<br />
of <strong>the</strong> CpG island methylator phenotype (CIMP) markers.<br />
Patients and method: We analyzed tumor samples from 49 patients with metastatic<br />
colorectal cancer (mCRC) who were treated with 5-fluorouracil, leucovorin,<br />
irinotecan (FOLFIRI) and cetuximab (1st line 22 pts, 2nd line 27 pts).<br />
Pyrosequencing was used to identify KRAS mutation and hypermethylation of 6<br />
CpG island loci (p16, p14, MINT1, MINT2, MINT31, hMLH1) in DNA extracted<br />
from formalin-fixed paraffin-embedded specimens. To analyze <strong>the</strong> relation between<br />
methylation status of CIMP markers including p16 and clinical outcome, logistic<br />
regression and Cox regression were performed.<br />
Result: Hypermethylation of p16 gene was detected in 14 of 49 patients (28.6%) and<br />
was significantly associated with KRAS mutation (Fisher’s exact, P = 0.01) and CIMP+<br />
(Fisher’s exact, P = 0.002). Patients with p16 unmethylated tumors had significant<br />
longer time to progression (TTP, median 9.0 vs 3.5 months; log-rank, P = 0.001) and<br />
overall survival (OS, median 44.9 vs 16.4 months; log-rank, P = 0.008) than those with<br />
p16 methylated tumors. KRAS mutation was also associated with shortened TTP<br />
(median 8.9 vs 4.4 months; HR = 3.1, P = 0.008) and OS (median 44.9 vs 16.1 months;<br />
HR = 5.2, P < 0.0001). Patients with both KRAS and p16 aberrancy (n = 6) had<br />
markedly shortened TTP (median 2.8 months) compared with those with ei<strong>the</strong>r KRAS<br />
or p16 aberrancy (n = 11; median 8.6 months, P = 0.021) or those with nei<strong>the</strong>r of <strong>the</strong>m<br />
(n = 32; median 9.0 months, P C and c1843A > G) and two synonymous<br />
(c2221T > C and c1317C > T) common and putatively functional polymorphisms in<br />
<strong>the</strong> LRIG1 gene were selected. There were significant associations between LRIG1<br />
c1317C > T and c3158A > C polymorphisms and clinical outcome. OS was lower for<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds397 | ix185
patients harboring a T/T genotype than for patients with <strong>the</strong> C/C or C/T genotypes<br />
(p= 0.01). In <strong>the</strong> case of <strong>the</strong> c3158A > C polymorphism, patients harboring a C/C<br />
genotype had a lower OS than patients with an A/A or A/C genotypes (p = 0.047).<br />
Conclusions: In this study, we identified common germline variants in LRIG1 gene<br />
predicting clinical outcome in patients with mCRC receiving first-line<br />
oxaliplatin-based chemo<strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
545P MMP-9 AND VEGFR EXPRESSION HAS PROGNOSTIC<br />
SIGNIFICANCE AFTER RESECTION FOR PRIMARY TUMOR<br />
AND METASTATIC SITE IN COLORECTAL CANCER<br />
M.A. Lee 1 , S.T. Oh 2 , W.K. Kang 2 , S.W. Kim 3<br />
1 Medical Oncology, Seoul St. Mary’s Hospital, of <strong>the</strong> Catholic University, Seoul,<br />
KOREA, 2 Surgery, Seoul St. Mary’s Hospital, Seoul, KOREA, 3 Gastroenterology,<br />
Seoul St. Mary’s Hospital, Seoul, KOREA<br />
Background: Resection for metastatic lesion has been commonly done in stage<br />
colorectal cancer, showing better survival outcome than o<strong>the</strong>r GI malignancy.<br />
Although R0 resection in primary and metastatic lesion is done in stage IV cancer,<br />
recurrence should be developed and cure is rare. In <strong>the</strong> present study, we reviewed<br />
and analyzed <strong>the</strong> protein expression and <strong>the</strong> recurrence to determine <strong>the</strong> prognostic<br />
factor in stage IV colorectal cancer.<br />
Method: Tissue specimens from 130 patients with metastatic colorectal cancer were<br />
analyzed. All patients were diagnosed as metastatic colorectal cancer between Jan,<br />
2000 and Aug, 2008 at Seoul St. Mary’s hospital, <strong>the</strong> Catholic University. We<br />
performed immunohistochemical staining using tissue microarray for Wnt 3a, Wnt<br />
5a, VEGFR, and MMP-9. We analyzed <strong>the</strong> clinicopathological characteristics through<br />
<strong>the</strong> medical record and <strong>the</strong> association with protein expressions.<br />
Result: Of <strong>the</strong> 130 patients, Male was 78 (60%), and female was 52 (40%).<br />
Median age was 59.5 years old (range: 27-81). Colon cancer was 76 (58.5%) and<br />
rectal cancer was 54 (41.5%). 94 patients were initially diagnosed as stage IV,<br />
but took curative resection for primary lesion and metastasectomy. The o<strong>the</strong>r 36<br />
patients had recurrent disease as distant metastasis after curative surgery, and<br />
<strong>the</strong>n took metastasectomy. The Wnt 5 expression showed <strong>the</strong> tendency of<br />
positive perineural invasion (p = 0.065), but <strong>the</strong>re was no correlation between<br />
protein expression and o<strong>the</strong>r pathological factors. As a prognostic factor for<br />
recurrence, Negative MMP expression showed significantly longer time t o<br />
recurrence (TTR) than positive group (13mon vs, 10 months, p = 0.010) and<br />
VEGFR expression showed a correlation with TTR (15.7 mon for negative vs.<br />
11.1 mon for positive, p = 0.060). There was no correlation between recurrence<br />
and pathological findings such as lymphatic, vascular or perineural invasion, and<br />
o<strong>the</strong>r protein expressions.<br />
Conclusion: VEGFR and MMP-9 expression showed prognostic significance for<br />
recurrence in stage IV or recurrent colorectal cancer after metastasectomy. Unlikely<br />
<strong>the</strong> stage III colorectal cancer, pathological findings such as lymphovascular or<br />
perineural invasion did not have association with recurrence.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
546P NEUROPILIN-1 (NRP1) EXPESSION IN TUMOR METASTASIS<br />
OF PRIMARY AND COLORECTAL CANCER: IMPLICATIONS<br />
FOR ANTIANGIOGENIC THERAPY<br />
M.J. Ortiz-Morales1 , C. Morales2 , A. Gómez3 , G. Pulido4 , M.T. Cano Osuna5 ,<br />
J. Jiménez6 , P. Sánchez6 , M. Medina7 , J. De La Haba Rodriguez8 ,E.<br />
Aranda Aguilar8 1<br />
Medical Oncology, Hospital Universitario Reina Sofía, Córdoba, SPAIN,<br />
2<br />
Medicine University, Department of Cell Biology, Physiology and Immunology,<br />
Córdoba, SPAIN, 3 Medical Oncology, Hospital Reina Sofía, Córdoba, SPAIN,<br />
4<br />
Medical Oncology, Universitary Hospital Reina Sofía, Córdoba, SPAIN,<br />
5<br />
Oncologia Medica, Hospital Universitario Reina Sofia, Cordoba, SPAIN,<br />
6<br />
Medical Oncology, Universitay Hospital Reina Sofia, Córdoba, SPAIN,<br />
7<br />
Pathological Anatomy, Universitary Hospital Reina Sofía, Córdoba, SPAIN,<br />
8<br />
Medical Oncology, Reina Sofía Hospital. Biomedical Research Institute (IMIBIC),<br />
Cordoba, SPAIN<br />
Introduction and objective: Vascular development is critical in tumor biology and<br />
targeted <strong>the</strong>rapies against angiogenesis process have proven <strong>the</strong>ir <strong>the</strong>rapeutic efficacy.<br />
Neuropilin-1 (NPR1), a membrane glycoprotein that works as a receptor for<br />
semaphorins, is also a co-receptor for VEGF-A165 and it is expressed in endo<strong>the</strong>lial<br />
cells and in many o<strong>the</strong>r tumors. Very few studies about this protein in primary and<br />
secondary tumors have been reported with contradictory conclusions 1,2 . The aim of<br />
this study is to analyze <strong>the</strong> relationship between <strong>the</strong> expression of NRP1 in colorectal<br />
cancer patients in primary tumor and metastases and clinical and pathologic features,<br />
treatment response, progression-free interval and overall survival.<br />
Patients and methods: From 1995 to 2010, 70 patients with available biological<br />
material in paraffin of primary tumor and metastases (liver and/or lung) have been<br />
selected. NRP1 expression was performed using immunohistochemistry with<br />
Annals of Oncology<br />
neuropilin-1 Rabbit Monoclonal Antibody Catalog # 2621-1 (ATOM) at 1:75<br />
dilution. Vascular endo<strong>the</strong>lium was used as positive control and tumor sample<br />
without antibody as negative control. Clinical and pathological data of patients,<br />
treatments administered, toxicity, response, progression-free interval and overall<br />
survival were registered.<br />
Results: The mean age of patients was 63 years. 51 patients (85%) were<br />
adenocarcinoma and 46 patients (76%) were moderately differentiated. 34 patients<br />
(56.7%) presented metastatic disease at <strong>the</strong> moment of primary tumor diagnosis.<br />
NRP1 expression exists in 100% (120) of samples analyzed.<br />
Conclusions: In our study, in contrast to latest published data 2 , no differences about<br />
intensity and frequency of expression of NRP1 were found between primary and<br />
metastatic samples. It is not possible to establish any relationship between tumor<br />
response to treatment and evolution. References: 1. Parikh AA, Fan F, Liu WB, et al.<br />
Neuropilin-1 in human colon cancer: expression, regulation, and role in induction of<br />
angiogenesis. Am J Pathol 2004;164:2139-51. 2. Jubb AM, Strickland LA, Liu SD,<br />
Mak J, Schmidt M, Koeppen H. Neuropilin-1 expression in cancer and development.<br />
J Pathol <strong>2012</strong>;226:50-60.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
547P PROGNOSTIC SIGNIFICANCE OF COMBINED POSITIVITY OF<br />
LYMPHATIC, VASCULAR, AND PERINEURAL INVASION<br />
(TRIPLE POSITIVE) IN STAGE II/III COLORECTAL CANCER; A<br />
NEW PARADIGM WORTH TO INVESTIGATE?<br />
F. Dane 1 , M.A. Ozturk 1 , M. Koçar 1 , B.M. Atasoy 2 , B. Aktas 1 , F. Telli 1 ,<br />
M. Kanıtez 1 , M. Bes¸irog˘ lu 1 , P.F. Yumuk 1 , S.N. Turhal 1<br />
1 Internal Medicine Dpt., Medical Oncology Div., Marmara University Faculty of<br />
Medicine, Istanbul, TURKEY, 2 Radiation Oncology Dpt., Marmara University<br />
Faculty of Medicine, Istanbul, TURKEY<br />
Background: Despite <strong>the</strong> studies showing <strong>the</strong> impact of each lymphatic, vascular or<br />
perineural invasion on prognosis separately, <strong>the</strong> exact effect of <strong>the</strong>se parameters in<br />
toge<strong>the</strong>r (triple positive) on prognosis is not known. In this study, we assessed <strong>the</strong><br />
pathological features and <strong>the</strong> survival outcomes of triple positive colorectal cancer<br />
patients.<br />
Methods: The files of stage II/III colorectal cancer (CRC) patients (n = 532) who<br />
received adjuvant systemic treatment following curative resection in our center were<br />
analyzed, retrospectively. Tumors with vascular, lymphatic, and perineural invasions<br />
were called triple positive (TP), all o<strong>the</strong>rs were called non-triple positive (NTP)<br />
tumors. Patients with unknown vascular, lymphatic or perineural invasion status (n<br />
= 93) were excluded from <strong>the</strong> analysis. Adjuvant <strong>the</strong>rapy was consisted of ei<strong>the</strong>r<br />
fluorouracil or oxaliplatin-based chemo<strong>the</strong>rapy (CT) regimens. Rectal cancer patients<br />
were given adjuvant radiation <strong>the</strong>rapy also. Survival was determined using <strong>the</strong><br />
Kaplan-Meier method, with differences determined by multivariate analysis using <strong>the</strong><br />
Cox multiple hazards model. Results were compared using <strong>the</strong> log-rank test.<br />
Results: A total of 439 patients (243 male: 196 female) with stage II/III colorecral<br />
cancer who received adjuvant <strong>the</strong>rapy were evaluated retrospectively. The median age<br />
was 60 (range: 23–84 years). Median follow-up was 36 months. Fifteen percent of <strong>the</strong><br />
patients were TP. The rate of TP tumors were 4%, 13,6%, and 29% in T2, T3, and T4<br />
tumors, respectively (p:0.001). The rate of TP tumors were 5,6%, 13,9%, and 40,5%<br />
in N0, N1, and N2 tumors, respectively (p:0.0001). There were no relation between<br />
TP tumors rates and age, gender or tumor localization (p > 0.05). Five years DFS and<br />
OS rates were 37,7% vs 64,7% (p:0.0001) and 53,4% vs 78,1% (p:0.0001) for TP and<br />
NTP tumors, respectively.<br />
Conclusion: Our findings revealed that patients with TP tumors have inferior<br />
survival outcomes when compared to NTP tumors. However results of multivariate<br />
analyses for DFS and cancer specific OS did not support <strong>the</strong> preanalysis hypo<strong>the</strong>sis<br />
of TP being a poor prognostic sign in early stage CRC patients. Never<strong>the</strong>less, we<br />
believe that accurate answer to this question can be given via retrospective analysis of<br />
prospectively collected data from multi-center clinical trials.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
548P MUTATION OF EITHER RAS OR BRAF CORRELATES WITH<br />
MGMT METHYLATION AND MUTATION OF PIK WITH PTEN<br />
METHYLATION, BUT NONE OF THESE IS ASSOCIATED WITH<br />
STAGE IN COLORECTAL CANCER<br />
B. Metzger1 , M.A. Dicato2 , G. Mahon3 , S. Obertin3 , J. Kayser3 1<br />
Laboratory, Foundation for Research on Cancer, Luxembourg, LUXEMBOURG,<br />
2<br />
Hematology-Oncology, Hospital Centre of Luxembourg, LUXEMBOURG,<br />
3<br />
Foundation for Research On Cancer, Hospital Centre of Luxembourg,<br />
LUXEMBOURG<br />
Background: In a previous study of 222 patients we showed how epigenetic and<br />
genetic changes during oncogenic progression could possibly explain <strong>the</strong> adenomacarcinoma<br />
sequence: first, methylation of promoters of H-cadherin gene followed by<br />
MGMT methylation, K-ras oncogene G to A point mutations, activation of B-raf<br />
gene by a V600E mutation finally methylation of E-cadherin. (ASCO 2011,<br />
ix186 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
abstr.3608) We extended <strong>the</strong> study by examining PTEN, PIK exon 9 and 20 for<br />
mutations and methylation and correlated all <strong>the</strong> genes to tumor stage. We divided<br />
TNM into early stage I & II and late III & IV.<br />
Method: Ethical approval was obtained. DNA was extracted from tumor samples<br />
obtained from CRC patients by resection. The PTEN methylation was analyzed by<br />
methylation-specific PCR. and analyzed by gel electrophoresis after Sybr green<br />
staining and UV-photography.<br />
Results: Data were available for 117 patients. Correlation coefficients were calculated<br />
and <strong>the</strong>ir significance assessed using Chi-squared: RAS/BRAF ei<strong>the</strong>r mutant (mut)<br />
with late stage, P = 0.123 (suggestive), RAS/BRAF ei<strong>the</strong>r mut with MGMT<br />
methylated, P = 0.017 (significant); PIK mut with PTEN methylated, P = 0.044<br />
(significant); and PIK mut with CDH13 methylated, P = 0.123 (suggestive).<br />
Concerning RAS/BRAF and stage, 86% of RAS/BRAF ei<strong>the</strong>r mut tumours, were late<br />
stage, while only 53% of wild type (wt) tumors were late stage. For RAS/BRAF and<br />
MGMT, 76% of RAS/BRAF ei<strong>the</strong>r mut were MGMT methylated, but 53% of wt<br />
tumors were methylated. PIK mut tumors were also PTEN methylated, and CDH13<br />
methylated. Results are tumor specific as all blood controls were unmethylated resp.<br />
wt.<br />
Conclusion: With PIK, PTEN and CDH13 no significant correlation was noted<br />
with ei<strong>the</strong>r MGMT unmethylated or methylated nor with RAS/BRAF ei<strong>the</strong>r wt or<br />
mut. RAS/BRAF correlated significantly with MGMT (p = 0.017), methylated PIK,<br />
PTEN and CDH13 did not correlate with early or late stage. There was a<br />
tendency, of RAS/BRAF mut to be associated with late stage. Of all <strong>the</strong>se markers<br />
none correlates in a significant fashion with early or late stages and as of now,<br />
despite multiple genetic and epigenetic data sets, no predictive statement can be<br />
made.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
549P PROGNOSTIC ROLE OF KRAS MUTATIONS DETECTED BY<br />
HIGH-SENSITIVITY TAQMELT PCR ASSAY IN METASTATIC<br />
COLORECTAL CANCER<br />
J. Garcia Foncillas 1 , S. Zazo 2 , C. Carames 1 , G. Serrano 1 , A. Leon 1 , A. Campos 3 ,<br />
J.I. Martin-Valades 1 , C. Cañadas 2 , T. Hernandez-Guerrero 1 , F. Rojo 2<br />
1 Department of Oncology, University Hospital “Fundacion Jimenez Diaz”, Madrid,<br />
SPAIN, 2 Pathology, Hospital Universitario. Fundación Jimenez Diaz, Madrid,<br />
SPAIN, 3 Department of Oncology, Hospital Infanta Elena, Madrid, SPAIN<br />
Background: KRAS mutation is present in approximately 35-40% of patients with<br />
metastatic colorectal cancer (mCRC) and has been established as a predictive marker<br />
of resistance to anti-EGFR <strong>the</strong>rapy, but its role as prognostic factor is not yet clear.<br />
This study is aimed to analyze <strong>the</strong> prevalence and <strong>the</strong> impact in prognosis of<br />
expanded number of KRAS mutations in caucasian mCRC population and <strong>the</strong><br />
sensitivity of <strong>the</strong> TaqMelt PCR assay cobas KRAS Mutation Test.<br />
Methods: A single institution retrospective cohort of 669 consecutive mCRC patients<br />
between 2000-9 with clinical follow-up was studied for frequent 7 mutations in<br />
codons 12/13 by ARMS-scorpion real-time PCR (Therascreen, Qiagen) and TaqMelt<br />
PCR assay cobas KRAS Mutation Test (Roche), which are designed to detect 19<br />
mutations in KRAS codons 12, 13 and 61. DNA was obtained by cobas DNA<br />
preparation kit (Roche) from one single 5um FFPE tissue section and by QIAamp<br />
DNA FFPE Tissue Kit (Qiagen) from 50um of tissue.<br />
Results: KRAS mutation was detected by <strong>the</strong> cobas KRAS Mutation Test in 41.2%<br />
of mCRC patients and was correlated with poor overall survival (OS) (p = 0.013),<br />
OS from <strong>the</strong> metastatic diagnosis for metachronous disease (p = 0.025), disease-free<br />
survival for metastatic disease (p = 0.012) and time to progression (p = 0.046).<br />
KRAS mutation was significantly associated with tumor grade (p = 0.025) and liver<br />
as first site of dissemination (p = 0.047). However, KRAS mutations detected by<br />
Therascreen did not impact on prognosis. The median of DNA concentration<br />
obtained by cobas and QIAamp was 120ng/ul and 80ng/ul, respectively. The<br />
frequency of invalid cases was 5.7% (cobas) and 17.9% (Therascreen). Finally,<br />
cobas identified 19.2% additional KRAS mutations not detected by Therascreen.<br />
Next Generation Sequencing by 454 GS FLX+ System analysis is ongoing to<br />
validate discrepant mutations.<br />
Conclusions: The cobas KRAS Mutation Test is a robust and reproducible assay that,<br />
1) obtains superior DNA recovery from very small amount of FFPE tissue; 2) detects<br />
up to 19.2% of mutations not detected by o<strong>the</strong>r methods; and, 3) KRAS mutations<br />
detected by cobas correlate with poor outcome in mCRC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
550P TP, TS AND DPD AS POTENTIAL PREDICTORS OF OUTCOME<br />
FOLLOWING CAPECITABINE PLUS OXALIPLATIN (XELOX) VS.<br />
BOLUS 5-FLUOROURACIL/LEUCOVORIN (5-FU/LV) AS<br />
ADJUVANT THERAPY FOR STAGE III COLON CANCER:<br />
UPDATED BIOMARKER FINDINGS FROM STUDY NO16968<br />
(XELOXA)<br />
H. Schmoll1 , J. Tabernero2 , J.A. Maroun3 , F. De Braud4 , T. Price5 ,E.Van<br />
Cutsem6 , M. Hill7 , S. Hoersch8 , K. Rittweger9 , D. Haller10 1 2<br />
Internal Medicine, University Clinic Halle (Saale), Halle, GERMANY, Medical<br />
Oncology, Vall d’Hebron University Hospital, Barcelona, SPAIN, 3 Medical<br />
Oncology, The Ottawa Hospital Regional Cancer Centre, Ottawa, ON, CANADA,<br />
4<br />
Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano,<br />
Milano, ITALY, 5 Oncology, The Queen Elizabeth Hospital, Adelaide, SA,<br />
AUSTRALIA, 6 Digestive Oncology, University Hospital Gasthuisberg/Leuven,<br />
Leuven, BELGIUM, 7 Medical Oncology, Kent Oncology Centre, Maidstone,<br />
UNITED KINGDOM, 8 Biostatistics, Dr. Manfred Köhler GmbH; working on behalf<br />
of Roche PDBB (Biostatistics), Freiburg, GERMANY, 9 Global Development,<br />
Hoffmann-La Roche Inc., Nutley, NJ, UNITED STATES OF AMERICA,<br />
10<br />
Hematology/oncology, University of Pennsylvania, Philadelphia, PA, UNITED<br />
STATES OF AMERICA<br />
Background: In NO16968, XELOX was superior in terms of disease-free survival<br />
(DFS) and overall survival (OS) to bolus 5-FU/LV as adjuvant <strong>the</strong>rapy for stage III<br />
colon cancer [Schmoll et al. ASCO GI <strong>2012</strong>]. Three key enzymes appear to have <strong>the</strong><br />
potential to predict efficacy and/or safety of fluoropyrimidine-based treatment:<br />
thymidine phosphorylase (TP), thymidylate synthase (TS), and dihydropyrimidine<br />
dehydrogenase (DPD). We evaluated <strong>the</strong> association between baseline TP, TS and<br />
DPD and outcome (DFS and OS).<br />
Methods: Patients (pts) with stage III colon cancer received ei<strong>the</strong>r XELOX (8 cycles,<br />
24w) or bolus 5-FU/LV (Mayo Clinic, 6 cycles, 24w; Roswell Park, 4 cycles, 32w).<br />
The primary study endpoint was DFS; secondary endpoints included OS. TP, TS and<br />
DPD expression levels were determined in formalin-fixed, paraffin-embedded tissues<br />
by RT-PCR, and <strong>the</strong> median used as a cut-off point: high (above median) vs. low<br />
(below median).<br />
Results: The biomarker population included 498 (26%) of 1886 pts entered (XELOX,<br />
n = 242; 5-FU/LV, n = 256). Baseline demographics, tumour characteristics, cancer<br />
history and efficacy (DFS and OS) were similar to those in <strong>the</strong> main study<br />
population. Cox regression analysis for DFS is shown in <strong>the</strong> table. In <strong>the</strong> XELOX<br />
group pts with low tumour DPD and TP levels and a high TP/DPD ratio appeared<br />
to have significantly better DFS; this effect was not observed with 5-FU/LV.<br />
XELOX 5-FU/LV<br />
Covariate<br />
(high vs. low) HR 95% CI p value HR 95% CI p value<br />
DPD 2.45 1.55–3.86 0.0001 0.69 0.47–1.00 NS<br />
TP 1.73 1.10–2.72 0.0186 0.81 0.55–1.18 NS<br />
TS 0.90 0.58–1.40 NS 0.91 0.62–1.33 NS<br />
TP/DPD ratio 0.54 0.34–0.86 0.0091 0.76 0.51–1.13 NS<br />
Conclusions: These exploratory findings suggest that low tumour levels of DPD may<br />
be predictive for XELOX efficacy when given as adjuvant <strong>the</strong>rapy in pts with resected<br />
stage III colon cancer. There was no correlation between DPD levels and outcome in<br />
<strong>the</strong> 5-FU/LV group. These data raise <strong>the</strong> possibility of predictive markers for XELOX<br />
but, until validated prospectively, would currently not have a role in treatment<br />
decisions.<br />
Disclosure: H. Schmoll: Consultant or Advisory Board: Roche Research Funding:<br />
Roche. J. Tabernero: Consultant or Advisory Board: Roche. J.A. Maroun:<br />
Consultant or Advisory Board: Roche. Honoraria: Roche. Research Funding: Roche.<br />
F. De Braud: Honoraria: Roche. T. Price: Consultant or Advisory Board: Roche. E.<br />
Van Cutsem: Research Funding: Roche. M. Hill: Consultant or Advisory Board:<br />
Roche. Honoraria: Roche. Research Funding: Roche. S. Hoersch: Employed by Dr.<br />
Manfred Köhler GmbH/Roche. K. Rittweger: Employed by Hoffmann-La Roche<br />
Inc. D. Haller: Consultant or Advisory Board: Roche. Honoraria: Roche. Research<br />
Funding: Roche.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds397 | ix187
551P ADJUVANT CHEMOTHERAPY (AC) USE AND OUTCOMES IN<br />
STAGE II COLON CANCER (CC) WITH VS. WITHOUT POOR<br />
PROGNOSTIC FEATURES<br />
A. Kumar, H. Kennecke, H. Lim, R. Woods, D. Renouf, C. Speers, W. Cheung<br />
Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, CANADA<br />
Background: AC is frequently considered in patients (pts) with “high risk” stage II<br />
CC, defined by <strong>the</strong> presence of >/ = 1 poor prognostic features: obstruction or<br />
perforation, T4 stage,
Annals of Oncology<br />
(Siemens Syngo Via Oncology) and manual measurement of <strong>the</strong> LD (RECIST 1.1)<br />
and <strong>the</strong> LOD. Agreement between <strong>the</strong> tumor volume algorithm and volumetry for<br />
each rater and <strong>the</strong> corresponding inter rater agreement (IA) were investigated using<br />
Bland-Altman (BA) plots. Agreement between <strong>the</strong> RECIST-based and<br />
volumetry-based relative changes was quantified by intraclass correlation (ICC)<br />
where 1.0 would indicate perfect agreement.<br />
Results: 222 target lesions from 25 pts were measured at 99 TAs. BA plots indicated<br />
that <strong>the</strong> volume algorithm showed negligible constant bias for both raters (rater 1,<br />
0.09 with p = 0.25, and rater 2 -0.05 with p = 0.41). IA with regard to <strong>the</strong> volumetry<br />
showed a smaller constant bias (-0.16 with p = 0.17) compared with <strong>the</strong> volume<br />
algorithm (-0.31 with p = 0.04). The relative change in tumor size between baseline<br />
and first TA was investigated. The ICCs for RECIST-based versus volumetry-based<br />
relative changes for <strong>the</strong> 2 raters were 0.79 and 0.62. Application to mCRC patients<br />
from <strong>the</strong> CRYSTAL (n = 1198) and OPUS (n = 337) studies showed <strong>the</strong> ICCs for<br />
RECIST-based versus volume algorithm-based relative changes to be 0.60 and 0.77.<br />
Conclusions: The algorithm for estimating <strong>the</strong> tumor volume was validated as<br />
demonstrated by <strong>the</strong> negligible bias and <strong>the</strong> BA plots. The moderate ICCs for early<br />
changes in tumor size in <strong>the</strong> 25 Munich pts and those from <strong>the</strong> CRYSTAL and<br />
OPUS studies indicate clear differences between RECIST- and volume-based TAs and<br />
suggest that RECIST underestimates both tumor shrinkage and tumor growth.<br />
Disclosure: R. Laubender: RPL receives travel support and research funding by Merck<br />
KGaA. U. Sartorius: The author is an employee of Merck KGaA. M. Schlichting: The<br />
author is an employee of Merck KGaA. S. Stintzing: The author receives: Honoraria<br />
and travel support from Merck Serono and Roche AG Honoraria from Amgen GmbH.<br />
A. Graser: The author declares that he is a member of <strong>the</strong> Siemens speakers’ bureau<br />
and that he receives grant money from Bayer Pharma. V. Heinemann: The author<br />
declares: Honoraria (lectures) from Merck, Roche, Sanofi Honoraria (Ad Boards) from<br />
Merck, Roche, Sanofi Research support from Merck, Roche, Sanofi.<br />
555P EFFICACY AND SAFETY OF BEVACIZUMAB IN METASTATIC<br />
COLORECTAL CANCER (MCRC): FIRST-LINE ANALYSIS OF<br />
POOLED DATA FROM RANDOMIZED CONTROLLED TRIALS<br />
(RCTS)<br />
F.F. Kabbinavar 1 , H.I. Hurwitz 2 , N.C. Tebbutt 3 , B.J. Giantonio 4 , Z. Guan 5 ,<br />
L. Mitchell 6 , D. Waterkamp 7 , J. Tabernero 8<br />
1 Thoracic Oncology and Kidney Cancer Programs, David Geffen School of<br />
Medicine at UCLA, Los Angeles, CA, UNITED STATES OF AMERICA, 2 Division<br />
of Hematology and Oncology, Duke University Medical Center, Durham, NC,<br />
UNITED STATES OF AMERICA, 3 Austin Health, University of Melbourne,<br />
Melbourne, VIC, AUSTRALIA, 4 The Abramson Cancer Center, University of<br />
Pennsylvania, Philadelphia, PA, UNITED STATES OF AMERICA, 5 Cancer Center,<br />
Sun Yatsen University, Guangzhou, CHINA, 6 Global Medical Affairs Biometrics,<br />
F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, 7 Global Medical Affairs,<br />
F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, 8 Medical Oncology /<br />
Gastrointestinal Tumors Group, Vall d’Hebron University Hospital / VHIO,<br />
Barcelona, SPAIN<br />
Background: Bevacizumab (BV) with chemo<strong>the</strong>rapy (CT) is a standard treatment for<br />
mCRC. This analysis pooled individual patient data from <strong>the</strong> clinical databases of six<br />
RCTs (phase 2 or 3) of BV to fur<strong>the</strong>r define clinical outcomes with first-line<br />
treatment, including within subgroups.<br />
Methods: Patient data were pooled from first-line (AVF2107, NO16966, ARTIST,<br />
AVF2192, AVF0780, AGITG MAX) mCRC trials of BV. All analyses were based on<br />
<strong>the</strong> intent-to-treat population. Overall and progression-free survival estimates (OS,<br />
PFS) were calculated by Kaplan-Meier methods. To assess differences in time to<br />
response variables by treatment arm (CT vs BV + CT), stratified random (overall)<br />
and fixed (subgroup comparisons) models were used to estimate pooled hazard ratios<br />
(HRs) and 95% confidence intervals (CIs), with each study included as a stratum.<br />
Overall: BV + CT vs CT<br />
HR (95% CI) P value<br />
OS 0.81 (0.70 − 0.93) .0034<br />
PFS<br />
Subgroup comparisons: BV + CT vs<br />
CT<br />
0.58 (0.46 − 0.73)
experienced significantly more ≥ grade 2 neurotoxicity (51.2% vs. 12.5%, P = 0.001)<br />
(Table-1). Neurotropin was <strong>the</strong> only factor that affected <strong>the</strong> incidence of ≥ grade 2<br />
neurotoxicity in <strong>the</strong> Kaplan-Meier log rank and <strong>the</strong> multivariate Cox proportional<br />
hazards regression analysis.<br />
Conclusion: Neurotropin combined with oxaliplatin decreases chronic neurotoxicity<br />
effectively and safely.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
557P A RANDOMIZED, CONTROLLED TRIAL OF CETUXIMAB PLUS<br />
CHEMOTHERAPY FOR PATIENTS WITH KRAS WILD-TYPE<br />
UNRESECTABLE COLORECTAL LIVER-LIMITED METASTASES<br />
J. Xu, L. Ye, L. Ren, Y. Wei<br />
Department of General Surgery, Zhongshan Hospital Fudan University,<br />
Shanghai, CHINA<br />
Background: To assess <strong>the</strong> effect of cetuximab combined with chemo<strong>the</strong>rapy in<br />
first-line treatment for unresectable colorectal liver metastases (CLM).<br />
Methods: After resection of <strong>the</strong> primary focus, patients (pts) with non-resectable<br />
synchronous liver-limited metastases from wild-type KRAS colorectal cancer were<br />
randomly assigned to received chemo<strong>the</strong>rapy (FOLFIRI or mFOLFOX6) plus<br />
cetuximab (arm A) or chemo<strong>the</strong>rapy alone (arm B). The primary end point was <strong>the</strong><br />
rate of secondary resection for liver metastases. Secondary end points included tumor<br />
response and survival.<br />
Results: From June 2008 to December 2011, 116 pts were eligible (59 in arm A and<br />
57 in arm B). The 3-year overall survival (OS) rate and median survival time (MST)<br />
of <strong>the</strong> total pts was 32% and 27.5 months (mo), respectively. R0 resection rate for<br />
liver metastases was 30.5% (18/59) in arm A and 8.8% (5/57) in arm B, with<br />
significant difference (Odds ratio = 4.57, p< .01). In R0 resected 18 pts from arm A,<br />
<strong>the</strong> median disease free survival and MST was 11.4 and 46.6 mo. The pts in arm A<br />
had improved objective response (OR, 66.1% v 33.3%, Odds ratio = 3.90, p< .01),<br />
increased 3-year OS rate (43% v 21%, p= .01) and prolonged MST (32.8 v 22.8 mo,<br />
HR =0.49, p= .01) compared with those in arm B. Fur<strong>the</strong>rmore, for <strong>the</strong> pts without<br />
liver surgery, people from arm A also got more survival benefit than those from arm<br />
B on 3-year OS rate (25% v 17%, p= .047), MST (28.2 v 21.2 mo, HR =0.55, p= .047)<br />
and progressives free survival (8.3 v 5.2 mo, HR =0.64, p= .03). In addition, in arm<br />
A, pts who experienced resection of liver metastases were significantly improved<br />
3-year OS rate (74% v 25%, p= .02) and MST (46.6 v 28.2 mo, HR = 0.29, p= .02)<br />
than those without liver surgery, and <strong>the</strong> pts harboring BRAF wild-type tumors<br />
gained more benefit on MST (35.8 v 23.4 mo, HR =0.39, p= .045) ra<strong>the</strong>r than on OR<br />
( 70.0% v 44.4%, Odds ratio = 2.92, p > .05), when compared to those with mutated<br />
BRAF tumors.<br />
Conclusion: For initially unresectable CLM population with KRAS wild-type,<br />
cetuximab combined with chemo<strong>the</strong>rapy could improve resectability of liver<br />
metastases, response rates and survival compared with chemo<strong>the</strong>rapy alone<br />
(ClinicalTrials.gov number NCT01564810).<br />
Disclosure: All authors have declared no conflicts of interest.<br />
558P UNDERSTANDING THE VALUE OF RESPONSE AND EARLY<br />
TUMOUR SHRINKAGE (ETS) IN PTS WITH WT KRAS MCRC<br />
TREATED WITH PANITUMUMAB (P) PLUS FOLFOX (F)<br />
J. Douillard 1 , S. Siena 2 , J. Tabernero 3 , M. Peeters 4 , C. Davison 5 , S. Braun 6 ,<br />
R. Sidhu 7<br />
1 Medical Oncology, Centre René Gauducheau (ICO) Institut de Cancerologie de<br />
l’Ouest, Nantes, FRANCE, 2 Department of Medical Oncology, Ospedale<br />
Niguarda Ca’ Granda, Milan, ITALY, 3 Oncology Department, Vall d’Hebron<br />
University HospitalMedical Oncology Service, Barcelona, SPAIN, 4 Department Of<br />
Medical Oncology, University Hospital Antwerp, Antwerp, BELGIUM,<br />
5 Biostatistics, Amgen Ltd., Uxbridge, UNITED KINGDOM, 6 Medical<br />
Development, Amgen (Europe) GmbH, Zug, SWITZERLAND, 7 Medical<br />
Development, Amgen Inc., Thousand Oaks, UNITED STATES OF AMERICA<br />
Introduction: In clinical trials, tumour response is considered clinically<br />
meaningful when a lesion shrinks by ≥30%, according to RECIST (ORR). It<br />
has been purported that in pts with WT KRAS mCRC treated with an<br />
anti-EGFR mAb, both ORR and ETS (week 8 [W8]; ≥20%) predict improved<br />
OS compared with standard treatment. We explore <strong>the</strong> validity of <strong>the</strong>se<br />
hypo<strong>the</strong>ses.<br />
Methods: Using final analysis data from PRIME, we calculated median OS and PFS<br />
in pts with WT KRAS mCRC who did or did not achieve: a RECIST response (≥/<<br />
30%); or ETS (≥/ < 20%) at W8. We calculated <strong>the</strong> binary correlation coefficients<br />
(Phi) for <strong>the</strong> association between meeting <strong>the</strong> above shrinkage criteria at W8 (yes/<br />
no) and OS at 2 years.<br />
Results: Consistent with <strong>the</strong> previously published finding that ORR is higher with P<br />
+ F vs F, at W8 more pts treated with P + F (vs F) had a RECIST response (Table).<br />
Irrespective of treatment arm, median OS and PFS were significantly longer in pts<br />
who achieved ei<strong>the</strong>r ETS or a RECIST response (vs pts who did not; Table). Pts<br />
Annals of Oncology<br />
receiving P + F (vs F) showed longer median OS and PFS in each shrinkage group.<br />
OS trends favoured <strong>the</strong> P arm for pts achieving ETS (vs F alone; Table). However,<br />
outcomes were similar between arms in pts that achieved a RECIST response at W8.<br />
The correlation coefficients between meeting <strong>the</strong> ≥30% or ≥20% criterion and OS at<br />
2 years were 0.21 and 0.27, respectively.<br />
Conclusions: Regardless of treatment arm, pts achieving a RECIST response<br />
(≥30%) or ETS (≥20%) at W8 demonstrated improved PFS and OS compared<br />
with those who did not. Trends toward longer OS were observed in pts treated<br />
with P + F achieving ETS compared with F alone. Potential imbalances in<br />
post-protocol anti-EGFR mAb use and resection rate limit <strong>the</strong> interpretation of<br />
ORR in predicting OS. The poor Phi values found in PRIME between W8<br />
tumour shrinkage and 2-year OS suggest that ORR and ETS alone in <strong>the</strong><br />
first-line treatment of mCRC are inappropriate surrogates for predicting OS.<br />
FOLFOX Panitumumab + FOLFOX<br />
Annals of Oncology<br />
significantly improved survival with an acceptable toxicity profile. However, more<br />
evidence is needed that current treatment options are tolerable and efficacious in<br />
older pts. Here, we assessed efficacy and safety according to age in <strong>the</strong> ML18147<br />
study.<br />
Methods: Pts with unresectable, histologically confirmed mCRC who progressed
functioning scales. Exploratory analyses included <strong>the</strong> change from baseline QoL<br />
scores by severity of skin reactions, <strong>the</strong> change in reported symptoms from baseline<br />
according to tumor response and treatment, and <strong>the</strong> effect of symptomatic status at<br />
baseline on response and survival.<br />
Results: QoL was evaluable in 627/666 pts (94%) with KRAS wild-type<br />
tumors, 52% received FOLFIRI, and 48% FOLFIRI plus cetuximab. No<br />
significant differences for GHS/QoL (p = 0.12) and social functioning scores<br />
(p = 0.43) were found between <strong>the</strong> treatment arms. In pts receiving cetuximab,<br />
<strong>the</strong>meanchangefrombaselineinGHS/QoLwas3.00inptswithoutskin<br />
reactions compared with -1.09 and -0.51 in those with grade I and grade<br />
II-IV early skin reactions, respectively. Social functioning score worsened in<br />
pts with no skin reactions (mean -6.41) compared with a slight improvement<br />
in those with grade I (mean 1.64) and grade II-IV (mean 1.48) early skin<br />
reactions, respectively. Tumor response was higher (58% vs 40%, p = 0.0002)<br />
and survival longer (hazard ratio 1.68, p < 0.0001) in asymptomatic versus<br />
symptomatic pts at baseline. FOLFIRI plus cetuximab increased tumor<br />
response in symptomatic (65% vs 52%, p = 0.0388) and asymptomatic pts at<br />
baseline (52% vs 31%, p = 0.0034), and in pts whose tumors had responded,<br />
maximum symptom relief from baseline occurred earlier (8 vs 16 weeks)<br />
compared with FOLFIRI alone.<br />
Conclusions: Adding cetuximab to FOLFIRI improved clinical outcome without<br />
negatively impacting on QoL, improving response despite baseline symptoms<br />
and leading to earlier symptom relief in pts whose tumors had responded.<br />
Symptom status at baseline was demonstrated to be a useful prognostic factor<br />
in mCRC.<br />
Disclosure: C. Köhne: The author reports honoraria from Pfizer and Merck KGaA.<br />
G. Folprecht: The author reports consultant/advisory roles for Merck KGaA, Roche<br />
and BMS, honoraria from Merck KGaA, Pfizer, Roche and Novartis and research<br />
funding from Merck KGaA. P. Rougier: The author reports, in relation to <strong>the</strong> topic<br />
concerned, honoraria for three years from Merck KGaA for participation at scientific<br />
boards and symposia. D. Curran: The author acted as a consultant (on statistical and<br />
QoL analysis) for Merck KGaA. U. Sartorius: The author is an employee of Merck<br />
KGaA. I. Griebsch: At <strong>the</strong> time of this research, <strong>the</strong> author was an employee of<br />
Merck KGaA. E. Van Cutsem: The author has received research funding from Merck<br />
KGaA. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
562P BEVACIZUMAB BEYOND PROGRESSION: HOW TO MONITOR<br />
TREATMENT EFFICACY? RESULTS OF A FUNCTIONAL<br />
IMAGING STUDY IN MURINE COLORECTAL CANCER<br />
L. Heijmen 1 , E.E.G.W. Ter Voert 2 , C.J.A. Punt 3 , L. De Geus-Oei 4 , A. Heerschap 2 ,<br />
J. Bussink 5 , V. Zerbi 2 , W.J.G. Oyen 6 , O. Boerman 4 , H.W.M. van Laarhoven 3<br />
1 Medical Oncology, Radboud University Medical Centre, Nijmegen,<br />
NETHERLANDS, 2 Radiology, Radboud University Medical Centre, Nijmegen,<br />
NETHERLANDS, 3 Department of Medical Oncology, Academic Medical Center,<br />
Amsterdam, NETHERLANDS, 4 Nuclear Medicine, Radboud University Medical<br />
Centre, Nijmegen, NETHERLANDS, 5 Radiation Oncology, Radboud University<br />
Medical Centre, Nijmegen, NETHERLANDS, 6 Department of Nuclear Medicine,<br />
Radboud University Nijmegen Medical Centre, Nijmegen, NETHERLANDS<br />
Introduction: The BRiTE study suggested that bevacizumab beyond progression to<br />
first line <strong>the</strong>rapy is beneficial for survival in advanced stage colorectal cancer.<br />
However, since response to bevacizumab cannot always be predicted by tumor size<br />
measurements, we studied utility of several functional imaging modalities to assess<br />
efficacy of bevacizumab beyond progression (BBP).<br />
Methods: 26 BALB/c nude mice with s.c. LS174T xenografts (diameter >0.4 cm)<br />
were treated with daily capecitabine (200 mg/kg), weekly oxaliplatin (3mg/kg) and<br />
2x/weekly bevacizumab (5 mg/kg). Tumor volume was assessed using caliper<br />
measurements. Tumors were considered progressive on <strong>the</strong> treatment regimen when<br />
volume was ≥1.5 times initial volume at 2 succeeding measurements. In 13 mice<br />
bevacizumab treatment was continued (BBP group), while <strong>the</strong> control group received<br />
saline injections. Within 3 days after progression, imaging was performed: FDG-PET,<br />
diffusion weighted imaging (DWI), T2*, dynamic contrast enhanced MRI<br />
(DCE-MRI). Measurements were repeated 7 and 10 days after <strong>the</strong> first<br />
measurements. Linear mixed models were used to assess differences between <strong>the</strong> 2<br />
groups over time. After <strong>the</strong> last measurement, tumors were snap-frozen and<br />
immunohistochemically examined for 9F1 (vasculature), glucose transporter 1<br />
(GLUT-1), carbonic anhydrase IX (CAIX) and Ki67 (proliferation) expression.<br />
Results: Tumor growth after progression was more pronounced in <strong>the</strong> control group<br />
(p < 0.01). FDG-PET showed a trend towards higher FDG uptake in <strong>the</strong> control<br />
group (p = 0.08). DWI, T2* and DCE-MRI parameters were not significantly<br />
different in <strong>the</strong> 2 groups. Immunohistochemical analyses showed a trend towards<br />
lower Ki67 expression (fraction 0.027 vs 0.041 p = 0.05) and higher CAIX fraction<br />
(0.21 vs. 0.10 p < 0.01) in <strong>the</strong> BBP group. The relative vascular area was lower in <strong>the</strong><br />
BBP group (0.029 vs. 0.042 p = 0.03). Vascular density (104 vs. 127 vessels/mm 2 p=<br />
0.16) and GLUT-1 expression (0.08 vs 0.11 p = 0.48) did not significantly differ.<br />
Conclusion: Bevacizumab after progression had significant effects on tumor<br />
microenvironment. FDG-PET may be a sensitive functional imaging technique to<br />
assess <strong>the</strong> effects of bevacizumab.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
563P SKIN RASH AND OUTCOME IN COLORECTAL CANCER (CRC)<br />
PATIENTS TREATED WITH ANTI-EGFR MONOCLONAL<br />
ANTIBODIES<br />
F. Petrelli 1 , K.F. Borgonovo 2 , M. Cabiddu 3 , M. Ghilardi 4 , M. Cremonesi 3 ,<br />
F. Maspero 3 , S. Barni 3<br />
1 UO Oncologia, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio, ITALY,<br />
2 Medical Oncology Division, A.O. Treviglio-Caravaggio, Treviglio, ITALY, 3 Medical<br />
Oncology Division, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio, ITALY,<br />
4 Medical Oncology Division, A.O. Trevilgio-Caravaggio, Treviglio, ITALY<br />
Introduction: The most common toxicity associated with anti-EGFR monoclonal<br />
antibodies (MoAbs) is an acneiform rash, that occurs in nearly all patients. One<br />
of <strong>the</strong> more interesting and useful clinical observations regarding EGFR-targeted<br />
<strong>the</strong>rapy has been <strong>the</strong> association of clinical benefit with development of skin<br />
rash. We have performed a systematic review and a pooled analysis of <strong>the</strong><br />
predictive value of skin rash for patients with advanced CRC treated with<br />
cetuximab (C) and panitumumab (P) in prospective clinical trials or in<br />
retrospective case series.<br />
Materials and methods: We searched PubMed and ASCO Meetings for<br />
publications reporting <strong>the</strong> correlation of skin rash with survival and/or response<br />
rate. The lower limit date for <strong>the</strong> search was February 11,<strong>2012</strong> with no upper<br />
limit. The primary outcome was overall survival as a function of severity of<br />
cutaneous toxicity in patients treated with C or P (OS). Secondary endpoints were<br />
<strong>the</strong> predictive role of skin rash for progression free survival/time to progression<br />
and response rate (ORR).<br />
Results: Fourteen publications (for a total of 3,833 patients) were included in this<br />
meta-analysis. All included studies enrolled patients with advanced disease. For <strong>the</strong><br />
primary endpoint (OS) 11 trials had available data; <strong>the</strong> occurrence of skin rash was<br />
significantly associated with reduced risk of death in patients treated with C or P<br />
(HR 0.51, P < 0.00001). For <strong>the</strong> association of risk of progression with skin rash (data<br />
available from 5 trials) <strong>the</strong> HR was significant too (HR 0.58, P < 0.00001). According<br />
to response rate analysis (15 trials available) skin rash was a significant predictor of<br />
activity with a RR of 2.23 (P < 0.00001) for patients with toxicity compared to<br />
patients with no or low-grade toxicity. ORR was 35% compared with 13% for<br />
high-grade compared to low-grade skin toxicity arms. The results appear similar for<br />
C and P trials for all <strong>the</strong> endpoints.<br />
Conclusion: Skin rash represents an early predictive biomarker of response, however<br />
<strong>the</strong> prognostic value of this event is presently unknown.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
564P QUALITY-ADJUSTED SURVIVAL IN PATIENTS WITH<br />
WILD-TYPE (WT) KRAS METASTATIC COLORECTAL CANCER<br />
(MCRC) RECEIVING FIRST-LINE THERAPY WITH<br />
PANITUMUMAB PLUS FOLFOX VERSUS FOLFOX ALONE<br />
J. Wang 1 , Z. Zhao 2 , B. Barber 2 , J. Zhang 1 , B. Sherrill 3 , S. Braun 4 , R. Sidhu 5 ,<br />
M. Gallagher 2 , J. Douillard 6<br />
1 Biostatistics, RTI Health Solutions, Research Triangle Park, NC, UNITED<br />
STATES OF AMERICA, 2 Global Health Economics, Amgen Inc., Thousand<br />
Oaks, CA, UNITED STATES OF AMERICA, 3 Biometrics, RTI Health Solutions,<br />
Research Triangle Park, NC, UNITED STATES OF AMERICA, 4 Amgen (Europe)<br />
GmbH, Zug, SWITZERLAND, 5 Department of Clinical Research, Amgen Inc.,<br />
Thousand Oaks, CA, UNITED STATES OF AMERICA, 6 Medical Oncology, Centre<br />
René Gauducheau (ICO) Institut de Cancerologie de l’Ouest, St Herblain,<br />
FRANCE<br />
Background: Panitumumab plus FOLFOX significantly improved progression-free<br />
survival (PFS) in patients with WT KRAS mCRC. The objective of this analysis was<br />
to use <strong>the</strong> quality-adjusted time without symptoms of disease or toxicity of treatment<br />
(Q-TWiST) method to compare quality-adjusted survival between <strong>the</strong> treatment<br />
arms.<br />
Methods: Patients with mCRC were randomized to panitumumab plus FOLFOX or<br />
FOLFOX alone in a phase III clinical trial. For each treatment arm, <strong>the</strong> area under<br />
<strong>the</strong> survival curve, which was estimated using <strong>the</strong> Weibull distribution, was<br />
partitioned into health states: toxicity (TOX), time without symptoms of disease<br />
progression or toxicity (TWiST, i.e., PFS minus TOX), and relapse period (REL, i.e.,<br />
overall survival (OS) minus PFS); and adjusted using utility weights derived from<br />
patient-reported EuroQoL 5-dimensions measures. The null hypo<strong>the</strong>sis of no<br />
difference between treatment groups was tested based on <strong>the</strong> normal approximation<br />
with standard errors calculated by <strong>the</strong> bootstrap method. Sensitivity analyses were<br />
performed using <strong>the</strong> standard Q-TWiST approach with means restricted to median<br />
OS.<br />
Results: Of 1,183 patients who were randomly assigned, 1,096 patients (93%) had<br />
available tumor KRAS status, of which 656 patients (60%) had WT KRAS tumors<br />
(panitumumab plus FOLFOX, n = 325; FOLFOX alone, n = 331) and were included<br />
in this analysis. Compared to patients treated with FOLFOX alone, <strong>the</strong> panitumumab<br />
plus FOLFOX group had significantly longer quality-adjusted PFS (8.5 versus 7.2<br />
months, respectively; 1.3 additional quality-adjusted months; p = 0.02) and<br />
quality-adjusted OS (22.4 versus 18.6 months; 3.8 additional quality-adjusted<br />
ix192 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
months; p = 0.04). When analysis was restricted to 24 months follow-up, <strong>the</strong><br />
Q-TWiST advantage was smaller but still significant (14.0 versus 13.0 months; 1.0<br />
additional quality-adjusted month; p = 0.04).<br />
Conclusions: This Q-TWiST analysis showed that in patients with previously<br />
untreated WT KRAS mCRC, panitumumab plus FOLFOX significantly improved <strong>the</strong><br />
duration of <strong>the</strong> quality-adjusted survival compared with FOLFOX alone.<br />
Disclosure: J. Wang: The study was funded by Amgen Inc. Z. Zhao: Employed and<br />
stock owner of Amgen Inc. B. Barber: Employed and stock owner of Amgen Inc. J.<br />
Zhang: The study was funded by Amgen Inc. B. Sherrill: The study was funded by<br />
Amgen Inc. S. Braun: Employed and stock owner of Amgen Inc. R. Sidhu: Employed<br />
and stock owner of Amgen Inc. M. Gallagher: Employed and stock owner of Amgen<br />
Inc. J. Douillard: The study was funded by Amgen Inc.<br />
565P BEVACIZUMAB (BEV) + CHEMOTHERAPY (CT) BEYOND FIRST<br />
PROGRESSION IN PATIENTS (PTS) WITH METASTATIC<br />
COLORECTAL CANCER (MCRC) PREVIOUSLY TREATED WITH<br />
BEV-BASED THERAPY: OVERALL SURVIVAL SUBGROUP<br />
FINDINGS FROM ML18147<br />
J.M. Vieitez de Prado 1 , C. Borg 2 , D. Arnold 3 , R. Greil 4 , E.J.D. Van Cutsem 5 ,<br />
R. von Moos 6 , J. Bennouna 7 , I. Reyes-Rivera 8 , B. Bendahmane 9 , S. Kubicka 10<br />
1 Medical Oncology, Hospital Central de Asturias (HUCA), Oviedo, SPAIN,<br />
2 Medical Oncology, University Hospital Besançon, Besançon, FRANCE,<br />
3 Medical Oncology, Hubertus Wald Tumor Center, University Cancer Center<br />
Hamburg (UCCH), Hamburg, GERMANY, 4 Oncology Centre, III Medizinische<br />
Universitätsklinik Salzburg, Salzburg, AUSTRIA, 5 Digestive Oncology, University<br />
Hospital Gasthuisberg, Leuven, BELGIUM, 6 Medical Oncology, Kantonal<br />
Hospital Graubünden, Chur, SWITZERLAND, 7 Medical Oncology, Institut de<br />
Cancérologie de l’Ouest, Nantes, FRANCE, 8 Statistics, Genentech Inc., South<br />
San Francisco,CA, UNITED STATES OF AMERICA, 9 GPS Oncology,<br />
F. Hoffmann-La Roche, Basel, SWITZERLAND, 10 Internal Medicine, Cancer<br />
Center Reutlingen, Reutlingen, GERMANY<br />
Background: ML18147 evaluated <strong>the</strong> benefit of continuing BEV + standard CT as<br />
second-line (2L) treatment for pts with mCRC progressing after first-line (1L)<br />
BEV-containing <strong>the</strong>rapy. Here we report results of pre-specified subgroup and<br />
exploratory KRAS mutation analyses.<br />
Methods: Pts with unresectable, histologically confirmed mCRC progressing within 3<br />
mo after discontinuing 1L BEV were randomised to 2L fluoropyrimidine + oxaliplatin<br />
or irinotecan (crossed over from 1L) ± BEV (2.5 mg/kg/wk equivalent). The primary<br />
endpoint was overall survival (OS). Subgroup analyses for OS were performed using<br />
<strong>the</strong> same statistical method as for <strong>the</strong> primary analysis.<br />
Results: 409 pts were randomised to BEV + CT and 411 to CT (1 pt not treated).<br />
Median OS was 11.2 mo for BEV + CT vs 9.8 mo for CT (unstratified HR = 0.81;<br />
95% CI 0.69–0.94; p = 0.0062). Subgroup analyses for OS were generally consistent<br />
with <strong>the</strong> overall population (Table). While <strong>the</strong> treatment effect in female pts<br />
appeared to be lower, <strong>the</strong> treatment-gender interaction test was not statistically<br />
significant.<br />
Category Subgroup N HR for OS 95% CI<br />
All All 819 0.81 0.69–0.94<br />
Gender Female<br />
294 0.99 0.77–1.28<br />
Male<br />
525 0.73 0.60–0.88<br />
Age 9mo 369 0.73 0.58–0.92<br />
First-line chemo<strong>the</strong>rapy Oxaliplatin-based 343 0.79 0.62–1.00<br />
Irinotecan-based 476 0.82 0.67–1.00<br />
Time from last BEV dose ≤42 d<br />
630 0.82 0.69–0.97<br />
>42d 189 0.76 0.55–1.06<br />
Liver metastases only No<br />
592 0.81 0.67–0.97<br />
Yes<br />
226 0.79 0.59–1.05<br />
No. of organs with metastasis 1<br />
307 0.83 0.64–1.08<br />
>1<br />
511 0.77 0.64–0.94<br />
KRAS mutation data were available from an exploratory analysis in 616 pts (75%);<br />
median OS for KRAS wild-type (WT) pts was 15.4 mo for BEV + CT vs 11.1 mo<br />
for CT (HR = 0.69, 95% CI 0.53–0.90; p = 0.0052); in KRAS mutant (MT) pts<br />
median OS was 10.4 vs 10.0 mo, respectively (HR = 0.92; 95% CI 0.71–1.18; p =<br />
0.4969). Median PFS for KRAS WT pts was 6.4 mo for BEV + CT vs 4.5 mo for<br />
CT (HR = 0.61; 95% CI 0.49–0.77; p < 0.0001); in KRAS MT pts median PFS was<br />
5.5 vs 4.1 mo, respectively (HR = 0.70; 95% CI 0.56–0.89; p = 0.0027). No<br />
treatment interaction by KRAS status was seen for OS (p = 0.1266) or PFS (p =<br />
0.4436).<br />
Conclusions: ML18147 showed that BEV + CT continued beyond progression<br />
significantly improves survival vs CT alone. Findings from <strong>the</strong> subgroup analyses for<br />
OS were generally consistent with <strong>the</strong> overall population.<br />
Disclosure: J.M. Vieitez de Prado: Involved in corporate-sponsored trials for Roche.<br />
D. Arnold: Consultant / Advisory Board: Roche. Honoraria: Roche. Research<br />
funding: Roche. R. Greil: Honoraria: Roche Research support: Roche. E.J.D. Van<br />
Cutsem: Research funding: Roche. R. von Moos: Consultant/advisory board: Roche.<br />
Honoraria: Roche. Research funding: Roche. J. Bennouna: Consultant / advisory<br />
board: Roche. Honoraria: Roche. I. Reyes-Rivera: Employed by Genentech Inc. B.<br />
Bendahmane: Employed by F. Hoffmann-La Roche. S. Kubicka: Consultant /<br />
advisory board: Roche. Honoraria: Roche. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
566P RANDOMIZED PHASE II STUDY OF OXALIPLATIN AND S-1<br />
(OS) VERSUS OXALIPLATIN AND CAPECITABINE (XELOX) IN<br />
PATIENTS WITH METASTATIC OR RECURRENT COLORECTAL<br />
CANCER<br />
D.Y. Zang 1 , I.J. Chung 2 ,H.Oh 3 , K.U. Park 4 , K.H. Lee 5 , B. Han 1 , D.R. Choi 1 ,H.<br />
S. Kim 1 , J.H. Kim 1<br />
1 Internal Medicine, Hallym University Medical Center Hallym University College of<br />
Medicine, Anyang, KOREA, 2 Medical Oncology, Chonnam National University<br />
Hwasun Hospital, Jeollanamdo, KOREA, 3 Internal Medicine, Gangneung Asan<br />
Hospital, Gangneung, KOREA, 4 Internal Medicine, Dongsan Medical Center,<br />
Keimyung University, Daegu, KOREA, 5 Internal Medicine, Yeungnam University<br />
Hospital, Daegu, KOREA<br />
Background: Combination oxaliplatin and S-1 (OS) or oxaliplatin and capecitabine<br />
(XELOX) chemo<strong>the</strong>rapy have shown significant efficacy in advanced colorectal<br />
cancer. To evaluate those efficacy and safety, we performed a randomized phase II<br />
study in patients with metastatic or recurrent colorectal cancer.<br />
Methods: Eligible patients were those who had measurable lesions and had no<br />
previous history of chemo<strong>the</strong>rapy except adjuvant chemo<strong>the</strong>rapy. Eight-eight patients<br />
were randomly assigned to receive oxaliplatin 130 mg/m 2 was administered<br />
intravenously on day 1 and S-1 80 mg/m 2 (OS, arm A) or capecitabine 2,000 mg/m 2<br />
(XELOX, arm B) was administered orally on days 1-14. Cycles were repeated every<br />
21 days. Patients were treated until proved to have disease progression or<br />
unacceptable toxicity. The primary endpoint of <strong>the</strong> study was to assess <strong>the</strong> overall<br />
response rate (ORR).<br />
Results: Characteristics of <strong>the</strong> patients were well-balanced between arms, except for<br />
primary disease site, where <strong>the</strong> percentage of colon, rectosigmoid, and rectum were<br />
42%, 16%, and 42% (arm A) and 58%, 22%, and 20% (arm B), and number of<br />
metastatic organs, where <strong>the</strong> percentage of less than 1 and more than 2 were 53%<br />
and 47% (arm A) and 67% and 33% (arm B). A total of 284 cycles (median 6, range<br />
1-39) in Arm A; 298 cycles (median 5, range 1-19) in arm B were administered.<br />
Eighty-three (41 for arm A and 42 for arm B) patients were evaluated for toxicity<br />
and response. The main toxicities were thrombocytopenia [grade 1/2/3/4 = 8/10/7/1<br />
patients (A); 10/10/7/5 (B)], neutropenia [grade 1/2/3/4 = 9/8/1/0 (A); 8/12/5/2 (B)],<br />
anemia [grade 1/2/3/4 = 21/13/3/1 (A); 20/11/4/0 (B)], peripheral neuropathy [grade<br />
1/2/3 = 11/10/0 (A); 11/8/3 (B)], and hand-foot syndrome [grade 1/2/3 = 2/0/0 (A);<br />
7/1/2 (B)]. There were 3 CR, 11 PR, 25 SD and 2 PD (A); 5 CR, 13 PR, 16 SD and 7<br />
PD (B). The confirmed ORR in <strong>the</strong> intention-to-treat population was 32.6% (95% CI:<br />
18.6-47.4%) in arm A and 40.0% (95% CI, 25.0-55.0%) in arm B. The median time<br />
to progression was 6.7 (95% CI, 4.8-8.7) months (A) and 8.0 (95% CI, 6.3-9.6)<br />
months (B). The median survival time was 19.0 (95% CI, 7.6-30.5) months (A) and<br />
22.1 (95% CI, 17.9-26.3) months (B).<br />
Conclusion: These data suggest that both OS and XELOX regimens are active and<br />
are well tolerated regimens in patients with metastatic or recurrent colorectal cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
567P NEOADJUVANT MULTIDISCIPLINARY PHASE II STUDY<br />
(BRANCH) OF AN EARLY BEVACIZUMAB SCHEDULE PLUS<br />
CHEMO-RADIATION THERAPY IN RECTAL CANCER:<br />
EFFICACY, SAFETY, AND BIOMARKERS<br />
A. Avallone, E. Di Gennaro, L. Aloj, P. Delrio, B. Pecori, F. Tatangelo, A. Petrillo,<br />
V.R. Iaffaioli, S. Lastoria, A. Budillon<br />
Gastrointestinal Oncology, National Cancer Institute of Naples, Fondazione G.<br />
Pascale, Naples, ITALY<br />
Background: In BRANCH study we assess <strong>the</strong> safety and efficacy of an experimental<br />
schedule of early (4 days before) bevacizumab (BEV) added to neoadjuvant<br />
chemo<strong>the</strong>rapy (CT) and radio<strong>the</strong>rapy (RT) in poor-risk locally advanced rectal<br />
cancer (pLARC) patients (pts) and explore <strong>the</strong> potential of circulating endo<strong>the</strong>lial<br />
cells (CECs) and tumor lesion glycolysis (TLG) as surrogate markers of pathological<br />
response(PR).<br />
Patients and methods: 46 pts (cT4, cN + , cT3≤ 5 cm from <strong>the</strong> anal verge and/or<br />
positive circumferential margin, M1 resectable) received 3 biweekly courses of<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds397 | ix193
oxaliplatin (100 mg/m 2 )/raltitrexed (2.5 mg/m 2 ) on day 1, and 5-FU (800 mg/<br />
m 2 )/folinic acid (250 mg/m 2 ) on day 2 during pelvic RT (45 Gy). BEV (5 mg/kg)<br />
was given biweekly 4 days before beginning of CT/RT for 2 courses. Toxicity<br />
was graded with NCI-CTC v.3. PR was defined using Mandard tumor regression<br />
grade (TRG). According to <strong>the</strong> Simon’s two-stage design, assuming an<br />
hypo<strong>the</strong>sis of a 50% TRG1 (complete tumor regression) (α error = 0.05, β error<br />
= 0.20), at least 6/16 TRG1 should be obtained to continue accrual to 46 pts.<br />
CECs and TLG were evaluated at baseline (BL) on day 10 and before surgery,<br />
by flow cytometry and FDG-PET, respectively. Statistical analysis was by<br />
Mann-Whitney test.<br />
Results: We obtained 23 TRG1 (50%), 14 TRG2 (30%) and 8 TRG3-4 (17%).<br />
Grade ¾ neutropenia was <strong>the</strong> most common adverse event (13/46 pts, 28%).<br />
TLG reduction on day 10 vs BL was significantly higher in responders TRG1-2<br />
compared to non-responders TRG3-4 pts (median -72%, range -90% + 31% vs<br />
-38%, range -45% + 25%; p < 0.05). Median CECs at BL were higher in TRG1-2<br />
vs TRG3-4 pts (median 0.22/µl, range 0-3.98 vs 0/µl, range 0-0.174; p = 0.009).<br />
Moreover, in TRG1-2 pts CECs were significantly reduced on day 10 vs BL<br />
(median 0.014/µl, range 0-2.29; p = 0.002). This pattern was not seen in TRG3-4<br />
pts with a tendency toward increased levels (median 0.316/µl, range 0-2.64; p =<br />
0.097). In both TRG 1-2 and TRG 3-4 preoperative CECs and PET-CT studies<br />
were not predictive of PR.<br />
Conclusions: Current scheme of BEV plus CT and RT appears safe and active,<br />
yielding high rate of TRG1 and TRG2 responses in pLARC. Early FDG-PET and<br />
CECs evaluation emerged as potential biomarkers for treatment selection to be<br />
incorporated in design of future studies with this regimen. CEP and citochine data<br />
will be provided at <strong>the</strong> meeting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
568P SAFETY AND EFFICACY OF INTRAVENOUS CETUXIMAB (CET)<br />
AND HEPATIC ARTERY INFUSION OF IRINOTECAN,<br />
5-FLUOROURACIL AND OXALIPLATIN IN PATIENTS WITH<br />
UNRESECTABLE LIVER METASTASES FROM WT KRAS<br />
COLORECTAL CANCER (CRC): RESULTS FROM OPTILIV<br />
EUROPEAN PHASE II TRIAL<br />
F. Levi 1 , V. Boige 2 , P. Rougier 3 , M. Hebbar 4 , D. Smith 5 , C. Focan 6 ,<br />
R. Guimbaud 7 , C. Carvalho 8 , M. Bouchahda 1 , M. Ducreux 2<br />
1 Chrono<strong>the</strong>rapy Unit, Medical Oncology Department, Inserm, U776, Paul<br />
Brousse Hospital, Villejuif, FRANCE, 2 Oncologie Digestive, Institut de<br />
Cancérologie Gustave Roussy, Villejuif, FRANCE, 3 Digestive Oncology, Hopital<br />
European George Pompidou, Paris, FRANCE, 4 Department: Unité D’oncologie<br />
Médicale, CHRU de Lille - Hôpital Huriez, Lille, FRANCE, 5 Oncologie Digestive,<br />
Hôpital Saint André, Bordeaux, FRANCE, 6 Département D’oncologie,<br />
CHC-Clinique Saint-Joseph, Liege, BELGIUM, 7 Oncologie Médicale, CHU<br />
Toulouse Purpan, Toulouse Cedex, FRANCE, 8 Unidade de Oncologia, Hospital<br />
Prof. Doutor Fernando Fonseca, Amadora, PORTUGAL<br />
Background: Hepatic artery infusion (HAI) of chronomodulated (Chrono)<br />
irinotecan (I), 5-Fluorouracil (F) and oxaliplatin (O), or flat O combined with<br />
intravenous (iv) F-Leucovorin allowed secondary metastases resections and prolonged<br />
survival in patients (pts) with CRC liver metastases despite prior failure of iv<br />
chemo<strong>the</strong>rapy (Bouchahda, Cancer 2009; Goere, Ann Surg 2010).<br />
Purpose: To prospectively evaluate safety and efficacy of combining iv Cet with HAI<br />
of IFO in pts with CRC liver metastases.<br />
Methods: This Phase II trial involved pretreated pts with unresectable CRC liver<br />
metastases receiving iv Cet (500 mg/m 2 ) and Chrono or Conventional (Conv) HAI<br />
of I (180 mg/m 2 ), F (2800 mg/m 2 ), and O (85 mg/m 2 ) q2 weeks. Liver metastases<br />
were resected whenever adequately downstaged.<br />
Results: Accrual of 64 pts (42 M, 22F; age, 33-76 years; 4 ongoing) was<br />
complete at 9 centers (4 countries) on 13/03/<strong>2012</strong>. In 62 monitored pts: PS 0/1/<br />
2 (61/36/3%), bilobar liver lesions (84%), a median of 9 metastases (1-50; largest<br />
diameter, 54 mm; range, 15-172) involving a median of 6 segments (1-8). Pts<br />
received one (44%), two (30%) or three (26%) prior iv chemo<strong>the</strong>rapy lines. A<br />
median of 5 courses (1-13) was given to 59 pts (Chrono, 18; Conv, 41; 3 never<br />
treated), with artery occlusion as main cause of withdrawal (53%). Main grade<br />
3-4 toxicities per pt were neutropenia (39%), abdominal pain (25%), fatigue<br />
(17%), diarrhea (15%), and nausea (10%). Grade 3 sensory neuropathy occurred<br />
in 3% of <strong>the</strong> pts. Intent-to-treat objective tumor response rate was 45% [95%<br />
CL,31-59], including 2 radiological complete responses. Disease control rate was<br />
83%. Per-protocol secondary liver surgery rate was 33.3% [20.4-46.2]. One pt<br />
had pathologic complete response in 24/25 metastases in all liver segments (1-6<br />
cm) and has been disease-free for 25+ months and alive at 38+ months. Median<br />
progression-free survival (41 events) was 9.1 months [6.5-11.6]. Preliminary<br />
median survival (19 events) is 28.6 months [16.3-40.9].<br />
Conclusions: The combination of intravenous cetuximab with triplet HAI<br />
chemo<strong>the</strong>rapy offers a safe and highly effective treatment option for patients with<br />
chemo<strong>the</strong>rapy- refractory CRC liver metastases. Support: ARTBC International,<br />
Villejuif; Merck-Serono & Pfizer (France).<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
569P SOMORE TRIAL: COMBINING SORAFENIB (SOR) WITH<br />
CAPECITABINE (CAP) YIELDS HIGHLY ENCOURAGING<br />
SURVIVAL RESULTS AND ELEVATED METABOLIC RESPONSE<br />
RATE IN CHEMOREFRACTORY METASTATIC COLORECTAL<br />
CANCER (MCRC)<br />
A. Deleporte 1 , A. Hendlisz 1 , T. Delaunoit 2 , R. Marechal 3 , M. Peeters 4 ,<br />
S. Holbrechts 5 , M. van den Eynde 6 , G. Houbiers 7 , M. Moreau 8 , P. Flamen 9<br />
1 Medical Oncology, Institut Jules Bordet, Brussels, BELGIUM,<br />
2 Gastroenterology, Entité Jolimontoise, La Louviere, BELGIUM, 3 Service<br />
Médico-Chirurgical de Gastroentérologie, Hopital Universitaire Erasme, Brussels,<br />
BELGIUM, 4 Medical Oncology, Universitair Ziekenhuis Antwerpen, Antwerpen,<br />
BELGIUM, 5 Medical Oncology, Hopital Ambroise Pare, Mons, BELGIUM,<br />
6 Medical Oncology, Cliniques universitaires St-Luc, Brussels, BELGIUM,<br />
7 Gastroenterology, Hopital Saint Joseph, Liege, BELGIUM, 8 Data Center, Institut<br />
Jules Bordet, Brussels, BELGIUM, 9 Nuclear Medicine, Institut Jules Bordet,<br />
Brussels, BELGIUM<br />
Background: Several phases I and II trials including mCRC and metastatic breast<br />
cancer patients have suggested an interesting clinical activity in solid tumors with a<br />
SOR-CAP combination. SoMore’s aim is to assess its potential benefit in<br />
chemorefractory mCRC and <strong>the</strong> predictive value of early metabolic response (MR)<br />
on survival.<br />
Methods: SoMore (EUDRACT 2010-023695-91) is a multicentric phase II in PS<br />
0-1 chemorefractory mCRC pts. Two co-primary objectives were defined 1) to<br />
demonstrate that overall survival (OS) at 6 months is > 30% (67 pts needed to<br />
have 90% power to detect a true rate of 50% at 1-sided level 2.5%); 2) to<br />
compare OS between early PET responders and non responders (62 deaths<br />
required before analysis -on pts assessable for MR- to detect a true HR < 0.385,<br />
assuming a 67% rate of early responders). Pts received a 1st cycle of SOR<br />
(600mg/day) CAP (1700 mg/m 2 /day, day 1-14 every 21 days), <strong>the</strong>n subsequent<br />
cycles with a SOR dose of 800mg/day until progression or unacceptable<br />
toxicity. FDGPET-CT was performed at baseline and before second cycle.<br />
Investigator-independent centralized PET analysis was carried out with<br />
metabolic non response defined by < 15% FDG uptake decrease in a dominant<br />
proportion (≥50%) of predefined target lesions (SUVmax> 2.5 liver uptake;<br />
size > 15 mm).<br />
Results: Between February and October 2011, 92 eligible pts were recruited in 6<br />
centers: 50 male pts (54%), ECOG PS 0/1 : 51 (55%)/41 (45%), median age of 61<br />
years. A median of 5 treatment cycles were given (0-18 + , treatment ongoing in 11<br />
pts). No toxic death was observed. Grade III-IV toxic reactions were reported in 53%<br />
of <strong>the</strong> pts, mainly fatigue (17%), hand-foot skin reaction (13%), diarrhea (13%). 3/81<br />
pts stopped <strong>the</strong>ir treatment due to toxicity. OS rate at 6 months was 65/92 (71%,<br />
95% CI : 61%-79%), significantly higher than 50% (p < 0.001). PET showed a MR in<br />
65% [54%-74%] of <strong>the</strong> 79 evaluable pts. Data are not yet mature to analyze <strong>the</strong><br />
predictive value of PET on survival.<br />
Conclusions: SoMore largely met one of its primary objectives with an observed 71%<br />
OS at 6 months for this heavily pretreated mCRC population with manageable<br />
toxicity. Data about PET assessment according to mOS and PFS will likely be mature<br />
at <strong>the</strong> time of <strong>the</strong> meeting and presented if available.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
570P EFFECT OF POST-PROTOCOL ANTI-EPIDERMAL GROWTH<br />
FACTOR RECEPTOR (EGFR) MONOCLONAL ANTIBODY (MAB)<br />
THERAPY ON SURVIVAL OUTCOMES IN PATIENTS WITH<br />
WILD-TYPE (WT) KRAS METASTATIC COLORECTAL CANCER<br />
(MCRC) TREATED WITH PANITUMUMAB (PMAB) PLUS<br />
CHEMOTHERAPY<br />
J-Y. Douillard 1 , M. Peeters 2 , A. Rong 3 , S. Siena 4 , S. Braun 5 , R. Sidhu 3 , T. Price 6<br />
1 Centre René Gauducheau, Nantes, FRANCE, 2 University Hospital Antwerp,<br />
Antwerp, BELGIUM, 3 Amgen Inc., Thousand Oaks, CA, UNITED STATES OF<br />
AMERICA, 4 Ospedale Niguarda Ca’ Granda, Milan, ITALY, 5 Amgen GmbH, Zug,<br />
Switzerland, 6 Queen Elizabeth Hospital and University of Adelaide, Woodville,<br />
AUSTRALIA<br />
Background: Results from two randomized, multi-centre, phase III studies of pmab<br />
plus chemo<strong>the</strong>rapy (FOLFOX4 in 1 st -line [PRIME]; FOLFIRI in 2 nd -line [181])<br />
demonstrated a trend toward improved overall survival (OS) in <strong>the</strong> experimental<br />
arms vs chemo<strong>the</strong>rapy alone, analysing <strong>the</strong> ITT populations. We evaluated <strong>the</strong><br />
hypo<strong>the</strong>sis that crossover to post-protocol anti-EGFR mAb-containing <strong>the</strong>rapy in <strong>the</strong><br />
control arms may have attenuated OS outcomes.<br />
Methods: For this retrospective analysis, we used data of both PRIME and 181<br />
study final analyses prespecified to occur at 30 months after <strong>the</strong> last patient was<br />
enrolled. We conducted sensitivity analyses to estimate OS outcomes using<br />
statistical procedures: (1) estimating <strong>the</strong> effect of randomized treatment as if no<br />
patients in <strong>the</strong> chemo<strong>the</strong>rapy arm received subsequent anti-EGFR mAb-containing<br />
<strong>the</strong>rapy a ; (2) identifying <strong>the</strong> survival differences that would have been observed had<br />
all patients stayed on protocol treatment b ; (3) modifying <strong>the</strong> Cox<br />
proportional-Hazards model, allowing for a time-dependent covariate with value 0<br />
ix194 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Table: 570P<br />
up to <strong>the</strong> point of subsequent <strong>the</strong>rapy and a value of 1 from <strong>the</strong>n on; (4)<br />
censoring patients at <strong>the</strong> time of subsequent anti-EGFR use and adjusting <strong>the</strong><br />
informative censoring with <strong>the</strong> inverse probability-of-censoring weighted (IPCW)<br />
analysis d-f .<br />
Results: Table.<br />
Conclusions: Patients receiving chemo<strong>the</strong>rapy alone crossed over earlier and more<br />
frequently to post-protocol anti-EGFR treatment versus those receiving combination<br />
<strong>the</strong>rapy. All analyses produced results indicating that <strong>the</strong> lack of a statistically<br />
significant OS benefit estimate may have been due to selective crossover bias. The<br />
results also indicate that IPCW method may be particularly suited for detecting OS<br />
benefits that o<strong>the</strong>rwise would not be detected with an ITT approach that ignores<br />
selective crossover bias.<br />
Disclosure: J. Douillard: AMGEN: Participation in Advisory Boards, speaker in<br />
Symposia compensated MERCK:Participation in Advisory Boards, speaker in<br />
Symposia compensated, Research support ROCHE: Participation in Advisory Boards,<br />
speaker in Symposia compensatedM. Peeters: Consultant/advisory role for Amgen<br />
and also received honoraria and research funding. A. Rong: Employee of Amgen and<br />
holds Amgen stock. S. Siena: Advisory role for Amgen, AstraZeneca, Merck Serono,<br />
Roche, Celgene. S. Braun: Employee of Amgen and holds Amgen stock. R. Sidhu:<br />
Employee of Amgen and holds Amgen stock. T. Price: Consultant/advisory role for<br />
Amgen and received honoraria.<br />
571P BEVACIZUMAB (BEV) + CHEMOTHERAPY (CT) BEYOND FIRST<br />
PROGRESSION IN PATIENTS (PTS) WITH METASTATIC<br />
COLORECTAL CANCER (MCRC) PREVIOUSLY TREATED WITH<br />
FIRST-LINE BEV + CT (ML18147): EFFICACY AND SAFETY<br />
ANALYSES BY OXALIPLATIN VS IRINOTECAN-BASED CT<br />
P. Österlund 1 , V. Alonso-Orduna 2 , C. Schlichting 3 , T. André 4 , J. Sastre 5 ,<br />
R. Greil 6 , S. Kubicka 7 , I. Reyes-Rivera 8 , B. McCall 9 , E.J.D. Van Cutsem 10<br />
1 Medical Oncology, Helsinki University Central Hospital, Helsinki, FINLAND,<br />
2 Servicio De Oncología Médica, Hospital Universitario Miguel Servet, Zaragoza,<br />
SPAIN, 3 I. Chirurgische Klinik, Diakoniekrankenhaus Rotenburg GmbH,<br />
Rotenburg, GERMANY, 4 Medical Oncology, Hopital Saint-Antoine and Université<br />
Pierre et Marie Curie, Paris, FRANCE, 5 Medical Oncology, Servicio de Oncología<br />
Médica HC, Madrid, SPAIN, 6 Oncology Centre, III Medizinische Universitätsklinik<br />
Salzburg, Salzburg, AUSTRIA, 7 Internal Medicine, Cancer Center Reutlingen,<br />
Reutlingen, GERMANY, 8 Statistics, Genentech Inc., South San Francisco, CA,<br />
UNITED STATES OF AMERICA, 9 Product Development, Oncology, Genentech,<br />
Inc., South San Francisco, CA, UNITED STATES OF AMERICA, 10 Digestive<br />
Oncology, University Hospital Gasthuisberg, Leuven, BELGIUM<br />
Background: ML18147 is <strong>the</strong> first randomised study to show that continuing BEV +<br />
standard CT as second-line (2L) treatment significantly improves overall survival<br />
(OS) and progression-free survival (PFS) in pts with mCRC who progressed after<br />
receiving a standard first-line (1L) BEV-containing regimen. Here we evaluate<br />
outcome in <strong>the</strong> 2L setting using, as a stratification factor, 1L oxaliplatin vs<br />
irinotecan-based CT.<br />
PRIME 181<br />
Pmab +<br />
FOLFOX4 FOLFOX4<br />
Methods: Pts with unresectable, histologically confirmed mCRC who progressed<br />
within 3 months of discontinuing 1L BEV were randomised to 2L<br />
fluoropyrimidine-based CT ± BEV (2.5 mg/kg/wk equivalent). Choice of 2L<br />
oxaliplatin or irinotecan was dependent on <strong>the</strong> 1L regimen (crossover). OS, PFS,<br />
overall response rate (ORR) and adverse events (AEs) were analysed in <strong>the</strong> 2L setting<br />
using <strong>the</strong> 1L oxaliplatin or irinotecan-based CT as a stratification factor.<br />
Results: 820 pts were randomised from Feb 2006 to Jun 2010. Of <strong>the</strong>se, 343 received<br />
1L oxaliplatin-based CT and 476 received 1L irinotecan-based CT, after which <strong>the</strong>y<br />
crossed over to receive ei<strong>the</strong>r oxaliplatin or irinotecan-based CT in 2L. BEV + CT<br />
beyond progression prolonged OS and PFS, regardless of whe<strong>the</strong>r oxaliplatin or<br />
irinotecan-based CT was used in 1L (Table). ORR was low in CT and BEV +<br />
CT-treated pts in both groups. AEs associated with BEV were generally similar in pts<br />
treated with ei<strong>the</strong>r oxaliplatin or irinotecan-based CT.<br />
Outcome in 2L<br />
Pmab +<br />
FOLFIRI FOLFIRI<br />
Number of patients<br />
ITT analysis for OS<br />
n = 325 n = 331 n = 303 n = 294<br />
Median OS, months<br />
(95% CI)<br />
23.9 (20.3– 27.7) 19.7 (17.6–22.7) 14.5 (13.0–16.1) 12.5 (11.2–14.2)<br />
HR (95% CI)<br />
Post-protocol anti-EGFR mAb <strong>the</strong>rapy<br />
0.88 (0.73–1.06) 0.92 (0.78–1.10)<br />
Incidence, (%) 13 25 12 34<br />
Median time to use,<br />
months<br />
21.5 15.6 12.4 7.9<br />
OS sensitivity analyses on influence of post-protocol anti-EGFR mAb <strong>the</strong>rapy<br />
Branson-Whitehead,<br />
0.84 (0.68-1.05) 0.90 (0.71, 1.14)<br />
2002 a<br />
Robins and Tsiatis,<br />
1992 b<br />
Allison, 1995 c<br />
IPCW d-f<br />
0.83 (0.66-1.04) 0.89 (0.71, 1.13)<br />
0.68 (0.55-0.83) 1.03 (0.87, 1.23)<br />
0.74 (0.56-0.97) 0.71 (0.53, 0.94)<br />
a Branson and Whitehead, 2002; b Robins and Tsiatis, 1992; c Allison, 1995;<br />
d Rimawi & Hilsenbeck, <strong>2012</strong>; e Colleoni et al, 2011; f Robins & Finkelstein, 2000. Abbreviation: CI = confidence interval<br />
1L oxaliplatin-based CT 1L irinotecan-based CT<br />
CT (n =<br />
174)<br />
BEV + CT (n =<br />
169)<br />
CT (n =<br />
236)<br />
BEV +<br />
CT<br />
(n = 240)<br />
Median OS, months 10.0 12.0 9.3 10.9<br />
p-value 0.0524 0.0454<br />
HR (95% CI) 0.79 (0.62–1.00) 0.82 (0.67–1.00)<br />
Median PFS, months 4.2 6.2 3.8 5.4<br />
p-value 0.0005 1%<br />
of pts, %<br />
0.2414 0.7145<br />
Any 52 66 60 61<br />
Hypertension 0 1 2 2<br />
Bleeding/haemorrhage
572P PANERB STUDY: WHICH CATEGORY OF PATIENTS,<br />
SUFFERING FROM METASTATIC COLORECTAL CANCER, CAN<br />
BENEFIT FROM PANITUMUMAB TREATMENT AFTER<br />
CETUXIMAB-BASED REGIMEN FAILURE?<br />
J. Metges 1 , J.F. Ramée 2 , O. Dupuis 3 , P. Deguiral 4 , E. Boucher 5 , O. Cojocarasu 6 ,<br />
M. Ferec 7 , M. Porneuf 8 , J. Douillard 9 , F. Grude 10<br />
1 Medical Oncology, C.H.U. Morvan Institut de Cancerologie et d’Hematologie,<br />
Brest Cedex, FRANCE, 2 Medical Oncology, Centre Ca<strong>the</strong>rine de Sienne, Nantes,<br />
FRANCE, 3 Medical Oncology, Centre Jean Bernard, Le Mans, FRANCE,<br />
4 Medical Oncology, Pole Hospitalier Mutualiste Saint Nazaire, Saint Nazaire,<br />
FRANCE, 5 Medical Oncology, Centre Eugène Marquis, Rennes, FRANCE,<br />
6 Oncology, Centre Hospitalier Du Mans, Le Mans, FRANCE, 7 Medical Oncology,<br />
CH Morlaix, Morlaix, FRANCE, 8 Medical Oncology, Ch Saint Brieuc, Saint<br />
Brieuc, FRANCE, 9 Medical Oncology, Centre René Gauducheau (ICO) Institut de<br />
Cancerologie de l’Ouest, St Herblain Cedex, FRANCE, 10 ICO Paul Papin,<br />
Observatoire Dédié au Cancer, Angers, FRANCE<br />
Background: Metastatic colorectal cancer (mCRC) management has been clearly<br />
improved by targeted <strong>the</strong>rapies such as anti-HER1 drugs (panitumumab and<br />
cetuximab). As evaluation of <strong>the</strong>ir use sequentially after progression in <strong>the</strong> real<br />
world is strategic to assess health poliltics, no series of patients is currently<br />
available. The Observatory of cancer Bretagne-Pays de la Loire is a network of 50<br />
private and public cancer centers particularly focused on good practise for cancer<br />
drugs use.<br />
Methods: The aim of <strong>the</strong> study is to evaluate <strong>the</strong> use of Panitumumab Mono<strong>the</strong>rapy<br />
(PM) after previous treatment with Cetuximab-Based Regimen (CBR) in an<br />
homogeneous series of kras wild type unresectable mCRC according to EMA<br />
approval. Sex, age, localization of <strong>the</strong> tumor, successive chemo<strong>the</strong>rapeutic regimens,<br />
toxicities, response rate, progression free survival (PFS) and overall survival (OS)<br />
have been studied.<br />
Results: 106 patients (73 men, median age 64.4 years [36-86]) previously treated<br />
with CBR received PM at progression. The primary tumor site was colon (62%),<br />
rectum (35%) and both of <strong>the</strong>m (3%). Patients received successively 1 to 9 lines<br />
of treatment for mCRC. Objective responses (OR) were observed in 46% of <strong>the</strong><br />
patients under CBR and 17% responded again to PM. Disease stabilization was<br />
achieved in 17% of <strong>the</strong> patients treated with CBR and in 13% of <strong>the</strong> patients<br />
treated with PM. Amongst <strong>the</strong> patients who had an OR with CBR, 31% also had<br />
an OR with PM and 16% were stabilized with PM (clinical benefit 47%). In case<br />
of cetuximab resistance, only 14% of <strong>the</strong> patients had a clinical benefit with PM.<br />
The median PFS under CBR was 6.6 months IC95% [5.3-7.7] and 3.2 months<br />
IC95% [2.8 -3.5] under PM after CBR. The median OS for <strong>the</strong> patients who<br />
achieved a response with both targeted <strong>the</strong>rapies was 25.4 months IC 95%<br />
[22.4-42.6] vs 15.0 months IC 95% [12.9-18.3] for <strong>the</strong> patients who did not (p <<br />
0.0001).<br />
Conclusion: Our study clearly showed that patients with progression after response<br />
to cetuximab regimen had a potential opportunity of clinical benefit (47%) with<br />
panitumumab mono<strong>the</strong>rapy with a good response rate. OS was potentially increased<br />
in responders to <strong>the</strong> successive use of both targeted <strong>the</strong>rapies.<br />
Disclosure: J. Metges: conference for Amgen, MerckSerono and Amgen. O. Dupuis:<br />
participation in a scientific evening as moderator account for MerckSerono. M. Ferec:<br />
participation paid to a board VIFOR invitations congress by Roche, Amgen. J.<br />
Douillard: AMGEN : participation in advisory boards and steering committees,<br />
speaker in symposia, compensated MERCKSERONO: Research Funding,<br />
participation in advisory boards and steering committees, speaker in symposia,<br />
compensated. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
573P PHASE II STUDY OF 1ST-LINE COMBINED CHEMOTHERAPY<br />
BEVACIZUMAB WITH MODIFIED RPMI REGIMEN FOR<br />
ELDERLY OR FRAIL PATIENTS WITH UNRESECTABLE OR<br />
METASTATIC COLORECTAL CANCER (OGSG0802)<br />
M. Yoshida 1 ,T.Kato 2 , S. Iwamoto 3 , Y. Miyake 2 , M. Nakamura 4 ,T.Sato 5 ,<br />
D. Sakai 6 , M. Matsuoka 7 , T. Otsuji 7 , H. Furukawa 8<br />
1 Cancer Chemo<strong>the</strong>rapy Center, Osaka Medical College, Takatsuki, JAPAN,<br />
2 Department of Surgery, Minoh City Hospital, Osaka, JAPAN, 3 Surgery, Kansai<br />
Medical University School Hirakata Hospital, Osaka, JAPAN, 4 Aizawa<br />
Comprehensive Cancer Center, Aizawa Hospital, Matsumoto, JAPAN, 5 Kinki<br />
University Hospital, Faculty of Medicine, Medical Oncology, Osaka, JAPAN,<br />
6 Osaka Medical Center for Cancer and Cardiovascular Disease, Medical<br />
Oncology, Osaka, JAPAN, 7 Gastroenterology, Dongo Hospital, Nara, JAPAN,<br />
8 Surgery, Kinki University School of Medicine, Osaka, JAPAN<br />
Background/ Objectives: The first-line combined chemo<strong>the</strong>rapy RPMI regimen with<br />
bevacizumab (Bmab) in AVF2192g trial for elderly or frail patients (Pts) could be<br />
active to progression free survival (PFS), <strong>the</strong> secondary endpoint, although it may not<br />
prolong overall survival (OS), <strong>the</strong> primary endpoint. According to <strong>the</strong> results of<br />
efficacy and safety studies, a fluoropyrimidine (FU) + Bmab regimen is regarded as an<br />
option for 1st-line chemo<strong>the</strong>rapy. We planned a phase II study of modified RPMI<br />
regimen with Bmab for elderly or frail Pts.<br />
Annals of Oncology<br />
Methods: Pts with confirmed unresectable/metastatic colorectal cancer without<br />
previous chemo<strong>the</strong>rapy, and fulfilling at least one of <strong>the</strong> following characteristics<br />
were enrolled: Age ≧65 years, ECOG performance status 1 or 2, serum albumin ≦<br />
3.5g/dl, incompatible with receiving oxaliplatin or irinotecan, or prior abdominal/<br />
pelvic radio<strong>the</strong>rapy. Pts received modified RPMI regimen (5-FU 600 mg/m 2 and<br />
l-leucovorin 200 mg/m 2 bolus day 1, 8, 15) and Bmab 5 mg/kg day 1, 15, q4w) until<br />
disease progression or study withdrawal. The primary endpoint was overall response<br />
rate (ORR), and <strong>the</strong> secondary endpoints were PFS, OS, safety and treatment<br />
completion rate of treatment.<br />
Results: 41 Pts (mean age 76 years [range 56–90]; 55% male) were enrolled to this<br />
trial from 13 institutions. 28 Pts (68%) had objective progression and a patient<br />
(2.4%) died without progression. The ORR, <strong>the</strong> primary endpoint, <strong>the</strong> rate of best<br />
response, <strong>the</strong> disease control rate (CR + PR + SD) were 36.6%, 56.1%, 85.4%,<br />
respectively. The median PFS was 9.0 months (95%CI, 7.5–19.6) by independent<br />
central review. Median OS was 30.2 months (95%CI, 23.8–Not achieved). Mean 5-FU<br />
and Bmab dose intensity were 86.9% and 83.6%, respectively. The incidences of all<br />
grade/grade 3-4 adverse events: leukopenia (66/7), neutropenia (58/24),<br />
thrombocytopenia (39/2), nausea (29/0), diarrhoea (34/5), anorexia (32/10), fatigue<br />
(49/5), stomatitis (29/7) and hypertension (24/5). Grade 3 febrile neutropenia and<br />
grade 4 pulmonary embolism was observed in one patient.<br />
Conclusions: The modified RPMI regimen with Bmab showed activity, and was well<br />
tolerated by elderly or frail Pts. ORR and <strong>the</strong> median PFS of this regimen were<br />
similar to historical data with FU + Bmab. This regimen may be a good option not<br />
requiring percutaneous port placement for elderly or frail Pts. .<br />
Disclosure: M. Yoshida: The author received few payments for lectures from Chugai<br />
Pharmaceutical Co., Ltd. Grants for research were also provided to <strong>the</strong><br />
Chemo<strong>the</strong>rapy Center of Osaka Medical College by this pharmaceutical companies.<br />
All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
574P CLINICAL OUTCOME OF CETUXIMAB FOR METASTATIC<br />
COLORECTAL CANCER PATIENTS HARBORING KRAS<br />
CODON61, KRAS CODON146, BRAF, NRAS OR PIK3CA<br />
MUTATIONS<br />
E. Shinozaki 1 , H. Bando 2 , T. Nishina 3 , K. Yamazaki 4 , S. Kadowaki 5 , S. Yuki 6 ,<br />
S. Kajiura 7 , K. Tsuchihara 8 , S. Fujii 9 , T. Yoshino 10<br />
1 Gastrointestinal Oncology, Cancer Institute Hospital of Japanese Foundation for<br />
Cancer Research, Tokyo, JAPAN, 2 Department of Gastroenterology and<br />
Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa,<br />
Chiba, JAPAN, 3 Gastrointestinal Oncology, National Hospital Organization<br />
Shikoku Cancer Center, Matsuyama, JAPAN, 4 Gastrointestinal Oncology,<br />
Shizuoka Cancer Center, Shizuoka, JAPAN, 5 Division of Gastroenterology,<br />
Saitama Cancer Center, Saitama, JAPAN, 6 Department of Gastroenterology,<br />
Hokkaido University Hospital, Sapporo, JAPAN, 7 The Third Departoment of<br />
Internal Medicine, University of Toyama, Toyama, JAPAN, 8 Cancer Physiology<br />
Project, Research Center for Innovative Oncology, National Cancer Center<br />
Hospital East, Kashiwa, JAPAN, 9 Pathology Division, Research Center for<br />
Innovative Oncology, National Cancer Center Hospital East, Kashiwa, JAPAN,<br />
10 Department of Endoscopy & Gastrointestinal Oncology, National Cancer<br />
Center Hospital East, Kashiwa, Chiba, JAPAN<br />
Background: Retrospective pooled analyses have identified KRAS, BRAF, NRAS, and<br />
PIK3CA mutations as potentially negative predictive factors for colorectal cancer<br />
patients treated with Cetuximab (Cmab). We developed a novel kit that applies<br />
Luminex technology for detection of mutations in KRAS codon61, KRAS codon146,<br />
BRAF, NRAS, and PIK3CA in a single reaction (GENOSEARCH Mu-PACK).<br />
Methods: Formalin-fixed paraffin-embedded tumor samples and clinical data of<br />
colorectal cancer patients treated with Cmab-containing regimens were collected<br />
from 7 Japanese centers. KRAS, BRAF, NRAS and PIK3CA gene statuses were<br />
determined, both by our kit and by direct-sequencing (DS). Objective response,<br />
progression-free survival (PFS), and overall survival (OS) were evaluated in<br />
subgroups determined by mutation status.<br />
Results: A total of 83 samples were collected. The concordance rate between our<br />
kit and DS data was 100%. Our kit results identified 3 samples with mutations<br />
in KRAS codon 61 (3.6%), 2 in KRAS codon 146 (2.4%), 4 in BRAF (4.8%), 2<br />
in NRAS (2.4%), and 4 in PIK3CA (4.8%). We also identified 21 samples with<br />
mutations in KRAS codon 12, 13 (25.3%) by using Luminex technology. All of<br />
<strong>the</strong>se mutations, except for PIK3CA, were mutually exclusive. The response rate<br />
for all patients in <strong>the</strong> study was 24.4%, whereas <strong>the</strong> response rate for <strong>the</strong> group<br />
of patients with all wild-type tumors was 40.8%. The median PFS values of<br />
patients with all wild-type tumors (N = 49), with KRAS codon12, 13 mutation<br />
(N = 21), and with any of KRAS codon61, KRAS codon146, BRAF, NRAS, or<br />
PIK3CA mutations (N = 12) were, respectively, 6.4 months (95%CI: 2.9, 10.0),<br />
2.7 months (95%CI: 1.2, 4.2), and 1.6 months (95%CI: 1.5, 1.7) (Log Rank test,<br />
P < 0.0001). The median OS values were, respectively, 15.6 months (95%CI: 10.1,<br />
20.2), 8.2 months (95%CI: 5.7, 10.7), and 6.3 months (95%CI: 1.9, 10.7) (Log<br />
Rank test, P < 0.0001).<br />
Conclusions: Patients with KRAS codon61, KRAS codon146, BRAF, NRAS, and<br />
PIK3CA mutations may not derive clinical benefits from Cmab, nor would patients<br />
with KRAS codon 12, 13 mutations. This newly developed detection kit is robust and<br />
ix196 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
practical for examining a patient’s KRAS codon61, codon146, BRAF, NRAS, and<br />
PIK3CA gene status.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
575P BIOPSY SPECIMENS OBTAINED 7 DAYS AFTER STARTING<br />
CHEMORADIOTHERAPY (CRT) PROVIDES RELIABLE<br />
PREDICTORS OF RESPONSE TO CRT FOR RECTAL CANCER<br />
T. Suzuki 1 , S. Sadahiro 1 , A. Tanaka 1 , K. Okada 1 , A. Kamijo 1 , S. Kawada 2<br />
1 Gastrointestinal Surgery, Tokai University School of Medicine, Isehara, JAPAN,<br />
2 Radiology, Tokai University School of Medicine, Isehara, JAPAN<br />
Background: Preoperative CRT is a standard treatment for locally advanced<br />
rectal cancer (LARC). The histologic response to CRT or <strong>the</strong> downstaging has<br />
been reported to be closely related to oncologic outcomes. Various biomarkers<br />
in biopsy specimens obtained before CRT have been investigated as<br />
predictors of response, however, reliable predictive biomarkers remain to be<br />
established.<br />
Methods: The study group comprised 101 consecutive patients with LARC who<br />
received preoperative CRT of 45Gy with oral uracil/tegafur (UFT) or S-1. We<br />
evaluated histologic findings on H-E staining and immunohistochemical expressions<br />
of Ki67, p53, p21, and apoptosis in biopsy specimens obtained before CRT and 7<br />
days after starting CRT. These findings were contrasted with <strong>the</strong> rate of histologic<br />
marked regression and <strong>the</strong> degree of tumor shrinkage.<br />
Results: In biopsy specimens obtained before CRT, <strong>the</strong> degree of tumor shrinkage<br />
on barium enema (BE) were significantly greater in patients with p21-positive<br />
tumors (52 ± 11%) than in those with p21-negative tumors (45 ± 16%) (p < 0.01).<br />
In biopsy specimens obtained 7 days after starting CRT, <strong>the</strong> histologic marked<br />
regression according to <strong>the</strong> tumor regression grade (TRG) criteria was significantly<br />
higher in apoptosis-positive patients (57.1%) and p21-positive patients (49.2%)<br />
than in apoptosis-negative patients (30.1%) and p21-negative patients (20.0%) (p =<br />
0.02 and p < 0.01, respectively). The degrees of tumor shrinkage based on BE and<br />
on MRI were both significantly higher in apoptosis-positive patients (55 ± 12%, 81<br />
± 15%) and p21-positive patients (52 ± 13%, 74 ± 19%) than in apoptosis-negative<br />
patients (45 ± 15%, 68 ± 19%) and p21-negative patients (41 ± 13%, 66 ± 19%) (p <<br />
0.01, p < 0.01, p < 0.01 and p = 0.04, respectively). Histologic changes in H-E<br />
stained biopsy specimens significantly correlated with marked regression as well as<br />
with tumor shrinkage based on BE and MRI (p < 0.01, p < 0.01 and p = 0.03,<br />
respectively).<br />
Conclusions: Immunohistochemical expressions of p21 and apoptosis toge<strong>the</strong>r with<br />
histologic changes on H-E-stained biopsy specimens obtained 7 days after starting<br />
CRT are strong predictors of response to CRT.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
576P ADVERSE EVENTS IN ELDERLY PATIENTS ON ADJUVANT<br />
THERAPY WITH UFT/LV OR S-1 FOR STAGE III COLON<br />
CANCER: ACTS-CC TRIAL [TRICC0706]<br />
M. Ishiguro 1 , H. Uetake 1 , T. Ishikawa 1 , Y. Kusunoki 2 , F. Kinoshita 2 ,<br />
N. Kashiwagi 2 , Y. Nagata 2 , Y. Matsubara 2 , K. Sugihara 3<br />
1 Department of Translational Oncology, Tokyo Medical and Dental University,<br />
Graduate School, Tokyo, JAPAN, 2 Translational Research Informatics Center,<br />
Foundation for Biomedical Research and Innovation, Kobe, JAPAN, 3 Department<br />
of Surgical Oncology, Tokyo Medical and Dental University, Graduate School,<br />
Tokyo, JAPAN<br />
Background: The ACTS-CC trial is a phase III trial designed to validate<br />
non-inferiority of S-1 to UFT/ LV, a standard adjuvant <strong>the</strong>rapy for stage III colon<br />
cancer in Japan. We reported <strong>the</strong> safety profile of this trial (Brit J Cancer <strong>2012</strong>). To<br />
clarify <strong>the</strong> characteristics of adverse events (AEs) in elderly patients, subgroup<br />
analysis was performed.<br />
Methods: 20-80 aged patients with stage III colon cancer were randomly assigned to<br />
receive UFT/LV (UFT: 300 to 600 mg/day and, LV: 75 mg/day on days 1-28, followed<br />
by 7 days rest, 5 courses) or S-1 (80 to 120 mg/day on days 1-28, followed by 14 days<br />
rest, 4 courses). We compared treatment status and safety among group A (age ≤ 70),<br />
group B (age 71-75) and group C (age 76-80).<br />
Results: A total of 1,504 patients (756 in S-1 group, 748 in UFT/LV group,) were<br />
analyzed. The numbers of patients of group A, B and C were 506 (69%), 160<br />
(20%) and 90 (11%), and <strong>the</strong> rates of patients with PS 1 in each group were<br />
2.6%, 4.3% and 16.8%, respectively. Pre-treatment value of Hemoglobin of group<br />
B and C was lower than that of group A, while <strong>the</strong>re were no differences in that<br />
of neutrophils, platelets and creatinine. In S-1 treatment, incidences (any grades)<br />
of anemia (group A: 29%, B: 37%, C: 47%), anorexia (30%, 34%, 46%) and<br />
fatigue (25%, 29%, 39%) were higher in group C. In ≥ grade 3 AEs, incidences of<br />
anorexia (3%, 7%, 13%), diarrhea (4%, 3%, 7%) and fatigue (2%, 3%, 7%) were<br />
higher in group C. In UFT/LV treatment, incidence (any grades) of anorexia<br />
(22%, 33%, 30%) and anemia (24%, 32%, 35%) were higher in group B and C,<br />
while incidence of elevation of AST (23%, 15%, 12%) and ALT (25%, 15%, 12%)<br />
were higher in group A. The completion rates of S-1 treatment was lower in<br />
group C (group A: 78%, B: 77%, C: 69%), although those of UFT/LV did not<br />
differ among <strong>the</strong> groups. There was no difference in <strong>the</strong> rate of discontinuation<br />
due to AEs listed on <strong>the</strong> discontinuation criteria among <strong>the</strong> groups, while that<br />
due to AEs not listed on <strong>the</strong> criteria (i.e. physician’s judgment or patient’s<br />
request) was higher in group C.<br />
Conclusions: In elderly patients, subjective AEs such as anorexia and fatigue were<br />
common, and mild anemia was observed in one-third of ≥71 aged patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
577P EXTENSIVE LIVER RESECTIONS AND PREOPERATIVE<br />
REGIONAL INTRAARTERIAL CHEMOTHERAPY IN PATIENTS<br />
WITH LIVER COLORECTAL CANCER METASTASES AND<br />
UNFAVOURABLE PROGNOSTIC FACTORS<br />
S. Khays 1 , K. Mamontov 1 , A. Kotelnikov 2 , S. Lazarev 1 , A. Lazarev 3<br />
1 Liver and Pancreas Surgery, Altai Branch of N. N. Blokhin Russian Cancer<br />
Research Centre, Barnaul, RUSSIAN FEDERATION, 2 Liver and Pancreas<br />
Surgery, N. N. Blokhin Russian Cancer Research Centre, Moscow, RUSSIAN<br />
FEDERATION, 3 N. N. Blokhin Russian Cancer Research Centre, Altai Branch of<br />
N. N. Blokhin Russian Cancer Research Centre, Barnaul, RUSSIAN<br />
FEDERATION<br />
Objective: To analyze patients with negative prognostic factors, as well as overall and<br />
disease-free survival.<br />
Materials and methods: 101 patients with liver colorectal cancer metastases were<br />
enrolled in this local observational study. All patients undergone preoperative<br />
regional intraarterial chemo- or bio<strong>the</strong>rapy (group 1 - FOLFOX 6, group 2 -<br />
FOLFOX 6 + bevacizumab) followed by liver resection. Synchronous metastases – in<br />
54 patients (53%). Metachronous metastases – in 47 (47%). Bilobate lesion – in 62<br />
patients (62%). Solitary metastasis – in 46 (46%). Multiple metastasis – in 55 (54%).<br />
Partial regression of tumor was observed in 26 patients (26%), stabilization – in 53<br />
(53%). Progression – in 21 (21%). Extensive liver resection with resection of<br />
contralateral lobe was performed in 39 patients (39%). Standard hepatectomy – in 71<br />
(70%). Extended hepatectomy – in 30 (30%). Extrahepatic metastases – in 23 patients<br />
(23%). Metastases in lymph nodes of hepatoduodenal ligament – 18 (18%).<br />
Results: Univariate analysis revealed three unfavorable factors: bilobate lesion of <strong>the</strong><br />
liver (p = 0.04), multiple liver metastases (p= 0.00029), metastases to <strong>the</strong><br />
hepatoduodenal ligament (p = 0.001). Multivariate analysis revealed two unfavorable<br />
prognostic factors: multiple liver metastases (p = 0.015), metastases to <strong>the</strong><br />
hepatoduodenal ligament (p = 0.04). Overall survival with FOLFOX 6 + bevacizumab:<br />
Median – 33 months, 3-years - 36 ± 10, 5 years - 12 ± 7. With FOLFOX 6: Median –<br />
29 months, 3 years – 42 ± 7, 5 years – 14 ± 6. Overall survival in case of metastases to<br />
<strong>the</strong> lymph nodes of hepatoduodenal ligament. With metastases: Median – 27<br />
months, 3 years – no, 5 years – no. Without metastases: Median – 35 months, 3<br />
years - 49 ± 7, 5 years – 16 ± 6. Overall survival depending on <strong>the</strong> number of liver<br />
foci. Solitary foci: Median – 35 months, 3 years - 42 ± 10, 5 years – 23 ± 10. Multiple<br />
foci: Median – 28 months, 3 years – 51 ± 10, 5 years – 12 ± 7.<br />
Conclusion: The main criteria characterizing tumor aggressiveness are <strong>the</strong> number of<br />
liver foci and metastases to <strong>the</strong> hepatoduodenal ligament, which determine tumor<br />
spreading.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
578P COMPARISON OF PATHOLOGICAL RESPONSES (PR)<br />
OBSERVED ON COLORECTAL CANCER METASTASES (CRCM)<br />
RESECTED AFTER DIFFERENT PREOPERATIVE<br />
TREATMENTS<br />
M. van den Eynde 1 , M. Gizzi 2 , G. Pairet 3 , P. Lefesvre 4 , V. Lannoy 5 , J. Gigot 6 ,<br />
B. Navez 6 , J. Canon 2 , C. Sempoux 3 , J. Carrasco 2<br />
1 Medical Oncology, Cliniques Universitaires St-Luc, Brussels, BELGIUM,<br />
2 Medical Oncology, Grand Hopital de Charleroi, Charleroi, BELGIUM,<br />
3 Pathology, Cliniques Universitaires St-Luc, Brussels, BELGIUM, 4 Pathology, IPG<br />
Loverval, Loverval, BELGIUM, 5 Centre du Cancer, Cliniques Universitaires<br />
St-Luc, Brussels, BELGIUM, 6 Surgery, Cliniques Universitaires St-Luc, Brussels,<br />
BELGIUM<br />
Background: Irinotecan (IR) or oxaliplatin (OX)-based regimens optionally<br />
combined with anti-VEGF or anti-EGFR Target Therapies (TT) are used as<br />
preoperative treatment for metastatic colorectal patients before resection of CRCM.<br />
Best combination remains unclear. The study purpose was to compare PR observed<br />
on resected CRCM after different preoperative treatments.<br />
Methods: 114 patients engaged for CRCM resection after 2005 were included in this<br />
retrospective analysis. PR was evaluated on 296 resected CRCM according to <strong>the</strong><br />
pathological Tumor Regression Grading scale (TRG), grading PR from complete<br />
(TRG1) to absent (TRG5). Mean TRG of resected metastasis was compared based on<br />
Kruskall-Wallis and Mann-Whitney tests. Cumulative PFS were calculated by<br />
Kaplan-Meir method and compared by log-rank test.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds397 | ix197
Results: 92/114 patients were preoperatively treated. Mean TRG after OX without TT<br />
was better than mean TRG after IR without TT (p = .044). No difference was<br />
observed between mean TRG after chemo<strong>the</strong>rapy alone compared to mean TRG after<br />
chemo<strong>the</strong>rapy + anti-VEGF (p = .53) or to mean TRG after chemo<strong>the</strong>rapy +<br />
anti-EGFR (p = .39). Subgroup analysis revealed that mean TRG after IR +<br />
anti-EGFR was better than mean TRG after OX + anti-EGFR (p = .031), and that<br />
mean TRG after OX + anti-VEGF was better than mean TRG after IR + anti-VEGF<br />
(p = .001). PFS analysis for <strong>the</strong> 92 preoperatively treated patients revealed that 13<br />
patients with major PR (TRG ≤ 2), had a significantly improved PFS compared to 79<br />
patients with minor or no PR (TRG > 2) (median PFS= 33.7 vs 22.9 month p= .018).<br />
Conclusion: PR observed on resected CRCM after a preoperative treatment does not<br />
seem to be linked to <strong>the</strong> TT (anti-VEGF or anti-EGFR) but ra<strong>the</strong>r to <strong>the</strong><br />
chemo<strong>the</strong>rapy/TT association with a significant advantage for OX + anti-VEGF or<br />
IR + anti-EGFR combinations.<br />
Preoperative strategy Patients (n) Metastases (n) TRG mean 95% CI<br />
No treatment 22 54 4.33 4.11- 4.55<br />
Chemo alone 38 86 3.19 2.95 - 3.43<br />
OX 28 68 3.16 2.89-3.43<br />
IR 8 11 3.91 3.44-4.38<br />
O<strong>the</strong>r 2 7 ND ND<br />
Anti-VEGF + chemo 38 120 3.32 3.10 - 3.54<br />
OX 8 27 2.63 2.18 - 3.08<br />
IR 29 80 3.53 3.27 - 3.78<br />
O<strong>the</strong>r 1 13 ND ND<br />
Anti-EGFR + chemo 16 36 2.97 2.50 - 3.44<br />
OX 9 16 3.56 2.98 - 4.15<br />
IR 6 19 2.47 1.77 - 3.18<br />
O<strong>the</strong>r 1 1 ND ND<br />
Disclosure: All authors have declared no conflicts of interest.<br />
579P ASSESSMENT AND COMPARISON OF TREATMENT EFFICACY<br />
IN PATIENTS WITH COLORECTAL CANCER (CRC), USING A<br />
NOVEL METHODOLOGY TO ESTIMATE THE RATE OF TUMOR<br />
REGRESSION (D) AND GROWTH (G)<br />
M. Blanco Codesido 1 , J. Wilkerson 2 , L. Rodriguez Gayo 3 , M. Rodriguez Alonso 3 ,<br />
P. Nava Garcia 3 , A. Matas Ochoa 3 , A.J. Muñoz Martín 3 , S. Álvarez Suárez 3 ,P.<br />
García Alfonso 3 ,T.Fojo 2<br />
1 Servicio De Oncología Médica, Hospital General Univ. Gregorio Marañon,<br />
Madrid, SPAIN, 2 Medical Oncology Branch Center for Cancer Research,<br />
National Cancer Institute, Be<strong>the</strong>sda, MD, UNITED STATES OF AMERICA,<br />
3 Servicio Oncología, Hospital Universitario Gregorio Marañon, Madrid, SPAIN<br />
Introduction: Novel methods of assessing treatment efficacy should prove helpful in<br />
drug development and in <strong>the</strong> management of cancer patients (pts). We have<br />
developed a novel method to analyze tumor response to <strong>the</strong>rapy by quantifying <strong>the</strong><br />
rate of tumor regression (d) and growth (g). We have shown g is slower when pts are<br />
on effective <strong>the</strong>rapy and that g correlates with survival. We utilized this novel<br />
methodology in pts with a diagnosis of CRC to compare <strong>the</strong> efficacy of oxaliplatinand<br />
irinotecan-containing regimens (OCR, ICR). Unlike PFS, an incremental<br />
measure of efficacy, g is a continuous variable and can more accurately assess<br />
differences between treatments. Because calculations of g are indifferent to<br />
assessment intervals, estimating a tumor’s g allows comparison of efficacy across<br />
trials.<br />
Methods: Using tumor measurements obtained for RECIST assessments or serum<br />
CEA levels and a two-phase ma<strong>the</strong>matical equation we determined d and g in 70 pts<br />
at each evaluation.<br />
Results: 70 pts (47 male, 23 female) with metastatic CRC were studied. The median<br />
g value with OCR (.00132) was statistically similar (p = 0.573) to that observed with<br />
ICR (.00148). Both <strong>the</strong>rapies also had similar effects on d (OCR = 0.00529; ICR =<br />
0.00451; p = 0.716). Similar results were seen using serum CEA levels. Fur<strong>the</strong>rmore,<br />
in an individual pt, statistically valid g and d values could be estimated long before<br />
tumor quantity increased, providing an early indicator of treatment failure.<br />
Importantly, in <strong>the</strong> majority of pts receiving prolonged treatment <strong>the</strong> growth rate<br />
constant did not change, despite rising tumor quantities, indicating resistance is<br />
intrinsic. Additional data being ga<strong>the</strong>red should allow us to compare relative effects<br />
on g in first and subsequent lines to discriminate between <strong>the</strong> effects observed in<br />
tumor shrinkage and <strong>the</strong> impact on tumor growth.<br />
Conclusions: In this cohort of CRC patients <strong>the</strong> data suggest both OCR and ICR<br />
have similar efficacy. The evidence in pts receiving long term <strong>the</strong>rapy demonstrating<br />
no change in g over time suggest resistance is intrinsic and not acquired, and would<br />
support a strategy of continued treatment with a tolerable regimen given <strong>the</strong> similar<br />
efficacy of <strong>the</strong> commonly used combinations.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
580P HEPATIC ARTERIAL INFUSION (HAI) OF OXALIPLATIN PLUS<br />
INTRAVENOUS (IV) FLUOROURACIL (FU), LEUCOVORIN (LV)<br />
AND CETUXIMAB FOR FIRST-LINE TREATMENT OF<br />
UNRESECTABLE COLORECTAL LIVER METASTASES (CRLM):<br />
FINAL RESULTS OF A MULTICENTER PHASE 2 STUDY<br />
(CHOICE)<br />
D. Malka 1 , V. Boige 1 , M. Faron 2 , C. Caramella 3 , E. Boucher 4 , P. Rivera 5 ,T.De<br />
Baere 3 , D. Goéré 6 , J. Pignon 2 , M. Ducreux 1<br />
1 Oncologic Medicine, Institut Gustave Roussy, Villejuif, FRANCE, 2 Biostatistics<br />
and Epidemiology, Institut Gustave Roussy, Villejuif, FRANCE, 3 Radiology, Institut<br />
Gustave Roussy, Villejuif, FRANCE, 4 Medical Oncology, Centre Eugène Marquis,<br />
Rennes, FRANCE, 5 Medical Oncology, CHU, Toulouse, FRANCE, 6 Surgery,<br />
Institut Gustave Roussy, Villejuif, FRANCE<br />
Background: To determine <strong>the</strong> efficacy and tolerance of HAI oxaliplatin plus iv FU/<br />
LV and cetuximab in patients (pts) with unresectable CRLM.<br />
Methods: Main eligibility criteria for this phase 2 study were: histologically proven<br />
colorectal adenocarcinoma; tumor wild-type (wt) KRAS status (protocol amendment<br />
in 09/2008); unresectable CRLM; no extrahepatic disease (except primary with<br />
absent/mild symptoms, and ≤ 3 nonspecific lung nodules ≤ 5 mm in diameter); no<br />
prior chemo<strong>the</strong>rapy for metastatic disease; WHO performance status 0-1. After<br />
surgical or percutaneous insertion of an implantable HAI ca<strong>the</strong>ter, pts were treated<br />
with HAI oxaliplatin (100 mg/m 2 in 2 hrs) plus iv modified LV5FU2 regimen (LV,<br />
400 mg/m 2 in 2 hrs; FU, 400 mg/m 2 bolus <strong>the</strong>n 2400 mg/m 2 in 46 hrs) every two<br />
weeks plus iv cetuximab (400 mg/m 2 <strong>the</strong>n 250 mg/m 2 /week, or 500 mg/m 2 every two<br />
weeks) until disease progression, limiting toxicity, or CRLM resection. Primary<br />
endpoint was objective response rate (ORR) (RECIST 1.0). Secondary endpoints<br />
included toxicity (NCI CTC-AE v3.0), disease control rate (DCR), resection rate,<br />
progression-free survival (PFS), and overall survival (OS).<br />
Results: A total of 36 pts were included in 8 centers from 11/2006 to 12/2009. Most<br />
of <strong>the</strong> 35 eligible pts (male, 63%; median age, 54 yrs [range, 33-75]) had extensive<br />
disease (≥ 4 CRLM, 88%; bilobar CRLM, 91%). Pts received a median of 10 cycles<br />
(range, 1-41). Main severe toxicity was abdominal pain (40%), neutropenia (37%),<br />
peripheral neuropathy (34%) and rash (29%). Among 32 evaluable pts, ORR was<br />
87% and DCR was 97%. Among <strong>the</strong> evaluable pts with wt KRAS (n = 27) or wt<br />
KRAS/BRAF (n = 24) tumor status, ORR were 89% and 96% and DCR 96% and<br />
100%, respectively. Overall, 23 of <strong>the</strong> 35 pts (66%) underwent curative-intent<br />
resection and/or radiofrequency ablation (wt KRAS pts, 21 [70%]; wt KRAS/BRAF<br />
pts, 20 [74%]). After a median follow-up of 48 months, median PFS was 29 months<br />
(median OS, not reached).<br />
Conclusions: First-line HAI oxaliplatin plus iv LV5FU2 and cetuximab seems<br />
feasible and highly effective in pts with unresectable CRLM.<br />
Disclosure: D. Malka: Membership on an advisory board: Roche Research funding:<br />
Amgen, Merck Serono, Sanofi-Aventis. M. Ducreux: Membership on an advisory<br />
board: Roche, Pfizer, Sanofi-Aventis, Merck Serono, Amgen Research funding: Roche,<br />
Merck Serono, Pfizer. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
581P SENSITIVITY ANALYSES OF PROGRESSION-FREE SURVIVAL<br />
(PFS) OF AFLIBERCEPT-FOLFIRI VERSUS PLACEBO-FOLFIRI<br />
IN METASTATIC COLORECTAL CANCER (MCRC): RESULTS<br />
FROM THE VELOUR STUDY<br />
E. Van Cutsem 1 , J. Tabernero 2 , R. Lakomy 3 , J. Prausova 4 , P. Ruff 5 ,<br />
V. Moiseyenko 6 , D. Ferry 7 , E. Boelle 8 , J. McKendrick 9 , C. Allegra 10<br />
1 Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, BELGIUM,<br />
2 Oncology Department, Vall d’Hebron University HospitalMedical Oncology<br />
Service, Barcelona, SPAIN, 3 Department of Clinical Oncology, Masaryk Memorial<br />
Cancer Institute, Brno, CZECH REPUBLIC, 4 Oncology, University Hospital Motol,<br />
Prague, CZECH REPUBLIC, 5 Medical Oncology, University of Witwatersrand<br />
Medical School, Johannesburg, SOUTH AFRICA, 6 Oncology, St-Petersburg<br />
Medical Academy, St-Petersburg, RUSSIAN FEDERATION, 7 Oncology, Box Hill<br />
Hospital, West Midlands, UNITED KINGDOM, 8 Research and Development,<br />
Sanofi, Vitry-sur-Seine, FRANCE, 9 Oncology, Box Hill Hospital, Victoria,<br />
AUSTRALIA, 10 Oncology, University of Florida, Gainesville, FL, UNITED STATES<br />
OF AMERICA<br />
Background: The VELOUR study [NCT00561470] in previously treated mCRC<br />
showed significant improvement in overall survival (13.5 vs 12.06 months; P =<br />
0.0032) and PFS (6.9 vs 4.67 months; P = 0.00007) with aflibercept-FOLFIRI vs<br />
placebo-FOLFIRI. Two sensitivity analyses (SAs) were performed to assess robustness<br />
of PFS observed in <strong>the</strong> primary analysis.<br />
Methods: In <strong>the</strong> primary PFS analysis, an Independent Review Committee (IRC)<br />
assessed disease progression per radiological tumor progression. The primary PFS<br />
analysis was performed at a conservative α level of 0.0001. In SA #1, patients with<br />
documented radiological progression or death occurring >9 weeks after <strong>the</strong> last valid<br />
tumor assessment without progression and patients who received fur<strong>the</strong>r anti-cancer<br />
<strong>the</strong>rapy without documented progression were censored at <strong>the</strong> last valid tumor<br />
assessment date. In SA #2, PFS was per <strong>the</strong> investigators’ assessment of lesions;<br />
clinical progression was considered as an event.<br />
ix198 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Results: SA #1 (Table) showed significant improvement in PFS with<br />
aflibercept-FOLFIRI compared to placebo-FOLFIRI (P < 0.00001), thus confirming<br />
primary PFS analysis. SA #2 also showed an improvement in PFS with aflibercept vs<br />
placebo; difference was not significant (P = 0.0017) at <strong>the</strong> 0.0001 α level.<br />
Discrepancies between IRC and investigators’ assessments were noted in placebo (n<br />
= 273, 45.8%) and aflibercept (n = 231, 39.3%) arms. An unstratified log-rank test<br />
comparing primary PFS in <strong>the</strong> two arms was consistent with <strong>the</strong> stratified analysis,<br />
showing a significant difference in PFS with aflibercept (P = 0.00005). Aflibercept<br />
showed typical anti-VEGF side effects.<br />
Conclusion: The data from <strong>the</strong>se PFS sensitivity analyses (SAs) are consistent with<br />
<strong>the</strong> primary analysis of PFS in VELOUR, fur<strong>the</strong>r supporting <strong>the</strong> statistically<br />
significant and clinically meaningful improvement in PFS seen in <strong>the</strong> primary<br />
analysis. Funded by Sanofi & Regeneron<br />
Analysis: PFS<br />
(months) Placebo N = 614 Aflibercept N = 612 HR [99.99% CI]<br />
Primary: 4.67 4.07 – 5.55 6.90 5.88 – 7.85 0.758 [0.578 – 0.995]<br />
SA #1: 4.53 4.07 – 5.68 6.97 6.05 – 8.51 0.654 [0.477 – 0.895]<br />
SA #2: 4.50 4.04 – 5.55 6.24 5.49 – 7.19 0.814 [0.630 – 1.052]<br />
Disclosure: E. Van Cutsem: I have received research funding from Sanofi.<br />
J. Tabernero: I have an advisory relationship with sanofi, for which I have been<br />
compensated. R. Lakomy: I have received research funding from Sanofi. P. Ruff: I<br />
have received honorarium from Amgen, Merck AG, Roche, Sanofi and Pfizer. I have<br />
received research funding from Amgen, Merck AG, Sanofi and Pfizer. I have received<br />
travel grants from Amgen, Roche, and Pfizer. D. Ferry: I have an advisory<br />
relationship with Sanofi. I have received honorarium from Sanofi. E. Boelle: I am an<br />
employee of Sanofi. C. Allegra: I have an advisory relationship with Sanofi. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
582P A PHASE II STUDY OF COMBINED CETUXIMAB, IRINOTECAN,<br />
OXALIPLATIN AND UFT (ESCOUT) IN PATIENTS WITH<br />
ADVANCED COLORECTAL CANCER (ACRC) INCORPORATING<br />
ANALYSIS OF CIRCULATING TUMOUR CELLS (CTCS)<br />
M. Krebs 1 , S. Gollins 2 , I. Chau 3 , J. Hasan 4 , M. Braun 4 , K. Morris 1 , J. Beech 4 ,<br />
G. Adaway 4 , C. Dive 1 , M.P. Saunders 4<br />
1 Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer<br />
Research, Manchester, UNITED KINGDOM, 2 Clinical Oncology, North Wales<br />
Cancer Treatment Centre, Wales, UNITED KINGDOM, 3 Medicine, Royal Marsden<br />
Hospital, Sutton, UNITED KINGDOM, 4 Medical Oncology, The Christie NHS<br />
Foundation Trust, Manchester, UNITED KINGDOM<br />
Introduction: Patients (pts) with ≥3 CTCs/7.5ml blood at baseline, enumerated by<br />
<strong>the</strong> CellSearch® (Veridex) system, have poor overall survival (OS)1. CTC guided<br />
treatment strategies may improve pt outcomes. This study investigated <strong>the</strong> efficacy of<br />
combining 4 active agents and evaluated CTC numbers for prognostic and<br />
pharmacodynamic utility.<br />
Methods: Pts with previously untreated, inoperable, ACRC and wtKRAS were<br />
eligible. Chemo<strong>the</strong>rapy was administered every 28 days with Cetuximab 400 mg/m 2<br />
D1 & D15 and UFT 250 mg/m 2 with calcium folinate 30mg TDS D1-21. UFT dose<br />
was reduced by 1 caps/day for grade 2/3 diarrhoea. Irinotecan 180 mg/m 2 D1 and<br />
oxaliplatin 100 mg/m 2 D15 alternated to reduce long-term toxicity of each drug.<br />
Treatment was continued until disease progression. The primary end-point was<br />
response rate (RR) and secondary endpoints included progression free survival (PFS),<br />
OS, toxicity and CTC number. Blood samples (7.5ml) for CTC analysis were drawn<br />
at baseline and D15. CTCs were enumerated using <strong>the</strong> CellSearch® system. Results:<br />
Forty-eight pts were recruited; 46 were evaluable for response and 42 for CTC<br />
enumeration. A 67% RR was achieved with disease control in 91% - CR 2 pts (4%),<br />
PR 29 (63%) & SD in 11pts (24%). Two pts with inoperable colonic tumours had<br />
curative resections after chemo<strong>the</strong>rapy; no patients had liver only disease. Grade 3<br />
toxicities included diarrhoea (21%), lethargy (17%), neutropenia (8%), paras<strong>the</strong>sia<br />
(17% G2, no G3) and alopecia (4% G2). Only 14 pts have died so OS is expected to<br />
increase with longer review. At baseline 50% pts had ≥3 CTCs suggesting this cohort<br />
comprised a poor prognostic group; median PFS/OS of <strong>the</strong>se pts was 8.5/18.8<br />
months(m), considerably better than expected (cf 6.1/11.6m in Cohen1). Pts with 5 Ug/L<br />
(primary tumor is a “secretor”) whilst 50.5% did not have elevated pre-op CEA<br />
(“non-secretor”). The pre-op CEA value is prognostic (continuous variable, p <<br />
0.01). During follow-up, all non-secretors and 58% of secretors achieved a trough<br />
CEA < 5 Ug/L. Achieving a trough CEA 5 Ug/<br />
L prior to relapse was observed in 51% of all patients. This new rise was more<br />
likely to be observed among patients whose initial primary was secretory (p <<br />
0.01). The median time from new rise in CEA to clinical relapse was 2.4 months.<br />
This was not different between initial secretors and non-secretors. At clinical<br />
relapse, 82% of initial secretors vs 47% of initial non-secretors had elevated CEA<br />
(p < 0.01).<br />
Conclusions: Pre-operative CEA levels prior to initial surgery influence CEA<br />
dynamics post curative resection in patients with recurrent colorectal cancer. Among<br />
secretors, fall to baseline CEA is associated with longer time to recurrence. Among<br />
all patients, a new rise in CEA is more likely to occur in patients whose initial<br />
primary is secretory. Once this new rise occurs, median time to recurrence is 2.4<br />
months and this duration is not dependent on initial secretory status.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
584P FDG-PET TUMOR LOAD PARAMETERS MEASURED BY TOTAL<br />
LESION GLYCOLYSIS AS PREDICTORS OF TREATMENT<br />
RESPONSE AND OUTCOME IN METASTATIC COLORECTAL<br />
CANCER<br />
H. El Mansy 1 , C. Garcia 2 , A. Deleporte 1 , L. Ameye 3 , A. Hendlisz 1 , P. Flamen 2<br />
1 Medical Oncology, Institut Jules Bordet, Brussels, BELGIUM, 2 Nuclear<br />
Medicine, Institut Jules Bordet, Brussels, BELGIUM, 3 Data Centre, Institute Jules<br />
Bordet, Brussels, BELGIUM<br />
Objectives: Early metabolic response measured by <strong>the</strong> change of FDG maximum<br />
Standardized Uptake Value (SUVmax) on PET-CT after 1 cycle of chemo<strong>the</strong>rapy in<br />
patients with metastatic colorectal cancer (mCRC) can predict negative objective<br />
response and is correlated to Overall Survival (OS) (Hendlisz et al. 2011). The aim of<br />
this work is to assess <strong>the</strong> correlation between <strong>the</strong> change in FDG-PET whole body<br />
metabolic tumoral load parameters and <strong>the</strong> RECIST response, progression free<br />
survival (PFS), OS.<br />
Methods: FDG-PET/CT scans were performed at baseline and on Day 14, in 41<br />
patients with unresectable mCRC undergoing a biweekly chemo<strong>the</strong>rapy regimen.<br />
Patients were followed-up for up to 28 months. The change in Functional Tumor<br />
Volume (FTV) and Total Lesion Glycolysis (TLG) (TLG = FTV x SUVmean) of all<br />
<strong>the</strong> lesions was calculated using a fixed threshold segmentation algorithm (threshold<br />
for segmentation = SUV mean of 30 mm sphere in <strong>the</strong> right lobe of <strong>the</strong> liver plus 3<br />
standard deviations) corrected to lean body mass (Wahl et al 2009). Predictive and<br />
prognostic value was tested through correlation with RECIST response (using<br />
independent dedicated CT), PFS and OS. A cutoff value for TLG responding patients<br />
was set at 40% or more decrease in <strong>the</strong> baseline value.<br />
Results: 39 patients were evaluable for analysis. The median OS was 20 months (95%<br />
CI, 10 to 28), <strong>the</strong> change in whole body FTV and TLG were significantly related to<br />
RECIST response (p-value: 0.015 and 0.0038), to PFS (P-value: 0.009, 0.018) and to<br />
OS (p-value: 0.002, 0.0027). Patients with > 40% decrease in TLG have better PFS:<br />
median 12 months compared to median 3 months in <strong>the</strong> rest of <strong>the</strong> patients [log<br />
rank test p-value 0.004; HR 0.31 (95% CI, 0.14 to 0.72)], and a better median OS 27<br />
months compared to 11 months [log rank test p-value 0.05; HR 0.38 (95% CI, 0.14<br />
to 1.04)].<br />
Conclusions: Changes in <strong>the</strong> metabolic tumoral load parameters after one cycle of<br />
standard chemo<strong>the</strong>rapy for mCRC are predictors of RECIST response, progression<br />
free and overall survival.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds397 | ix199
585P CHANGES IN THE INTESTINAL ENVIRONMENTS OF<br />
PATIENTS WITH COLORECTAL CANCER OR ADENOMA<br />
S. Ohigashi 1 , K. Sudo 1 , H. Onodera 1 , D. Kobayashi 2 , O. Takahashi 3 ,<br />
T. Takahashi 4 , T. Asahara 4 , K. Nomoto 4<br />
1 Gastroenterological Surgery, St. Luke’s International Hospital, Tokyo, JAPAN,<br />
2 General Internal Medicine, St. Luke’s International Hospital, Tokyo, JAPAN,<br />
3 Center for Clinical Epidemiology, St. Luke’s Life Science Institute, Tokyo,<br />
JAPAN, 4 Microbiological Research, Yakult Central Institute, Tokyo, JAPAN<br />
Background: An increasing amount of evidence suggests a role for microbiota in<br />
colorectal cancer (CRC). However, it remains unclear whe<strong>the</strong>r microbial dysbiosis is<br />
<strong>the</strong> cause or <strong>the</strong> result of CRC onset. We analyzed <strong>the</strong> intestinal environments to<br />
determine whe<strong>the</strong>r <strong>the</strong> changes differed with <strong>the</strong> stage of CRC.<br />
Patients and methods: We analyzed 13 groups of microbiota, 8 types of organic<br />
acids, and pH in fecal matter obtained from <strong>the</strong> following groups: individuals with<br />
CRC, individuals with adenoma, and individuals with normal intestinal tracts.<br />
Ninety-three patients with CRC and 49 healthy individuals (22 with adenoma and 27<br />
without adenoma) were enrolled. The fecal microbiota was identified using reverse<br />
transcription-quantitative PCR.<br />
Results: The counts of total bacteria (10.3 ± 0.7 vs. 10.8 ± 0.3 log 10 cells/g of feces; P<br />
< 0.001), 5 groups of obligate anaerobe (Clostridium coccoides group, C. leptum<br />
subgroup, Bacteroides fragilis group, Bifidobacterium, and Atopobium cluster), and 2<br />
groups of facultative anaerobes (Enterobacteriaceae and Staphylococcus) were<br />
significantly lower in <strong>the</strong> cancer group than in <strong>the</strong> healthy individuals. While <strong>the</strong><br />
concentrations of short chain fatty acids (SCFA) such as acetic acid, propionic acid,<br />
and butyric acid were significantly decreased in <strong>the</strong> CRC group, <strong>the</strong> pH was<br />
increased in <strong>the</strong> CRC group (7.4 ± 0.8 vs. 6.9 ± 0.6; P < 0.001). Comparison among<br />
<strong>the</strong> CRC, adenoma, and non-adenoma groups revealed that fecal SCFAs<br />
concentrations and pH in <strong>the</strong> adenoma group were intermediate to <strong>the</strong> CRC group<br />
and <strong>the</strong> non-adenoma group. Within <strong>the</strong> CRC group, no differences in ei<strong>the</strong>r<br />
microbiota or organic acids were observed among T-stages or Dukes stages.<br />
Conclusions: CRC patients showed significant changes in <strong>the</strong> fecal microbiota, SCFA<br />
concentrations, and pH. These changes are not a result of CRC progression but are<br />
involved in CRC onset.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
586P DOES THE COMPLIANCE TO ADJUVANT CHEMOTHERAPY<br />
DEPEND ON NEOADJUVANT RADIATION THERAPY<br />
MODALITY?<br />
K. Chan 1 , T. Vuong 2 , P. Kavan 2 , T. Niazi 2 , C. Holcroft 3 , E. Ferland 4 , J. Sturgeon 2 ,<br />
D. Melnychuk 2 , T. Alcindor 2 , G. Batist 2<br />
1 Medicine, McGill University, Montreal, QC, CANADA, 2 Oncology, McGill<br />
University, Montreal, QC, CANADA, 3 Clinical Epidemiology, McGill University,<br />
Montreal, QC, CANADA, 4 Oncology, Pierre Boucher Hospital, Longueuil, QC,<br />
CANADA<br />
One of <strong>the</strong> standard approach for <strong>the</strong> locally advanced rectal cancer patients is<br />
neoadjuvant chemoradiation <strong>the</strong>rapy (CRT), followed by total mesorectal excision<br />
(TME) and adjuvant chemo<strong>the</strong>rapy (ACT). ACT compliance has been a major<br />
concern for <strong>the</strong>se patients. In this study we assessed <strong>the</strong> possible impact of<br />
neoadjuvant radiation <strong>the</strong>rapy (RT) modality on ACT compliance.<br />
Methods: We, retrospectively, analyzed <strong>the</strong> data of 114 locally advanced rectal cancer<br />
patients, after neoadjuvant RT and referred for consideration of ACT, at McGill<br />
University hospitals. ACT compliance was defined as pts who received at least 6 cycles<br />
of ACT and optimal dose compliance (ODC) was defined as pts who received at least<br />
85% of <strong>the</strong> recommended chemo<strong>the</strong>rapy dose. Neoadjuvant RT modalities included<br />
high dose rate endorectal brachy<strong>the</strong>rapy (HDREBT) alone with no chemo<strong>the</strong>rapy;<br />
conformal external beam RT (3D-CRT) with chemo<strong>the</strong>rapy and intensity-modulated<br />
RT (IMRT) with chemo<strong>the</strong>rapy. We applied a chi-square test for 2-way categorical<br />
associations and multivariable logistic regression with compliance as <strong>the</strong> outcome.<br />
Results: The data of 114 consecutive locally advanced rectal cancer patients, mean age<br />
64y (range:32-85), were analyzed. 41 patients (36%) were treated with neoadjuvant<br />
HDREBT alone, 33 (29%) with 3D-CRT and chemo<strong>the</strong>rapy, and 40 (35%) with IMRT<br />
and chemo<strong>the</strong>rapy. The HDREBT dose was 26 Gy in 4 consecutive fractions alone and<br />
that of 3D-CRT and IMRT was 50 Gy in 25 fractions, Monday to Friday with<br />
concurrent 5-FU. 41 pts (36%) received FOLFOX, 13 (11%) XELOX, 11 (10%) 5-FU, 7<br />
(6%) Xeloda and 9 (8%) received o<strong>the</strong>r chemo<strong>the</strong>rapy, while 33 pts refused <strong>the</strong> ACT.<br />
ACT compliance after HDREBT, 3D-CRT and IMRT were respectively: 70.7%, 45.5%,<br />
37.5% (p = 0.008). Age was a negative factor (p < 0.001) but not gender (p = 0.61) on<br />
ACT compliance. In a multivariate analysis and adjusting for age and gender, HDREBT<br />
continued to lead to better ACT compliance compared to 3D-CRT (p = 0.020) and<br />
IMRT (p < 0.001) and <strong>the</strong>re was no difference clinically between EBRT and IMRT.<br />
Similarly, ODC rate for HDREBT, 3D-CRT and IMRT were respectively: 63.4%, 21.2%<br />
and 32.5% (p = 0.001).<br />
Conclusion: Our data suggests that neoadjuvant HDREBT yields significantly higher<br />
rates of ACT compliance and ODC compared to 3D-CRT with chemo<strong>the</strong>rapy and<br />
IMRT with chemo<strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
587P POST-MARKETING SURVEY OF PANITUMUMAB IN<br />
JAPANESE PATIENTS WITH UNRESECTABLE COLORECTAL<br />
CANCER: INTERIM REPORT OF 3,005 PATIENTS<br />
K. Sugihara 1 , N. Boku 2 , A. Gemma 2 , N. Yamazaki 2 , K. Muro 2 , T. Hamaguchi 2 ,<br />
T. Yoshino 2 , H. Ueno 3 , A. Ohtsu 2<br />
1 Surgical Oncology, Tokyo Medical and Dental University, Tokyo, JAPAN,<br />
2 Vectibix Safety Evaluation Committee, Vectibix Appropriate Use Committee,<br />
Osaka, JAPAN, 3 Pharmacovigilance Department, Takeda Pharmaceutical<br />
Company Limited, Osaka, JAPAN<br />
Background: Panitumumab (P-mab) was approved in April 2010 in Japan for<br />
treatment of unresectable, advanced or recurrent colorectal cancer with wild-type<br />
KRAS, both in mono<strong>the</strong>rapy and in combination with chemo<strong>the</strong>rapy for all lines of<br />
treatment.<br />
Objectives: To investigate <strong>the</strong> status of post-marketing use and adverse drug<br />
reactions (ADRs) of P-mab in Japan, and to assess <strong>the</strong> safety and efficacy of P-mab<br />
in Japanese patients.<br />
Methods: All-case surveillance (all patients were registered before starting P-mab<br />
<strong>the</strong>rapy by <strong>the</strong> central registration method) was conducted since <strong>the</strong> product launch.<br />
All <strong>the</strong> patients were examined for eligibility requirements such as KRAS genotype,<br />
patient performance status and combination regimen and registered for this study<br />
before starting P-mab <strong>the</strong>rapy.<br />
Results: Between June 2010 until November 2010, 3,091 patients were enrolled.<br />
Background information of <strong>the</strong> 3,005 patients that were collected by October 2011<br />
was as follows: male/female: 1,912/1,093, mean age: 65.0 years (range 18–90),<br />
colorectal cancer: 3,005, KRAS genotype wild/ mutant/ not determinable: 2,925/3/77,<br />
first line/ second line/third line or later treatment: 312/542/2,150, PS 0-1/2/3/4:2,743/<br />
236/22/4 and P-mab mono<strong>the</strong>rapy/combination with chemo<strong>the</strong>rapy: 1,232/1,766.<br />
Combination regimens: FOLFOX/ FOLFIRI/ o<strong>the</strong>r anticancer agents were 563/1,004/<br />
456. Overall incidence of ADRs was 83.7%, Grade 3 or higher ADRs were 24.7%.<br />
Incidence of ADRs of special interest for this surveillance: skin disorder / interstitial<br />
lung disease/ infusion reaction/ electrolyte abnormality/ cardiac disorder were 77.8%/<br />
1.3%/ 1.5%/ 18.3%/ 0.2%. The median survival time of patients with P-mab<br />
mono<strong>the</strong>rapy as third line treatment was 10.3 months.<br />
Conclusion: P-mab was administered to patients who met <strong>the</strong> eligibility<br />
requirements and <strong>the</strong> appropriate use was confirmed. The safety profile of P-mab in<br />
<strong>the</strong> post-marketing use was similar to that previously reported in <strong>the</strong> clinical trials.<br />
The risk/benefit balance for use of P-mab in patients with unresectable colorectal<br />
cancer remains favorable.<br />
Disclosure: K. Sugihara: Membership on advisory board: Takeda, Merck Serono,<br />
Chugai Sponsored research and honoraria: Takeda, Taiho, Chugai, Yakult,<br />
Bristol-Myers Squibb, Merck Serono, Daiichi-sankyo. Sponsored research: Kyowa<br />
Hakko Kirin No o<strong>the</strong>r conflict of interest. N. Boku: Membership on advisory board<br />
and honoraria: Takeda No o<strong>the</strong>r conflict of interest. A. Gemma: Membership on<br />
advisory board and honoraria: Takeda No o<strong>the</strong>r conflict of interest. N. Yamazaki:<br />
Membership on advisory board and honoraria: Takeda, Bristol-Myers Squibb, Merck<br />
Serono No o<strong>the</strong>r conflict of interest. K. Muro: Membership on advisory board:<br />
Takeda Honoraria: Takeda, Yakult, Chugai, Taiho, Bristol-Myers Squibb,<br />
Daiichi-sankyo, Merck Serono No o<strong>the</strong>r conflict of interest. T. Hamaguchi:<br />
Membership on advisory board: Takeda Honoraria: Takeda, Daiichi-sankyo No o<strong>the</strong>r<br />
conflict of interest. T. Yoshino: Sponsored research: Bayer, Taiho, Daiichi-sankyo,<br />
Quintiles Membership on advisory board: Takeda Honoraria: Chugai, Takeda,<br />
Bristol-Myers Squibb, Yakult, Merck Serono No o<strong>the</strong>r conflict of interest. H. Ueno:<br />
Emproyee of Takeda Pharmaceutical Co., Ltd. who sponsored this survey No o<strong>the</strong>r<br />
conflict of interest. A. Ohtsu: Membership on advisory board,consultant: Takeda,<br />
Daiichi-sankyo, Novartis Pharma, Chugai, Taiho Honoraria: Takeda, Daiichi-sankyo,<br />
Taiho, GlaxoSmithKline, Pfizer, Yakult, Bristol-Myers Squibb, Merck Serono No<br />
o<strong>the</strong>r conflict of interest.<br />
588P HRQOL DURING ADJUVANT CHEMOTHERAPY WITH<br />
CAPECITABINE IN PATIENTS AFTER SURGERY FOR COLON<br />
CANCER: ADDITIONAL STUDY OF JFMC37-0801<br />
Y. Kinugasa 1 , T. Shiroiwa 2 , M. Nakamura 3 , R. Nezu 4 , S. Hazama 5 , T. Fukuda 6 ,<br />
M. Ishiguro 7 , J. Sakamoto 8 , S. Saji 8 , N. Tomita 9<br />
1 Colon and Rectal Surgery, Shizuoka Cancer Center, Shizuoka, JAPAN,<br />
2 Department of Hygiene and Public Health, Teikyo University School of Medicine,<br />
Tokyo, JAPAN, 3 Aizawa Comprehensive Cancer Center, Aizawa Hospital,<br />
Nagano, JAPAN, 4 Department of Surgery, Osaka Rosai Hospital, Osaka, JAPAN,<br />
5 Department of Digestive Surgery and Surgical Oncol, Yamaguchi University<br />
Graduate School of Medicine, Yamaguchi, JAPAN, 6 Center for Public Health<br />
Informatics, National Institute of Public Health, Saitama, JAPAN, 7 Department of<br />
Surgical Oncology, Tokyo Medical and Dental University, Graduate School,<br />
Tokyo, JAPAN, 8 Japanese Foundation for Multidisciplinary Treatment of Cancer,<br />
Tokyo, JAPAN, 9 Division of Lower Gi, Department of Surgery, Hyogo College of<br />
Medicine, Hyogo, JAPAN<br />
Objectives: The JFMC37-0801 trial is a phase III trial designed to validate<br />
superiority of 1-year treatment with capecitabine to 6 months treatment as adjuvant<br />
chemo<strong>the</strong>rapy for stage III colon cancer. Health related quality of life (HRQOL) and<br />
ix200 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
cost-effectiveness have been evaluated as an additional study. We analyzed impact of<br />
prolonged treatment with capecitabine on patients’ HRQOL.<br />
Methods: Capecitabine (2500 mg/m 2 /day) was orally given on days 1-14, followed by<br />
a 7-day rest. Enrolled patients were randomly assigned to group A (received 8<br />
courses of capecitabine) or group B (16 courses). In patients agreed to participate to<br />
<strong>the</strong> additional study, HRQOL was evaluated by self-administered questionnaire at <strong>the</strong><br />
start of <strong>the</strong> protocol treatment, 3, 6, 9, 12, 15 and 18 months. The questionnaire<br />
includes Functional Assessment of Cancer <strong>the</strong>rapy-C (FACT-C) and EuroQol 5<br />
Dimension (EQ-5D).<br />
Results: In 1306 patients enrolled to <strong>the</strong> JFMC37-0801 trial, HRQOL of 171<br />
participants (81 in group A, 90 in group B) were evaluated. Mean age of <strong>the</strong> patients<br />
in group A and B was 63.3 and 64.5 years-old, respectively. Among a total of 1197<br />
points of survey, 959 questionnaires (80.1%) were retrieved. Recovery rates of<br />
questionnaires tended to decrease with time after finishing treatment. Through <strong>the</strong><br />
entire survey period, mean score of FACT-C (96.9-103) and EQ-5D (0.85-0.93) were<br />
satisfactory. In longitudinal analysis of <strong>the</strong> change from baseline score, <strong>the</strong> scores<br />
tended to increase after finishing <strong>the</strong> treatment period in both group A and group<br />
B. Significant difference between <strong>the</strong> score of group A and group B was not observed<br />
in each survey point. No difference by age and tumor stage was also observed.<br />
Conclusions: HRQOL of <strong>the</strong> patients received postoperative adjuvant chemo<strong>the</strong>rapy<br />
with capecitabine was satisfactory through <strong>the</strong> survey period. There was no<br />
significant difference of HRQOL between 8 and 16 courses of capecitabine treatment.<br />
Disclosure: J. Sakamoto: Junichi Sakamoto is a director of <strong>the</strong> Japanese Foundation<br />
for Multidisciplinary Treatment of Cancer (JFMC). S. Saji: Shigetoyo Saji is a director<br />
of <strong>the</strong> Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC). All<br />
o<strong>the</strong>r authors have declared no conflicts of interest.<br />
589P SURVIVAL ANALYSIS OF 1,061 PATIENTS WITH<br />
SYNCHRONOUS COLORECTAL HEPATIC METASTASES<br />
J. Xu, Y. Zhong, D. Zhu, Y. Wei, L. Ren<br />
Department of General Surgery, Zhongshan Hospital Fudan University,<br />
Shanghai, CHINA<br />
Objectives: To investigate survival and to identify prognostic factors in patients with<br />
synchronous colorectal hepatic metastasis.<br />
Methods: Clinical, pathologic and follow-up data were retrospectively collected from<br />
1,061 consecutive patients treated for synchronous colorectal hepatic metastases at<br />
Zhongshan Hospital between 2000 and 2010. The prognostic values of different<br />
factors were studied through univariate and multivariate analyses.<br />
Results: For patients with resectable hepatic metastases, <strong>the</strong> total expense per patient<br />
in <strong>the</strong> simultaneous resection group was lower than that in <strong>the</strong> staged resection<br />
group (25,693 RMB vs. 34,129 RMB, P < 0.050), and <strong>the</strong>re were no significant<br />
differences in <strong>the</strong> complication rates (24.5% vs. 20.5%) or median overall survival<br />
(48.5 vs. 47.0 months) between <strong>the</strong> simultaneous and staged resection groups. For<br />
patients with unresectable hepatic metastases, resection of <strong>the</strong> primary tumor was<br />
associated with improved median overall survival (19.0 vs. 9.3 months, P < 0.001). Six<br />
factors were found to be independent predictors of poor survival by multivariate<br />
analysis: a poorly differentiated primary tumor, number of hepatic metastases ≥ 4,<br />
maximum hepatic metastasis size ≥ 5 cm, extra-hepatic metastases, no resection of<br />
<strong>the</strong> primary tumor and no surgical treatment of hepatic metastases. Giving one point<br />
to each of <strong>the</strong> above factors, all of <strong>the</strong> patients were divided into low-risk (0-1<br />
points), medium-risk (2-3 points) and high-risk (4-6 points) groups with 5-year<br />
survival rates of 51%, 16% and 0%, respectively (P < 0.001).<br />
Conclusions: Simultaneous resection of <strong>the</strong> primary tumor and hepatic metastases<br />
were accepted as prognostic factors in patients with resectable synchronous colorectal<br />
hepatic metastases. Resection of <strong>the</strong> primary tumor was recommended at <strong>the</strong> right<br />
time for asymptomatic patients with unresectable hepatic metastases. A prediction<br />
model using <strong>the</strong> above six factors can be used to guide <strong>the</strong> clinical management of<br />
patients with synchronous colorectal hepatic metastases.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
590P PHASE 1B STUDY OF A NOVEL ORAL PPAR-GAMMA<br />
AGONIST, EFATUTAZONE IN COMBINATION WITH FOLFIRI IN<br />
JAPANESE PATIENTS WITH METASTATIC COLORECTAL<br />
CANCER WHO FAILED THE FIRST-LINE THERAPY<br />
T. Yoshino 1 , S. Yuki 2 , K. Yamazaki 3 , N. Machida 3 , Y. Komatsu 4 , R. Oyama 5 ,<br />
Y. Yachi 5 , H. Onuma 5 , A. Ohtsu 6<br />
1 Department of Gastroenterology & GI Oncology, National Cancer Center<br />
Hospital East, Kashiwa, JAPAN, 2 Department of GI, Hokkaido University<br />
Hospital, Hokkaido, JAPAN, 3 Division of Gastrointestinal Oncology, Shizuoka<br />
Cancer Center, Shizuoka, JAPAN, 4 Cancer Center, Hokkaido University Hospital,<br />
Hokkaido, JAPAN, 5 Clinical Developmental Department II, Daiichisankyo CO.,<br />
LTD, Tokyo, JAPAN, 6 Research Center for Innovative Oncology, National Cancer<br />
Center Hospital East, kashiwa, JAPAN<br />
Background: Efatutazone is a highly-selective peroxisome proliferator-activated<br />
receptor gamma (PPAR-gamma) agonist of thiazolidinedione (TZD) class, which<br />
shows higher potency than rosiglitazone. The recommended dose (RD) is 0.50 mg<br />
twice-daily (BID) in accordance with pharmacokinetics (PK), pharmacodynamics<br />
(PD, adiponectin) and safety analyses in US and Japanese phase 1 studies. This study<br />
assessed <strong>the</strong> safety, tolerability, antitumor activity, PK, PD, and determined <strong>the</strong> RD<br />
of efatutazone in combination with FOLFIRI in Japanese patients.<br />
Materials and methods: This was an open-label, dose-escalation study using a 3 + 3<br />
design. Each patient participated in only 1 dose group and received oral efatutazone<br />
0.25 or 0.50 mg BID with every 2-week administration of FOLFIRI (Irinotecan 180<br />
mg/m 2 IV infusion over 90 minutes,l-LV 200 mg/m 2 IV infusion over 120 minutes,<br />
and 5-FU IV continuous infusion 2400 mg/m 2 over 46 hours). After determining <strong>the</strong><br />
RD of efatutazone, 9 additional patients were enrolled for <strong>the</strong> fur<strong>the</strong>r assessment of<br />
efatutazone. PK samples for efatutazone, Irinotecan and SN-38 were collected to<br />
assess <strong>the</strong> drug–drug interaction. PD samples were also collected. All patients<br />
provided written informed consent.<br />
Results: A total of 15 patients were enrolled (7 male and 8 female; median age of 63<br />
years old, range: 41–73 years). Dose-limiting toxicities were not observed, and <strong>the</strong><br />
maximum tolerated dose (MTD) was not reached. Most patients experienced edema<br />
(80.0%) and weight increase (100.0%) which were manageable with diuretics. The<br />
most common haematological toxicities were neutropenia and anaemia, managed<br />
with supportive <strong>the</strong>rapy and/or modification of FOLFIRI. Seven out of 15 patients<br />
showed stable disease (SD). Efatutazone increased plasma adiponectin levels. Plasma<br />
concentration of efatutazone increased according to dose. Efatutazone doesn’t affect<br />
plasma concentration of Irinotecan and SN-38.<br />
Conclusions: Efatutazone in combination with FOLFIRI is a novel anticancer<br />
<strong>the</strong>rapy, which is tolerated in Japanese patients with metastatic colorectal cancer.<br />
Although <strong>the</strong> MTD was not reached, 0.50 mg BID, corresponding to <strong>the</strong> RD in<br />
western patients, was selected as <strong>the</strong> RD for Japanese patients based on safety<br />
analyses. Full safety data and clinical activity data will be presented.<br />
Disclosure: T. Yoshino: I have honoraria with Chugai, Takeda, Bristol-Myers<br />
Squibb, Yakult and Merck Serono. I have research funding from Bayer,Taiho,<br />
Daiichi-sankyo and Quintiles. I have received consulting fee from Takeda. Y.<br />
Komatsu: Y.Komatsu has honoraria with DAIICHI SANKYO COMPANY,<br />
LIMITED, YAKULT HONSHA CO., LTD, Pfizer. Y.Komatsu has research<br />
funding from DAIICHI SANKYO COMPANY, LIMITED, YAKULT HONSHA<br />
CO., LTD, Pfizer. R. Oyama: R.Oyama is an employee of Daiichisankyo CO.,<br />
LTD. Y. Yachi: Y.Yachi is an employee of Daiichisankyo CO.,LTD. H. Onuma:<br />
H.Onuma is an employee of Daiichisankyo CO., LTD. A. Ohtsu: A.Ohtsu has an<br />
advisory role and/or honoraria with Takeda Pharmaceutical Co., Ltd, DAIICHI<br />
SANKYO, Novartis, CHUGAI PHARMACEUTICAL CO., LTD, TAIHO<br />
Pharmaceutical Co., Ltd, Glaxosmithkline, Pfizer, YAKULT HONSHA, Merck<br />
Serono, Bristol-Myers Squibb. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
591P COLON CANCER ADJUVANT MFOLFOX-6 – SURVIVAL IMPACT<br />
OF OXALIPLATIN REDUCED DOSE-INTENSITY<br />
A.F. Carneiro 1 , J. Godinho Bexiga 1 , D.S. Marques 1 , C. Faustino 1 , N. Sousa 2 ,<br />
M. Machado 2 , P. Ferreira 1 , A. Raimundo 1 , R. Fragoso 1<br />
1 Medical Oncology, Instituto Portugues de Oncologia Centro do Porto, Porto,<br />
PORTUGAL, 2 Medical Oncology/Hematology, Instituto Portugues de Oncologia<br />
Centro do Porto, Porto, PORTUGAL<br />
Background: Adjuvant colon cancer treatment may include <strong>the</strong> oxaliplatin/<br />
fluoropirimidine combination. This association has shown benefit on progression free<br />
survival (PFS) and overall survival (OS) compared to fluoropirimidine mono<strong>the</strong>rapy<br />
in <strong>the</strong>se patients. Adverse events are frequent and may cause delay on treatment<br />
delivery or drug dose reduction. The survival impact of oxaliplatin reduced dose<br />
intensity (RDI) is unknown.<br />
Objective: Evaluation of survival impact of oxaliplatin RDI in colon cancer<br />
patients treated with adjuvant mFOLFOX-6. Material and methods: A consecutive<br />
series of colon cancer patients treated with adjuvant mFOLFOX-6 at our<br />
institution between 09/2004 and 11/2009. The impact of Oxaliplatin < 75%<br />
(group A) and ≥ 75% (group B) on PFS and OS was estimated with a Cox<br />
Proportional Hazards model.<br />
Results: There were no differences in age, sex, ECOG, comorbidity, histologic grade<br />
and stage distribution between groups. Two hundred and seventy seven (277)<br />
patients were identified (53% in group A). Fifty nine percent (59%) of patients<br />
completed <strong>the</strong> 12 mFOLFOX-6 cycles and <strong>the</strong> median duration of adjuvant<br />
chemo<strong>the</strong>rapy was 6,5 months. The mean oxaliplatin dose-intensity was 71%<br />
(median 74%). Adverse events led to dose reduction and drug suspension in 53%<br />
and 40% of patients, respectively. There were 3 deaths during treatment. The main<br />
causes to RDI were grade ≥ 3 hematologic toxicity (47%) and neuropathy (12%) –<br />
median cumulative oxaliplatin dose at first neurologic severe event was 1024 mg.<br />
There were no differences in PFS and OS between RDI groups, nei<strong>the</strong>r after stage<br />
stratification.<br />
Conclusion: In our cohort patient’s characteristics and toxicity profile were similar<br />
to published trials. FOLFOX conclusion rate was inferior than <strong>the</strong> described in<br />
MOSAIC trial (59% vs 74,7%). Despite <strong>the</strong> inferior accomplishment rate, <strong>the</strong>re was<br />
no impact in PFS and OS in oxaliplatin RDI < 75% group.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds397 | ix201
592P PHASE II TRIAL OF COMBINED CHEMOTHERAPY WITH<br />
IRINOTECAN, S-1, AND BEVACIZUMAB (IRIS/BEV) IN<br />
PATIENTS WITH METASTATIC COLORECTAL CANCER<br />
-UPDATED ANALYSIS-. HOKKAIDO GASTROINTESTINAL<br />
CANCER STUDY GROUP (HGCSG) TRIAL<br />
K. Hatanaka 1 , S. Yuki 2 , T. Miyagishima 3 ,T.Kato 4 , M. Nakamura 5 , M. Kudo 6 ,<br />
M. Tateyama 7 , M. Asaka 8 , Y. Sakata 9 , Y. Komatsu 10<br />
1 Gastroenterology, Hakodate City Hospital, Hakodate, JAPAN,<br />
2 Gastroenterology, Hokkaido University Hospital, Sapporo, JAPAN, 3 Internal<br />
Medicine, Kushiro Rosai Hospital, Kushiro, JAPAN, 4 Gastoroenterology,<br />
Hokkaido Gastoroenterology Hospital, Sapporo, JAPAN, 5 Gastroenterology,<br />
Sapporo City General Hospital, Sapporo, JAPAN, 6 Gastroenterology, Sapporo<br />
Hokuyu Hospital, Sapporo, JAPAN, 7 Internal Medicine, Tomakomai Nisshou<br />
Hospital, Tomakomai, JAPAN, 8 Cancer Preventive Medicine, Hokkaido<br />
University, Sapporo, JAPAN, 9 Medical Oncology, Misawa City Hospital, Misawa,<br />
JAPAN, 10 Cancer Center, Hokkaido University Hospital, Sapporo, JAPAN<br />
Background: The FIRIS study (Muro K et al. Lancet Oncol 2010;11:853–860)<br />
previously demonstrated <strong>the</strong> non-inferiority of Irinotecan plus S-1(IRIS) to FOLFIRI<br />
for metastatic colorectal cancer(mCRC), with progression-free survival (PFS) as <strong>the</strong><br />
primary endpoint. We previously reported that IRIS plus bevacizumab (IRIS/bev) is<br />
very effective as first-line treatment (Komatsu Y et al. <strong>ESMO</strong> 2010). We now report<br />
<strong>the</strong> updated results of this study.<br />
Methods: Eligible patients had to have mCRC with a confirmed diagnosis of<br />
adenocarcinoma, an age of >20 years, ECOG performance status (PS) of 0-1, and no<br />
history of prior chemo<strong>the</strong>rapy. S-1 40-60 mg twice daily p.o. was given on days 1-14<br />
and irinotecan 100 mg/m 2 and bevacizumab 5 mg/kg i.v. were given on days 1 and 15<br />
of a 28-day cycle. The primary endpoint was safety. The secondary endpoints included<br />
overall response (OR), progression-free survival (PFS), and overall survival (OS).<br />
Results: The target number of 53 patients was enrolled as of March 2009. The results<br />
are reported for 52 patients with evaluable lesions. The clinical characteristics of <strong>the</strong><br />
patients were as follows. The median age was 63.5 years (range, 48 to 82). The male:<br />
female ratio was 3:2. The performance status on <strong>the</strong> Eastern Cooperative Oncology<br />
Group scale was 0. In January <strong>2012</strong>, on safety analysis, <strong>the</strong> incidence of grade 3 or 4<br />
neutropenia was 27%. The incidences of o<strong>the</strong>r grade 3 or 4 adverse reactions were as<br />
follows: diarrhea, 17%; anorexia, 4%; stomatitis, 2%; hypertension, 21%; and<br />
gastrointestinal perforation, 0%. The overall response rate was 63.5%. Three patients<br />
had complete response. Thirty patients had partial response, 16 had stable disease,<br />
none had progressive disease, and 3 were not evaluable. Median progression-free<br />
survival was 17.0 months and median survival time was 39.6 months.<br />
Conclusions: IRIS/Bev is a remarkably active and generally well-tolerated first-line<br />
treatment for patients with mCRC. Randomized control trial comparing this regimen<br />
with oxaliplatin containing regimen (XELOX or mFOLFOX6 plus bevacizumab:<br />
TRICOLORE study) is already started.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
593P CLINICAL OUTCOME OF SYSTEMIC CHEMOTHERAPY FOR<br />
COLORECTAL PERITONEAL CARCINOMATOSIS<br />
Y. Sasaki 1 , T. Hamaguchi 2 , Y. Yamada 3 , Y. Shimada 2 , K. Kato 2 , S. Iwasa 2 ,<br />
Y. Honma 2<br />
1 Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo,<br />
JAPAN, 2 Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo,<br />
JAPAN, 3 Division of Gastrointestinal Oncology, National Cancer Center Hospital,<br />
Tokyo, JAPAN<br />
Background: Peritoneal carcinomatosis (PC) is <strong>the</strong> second leading cause of death in<br />
patients with metastatic colorectal cancer. Despite improved survival after<br />
cytoreduction and hyper<strong>the</strong>rmic intraperitoneal chemo<strong>the</strong>rapy, systemic<br />
chemo<strong>the</strong>rapy is not typically considered.<br />
Purpose: This study investigated <strong>the</strong> characteristics and clinical outcomes of<br />
colorectal PC patients treated with systemic chemo<strong>the</strong>rapy.<br />
Methods: This was a retrospective review of patients with colorectal PC presenting to<br />
<strong>the</strong> National Cancer Center Hospital from July 2004 to October 2009. Data collected<br />
included patient characteristics, sites of metastases, chemo<strong>the</strong>rapy regimen,<br />
histopathological data, gene variations (KRAS and BRAF), and duration of survival.<br />
Results: PC was confirmed in 50 patients. The median overall survival (OS) of <strong>the</strong><br />
PC patients were similar to those of <strong>the</strong> non-PC patients (n = 133) (23 vs. 25<br />
months, p = 0.94). In <strong>the</strong> PC group, 37 patients (74%) were treated with an<br />
oxaliplatin regimen and 9 patients (18%) were treated with an irinotecan regimen<br />
as first-line chemo<strong>the</strong>rapy, among whom 15 patients (30%) also received<br />
bevacizumab combined with oxaliplatin or irinotecan. Although <strong>the</strong>re was no<br />
statistically significant difference in progression-free survival (PFS) between<br />
oxaliplatin (10 months) and irinotecan (8 months) regimens (p = 0.58), addition of<br />
bevacizumab resulted in longer PFS (18 months) compared to those without<br />
bevacizumab (9 months) (p = 0.26). The median OS for patients with isolated PC<br />
was 32 months, compared with 20 months for PC patients with extraperitoneal<br />
metastases (p = 0.08). Of 50 patients, 33 patients (66%) had available gene status<br />
Annals of Oncology<br />
results. KRAS mutations were found in 36% of patients, while BRAF mutations were<br />
identified in 20%. The treatment effect on OS in <strong>the</strong> wild-type BRAF group was<br />
greater compared to <strong>the</strong> mutant group (32 vs. 18 months, p = 0.16).<br />
Conclusion: Colorectal PC versus non-PC derive <strong>the</strong> same benefits from systemic<br />
chemo<strong>the</strong>rapy, and optimal regimens warrant fur<strong>the</strong>r prospective study.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
594P CANADIAN ECONOMIC ANALYSIS OF BEVACIZUMAB,<br />
CETUXIMAB, AND PANITUMUMAB IN THE FIRST LINE<br />
TREATMENT OF KRAS WILD-TYPE METASTATIC<br />
COLORECTAL CANCER (MCRC)<br />
D. Lawrence 1 , M. Maschio 2 , S. Yunger 3 , J. Easaw 4 , N. Aucoin 5 , M. Weinstein 6<br />
1 Health Economics & Outcomes, Optum Insight, Burlington, ON, CANADA, 2 Life<br />
Sciences, Optum Insight, Burlington, ON, CANADA, 3 Public Affairs, Hoffmann La<br />
Roche, Mississiauga, ON, CANADA, 4 Medical Oncology, Tom Baker Cancer<br />
Centre, Calgary, AB, CANADA, 5 Medical Oncology, Cité-de-la-Santé Hospital,<br />
Laval, QC, CANADA, 6 Harvard School of Public Health, Harvard University,<br />
Boston, MA, UNITED STATES OF AMERICA<br />
Background: CRC is <strong>the</strong> second leading cause of cancer death in Canada.<br />
Bevacizumab, a recombinant humanised monoclonal antibody that selectively binds<br />
to human vascular endo<strong>the</strong>lial growth factor, is approved and funded for first line<br />
mCRC use in Canada. A substudy has also confirmed its effectiveness in KRAS<br />
wild-type patients. Recent evidence has also shown clinical benefit from<br />
anti-epidermal growth factor treatments panitumumab and cetuximab in <strong>the</strong>se<br />
patients. Objective: We assessed cost-effectiveness of fluoropyrimidine-based<br />
chemo<strong>the</strong>rapy (FBC) alone and in combination with bevacizumab, panitumumab or<br />
cetuximab for first line treatment of KRAS wild-type mCRC patients.<br />
Methods: Cost-effectiveness to <strong>the</strong> Canadian health care system was estimated using<br />
separately reported trial survival and adverse event results for each comparator. We<br />
used a Markov model calibrated to progression-free/overall survival, and calculated<br />
quality-adjusted life years (QALYs). Health-state resource utilization was derived<br />
from published data and Canadian oncologist input. Health state utilities and unit<br />
prices were obtained from published literature and standard Canadian sources.<br />
Results: Results per patient over a lifetime horizon, to a maximum 10 years with 5%<br />
discounting are presented below. Comparators are ordered by total cost, and <strong>the</strong><br />
incremental cost-effectiveness ratio (ICER) of each is determined against <strong>the</strong> previous<br />
non-dominated <strong>the</strong>rapy.<br />
Comparator Total Cost Total QALYs Δ Cost Δ QALYs ICER<br />
FBC $39,061 1.354 - - -<br />
Bevacizumab + FBC $104,054 1.848 $64,993 0.494 $131,631<br />
Panitumumab + FBC $151,776 1.806 $47,722 -0.041 Dominated<br />
Cetuximab + FBC $161,596 1.865 $57,542 0.017 $3,327,501<br />
Conclusion: For first line treatment of KRAS wild-type mCRC in Canada,<br />
bevacizumab + FBC is associated with substantially lower costs than panitumumab +<br />
FBC or cetuximab + FBC. All three biologics may be associated with similar QALYs,<br />
although; this conclusion was based on <strong>the</strong> limitation of modelling life expectancy<br />
from separate trials. Given <strong>the</strong>se findings, bevacizumab seems likely to offer <strong>the</strong> best<br />
value for money for this patient population.<br />
Disclosure: D. Lawrence: Donna Lawrence is an employee of OptumInsight under<br />
contract with Roche. M. Maschio: Michael Maschio is an employee of OptumInsight<br />
under contract with Roche. S. Yunger: Simon Yunger is employee of Roche Canada.<br />
N. Aucoin: Dr. Aucoin has participated in advisory boards with Roche and Amgen.<br />
M. Weinstein: Dr. Weinstein is a consultant to OptumInsight for research under<br />
contract with Roche. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
595P THE INTERIM ANALYSIS OF NUTRITION AND IMMUNE<br />
RECOVERY AND STRESS RESPONSE AFTER LAPAROSCOPY<br />
OR OPEN SURGERY WITH FAST TRACK OR CONVENTIONAL<br />
TREATMENT (FTMDT TRIAL) IN RESECTABLE COLORECTAL<br />
CANCER<br />
K.F. Ding, D. Xu, J. Li, Y.M. Song, J.W. Wang, F.F. Sun, J.J. Zhou, J. Zhou,<br />
Y. Liu, S.Z. Zhang<br />
Department of Surgical Oncology, 2nd Affiliated Hospital of Zhejiang University,<br />
Hangzhou, CHINA<br />
Objective: To study <strong>the</strong> detailed effect of laparoscopy or open surgery with fast track<br />
or conventional treatment on patient’s postoperative nutrition and immune recovery<br />
and stress response.<br />
Methods: Patients with resectable colon cancer and high rectal cancer were<br />
randomized to 4 groups: (1) Laparoscopy with fast track treatment (LAFT); (2) Open<br />
surgery with fast track treatment (OSFT); (3) Laparoscopy with conventional<br />
ix202 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
treatment (LAC); (4) Open surgery with conventional treatment (OSC). Blood<br />
samples were collected preoperatively (baseline), and 12, 96 hours after surgery.<br />
Peripheral blood levels of albumin, prealbumin, Ig G, Ig A, Ig M and C-reactive<br />
protein (CRP) were analyzed.<br />
Results: 19 patients were randomized for LAFT group, 18 for OSFT, 17 for LAC,<br />
and 19 for OSC. The four groups were balanced with respect to patients’<br />
characteristics. Mean albumin level (in percentage from baseline) was 94.35 in <strong>the</strong><br />
LAFT group, 88.16 in <strong>the</strong> LAC group, 79.05 in <strong>the</strong> OSFT group, and 76.50 in <strong>the</strong><br />
OSC group. Only in LAFT and LAC groups, <strong>the</strong> albumin level of 96 hours was<br />
higher than that of 12 hours, indicating <strong>the</strong> better potency of postoperative<br />
recovery of nutrition status. Similarly, postoperative Ig G levels were also highest in<br />
<strong>the</strong> LAFT group and showed <strong>the</strong> same rank with albumin levels in <strong>the</strong> 4 groups.<br />
Repeated-measures (2-way ANOVA) indicated <strong>the</strong> difference of albumin and Ig G<br />
can be attributed to surgery type and not perioperative treatment (P < 0.05). CRP<br />
levels were highest in <strong>the</strong> OSC group and lowest in <strong>the</strong> LAFT group. Fur<strong>the</strong>r<br />
repeated-measures (2-way ANOVA) also indicated it can be attributed to surgery<br />
type (P < 0.05). No significant differences were seen between <strong>the</strong> 4 groups with<br />
respect to prealbumin, Ig A or Ig M. No differences in postoperative complication<br />
rates such as anastomotic leakage, ileus and wound infection were observed<br />
between <strong>the</strong> groups.<br />
Conclusions: Our FTMDT randomized trial indicats: 1. laparoscopic surgery<br />
shortens <strong>the</strong> period of postoperative nutrition and immune recovery while fast track<br />
treatment retards <strong>the</strong> decrease of postoperative nutrition and immune levels;<br />
2. Combined laparoscopic surgery with fast track treatment provides best<br />
postoperative recovery of nutrition and immune status and lowest stress response.<br />
This study was registered under NCT01080547 (ClinicalTrials.gov).<br />
Disclosure: All authors have declared no conflicts of interest.<br />
596P ADVERSE EVENTS (AES) ASSOCIATED WITH BEVACIZUMAB<br />
(BV) IN OLDER PATIENTS (PTS) WITH METASTATIC<br />
COLORECTAL CANCER (MCRC)<br />
V. Shankaran 1 , D. Mummy 1 , L. Koepl 1 , D. Blough 2 , Y.M. Yim 3 ,E.Yu 3 ,<br />
S. Ramsey 1<br />
1 Cancer Prevention, Fred Hutchinson Cancer Research Center, Seattle, WA,<br />
UNITED STATES OF AMERICA, 2 Pharmacy, University of Washington, Seattle,<br />
WA, UNITED STATES OF AMERICA, 3 Health Economics and Outcomes<br />
Research, Genentech, Inc., San Francisco, CA, UNITED STATES OF AMERICA<br />
Background: The relative safety of BV in older mCRC pts is understudied. The<br />
objectives of this analysis are to investigate treatment-related AE incidence and to<br />
determine factors associated with AEs in a population-based sample of older mCRC<br />
pts.<br />
Methods: Pts age ≥ 65 diagnosed (Dx) with mCRC in 2001-7 were identified from<br />
SEER-Medicare. First-line (1L) chemo<strong>the</strong>rapy (CTx) was identified by claims<br />
within 3 months of Dx; pts were categorized as receiving no 1L CTx, 1L CTx<br />
alone, or 1L CTx + BV. Pts were also categorized by Dx period (2001-3 vs.<br />
2005-7); pts Dx in 2004 were excluded as BV use could not be reliably identified<br />
in that year. Preexisting conditions (PCs) identified in <strong>the</strong> year prior to Dx were<br />
grouped into 5 categories (cardiovascular (CV), cerebrovascular (CNS),<br />
gastrointestinal (GI), tissue integrity (TI), and pulmonary (Pulm). Claims for <strong>the</strong>se<br />
conditions between start of 1L CTx and end of follow-up were identified as AEs.<br />
AE incidence rates were determined by Dx year and 1L CTx cohort. We used a<br />
competing risks regression model to compare time to 1st AE for pts who received<br />
1L CTx + BV in 2005-7 to pts who received 1L CTx alone in 2001-7. Similar<br />
models were constructed for specific serious AEs (stroke, DVT/PE, GI bleed, GI<br />
perforation).<br />
Results: 6,899 pts (median age 77) were identified. In 2001-3, 37% of pts received<br />
1L CTx alone; in 2005-7, 21% and 19% of pts received 1L CTx alone and 1L<br />
CTx + BV. AE incidence was similar between pts receiving 1L CTx alone in<br />
2001-3 (135 AEs / 100,000 person-days (PD)) and 1L CTx + BV in 2005-7 (140<br />
AEs / 100,000 PD). Time to 1st AE was not shorter in pts receiving 1L CTx + BV<br />
in 2005-7 compared with 1L CTx alone in 2001-7 (HR 0.99, p = 0.90). Similarly,<br />
receipt of 1L CTx + BV was not associated with a shorter time to specific AE.<br />
(Table)<br />
Conclusions: Older pts who received 1L CTx + BV had nei<strong>the</strong>r increased AE<br />
incidence nor decreased time to 1st AE compared with pts who received 1L CTx<br />
alone. BV utilization may not increase AE risk among elderly mCRC pts.<br />
Time to 1st AE: BV vs. 1L CTx alone<br />
AE Type HR 95% CI<br />
Any AE 0.99 0.90-1.10<br />
Stroke 1.04 0.95-1.15<br />
DVT/PE 1.03 0.94-1.14<br />
GI bleed 1.03 0.94-1.14<br />
GI perforation 1.05 0.95-1.15<br />
Models adjusted for: age, comorbidity, race, gender, CTx backbone, PC<br />
Disclosure: V. Shankaran: This research activity received industry funding from<br />
Genentech, Inc. D. Mummy: This research activity received industry funding from<br />
Genentech, Inc. L. Koepl: This research activity received industry funding from<br />
Genentech, Inc. D. Blough: This research activity received industry funding from<br />
Genentech, Inc. Y.M. Yim: Financial interests include employment at Genentech, Inc.<br />
as as health economist and ownership in Genentech stocks. E. Yu: Financial interests<br />
include employment at Genentech, Inc. as Associate Director and stock ownership in<br />
Roche. S. Ramsey: This research activity received industry funding from Genentech,<br />
Inc.<br />
597P OVERALL SURVIVAL IN METASTATIC COLORECTAL CANCER<br />
(MCRC) PATIENTS RECEIVING 2ND-LINE THERAPY: A<br />
SYSTEMATIC REVIEW<br />
A.L. Martin 1 ,Y.Xu 1 , K. Knopf 2 , S.U. Iqbal 3 , J. Jasso-Mosqueda 4<br />
1 Health Economics, United Biosource Corporation, Lexington, MA, UNITED<br />
STATES OF AMERICA, 2 Oncology, California Pacific Medical Center,<br />
San Francisco, CA, UNITED STATES OF AMERICA, 3 Global Evidence and Value<br />
Development, Sanofi, Cambridge, MA, UNITED STATES OF AMERICA, 4 Global<br />
Evidence & Value Development, Sanofi, Chilly-Mazarin, FRANCE<br />
Background: Currently, oxaliplatin or irinotecan-based regimens are <strong>the</strong> standard of<br />
care (SOC) in 1 st – and 2 nd -line <strong>the</strong>rapy of mCRC, often combined with bevacizumab<br />
or an EGFR inhibitor. A systematic literature review was conducted to address gaps<br />
in <strong>the</strong> current evidence and gain an understanding of <strong>the</strong> clinical efficacy of 2 nd -line<br />
chemo<strong>the</strong>rapy in patients with mCRC.<br />
Methods: Searches were conducted in EMBASE, PubMed, CENTRAL, and key<br />
congresses using keywords for CRC and chemo<strong>the</strong>rapy to identify relevant<br />
randomized trials assessing 2 nd -line clinical efficacy, published between 1992 and<br />
April <strong>2012</strong>.<br />
Results: Twenty-three primary trials evaluating 2 nd -line treatment of mCRC were<br />
identified for inclusion. Chemo<strong>the</strong>rapeutic agents investigated included irinotecan<br />
mono<strong>the</strong>rapy (k = 11), FOLFOX4 (k = 6), FOLFIRI (k = 4), IROX (k = 3), irinotecan/<br />
5-FU/FA (k = 3) and IRIS (k = 1). FU-based regimens were <strong>the</strong> most common prior<br />
<strong>the</strong>rapy, with 13 studies reporting that 100% of patients received FU as 1st-line<br />
<strong>the</strong>rapy for metastatic disease. Eight studies excluded patients who previously<br />
received irinotecan. Of <strong>the</strong> included studies, <strong>the</strong> VELOUR trial, comparing<br />
aflibercept + FOLFIRI versus FOLFIRI, was <strong>the</strong> only trial evaluating <strong>the</strong> current SOC<br />
(FOLFIRI based regimens) in patients who received oxaliplatin-based chemo<strong>the</strong>rapy<br />
as a 1st-line agent. Overall survival (OS) ranged from 6.4 to 18 mos across studies.<br />
The addition of specific targeted agents to chemo<strong>the</strong>rapy regimens demonstrated<br />
significant incremental survival gains. Addition of bevacizumab to FOLFOX4 in <strong>the</strong><br />
2 nd -line setting was associated with a median OS of 12.9 mos, compared with 10.8<br />
mos for FOLFOX4 alone. Similarly, <strong>the</strong> addition of panitumumab to FOLFIRI<br />
improved median OS from 12.5 mos to 14.5 mos in KRAS wild type patients and<br />
addition of aflibercept improved median OS from 12.1 mos to 13.5 mos.<br />
Conclusions: OS in 2 nd -line trials showed significant survival gains when targeted<br />
agents were added to chemo<strong>the</strong>rapy regimens. However, variability in treatment<br />
choices, prior chemo<strong>the</strong>rapy regimen, patient selection and study approaches may<br />
hamper efforts to conduct reliable pooled analyses on outcomes to examine<br />
comparative effectiveness. VELOUR was one of <strong>the</strong> few trials that investigated<br />
patients who had received <strong>the</strong> current SOC in <strong>the</strong>ir 1st-line <strong>the</strong>rapy.<br />
Disclosure: A.L. Martin: I am an employee of United BioSource Corporation (UBC),<br />
which received funding from Sanofi to conduct <strong>the</strong> study on which this abstract is<br />
based. Y. Xu: I am an employee of United BioSource Corporation (UBC), which<br />
received funding from Sanofi to conduct <strong>the</strong> study on which this abstract is based. K.<br />
Knopf: I am a paid consultant of United BioSource Corporation (UBC), which<br />
received funding from Sanofi to conduct <strong>the</strong> study on which this abstract is based. S.<br />
U. Iqbal: I am a paid employee of Sanofi which provided funding to conduct <strong>the</strong><br />
study on which this abstract is based. J. Jasso-Mosqueda: I am a paid employee of<br />
Sanofi which provided funding to conduct <strong>the</strong> study on which this abstract is based.<br />
598P A PROSPECTIVE MULTICENTER FEASIBILITY STUDY WITH<br />
SHORT-TIME INFUSION OF PANITUMUMAB (SHIP TRIAL)<br />
K. Akiyoshi 1 , T. Hamaguchi 1 , Y. Nagai 2 , H. Yasui 3 , G. Sakai 4 , S. Akatsuka 5 ,<br />
A. Hosokawa 6 , S. Hirai 7 , K. Yoshimura 8 , Y. Shimada 1<br />
1 Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo,<br />
JAPAN, 2 Clinical Trial Support Office, National Cancer Center Hospital, Tokyo,<br />
JAPAN, 3 Medical Oncology, Kyoto Medical Center, Kyoto, JAPAN, 4 Division of<br />
Gastrointestinal Medicine, Saiseikai Utsunomiya Hospital, Utsunomiya, JAPAN,<br />
5 Division of Medical Oncology, Yokohama Rosai Hospital, Yokohama, JAPAN,<br />
6 Gastroenterology, Toyama University, Toyama, JAPAN, 7 Division of<br />
Gastrointestinal Medicine, Toyama Prefectural Central Hospital, Toyama, JAPAN,<br />
8 Dept. Clinical Trial Design & Management, Translational Research Center, Kyoto<br />
University Hospital, Kyoto, JAPAN<br />
Background: Panitumumab (Pmab) is now considered to be <strong>the</strong> standard treatment<br />
for metastatic colorectal cancer. Pmab infusions are normally administered over 60<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds397 | ix203
minutes. In a previous study, 30-minute infusions of panitumumab showed similar<br />
safety, pharmacokinetics, and frequency of infusion reaction to 60-minute infusions.<br />
Because Pmab consists of fully human monoclonal antibodies, infusion reactions<br />
occur less frequently than with cetuximab, chimeric monoclonal antibodies.<br />
Short-time infusion of Pmab has <strong>the</strong> potential to improve patient convenience and<br />
reduce costs.<br />
Purpose: We evaluated <strong>the</strong> safety of short-time infusion of panitumumab in a<br />
prospective multicenter study.<br />
Methods: Between January 2011 and December 2011, from 14 centers in Japan, a<br />
phase II study of Pmab + irinotecan (CPT-11) or Pmab mono<strong>the</strong>rapy in KRAS<br />
wild-type metastatic colorectal cancer refractory to CPT-11, oxaliplatin, and<br />
fluoropyrimidines was performed. As an additional study, <strong>the</strong> initial dose of Pmab<br />
was administered over 60 minutes, followed by 30-minute infusion; <strong>the</strong>n, all<br />
subsequent doses were to be administered over 15 minutes.<br />
Results: Forty-eight patients were enrolled. Their characteristics were median age of<br />
62 (32-75); male/female, 27/21; Performance Status 0/1/2, 23/24/1; primary lesion in<br />
colon/rectum, 21/27; and treatment regimen of CPT-11 + Pmab/Pmab mono<strong>the</strong>rapy,<br />
43/5. The number of patients and doses with 60-/30-/15-minute administration were<br />
48/45/38 cases and 67/56/206 doses, respectively. In all cases with 60-/30-/15-minute<br />
infusion, infusion reaction was not encountered. Grade 3/4 toxicities included<br />
anorexia 8%, stomatitis 4%, diarrhea 6%, fatigue 4%, rash acneiform 6%, perionychia<br />
4%, leucopenia 8%, neutropenia 8%, anemia 15%, hyponatremia 4%, and<br />
hypomagnesemia 4%. This was similar to <strong>the</strong> results from previous clinical studies<br />
on panitumumab.<br />
Conclusion: In this study, no infusion reactions with 60-/30-/15-minute<br />
administration of panitumumab and no increase of frequency of adverse events were<br />
observed. This is <strong>the</strong> first prospective study describing <strong>the</strong> feasibility of short-time<br />
infusion of panitumumab. This study suggests that 15-minute infusions of<br />
panitumumab are feasible in patients who tolerate a 60- and <strong>the</strong>n 30-minute infusion<br />
sequence.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
599P EARLY TUMOR SHRINKAGE (ETS) FOR THE PREDICTION OF<br />
EFFICACY IN METASTATIC COLORECTAL CANCER (MCRC):<br />
POST-HOC ANALYSIS FROM AN IRINOTECAN-BASED<br />
RANDOMIZED FIRST-LINE TRIAL<br />
C. Giessen 1 , R. Laubender 2 , S. Stintzing 1 , L. Fischer von Weikersthal 3 ,<br />
D. Quietzsch 4 , U. Vehling-Kaiser 5 , D. Oruzio 6 , H. Lambertz 7 , A. Schalhorn 1 ,<br />
V. Heinemann 1<br />
1 Department of Medical Oncology and Comprehensive Cancer Center, University<br />
of Munich, Munich, GERMANY, 2 University of Munich, Institute of Medical<br />
Informatics, Biostatistics, and Epidemiology, München, GERMANY, 3 Department<br />
of Medical Oncology, Klinikum St. Marien, Amberg, GERMANY, 4 Department of<br />
Medical Oncology, Klinikum Chemnitz, Chemnitz, GERMANY, 5 Onkologische<br />
Schwerpunktpraxis, Onkologisches und Palliativmedizinisches Netzwerk<br />
Landshut, Landshut, GERMANY, 6 II. Medizinische Klinik, Klinikum Augsburg,<br />
Augsburg, GERMANY, 7 Zentrum Fuer Innere Medizin - Onkologie, Klinikum<br />
Garmisch-Partenkirchen, Garmisch-Partenkirchen, GERMANY<br />
Background: Early tumor shrinkage (ETS) has been highlighted as a favorable<br />
prognostic factor related to progression-free survival (PFS) and overall survival (OS)<br />
in cytotoxic chemo<strong>the</strong>rapy with or without cetuximab. We investigated ETS ≥20%<br />
and
Annals of Oncology<br />
did not modify CSS, irrespective of AC choice (interaction p for capecitabine and<br />
age = 0.26; interaction p for FOLFOX and age = 0.40).<br />
Conclusions: EPs with stage III CC frequently received ei<strong>the</strong>r no adjuvant treatment<br />
or capecitabine mono<strong>the</strong>rapy due to advanced age and comorbidities. The treatment<br />
effect of AC on CSS is similar across age groups, with comparable side effects and<br />
rates of discontinuation between EPs and YPs. AC should not be withheld from CC<br />
patients based on advanced age alone.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
602P COMPARATIVE BUDGET IMPACT ANALYSIS OF TREATMENT<br />
SEQUENCES IN METASTATIC COLORECTAL CANCER<br />
(MCRC): FROM FIRST (1ST) LINE TO THIRD (3RD) LINE<br />
THERAPIES<br />
J.A. Maroun 1 , T. Boucher 2 , K. Alloul 3<br />
1 Medical Oncology, The Ottawa Hospital Regional Cancer Centre, Ottawa, ON,<br />
CANADA, 2 Evidence Value and Access, Sanofi Canada, Montréal, QC,<br />
CANADA, 3 Health Economics and Health Outcomes, Sanofi Canada, Montreal,<br />
QC, CANADA<br />
Background: In <strong>the</strong> context of personalized cancer care, patients (pts) should receive<br />
<strong>the</strong> <strong>the</strong>rapy that best meets <strong>the</strong>ir needs while optimizing <strong>the</strong> use of healthcare<br />
resources. A budget impact model was developed to compare each of <strong>the</strong> most<br />
commonly used mCRC treatment sequences – from 1 st line to 3rd line in a Canadian<br />
context.<br />
Methods: This Excel based model considers <strong>the</strong> price of each agent, <strong>the</strong> number of<br />
cycles per treatment course, <strong>the</strong> relative dose intensity of <strong>the</strong> regimens to determine <strong>the</strong><br />
cost of <strong>the</strong> most commonly used mCRC <strong>the</strong>rapies and calculates <strong>the</strong> costs per overall<br />
sequence from 1 st line to 3 rd line. It takes into account <strong>the</strong> percentage of pts who benefit<br />
from a R0 resection post 1 st line chemo<strong>the</strong>rapy and who forego subsequent treatments.<br />
Factors such as different percentage use of 1 st line FOLFOX vs FOLFIRI and pts’<br />
volumes per line of <strong>the</strong>rapy are considered in this model. Users can choose <strong>the</strong><br />
scenarios <strong>the</strong>y would like to examine. Key variables can be extracted through expert<br />
opinion, <strong>the</strong> literature or, to assess real-world local practices, through chart reviews.<br />
Results: As scenarios considered, <strong>the</strong> budgetary impact of <strong>the</strong> 1 st line use of FOLFOX<br />
or FOLFIRI both given with bevacizumab (bev) on 1 st to 3 rd line <strong>the</strong>rapy costs was<br />
assessed. The relative use of FOLFOX and FOLFIRI with bev was varied from 80% use<br />
of FOLFOX and 20% use of FOLFIRI to <strong>the</strong> opposite. As key variables, <strong>the</strong> model<br />
compares, as 1 st line <strong>the</strong>rapy, 18 cycles of FOLFIRI and bev to 8 cycles of mFOLFOX6<br />
followed by 10 cycles of 5FU/LV given with 18 cycles of bev. Also 80% of 1 st line pts<br />
receive a second line chemo<strong>the</strong>rapy. Assuming a cohort of a 100 pts, when FOLFOX’s<br />
1 st line use varies from 80% to 20%, <strong>the</strong> budget varies from $4.14M to $3.85M, with all<br />
pts undergoing a R0 resection varying from 11.8 to 8.2 pts.<br />
Conclusions: Focusing on drug costs only, this dynamic and flexible model goes<br />
beyond <strong>the</strong> comparison of upfront 1 st line mCRC costs and considers cascading costs<br />
on subsequent lines (2 nd and 3 rd line) and consequences. It can be used to assess<br />
variability in local and provincial practice patterns and <strong>the</strong>ir impact on overall budget<br />
costs and number of pts benefiting from a R0 resection.<br />
Disclosure: J.A. Maroun: Advisory board member for Roche and Sanofi. Involved in<br />
research projects with Roche and Sanofi. T. Boucher: Employee of Sanofi. K. Alloul:<br />
Employee of Sanofi Canada Inc.<br />
603P FREQUENCY OF SECOND AND THIRD LINE TREATMENT<br />
AMONG ELDERLY MEDICARE STAGE 4 COLON CANCER<br />
PATIENTS<br />
C.D. Mullins 1 , K. Bikov 2 , E. Onukwugha 2 , N. Hanna 3 , B. Seal 4<br />
1 PHSR, Univ of MD, Baltimore, MD, UNITED STATES OF AMERICA, 2 PHSR,<br />
Univ of MD, Baltimore, MD, UNITED STATES OF AMERICA, 3 Surgery, Univ of<br />
MD, Baltimore, MD, UNITED STATES OF AMERICA, 4 Health Economics and<br />
Outcomes Research, Bayer HealthCare, Wayne, NJ, UNITED STATES OF<br />
AMERICA<br />
Background: Stage 4 colon cancer (CC4) patients may receive multiple lines of<br />
chemo<strong>the</strong>rapy and/or biologics as treatment (TX) to improve survival or quality of life.<br />
The tendency to use less aggressive treatment with elderly CC4 patients suggests that<br />
elderly CC4 patients may receive fewer TX lines than equivalent younger patients.<br />
Methods: Elderly (65+) SEER-Medicare patients diagnosed with CC4 in 2003-2007<br />
were followed through death or 2009 to examine variation across sub-groups in <strong>the</strong><br />
number of TX lines. We examined NCCN treatments that included any combination<br />
of 5-fluorouracil and/or (levo) leucovorin (5FU/LV), irinotecan (IRI), oxaliplatin<br />
(OX), and bevacizumab, cetuximab, or panitumumab (collectively identified as<br />
BIOLOGICS). Certain non-NCCN treatments were also considered as possible last<br />
TX line. A hierarchy categorized treatments as: 1) IROX (IRI + OX); 2) IRI or OX; 3)<br />
5FU/LV; 4) BIOLOGICS without chemo<strong>the</strong>rapy; and 5) o<strong>the</strong>r TX. Gaps in TX or<br />
changes from OX or IRI to 5FU/LV were not considered new lines.<br />
Results: Of 7,937 elderly CC4 patients, 3,263 (41%) received any TX, while 1,166<br />
(15% of all, 36% of TX) and 244 (3% of all, 7% of TX) received second and third<br />
line TX, respectively. Fewer than 1% of treated patients had a fourth TX line. Among<br />
<strong>the</strong> TX group, relatively younger (p < 0.01), married (48 vs. 39%, p < 0.01) and urban<br />
(45 vs. 39, p = 0.04) patients were more likely to go on to second line TX. Medicare<br />
buy-in coverage, which generally indicates dual Medicaid-Medicare coverage (40 vs.<br />
45%, p = 0.05), lowered <strong>the</strong> likelihood of second line TX. Having comorbidities<br />
impacted receipt of initial TX (CCI = 0: 44%, CCI = 1: 42%, CCI = 2: 28%; p < 0.01)<br />
and <strong>the</strong> likelihood of second (CCI = 0: 46%, CCI = 1: 42%, CCI = 2: 39%; p= 0.02)<br />
but not third TX (CCI = 0: 19%, CCI = 1: 21%, CCI = 2: 15%; p = 0.3) lines<br />
conditional upon receipt of prior line treatment. There was no significant association<br />
between second line TX and race/ethnicity or gender. There was no significant<br />
association between <strong>the</strong> examined characteristics and receipt of third line TX.<br />
Conclusions: One in three elderly CC4 patients who received initial TX received a<br />
second TX line. The likelihood of having a second TX line was associated with age,<br />
marital status, urbanicity, and comorbidity burden. Only one in fourteen elderly CC4<br />
patients had a third TX.<br />
Disclosure: C.D. Mullins: C. Daniel Mullins, PhD receives consulting income from<br />
Amgen, Bayer, BMS, Celgene, GSK, Mitsubishi, Novartis, Novo Nordisk, Novartis,<br />
and Pfizer. He also receives research funding from Bayer and Pfizer. E. Onukwugha:<br />
Ebere Onukwugha receives consulting income from Pfizer and grant support from<br />
Bayer, Novartis, and Pfizer. B. Seal: Brian Seal is an employee of Bayer HealthCare.<br />
All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
604P PROGNOSTIC VALUE OF STEM CELL QUANTIFICATION IN<br />
STAGE II COLON CANCER<br />
M.A.V. Salgado 1 , J.C.M. Montero 2 , M. Devesa 1 , J.D. Trill 1 , V. Abraira 1 ,<br />
A. Riquelme 3 , A. Carrato 1<br />
1 Medical Oncology, Hospital Universitario Ramon y Cajal, Madrid, SPAIN,<br />
2 Pathologist, Instituto Oftalmico/Hospital Universitario Gregorio Marañon, Madrid,<br />
SPAIN, 3 Medical Oncology, Hospital Infanta Cristina Parla, Madrid, SPAIN<br />
Background: Cancer stem cells (CSCs) are a subset of tumor cells with capacity to<br />
self-renew and generate <strong>the</strong> diverse cells that comprise <strong>the</strong> tumor. They are considered<br />
cancer (Ca) initiating cells responsible for tumor recurrence and maintenance. These<br />
cells express pluripotency markers (CD133 and NANOG) and do not express markers<br />
of differentiation as cytokeratin 20 (CK20). The potential prognostic value of CSCs in<br />
colorectal cancer has been studied with conflicting results. However some of <strong>the</strong>se series<br />
were based on heterogeneous situations, involving rectal and colon cancer (CC) and<br />
different tumor stages (I-IV). The aim of this study is to evaluate <strong>the</strong> prognostic value of<br />
CSCs in a highly homogeneous population of stage II CC.<br />
Methods: One hundred stage II CC patients (pts) treated by <strong>the</strong> same surgical team<br />
at Ramon y Cajal University Hospital between 1977 and 2005 were retrospectively<br />
analyzed. None of <strong>the</strong> pts received adjuvant chemo<strong>the</strong>rapy. Inmunohistochemistry<br />
expression of CD133, NANOG and CK20 was scored on paraffin sections using four<br />
levels: 50% positivity. Kaplan-Meier analysis and log<br />
rank test were used to compare survival.<br />
Results: Median age: 68 years (45-92). Median follow up: 5.8 years. Recurrent<br />
disease: 17 (17%). Expression of CD133 was shown in 60% of <strong>the</strong> tumors, in 95% for<br />
NANOG and 78% for CK20. No correlation was found among expression levels of<br />
CD133, NANOG or CK 20 and relapse-free survival (RFS) and overall survival (OS).<br />
Conclusions: Stem Cell quantification defined by CD133 and NANOG expression<br />
has no correlation with RFS or OS in this cohort of Stage II CC. Therefore, our<br />
results suggest that CSCs may not play a major role in early phases of CC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
605P PHASE II TRIAL OF PANITUMUMAB IN COMBINATION WITH<br />
OXALIPLATIN AND CAPECITABINE CHEMOTHERAPY AS 1ST<br />
LINE THERAPY IN PATIENTS WITH COLORECTAL CANCER<br />
AND ADVANCED LIVER METASTASES: THE METAPAN STUDY<br />
F. Leone 1 , D. Marino 2 , S. Artale 3 , C. Cagnazzo 2 , S. Cascinu 4 , A.A. Martoni 5 ,<br />
A. Sobrero 6 , M. Tampellini 7 , S. Siena 3 , M. Aglietta 8<br />
1 Oncological Sciences, Fondazione Piemontese per la Ricerca sul Cancro Onlus,<br />
Candiolo, ITALY, 2 Medical Oncology, Fondazione Piemontese per la Ricerca sul<br />
Cancro Onlus-IRCC Institute for Cancer Research and Treatment, Candiolo,<br />
ITALY, 3 Struttura Complessa di Oncologia Falck, A.O. Ospedale Niguarda Ca’<br />
Granda, Milano, ITALY, 4 Clinica di Oncologia Medica, AOU Ospedali Riuniti<br />
Ancona Università Politecnica delle Marche, Ancona, ITALY, 5 Medical Oncology<br />
Unit, S. Orsola-Malpighi University Hospital, Bologna, ITALY, Bologna, ITALY,<br />
6 Oncologia Medica, Azienda Ospedaliera Universitaria S. Martino di Genova,<br />
Genova, ITALY, 7 Dipartimento di Oncologia Medica, Azienda Ospedaliera San<br />
Luigi, Orbassano, ITALY, 8 Div Oncologia ed Ematologia, Fondazione Piemontese<br />
per la Ricerca sul Cancro Onlus, Candiolo, ITALY<br />
Background: Preoperative chemo<strong>the</strong>rapy improves outcome in potentially resectable<br />
colorectal cancer with liver metastases. We evaluated <strong>the</strong> activity of a neoadiuvant<br />
treatment with capecitabine–oxaliplatin (XELOX) associated with <strong>the</strong> anti-EGFR<br />
antibody Panitumumab in patients with unresectable, liver-only, metastatic colorectal<br />
cancer (CRC).<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds397 | ix205
Patients and methods: Chemo<strong>the</strong>rapy-naïve patients with unresectable liver<br />
metastases of CRC and no o<strong>the</strong>r metastatic sites were enrolled. Criteria of<br />
unresectability were defined as: more than3livermetastasesincluding>50%<br />
hepatic involvement and requiring a major hepatectomy with controlateral<br />
wedge resection or any metastases requiring a resection that does not preserve<br />
two contiguous hepatic segments. Since November 2008 only patients bearing<br />
wild type KRAS were included. All patients received neoadjuvant XELOX plus<br />
panitumumab (P-XELOX) and were reevaluated for resectability every four<br />
cycles. Primary endpoint was radiological objective response rate (ORR).<br />
Secondary endpoints were overall survival (OS), progression free survival<br />
(PFS), percentage of patients whose disease became radically resectable, and<br />
safety.<br />
Results: Forty-nine patients were recruited, of which 35 were KRAS wild type, and<br />
14 (enrolled before study amendment), were unknown (9 patients) or mutated (5<br />
patients). Forty-six were evaluable for response. Following neoadjuvant P-XELOX,<br />
<strong>the</strong> ORR in <strong>the</strong> general population was 54%, with 3 CR, 22 PR, 14 SD. In wild type<br />
KRAS patients ORR reached 65% (3 CR, 18 PR, 7 SD), and this allowed 15 patients<br />
with initial unresectable liver metastasis to be converted to resectability. Survival<br />
analysis showed median PFS and OS of 8.5 months and 22.1 months, respectively.<br />
Resected patients had significantly better OS if compared to unresected (p =<br />
0.00014). The most common toxicities were cutaneous, gastrointestinal, and<br />
neurologic.<br />
Conclusion: Neoadjuvant P-XELOX yields high response rates for patients with<br />
metastatic CRC and extensive liver involvement, and leads to remarkable conversion<br />
to resectability of liver metastasis.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
606P BODY MASS INDEX AND IMPAIRED FASTING BLOOD<br />
GLUCOSE AS PREDICTIVE FACTORS OF EFFICACY IN<br />
CETUXIMAB-BASED COLORECTAL CANCER TREATMENT<br />
F.M. Guida1 , F. Pantano1 , E. Vasile2 , M. Rodriguez Garrote3 , E. Grande3 ,<br />
N. Silvestris4 , B. Vincenzi1 , D. Santini1 , A. Falcone5 , G. Tonini1 1 2<br />
Medical Oncology, University Campus Bio-Medico, Rome, ITALY, Oncologia,<br />
Trapianti e Nuove Tecnologie in Medicina, Polo Oncologico - Azienda<br />
Ospedaliero-Universitaria Pisana - Istituto Toscano Tumori, Pisa, ITALY, 3 Medical<br />
Oncology, University Hospital, Madrid, Madrid, SPAIN, 4 Medical and<br />
Experimental Oncology Unit, Cancer Institute Giovanni Paolo II, Bari, ITALY,<br />
5<br />
Dept. of Oncology-Presidio Ospedaliero, Azienda Ospedaliero Univesitaria S.<br />
Chiara, Pisa, ITALY<br />
Introduction: Cetuximab is an anti-EGFR monoclonal antibody with antitumor<br />
efficacy in metastatic colorectal cancer harboring wild-type K-Ras gene.<br />
However, not all patients K-Ras wild-type benefit from Cetuximab,<br />
underscoring <strong>the</strong> need for additional markers to help in patient selection.<br />
Preclinical evidences suggest that <strong>the</strong> EGFR and Insulin-like Growth Factor-1<br />
Receptor (IGF-1R) pathways interact to drive tumor growth and survival. It’s<br />
well known that in hyperinsulinemic state, higher insulin levels upregulate<br />
IGF-1 production, leading this state a potential biomarker for Cetuximab<br />
efficacy. The aim of our study was to evaluate <strong>the</strong> feasibility to stratify patients<br />
more likely to benefit from Cetuximab treatment using two well known signs<br />
of hyperinsulinemic state such as <strong>the</strong> high Body Mass Index (BMI) and<br />
impaired Fasting Blood Glucose (FBG).<br />
Methods: We retrospectively collected 250 K-Ras wild-type metastatic colorectal<br />
cancer patients treated with Cetuximab containing regimens in first to fifth line<br />
setting. From this cohort we selected 76 patients treated with Cetuximab +<br />
CPT11 after failure of first line CPT11 based containing regimen. We divided<br />
this population into two groups according to <strong>the</strong> presence of both elevated BMI<br />
(cut-off 24.99 sec. WHO Criteria) and high FBG (cut-off 100 mg/dL sec<br />
American Diabetes Association) and we evaluated <strong>the</strong> Time To Progression<br />
(TTP) of <strong>the</strong>se two groups.<br />
Results: We found a statistically significant lower TTP in patients with both elevated<br />
BMI and FBG compared to patients with presence of none or only one of <strong>the</strong> two<br />
parameters (median TTP 4.3 months, CI95%:2.5-5.4 vs 5.6 months, CI95%:2.5-5.8;<br />
P = 0.034).<br />
Conclusions: The statistically significant poorer outcome in patients with both<br />
BMI and FBG treated with Cetuximab + CPT11 after CPT11 failure could be<br />
explained by <strong>the</strong> reduction of Cetuximab efficacy due to <strong>the</strong> probable presence of<br />
upregulation of vicar pathways such as IGF-1R linked to hyperinsulinemic state.<br />
If confirmed in larger populations and in perspective studies <strong>the</strong><br />
hyperinsulinemic state may represent a new predictive marker of efficacy in this<br />
type of population.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
607P EFFICACY AND SAFETY OF TWO NEOADJUVANT<br />
STRATEGIES WITH BEVACIZUMAB IN LOCALLY ADVANCED<br />
RESECTABLE RECTAL CANCER: INTERIM RESULTS OF A<br />
RANDOMIZED, NON-COMPARATIVE PHASE II STUDY<br />
J. Bosset 1 , G. Mantion 2 ,T.André 3 , F. Boudghène 4 , F. Piard 5 , F. Mornex 6 ,<br />
P. Maingon 7 , A. Adenis 8 , M. Piutti 9 , C. Borg 10<br />
1 Radio<strong>the</strong>rapy, CHU Jean Minjoz, Besançon, FRANCE, 2 Service de Chirurgie<br />
Digestive Et Vasculaire, Hôpital Jean Minjoz, Besançon, FRANCE, 3 Medical<br />
Oncologie, Hôpital Saint Antoine, Paris, FRANCE, 4 Service Imagerie Médicale,<br />
Hôpital Tenon, Paris, FRANCE, 5 Service D’anatomo-pathologie, CHU de Dijon,<br />
Dijon, FRANCE, 6 Radiothérapie-oncologie, Centre Hospitalier Lyon-Sud, Lyon,<br />
FRANCE, 7 Radiothérapie, Centre Georges-François-Leclerc, Dijon, FRANCE,<br />
8 Medical Oncology, Centre Oscar Lambret, Lille Cedex, FRANCE, 9 Responsable<br />
Etudes Cliniques, Laboratoires Roche, Boulogne-Billancourt, FRANCE, 10 Medical<br />
Oncology, Hopital Minjoz, Besançon, FRANCE<br />
Background: Current <strong>the</strong>rapy of locally advanced resectable rectal cancer<br />
(LARC) involves a combination of chemo<strong>the</strong>rapy (CT), radiation <strong>the</strong>rapy, (RT)<br />
and total mesorectal excision (TME) surgery. Two neoadjuvant strategies with<br />
bevacizumab (Bv) were assessed in a randomized, open-label, multicentre, phase<br />
II study.<br />
Method: Patients (pts) were treated with a sequential strategy including induction<br />
Bv/6 cycles (5mg/2weeks) + Folfox4, followed by CT-RT (Bv/6 cycles + 5-FU/5<br />
cycles) + RT(45Gy) <strong>the</strong>n TME in Arm A and <strong>the</strong> same CT-RT, <strong>the</strong>n TME in Arm<br />
B. Primary end-point was tumor sterilization rate (pCR) - at least 10% in each arm.<br />
Efficacy and safety were reviewed by an independent committee. Results at 8 weeks<br />
post-surgery are presented.<br />
Results: Pts characteristics in Arm A (n = 46) and in Arm B (n= 45) were: men 67%,<br />
age 60 ± 9 years, ECOG score 0 (85%), mid-rectum (60%), low-rectum (40%), MRI<br />
stage: T3N0M0/T3N1M0/T3N2M0 (20%/65%/15%). In Arm A, 94% pts completed<br />
induction and 91% had CT-RT and surgery; in Arm B 100% had CT-RT and 98%<br />
surgery. Resection was macroscopically complete in 91% pts. Median post-surgery<br />
hospitalization duration was 15 [0-84] days. In <strong>the</strong> ITT population, pCR (ypT0-N0)<br />
rate was 23.8% [12.1%-39.5%] in Arm A (p = 0.015) and 11.4% [3.8%-24.6%] in Arm<br />
B (p = 0.91), both compared to <strong>the</strong> 10% pCR initial hypo<strong>the</strong>sis. Central review found<br />
similar results for pCR. At surgery and 4 weeks post-surgery grade 3/4 adverse events<br />
(AE) were reported in 10 (22%) of pts in both arms. At 8 weeks post-surgery, grade<br />
3/4 adverse events (AE) were reported in 59% of pts in Arm A and 36% in Arm<br />
B. Grade 3/4 AEs of special interest for bevacizumab were reported in 20% of pts in<br />
Arm A and 22% in Arm B. No death was reported at 8 weeks post-surgery follow-up.<br />
Conclusions: Interim results in patients with LARC treated with 2 neoadjuvant<br />
strategies showed that bevacizumab combination to neoadjuvant CT-RT did not<br />
significantly increase pCR in Arm B. The neoadjuvant strategy assessed in Arm A<br />
seems promising and deserves fur<strong>the</strong>r investigation. Safety was comparable in Arms<br />
A and B at 8 weeks post-surgery.<br />
Disclosure: T. André: Consultant: Roche Honoraries: Amgen, Merck, Sanofi. F.<br />
Boudghène: Honoraries : Roche. M. Piutti: Employment: Roche. All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
608P EXCITE: A PHASE II TRIAL OF PREOPERATIVE CETUXIMAB,<br />
IRINOTECAN AND CAPECITABINE PLUS RADIOTHERAPY (RT)<br />
IN MRI-DEFINED LOCALLY ADVANCED RECTAL CANCER<br />
(LARC)<br />
S. Gollins 1 , A.S. Myint 2 , M.P. Saunders 3 , S. Susnerwala 4 , D. Sebag-Montefiori 5 ,<br />
S. Beare 6 , E. Williams 6 , N. West 7 , M. Jitlal 6<br />
1 Clinical Oncology, North Wales Cancer Treatment Centre, Rhyl, UNITED<br />
KINGDOM, 2 Clinical Oncology, Clatterbridge Cancer Centre, Liverpool, UNITED<br />
KINGDOM, 3 Clinical Oncology, The Christie Hospital NHS Foundation Trust,<br />
Manchester, UNITED KINGDOM, 4 Clinical Oncology, Royal Preston Hospital,<br />
Preston, UNITED KINGDOM, 5 Oncology, University of Leeds, Leeds, UNITED<br />
KINGDOM, 6 CR UK & UCL Cancer Trials Centre, University College London,<br />
London, UNITED KINGDOM, 7 Pathology & Tumour Biology, University of Leeds,<br />
Leeds, UNITED KINGDOM<br />
Introduction: This phase II trial examined combining cetuximab, irinotecan and<br />
capecitabine concurrently with RT in <strong>the</strong> preoperative downstaging of LARC.<br />
Methods: Patients (pts) had rectal adenocarcinoma with locally advanced/borderline<br />
unresectable disease on MRI. KRAS/BRAF was not assessed before treatment. Pts<br />
had pelvic RT to 45 Gy in 25 daily fractions over 5 weeks with concurrent oral<br />
capecitabine at 650 mg/m 2 twice daily 5 days/week. They also received intravenous<br />
(IV) cetuximab at 400 mg/m 2 one week before RT <strong>the</strong>n weekly at 250 mg/m 2 weeks<br />
1-5 of RT plus IV irinotecan weekly at 60 mg/m 2 weeks 1-4 of RT. Surgical resection<br />
ix206 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
was stipulated at 8 weeks after chemoradiation (CRT) with primary end point<br />
histological circumferential resection margin (CRM) negative rate.<br />
Results: From Apr 2009-Oct 2011 82 pts were recruited. At baseline: male/female 61/<br />
21, median age 62, WHO PS 0/1/missing 60/19/3. On MRI tumour was T2/3/4 in 6/<br />
67/9 and N0/1/2 in 14/41/27 pts, mesorectal fascia or levator-sphincter complex was<br />
threatened (≤ 1mm gap) in 45 (55%), definitely involved in 21 (26%) and breached<br />
in 16 pts (20%). 2 pts did not commence RT and were withdrawn from trial<br />
treatment. The no. (%) of significant acute toxicities were diarrhoea grade (Gr)3 20<br />
(25%), acneiform rash Gr3 7 (9%), fatigue Gr3 6 (8%), thrombotic event Gr3 1 (1%)<br />
and Gr4 5 (6%) and febrile neutropenia Gr3 1 (1%) and Gr4 1 (1%). 75 pts had<br />
surgery (36 anterior resection, 37 abdominoperineal, 2 Hartmans). Post-resection<br />
histology showed a negative CRM (>1mm) in 67 (89%), a pathological complete<br />
response (pCR) (T0N0) in 14 (19%), T0/1/2/3/4 in 15/2/16/40/2 and N0/1/2 in 51/<br />
15/9 pts. 38 of <strong>the</strong> 75 resected pts (51%) had <strong>the</strong>ir T and 49 of 63 (78%) <strong>the</strong>ir N1-2<br />
stage downstaged. 5 pts with a clinical CR (cCR) post CRT did not have surgery and<br />
were alive with no evidence of disease at 8, 12, 14, 24 and 26 m.<br />
Conclusion: EXCITE is <strong>the</strong> largest reported phase II trial of a triplet CRT regime<br />
including EGFR targeted <strong>the</strong>rapy in LARC, showing acceptable toxicity and<br />
compliance. In MRI-defined locally advanced/borderline unresectable disease a<br />
combined pCR + cCR rate of 19/80 (24%) is promising. Data on KRAS and BRAF<br />
influence will be available by Aug <strong>2012</strong>.<br />
Disclosure: S. Gollins: Research funding grants from Merck and Pfizer Honoraria<br />
from Roche (Advisory Boards). All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
609P FIRST RESULTS FROM THE PHASE I DUAL RECTAL<br />
ANGIOGENESIS MEK INHIBITION RADIOTHERAPY<br />
(DREAMTHERAPY) TRIAL IN LOCALLY ADVANCED RECTAL<br />
CANCER<br />
F.E. Marti Marti 1 ,A.Backen 2 , A.G. Renehan 3 , A. Jackson 4 , P. Manoharan 5 ,<br />
O. Ataman 6 , V. Misra 7 , G.C. Jayson 1 , C. Dive 2 , M.P. Saunders 7<br />
1 Medical Oncology, The Christie NHS Foundation Trust, Manchester, UNITED<br />
KINGDOM, 2 Clinical and Experimental Pharmacology, The Paterson Institue for<br />
Cancer Research, Manchester, UNITED KINGDOM, 3 Surgery, The Christie<br />
Hospital NHS Foundation Trust and Paterson Institute for Cancer Research,<br />
Manchester, UNITED KINGDOM, 4 Radiology, Wolfson Molecular Imaging Centre,<br />
Manchester, UNITED KINGDOM, 5 Radiology, The Christie Hospital NHS<br />
Foundation Trust, Manchester, UNITED KINGDOM, 6 Rockit, Astra Zeneca,<br />
Alderley Park, UNITED KINGDOM, 7 Clinical Oncology, The Christie Hospital NHS<br />
Foundation Trust, Manchester, UNITED KINGDOM<br />
Background: Less than 15% of patients (pts) receiving pre-operative chemoradiation<br />
(CRT) for rectal cancer have a complete pathological response (pCR). We tested <strong>the</strong><br />
hypo<strong>the</strong>sis that <strong>the</strong> addition of cediranib (a VEGFR TKI) or selumetinib (a MEK<br />
inhibitor), in combination with CRT, increases <strong>the</strong> proportion of complete<br />
responders. A translational protocol was also developed to study potential predictive<br />
biomarkers.<br />
Methods: This hypo<strong>the</strong>sis was evaluated in a dual phase I design. The drugs are<br />
evaluated in parallel in an intertwined design: once a cohort of pts on cediranib<br />
completed treatment and during <strong>the</strong> toxicity assessment period, ano<strong>the</strong>r cohort of<br />
pts was commenced on selumetinib at <strong>the</strong> next dose level. Alternating cohorts<br />
maximised <strong>the</strong> efficacy of <strong>the</strong>ir evaluation. The analysis here is for cediranib only. Pts<br />
received CRT (45Gy in 25#, capecitabine 825 mg/m 2 twice daily for 35 days) in three<br />
cohorts with cediranib: 15 mg, 20 mg and 30 mg/once daily (OD). Dose escalation<br />
was done upon fulfilment of <strong>the</strong> safety criteria outlined in <strong>the</strong> protocol. Cediranib<br />
was commenced 10 days prior to <strong>the</strong> start of CRT and continued throughout. Pts<br />
were followed up until and <strong>the</strong>n after surgery. Safety, RECIST and pathological data<br />
were collected. In addition, blood, tissue and DCE-MRIs were obtained at baseline,<br />
post-mono<strong>the</strong>rapy, throughout and post CRT for <strong>the</strong> study of candidate biomarkers.<br />
Results: 15 mg cohort: 3 pts were recruited. 2 pts had a pCR and <strong>the</strong> 3rd pt had a<br />
clinical complete response (cCR) not requiring surgery. 20 mg cohort: 3 pts were<br />
treated. 1 had a cCR and ypT3N0 on resection. The o<strong>the</strong>r 2 had partial responses on<br />
MRI with ypT3N0 and ypT3N2 pathologically. 30 mg cohort: 3 pts were recruited at<br />
this dose level. Two pts had a cCR and <strong>the</strong> o<strong>the</strong>r one is waiting restaging. There was<br />
one DLT in this cohort (Grade III lethargy). This cohort will be expanded to a<br />
maximum n = 6. As yet, all pts have had R0 resections and completed all planned<br />
treatment (except pt with DLT who did not complete capecitabine). cCR pts remain<br />
disease free and have not had surgery.<br />
Conclusions: The addition of cediranib to pre-operative CRT is a well tolerated<br />
regimen. All pts have responded with 5 out of 8 evaluable pts (62.5%) having ei<strong>the</strong>r a<br />
pCR (n = 2) or cCR (n = 3). Updated clinical data, proposed optimal dose and<br />
translational data will be available for presentation at <strong>the</strong> meeting.<br />
Disclosure: F.E. Marti Marti: Dr Marti’s research fellowship is funded in equal parts<br />
by Cancer Research UK and Astra Zeneca. O. Ataman: Dr Ataman is an<br />
Astra Zeneca employee. G.C. Jayson: AZ advisory boards and research funding. M.<br />
P. Saunders: I have previously been a paid advisor on an AZ trial with<br />
AZD2171 (Horizon II). However, I have no conflicts on <strong>the</strong> use of this agent<br />
in <strong>the</strong> DREAM<strong>the</strong>rapy trial. All o<strong>the</strong>r authors have declared no conflicts<br />
of interest.<br />
610P UTILITY OF MAGNETIC RESONANCE IMAGING FOLLOWING<br />
LONG-COURSE PRE-OPERATIVE CHEMO-RADIOTHERAPY<br />
FOR LOCALLY ADVANCED RECTAL CANCER<br />
D.J. Lucey 1 , A. Murphy 2 , V. Curran 3 , M. McCourt 4 , E. Andrews 4 ,M.O’Riordain 3 ,<br />
D.G. Power 5 ,S.O’Reilly 5 , P.J. Kelly 4<br />
1 Radio<strong>the</strong>rapy Department, Cork University Hospital, Cork, IRELAND, 2 Medical<br />
Oncology Department, Cork University Hospital, Cork, IRELAND, 3 Surgery,<br />
Mercy University Hospital, Cork, IRELAND, 4 Surgery, Cork University Hospital,<br />
Cork, IRELAND, 5 Medical Oncology, Cork University Hospital, Cork, IRELAND<br />
Aims/Rationale: Neoadjuvant chemoradio<strong>the</strong>rapy (CRT) for locally advanced rectal<br />
cancer is associated with improved local control and results in tumour down-staging.<br />
The purpose of this study was to assess whe<strong>the</strong>r MRI performed following<br />
chemoradio<strong>the</strong>rapy alters surgical management.<br />
Methods: All patients with locally advanced (cT3-4 or cN+ by endorectal ultrasound,<br />
computed tomography, or magnetic resonance imaging) rectal adenocarcinoma<br />
diagnosed in 2010 and 2011 at Cork University Hospital/Mercy University Hospital<br />
and treated with long course preoperative CRT followed by radical resection were<br />
identified and <strong>the</strong>ir records were retrospectively reviewed from prospectively<br />
maintained institutional databases . Only patients who had MRI pre- and<br />
post-neoadjuvant <strong>the</strong>rapy were eligible for inclusion.<br />
Results: Thirty patients had MRI pre- and post long course chemoradio<strong>the</strong>rapy.<br />
Male: Female was 3:2, <strong>the</strong> median age was 60 (range 36-77). Abdominoperineal<br />
resection was performed in 12 of <strong>the</strong>se patients, and anterior resection in 18 patients.<br />
The median radiation dose was 50.4 Gy with concurrent 5FU-based chemo<strong>the</strong>rapy.<br />
Median time from completion of CRT to post-treatment MRI was 30 days, and <strong>the</strong><br />
median time to surgery from <strong>the</strong> 2 nd MRI was 23 days. Only 1 of <strong>the</strong> 30 patients<br />
(3.3%) showed disease progression on <strong>the</strong> repeat scan and R0 resection was achieved<br />
in this case. Three patients (10%) achieved pathologic complete remission and none<br />
of <strong>the</strong>se had a radiographic CR on post-treatment MRI. Two patients (6.6%) had<br />
positive circumferential resection margins and nei<strong>the</strong>r was predicted by<br />
post-treatment MRI.<br />
Conclusions: MRI following neoadjuvant <strong>the</strong>rapy prior to surgical resection did not<br />
alter clinical management in this small retrospective series. The utility of post CRT<br />
MRI prior to definitive resection is unclear and international guidelines do not<br />
recommend this approach.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
611P EFFECTS OF RADIOTHERAPY (RT) AND<br />
CHEMORADIOTHERAPY (CRT) ON LYMPH NODES (LNS) IN<br />
PATIENTS WITH RECTAL CANCER: EVALUATION OF<br />
NUMBERS OF RETRIEVED LNS AND LN SIZE<br />
K. Okada1 , S. Sadahiro2 , T. Suzuki1 , A. Tanaka1 , A. Kamijo1 1<br />
Gastrointestinal Surgery, Tokai University School of Medicine, Isehara, JAPAN,<br />
2<br />
Gastrointestinal Surgery, Tokai University School of Medicine Isehara Campus,<br />
Isehara, JAPAN<br />
Background: In patients with colorectal cancer, retrieval of 12 or more LNs has been<br />
reported to be associated with better outcomes. Preoperative RT or CRT reduces <strong>the</strong><br />
number of retrieved LNs. The effects of RT and CRT on LNs may be different<br />
between LNs inside and LNs outside <strong>the</strong> radiation field.<br />
Methods: The study group comprised 368 patients with a cStage II/Stage III<br />
adenocarcinoma of <strong>the</strong> rectum between 1991 and 2010. 108 received surgery alone<br />
(S group), 158 received preoperative RT with 20 Gy in 10 frs. plus IORT with 15 Gy<br />
(RT20 group), and 102 received preoperative RT 40 or 45 Gy in 20 or 25 frs. plus<br />
concurrent chemo<strong>the</strong>rapy with oral UFT or S-1 (RT45 group). The sizes of LNs<br />
(shortest axis, longest axis, and area) were measured on specimens stained with<br />
hematoxylin and eosin, using a computer digitizer. LNs were divided into 2 groups<br />
according to <strong>the</strong>ir distribution, inside <strong>the</strong> radiation field and outside.<br />
Results: The total number of retrieved LNs was 1718 in <strong>the</strong> S group, 2337 in <strong>the</strong><br />
RT20 group, and 917 in <strong>the</strong> RT45 group. The total number of retrieved LNs was<br />
significantly lower in <strong>the</strong> RT45 group (9.0 ± 6.9) than in <strong>the</strong> S group (15.8 ± 10.6)<br />
and <strong>the</strong> RT20 group (14.8 ± 9.1). (p < 0.001, p < 0.001) The numbers of retrieved LNs<br />
within <strong>the</strong> radiation field were significantly lower in <strong>the</strong> RT20 group (4.6 ± 4.0) and<br />
<strong>the</strong> RT45 group (4.1 ± 4.0) than in <strong>the</strong> S group (6.4 ± 5.8). (p < 0.008,p < 0.001) The<br />
numbers of retrieved LNs outside <strong>the</strong> radiation field did not differ significantly<br />
among <strong>the</strong> groups. As compared with <strong>the</strong> S group (4.9 ± 3.1mm), LNs inside <strong>the</strong><br />
radiation field were significantly smaller in <strong>the</strong> RT20 (4.4 ± 2.5mm) group and <strong>the</strong><br />
RT45 group (4.1 ± 2.7mm). LNs outside <strong>the</strong> radiation field were also significantly<br />
smaller in <strong>the</strong> RT20 group and <strong>the</strong> RT45 group than in <strong>the</strong> S group although <strong>the</strong><br />
numbers of LNS did not differ significantly. These findings were most likely caused<br />
by <strong>the</strong> effects of concurrent chemo<strong>the</strong>rapy.<br />
Conclusions: Our results showed that <strong>the</strong> response of LNs to RT/CRT differed<br />
between inside and outside of <strong>the</strong> radiation field. The numbers of retrieved LNs<br />
should be separately assessed inside and outside <strong>the</strong> radiation field to ensure accurate<br />
disease staging.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds397 | ix207
612P ARE PATIENTS WITH RESECTABLE RECTAL CANCER<br />
BETTER OFF IN THE ERA OF MULTIDISCIPLINARY CARE?<br />
V.T. Broadbridge, J. Hardingham, K. Pittman, A. Townsend, M. Colbeck,<br />
B. Hooper, T. Price<br />
Department of Medical Oncology, The Queen Elizabeth Hospital, Woodville<br />
South, SA, AUSTRALIA<br />
Introduction: The management of rectal cancer (RC) has evolved with <strong>the</strong><br />
introduction of Total Mesorectal Excision Surgery (TME), use of Magnetic<br />
Resonance Imaging (MRI) for staging, changes in chemo<strong>the</strong>rapy and radio<strong>the</strong>rapy<br />
and multidisciplinary meetings (MDTs). The timing of <strong>the</strong>rapy for T3/4 and/or node<br />
positive RC has also changed with neoadjuvant chemoradio<strong>the</strong>rapy (CRT) becoming<br />
standard based on lower local recurrence rates. Given <strong>the</strong>se changes in management<br />
over time, we assessed disease free survival (DFS), overall survival (OS) and rates of<br />
local and distant recurrences of patients treated at The Queen Elizabeth Hospital<br />
(TQEH) between 1992 to 2006.<br />
Method: Demographic and outcome data of patients diagnosed with early stage RC<br />
from TQEH Cancer Registry from 2 different time cohorts 1992-99 (A) and 2000-06<br />
(B) were analysed. Survival analysis was by Kaplan-Meier method and prognostic<br />
factors were analysed using cox proportional hazards regression.<br />
Results: 423 patients were identified; 235 in A, 188 in B. Patient characteristics<br />
were generally similar. Median age A 68.1 yrs (range 32-94), B was 67.4 yrs<br />
(range 25-92). More patients had stage B in cohort A (47%) v B (39%). 56% of<br />
patients had surgery alone in cohort A compared to 47% in cohort B. Rates of<br />
any “adjuvant” <strong>the</strong>rapy was similar (A = 41% v B = 46%), although <strong>the</strong>re was a<br />
doubling in proportion of patients who received neoadjuvant CRT in <strong>the</strong> latter<br />
cohort (A= 7.2% v B= 16%). There was a significant improvement in rate of 5<br />
year local/distal recurrence; A 87%/71% v B 95%/81%, p < 0.0001. 5 year DFS<br />
improved over time; A 65.2% v B 73.3%, p = 0. 03. 5 year OS was A 66.1% v B =<br />
78.4% and median OS for A was 14.62 years and not reached for cohort B (p =<br />
0.007). Stage and cohort B were prognostic for OS while age, sex, preoperative RT<br />
and any chemo<strong>the</strong>rapy were not.<br />
Conclusion: There has been significant improvement in DFS, OS and local and<br />
distant recurrence rates in patients diagnosed with early stage RC. The trend to<br />
greater use of neoadjuvant CRT in <strong>the</strong> latter cohort is consistent with changes in<br />
practice, and this may be a factor in improved local control, but does not appear to<br />
impact on survival. O<strong>the</strong>r factors likely to have improved overall outcomes include:<br />
increased TME rates, improved preoperative staging including use of MRI and<br />
potentially <strong>the</strong> introduction of MDTs.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
613P PPPP1R13L VARIANT ASSOCIATED WITH PROGNOSIS FOR<br />
PATIENTS WITH RECTAL CANCER<br />
J.G. Kim, B.W. Kang, S.J. Lee, Y.J. Lee, Y.S. Chae<br />
Oncology/Hematology, Kyungpook National University Medical Center, Daegu,<br />
KOREA<br />
Backgroud: Genetic variants related to apoptosis and DNA repair pathways may<br />
play a meaningful role in cancer progression as well as carcinogenesis. Among<br />
<strong>the</strong>m, ERCC1 and PPP1R13L polymorphisms was shown to synergistically affect<br />
<strong>the</strong>se pathways. The aim of this study was to investigate <strong>the</strong> association between<br />
<strong>the</strong>se genetic variants and prognosis of colorectal cancer (CRC) operated<br />
curatively.<br />
Methods: A total of 349 CRC patients underwent curative surgery were<br />
consecutively enrolled between March 2003 and August 2006. DNA was<br />
extracted from fresh frozen normal tissue and each polymorphism (ERCC1<br />
rs11615 and rs735482; PPP1R13L rs1005165 and rs967591) was genotyped by<br />
polymerase chain reaction-restriction fragment length polymorphism<br />
(PCR-RFLP).<br />
Results: No statistical significance between <strong>the</strong>se 4 variants and survival in a<br />
multivariate analysis for all CRC patients. However, <strong>the</strong> CC genotype of <strong>the</strong><br />
PPP1R13L rs1005165 was significantly associated with worse survival in 164<br />
patients with rectal cancer (HR = 2.10 and P = 0.037 for RFS; HR = 2.27 and P =<br />
0.039 for DSS, respectively) as a recessive model of <strong>the</strong> C allele in a multivariate<br />
analysis. Meanwhile, no statistical differences in clinicopathologic characteristics<br />
were observed according to <strong>the</strong> PPPIR13L rs1005165 genotype in patients with<br />
rectal cancer.<br />
Conclusions: Our results suggest that PPP1R13L rs1005165 variant is possible<br />
prognostic marker for patients with rectal cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
614P NEOADJUVANT TREATMENT IN RECTAL CANCER: LONG- VS<br />
SHORT-COURSE RADIOTHERAPY<br />
J. Casalta-Lopes1 , I. Nobre-Góis1 , T. Teixeira1 , M. Borrego1 , P. Soares1 ,A.Sá2 1 2<br />
Radiation Oncology, CHUC, Coimbra, PORTUGAL, Medical Oncology, CHUC,<br />
Coimbra, PORTUGAL<br />
Introduction: Two schemes for pre-operative radio<strong>the</strong>rapy (RT) in locally advanced<br />
rectal carcinoma (RC) are possible: long-course irradiation (45 – 50.4 Gy / 25 – 28<br />
fr) with chemo<strong>the</strong>rapy (CHT), followed by surgery after 6 to 8 weeks; and<br />
short-course irradiation (25 Gy / 5 fr), followed by surgery usually 1 week after.<br />
Some studies have shown a downstaging effect with delayed surgery in short-course<br />
irradiation Goal: Compare results of different irradiation schemes for neoadjuvant<br />
treatment of RC in a Radiation Oncology Department.<br />
Methods: Patients with RC treated pre-operatively between 2002 and <strong>2012</strong> were<br />
included. RT was performed according to 2 schemes: long-course scheme (GROUP<br />
1) using only RT (GROUP 1A), with oral CHT (GROUP 1B) or infusion CHT<br />
(GROUP 1C); and short-course scheme (GROUP 2).<br />
Results: 265 patients were included, 227 in GROUP 1. GROUP 1A were older than<br />
GROUP 1B and 1C (p < 0.001). Grade 3 and 4 toxicity was only observed in <strong>the</strong><br />
groups treated with concomitant CHT. Median time to surgery was 7 weeks.<br />
Response to treatment was statistically different regarding node downstaging (58.3%<br />
vs 77.1% vs 55.8%; p = 0.015) and locoregional response (56.3 vs 82.6% vs 70.5%;<br />
p = 0.020). GROUP 2 patients were older than those from GROUP 1 (p < 0.001), had<br />
lower Karnofsky index (p = 0.004) and several comorbidities. 15.8% patients (vs 0%)<br />
were considered M1 and more tumours were fur<strong>the</strong>r than 5 cm from <strong>the</strong> anal margin<br />
in GROUP 2 (68.4% vs 49.8%; p = 0.033). No acute toxicity was observed in GROUP<br />
2 and median time to surgery was 2 weeks, with 65.7% of locoregional response.<br />
Considering time to surgery (≤1 week vs >1 week) <strong>the</strong>re were significant differences<br />
in locoregional response (28.6% vs 75.0%, p = 0.033), with 2 complete responses in<br />
those with greater time to surgery.<br />
Conclusions: These results are according to literature: long-course scheme with<br />
concomitant CHT provided better locoregional response, although with some acute<br />
toxicity; a higher time to surgery in short-course scheme appears to have better<br />
results, with no increase in surgical complications. Short-course irradiation with<br />
surgery delay appears to be a useful alternative to long-course radiochemo<strong>the</strong>rapy,<br />
namely in patients with advanced age and associated comorbidities.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1704P PROSPECTIVE FEASIBLE STUDY TO EVALUATE<br />
NEOADJUVANT-SYNCHRONUS S-1 + RT FOR LOCALLY<br />
ADVANCED RECTAL CANCER: A MULTICENTER PHASE-II<br />
TRIAL (UMIN ID03396)<br />
M. Inomata<br />
Department of Gastroenterological Surgery, Oita University Faculty of Medicine,<br />
Oita, JAPAN<br />
Background: Fluorouracil-based chemoradio<strong>the</strong>rapy (CRT) is regarded as a standard<br />
perioperative treatment in locally advanced rectal cancer. We investigated <strong>the</strong> efficacy<br />
and safety of substituting fluorouracil with <strong>the</strong> oral prodrug TS-1.<br />
Methods: A multi-institutional (17 specialized centers), interventional phase II trial,<br />
was conducted from April 2009 to August 2011.This study is registered with<br />
UMIN-CTR, number C003396. For inclusion, patients must fulfill <strong>the</strong> following<br />
requirements before neoadjuvant CRT: (i) histologically proven rectal carcinoma; (ii)<br />
tumor located in <strong>the</strong> rectum (upper,lower); (iii) cancer classified as T3-4, N0–3 and<br />
M0; Two cycles of neoadjuvant CRT with TS-1 (100 mg/m 2 on days 1-5, 8-12, 22-26,<br />
and 29-33) is administered, and irradiation (total 45Gy/25fr, 1.8Gy/day, on days 1-5,<br />
8-12, 15-19, 22-26, and 29-33) is performed. Total mesorectal excision with D3<br />
lymphadenectomy is performed during <strong>the</strong> 4th and 8th week after <strong>the</strong> end of <strong>the</strong><br />
neoadjuvant CRT. The primary end-point is rate of complete treatment of<br />
neoadjuvant CRT. Secondary endpoints are response rate of neoadjuvant CRT,<br />
short-term clinical outcomes, rate of curative resection, and pathological response<br />
(grade2/3).<br />
Results: This trial included 37 patients. A complete treatment of neoadjuvant CRT<br />
was found in 83.3% of patients (95%CI;71.2 ∼ 95.5%), and an adverse event (grade 3/<br />
4) occurred in 4 patients(11.1%). A rate of an overall downstaging (PR/CR;RECIST<br />
1.0) was 83.3% (95%CI; 71.2 ∼ 95.5%), and a pathologic response rate was 50.0%<br />
(95%CI; 33.7 ∼ 66.3%).<br />
Conclusion: Our prospective phase-II study demonstrated that a<br />
neoadjuvant-synchronus TS-1 + RT for locally advanced rectal cancer was feasible in<br />
terms of pathological response and adverse events.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix208 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
615 SINGLE NUCLEOTIDE POLYMORPHISMS (SNP’S) IN THE P53,<br />
SMAD7 AND TGFBR1 GENES ASSOCIATED WITH ADVANCED<br />
COLORECTAL CANCER IN CAUCASIAN PATIENTS COMPARED<br />
TO HEALTHY CONTROLS<br />
M. Pauly 1 , G. Mahon 1 , M.A. Dicato 2 , B. Metzger 1 , A. Menzel 3<br />
1 Laboratory, Foundation for Research on Cancer, Luxembourg, LUXEMBOURG,<br />
2 Hematology- Oncology, Centre Hospitalier de Luxembourg, Luxembourg,<br />
LUXEMBOURG, 3 Biology Moléculaire, Laboratoires Réunis, Junglinster,<br />
LUXEMBOURG<br />
Background: In order to evaluate various SNP’s in different genes and<br />
chromosomal locations in Caucasian patients as markers of <strong>the</strong> predisposition to<br />
<strong>the</strong> colorectal cancer (CRC) disease, we analyzed <strong>the</strong> frequency of different<br />
tumour-associated single-nucleotide polymorphisms in several genes including p53<br />
and SMAD7 of Caucasian CRC patients as compared to a healthy Caucasian<br />
control population.<br />
Method: Tumour samples were obtained from 188 CRC patients and from<br />
leukocytes of 98 healthy control individuals. After gDNA extraction, selected<br />
amplicons were amplified by PCR, followed by melting curve analysis. The statistical<br />
evaluation was carried out using <strong>the</strong> Chi-squared test.<br />
Results: Comparing <strong>the</strong> patients to <strong>the</strong> controls, a significant difference in <strong>the</strong><br />
genotype distribution of <strong>the</strong> G429C SNP in <strong>the</strong> p53 gene was observed (P = 0.046).<br />
Similarly, a significant difference was found for rs4939827 C > T in <strong>the</strong> SMAD7 gene<br />
(P = 0.037), although no significant differences were found for rs4464148 T > C (P =<br />
0.585) or rs12953717 C > T (P = 0.197) also in SMAD7. Differences in genotype<br />
distribution for CHR9 C > A rs719725 and CHR8 G > A rs7014346 were almost<br />
significant (P = 0.050 and P = 0.054 respectively). Significant results previously<br />
reported for two o<strong>the</strong>r genes were confirmed:- PAI, 5G vs. 4G, rs1799899 (P = 0.047)<br />
and TGFBR1 A > G rs334348, G > A rs334349 and A > C rs1591 (P < 0.0001). No<br />
significant differences were found for SNP’s in 9 o<strong>the</strong>r genes.<br />
Conclusion: The results for p53, SMAD7, PAI, CHR8 and CHR9 are suggestive<br />
ra<strong>the</strong>r than conclusive and invite confirmation through fur<strong>the</strong>r study. Concerning <strong>the</strong><br />
association between <strong>the</strong> TGFBR1 SNP’s and colorectal cancer, <strong>the</strong> results are<br />
significant (p < 0.0001). For example, with <strong>the</strong> TGFBR1 SNP rs334348, <strong>the</strong> frequency<br />
of <strong>the</strong> GG genotype was as much as 43% for <strong>the</strong> CRC patients but 11% for <strong>the</strong><br />
controls, while <strong>the</strong> frequency of <strong>the</strong> AA genotype was only 18% for <strong>the</strong> patients and<br />
43% for <strong>the</strong> controls.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
616 EARLY LYMPH NODE METASTASIS: ALTERED MICRORNA<br />
EXPRESSION IN COLON CANCER<br />
M. Rammer 1 , H. Rumpold 2 , H. Bösmüller 3 , R. Marschon 1 , T. Malli 1 ,<br />
W. Kranewitter 1 , M. Erdel 1 , S. Deutschbauer 1 , A.L. Petzer 2 , G. Webersinke 1<br />
1 Laboratory for Molecular Biology and Tumor Cytogenetics, Barmherzige<br />
Schwestern Hospital, Linz, Linz, AUSTRIA, 2 Interne I:hematology and Oncology,<br />
Krankenhaus der Barmherzigen Schwestern, Linz, AUSTRIA, 3 Clinical Pathology,<br />
Barmherzige Schwestern Hospital, Linz, Linz, AUSTRIA<br />
Recently several studies confirmed <strong>the</strong> regulatory potential of microRNAs<br />
(miRNAs). Via incomplete complementarity, miRNAs bind to mRNA targets<br />
<strong>the</strong>reby causing translational inhibition or target decay. Alterations of miRNA<br />
expression can be associated with various tumors. Fur<strong>the</strong>rmore, different miRNA<br />
levels were found to be linked with distinct tumor stages and could have a<br />
predictive and prognostic value, even regarding treatment response. The aim of<br />
<strong>the</strong> study is evaluating miRNÀs that correlate with early lymph node metastasis.<br />
Therefore, we compare formalin fixed, paraffin-embedded primary tissue of stage<br />
T4 colon tumors without lymph node metastasis with stage T1/2 tumors<br />
exhibiting lymph node metastasis. In order to initially scan for differentially<br />
expressed miRNAs, miRNA arrays (n = 8) were performed. A selection of miRNAs<br />
(miR-1207-5p, miR-146b-5p, miR-15a, miR-21, miR-494) showing distinct<br />
expression was <strong>the</strong>n validated in a patient collective via RT qPCR. MiR-191 and<br />
miR-720 were chosen as endogenous controls, since <strong>the</strong>y showed consistent<br />
expression in <strong>the</strong> preliminary array analysis. According to our array results, eight<br />
miRNAs displayed an elevated expression in T4 tumors without lymph node<br />
metastasis compared to three miRNAs higher expressed in <strong>the</strong> second group<br />
investigated. The significantly elevated expression (≥2-fold) was confirmed via RT<br />
qPCR for two (miR-146b-5p, miR-21) and one miRNA (miR-494), respectively.<br />
Some of our miRNA expression data correlates with that presented in studies<br />
regarding metastasis in colon cancer and o<strong>the</strong>r malignancies. Never<strong>the</strong>less, several<br />
miRNAs diverge compared to studies from o<strong>the</strong>r groups, e.g. miR-21. This could<br />
be due to differences in <strong>the</strong> tumor stages examined in <strong>the</strong>se studies. To our<br />
knowledge, miRNA expression in <strong>the</strong> colon cancer stages investigated here has not<br />
been compared so far. To validate our findings concerning miRNA expression<br />
patterns in colon tumors associated with early lymph node metastasis, we will<br />
investigate a larger cohort. This fur<strong>the</strong>r enhances our understanding of disease<br />
progression. Moreover, it implies <strong>the</strong> possibility of distinguishing stage and<br />
metastatic potential in biopsy specimen for novel <strong>the</strong>rapeutic strategies.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
617 WNT 5A EXPRESSION HAS ASSOCATION WITH VEGFR AND<br />
MMP-9 EXPRESSION IN PRIMARY OR METASTATIC TUMOR<br />
TISSUE IN COLORECTAL CANCER<br />
S.Y. You 1 , M.A. Lee 1 , S.T. Oh 2 , W.K. Kang 2<br />
1 Medical Oncology, Seoul St. Mary’s Hospital, of <strong>the</strong> Catholic University, Seoul,<br />
KOREA, 2 Surgery, Seoul St. Mary’s Hospital, Seoul, KOREA<br />
Background: It has been known that various molecular changes can develop as<br />
cancer progresses. However, it is difficult to confirm <strong>the</strong> progressive change in <strong>the</strong><br />
human tissue because adequate tumor tissue cannot be obtained from metastatic site.<br />
Resection for metastatic lesion is commonly done in metastatic colorectal cancer in<br />
spite of palliative surgery. The Wnt, VEGFR, and MMP protein expression have been<br />
explored in advanced cancer due to its association with invasion and metastasis. We<br />
investigated <strong>the</strong>se protein expressions in primary tumor and metastatic site to get <strong>the</strong><br />
basic information of <strong>the</strong> role of <strong>the</strong>se proteins in cancer progression.<br />
Method: Tissue specimens from 130 patients with metastatic colorectal cancer were<br />
analyzed. All patients took resection for primary tumor and metastatic lesion<br />
between Jan, 2000 and Aug, 2008 at Seoul St. Mary’s hospital, <strong>the</strong> Catholic<br />
University. We performed immunohistochemical staining using tissue microarray<br />
from <strong>the</strong> primary tumor tissue and metastatic site for Wnt 3a, Wnt 5a, VEGFR, and<br />
MMP-9.<br />
Result: Of <strong>the</strong> 100 patients, Male was 59, and female was 41. Colon cancer was 60<br />
and rectal cancer was 40. In primary tumor, Wnt 3 & 5 expression was 72% and<br />
70% respectively. VEGFR expression was 24% and MMP-9 was 39%. In metastatic<br />
site, Wnt 3 & 5 expression rate were slightly decreased to 66%. However, VEGFR<br />
expression rate was slightly increased to 30% and MMP-9 expression rate was same.<br />
In concordance rate between primary and metastatic site, Wnt 3a expression showed<br />
68% and 62% in Wnt 5a, 66% in VEGFR, 68% in MMP-9. There was no significant<br />
change of expression between primary and metastatic site. There was no association<br />
between Wnt 3a expression and VEGFR or MMP-9 expression both in primary<br />
tumor and metastatic site. However, Wnt 5a expression showed significantly<br />
correlation with negative VEGFR expression (p = 0.02 both in primary tumor and<br />
metastatic site. Wnt 5a expression was also associated with negative MMP-9<br />
expression in primary tumor tissue (p = 0.022).<br />
Conclusion: We could not find any significant change in protein expression between<br />
primary and metastatic site. However, <strong>the</strong>re was a tendency of more VEGFR<br />
expression in metastatic site than primary tumor. The Wnt 5 expression was<br />
associated significantly negative expression of VEGFR and MMP-9.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
618 AN EXPLORATORY ANALYSIS OF AMPK AND ACC ACTIVATION<br />
IN COLORECTAL PRIMARY TUMORS AND THEIR<br />
CORRESPONDING METASTASIS<br />
F. Bergamo 1 , G. Griguolo 2 , E. Zulato 3 , G. Esposito 3 , M. Nardin 3 , C. Mescoli 4 ,<br />
M. Rugge 5 , V. Zagonel 6 , S. Lonardi 1 , S. Indraccolo 3<br />
1 Medical Oncology Unit 1, Istituto Oncologico Veneto -IRCSS, Padua, ITALY,<br />
2 University of Padova - School of Medicine, University of Padova - School of<br />
medicine, Padova, ITALY, 3 Istituto Oncologico Veneto - Irccs, Istituto Oncologico<br />
Veneto - IRCCS, Padova, ITALY, 4 Istituto di Anatomia Patologica, University of<br />
Padova, Padova, ITALY, 5 Pathology and Cytopathology Unit, University of<br />
Padova, Padova, ITALY, 6 Medical Oncology Unit 1, Istituto Oncologico Veneto,<br />
Padua, ITALY<br />
Background: AMPK is a well known oncosuppresor, with prognostic significance in<br />
many neoplasms; it acts as a central metabolic sensor in cells, activated in<br />
energy-stress conditions. ACC is a central enzyme in cell metabolism activated<br />
through phosphorilation by AMPK. In pre-clinical models AMPK activation level<br />
correlates with necrotic response when tumors are treated with Bevacizumab. Our<br />
goal was 1) to evaluate <strong>the</strong> concordance of <strong>the</strong>se markers’ activation in primary<br />
tumours and in <strong>the</strong> corresponding metastasis, 2) to investigate <strong>the</strong>ir correlation with<br />
clinical data, in particular radiological response to FOLFIRI plus Bevacizumab.<br />
Methods: This retrospective study analyzed histological pre-treatment material from<br />
32 patients with mCRC treated with FOLFIRI-Bevacizumab to evaluate AMPK and<br />
ACC activation in primary CRC and its metastasis using immunohistochemistry. The<br />
intensity was scored from 0 (negative) to 3 (intense), and <strong>the</strong>n dichotomized in low<br />
(0-1) and high (2-3) activation categories. pAMPK and pACC intensity scores in<br />
primary tumors and metastasis were compared using Spearman’s correlation test.<br />
Radiological response has been going to be evaluated using both RECIST and<br />
morphologic criteria (Chun Criteria).<br />
Results: pAMPK was defined high in 20 (63%) primary and in 21 (66%) of <strong>the</strong><br />
corresponding metastases while pACC in 23 (72%) primary tumors and 19 (59%)<br />
metastases. As attended from biological knowledge, AMPK and ACC activation<br />
correlated significatively in primary tumors (p = 0.0007). ACC activation in primary<br />
tumors correlated significatively with its activation in <strong>the</strong>ir metastasis (p = 0.04),<br />
while AMPK activation in primary tumors and in metastasis showed a correlation<br />
not reaching statistical significance (p = 0.13). Correlation between AMPK and ACC<br />
activation and radiological morphological response was still not possible at time of<br />
writing.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds397 | ix209
Conclusions: AMPK and ACC activation showed a weak correlation in primary and<br />
metastastatic tumors, possibly due to <strong>the</strong> small number of patients and <strong>the</strong> higher<br />
heterogeneity of <strong>the</strong> metastatic tissue. The opportunity to use <strong>the</strong>se biomarkers to<br />
predict a necrotic response to bevacizumab treatment is under investigation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
619 DIFFERENTIAL ANTIGENIC EXPRESSION IN COLORECTAL<br />
CANCER, MUCOSA ADJACENT TO COLORECTAL CANCER,<br />
AND NORMAL COLORECTAL MUCOSA<br />
A. Zwenger 1 , G. Grosman 2 , S. Demichellis 3 , A. Segal-Eiras 3 , M.V. Croce 3<br />
1 Oncologia, Hospital Provincial Neuquen, Neuquen, ARGENTINA, 2 Patologia,<br />
Hospital Provincial Neuquen, Neuquen, ARGENTINA, 3 Centre for Basic and<br />
Applied Immunological Research, Faculty of Medical Sciences National University<br />
of La Plata, La Plata, ARGENTINA<br />
Introduction: Despite of an excellent oncologic surgery with broad normal tissue<br />
margins, <strong>the</strong> mucosa next to <strong>the</strong> bed anastomosed is a frequent place of tumoral<br />
recurrence on colorectal cancer. Objective: This study was performed to evaluate <strong>the</strong><br />
expression of mucins and carbohydrates associated antigens in normal mucosa<br />
colorectal specimens (NMC), mucosa adjacent to colorectal cancer (MACCR) and<br />
malignant colorectal tumour samples (CCR).<br />
Methods: Ninety colorectal cancer tumour samples and <strong>the</strong>ir MACCR, and also 68<br />
NMC were included. Monoclonal antibodies (MAbs) against <strong>the</strong> following antigens<br />
were employed: anti-MUC1 (HMFG1), MUC2 (H-300) and MUC5AC (45M1),<br />
anti-Tn (HB-Tn1), Lex (KM380), sLex (KM93), Ley (C70) and sLea (1116-N5-19-9).<br />
An immunohistochemical approach following standard procedures was performed.<br />
Statistical analysis: an univariate statistical analysis with Chi2 was applied.<br />
Results: Malignant samples expressed MUC1 in 94% of cases, MUC2 in 52.4%,<br />
MUC5AC in 14.3%, Tn in 41%, Lex in 74.4%, sLex in 66.7%, Ley in 91.8% and sLea<br />
in 90.7%. Taking into account MUC2 and Ley expression, a positive correlation was<br />
found between MACCR and CCR: MUC2, P = .0006 and Ley, P = .0008. In<br />
malignant samples, MUC1 expression was increased compared to NMC (P = .04),<br />
also this mucin was 22.2% higher in MACCR than NMC. The expression of sLex<br />
and Ley was higher in CCR than NMC (179% and 33.6%, respectively). Expression<br />
of most antigens showed an increased tendency from NMC to MACCR and CCR:<br />
MUC1 (27.9%, 34.1% and 94%, respectively), Lex (60.9%, 30.5% and 74.4%,<br />
respectively), sLex (23.9%, 16.9% and 66.7%, respectively), Ley (68.7%, 78.3% and<br />
91.8%, respectively) and sLea (62.1%, 45.6% and 90.7%, respectively). On <strong>the</strong> o<strong>the</strong>r<br />
hand, MUC5AC expression decreased in <strong>the</strong> mentioned sequence (51.5%, 20.7% and<br />
14.3, respectively).<br />
Conclusion: Our results may support <strong>the</strong> hypo<strong>the</strong>sis that <strong>the</strong> MACCR could be an<br />
intermediate point or “transitional zone” between NMC and CCR. Fur<strong>the</strong>r studies<br />
are needed in order to correlate <strong>the</strong>se findings with clinical outcomes.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
620 IMPACT OF THE INTERVAL BETWEEN SURGERY AND<br />
ADJUVANT MFOLFOX6 ON SURVIVAL OF COLON CANCER<br />
PATIENTS<br />
J. Godinho Bexiga, F. Carneiro, D.S. Marques, N. Sousa, C. Faustino,<br />
A. Raimundo, M. Machado, P. Ferreira, M. Fragoso<br />
Medical Oncology, Portuguese Institute of Oncology of Oporto, Oporto,<br />
PORTUGAL<br />
Background: Adjuvant chemo<strong>the</strong>rapy with <strong>the</strong> association of Oxaliplatin and<br />
Fluoropyrimidines has shown to reduce recurrence risk and improve survival in stage<br />
III colon cancer patients in comparison to Fluoropyrimidines alone. The ideal timing<br />
for <strong>the</strong> start of adjuvant chemo<strong>the</strong>rapy has not been defined. Our aim was to<br />
determine <strong>the</strong> impact of <strong>the</strong> interval between surgery and <strong>the</strong> start of adjuvant<br />
chemo<strong>the</strong>rapy on survival of colon cancer patients.<br />
Material and methods: Retrospective cohort study, in a Portuguese cancer centre, of<br />
colon cancer (CC) patients treated with mFOLFOX6 in <strong>the</strong> adjuvant setting, from<br />
Table: 621<br />
Group<br />
5-year<br />
RFS HR [95% CI]<br />
September 2004 till November 2009. Two groups of patients were defined according<br />
to <strong>the</strong> timing of adjuvant chemo<strong>the</strong>rapy (CT): ≤ 8weeks or >8 weeks after surgery.<br />
Efficacy was evaluated by overall survival (OS) and disease-free survival (DFS).<br />
Hazard ratios and 95% confidence intervals were calculated with <strong>the</strong> use of <strong>the</strong> Cox<br />
proportional hazards model.<br />
Results: Two hundred and seventy seven patients were treated with adjuvant<br />
mFOLFOX6 and followed for a median time of 45 months. Median age was 62 years<br />
(28-79); 57% were male and 77% had stage III CC. Median time to <strong>the</strong> start of CT<br />
was 8 weeks (P25 = 7, P75 = 10). The group of patients that started CT > 8 weeks<br />
after surgery was older (mean age: 62 vs 59 years, p = 0.001) and tended to<br />
accomplish lower relative dose-intensity of Oxaliplatin and 5-Fluorouracil (69,5% vs<br />
72% and 73% vs 76%, respectively; p > 0.05). There was a tendency to lower OS and<br />
DFS in <strong>the</strong> group that started CT >8 weeks after surgery. At 3 years, <strong>the</strong> probability<br />
of OS was 83% vs 90% (p = 0.118), and DFS: 75% vs 77% (p = 0.751). Multivariate<br />
analysis showed that <strong>the</strong> interval between surgery and <strong>the</strong> start of adjuvant CT had<br />
no impact in OS nor DFS.<br />
Conclusions: Our data point to a tendency to better survival when CT is started<br />
within 8 weeks of surgery, streng<strong>the</strong>ning <strong>the</strong> need for a timely referral of<br />
patients to adjuvant treatment. The small sample size and <strong>the</strong> short follow-up<br />
might explain why we were unable to find statistical significance in this<br />
association.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
621 IS ADJUVANT CHEMOTHERAPY (CT) BENEFICIAL TO STAGE II<br />
COLON CANCER (CC) WITH ELASTIC LAMINANL INVASION<br />
(ELI)?<br />
M. Yokota 1 , M. Kojima 2 , S. Nomura 3 , A. Koyama 1 , M. Sugito 1 , M. Ito 1 ,<br />
A. Kobayashi 1 , Y. Nishizawa 1 , A. Ochiai 2 , N. Saito 1<br />
1 Department of Gastrointestinal Oncology, Colorectal Surgery, National Cancer<br />
Center Hospital East, Kashiwa, JAPAN, 2 Research Center for Innovative<br />
Oncology, Pathology, National Cancer Center Hospital East, Kashiwa, JAPAN,<br />
3 Research Center for Innovative Oncology, Clinical Trial Section, National Cancer<br />
Center Hospital East, Kashiwa, JAPAN<br />
Background: The peritoneal elastic lamina (PEL) is situated just under <strong>the</strong> visceral<br />
peritoneum and invests intestine wall. We defined cases with tumor invasion beyond<br />
<strong>the</strong> PEL as positive for ELI (ELI (+)). We have reported that PEL can be a useful<br />
pathologic hallmark to classify <strong>the</strong> level of tumor invasion in CC, and represented as<br />
an independent risk factor for recurrence free survival (RFS) for stage II CC (Kojima<br />
et al. Am J Surg Pathol. 2010;34:1351-60). We evaluated <strong>the</strong> necessity of adjuvant CT<br />
for stage II CC with ELI (+).<br />
Methods: We screened a database of 436 patients (pts) who underwent curative<br />
resection for pT3 and pT4a CC in our hospital between 1996 and 2006,<br />
excluding 3 stage II pts who received adjuvant CT. RFS and overall survival<br />
(OS) were analyzed to assess <strong>the</strong> prognostic characteristics of stage II pts with<br />
ELI (+). Of 436 pts in <strong>the</strong> database, we performed Cox regression analysis.<br />
Covariates included age (
Annals of Oncology<br />
622 RANDOMIZED, OPEN-LABEL STUDY OF THE BIOLOGICAL<br />
EFFECTS OF BLP25 LIPOSOME (L-BLP25) IMMUNOTHERAPY<br />
IN RECTAL CANCER PATIENTS UNDERGOING NEOADJUVANT<br />
CHEMORADIOTHERAPY: SPRINT STUDY DESIGN<br />
T.J.M. Ruers 1 , D. Aust 2 , M. van den Eynde 3 , G. Folprecht 4 , J. Carrasco 5 ,<br />
M. Fuchs 6 , J.M. Smit 7 , A. Victor 8 , S. Quaratino 9<br />
1 Department of Surgical Oncology, Nederlands Kanker Instituut - Antoni van<br />
Leeuwenhoek Ziekenhuis, Amsterdam, NETHERLANDS, 2 Institute of Pathology,<br />
Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden,<br />
Dresden, GERMANY, 3 Medical Oncology, Cliniques universitaires St-Luc,<br />
Brussels, BELGIUM, 4 Department of Internal Medicine I, Universitätsklinikum Carl<br />
Gustav Carus an der Technischen Universität Dresden, Dresden, GERMANY,<br />
5 Medical Oncology, Grand Hopital de Charleroi, Charleroi, BELGIUM,<br />
6 Gastroenterology Clinic, Klinikum Bogenhausen, München, GERMANY, 7 Internal<br />
Medicine, Gelre Ziekenhuizen, Apeldoorn, NETHERLANDS, 8 Global Biostatistics/<br />
oncology, Merck KGaA, Darmstadt, GERMANY, 9 Global Clinical Development,<br />
Merck KGaA, Darmstadt, GERMANY<br />
Background: Neoadjuvant chemoradio<strong>the</strong>rapy (NCR) followed by radical resection is<br />
<strong>the</strong> standard of care for patients with stage II-III rectal cancer. L-BLP25 (Stimuvax®)<br />
is an antigen-specific cancer immuno<strong>the</strong>rapeutic agent targeting <strong>the</strong> mucin 1<br />
(MUC1) antigen. It may act by inducing <strong>the</strong> proliferation of interferon (IFN)-γ<br />
secreting MUC1-specific CD4+ T-cells and <strong>the</strong> generation of cytotoxic T<br />
lymphocytes capable of killing MUC1-expressing tumours. In <strong>the</strong> SPRINT<br />
(Stimuvax® [L-BLP25] in Rectal cancer In Neoadjuvant chemoradioTherapy) study,<br />
we will evaluate immune responses to L-BLP25 in patients with rectal cancer<br />
undergoing NCR.<br />
Study design: SPRINT is a phase II, multi-centre, open-label study in which patients<br />
(n = 24/arm) with resectable stage II-III rectal cancer are randomized to NCR<br />
(capecitabine 825 mg/m 2 twice-daily for 5–7 d/wk; 45–52 Gy in fractions of 1.8/2 Gy<br />
for ≥5 wk) alone, NCR + L-BLP25, or NCR + L-BLP25 + cyclophosphamide (CPA).<br />
L-BLP25 is administered as 8 consecutive weekly subcutaneous doses (930 µg)<br />
beginning on <strong>the</strong> first day of NCR, followed by a final injection 7–9 d before surgery.<br />
CPA (300 mg/m 2 ; maximum 600 mg) is given as a single intravenous infusion 3 d<br />
before <strong>the</strong> first L-BLP25 dose. Surgery will be performed 6–8 wk after <strong>the</strong> end of<br />
NCR. The primary objective is to assess L-BLP25-induced changes in immune<br />
response profile. The intra-tumoural response will be evaluated based on analysis of<br />
tumour-infiltrating lymphocytes (especially CD8+ and CD45RO+). Peripheral<br />
antigen-specific response will be assessed by measuring IFN-γ secretion by peripheral<br />
blood mononuclear cells (ELIspot assay) in response to MUC1 and<br />
carcinoembryonic antigen (CEA) as a test for ‘antigen spreading’. Secondary<br />
objectives include <strong>the</strong> assessment of additional immunological changes and<br />
correlation of intratumoural, peripheral and skin delayed-type hypersensitivity<br />
responses. Safety and pathological anti-tumour responses in resection specimens will<br />
be evaluated.<br />
Disclosure: A. Victor: Anja Victor is an employee of Merck KGaA Germany.<br />
S. Quaratino: Sonia Quaratino is an employee of Merck KGaA. All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
623 EUROPEAN ORGANIZATION FOR RESEARCH AND<br />
TREATMENT OF CANCER QLQ-C30 AND FUNCTIONAL<br />
ASSESSMENT OF CANCER THERAPY-GENERAL FOR THE<br />
MEASUREMENT OF QUALITY OF LIFE IN COLORECTAL<br />
CANCER PATIENTS WHO RECEIVED ADJUVANT<br />
CHEMOTHERAPY: A COMPARISON<br />
A. Tsunoda 1 , Y. Tsunoda 2<br />
1 Surgery, Kameda Medical Center, Kamogawa City, JAPAN, 2 Breast Center,<br />
Kameda Medical Center, Kamogawa City, JAPAN<br />
Purpose: Quality of life (QOL) was measured using <strong>the</strong> European Organization for<br />
Research and Treatment of Cancer QLQ-C30 (QLQ-C30) and Functional<br />
Assessment of Cancer Therapy-General (FACT-G) in colorectal cancer patients who<br />
received adjuvant chemo<strong>the</strong>rapy with oral uracil/tegafur plus leucovorin, and two<br />
QOL measurements were compared.<br />
Methods: QOL was assessed prospectively at baseline (pretreatment) and at 5-week<br />
intervals during treatment, using QLQ-C30 and FACT-G, and were compared with<br />
reference to <strong>the</strong> corresponding scales.<br />
Results: The study group comprised 58 men and 41 women, with a mean age of 65<br />
years (range, 30 to 80). The disease stage was stage II in 51 patients and stage III in<br />
48. The 99 patients had received a total of 444 treatment cycles (median, 5 cycles;<br />
range, 0.1 to 5 cycles). The most common type of toxicity was fatigue. However, <strong>the</strong><br />
incidence of grade 3 or 4 fatigue was very low. The most common type of<br />
hematological toxicity was anemia, which was generally mild. Six patients had grade<br />
3 diarrhea and 6 had grade 3 anorexia. QOL was not evaluated ei<strong>the</strong>r before or after<br />
treatment in 5 of <strong>the</strong> 99 enrolled patients; both baseline and post-treatment<br />
evaluations were available for <strong>the</strong> o<strong>the</strong>r 94 patients. Of 94 patients, <strong>the</strong> numbers of<br />
patients who completed <strong>the</strong> QOL questionnaires were 90 (96%) at baseline, and 87<br />
(93%), 85 (90%), 88 (94%), 84 (89%), and 81 (86%), consecutively. The mean<br />
number of evaluations per patient was 6.2 (range, 3-7). The post-treatment<br />
assessments changed significantly from <strong>the</strong> baseline values and favored<br />
post-treatment for all scales except social well-being of <strong>the</strong> FACT-G. All scales except<br />
social well-being in patients with Grade 0-1 toxicities were better than those with<br />
Grade 2-3 toxicities. Social well-being in patients with Grade 2-3 toxicities were<br />
worse than those with Grade 0-1. When corresponding scales between <strong>the</strong> two QOL<br />
questionnaires were compared, a high correlation for physical domain or emotional<br />
domain was found. However, no correlation was noticed for <strong>the</strong> social domain.<br />
Conclusion: The social domain of <strong>the</strong> two QOL questionnaires may evaluate<br />
different aspects of QOL each o<strong>the</strong>r.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
624 PATHOLOGICAL RESPONSE OF SYNCHRONOUS LIVER<br />
METASTASES FROM COLORECTAL CANCER TREATED WITH<br />
BEVACIZUMAB PLUS MFOLFOX6 IN AN ANALYSIS OF A PHASE<br />
II STUDY OF NEOADJUVANT CHEMOTHERAPY<br />
Y. Katayose 1 , J. Yamauchi 2 , M. Oikawa 3 , N. Sakurai 4 , H. Musya 5 ,<br />
H. Shimamura 6 , K. Miura 7 , K. Nakagawa 1 , S. Egawa 7 , M. Unno 7<br />
1 Intergrated Surgery and Oncology, Tohoku University Graduate School of<br />
Medicine, Sendai, JAPAN, 2 Surgery, Sendai Kosei Hospital, Sendai, JAPAN,<br />
3 Surgery, Sendi city medical center, Sendai, JAPAN, 4 Surgery, Yamagata central<br />
hospital, Yamagata, JAPAN, 5 Surgery, Tohoku Rosai Hospital, Sendai, JAPAN,<br />
6 Surgery, Sendai Medical Center, Sendai, JAPAN, 7 Surgery, Tohoku University<br />
Graduate School of Medicine, Sendai, JAPAN<br />
Background: The prognosis of synchronous liver metastases (SLM) from colorectal<br />
cancer is poor. Therefore, we, <strong>the</strong> Miyagi Hepato-biliary pancreatic clinical oncology<br />
group (Miyagi-HBPCOG), conducted a phase II study of neoadjuvant chemo<strong>the</strong>rapy<br />
for SLM to determine <strong>the</strong> appropriate initial treatment. Here, we assessed <strong>the</strong><br />
radiologic and pathological responses.<br />
Patients and methods: Patients were enrolled after R0-resection of <strong>the</strong> primary<br />
colorectal cancer and received 8 courses of mFOLFOX6 with bevacizumab (<strong>the</strong> first<br />
and last courses were mFOLFOX6 alone). The main inclusion criteria were SLM<br />
within 10 nodules, histologically confirmed, measurable disease. The primary<br />
endpoint was <strong>the</strong> response rate (RR).<br />
Result: Between June 2008, and November 2008, 47 patients were enrolled from 17<br />
centers. The median age was 62 years (range 32-72 yrs). The median number of<br />
metastases was 2 nodules, and <strong>the</strong> maximum diameter of tumors was 12.9 cm. Three<br />
patients were excluded from <strong>the</strong> evaluation of RR because <strong>the</strong>y did not receive any<br />
scheduled chemo<strong>the</strong>rapy. The overall RR was 70.5% (2 complete responses and 29<br />
partial responses). Eleven patients (25%) showed stable disease and 1 patient (2.3%)<br />
had progressive disease. The liver resections rate was 90.9% (40/44) and <strong>the</strong><br />
R0-resection rate was 86.3% (38/44). The pathological response was evaluated tumor<br />
regression grade (TRG1-5). Major response (TRG1 and 2) was 55%, partial response<br />
(TRG2) was 32.5%, and no response (TRG4 an 5) was 12.5%. This major response<br />
rate was high, so <strong>the</strong> progression-free survival and overall survival can be extended is<br />
expected. Necrosis was also graded as 1 to 4. Major necrosis of Grade 3 and 4 was<br />
52.5%, and Grade 2 was 17.5%, and Grades 0 and 1 of no necrosis were 30.0%.<br />
Although <strong>the</strong> necrosis rate slightly correlated with <strong>the</strong> pathological response, <strong>the</strong><br />
radiological response did not correlate with it.<br />
Conclusion: Pathological and radiological response of liver metastases treated with<br />
bevacizumab plus mFOLFOX6 appeared favorable. Therefore, <strong>the</strong> progression-free<br />
survival and overall survival could be expected to be extended. (Trials Registry:<br />
UMIN000001568).<br />
Disclosure: All authors have declared no conflicts of interest.<br />
625 FEASIBILITY REPORT OF A RANDOMIZED MULTICENTER<br />
CONTROLLED PHASE III TRIAL OF ADJUVANT UFT/LV<br />
THERAPY AFTER RESECTION FOR LIVER METASTASIS FROM<br />
COLORECTAL CARCINOMA<br />
J. Yamamoto 1 , K. Hatsuse 1 , N. Kokudo 2 , M. Oba 1 , T. Takayama 3 , S. Miyagawa 4 ,<br />
Y. Bandai 5 , K. Hasegawa 2 , A. Saiura 6 , M. Makuuchi 7<br />
1 Surgery, National Defense Medical College, Tokorozawa, JAPAN, 2 Hepato–<br />
Biliary–Pancreatic Surgery Division, Department of Surgery, Graduate School of<br />
Medicine, University of Tokyo, Tokyo, Bunkyo-ku, JAPAN, 3 Department of<br />
Digestive Surgery, Nihon University School of Medicine, Tokyo, JAPAN, 4 First<br />
Department of Surgery, Shinshu University School of Medicine, Matsumoto,<br />
JAPAN, 5 Department of Surgery, Social Insurance Chuo General Hospital,<br />
Tokyo, JAPAN, 6 Department of Gastrointestinal Surgery, Cancer Institute<br />
Hospital, Japanese Foundation for Cancer Research, Ariake Hospital, Tokyo,<br />
JAPAN, 7 Department of Hepatobiliary Pancreatic Surgery, Japanese Red Cross<br />
Medical Center, Tokyo, JAPAN<br />
There is no established evidence yet to support <strong>the</strong> of postoperative adjuvant<br />
chemo<strong>the</strong>rapy after resection of colorectal liver metastasis. A randomized multicenter<br />
controlled phase III trial was conducted and patients were recruited from 20<br />
hospitals to compare <strong>the</strong> efficacy of postoperative adjuvant UFT/LV <strong>the</strong>rapy (UTF:<br />
300 mg/m 2 /day and LV: 75 mg/day, Day 1-28, once every 5 weeks, 5 cycles) with that<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds397 | ix211
of surgical mono<strong>the</strong>rapy in patients with colorectal liver metastasis. A total of 180<br />
patients enrolled from January 2004 to December 2010 are currently under<br />
follow-up. The primary endpoint is recurrence-free survival time and <strong>the</strong> secondary<br />
endpoint is overall survival time, <strong>the</strong> results of which are awaited. It is expected that<br />
<strong>the</strong> patients who underwent liver resection in this study are different from <strong>the</strong> stage<br />
II or III colon cancer patients treated by surgery for primary diseases. We shall<br />
report <strong>the</strong> results of <strong>the</strong> interim analysis of compliance and safety in <strong>the</strong> 175 patients<br />
for whom <strong>the</strong> CRFs relevant to this study could be collected. Eighty-eight patients<br />
received surgical mono<strong>the</strong>rapy and 87 received surgery plus UFT/LV <strong>the</strong>rapy. There<br />
were no significant differences in <strong>the</strong> demographic or clinicopathological factors<br />
between <strong>the</strong> two groups. The rate of completion of UFT/LV <strong>the</strong>rapy (5 courses) was<br />
53.8% (43/80), and <strong>the</strong> rates of completion up to 3 and 6 months were 71.3% (57/80)<br />
and 53.8% (43/80), respectively. The mean rate of dose intensity was 70.1%. Of <strong>the</strong><br />
37 patients in whom <strong>the</strong> treatment was discontinued, <strong>the</strong> reason for <strong>the</strong><br />
discontinuation was adverse events in 26 patients (in conflict with discontinuation<br />
criteria in 7 patients and no conflict in 19) and appearance of recurrence in 8<br />
patients. Adverse events of CTCAE grade 3 or higher observed in <strong>the</strong> UFT/LV Group<br />
included decrease in hemoglobin (3.8%), increase in AST/ATL (2.6%), febrile<br />
neutropenia (1.3%), hyperbilirubinemia (1.3%), diarrhea (5.0%), loss of appetite<br />
(2.5%), and nausea (2.5%). There were no treatment-related deaths. The incidence<br />
rates of <strong>the</strong>se symptoms are not greatly different from those reported in relation to<br />
<strong>the</strong> safety profile after surgery for stage III colon cancer from <strong>the</strong> ACTS-CC study,<br />
which suggested that <strong>the</strong> tolerability of UFT/LV <strong>the</strong>rapy was maintained even in<br />
stage IV colorectal cancer patients treated by hepatectomy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
626 WHAT TO CHOOSE AS RADICAL LOCAL TREATMENT FOR<br />
LUNG METASTASES FROM COLO-RECTAL CANCER:<br />
SURGERY, RADIOFREQUENCY ABLATION OR STEREOTACTIC<br />
RADIOTHERAPY?<br />
R. Schlijper 1 , D. De Ruysscher 2 , J.P. Grutters 3 , R. Houben 4 , A.C. Dingemans 5 ,<br />
J.E. Wildberger 6 , D.V. Raemdonck 7 , E. Van Cutsem 8 , G. Lammering 4 ,<br />
P. Lambin 2<br />
1 Faculty of Health, Medicine and Life Sciences, School of Medicine, Maastricht<br />
University, Maastricht, NETHERLANDS, 2 Maastro Clinic, Maastricht University<br />
Medical Center (MUMC), Maastricht, NETHERLANDS, 3 Department of Health<br />
Service Research, School for Public Health and Primary Care (CAPHRI),<br />
Maastricht University, Maastricht, NETHERLANDS, 4 Department of Radiation<br />
Oncology, Maastro Clinic, Maastricht, NETHERLANDS, 5 Pulmonology,<br />
Maastricht University Medical Center (MUMC), Maastricht, NETHERLANDS,<br />
6 Department of Radiology, Maastricht University Medical Center, Maastricht,<br />
NETHERLANDS, 7 Department of Thoracic Surgery, University Hospital Leuven,<br />
Leuven, BELGIUM, 8 Digestive Oncology, University Hospital Leuven, Leuven,<br />
BELGIUM<br />
Background: Long-term survival can be obtained with local treatment of lung<br />
metastases from colorectal cancer. However, it is unclear as to what <strong>the</strong> optimal local<br />
<strong>the</strong>rapy is: surgery, radiofrequency ablation (RFA) or stereotactic radio<strong>the</strong>rapy<br />
(SBRT).<br />
Methods: After a systematic review, 27 studies were included matching with <strong>the</strong> a<br />
priori selection criteria, <strong>the</strong> most important being at least 50 patients and a follow-up<br />
period of ≥ 24 months. However, no SBRT studies were eligible. The review was<br />
<strong>the</strong>refore conducted on 4 RFA and 23 surgical series.<br />
Results: Four of <strong>the</strong> surgical studies were prospective, all o<strong>the</strong>rs were retrospective.<br />
No randomized trial was found. The reported data differed between <strong>the</strong> studies,<br />
which led to difficulties in <strong>the</strong> analyses. Treatment-related mortality rates for RFA<br />
and surgery were 0% and 1.4-2.4%, respectively, whereas morbidity rates were<br />
reported inconsequently but seemed <strong>the</strong> lowest for surgery. Weighted 2- and 5-year<br />
survival were 69.6% and 40.7% for RFA and 76.5% and 44.9% for surgery.<br />
Conclusion: Due to <strong>the</strong> lack of phase III trials, no firm conclusions can be drawn,<br />
although most evidence supports surgery. High-quality trials comparing currently<br />
used treatment modalities such as SBRT, RFA and surgery are needed.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
627 RESULTS OF ADJUVANT CHEMOTHERAPY AFTER HEPATIC<br />
AND/OR LUNG METASTASES RESECTION OF COLORECTAL<br />
CANCER<br />
E.I. Gutiérrez Damian 1 , A. Sancho Gutiérrez 1 , M. Arruti 1 , S. Carrera 2 , I. Rubio 1 ,<br />
I. Marrodan 1 , A. Muñoz 1 , E. Azkona 1 , A. Buque 1 , G. Lopez-Vivanco 1<br />
1 Medical Oncology, Hospital of Cruces, Barakaldo, SPAIN, 2 Oncology, Hospital<br />
de Cruces, Barakaldo, Vizcaya, SPAIN<br />
Background: Adjuvant chemo<strong>the</strong>rapy following metastases resection of colorectal<br />
cancer is recommended although <strong>the</strong> benefit has not been clearly demonstrated in<br />
clinical trials.<br />
Annals of Oncology<br />
Methods: We have performed a retrospective review of patients (pt) with hepatic<br />
and lung metastases treated with surgery and adjuvant chemo<strong>the</strong>rapy in our<br />
institution, from January-96 to December-11.<br />
Results: One hundred ninety one patients were identified. Patient<br />
characteristics: median age 62 years (23-81). Sex: 114 male (60%) 77 female<br />
(40%). Primary tumour location: colon 129 (67.5%) rectal 62 (32.5%).<br />
Metastases location: hepatic 143 (75%), lung 46 (24%) lung and hepatic 2<br />
(1%). Primary tumour stage: I stage 2 (1%) II stage 50 (26%) III stage 87<br />
(46%) IV stage 52 (27%). Adjuvant chemo<strong>the</strong>rapy: 5-Fluorouracil + Leucovorin<br />
70 (36.6%), Irinotecan-based 9 (4.7%) Oxaliplatin-based 112 (58.6%).<br />
Presurgical CEA: normal 146 pt (76%) increased 45 (24%). Number of<br />
metastases: one 87 pt (45%), two 65 (34%), three 18 pt (9%), more than<br />
three 21 pt (11%). Treatment compliance: 149 pt (78%) completed planned<br />
treatment; 42 pt (22%) did not complete it due to toxicity or progressive<br />
disease. Recurrence was diagnosed in 105 pt (55%). Surgery for relapsed<br />
disease was performed in 105 pt (38%). Median overall survival has not been<br />
reached, as only 77 pt have died. Estimated 5-years survival is 62%. Median<br />
progression free survival is 30 months. Significant factors for survival: sex<br />
(better female), node positive primary tumour, increased CEA, and more<br />
than 3 metastases. There were no differences between chemo<strong>the</strong>rapy<br />
schedules.<br />
Conclusion: Surgery of hepatic and lung metastases from colorectal cancer has a<br />
curative goal. Adjuvant chemo<strong>the</strong>rapy could achieve an improvement of survival<br />
by decreasing recurrence rate. We must emphasize that patients included in this<br />
analysis have good prognostic factors so results should be interpreted with<br />
caution.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
628 PROGNOSTIC ROLE OF ERCC1, BAX AND TP53 IN<br />
ADVANCED COLORECTAL CANCER (CRC) PTS RANDOMLY<br />
ASSIGNED TO FIRST-LINE UFT/LEUCOVORIN (LV) PLUS<br />
IRINOTECAN (TEGAFIRI) VERSUS UFT/LV PLUS<br />
OXALIPLATIN (TEGAFOX)<br />
F. Pietrantonio 1 , P. Biondani 1 , M. Milione 2 , F. Perrone 2 , F.G.M. De Braud 1 ,<br />
G. Bertarelli 3 , L. Mariani 3 , F. Melotti 2 , G. Montemurro 2 , M. Di Bartolomeo 1<br />
1 Oncologia Medica 1, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano,<br />
ITALY, 2 Pathology Department, Fondazione IRCCS - Istituto Nazionale dei<br />
Tumori, Milano, Milan, ITALY, 3 Medical Statistics, Biometry, and Bioinformatics,<br />
Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano, Milan, ITALY<br />
Background: Currently, no validated biomarkers are available to tailor first-line<br />
chemo<strong>the</strong>rapy in advanced CRC. In particular, Bax expression may be related<br />
to chemosensitivity, although Bax-negative CRC may display higher responses<br />
to irinotecan (Fallik et al, Cancer Res 2003). Candidate apoptosis-related<br />
biomarkers were assessed in patients enrolled into a multicenter, phase II,<br />
randomized trial of TEGAFIRI vs TEGAFOX (Bajetta et al, Br J Cancer<br />
2007).<br />
Methods: Tissue blocks were available for a subset of 49 pts who provided<br />
written consent and were enrolled from August 2002 to October 2004 at <strong>the</strong><br />
coordinator center “Istituto Nazionale dei Tumori” of Milan. ERCC1, Bax and<br />
TP53 expression assessed by immunohistochemistry, with dicotomic<br />
discrimination. Association with RECIST response by logistic univariate regression<br />
and corrected Chi square test; interaction of significant biomarkers and treatment<br />
arm by logistic regression model. Progression-free (PFS) and overall survival (OS)<br />
curves were plotted by <strong>the</strong> Kaplan-Meier method and compared by log-rank test.<br />
Correlation with PFS and OS by univariate and multivariate Cox’s proportional<br />
hazard model.<br />
Results: Overall, 41% response rate (20/49, 4 CR/16 PR/19 SD/10 PD). ERCC1<br />
and TP53 failed to show any correlation with outcome. Responses significantly<br />
lower in Bax-positive vs Bax-negative (Odds Ratio [OR] = 0.26; p = 0.03 by logistic<br />
regression): 25% (6/24) vs 56% (14/25) (p = 0.05 by Chi square). No significant<br />
differences in terms of outcome in TEGAFOX-treated pts, while Bax-positive pts in<br />
TEGAFIRI subgroup had lower response rate as compared to Bax-negative (OR =<br />
0.11; p = 0.03 by logistic regression): 18% (8/12) vs 67% (2/11) (p = 0.05 by Chi<br />
square). In <strong>the</strong> overall population and both treatment subgroups, no significant<br />
differences in terms of PFS and OS according to selected biomarkers. Data on<br />
TP53 gene sequencing by means of polymerase-chain reaction will be presented at<br />
<strong>the</strong> Congress.<br />
Conclusion: Doublet UFT-based chemo<strong>the</strong>rapy and, in particular, irinotecan-based<br />
treatment produced higher response rates in Bax-negative advanced CRC. Fur<strong>the</strong>r<br />
prospective evaluation of Bax in patients undergoing triplet chemo<strong>the</strong>rapy and<br />
anti-EGFR containing regimens is warranted.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix212 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
629 DIFFERENT CLINICAL OUTCOME OF METASTATIC<br />
COLORECTAL CANCER (MCRC) PATIENTS TREATED WITH<br />
INTENSIVE TRIPLET CHEMOTHERAPY PLUS BEVACIZUMAB<br />
(FIR-B/FOX) ACCORDING TO KRAS GENOTYPE AND DISEASE<br />
EXTENSION<br />
G. Bruera 1 , K. Cannita 1 , D. Di Giacomo 2 , A. Lamy 3 , A. Dal Mas 4 , T. Frebourg 5 ,J.<br />
C. Sabourin 6 , M. Tosi 5 , C. Ficorella 1 , E. Ricevuto 1<br />
1 Medical Oncology, S. Salvatore Hospital, University of L’Aquila, L’Aquila, ITALY,<br />
2 Department of Experimental Medicine, University of L’Aquila, L’Aquila, ITALY,<br />
3 Laboratory of Tumor Genetics, University Hospital, Rouen, Rouen, FRANCE,<br />
4 Pathology, S. Salvatore Hospital, L’Aquila, ITALY, 5 INSERM U614, University of<br />
Rouen, Rouen, FRANCE, 6 Department of Pathology, INSERM U614, Rouen<br />
University Hospital, Rouen, FRANCE<br />
Background: Bevacizumab (BEV) plus triplet chemo<strong>the</strong>rapy can increase efficacy of<br />
first-line treatment of MCRC (Bruera G et al, BMC Cancer 2010, 10:567),<br />
particularly if integrated with secondary liver surgery in liver-limited (L-L) patients<br />
(pts) (Bruera G et al, Clin Colorectal Cancer <strong>2012</strong>). Clinical outcome of FIr-B/FOx<br />
regimen was evaluated according to KRAS genotype in L-L and o<strong>the</strong>r MCRC pts.<br />
Methods: Tumoral and metastatic samples were screened for KRAS codon 12 and<br />
13, and BRAF mutations by SNaPshot and/or direct sequencing. MCRC pts were<br />
classified as L-L and o<strong>the</strong>r or multiple metastatic (O/MM). Activity and efficacy were<br />
evaluated and compared using log-rank test.<br />
Results: Fifty-nine pts were evaluated: 31 KRAS wild-type, 53%; 28 KRAS mutant,<br />
47%. At 21.5 months median follow-up, objective response rate (ORR),<br />
progression-free survival (PFS) and overall survival (OS) were, respectively: KRAS<br />
wild-type 90%, 14 months, 38 months; KRAS mutant 67%, 11 months, 20 months.<br />
PFS and OS were, respectively: overall in 25 L-L compared to 32 O/MM evaluable<br />
pts, 17 and 12 months, 47 and 21 months, significantly different; in KRAS wild-type,<br />
12 L-L compared to 18 O/MM, 21 and 12 months, 47 and 28 months, significantly<br />
different; in KRAS mutant, 13 L-L compared to 14 O/MMS, 11 months equivalently,<br />
39 and 19 months, not significantly different.<br />
Conclusion: First line FIr-B/FOx regimen can increase activity and efficacy of KRAS<br />
wild-type and mutant MCRC pts; integration with secondary liver surgery<br />
significantly discriminates increased clinical outcome in KRAS wild-type L-L<br />
compared to O/MM pts while not in KRAS mutant pts.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
630 POTENTIAL BIOMARKERS FOR RESPONSE TO CETUXIMAB IN<br />
PATIENTS WITH METASTATIC COLORECTAL CANCER (MCRC).<br />
A HELLENIC COOPERATIVE ONCOLOGY GROUP STUDY<br />
E. Razis 1 , M. Bobos 1 , W. De Roock 2 , M. Bai 1 , A. Gousia 1 , I. Xanthakis 1 ,<br />
E. Tsolaki 1 , P. Papakostas 1 , S. Tejpar 3 , G. Fountzilas 1<br />
1 Data Office, Hellenic Cooperative Oncology Group (HeCOG), A<strong>the</strong>ns, GREECE,<br />
2 Human Genetics, Katholieke Universiteit Leuven, Leuven, BELGIUM, 3 Digestive<br />
Oncology Unit, University Hospital Gasthuisberg, Leuven, BELGIUM<br />
Background: Cetuximab has improved outcome of patients (pts) with mCRC. KRAS<br />
has emerged as a marker of resistance to monoclonal antibodies against EGFR,<br />
including cetuximab. Fur<strong>the</strong>r biomarkers for response to cetuximab are being explored.<br />
Methods: In a heterogeneous cetuximab-treated population we retrospectively<br />
evaluated formalin-fixed paraffin-embedded tissue for EGFR and PTEN by<br />
Fluorescence In Situ Hybridization (FISH) and for PIK3CA and KRAS mutations by<br />
PCR and examined <strong>the</strong> association of <strong>the</strong>se markers with patient outcome.<br />
Results: Two hundred twenty-three cetuximab-treated mCRC pts were identified,<br />
of which 38 were treated in first line, 107 in second and 78 in ≥ 3 rd line.<br />
Cetuximab was used with irinotecan-based <strong>the</strong>rapy in 54.3% and with oxaliplatin<br />
in 26.9% of <strong>the</strong> cases. Two pts achieved a complete response, 53 a partial<br />
response and 65 stable disease for a clinical benefit rate of 63.2%. EGFR<br />
amplification was noted in 5 cases, PTEN deletion in 58 and PTEN gain in<br />
2. Finally, KRAS was mutated in 72 cases, and PIK3CA in 37. The mutations<br />
detected for KRAS were G12 (45 pts, 62.5%), G13 (16 pts, 22.2%), G61 (4 pts,<br />
5.6%) and A146 (7 pts, 9.7%) and for PIK3CA Exon9 (20 pts, 54.1%), Exon20<br />
(5 pts, 13.5%) and o<strong>the</strong>r (12 pts, 32.4%). No associations were found between<br />
<strong>the</strong>se markers. PTEN deletion was associated with a higher overall response rate<br />
(ORR) (p = 0.031), while <strong>the</strong> o<strong>the</strong>r markers were not. Progression-free survival<br />
(PFS) and survival were calculated from initiation of cetuximab. PFS was<br />
numerically associated with EGFR gain but <strong>the</strong> numbers (5 gain vs. 138 normal)<br />
do not allow for a sound result. Additionally, given <strong>the</strong> different impact of<br />
diverse KRAS mutations on outcome, we evaluated <strong>the</strong> outcome in relation to<br />
<strong>the</strong> G12 mutations. The latter exhibited a trend for decreased survival (p =<br />
0.057).<br />
Conclusions: After a median follow up of 55.3 months (5.8-88.4 months), PTEN<br />
deletion was associated with improved ORR to cetuximab. Fur<strong>the</strong>r examination of<br />
EGFR and PTEN by immunohistochemistry is in progress.<br />
Disclosure: E. Razis: Dr E. Razis received research grant from Merck S.A. and Roche<br />
(Hellas) S.A. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
631 BRAFV600E MUTATION ANALYSIS IN PATIENTS WITH<br />
METASTATIC COLORECTAL CANCER (MCRC) IN DAILY<br />
CLINICAL PRACTICE: CORRELATIONS WITH CLINICAL<br />
CHARACTERISTICS, PROGNOSTIC AND PREDICTIVE VALUES<br />
Z. Saridaki 1 , M. Tzardi 2 , M. Sfakianaki 3 , C. Papadaki 3 , K. Mpananis 3 ,<br />
E. Tsakalaki 3 , M. Trypaki 3 , I. Messaritakis 3 , V. Georgoulias 4 , J. Souglakos 4<br />
1 Laboratory of Tumor Cell Biology, University of Crete, School of Medicine,<br />
Heraklion, GREECE, 2 Laboratory of Pathology, University of Crete, School of<br />
Medicine, Heraklion, GREECE, 3 Laboratory of Tumor Cell Biology, School of<br />
Medicine, University of Crete, Heraklion, GREECE, 4 Medical Oncology, University<br />
Hospital of Heraklion, Heraklion, GREECE<br />
Aim: To evaluate <strong>the</strong> usefulness of <strong>the</strong> BRAFV600E detection in <strong>the</strong> daily clinical<br />
practice, it’s clinical correlations and prognostic/predictive values in a prospective<br />
database of patients with mCRC.<br />
Patients and methods: 442 mCRC patients treated with systemic chemo<strong>the</strong>rapy ±<br />
biologics at <strong>the</strong> Medical Oncology Department of <strong>the</strong> University Hospital of Heraklion<br />
from 1-07-07 were prospectively analyzed. The BRAF mutation was assessed by<br />
RT-qPCR using <strong>the</strong> allelic discrimination method. The laboratory findings were<br />
correlated with patients’ clinical-pathologic characteristics and <strong>the</strong> treatment outcome.<br />
Results: The median age was 68 years of age (21-89) while 37% of <strong>the</strong>m were > 65 old;<br />
61% were male, in 71% of <strong>the</strong>m <strong>the</strong> primary tumor was located in <strong>the</strong> colon and in<br />
29% in <strong>the</strong> rectum 48% of <strong>the</strong> tumors were low grade and 21% presented mucinous<br />
features. Salvage cetuximab or panitumumab <strong>the</strong>rapy was administered to 228 patients<br />
with KRASwt tumors. The BRAF mutation was detected in 32 (7.5%) patients.<br />
Statistically significant higher incidence of <strong>the</strong> BRAF mutation was observed in patients<br />
with ECOG-PS 2 (p = 0.0001), > 65 years old (p = 0.001), primaries located in <strong>the</strong> right<br />
colon (p = 0.004), lowgrade tumors (p = 0.001) and in those with mucinous features<br />
(p = 0.021). Patients whose tumors harbored <strong>the</strong> BRAF mutation had a reduced<br />
progression-free survival (PFS) (4.1 months) compared with <strong>the</strong> wild-type (wt) (11.4<br />
months, p < 0.0001). The overall survival (OS) of <strong>the</strong> patients with BRAF mutation was<br />
statistically significantly shorter (13.5 months) compared with <strong>the</strong> wt ones (33.3<br />
months, p < 0.0001). In <strong>the</strong> multivariate analysis <strong>the</strong> BRAF mutation detection<br />
emerged as independent factor associated with reduced PFS (HR: 4.1, 95% CI 2.7-6.2,<br />
p < 0.0001) and OS (HR: 5.9, 95% CI 3.7-9.5, p < 0.0001). Among <strong>the</strong> patients treated<br />
with anti-EGFR moAbs salvage <strong>the</strong>rapy, <strong>the</strong> BRAF mutation was correlated with<br />
reduced PFS (2.2 vs 6.0 months, p < 0.0001) and OS (4.3 vs 17.4 months, p < 0.0001).<br />
Conclusion: Our results document <strong>the</strong> unfavorable prognostic value of <strong>the</strong><br />
BRAFV600E mutation and advocate in favor of its predictive value towards<br />
anti-EGFR moAbs <strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
632 EPIDEMIOLOGY PROJECTION TRENDS FOR METASTATIC<br />
COLORECTAL CANCER (MCRC) PATIENTS RECEIVING<br />
SECOND LINE (2L) THERAPY IN EU AND US<br />
O. Moulard 1 , J. Mehta 2 , S. Naoshy 2 , R. Olivares 1 , S.U. Iqbal 2 , I. Chau 3<br />
1 Evidence and Value Development, Sanofi, Chilly Mazarin, FRANCE, 2 Evidence<br />
and Value Development, Sanofi, Cambridge, MA, UNITED STATES OF<br />
AMERICA, 3 Medicine, Royal Marsden Hospital, Sutton, UNITED KINGDOM<br />
Background: Worldwide, CRC is <strong>the</strong> third most common cancer in men (663,000<br />
cases, 10% of <strong>the</strong> total) and second in women (571,000 cases, 9.4% of <strong>the</strong> total)<br />
(IARC 2008). Due to demographic expansion and an ageing population, <strong>the</strong> annual<br />
number of newly diagnosed and treated CRC cases is expected to increase in Western<br />
countries. Hence, epidemiology projection estimates by line of <strong>the</strong>rapy are needed to<br />
support clinical, economic and resource planning.<br />
Methods: Epidemiological data was obtained using <strong>the</strong> CancerMPact® database<br />
(accessed Oct 2011), which includes line of <strong>the</strong>rapy estimations through <strong>the</strong> US<br />
National Oncology Data Alliance and survey of a representative physician sample.<br />
Data was grouped by stage at diagnosis and stage IV refers to metastatic patients.<br />
Results: From 2010-2020, <strong>the</strong> distribution of mCRC patients receiving 2L differs by<br />
country in EU. The highest number of treated patients is in Germany, followed by<br />
Italy and UK. Among all treated mCRC patients, about 42% of patients in EU and<br />
45% of patients in US will go on to 2L. By 2020, <strong>the</strong> percentage of patients receiving<br />
1L and 2L will increase by about 15% across US and EU. Over a 10 year period, <strong>the</strong><br />
number of treated patients for each line of <strong>the</strong>rapy will increase by 19%, 11%, 15%,<br />
20%, and 14% for France, Germany, Italy, Spain and UK, respectively. The table<br />
below refers to <strong>the</strong> number of metastatic patients by line of <strong>the</strong>rapy.<br />
Conclusions: Despite improvement in survival rates, approximately half of patients<br />
in US and EU who receive 1L go on to 2L. In addition to survey data, real world<br />
data and disease based registries can help validate <strong>the</strong>se projection estimates. The<br />
projected increase in mCRC patients by 10-20% across <strong>the</strong> EU has implications for<br />
disease management and health resource planning in oncology.<br />
Disclosure: O. Moulard: I am an employee of Sanofi. J. Mehta: I am an employee of<br />
Sanofi. S. Naoshy: I am an employee of Sanofi. R. Olivares: I am an employee of<br />
Sanofi. S.U. Iqbal: I am an employee of Sanofi. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds397 | ix213
Table: 632<br />
633 AFLIBERCEPT/FOLFIRI (AF) VS PLACEBO/FOLFIRI (PF) IN<br />
METASTATIC COLORECTAL CANCER (MCRC): POST-HOC<br />
ANALYSIS OF SURVIVAL EXCLUDING ADJUVANT (ADJ)-ONLY<br />
PATIENTS IN THE VELOUR TRIAL<br />
F. Joulain 1 , U. Iqbal 2 , F. Diamand 3 , E. Van Cutsem 4 , J. Tabernero 5 , C. Allegra 6<br />
1 Global Evidence and Value Development, Sanofi, Chilly Mazarin, FRANCE,<br />
2 Research and Development, Sanofi, Cambridge, MA, UNITED STATES OF<br />
AMERICA, 3 Evidence and Value Development, Keyrus Biopharma,<br />
Levallois-Perret, FRANCE, 4 Digestive Oncology Unit, University Hospital<br />
Gasthuisberg, Leuven, BELGIUM, 5 Oncology Department, Vall d’Hebron<br />
University HospitalMedical Oncology Service, Barcelona, SPAIN, 6 Oncology,<br />
University of Florida, Gainesville, FL, UNITED STATES OF AMERICA<br />
Background: A small proportion of poor prognosis CRC patients (pts) treated with<br />
ADJ <strong>the</strong>rapy relapse within 6 months of treatment, and progress to mCRC (Sargent<br />
JCO 2007;25:4569). The VELOUR phase III trial evaluated <strong>the</strong> novel fusion protein<br />
aflibercept (VEGF Trap) plus FOLFIRI in mCRC pts previously treated with<br />
oxaliplatin. In this study 10% of pts directly progressed from ADJ setting to first-line.<br />
Median and mean overall survival (OS) was determined for VELOUR pts excluding<br />
those that progressed directly from <strong>the</strong> ADJ setting.<br />
Method: Baseline characteristics and efficacy were determined for <strong>the</strong> ITT pts<br />
excluding ADJ-only pts. Since some pts were alive at <strong>the</strong> time of final analysis, mean<br />
OS was estimated by extrapolating <strong>the</strong> trial Kaplan-Meier curve using a survival<br />
function. The goodness-of-fit of parametric distributions was evaluated by AIC, BIC<br />
criteria. Survival functions were fit to each treatment (TXT) arm separately or by<br />
combining <strong>the</strong> two arms and using TXT as a covariate to control for variation.<br />
Results: Of 1226 pts enrolled in VELOUR, 60 (9.8%) AF pts and 64 (10.4%) pF<br />
pts received oxaliplatin in ADJ setting only. Excluding <strong>the</strong>se pts, baseline<br />
characteristics remained similar between <strong>the</strong> 2 arms. Median age was 61 years,<br />
60% of pts were male, 30% of pts were randomized in <strong>the</strong> prior bevacizumab<br />
stratum and very few pts had ECOG PS 2 (2.1%) as per IVRS. 43.6% of pts had<br />
1 or less metastatic site at baseline and 25.4% had liver metastasis only. Median<br />
OS was significantly improved with AF vs pF (13.8 vs 11.9 months; adjusted HR<br />
= 0.80 [95% CI: 0.69 to 0.92]). For mean OS, <strong>the</strong> loglogistic function provided <strong>the</strong><br />
best fit of <strong>the</strong> VELOUR data for <strong>the</strong> ITT population excluding ADJ-only pts both<br />
with and without TXT as covariate.<br />
Conclusion: Excluding ADJ-only pts, <strong>the</strong> VELOUR trial increased median OS (1.9 vs<br />
1.4) and mean OS (5.1 vs 4.7) with AF compared to pF, thus reinforcing <strong>the</strong><br />
<strong>the</strong>rapeutic benefit of AF in clinically relevant patient populations.<br />
Disclosure: F. Joulain: I am an employee of Sanofi. U. Iqbal: I am an employee of<br />
Sanofi. F. Diamand: I am an employee of Sanofi. E. Van Cutsem: I have received<br />
research funding from Sanofi. J. Tabernero: I have an advisory relationship with<br />
Sanofi, Roche, and Regeneron. C. Allegra: I have an advisory relationship with<br />
Sanofi.<br />
Table: 633<br />
Number of patients<br />
Year Line<br />
France Germany Italy Spain UK EU 5 US<br />
2010 1L 13705 25590 18171 9590 16646 83702 40484<br />
2L 8212 15378 10904 5746 9988 50228 27217<br />
3L 3117 5846 4125 2177 3792 19057 14602<br />
4L+ 695 1296 868 474 840 4173 5429<br />
Total stage IV* 19344 36313 25408 13432 23372 117869 60703<br />
2020 1L 16273 28410 20956 11533 19060 96232 47447<br />
2L 9755 17048 12592 6916 11434 57745 31672<br />
3L 3704 6476 4767 2622 4341 21910 16999<br />
4L+ 825 1439 1002 571 961 4798 6324<br />
Total stage IV* 22947 39931 29361 16194 26733 135166 69391<br />
* a patient may receive multiple lines of <strong>the</strong>rapy in a given year Source: CancerMPact® Kantar Health (www.cancermpact.com)<br />
634 SECOND AND THIRD LINE CHEMOTHERAPY REGIMENS IN<br />
ELDERLY MEDICARE STAGE 4 COLON CANCER PATIENTS<br />
K. Bikov 1 , C.D. Mullins 2 , E. Onukwugha 2 , B. Seal 3 , N. Hanna 4<br />
1 Pharmaceutical and Health Services Research, University of Maryland,<br />
Baltimore, MD, UNITED STATES OF AMERICA, 2 Phsr, Univ of MD, Baltimore,<br />
MD, UNITED STATES OF AMERICA, 3 Health Economics and Outcomes<br />
Research, Bayer HealthCare, Wayne, NJ, UNITED STATES OF AMERICA,<br />
4 Surgery, Univ of MD, Baltimore, MD, UNITED STATES OF AMERICA<br />
Background: NCCN guidelines for stage 4 colon cancer (CC4) patients provide<br />
general guidance on which chemo<strong>the</strong>rapies and targeted <strong>the</strong>rapies improve survival<br />
or quality of life but do not provide specific treatment (TX) recommendations. The<br />
guidelines suggest that TX is highly individualized and no single treatment is right<br />
for everyone. This leads to variation in both <strong>the</strong> number and types of TX lines,<br />
especially for elderly patients where <strong>the</strong>re are larger evidence gaps.<br />
Methods: Elderly (65+) SEER-Medicare patients diagnosed with CC4 in 2003-2007<br />
were followed through death or 2009 to examine variation across sub-groups in<br />
<strong>the</strong> number of TX lines. We examined NCCN treatments that included any<br />
combination of 5-fluorouracil and/or (levo) leucovorin (5FU/LV), irinotecan (IRI),<br />
oxaliplatin (OX), and bevacizumab, cetuximab, or panitumumab (collectively<br />
identified as BIOLOGICS). Certain non-NCCN treatments were also considered as<br />
possible last TX line. A hierarchy categorized treatments as: 1) IROX (IRI + OX);<br />
2) IRI or OX; 3) 5FU/LV; 4) BIOLOGICS without chemo<strong>the</strong>rapy; and 5) o<strong>the</strong>r<br />
TX. Gaps in TX or changes from OX or IRI to 5FU/LV were not considered new<br />
lines.<br />
Results: Of 3,263 CC4 patients who received TX, 1,166 (36%) went on to second<br />
line TX. The most common sequences of TX lines were OX to IRI (49%), IRI to<br />
OX (14%), 5FU/LV to OX (12%) and 5FU/LV to IRI (12%). Approximately 6%<br />
switched from chemo<strong>the</strong>rapy to BIOLOGICS alone only 3.6% ever used IROX. Of<br />
second line patients, 244 (21%) had a third line of treatment. The most frequent<br />
sequence for 3 TX lines were 5FU/LV to OX to IRI (26%), OX to IRI to<br />
MNCLA alone (25%); 5FU/LV to IRI to OX (14%); and IRI to OX to MNCLA<br />
alone (6%).<br />
Conclusions: The number of TX lines and <strong>the</strong> sequence of TX regimens vary<br />
considerably across elderly CC4 patients. OX to IRI for first and second line TX was<br />
<strong>the</strong> most common sequence. The choice of initial and subsequent treatment<br />
regimens impacts <strong>the</strong> total number of treatment lines receipt and survival. Fur<strong>the</strong>r<br />
investigation is warranted to examine <strong>the</strong> relationship between patient and provider<br />
characteristics and choice of treatment.<br />
Disclosure: C.D. Mullins: C. Daniel Mullins, PhD receives consulting income from<br />
Amgen, Bayer, BMS, Celgene, GSK, Mitsubishi, Novartis, Novo Nordisk, Novartis,<br />
and Pfizer. He also receives research funding from Bayer and Pfizer. E. Onukwugha:<br />
Ebere Onukwugha receives consulting income from Pfizer and grant support from<br />
Bayer, Novartis, and Pfizer. B. Seal: Brian Seal is an employee of Bayer HealthCare.<br />
All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
Median OS (months) Restricted Mean OS (months) over 15 years<br />
AF (N = 552) pF (N = 550) Δ<br />
Δ<br />
ITT Loglogistic AF pF Δ<br />
Annals of Oncology<br />
13.8 11.9 1.9 1.4 TXT group independently 22.7 17.6 5.1 4.7<br />
TXT group as covariate 21.5 18.5 3.0 2.5<br />
ix214 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong><br />
Δ<br />
ITT
Annals of Oncology<br />
635 USE OF PALLIATIVE CHEMOTHERAPY AND TARGETED<br />
AGENTS IN ELDERLY PATIENTS WITH METASTATIC<br />
COLORECTAL CANCER (MCRC)<br />
W.Y. Cheung, D. Renouf, H. Lim, H. Kennecke<br />
Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, CANADA<br />
Background: Elderly patients are increasingly diagnosed with advanced cancers, but<br />
<strong>the</strong>y are consistently underrepresented in clinical trials, which may lead to<br />
undertreatment. Our aims were to 1) evaluate <strong>the</strong> impact of advanced age on<br />
patterns of first-line chemo<strong>the</strong>rapy and bevacizumab use in mCRC, 2) examine <strong>the</strong><br />
reasons for treatment choices and 3) compare adverse events and treatment<br />
discontinuations in elderly vs young patients.<br />
Methods: A random sample of mCRC patients diagnosed from 2006 to 2007 and<br />
referred to any 1 of 5 regional cancer centers in British Columbia, Canada was<br />
reviewed. Summary statistics were used to describe treatment patterns between <strong>the</strong><br />
elderly (>/ = 70 years) and young (
factors play <strong>the</strong> determining role in a patient’s response to LCRT and this area<br />
requires fur<strong>the</strong>r investigation to determine who may undergo a complete response.<br />
Group A (%) Group B (%)<br />
T stage T2 0 3 (6.7)<br />
T3 10 (77) 36 (80)<br />
T4 3 (23) 6 (13.3)<br />
N stage N0 4 (31) 7 (15)<br />
N1 4 (31) 12 (27)<br />
N2 5 (38) 26 (58)<br />
Sex Male 11 (85) 36 (78)<br />
Female 2 (15) 10 (22)<br />
Tumour height Low 11 (85) 30 (65)<br />
Mid 2 (15) 12 (26)<br />
Upper 0 4 (9)<br />
Disclosure: All authors have declared no conflicts of interest.<br />
639 STUDY OF THE EFFECT OF RADICAL SURGERY COMBINED<br />
WITH PRE- OR POSTOPERATIVE RADIOTHERAPY IN<br />
TREATMENT OF RESECTABLE RECTAL CANCER<br />
E. Atif 1 , H. Sakr 2 , S. Teama 2 , D. Zayed 2<br />
1 Surgical Gastroenterology Center, Mansoura University, Egypt, Mansoura,<br />
EGYPT, 2 Clinical Oncology and Nuclear Medicine, Mansoura University, Egypt,<br />
Mansoura, EGYPT<br />
Back ground: preoperative radio<strong>the</strong>rapy in resectable rectal cancer has a number of<br />
potential advantages, most importantly, preventing local recurrence, increasing<br />
survival and down-staging effect.<br />
Purpose: This study was done to compare between <strong>the</strong> effect of preoperative<br />
radio<strong>the</strong>rapy and postoperative radio<strong>the</strong>rapy in treatment of resectable rectal<br />
carcinoma. The primary endpoints are local recurrence rate, overall survival (OS) and<br />
disease free survival (DFS). The secondary endpoints are to evaluate down-staging,<br />
treatment toxicity, and ability to do sphincter preservation, aiming at choosing <strong>the</strong><br />
optimal treatment modality.<br />
Patients and methods: This study included 100 patients with resectable rectal<br />
carcinoma who presented to Surgical Gastro Entrology Center and Clinical Oncology<br />
and Nuclear Medicine Department, Mansoura University during <strong>the</strong> period between<br />
January 2007 and September 2009. The included patients were randomized in two<br />
groups; group I: 50 patients received preoperative radio<strong>the</strong>rapy and group II: 50<br />
patients received postoperative radio<strong>the</strong>rapy. Concurrent 5-fluorouracil- based<br />
chemo<strong>the</strong>rapy was given to all patients. Two major types of surgery were done:<br />
abdomino-perineal resection with a permanent colostomy and low anterior resection<br />
with colorectal or coloanal anastomosis.<br />
Results: Preoperative radio<strong>the</strong>rapy resulted in pathologic complete response in 3<br />
patients. T down-staging occurred in 18 out of 50 patients (36%) with statistically<br />
significant difference (p = 0.008). N down-staging occurred in 10 out of 24 patients.<br />
Sphincter preservation was more in group I. Delayed wound healing was <strong>the</strong> most<br />
common postoperative complication in group I with no significant difference. After a<br />
median follow up of 18 months, local recurrence rate and distant metastasis were<br />
higher in group II. The 2-years disease free survival was 72% and 60% in group I<br />
and II respectively with no statistically significant difference between both groups.<br />
Conclusion: This study concluded that preoperative radio<strong>the</strong>rapy is better than<br />
postoperative radio<strong>the</strong>rapy as regard local control, Sphincter preservation with higher<br />
disease free survival and overall survival. No difference in treatment toxicity between<br />
both groups.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
640 THE PREDICTIVE ROLE OF MTHFR AND ABCG2 SINGLE<br />
NUCLEOTIDE POLYMORPHISMS ON THE OUTCOME OF<br />
ADVANCED COLORECTAL CANCER TREATED WITH<br />
FIRST-LINE CHEMOTHERAPY<br />
J. Zhao, W. Zhang, W. Li, J. Li, W. Guo, S. Cai, M. Sun, Z. Zhang, D. Zhu, Q. Yu<br />
Department of Medical Oncology, Fudan University Shanghai Cancer Center,<br />
Shanghai, CHINA<br />
Objective: Chemo<strong>the</strong>rapy with 5-fluorouracil and oxaliplatin (FOLFOX or XELOX)<br />
or irinotecan (FOLFIRI) has become <strong>the</strong> mainstay of treatment for advanced<br />
colorectal cancer. Since not all patients would benefit from <strong>the</strong> chemo<strong>the</strong>rapy <strong>the</strong>y<br />
received, exploring factors that would predict better effectiveness remains meaningful<br />
for understanding <strong>the</strong> concept of individual treatment. The purpose of this study is<br />
to confirm <strong>the</strong> predictive role of a serial of SNPs, MTHFR C677T, A1298C, ABCG2<br />
G34A and C421A, as well as <strong>the</strong> clinical features for <strong>the</strong> efficacy of first-line<br />
chemo<strong>the</strong>rapy in advanced colorectal cancer.<br />
Annals of Oncology<br />
Methods: Patients with advanced colorectal cancer and treated with first-line<br />
standard FOLFOX/XELOX or FOLFIRI regimens between January 2009 and May<br />
2011 at Fudan University Shanghai Cancer Center were retrospectively studied. Gene<br />
polymorphisms of MTHFR and ABCG2 were detected using gene sequencing<br />
method, after DNA extraction from peripheral blood karyocytes and PCR<br />
amplification.<br />
Results: Of all 154 patients, patients with 3 ∼ 4 of <strong>the</strong> favorable genotypes (MTHFR<br />
677C/C, MTHFR 1298 A/A, ABCG2 G/A or A/A⍰ and ABCG2 421C/A or A/A)<br />
had a longer PFS than those with 0 ∼ 2 above genotypes (9.8m vs. 7.5m, P = 0.013;<br />
HR = 0.627, 95%CI: 0.427 ∼ 0.920, P = 0.017) The radical resection of primary lesion<br />
was also found as an independent factor for both PFS (HR = 0.524, 95%CI: 0.320 ∼<br />
0.859, P = 0.010) and OS (HR = 0.291, 95%CI: 0.147 ∼ 0.575, P = 0.000). Interestingly,<br />
stratified univariate analysis revealed that patients with 2 ∼ 4 genotypes of MTHFR<br />
677C/C、MTHFR 1298 A/C or C/C、ABCG2 34G/G and ABCG2 421C/A or A/A<br />
would benefit more from FOLFOX/XELOX than FOLFIRI as first-line chemo<strong>the</strong>rapy<br />
(FOLFIRI: HR = 1.722, 95%CI: 1.026 ∼ 2.892, P = 0.040, compared with FOLFOX/<br />
XELOX). In contrast, patients with 0 or 1 above-mentioned genotype would have<br />
better outcomes if receiving FOLFIRI (FOLFIRI: HR = 0.422, 95%CI: 0.205 ∼ 0.870,<br />
P = 0.019, compared with FOLFOX/XELOX).<br />
Conclusions: SNPs detection may play a predictive role in selecting first-line<br />
chemo<strong>the</strong>rapy for advanced colorectal cancer patients. Radical resection of primary<br />
lesion is an independent factor for both PFS and OS.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
641 PROGNOSTIC VALUE OF BRAF AND KRAS MUTATIONS IN<br />
COLORECTAL CANCER PATIENTS<br />
E.P. Murata1 , A. Stradella1 , D. Páez1 , M. Tobeña Puyal1 , A. Sebio Garcia1 ,<br />
A. Gonzalez1 , E. Targarona1 , M. Baiget2 , A. Barnadas1 , M. Martín-Richard1 1<br />
Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, SPAIN,<br />
2<br />
Deparment of Genetics, Hospital de la Santa Creu i Sant Pau, Barcelona,<br />
SPAIN<br />
Background: KRAS mutation has been established as a predictive marker of<br />
resistance to antiEGFR <strong>the</strong>rapy in patients (pts) with colorectal cancer (CRC) but <strong>the</strong><br />
role of BRAF is not yet clear. Both gene mutations have also been studied as<br />
prognostic factors but results are contradictory. AntiEGFR <strong>the</strong>rapies impair<br />
evaluation of KRAS and BRAF as prognostic factors when overall survival is an<br />
endpoint. We hypo<strong>the</strong>sized that if KRAS or BRAF were prognostic factors, <strong>the</strong>y<br />
would influence time to relapse (TTR) after complete tumor resection.<br />
Methods: Patients who underwent surgery between 2007 and 2011 for stage II and<br />
III CRC were retrieved from our database. Codon 12 and 13 KRAS mutations and<br />
V600E BRAF mutation were analyzed. Clinical characteristics and mutation status<br />
were correlated with TTR.<br />
Results: We analyzed 170 pts with a median age of 66 (26 – 86) years. Tumors were<br />
located in <strong>the</strong> right colon in 27% of pts, in <strong>the</strong> transverse colon in 3%, in <strong>the</strong> left<br />
colon in 41%, and in <strong>the</strong> rectum in 29%. Most (55.3%) were stage III; 59% received<br />
adjuvant chemo<strong>the</strong>rapy. KRAS and BRAF mutations were present in 66 (38.8%) and<br />
5 (2.9%) pts respectively, and both were mutually exclusive. The most frequent KRAS<br />
mutations were: G12D (39.3%), G12V (27.2%), G13D (15.1%). Median TTR was 71<br />
weeks (w) (13 – 520w). V600E BRAF mutation was <strong>the</strong> only factor associated with<br />
TTR. TTR was 42 w in tumors with <strong>the</strong> BRAF mutation and 74 w in wild-type<br />
tumors (p = 0.041). Among KRAS mutations, KRAS G12V conferred a significantly<br />
longer TTR (100w) than <strong>the</strong> o<strong>the</strong>r subtype mutations (69 w; p = 0.05).<br />
Conclusions: Our results suggest that V600E BRAF mutation is a negative prognostic<br />
factor in CRC, conferring a shorter time to relapse. Additionally, <strong>the</strong> KRAS G12V<br />
determines a different behavior among KRAS mutation tumors.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
642 NOTCH AND DLL4 EXPRESSION IN BEVACIZUMAB-TREATED<br />
COLON CANCER PATIENTS<br />
<strong>Abstract</strong> withdrawn in exceptional circumstances<br />
ix216 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
<strong>Abstract</strong> withdrawn in exceptional circumstances<br />
643 CETUXIMAB PLUS MFOLFOX-6 AS FIRST-LINE THERAPY FOR<br />
UNRESECTABLE LIVER METASTASIS FROM COLORECTAL<br />
CANCER: AN OPEN, NON-RANDOMIZED, MULTICENTER<br />
PHASE II CLINICAL TRIAL<br />
S. Cai 1 , W. Zhang 2 ,W.Li 2 ,Y.Xu 1 ,W.Gu 1 , Z. Guan 1 , J. Cai 3 , C. Song 4 ,J.Xu 5 ,<br />
P. Chi 6<br />
1 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center,<br />
Shanghai, CHINA, 2 Department of Medical Oncology, Fudan University Shanghai<br />
Cancer Center, Shanghai, CHINA, 3 Department of Abdominal Surgery, Cancer<br />
Hospital & Institute Chinese Academy of Medical Sciences Peking Union Medical<br />
College, Beijing, CHINA, 4 Department of Colorectal Surgery, Liaoning Cancer<br />
Hospital, Liaoning Province, CHINA, 5 Department of Colorectal Surgery,<br />
Zhongshan Hospital of Fudan University, Shanghai, CHINA, 6 Department of<br />
Colorectal Surgery, Fujian medical university Union hospital, Fujian Province,<br />
CHINA<br />
Background: This study is for KRAS wildtype patients with unresectable liver only<br />
metastasis of colorectal cancer, using cetuximab + modified FOLFOX-6 as first-line<br />
chemo<strong>the</strong>rapy, to observe whe<strong>the</strong>r <strong>the</strong> addition of targeted drug fur<strong>the</strong>r increases <strong>the</strong><br />
curative resection rate and improves long-term survival for patients.<br />
Methods: Up to May 1st,a total of 82 KRAS wild-type patients enrolled and received<br />
cetuximab (500 mg/m 2 q2w)Plus mFOLFOX-6 including oxaliplatin 85 mg/m 2 plus<br />
CF 400 mg/m 2 and 5-FU as a 400 mg/m 2 bolus followed by 2400 mg/m 2 infusion<br />
over 46 hours on day 1, repeated every 2 weeks for maximum of nine cycles. The<br />
primary endpoint was R0 resection rate.<br />
Findings: The objective response rate (RR) was 81.82% ± 5.81% among 44 patients with<br />
efficacy assessment. Among 38 cases went through surgical evaluation (finished<br />
medication), 16 cases went through R0 resection and R0 resection rate was 42.11% ±<br />
8.01%, 4 cases went through R1 resection and R1 resection rate was 10.53% ± 4.98%, and<br />
4 cases went through R0 + RFA. There were AEs reported in 64 cases, mainly including<br />
rash and malaise. One SAE was reported and <strong>the</strong> subject was withdrawn due to allergy.<br />
Interpretation: Cetuximab + mFOLFOX-6 was well tolerated and provided good RR,<br />
R0 resection rates, which would be potentially used as a first-line treatment for<br />
patients with unresectable liver only metastasis of colorectal cancer. Funding: This<br />
study was supported by Fudan University Shanghai Cancer Center; Merck KGaA<br />
Darmstadt, Germany.<br />
Funding: This study was supported by Merck KGaA Darmstadt, Germany and<br />
Sanofi-aventis.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
644 OUTCOME OF PATIENTS WITH COLORECTAL LIVER<br />
METASTASIS: ANALYSIS OF 1613 CONSECUTIVE CASES<br />
J. Xu, D. Zhu, L. Ren, Y. Wei, H. Wu, Y. Zhong<br />
Department of General Surgery, Zhongshan Hospital Fudan University,<br />
Shanghai, CHINA<br />
Objective: To evaluate <strong>the</strong> long-time outcome of patients with colorectal liver metastasis<br />
(CRLM) undergoing different types of <strong>the</strong>rapy and identify prognosis factors.<br />
Methods: From 2000 to 2010, 1613 consecutive patients with CRLM were identified.<br />
Clinicopathological and outcome data were collected and analyzed by univariate and<br />
multivariate analyses.<br />
Results: Synchronous liver metastasis (SLM), female, grade III-IV, T4 and N positive of<br />
primary tumor, bilobar disease, number of liver metastases ≥ 4, size of largest liver<br />
metastases ≥ 5 cm, serum CEA level ≥5 ng/ml and CA19-9 level ≥ 37u/ml were <strong>the</strong><br />
predictors of adverse outcome using univariate analysis. The median survival and<br />
five-year survival rate for patients after resection of liver metastases was 49.8 months<br />
and 47%, better than that for those after o<strong>the</strong>r <strong>the</strong>rapy. In addition, patients without<br />
treatment had <strong>the</strong> poorest survival. Sixty-four initially unresectable patients underwent<br />
surgery after conversion <strong>the</strong>rapy with a median survival of 36.9 months and a five-year<br />
survival of 30%. By multivariate analysis, SLM, poorly differentiated primary tumor,<br />
number of liver metastases ≥ 4, size of largest liver metastases ≥ 5 cm, and no surgical<br />
treatment of liver metastases were found to be independent predictors of poor survival.<br />
Conclusions: Patients with CRLM could get long-term survival benefit from different<br />
types of <strong>the</strong>rapy, and resection of liver metastases was <strong>the</strong> optimal strategy. A<br />
predictive model using <strong>the</strong>se above five factors may be of use in stratifying patients<br />
who may benefit from intensive surveillance and adjuvant <strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
645 THE PROGNOSTIC SIGNIFICANCE OF TYMIDINE KINASE<br />
ACTIVITY LEVELS IN METASTATIC COLORECTAL CANCER<br />
E.S. Seber 1 , T. Korkmaz 2 , K. Okutur 3 , F. Dane 4 , P.F. Yumuk 4 , B. Aktas 5 ,<br />
M. Kanıtez 4 , G. Demir 3 , S.N. Turhal 1<br />
1 Medical Oncology, Marmara University Hospital, Istanbul, TURKEY, 2 Medical<br />
Oncology Department, Dr Lutfi Kirdar Kartal Research and Educational Hospital,<br />
Istanbul, TURKEY, 3 Medical Oncology Department, Bilim University, Istanbul,<br />
TURKEY, 4 Medical Oncology Department, Marmara University Hospital, Istanbul,<br />
TURKEY, 5 Internal Medicine Dpt, Medical Oncology Division, Marmara University<br />
Faculty of Medicine, Istanbul, TURKEY<br />
Aim and background: Serum thymidine kinase 1 (TK1) is a sensitive marker of tumor<br />
cell proliferation. It has been reported as a predictive factor for response rate and disease<br />
free survival for hematological and early stage solid organ tumors but its importance as<br />
a prognostic factor in metastatic solid organ malignancies is not well studied. In this<br />
study we aimed to investigate <strong>the</strong> prognostic significance of serum TK1 activity in<br />
metastatic colorectal cancer (MCRC) patients receiving palliative chemo<strong>the</strong>rapy.<br />
Method: We prospectively measured serum TK1 activity immediately before <strong>the</strong> first<br />
and second cycle of <strong>the</strong> treatment in 46 consecutive metastatic MCRC patients. 10<br />
healthy volunteers were also included as a control group. TK1 activity was measured<br />
by means of high sensitive non-radioactive DIVITUM assay. The patients’<br />
performance status, age, gender, weight loss, hematological and biochemical<br />
parameters, serum CEA and CA 19.9 levels and serum TK1 activity levels relation<br />
with survival were analyzed.<br />
Results: The mean TK1 level in <strong>the</strong> study group was significantly higher than <strong>the</strong><br />
controls (162.1± 27.8 vs 32.97 ± 7.307; p < 0.03, respectively). In multivariate analysis<br />
adjusted for known clinicopathological risk factors, serum tumor markers,<br />
hemoglobin levels and trombosit count TK1 levels before chemo<strong>the</strong>rapy and weight<br />
loss remained as independent prognostic factors ( p = 0.001; 0.018, respectively).<br />
Patients with TK1 activity level above 65 Du/L and 230 Du/L had a longer PFS (624<br />
vs. 231 days) and OS time respectively (p
<strong>Abstract</strong> withdrawn in exceptional circumstances<br />
647 PREDICTIVE MARKERS FOR OVERALL AND<br />
PROGRESSION-FREE SURVIVAL WITH CAPOX IN<br />
SECOND-LINE CHEMOTHERAPY OF METASTATIC<br />
COLORECTAL CANCER<br />
M.D.P. Solís Hernández, P. Jimenez Fonseca, Q. Perez, C. Alvarez Fernandez,<br />
L. Ruiz, D. Rodríguez Rubí, W. Li, M.L. Sánchez, L. Faez, J.M. Viéitez<br />
Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, SPAIN<br />
Background: Age, sex, Karnofsky (KPS), number of metastatic sites (NMS), primary<br />
tumour localization, baseline CEA, CEA response, scan response and k-RAS status<br />
are focused on progression free survival (PFS) and overall survival (OS) as predictive<br />
factors in chemo<strong>the</strong>rapy metastatic colorectal cancer (mCRC). This study aims to<br />
find which might generate impact on PFS and OS for a second line <strong>the</strong>rapy.<br />
Patients and methods: 138 patients treated with capecitabine and oxaliplatin<br />
(CAPOX) in second-line from 2002 to 2010 were analyzed. Cox hazard model was<br />
employed to build univariante and multivariate analysis.<br />
Results: PFS and OS were 3.5 and 7.85 months, respectively. Among all evaluated<br />
factors, only KPS ≥70, CEA response and scan response were associated with better<br />
PFS and OS on univariate analysis with statistical significance. Age 2 sites, HR = 1.25, p = 0.0043) were predictive for worst PFS and OS,<br />
respectively. (See table 2)<br />
Conclusion: These findings suggest that scan response and good KPS may predict<br />
better PFS and OS in mCRC while primary tumour localization, CEA response and<br />
NMS should be fur<strong>the</strong>r validated.<br />
Table 1 – PFS and OS univariate analyses<br />
N Median P-value<br />
PFS KPS
Annals of Oncology<br />
649 USE OF CETUXIMAB (CTX) IN 1ST-LINE THERAPY OF<br />
METASTATIC COLORECTAL CANCER (MCRC): PATIENT<br />
CHARACTERISTICS, SAFETY AND EFFECTIVENESS IN THE<br />
EREBUS COHORT<br />
D. Smith 1 , M. Rouyer 2 , E. Mitry 3 , E. Francois 4 , A. Monnereau 5 , A. Sa-Cunha 6 ,<br />
J. Jove 2 , P. Noize 2 , N. Moore 2 , A. Fourrier-Réglat 2<br />
1 Oncologie Digestive, Hôpital Saint André, Bordeaux, FRANCE, 2 Pharmacology<br />
Department, University Hospital, Bordeaux, FRANCE, 3 Oncologie Médicale,<br />
Institut Curie, Paris, FRANCE, 4 Medical Oncology, Antoine Lacassagne Cancer<br />
Institute, Nice, FRANCE, 5 Statistic Department, Institut Bergonié, Bordeaux,<br />
FRANCE, 6 Digestive Surgery, Haut Lévêque Hospital, Pessac, FRANCE<br />
Background: CTX has demonstrated improved survival outcomes in mCRC but<br />
information in real-life is sparse.<br />
Methods: EREBUS is a French multicentre cohort with 92 centres. Patients initiating<br />
CTX 1 st -line <strong>the</strong>rapy for unresectable mCRC in 2009 and 2010 were identified from<br />
dispensation registries and followed 12 months. Presented here is preliminary data<br />
for those included in 2009.<br />
Results: A total of 205 patients were included, all had wild-type (wt) KRAS gene.<br />
Median age: 64 yrs, 67.3% male, 65.8% ECOG = 0-1, 61% cardiovascular history,<br />
78.5% colon primary site, 55.6% primary tumor resection, 73.7% synchronous<br />
metastasis, single metastatic site: 52.7% (39% exclusively liver). A multidisciplinary<br />
team considered 1 st -line as palliative for 61.5% of pts, and 37.1% as potentially<br />
resectable. CTX was combined with oxaliplatin-based regimens: 37.6%,<br />
irinotecan-based regimens: 55.6%, and o<strong>the</strong>r regimens: 6.8%. For those receiving<br />
CTX + oxaliplatin (n = 77): median duration of CTX use was 3.6 months and 63.6%<br />
were treated every 2 weeks. For those receiving CTX + irinotecan (n = 114): it was 4.7<br />
months and 81.6% treated every 2 weeks. Response rate (CR + PR) according to<br />
physician evaluation was 48.6% for CTX + oxaliplatin and 46.8% for CTX +<br />
irinotecan. 1-yr OS was 59.9% (95%CI 47.6-70.2) and median PFS was 8.6 months<br />
(6.3-10.5) for CTX + oxaliplatin. 1-yr OS was 69.1% (59.6-76.7) and median PFS was<br />
9.3 months (7.4-10.5) for CTX + irinotecan. Incidence of any grade 3/4 event was<br />
58% for CTX + oxaliplatin and 57% for CTX + irinotecan: neutropenia (18.2% and<br />
19.3%, respectively), skin reaction (11.7% and 14%), as<strong>the</strong>nia (11.7% and 14.9%),<br />
hypokalaemia (13% and 4.4%), diarrhoea (6.5% and 10.5%) and infusion-related<br />
reactions (1.3% and 0.9%). Surgical evaluation was performed in 27.8%: 31.2% CTX<br />
+ oxaliplatin and 24.6% CTX + irinotecan.<br />
Conclusions: In France, CTX was frequently combined with irinotecan-based<br />
regimens in 1 st -line wt KRAS mCRC. These results indicate a high proportion of<br />
exclusive liver metastases, and a high proportion of patients undergoing surgery.<br />
Effectiveness and safety profile of CTX in real-life were in line with pivotal trials.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
650 PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS OF<br />
FLUOROURACIL IN CHINESE COLORECTAL CANCER<br />
PATIENTS<br />
Z. Wang, L. Zhao, F. Wang, Y. Lin, Y. Huang, F. Xu, C. Xue, H. Zhao, Z. Li<br />
Department of Medical Oncology, Cancer Center of Sun Yat-Sen University,<br />
Guangzhou, CHINA<br />
Background: Pharmacokinetic (PK) variability of 5-FU (fluorouracil) has been<br />
demonstrated for +30 years and a significant link between 5-FU exposure and<br />
<strong>the</strong>rapeutic response has been identified. A maximum tolerated exposure (MTE)<br />
using area under curve (AUC) has been characterized for various regimens and<br />
<strong>the</strong>rapeutic drug management (TDM) has been used to achieve effective dosing.<br />
In China <strong>the</strong> regimen most used to treat colorectal (CRC) cancer are FOLFOX<br />
or FOLFIRI. The objective of this study was to characterize <strong>the</strong> PK variability of<br />
5-FU in this population and examine <strong>the</strong> relationship between AUC and<br />
toxicity.<br />
Methods: Seventy-five treatment naïve colorectal cancer patients were treated with<br />
mFOLFOX6(Oxaliplatin 100 mg/m 2 ,d1; LV 400 mg/m 2 ,d1;5-FU 3g/m2,IV 46h,<br />
biweekly) or mFOLFIRI (Irrinotecan 180 mg/m 2 , d1;LV 400 mg/m 2 ,d1;5-FU 3g/m2,<br />
IV 46h,biweekly). Blood samples were collected at steady state 18 hrs after <strong>the</strong> start<br />
of 5-FU infusion. Plasma was analyzed by a 5-FU immunoassay and AUC was<br />
calculated. We examined <strong>the</strong> relationship between 5-FU AUC and 5-FU-related<br />
toxicities.<br />
Results: The patient AUC values varied widely, ranging from 6 to 57 mg • h/L. 44%<br />
of <strong>the</strong> patients were in <strong>the</strong> 20-30 mg• h/L target range of 29% were below and 27%<br />
were above. Toxicity was recorded for 75 patients. Severe mucositis or<br />
myelosuppression occurred in 9 of 20 patients with AUCs greater than <strong>the</strong> target<br />
range and in 3 of 55 patients in or below <strong>the</strong> target range (p = 0.00018). ROC<br />
analysis for 5-FU AUC and severe mucositis identified a cut-point of 39 mg• h/L,<br />
Area under <strong>the</strong> ROC curve = 0.870, efficiency = 88.0% (p < 0.001).<br />
Conclusions: Results of this observational study demonstrate wide PK-variability of<br />
5-FU exposure and a significant relationship between severe toxicity and AUC in<br />
colorectal cancer patients. The lower percentage of patients below <strong>the</strong> target range<br />
compared to European population suggests lower clearance of 5-FU in Asian<br />
population. The study confirms that <strong>the</strong> MTE in this population is similar to a<br />
European CRC population treated with mFOLFOX6 or FOLFIRI. TDM using <strong>the</strong><br />
target range of 20-30 mg• h/L may have benefit in lowering toxicity in colorectal<br />
cancer patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
651 RETROSPECTIVE ANALYSIS OF PATHOLOGICAL RESPONSE IN<br />
COLORECTAL CANCER LIVER METASTASES FOLLOWING<br />
TREATMENT WITH BEVACIZUMAB: UPDATED FINDINGS<br />
<strong>Abstract</strong> withdrawn in exceptional circumstances<br />
652 PRIMARY RESISTANCE TO FIRST-LINE BEVACIZUMAB IN<br />
METASTATIC COLORECTAL CANCER: IMPLICATIONS ON<br />
PROGNOSIS<br />
E. Maccaroni 1 , R. Giampieri 1 , M. Scartozzi 1 , M. Del Prete 1 , A. Bittoni 2 ,<br />
L. Faloppi 3 , M. Bianconi 3 , S. Cascinu 4<br />
1 Clinica di Oncologia Medica, AOU Ospedali Riuniti Ancona Università<br />
Politecnica delle Marche, Ancona, ITALY, 2 Clinica di Oncologia Medica, Ospedali<br />
Riuniti di Ancona, Ancona, ITALY, 3 Clinica di Oncologia Medica, AOU Ospedali<br />
Riuniti Ancona Universit, Ancona, ITALY, 4 Dipartimento di Medicina Clinica E<br />
Biotecnologie A, University of Ancona, Ancona, ITALY<br />
A role of Bevacizumab after first-line failure is currently in study. We focused our<br />
analysis on patients who progressed directly under first-line Bevacizumab and<br />
assessed if lack of effect could be managed with second line chemo<strong>the</strong>rapy. We<br />
conducted a retrospective analysis on metastatic colorectal cancer patients treated in<br />
<strong>the</strong> 2008-2011 period with first-line Bevacizumab. Stratification criteria were sex, age,<br />
performance status, metastatic sites, metachronous vs synchronous metastases,<br />
chemo<strong>the</strong>rapy backbone, K-ras status. Chest-abdomen CT scan was performed every<br />
3 months. Response was scored according to RECIST criteria. Progression free<br />
survival and overall survival were defined as usual. 146 patients were eligible for<br />
analysis. 60 (41%) partial responses, 54 (37%) stable disease and 32 (22%)<br />
progressions were seen. Median overall survival was 18.5 months and median<br />
progression free survival was 8.2 months. No significant differences were seen in<br />
regards to stratification criteria for different response groups. Progression free<br />
survival for patients who achieved a partial response, a stable disease or progression<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds397 | ix219
were respectively 10.6 vs 8.5 vs 3.0 months (p < 0.0001). Overall survival for patients<br />
who achieved a partial response, a stable disease or progression were respectively 21.3<br />
vs 19.7 vs 9.1 months (p < 0.0001). All 32 patients who directly progressed under<br />
Bevacizumab based-treatment received a second line chemo<strong>the</strong>rapy regimen and in<br />
16 (50%) it was anti-EGFR based (ei<strong>the</strong>r Cetuximab or Panitumumab). Remaining<br />
16 patients received standard chemo<strong>the</strong>rapy. Only a trend towards better overall<br />
survival for anti-EGFR based regimens (10 vs 7.78 months, p = 0.26) was seen.<br />
Monoclonal antibodies increased expected survival for metastatic colorectal cancer,<br />
reaching 20 months and more in historical series. In our analysis a dismal survival of<br />
9.1 months was seen for patients who directly progress under first-line Bevacizumab,<br />
regardless of <strong>the</strong> treatment received in second-line. It is thus suggested that, even if<br />
overall survival is <strong>the</strong> primary end-point of <strong>the</strong>rapy, disease control rate should also<br />
be considered, because failure of first-line treatment may jeopardize global outcome.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
653 JAPANESE COHORT STUDY OF FIRST LINE CHEMOTHERAPY<br />
(CT) FOR METASTATIC COLORECTAL CANCER (MCRC)<br />
CONTAINING FLUOROPYRIMIDINE, OXALIPLATIN AND<br />
BEVACIZUMAB: EMERALD STUDY, FIRST REPORT<br />
K. Taku 1 , K. Ohata 1 , K. Yamazaki 2 , G. Nishikawa 1 , M. Watanabe 3 ,S.Sato 3 ,<br />
T. Oshima 3 , H. Hirano 1 , T. Amano 4 , Y. Ohashi 5<br />
1 Division of Medical Oncology, Shizuoka General Hospital, Shizuoka, JAPAN,<br />
2 Gastrointestinal Oncology and Endoscop, Shizuoka Cancer Center, Shizuoka,<br />
JAPAN, 3 Division of Surgery, Shizuoka General Hospital, Shizuoka, JAPAN,<br />
4 Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo,<br />
JAPAN, 5 Department of Biostatistics, School of Public Health, University of<br />
Tokyo, Tokyo, JAPAN<br />
Background: An observational cohort study plays a crucial role to understand <strong>the</strong><br />
current status of clinical practice and can be utilized as database for multi-purpose<br />
outcome research. Such database is available in Europe and <strong>the</strong> United States based<br />
on several cohort studies especially in mCRC, while <strong>the</strong>re is no database available<br />
including treatments for mCRC patients in Japan.<br />
Methods: According to <strong>the</strong> Japanese Ethical Guideline for Epidemiologic Study, we<br />
planned and conducted a large cohort study in Japan. Data from more than 1000<br />
patients were planned to be collected between October 2010 and September 2011<br />
with 2-year follow-up period. Enrollment criteria included documented mCRC and<br />
first line CT containing fluoropyrimidine, oxaliplatin and bevacizumab, started<br />
treatment in or after January 2010, tumor response image assessment available, safety<br />
assessment available and able to offer information outside of originally enrolled<br />
studies. The primary objectives are to evaluate overall survival, liver resection rate, R0<br />
liver resection rate; <strong>the</strong> secondary objectives are to evaluate response rate,<br />
progression-free survival, sub-group analysis by treatment regimens and by KRAS<br />
gene status, and safety.<br />
Results: From October 2010 to September 2011, 1270 patients were recruited from<br />
132 centers in Japan. The background of patients were as <strong>the</strong> following; male/female,<br />
766/504; median age of 65 (range, 21-89); ECOG PS 0/1/2/3, 1045/203/17/5;<br />
FOLFOX/ CapeOX/ o<strong>the</strong>rs with bevacizumab, 563/667/40, KRAS gene status at<br />
baseline was wild/mutant/unknown, 286/223/761; CEA median of 13.8 (range, 0.0–<br />
90055.0 ng/ml) and comorbidity no/yes, 798/472.<br />
Conclusion: We have started <strong>the</strong> large Japanese cohort study which investigates first<br />
line CT containing fluoropyrimidine, oxaliplatin and bevacizumab for metastatic<br />
colorectal cancer. We performed a preplanned interim analysis. We present <strong>the</strong> first<br />
report of 6-month efficacy and safety data on 500 patients at <strong>the</strong> <strong>ESMO</strong> <strong>2012</strong><br />
Congress. The final results will be available in 2013. This study is sponsored by <strong>the</strong><br />
Public Health Research Center Foundation CSPOR in Japan.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
654 ANTITUMOR AND ANTIANGIOGENIC ACTIVITY OF SORAFENIB<br />
ON COLORECTAL CANCER<br />
S. Kilickap 1 , A. Altun 2 , N.A. Babacan 1 , H. Ataseven 3 , T. Kaya 2<br />
1 Medical Oncology, Cumhuriyet University Faculty of Medicine, Sivas, TURKEY,<br />
2 Pharmacology, Cumhuriyet University Faculty of Medicine, Sivas, TURKEY,<br />
3 Gastroenterology, Cumhuriyet University Faculty of Medicine, Sivas, TURKEY<br />
Background: Addition to standard chemo<strong>the</strong>rapy regimens of targeted biological<br />
agents such as bevacizumab and cetuximab has led to improved outcomes in<br />
colorectal cancer (CRC). We aimed to investigate antitumoral and antiangiogenic<br />
(AAG) effects of sorafenib (SRF) in CRC cells.<br />
Methods: The effect on proliferation of SRF was evaluated by using real-time cell<br />
analysis system (xCELLigence) in DLD-1 CRC cells. After <strong>the</strong> optimal seeding<br />
concentration for proliferation of <strong>the</strong> DLD-1 was determined, <strong>the</strong> cells were exposed<br />
to 10 µL of medium containing SRF 200 mg (500, 250, 125, 62.5, 31.25, 15.62, 7.81,<br />
3.9, 1.95, 0.97 and 0.48 nM/well). Controls received ei<strong>the</strong>r medium only, or medium<br />
+ SRF with a final concentration of 500 nM. The effects of SRF on angiogenesis were<br />
studied with chorioallantoic membrane (CAM) model. Angiogenesis was evaluated<br />
by using Burgermeister’s scoring system.<br />
Annals of Oncology<br />
Results: We used <strong>the</strong> 40,000 cells/well concentration in <strong>the</strong> xCELLigence assay to<br />
examine <strong>the</strong> antiproliferative effect elicited by SRF, as <strong>the</strong> concentration displayed <strong>the</strong><br />
lowest variation. SRF treated DLD-1 cells exhibited decreasing cell index values in a<br />
concentration-dependent manner. 500, 250, 125, 62.5 and 31.5 nM SRF caused<br />
statistically significant cytotoxic effect on DLD-1 cells. There was no a significantly<br />
difference between <strong>the</strong>se concentrations. Also, 15.6 and 7.8 nM SRF led to cytotoxic<br />
effect, but <strong>the</strong>se effects were significantly lower than <strong>the</strong> 500, 250, 125, 62.5 and 31.5<br />
nM SRF. The cytotoxic effect of SRF on DLD-1 cells gradually diminished with<br />
decreasing concentrations (p < 0,001). At 24-hours after treatment with SRF, an IC50<br />
value of (IC50) 1.26x10 −9 M was achieved. The eggs on which a 10 µl-agarose pellet<br />
with no drug was installed demonstrated no significant AAG effect (average AAG<br />
score = 0.1). The AAG effect of SRF compared with bevacizumab and negative control.<br />
The AAG effects of <strong>the</strong> drugs were similar and higher compared to <strong>the</strong> negative<br />
control (p < 0.05). AAG scores of SRF in 100, 10 and 1 nM concentrations were 1.05,<br />
0.75, and 0.55, respectively. The AAG effect on CAM of SRF was dose-dependent. The<br />
AAG score with <strong>the</strong> 100 nM was significantly higher than 1 nM (p = 0.043).<br />
Discussion: SRF has antitumor and AAG effects on human colorectal cancer cell<br />
line. These effects have positively correlated with its concentration.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
655 THE EFFICACY AND SAFETY OF BEVACIZUMAB BEYOND<br />
FIRST PROGRESSION IN JAPANESE PATIENTS TREATED WITH<br />
FIRST-LINE MFOLFOX6 FOLLOWED BY SECOND-LINE FOLFIRI<br />
IN ADVANCED COLORECTAL CANCER: A MULTICENTER,<br />
SINGLE-ARM PHASE II TRIAL (CCOG-0801); FINAL REPORT<br />
G. Nakayama 1 , K. Ishigure 2 , A. Ishiyama 3 , K. Uehara 4 , T. Fujii 1 , N. Hayashi 1 ,<br />
Y. Ando 5 , Y. Kodera 1<br />
1 Department of Gastroenterological Surgery (Surgery II), Nagoya University<br />
Graduate School of Medicine, Nagoya, JAPAN, 2 Department of Surgery, Konan<br />
Kosei Hospital, Konan, JAPAN, 3 Department of Surgery, Okazaki City Hospital,<br />
Okazaki, JAPAN, 4 Department of Surgical Oncology, Nagoya University Graduate<br />
School of Medicin, Nagoya, JAPAN, 5 Department of Clinical Oncology and<br />
Chemo<strong>the</strong>rapy, Nagoya University Hospital, Nagoya, JAPAN<br />
Purpose: The aim of this study was to evaluate <strong>the</strong> efficacy and safety of <strong>the</strong> planned<br />
continuation of bevacizumab beyond first progression in Japanese patients with<br />
metastatic colorectal cancer (mCRC).<br />
Methods: Previously untreated patients with assessable disease were treated with<br />
mFOLFOX6 plus bevacizumab until tumor progression, followed by FOLFIRI plus<br />
bevacizumab. The primary endpoint of <strong>the</strong> study was <strong>the</strong> second progression-free<br />
survival (2nd PFS), defined as duration from enrollment until progression after<br />
second-line <strong>the</strong>rapy. Secondary endpoints of <strong>the</strong> study were overall survival (OS),<br />
survival beyond first progression (SBP), progression free survival (PFS), response rate<br />
(RR), disease control rate (DCR) and safety.<br />
Results: In <strong>the</strong> first-line setting, 47 patients treated with mFOLFOX6 plus bevacizumab<br />
achieved RR of 61.7%, DCR of 89.4% and median PFS of 13.1 months (95% CI, 8.7 to<br />
17.5 months). Thirty one patients went on to receive second-line <strong>the</strong>rapy with FOLFIRI<br />
plus bevacizumab and achieved RR of 27.6%, DCR of 62.1% and median PFS of 7.5<br />
months (95% CI, 5.5 to 9.5 months). Median 2nd PFS, <strong>the</strong> primary endpoint, was 18.0<br />
months (95% CI, 13.7 to 22.3 months). The median OS was 30.8 months (95% CI, 27.7<br />
to 33.9 months), and median SBP was 19.6 months (95% CI, 14.3 to 24.9 months), after<br />
median follow up period of 35.9 months. No critical events associated with<br />
bevacizumab were observed during <strong>the</strong> second-line <strong>the</strong>rapy.<br />
Concluson: The planned continuation of bevacizumab during second-line treatment<br />
is feasible for Japanese mCRC patients. A prospective randomized control study to<br />
confirm efficacy is warranted.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
656 SURVIVAL OUTCOMES IN METASTATIC COLORECTAL CANCER<br />
(CRC) WITH HIGH-LEVEL MICROSATELLITE INSTABILITY<br />
(MSI-H)<br />
M.J. Overman 1 , S. Kopetz 1 , S. Wong 2 , J. Tie 2 , S. Kosmider 2 , A. Jacob 1 ,<br />
E. Vilar 3 , P. Gibbs 2 , J. Desai 2 ,B.Tran 2<br />
1 Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer<br />
Center, Houston, TX, UNITED STATES OF AMERICA, 2 Medical Oncology, Royal<br />
Melbourne Hospital, Melbourne, VIC, AUSTRALIA, 3 Clinical Cancer Prevention,<br />
University of Texas MD Anderson Cancer Center, Houston, TX, UNITED STATES<br />
OF AMERICA<br />
Background: The MSI-H phenotype is present in 15% of early stage CRC and<br />
confers good prognosis in this population. In metastatic CRC, MSI-H is rare and its<br />
impact on outcomes is unknown. We describe survival outcomes and responses to<br />
chemo<strong>the</strong>rapy for <strong>the</strong> largest reported cohort of MSI-H metastatic CRC.<br />
Methods: A retrospective review of metastatic CRC patients (pts) with MSI-H<br />
(defined as ≥2 DNA microsatellite markers with instability by PCR) from two<br />
institutions was conducted. Pts from Royal Melbourne Hospital (Australia) were<br />
identified using a prospective CRC database. Pts from The University of Texas MD<br />
ix220 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Anderson Cancer Center (United States) were identified from an institutional<br />
database. Statistical analyses utilized Kaplan-Meier method and Log-rank test.<br />
Results: 55 pts with metastatic MSI-H CRC were identified. Median age was 67 years<br />
(range: 20-90), 63% had poor differentiation, and 64% of primary tumors originated<br />
in <strong>the</strong> right colon. 25 (45%) pts had stage IV disease at presentation, while 30 (55%)<br />
pts presented with stage II/III disease (median time to development of metastases was<br />
9 months). 42 pts have died and median overall survival (OS) from <strong>the</strong> time of<br />
metastatic disease was 15.3 months. 14 pts underwent R0/R1 metastatectomies with<br />
median time to recurrence of 25.4 months and median OS from metastatectomy of<br />
33.7 months. 31 pts were evaluable for response to front-line systemic chemo<strong>the</strong>rapy:<br />
single agent 5-FU in 7, oxaliplatin-based in 14, and irinotecan-based in 10.<br />
Radiographic response was seen in 11 pts (35%) and <strong>the</strong> median time to progression<br />
(TTP) and OS were 4.2 months and 11.6 months, respectively. No statistically<br />
significant differences in TTP or OS were seen between chemo<strong>the</strong>rapy subtypes. BRAF<br />
mutation status was known in 47 pts: 14 pts had a BRAF V600E mutation, 33 pts were<br />
wildtype (wt). In comparison to BRAF wt pts, BRAF V600E pts demonstrated<br />
significantly worse median OS; 10.1 v 17.4 months, HR 2.6 (95%CI: 1.1-6.1), P =0.03.<br />
Conclusions: Compared to historical controls, pts with MSI-H metastatic CRC do<br />
not appear to have improved outcomes. BRAF V600E mutation is a poor prognostic<br />
factor in MSI-H metastatic CRC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
657 ADJUVANT MFOLFOX6 IN THE TREATMENT OF ELDERLY<br />
COLON CANCER PATIENTS<br />
J. Godinho Bexiga, F. Carneiro, D.S. Marques, N. Sousa, A. Raimundo,<br />
M. Machado, P. Ferreira, C. Faustino, M. Fragoso<br />
Medical Oncology, Portuguese Institute of Oncology of Oporto, Oporto,<br />
PORTUGAL<br />
Background: In Europe, more than 60% of new cancer cases and more than 70% of<br />
cancer deaths occur in elderly patients. Approximately 50% of colorectal cancer cases<br />
occur in patients ≥ 70 years. Despite this, elderly patients are under-represented in<br />
clinical trials. Adjuvant chemo<strong>the</strong>rapy with Fluoropyrimidines and Oxaliplatin is <strong>the</strong><br />
recommended treatment for stage III colon cancer. Our aim was to determine <strong>the</strong><br />
effectiveness of mFOLFOX6 in <strong>the</strong> adjuvant treatment of elderly colon cancer<br />
patients.<br />
Material and methods: Retrospective cohort study of colon cancer (CC) patients<br />
treated with adjuvant mFOLFOX6, in a Portuguese cancer centre, from September 2004<br />
till November 2009. Elderly patients were defined as having ≥ 70 years old. Toxicity was<br />
evaluated using Common terminology criteria for adverse events (CTCAE), v<br />
3. Comorbidity was assessed by Charlson’s Index. The primary efficacy variable was<br />
disease-free survival (DFS). Secondary endpoints were cancer-specific survival (CSS),<br />
overall survival (OS) and toxicity grade ≥ 3. Hazard ratios and 95% confidence intervals<br />
were calculated with <strong>the</strong> use of <strong>the</strong> Cox proportional hazards model.<br />
Results: In <strong>the</strong> study period, 277 patients were treated with adjuvant mFOLFOX6. Fifty<br />
three patients (19.1%) were ≥ 70 years and of <strong>the</strong>se, 76.8% were male and 80% had stage<br />
III CC. Elderly patients were more likely to be male and have a higher comorbidity<br />
index than younger patients (p< 0.05). Patients older than 70 were more prone to<br />
grade ≥ 3 toxicity and a lower mean relative dose-intensity (Oxaliplatin: 66% vs 72%, p<br />
= 0.062; 5-Fluorouracil: 70% vs 76%, p = 0.01). With a median follow-up time of 45<br />
months, elderly patients had 3 year DFS, CSS and OS of 82%, 92% and 84%,<br />
respectively. Survival wasn’t significantly lower than that of patients aged < 70 (DFS: HR<br />
0.612, p = 0.243; CSS: HR 0.533, p = 0.166; OS: HR 1.226, p = 0.674).<br />
Conclusions: Adjuvant mFOLFOX6 is feasible in elderly patients and its benefit is<br />
similar to that of younger patients. Selection bias might explain <strong>the</strong> good results of<br />
this study and limit <strong>the</strong> external validity of our conclusions.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
658 USE OF COMPREHENSIVE GERIATRIC ASSESSMENT<br />
PARAMETERS TO PREDICT CHEMOTHERAPY TOXICITY IN<br />
ELDERLY PATIENTS WITH COLORECTAL CANCER: A<br />
PROSPECTIVE MONO-CENTER STUDY<br />
H. Djedi 1 , K. Bouzid 2<br />
1 Onco-Hematologie, CHU Annaba, Annaba, ALGERIA, 2 Medical Oncology,<br />
Centre Pierre et Marie Curie, Algiers, ALGERIA<br />
Background: Despite <strong>the</strong> younger age of Algerian population, Colorectal cancer that<br />
represent <strong>the</strong> second most common malignancy, occurred in Older patients (age ≥ 65<br />
y) in approximately one quarter of cases . Unfortunately, <strong>the</strong>re is little studies<br />
including <strong>the</strong>se geriatric population.<br />
Purpose: The aim of this study is to identify parameters of Comprehensive Geriatric<br />
Assessment “CGA“ that may represent risk factors for chemo<strong>the</strong>rapy toxicity in older<br />
adults with colorectal cancer than to develop a predicting risk scoring for<br />
chemo<strong>the</strong>rapy toxicity.<br />
Patients and methods: A prospective study in our department collected on 2 years 66<br />
patients age 65 years or older . Application of oncologic data and geriatric assessment<br />
variables (function, comorbidity, cognition, psychological state, social activity/support,<br />
and nutritional status) selected 49 patients illegible for chemo<strong>the</strong>rapy. Mean age: 71 y<br />
(range 65-81 y), gender: 27 women, 22 men. Localization: colon: 36pts/ rectum: 12pts/<br />
multifocal: 1pt. Balducci 1: 13 pts / Balducci 2 : 36 pts. All patients were evaluated for<br />
grade ¾ chemo-toxicity as defined by <strong>the</strong> version 4.0 of National Cancer Institute<br />
Common Terminology Criteria for Adverse Events.<br />
Results: After a total of 394 courses, 34 pts presents Grade ¾ toxicity. It<br />
occurred in 25,5% of cures and included neuropathy: 5%, diarrhea 5,6%,<br />
hand-foot syndrome 2,8%, neutropenia 0,8%, thrombocytopenia 0,8%, Anemia<br />
6% . According to univariate and multivariate analyses: age (≤ or ⍰ 70 y),<br />
Balducci groups, anemia and number of drugs used (mono vs<br />
poly-chemo<strong>the</strong>rapy) were identified to be risk factors significantly associated with<br />
chemo-toxicity (p⍰0,05, IC95). A simple predictive model for grade ¾<br />
chemo-toxicity was developed using regression coefficients from <strong>the</strong> multivariate<br />
model.The scoring system (range 0 to 13) stratification schema 3 groups : pts at<br />
low (0 to 3 points), intermediate (4 to 7 points), or high risk (8 to 13 points) of<br />
chemo<strong>the</strong>rapy toxicity (p = 0,0112).<br />
Conclusions: Results of our study suggest that <strong>the</strong> incorporation of a mini- CGA in<br />
our daily practice can help physicians to establish a personalized <strong>the</strong>rapeutic decision<br />
for elderly colorectal cancers based on chemo-toxicity risk stratification.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
659 BASELINE CEA SERUM LEVELS PREDICT THE EFFICACY OF<br />
BEVACIZUMAB-BASED TREATMENT IN ADVANCED<br />
COLORECTAL CANCER<br />
<strong>Abstract</strong> withdrawn in exceptional circumstances<br />
660 BRAIN METASTASES IN GASTROINTESTINAL CANCERS<br />
D. Erdem 1 , I. Yücel 1 , B. Yilmaz 1 , G. Demirag 1 , E. Kut 1 , F. Cilingir 2 , Y. Kemal 1 ,<br />
F. Teker 1<br />
1 Medical Oncology, Ondokuzmayis University, Samsun, TURKEY, 2 Internal<br />
Medicine, Ondokuzmayis University, Samsun, TURKEY<br />
Aim: Only 4% of cranial metastasis occur with gastrointestinal cancer. The aim of<br />
this study is to evaluate <strong>the</strong> characteristics of cranial metastasis derived from<br />
gastrointestinal system tumors.<br />
Material-method: 1863 patients diagnosed with gastrointestinal cancers between<br />
1997-2011 years were included. Among <strong>the</strong> patients; 51 esophageal cancer, 516<br />
gastric cancer, 5 small intestine tumor, 878 colorectal cancer, 11 gallbladder cancer,<br />
190 pancreas cancer, 119 hepatocellular cancer, 63 cholangiocarcinoma and 30 GIST<br />
were involved. SPSS 16 is used.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds397 | ix221
Results: 20 gastrointestinal cancer patients with cranial metastases (1.07%) were<br />
included. The average age was 54.6 ± 1.1 years and 70% (n = 14) of <strong>the</strong> patients were<br />
male. 20 patients cancers were as follows: 4 gastric cancer (20%), 15 colorectal cancer<br />
( 75%) and 1 pancreas cancer (5%). 3 patients had no extracranial metastases (15%).<br />
Lung metastases was <strong>the</strong> most common extracranial metastatic site in general, but<br />
liver was <strong>the</strong> most solitary extracranial metastatic site. The median interval of<br />
diagnosis-recurrence/metastases was 20.6 months (range 0-89 months) and <strong>the</strong><br />
median interval of diagnosis-cranial metastases was 30.1 months (range 0-138<br />
months). Mean OS was 36.6 months in 3 patients without extracranial metastases<br />
and 31.6 months in 17 patients with extracranial metastases.<br />
Discussion: The most common primary sites that intend to metastasize to brain are<br />
lung and breast. Gastrointestinal tumors rarely metastasize to cranium. Our results<br />
were similar with literature: 0.7% of cranial metastases in gastric cancer and 1.7%<br />
cranial metastases in colorectal cancer.The arguing site in our study were as follows:<br />
in <strong>the</strong> literature lung was <strong>the</strong> most common site of extracranial metastases; but in our<br />
study despite being general most common extracranial metastatic site, it was not <strong>the</strong><br />
solitary site of metastases. In 10 metastatic patients at <strong>the</strong> diagnosis, 5 were solely<br />
had liver metastases without lung metastases.<br />
Conclusion: Cranial metastases is a rare and late sign of gastrointestinal cancers. By<br />
new approaches in diagnosis and <strong>the</strong>rapy of cancer, cranial metastases is more<br />
common. All symptomatic patients and asymptomatic patients with liver or lung<br />
metastases may be suggested to be screened for brain.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
661 TUMORS OF THE APPENDIX: THE EXPERIENCE OF<br />
IPO-PORTO<br />
T. Malheiro Sarmento1 , M.H. Abreu1 , R. Fragoso2 , M. Machado1 , N. Sousa1 ,<br />
C. Faustino1 , P. Ferreira1 1<br />
Medical Oncology, Portuguese Oncology Institute of Porto, Porto, PORTUGAL,<br />
2<br />
Medical Oncology, Instituto Portugues de Oncologia Centro do Porto, Porto,<br />
PORTUGAL<br />
Introduction: Malignant neoplasms of ileocecal appendix are rare, an clinical<br />
features are unspecific, often mimicking acute appendicitis. They are diagnosed in<br />
about 1% of appendicectomy specimens. The most common histologic types are<br />
mucinous adenocarcinoma, intestinal-type adenocarcinoma and carcinoid tumor.<br />
Methods: The authors reviewed <strong>the</strong> primary appendix carcinomas treated in Instituto<br />
Português de Oncologia Francisco Gentil-Porto (IPOFG-Porto) between January<br />
2000 and June 2011.<br />
Results: Fourty two patients were treated during this period: 30 women (71%) and 12<br />
men, aged between 20 and 90 years old (median age 58). Mucinous adenocarcinoma<br />
was <strong>the</strong> most common histologic subtype, with 27 cases (64%), followed by<br />
adenocarcinoma NOS (10 cases - 24%); carcinoids were 5 cases (12%). Fifteen percent<br />
presented as stage IV, 7% stage III, 24% stage II and 19% stage I. The primary treatment<br />
was surgery: 16 patients were submitted to appendicectomy, 6 patients to<br />
appendicectomy, ooforectomy and hysterectomy, 12 to hemicolectomy. Of patients<br />
submitted to appendicectomy, 11 (50%) had a second laparotomy in order to perform<br />
hemicolectomy. Five percent of <strong>the</strong> patients received adjuvant chemo<strong>the</strong>rapy<br />
(mFOLFOX6). Hyper<strong>the</strong>rmic Intraoperative Peritoneal Chemo<strong>the</strong>rapy (HIPEC) was<br />
performed in 18 patients with stage IV disease (peritoneal carcinomatosis). The median<br />
follow-up was 35 months. Thirty three percent of <strong>the</strong> patients (n = 14) died because of<br />
disease progression and 62% (n = 26) were alive with no evidence of disease.<br />
Conclusion: Appendiceal carcinomas are rare tumours and <strong>the</strong>re is limited evidence<br />
on <strong>the</strong> indications for right hemicolectomy. The role of adjuvant chemo<strong>the</strong>rapy for<br />
adenocarcinoma of <strong>the</strong> appendix is unknown. Optimal treatment of patients with<br />
intraperitoneal dissemination of appendiceal adenocarcinoma (mucinous peritoneal<br />
carcinomatosis) is unclear. Selected patients treated with aggressive surgical<br />
cytoreduction and HIPEC may have a favorable outcome in long term, but patient<br />
selection and <strong>the</strong> experience of <strong>the</strong> treating team are critical. The benefit of systemic<br />
chemo<strong>the</strong>rapy for advanced disease is unknown.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
662TiP PILOT STUDY OF TIGATUZUMAB (CS-1008) IN<br />
COMBINATION WITH FOLFIRI IN PATIENTS WITH<br />
METASTATIC COLORECTAL CANCER (CRC)<br />
G. Kim1 , M. Borad2 , H. Pitot3 , J. Rubin3 , J. Greenberg4 , P. McCroskery4 ,<br />
R. Beckman4 , A. Gro<strong>the</strong>y3 1 2<br />
GI Oncology, Mayo Clinic, Jacksonville, FL, UNITED STATES OF AMERICA, GI<br />
Oncology, Mayo Clinic, Scottsdale, AZ, UNITED STATES OF AMERICA, 3 GI<br />
Oncology, Mayo Clinic, Rochester, MN, UNITED STATES OF AMERICA,<br />
4<br />
Development, Daiichi Sankyo Pharma, Edison, NJ, UNITED STATES OF<br />
AMERICA<br />
Background: Tigatuzumab (T) is a humanized monoclonal antibody that acts as a<br />
death receptor 5 (DR5) agonist. Preclinical studies have shown that T mono<strong>the</strong>rapy<br />
induces apoptosis in DR5-positive CRC cell lines and significantly inhibits growth in<br />
Annals of Oncology<br />
CRC xenograft models. T combined with FOLFIRI (folinic acid, 5-fluorouracil<br />
(5-FU), irinotecan) has demonstrated enhancement of preclinical antitumor activity.<br />
This pilot study assessed efficacy and safety of this combination <strong>the</strong>rapy in patients<br />
(pts) with metastatic CRC.<br />
Methods: This was an open-label, single-arm, multicenter study of T plus FOLFIRI<br />
in pts with histologically-confirmed metastatic CRC, an ECOG (Eastern Cooperative<br />
Oncology Group) score ≤ 2, and adequate organ and bone marrow function. Pts were<br />
non-homozygous for UGT1A1*28 allele. T was initially administered intravenously<br />
(IV) at 6 mg/kg and <strong>the</strong>reafter at 2 mg/kg weekly with one treatment cycle = 4 weeks<br />
(wks). FOLFIRI was administered IV at wks 1 and 3: irinotecan 180mg/m 2 , folinic<br />
acid (leucovorin) 400mg/m 2 and 5-FU 400mg/m 2 bolus followed by 2400 mg/m 2<br />
over 46-48 hours. Radiographic assessments were performed every 8 wks.<br />
Results: Treated pts (n = 21) had a median of 3 prior <strong>the</strong>rapies; 10 (48%) had prior<br />
FOLFIRI. All pts experienced ≥1 treatment-emergent adverse event (TEAE); <strong>the</strong><br />
most common T-related TEAEs were fatigue (12 pts; 57%) and nausea (8 pts; 38%).<br />
17 pts (81%) experienced a ≥ grade 3 TEAE; <strong>the</strong> most common was neutropenia (9<br />
pts; 43%) which was partly attributed to T in 5 pts (24%). Serious AEs (SAEs)<br />
occurred in 15 pts (71%). The most common SAE was anemia (3 pts; 14%), all<br />
unrelated to T. There was 1 SAE of neutropenia related to T. Median progression-free<br />
survival (PFS) was 3.7 months. 2 pts had unconfirmed partial response; 9 pts had<br />
stable disease. The trial is ongoing.<br />
Conclusions: T displays acceptable safety and tolerability when combined with<br />
FOLFIRI. The observed median PFS compares favorably with historical results in 3 rd /<br />
4 th line treated pts, but study size and single arm design preclude formal conclusions.<br />
The SAEs reported were comparable to those reported for T in combination with<br />
o<strong>the</strong>r chemo<strong>the</strong>rapies.<br />
Disclosure: J. Greenberg: Full-time employee of and stockholder in Daiichi Sankyo<br />
Pharmaceutical Development. P. McCroskery: Full-time employee of and stockholder<br />
in Daiichi Sankyo Pharmaceutical Development. Stockholder in Johnson & Johnson<br />
Corporation. R. Beckman: Full-time employee of and stockholder in Daiichi Sankyo<br />
Pharmaceutical Development. Stockholder in Johnson & Johnson Corporation. A.<br />
Gro<strong>the</strong>y: Contracted researcher for Daiichi Sankyo Pharmaceutical Development. All<br />
o<strong>the</strong>r authors have declared no conflicts of interest.<br />
663TiP AXE BEAM: ENCOURAGING EARLY RESULTS OF A<br />
NEO-ADJUVANT BEVACIZUMAB, CAPECITABINE +/-<br />
OXALIPLATIN AND RADIATION MULTIMODALITY REGIMEN<br />
FOR LOCALLY ADVANCED RECTAL CANCER<br />
G. Chiritescu 1 , K. Dumon 1 , P. Vergauwe 2 , J. Arts 3 ,A.D’Hoore 4 , A. Debucquoy 5 ,<br />
M. Verstraete 5 , X. Sagaert 6 , K. Haustermans 5 , E. Van Cutsem 1<br />
1 Digestive Oncology, University Hospital Leuven, Leuven, BELGIUM,<br />
2 Gastroenterology, A.Z. Groeninge, Kortrijk, BELGIUM, 3 Gastroenterology, A.Z.<br />
Sint Lucas, Brugge, BELGIUM, 4 Abdominal Surgery, University Hospital Leuven,<br />
Leuven, BELGIUM, 5 Lab of Experimental Radio<strong>the</strong>rapy, Department of Radiation<br />
Oncology, University Hospital Leuven, Leuven, BELGIUM, 6 Pathology, University<br />
Hospital Leuven, Leuven, BELGIUM<br />
In an academic multicentric phase II study, patients (pts) with locally advanced<br />
rectal cancer are randomized to receive bevacizumab (5mg/kg), capecitabine<br />
(1650mg/m 2 /day) and radio<strong>the</strong>rapy (1.8Gy/day) with (Arm A) or without (Arm B)<br />
oxaliplatin (50mg/m 2 ). Chemoradio<strong>the</strong>rapy (CRT) starts at 2 weeks after 1 st infusion<br />
of bevacizumab and continues for 5 weeks. Total mesorectal excision is planned at<br />
6-8 weeks post CRT. Immunohistochemical staining to study <strong>the</strong> functionality of<br />
blood vessels and Luminex analyses to assess <strong>the</strong> changes in circulating VEGF<br />
ligands are performed on tissues and blood samples from consenting pts.<br />
Pathological complete response (pCR) rate, safety profile and identification of<br />
biomarkers for early response prediction are <strong>the</strong> main endpoints.<br />
Results: Sixty five pts with median age 60 have been enrolled to date. Fifty seven pts<br />
completed <strong>the</strong> full protocol scheme, with a relative dose intensity of 97% for<br />
bevacizumab, 95% for capecitabine and 93% for oxaliplatin. Preliminary safety data<br />
from 60 evaluable pts show that <strong>the</strong> regimen is generally well tolerated. Most severe<br />
adverse events were post-operative (wound infections, leaks) in 9 pts, equally<br />
distributed between arms. During CRT, grade 3 toxicities were more frequent in Arm<br />
A: fatigue (1), diarrhea (2), infection (2), febrile neutropenia (1), sensory neuropathy<br />
(1). Two pts deceased due to disease progression and one due to lung embolism<br />
post-surgery. Fifty two pts are evaluable for response. pCR was seen in 11 pts, 30%<br />
(8/26) in Arm A and 12% (3/26) in Arm B (p = 0.08). The rate of good responders<br />
(Dworak TRG 3,4) was higher in Arm A 18/26 versus Arm B 10/26 (p = 0.05).<br />
Changes in <strong>the</strong> pericyt coverage of <strong>the</strong> blood vessels, proliferation of <strong>the</strong> tumour cells<br />
and plasma concentrations of PDGF-AA, PDGF-BB and VEGF were observed and<br />
will be fur<strong>the</strong>r assessed.<br />
Conclusions: Chemoradio<strong>the</strong>rapy in combination with bevacizumab showed an<br />
acceptable safety profile in this patient population. Adding oxaliplatin determined a<br />
slight increase of toxicity but might enhance <strong>the</strong> percentage of responders. PDGF<br />
may be a predictor of response in this setting. Fur<strong>the</strong>r analyses are ongoing.<br />
Conducted with support from Roche and Sanofi Aventis.<br />
Disclosure: K. Haustermans: The author has received research funding from Roche.<br />
E. Van Cutsem: The author has received research funding by Roche and Sanofi<br />
Aventis. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
ix222 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
664TiP A PHASE I TRIAL OF IRINOTECAN (IRI) AND BKM120 IN<br />
PREVIOUSLY TREATED PATIENTS (PTS) WITH METASTIC<br />
COLORECTAL CANCER (MCRC)<br />
J.C. Baranda 1 , G. Reed 2 , S. Williamson 1 , E. Dickman 1 , M. Stoltz 1 , R. Madan 3 ,<br />
L. Wright 1 , K. Bhalla 1 , A. Godwin 3<br />
1 Hematology and Medical Oncology, University of Kansas Cancer Center,<br />
Westwood, KS, UNITED STATES OF AMERICA, 2 Pharmacology. Toxicology and<br />
Therapeutics, University of Kansas Medical Center, Kansas City, KS, UNITED<br />
STATES OF AMERICA, 3 Pathology and Laboratory Medicine, University of<br />
Kansas Medical Center, Kansas City, KS, UNITED STATES OF AMERICA<br />
Background: Reversal of Iri resistance may result with use of Iri plus anti-EGFR<br />
antibody in pts with kras wild-type mCRC. BKM120 is an oral pan-class PI3K<br />
inhibitor. The published results of a phase I trial of single agent BKM120 showed<br />
that BKM120 was well-tolerated and safe with favorable PK profile and promising<br />
anti-tumor effect.<br />
Methods: The primary objective of this phase I trial is to identify <strong>the</strong> maximum<br />
tolerated dose (MTD) for Iri and BKM120 combination in previously treated<br />
mCRC. The secondary objectives are to characterize <strong>the</strong> PK of Iri with or<br />
without BKM120 as well as PK of BKM120 when administered with Iri, to<br />
determine clinical response to <strong>the</strong> combination, and to correlate <strong>the</strong> expression<br />
of biomarkers associated with PI3K signaling pathway with clinical response to<br />
<strong>the</strong> combination of Iri plus BKM120. A traditional 3 + 3 dosing scheme is used<br />
for dose escalation. Iri is given intravenously every 14 days and BKM daily. Iri<br />
starts on cycle 1 day 1 while BKM120 starts after 24 hours after <strong>the</strong> first dose<br />
of Iri to allow us to monitor <strong>the</strong> PK of Iri both in <strong>the</strong> absence and presence of<br />
BKM120. The patients are assessed for safety and toxicities every cycle (q14<br />
days).<br />
Results: Eleven pts have been enrolled: six were evaluable for toxicity: 3 in<br />
cohort 0 (Iri 120 mg/m 2 + BKM120 50 mg/d) and 3 in cohort 1 (Iri 150 mg/m 2<br />
+ BKM 120 50 mg/d). The most common drug related adverse events were<br />
nausea and vomiting, diarrhea, fatigue, hyperglycemia, and elevation of<br />
transaminases. One dose limiting toxicity (DLT), genital mucositis, was observed<br />
in a male pt in Cohort 1. This resolved in less than 7 days but pt missed more<br />
than 7 days of BKM120. The MTD has not been reached. Of <strong>the</strong> 4 pts who<br />
have completed 4 cycles of <strong>the</strong>rapy 3 had stable disease and one had progressive<br />
disease. The cycle 1 vs cycle 2 PK for cohort 0 showed SN-38 mean Cmax2/<br />
Cmax1 was 0.89 + 0.16 and mean AUC2/AUC1 1.07 + 0.16. The Iri PKs for<br />
subsequent cohorts and BKM120 PKs as well as <strong>the</strong> molecular correlates will be<br />
presented.<br />
Conclusion: This is <strong>the</strong> first human trial of <strong>the</strong> combination of Iri and BKM120. No<br />
significant toxicities have been observed and <strong>the</strong> PK of Iri does not seem to be<br />
affected by BKM120. These preliminary data support continuing <strong>the</strong> effort to find<br />
<strong>the</strong> MTD for <strong>the</strong> combination of Iri and BKM120 for use in phase II trials and to<br />
identify potential biomarkers of response and toxicities.<br />
Disclosure: J.C. Baranda: Research Funds: Novartis, Roche. K. Bhalla: Novartis,<br />
Research Funding Novartis, honorarium, advisor. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
665TiP USE OF PANITUMUMAB IN PATIENTS WITH RECURRENT<br />
OR PROGRESSIVE COLORECTAL CANCER - AN INTERIM<br />
ANALYSIS OF THE VECTIS STUDY<br />
R. Lakomy 1 , W. Rogowski 2 , B. Pikó 3 , C. András 4 , E. Molnar 5<br />
1 Department of Clinical Oncology, Masaryk Memorial Cancer Institute, Brno,<br />
CZECH REPUBLIC, 2 Department of Oncology, ZOZ MSWiA z Warminsko<br />
Mazurskim Centrum Onkologii, Olsztyn, POLAND, 3 Dep. of Clinical Oncology,<br />
3Pándy Kálmán County Hospital, Center of Oncology, Gyula, Gyula, HUNGARY,<br />
4 Dpt. of Clinical Oncology, 4Medical University, Dpt. of Oncology, Debrecen,<br />
Debrecen, HUNGARY, 5 Medical, Amgen, Budapest, HUNGARY<br />
Registry Number: 20080618<br />
Background: Panitumumab (Pmab; Vectibix®) is a fully human monoclonal antibody,<br />
which binds specifically to <strong>the</strong> human epidermal growth factor receptor (EGFr). Skin<br />
toxicity (ST), a pharmacological effect observed with EGFr inhibitors, appears in<br />
almost all patients (pts) treated with Pmab and is usually mild to moderate in severity.<br />
The VECTIS study was designed to determine <strong>the</strong> safety and efficacy of Pmab as<br />
mono<strong>the</strong>rapy in daily practice with special reference to ST and its management.<br />
Methods: This is an open-label, prospective, non-interventional study collecting data<br />
from pts from CEE countries, aged ≥18 years, who have EGFr expressing mCRC<br />
with wild type KRAS gene tumour status receiving Pmab mono<strong>the</strong>rapy (6 mg/kg<br />
Q2W) after failure of chemo<strong>the</strong>rapy regimens containing 5-FU, oxaliplatin and<br />
irinotecan. This interim analysis includes <strong>the</strong> data collected between 12/2008 and 06/<br />
2011 from pts in Hungary, Poland, and <strong>the</strong> CzechRepublic. The observation period<br />
was limited to 18 cycles.<br />
Results: At <strong>the</strong> time of reporting, 177/205 (86.3%) enrolled pts have experienced a<br />
total of 266 ST events with an incidence rate (IR) (events per pt per year) of 3.47<br />
(95% confidence interval [CI] = 3.07, 3.91); 15 pts experienced Grade 3 ST with an<br />
IR of 0.20 (95% CI = 0.11, 0.32) and no pts had ST Grade ≥4. Of <strong>the</strong> recorded ST<br />
events, 25.9% have resolved; 3.4% have resolved with consequences; 19.9% continue<br />
but are improving; and 50.8% have not resolved. Overall, 69.8% of pts required<br />
<strong>the</strong>rapeutic measures for ST. Four serious Adverse Drug Reactions (ADRs) were<br />
reported. Of 6 deaths that occurred, none was related to Pmab. Four pts have<br />
stopped Pmab <strong>the</strong>rapy due to ADRs including ST or o<strong>the</strong>r toxicity.<br />
Overall<br />
(N = 205) % (95% CI)<br />
ST Grade ≥ 2<br />
(N = 112) % (95% CI)<br />
Tumor response 26.8 (20.9, 33.4) 30.4 (22.0, 39.8)<br />
Disease control rate 67.8 (60.9, 74.1) 70.5 (61.2, 78.8)<br />
Free from progression (18 cycles) 12.7 (8.5, 18.0) 13.4 (7.7, 21.1)<br />
A statistically significant positive correlation was observed between severity of ST and<br />
<strong>the</strong> best response (r = 0.13) as well as tumor response (r = 0.15).<br />
Conclusion: In clinical practice, Pmab mono<strong>the</strong>rapy appears to be well tolerated and<br />
effective in pts who have heavily pre-treated mCRC with wild-type KRAS status. This<br />
study is sponsored by Amgen GmbH CEE Headquarters.<br />
Disclosure: R. Lakomy: Vectis study. W. Rogowski: Vectis study, Pegfilgrastim study.<br />
B. Pikó: Vectis study, Pegfilgrastim study. C. András: Vectis study, Pegfilgrastim<br />
study, Amgen sponsored scientific event speaker. E. Molnar: employment possition<br />
Amgen, stock<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds397 | ix223
abstracts<br />
gastrointestinal tumors, non-colorectal<br />
666O TH-302 + GEMCITABINE (G + T) VS GEMCITABINE (G) IN<br />
PATIENTS WITH PREVIOUSLY UNTREATED ADVANCED<br />
PANCREATIC CANCER (PAC)<br />
M. Borad 1 , S. Reddy 2 , N. Bahary 3 , H. Uronis 4 , D.S. Sigal 5 , A.L. Cohn 6 ,<br />
W. Schelman 7 , J. Stephenson 8 , C. Eng 9 , D.P. Ryan 10<br />
1 Oncology, Mayo Clinic Cancer Center - Arizona, Scottsdale, AZ, UNITED<br />
STATES OF AMERICA, 2 Oncology, Louisiana State University Health Sciences<br />
Center, Shreveport, LA, UNITED STATES OF AMERICA, 3 Oncology, University of<br />
Pittsburgh Medical Center, Pittsburgh, PA, UNITED STATES OF AMERICA,<br />
4 Oncology, Duke University, Durham, NC, UNITED STATES OF AMERICA,<br />
5 Oncology, Scripps Clinical Medical Group, La Jolla, CA, UNITED STATES OF<br />
AMERICA, 6 Oncology, Rocky Mountain Cancer Centers, Denver, CO, UNITED<br />
STATES OF AMERICA, 7 Oncology, University of Wisconsin, Madison, WI,<br />
UNITED STATES OF AMERICA, 8 Oncology, Institute for Translational Oncology<br />
Research, Greenville, SC, UNITED STATES OF AMERICA, 9 Clinical Operations,<br />
Threshold Pharmaceuticals, South San Francisco, CA, UNITED STATES OF<br />
AMERICA, 10 Oncology, Massachusetts General Hospital, Boston, MA, UNITED<br />
STATES OF AMERICA<br />
Background: TH-302 is a hypoxia targeted prodrug with a hypoxia-triggered<br />
2-nitroimidazole component designed to release <strong>the</strong> DNA alkylator,<br />
bromo-isophosphoramide mustard (Br-IPM), when reduced in severe hypoxia. A<br />
randomized Phase 2B study (NCT01144455) was conducted to assess <strong>the</strong> benefit of<br />
G + T to standard dose G as first-line <strong>the</strong>rapy of PAC.<br />
Materials and methods: An open-label multi-center study of two dose levels of<br />
TH-302 (240 mg/m 2 or 340 mg/m 2 ) in combination with G versus G alone<br />
(randomized 1:1:1). G (1000 mg/m 2 ) and T were administered IV over 30-60 minutes<br />
on Days 1, 8 and 15 of a 28-day cycle. Patients on <strong>the</strong> G could crossover after<br />
progression and be randomized to a G + T arm. The primary efficacy endpoint was a<br />
comparison of progression-free survival (PFS) between <strong>the</strong> combination arms and G<br />
alone (80% power to detect 50% improvement in PFS with one-sided alpha of 10%).<br />
Summary PFS outcome has previously been reported; more detailed PFS as well as<br />
<strong>the</strong> initial overall survival (OS) data are presented.<br />
Results: 214 pts were treated; 164 (77%) Stage IV and 50 (23%) Stage IIIB. Median<br />
age 65 (range 29-86); 126 M/88 F; 40% ECOG 0/60% ECOG 1. Receiving 6 or<br />
more cycles: 32% G; 45% G + T240; 55% G + T340. Median PFS was 3.6 mo in G<br />
vs 5.5 mo in G + T240 (p = 0.031) and 6.0 mo in G + T340 (p = 0.008). Poorer<br />
prognostic factors (older age, poorer performance status, reduced albumin) were<br />
associated with larger treatment effect. Median OS was 7.0 mo in G vs 9.0 in G +<br />
T240 and 9.5 mo in G + T340. RECIST best response was 12% in G vs 17% in G +<br />
T240 and 27% in G + T340. CA19-9 decreases were significantly greater G + T340.<br />
A >50% CA19-9 decrease was 52% with G vs 50% with G + T240 and 70% with G<br />
+ T340. AEs leading to discontinuation were: 16% G, 15% G + T240 and 11% G +<br />
T340. Rash (45% in G + T340) and stomatitis (36% in G + T340) were greater in<br />
combination, 4 pts Grade 3 rash. Grd 3/4 thrombocytopenia were 11% G, 39% G<br />
+ T240 and 59% G + T340 and Grd 3/4 neutropenia were 28% G, 56% G + T240<br />
and 59% G + T340.<br />
Conclusions: The combination of G plus TH-302 improved <strong>the</strong> efficacy of G. A<br />
TH-302 dose of 340 mg2 was identified for future studies. Skin and mucosal toxicity<br />
and myelosuppression were <strong>the</strong> most common TH-302 related AEs with no increase<br />
in treatment discontinuation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology 23 (Supplement 9): ix224–ix257, <strong>2012</strong><br />
doi:10.1093/annonc/mds398<br />
667PD A RANDOMISED MULTICENTRE TRIAL OF EPIRUBICIN,<br />
OXALIPLATIN AND CAPECITABINE (EOC) + PANITUMUMAB<br />
IN ADVANCED OESOPHAGO-GASTRIC CANCER (REAL3):<br />
UPDATED RESULTS<br />
T.S. Waddell 1 , J. Reis-Filho 2 , D. Gonzalez-De-Castro 3 , I. Chau 1 ,<br />
A. Wo<strong>the</strong>rspoon 4 , S. Gupta 5 , C. Saffery 1 , G. Middleton 6 , J. Wadsley 7 ,<br />
D. Cunningham 1<br />
1 Department of Medicine, Royal Marsden Hospital, Sutton, UNITED KINGDOM,<br />
2 Department of Molecular Pathology, Institute for Cancer Research, London,<br />
UNITED KINGDOM, 3 Department of Molecular Diagnostics, Institute for Cancer<br />
Research, Sutton, UNITED KINGDOM, 4 Department of Histopathology, Royal<br />
Marsden Hospital, London, UNITED KINGDOM, 5 Statistics Department, Royal<br />
Marsden Hospital, London, UNITED KINGDOM, 6 St. Lukes Cancer Centre,<br />
Royal Surrey County Hospital, Guildford, UNITED KINGDOM, 7 Department of<br />
Oncology, Weston Park Hospital, Sheffield, UNITED KINGDOM<br />
Background: EGFR overexpression occurs in 30-90% of oesophago-gastric<br />
adenocarcinomas (OGA), and correlates with poor prognosis. The REAL-3 trial<br />
evaluated <strong>the</strong> addition of <strong>the</strong> anti-EGFR antibody panitumumab (P) to epirubicin,<br />
oxaliplatin and capecitabine (EOC) in advanced OGA.<br />
Methods: Patients with untreated, metastatic or locally advanced OGA were<br />
randomised to EOC (E 50mg/m 2 , O 130mg/m 2 , C 1250mg/m 2 /day) or mEOC + P (E<br />
50mg/m 2 , O 100mg/m 2 , C 1000mg/m 2 /day, P 9mg/kg). Primary endpoint was overall<br />
survival (OS); secondary endpoints were progression-free survival (PFS), response<br />
rate (RR), toxicity, and biomarker evaluation. Response was evaluated by RECIST<br />
after 4 and 8 cycles.<br />
Results: 553 patients were recruited (EOC 275, mEOC + P 278). Median OS was 11.3<br />
months with EOC compared to 8.8 months with mEOC + P (HR 1.37: 95% CI<br />
1.07-1.76, p = 0.013). Median PFS was 7.4 and 6.0 months respectively (HR 1.22:<br />
95% CI 0.98-1.52, p = 0.068), with RR being 42% compared to 46% (odds ratio 1.16:<br />
95% CI 0.81-1.57, p = 0.467). In <strong>the</strong> mEOC + P arm, OS was significantly improved<br />
in patients with G1-3 rash (77%, n = 209) on treatment compared to those without<br />
(23%, n = 63); median OS 10.2 vs 4.3 months (p < 0.001), with similar significant<br />
improvements seen in RR and PFS. Multivariate analysis demonstrated a negatively<br />
prognostic role for KRAS mutation (HR 2.1: 95% CI 1.10-4.05, p = 0.025) and<br />
PIK3CA mutation (HR 3.2: 95% CI 1.01-10.40, p = 0.048). The above information is<br />
being presented at ASCO <strong>2012</strong>. Updated translational results will be available for<br />
presentation at <strong>ESMO</strong> Congress. This will include correlation of rash with toxicity<br />
endpoints and data relating to EGFR and KRAS amplification in this population.<br />
Disclosure: I. Chau: I have a compensated advisory role with Roche. I have also<br />
received honoraria and research funding from Roche. D. Cunningham: I have<br />
received research funding from Amgen, Roche, Merck-Serono. I have undertaken<br />
uncompensated advisory roles for Amgen and Roche. I have provided an<br />
uncompensated expert testimony for Amgen. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
668PD NON INFERIORITY ANALYSIS OF MULTICENTER PHASE III<br />
COMPARING CISPLATIN/S-1 (CS) WITH CISPLATIN/5-FU<br />
(CF) AS FIRST-LINE THERAPY IN PATIENTS WITH<br />
ADVANCED GASTRIC CANCER (FLAGS): METHODOLOGY<br />
AND RESULTS<br />
J.A. Ajani 1 , W. Rodriguez Pantigoso 2 , G. Bodoky 3 , V. Moiseyenko 4 ,<br />
M. Lichinitser 5 , V.A. Gorbunova 5 , I. Vynnychenko 6 , I. Lang 3 , S. Falcon 1<br />
1 Gastrointestinal Medical Oncology, MD Anderson, Cancer Center, Houston, TX,<br />
UNITED STATES OF AMERICA, 2 Oncologia Y Radioterapia, Instituto de<br />
Oncologia Y RadioterapiaClinica Rica, Clinica Vesa, Lima, PERU, 3 Department of<br />
Oncology, St.László Hospital, Budapest, HUNGARY, 4 Medical Oncology, N.N.<br />
Petrov Research Inst. of Oncology, St. Petersburg, RUSSIAN FEDERATION,<br />
5 Department of Chemo<strong>the</strong>rapy, N.N. Blokhin Russian Cancer Research Center,<br />
Moscow, RUSSIAN FEDERATION, 6 Medical Oncology, Sumy Regional Oncology<br />
Centre, Sumy, UKRAINE<br />
Background: S-1, a new generation of oral fluoropyrimidine, is active against Advanced<br />
Gastric Cancer (AGC). The primary analysis of FLAGS (JCO 2010; vol.28 p 1547-53)<br />
did not show any differences in overall survival (OS) between CS and CF. S-1 has been<br />
registered in Europe, with supportive analyses including non-inferiority (NI) analysis.<br />
Methods: 1,053 (1,029 treated; CS = 521/CF = 508) patients (non Asian 88 + %) with<br />
untreated, advanced gastric (83.1 %) / gastroesophageal (16.5%) adenocarcinoma<br />
were randomized to ei<strong>the</strong>r S-1 (25 mg/m 2 bid, d 1-21)/cisplatin (75 mg/m 2 d1)q28<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
Annals of Oncology<br />
d or 5-FU (1,000 mg/m 2 /d1-5 infusion)/cisplatin (100 mg/m 2 d 1) q 28 d. OS<br />
analyses for non-inferiority, by pre-specified stratifications, were performed.<br />
Results: OS for NI from CS (8.6 months) compared to CF (7.9 months) had a HR =<br />
0.92 (two-sided 95% CI, 0.80-1.05). HR = 1.05 being lower than HR = 1.10 non<br />
inferiority margin, derived from a literature meta-analysis, CS remains statistically<br />
significantly non-inferior (p = 0.0068) to CF. The 74% preserved control effect by CS<br />
is well above <strong>the</strong> suggested 50% by Rothmann et al. (Statist-Med2003; 22:239-264),<br />
based on which <strong>the</strong> 1.10 non-inferiority margin was derived. Moreover, statistically<br />
significant safety advantages for <strong>the</strong> CS arm were observed for <strong>the</strong> rates of G3/4<br />
neutropenia (18.6%, CS; 40.0%, CF), G3/4 febrile neutropenia (1.7%, CS; 6.9%, CF),<br />
G3/4 stomatitis (1.3%, CS; 13.6%, CF), renal adverse events (all grades: 18.8%, CS;<br />
33.5%, CF), and severe hypokalemia (3.6%, CS; 10.8%, CF). On <strong>the</strong> o<strong>the</strong>r safety<br />
items, no significant differences were noted between CS and CF, especially regarding<br />
Head and Foot Syndrome which was anecdotal and limited to grade 1/2.<br />
Treatment-related deaths were significantly reduced with CS compared to CF<br />
(respectively 2.5% and 4.9%).<br />
Conclusion: CS is non-inferior to CF while providing safety advantages for <strong>the</strong><br />
patients and is a treatment alternative in advanced gastric carcinoma.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
669PD MET AS PROGNOSTIC FACTOR AND THERAPEUTIC TARGET<br />
IN PRETREATED HEPATOCELLULAR CARCINOMA (HCC):<br />
FINAL RESULTS OF A RANDOMIZED CONTROLLED PHASE<br />
2 TRIAL (RCT) WITH TIVANTINIB (ARQ 197)<br />
B. Daniele 1 , L. Rimassa 2 , C. Porta 3 , I. Borbath 4 , S. Salvagni 5 , J. van Lae<strong>the</strong>m 6 ,<br />
H. van Vlierberghe 7 , R. von Roemeling 8 , G. Abbadessa 9 , A. Santoro 10<br />
1 Clinical Oncology, G. Rummo Hospital, Benevento, ITALY, 2 Oncology<br />
Hematology, Humanitas Cancer Center, Istituto Clinico Humanitas IRCCS,<br />
Rozzano, ITALY, 3 Oncologia Medica, Ospedale San Matteo, Pavia, ITALY,<br />
4 Gastro-Enterology, Cliniques Universitaires St. Luc, Brussels, BELGIUM,<br />
5 Oncology, Azienda Ospedaliera Parma, Parma, ITALY, 6 Gastroenterology,<br />
Erasme University Hospital, Brussels, BELGIUM, 7 Gastroenterology, Ghent<br />
University Hospital, Ghent, BELGIUM, 8 Clinical Development Oncology, Daiichi<br />
Sankyo Pharma Development, Edison, NJ, UNITED STATES OF AMERICA,<br />
9 Clinical Development, ArQule, Inc, Woburn, MA, UNITED STATES OF<br />
AMERICA, 10 Oncology Hematology, Humanitas Cancer Center, Istituto Clinico<br />
Humanitas, Rozzano, ITALY<br />
Background: Tivantinib (T), a selective, oral inhibitor of MET, <strong>the</strong> hepatocyte<br />
growth factor (HGF) receptor, was tolerated in HCC as mono<strong>the</strong>rapy and with<br />
sorafenib.<br />
Methods: Multi center RCT; key selection criteria: unresectable HCC, 1 prior<br />
systemic <strong>the</strong>rapy, PS
Day 8. A second identical course was administered after a 2-week break. If patients<br />
could not swallow <strong>the</strong> oral S-1 capsule, it was administered in powder form. In<br />
patients who showed an objective response to CRT, at least 2 courses of<br />
chemo<strong>the</strong>rapy with S-1 and cisplatin were administered.<br />
Results: Eighty-three patients participated, 12 with Stage II and 71 with Stage III<br />
LAEC. Seventy-seven patients (92.7%) completed CRT. The most frequent adverse<br />
events were Grades 3 and 4 neutropenia (38.6%); thrombocytopenia (13.3%), and<br />
anemia (9.6%). One patient died on Day 20 from febrile bone marrow aplasia.<br />
Non-hematological adverse events were mild. The most common were Grade 2<br />
nausea (32.5%); esophageal pain and oral mucositis (16.9% each); and renal<br />
dysfunction (10.8%). Adverse events from <strong>the</strong> first course of CRT resolved during <strong>the</strong><br />
2 weeks interval. Complete response rates in patients with Stage II and Stage III<br />
LAEC were 91.7% and 67.6%, respectively. No relapse occurred in patients with Stage<br />
II disease, and relapses occurred in 21 (43.8%) of 48 patients with Stage III disease<br />
who achieved CR. Median PFS for patients with Stage II and III patients was 6.6 and<br />
1.6 years, respectively. Median survival time was 7 years for Stage II and 2.6 years for<br />
Stage III LAEC.<br />
Conclusions: CRT combined with S-1 plus cisplatin showed promising safety and<br />
efficacy, as well as potential to become a standard treatment for LAEC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
672P EFFECTS OF NEOADJUVANT CHEMORADIOTHERAPY ON<br />
POSTOPERATIVE MORBIDITY AND MORTALITY ASSOCIATED<br />
WITH ESOPHAGEAL CANCER<br />
Y. Hamai, J. Hihara, M. Emi, Y. Aoki, M. Okada<br />
Surgical Oncology, Research Institute for Radiation Biology and Medicine,<br />
Hiroshima University, Hiroshima, JAPAN<br />
Background: The results of clinical trials and meta-analyses suggest that neoadjuvant<br />
chemoradio<strong>the</strong>rapy (CRT) followed by esophagectomy confers a survival benefit<br />
upon patients with locally advanced esophageal cancer compared with<br />
esophagectomy alone. However, whe<strong>the</strong>r neoadjuvant CRT increases <strong>the</strong> risk of<br />
postoperative morbidity and mortality remains controversial.<br />
Methods: Data from 206 patients who underwent transthoracic esophagectomy with<br />
gastric tube reconstruction and cervical anastomosis between May 2003 and October<br />
2011 were reviewed. Neoadjuvant CRT comprised 40 Gy of radiation and concurrent<br />
chemo<strong>the</strong>rapy with 5FU plus one of docetaxel, cisplatin or combined docetaxel/<br />
cisplatin. We compared <strong>the</strong> surgical outcomes of 114 patients (55%) who underwent<br />
esophagectomy alone (group 1) and 92 (45%) who received neoadjuvant CRT followed<br />
by esophagectomy (group 2). We also assessed preoperative factors that influence<br />
postoperative major morbidity including anastomotic leak, graft necrosis, multilobar<br />
pneumonia, empyema, chylothorax and recurrent nerve palsy with tracheotomy.<br />
Results: The operative duration, blood loss and overall postoperative morbidity rates<br />
were 403 ± 79 and 421 ± 76 min (p = 0.10), 560 ± 407 and 589 ± 446 mL (p = 0.62)<br />
and 45% and 55% (p = 0.13) in groups 1 and 2, respectively. Rates of anastomotic<br />
leak (8.8 vs. 14.1%; p = 0.23), pneumonia (8.8 vs.13.0%; p = 0.32), recurrent nerve<br />
palsy (14.9 vs.9.8%; p = 0.27) and all o<strong>the</strong>r complications did not significantly differ<br />
between <strong>the</strong> groups. The 30-day mortality rate was 0% in each group and hospital<br />
mortality rates were 0.9 and 1.0% in groups 1 and 2, respectively (p = 0.88).<br />
Univariate analysis of preoperative factors indicated that advanced age, a history of<br />
cardiovascular disease, a high serum creatinine and advanced tumor stage were<br />
significantly associated with postoperative major morbidity, whereas neoadjuvant<br />
CRT was unrelated to <strong>the</strong> incidence of major morbidity. Multivariable analysis<br />
revealed cardiovascular disease (Odds ratio, 2.46; 95%CI, 1.27 - 4.78; p = 0.008) and<br />
advanced tumor stage (Odds ratio, 2.24; 95%CI, 1.15 - 4.35; p = 0.017) as<br />
independent covariates for major morbidity.<br />
Conclusion: Neoadjuvant CRT is safe and does not increase <strong>the</strong> incidence of<br />
postoperative morbidity and mortality compared with esophagectomy alone.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
673P INTERSTITIAL PULMONARY DISORDER IN PATIENTS WITH<br />
ESOPHAGEAL SQUAMOUS CELL CARCINOMA TREATED<br />
WITH DOCETAXEL AFTER CHEMORADIOTHERAPY<br />
Y. Ezoe 1 , M. Muto 2 , K. Ueda 2 , Y. Ozaki 2 , I. Aoyama 2 , T. Horimatsu 2 , S. Morita 2 ,<br />
S. Miyamoto 2 , T. Chiba 2<br />
1 Department of Multidisciplinary Cancer Treatment, Kyoto University, Kyoto,<br />
JAPAN, 2 Department of Gastroenterology and Hepatology, Kyoto University,<br />
Kyoto, JAPAN<br />
Background and aims: Docetaxel (DOC) is a key drug in second-line chemo<strong>the</strong>rapy<br />
after <strong>the</strong> failure of chemoradio<strong>the</strong>rapy (CRT) for esophageal cancer. Interstitial<br />
pulmonary disorder (IPD) is one of <strong>the</strong> fatal adverse effects of DOC, but its<br />
frequency and risk factors have not been clarified. The aim of this study was to<br />
determine <strong>the</strong> frequency of and risk factors for IPD in patients with esophageal<br />
squamous cell carcinoma (ESCC), who were treated with DOC after <strong>the</strong> failure of<br />
CRT.<br />
Annals of Oncology<br />
Patients and methods: We retrospectively reviewed <strong>the</strong> clinical data for 115 patients<br />
with ESCC who had been treated with CRT at Kyoto University Hospital from April<br />
2007 to March 2011. Thirty-seven of <strong>the</strong>se patients had been treated with DOC after<br />
CRT (D group) and 78 had not been treated with DOC (non-D group). We<br />
compared <strong>the</strong> incidence of IPD in <strong>the</strong> two groups and also identified <strong>the</strong> risk factors<br />
for IPD.<br />
Results: The incidence of grade 3/4 IPD in <strong>the</strong> D and non-D groups was 10.8%<br />
(4/37) and 1.3% (1/78), respectively (P = 0.035). A median of 4 cycles of DOC<br />
was administered (range, 2–7). The median total radiation dose was 60 Gy. The<br />
mean value for V20 (% total lung volume receiving ≥20Gy) in patients with<br />
grade 3/4 IPD was greater than that in patients without IPD (20.0% vs 12.3%,<br />
respectively; P = 0.012). The V20 value was greater than 20% in 80% (4/5) of<br />
patients with grade 3/4 IPD. The mean lung dose (MLD) in patients with grade<br />
3/4 IPD was also greater than that in patients without IPD (11.1 Gy vs 6.6 Gy,<br />
respectively; P < 0.01).<br />
Conclusion: The incidence of grade 3/4 IPD was 10.8% in patients who received<br />
DOC after CRT. IPD must be considered when DOC is administered to patients who<br />
have already received radio<strong>the</strong>rapy with high V20 and MLD in <strong>the</strong>ir first-line CRT.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
674P PROGNOSIS IMPACT OF POSTOPERATIVE RADIATION IN<br />
PATIENTS WITH RADICAL ESOPHAGECTOMY AND<br />
PATHOLOGIC LYMPH NODES POSITIVE ESOPHAGEAL<br />
CANCER<br />
Y. Xu 1 ,W.Mao 1 , X.J. Sun 1 , Y.D. Zheng 1 , Y. Jiang 2 , J. Liu 2<br />
1 Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou,<br />
CHINA, 2 Department of Surgery, Zhejiang Cancer Hospital, Hangzhou, CHINA<br />
Purpose: Though postoperative radiation for esophageal cancer is offered in selected<br />
cases, <strong>the</strong>re is conflicting evidence as to whe<strong>the</strong>r it improves overall survival (OS).<br />
We performed a retrospective investigation to analyze <strong>the</strong> prognosis impact of<br />
adjuvant radiation in a large cohort of patients.<br />
Methods and materials: From 2002 to 2008, 545 patients underwent radical<br />
esophagectomy (R0) with or without postoperative radiation were eligible for<br />
retrospectively analysis. Patients were grouped to surgery only (n = 346) and surgery<br />
plus postoperative radiation <strong>the</strong>rapy (PORT) (n = 199). Radiation dose was 50 Gy in<br />
25 fractions. Kaplan-Meier and Cox regression analysis were used to compare OS.<br />
Results: The use of PORT was associated with significantly improved OS (p =0.006).<br />
The median OS was 31 months in <strong>the</strong> group receiving PORT and 21 months in <strong>the</strong><br />
group undergoing surgery alone. The addition of PORT improved OS at 3 years from<br />
38.3 to 45.8% compared with surgery alone. For American Joint Committee on<br />
Cancer (AJCC) stage III esophageal cancer (T1-2N2M0, T3N1-2M0, T4N1-3M0),<br />
<strong>the</strong>re was significant improvement on OS (p < 0.001) in PORT group, for not only<br />
metastatic lymph-node ratio 0.25 (p = 0.013). However, for stages IIB disease (T1-2N1M0) <strong>the</strong>re was no<br />
significant differences.<br />
Conclusions: This large population-based analysis supports <strong>the</strong> use of PORT for<br />
pathologic lymph nodes positive stage III esophageal cancer. Our results suggest<br />
that a subset of such patients may benefit from aggressive local <strong>the</strong>rapy. As a<br />
retrospective study, our results do not have <strong>the</strong> same strength as a prospective<br />
study, however, it provides a basis for <strong>the</strong> design of future randomized,<br />
prospective clinical trials.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
675P A CLINICO-MOLECULAR RISK STRATIFICATION MODEL FOR<br />
RESECTED GASTRIC CANCER: PROGNOSTIC IMPACT OF<br />
HER2, FHIT AND APC EXPRESSION STATUS<br />
E. Bria 1 , G. De Manzoni 2 , S. Beghelli 3 , A. Tomezzoli 4 , S. Barbi 4 , M. Frizziero 1 ,<br />
I. Sperduti 5 , S. Bersani 4 , G. Tortora 1 , A. Scarpa 4<br />
1 Medical Oncology, Azienda Ospedaliera Universitaria Integrata Verona-”Borgo<br />
Roma”, Verona, ITALY, 2 1st Division of General Surgery, University of Verona,<br />
Verona, ITALY, 3 Pathology, ARC-NET Applied Research on Cancer Center,<br />
Verona, ITALY, 4 Pathology and Diagnostics, University of Verona, Verona, ITALY,<br />
5 Biostatistics, Regina Elena Institute, Roma, ITALY<br />
Purpose: In order to complement <strong>the</strong> prognostic power of clinical parameters for<br />
resected gastric cancer, a stratification model to predict individual patient risk was<br />
developed taking into account 11 molecular factors.<br />
Methods: Clinicopathological and molecular data (expression of Cdx2, Apc,<br />
ß-Catenin, E-Cadherin, Fhit, p53, Her2; HER2 and TOPO2A gene copy number;<br />
PIK3CA mutations; microsatellite instability-MSI) were correlated to cancer-specific/<br />
overall survival (CSS/OS) using a Cox model. A logistic equation including regression<br />
analysis coefficients was constructed to estimate individual patients’ probability (IPP)<br />
of death. Internal cross-validation (100 simulations, 80% of <strong>the</strong> dataset) was<br />
accomplished. Ratios from <strong>the</strong> multivariate model served to derive a prognostic<br />
continuous score to identify risk classes.<br />
ix226 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Results: Two-hundred-eight patients were studied (median follow-up 20 months). At<br />
multivariate analysis, sex (HR 1.53, p = 0.04), stage (HR 5.40, p < 0.0001), margins<br />
(HR 2.69, p < 0.0001), localization (HR 1.64, p = 0.008), resected nodes (HR 1.55, p =<br />
0.02), APC (HR 1.91, p = 0.001), FHIT (HR 1.54, p = 0.05) and HER-2 (HR 1.92, p =<br />
0.08), were independent predictors for CSS; <strong>the</strong> same factors (plus age and except<br />
Fhit) predicted OS. Multivariate model predicted IPP with high prognostic accuracy<br />
(0.87 for CSS; 0.91 for OS). A 2-class risk stratification model, developed on <strong>the</strong> basis<br />
of <strong>the</strong> ROC generated cut-off prognostic score (AUC 0.87; Sensitivity 85.3%,<br />
Specificity 78.9%), significantly separated low and high risk patients for CSS (16.4%<br />
and 82.5%, p < 0.0001) and OS (15.6% and 79.7%, p < 0.0001), with a prognostic<br />
performance of 0.82 for CSS and 0.81 for OS. A fur<strong>the</strong>r 3-class-model differentiated<br />
low, intermediate, and high-risk patients for CSS (7.3%, 37.3%, and 89.7%, p <<br />
0.0001) and OS (0%, 23.3%, and 84.8%, p < 0.0001).<br />
Conclusions: The concurrent evaluation of <strong>the</strong> expression of Apc, Fhit, Her2 proteins<br />
and clinicalpathological parameters (Stage, Resected Nodes, Margins, Location, Sex)<br />
may powerfully discriminate <strong>the</strong> prognosis of resected gastric cancer patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
676P THE PROGNOSTIC VALUE OF TUMOR-INFILTRATING<br />
NEUTROPHILS IN GASTRIC ADENOCARCINOMA AFTER<br />
RESECTION<br />
J. Xia 1 , J. Zhao 1 ,S.So 2 ,K.Pan 1 ,W.Wang 3 ,X.Li 4 , J. Chen 1 , D. Wang 1<br />
1 Bio<strong>the</strong>rapy, Cancer Center, Sun Yat-sen University, Guangzhou, CHINA,<br />
2 Medical Corporation Zuiseikai, Tokyo, JAPAN, 3 Gastric and Pancreatic Surgery,<br />
Cancer Center, Sun Yat-sen University, Guangzhou, CHINA, 4 Thoracic<br />
Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, CHINA<br />
Background: Several pieces of evidence indicate that tumor-infiltrating neutrophils<br />
(TINs) are correlated to tumor progression. In <strong>the</strong> current study, we explore <strong>the</strong><br />
relationship between TINs and clinicopathological features of gastric adenocarcinoma<br />
patients. Fur<strong>the</strong>rmore, we investigated <strong>the</strong> prognostic value of TINs.<br />
Patients and methods: The study was comprised of two groups, training group (115<br />
patients) and test group (97 patients). Biomarkers (intratumoral CD15+ neutrophils)<br />
were assessed by immunohistochemistry. The relationship between clinicopathological<br />
features and patient outcome were evaluated using Cox regression and Kaplan-Meier<br />
analysis.<br />
Results: Immunohistochemical detection showed that <strong>the</strong> tumor-infiltrating<br />
neutrophils (TINs) in <strong>the</strong> training group ranged from 0.00-115.70 cells/<br />
high-power microscopic field (HPF) and <strong>the</strong> median number was 21.60 cells/<br />
HPF. Based on <strong>the</strong> median number, <strong>the</strong> patients were divided into high and low<br />
TINs groups. Chi-square test analysis revealed that <strong>the</strong> density of CD15+ TINs<br />
was positively associated with lymph node metastasis (p = 0.024), distance<br />
metastasis (p = 0.004) and UICC (International Union Against Cancer) staging<br />
(p = 0.028). Kaplan-Meier analysis showed that patients with a lower density of<br />
TINs had a better prognosis than patients with a higher density of TINs (p =<br />
0.002). Multivariate Cox’s analysis showed that <strong>the</strong> density of CD15+ TINs was<br />
an independent prognostic factor for overall survival of gastric adenocarcinoma<br />
patients. Using ano<strong>the</strong>r 97 patients as a test group and basing on <strong>the</strong> median<br />
number of TINs (21.60 cells/HPF) coming from <strong>the</strong> training group,<br />
Kaplan-Meier analysis also showed that patients with a lower density of TINs<br />
had a better prognosis than patients with a higher density of TINs (p = 0.032).<br />
The results verify that <strong>the</strong> number of CD15+ TINs can predict <strong>the</strong> survival of<br />
gastric adenocarcinoma surgical patients.<br />
Conclusions: The presence of CD15+ TINs is an independent and unfavorable factor<br />
in <strong>the</strong> prognosis of gastric adenocarcinoma patients. Targeting CD15+ TINs may be<br />
a potential intervenient <strong>the</strong>rapy in <strong>the</strong> future.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
677P SURVIVAL IMPACT OF HER2 STATUS IN PATIENTS WITH<br />
GASTRIC CANCER: A MULTICENTER LARGE-SCALE STUDY<br />
IN JAPAN<br />
Y. Kurokawa 1 , N. Matsuura 2 , Y. Kimura 3 , R. Kawabata 4 , S. Adachi 5 , J. Fujita 6 ,<br />
K. Nishikawa 7 , S. Takiguchi 1 , M. Mori 1 , Y. Doki 1<br />
1 Gastroenterological Surgery, Osaka University, Osaka, JAPAN, 2 Molecular<br />
Pathology, Osaka University, Osaka, JAPAN, 3 Surgery, NTT West Osaka<br />
Hospital, Osaka, JAPAN, 4 Surgery, Sakai City Hospital, Osaka, JAPAN,<br />
5 Surgery, Ikeda Municipal Hospital, Osaka, JAPAN, 6 Surgery, Toyonaka<br />
Municipal Hospital, Osaka, JAPAN, 7 Surgery, Osaka General Medical Center,<br />
Osaka, JAPAN<br />
Background: Although it has been proven in <strong>the</strong> ToGA study that HER2 expression is<br />
a predictive factor of trastuzumab treatment, <strong>the</strong> relation between HER2 status and<br />
prognosis in gastric cancer patients was still unknown. A multicenter large-scale study<br />
was conducted to evaluate <strong>the</strong> prognostic value of HER2 status in gastric cancer.<br />
Methods: A total of 1152 cases with gastric cancer which was surgically resected<br />
between 2000 and 2006 were registered to this study. The neoadjuvant treatment<br />
cases were excluded. Tumors were centrally tested for HER2 status with<br />
immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH). HER2<br />
expressions of resected tissues were evaluated according to <strong>the</strong> same criteria with <strong>the</strong><br />
ToGA study. The relation between HER2 expression and clinicopathological factors<br />
was examined by Fisher’s exact test. The hazard ratio (HR) for death in<br />
HER2-positive cases was estimated, and overall survivals (OS) were compared<br />
between HER2-positive and HER2-negative cases using log-rank test.<br />
Results: The number of cases with IHC 0 / 1+ / 2+ / 3+ was 662 / 208 / 120 / 162, and<br />
eighteen of IHC 2+ cases showed FISH-positive. In total, <strong>the</strong> proportion of<br />
HER2-positive was 15.6% (180/1152). HER2-positive cases were more frequent in<br />
differentiated type tumors (P < 0.001), in upper body tumors (P = 0.065), and in T3-4b<br />
tumors (P = 0.074). OS in HER2-positive cases was clearly worse than in HER2-negative<br />
cases (HR 1.55 (95%CI, 1.21-1.97); P < 0.001). According to <strong>the</strong> tumor stage<br />
classification, <strong>the</strong> HR (95%CI) in HER2-positive cases and P values were as follows;<br />
Stage I: 2.05 (1.14-3.68), P = 0.015; Stage II: 1.87 (1.001-3.47), P = 0.046; Stage III: 1.46<br />
(0.95-2.27), P = 0.085; Stage IV: 1.41 (0.93-2.14), P = 0.101. There was no subgroup<br />
which showed interaction between HER2 status and any background factors. The Cox<br />
multivariate analysis with nine background factors revealed that HER2 expression was<br />
an independent prognostic factor (HR 1.55 (95%CI, 1.19-2.02); P = 0.001).<br />
Conclusions: HER2 expression is an independent factor of poor prognosis in<br />
resected gastric cancer, showing trends of higher HR in earlier stage.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
678P CLINICAL SIGNIFICANCE OF HER2 OVEREXPRESSION IN<br />
GASTRIC AND GASTROESOPHAGEAL JUNCTION CANCERS<br />
M. Baykara 1 , M. Benekli 2 , O. Ekinci 2 , U. Coskun 2 , E.P. Eser 2 , O. Polat 3 ,<br />
U. Demirci 4 , A. Uner 2 , A. Ozet 2 , S. Buyukberber 2<br />
1 Medical Oncology, Gazi University Medical Faculty, Ankara, TURKEY, 2 Medical<br />
Oncology, Gazi University Faculty of Medicine, Ankara, TURKEY, 3 Internal<br />
Medicine, Gazi University Medical Faculty, Ankara, TURKEY, 4 Department of<br />
Medical Oncology, Ataturk Education and Research Hospital, Ankara, TURKEY<br />
Objectives: In this study, we investigated <strong>the</strong> rate of HER2 overexpression in gastric<br />
and gastroesophageal junction cancers (GC, GEJC), and <strong>the</strong> relationship with HER2<br />
expression and clinical, pathological parameters and prognosis.<br />
Materials and methods: Surgery or biopsy specimen of 285 (202 male, 83 female)<br />
patients with GC or GEJC, <strong>the</strong> presence of HER2 overexpression by<br />
immunohistochemistry (IHC) and silver insitu hybridization (SISH) were evaluated.<br />
The relationship between HER2 positivity and tumor size (TS), histopathology (H),<br />
grade (G), serosal invasion (SI), lenfovascular invasion (LVI), perineural invasion<br />
(PNI), Lauren and Borrmann type, tumor location (TL), TNM stage, local recurrence<br />
(LR) and metastasis (M) and survival (OS) were investigated.<br />
Results: HER2 IHC scores were; 194 (68.1%) IHC 0, 34 (11.9%) IHC +1, 30 (10.5%)<br />
IHC +2, 27 (9.5%) IHC +3. Twelve of 30 (4.2%) patients with IHC +2, SISH positive,<br />
and 18 patients SISH negative. The number of patients evaluated with IHC +3 or<br />
IHC +2 and SISH positive, HER2 positivity was 13.7%. There was no relationship<br />
between HER2 positivity and <strong>the</strong> age, gender, TNM stage, TS, TL, LR, M, LVI, PNI,<br />
and Borrmann type. HER2 positivity was higher in intestinal type tumors than in<br />
diffuse type (16.7% vs 6.9%, p = 0.075). HER2 positivity was significantly higher in<br />
well-moderately diferantiated tumors than poorly diferantiated tumors (24.3% and<br />
23.4% vs 7.3%, p = 0.001). HER2 positivity was higher in adenocarcinomas than <strong>the</strong><br />
o<strong>the</strong>r histologic subtypes; 19.4% of adenocarcinomas, 4.2% of signet-ring cell<br />
carcinomas were HER2-positive (p = 0.013). HER2 pozitivity was no significant effect<br />
on median OS (22.7 vs 18.4 months, p = 0.81). But in <strong>the</strong> early stage median OS of<br />
HER2-positive patients was shorter than HER2-negative patients (54.9 months vs not<br />
reach, p = 0.022). However patients with advaced stage HER2-positive and –negative<br />
<strong>the</strong>re was no significant difference between <strong>the</strong> median OS rates.<br />
Conclusion: HER2 positivity is associated with <strong>the</strong> degree of tumor differantiation<br />
and histopathology in GC and GEJC. Patients with early-stage, HER2 positivity is<br />
related to poor prognosis.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
679P IDENTIFICATION OF RISK FACTORS OF RELAPSE AFTER<br />
CURATIVE SURGICAL RESECTION IN STAGE I GASTRIC<br />
CANCER<br />
J. Park 1 , M.H. Ryu 2 , H.J. Kim 3 ,B.Ryoo 2 , I. Park 4 , Y.S. Park 5 , S.T. Oh 6 ,<br />
J.H. Yook 6 , B.S. Kim 6 , Y. Kang 2<br />
1 Oncology, Internal Medicine, Asan Medical Center, Seoul, KOREA, 2 Division of<br />
Oncology, Dept of Internal Medicine, Asan Medical Center, Seoul, KOREA,<br />
3 Clinical Epidemiology and Biostatistics, Asan Medical Center, Seoul, KOREA,<br />
4 Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul,<br />
KOREA, 5 Department of Pathology, Asan Medical Center, Seoul, KOREA,<br />
6 Department of Surgery, Asan Medical Center, Seoul, KOREA<br />
Background: The <strong>the</strong>rapeutic benefit of adjuvant chemo<strong>the</strong>rapy is well established in<br />
stage (by AJCC 6th edition) II or III gastric cancer (GC). However, it has not been<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds398 | ix227
proven in stage I GC. The aim of this study was to identify risk factors of relapse in<br />
stage I GC, and to find out patients at high risk of relapse.<br />
Methods: We retrospectively reviewed <strong>the</strong> medical records of 2783 patients with<br />
pathologically confirmed stage I GC who underwent curative surgical resection<br />
alone in Asan Medical Center between 2003 and 2007. Clinicopathologic<br />
parameters of exploration included: age, sex, histologic differentiation, WHO<br />
classification, Lauren classification, size, location, multiplicity, stage,<br />
lymphovascular or perineural invasion, preoperative serum levels of tumor<br />
markers (CEA, CA 19-9, CA 72-4), and type of surgery. Then, we performed<br />
univariate and multivariate analysis to correlate each parameter with relapse-free<br />
survival (RFS) and overall survival (OS).<br />
Results: With a median follow-up of 54 months (range, 0-60), 213 (7.7 %) patients<br />
experienced recurrence or death, and 5-year RFS and OS was 90% and 94%,<br />
respectively. In univariate analysis, RFS was significantly related with age, sex,<br />
differentiation, WHO and Lauren classification, size, stage, lymphovascular invasion,<br />
perineural invasion, and serum levels of CEA and CA 19-9. The multiplicity of<br />
tumor instead of size was significantly related with OS. In multivariate analysis, 6<br />
factors (age over 65 years, male, stage Ib, lymphovascular invasion, perineural<br />
invasion, and elevated level of CEA) remained independent poor prognostic factors<br />
for RFS (p
Annals of Oncology<br />
2; 10 cases and grade 3; 14 cases, respectively. Surgery related morbidity was 13.0%<br />
and R0 resection rate was 98.1% (53/54). Grade 3/4 adverse events were acceptable<br />
such as leucopenia (8.9%), neutropenia (17.9%), febrile neutropenia (7.1%), anorexia<br />
(10.7%), and diarrhea (8.9%). There was no treatment related death and no major<br />
surgical complications except for one.<br />
Conclusions: Neoadjuvant DCS chemo<strong>the</strong>rapy demonstrated a high histological<br />
response rate, acceptable feasibility and a sufficient R0 resection rate. This divided<br />
DCS regimen is attractive as NAC for pts with locally AGC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
683P POSTOPERATIVE RADIOCHEMOTHERAPY WITH<br />
CAPECITABINE FOR GASTRIC ADENOCARCINOMA<br />
M. Skoblar Vidmar<br />
Radio<strong>the</strong>rapy, Institute of Oncology, Ljubljana, SLOVENIA<br />
Background: Complete removal of malignancy represents <strong>the</strong> treatment of choice in<br />
nonmetastatic gastric cancer. The Intergroup Study INT-0116 reported a significant<br />
improvment in survival with adjuvant radiochemo<strong>the</strong>rapy. In Slovenia, <strong>the</strong> program<br />
of adjuvant radiochemo<strong>the</strong>rapy with 5-fluorouracil and leucovorin was introduced<br />
into clinical practice in 2001. Capecitabine is an oral 5-FU prodrug and we assume<br />
that it can replace standard chemo<strong>the</strong>rapy.<br />
Patients and methods: During 2006-2010, 101 patients with <strong>the</strong> mean age of 59<br />
years, were treated for gastric adenocarcinoma, stage Ib-IIIC, with post-operative<br />
radiochemo<strong>the</strong>rapy with capecitabine. Radical (R0) and non-radical (R1) resection of<br />
<strong>the</strong> tumor was performed in 97 and 4 patients, respectively. Treatment was started<br />
with <strong>the</strong> first cycle of chemo<strong>the</strong>rapy with oral capecitabine (1250 mg m 2 twice daily<br />
on day 1-14), radio<strong>the</strong>rapy with <strong>the</strong> total dose of 45 Gy was added after 3 weeks.<br />
Patients were irradiated on linear accelerator with 15MV photon beams for five days<br />
per week, at a daily dose of 1.8 Gy. During radio<strong>the</strong>rapy patients received<br />
capecitabine in lower dose (825 mg/m 2 twice daily, 7 days per week), but one dose<br />
was taken 1 hour before irradiation and <strong>the</strong> second twelve hours after. Three cycles<br />
of chemo<strong>the</strong>rapy were added after <strong>the</strong> end of radio<strong>the</strong>rapy in 3-week intervals.<br />
Results: Postoperative ChT started 2.6–11.3 weeks after surgery (median 6 weeks).<br />
The treatment was completed according to <strong>the</strong> protocol in 59 patients. No death<br />
occurred due to <strong>the</strong> <strong>the</strong>rapy. Stomatitis, dysphagia, nausea and vomiting, diarrhea,<br />
hand foot syndrome, stenocardia and alopecia of grade three occurred in 1, 0, 5, 2, 9,<br />
4 and 3 patients, respectively. Some 56 patients lost weight as measured with respect<br />
to <strong>the</strong> weight <strong>the</strong>y had at <strong>the</strong> beginning of treatment. The maximum body weight<br />
loss was 18.9% (mean 6.2%). The median follow-up time of 66 survivors was 4 years<br />
(range 2.5-5.7 years). At 5 years, locoregional control (LRC), disease-free survival<br />
(DFS), disease-specific survival (DSS) and overall survival (OS) rates were 95%, 69%,<br />
74%, and 63%, respectively.<br />
Conclusion: In operable gastric carcinoma, postoperative radiochemo<strong>the</strong>rapy with<br />
capecitabine is feasible and its toxicity is low.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
684P RESULTS OF TREATMENT OF LOCALLY ADVANCED GASTRIC<br />
CANCER IN THE ELDERLY PATIENTS<br />
D. Egamberdiev, M. Djuraev, S. Khudayorov, O. Nematov, A. Babaev, H. Tuyev<br />
Abdominal Oncology, National Cancer Center of Uzbekistan, Tashkent,<br />
UZBEKISTAN<br />
Background: Although <strong>the</strong> incidence of gastric cancer has declined in <strong>the</strong> general<br />
population, it is <strong>the</strong> second most frequent cancer in Uzbekistan with its incidence in<br />
<strong>the</strong> elderly increasing as a result of increased life expectancy. This present study tried<br />
to determine <strong>the</strong> role of age on outcomes of surgical treatment for gastric cancer in<br />
Uzbek population.<br />
Methods: The study reviewed 288 patients who underwent gasterectomy for locally<br />
advanced gastric cancer. The clinicopathological features of elderly patients (≥75<br />
years, n = 167) and younger patients (
Conclusions: Longer OS to FOLFOX was associated with low levels of both MMSET<br />
and 53BP1, while longer OS to second-line docetaxel was associated with high levels<br />
of both MMSET and BRCA1. MMSET, toge<strong>the</strong>r with 53BP1 or BRCA1 can be useful<br />
for customizing chemo<strong>the</strong>rapy in advanced gastric cancer p.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
687P UPDATED EFFICACY, BIOMARKER, AND<br />
EXPOSURE-RESPONSE DATA FROM A PHASE 2 STUDY OF<br />
RILOTUMUMAB (R) PLUS EPIRUBICIN, CISPLATIN, AND<br />
CAPECITABINE (ECX) IN GASTRIC (G) OR<br />
ESOPHAGOGASTRIC JUNCTION (EGJ) CANCER<br />
I. Davidenko 1 , T. Iveson 2 , R.C. Donehower 3 , S. Tjulandin 4 , A. Deptala 5 , Y. Jiang 6 ,<br />
M. Zhu 7 , K.S. Oliner 8 , S. Dubey 9 , E. Loh 9<br />
1 Chemo<strong>the</strong>rapy, Clinical Oncology Dispensary #1, Krasnodar, RUSSIAN<br />
FEDERATION, 2 Medical Oncology, Southampton General Hospital,<br />
Southampton, UNITED KINGDOM, 3 Cancer Center, Johns Hopkins, Baltimore,<br />
MD, UNITED STATES OF AMERICA, 4 Clinical Pharmacology and Chemo<strong>the</strong>rapy,<br />
Russian Cancer Research Center, Moscow, Moscow, RUSSIAN FEDERATION,<br />
5 Department of Oncology and Hematology, Central Clinical Hospital<br />
MSWIA-WarsawMedical University of Warsaw, Warsaw, POLAND, 6 Global<br />
Biostatistical Science, Amgen Inc., Thousand Oaks, CA, UNITED STATES OF<br />
AMERICA, 7 Pharmacokinetics & Drug Metabolism, Amgen Inc., Thousand Oaks,<br />
CA, UNITED STATES OF AMERICA, 8 Molecular Sciences - Ivd, Amgen Inc.,<br />
Thousand Oaks, CA, UNITED STATES OF AMERICA, 9 Oncology, Amgen Inc.,<br />
South San Francisco, CA, UNITED STATES OF AMERICA<br />
Background: R (AMG 102) is an investigational, fully human monoclonal antibody<br />
to hepatocyte growth factor/scatter factor, <strong>the</strong> MET receptor ligand. Safety and<br />
efficacy of a placebo-controlled, double-blind, randomized phase 2 study of R + ECX<br />
in G/EGJ cancer from a 12.5-month (mo) follow up were previously reported (Iveson<br />
et al, Eur J Cancer. 2011; 47(suppl 1):S443. abstract 6.504). Updated data from a<br />
21.7-mo follow up are presented.<br />
Methods: Eligibility included unresectable, locally advanced or metastatic G/EGJ<br />
adenocarcinoma; ECOG PS ≤1; and no prior systemic <strong>the</strong>rapy for this disease.<br />
Patients (pts) were randomized 1:1:1 to ECX (50 mg/m 2 IV day 1, 60 mg/m 2 IV day<br />
1, 625 mg/m 2 BID orally days 1–21, respectively) + R 15 mg/kg (Arm A); R 7.5 mg/<br />
kg (Arm B); or placebo (Arm C) IV day 1 every 3 weeks. Overall survival (OS) and<br />
progression-free survival (PFS) were evaluated. MET protein was measured in<br />
archival tumor samples by IHC. R serum concentrations for all pts were measured.<br />
Individual R steady-state C minss were estimated with a population PK model.<br />
Results: 121 pts (Arms A/B/C: 40/42/39) were randomized Oct 2009 to June 2010.<br />
See table for data (Jan 16, <strong>2012</strong> cutoff).<br />
Conclusions: Within <strong>the</strong> context of a small, randomized phase 2 study, R + ECX<br />
improved outcomes in G/EGJ cancer pts. The treatment effect was strongest in pts<br />
with high MET tumors and high R exposure. Consistent with previously reported<br />
data, <strong>the</strong>se results show continued separation of Arm A + B vs C beyond 16 mo. A<br />
planned phase 3 study will test <strong>the</strong> safety and efficacy of R + ECX in MET-positive<br />
G/EGJ cancer.<br />
Disclosure: T. Iveson: Dr. Iveson received research funding and travel payment<br />
from Amgen Inc. Y. Jiang: Dr. Jiang is an employee of and owns stock in Amgen<br />
Inc. M. Zhu: Dr. Zhu is an employee of and owns stock in Amgen Inc. K.S.<br />
Oliner: Dr. Oliner is an employee of and owns stock in Amgen Inc. S. Dubey: Dr.<br />
Dubey is an employee of and owns stock in Amgen Inc. E. Loh: Dr. Loh is an<br />
employee of and owns stock in Amgen Inc. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
Table: 687P<br />
688P A RANDOMISED PHASE III CLINICAL TRIAL OF COMBINED<br />
THERAPY WITH CPT-11/CDDP VERSUS CPT-11 ALONE IN<br />
PATIENTS WITH ADVANCED OR RECURRENT GASTRIC<br />
CANCER RESISTANT TO S-1(TRICS STUDY): SAFETY<br />
ANALYSIS<br />
H. Hasegawa 1 , K. Nishikawa 2 , H. Inagaki 3 , S. Akamaru 4 , S. Tokunaga 5 ,<br />
M. Takagi 6 , S. Tamura 7 , S. Morita 8 , J. Sakamoto 9 , T. Tsujinaka 10<br />
1 Gastroenterology, National Hospital Organization Osaka National Hospital,<br />
Osaka, JAPAN, 2 Surgery, Osaka General Medical Center, Osaka, JAPAN,<br />
3 Surgery, GifuCentral Hospital, Gifu, JAPAN, 4 Surgery, Osaka Kose-Nenkin<br />
Hospital, Osaka, JAPAN, 5 Clinical Oncology, Osaka city General Hospital, Osaka,<br />
JAPAN, 6 Surgery, Shizuoka General Hospital, Shizuoka, JAPAN, 7 Surgery,<br />
Kansai Rosai Hospital, Amagasaki, JAPAN, 8 Biostatistics and Epidemiology,<br />
Yokohama City University Medical Center, Yokohama, JAPAN, 9 Social Life<br />
Science, Nagoya Universty, Nagoya, JAPAN, 10 Surgery, National Hospital<br />
Organization Osaka National Hospital, Osaka, JAPAN<br />
Background: There has been no established regimen as <strong>the</strong> second-line treatment for<br />
advanced gastric cancer (AGC), though CPT-11 showed survival benefit over BSC.<br />
Combination of CPT-11 with CDDP is one of <strong>the</strong> promising regimens as <strong>the</strong><br />
second-line chemo<strong>the</strong>rapy after S-1 mono-<strong>the</strong>rapy.<br />
Methods: This study was designed as a randomized, multicenter phase III study<br />
comparing CPT-11 + CDDP vs. CPT-11 alone in patients with advanced or recurrent<br />
gastric cancer resistant to S-1 mono-<strong>the</strong>rapy or prior adjuvant chemo<strong>the</strong>rapy using<br />
S-1. Eligibility criteria include: histologically confirmed gastric adenocarcinoma,<br />
showing PD after receiving S-1 mono-<strong>the</strong>rapy or recurrence within 6 months after or<br />
during S-1 adjuvant chemo<strong>the</strong>rapy, age over 20 years old, PS:0-2, adequate organ<br />
functions and written informed consent. Patients received ei<strong>the</strong>r CPT-11 150 mg/<br />
m 2 day1 / q 2W (Arm A) or CPT-11 60mg/m 2 day1 +CDDP 30mg/m 2 day1/ q 2W<br />
(Arm B). Stratification was made according to PS, advanced or recurrence cases,<br />
institution and presence or absence of measurable target lesions. Primary endpoint is<br />
overall survival. Secondary endpoints are time to treatment failure (TTF), response<br />
rate, and safety (frequency and severity of adverse events). Calculated sample size<br />
was 160 assuming 74 events with alpha error 0.05 and beta error 0.2 to detect<br />
differences in survival. Planned number was 200 considering 40 for ineligibility or<br />
dropout.<br />
Results: 168 patients were enrolled between 2007 and 2011. Arm A (n = 84) and<br />
Arm B (n = 84) were well balanced for baseline factors.Median age was 67 years old<br />
and median number of treatment courses was 5 (range: 1-39).Relative dose intensity<br />
(RDI) in Arm A was 97.5% and RDI in Arm B was 98.9%. The most common grade<br />
3/4 toxicities in Arm A vs. Arm B were, neutropenia; 26.2 vs. 15.5%, anemia; 44.0 vs.<br />
27.3%, diarrhea; 0 vs. 11.9%, anorexia; 4.8 vs. 6.0%, nausea and vomiting; 3.5 vs.<br />
6.0%. 17.9% in Arm A and 10.7% in Arm B required dose modification for <strong>the</strong>se<br />
toxicities.<br />
Conclusions: In this initial safety analysis, <strong>the</strong> incidence and severity of adverse<br />
events in both Arms were acceptable as second-line treatment. Final efficacy results<br />
will be performed at <strong>the</strong> end of this year.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Median OS (80% CI), mo OS HR (95% CI) Median PFS (80% CI), mo PFS HR (95% CI)<br />
All pts Arm A + B n = 82 10.6 (9.5–12.0) 5.7 (5.1–6.9)<br />
Arm C n = 39 8.9 (5.7–10.6) 4.2 (3.7–4.6)<br />
Arm A + B vs C 0.70 (0.45–1.09) 0.60 (0.39–0.91)<br />
MET H * Arm A + B n = 27 11.5 (9.2–12.1) 6.9 (5.5–7.5)<br />
Arm C n = 11 5.7 (4.5–10.4) 4.6 (3.7–5.2)<br />
Arm A + B vs C 0.34 (0.15–0.78) 0.44 (0.20–0.96)<br />
MET H *, R H†<br />
Arm A + B n = 13 17.6 (13.3–21.0) 10.7 (6.9–15.3)<br />
Arm C n = 11 5.7 (4.5–10.4) 4.6 (3.7–5.2)<br />
Arm A + B vs C 0.18 (0.06–0.52) 0.19 (0.06–0.57)<br />
*Pts with >50% tumor cells MET positive, † Pts with R median C minss ≥ 94 µg/mL.<br />
Annals of Oncology<br />
ix230 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
689P DISEASE PROGRESSION CLINICALLY JUDGED WITHOUT<br />
CONFIRMATION BY IMAGE DIAGNOSIS IN A RANDOMIZED<br />
PHASE III TRIAL OF ADVANCED GASTRIC CANCER<br />
(JCOG9912)<br />
H. Kawai 1 , N. Boku 2 , Y. Yamada 3 , N. Fuse 4 , H. Yasui 5 , A. Sawaki 6 , W. Koizumi 7 ,<br />
J. Mizusawa 8 , K. Nakamura 8 , A. Takashima 8<br />
1 Department of Endoscopy, Nagoya City West Medical Center, Nagoya, JAPAN,<br />
2 Department of Clinical Oncology, St. Marianna University School of Medicine,<br />
Kawasaki, JAPAN, 3 Medical Oncology, National Cancer Center Hospital, Tokyo,<br />
JAPAN, 4 Division of Gastrointestinal Oncology and Digestive Endoscopy,<br />
National Cancer Center Hospital East, Kashiwa, JAPAN, 5 Division of GI<br />
Oncology, Shizuoka Cancer Center, Shizuoka, JAPAN, 6 Department of Clinical<br />
Oncology, Nagoya Daini Red Cross Hospital, Nagoya, JAPAN, 7 Department of<br />
Gastroenterology/gastrointestinal Oncology, Kitasato University Schoool of<br />
Medicine, Sagamihara, JAPAN, 8 Japan Clinical Oncology Group Data Center,<br />
Multi-Institutional Clinical Trial Support Center, National Cancer Center, Tokyo,<br />
JAPAN<br />
Background: In advanced gastric cancer (AGC), some type of progression such as<br />
peritoneal metastasis are hardly detected by imaging, and progression was sometimes<br />
judged clinically (C-PD) apart from imaging-determined progression (I-PD). Thus,<br />
C-PD is regarded as a PFS event as well as I-PD in most cooperative group trials.<br />
However, it has rarely been reported how often C-PD is observed in <strong>the</strong> clinical trials<br />
of AGC. Objectives of this study are to evaluate <strong>the</strong> proportion of C-PD and to<br />
compare <strong>the</strong> backgrounds and outcomes between C-PD and I-PD.<br />
Methods: JCOG9912 is a large-scale randomized phase III trial comparing 5-FU<br />
continuous infusion (5-FUci), irinotecan plus cisplatin and S-1 in AGC. Among all<br />
randomized patients (n = 704), protocol treatments were terminated in 697 patients<br />
at <strong>the</strong> final analysis, and <strong>the</strong> reasons for off-treatment were prospectively classified as<br />
PD (n = 545), toxicities (n = 59), patient’s refusal (n = 73), death (n = 3) and o<strong>the</strong>rs<br />
(n = 17). We retrospectively categorized patients with PD to I-PD and C-PD by<br />
reviewing <strong>the</strong> case report forms.<br />
Results: The proportion of C-PD was only 4.4% (I-PD: n = 520, C-PD: n = 24,<br />
unknown: n = 1) among those who terminated treatment due to PD. There were<br />
some differences in patient backgrounds between I-PD and C-PD; age (median 63,<br />
61.5 years old), diffuse type (51.0%, 70.8%), target lesion (+) (77.5%, 66.7%), sum of<br />
longest diameter of target lesions (median 9.3cm, 7.9cm), treatment arm of 5-FUci<br />
(36.2%, 45.8%), and second line chemo<strong>the</strong>rapy (+) (83.1%, 70.8%). Median PFS in<br />
I-PD and C-PD were 3.7 months and 3.8 months (HR = 0.94 [0.63-1.42] in<br />
univariate analysis, HR = 0.93 [0.61-1.42] in multivariate analysis. Median OS in<br />
I-PD and C-PD were 11.1 months and 9.3 months (HR = 1.19 [0.78-1.80] in<br />
univariate analysis, HR = 1.25 [0.82-1.93] in multivariate analysis).<br />
Conclusions: The proportion of C-PD was far less than expected. Although <strong>the</strong> PFS<br />
in I-PD and C-PD were almost identical, <strong>the</strong>re were some differences in patient<br />
background and clinical courses after PD.<br />
Disclosure: N. Fuse: I have research funding to disclose from Taiho Pharmaceutical<br />
and Yakult Honsha. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
690P A RANDOMIZED, CONTROLLED PHASE III TRIAL OF<br />
DOCETAXEL, CISPLATIN AND FLUOROURACIL (DCF) VERSUS<br />
CISPLATIN PLUS FLUOROURACIL (CF) AS FIRST-LINE<br />
THERAPY IN CHINESE ADVANCED GASTRIC CANCER<br />
L. Shen 1 ,R.Xu 2 , J. Wang 3 ,Y.Bai 4 , T. Liu 5 , S. Jiao 6 ,J.Xu 7 , Y. Liu 8 ,N.Fan 9<br />
1 GI Department of Oncology, Peking University Cancer Hospital, Beijing, CHINA,<br />
2 Department of Medical Oncology, Sun Yat-Sen University Cancer Center,<br />
Guangzhou, CHINA, 3 Department of Oncology, Chinese Academy of Medical<br />
Sciences, Cancer Institute and Hospital, Beijing, CHINA, 4 Department of<br />
Oncology, Heilongjiang Cancer Hospital, Haerbin, CHINA, 5 Department of<br />
Oncology, Zhongshan Hospital Fudan University, Shanghai, CHINA,<br />
6 Department of Oncology, PLA General Hospital (301 Hospital), Beijing, CHINA,<br />
7 Department of Oncology, 307 Hospital of PLA, Beijing, CHINA, 8 Department of<br />
Oncology, The First Affiliated Hospital of China Medical University, Shenyang,<br />
CHINA, 9 Department of Onclogy, Fujian Provincial Tumor Hospital, Fuzhou,<br />
CHINA<br />
Background: Gastric cancer is <strong>the</strong> second prevalent cancer in China accounting for<br />
more than 200,000 deaths per year. Effective regimens are needed to improve <strong>the</strong><br />
outcome for gastric cancer patients. TAX 325 study has demonstrated OS benefit and<br />
high toxicity of DCF regimen compared with CF in western population. Thus we<br />
investigated <strong>the</strong> effect of modified DCF (mDCF) regimen in Chinese patients with<br />
advanced gastric cancer in this prospective, multicenter, open-label, randomized and<br />
parallel-controlled phase III study.<br />
Methods: Eligible no prior palliative chemo<strong>the</strong>rapy, advanced gastric cancer patients<br />
were randomized to ei<strong>the</strong>r mDCF (Docetaxel 60mg/m 2 1-hour intravenous infusion<br />
(IV) and cisplatin 60mg/m 2 1-3-hour IV on day 1, followed by fluorouracil 600mg/<br />
m 2 /d continuous IV for 5 days, every 3 weeks) or modified CF (mCF) (cisplatin<br />
75mg/m 2 1-3-hour IV on day 1, followed by fluorouracil 600mg/m 2 /d continuous IV<br />
for 5 days, every 3 weeks). Treatment continued until disease progression,<br />
unacceptable toxicity, death, or consent withdrawal. The primary end point was<br />
progression-free survival (PFS).<br />
Results: Between Nov 2008 and Dec 2010, a total of 241 patients were randomized,<br />
234 patients were treated and analyzed (mDCF = 119, mCF = 115) PFS was<br />
prolonged with mDCF vs mCF significantly (HR, 0.63; 95% CI, 0.48 to 0.85; P =<br />
0.0018; median PFS, 7.2 months vs.4.9 months), <strong>the</strong> trend of OS improvement was<br />
seen (HR, 0.78; 95% CI, 0.58 to 1.05; P = 0.099; median OS 10.2 months vs. 8.5<br />
months), Overall best response rate (ORR) was improved significantly with mDCF vs<br />
mCF (58% vs 39%, P = 0.0244). Treatment related grade 3/4 AEs occurred in 75.6%<br />
(DCF) vs 33.0% (CF), P < 0.0001. The most frequent 3/4 AEs included neutropenia<br />
(60.5% vs 8.7%), diarrhea (12.6% vs 0), vomiting (7.6% vs 11.3%) and febrile<br />
neutropenia (12.6% vs 0).<br />
Conclusion: mDCF regimen significantly improved PFS and ORR. The safety profile<br />
was consistent with previous report. mDCF should be considered as an option for<br />
untreated Chinese advanced gastric cancer patients. This study was funded by Sanofi,<br />
ClinicalTrials.gov identifier: NCT00811447.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
691P EVEROLIMUS (EVE) EXPOSURE IN PATIENTS (PTS) WITH<br />
PREVIOUSLY TREATED ADVANCED GASTRIC CANCER (AGC)<br />
S. Al-Batran 1 , N. Tebbutt 2 ,J.Xu 3 , G. Luppi 4 , H. Smith 5 , C. Costantini 6 ,<br />
W. Cheung 5 , S. Rizvi 7 , T. Sahmoud 8 , L. Shen 9<br />
1 Medizinische Klinik Ii für Hämatologie und Onkologie, Institut für klinische<br />
Forschung (IKF) am Krankenhaus Nordwest - UCT, Universitäres Centrum für<br />
Tumorerkrankungen Frankfurt, Frankfurt, GERMANY, 2 Medical Oncology, Austin<br />
Hospital, Heidelberg, AUSTRALIA, 3 Gastrointestinal Oncology, 307 Hospital of<br />
PLA, Beijing, CHINA, 4 Oncology, Azienda-Ospedaliero Universitaria di Modena,<br />
Modena, ITALY, 5 Oncology, Novartis Pharmaceuticals Corporation, Florham<br />
Park, NJ, UNITED STATES OF AMERICA, 6 Oncology, Novartis Pharma AG,<br />
Basel, SWITZERLAND, 7 Oncology Clinical Research and Development, Novartis<br />
Pharmaceuticals, Florham Park, NJ, UNITED STATES OF AMERICA, 8 2W274,<br />
Novartis Pharmaceuticals, Florham Park, NJ, UNITED STATES OF AMERICA,<br />
9 Internal Medicine, Peking University Cancer Hospital, Beijing, CHINA<br />
Background: In GRANITE 1, EVE did not significantly improve overall survival<br />
(OS) over best supportive care (BSC) in previously treated AGC (median OS 5.4 mo<br />
with EVE vs 4.3 mo with BSC; HR, 0.90; P = .1244). Median progression-free survival<br />
(PFS) was 1.7 mo with EVE vs 1.4 mo with BSC (HR, 0.66; P < .0001). This analysis<br />
examined EVE exposure and its relationship with efficacy and safety.<br />
Methods: Pts with confirmed AGC who progressed after 1 or 2 chemo<strong>the</strong>rapy lines<br />
were randomized 2:1 to EVE 10 mg/d + BSC or placebo + BSC. Primary endpoint was<br />
OS. EVE C min and C max were determined in whole blood from samples collected<br />
predose and 1 and 2 h postdose on day 1 of wk 5 using liquid chromatography/mass<br />
spectrometry (lower limit of quantification 0.3 ng/mL). Cox models adjusted for<br />
region (Asia/rest of world [ROW]) and gastrectomy (yes/no) were used to explore<br />
relationships between PFS and time-normalized (TN) EVE Cmin. A linear<br />
mixed-effects model was used to explore <strong>the</strong> relationship between change from<br />
baseline in target lesion size and TN C min. Kaplan-Meier curves for select adverse<br />
events (AEs) by TN C min categories were prepared.<br />
Results: 656 pts were enrolled from Jul 2009 to Dec 2010 and received EVE (n =<br />
439) or placebo (n = 217). Median age was 62 y, 74% were men, 55% were from Asia,<br />
and 50% had previous gastrectomy. Mean ± SD Cmin and Cmax were 16.1 ± 10.8 ng/<br />
mL and 72.8 ± 36.5 ng/mL in pts receiving EVE 10 mg/d at sampling. EVE Cmin and<br />
C max were similar in pts from Asia and ROW and in pts with and without<br />
gastrectomy. No significant relationship between TN C min and PFS was observed<br />
(HR, 0.83; 95% CI, 0.65-1.06). A 2.72-fold increase in TN C min corresponded to a<br />
significant 7.6% reduction from baseline in target lesion volume. No differences in<br />
noninfectious pneumonitis, stomatitis/oral mucositis, or infection/infestation risk in<br />
pts with TN Cmin
692P PRELIMINARY SAFETY DATA FROM A RANDOMIZED PHASE<br />
II STUDY COMPARING DOSE-ESCALATED WEEKLY<br />
PACLITAXEL VERSUS STANDARD-DOSE WEEKLY<br />
PACLITAXEL FOR PATIENTS WITH PREVIOUSLY TREATED<br />
ADVANCED GASTRIC CANCER<br />
S. Yuki1 , K. Shitara2 , D. Takahari2 , M. Nakamura3 , C. Kondo2 , T. Tsuda4 ,T.Kii5 ,<br />
Y. Tsuji6 , I. Oze7 , K. Muro2 1<br />
Department of Gastroenterology, Hokkaido University Hospital, Sapporo,<br />
JAPAN, 2 Department of Clinical Oncology, Aichi Cancer Center Hospital,<br />
Nagoya, JAPAN, 3 Department of Gastroenterology, Sapporo City General<br />
Hospital, Sapporo, JAPAN, 4 Department of Clinical Oncology, Saint Marianna<br />
University School of Medicine, Kawasaki, JAPAN, 5 Cancer Chemo<strong>the</strong>rapy<br />
Center, Osaka Medical College, Osaka, JAPAN, 6 Department of Medical<br />
Oncology, KKR sapporo medical center Tonan hospital, Sapporo, JAPAN,<br />
7<br />
Division of Epidemiology and Prevention, Aichi Cancer Center Research<br />
Institute, Nagoya, JAPAN<br />
Background: Recently, we studied <strong>the</strong> effects of neutropenia occurring during<br />
second-line chemo<strong>the</strong>rapy with weekly paclitaxel in a retrospective analysis of 242<br />
patients with advanced gastric cancer, and observed better survival among patients<br />
with neutropenia compared to patients without neutropenia (Shitara K, et al. Annals<br />
of Oncol. 2011). Therefore, we conducted a multi-institutional, open-label,<br />
randomized phase II trial comparing dose-escalated weekly paclitaxel with dose<br />
adjustments determined by degree of neutropenia versus standard-dose weekly<br />
paclitaxel for patients with previously treated advanced gastric cancer (protocol ID<br />
UMIN000004055).<br />
Patients and methods: Patients with advanced or recurrent gastric cancer that<br />
progressed during one or more previous chemo<strong>the</strong>rapy regimens were included.<br />
Ninety patients were randomized to a standard dose of weekly paclitaxel (80 mg/m 2 ,<br />
Arm A) or an escalated dose of weekly paclitaxel (80 mg/m 2 on day 1, 100 mg/m 2 on<br />
day 8, and 120 mg/m 2 on day 15 unless severe toxicity is observed, Arm B). The<br />
primary endpoint was overall survival. Secondary endpoints included objective<br />
response rate, disease control rate, progression-free survival, and adverse events. We<br />
present <strong>the</strong> preliminary safety data from <strong>the</strong> first 8 weeks.<br />
Results: From September 2010 to November 2011, a total of 90 patients were<br />
enrolled at 13 institutions. One patient in Arm B did not receive paclitaxel. The dose<br />
of paclitaxel was escalated to 100 mg/m 2 in 41 patients (91.1%) and <strong>the</strong>n to 120 mg/<br />
m 2 in 29 patients (64.4%) in Arm B. In <strong>the</strong> first 8 weeks, 25 (55.5%) patients in Arm<br />
A patients and 20 (46.7%) patients in Arm B required dose reduction or treatment<br />
delay. Frequencies of grade 1 or more neutropenia were 66.7% in Arm A and 86.4%<br />
in Arm B, and grade 3 or more neutropenia frequencies were 31.1% in Arm A and<br />
38.6% in Arm B. Grade 1 or more sensory neuropathy frequencies were 55.6% in<br />
Arm A and 68.1% in Arm B. Two patients in Arm A and one patient in Arm B<br />
experienced febrile neutropenia. No treatment-related deaths occurred.<br />
Conclusions: Preliminary safety data during <strong>the</strong> first 8 weeks of treatment indicate<br />
comparable compliance between <strong>the</strong> two arms, despite <strong>the</strong> substantial number of<br />
patients who underwent dose escalation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
693P EFFICACY AND SAFETY OF DOSE-DENSE CHEMOTHERAPY<br />
WITH MODIFIED TCF REGIMEN (TCF-DD) IN ELDERLY<br />
PATIENTS WITH METASTATIC GASTRIC CANCER (MGC)<br />
G. Tomasello, W. Liguigli, S. Lazzarelli, R. Poli, F.M. Negri, L. Toppo, M. Ratti,<br />
M. Brighenti, F. Gerevini, R. Passalacqua<br />
Oncology Division, Istituti Ospitalieri di Cremona, Cremona, ITALY<br />
Background: GC is more common in elderly patients (pts). Most oncologists are<br />
reluctant to treat this pts population with <strong>the</strong> most active poli-chemo<strong>the</strong>rapy<br />
combinations because of safety concerns. Subgroup analysis of elderly pts enrolled in<br />
European studies show limited and conflicting data. We previously reported on <strong>the</strong><br />
feasibility and high activity of a dose-dense TCF regimen (TCF-dd) (Tomasello<br />
2010). This study aims to evaluate <strong>the</strong> efficacy and safety of this schema in <strong>the</strong><br />
elderly pts subgroup (≥ 65 years).<br />
Methods: From 11/04 to 05/12, 111 consecutive pts with MGC (median age 65,<br />
range 31-81) were enrolled in a single-centre phase II study. Pts received Docetaxel<br />
70 mg/m 2 d1, CDDP 60 mg/m 2 d1, l-AF 100 mg/m 2 d1-2 followed by 5-FU 400 mg/<br />
m 2 bolus d1-2, and <strong>the</strong>n 600 mg/m 2 as a 22h c.i. d1-2, q2w, plus G-CSF d3. Pts ≥<br />
65y (56) received <strong>the</strong> same schedule reduced by 30%.<br />
Results: 96 pts evaluable for response and all for toxicity. In pts ≥ 65y we observed 4<br />
CR (7%) 25 PR (45%) 10 SD (18%) 7 PD (13%); in younger pts: 2 CR (4%) 30 PR<br />
(55%) 9 SD (16%) 9 PD (17%); ORR by ITT 56% (95% IC 45-64). Median OS was<br />
11.9 months (9,4-14,8); in elderly and younger pts 11,2 (8,4-11,1) and 12,7 (9-16,5)<br />
respectively. Out of 48 evaluable pts ≥ 65y, 26 (54%) were treated at full doses<br />
without any delay. In <strong>the</strong> elderly most frequent G3-4 toxicities were neutropenia<br />
(14%) thrombocytopenia (15%) febrile neutropenia (7%) as<strong>the</strong>nia (27%) and<br />
hypokalemia (17%); in <strong>the</strong> younger: neutropenia (56%) thrombocytopenia (21%)<br />
febrile neutropenia (16%) as<strong>the</strong>nia (43%) hypokalemia (21%).<br />
Annals of Oncology<br />
Conclusions: This study shows that elderly pts can be treated with a TCF-dd<br />
regimen reduced by 30% achieving similar efficacy results of younger patients with<br />
lesser toxicity.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
694P PROGRESSION-FREE SURVIVAL AND POSTPROGRESSION<br />
SURVIVAL IN PATIENTS WITH ADVANCED GASTRIC CANCER<br />
TREATED WITH FIRST-LINE CHEMOTHERAPY<br />
K. Shitara 1 , K. Matsuo 2 , K. Muro 3 , A. Ohtsu 1<br />
1 Gastroenterology & Gastrointestinal Oncology, National Cancer Center Hospital<br />
East, Kashiwa, JAPAN, 2 Aichi Cancer Center Research Institute, Aichi Cancer<br />
Center, Nagoya, JAPAN, 3 Clinical Oncology, Aichi Cancer Center Hospital,<br />
Nagoya, JAPAN<br />
Background: Progression-free survival (PFS) has been reported to be moderately<br />
correlated to overall survival (OS) in patients with advanced gastric cancer (AGC) who<br />
received first-line chemo<strong>the</strong>rapy (Shitara, K et al. Invest New Drug 2011; Shitara K<br />
and Burzykowski T. On behalf of GASTRIC. ASCO 2011). Impact of post progression<br />
survival (PPS) on OS of patients with AGC has not yet been reported in detail.<br />
Methods: We retrospectively analyzed AGC patients who received first-line<br />
chemo<strong>the</strong>rapy including fluoropyrimidine plus platinum with confirmed disease<br />
progression. We partitioned OS into PFS and PPS and analyzed <strong>the</strong> correlation<br />
between OS and ei<strong>the</strong>r PFS or PPS by Spearman rank correlation coefficient (r).<br />
Subgroup analyses were performed according to treatment setting (clinical trial or<br />
practice) and presence of measurable lesion. Multivariate analysis was also conducted<br />
to evaluate prognostic factors for PPS.<br />
Results: Between April 2005 to May 2011, 291 AGC patients met inclusion criteria.<br />
One-hundred five patients (36%) included in clinical trials and 246 patients (85%)<br />
received second-line chemo<strong>the</strong>rapy. Median PFS, PPS, and OS were 5.3 months, 8.1<br />
months. 14.8 months, respectively. PFS and OS showed a correlation with r of 0.75 (95%<br />
CI, 0.69- 0.81). PPS and OS also showed a correlation with r of 0.87 (95% CI, 0.84- 0.91).<br />
Correlations tend to be higher between PSS and OS than that of PFS and OS in subset of<br />
patients in clinical trials (r = 0.84 vs. r = 0.72) or patients with measurable lesion (r = 0.87<br />
vs. r = 0.72). According to <strong>the</strong> multivariate analysis, performance status at progression and<br />
second-line chemo<strong>the</strong>rapy were significantly associated with length of PPS.<br />
Conclusion: Our results indicate that both PFS and PSS is correlated with OS in<br />
first-line chemo<strong>the</strong>rapy for advanced AGC, thus suggest <strong>the</strong> importance of reporting<br />
detailed patients characteristic and treatment course after disease progression in<br />
clinical trials of first-line chemo<strong>the</strong>rapy for AGC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
695P QUALITY OF LIFE IN FLAGS TRIAL A RANDOMIZED,<br />
COMPARATIVE, OPEN LABEL, MULTICENTER, PHASE 3 OF<br />
S-1 + CISPLATIN (CS) COMPARED TO 5-FU + CISPLATIN (CF)<br />
IN UNTREATED ADVANCED GASTRIC CANCER (AGC)<br />
PATIENTS<br />
G. Bodoky 1 , A. Carrato 2 , A. Ravaioli 3 , J.A. Ajani 4<br />
1 Dept of Medical Oncology, Szent Laszlo Korhaz, Budapest, HUNGARY,<br />
2 Medical Oncology, Hospital Ramon y Cajal, Madrid, SPAIN, 3 Primario<br />
Oncologia Medica, Ospedale “Infermi” di Rimini, Rimini, ITALY, 4 Gastrointestinal<br />
Medical Oncology, MD Anderson, Cancer center, Houston, TX, UNITED STATES<br />
OF AMERICA<br />
Background: FLAGS’ primary objective was overall survival. We report below <strong>the</strong><br />
Patient-Reported Outcomes (PRO) (i.e., Quality-of-Life [QoL]) which was one of <strong>the</strong><br />
secondary objectives.<br />
Methods: All patients who completed at least one PRO assessment were eligible for<br />
analysis. The primary PRO endpoint was <strong>the</strong> Trial Outcome Index (TOI) of <strong>the</strong><br />
Functional Assessment of Cancer Therapy – Gastric (FACT-Ga). Patients completed<br />
<strong>the</strong> FACT-Ga at <strong>the</strong> beginning of Cycles 1, 2, 3, 4, 6 and <strong>the</strong>n every 3 cycles prior to<br />
treatment administration. All individual subscales in <strong>the</strong> FACT-Ga were also<br />
evaluated as secondary endpoints. The Chemo<strong>the</strong>rapy Convenience and Satisfaction<br />
Questionnaire (CCSQ) was administered at <strong>the</strong> beginning of <strong>the</strong> first 4 cycles.<br />
Results: Of <strong>the</strong> 508 patients dosed at cycle 1 in <strong>the</strong> CF arm, and <strong>the</strong> 521 in <strong>the</strong> CS<br />
arm, 456 and 498 respectively completed at least one question on <strong>the</strong> FACT-Ga and<br />
445 and 486 respectively completed at least 37 items. Compliance to questionnaire<br />
fulfillment was more than 80% through Cycle 9. Although <strong>the</strong>re were no overall<br />
difference in FACT-Ga scores between <strong>the</strong> treatment arms and minimal changes over<br />
time, an advantage for CS relative to CF was observed for Physical Well-Being<br />
(PWB) (51.7% versus 45.1%, p = 0.044). CS treated patients experienced significantly<br />
longer time to worsening in PWB scores, with a median time of 4.5 months (95%<br />
CI: 3.0 – 5.1) compared to 3.0 months (2.8 – 4.6) with CF (p = 0.014).Patients<br />
receiving CS reported higher best and worst score of PWB, Chemo<strong>the</strong>rapy<br />
Convenience and Chemo<strong>the</strong>rapy Concerns scores.<br />
Conclusions: Even if <strong>the</strong>re is little evidence to indicate any difference in FACT-Ga<br />
scores, some advantage to CS relative to CF was observed for PWB, one of <strong>the</strong><br />
ix232 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
secondary PRO endpoints. This advantage was generally consistent across analysis<br />
method: time to worsening, best post-baseline score, and worst post-baseline score.<br />
CS treated patients did report significantly better Chemo<strong>the</strong>rapy Convenience and<br />
Concerns scores, <strong>the</strong> difference was approximately one-half of a standard deviation<br />
generally considered to be a meaningful difference.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
696P A MULTI-CENTER PHASE II STUDY AND PREDICTIVE<br />
BIOMARKER ANALYSIS OF COMBINED CETUXIMAB AND<br />
MODIFIED FOLFIRI AS SECOND-LINE TREATMENT IN<br />
PATIENTS WITH METASTATIC GASTRIC CANCER<br />
L. Jin<br />
Medical Oncolgy, Fudan University Cancer Center, Shanghai, CHINA<br />
Background: This study was conducted to explore potential biomarkers for<br />
predicting clinical outcome of cetuximab in combination with modified FOLFIRI<br />
(mFOLFIRI) and to analyze safety of this regimen as a second-line treatment in<br />
metastatic gastric cancer patients.<br />
Methods: A total of 61 patients received an initial intravenous (IV) dose of<br />
cetuximab (400 mg/m 2 ) and weekly doses (250 mg/m 2 ) <strong>the</strong>reafter. On day 2 of each<br />
14-day period, patients received IV irinotecan (180 mg/m 2 ), leucovorin (200 mg/m 2 ),<br />
and an IV bolus dose of 5-FU (400 mg/m 2 ) followed by a continuous infusion of<br />
5-FU (2400 mg/m 2 ) for 46 hours. The primary endpoint was time-to-progression<br />
(TTP).<br />
Findings: The response rate (RR) was 33.3% among 54 evaluable patients. In <strong>the</strong><br />
intention-to-treat (ITT) analysis, median TTP was 4.6 months (95% confidential<br />
interval [CI]: 3.6-5.6 months) and median overall survival (OS) was 8.6 months (95%<br />
CI: 7.3-9.9 months). It was demonstrated that plasma vascular endo<strong>the</strong>lial growth<br />
factor (VEGF) levels could be a predictive factor for <strong>the</strong> treatment prognosis. In<br />
patients with low (≤12.6 pg/ml) and high (>12.6 pg/ml) baseline plasma VEGF<br />
levels, RR values were 55.0% and 5.3%, respectively (P = 0.001); median TTP values<br />
were 6.9 months and 2.8 months, respectively (P = 0.0005); and median OS values<br />
were 12 months and 5 months, respectively (P < 0.0001). None of <strong>the</strong>se patients<br />
exhibited KRAS, BRAF, or PIK3CA mutations.<br />
Interpretation: Low baseline plasma VEGF levels were identified as a potential<br />
predictive biomarker of prognosis. Combination <strong>the</strong>rapy comprising cetuximab and<br />
mFOLFIRI was well tolerated, which would be potentially used as a second-line<br />
treatment for patients with advanced gastric cancer.<br />
Funding: This study was supported by Fudan University Shanghai Cancer Center;<br />
Merck KGaA Darmstadt, Germany, and National “Eleventh Five-year plan” new<br />
drug discovery major projects of P. R. China.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
697P FINAL ANALYSIS OF RANDOMIZED PHASE III STUDY<br />
WJOG4007 COMPARING IRINOTECAN (CPT-11) WITH<br />
WEEKLY PACLITAXEL (WPTX) IN ADVANCED GASTRIC<br />
CANCER (AGC) REFRACTORY TO CHEMOTHERAPY (CT) OF<br />
FLUOROPYRIMIDINE PLUS PLATINUM (FP)<br />
T. Nishina 1 , S. Hironaka 2 , A. Tsuji 3 , K. Suzuki 4 , T. Otsuji 5 , T. Shibata 6 , S. Morita 7 ,<br />
I. Okamoto 8 , N. Boku 9 , I. Hyodo 10<br />
1 Gastrointestinal Oncology, National Hospital Organization Shikoku Cancer<br />
Center, Matsuyama, JAPAN, 2 Clinical Trial Promotion Centre, Chiba Cancer<br />
Center Hospital, Chiba, JAPAN, 3 Department of Medical Oncology, Kochi Health<br />
Sciences Center, Kochi City, JAPAN, 4 Gastrointestinal Oncology, Kushiro City<br />
General Hospital, Kushiro, JAPAN, 5 Gastrointestinal Oncology, Dongo Hospital,<br />
Yamatotakata, JAPAN, 6 Gastrointestinal Oncology, Fujita Health University,<br />
Toyoake, JAPAN, 7 Biostatistics and Epidemiology, Yokohama City University<br />
Medical Center, Yokohama, JAPAN, 8 Medical Oncology, Kinki University School<br />
of Medicine, Osakasayama, JAPAN, 9 Department of Clinical Oncology,<br />
St. Marianna University School of Medicine, Kawasaki, JAPAN, 10 Gastrointestinal<br />
Oncology, University of Tsukuba, Tsukuba, JAPAN<br />
Background: We previously reported <strong>the</strong> primary results of WJOG4007 trial<br />
comparing wPTX with CPT-11 for AGC refractory to combination CT of FP (Ueda<br />
et al. ASCO <strong>2012</strong>). This trial failed to demonstrate <strong>the</strong> superiority of CPT-11 to<br />
wPTX in OS. Here, we report <strong>the</strong> results of subgroup analysis, cross-over effect and<br />
patients’ general conditions at <strong>the</strong> time of discontinuation of protocol treatments.<br />
Methods: The main inclusion criteria were; 1) refractory to combination CT of FP,<br />
2) no prior CPT-11 or taxane, 3) no severe peritoneal metastasis. Pts with AGC<br />
refractory to <strong>the</strong> 1st-line FP regimen were randomized 1:1 to ei<strong>the</strong>r CPT-11 (150 mg/<br />
m 2 , days1, 15, q4w) or wPTX (80 mg/m 2 , days 1, 8, 15, q4w). Cross-over treatment<br />
between PTX and CPT-11 was recommended for <strong>the</strong> third line chemo<strong>the</strong>rapy.<br />
Results: Between Aug 2007 and Aug 2010, 223 pts were enrolled and 219 were<br />
eligible; 108 pts were randomized to wPTX and 111 pts to CPT-11. Median OS for<br />
wPTX and CPT-11 was 9.5 and 8.4 months (HR 1.13; 95% CI, 0.86-1.49; p = 0.38).<br />
Subgroup analysis in OS revealed slightly favorable tendency of wPTX for almost all<br />
factors such as age, gender, PS, prior gastrectomy, histological type, presence of<br />
target lesion, peritoneal metastasis, number of metastatic sites. At <strong>the</strong> treatment<br />
discontinuation, 85 pts (80%) with wPTX and 77 with CPT-11 (70%) maintained PS<br />
0-1 (p = 0.12), and 2 (2%) and 13 pts (12%) were complicated with infection (p =<br />
0.006), respectively. Thereafter, proportion of pts receiving third line CT was higher<br />
in wPTX (89%) than CPT-11 (71%) (p = 0.04). As for <strong>the</strong> cross-over effect, among<br />
86 pts (80%) in <strong>the</strong> wPTX group who received CPT-11 containing regimens in <strong>the</strong><br />
subsequent chemo<strong>the</strong>rapy and 74 pts (67%) in <strong>the</strong> CPT-11 group who received<br />
taxane containing regimens, survival curves were quite similar (10.1months, HR 0.96;<br />
95%CI, 0.69-1.32).<br />
Conclusions: In this trial, while patients in <strong>the</strong> wPTX group showed better condition<br />
at <strong>the</strong> time of treatment discontinuation, a higher rate of subsequent CT and<br />
cross-over CT, quite similar survival curves were observed in pts of both arms who<br />
received cross-over treatments. It is speculated that <strong>the</strong> better condition at <strong>the</strong> end of<br />
<strong>the</strong> second line chemo<strong>the</strong>rapy resulting in higher proportion of <strong>the</strong> third line<br />
chemo<strong>the</strong>rapy might contribute to more favorable overall survival with wPTX than<br />
CPT-11.<br />
Disclosure: T. Nishina: Honoralia from Yakult Honsha, Daiichi Sankyo. I. Hyodo:<br />
Honoralia from Yakult Honsha and Daiichi-Sankyo. All o<strong>the</strong>r authors have declared<br />
no conflicts of interest.<br />
698P PHASE II STUDY OF INTRAVENOUS AND INTRAPERITONEAL<br />
PACLITAXEL COMBINED WITH S-1 FOR GASTRIC CANCER<br />
WITH METASTASES TO THE DISTANT PERITONEUM<br />
H. Ishigami 1 , J. Kitayama 2 , H. Yamaguchi 2 , S. Emoto 2 , T. Watanabe 2<br />
1 Department of Outpatient Chemo<strong>the</strong>rapy, The University of Tokyo, Tokyo,<br />
JAPAN, 2 Department of Surgical Oncology, The University of Tokyo, Tokyo,<br />
JAPAN<br />
Background: Intraperitoneal (i.p.) chemo<strong>the</strong>rapy is a promising treatment option for<br />
gastric cancer with peritoneal metastasis. We previously carried out phase I and phase<br />
II studies of intravenous (i.v.) and i.p. paclitaxel (PTX) combined with S-1, and<br />
verified <strong>the</strong> safety and efficacy in gastric cancer with macroscopic peritoneal metastasis<br />
and/or cancer cells on peritoneal cytology (Oncology 2009, Ann Oncol 2010). This<br />
regimen was approved as an advanced medical treatment by <strong>the</strong> Ministry of Health,<br />
Labour and Welfare of Japan, and fur<strong>the</strong>r clinical studies were required for approval of<br />
coverage by <strong>the</strong> Japanese Health Insurance System. Therefore, we carried out ano<strong>the</strong>r<br />
phase II study in gastric cancer patients with macroscopic peritoneal metastasis.<br />
Patients and methods: Gastric cancer patients with macroscopic peritoneal<br />
metastasis confirmed by staging laparoscopy were enrolled. PTX was administered i.<br />
v. at 50 mg/m 2 and i.p. at 20 mg/m 2 on days 1 and 8. S-1 was administered orally<br />
twice daily at 80 mg/m 2 /day for 14 consecutive days followed by 7 days rest. The<br />
primary endpoint was <strong>the</strong> 1-year overall survival rate. Secondary endpoints were <strong>the</strong><br />
response rate, efficacy against malignant ascites and safety.<br />
Results: Thirty-five patients were enrolled. All patients had several to numerous<br />
metastases to <strong>the</strong> distant peritoneum. The median number of courses was 11 (range<br />
2-29). The 1-year overall survival rate was 77% (95% CI, 63-91%). The overall response<br />
rate was 71% in 7 patients with target lesions. Malignant ascites disappeared or decreased<br />
in 6 of 9 (67%) patients with massive ascites. Cancer cells ceased to be detected by<br />
peritoneal cytology in 28 of 29 (97%) patients. The incidences of grade 3/4 hematological<br />
and non-hematological toxicities were 34% and 9%, respectively, all of which were<br />
manageable and reversible. The frequent grade 3/4 toxicities included neutropenia (34%),<br />
leukopenia (23%) and anemia (9%). There were no treatment-related deaths.<br />
Conclusion: Combination chemo<strong>the</strong>rapy of weekly i.v. and i.p. PTX combined with<br />
S-1 is well tolerated and active in gastric cancer patients with macroscopic peritoneal<br />
metastasis.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
699P HER2 STATUS IN ADVANCED GASTRIC CARCINOMA<br />
PATIENTS TREATED WITH TRASTUZUMAB<br />
C. Gomez-Martin 1 , J.C. Plaza 2 , E. Del Valle 3 , F. Pons Valladares 4 ,P.<br />
Jimenez Fonseca 5 , A. Salud 6 , A. Leon 7 , F. Rivera 8 , E. Garralda 1 , F. Lopez-Rios 2<br />
1 Clinical Research Programme, Spanish National Cancer Research Center,<br />
Madrid, SPAIN, 2 Laboratorio Dianas Terapeuticas, Hospital Universitario<br />
Madrid-Norte Sanchinarro, Madrid, SPAIN, 3 Pathology Department, Hospital<br />
Universitario Miguel Servet, Zaragoza, SPAIN, 4 Medical Oncology, Hospital del<br />
Mar, Barcelona, SPAIN, 5 Medical Oncology, Hospital Universitario Central de<br />
Asturias, Oviedo, SPAIN, 6 Medical Oncology, Hospital Universitario Arnau de<br />
Vilanova, Lerida, SPAIN, 7 Medical Oncology, Fundacion Jimenez Diaz, Madrid,<br />
SPAIN, 8 Medical Oncology, Hospital Universitario Marques de Valdecilla,<br />
Santander, SPAIN<br />
Background: Trastuzumab (T) added to standard chemo<strong>the</strong>rapy increases overall<br />
survival for HER2 positive advanced gastric carcinoma (AGC) patients. The approval<br />
of T by <strong>the</strong> EMA in AGC was linked to <strong>the</strong> determination of <strong>the</strong> HER2-status by<br />
immunohistochemistry (IHC), and hybridization was only permitted in <strong>the</strong> 2+<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds398 | ix233
subgroup. Taking into consideration <strong>the</strong> previous highs and lows in breast carcinoma<br />
HER2 testing, we sought to evaluate <strong>the</strong> use of Dual Colour Silver-staining in situ<br />
Hybridization (dc-SISH) for selecting patients with AGC as candidates to anti-HER2<br />
<strong>the</strong>rapies.<br />
Material and methods: Sixty-nine AGC patients meeting a previously set of specific<br />
inclusion criteria were included: previous treatment with Trastuzumab-based<br />
chemo<strong>the</strong>rapy, adequate follow-up, available pathology data and suitable sample for<br />
molecular analyses. IHC results were determined by <strong>the</strong> Pathway anti HER2/neu<br />
(4B5) antibody in <strong>the</strong> fully automated platform BenchMark ULTRA® (Ventana<br />
Medical Systems, Inc, Tucson, AZ). Automated dc-SISH was performed on Ventana<br />
Benchmark XT (Ventana Medical Systems, Tucson, AZ). INFORM HER2 DNA<br />
Probe and INFORM Chromosome 17 Probe was visualized on <strong>the</strong> same slide<br />
following <strong>the</strong> manufacturer’s protocols. Gene to CEN-17 ratio was calculated using<br />
<strong>the</strong> cut-off value of HER2/CEN-17 ratio ≥2 as amplified. IHC evaluation was<br />
performed according to published guidelines.<br />
Results: All cases were amplified. Low polisomy was present in 4 cases. Heterogeneity<br />
was observed in 24 (34.78%) cases. A statistically significant relationship was found<br />
between IHC and dc-SISH results (p < 0.0001), with 94% of IHC 3+ expressing dc-SISH<br />
ratio >4. Median OS was 19.8 months (95% CI: 13.4 – 23.9 months) for <strong>the</strong> entire<br />
population. Mean OS was significantly longer in <strong>the</strong> group of patients with amplification<br />
ratio >4 (21.4 vs. 8.0 months, HR 0.41; p = 0.0087; CI95% 0.2126 – 0.8180). No<br />
differences were observed in OS according to IHC results when stratified in two groups<br />
(3+ vs 0/1 + 2+) (21.0 vs 10.9 months, HR 0.5288, CI95% 0.2469 – 1.1325, p = 0.0955).<br />
Conclusions: Dc-SISH amplification ratio >4 predicts OS benefit in AGC patients<br />
treated with trastuzumab in this study. Characterization in a larger cohort of patients<br />
is ongoing.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
700P A PHASE I DOSE-FINDING STUDY OF VORINOSTAT (V)<br />
COMBINED WITH CAPECITABINE (X) AND CISPLATIN (P) AS<br />
FIRST-LINE THERAPY IN PATIENTS WITH ADVANCED<br />
GASTRIC CANCER<br />
C. Yoo, M.H. Ryu, B. Ryoo, D.H. Koo, I. Park, Y. Kang<br />
Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul,<br />
KOREA<br />
Background: The purpose of this trial is to determine <strong>the</strong> recommended dose (RD) of<br />
vorinostat (V), a histone deacetylase inhibitor, in combination with capecitabine (X) and<br />
cisplatin (P) and to explore feasibility of V-XP at <strong>the</strong> RD in advanced gastric cancer.<br />
Patients and methods: The standard 3 + 3 method was used to determine <strong>the</strong> RD of<br />
3-weekly V-XP during <strong>the</strong> first cycle. The doses of X (days 1-14, p.o.), P (day 1, i.v.),<br />
and V (days 1-14, p.o.) were escalated as following scheme; X 1,600 mg/m 2 /day, P<br />
60 mg/m 2 , V 300 mg/day in level 1; X 1,600 mg/m 2 /day, P 60 mg/m 2 , V 400 mg/day<br />
in level 2A; X 2,000 mg/m 2 /day, P 60 mg/m 2 , V 300 mg/day in level 2B; X 2,000 mg/<br />
m 2 /day, P 60 mg/m 2 , V 400 mg/day in level 3; X 2,000 mg/m 2 /day, P 80 mg/m 2 ,V<br />
400 mg/day in level 4.<br />
Results: A total of 24 patients were enrolled. Median age was 50 years (range, 25-66),<br />
and 11 (46%) were male. Dose limiting toxicity (DLT) was noted in 1 of 6 in level 1<br />
(Grade 4 thrombocytopenia), 0 of 3 in level 2A, 1 of 6 in level 2B (Grade 3 fatigue), 1<br />
of 6 in level 3 (Grade 3 stomatitis) and 2 of 3 in level 4 (Grade 4 thrombocytopenia,<br />
and discontinuation of X or V more than 25% of prescribed dosage due to Grade 3<br />
anorexia and Grade 3 fatigue). Level 4 was maximal tolerated dose, and RD was<br />
determined as level 3. Six additional patients were enrolled at level 3 to confirm <strong>the</strong><br />
feasibility, and DLT was not occurred. In 12 patients who received dose level 3, median<br />
6 cycles (range, 3-10) of chemo<strong>the</strong>rapy were given and most frequent Gr 3/4 toxicities<br />
were neutropenia (n = 5, 42%) and anorexia (n = 3, 25%). In overall, <strong>the</strong> objective<br />
responses were confirmed in 9 (47%) out of 19 patients with measurable lesions. With<br />
a median follow-up of 9 months, median progression-free survival was 7 months (95%<br />
confidence interval, 4 to 10 months), and median overall survival was not reached.<br />
Conclusion: Major DLTs of V-XP were thrombocytopenia, fatigue, anorexia and<br />
stomatitis. The 3-weekly schedule of X (2,000 mg/m 2 /day on day 1-14), P (60 mg/m 2<br />
on day 1), and V (400 mg/day on day 1-14) is recommended for fur<strong>the</strong>r<br />
development of this regimen in patients with advanced gastric cancer.<br />
Disclosure: Y. Kang: Research fund from MSD. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
701P BIMONTHLY REGIMEN OF HIGH DOSE LEUCOVORIN,<br />
INFUSIONAL 5-FLUOROURACIL, DOCETAXEL AND CISPLATIN<br />
(MODIFIED DCF) IN ADVANCED GASTRIC ADENOCARCINOMA<br />
I.T. Unek 1 , T. Akman 1 , I. Oztop 2 , O.U. Unal 1 , T. Salman 1 , A.U. Yilmaz 1<br />
1 Medical Oncology, Dokuz Eylul University Faculty of Medicine, Izmir, TURKEY,<br />
2 Medical Oncology, Oncology Institute, Izmir, TURKEY<br />
The combination of docetaxel, cisplatin and 5-fluorouracil (DCF) is an effective but<br />
highly toxic regimen for <strong>the</strong> treatment of advanced gastric cancer. In <strong>the</strong> palliative<br />
chemo<strong>the</strong>rapy of tumors, it is necessary to improve <strong>the</strong> drug safety while<br />
ensuring efficacy. We developed a modified DCF regimen with goal to minimize<br />
toxicity without compromising efficacy. In our study, seventy patients with<br />
advanced gastric cancer were treated. Each 2-week cycle consisted of docetaxel<br />
(60 mg/m 2 ), cisplatin (50 mg/m 2 ), 5-fluorouracil (400 mg/m 2 )IVbolusand<br />
5-fluorouracil (2400 mg/m 2 ) IV over 46 hours plus leucovorin (400 mg/m 2 )IV<br />
over 2 hours. The median progression-free survival and overall survival were 9.0<br />
months (95% CI, 7.1-10.9) and 10.8 months (95% CI, 7.4-14.2), respectively;<br />
<strong>the</strong> 1-year and 2-year survival rates were 46.3% and 18.4%, respectively.<br />
Twenty-nine (41.4%) partial responses, 19 (27.1%) stable disease, and 22<br />
(31.4%) progression of disease were observed. Grade 3-4 toxicities included<br />
neutropenia (37.1%), febrile neutropenia (15.7%), thrombocytopenia (10.0%),<br />
anemia (8.6%), nausea and vomiting (10.0%), stomatitis (5.7%), infection<br />
(8.6%), diarrhea (2.9%). In summary, our results show that a modified DCF<br />
regimen may have tolerable toxicities and be an effective and convenient<br />
palliative treatment of advanced gastric cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
702P INTRAPERITONEAL INFUSION OF DOCETAXEL COMBINED<br />
WITH ORAL S-1 FOR METASTATIC OR RECURRENT GASTRIC<br />
CANCER PATIENTS WITH PERITONEAL METASTASIS<br />
H. Yabusaki, N. Atsushi, A. Matsuki, M. Aizawa<br />
Surgery, Niigata Cancer Center Hospital, Niigata, JAPAN<br />
Introduction: Though many modalities of chemo<strong>the</strong>rapy have been tried for<br />
metastatic or recurrent gastric cancer (GC) patients (pts) with peritoneal<br />
dissemination, it remains uncontrollable yet. Docetaxel (DOC) and S-1 have different<br />
mechanisms of anti-tumor activity and <strong>the</strong>y are effective against advanced GC.<br />
Recently, intraperitoneal administration (IP) of DOC has proved to be effective for<br />
peritoneal dissemination.<br />
Material and methods: Eligibility included metastatic or recurrent GC with<br />
peritoneal dissemination, capability of oral intake, adequate organ function, and good<br />
PS (0-2). IP ca<strong>the</strong>ters were placed for all patients after histological confirmation of<br />
peritoneal dissemination by laparoscopy or laparotomy. The treatment of oral S-1<br />
(80 mg/m 2 daily day 1-14, q4w) and DOC (35 ∼ 45 mg/m 2 ip day 1 and 15, q4w)<br />
was repeated every 4 weeks until disease progression or unacceptable toxicities.<br />
Results: Between Aug. 2001 and Mar. <strong>2012</strong>, 52 pts (P3; 25, P2; 4, P0CY1; 23)<br />
including 27 males and 25 females, with a median age of 59 (21-80) were enrolled.<br />
Total No. of cycle was 334, <strong>the</strong> median No. of cycle was 6 (2-15), reduced courses<br />
were 109, delayed courses (>7 days) were 46. Reductive gastrectomy was performed<br />
for 7 cases. The grade 3/4 toxicities were neutropenia (5.8%), anemia (7.7%),<br />
anorexia (13.5%), fatigue (9.6%), and diarrhea (9.6%), respectively. However febrile<br />
neutropenia, grade 4 non-hematological toxicities and TRD were not observed. The<br />
incidence of cancer cell positive cytology (CY1) changed to negative (CY0) was<br />
61.0% (25/41), but no obvious peritoneal metastasis (P1-P3) disappeared. The MST<br />
was 11.1 months and l-, 2- and 3-year survival rate was 48.1%, 23.1 and 9.6%,<br />
respectively.<br />
Conclusions: With respect to low toxicity and high feasibility, IP infusion of DOC<br />
with oral S-1 is an alternate treatment for metastatic or recurrent GC with peritoneal<br />
dissemination.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
703P SMALL BOWEL ADENOCARCINOMA PHENOTYPE<br />
ACCORDING TO THE PRIMARY LOCALISATION<br />
Annals of Oncology<br />
T. Aparicio 1 , M. Svrcek 2 , A. Laforest 3 , A. Zaanan 4 , P. Afchain 5 , E. Mitry 6 ,<br />
J. Taieb 4 , F. Di Fiore 7 , J. Gornet 8 , P. Laurent-Puig 3<br />
1 Gastroenterology, Hopital Avicenne, Bobigny Cedex, FRANCE, 2 Pathology,<br />
Hôpital Saint Antoine, AP-HP, Paris, FRANCE, 3 Umr-s775, Université Paris<br />
Descartes, Paris, FRANCE, 4 Gastroenterology, Hôpital Européen Georges<br />
Pompidou, APHP, Paris, FRANCE, 5 Oncology, Hôpital Saint Antoine, AP-HP,<br />
Paris, FRANCE, 6 Oncology, Institut Curie, Paris, FRANCE, 7 Digestive Oncology<br />
Unit, C.H.U. Charles Nicolle, Rouen, FRANCE, 8 Gastroenterology, Hôpital Saint<br />
Louis, Paris, FRANCE<br />
Background: Small bowel adenocarcinoma (SBA) is a rare tumor with poor<br />
prognosis. Data about molecular biology on SBA carcinogenesis are lacking.<br />
Methods: We characterised a number of candidate oncogenic pathways and <strong>the</strong><br />
immunophenotype according to <strong>the</strong> primary localisation of patients with SBA treated<br />
in 11 centers between 1996 and 2008. Tissue microarrays were constructed from<br />
tumour samples and DNAs were extracted from formalin fixed paraffin embedded<br />
samples. HER2, b catenin, TP53 and mismatch repair (MMR) protein expression<br />
were assessed by immunohistochemistry. Overexpression of TP53 was defined as<br />
more than 50% of cells with nuclear staining. Abnormal expression of b catenin was<br />
defined as a nuclear staining. KRAS mutation was investigated. Patients were enrolled<br />
in <strong>the</strong> study at all stage of <strong>the</strong> disease.<br />
ix234 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Results: Samples from 63 patients were obtained, ampullary tumours were excluded.<br />
The median age was 58 years. Tumour stages were I-II n = 19 (30%), III n = 22 (35%),<br />
IV n = 20 (32%) and undefined n = 2 (3%). A HER2 surexpression (3+) was observed<br />
in 2/51 (3.9%) cases both in ileum. Overexpression of TP53 was observed in 23/53<br />
(43%). Abnormal expression of b catenin was observed in 11/52 (21%) cases. A loss of<br />
MMR proteins occurred in 7/55 (13%) cases (3 MLH1, 2 MSH2, 2 MSH6), none was<br />
stage IV. A KRAS mutation was observed in 19/48 (40%) cases that involved codon 12<br />
in 13 (68%) cases or G > A transition in 16 (84%). Tumours with KRAS mutation were<br />
stage IV in 31% of <strong>the</strong> cases. Survival analysis will be available at <strong>the</strong> meeting.<br />
Conclusion: This large study suggests that molecular phenotype of SBA is close to<br />
colon phenotype with low level of HER 2 surexpression and high level of KRAS<br />
mutation. Ileum tumours seem to have a different phenotype than proximal tumours.<br />
Duodenum n = 32<br />
(51%)<br />
Jejunum n = 18<br />
(28%)<br />
Ileum n = 13<br />
(21%)<br />
Stage IV n = 20 9 (45%) 6 (30%) 5 (25%)<br />
HER2 surexpression n = 2 0 (0%) 0 (0%) 2 (100%)<br />
TP53 overexpression n = 23 12 (52%) 6 (26%) 5 (22%)<br />
Abnormal b catenin n = 11 4 (36%) 2 (18%) 5 (45%)<br />
Abnormal MMR n = 7 3 (43%) 4 (57%) 0 (0%)<br />
KRAS mutation n = 19 11 (58%) 6 (32%) 2 (10%)<br />
Disclosure: All authors have declared no conflicts of interest.<br />
704P COST-EFFECTIVENESS OF THREE-YEARS OF ADJUVANT<br />
IMATINIB IN GASTROINTESTINAL STROMAL TUMORS (GIST)<br />
IN CANADA<br />
A. Parthan 1 , M. Sanon 1 , J. Coombs 2 , K. El Ouagari 3<br />
1 Health Economics and Outcomes Research, OptumInsight, Medford, MA,<br />
UNITED STATES OF AMERICA, 2 Health Economics, Novartis Pharmaceuticals,<br />
Florham Park, NJ, UNITED STATES OF AMERICA, 3 Health Economics, Novartis<br />
Pharmaceuticals Canada Inc, Quebec, QC, CANADA<br />
Background: Recent clinical trial data have demonstrated that 3 years (yrs) of<br />
adjuvant imatinib <strong>the</strong>rapy for patients with surgically resected GIST leads to a<br />
significant improvement in recurrence free survival & overall survival vs. 1 yr of<br />
<strong>the</strong>rapy. The objective of this study is to assess cost-effectiveness of treating with 3<br />
yrs vs. 1 yr of adjuvant imatinib in Canada from a payer’s perspective.<br />
Methods: A Markov model was developed to predict GIST recurrence, treatment<br />
(txt) costs, & quality-adjusted survival over a lifetime horizon. Patients transitioned<br />
between 3 health states: free of GIST recurrence, GIST recurrence, & death. Monthly<br />
recurrence & mortality rates for 3 yr & 1 yr imatinib were derived from SSGXVIII/<br />
AIO clinical trial. The 5 yr recurrence rate observed in <strong>the</strong> trial was extrapolated for<br />
<strong>the</strong> remaining duration of <strong>the</strong> model horizon. First recurrence after active txt was<br />
treated with imatinib 400 mg daily and recurrence during active txt was treated with<br />
800mg daily. For subsequent disease progression, patients were treated with imatinib<br />
800mg, sunitinib or best supportive care. After 5 years, txt specific mortality rate was<br />
applied for patients with recurrence. Costs & utilities were derived from published<br />
literature. Expected costs & quality-adjusted life years (QALYs) were estimated for<br />
each txt strategy. Costs & QALYs were discounted at 5% per yr. Extensive sensitivity<br />
analyses were conducted.<br />
Results: Patients on 3 yrs of imatinib had higher QALYs (7.70 vs 6.54) vs. 1yr of<br />
imatinib. Total lifetime cost per patient was $182,000 with 3 yrs vs. $134,500 for 1 yr<br />
of imatinib <strong>the</strong>rapy. Incremental cost effectiveness ratio of 3 yrs of imatinib vs 1 yr of<br />
imatinib was $40,877/QALY. Model results were sensitive to rate of GIST recurrence<br />
beyond 5 yrs. At a threshold of $100,000 or $50,000/QALY, 3yr imatinib <strong>the</strong>rapy was<br />
cost-effective in 100% of simulations vs. 1 yr of imatinib.<br />
Conclusions: Model results suggest that treating patients with 3 yrs of imatinib is<br />
cost-effective vs. 1 yr of imatinib below <strong>the</strong> commonly used threshold in Canada.<br />
Both clinical & economic results suggest treating surgically resected GIST patients<br />
with 3 yrs of imatinib would result in improved quality-adjusted & overall<br />
survival.<br />
Disclosure: A. Parthan: Study was sponsored by Novartis and I have consulting<br />
relationship with Novartis. M. Sanon: The study was sponsored by Novartis and I<br />
had consultancy relationship with Novartis at <strong>the</strong> time of <strong>the</strong> study. J. Coombs:<br />
Employed at Novartis and holds Stock for Novartis. K. El Ouagari: employed at<br />
Novartis and owns stocks for Novartis<br />
705P PHASE I TRIAL OF SUNITINIB PLUS IMATINIB IN PATIENTS<br />
WITH METASTATIC OR UNRESECTABLE GASTROINTESTINAL<br />
STROMAL TUMORS (GIST)<br />
A. Lopez Pousa 1 , L. Paz-Ares 2 , C. Pericay 3 , X. Garcia Del Muro 4 , M.J. Flor 5<br />
1 Medical Oncology, Hospital de la Sta. Creu i St. Pau, Barcelona, SPAIN,<br />
2 Oncology Service, Hospital Virgen del Roc, Seville, SPAIN, 3 Medical Oncology,<br />
Corporació Sanitària Parc Taulí Institut Universitari, Sabadell, SPAIN, 4 Medical<br />
Oncology, Institut Catala d’oncologia, L’Hospitalet de Llobregat, SPAIN,<br />
5 Oncology Service, Hospital Virgen del Rocio, Seville, SPAIN<br />
Background: Patients (Pts) with GIST harboring mutations in KIT exon 9 or wild<br />
type tumors showed better responses to sunitinib along with longer median<br />
progression-free survival (PFS) rates compared with exon 11 mutant tumors pts. We<br />
have hypo<strong>the</strong>sized that <strong>the</strong> combination of S plus I in unresectable GIST would be<br />
synergistic and associated to a tolerable side effect profile.<br />
Methods: This is a phase I, dose-escalation study to determine <strong>the</strong><br />
maximum-tolerated dose (MTD), safety and antitumor activity measured by response<br />
rate of S plus I in naive patients with metastatic or unresectable GIST. Pts with<br />
adequate organ function, performance status (ECOG) 0-1, age >18 years, were<br />
eligible. Treatment consisted on oral S 25mg/day d1-28 combined with oral I 300mg/<br />
day d1-28 (level I) or oral I 400mg/day d1-28 (level II).<br />
Results: 3 pts were enrolled on Level I. No DLTs were observed. At level II 7 pts<br />
were enrolled and 1 DLT was observed (posterior reversible encephalopathy<br />
syndrome on day19). Although 1DLT was observed in 7 pts, decision was not to<br />
increase <strong>the</strong> S dose to 37.5 mg due to toxicity. O<strong>the</strong>r non-DLTs adverse events<br />
were G4 hyperbilirubinemia in cycle 2 and G4 intratumoral haemorrhage in cycle<br />
3.TheMTDwasdeterminedasI400mg/dayandS25mg/day.O<strong>the</strong>rtoxicities<br />
were neutropenia, diarrhoea, vomiting, as<strong>the</strong>nia, musculoskeletal pain, anaemia<br />
and bacteraemia. Median time on treatment with <strong>the</strong> combination was 16 weeks<br />
(range 12-152) on level I and 20 weeks (range 3-88) on level II. 66% of patients<br />
completed 20 weeks of treatment. Serious Adverse Events were reported in 4 pts; 3<br />
deaths were reported, one due to disease progression, ano<strong>the</strong>r due to reversible<br />
encephalopathy syndrome and <strong>the</strong> last one due to septic shock. A partial response<br />
was achieved in 6 (60%) pts; complete response in 2 (1 wild-type) (20%) and<br />
stable disease in 1 (10%).<br />
Conclusions: Sunitinib 25mg/day plus Imatinib 400mg/day is <strong>the</strong> MTD and a safe<br />
and well tolerated combination in pts with metastatic or unresectable GIST. Response<br />
rates seems to be higher than those expected and previously observed with S or I<br />
mono<strong>the</strong>rapy. This study was supported by an Independent Investigator Research<br />
grant from Pfizer, Inc<br />
Disclosure: All authors have declared no conflicts of interest.<br />
706P COST-EFFECTIVENESS ANALYSIS OF THREE YEAR VERSUS<br />
ONE YEAR IMATINIB FOR THE TREATMENT OF PATIENTS AT<br />
HIGH RISK OF DISEASE RECURRENCE FOLLOWING<br />
SURGICAL RESECTION OF KIT (CD117) POSITIVE<br />
GASTROINTESTINAL STROMAL TUMOURS (GIST)<br />
B. Nagy 1 ,L.Gray 2 , S.E. Ward 1<br />
1 Health Economics and Decision Science, University of Sheffield, Sheffield,<br />
UNITED KINGDOM, 2 Health Economics & Research Outcome, Novartis<br />
Pharmaceuticals UK Ltd, Frimley, UNITED KINGDOM<br />
Background: Imatinib is licensed for <strong>the</strong> adjuvant treatment of adult patients who<br />
are at significant risk of disease recurrence following resection of KIT (CD117)<br />
positive GIST. The SSG Phase III trial has shown significant survival benefits for<br />
patients who received three years of treatment with Glivec® (imatinib) after surgery to<br />
remove KIT (CD117)-positive GIST (KIT+ GIST) compared to one year of<br />
treatment. Aim: To evaluate <strong>the</strong> cost-effectiveness of three years’ imatinib adjuvant<br />
<strong>the</strong>rapy in comparison with one year <strong>the</strong>rapy for adult patients at high risk of disease<br />
recurrence following surgical resection of KIT (CD117) positive GIST in Scotland.<br />
Methods: The economic model predicts long-term survival for patients on three<br />
years of adjuvant imatinib compared with those on one year of <strong>the</strong>rapy. A Markov<br />
state-transition model was used to simulate patient pathways over a lifetime horizon.<br />
Patients were grouped into three primary health states: (1) free of recurrent GIST; (2)<br />
recurrent GIST; and (3) death (from GIST or o<strong>the</strong>r causes). Efficacy data were<br />
derived from a retrospective review of <strong>the</strong> SSG study to identify high risk patients, as<br />
defined by <strong>the</strong> Miettinen risk criteria. Costs (drug costs, hospital appointments for<br />
administration and monitoring, and treatment for adverse events) and health related<br />
quality of life values were assigned to each health state. Cost-effectiveness was<br />
expressed in terms of incremental cost per quality-adjusted life-years (QALYs)<br />
gained.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds398 | ix235
Results: Three years of adjuvant imatinib <strong>the</strong>rapy for patients at high risk of<br />
recurrence was predicted to achieve an additional 1.58 QALYS compared with one<br />
year of treatment. These health benefits are gained at an estimated incremental cost<br />
per QALY of £14,108. These results were robust to changes in key model parameters.<br />
Conclusions: The analysis suggests that, for patients at high risk of recurrence<br />
following surgical resection of localised GIST, three years of adjuvant imatinib<br />
treatment leads to improved long term quality-adjusted survival compared with one<br />
year’s <strong>the</strong>rapy. Extended adjuvant treatment with imatinib represents good value for<br />
money according to currently accepted standards of cost-effectiveness in Scotland.<br />
Disclosure: L. Gray: I am an employee of Novartis Pharmaceuticals UK Ltd,<br />
manufacturer of imatinib. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
707P A COST-EFFECTIVENESS ANALYSIS OF THREE YEARS OF<br />
ADJUVANT IMATINIB IN KIT+ GASTROINTESTINAL STROMAL<br />
TUMORS (GIST) IN GREECE<br />
M. Raikou 1 , I. Boukovinas 1 , M. Geitona 2<br />
1 Social Policy, London School of Economics & Political Sciences, London,<br />
UNITED KINGDOM, 2 Social Policy, University of Peloponnese, A<strong>the</strong>ns, GREECE<br />
Background and objective: Clinical studies have demonstrated <strong>the</strong> clinical benefit of<br />
adjuvant imatinib for patients who undergo complete gross resection for KIT+ GIST<br />
both in terms of overall and recurrence-free survival. The aim of this study is to<br />
assess <strong>the</strong> cost-effectiveness of <strong>the</strong> following treatment options a) 3 yr adjuvant<br />
imatinib (IM) vs 1yr IM, b) 3yr IM vs. surgical resection only c) lifetime IM vs. 1 yr<br />
IM as adjuvant <strong>the</strong>rapy in patients with KIT GIST, from <strong>the</strong> perspective of <strong>the</strong> Greek<br />
National Health Service (NHS).<br />
Methods: A Markov transition state model was developed and populated with data<br />
from published literature and expert opinion. All patients enter <strong>the</strong> model free of<br />
recurrence and over subsequent cycles, a patient may remain free of GIST, may enter<br />
a state of recurrent GIST or may die of GIST or o<strong>the</strong>r causes. The mean starting<br />
patient age was 58 years old and <strong>the</strong> discount rate 3% per year. Resource utilization<br />
reflects Greek disease management. Pharmaceutical and adverse events cost was<br />
based on <strong>2012</strong> prices. Extensive sensitivity analysis was also undertaken.<br />
Results: Mean total cost per patient was estimated at €72,899 for 1 yr of adjuvant IM<br />
versus €112,910 for 3yr IM. Effectiveness was estimated to be 10.80 and 12.76<br />
life-years and 7.63 and 9.19 QALYs respectively for 1yr vs. 3yr. The incremental<br />
cost-effectiveness was thus €20,387 per life-year gained and €25,700 per QALY<br />
gained over a patient’s lifetime. These results were most sensitive to <strong>the</strong> rate of GIST<br />
recurrence beyond 5 years. The incremental cost of 3 years of IM versus surgical<br />
resection alone was €14,649 per life-year gained and €18,448 per QALY gained and<br />
€65,943 per life-year gained and €82,851 per QALY gained over a patient’s lifetime<br />
for lifetime IM treatment versus 1 year of imatinib. These results were most sensitive<br />
to <strong>the</strong> monthly cost of IM.<br />
Conclusions: This analysis has shown that 3yr adjuvant IM <strong>the</strong>rapy is considered<br />
highly cost-effective for <strong>the</strong> Greek NHS when compared to ei<strong>the</strong>r 1yr adjuvant IM or<br />
surgical resection alone. Lifetime vs. 1y adjuvant IM is associated with a moderate<br />
incremental cost-effectiveness ratio that is far below <strong>the</strong> acceptable threshold of<br />
€100.000 for life-threatening diseases.<br />
Disclosure: M. Raikou: This study was sponsored by Novartis Hellas S.A. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
708P REAL-LIFE MANAGEMENT OF ADVANCED<br />
GASTROINTESTINAL STROMAL TUMORS (GIST) TREATED<br />
WITH IMATINIB IN FRANCE<br />
O. Bouché 1 , A. Le Cesne 2 , M. Rios 3 , L. Chaigneau 4 , B. Bui 5 , P. Xavier 6 , J. Blay 7<br />
1 Hepatology-gastroenterology, Hopital Robert Debré, Reims, FRANCE, 2 Dept.<br />
Medical Oncology, Institut Gustave Roussy, Villejuif, FRANCE, 3 Oncologie, Centre<br />
Alexis Vautrin, Vandoeuvre-lès-Nancy, FRANCE, 4 Oncologie, Hopital Jean<br />
Minjoz, Besancon, FRANCE, 5 Oncology, Institute Bergoni, Bordeaux Cedex,<br />
FRANCE, 6 Oncology, Novartis, Rueil Malmaison, FRANCE, 7 University Claude<br />
Bernard Lyon I, Centre L, Lyon Cedex, FRANCE<br />
Introduction: GISTs are rare tumors of <strong>the</strong> gastrointestinal tract. Imatinib has been<br />
approved for <strong>the</strong> treatment of Kit+ unresectable or metastatic GIST since 2002.<br />
However, information is lacking in <strong>the</strong> real-life, non-trial setting on <strong>the</strong> efficacy, use,<br />
and safety of imatinib, and <strong>the</strong> quality of life of imatinib-treated patients. The<br />
EPIGIST study was set up in 2006 in France to obtain this information.<br />
Annals of Oncology<br />
Method: EPIGIST is a multicenter, observational, longitudinal follow-up cohort<br />
study conducted in France on patients diagnosed with a Kit + unresectable or<br />
metastatic GIST, treated with imatinib for <strong>the</strong> first time, between its market<br />
introduction and 2011. Sites were selected at random from a national file of<br />
oncologists, gastroenterology surgeons, and gastroenterologists. The intended<br />
follow-up period was 3 years. A clinical case report form was completed at<br />
enrollment and at each visit.<br />
Results: 31 sites enrolled at least one patient. A total of 164 patients were enrolled,<br />
151 were analyzed. Median age at diagnosis was 60 years (range: 21–86 years), sex<br />
ratio was predominantly male (58%). The commonest locations of <strong>the</strong> primary GIST<br />
at diagnosis were stomach (46%) and small intestine (37%). 85 (56%) analyzed<br />
patients had localized disease at diagnosis, and 42 (49%) were at high risk of relapse<br />
according to Miettinen’s classification; 60 (70%) had developed metastatic disease by<br />
<strong>the</strong> time imatinib <strong>the</strong>rapy was instituted (median 13 months after diagnosis; range 0–<br />
135 months). The starting dose of imatinib for 148 (98%) patients was 400 mg/day.<br />
The estimated 4-year overall survival was 60.7% (95% CI: [51.4%; 68.8%]), with a<br />
median follow-up of 4 years. Adverse events disorders were gastrointestinal (70%),<br />
general disorders and administration site conditions (70%), eye (38%),<br />
musculoskeletal and connective tissue (35%), and skin and subcutaneous tissue<br />
(34%).<br />
Conclusion: The EPIGIST observational study confirms that <strong>the</strong> results of <strong>the</strong><br />
clinical studies are maintained in <strong>the</strong> real-life setting. The indications for imatinib<br />
have been recently extended to include <strong>the</strong> adjuvant treatment of patients at<br />
significant risk of relapse following resection of Kit+ GIST. This population is not<br />
described in this study.<br />
Disclosure: O. Bouché: Consulting fees from Novartis and Pfizer. A. Le Cesne:<br />
Honorary Grants from Novartis, Pfizer, Pharmamar. P. Xavier: Employment full time<br />
Novartis. J. Blay: Research grants: Novartis, Roche, GSK, Pfizer, Pharmamar<br />
Consulting fees: Novartis, Roche, GSK, Pfizer, Pharmamar. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
709P THE HENT1 IMMUNOHISTOCHEMISTRY DIAGNOSTIC TEST<br />
IS PREDICTIVE OF GEMCITABINE OUTCOME IN PANCREATIC<br />
DUCTAL ADENOCARCINOMA<br />
M. Raponi 1 , J. Isaacson 1 , H. Hahn 2 , M. Bartosiewicz 1 , A. Magnusson 2 , K. Lin 1 ,<br />
L. Rolfe 3 , A. Allen 1 , V. Picozzi 2<br />
1 Clovis Oncology, Clovis Oncology, San Francisco, CA, UNITED STATES OF<br />
AMERICA, 2 Pathology, Virginia Mason Medical Center, Seattle, WA, UNITED<br />
STATES OF AMERICA, 3 Sheraton House, Clovis Oncology UK Ltd, Cambridge,<br />
UNITED KINGDOM<br />
Human equilibrative nucleoside transporter 1 (hENT1) is <strong>the</strong> primary membrane<br />
channel through which gemcitabine (GEM) enters pancreatic tumor cells. Patients<br />
(pts) whose resected pancreatic ductal adenocarcinoma (PDAC) express low levels of<br />
hENT1 may derive little benefit from GEM <strong>the</strong>rapy. Recently, a validated diagnostic<br />
immunohistochemistry (IHC) test has been developed. Here, we prospectively test<br />
this diagnostic in a series of 204 retrospectively collected formalin-fixed<br />
paraffin-embedded (FFPE) PDAC tissues. 134 primary and 70 metastatic PDAC<br />
pre-treatment specimens were dichotomized into high versus low hENT1 tumor<br />
expression. Overall, 39% of primary and 23% of metastatic cases had high levels of<br />
tumoral hENT1. In <strong>the</strong> primary tumor set 90/134 pts went on to receive GEM-based<br />
<strong>the</strong>rapy; pts with high hENT1 tumor levels had a median overall survival (OS) of 35<br />
months compared to 15 months in those with low levels of tumoral hENT1 (HR =<br />
0.48). In 44 non-GEM treated pts <strong>the</strong>re was no association between hENT1 tumor<br />
expression and overall survival (median OS of 26 versus 28 months in pts with<br />
hENT1 high and low, respectively; HR = 0.8). In 63/70 metastatic specimens from<br />
patients treated with GEM <strong>the</strong> median OS was 25 versus 10 months (HR = 0.64) for<br />
high versus low hENT1 tumors respectively. In conclusion, we have prospectively<br />
tested <strong>the</strong> utility of <strong>the</strong> hENT1 IHC diagnostic in predicting clinical outcome in an<br />
institutional series of FFPE tumors from PDAC pts. The assay was effective in<br />
identifying GEM-treated pts with a poorer OS outcome using both primary and<br />
metastatic FFPE tumor tissues. This diagnostic is being prospectively tested in a<br />
global pivotal trial of CO-101 (CP-4126; a lipid drug conjugate of GEM designed to<br />
enter tumor cells independently of hENT1) versus GEM alone in metastatic PDAC<br />
(“LEAP“, NCT01124786).<br />
Disclosure: M. Raponi: Employee and stock holder of Clovis Oncology. J. Isaacson:<br />
Employee and stock holder of Clovis Oncology. M. Bartosiewicz: Employee and stock<br />
holder of Clovis Oncology. K. Lin: Employee and stock holder of Clovis Oncology. L.<br />
Rolfe: Employee and stock holder of Clovis Oncology. A. Allen: Employee and stock<br />
holder of Clovis Oncology. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
ix236 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
710P FIRGEM, A SEQUENTIAL FOLFIRI.3 (CPT-11 PLUS FOLINIC<br />
ACID PLUS 5-FU) FOLLOWED BY GEMCITABINE OR<br />
GEMCITABINE ALONE IN PATIENTS WITH PREVIOUSLY<br />
UNTREATED METASTATIC PANCREATIC ADENOCARCINOMA:<br />
RESULTS OF A RANDOMIZED MULTICENTER AGEO PHASE II<br />
TRIAL<br />
I. Trouilloud 1 , A.C. Dupont-Gossard 2 , P. Artru 3 , T. Lecomte 4 , M. Gauthier 5 ,<br />
T. Aparicio 6 , A. Thirot-Bidault 7 , D. Malka 8 , F. Bonnetain 9 , J. Taieb 1<br />
1 Oncologie Digestive, Hopital Europeen Georges Pompidou, Paris, FRANCE,<br />
2 Hepato-Gastro-Enterologie, CHU Jean Minjoz, Besancon, FRANCE, 3 Oncologie<br />
Digestive, Hopital Prive Jean Mermoz, Lyon, FRANCE,<br />
4 Hepato-Gastro-Enterologie, Hopital Trousseau, Tours, FRANCE, 5 Biostatistic<br />
Unit, Georges-François Leclerc Cancer Center, Dijon, FRANCE,<br />
6 Hepato-Gastro-Enterologie, Hopital Avicenne, Bobigny, FRANCE,<br />
7 Hepato-Gastro-Enterologie, Bicetre Hospital, Kremlin-Bicetre, FRANCE,<br />
8 Oncologic Medicine, Institut Gustave Roussy, Villejuif, FRANCE, 9 Biostatistic and<br />
Epidemiological Unit (ea 4184), Centre Georges François Leclerc, Dijon,<br />
FRANCE<br />
Background: CPT-11 showed modest activity and tolerability in metastaic pancreatic<br />
cancer (MPA). We developed a new strategy to improve efficacy and tolerability of<br />
CPT-11 based regimen in MPA patients (pts).<br />
Methods: Chemo<strong>the</strong>rapy-naive pts with histologically proven MPA, bilirubin levels <<br />
1.5 ULN and performance status (PS) 0-1 were randomized in a phase II trial to<br />
receive ei<strong>the</strong>r FOLFIRI.3 (CPT-11 90 mg/m 2 as a 60-min infusion on day (D) 1,<br />
leucovorin 400 mg/m 2 as a 2-hr infusion on day 1, followed by 5-FU 2000 mg/m 2 as<br />
a 46-hr infusion and CPT-11 90 mg/m 2 , repeated on D3, at <strong>the</strong> end of <strong>the</strong> 5-FU<br />
infusion, every 2 weeks) for 2 months alternarting with Gemcitabine (G) (1000 mg/<br />
m 2 at a fixed dose rate of 10 mg/m 2 /min on D1, D8, D15, D29, D36 and D43) for 2<br />
months (arm A) or G alone (arm B). Using Fleming design <strong>the</strong> primary end point<br />
was rate of progression free survival (PFS) at 6 months from (H0) 25% over (H1)<br />
45% needing to include 49 pts/arm.<br />
Results: Between 2007 and 2011, 98 pts were enrolled (males: 59, median age: 62<br />
years, PS 0: 32%). Median follow-up was 23 months. Grade 3-4 toxicities per pts (%)<br />
in arm A/B were diarrhea 13/0, nausea-vomiting 11/4, neutropenia 51/25 and febrile<br />
neutropenia 4/0. No toxic death occurred. Response rate were 40 and 11% as disease<br />
control rate (CR + PR + SD) were 73 and 52% in arm A and B, respectively. The<br />
primary endpoint of <strong>the</strong> trial was met with rate of PFS at 6 months of 48% (95% CI:<br />
33-63) in arm A while in arm B PFS was 30% (95% CI: 17 - 44). One year PFS was<br />
23% (95%CI: 11.5-36) and 11% (95%CI: 4-21), respectively.<br />
Conclusions: FIRGEM strategy is feasible and efficient with a manageable toxicity<br />
profile in good condition pts with MPA. A phase III trial comparing this strategy<br />
with <strong>the</strong> FOLFIRINOX triplet <strong>the</strong>rapy focusing on quality of life should now be<br />
performed.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
711P DOES FDG-PET-CT BASED RE-STAGING INFLUENCES<br />
INITIAL MANAGEMENT DECISION AND CLINICAL OUTCOME<br />
IN PATIENTS WITH LOCALLY ADVANCED PANCREATIC<br />
CARCINOMA PLANNED TO UNDERGO<br />
CHEMORADIOTHERAPY?<br />
C. Parlak 1 , O.C. Guler 1 , U. Selek 2 , O. Ozyilkan 3 , E. Topkan 1<br />
1 Department of Radiation Oncology, Baskent University Adana Medical Faculty,<br />
Adana, TURKEY, 2 Department of Radiation Oncology, American Hospital-<br />
University of Texas M.D. Anderson Radiation Oncology Center, Istanbul,<br />
TURKEY, 3 Medical Oncology, Baskent University Faculty of MedicineAdana<br />
Uygulama Ve Arastirma Mer., Adana, TURKEY<br />
Background: Impact of re-staging with 18F-fluoro-deoxy-glucose positron emission<br />
tomography (PET-CT) on management decision and clinical outcomes in patients<br />
with locally-advanced pancreatic carcinoma (LAPC) initially planned to undergo<br />
concurrent chemoradio<strong>the</strong>rapy (CRT) was investigated.<br />
Materials and methods: Seventy-one consecutive patients with conventionally staged<br />
LAPC were re-staged with PET-CT before CRT. Patients were categorized into<br />
non-metastatic (M0) and metastatic (M1) groups according to PET-CT findings.<br />
M0patients underwent 50.4 Gy (1.8 Gy/fr) of radio<strong>the</strong>rapy and concurrent 5-FU<br />
followed by maintenance gemcitabine.<br />
Results: Re-staging PET-CT revealed conventional imaging occult distant metastases<br />
in 19 cases (26.8%). Of 52 patients with LAPC confirmed by PET-CT, additional<br />
regional lymph nodes were identified to be involved in 7 (13.4%), mandating<br />
enlargement of radiation field. Taken toge<strong>the</strong>r, PET-CT results changed or revised<br />
initial management decision in 37.2% patients. Median follow-up times for <strong>the</strong><br />
whole, M 0 and M 1 cohorts were 11.3, 14.5, and 6.2 months, respectively. Median<br />
overall, locoregional progression-free, and progression-free survivals for <strong>the</strong> same<br />
cohorts were 11.4, 7.8, and 5.1 months,16.1, 9.9, and 7.4 months, and 6.2, 3.4, and<br />
2.5 months, respectively. Survival differences between M0 and M1 cohorts were<br />
statistically significant (p < 0.05, for each).<br />
Conclusions: Current results demonstrated <strong>the</strong> importance of PET-CT based<br />
re-staging of LAPC in selection of suitable patients for CRT, prevention of useless<br />
aggressive treatment in metastatic cases, and precise estimation of survival outcomes<br />
of LAPC patients following radical CRT.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
712P MISTLETOE EXTRACT THERAPY VERSUS NO<br />
ANTINEOPLASTIC THERAPY IN PATIENTS WITH LOCALLY<br />
ADVANCED OR METASTATIC PANCREATIC CANCER: A<br />
RANDOMIZED CLINICAL PHASE III TRIAL ON OVERALL<br />
SURVIVAL<br />
D. Galun 1 , W. Tröger 2 , M. Reif 3 , A. Schumann 4 , N. Stanković 5 , M. Milićević 1<br />
1 HPB Surgical Department, First Surgical Clinic of <strong>the</strong> Clinical Centre of Serbia,<br />
Belgrade, SERBIA, 2 Directorship, CRDT, Freiburg, GERMANY, 3 Directorship,<br />
Institute for Clinical Research, Berlin, GERMANY, 4 Biometry, Institute for Clinical<br />
Research, Berlin, GERMANY, 5 Data Management, Clinicoboss, Niš, SERBIA<br />
Purpose: To compare <strong>the</strong> overall survival (OS) and quality of life (QoL) of advanced<br />
pancreatic cancer patients receiving mistletoe extract (ME) <strong>the</strong>rapy or no<br />
antineoplastic <strong>the</strong>rapy.<br />
Patients and methods: In this prospective, parallel, open label, monocenter,<br />
group-sequential, randomized phase III study patients with locally advanced or<br />
metastatic adenocarcinoma of <strong>the</strong> pancreas were stratified according to <strong>the</strong>ir prognosis<br />
index, a binary composite of age, tumor stage and performance status, and were evenly<br />
randomized to s.c. injections of ME (Iscador® Qu special) in a dose-escalating manner<br />
from 0.01 mg up to 10 mg three times per week, or no antineoplastic <strong>the</strong>rapy<br />
(control). All patients received best supportive care. The primary endpoint was<br />
12-month OS to be repeatedly assessed in three subsequent group-sequential analyses.<br />
Secondary efficacy parameters were <strong>the</strong> QoL dimensions of <strong>the</strong> core questionnaire of<br />
<strong>the</strong> European Organisation for Research and Treatment of Cancer.<br />
Results: This first interim analysis includes data from 220 patients. Baseline<br />
characteristics were well balanced between <strong>the</strong> ME and control groups. Median OS for<br />
ME versus control patients was 4.8 vs. 2.7 months (prognosis-group adjusted hazard<br />
ratio, HR = 0.49; p < 0.0001); within <strong>the</strong> ‘good’ prognosis subgroup 6.6 vs. 3.2 months<br />
(HR = 0.43; p < 0.0001); within <strong>the</strong> ‘poor’ prognosis subgroup 3.4 vs. 2.0 months (HR<br />
= 0.55; p = 0.0031). Thirteen of <strong>the</strong> 15 QoL dimensions significantly favored ME. The<br />
‘Global Health Status/QoL’ was sig-nificantly higher for ME versus control patients by<br />
23.5 points (average patients’ post-baseline median: 54.2 ± 8.17 vs. 30.7 ± 8.46; p <<br />
0.0001). No ME-related serious or non-serious adverse events were observed.<br />
Conclusion: In this analysis ME <strong>the</strong>rapy showed a significant and clinically relevant<br />
increase of OS and quality of life. The independent data monitoring committee<br />
recommended <strong>the</strong> termination of <strong>the</strong> trial due to proven efficacy. ME may provide an<br />
effective second-line <strong>the</strong>rapy for patients with locally advanced or metastatic<br />
pancreatic cancer after failure of, or ineligibility for, first-line <strong>the</strong>rapies.<br />
Disclosure: D. Galun: Danijel Galun has received financial compensation for <strong>the</strong><br />
conduct of <strong>the</strong> submitted study by <strong>the</strong> Society of Cancer Research, Arlesheim.<br />
O<strong>the</strong>rwise, no payments were received. W. Tröger: Wilfried Tröger has received<br />
financial compensation for <strong>the</strong> conduct of <strong>the</strong> submitted study and ano<strong>the</strong>r clinical<br />
trial in breast cancer by <strong>the</strong> Society of Cancer Research, Arlesheim. O<strong>the</strong>rwise, no<br />
payments were received. M. Reif: The non-profit organization Society for Clinical<br />
Research receives donations from different institutions including <strong>the</strong> sponsor of <strong>the</strong><br />
submitted study, <strong>the</strong> Society of Cancer Research, Arlesheim. A. Schumann: The<br />
non-profit organization Society for Clinical Research receives donations from<br />
different institutions including <strong>the</strong> sponsor of <strong>the</strong> submitted study, <strong>the</strong> Society of<br />
Cancer Research, Arlesheim. N. Stanković: Nikola Stanković has received financial<br />
compensation for <strong>the</strong> conduct of <strong>the</strong> submitted study by <strong>the</strong> Society of Cancer<br />
Research, Arlesheim. O<strong>the</strong>rwise, no payments were received. M. Milićević: Miroslav<br />
Milićević has received financial compensation for <strong>the</strong> conduct of <strong>the</strong> submitted study<br />
by <strong>the</strong> Society of Cancer Research, Arlesheim. O<strong>the</strong>rwise, no payments were received.<br />
713P NEOADJUVANT GEMOX FOLLOWED BY GEM-BASED<br />
CHEMORADIATION FOR LOCALLY ADVANCED<br />
UNRESECTABLE PANCREATIC CANCER<br />
V. Vaccaro 1 , I. Sperduti 2 , E. Bria 3 , B. Saracino 1 , M.S. Pino 4 , G. Grazi 5 ,<br />
A. Gelibter 1 , G. Vallati 6 , F. Cognetti 1 , M. Milella 1<br />
1 Medical Oncology, Regina Elena National Cancer Institute, Roma, ITALY,<br />
2 Biostatistics, Regina Elena Institute, Roma, ITALY, 3 Medical Oncology, Azienda<br />
Ospedaliera Universitaria Integrata Verona-”Borgo Roma”, Verona, ITALY,<br />
4 Medical Oncology, USL 10 Firenze, Firenze, ITALY, 5 Surgical Oncology, Regina<br />
Elena National Cancer Institute, Roma, ITALY, 6 Radiology, Regina Elena National<br />
Cancer Institute, Roma, ITALY<br />
Purpose: To asses activity, safety and secondary resectability in unresectable locally<br />
advanced pancreatic cancer (LAPC) patients (pts).<br />
Methods: Unresectable LAPC pts were eligible for this phase II study. Primary<br />
endpoint was clinical benefit (CB = CR + PR + SD). A sample size of 37 pts was<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds398 | ix237
considered sufficient to give an 80% probability of rejecting a baseline clinical benefit<br />
rate of 55%, with an exact 5% one-sided significance test when <strong>the</strong> true disease<br />
control rate was 75%. The drug regimen would have been considered interest if at<br />
least 26 patients showed clinical benefit. Neoadjuvant induction chemo<strong>the</strong>rapy<br />
(CHT) encompassed gemcitabine (GEM) 1000 mg/m 2 (100-min infusion on d1) and<br />
oxaliplatin 100 mg/m 2 (2-hr infusion on d2) every 2 wks, for 6 cycles. After CHT pts<br />
were restaged for surgery and/or chemoradiation (CRT) consolidation (EBRT up to a<br />
total dose of 50.4 Gy plus concomitant GEM 300 mg/m 2 /week). After CRT<br />
completion, pts were restaged to evaluate secondary surgery.<br />
Results: From January 2005 to January <strong>2012</strong>, 35 pts (M/F: 17/18; median age: 68 yrs,<br />
range: 46-78; ECOG PS 0-1/2: 28/7) entered <strong>the</strong> study. A median of 5 (range 1-7)<br />
CHT induction cycles were delivered. Toxicity was mild, with G3-4 neutropenia in 2<br />
pts (6%), G3 thrombocytopenia in 1 pt (3%), G3 transaminase elevation in 5 pts<br />
(14%), and G3 diarrhea in 2 pts (6%). CHT dose was reduced or delayed in 8 and 7<br />
pts, respectively. Nine confirmed PR and 17 SD were observed for a CB of 74% (95%<br />
confidence interval [CI], 56.7-87.5%). A decrease in serum CA 19.9 ≥50% of <strong>the</strong><br />
baseline was observed in 14 of 23 evaluable pts. Nine-teen pts completed CRT,<br />
including 5 pts who subsequently underwent surgery; 1 pt underwent surgery<br />
without CRT. Toxicity for <strong>the</strong> CRT phase was mild, with G3 thrombocytopenia in 1<br />
pt (3%) and G3 neutropenia in 3 pts (8%). Median overall survival (OS) and<br />
progression free survival (PFS) for all 35 patients were 10 (95% CI, 8-12) and 9 mos<br />
(95% CI, 6-12), respectively. One-yr OS and PFS rates were 26% and 30%,<br />
respectively.<br />
Conclusions: The regimen under study is active and well tolerated. Although an<br />
encouraging response rate was reported, OS remains poor, calling for a better<br />
selection strategy for LAPC pts who are candidates to neoadjuvant treatment.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
714P MODIFIED FOLFOXIRI IN ADVANCED PANCREATIC CANCER<br />
L. Ginocchi, E. Vasile, S. Caponi, M. Lucchesi, C. Caparello, V. Da Prat,<br />
M. Baretti, M. Lencioni, S. Ricci, A. Falcone<br />
Oncologia, Trapianti e Nuove Tecnologie in Medicina, Polo Oncologico - Azienda<br />
Ospedaliero-Universitaria Pisana - Istituto Toscano Tumori, Pisa, ITALY<br />
Background: The combination regimen of 5-fluorouracil/folinic acid, oxaliplatin and<br />
irinotecan named FOLFIRINOX has been proposed as a new standard of care for<br />
metastatic pancreatic cancer patients. However, FOLFIRINOX was associated with<br />
high incidence of grade 3 and 4 toxicities (neutropenia in 45.7% of patients with<br />
G-CSF use in 42.5% of patients; febrile neutropenia in 5.4%; diarrhea in 12.7%). Our<br />
group had developed a very similar schedule in colorectal cancer named FOLFOXIRI<br />
which contains no bolus 5-fluorouracil and a slight lower dose of irinotecan.<br />
Methods: The objective of this study was to prospectively evaluate <strong>the</strong> tolerability<br />
and activity of a modified (m) FOLFOXIRI regimen in metastatic or locally advanced<br />
pancreatic cancer patients. The regimen included a lower dose of irinotecan<br />
(administered at 150 mg/sqm on day 1 every 14 days) and of infusional<br />
5-fluorouracil (2800 mg/sqm administered as a 48-hour continuous infusion on days<br />
1 to 3 every 14 days). Folinic acid and oxaliplatin remained unchanged.<br />
Results: Thirty-nine patients with cytological or histological diagnosis of pancreatic<br />
adenocarcinoma have been treated with mFOLFOXIRI from august 2010 onwards; 17<br />
had metastatic disease while 22 had locally advanced disease. A total of 260 cycles<br />
have been administered so far. The grade 3-4 toxicities reported are: neutropenia in<br />
35.9% of patients; thrombocytopenia 2.6%; diarrhea 5.1%; stomatitis 7.7%; nausea/<br />
vomiting 5.1%; fatigue 2.6%; liver toxicity 5.1%; sensory neuropathy 5.1%. No toxic<br />
deaths and no febrile neutropenia have been occurred. G-CSF has been used in seven<br />
patients (18%). A delay in <strong>the</strong> administration of chemo<strong>the</strong>rapy was required in 12<br />
patients (31%) and a reduction of doses in 7 cases (18%). Among 30 evaluable<br />
patients 11 partial responses (36.7%) and 14 stable disease (46.7%) have been<br />
observed. Median progression-free survival (PFS) was 11.5 months and median<br />
overall survival (OS) 25.5 months. For metastatic patients only, response rate resulted<br />
33% with a PFS and OS of 8.4 and 14.8 months, respectively.<br />
Conclusions: The mFOLFOXIRI regimen as we used resulted feasible and quite well<br />
tolerated and it maintained its good activity in metastatic pancreatic cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
715P TIMING AND PATTERNS OF DISEASE PROGRESSION<br />
FOLLOWING CONCURRENT RADIOCHEMOTHERAPY IN<br />
PATIENTS WITH UNRESECTABLE LOCALLY-ADVANCED<br />
PANCREAS CANCER<br />
C. Parlak 1 , O.C. Guler 1 , O. Ozyilkan 2 , E. Topkan 1<br />
1 Department of Radiation Oncology, Baskent University Adana Medical Faculty,<br />
Adana, TURKEY, 2 Medical Oncology, Baskent University Faculty of<br />
MedicineAdana Uygulama Ve Arastirma Mer., Adana, TURKEY<br />
Background: Timing and patterns of disease progression in patients with<br />
unresectable locally-advanced pancreas carcinoma (LAPC) treated with definitive<br />
concurrent radiochemo<strong>the</strong>rapy (C-RCT) was analyzed.<br />
Annals of Oncology<br />
Materials and method: Fifty-two patients with histologic proof of LAPC underwent<br />
50.4 Gy (1.8 Gy per fraction) of C-RCT with 5-FU followed by maintenance<br />
gemcitabine. Disease was considered to be unresectable if contrast-enhanced CT or<br />
staging laparoscopy/laparotomy revealed a low likelihood of complete resection and/<br />
or any of <strong>the</strong> following: involvement of superior mesenteric artery/cealiac trunk,<br />
encasement of 180 degrees or more of <strong>the</strong> circumference of superior mesenteric/<br />
portal vein, and/or evidence of narrowing of or thrombus within <strong>the</strong> superior<br />
mesenteric/portal vein. Elective nodal irradiation was not adopted. Primary aim was<br />
to assess timing and patterns of disease progression.<br />
Results: Treatment was well tolerated and all patients were able to receive intended<br />
C-RCT regimen. At median 17.4 months of follow-up 38 (73.1%) were dead. Median,<br />
1- and 2-year overall- and progression-free survival estimates were 16.1 months,<br />
61.2% and 22.6%, and 7.4 months, 27% and 12.3% respectively. Analysis for timing<br />
of disease progression revealed that 7 (13.5%), 15 (28.8%), 20 (38.5%), and 22<br />
(42.3%) patients experienced disease progression at 3, 4, 5, and 6 months,<br />
respectively, since initiation of R-RCT. Interestingly, although <strong>the</strong>re were no isolated<br />
local or regional failures during this early follow-up period, all failures were<br />
presented as distant metastases with/without local/regional disease progression.<br />
Conclusion: Results of this study demonstrated that, despite aggressive staging and<br />
treatment strategies, early distant disease progression are common source of<br />
treatment failures in unresectable LAPC. Present findings impact <strong>the</strong> urgent need for<br />
more efficacious chemo<strong>the</strong>rapeutic agents for control of distant metastatatic tumor<br />
deposits and better treatment strategies, such as induction chemo<strong>the</strong>rapy followed by<br />
C-RCT, to eliminate early treatment failures and unnecessary and futile C-RCT in<br />
metastatic disease state.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
716P FOLFIRINOX FOR LOCALLY ADVANCED PANCREATIC<br />
ADENOCARCINOMA. RESULTS OF AN AGEO MULTICENTRIC<br />
PROSPECTIVE STUDY<br />
L. Mar<strong>the</strong>y 1 , A. Sa-Cunha 2 , J.F. Blanc 3 , A. Cueff 4 , E. Francois 5 , I. Trouilloud 6 ,<br />
D. Malka 7 , J. Bachet 8 , R. Coriat 9 , J. Taieb 10<br />
1 Gastroenterology, Bicêtre Hospital, Kremlin Bicêtre, FRANCE, 2 Digestive<br />
Surgery, Haut Lévêque Hospital, Pessac, FRANCE, 3 Digestive Oncology, Saint<br />
André Hospital, Bordeaux, FRANCE, 4 Biostatistics and Epidemiology, Georges<br />
Leclerc Cancer Institute, Dijon, FRANCE, 5 Medical Oncology, Antoine<br />
Lacassagne Cancer Institute, Nice, FRANCE, 6 Digestive Oncology, European<br />
Georges Pompidou Hospital, Paris, FRANCE, 7 Medical Oncology, Gustave<br />
Roussy Cancer Institute, Villejuif, FRANCE, 8 Gastroenterology, Pitié-Salpêtrière<br />
Hospital, Paris, FRANCE, 9 Digestive Oncology, Cochin Hospital, Paris, FRANCE,<br />
10 Oncologie Digestive, Hopital Europeen Georges Pompidou, Paris, FRANCE<br />
Background: The FOLFIRINOX regimen improves survival when compared to<br />
gemcitabine as first line treatment for patients (pts) with metastatic pancreatic<br />
cancer (1). There is no such data in non resecable, non metastatic, locally advanced<br />
pancreatic adenocarcinoma (LAPA). The aim of this study was to evaluate <strong>the</strong> safety<br />
and efficacy of FOLFIRINOX in this setting.<br />
Methods: From February 2010 to February <strong>2012</strong>, all pts from eleven French<br />
hospitals, who started FOLFIRINOX for a pathologically proven LAPA were included<br />
in a prospective database. Non resectability was determined by each local<br />
multidisciplinary staff. The absence of metastases was assessed by TAP CT-scans.<br />
FOLFIRINOX was administered every 2 weeks (oxaliplatin 85 mg/m 2 ; irinotecan 180<br />
mg/m 2 ; leucovorin 400 mg/m 2 ; fluorouracil 400 mg/m 2 as bolus and 2400 mg/m 2 as<br />
46-hour continuous infusion).<br />
Results: Seventy seven pts were enrolled. We report <strong>the</strong> preliminary analysis of <strong>the</strong><br />
first 53 pts as data collection is still ongoing. Patients characteristics were M/F: 30/23;<br />
median age 63 (46-79); PS 0/1/2 : 24/28/1. twenty one pts had a bilary stent before<br />
starting treatment. The median number of cycles administered was 5 (1-30). There<br />
were no treatment-related deaths and 8% of pts stopped treatment because of<br />
toxicity. Grade 3-4 toxicities were neutropenia (15%), nausea (13%), diarrhea (8%),<br />
anemia (2%), and thrombopenia (2%). Grade 2-3 sensitive neuropathy occured in<br />
19% of pts. Dose reduction was necessary in 28% and prophylactic GCSF was used<br />
in 86% of pts. Partial response rate was 30% [95 CI% 17%-43%], and 53% of pts<br />
showed stable disease [95% CI 39%-67%], resulting in a disease control rate of 83%<br />
[95% CI 73%-93%]. Closure external radio<strong>the</strong>rapy was performed in 62% of pts and<br />
32% underwent surgical resection of <strong>the</strong>ir tumour. With a median follow up of 8.5<br />
months [95% CI 7-11], median overall and progression free survivals have not been<br />
reached. One year overall and progression free survival rates were 80% [95% CI<br />
57%-92%] and 54% [95% CI 29%-74%], respectively.<br />
Conclusion: FOLFIRINOX in LAPA seems efficient with a manageable toxicity<br />
profile and led to secondary potentially curative surgery in approximately one third<br />
of <strong>the</strong> pts. These promising results are encouraging to test this regimen in a phase 3<br />
trial. (1) Conroy et al. NEJM 2011; 364: 1817<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix238 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
717P GEMCITABINE COMBINED WITH THE MTOR INHIBITOR<br />
TEMSIROLIMUS(CCI-779) IN PATIENTS WITH INOPERABLE<br />
OR METASTATIC PANCREATIC CANCER (HE 3/07). A PHASE I<br />
STUDY BY THE HELLENIC COOPERATIVE ONCOLOGY GROUP<br />
V. Karavasilis, G. Pen<strong>the</strong>roudakis, J. Sgouros, S.T. Dimoudis, I. Varthalitis,<br />
E. Samantas, G. Fountzilas<br />
Data Office, Hellenic Cooperative Oncology Group, A<strong>the</strong>ns, GREECE<br />
Aim: To investigate <strong>the</strong> feasibility of <strong>the</strong> gemcitabine (G) and mTOR inhibitor<br />
temsirolimus (T) combination and define <strong>the</strong> maximum tolerated dose (MTD) in<br />
patients with inoperable or metastatic pancreatic cancer (MPC).<br />
Methods: Eligible patients with histologically confirmed inoperable or MPC were<br />
entered into <strong>the</strong> trial. Available biopsy material for subsequent translational research<br />
analysis was mandatory for inclusion in <strong>the</strong> study. G was given bi-weekly and T was<br />
administered on a weekly basis. Each cycle consisted of four consecutive weeks of<br />
treatment. First dose level was set at G 800 mg/m 2 and T 10 mg. G was escalated in<br />
increments of 200 mg/m 2 and T in increments of 5 mg.<br />
Results: A total of 30 patients [16M/14F, median age: 63y, PS: 1 (63%)] were<br />
enrolled for <strong>the</strong> pre-planned six dose levels. Up to date, 80 complete cycles of<br />
treatment were delivered. Four patients did not complete <strong>the</strong> first cycle due to rapid<br />
disease progression and were <strong>the</strong>refore replaced. Ano<strong>the</strong>r patient was found ineligible<br />
and was replaced, as well. Ten patients received four or more cycles of treatment.<br />
MTD was not achieved and <strong>the</strong> study was terminated at <strong>the</strong> sixth dose level of G<br />
1000 mg/m 2 and T 25 mg. Dose-limiting toxicity (DLT) was thrombocytopenia of<br />
grade 4, which occurred at <strong>the</strong> first dose level. Non-DLT grade III toxicities were<br />
neutropenia (9 patients), abnormal liver biochemistry (8 patients) and fatigue (1<br />
patient). Toxicities below <strong>the</strong> grade III level were mild, <strong>the</strong> most predominant being<br />
anemia, neutropenia, raised liver function tests and fatigue. Two patients at <strong>the</strong> final<br />
level of G 1000 mg/m 2 and T 25 mg are still on treatment. This dose is <strong>the</strong><br />
recommended dose for phase II evaluation. With regard to response, two partial<br />
responses were documented and 11 patients had stable disease.<br />
Conclusion: Combination of G and T is feasible in patients with inoperable or MPC<br />
with manageable side effects. The activity of this combination is currently<br />
investigated in a recently initiated phase II study.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
718P A THREE-STEP STRATEGY OF INDUCTION CHEMOTHERAPY,<br />
CHEMO-RADIOTHERAPY AND SURGERY IN LOCALLY<br />
ADVANCED PANCREATIC CANCER (LAPC). A SINGLE<br />
INSTITUTIONAL EXPERIENCE<br />
O.E. Carranza Rua 1 , E. Arevalo 1 , J.P. Fusco 1 , E. Castanon Alvarez 1 , L. Zubiri 1 ,J.<br />
A. Gonzalez 2 , L. Arbea 3 , F. Pardo 4 , S. Martin Algarra 1 , J. Rodriguez 5<br />
1 Medical Oncology, Clinica Universitaria de Navarra, Pamplona, SPAIN,<br />
2 Radiation Oncologist, Clinica Universidad de Navarra, Pamplona, SPAIN,<br />
3 Radiation Oncology, Clinica Universidad de Navarra, Pamplona, SPAIN,<br />
4 Surgical Oncology, Clinica Universidad De Navarra, Pamplona, SPAIN, 5 Medical<br />
Oncology, Clinica Universidad de Navarra, Pamplona, SPAIN<br />
Background: Pancreatic cancer is one of <strong>the</strong> most highly fatal cancers. A growing<br />
evidence suggests that even potentially resectable patients (pts) benefit from a<br />
multidisciplinary approach aimed to improve resectability and reduce recurrence. We<br />
report our experience after a long-term follow-up.<br />
Methods: From December 2005 to July 2011, 69 histologically confirmed LAPC,<br />
endoscopic ultrasound (EUS) staged T3/T4, N0/N1 were scheduled to receive<br />
induction gemcitabine-oxaliplatin-based chemo<strong>the</strong>rapy followed by<br />
chemo-radio<strong>the</strong>rapy with weekly oxaliplatin and capecitabine (mean radio<strong>the</strong>rapy<br />
dose of 50.4 Gys) and salvage surgery when feasible. Adjuvant chemo<strong>the</strong>rapy was<br />
considered depending on results of <strong>the</strong> pathologic report.<br />
Results: The median age was 63 years (range 35-83 years). Male to female ratio was<br />
37/32. Forty-one pts (59%) completed <strong>the</strong> whole program (group A), whereas 26<br />
(37%) received chemo and chemo-radio<strong>the</strong>rapy but were not eligible for surgery<br />
(group B). Two patients (3%) progressed after induction chemo<strong>the</strong>rapy (group C).<br />
Endoscopic stent placement was performed in thirty-four pts (49%). Toxicity profile<br />
was mild, with no grade 4 toxicity being documented. Grade 3 toxicity included:<br />
leucopenia (7%), neutropenia (11%), as<strong>the</strong>nia (13%) and nausea, diarrhea and<br />
anorexia (1% each). On an intent to treat basis, <strong>the</strong> R0 resection rate was 55% (38/<br />
69). Among resected patients, local and distant failure rates were 5 and 55%<br />
respectively. After a median follow up of 43 months (range 9 to 88), median PFS was<br />
17, 9 and 1 month in groups A, B and C respectively. Median overall-survival (mOS)<br />
was 13 and 4 months in groups B and C. In group A mOS has not been reached.<br />
The 2 and 3-year actuarial overall survival in this group are 71% and 45%<br />
respectively.<br />
Conclusions: Our data suggest that this three-step strategy is feasible and active in<br />
LAPC patients Correlative molecular analysis seem warranted to rule out <strong>the</strong> subset<br />
of pts most likely to benefit from this approach.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
719P DENDRITIC CELL VACCINATION IN COMBINATION WITH<br />
OK432, GEMCITABINE AND/OR S-1 IN PATIENTS WITH<br />
ADVANCED PANCREATIC OR BILIARY TRACT CANCER<br />
M. Ogasawara, S. Ota<br />
Internal Medicine, Sapporo Hokuyu Hospital, Sapporo, JAPAN<br />
Background: Although dendritic cells (DCs) are potent antigen presenting cells that<br />
can generate T cells specific to tumor antigens, efficacy of immuno<strong>the</strong>rapy using DCs<br />
is so far limited. To improve <strong>the</strong> efficacy of this modality, we conducted a clinical<br />
trial of DC vaccination in combination with gemcitabine (GEM) and/or S-1 for<br />
patients with advanced pancreatic or biliary tract cancer. The advantages of using<br />
<strong>the</strong>se drugs are immunomodulatory functions including <strong>the</strong> inhibition of regulatory<br />
T cells (Tregs). OK432, a toll like receptor (TLR) 4 agonist, was employed to enhance<br />
activation of DCs both in vitro and in vivo.<br />
Methods: 31 patients (17 males, 14 females; aged 27-81 years, median 61 years) with<br />
advanced pancreatic (24) or biliary tract (7) cancer refractory to standard treatment<br />
were treated with DC vaccination in combination with OK432 and GEM and/or S-1<br />
from 2009 to 2011. Autologous DCs were generated from adherent mononuclear<br />
cells using standard protocols. Wilms’ tumor 1 (WT1) and/or MUC1 peptide-loaded<br />
mature DCs were administered intradermally every 2 weeks for 7 times. Induction of<br />
vaccine-induced T cell responses was monitored using HLA-tetramer assays.<br />
Results: The treatment was well tolerated and none of <strong>the</strong> patients experienced more<br />
than grade 3 adverse events during <strong>the</strong> treatment period. Of 31 patients, 5 patients had<br />
partial response (PR), 14 had stable disease (SD), 2 had mixed response and 10 had<br />
progressive disease following one course of <strong>the</strong> treatment. Median overall survival was<br />
289 days for all patients, which was longer than that of <strong>the</strong> patients treated with GEM<br />
and/or S-1.Survival of patients achieving PR or SD (responder) after one course of DC<br />
vaccination was longer than those who did not respond to <strong>the</strong> treatment (p < 0.01).<br />
Increased numbers of cancer antigen-specific cytotoxic T cells and decreased numbers<br />
of Tregs was observed in responders after one course of treatment.<br />
Conclusions: DC vaccine-based immuno<strong>the</strong>rapy combined with a TLR agonist and<br />
chemo<strong>the</strong>rapy was demonstrated to be safe and more effective in patients with<br />
advanced pancreatic or biliary tract cancer compared with chemo<strong>the</strong>rapy alone.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
720P PANCREATIC DUCTAL ADENOCARCINOMA: A<br />
HOMOGENEOUS MORPHOLOGICALLY BUT MOLECULARLY<br />
HETEROGENEOUS TUMOR. IMPLICATIONS FOR ITS<br />
MANAGEMENT<br />
L. Faloppi 1 , A. Mandolesi 2 , M. Scartozzi 1 , C. Loretelli 1 , M. Bianconi 1 , A. Bittoni 1 ,<br />
R. Giampieri 1 , M. Del Prete 1 , I. Bearzi 2 , S. Cascinu 1<br />
1 Clinica di Oncologia Medica, AOU Ospedali Riuniti Ancona Università<br />
Politecnica delle Marche, Ancona, ITALY, 2 Anatomia Patologica, AOU Ospedali<br />
Riuniti Ancona Università Politecnica delle Marche, Ancona, ITALY<br />
Pancreatic cancer has not achieved significant improvements in <strong>the</strong>rapeutic results,<br />
probably due to a poor comprehension of <strong>the</strong> underlying molecular mechanisms.<br />
The aim of our study was to classify pancreatic tumors in categories from a<br />
molecular point of view, in order to better identify <strong>the</strong> main pathogenetic molecular<br />
alterations potentially useful as targets for new drugs. In 110 histological samples of<br />
pancreatic ductal adenocarcinoma were performed immunohistochemical evaluations<br />
of K-ras, stromal IL-6 (IL-6s), tumoral IL-6 (IL-6t), Cox-2, EGFR, Her2, Her3,<br />
MLH1, MSH2, MSH3 and molecular biology assessment of CD24, MUC6, HGF,<br />
MET, SMAD4, CDKN2A, PGF, VEGF-A/B, VEGFR-1/2, PDGFRB, WNT1, BMP4,<br />
stemness (ALCAM, PROM1, OCT3/4, CD44, LGR5,), Hedgehog (SHH, DHH, IHH,<br />
SMO, PTCH1, PTCH2), SPARC, NOTCH1, BRCA1, BRCA2. A preliminary analysis<br />
showed that <strong>the</strong> positivity of <strong>the</strong> inflammation mediators stromal IL-6, tumoral IL-6,<br />
Cox-2 allowed to differentiate two categories of pancreatic tumors: inflammatory<br />
tumors, associated with an intense desmoplastic reaction and alteration of EGFR and<br />
MLH1, and on <strong>the</strong> contrary tumors not associated with inflammation. Within <strong>the</strong>se<br />
two groups statistical significant differences were found for EGFR and MLH1. An<br />
overexpression of EGFR was found in triple (97%) and double (88%) positive<br />
tumors, compared to negative or single positive (52%) (p0.0002). An higher rate of<br />
loss of MLH1 expression was found in triple positive tumors (69%), compared to<br />
double positive (40%) and negative or single positive (27%) (p0.02). Inflammation<br />
has been identified as a significant factor in <strong>the</strong> development of o<strong>the</strong>r malignancies.<br />
Mediators of <strong>the</strong> inflammatory pathway have been shown to be involved in<br />
proliferation, loss of tumor suppressor function, oncogene overexpression, all of<br />
which may lead to malignancy. Although definitive results concerning all <strong>the</strong><br />
molecular factors analyzed will be presented during <strong>the</strong> <strong>ESMO</strong> <strong>2012</strong> congress,<br />
inflammation and its related molecular alterations may be specific targets for novel<br />
agents potentially useful for <strong>the</strong> treatment of <strong>the</strong>se malignancies.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds398 | ix239
721P FIRST-LINE TREATMENT WITH FOLFIRINOX IN ADVANCED,<br />
INOPERABLE PANCREATIC CANCER (APDAC) PATIENTS<br />
(PTS): SUPPORTIVE MEASURES OPTIMIZATION FOR A SAFE<br />
ADMINISTRATION IN ROUTINE CLINICAL PRACTICE<br />
V. Vaccaro 1 , E. Bria 2 , I. Sperduti 3 , F. Massari 2 , M.S. Pino 4 , E. Lucchini 2 ,<br />
A. Gelibter 1 , F. Cognetti 5 , G. Tortora 2 , M. Milella 1<br />
1 Medical Oncology, Regina Elena National Cancer Institute, Roma, ITALY,<br />
2 Medical Oncology, Azienda Ospedaliera Universitaria Integrata Verona-”Borgo<br />
Roma”, Verona, ITALY, 3 Biostatistics, Regina Elena Institute, Roma, ITALY,<br />
4 Medical Oncology, USL 10 Firenze, Firenze, ITALY, 5 Division Medical Oncology<br />
A, Istituto Regina Elena, Roma, ITALY<br />
Purpose: Although FOLFIRINOX has become one of <strong>the</strong> standard option for <strong>the</strong><br />
treatment of aPDAC, tolerability and safety issues, with particular regard to<br />
hematologic toxicity and increased risk of AE in pts carrying biliary stents, may<br />
represent a barrier for <strong>the</strong> routinely adoption in clinical practice.<br />
Methods: The clinical reports of 36 aPDAC pts undergone 1st-line FOLFIRINOX in<br />
2 different institutions were reviewed. Toxicities, activity and efficacy were<br />
determined according to 1) primary G-CSF prophylaxis (dd 7-9-11; yes/no 21/15<br />
pts), and 2) presence/absence biliary stent.<br />
Results: Pts characteristics: N°: 36; cycles: 241, M/F: 22/14; median age: 57 yrs [range<br />
37-70]; ECOG PS 0/1: 33/3; stage III/IV: 10/26. G3/4 toxicity occurred in 50% reduction in CA19.9.<br />
Conclusions: These data indicate that FOLFIRINOX seems to be well tolerated and<br />
easily manageable in young (50%, no PD after 6 months of CT were randomized to O (arm A) or MS at 37.5 mg<br />
daily until PD or a maximum of 6 months (arm B). Functional polymorphisms of 6<br />
genes involved in sunitinib activity, metabolism and transport (VEGFA, VEGFR-2,<br />
CYP3A5, CYP1A1, ABCB1, ABCG2) were studied in genomic DNA from baseline<br />
blood samples, using PCR Taqman®-probes-based assays. Associations of genotypes<br />
with overall survival (OS) and progression-free survival (PFS) were evaluated by<br />
Log-rank test. Genotyping was successfully performed in all <strong>the</strong> DNA samples of 43<br />
consenting pts of 55 enrolled in <strong>the</strong> trial (78%; arm A/B: 83%/73%; p = 0.39).<br />
Significantly longer OS was observed in 7 pts harbouring <strong>the</strong> ABCB1 3435TT<br />
genotype (group-1; median OS 20 months) as compared to 36 pts with 3435CC/CT<br />
genotype (group-2; median OS 7 months; p = 0.027). Median OS was 26 months in 4<br />
group-1 arm B pts, 7 months in 15 group-2 arm B pts (p = 0.12); 16 months in 3<br />
group-1 arm A pts and 9 months in 21 group-2 arm A pts (p = 0.67). No OS<br />
difference was observed in 28 pts harbouring <strong>the</strong> VEGFA -634GC-CC genotype<br />
ix240 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
(group-3; median OS 10 months) as compared to 15 pts with -634GG genotype<br />
(group-4; median OS 8 months; p = 0.15). However, median OS was 13 months in<br />
13 group-3 arm B pts, 6 months in 6 group-4 arm B pts (p = 0.016); 9 months in<br />
15 group 3 arm A pts and 11 months in 9 group 4 arm A pts (p = 0.67). These<br />
results suggest that polymorphisms of genes involved in expression of <strong>the</strong> main<br />
ligand for VEGFR2 (VEGFA 634G > C) and of efflux transporters (ABCB1 3435C ><br />
T) are promising candidates as predictive marker for selecting pts with MPA who<br />
may benefit of MS. Given <strong>the</strong> small sample size of <strong>the</strong>se analyses, a larger<br />
confirmatory trial is necessary and appears worthwhile.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
725P PATHOLOGICAL PROOF AND SURVIVAL FOR PATIENTS WITH<br />
BILIARY-TRACT OR PANCREATIC TUMOR<br />
C. Desauw 1 , F. El Hajbi 2 , K. Ligier 3 , A. Duhamel 4 , F. Richard 4 , C. Rose 2<br />
1 Medical Oncology, C.H.U. Claude Huriez, Lille, FRANCE, 2 Hôpital St Vincent De<br />
Paul. Service D’Onco-Hématologie, Université Catholique de Lille, Lille, FRANCE,<br />
3 Registre Général Des Cancers De Lille Et De Sa Région, Centre de Référence<br />
Régional en Cancérologie, Lille, FRANCE, 4 Unité de Biostatistiques, EA2694,<br />
Univ Lille Nord de France, Lille, FRANCE<br />
As recommended by <strong>ESMO</strong>, a final pathological diagnosis (PD) has to be obtained<br />
before any chemo<strong>the</strong>rapy, radio<strong>the</strong>rapy or o<strong>the</strong>r non-surgical oncological <strong>the</strong>rapy for<br />
pancreatic or biliary tract cancer. PD is also required for inclusion in a clinical trial.<br />
In practice, it is sometimes difficult to obtain this pathological proof because of<br />
difficult access or poor performance status. Treatment decision is <strong>the</strong>n collegial,<br />
based on a clinical, radiological and biological suspicion. We studied patient survival<br />
based on availability of PD from <strong>the</strong> cancer registry of Lille and its region (800 000<br />
inh. - North France). We reviewed patients records over 15 years old diagnosed in<br />
2005 or 2008 for a pancreatic or biliary tract cancer (neuroendocrine excluded). The<br />
point was made on 01/12/2011. Patients were divided into 5 groups: PD and surgery<br />
(PD-Surg), PD and radio<strong>the</strong>rapy or chemo<strong>the</strong>rapy (PD-RC), PD and untreat<br />
(PD-Un), no PD and radio<strong>the</strong>rapy or chemo<strong>the</strong>rapy (noPD-RC), no PD and untreat<br />
(noPD-Un). Observed survival analysis was obtained from Kaplan-Meier method<br />
and statistical significance from log-rank test. Males accounted for 45.8% of 260<br />
patients. The average age was 71.8 years (+/- 12.1). 59.6% were diagnosed as pancreas<br />
cancer. PD was not obtained in 54.2% (60% in pancreas and 45.7% in biliary tract<br />
respectively). Seven patients were lost of follow-up.<br />
PD-Surg PD-RC noPD-RC PD-Un noPD-Un<br />
n (%) 45 (17.3) 44 (16.9%) 37 (14.2%) 30 (11.5%) 104 (40%)<br />
Median<br />
survival (days)<br />
709 198 203 76 60<br />
2 years<br />
survival<br />
p > 0.2 p > 0.9<br />
46.7% 6.8% 2.9% 0% 2.1%<br />
27 patients were alive beyond 24 month: 21 in PD-Surg group, 3 in PD-RC, 1 in<br />
noPD-RC and 2 in noPD-Un. In conclusion, <strong>the</strong> absence of PD is common in<br />
clinical practice, without apparent impact on survival. 14.2% of patient were treated<br />
without PD. These patients are not take account in current recommendations.<br />
Centralized monitoring of this condition would be required. In <strong>the</strong> absence of<br />
treatment plan, PD is not essential.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
726P NEOADJUVANT MODIFIED FOLFOXIRI IN LOCALLY<br />
ADVANCED PANCREATIC CANCER<br />
E. Vasile 1 , N. De Lio 2 , C. Cappelli 3 , L. Ginocchi 1 , S. Caponi 1 , A. Sainato 4 ,<br />
C. Greco 4 , F. Mosca 5 , A. Falcone 1 , U. Boggi 2<br />
1 Oncologia, Trapianti e Nuove Tecnologie in Medicina, Polo Oncologico -<br />
Azienda Ospedaliero-Universitaria Pisana - Istituto Toscano Tumori, Pisa, ITALY,<br />
2 Dipartimento di Oncologia, dei Trapianti e delle Nuove Tecnologie In Medicina,<br />
U.O. Chirurgia Generale e Trapianti - Azienda Ospedaliero-Universitaria Pisana,<br />
Pisa, ITALY, 3 Dipartimento Di Radiodiagnostica e Radiologia Interventistica,<br />
Azienda Ospedaliero-Universitaria Pisana, Pisa, ITALY, 4 Dipartimento di<br />
Oncologia, dei Trapianti e delle Nuove Tecnologie In Medicina, U.O. Radioterapia<br />
- Azienda Ospedaliero-Universitaria Pisana, Pisa, ITALY, 5 Dipartimento di<br />
Oncologia, dei Trapianti e delle Nuove Tecnologie In Medicina, U.O. Chirurgia<br />
Generale 1 Universitaria - Azienda Ospedaliero-Universitaria Pisana, Pisa, ITALY<br />
Background: FOLFIRINOX has shown high activity in metastatic pancreatic cancer<br />
patients. Considering its activity, <strong>the</strong> regimen could be of interest also for patients<br />
with inoperable locally advanced disease. Our group had developed a very similar<br />
schedule in colorectal cancer named FOLFOXIRI which contains no bolus<br />
5-fluorouracil and a slight lower dose of irinotecan with good tolerance and activity.<br />
Methods: We have performed a phase II trial in order to prospectively evaluate <strong>the</strong><br />
activity of a modified (m)FOLFOXIRI regimen in locally advanced pancreatic cancer.<br />
mFOLFOXIRI consisted of: oxaliplatin 85 mg/sqm, irinotecan 150 mg/sqm and<br />
folinic acid 200 mg/sqm on day 1, plus infusional 5-fluorouracil 2800 mg/sqm<br />
administered in 48 hours on days 1 to 3, with cycle repeated every 14 days. The<br />
study enrolled patients with cytological or histological diagnosis of pancreatic<br />
adenocarcinoma, stage III locally advanced disease without evidence of metastatic<br />
disease, ECOG performance status (PS) 0 or 1, age 18-75. The primary end-point of<br />
<strong>the</strong> study was <strong>the</strong> percent of patients who can achieve radical surgical resection after<br />
chemo<strong>the</strong>rapy; <strong>the</strong> trial was designed with a percentage of low activity of 30% and a<br />
percentage of interest of 50% with an α and β error of 0.05 and 0.20.<br />
Results: Twenty-two patients have been so far enrolled; 8 men and 14 women; PS<br />
was 0 in 10 patients. Median age was 60 years (range 44-75). Celiac axis was involved<br />
in 7 patients, superior mesenteric artery in 10 cases, both arteries in 5 patients.<br />
Among <strong>the</strong> 15 patients so far evaluated, 6 partial responses (40%) and 9 stable<br />
disease (60%) have been observed. A local treatment after chemo<strong>the</strong>rapy was received<br />
by 9 patients until now: 5 (55.5%) underwent to radical surgery; 1 underwent an<br />
explorative laparotomy with evidence of liver metastases; 3 received concomitant<br />
chemo-radio<strong>the</strong>rapy with gemcitabine. Median progression-free survival was 24.5<br />
months and median overall survival was 30.1 months.<br />
Conclusions: Chemo<strong>the</strong>rapy with mFOLFOXIRI seems active in locally advanced<br />
pancreatic cancer patients and may allow to obtain a downstaging of disease leading<br />
some patient to achieve a curative surgical resection. Longer follow up is needed to<br />
better evaluate long-term outcome of this strategy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
727P COMPARISON IN 1323 PATIENTS OF PREOPERATIVE<br />
IMAGING STAGING AND PATHOLOGICAL EXAMINATION OF<br />
RESECTED PANCREATIC HEAD ADENOCARCINOMA: SERIES<br />
OF THE ASSOCIATION FRANçAISE DE CHIRURGIE<br />
M. Gilabert 1 , J.M. Boher 2 , J.L. Raoul 3 , O. Turrini 3 ,F.Paye 4 , P. Bachellier 5 ,<br />
J. Delpero 6 , G. Afc 7<br />
1 Medical Oncology, Institut Paoli Calmettes, Marseille Cedex, FRANCE,<br />
2 Bioinformatics, Institut Paoli-Calmettes, marseille, FRANCE, 3 Oncology, Institut<br />
Paoli-Calmettes, Marseille, FRANCE, 4 Surgery, Hopital Saint Antoine, Paris,<br />
FRANCE, 5 Surgery, Hopital de Hautepierre, Strasbourg, FRANCE, 6 Surgical<br />
Oncology, Institut Paoli-Calmettes, Marseille, FRANCE, 7 France, Association<br />
Francaise de Chirurgie, France, FRANCE<br />
Resection is possible in less than 15% of pancreatic ductal adenocarcinoma (PDAC)<br />
patients. Prognosis is dismal and particularly related to arterial, venous or lymph<br />
node invasion. In this retrospective analysis were compared imaging preoperative<br />
data and pathological reports on arterial, venous and lymph node invasion in a large<br />
series of PDAC benefiting from pancreaticoduodenectomy. Retrospective series of<br />
1323 patients resected for a PDAC of <strong>the</strong> head of pancreas in 35 French and 2 Swiss<br />
centers, data analyzed by <strong>the</strong> Association Française de Chirurgie; 142 with (95<br />
chemoradio<strong>the</strong>rapy, 47 chemo<strong>the</strong>rapy; given to a borderline tumor in 65% and<br />
systematically in 35%) and 1181 without preoperative treatment. Preoperative<br />
imaging consisted in: ceCTscan (97%), ceMRI (45%), US (65%) and endoscopic US<br />
(59%). Were calculated concordance, Sensibility, Specificity, PPV and NPV of<br />
preoperative data compared to pathological conclusions. Artery-Artery + Vein-Vein+<br />
LN- LN+ Imaging negative 1047 16 788 137 246 613 positive 17 9 40 130 38 157<br />
Concordance 97% 84% 38% Se 36% 49% 20% Spe 98% 95% 87% PPV 35% 76% 80%<br />
NPV 98% 85% 29%. In conclusion, in this biased series of patients who were<br />
operated on from a PDAC, <strong>the</strong> value of preoperative imaging “in <strong>the</strong> real life” is not<br />
optimal, particularly regarding arterial and lymph node involvement<br />
Disclosure: All authors have declared no conflicts of interest.<br />
728P RANDOMIZED PHASE II TRIAL OF S-1 VERSUS S-1 PLUS<br />
OXALIPLATIN (SOX) IN PATIENTS WITH GEMCITABINE<br />
REFRACTORY PANCREATIC CANCER<br />
T. Okusaka 1 , S. Ohkawa 2 , H. Isayama 3 , A. Fukutomi 4 , K. Yamaguchi 5 , M. Ikeda 6 ,<br />
A. Funakoshi 7 , M. Nagase 8 , S. Nakamori 9 , Y. Hamamoto 10<br />
1 Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center<br />
Hospital, Tokyo, JAPAN, 2 Department of Gastroenterology, Kanagawa Cancer<br />
Center Hospital, Kanagawa, JAPAN, 3 Department of Gastroenterology, Graduate<br />
School of Medicine The University of Tokyo, Tokyo, JAPAN, 4 Division of<br />
Gastrointestinal, Shizuoka Cancer Center, Shizuoka, JAPAN, 5 Division of<br />
Gastroenterology, Saitama Cancer Center, Saitama, JAPAN, 6 Division of<br />
Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East,<br />
Chiba, JAPAN, 7 Department of Gastroenterology, National Kyushu Cancer<br />
Center, Fukuoka, JAPAN, 8 Department of Medical Oncology, Jichi Medical<br />
University Hospital, Tochigi, JAPAN, 9 Department of Surgery, Osaka National<br />
Hospital, Osaka, JAPAN, 10 Tochigi, Department of Clinical Oncology, Tochigi<br />
Cancer Center, Tochigi, JAPAN<br />
Background: Gemcitabine (Gem) mono<strong>the</strong>rapy or Gem-based combination <strong>the</strong>rapy<br />
is used as standard first-line <strong>the</strong>rapy for advanced pancreatic cancer (PC). There is<br />
no consensus on second-line <strong>the</strong>rapy in patients (pts) with disease progression (PD)<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds398 | ix241
after Gem-based <strong>the</strong>rapy. The addition of oxaliplatin (L-OHP) to 5-FU/LV, however,<br />
yielded a significant improvement in overall survival (OS) and progression-free<br />
survival (PFS) in a second-line setting in <strong>the</strong> CONKO 003 trial. As S-1, an oral<br />
fluoropyrimidine derivative, is commonly used to treat advanced PC ra<strong>the</strong>r than<br />
5-FU/LV in Japan, we conducted a randomized phase II trial to evaluate <strong>the</strong> efficacy<br />
and safety of S-1 plus L-OHP (SOX) compared with S-1 alone in a second-line<br />
setting.<br />
Material and methods: The inclusion criteria were as follows: 1) histologically or<br />
cytologically proven pancreatic adenocarcinoma or adenosquamous carcinoma; 2)<br />
confirmed PD after Gem treatment; 3) ECOG PS, 0-1; 4) measurable metastatic<br />
lesion based on RECIST criteria; 5) age ≥ 20 years. Patients were randomized to<br />
receive ei<strong>the</strong>r S-1 (80/100/120 mg/day based on BSA, po, d1-28, q6w; Arm A) or<br />
SOX (L-OHP 100 mg/m 2 , iv, d1 plus S-1 80/100/120 mg/day based on BSA, po,<br />
d1-14, q3w; Arm B). The primary endpoint was PFS to detect <strong>the</strong> superiority of Arm<br />
B over Arm A.<br />
Results: Of a total of 271 pts enrolled between January 2009 and July 2010, 264 were<br />
eligible (130 randomized to Arm A and 134 to Arm B). Median PFS in Arm A and<br />
B was 2.8 and 3.0 months, respectively (HR= 0.838; 95% CI, 0.649-1.082; P = 0.1795)<br />
with a median follow-up time of 12.6 months. Median OS in Arm A and B was 7.0<br />
and 7.5 months, respectively (HR = 1.031; 95% CI, 0.791-1.344; P = 0.8235) with a<br />
median follow-up time of 13.8 months. Response rate (RR) was 11.5% in Arm A (15/<br />
130; 95% CI, 6.6-18.3) and 20.9% in Arm B (28/134; 95% CI, 14.4-28.8)(P = 0.0395).<br />
The incidences of grade 3/4 toxicities were as follows: neutropenia (11.4% and<br />
14.0%), thrombocytopenia (3.8% and 9.8%), anorexia (11.4% and 12.5%), diarrhea<br />
(4.5% and 5.1%) and nausea (3.0% and 9.8%) in Arm A and B, respectively. Both<br />
regimens were tolerable.<br />
Conclusions: Although SOX showed an advantage in RR, it provided no significant<br />
improvement in PFS or OS compared with S-1 alone.<br />
Disclosure: T. Okusaka: The study detailed in <strong>the</strong> abstract was funded by a<br />
pharmaceutical company. S. Ohkawa: The study detailed in <strong>the</strong> abstract was funded<br />
by a pharmaceutical company. H. Isayama: The study detailed in <strong>the</strong> abstract was<br />
funded by a pharmaceutical company. A. Fukutomi: The study detailed in <strong>the</strong><br />
abstract was funded by a pharmaceutical company. K. Yamaguchi: The study detailed<br />
in <strong>the</strong> abstract was funded by a pharmaceutical company. M. Ikeda: The study<br />
detailed in <strong>the</strong> abstract was funded by a pharmaceutical company. A. Funakoshi: The<br />
study detailed in <strong>the</strong> abstract was funded by a pharmaceutical company. M. Nagase:<br />
The study detailed in <strong>the</strong> abstract was funded by a pharmaceutical company. S.<br />
Nakamori: The study detailed in <strong>the</strong> abstract was funded by a pharmaceutical<br />
company. Y. Hamamoto: The study detailed in <strong>the</strong> abstract was funded by a<br />
pharmaceutical company.<br />
729P PROFILE OF DOSES TO ORGANS AT RISK USING 3-D<br />
CONFORMAL RADIOTHERAPY (3-DCRT) VERSUS INTENSITY<br />
MODULATED RADIOTHERAPY (IMRT) IN POSTOPERATIVE<br />
RADIOTHERAPY OF PERIAMPULLARY CANCERS:<br />
IMPLICATIONS FOR RADIATION DOSE ESCALATION<br />
A. Bahl 1 , R. Kapoor 2 , P. Tomar 1 , A.O. Singh 1 , R. Gupta 3 , S.C. Sharma 1<br />
1 Department of Radio<strong>the</strong>rapy, Post Graduate Institute of Medical Education and<br />
Research (PGIMER), Chandigarh, INDIA, 2 Radiation Oncology, PGIMER,<br />
Chandigarh, INDIA, 3 General Surgery, PGIMER, Chandigarh, INDIA<br />
Introduction: Periampullary cancers are treated with Whipple’s surgery in<br />
combination with radio<strong>the</strong>rapy & chemo<strong>the</strong>rapy. The common cause of treatment<br />
failure in <strong>the</strong>se patients is recurrence in <strong>the</strong> tumor bed & regional lymph nodes. A<br />
treatment approach aiming to increase <strong>the</strong> local control rate, by escalating radiation<br />
dose is likely to translate into a better survival.The purpose of <strong>the</strong> present study was<br />
to do a dosimetric analysis of <strong>the</strong> doses to organs at risk in postoperative<br />
radio<strong>the</strong>rapy using a dose of 45Gy/25 fractions and to assess <strong>the</strong> feasibility of<br />
radiation dose escalation.<br />
Material & methods: Ten patients of periampullary cancers in head of pancreas were<br />
selected. All patients had undergone Whipple’s surgery. IMRT and 3DCRT plans<br />
were generated for each patient. IMRT contouring was done as per RTOG guidelines.<br />
3DCRT planning was done using one anterior and two lateral fields. A dose of 45Gy/<br />
25 fractions was prescribed to <strong>the</strong> Planning Target volume. Dosimetric evaluation of<br />
doses to liver, kidneys, stomach, bowel bag, spinal cord was done using ‘QUANTAC’<br />
parameters. For statistical analysis <strong>the</strong> data was arranged in SPSSv18. ‘t’ test was used<br />
to compare <strong>the</strong> mean doses. A ‘p’ value of < 0.05 was considered significant.<br />
Results: Dose to <strong>the</strong> bowel bag was less using IMRT versus 3-DCRT with a V45 of<br />
80.91 ± 57.40 cc (Mean volume ± Standard deviation) versus 212.28 ± 159.04cc (p =<br />
0.03).The mean doses to liver, stomach, spinal cord, Rt kidney & Lt. kidney using<br />
3-DCRT were 24.59± 3.90 Gy (Mean Dose ± Standard deviation), 21.90 ± 6.73 Gy,<br />
26.50 ± 14.72 Gy, 14.14 ± 3.90 Gy, 13.71 ± 3.83 Gy respectively. With IMRT <strong>the</strong> doses<br />
to <strong>the</strong> above structures were 22.91 ± 3.14Gy (p = 0.32), 20.71 ± 5.78 Gy (p = 0.69),<br />
24.77 ± 7.93Gy (p = 0.76), 11.55 ± 4.12 Gy (p = 0.19), 13.72 ± 2.44 Gy (p = 0.99)<br />
respectively.<br />
Conclusions: With a prescription of 45Gy/25# <strong>the</strong> dose to bowel bag is significantly<br />
reduced using IMRT compared to 3-DCRT. The doses received by o<strong>the</strong>r organs are<br />
lower with IMRT compared to 3-DCRT though not statistically significant. The<br />
Annals of Oncology<br />
profile of doses received by organs at risk leaves ample scope of dose escalation using<br />
IMRT.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
730P MULTICENTRIC PHASE II RANDOMIZED TRIAL COMPARING<br />
CHEMORADIATION (CHRT) WITH 5-FLUOROURACIL,<br />
CISPLATIN (CDDP) AND 50 GY VERSUS CHEMOTHERAPY<br />
ALONE (CH) WITH GEMCITABINE (G) PLUS OXALIPLATIN (O)<br />
FOR LOCALLY ADVANCED BILIARY TRACT CANCER<br />
(FFCD9902)<br />
J.M. Phelip 1 , V. Vendrely 2 , J. Jouve 3 , F. Subtil 4 , M. Gasmi 5 , P. Michel 6 ,<br />
D. Smith 7 , J. Seitz 8 , L. Bedenne 9 , B. Chauffert 10<br />
1 Gastroenterologie and Digestive Oncology, University Jean Monnet, Saint<br />
Etienne, FRANCE, 2 Service d’Oncologie Médicale et Radiothérapie, Hôpital Saint<br />
André, Bordeaux Cedex, FRANCE, 3 Hepatogastrolentorology Department, CHU<br />
le Bocage, Dijon Cedex, FRANCE, 4 Data Center, FFCD, Dijon Cedex, FRANCE,<br />
5 Hepatogastroenterology Department, Hôpital Nord, Marseille Cedex, FRANCE,<br />
6 Gastroenterology and Digestive Oncology, CHU de Rouen, Rouen, FRANCE,<br />
7 Oncologie Digestive, Hôpital Saint André, Bordeaux, FRANCE, 8 Oncologie<br />
Digestive, Hôpital de la Timone, Marseille, FRANCE, 9 Hepatogastroenterology<br />
Department, University Hospital, Dijon Cedex, FRANCE, 10 Medical Oncology,<br />
University Hospital, Amiens Cedex, FRANCE<br />
Background: No study is available to determine <strong>the</strong> best strategy for inoperable<br />
locally advanced biliary tract cancer. CHRT has shown its efficacy in small series to<br />
control <strong>the</strong> local evolution. However CHRT results were not compared to palliative<br />
CH.<br />
Methods: This prospective multicentric phase II trial randomized patients with hilar<br />
or extrahepatic non metastatic and locally advanced biliary tract cancer between<br />
CHRT (50 Gy plus 5FU infusion 300 mg/m 2 /D, D1 to D33 and CDDP 20 mg/m 2 /D<br />
D1 to D4 and D29 to D32 or CDDP 80 mg/m 2 D1 and D29) and CH (G 1000 mg/<br />
m 2 D1 + O 100mg/m 2 D1; D1 = D15, 6 months). Main inclusion criteria required<br />
WHO performance status
Annals of Oncology<br />
(NEJM 2010; 362:1273). No second line regimen is established although small<br />
retrospective series suggest that chemo<strong>the</strong>rapy may be active in selected patients. We<br />
present results of a large retrospective series of patients undergoing second-line<br />
chemo<strong>the</strong>rapy at institutions across <strong>the</strong> UK that use <strong>the</strong> ABC-02 standard of<br />
Cisplatin and Gemcitabine (CisGem) as first-line treatment.<br />
Methods: Patients with ABC, previously treated with CisGem and who went on to<br />
receive second-line chemo<strong>the</strong>rapy, were identified from institutional databases.<br />
Demographic data, response and survival outcome measures were collected according<br />
to an agreed proforma.<br />
Results: Sixty-three eligible patients (median age: 61.6 years (range: 39.8 – 78.3<br />
years)) were identified between Feb 2007 and Feb 2011, from 9 centres. Patients were<br />
treated mostly with a platinum based regimen (n = 42), ei<strong>the</strong>r a re-challenge of<br />
CisGem (n = 17), an oxaliplatin/ infused 5-FU regimen (mFOLFOX, n = 17) or<br />
oxaliplatin with capecitabine (n = 4). Most patients had a performance status of<br />
0 or 1. A median PFS of 4.0 months (95% CI: 3.3 – 5.6 months) and an OS of 8.1<br />
months (95% CI: 5.3 – 11.4 months) following second line <strong>the</strong>rapy were<br />
demonstrated. Patients had an overall OS of 19.5 months (95% CI: 17.0 – 25.2<br />
months) from <strong>the</strong> start of first-line <strong>the</strong>rapy; this compares with a median OS of 11.7<br />
months from <strong>the</strong> ABC-02 study.<br />
Conclusions: Use of second-line chemo<strong>the</strong>rapy in advanced BTC is of potential<br />
benefit. These data, although retrospective, suggests <strong>the</strong>re is a population suitable for<br />
second-line, prospective randomised studies with chemo<strong>the</strong>rapy or targeted agents<br />
and provide baseline outcome data with which to statistically design such studies.<br />
Updated data will be shown.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
732P FINAL RESULTS OF A RANDOMIZED PHASE II STUDY OF<br />
TSU-68 AFTER TRANSARTERIAL CHEMOEMBOLISATION IN<br />
JAPANESE PATIENTS WITH UNRESECTABLE<br />
HEPATOCELLULAR CARCINOMA.CHEMOEMBOLIZATION<br />
S. Kaneko 1 , Y. Inaba 2 , F. Kanai 3 , T. Aramaki 4 , T. Yamamoto 5 , T. Tanaka 6 ,<br />
K. Yamakado 7 , M. Kudo 8 , K. Imanaka 9 ,Y.Arai 10<br />
1 Department of Gastroenterology, Kanazawa University Hospital, Ishikawa,<br />
JAPAN, 2 Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital,<br />
Aichi, JAPAN, 3 Gastroenterology, Chiba University Hospital, Chiba, JAPAN,<br />
4 Diagnostic Radiology, Shizuoka Cancer Center Hospital, Shizuoka, JAPAN,<br />
5 Diagnostic Imaging, Tochigi Cancer Center, Tochigi, JAPAN, 6 Radiology, Nara<br />
Medical University Hospital, Nara, JAPAN, 7 Radiology, Mie University Hospital,<br />
Mie, JAPAN, 8 Gastroenterology and Hepatology, Kinki University Hospital,<br />
Osaka, JAPAN, 9 Hepatobiliary and Pancreatic Oncology, Osaka Medical Center<br />
for Cancer and Cardiovascular Diseases, Osaka, JAPAN, 10 Diagnostic<br />
Radiology, National Cancer Center Hospital, Tokyo, JAPAN<br />
Purpose: TSU-68 is an antitumor drug that acts by inhibiting angiogenesis. We<br />
evaluated <strong>the</strong> efficacy and safety of TSU-68 in combination with transca<strong>the</strong>ter arterial<br />
chemoembolization (TACE) in patients with intermediate-stage hepatocellular<br />
carcinoma (HCC).<br />
Methods: In this multicenter, open-label phase II study, we randomly assigned<br />
patients with HCC who had been treated by TACE to receive ei<strong>the</strong>r 200 mg TSU-68<br />
twice daily or no medication. TACE was performed according to <strong>the</strong> standard<br />
technique using anticancer drugs, lipiodol, and gelatin sponge. TACE was completed<br />
for all patients within <strong>the</strong> 2 weeks prior to randomization. The primary endpoint was<br />
progression-free survival (PFS) and <strong>the</strong> secondary endpoints were safety and<br />
biomarker assessments.<br />
Results: In total, 103 patients were enrolled. Median PFS was 5.2 months in <strong>the</strong><br />
TSU-68 group and 4.0 months in <strong>the</strong> control group (HR in <strong>the</strong> TSU-68 group,<br />
0.699; p = 0.054, log-rank test with a 2.5% one-sided significance level). Fatigue,<br />
elevated aspartate aminotransferase (AST), elevated alkaline phosphatase, edema,<br />
and anorexia were more frequent in <strong>the</strong> TSU-68 group than in <strong>the</strong> control group.<br />
The most frequent grade 3/4 adverse events were AST elevation (46% of patients<br />
in <strong>the</strong> TSU-68 group and 12% of controls) and alanine aminotransferase elevation<br />
(26% of patients in <strong>the</strong> TSU-68 group and 8% of controls). Subgroup analyses<br />
suggested that treatment with TSU-68 may extend PFS for patients with Child–<br />
Pugh A liver function and those with hepatitis C. Among patients with baseline<br />
t-PA concentrations below <strong>the</strong> median value, <strong>the</strong> PFS of <strong>the</strong> TSU-68 group was<br />
longer than that of <strong>the</strong> control group. TSU-68 treatment may also improve PFS<br />
among patients with VCAM-1, ELAM-1, IL-8, or PDGF-BB levels above <strong>the</strong><br />
median values.<br />
Conclusion: TSU-68 was well tolerated, and may provide longer PFS after TACE<br />
than was observed for controls. This result suggests that TSU-68 combined with<br />
sequential and repeated TACE sessions may provide additional clinical benefits to<br />
patients, including prolongation of overall survival. A randomized placebo-controlled<br />
phase III global study was initiated in 2010 to evaluate <strong>the</strong> survival benefit of TSU-68<br />
in combination with repeated TACE.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
733P 3-MONTHS POSTRESECTION ALPHA-FETOPROTEIN: AN<br />
INDEPENDENT PROGNOSTIC TOOL IN PATIENTS WITH<br />
HEPATOCELLULAR CARCINOMA ON CIRRHOSIS<br />
M. Allard, A. Sa-Cunha, E. Vibert, B. Paule, G. Pelletier, M. Sebagh, C. Guettier,<br />
D. Castaing, R. Adam<br />
Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, Villejuif, FRANCE<br />
Background: Alpha Fetoprotein (AFP) is a major tumor marker in patients with<br />
hepatocellular carcinoma (HCC). Our aim was to assess <strong>the</strong> prognostic value of AFP<br />
measured within <strong>the</strong> 3-months following partial hepatectomy for HCC on cirrhosis.<br />
Methods: All patients treated for HCC on cirrhosis by partial hepatectomy with<br />
intention to treat between January 1990 and December 2010 and presenting an<br />
elevation of AFP (>15ng/ml) at diagnosis were included in <strong>the</strong> study. The AFP value<br />
within <strong>the</strong> 90 postoperative days was retrospectively collected and analyzed as a<br />
dichotomized variable (normalization or absence of normalization). Performed on<br />
<strong>the</strong> whole study population, Cox proportional hazards models were utilized to assess<br />
<strong>the</strong> impact of postresection AFP normalization on overall survival (OS).<br />
Results: Among 271 patients treated for HCC on cirrhosis by liver resection, 145<br />
(53%) patients presented an elevation of AFP level (>15ng/ml). The AFP value was<br />
available within <strong>the</strong> 90 postoperative days in 96 patients (66%). Missing data were<br />
related to <strong>the</strong> 7 post-operative deaths, <strong>the</strong> 22 patients lost from follow up, and <strong>the</strong> 20<br />
patients for which <strong>the</strong> first post-operative AFP measurement was performed beyond<br />
<strong>the</strong> 90 postoperative days. 5 years-OS after liver resection and median survival were<br />
45% and 54 months in <strong>the</strong> group with post-resection AFP normalization versus 24%<br />
and 23 months in <strong>the</strong> group without postresection AFP normalization, respectively<br />
(P = 0,02). There was a significant decline of disease-free survival in <strong>the</strong> group<br />
without postresection AFP normalization experiencing median survival of 6 months<br />
versus 19 months (P < 0,001). At multivariate analysis, postresection AFP<br />
normalization within <strong>the</strong> 90 post-operative days (OR: 2,38; CI: 1,32-4,28; P = 0,004)<br />
and microvascular invasion (OR: 4; CI: 2,1-7,6; P < 0,001) were two independent<br />
predictors of OS. Interestingly, among patients without AFP normalization, 13 had<br />
no vascular invasion but all of <strong>the</strong>m developed fur<strong>the</strong>r recurrence.<br />
Conclusion: This study emphasizes <strong>the</strong> role of AFP in <strong>the</strong> 3-months period<br />
following HCC resection on cirrhotic livers, which should be considered more<br />
systematically to help postresection management.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
734P THE ROLE OF TUMOUR VASCULAR ENDOTHELIAL GROWTH<br />
FACTOR (VEGF) AND VASCULAR ENDOTHELIAL GROWTH<br />
FACTOR RECEPTORS (VEGFR) POLYMORPHISMS IN THE<br />
PREDICTION OF CLINICAL OUTCOME FOR ADVANCED<br />
HEPATOCELLULAR CARCINOMA RECEIVING SORAFENIB<br />
L. Faloppi 1 , M. Scartozzi 1 , G. Svegliati Baroni 2 , C. Loretelli 1 , S. De Minicis 3 ,<br />
A. Mandolesi 4 , M. Bianconi 1 , I. Bearzi 1 , A. Benedetti 2 , S. Cascinu 1<br />
1 Clinica di Oncologia Medica, AOU Ospedali Riuniti Ancona Università<br />
Politecnica delle Marche, Ancona, ITALY, 2 Clinica di Gastroenterologia, UNIVPM,<br />
Ancona, ITALY, 3 Clinica di Gatroenterologia, Università Politecnica delle Marche,<br />
Ancona, ITALY, 4 Anatomia Patologica, AOU Ospedali Riuniti Ancona Università<br />
Politecnica delle Marche, Ancona, ITALY<br />
Hepatocellular carcinoma (HCC) still represents a medical challenge in cancer <strong>the</strong>rapy. In<br />
recent years <strong>the</strong> introduction of new targeted <strong>the</strong>rapies has radically changed <strong>the</strong><br />
approach to <strong>the</strong> disease and patients outcome. Currently <strong>the</strong> <strong>the</strong>rapeutic stronghold is a<br />
TKIs directed against <strong>the</strong> VEGF family sorafenib. Polymorphisms of VEGF and its<br />
receptor genes are involved in regulating angiogenesis and lymphangiogenesis and thus<br />
in growth tumor control. The aim of our study is to evaluate <strong>the</strong> potential predictive and<br />
prognostic role of VEGF and VEGFR polymorphisms in determining <strong>the</strong> clinical<br />
outcome of HCC patients receiving sorafenib. 41 histologic samples (biopsies and<br />
surgical specimens) of HCC patients receiving sorafenib were tested for VEGF-A,<br />
VEGF-C and VEGFR-1,2,3 singlenucleotide polymorphisms (SNPs). Patients time to<br />
progression (TTP) and overall survival (OS) were analysed. VEGF-AI rs25648 C > T<br />
polymorphism was statistically significant in OS (15.0 months for C vs 9.4 months for T;<br />
p = 0.025). VEGF-AII rs10434 G > A was statistically significant for TTP (4.1 months for<br />
G vs 1.2 months for A; p = 0.0076) and OS (14.2 months for G vs 1.7 for A; p < 0.0001).<br />
VEGF-CII rs7664413 C > T was significant in TTP (13.4 months for C vs 2.0 for T; p =<br />
0.0125) and OS (14.7 months for C vs 5.6 for T; p = 0.0007). VEGR2-I rs1870377 A > T<br />
was significant in TTP (19.9 months for A vs 3.0 for T; p = 0.0271) and OS (29.6 months<br />
for A vs 11.9 for T; p = 0.0096). In our analysis patients with G polymorphism at rs10434,<br />
C polymorphism at rs7664413 and A polymorphism at rs1870377 have a better response<br />
(PFS and OS) during treatment with sorafenib. Patients with C polymorphism of<br />
rs7664413 and A polymorphism of rs1870377 show a favourable impact in this setting.<br />
Notably, VEGFR polymorphism result closely related to <strong>the</strong> treatment response and <strong>the</strong><br />
specific signalling of sorafenib. Thus analysis of VEGF and its receptor genes<br />
polymorphisms represents a clinical tool to identify patients with favourable response to<br />
sorafenib presumably related to a more efficient control of tumor growth.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds398 | ix243
735P RADIOGRAPHIC PARAMETERS IN PREDICTING OUTCOME<br />
OF PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC)<br />
TREATED WITH YTTRIUM-90 MICROSPHERE<br />
RADIOEMBOLIZATION (SIRT)<br />
M. Salem 1 , N. Jain 1 , S. Taylor 1 , G. Dyson 1 , J. Beebe-Dimmer 1 , I.P. Le 2 ,<br />
M. Choi 1 , A.F. Shields 1 , J.J. Critchfield 1 , P.A. Philip 1<br />
1 Oncology, Karmanos Cancer Center, Wayne State University, Detroit, MI,<br />
UNITED STATES OF AMERICA, 2 Department of Internal Medicine, Wayne State<br />
University, Detroit, MI, UNITED STATES OF AMERICA<br />
Background: The predictive role of radiographic parameters in HCC pts undergoing<br />
transarterial hepatic selective internal radio<strong>the</strong>rapy (SIRT) is not fully characterized.<br />
The objective of this retrospective study was to determine whe<strong>the</strong>r radiographic<br />
parameters at baseline and/or radiographic changes following SIRT predict outcome<br />
in HCC pts treated with Yttrium-90 glass microsphere radioembolization.<br />
Methods: Baseline and post-SIRT CT images (median of 6 weeks) were analyzed.<br />
Various features such as tumor size; attenuation; margins; enhancement; and amount<br />
of tumor necrosis were examined. Selected radiographic parameters were evaluated &<br />
correlated with PFS & OS. Objective response was assessed by RECIST 1.1 and<br />
Morphology, Attenuation, Size, and Structure (MASS) criteria (favorable (FR) vs.<br />
non favorable). Differences were analyzed using Wilcoxon Signed Rank Test and<br />
Fisher’s Exact Test. Kaplan-Meier methods were used to estimate survival curves.<br />
Cox regression was used in uni- and multi- variable survival analyses<br />
Results: Twenty-four pts (79% M; median age 63 y) received a median radiation dose of<br />
1.965 GBq. On post-SIRT CT, 65% of tumors had decreased longest diameter (median<br />
decrease 8%, p = 0.27); 64% had decreased attenuation (median decrease 18 HU, p =<br />
0.067), and 45% demonstrated increased tumor necrosis (p < 0.001). RECIST-defined<br />
partial response was seen in 10% of pts, stable disease in 80% and 10% had disease<br />
progression. Median PFS and OS were 4.4 and 11.6 months, respectively. Of <strong>the</strong> 9 pts<br />
who were response evaluable by MASS criteria, FR was a predictor of PFS (p = 0.03)<br />
with median time to progression not being reached vs. 5.5 months for <strong>the</strong> non-FR<br />
group. In univariate analyses, well-defined tumor margins, lower hepato-pulmonary<br />
shunt fraction and peripheral hypervascularity were associated with prolonged PFS. On<br />
multivariate analysis, tumor margins and shunt fraction were correlated with PFS<br />
whereas extrahepatic disease and liver cirrhosis were independent predictors of OS.<br />
Conclusions: In pts with HCC, pre-treatment tumor margins and shunt fraction<br />
may be developed as biomarkers to identify pts who are unlikely to benefit from<br />
SIRT. In addition, response evaluation by MASS criteria may provide better and<br />
earlier determination of lack of benefit from SIRT and <strong>the</strong> need for fur<strong>the</strong>r <strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
736P THE USE OF SECOX (SORAFENIB, OXALIPLATIN,<br />
CAPCITABINE) AS THE TREATMENT OF ADVANCED<br />
HEPATOCELLULAR CARCINOMA (HCC) – A SINGLE CENTER<br />
RETROSPECTIVE STUDY<br />
J. Chiu 1 ,V.Tang 1 , P. Chan 2 , R. Leung 1 , H. Wong 1 , R. Poon 3 , S.T. Fan 3 ,T.Yau 1<br />
1 Medicine, Queen Mary Hospital, The University of Hong Kong, HONG KONG,<br />
2 Medicine, Ruttonjee Hospital, HONG KONG, 3 Surgery, Queen Mary Hospital,<br />
The University of Hong Kong, HONG KONG<br />
Background: Combining sorafenib with chemo<strong>the</strong>rapy can potentially provide a new<br />
regime with enhanced benefit. Phase II study has demonstrated promising activity in<br />
combining sorafenib, oxaliplatin and capecitabine (SECOX) in treating advanced<br />
HCC. We reported our experience in using this regime in our centre.<br />
Methods: This retrospective study included all consecutive advanced HCC patients<br />
treated in our centre with SECOX regimen: daily oral sorafenib 400 mg B.D., oxaliplatin<br />
85 mg/m 2 infusion on D1, and oral capecitabine 850 mg/m 2 B.D. from D1-7 every 2<br />
weeks. Univariate and multivariate analyses were employed to explore <strong>the</strong> potential<br />
predictive factors for overall survival benefits treated with this combination.<br />
Results: 89 patients were included in <strong>the</strong> analysis with 29 patients previously enrolled<br />
in <strong>the</strong> phase II trial and 60 patients treated outside <strong>the</strong> clinical trial in our centre. Of<br />
89 patients received SECOX (male, 85%; median age, 53 year; hepatitis B carrier,<br />
91%), 72 (81%) patients had CP A and 17 (29%) patients had CP B. Moreover,<br />
42.7% patients had ECOG performance status (PS) 0, 53.9 % patients had PS 1 and<br />
3.4% patients had PS 2. The most common grade 3 or 4 drug-related toxicities were<br />
hand-foot syndrome (10.5%), diarrhea (5.8%), and hypertension (5.8%). G3/4<br />
thrombocytopenia was found in 18.1% and neutropenia was present in 6.0%. The<br />
overall response rate was 14.6%, with one (1.1%) patient had complete response and<br />
12 (13.5%) patients achieved partial response. Moreover, 30 (33.7%) patients had<br />
stable disease. Overall, 48.3% patients derived benefits from SECOX. The<br />
progression-free survival (PFS) was 4.1 months (95% C.I. 3.6-4.6) and median overall<br />
survival (OS) was 11.0 months (95% C.I. 8.2-12.3). Patients with CP A cirrhosis had<br />
better PFS (4.2 vs 2.9 months, p = 0.027) and OS (11.8 vs 5.0 months, p = 0.003)<br />
than CP B patients. Multivariate analysis revealed that both ECOG 1-2 (p = 0.005)<br />
and vascular involvement (p = 0.048) were associated with worse overall survival.<br />
Conclusions: The SECOX regime had promising activity in advanced HCC with<br />
good tolerability, especially in Child-Pugh A patients with good performance status.<br />
Annals of Oncology<br />
Disclosure: R. Poon: Advisory board with Bayer. T. Yau: Advisory board with Bayer.<br />
All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
737P PHASE I/II TRIAL OF LENVATINIB (E7080), A<br />
MULTI-TARGETED TYROSINE KINASE INHIBITOR, IN<br />
PATIENTS (PTS) WITH ADVANCED HEPATOCELLULAR<br />
CARCINOMA (HCC)<br />
K. Ikeda 1 , H. Kumada 2 , M. Kudo 3 , S. Kawazoe 4 , Y. Osaki 5 , M. Ikeda 6 ,<br />
T. Okusaka 7 , T. Suzuki 8 , J.P. O’Brien 9 , K. Okita 10<br />
1 Department of Hepatology, Toranomon Hospital, Tokyo, JAPAN, 2 Department<br />
of Hepatology, Toranomon Hospital Kajigaya, Kanagawa, JAPAN, 3 Department<br />
of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka,<br />
JAPAN, 4 Department of Internal Medicine, Saga prefectural Hospital Koseikan,<br />
Saga, JAPAN, 5 Department of Gastroenterology and Hepatology, Osaka Red<br />
Cross Hospital, Osaka, JAPAN, 6 Division of Hepatobiliary and Pancreatic<br />
Oncology, National Cancer Center Hospital East, Chiba, JAPAN, 7 Division of<br />
Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo,<br />
JAPAN, 8 Oncology Clinical Development, Eisai, Tokyo, JAPAN, 9 Oncology, Eisai<br />
Inc., Woodcliff Lake, NJ, UNITED STATES OF AMERICA, 10 Department of<br />
Gastroenterology and Hepatology, Shimonoseki Kohsei Hospital, Yamaguchi,<br />
JAPAN<br />
Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3,<br />
FGFR1-4, RET, KIT and PDGFRβ. The inherent vascularity of HCC makes it a target for<br />
VEGF inhibitors and o<strong>the</strong>r molecular mediators of angiogenesis like FGFR and PDGFR.<br />
The current study established a MTD of lenvatinib for HCC patients with Child-Pugh A<br />
of 12 mg qd. The current presentation is a report on <strong>the</strong> efficacy and safety of lenvatinib.<br />
Methods: Between July 9, 2010 and June 22, 2011, 46 pts with advanced HCC and<br />
Child-Pugh A status were enrolled in Japan (n = 43) and Korea (n = 3). Pts may have<br />
received up to one prior treatment regimen including sorafenib. Pts were treated with a<br />
starting dose of lenvatinib 12 mg once daily in 28 day cycles until disease progression<br />
or development of unmanageable toxicities. Response was assessed by RECIST 1.1<br />
(modified to evaluate viable lesions) by independent radiologist review (IRR).<br />
Results: 46 pts were enrolled (med age: 67; M: 72%) and were evaluable for response.<br />
76% of pts required dose adjustments for management of toxicity. The most common<br />
adverse events were hypertension 76% (Gr3: 54%), palmar-plantar erythrodysaes<strong>the</strong>sia<br />
syndrome 65% (Gr3: 9%), anorexia 59% (Gr3: 2.2%), proteinuria 54% (Gr3: 17%),<br />
fatigue 54% (Gr3: 0%), and thrombocytopenia 52% (Gr3: 33%). A higher level of<br />
toxicity was observed in pts weighing < 60 kg compared to pts ≥ 60 kg correlating with<br />
differences in drug exposure. ORR based on IRR is (PR = 32.6%, SD = 45.7%). Median<br />
Time to progression (TTP) is 7.49 mo (95% CI: 5.45 - 9.43)(based on minimum 6 mo.<br />
f/u, with 56.5% progression events) based on IRR. Median overall survival (OS) is 13.9<br />
mo (95% CI: 11.8 -) (based on minimum 8 mo. f/u, with 46% death events). OS data<br />
has not yet matured and will be reported in <strong>the</strong> future.<br />
Conclusions: In this Phase I/II study, lenvatinib administered to patients with<br />
advanced HCC was not associated with any new toxicities associated with TKI class<br />
and was managed by dose adjustments. A weight-based starting dose (
Annals of Oncology<br />
advanced HCC, tivantinib mono<strong>the</strong>rapy improved time to progression by 56%.<br />
However, in that study at <strong>the</strong> standard phase 2 dose of 360 mg twice daily (BID),<br />
tivantinib exposure was increased, and <strong>the</strong> absolute incidence of severe neutropenia<br />
increased approximately 6% compared to pts with solid tumors from previous<br />
studies. An exposure-response analysis was conducted to explore <strong>the</strong> relationship<br />
between neutropenia and tivantinib pharmacokinetics (PK).<br />
Methods: Tivantinib plasma concentration and incidence of grade ≥ 2 neutropenia<br />
were pooled from phase 1/1b and 2 studies. A population PK model (NONMEM<br />
v.7.1.0) was used to predict tivantinib exposure in HCC. The relationship between<br />
tivantinib exposure and neutropenia was evaluated by logistic regression analysis<br />
(S plus v8.0).<br />
Results: Data were available from 289 cancer pts, including 73 pts with HCC and<br />
mild-to-moderate hepatic impairment. Cases of grade ≥ 3 (n = 28) and grade ≥ 2<br />
(n = 40) neutropenia were included in <strong>the</strong> analysis. Based on <strong>the</strong> population PK<br />
analysis, tivantinib clearance was reduced approximately 67% in HCC pts, resulting<br />
in approximately 3 times higher exposure compared with o<strong>the</strong>r cancer pts. There was<br />
a significant (P < .001) relationship between tivantinib exposure and incidence of<br />
grade ≥ 2/3 neutropenia. By reducing <strong>the</strong> tivantinib starting dose from 360 to 240 mg<br />
BID, <strong>the</strong> incidence of grade ≥ 3 neutropenia is modeled to decrease from 28% to 16%<br />
in HCC pts. Fur<strong>the</strong>r reduction in <strong>the</strong> risk of neutropenia (∼6%) was achieved with<br />
intensive clinical monitoring and an aggressive dose-reduction schema.<br />
Conclusions: Based on <strong>the</strong> current analysis, <strong>the</strong> increased incidence of neutropenia<br />
in HCC pts compared to pts with o<strong>the</strong>r solid tumors resulted from increased<br />
tivantinib exposure due to hepatic impairment. Consistent with <strong>the</strong> model, <strong>the</strong> risk of<br />
neutropenia was successfully managed in HCC pts by implementing dose reduction<br />
and tighter clinical monitoring without compromising efficacy.<br />
Disclosure: H. Zahir: H Zahir is an employee of Daiichi Sankyo, Inc. H. Kastrissios:<br />
H Kastrissios is an employee of Pharsight Corporation and was retained by Daiichi<br />
Sankyo to provide scientific consulting services on tivantinib. M. Jansen: M Jansen is<br />
an employee of Daiichi Sankyo, Inc. R. Savage: R Savage is currently an employee of<br />
ArQule. I participate in <strong>the</strong> ESPP employee stock purchase plan and receive stock<br />
options as part of my compensation package as an employee of ArQule.<br />
G. Abbadessa: G Abbadessa is an employee of ArQule, Inc. and owns Arqule stock<br />
options. F. Chai: F Chai is an employee of ArQule, Inc., <strong>the</strong> sponsor of <strong>the</strong> studies.<br />
F Chai holds ArQule stock. B. Schwartz: B Schwartz is currently an employee (Chief<br />
Medical officer) of ArQule and own stock in <strong>the</strong> company. R. Miller: R Miller is a<br />
full time employee of Daiichi Sankyo Pharma Development. T. Tokui: T Tokui is an<br />
employee of Daiichi Sankyo Co., Ltd. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
739P PHASE 1 EXPERIENCE OF TIVANTINIB IN PATIENTS WITH<br />
HEPATOCELLULAR CARCINOMA (HCC) OR BILIARY TRACT<br />
CANCER (BTC)<br />
F. Chai 1 , G. Abbadessa 2 , R. Savage 3 , H. Zahir 4 , Y. Chen 2 , M. Lamar 5 ,<br />
J. Kazakin 6 , D. Ferrari 2 , R. von Roemeling 7 , B. Schwartz 2<br />
1 Medical Administration, ArQule, Inc., Woburn, MA, UNITED STATES OF<br />
AMERICA, 2 Clinical Development, ArQule, Inc., Woburn, MA, UNITED STATES<br />
OF AMERICA, 3 Preclinical Development and Clinical Pharmacology, ArQule, Inc.,<br />
Woburn, MA, UNITED STATES OF AMERICA, 4 Clinical Pharmacology, Daiichi<br />
Sankyo, Inc., Edison, NJ, UNITED STATES OF AMERICA, 5 Clinical Operations,<br />
ArQule, Inc., Woburn, MA, UNITED STATES OF AMERICA, 6 Arqule, Inc., ArQule,<br />
Inc., Woburn, MA, UNITED STATES OF AMERICA, 7 Clinical Development<br />
Oncology, Daiichi Sankyo Pharma Development, Edison, MA, UNITED STATES<br />
OF AMERICA<br />
Background: Tivantinib is a selective MET inhibitor that is extensively metabolized<br />
by <strong>the</strong> liver. Since 2006, > 700 cancer patients (pts) have been treated with tivantinib.<br />
Herein we summarize safety, pharmacokinetic (PK), and efficacy data for pts with<br />
HCC or BTC treated with tivantinib in phase 1 clinical trials.<br />
Methods: Adverse events (AEs) were assessed using Common Terminology Criteria<br />
for Adverse Events (CTCAE) version 3.0. Tumor responses were assessed via<br />
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. PK parameters<br />
were calculated using blood samples collected on day 1 and on day 2 or day 15 of<br />
cycle 1.<br />
Results: 53 pts (median age, 63 y) with HCC (n = 42; 79%), cholangiocarcinoma<br />
(n = 10; 19%), or gallbladder adenocarcinoma (n = 1; 2%) were included. Of <strong>the</strong>se, 23<br />
pts (43%) received tivantinib mono<strong>the</strong>rapy, and 30 pts (57%) received tivantinib in<br />
combination with sorafenib (n = 20; 38%), gemcitabine (n = 8; 15%), or erlotinib<br />
(n = 2; 4%). Starting tivantinib BID doses were < 240 mg in 3 (6%), 240 mg in 11<br />
(21%), and 360 mg in 39 (74%) pts. Common treatment-emergent AEs (≥ 15% of<br />
pts) were fatigue and anemia (45% each); diarrhea (40%); neutropenia and anorexia<br />
(38% each); as<strong>the</strong>nia (30%); thrombocytopenia, peripheral edema, pyrexia, and<br />
nausea (25% each); hyperbilirubinemia (23%); vomiting and alopecia (21% each);<br />
rash (19%); leukopenia (17%); and palmar-plantar erythrodyses<strong>the</strong>sia syndrome,<br />
dyspnea, and ascites (15% each). Tivantinib PK analysis indicated peak plasma levels<br />
2 h after oral administration (range, 1-6 h). Tivantinib exposure was higher in pts<br />
with HCC vs pts with BTC (12,385 vs 5,992 ng·h/mL). Best responses were complete<br />
response in 1 pt (2%), partial response in 2 pts (4%), and stable disease (SD) in 30<br />
pts (57%). Response rate and disease control rate were 6% and 62%, respectively.<br />
Conclusions: Tivantinib demonstrated a manageable safety profile and was well<br />
tolerated at doses up to 360 mg BID in pts with BTC and up to 240 mg BID in pts<br />
with HCC. Only pts with HCC had increased exposure, presumably due to<br />
disease-specific hepatic impairment. Encouraging clinical activity (primarily SD) was<br />
observed in this pt population.<br />
Disclosure: F. Chai: F Chai is an employee of ArQule, Inc., <strong>the</strong> sponsor of <strong>the</strong><br />
studies and holds ArQule stock. G. Abbadessa: G Abbadessa is an employee of<br />
ArQule, Inc. and owns ArQule stock options. R. Savage: R Savage is currently an<br />
employee of ArQule and participates in <strong>the</strong> ESPP employee stock purchase plan and<br />
receives stock options as part of his compensation package as an employee of<br />
ArQule. H. Zahir: H Zahir is an employee of Daiichi Sankyo, Inc. Y. Chen: Y Chen<br />
is an ArQule employee and own ArQule stocks. M. Lamar: M Lamar is an employee<br />
of ArQule, Inc. J. Kazakin: J Kazakin is an employee of ArQule, Inc. and has<br />
ArQule’s stock options. D. Ferrari: D Ferrari is an ArQule Inc. employee and<br />
currently owns ArQule stock. R. von Roemeling: R von Roemeling is an employee of<br />
Daiichi Sankyo Pharma Development. B. Schwartz: B Schwartz is currently an<br />
employee of ArQule Inc. and own stock in <strong>the</strong> company.<br />
740P PHASE I STUDY OF NINTEDANIB (BIBF 1120) IN EUROPEAN<br />
PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA<br />
D. Palmer 1 , A.B. Loembé 2 , M. Studeny 2 , J. Hocke 3 ,T.Meyer 4<br />
1 Liverpool Cancer Research Uk Centre, University of Liverpool, Liverpool,<br />
UNITED KINGDOM, 2 Oncology, Boehringer Ingelheim RCV GmbH & Co KG,<br />
Vienna, AUSTRIA, 3 Oncology, Boehringer Ingelheim Pharma GmbH & Co.KG,<br />
Biberach an der Riss, GERMANY, 4 UCL Cancer Institute, University College<br />
London, London, UNITED KINGDOM<br />
Background: Caucasian and Asian patients (pts) with hepatocellular carcinoma<br />
(HCC) tolerate anticancer drugs differently. This open-label, multicentre, phase I/<br />
randomised phase II study (NCT01004003; phase II in progress) evaluated <strong>the</strong><br />
efficacy, safety and pharmacokinetics of nintedanib (a triple angiokinase inhibitor<br />
targeting VEGFRs, PDGFRs and FGFRs) versus sorafenib in pts with advanced HCC<br />
from Europe. Initial phase I results are reported.<br />
Methods: Pts (ECOG performance status ≤2, Child-Pugh [CP] score ≤7) with<br />
histologically/cytologically confirmed HCC and no prior systemic <strong>the</strong>rapy were<br />
enrolled in <strong>the</strong> phase I trial and stratified into two groups: (I) AST and ALT ≤2 x<br />
upper limit of normal (ULN), and CP 5–6; (II) AST or ALT >2 to ≤5 x ULN, or CP<br />
7. Utilising a 3 + 3 design, cohorts received oral nintedanib continuously in 28-day<br />
courses, starting at 50mg bid (group II) or 100mg bid (group I) and escalating up to<br />
200mg bid in 50mg bid intervals. Therapy was continued until no clinical benefit or<br />
undue toxicity. The phase I primary endpoint was <strong>the</strong> maximum tolerated dose<br />
(MTD) of nintedanib in Course 1.<br />
Results: A total of 28 pts (71% Caucasian) have been treated: 13 in group I (median<br />
[range] days: 345 [2–757]; 100/150/200mg bid, n = 6/3/4) and 15 in group II (median<br />
[range] days: 74 [17–428]; 50/100/150/200mg bid, n = 3/4/4/4). No dose-limiting<br />
toxicities (DLTs) were seen in group I or II during Course 1 at doses up to 200mg<br />
bid, which was <strong>the</strong> MTD of nintedanib. After <strong>the</strong> dose-escalation phase and<br />
determination of MTD, seven pts reported DLTs at various dose levels (CTCAE<br />
Grade [G]3 bilirubin increase, G3 AST increase, G4 amylase increase, G3<br />
hypertension/ALP increase, G3 amylase increase, G5 multi-organ failure, G3<br />
bilirubin increase). The most frequent adverse events (AEs) in both groups, by<br />
system organ class, were gastrointestinal (89%) and general/administration site (39%)<br />
disorders. Class-related AEs (any grade) were uncommon (hypertension [n = 2], rash<br />
[n = 3]). Hepatic enzyme data will be presented.<br />
Conclusions: Nintedanib has an acceptable safety profile in pts with advanced HCC<br />
at <strong>the</strong> same dose used in o<strong>the</strong>r cancers (200 mg bid).<br />
Disclosure: D. Palmer: Daniel Palmer: research funding from Boehringer Ingelheim.<br />
A.B. Loembé: Arsene-Bienvenu Loembé: employee of Boehringer Ingelheim. M.<br />
Studeny: Matus Studeny: employee of Boehringer Ingelheim. J. Hocke: Julia Hocke:<br />
employee of Boehringer Ingelheim. T. Meyer: Tim Meyer: research funding from<br />
Boehringer Ingelheim<br />
741P VALIDATION OF PROGNOSTIC VALUE OF AJCC 7TH STAGING<br />
SYSTEM IN PATIENTS WITH RESECTED HEPATOCELLULAR<br />
CARCINOMA (HCC)<br />
S.F. Ang1 ,H.Li2 , S. Choo1 , I.B. Tan1 , M.H. Tan1 , H.C. Toh1 1<br />
Medical Onocology, National Cancer Center Singapore, SINGAPORE,<br />
2<br />
Department of Clinical Research, Singapore General Hospital, Singapore,<br />
SINGAPORE<br />
Background: Accurate cancer staging is essential to determine prognosis and<br />
appropriate treatment. The American Joint Committee on Cancer (AJCC) Staging<br />
Manual 7th edition for HCC released in 2010 subdivided stage III HCC to IIIA<br />
(multiple tumors of which any are greater than five centimeters, but lack major<br />
vessel invasion, T3A) and IIIB (invasion of major vessels, T3B). Both were previously<br />
classified as stage IIIA in <strong>the</strong> AJCC 6th. T4N0M0 and patients with node-positive<br />
disease (N1) are upstaged to stage IIIC and IVA respectively. The aim of our study is<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds398 | ix245
validate <strong>the</strong> revised AJCC 7th staging system based on outcomes of patients<br />
undergoing liver resection for HCC from a single institution.<br />
Methods: Records for all patients undergoing potentially curative surgery for<br />
localized HCC between 1992 – 2007 were retrospectively reviewed. Pathological<br />
staging were determined post-operatively. Survival curves were plotted with <strong>the</strong><br />
Kaplan–Meier method and were compared by using a log-rank test for various<br />
disease stages based on AJCC 7th staging system.<br />
Results: 543 patients were included (439 male) and 80% were Chinese ethnicity. 303<br />
patients were chronic hepatitis B carriers. The median follow up was 1.78 years with<br />
282 relapsed patients (51.9%) and 189 deaths (34.8%). Median survival (MS) and<br />
time-to-relapse (TTR) were 4.83 years and 2.00 years respectively. MS for AJCC 7<br />
stage I, II, III and IV were 6.35, 4.44, 2.41 and 0.49 years respectively (p
Annals of Oncology<br />
Methods: Phase I pts had histologically, cytologically or clinically confirmed HCC,<br />
ECOG performance status ≤2, Child-Pugh (CP) score ≤7, and ≤1 line of prior<br />
systemic <strong>the</strong>rapy. Using a 3 + 3 design, pts were stratified into two groups by liver<br />
function and CP score: (I) AST and ALT ≤2 x upper limit of normal (ULN), and CP<br />
5–6; (II) AST or ALT >2 x to ≤5 x ULN, or CP 7. Nintedanib (given continuously in<br />
28-day courses) was started at 50mg bid (group II) or 100mg bid (group I) and<br />
increased in 50mg bid increments up to 200mg bid. Therapy was continued until no<br />
clinical benefit or undue toxicity. The phase I primary endpoint was <strong>the</strong><br />
maximum-tolerated dose (MTD) of nintedanib.<br />
Results: Overall, 35 pts have received nintedanib: 11 in group I(100/150/200 mg<br />
bid, n = 4/3/4; median [range] duration: 140 [10–337] days) and 24 in group II<br />
(50/100/150/200 mg bid, n = 3/7/3/11; median [range] duration: 81 [2–587] days).<br />
In group I, no dose-limiting toxicities (DLTs) were seen at any dose during <strong>the</strong><br />
first course. In group II, one pt experienced a DLT (CTCAE Grade [G] 3 AST<br />
increase) at 100 mg bid in Course 1 (dose-escalation phase). The MTD of<br />
nintedanib was thus 200 mg bid in both groups. DLTs seen after MTD<br />
assessment were G4 gastrointestinal (GI) haemorrhage/anaemia (50 mg bid), G3<br />
ALT increase (150 mg bid), G3 GI haemorrhage (150 mg bid), G3 hypertension<br />
(200 mg bid; n = 2) and G4 gastric ulcer (200 mg bid). The most common<br />
adverse events, by system organ class, were GI (83%) and general/administration<br />
site disorders (51%), and investigations (51%). Hypertension and rash (any<br />
grade) occurred in 6 and 8 pts, respectively.<br />
Conclusions: Nintedanib has an acceptable safety profile in this Asian HCC<br />
population. As in o<strong>the</strong>r cancer types and European HCC pts, <strong>the</strong> MTD of nintedanib<br />
was 200 mg bid.<br />
Disclosure: C. Yen: Chia-Jui Yen: research funding from Boehringer Ingelheim. Y.<br />
Shen: Ying-Chun Shen: research funding from Boehringer Ingelheim. H. Shiah:<br />
Her-Shyong Shiah: research funding from Boehringer Ingelheim. J. Chen: Jo-Pai<br />
Chen: research funding from Boehringer Ingelheim. C. Hsu: Chiun Hsu: research<br />
funding from Boehringer Ingelheim. C. Hsu: Chih-Hung Hsu: research funding from<br />
Boehringer Ingelheim. D.C. Huang: Dennis Chin-Lun Huang: employee of<br />
Boehringer Ingelheim. J. Hocke: Julia Hocke: employee of Boehringer Ingelheim. W.<br />
Su: Wu-Chou Su: research funding from Boehringer Ingelheim. A. Cheng: Ann-Lii<br />
Cheng: research funding from Boehringer Ingelheim.<br />
745P PACLITAXEL AND CISPLATIN COMBINED WITH<br />
INTENSITY-MODULATED RADIOTHERAPY FOR UPPER<br />
ESOPHAGEAL CARCINOMA<br />
L. Tu 1,2 , L. Sun 1,2 , Y. Gong 1,2 , Y. Liu 1 , L. Zhou 1,2 , X. Zhou 1 ,Y.Xu 1 , J. Wang 1 ,<br />
M. Hou 1 ,Y.Lu 1,2<br />
1 Department of Thoracic Oncology, Cancer Center, West China Hospital,<br />
Sichuan University, CHINA, 2 State Key Laboratory of Bio<strong>the</strong>rapy, West China<br />
Hospital, Sichuan University, Chengdu, CHINA<br />
Purpose: Concurrent radio-chemo<strong>the</strong>rapy has been recommended as a standard<br />
<strong>the</strong>rapy in patients with upper esophageal carcinoma which is not suitable for<br />
surgery. Although INT 0123 trial indicated that <strong>the</strong> 5-fluorouracil (5-FU) plus<br />
cisplatin (DDP) combined with radio<strong>the</strong>rapy was <strong>the</strong> initial strategy, <strong>the</strong> optimal<br />
management of upper esophageal carcinoma remains undetermined. This study was<br />
conducted to evaluate <strong>the</strong> effectiveness and safety of intensity-modulated<br />
radio<strong>the</strong>rapy (IMRT) and concurrent paclitaxel plus cisplatin (TP regimen) for upper<br />
esophageal carcinoma.<br />
Materials and methods: 36 patients of upper esophageal carcinoma were<br />
retrospectively analyzed. Patients were treated with IMRT (median 60 Gy) combined<br />
with concurrent TP regimen chemo<strong>the</strong>rapy. The Kaplan-Meier analysis was<br />
performed in statistical analysis. Toxicities were recorded according to <strong>the</strong> NCI CTC<br />
version 3.0.<br />
Results: 36 patients aged 43-73 years (median 57 years). The median follow-up<br />
period was 14.0 months. The 1-year and 2-year survival rates were 83.3% and 42.8%,<br />
respectively. The median progression-free survival (PFS) time and overall survival<br />
(OS) time were 12.0 (95% CI 8.6-15.4 months) and 18.0 months (95% CI 14.2-21.8<br />
months), respectively. Grade 3 neutropenia, radiation-induced esophagitis and<br />
radiodermatitis were observed in 5 (13.9%), 3 (8.3%) and 8 (22.2%) patients,<br />
respectively. There were two treatment-related deaths due to esophageal perforation<br />
and hemorrhea.<br />
Conclusions: For those patients with upper esophageal carcinoma, IMRT combined<br />
with concurrent TP regimen chemo<strong>the</strong>rapy was an effective treatment. However,<br />
special attention should be paid to <strong>the</strong> occurrence of perforation and hemorrhea.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
746P PHASE I/II STUDY OF NC-6004, A NOVEL MICELLAR<br />
FORMULATION OF CISPLATIN, IN COMBINATION WITH<br />
GEMCITABINE IN PATIENTS WITH PANCREATIC CANCER<br />
IN ASIA – RESULTS OF PHASE I<br />
W. Su 1 , L. Chen 1 ,C.Li 2 , J. Chen 3 ,Y.Lin 4 , S. Choo 5 , Y. Matsumura 6<br />
1 Internal Medicine, National Cheng Kung University Hospital, Tainan, TAIWAN,<br />
2 Merdicine, Taipei Veterans General Hospital, Taipei, TAIWAN, 3 Internal Medicine,<br />
Chang Gung Memorial Hospital, Taipei, TAIWAN, 4 Oncology, National Taiwan<br />
University Hospital, Taipei, TAIWAN, 5 Medical Oncology, National Cancer Center<br />
Singapore, SINGAPORE, 6 Innovative Oncology, National Cancer Center Hospital<br />
East, Kashiwa, JAPAN<br />
Introduction: NC-6004 is a cisplatin-incorporated polymeric micelle with a size of<br />
30 nm in diameter composed of polyethylene glycol-polyglutamic acid block<br />
co-polymer via polymer-metal complex formation. A phase I study of NC-6004<br />
mono<strong>the</strong>rapy in patients with advanced solid tumours confirmed that NC-6004<br />
exhibits delayed and sustained release of cisplatin characterized by lower Cmax and<br />
higher AUC compared to an equivalent dose of cisplatin, resulting in <strong>the</strong> reduction<br />
of cisplatin-related toxicity, and 2 out of 17 patients with pancreatic cancer<br />
demonstrated <strong>the</strong> evidence of disease stabilization. Preclinical studies demonstrated<br />
that NC-6004 in combination with gemcitabine (GEM) was effective against<br />
pancreatic cancer. On <strong>the</strong> basis of <strong>the</strong>se results, phase I part of a phase I/II study of<br />
NC-6004 in combination with GEM in patients with pancreatic cancer has been<br />
conducted at 4 sites in Taiwan and 1 site in Singapore. The objectives of <strong>the</strong> study<br />
were to determine <strong>the</strong> MTD and RD of NC-6004 in combination with GEM in <strong>the</strong><br />
treatment of pancreatic cancer for <strong>the</strong> following phase II study.<br />
Methods: A total of 19 patients with pancreatic cancer were treated with NC-6004 at<br />
a dose of 30, 60, 90 and 120 mg/m 2 once every 3 weeks, and GEM at 1000 mg/m 2<br />
twice every 3 weeks on Day 1 and 8. The 2-dose oral steroid regimen was<br />
implemented to reduce <strong>the</strong> risk of hypersensitivity.<br />
Results: Two DLTs occurred at 120 mg/m 2 , which led to <strong>the</strong> conclusion that <strong>the</strong><br />
MTD and <strong>the</strong> RD of NC-6004 in combination with GEM are 120 mg/m 2 and<br />
approximately 90 mg/m 2 , respectively. In <strong>the</strong> interim analysis of ITT population for<br />
efficacy evaluation (17 patients), no patient had CR based on RECIST criteria,<br />
however best overall response (BOR) of PR was found in 1 (5.9%) and 10 (58.8%)<br />
had a BOR of SD, resulting in <strong>the</strong> disease control ratio of 64.7%. Because of <strong>the</strong><br />
stringent prophylactic steroid regimen, eight out of 19 (42.1%) completed <strong>the</strong><br />
per-protocol period (8 cycles; 24 weeks), and 1 of <strong>the</strong>m reached cycles up to 20.<br />
Conclusion: Treatment with NC-6004 in combination with GEM was relatively well<br />
tolerated, and exhibited modest efficacy in patients with pancreatic cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
747P PREVALENCE, CLINICAL FEATURES AND PROGNOSIS OF<br />
DIFFUSE MALIGNANT PERITONEAL MESOTHELIOMA<br />
(DMPM): DO PATIENTS IN CLINICAL TRIALS REFLECT THE<br />
REAL WORLD?<br />
F. Grosso 1 , D. Degiovanni 2 , A. Roveta 1 , S. Barbero 3 , R. Libener 1 , F. Musante 4 ,<br />
O. Testori 5 , D. Mirabelli 6 , P.G. Betta 7 , M. Botta 8<br />
1 Oncology, SS Antonio e Biagio General Hospital, Alessandria, ITALY, 2 Palliative<br />
Care, S Spirito General Hospital, Casale Monferrato, ITALY, 3 Radiology, S Spirito<br />
General Hospital, Casale Monferrato, ITALY, 4 Radiology, SS Antonio e Biagio<br />
General Hospital, Alessandria, ITALY, 5 Nuclear Medicine, SS Antonio e Biagio<br />
General Hospital, Alessandria, ITALY, 6 Epidemiology Cancer Unit, University of<br />
Tumor, Turin, ITALY, 7 LILT, SS Antonio e Biagio General Hospital, Alessandria,<br />
ITALY, 8 Oncology, S Spirito General Hospital, Casale Monferrato, ITALY<br />
Background: Peritoneum is <strong>the</strong> second most frequent site of origin of malignant<br />
meso<strong>the</strong>lioma (MM). DMPM is <strong>the</strong> most frequent primary peritoneal malignancy in<br />
developed countries. Highly specialized centres have reported improved outcomes<br />
following an aggressive loco-regional approach, including cytoreductive surgery<br />
(CRS) and perioperative intraperitoneal chemo<strong>the</strong>rapy (PIC), with median overall<br />
survival (OS) approaching 50 months and almost 50% relapse-free patients at 5<br />
years. Conversely, in population based studies prognosis still remains very poor with<br />
OS in <strong>the</strong> range of 5.7-10. To describe clinical features and prognosis in unselected<br />
consecutive patients, we report on <strong>the</strong> clinical outcome of a series of DMPM treated<br />
at a single Oncological Department, in a highly asbestos-polluted area in Piedmont.<br />
Patients and methods: By using our database (MesoDB), we retrieved DMPM<br />
patients diagnosed between November 1993 and September 2011 at Alessandria and<br />
CasaleMonferratoHospitals. All cases were confirmed by <strong>the</strong> same expert<br />
pathologists.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds398 | ix247
Results: Among 862 MM we identified 35 patients, 9 F and 26 M. Median age at<br />
diagnosis was 67 years, IQR 61-73, range 30-83. Occupational asbestos exposure was<br />
definite in 23 and probable in 2 patients, whereas environmental in 10. The histological<br />
diagnosis followed a laparoscopic/laparotomic procedure in 25 patients, <strong>the</strong> o<strong>the</strong>r 10 had<br />
only US-guided, fine-needle aspiration biopsy. Only 1 patient in <strong>the</strong> series underwent<br />
CRS and PIC. The o<strong>the</strong>rs were deemed unsuitable for surgery. Ten patients had systemic<br />
chemo<strong>the</strong>rapy, 6 pemetrexed and 2 raltritrexed-based. The o<strong>the</strong>r 25 received only best<br />
supportive care and among <strong>the</strong>se 3 received also subcutaneous IFNbeta or IL2 and 1<br />
intraperitoneal IFNbeta. PFS of <strong>the</strong> 12 patients receiving systemic <strong>the</strong>rapy was 3.9<br />
months (range 1-7,7). Median OS was 6.1 months (95%CI 2-8,7).<br />
Conclusions: DMPM accounts for 5% of MMs in our mesoDB, a percentage lower<br />
than reported in <strong>the</strong> literature. Outcomes in our patients were more disappointing<br />
compared to those reported by referral centres, but similar to population-based<br />
studies. These differences emphasize <strong>the</strong> strict selection of patients enrolled into<br />
aggressive loco-regional treatment programs and <strong>the</strong> need for new <strong>the</strong>rapeutic<br />
approaches suitable for <strong>the</strong> real clinical practice setting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
748 EXPRESSION AND CLINICAL SIGNIFICANCE OF NPRA<br />
IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA<br />
J. Wang 1 , Z. Zhao 1 , H. Fang 2 , E. Tangsakar 1 , J. Zhang 1<br />
1 Department of Surgical Oncology, First Affiliated Hospital, Medical School, Xi’an<br />
Jiaotong University, Xi’an, CHINA, 2 Department of Thoracic Surgery, Second<br />
Hospital of Yulin, Yulin, CHINA<br />
Background and objective: Esophageal cancer is a main reason of cancer related<br />
mortality, and <strong>the</strong> tumer targeted <strong>the</strong>rapy is a new and effective treatment. NPRA<br />
(natriuretic peptide receptor A), as a new oncogene, that promotes tumorigenesis in<br />
several cancer types, might represent a novel <strong>the</strong>rapeutic target in esophageal cancer.<br />
In this study we suggested that <strong>the</strong> expression and clinical significance of NPRA in<br />
esophageal squamous cell carcinoma (ESCC).<br />
Methods: The expression of NPRA in 45 cases of ESCC tissues, 40 cases of adjacent<br />
tissues, 30 positive Lymph node tissues and 24 negative Lymph node tissues were<br />
assessed by SP immunohistochemical method. No patients received preoperative<br />
chemo<strong>the</strong>rapy, radiation <strong>the</strong>rapy, and immune <strong>the</strong>rapy and all of patients were<br />
confirmed for ESCC by pathologist at Department of Thoracic Oncosurgery, <strong>the</strong> First<br />
Affiliated Hospital of Xi , an Jiaotong University.<br />
Results: In esophageal squamous cells, <strong>the</strong> expression of NPRA was strongly detected<br />
in cytoplasm, while undetectable or very weak in nuclear. The positive rates of<br />
NPRA in <strong>the</strong> cancer tissues was 71.1%, while that in <strong>the</strong> adjacent tissues group was<br />
17.5%, and showed 63.32% and 24.3% in <strong>the</strong> positive Lymph node tissues and<br />
negative Lymph node tissues respectively, <strong>the</strong>re was a significant difference between<br />
<strong>the</strong> two groups ( P>0.05). Clinicopathological analyses revealed that increased<br />
cytoplasmic NPRA expression correlated with differentiation and TNM stage, while<br />
showed no statistically significant among <strong>the</strong> association of age, gender, and lymph<br />
node metastasis.<br />
Conclusion: Our findings demonstrate that <strong>the</strong> NPRA has high expression in ESCC<br />
tissues, and <strong>the</strong> positive rate is closely correlated with <strong>the</strong> differentiation and TNM<br />
stage, and suggest that NPRA represents a potential <strong>the</strong>rapeutic target.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
749 A PHASE II TRIAL OF NEOADJUVANT CONCURRENT<br />
CHEMO-RADIOPTHERAPY CONTAINING CISPLATIN AND 5-FU<br />
FOLLOWED BY RESECTION FOR ESOPHAGEAL CARCINOMA<br />
K. Anvari, S.A. Aledavood, M. Seilanian Tousi, F. Nosrati<br />
Cancer Research Center, Omid Hospital, Faculty of Medicine, Mashhad<br />
University of Medical Sciences, Mashhad, IRAN<br />
Introduction: Combined modality treatments have been adopted to improve survival<br />
in patients with esophageal carcinoma. In this trial, we evaluated <strong>the</strong> efficacy and<br />
toxicity of a preoperative concurrent chemoradio<strong>the</strong>rapy protocol in patients with<br />
locally advanced esophageal carcinoma.<br />
Method and material: Between 2006 and 2011, eligible patients with locally<br />
advanced esophageal carcinoma underwent concurrent radio<strong>the</strong>rapy (40 Gy/20<br />
fractions) and chemo<strong>the</strong>rapy (cisplatin 20 mg/m 2 for 4 days plus 5-FU 700 mg/m 2<br />
24-hour infusion for 4 days on <strong>the</strong> first and <strong>the</strong> last week of radiation <strong>the</strong>rapy). In<br />
patients with unsuitable hematological or general condition only one cycle of<br />
chemo<strong>the</strong>rapy was prescribed. The patients underwent esophagectomy 3 to 4 weeks<br />
following radiation <strong>the</strong>rapy. Pathologic response, overall survival rate, toxicity and<br />
feasibility were evaluated.<br />
Results: 197 patients with a median age of 59 (range; 27-70) with a female to male<br />
ratio of 100/97 entered <strong>the</strong> protocol. 194 cases (98.5%) had esophageal SCC. Grades<br />
3-4 of toxicity were as follows: neutropenia in 41 (21%) and esophagitis in 5 (2.5%)<br />
cases. There were 11 (5.6%) early death probably due to treatment related toxicities.<br />
The o<strong>the</strong>r reasons for not completing <strong>the</strong> protocol were as follows: toxicity in 6 (3%),<br />
refusing surgery in 35 (17.8%), improper general condition for surgery in 18 cases<br />
(9.1%). 127 cases (64.5%) completed <strong>the</strong> protocol among which 60 cases received 2<br />
courses of chemo<strong>the</strong>rapy. For patients who underwent surgery, <strong>the</strong> complete<br />
pathological response was shown in 38 cases (29.9%) with a 5-year overall survival<br />
rates of 47.2 % and median overall survival of 33 months. There were no significant<br />
difference in overall survival rates in patients receiving one or two cycles of<br />
chemo<strong>the</strong>rapy (log-rank p = 0.64).<br />
Conclusion: The pathological response rate and <strong>the</strong> overall survival rate are<br />
promising in patients who completed <strong>the</strong> protocol as receiving at least one cycle of<br />
chemo<strong>the</strong>rapy. However, <strong>the</strong> toxicity rates were relatively high. prescribing two cycles<br />
of chemo<strong>the</strong>rapy resulted in no significant improvement in survival rate as compared<br />
with those receiving one cycle.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
750 HER2 STATUS IN OESOPHAGOGASTRIC JUNCTION AND<br />
GASTRIC CANCER – THE IRISH LANDSCAPE<br />
A. Jayaram 1 , J.E. Battley 2 , M.Y. Teo 3 , R. Abdul Rahman 4 , R. Bambury 2 ,<br />
M.W. Bennett 5 , M. Margaret Sheehan 6 , R. McDermott 3 , D.G. Power 7 ,<br />
G. Leonard 8<br />
1 MA, Galway University Hospital, Galway, IRELAND, 2 Medical Oncology, Cork<br />
University Hospital, Cork, IRELAND, 3 Dept. of Medical Oncology, AMNCH<br />
Adelaide and Meath Hospital, Dublin, IRELAND, 4 Medical Oncology, AMNCH<br />
Adelaide and Meath Hospital, Dublin, IRELAND, 5 Pathology, Cork University<br />
Hospital, Cork, IRELAND, 6 Pathology, Galway University Hospital, Galway,<br />
IRELAND, 7 Medical Oncology, Mercy University Hospital, Cork, IRELAND,<br />
8 Medical Oncology, University College Hospital Galway, Galway, IRELAND<br />
HER2 is overexpressed in ∼ 7-34% of gastroesophageal (GE) adenocarcinomas. The<br />
ToGA study, established <strong>the</strong> benefit of trastuzumab in combination with<br />
chemo<strong>the</strong>rapy in HER2(+) metastatic GE tumours. In this study, 22% of patients<br />
were HER2(+) {immunohistochemistry (IHC)3+ or fluorescence insitu hybridization<br />
(FISH)(+)}. We report a multi-center Irish experience by examining HER2 status by<br />
IHC and FISH in GE tumours.<br />
Methods: Database from three regional cancer centres were examined to identify pts<br />
with junctional or gastric adenocarcinoma. HER2 testing was performed on biopsy<br />
or resection specimens of patients with early stage and metastatic GE tumors<br />
between 2008–2011. We defined HER2 positive as IHC3+ or FISH(+)<br />
{HER2:17ch ≥ 2}. In addition, age, gender, histology, stage of disease, were recorded.<br />
Clinicopathologic characteristics were extracted and compared with t-test or Fisher’s<br />
exact as appropriate.<br />
Results: Between 2008 and 2011, 177 pts were identified. Median age was 68 years<br />
(range: 25 – 96), 36% were male. Gastric tumours were identified in 51%, while 53%<br />
were metastatic at diagnosis. Median number of metastatic sites was 1 (0 – 4). IHC<br />
and FISH were performed on 170 pts (96%) and 131 (74%) of patients. Distribution<br />
of IHC score of 0, 1, 2 and 3 were 38%, 32%, 19% and 11%, respectively. With<br />
respect to tumour heterogeneity of HER2 amplification, in IHC3 + , 50% were<br />
FISH(+), IHC2 + , 21.1% were FISH(+) and IHC1 + , 3.7% were FISH(+). Overall<br />
HER2(+) rate for <strong>the</strong> cohort was 16.4% (n = 29). Comparing patients with HER2(+)<br />
and HER2(-)disease, gender (males, 38 vs 38%, p = .84), age(69 vs 68, p = .79) and<br />
site distribution gastric, (45 vs 52%, p = .54) were identical .The rate of metastasis at<br />
diagnosis were similar, at 54 vs 53%. Presence of metastases in <strong>the</strong> liver (69 vs 48%,<br />
p = .22), peritoneum (38 vs 49%, p = .55), brain (8 vs 3%, p = .44) were comparable<br />
in both patient cohorts.<br />
Conclusions: HER2(+) GE adenocarcinomas in <strong>the</strong> analyzed cohort displays similar<br />
pattern of heterogeneity in IHC staining and FISH positivity but with lower<br />
incidence (16.4%) of HER2 amplification than was reported in <strong>the</strong> ToGA study.<br />
Fur<strong>the</strong>r analysis did not identify differences in clincopathologic characteristics in<br />
HER2 + ve patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
751 CLINICOPATHOLOGICAL SIGNIFICANCE OF<br />
HYPOXIA-INDUCIBLE FACTOR-1 ALPHA (HIF-1α)<br />
EXPRESSION IN GASTRIC CANCER<br />
Annals of Oncology<br />
T. Isobe, K. Aoyagi, K. Hashimoto, J. Kizaki, M. Miyagi, K. Koufuji, T. Sasatomi,<br />
K. Shirouzu<br />
Department of Surgery, Kurume University School of Medicine, Kurume,<br />
Fukuoka, JAPAN<br />
Background: Hypoxia is a common feature of rapidly growing solid tumors.<br />
Therefore, cellular adaptation to hypoxia and altered glucose metabolism are<br />
fundamental to <strong>the</strong> biology of cancer cells. Hypoxia-inducible factor-1α (HIF-1α) is<br />
a transcription factor for over 60 genes recognized to control <strong>the</strong> delivery of oxygen<br />
and nutrients through <strong>the</strong> induction of angiogenesis and glycolysis under hypoxic<br />
condition. Therefore, Inhibition of expression of HIF-1α will be expected to <strong>the</strong><br />
tumor specific molecular target-based <strong>the</strong>rapy. In this study, we evaluated <strong>the</strong><br />
significance of HIF-1α expression in relation to <strong>the</strong> clinicopatholgical factors, <strong>the</strong><br />
ix248 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
prognosis, VEGF expression, and microvessel density (MVD) expressed as <strong>the</strong> mean<br />
count of CD34 immunostained vessels in gastric cancer.<br />
Methods: Paraffin-embedded tumor specimens from 128 patients who underwent<br />
gastrectomy at <strong>the</strong> Kurume University from 2004 to 2005 were used to assess <strong>the</strong><br />
clinical significance of HIF-1α expression. We used ABC method to perform an<br />
immunohistochemical analysis of HIF-1α, VEGF expression, and MVD.<br />
Results: 84(65.6%) of gastric cancer specimens were positive for HIF-1α expression.<br />
The multivariate analysis showed that <strong>the</strong> histology, depth of invasion, VEGF<br />
expression, and MVD were significantly associated with <strong>the</strong> HIF-1α expression. On<br />
relapse-free and overall survival curves, <strong>the</strong> HIF-1α negative group was significantly<br />
higher than <strong>the</strong> HIF-1α positive group. The HIF-1α expression was identified as<br />
significant predictor of relapse-free survival and overall survival by Multivariate Cox’s<br />
proportional hazard analyses.<br />
Conclusion: Overexpression of HIF-1α was found to be a poor prognostic factor for<br />
patients with gastric cancer and correlated with histology, depth of invasion, and VEGF.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
752 CLINICOPATHOLOGIC SIGNIFICANCE OF EXPRESSION OF<br />
NUCLEAR FACTOR KAPPA B AND VASCULAR ENDOTHELIAL<br />
GROWTH FACTOR IN GASTRIC CANCER PATIENTS<br />
H. Kwon 1 , K.W. Park 2 , S. Kim 3<br />
1 Internal Medicine, Dong-A University Medical Center, Busan, KOREA, 2 Internal<br />
Medicine, Dankook University, Cheonan, KOREA, 3 Pathology, Dong-A University<br />
Medical Center, Busan, KOREA<br />
Aim: Nuclear factor-κB (NF-κB) and vascular endo<strong>the</strong>lial growth factor (VEGF) are<br />
involved in cell proliferation, invasion, angiogenesis and metastases. The principal<br />
objective of this study was to assess <strong>the</strong> prognostic significance of NF-κB and VEGF<br />
expression in gastric cancer.<br />
Methods: The tumor tissues of 154 patients with gastric cancer, all of whom<br />
underwent potentially curative resection, were immunohistochemically evaluated<br />
using monoclonal antibodies against NF-κB and VEGF.<br />
Results: Positivity rates of NF-κB and VEGF were 44.2% and 39.6%, respectively.<br />
NF-κB expression in tumor tissues was correlated significantly with VEGF expression<br />
(p < 0.001). VEGF expression was related to Lauren’s classification (p = 0.002),<br />
differentiation (p = 0.043), depth of invasion (p = 0.005), carcinoembryonic antigen<br />
(p = 0.032), and stage (p = 0.026). However, NF-κB expression was not related to any<br />
of <strong>the</strong>se parameters. Univariate analysis demonstrated that NF-κB expression was<br />
significantly related with both 5-year disease free survival (65.2% vs. 46.4%, p =<br />
0.007), and 5-year overall survival (60.0% vs. 42.5%, p = 0.014). Multivariate analysis<br />
verified that NF-κB was independently associated with disease free survival (hazard<br />
ratio: 2.082, p = 0.005), and overall survival (hazard ratio: 1.841, p = 0.008). However,<br />
VEGF did not appear to be related to adverse clinical outcome.<br />
Conclusion: NF-κB expression in tumor tissue is associated with poor survival in<br />
gastric cancer patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
753 DOCETAXEL, CISPLATIN AND FLUOROURACIL AS<br />
PERIOPERATIVE CHEMOTHERAPY IN RESECTABLE<br />
GASTROESOPHAGEAL CARCINOMA: A RETROSPECTIVE<br />
ANALYSIS<br />
F. Fiteni 1 , Z. Lakkis 2 , T. Nguyen 1 , C. Borg 1 , B. Benzidane 1 , V. Nerich 3 ,B.Heyd 2 ,<br />
X. Pivot 1 , C.H.S. Kim 1<br />
1 Medical Oncology, Hopital Minjoz, Besançon, FRANCE, 2 Digestive Surgery,<br />
Hopital Minjoz, Besançon, FRANCE,, 3 Pharmacy, Hopital Minjoz, Besançon,<br />
FRANCE<br />
Introduction: Perioperative chemo<strong>the</strong>rapy has demonstrated a survival benefit versus<br />
surgery alone in resectable gastroesophageal adenocarcinoma (RGC). The association<br />
Docetaxel, cisplatin, and fluorouracil (DCF) is superior to cisplatin and fluorouracil<br />
in advanced gastric cancer. The efficacy and safety of perioperative DCF regimen in<br />
patients with RGC was retrospectively analyzed.<br />
Patients and methods: All patients with RGC assigned by <strong>the</strong> staff to receive<br />
perioperative DCF regimen were included in <strong>the</strong> analysis. Chemo<strong>the</strong>rapy consisted of<br />
three preoperative cycles of intravenous docetaxel 75 mg/m 2 and cisplatin 75 mg/m 2<br />
(day 1) plus fluorouracil 750 mg/m 2 (days 1 to 5) every 3 weeks followed by 3<br />
postoperative cycles of this regimen.<br />
Results: Forty-nine patients with gastric cancer were analysed (38 adenocarcinoma<br />
subtype and 11 Signet Ring Cell (SRC)). A total of 37 patients (76%) completed <strong>the</strong><br />
3 preoperative planned cycles of DCF, and 45 (92%) undergone to surgery. Then 16<br />
patients (33%) underwent postoperative chemo<strong>the</strong>rapy based on DCF never<strong>the</strong>less 5<br />
patients only (10%) completed 3 cycles. Among patients with adenocarcinoma,<br />
pathological complete response (pCR) rate was 8% and 45 % had a partial response<br />
(PR) above 50% (grade 1a/1b/2 according to Becker’s classification). Among patients<br />
with SRC, no pCR and 9% of PR were observed. Histological complete resection rate<br />
was 89% among patients with adenocarcinoma and 55% among patients with SRC.<br />
Median overall survival and progression-free survival were 58 months (95% CI,<br />
58-non achieved) and 43 months (95% CI, 16-non achieved) respectivelly.<br />
Conclusion: In patients with RGC, DCF perioperative regimen is feasible and<br />
significantly active. Prospective assessment is justified. One could consider to exclude<br />
SRC taking into account <strong>the</strong> poor activity observed.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
754 A PHASE I TRIAL OF BORTEZOMIB IN COMBINATION WITH<br />
EPIRUBICIN, CARBOPLATIN AND CAPECITABINE (ECARBOX)<br />
IN ADVANCED GASTRIC AND GASTRO-OESOPHAGEAL<br />
JUNCTION (GOJ) ADENOCARCINOMA<br />
R.C. Turkington, C. Purcell, R.H. Wilson, M.M. Eatock<br />
Nor<strong>the</strong>rn Ireland Cancer Centre, Belfast City Hospital, Belfast, UNITED<br />
KINGDOM<br />
Background: Combination chemo<strong>the</strong>rapy is <strong>the</strong> treatment of choice for patients with<br />
advanced oesophago-gastric cancer and efforts to incorporate novel agents into<br />
chemo<strong>the</strong>rapy regimens have been problematic. Bortezomib (Velcade®) attenuates <strong>the</strong><br />
action of <strong>the</strong> transcription factor NF-κB, and has shown preclinical activity alone<br />
and in combination with chemo<strong>the</strong>rapy in oesophago-gastric cell lines.<br />
Design: A Phase I dose-escalation study using a 3 + 3 design was performed with<br />
Bortezomib (Velcade®) in combination with Epirubicin 50 mg/m 2 day1, Carboplatin<br />
AUC 5 day 1 and Capecitabine 625 mg/m 2 BD days 1-21 every 21 days, in advanced<br />
or metastatic gastro-oesophageal adenocarcinoma. Bortezomib was administered at<br />
four dose levels of 0.7, 1.0, 1.3 and 1.6 mg/m 2 on days 1 + 8. Due to myelotoxicity<br />
<strong>the</strong> dose of capecitabine was reduced to 500 mg/m 2 after <strong>the</strong> first patient cohort. The<br />
primary end point was to define <strong>the</strong> maximum tolerated dose (MTD) of Bortezomib<br />
when combined with ECarboX with secondary end points of radiological response<br />
rate (RR) and toxicity.<br />
Results: 20 patients, 18 evaluable for response, were enrolled (6 gastric, 9 GOJ and 3<br />
oesophageal), 2 were Stage III and 16 Stage IV. The overall RR was 33.3% with 6<br />
patients achieving a partial response. An additional 7 patients had stable disease for<br />
an overall Disease Control Rate (DCR) of 61.1%. Common grade 3/4 adverse events<br />
included nausea, fatigue, anaemia, neutropenia and thrombocytopenia. The first 3<br />
patients developed grade 4 neutropenia and pyrexia resulting in a protocol<br />
amendment reducing <strong>the</strong> Capecitabine dose to 500 mg/m 2 BD. Bortezomib-induced<br />
pulmonary infiltrates occurred in one patient treated at dose level 2, requiring<br />
discontinuation of Bortezomib and withdrawal from <strong>the</strong> study. Recruitment is<br />
ongoing at dose level 4 and <strong>the</strong> MTD is yet to be defined.<br />
Conclusions: The addition of Bortezomib to amended combination chemo<strong>the</strong>rapy<br />
for locally advanced or metastatic gastro-oesophageal adenocarcinoma has not been<br />
previously investigated and is well tolerated. Response rates are comparable with<br />
standard chemo<strong>the</strong>rapy and updated data will be presented.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
755 OXALIPLATIN, IRINOTECAN, BEVACIZUMAB FOLLOWED BY<br />
DOCETAXEL, BEVACIZUMAB IN INOPERABLE GASTRIC<br />
CANCER. A MULTICENTER PHASE II TRIAL (AGMT GASTRIC-3)<br />
OF THE ARBEITSGEMEINSCHAFT MEDIKAMENTöSE<br />
TUMORTHERAPIE (AGMT)<br />
E. Wöll 1 , F. Keil 2 , J. Thaler 3 , B. Gruenberger 4 , M. Hejna 5 , W. Eisterer 6 ,<br />
M.A. Fridrik 7 , F. Romeder 8 ,R.Greil 8<br />
1 Internal Medicine, St. Vinzenz Krankenhaus Zams, Zams, AUSTRIA, 2 Internal<br />
Medicine, Hanusch Krankenhaus, Vienna, AUSTRIA, 3 Internal Medicine, Klinikum<br />
Wels Grieskirchen, Wels, AUSTRIA, 4 1 Medical Oncoloy, Krankenhaus der<br />
Barmherzigen Br, Vienna, AUSTRIA, 5 Internal Medicine, Medical University<br />
Vienna, Vienna, AUSTRIA, 6 Department of Internal Medicine, University Hospital<br />
Innsbruck, Innsbruck, AUSTRIA, 7 Internal Medicine 3, Allgemeines Krankenhaus<br />
Linz, Linz, AUSTRIA, 8 Internal Medicine III, University Hospital Salzburg,<br />
Salzburg, AUSTRIA<br />
Background: In previous phase II trials (AGMT-Gastric-1 and AGMT Gastric-2) we<br />
could show efficacy of oxaliplatin and irinotecan as well as oxaliplatin, irinotecan and<br />
cetuximab in advanced gastric cancer. Time to progression however was short suggesting<br />
acquired chemo<strong>the</strong>rapy resistance. To address this problem sequential chemo<strong>the</strong>rapy<br />
combined with bevacizumab is investigated in <strong>the</strong> presented Gastric-3 trial.<br />
Methods: Oxaliplatin 85 mg/m 2 biweekly (q2w) and irinotecan 125 mg/m 2 q2w are<br />
administered for <strong>the</strong> first three months followed by docetaxel 50mg/m 2 q2w for<br />
subsequent three months. Chemo<strong>the</strong>rapy is combined with bevacizumab 5 mg/kg<br />
q2w which is administered until progression. For this abstract 36 pt. with<br />
histologically proven unresectable and/or metastatic gastric adenocarcinoma treated<br />
in a first line setting have been evaluated. Median age: 62.5 years (range 26-80 years),<br />
PS 0: 25 patients, PS 1: 10 patients, missing: 1 patients, single metastatic site: 24<br />
patients, multiple metastases: 10 patients, missing: 2.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds398 | ix249
Results: Frequently reported adverse events (more than 20% of pts.) were<br />
predominantly grade 1 or 2 and included diarrhea (25/36, 69%), polyneuropathy<br />
(17/36, 47%), nausea (17/36, 47%), fatigue (15/36, 42%), neutropenia (13/36, 36%),<br />
abdominal pain (11/36, 31%), hypokalemia (9/36, 25%). Grade 3 and 4 toxicities<br />
included neutropenia (6/36, 17%), diarrhea (3/36, 8%), hypokalemia (3/36, 8%),<br />
anemia in (2/36, 6%), leucopenia (2/36, 6%), thrombocytopenia (1/36, 3%), nausea in<br />
(1/36, 3%). Weight loss Grade 1 was initially documented in 1/36 pts., (3%).<br />
Objective response rate after 3 cycles was available in 25 patients: CR 1/25 (4%), PR<br />
14/25 (56%), SD 8/25 (32%), PD 2/25 (8%). After 6 cycles <strong>the</strong>re were 12 evaluable<br />
patients with CR 2/12 (16.7%), PR 5/12 (41.7%), SD 4/12 (33.3%) and PD 1/12<br />
(8.3%). Median time to progression was 24 weeks, median overall survival was 48<br />
weeks. Progression total was 12/36 (33%).<br />
Conclusions: The combination of oxaliplatin and irinotecan with bevacizumab followed<br />
by docetaxel with bevacizumab is feasible and active in advanced gastric cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
756 CLINICAL OUTCOME OF ADVANCED GASTRIC CANCER (GC)<br />
PATIENTS RECEIVING FIRST-LINE CHEMOTHERAPY<br />
ACCORDING TO TUMOUR HISTOLOGY AND LOCATION<br />
A. Bittoni 1 , M. Scartozzi 1 , R. Giampieri 1 , L. Faloppi 1 , M. Bianconi 1 ,<br />
A. Mandolesi 2 , M. Del Prete 1 , M. Pistelli 2 , I. Bearzi 2 , S. Cascinu 1<br />
1 Clinica di Oncologia Medica, AOU Ospedali Riuniti Ancona Università<br />
Politecnica delle Marche, Ancona, ITALY, 2 Anatomia Patologica, AOU Ospedali<br />
Riuniti Ancona Università Politecnica delle Marche, Ancona, ITALY<br />
Background: In <strong>the</strong> daily clinical practice GC is considered as a single disease.<br />
However, preliminary data identified distinct subtypes characterized by relevant<br />
differences in epidemiology, carcinogenesis and gene expression profiles. Recently,<br />
a new classification has been proposed, based on Lauren’s histology and on anatomic<br />
tumour location, identifying three subtypes: type 1 (proximal non diffuse GC), type<br />
2 (diffuse GC) and type 3 (distal non diffuse GC). Aim of our analysis was to<br />
compare clinical outcome (in terms of response rate, RR, progression-free survival,<br />
PFS, and overall survival, OS) according to different GC subtypes (1,2,3) in patients<br />
(pts) receiving first-line chemo<strong>the</strong>rapy.<br />
Patients and methods: Advanced GC pts treated with a first-line combination<br />
chemo<strong>the</strong>rapy were included in our analysis. Pts were divided in three subgroups<br />
(type 1, type 2 and type 3) as previously defined.<br />
Results: A total of 202 advanced GC pts were included: most of pts belonged to type<br />
2 (50.5%) and type 3 (40.6%); type 1 included 18 pts (8.9%). The majority of pts<br />
(62%) received a three-drugs chemo<strong>the</strong>rapy combinations including a platinum<br />
derivate, a fluoropyrimidine with <strong>the</strong> addition of an anthracycline, a taxane or<br />
mytomicin C; <strong>the</strong> remaining patients received a platinum and fluoropyrimidine<br />
combination. The three pts subgroups resulted comparable for relevant clinical<br />
factors such as ECOG PS, tumour stage, number of metastatic sites, previous surgical<br />
resection, first-line combination and use of second-line treatments; as expected<br />
peritoneal carcinosis was more common in type 2 pts. RR was found to be higher in<br />
type 3 pts (RR = 45.1%) than in type 1 (27.8%) and type 2 (25.5%) (p = 0.017). Type<br />
2 pts presented a shorter PFS (median PFS 5.7 months) compared to type 1, median<br />
PFS = 6.9 months, and type 3, median PFS = 7.8 months (p = 0.0069). These<br />
differences did not translate in statistically significant differences in OS.<br />
Conclusions: Our results suggest that GC subtypes may be important predictors of<br />
benefit from chemo<strong>the</strong>rapy in advanced GC patients. Future clinical trials should<br />
take in account <strong>the</strong>se differences for a better stratification of patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
757 A RANDOMIZED, SINGLE CENTER PHASE II TRIAL OF<br />
CAPECITABINE PLUS CISPLATIN VERSUS TS-1 PLUS<br />
CISPLATIN AS FIRST LINE TREATMENT IN PATIENTS WITH<br />
ADVANCED OR METASTATIC GASTRIC CANCER<br />
J. Lee 1 , S.Y. Roh 2 , E. Jeon 1 , S.H. Hong 2 , Y.H. Ko 1 , H.S. Won 1 , H.J. An 1 ,<br />
K.W. Park 3 , J.H. Kim 1 , Y.S. Hong 1<br />
1 Division of Oncology, Department of Internal Medicine, Seoul St. Mary’s<br />
Hospital, Seoul, KOREA, 2 Medical Oncology, Catholic Medical Center, Seoul,<br />
KOREA, 3 Medical Oncology, Fatima Hospital, Daegu, KOREA<br />
Background: Platinum agents and oral fluoropyrimidines are widely used in <strong>the</strong><br />
treatment of advanced gastric cancer. This study was aimed to evaluate <strong>the</strong> efficacy<br />
and safety of two combination regimens (capecitabine plus cisplatin [XP] vs S-1 plus<br />
cisplatin [SP]) in patients with untreated recurrent or metastatic gastric cancer.<br />
Methods: Patients diagnosed as untreated recurrent or metastatic gastric cancer were<br />
randomly assigned to ei<strong>the</strong>r capecitabine (2500 mg/BSA/day; day 1-14) plus cisplatin<br />
(60 mg/BSA/day; day 1), every 3 weeks or TS-1 (80-120 mg/day; day 1-14) plus<br />
cisplatin (60 mg/BSA/day; day 1), every 3 weeks. Primary end point was overall<br />
response rate (ORR), accessed by RECIST criteria (ver. 1.0). The secondary end point<br />
was progression free survival (PFS), overall survival (OS), and toxicities.<br />
Results: 86 patients were anticipated to be enrolled, but 51 patients were randomized<br />
to XP (25 patients) arm or SP (26 patients) arm because enrollment was slower than<br />
Annals of Oncology<br />
expected. ORR of XP and SP was 52% (13 of 25 assessable patients) vs. 44% (15 of<br />
25 assessable patients), and no significant differences were found (P = 0.778). OS of<br />
XP vs. SP was 10.3 months (95% CI; 4.8-15.8) vs. 12 months (95% CI; 9.5-14.5),<br />
with no differences (P = 0.785). PFS was 4.6 months (95% CI; 4.6-5.2), 4.4 months<br />
(95% CI; 2.2-6.6) each (P = 0.68). The incidence of grade 3-4 neutropenia of XP vs.<br />
SP was 40% vs. 43.2%. There were no febrile neutropenia in XP arm, but 7.7% in SP<br />
arm. Grade 3-4 thrombocytopenia was 12%, 3.8% each. O<strong>the</strong>r grade 3-4 toxicities<br />
were; Nausea (4% vs. 0%), Stomatitis (12% vs. 3.8%), Hand-foot syndrome (16% vs.<br />
0%), Diarrhea (0% vs. 3.8%). Median relative dose intensity of capecitabine vs. TS-1<br />
was 78.7% (range 51.9-116.7%), 87.5% (range 57.1-166.7%).<br />
Conclusion: There were no significant differences in ORR, OS, and PFS between XP<br />
vs. SP arm. The incidence of grade 3-4 neutropenia was similar in both arms, but<br />
thrombocytopenia was relatively more common in XP arm. SP was more tolerable<br />
than XP in non-hematologic toxicities. Considering <strong>the</strong> usual dosage of capecitabine<br />
in mono<strong>the</strong>rapy is 2500 mg/BSA/day, capecitabine 2500 mg/BSA/day combined with<br />
cisplatin 60 mg/BSA may be overdosed, and higher rate of non-hematologic toxicity<br />
can be explained. Dosage of capecitabine when combined with cisplatin, needs to be<br />
fur<strong>the</strong>r adjusted for routine use.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
758 FEASIBILITY OF ORAL ADMINISTRATION OF S-1 FOR<br />
ADJUVANT CHEMOTHERAPY OF GASTRIC CANCER; 4-WEEK<br />
S-1 ADMINISTRATION FOLLOWED BY 2-WEEK REST VS.<br />
2-WEEK ADMINISTRATION FOLLOWED BY 1-WEEK REST<br />
T. Yamatsuji 1 , Y. Fujiwara 2 , H. Matsumoto 3 ,S.Hato 4 , T. Namikawa 5 ,<br />
K. Hanazaki 5 , M. Ninomiya 2 , T. Fujiwara 6 , T. Hirai 3 , Y. Naomoto 1<br />
1 Department of General Surgery, Kawasaki Hospital, Kawasaki Medical School,<br />
Okayama, JAPAN, 2 Department of Surgery, Hiroshima City Hospital, Hiroshima,<br />
JAPAN, 3 Digestive Surgery, Kawasaki Medical School, Kurashiki, JAPAN,<br />
4 Depatment of Surgery, Shikoku Cancer Center, Matsuyama, JAPAN,<br />
5 Department of Surgery, Kochi Medical School, Nankoku, JAPAN, 6 Department<br />
of Gastroenterological Surgery, Okayama University Graduate School of<br />
Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JAPAN<br />
Background: In 2006, ACTS-GC study revealed that S-1 is an effective adjuvant<br />
<strong>the</strong>rapy of gastric cancer. Following <strong>the</strong> study, S-1 is used as <strong>the</strong> standard treatment<br />
for adjuvant <strong>the</strong>rapy for gastric cancer in Japan. S-1 <strong>the</strong>rapy with 4-week<br />
administration followed by 2-week rest was continued for 6 months in 78%, and 12<br />
months in 66% of <strong>the</strong> patients. The compliance is <strong>the</strong> critical problems of <strong>the</strong><br />
<strong>the</strong>rapy. Tukuda et al. reported a randomized study of S-1 for adjuvant<br />
chemo<strong>the</strong>rapy of advanced head and neck cancer, showing that <strong>the</strong> feasibility of<br />
4-week administration followed by 2-week rest for 6 months was 29%, and 2-week<br />
administration followed by 1-week rest was 40%. They claimed that <strong>the</strong> 2-week<br />
administration followed by 1-week rest seems to be more feasible in adjuvant <strong>the</strong>rapy<br />
of squamous cell carcinoma of <strong>the</strong> head and neck. There is no study of <strong>the</strong> feasibility<br />
for S-1 in adjuvant chemo<strong>the</strong>rapy of gastric cancer. Here we conducted a study to<br />
evaluate <strong>the</strong> feasibility, safety and efficacy of S-1 in adjuvant chemo<strong>the</strong>rapy of gastric<br />
cancer.<br />
Method: The criteria for eligibility were histologically proven gastric cancer of stage<br />
II (excluding T1), IIIA or B with D2 lymph-node dissection. Patients were randomly<br />
assigned to ei<strong>the</strong>r arm A; S-1 administration for 4 weeks followed by a 2-week rest or<br />
arm B; S-1 administration for 2 weeks followed by a 1-week rest. In each arm, <strong>the</strong><br />
<strong>the</strong>rapy was continued for 12 months unless <strong>the</strong>re was any recurrence or severe<br />
adverse event. The primary end point was feasibility. The secondary were <strong>the</strong> safety<br />
of S-1, relapse-free and overall survival.<br />
Results: We randomly assigned 46 patients to <strong>the</strong> arm A or B between May 2008<br />
and February 2010. The first interim analysis showed <strong>the</strong> feasibility of <strong>the</strong> arm A and<br />
B, those were 83% and 100% in 6 months, 49% and 89% in 12 months respectively.<br />
S-1 administration for 2 weeks followed by a 1-week rest was more feasible in<br />
adjuvant chemo<strong>the</strong>rapy of gastric cancer (P = 0.0046). Adverse events of grade 3 in<br />
<strong>the</strong> arm A were anorexia (8.0%), nausea (4.0%). There is no event of grade 3 in <strong>the</strong><br />
arm B, and no event of grade 4 in both arms. Efficacy of <strong>the</strong> <strong>the</strong>rapies; relapse-free<br />
survival and overall survival will be reported in <strong>the</strong> few years.<br />
Conclusion: The schedule of 2-week administration followed by 1-week rest is more<br />
feasible for oral administration of S-1 in adjuvant chemo<strong>the</strong>rapy of gastric cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
760 DOCETAXEL, CISPLATIN, 5-FLUOROURACIL AND<br />
LEUCOVORIN AS FIRST-LINE THERAPY IN ADVANCED<br />
GASTRIC CANCER (AGC)<br />
E. Trusilova, N. Besova, V.A. Gorbunova<br />
Chemo<strong>the</strong>rapy, N.N. Blokhin Russian Cancer Research Center, Moscow,<br />
RUSSIAN FEDERATION<br />
Purpose: AGC is relatively chemosensitive, but a standard chemo<strong>the</strong>rapy (CT)<br />
regimen has yet to emerge, and responses are of short duration. Docetaxel-containing<br />
combinations are new option for pts with AGC. The V325 trial demonstrated <strong>the</strong><br />
ix250 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
efficacy benefit of adding docetaxel to CF (cisplatim + 5-fluorouracil) (DCF). DCF is<br />
associated with significant toxicity, making it less tolerable to pts. We modified <strong>the</strong><br />
original DCF regimen to reduce its toxicity without decreasing efficacy.<br />
Patients and methods: AGC pts received docetaxel 75 mg/m 2 and cisplatin 75 mg/<br />
m 2 in day2 with leucovorin 50 mg and 5-fluorouracil 500 mg/m 2 (3-hour infusion) in<br />
day 1-3 every 3w (TPF) instead of original DCF (docetaxel 75 mg/m 2 , cisplatin 75<br />
mg/m 2 in day 1 and fluorouracil 750 mg/m 2 in day 1-5 continuous infusion).<br />
Results: 39 CT-naïve pts with AGC were included in our study from Feb2008 to<br />
Dec2010 (20 female, 19 male). ECOG 0/1/2 were10/80/10% pts. ORR was 40% (16/39),<br />
SD – 40% (16/39), PD – 20% (7/39). Median PFS and median OS were evaluated in<br />
38pts and were 5,4m and 9,5m, respectively. Toxicity was moderate. Grade 3 and 4<br />
toxicities included leucopenia – 32,5 and 7,5%, neutropenia – 25 and 40%,<br />
thrombocytopenia – 2,5 and 0% pts, febrile neutropenia -1pt (2,5%); as<strong>the</strong>nia – 2,5 and<br />
0%, stomatitis – 2,5 and 0%, diarrhea – 12,5 and 0%, vomiting – 0 and 2,5% pts. We<br />
didn’t use G-CSF prophylaxis. There were no deaths and treatment discontinuation due<br />
to toxicity. At present 5 pts are still alive, in three of <strong>the</strong>m distant mts disappeared and<br />
operation became possible. Their survival is 28,5m (without PD), 32.9m with PD over<br />
10m after surgery and 42m with PD over 12m after surgery.<br />
Conclusion: Our data suggest that TPF regimen has <strong>the</strong> similar efficacy and better<br />
tolerability than <strong>the</strong> standard DCF. TPF regimen can be safely given in an ambulant<br />
setting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
761 SECOND-LINE DOCETAXEL (D) IN METASTATIC GASTRIC<br />
CANCER (MGC)<br />
C. Caparello 1 , M. Lencioni 1 , E. Vasile 1 , S. Caponi 1 , S. Santi 2 , M.G. Fabrini 3 ,<br />
L. Ginocchi 1 , M. Lucchesi 1 , S. Ricci 1 , A. Falcone 1<br />
1 Oncologia, Trapianti e Nuove Tecnologie in Medicina, Polo Oncologico -<br />
Azienda Ospedaliero-Universitaria Pisana - Istituto Toscano Tumori, Pisa, ITALY,<br />
2 Department of Gastroenterology, Esophageal Surgery Unit, Tuscany Regional<br />
Referral Center for <strong>the</strong> Diagnosis and Treatment of Esophageal Disease, Pisa,<br />
Italy, Pisa, ITALY, 3 Division of Radiation Oncology, S. Chiara Pisa Hospital, Pisa,<br />
Italy, Pisa, ITALY<br />
Background: Although second-line chemo<strong>the</strong>rapy with irinotecan or docetaxel<br />
seemed to confer an improvement in overall survival over best supportive care, at<br />
today no standard second-line chemo<strong>the</strong>rapy regimen is approved in MGC.<br />
Methods: The objective of our retrospective analysis was to evaluate <strong>the</strong> activity of a<br />
second-line taxane-based treatment in MGC patients (pts).<br />
Results: A total of forty-eight pts (M/F 40/8; ECOG PS at second-line treatment 0/1/<br />
2: 23/22/3) were included in <strong>the</strong> study; median age 67 years (range 38-86). All pts<br />
received a first-line fluoropyrimidine-based chemo<strong>the</strong>rapy; 42 in combination with<br />
platinum compounds (9 received a triplet with anthracyclines and 2 with Herceptin)<br />
and 6 in monochemo<strong>the</strong>rapy. 46 pts were evaluable for analysis: 37 pts received a<br />
docetaxel monochemo<strong>the</strong>rapy (16 weekly, 5 biweekly and 16 three-weekly schedule),<br />
10 a combination of docetaxel with fluorouracil, 1 with cisplatin. Grade 3 or 4<br />
toxicities included: anemia 3 pts, neutropenia 6 pts, diarrhea 1 patient, fatigue,<br />
vomiting and neurotoxicity 1 patient each, stomatitis 2 pts; 13 pts needed a delay of<br />
treatment and 5 a reduction of doses. Among 46 evaluable pts 7 (15.2%) experienced<br />
a partial response, 13(28.3%) a stable disease, 26(56.5%) a progression of disease. 24<br />
pts received a third-line chemo<strong>the</strong>rapy, 21 of <strong>the</strong>se an irinotecan-based treatment.<br />
Median progression-free survival was 4.3 months and median overall survival was 8.6<br />
months from <strong>the</strong> start of second-line treatment. No significant differences were<br />
found in mPFS, RR and toxicity profile between different treatment schedules. mPFS<br />
seemed to be longer in patients with PS 0 than in patients with PS 1 or 2 (5.4<br />
months versus 2.1 and 0.95 respectively; p = 0.046). No difference in mPFS was<br />
detected according to RR at first-line <strong>the</strong>rapy.<br />
Conclusions: Docetaxel in MGC second-line setting seems to have an encouraging<br />
activity with an acceptable toxicity profile.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
762 THIRD-LINE FOLFIRI IN METASTATIC GASTRIC CANCER<br />
PATIENTS<br />
C. Caparello 1 , E. Vasile 1 , M. Lencioni 1 , M.G. Fabrini 2 , M. Lucchesi 1 , L. Ginocchi 1 ,<br />
S. Caponi 1 , S. Santi 3 , S. Ricci 1 , A. Falcone 1<br />
1 Oncologia, Trapianti e Nuove Tecnologie in Medicina, Polo Oncologico -<br />
Azienda Ospedaliero-Universitaria Pisana - Istituto Toscano Tumori, Pisa, ITALY,<br />
2 Division of Radiation Oncology, S. Chiara Pisa Hospital, Pisa, Italy, Pisa, ITALY,<br />
3 Department of Gastroenterology, Esophageal Surgery Unit, Tuscany Regional<br />
Referral Center for <strong>the</strong> Diagnosis and Treatment of Esophageal Disease, Pisa,<br />
Italy, Pisa, ITALY<br />
Background: The use of systemic chemo<strong>the</strong>rapy increased median survival of advanced<br />
gastric cancer patients. Besides fluoropyrimidines and platinum compounds, different<br />
active agents such as docetaxel and irinotecan became available giving physicians <strong>the</strong><br />
opportunity to administer to patients fur<strong>the</strong>r lines of treatment. Second-line<br />
chemo<strong>the</strong>rapy with docetaxel or irinotecan showed improved overall survival over best<br />
supportive care. There are many patients progressed after two lines of <strong>the</strong>rapy who<br />
maintain a good performance status that could be evaluated for fur<strong>the</strong>r treatment.<br />
Methods: The aim of this retrospective analysis was to evaluate <strong>the</strong> activity of <strong>the</strong><br />
combination of 5-fluorouracil/folinic acid and irinotecan (FOLFIRI) as third-line<br />
treatment for metastatic gastric adenocarcinoma patients.<br />
Results: A total of twenty-one patients (M/F 16/5; ECOG Performance Status 0/1: 3/<br />
18) treated between 2009 and 2011 were included in <strong>the</strong> study; median age was 64<br />
years (range 38-77). All <strong>the</strong> patients had received first-line fluoropyrimidine plus<br />
platinum compound chemo<strong>the</strong>rapy; in 7 of <strong>the</strong>m a triple-drug combination with<br />
epirubicin was used; one patient with HER-2 positive tumor was treated with<br />
trastuzumab in combination with chemo<strong>the</strong>rapy. All patients had received taxanes in<br />
second-line (docetaxel in 18 and paclitaxel in 3 patients), in 5 cases in association with<br />
5-fluorouracil. A total of 151 cycles of third-line FOLFIRI were administered (median<br />
number 7; range 2-18). Treatment was well tolerated; grade 3 or 4 toxicities included<br />
neutropenia in 3 patients, diarrhea in 3 patients, as<strong>the</strong>nia and vomiting in 1 patient<br />
each; delay of treatment was required in 9 patients and a reduction of doses only in 3<br />
cases. Among <strong>the</strong> twenty evaluable patients, two (10%) partial responses and 8 (40%)<br />
stable disease were observed, thus obtaining a disease control in half of patients.<br />
Median duration of response was 7 months. Median progression-free survival was 3.8<br />
months. Median overall survival from <strong>the</strong> start of third-line treatment was 9.1 months.<br />
Conclusions: FOLFIRI was feasible and showed interesting activity also in third-line<br />
setting of largely pretreated selected metastatic gastric cancer patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
763 EPIDEMIOLOGICAL DATA OF PATIENTS WITH GASTRIC<br />
CANCER IN MEXICO<br />
G.C. Ruiz1 , N. Reynoso1 , C. Diaz1 , E.B. Ruiz1 , E. Trejo1 , A. Mohar-Betancourt2 1<br />
Medical Oncology, Instituto Nacional de Cancerologia, Mexico City, MEXICO,<br />
2<br />
Biomedical Research, Instituto Nacional de Cancerología (INCan), Mexico City,<br />
MEXICO<br />
Introduction: The gastric cancer is very common neaplasm in Asia and Central and<br />
SouthAmerica. With large differences among patients diagnosed and treated in<br />
Europe, America and Asia. We present some epidemiological data of patients with<br />
gastric cancer.<br />
Methods: Methodology was analyzed <strong>the</strong> database of all patients diagnosed of<br />
adenocarcinoma of <strong>the</strong> stomach from January 1999 to December 2011 served in <strong>the</strong><br />
Medical Oncology service.<br />
Results: We identified 1179 patients evaluated by Medical Oncology, <strong>the</strong>se 1130 with<br />
histology adenocarcinoma, 40 with stromal tumor gastro-intestinal, 3 with<br />
leiomiosarcoma, 3 with scamous cell and 3 with neuroendocrine tumor. Of <strong>the</strong> cases<br />
with adenocarcinoma, 56% were men with a mean age of 55.8 years +/- 13.6 and<br />
44% occured in women with a mean age of 52.2 years +/- 13.4 (p < 0.0001). The<br />
17.5% is presented in patients with 40 years o less. The more common histologic<br />
subtipe is diffuse in 54% versus 30% intestinal y 5% mixed (in 11% nondeterminate).<br />
In patients with diffuse type-adenocarcinoma 88% are poorly<br />
differentiated and 72% with signet ring cells. Gender difference was no observed, but<br />
in relation to age, for patients under 40 years 72% is diffuse versus 40% in over 40<br />
years (p < 0.0001). The location of <strong>the</strong> tumor is in <strong>the</strong> stomach in 86% of <strong>the</strong> cases<br />
versus 14% in <strong>the</strong> esophago-gastric junction, noting a significant difference in<br />
relation to sex, with 8.6% in women versus 18% in men (p < 0.0001). The stages<br />
were: 33 cases (2.8%) stage I, 34 cases (2.9%) stage II, 103 patients (8.7%) stage III,<br />
194 cases (18.8%) with disease locally advanced, non-surgical and 766 patients<br />
(68.0%) stage IV. Of <strong>the</strong> patients with stage IV, 18% was confirmed by surgical and<br />
histological findings or T4 or N3, M0 (AJCC 6th edition). The most common sites<br />
of metastases are <strong>the</strong> peritoneum/ascitis in 58%, liver 26%, retroperitoneal 13%,<br />
ovarian 9.6% and lung 7.3%.<br />
Conclusions: Gastric cancer in Mexico is a serious health problem, is diagnosed in<br />
young patients with poor prognostic factors as <strong>the</strong> diffuse histological type, poorly<br />
differentiated and signet-ring cells. The location of <strong>the</strong> tumor in esophago-gastric<br />
junction is more common in men. The diagnosis in made in most patients in<br />
advanced stages (III-IV).<br />
Disclosure: All authors have declared no conflicts of interest.<br />
764 FORTY-ONE CASES OF METASTASIS FROM GASTRIC CANCER<br />
TO THE CENTRAL NERVE SYSTEM: EXPERIENCE AT SINGLE<br />
CENTER<br />
H. Shoji1 , T. Hamaguchi1 , Y. Honma1 , S. Iwasa1 ,K.Kato1 , Y. Yamada2 ,<br />
Y. Shimada1 1<br />
Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, JAPAN,<br />
2<br />
Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo,<br />
JAPAN<br />
Background: Metastasis from gastric cancer to <strong>the</strong> central nerve system (CNS) is a<br />
rare entity, and <strong>the</strong>re is little information available regarding evaluation of <strong>the</strong>se<br />
patients. The purpose of this study was to evaluate <strong>the</strong> clinical characteristics of<br />
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gastric cancer patients with CNS metastasis and to clarify treatment outcomes in<br />
metastatic gastric cancer to <strong>the</strong> CNS.<br />
Methods: This retrospective study reviewed data from gastric cancer patients with<br />
CNS metastasis treated at our institution from 2000 to 2011.<br />
Results: 2195 patients with metastatic gastric cancer were included in this study.<br />
41 of <strong>the</strong>se patients (1.87%) were found to have CNS metastasis (32 men, 9<br />
women; median age, 62.0 years). Leptomeningeal metastases and brain metastases<br />
were identified in 11 and 30 patients; Stage IV disease and recurrence were<br />
identified in 25 and 16 cases; and main metastatic sites were lymph nodes,<br />
peritoneum, liver, and bone in 22, 12, 7 and 6 cases, respectively.<br />
Histopathologically, 29 patients (70.7%) had diffuse-type adenocarcinoma. Most<br />
frequent symptoms were headache, nausea/emesis, cataplexy, and convulsion.<br />
Thirty-six patients received systemic chemo<strong>the</strong>rapy. The median interval from <strong>the</strong><br />
initiation of systemic chemo<strong>the</strong>rapy to <strong>the</strong> diagnosis of CNS metastasis was 7.4<br />
months. Among leptomeningeal patients, 9 patients received symptomatic <strong>the</strong>rapy<br />
such as steroid and 2 patients received intra<strong>the</strong>cal chemo<strong>the</strong>rapy. Median survival<br />
time from <strong>the</strong> diagnosis of leptomeningeal metastases was 27 days. Among brain<br />
metastasis patients, 47% had a solitary lesion, while 53% had multiple lesions.<br />
Five patients received symptomatic <strong>the</strong>rapy (group 1), 18 patients received<br />
radio<strong>the</strong>rapy (group 2) such as whole-brain radiation <strong>the</strong>rapy or gamma knife<br />
radiosurgery, and 7 patients received resection ± radio<strong>the</strong>rapy (group 3). Median<br />
survival time from <strong>the</strong> diagnosis of brain metastases was approximately 1.8<br />
months for patients in group 1 and 2. Group 3 patients survived longer than<br />
group 1 and 2 patients at median 8.4 months.<br />
Conclusions: The treatment outcome in metastatic gastric cancer to <strong>the</strong> CNS was<br />
poor. Among brain metastases patients, patients who received resection ±<br />
radio<strong>the</strong>rapy showed a more favorable outcome compared to o<strong>the</strong>r treatment groups.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
765 RESULTS OF SURGERY OF GASTRIC LYMPHOMAS<br />
COMPLICATED WITH BLEEDING, STENOSIS AND<br />
PERFORATION<br />
V. Shalenkov, S. Nered, I. Stilidi<br />
Abdominal Surgery, N.N. Blokhin Russian Cancer Research Center of Russian<br />
Academy of Medical Sciences, RUSSIAN FEDERATION<br />
Background: Our purpose is to study results of surgery of patients with primary<br />
non-Hodgkin’s lymphomas complicated with bleeding, stenosis and perforation.<br />
Materials and methods: 66 patients with primary non-Hodgkin’s lymphomas were<br />
treated in our centre between 1984 and 2009 because of bleeding – 49, stenosis – 11,<br />
gastric perforation – 6. Group under study included 28 females and 38 males, mean<br />
age was 49. Bleedings from benign gastric ulcers and gastric perforations outside of<br />
tumor lesions’ zones were excluded from <strong>the</strong> study. The histological types: diffuse<br />
large B cell lymphoma – 50 patients (76%), MALT-lymphoma – 12 (18,5%), Burkitt’s<br />
lymphoma – 4 (6%). Localization of <strong>the</strong> lesions: overall – 29 patients (44%), antrum<br />
– 22 (33%), stomach’s body – 9 (15%), proximal part – 6 (9%). 26 patients (39%)<br />
had stage I, 19 (29%) – II, 21 (31,5%) – IV. 45 patients (68%) had complications<br />
before chemo<strong>the</strong>rapy, 8 (12%) – during <strong>the</strong> course, 13 (20%) – after. Patients after<br />
chemo<strong>the</strong>rapy had gastric perforation more frequent (in 20% of cases) than<br />
chemo-naive patients (4,3%, p = 0,063). Gastrectomy was performed for 47 patients<br />
(71%), subtotal gastrectomy – 12 (19%).<br />
Results: 43 (65,1%) patients had radical operations, 14 (21,2%) had palliative<br />
gastrectomy or gastric resection, 4 (6%) had bypass operations and 5 (7,5%) had only<br />
explorative laparotomy. Overall postoperative mortality was 11%. 35% patients had<br />
postoperative complications. The most frequent complications were<br />
subdiaphragmatic abscess (5,2%), postoperative wound infection (5,2%) and<br />
pneumonia (5,2%). Overall 3-, 10- and 10-year survival rate in <strong>the</strong> group under study<br />
was 75%, 65% and 40%, respectively; median survival was 100 months. Patients after<br />
radical operations had higher three- and five-year survival rates than patients after<br />
palliative gastrectomies and resections (82% and 73% vs. 51% and 44%), however<br />
ten-year survival rates in both groups were practically <strong>the</strong> same.<br />
Summary: Complications of gastric lymphomas can occur at any stage of <strong>the</strong> disease.<br />
Aggressive surgical approach allows to ablate affected organ and remove <strong>the</strong> source of<br />
fatal complications for 86% of patients. Due to postoperative chemo<strong>the</strong>rapy, more<br />
than half of patients survive 5 years after surgery.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
766 19-YEAR SINGLE CENTER EXPERIENCE IN THE<br />
MANAGEMENT OF PATIENTS WITH PRIMARY<br />
GASTROINTESTINAL (GI) LYMPHOMA<br />
Annals of Oncology<br />
W. Fischbach, N. Mueller<br />
Medizinische Klinik Ii, Klinikum Aschaffenburg, Aschaffenburg, GERMANY<br />
Introduction: Primay GI lymphoma are a rare disease. Multicenter studies were,<br />
<strong>the</strong>refore, initiated in <strong>the</strong> 90ies with various published results in subgroups of GI<br />
lymphoma who were not treated within a controlled clinical trial.<br />
Method: As a German reference center patients with GI lymphoma are regulary<br />
presented to our institution. From 1993 on, we saw 102 consecutive patients (59<br />
male and 43 female, age 31-89 years) with primary GI lymphoma: gastric MALT<br />
lymphoma = 76 (63 stage I, 6 stage II, 7 stage III/IV); secondary high MALT<br />
lymphoma = 3; diffuse large B-cell lymphoma (DLBCL) = 14 (stage I/II/III-IV) =<br />
8/4/2); Burkitt lymphoma = 1; intestinal follicular lymphoma (FL) grade I/II = 8<br />
(stage I/II/III-IV = 5/1/2). Treatment strategies were as follows: MALT-lymphoma:<br />
H. pylori eradication; radiation (RTx) and/or chemo<strong>the</strong>rapy (CTx) in stages ≥ II or<br />
in case of eradication failure; DLBCL: CTx except in 3 cases who were treated by<br />
H. pylori eradication only; FL: no <strong>the</strong>rapy, CTx or RTx.<br />
Results: 26/47 patients (55%) with MALT lymphoma achieved complete remission<br />
(CR) after exclusive H. pylori eradication. Application of all <strong>the</strong>rapeutic procedures<br />
resulted in CR = 53/76 (70%) and PR with watch-and-wait = 22/76 (29%). There was<br />
only 1 patient revealing progression. In DLBCL, 12 (86 5) achieved CR after 1-3 line<br />
<strong>the</strong>rapies. In FL, watch-and-wait resulted in long-term stable disease in n = 5, CR<br />
after RTx in 1 case, and stable disease after CTx in 2 cases.<br />
Conclusion: Despite a negative selection of patients being presented to our reference<br />
center <strong>the</strong> overall treatment results in all subgroups of GI lymphoma are excellent<br />
when all treatment options are offered in a sequential <strong>the</strong>rapeutic strategy.<br />
Watch-and-wait is a promising approach in MALT lymphoma with residual disease<br />
following H. pylori eradication and in FL.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
767 THE DIAGNOSIS OF MALIGNANT PANCREATIC TUMOURS BY<br />
CIRCULATING TUMOUR CELL DETECTION<br />
P. Basile 1 , I. Iwanicki-Caron 2 , E. Toure 3 , M. Antonietti 1 , S. Lecleire 1 , F. Di Fiore 4 ,<br />
J.C. Sabourin 3 , P. Michel 2<br />
1 Gastroenterology and Digestive Oncology, University Hospital of Rouen, Rouen,<br />
FRANCE, 2 Gastroenterology and Digestive Oncology, CHU de Rouen, Rouen,<br />
FRANCE, 3 Department of Pathology, Inserm U614, Rouen University Hospital,<br />
Rouen, FRANCE, 4 Digestive Oncology Unit, C.H.U. Charles Nicolle, Rouen,<br />
FRANCE<br />
Introduction: The fine needle aspiration by endoscopic ultrasound guide (EUS FNA)<br />
is a diagnostic examination of choice in solid tumour of <strong>the</strong> pancreas. This invasive<br />
technique has a sensitivity of about 70%. The search for circulating tumour cells<br />
(CTC) is a non invasive procedure, which could represent an alternative or<br />
complement to EUS FNA diagnostic. The objective of this prospective pilot study<br />
was to evaluate <strong>the</strong> diagnostic value of research CTC versus EUS FNA for <strong>the</strong><br />
diagnosis of a solid tumour of <strong>the</strong> pancreas (STP).<br />
Patients and methods: From 01/01 to 30/09/2011, all patients undergoing an EUS<br />
FNA for a STP were included. EUS FNA was performed with a 22 gauge needle and<br />
analyzed by two experienced pathologists. For detection of CTC, 10 ml of blood<br />
collected in <strong>the</strong> periphery before FNA was filtered by technology ScreencellCyto â,<br />
stained with Giemsa and analyzed by a cytologist. Peripheral cells were considered<br />
tumour if <strong>the</strong>y had <strong>the</strong> following morphology: kernel> 7 m, anisocytosis, membrane<br />
irregularities, presence of a large nucleolus.<br />
Results: Twenty six patients with TSP were included (14 men and 12 women), mean<br />
age was 64.2 years. The tumor was potentially resectable in 11 cases, 8 cases had a<br />
locoregional recurrence and 7 a metastatic extension. In total, 23/26 cases were<br />
analyzed due to technical failure of <strong>the</strong> CTC research (insufficient material) and two<br />
technical failures of EUS FNA. 20 patients had cancer objectified (including 15<br />
adenocarcinomas or 57%) by EUS FNA pancreatic histological analysis of <strong>the</strong><br />
specimen and/or clinical course. In this population of 26 patients <strong>the</strong> sensitivity of<br />
<strong>the</strong> search CTC was 60%, specificity 100%, positive predictive value 100% and<br />
negative predictive value of 27%. On <strong>the</strong> results of FNA sensitivity for <strong>the</strong> diagnosis<br />
of cancer was 75%, specificity 100%, PPV of 100% and NPV of 37.5%. In patients<br />
whose FNA was contributory to <strong>the</strong> sensitivity of CTC research was 83%, specificity<br />
54%, PPV of 66% and NPV of 75%.<br />
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Annals of Oncology<br />
Conclusion: The detection of CTC for <strong>the</strong> diagnosis of adenocarcinoma in case of<br />
tumours of <strong>the</strong> pancreas is a technique feasible, non-invasive, with a satisfactory<br />
diagnostic yield. The results of this pilot study, <strong>the</strong> continued progress in <strong>the</strong> analysis<br />
of CTC and a confirmation of this results in a higher independent population could<br />
allow us to propose this procedure in a first diagnostic step.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
768 GEMOX PLUS ERLOTINIB FOR THE TREATMENT OF<br />
METASTATIC PANCREATIC ADENOCARCINOMA<br />
T. Füreder 1 , G.V. Kornek 1 , I. Kührer 2 , C. Zielinski 3 , J. Klech 1 , W. Scheithauer 1<br />
1 Internal Medicine I, Medical University of Vienna, Vienna, AUSTRIA, 2 Surgery,<br />
Medical University of Vienna, Vienna, AUSTRIA, 3 Department of Medicine I and<br />
Clinical Division of Oncology, Medical University of Vienna and Central European<br />
Cooperative Oncology Group (CECOG), Vienna, AUSTRIA<br />
Introduction: Based on demonstration of a significant improvement in overall<br />
survival in a placebo-controlled phase III trial, gemcitabine in combination with<br />
erlotinib has been approved for <strong>the</strong> treatment of metastatic pancreatic cancer.<br />
In patients with good performance status, gemcitabine combination chemo<strong>the</strong>rapy,<br />
i.e. with oxaliplatin (GEMOX) is commonly being used. Although <strong>the</strong>re is some<br />
evidence that GEMOX plus erlotinib is beneficial in a subgroup of patients compared<br />
to GEMOX alone in cholangiocellular carcinoma no such data exist for pancreatic<br />
cancer. Thus, we performed this retrospective analysis in unselected patients to<br />
investigate <strong>the</strong> efficacy and safety of this chemo<strong>the</strong>rapy regimen.<br />
Patients and methods: Forty-four patients with metastatic adenocarcinoma of <strong>the</strong><br />
pancreas receiving off-protocol GEMOX in combination with erlotinib at a single<br />
institution between January 2006 and September 2011 were included in this analysis.<br />
Data collection included baseline demographic, clinical and toxicity data as well as<br />
objective response according to RECIST criteria, progression-free survival (PFS) and<br />
overall survival (OS).<br />
Results: A total of 44 patients were included in this study. The mean age was 60.5<br />
years, and <strong>the</strong> median ECOG performance score was 1 (range, 0-1). GEMOX in<br />
combination with erlotinib was first line regimen in 84% of <strong>the</strong> patients. Clinical<br />
response and disease stabilization was achieved in 45% of <strong>the</strong> patients. The median<br />
PFS was 4 months (range 0.5-43) and median overall survival was 9.6 months (range<br />
0.7-54.7). However, <strong>the</strong> subgroup of 20 patients, who benefited from this regimen in<br />
terms of abrogation of progression, had a PFS of 11.2 and an OS of 15.4 months.<br />
Myelosuppression was <strong>the</strong> most frequent side effect. The most common severe<br />
nonhematological toxicity was diarrhea (5/44).<br />
Conclusions: These data suggest that <strong>the</strong> combination of GEMOX plus erlotinib is<br />
safe and active in about half of <strong>the</strong> patients treated with this regimen. Identification<br />
of (bio)markers would be desirable in order to be able to select patients, who are<br />
most likely to benefit from this <strong>the</strong>rapeutic strategy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
769 CYCLIN E1 SUPPRESSION CONTRIBUTES TO<br />
SORAFENIB-INDUCED APOPTOSIS IN HEPATOCELLULAR<br />
CARCINOMA (HCC)<br />
C. Hsu 1 ,D.Ou 2 , Y. Cheng 3 ,Y.Lin 1 , Y. Chang 4 ,K.Yeh 2 , A. Cheng 5<br />
1 Department of Oncology, National Taiwan University Hospital, Taipei, TAIWAN,<br />
2 Graduate Institute of Oncology, National Taiwan University College of Medicine,<br />
Taipei, TAIWAN, 3 Gradualte Institute of Medical Technology, National Taiwan<br />
University College of Medicine, Taipei, TAIWAN, 4 Oncology, National Taiwan<br />
University Hospital, Taipei, TAIWAN, 5 Internal Medicine, National Taiwan<br />
University Hospital, Taipei, TAIWAN<br />
Background: We have found that sorafenib can inhibit cyclin E1 expression in HCC<br />
cells, which is independent of <strong>the</strong> inhibitory effects of sorafenib on mitogen-activated<br />
protein kinase-extracellular signal-regulated kinase/extracellular signal-regulated<br />
kinase signaling. The present study sought to clarify <strong>the</strong> role of cyclin E1 in<br />
sorafenib-induced apoptosis in HCC.<br />
Methods: A panel of HCC cell lines, including sorafenib-sensitive (Huh-7, HepG2)<br />
and sorafenib-resistant (Hep3B, Huh-7R and HepG2R) HCC cells, was tested.<br />
Apoptosis was measured by flow cytometry. Knockdown of cyclin E1 expression<br />
were used by RNA-interference. Over-expression of cyclin E1 was done by transient<br />
transfection of pCMV6-AC-GFP-CCNE1 vector (RG204289; Origene Technologies).<br />
The activity of pertinent signaling pathways, cell cycles-related proteins and<br />
expression of apoptosis-related proteins were measured by Western blotting.<br />
Results: Cyclin E1 mRNA and protein expressions were suppressed after sorafenib<br />
treatment in sorafenib-sensitive but not in sorafenib-resistant HCC cells. The changes<br />
in cyclin E2 or cyclin D1 expression after sorafenib treatment were not correlated<br />
with sorafenib sensitivity of HCC cells. Knockdown of cyclin E1 expression reversed<br />
<strong>the</strong> resistance of HCC cells to sorafenib in terms of cell growth and apoptosis<br />
induction, whereas over-expression of cyclin E1 increased <strong>the</strong> resistance of HCC cells<br />
to sorafenib. Combination of sorafenib and <strong>the</strong> cyclin-dependent kinase (CDK)<br />
inhibitor flavopiridol synergistically inhibited cell growth and induced apoptosis in<br />
HCC cells. The synergistic efficacy was associated with suppression of Bcl-XL<br />
expression in HCC cells.<br />
Conclusion: Cyclin E1 expression in HCC cells may serve a predictive biomarker<br />
for treatment efficacy. Combination of sorafenib and CDK inhibitors may improve<br />
<strong>the</strong> <strong>the</strong>rapeutic efficacy of sorafenib in HCC. (Supported by grants:<br />
NSC100-2314-B-002-058-MY3, NSC101-2325-B-002-039, and<br />
NHRI-EX101-9911BC)<br />
Disclosure: C. Hsu: Dr Chiun Hsu is a member of <strong>the</strong> speaker’s bureau of<br />
Bayer-Schering Pharma. A. Cheng: Dr Ann-Lii Cheng is a consultant for<br />
Sanofi-Aventis Inc.; Pfizer, Bayer Schering Pharma; Bristol-Myers Squibb (Taiwan)<br />
Ltd.; Boehringer Ingelheim Taiwan Limited; Novartis Inc. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
770 SORAFENIB VERSUS CAPECITABINE IN THE MANAGEMENT<br />
OF ADVANCED HEPATOCELLULAR CARCINOMA<br />
M. Abdelwahab 1 , M. Shaker 2 , S. Abdelwahab 1 , M. Elbassiouny 1 , M. Ellithy 1 ,<br />
O. Abdelrhman 1<br />
1 Clinical Oncology, Ain Shams University, Cairo, EGYPT, 2 Tropical Medicine,<br />
Ain Shams University, Cairo, EGYPT<br />
Background: The only approved systemic <strong>the</strong>rapy for patients with advanced<br />
hepatocellular carcinoma (HCC) till now is sorafenib. a preliminary study suggested<br />
that capecitabine, an oral fluoropyrimidine may be effective in advanced HCC. We<br />
have tested this hypo<strong>the</strong>sis in this phase 2 study.<br />
Methods: In this single centre, phase 2, open label trial, we randomly assigned 52<br />
patients with advanced HCC who had not received previous systemic treatment to<br />
receive ei<strong>the</strong>r sorafenib (at a dose of 400 mg twice daily) or capecitabine 1000 mg/m 2<br />
twice daily (day 1-day 14). Primary outcomes were progression free survival.<br />
Secondary outcomes included <strong>the</strong> overall survival and safety.<br />
Results: Median overall survival was 7.05 months in <strong>the</strong> sorafenib group and 5.07<br />
months in <strong>the</strong> placebo group (hazard ratio in <strong>the</strong> capecitabine group, 2.36; 95%<br />
confidence interval, 1.174-4.74; P < 0.016). The median progression free survival was<br />
6 months in <strong>the</strong> sorafenib group and 4 months in <strong>the</strong> capecitabine group (P < 0.005).<br />
Three patients in <strong>the</strong> sorafenib group (11.5%) and 1 patient in <strong>the</strong> capecitabine<br />
group (3%) had a partial response; one patient (3%) had a complete response in <strong>the</strong><br />
sorafenib group. hand–foot skin reaction was more frequent in <strong>the</strong> sorafenib group,<br />
hyperbilirubinemia was more common in <strong>the</strong> capecitabine group and diarrhea was<br />
equivalent between both groups.<br />
Conclusions: In patients with advanced HCC, capecitabine mono<strong>the</strong>rapy is inferior<br />
to sorafenib in terms of median progression free survival and overall survival and it<br />
should not be used alone for <strong>the</strong> treatment of advanced HCC but ra<strong>the</strong>r combination<br />
<strong>the</strong>rapy of capecitabine plus sorafenib should be considered for fur<strong>the</strong>r randomized<br />
clinical trials.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
771 LIVER SPECIFIC GRADED PROGNOSTIC ASSESSMENT CAN<br />
PREDICT THE OUTCOME FOR PATIENTS WITH BRAIN<br />
METASTASES FROM HEPATOCELLULAR CARCINOMA<br />
S. Lim 1 , S. Lee 1 , K. Han 2 , H. Choi 1<br />
1 Medical Oncology, Severance Hospital, Seoul, KOREA, 2 Gastroenterology,<br />
Severance Hospital, Seoul, KOREA<br />
Background: After <strong>the</strong> introduction of sorafenib which showed prolongation of<br />
survival in patients with advanced HCC, <strong>the</strong> incidence of brain metastasis seemed to<br />
increase. Assessment of prognostic factors might useful to decide treatment in<br />
patients with brain metastases. Although diagnosis-specific Graded Prognostic<br />
Assessment (GPA) has been identified for several cancer types, optimal treatment<br />
strategy for brain metastasis from HCC has not been well established.<br />
Methods: A total of 128 HCC patients were newly diagnosed with brain metastasis at<br />
Yonsei University Health Center between 1995 and 2011. Using SPSS program,<br />
univariate and multivariate analyses of <strong>the</strong> prognostic factors were performed. With<br />
<strong>the</strong> P value less than 0.10 as cutoff value, <strong>the</strong> significant prognostic factors were used<br />
to develop <strong>the</strong> HCC specific-GPA (HCC-GPA).<br />
Result: The median overall survival after brain metastasis in all patients was only 6.1<br />
weeks (95% confidence interval: 4.8-7.4 week). Significant prognostic factors were <strong>the</strong><br />
presence of extracranial lesion, and Child-Pugh-Class score. Using those variables, we<br />
newly developed HCC-GPA: extracranial metastasis (Yes: 0, No: 1 point), and<br />
Child-Pugh-Score (C:0, B:1, A:2 point). The median survival time from brain metastasis<br />
were significantly separated by HCC-GPA grouping (3.1 weeks in group 1 (HCC-GPA<br />
score 0 or 1.0, N = 50), 8.0 weeks in group 2 (HCC-GPA score 2.0, N = 55), and 22.0<br />
weeks in group 3 (HCC-GPA score 3.0, N = 13); p< 0.001 by log rank test).<br />
Conclusion: Although <strong>the</strong> overall prognosis of patients with brain metastasis from<br />
HCC is dismal, <strong>the</strong> present data showed that newly developed HCC-GPA score can<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds398 | ix253
discriminate <strong>the</strong> prognosis of HCC patients with brain metastasis. It can be used as a<br />
valuable tool to select patients who can be good candidates for active local treatment.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
772 TRANSCATHETER ARTERIAL CHEMOEMBOLISATION FOR<br />
HEPATOCELLULAR CARCINOMA IN CIRRHOSIS: FEASIBILITY<br />
OF HEPATIC RESECTION<br />
O. Nematov 1 , S. Navruzov 2 , M. Djuraev 1 , S. Khudayorov 1 , D. Egamberdiev 1 ,<br />
H. Tuyev 1<br />
1 Abdominal Oncology, National Cancer Center of Uzbekistan, Tashkent,<br />
UZBEKISTAN, 2 Administration, National Cancer Center of Uzbekistan, Tashkent,<br />
UZBEKISTAN<br />
Background: Hepatocelullar carcinoma (HCC) is <strong>the</strong> fifth most common cancer in<br />
<strong>the</strong> world. It mostly occurs in patients with cirrhosis. The aim of investigation is to<br />
evaluate <strong>the</strong> efficiency of transca<strong>the</strong>ter arterial chemoembolization (TACE) for<br />
unresectable HCC in cirrhosis and use of it in preoperative stage.<br />
Materials and methods: We evaluated data from 49 patients who had a confirmed<br />
diagnosis of HCC on cirrhosis. Median age of <strong>the</strong> patients was 56 years. Male – 35<br />
(71.4%, female – 14 (28.6%). In 33 (67.3%) cases tumor located in right lobe and in<br />
16 (32.7%) cases located in left lobe. In 7 (14.3%) cases tumor size consisted 8-12 cm,<br />
in 32 (65.3%) 12-15 cm and in 10 (20.4%) cases more than 15 cm. The underlying<br />
cirrhosis was staged as Child-Pugh A in 14(28.6%) cases and Child-Pugh B in 35<br />
(71.4%). We selectively ca<strong>the</strong>terized <strong>the</strong> tumour via arteria femoralis and used<br />
Doxorubicin with Lipiodol as embolic material.<br />
Results: In follow up, we carried out laboratory studies and CT. Three weeks after<br />
TACE <strong>the</strong>re are dominated tumours with <strong>the</strong> sizes 8-12 cm (in 16 (32.7 patients))<br />
due to reduction of tumour sizes. Reduction of tumour sizes averaged 26.7 ± 0.4 mm.<br />
There is noted physiological increase of opposite part of live from 1 up to 3 cm,<br />
averagely 23 ± 0.32 mm in 46 (93.9%) patients. Alpha-fetoprotein normalized in 37<br />
patients, which was high before manipulation. After TACE patients were restaged<br />
and Child-Pugh class A noted in 25 (51%), class B noted in 24 (49%) patients. There<br />
is not noted full clinical effect, partial effect noted in 21 (42.9%) patients, stable<br />
process in 13 (26.5%) patients. Twenty one of <strong>the</strong> 49 patients (49%) selected for<br />
surgical treatment according objective changes, reduction of tumour sizes and<br />
improvement of opposite part of liver after TACE.<br />
Conclusions: TACE is safe method, it provides reduction of tumour sizes, intensifies<br />
influx of arterial blood to <strong>the</strong> opposite part of liver which improves liver function<br />
and conducts to hypertrophy of remaining part of liver. In 49% of unresectable HCC<br />
patients TACE conducts to curative hepatic resection.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
773 IMPACT OF LYMPH NODE LEVEL ASSESSMENT FOR SURVIVAL<br />
ON TIME TO RELAPSE IN BILIARY TRACT CANCERS<br />
J. Martinez-Galan 1 , P. Ballesteros 2 , B. Gonzalez-Astorga 1 , J.A. Ortega 1 ,<br />
A. González-Vicente 1 , J. Soberino García 1 , C. González-Rivas 2 ,<br />
J. Ruíz Vozmediano 1 , T. Villegas 3 , J.R. Delgado 1<br />
1 Medical Oncology Department, Hospital Universitario Virgen de las Nieves,<br />
Granada, SPAIN, 2 Medical Oncology Department, Hospital Universitario de<br />
Ceuta, Ceuta, SPAIN, 3 Surgical Department, Hospital Virgen de las Nieves,<br />
Granada, SPAIN<br />
Background: Biliary tract cancers (BTCs) are relatively rare neoplasms encompass both<br />
cholangiocarcinoma (CC). The role of routine lymphadenectomy at <strong>the</strong> time of surgical<br />
resection remains poorly defined. We sought to identify factors associated with outcome<br />
following and examine <strong>the</strong> impact of lymph node (LN) assessment on survival.<br />
Methods: 43 patients who underwent curative intent surgery between 2000-2010<br />
were identified from a database. We calculated prognostic factors and impact lymph<br />
node (LN) assessment for survival.<br />
Results: A total of 43 patients were identified with no metastatic BTCs. The median<br />
age was 65 years (29–82 years); performance status of 0 in 33/43 (76%); PS1 in 8/43<br />
(19%) and PS2 in 2/43 (5%) pts. A histological diagnosis of adenocarcinoma was<br />
confirmed in 100%. Surgical resection was performed in all patients. After resection<br />
42% (18/43) had positive nodes.Adjuvant chemo<strong>the</strong>rapy had 31/43(72%), preferred<br />
with gemcitabine and a median number of cycles 6. Grade 3 or 4 toxicities rarely<br />
occurred. During median follow-up of 6.6 years tumor recurrence or metastatic<br />
disease occurred in 63% with median survival global were 2 years and 1.5 years for<br />
disease free survival.For stage T, <strong>the</strong> median survival global rates were 58 months<br />
(95% CI 44.6-71.3) for T1-T2 and 35 months (95% CI 23.3-46.8) for T3-T4 (p =<br />
0.015) and for median recidive-free survival were 23 months (95% CI 11.8-34) for<br />
T1-T2 and 14 months (95% CI 6.5-21) for T3-T4 (p = 0.05). For N stage, <strong>the</strong> median<br />
survival global were 58 months (95% CI 50.5-65.4) for negative nodes and 26<br />
months (95% CI 3.7-48.2) for positive nodes (p = 0.003) and for median recidive-free<br />
survival were 55 months (95% CI 31.7-57.5) for negative nodes and 10 months (95%<br />
CI 6.8-13) for positive nodes (p = 0.006). The patients who had nodal affectation in<br />
hepatic hilio had better recidive-free survival that those patients who had nodal<br />
affectation in celiac trunk p < 0.05.<br />
Conclusions: This represents a biliary cancer cohort with survival benchmarks<br />
obtained in <strong>the</strong> modern era of multidisciplinary care. Surgical resection and adjuvant<br />
chemo<strong>the</strong>rapy offers <strong>the</strong> optimal treatment outcome in patients with ICC. From our<br />
results depth of tumor invasion (T), <strong>the</strong> presence <strong>the</strong> lymph node metastases (N)<br />
and level nosal affections are <strong>the</strong> strongest predictors of relapse and survival<br />
Disclosure: All authors have declared no conflicts of interest.<br />
774 PSEUDOMYXOMA PERITONEI: PATHOLOGICAL AND<br />
THERAPEUTIC ASPECTS OF 26 CASES<br />
Annals of Oncology<br />
M. Nesrine 1 , A. Aloui 1 , R. Hela 1 , M. Ayadi 1 , N. Chaiet 1 , B. Allani 2 , H. Raies 1 ,<br />
A. Mezlini 1<br />
1 Medical Oncology, Salah Azaeiz Institute, Tunis, TUNISIA, 2 Medical Oncology,<br />
Institut Salah Azaiz, Tunis, TUNISIA<br />
Introduction: Pseudomyxoma peritonei is defined by mucus collection in <strong>the</strong><br />
peritoneal cavity with or without presence of neoplastic cells. Recent<br />
immunohistochemical and cytogenetic applications have confirmed <strong>the</strong> appendiceal<br />
origin. Surgical removal combined with hyper<strong>the</strong>rmic intraperitoneal chemo<strong>the</strong>rapy<br />
(HIPEC) is <strong>the</strong> main treatment. The aim of this study is to evaluate pathological and<br />
<strong>the</strong>rapeutic aspects of a Tunisian series of 25 cases.<br />
Methods: We retrospectively studied 25 patients, in a 17-year period from 1994 to<br />
2011. Data were collected from surgical records and included: Patient presentation,<br />
radiologic histological findings, surgical procedure, adjuvant <strong>the</strong>rapy and follow up.<br />
Initial and subsequent surgical treatment were conducted at <strong>the</strong> Salah Azaiez institute.<br />
Results: The mean age was 38 years (range 32-83 years) and 92% (23/25) were females.<br />
The most frequent symptom was abdominal distension (68%). Pathologic specimen<br />
showed peritoneal mucinosis carcinomatosis in 40% of patients and dessiminated<br />
peritoneal adenomucinosis in 20% of patients. The appendiceal origin was found in 60%<br />
of cases and ovarian origin in 28% of cases. All patients have been operated, one patient<br />
had neoadjuvant chemo<strong>the</strong>rapy. Only two patients had HIPEC. 52% (13 cases) has<br />
post-operative systemic chemo<strong>the</strong>rapy with complete response in 8 cases. Disease<br />
recurrence was noted in 48% of patients (12 cases). Second-look surgery has been<br />
performed in 8 cases. 8 patients had chemo<strong>the</strong>rapy after recurrence. The median patient<br />
follow-up was 36 months (range, 1 to 120 months). 1 and 3-year progression free<br />
survival was 40% and 12% respectively. Overall survival at 1, 3, 5 year was 80%, 40%,<br />
20% respectively. One patient developed bone metastases after 13 months of follow up.<br />
Conclusion: Pseudomyxoma peritonei is a rare disease that must be treated in<br />
specialized centers with complete surgical removal, per or immediate post operative<br />
intraperitoneal chemo<strong>the</strong>rapy and accurate histological classification.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
775 RELATIONS OF QOL TO TUMOR RESPONSE AND ADVERSE<br />
EVENTS IN UNRESECTABLE ADVANCED PANCREATIC<br />
CANCER PATIENTS IN THE GEST STUDY<br />
Y. Ohashi1 , T. Ioka2 , T. Okusaka3 1<br />
Department of Biostatistics, School of Public Health, The University of Tokyo,<br />
Tokyo, JAPAN, 2 Division of Hepatobiliary and Pancreatic Oncology, Osaka<br />
Medical Center for Cancer and Cardiovascular Diseases, Osaka, JAPAN,<br />
3<br />
Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center<br />
Hospital, Tokyo, JAPAN<br />
Background: The GEST study demonstrated <strong>the</strong> non-inferiority of S-1, but not <strong>the</strong><br />
superiority of gemcitabine plus S-1 (GS) to gemcitabine alone (G) with respect to<br />
overall survival in unresectable advanced pancreatic cancer patients (Ioka et al.<br />
ASCO 2011, <strong>Abstract</strong> 4007). The results of QOL evaluation based on EQ-5D<br />
demonstrated that S-1 and G were equivalent and GS was superior to G (Ohashi<br />
et al. ASCO 2011, <strong>Abstract</strong> 9070). We report <strong>the</strong> relations of QOL to adverse events<br />
and tumor response.<br />
Methods: Chemo<strong>the</strong>rapy was administered until PD, consent withdrawal, or<br />
unacceptable adverse events. EQ-5D questionnaires were filled in at baseline and<br />
6, 12, 24, 48, and 72 weeks and converted to 0-1 utility scores by <strong>the</strong> Japanese value<br />
set. We estimated <strong>the</strong> effects of adverse events (nausea, vomiting, diarrhea, fatigue,<br />
and anorexia leveled from 0 to 4 by CTC-AE) and of tumor response on EQ-5D<br />
utility scores, using a mixed-effects model for repeated measurements. Response was<br />
classified into 4 levels (CR/PR/SD or NE/PD).<br />
Results: A total of 736 patients were analyzed. Fatigue and anorexia were<br />
significantly associated with EQ-5D utility score; <strong>the</strong>y decreased <strong>the</strong> estimated score<br />
by 0.034/level (p < 0.001) and 0.032/level (p < 0.001), respectively. EQ-5D utility<br />
scores were not related to nausea, vomiting, or diarrhea after adjustment of fatigue<br />
and anorexia. Tumor response (leveled from 0(PD) to 3(CR)) significantly improved<br />
<strong>the</strong> estimated score by 0.054/level (p < 0.001); interactions between response and<br />
treatments were not significant. The improvement in EQ-5D utility score associated<br />
with a better response was most strongly attributed to decreased pain among 5<br />
questions.<br />
ix254 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Conclusions: QOL in <strong>the</strong> studied patient population was negatively affected by<br />
fatigue and anorexia, and was improved by good response probably through<br />
decreased pain.<br />
Disclosure: Y. Ohashi: I have an advisory relationship and research funding to<br />
disclose. Name of Entity: Taiho Pharmaceutical Co. Ltd. T. Ioka: I have an advisory<br />
relationship and research funding to disclose. Name of Entity: Taiho Pharmaceutical<br />
Co. Ltd. T. Okusaka: I have an advisory relationship and research funding to disclose.<br />
Name of Entity: Taiho Pharmaceutical Co. Ltd<br />
776TiP GAMMA (GEMCITABINE AND AMG 479 FOR METASTATIC<br />
ADENOCARCINOMA OF THE PANCREAS): A PHASE 3,<br />
MULTICENTER, RANDOMIZED, DOUBLE-BLIND,<br />
PLACEBO-CONTROLLED TRIAL OF GANITUMAB PLUS<br />
GEMCITABINE (G) OR PLACEBO PLUS G AS FIRST-LINE<br />
THERAPY FOR METASTATIC PANCREATIC CANCER<br />
<strong>Abstract</strong> withdrawn in exceptional circumstances.<br />
777TiP SECOND INTERIM ANALYSIS OF THE GLOBAL<br />
INVESTIGATION OF THERAPEUTIC DECISIONS IN<br />
HEPATOCELLULAR CARCINOMA AND OF ITS TREATMENT<br />
WITH SORAFENIB (GIDEON) STUDY ACCORDING TO<br />
DISEASE STAGE<br />
B. Daniele 1 , J. Turnes 2 , G. Bodoky 3 , C. Papandreou 4 , A. Hubert 5 , P. Stål 6 ,<br />
V.A. Gorbunova 7 , F. Serejo 8 , A. Croitoru 9 , P. Mathurin 10<br />
1 Medical Oncology Unit, G. Rummo Hospital, Benevento, ITALY,<br />
2 Gastroenterology Department, Hospital de Montecelo, Pontevedra, SPAIN,<br />
3 Department of Oncology, St László Hospital, Budapest, HUNGARY,<br />
4 Department of Medical Oncology, University Hospital of Larissa, Larissa,<br />
GREECE, 5 Gastrointestinal Cancer Center, Sharett Institute of Oncology,<br />
Jerusalem, ISRAEL, 6 Department of Gastroenterology and Hepatology,<br />
Karolinska University Hospital, Stockholm, SWEDEN, 7 Russian Scientific<br />
Research Oncology Centre, N. N. Blokhin Russian Cancer Research Center,<br />
Moscow, RUSSIAN FEDERATION, 8 Center of Gastroenterology, Liver Unit,<br />
Hospital de Santa Maria, Faculty of Medicine, Lisbon, PORTUGAL, 9 Hepatic<br />
Fundeni, FUNDENI Clinical Institute, Bucharest, ROMANIA, 10 Service Des<br />
Maladies De L’appareil Digestif, Hôpital Claude Huriez, Lille, FRANCE<br />
Background: GIDEON (NCT00812175) is an ongoing, global, prospective,<br />
non-interventional study of patients with unresectable hepatocellular carcinoma<br />
(HCC) receiving sorafenib (Nexavar®) in real-life practice. The aim is to evaluate<br />
sorafenib safety and efficacy in diverse settings and patient groups. The second<br />
interim analysis was triggered when ∼1500 patients had been treated for ≥ 4 months.<br />
We describe sorafenib use in Europe according to disease stage.<br />
Methods: Patient/disease characteristics (including Barcelona Clinic Liver Cancer<br />
[BCLC], tumour node metastases [TNM], Cancer for <strong>the</strong> Liver Italian Programme<br />
[CLIP]) and treatment history were recorded at enrolment; sorafenib dose,<br />
concomitant medications, performance status, liver function, adverse events (AEs)<br />
and efficacy are recorded at follow-up visits.<br />
Results: Of 1571 patients in <strong>the</strong> safety population, 588 are in Europe (see table). The<br />
majority of patients were BCLC-C (52.9%), TNM III (40.3%) or CLIP 1/2 (26.0%/<br />
25.9%), although sorafenib was also used in patients with early, intermediate and<br />
end-stage disease. Generally, AEs and serious AEs (SAEs) increased with advancing<br />
disease (AEs: 66.0%, 87.4%, 85.5%, 89.7%; SAEs: 22.6%, 37.8%, 38.3%, 58.6%; for<br />
BCLC-A, B, C and D; respectively), whereas sorafenib-related AEs and SAEs were<br />
comparable across BCLC groups (AEs: 60.4%, 74.1%, 68.5%, 41.4%; SAEs: 7.5%,<br />
15.4%, 10.3%, 10.3%; for BCLC-A, B, C and D; respectively). Evaluation will<br />
continue with more mature data.<br />
Medical oncologist<br />
(n = 189)<br />
Hepatologist/<br />
GI specialist<br />
(n = 332)<br />
EU total<br />
(n = 588)<br />
BCLC stage at study entry, % of n<br />
A 6.9 8.7 9.0<br />
B 19.6 27.7 24.3<br />
C 59.3 50.6 52.9<br />
D 3.2 5.4 4.9<br />
NE/missing 11.1 7.5 8.8<br />
TNM stage at study entry, % of n<br />
I 3.2 10.5 8.8<br />
II 8.5 12.3 10.2<br />
III 39.2 41.9 40.3<br />
IV 40.2 19.9 26.9<br />
NE/missing 9.0 15.4 13.8<br />
Child-Pugh score at start<br />
of sorafenib <strong>the</strong>rapy, % of n<br />
A 68.3 64.8 66.3<br />
B 13.8 26.8 21.6<br />
C 1.1 1.8 1.5<br />
NE/missing 16.9 6.6 10.5<br />
CLIP score at start of sorafenib <strong>the</strong>rapy, % of n<br />
0 14.8 8.4 11.9<br />
1 24.3 26.5 26.0<br />
2 24.3 26.5 25.9<br />
3 5.8 15.7 11.4<br />
4–6 4.2 11.4 8.7<br />
NE/missing 26.5 11.4 16.2<br />
NE, not evaluable<br />
Conclusions: These data reflect real-world sorafenib given to a broad range of<br />
patients, indicating a similar safety profile across <strong>the</strong> different disease stages.<br />
Evaluation is ongoing, with more mature data expected from <strong>the</strong> final analysis.<br />
Disclosure: B. Daniele: Dr B. Daniele has participated in advisory boards and<br />
received lecture fees from Bayer. J. Turnes: Dr J Turnes has participated in advisory<br />
boards for Roche Pharma. C. Papandreou: Prof. C Papandreou has participated in<br />
advisory boards for Bayer, Sanofi Aventis, Novartis, Bristol Meyers Squibb and<br />
Janssen. P. Stål: Prof. Stål has advised and received a grant from Bayer. A. Croitoru:<br />
Dr A Croitoru has consulted for and received an investigator fee from Bayer. P:<br />
Mathurin: Dr. P . Mathurin was paid speaking at symposia for Roche,<br />
Schering-Plough, Gilead Sciences, Bristol-Myers Squibb, Janssen-Cilag and Bayer<br />
Healthcare pharmaceutical companies. He is an investigator for Roche,<br />
Schering-Plough, Bristol-Myers Squibb, Gilead Sciences, Vertex pharmaceuticals<br />
Janssen-Cilag, Boeringher, Novartis and Bayer Healthcare companies. He is a<br />
member of <strong>the</strong> French boards of experts in Hepatology for Roche Schering-Plough,<br />
Gilead Sciences, Bayer Healthcare and Bristol-Myers Squibb pharmaceutical<br />
companies. He is consulting for <strong>the</strong> Gilead Sciences, Bristol-Myers Squibb, Bayer<br />
Healthcare and Vertex pharmaceutical Companies. All o<strong>the</strong>r authors have declared<br />
no conflicts of interest.<br />
778TiP INTERIM ANALYSIS OF OVERALL SURVIVAL PER<br />
SUBGROUPS IN THE PROSPECTIVE,<br />
NON-INTERVENTIONAL INSIGHT STUDY IN PATIENTS WITH<br />
HEPATOCELLULAR CARCINOMA TREATED WITH<br />
SORAFENIB<br />
T. Ganten 1 , E. Schott 2 , P. Galle 3 , T. Göhler 4 , P. Malfer<strong>the</strong>iner 5 , R. Stauber 6 ,<br />
R. Buder 7 , K. Achilles 8 , G. Gerken 9<br />
1 Medizinische Klinik, Gastroenterologie, Hepatologie und Infektiologie,<br />
Universitätsklinik Heidelberg, Heidelberg, GERMANY, 2 Medizinische Klinik,<br />
Hepatologie und Gastroenterologie, Charité- Campus Virchow Klinikum, Berlin,<br />
GERMANY, 3 I. Medizinische Klinik und Poliklinik, Universitätsmedizin der<br />
Johannes Gutenberg-Universität Mainz, Mainz, GERMANY, 4 Onkologische<br />
Praxis, Dresden, GERMANY, 5 Universitätsklinik für Gastroenterologie,<br />
Hepatologie und Infektiologie, Otto-von-Guericke Universität Magdeburg,<br />
Magdeburg, GERMANY, 6 Karl-Franzens-Universität Graz, Abteilung Innere<br />
Medizin, Gastroenterologie und Hepatologie, Graz, AUSTRIA, 7 Abteilung Innere<br />
Medizin, Konventspital Barmherzige Brüder, Linz, AUSTRIA, 8 Bayer HealthCare,<br />
Leverkusen, GERMANY, 9 Abteilung Gastroenterologie und Hepatologie,<br />
Universitätsklinik Essen, Essen, GERMANY<br />
Background: The efficacy of Sorafenib in patients (pts) with hepatocellular<br />
carcinoma (HCC) has been proven in randomized, controlled trials. INSIGHT is a<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds398 | ix255
prospective, non-interventional study, conducted in Germany and Austria in pts with<br />
HCC. The objectives of this study are <strong>the</strong> evaluation of safety and efficacy under<br />
practice conditions in both hospitals and private practices. Enrollment into INSIGHT<br />
is not restricted to a particular tumor stage. Recruitment into <strong>the</strong> study is ongoing.<br />
Methods: The second interim analysis (data cut-off 23 FEB <strong>2012</strong>) evaluated overall<br />
survival and safety data in relevant subgroups. All patients with HCC were observed<br />
for <strong>the</strong> duration of <strong>the</strong>ir sorafenib <strong>the</strong>rapy. In addition to baseline data <strong>the</strong><br />
performance status, tumor status (clinical and/or radiological), time to progression<br />
and overall survival time are documented. Documentation of adverse events<br />
comprises relationship with drug, seriousness, grade (CTCAE version 3.0), and<br />
outcome.<br />
Results: Until <strong>the</strong> data cut-off 623 pts have been enrolled; 618 of which are evaluable<br />
for safety and efficacy analyses. The table summarises major baseline characteristics<br />
toge<strong>the</strong>r with median overall survival (mOS) data for relevant subpopulations.<br />
Patients recruited n, Male n (%) 618, 528 (85)<br />
ECOG PS, n (%), 0, 1, 2 203 (33); 310 (50); 98 (16)<br />
BCLC-Stage n (%), A, B, C, D 80 (13); 149 (24); 319 (52); 12 (2)<br />
Child Pugh Stage, n (%), A(9), Missing<br />
264 (43); 99 (16); 12 (2); 243 (39)<br />
Months<br />
mOS total population (Events n = 164) 17,1<br />
mPFS total population (Events n = 408) 4,1<br />
mOS according to BCLC A, B, C, D 29,2; 19,6; 14,5; 4,0<br />
mOS according to Child Pugh A, B, C n.r.; 7,2; 4,0<br />
mOS Child Pugh B: 7, 8, 9 points 11,5; 9,5; 2,5<br />
mOS Duration of <strong>the</strong>rapy > 24 weeks<br />
(n = 176); >40 weeks (n = 91)<br />
19,8; 26,7<br />
n.r.-not reached<br />
Conclusions: Results of mOS in pts with HCC treated under daily practice<br />
conditions in hospitals and private practices confirm <strong>the</strong> general efficacy of Sorafenib<br />
known from registration trials and gives fur<strong>the</strong>r insight into pts with Child B/C<br />
cirrhosis and BCLC stage A/B. Fur<strong>the</strong>r demographic data and efficacy and safety<br />
results will be presented.<br />
Disclosure: T. Ganten: Advisory Boards and Cooperate-sponsored research (Bayer<br />
HealthCare Germany). E. Schott: ES has received lecture fees and travel support from<br />
Bayer and has acted as an advisor to Bayer. P. Galle: Advisory Boards, Speaker for<br />
Bayer. P. Malfer<strong>the</strong>iner: - Anstellungsverhältnis, Führungsposition: Klinikdirektor -<br />
Beratungs- bzw. Gutachtertätigkeit: Aptalis, Novartis - Honorare: Aptalis, Falk<br />
Foundation, Abbott, AstraZeneca - Finanzierung wissenschaftlicher Untersuchungen:<br />
Bayer, Novartis. K. Achilles: I am employee of Bayer Vital. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
779TiP A RANDOMIZED PHASE II TRIAL OF BIWEEKLY S-1 WITH<br />
PACLITAXEL (SPA) OR OXALIPLATIN (SOX) AS FIRST-LINE<br />
CHEMOTHERAPY IN ADVANCED GASTRIC CANCER<br />
PATIENTS: PRELIMINARY RESULTS<br />
M. Haibo, W. Fang, Y. Zheng, P. Zhao, C. Mao, X. Zhang, J. Qian, H. Jiang,<br />
Y. Zheng, N. Xu<br />
Department of Medical Oncology, The First Affiliated Hospital, School of<br />
Medicine, Zhejiang University, Hangzhou, CHINA<br />
Background: Gastric cancer patients are commonly treated with S-1-based<br />
chemo<strong>the</strong>rapy for three weeks or more to ensure two weeks of exposure at<br />
<strong>the</strong>rapeutic doses. Severe side effects of S-1 such as mucositis, diarrhea and<br />
neutropenia often occur in <strong>the</strong> second week of treatment. We evaluated <strong>the</strong> activity<br />
and safety of every o<strong>the</strong>r week S-1 regimens with paclitaxel or oxaliplatin<br />
combinations as first-line chemo<strong>the</strong>rapy in advanced gastric cancer patients. Patients<br />
and methods: Eligible patients with pathologically confirmed advanced gastric cancer<br />
patients were randomized into two arms. S-1 was administered orally (80 mg/m 2 /<br />
day) for 7 consecutive days in combination with paclitaxel 120 mg/m 2 (SPA) or<br />
oxaliplatin 85 mg/m 2 (SOX) on day 1 followed by a 7-day rest. Treatment continued<br />
in a biweekly manner until disease progressed, unacceptable toxicity was observed or<br />
<strong>the</strong> patient refused to continue. The primary endpoint was overall response rate<br />
(ORR). The secondary endpoints were progression-free survival (PFS), overall<br />
survival (OS) and safety.<br />
Results: Eighty-one gastric cancer patients were enrolled from June 2010 to March<br />
<strong>2012</strong>. Patients were randomized to receive SPA (43) or SOX (38). Results are<br />
presented for 76 patients. The ORR for arm A was 43.6%, and that for arm B was<br />
33.3% with no significant difference between <strong>the</strong> two arms (p = 0.35). The median<br />
PFS was 6.2 months for arm A vs. 5.1 months for arm B (p = 0.80); <strong>the</strong> median OS<br />
was 10.8 months for arm A and 10.0 months for arm B (p = 0.17). No<br />
treatment-related deaths occurred during <strong>the</strong> study. The most frequent toxicity was<br />
neutropenia (30.8% and 17.4% of grade 3/4 in arms A and B, respectively). The most<br />
common non-hematological toxicities were mucositis, diarrhea, and peripheral<br />
neuropathy, all in less than 5% of patients.<br />
Conclusions: These preliminary findings suggest that biweekly S-1-based regimens<br />
have an acceptable ORR with tolerable side effects in advanced gastric cancer<br />
patients. The study will continue until 100 patients have been enrolled.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
780TiP SAFETY AND EFFICACY OF ALBUMIN-BOUND PACLITAXEL<br />
AND OXALIPLATIN AND S-1 AS FIRST-LINE TREATMENT OF<br />
PATIENTS WITH ADVANCED GASTRIC CANCER<br />
H. Lou, H. Pan, Q. Pan, D. Li, W. Jin<br />
Medical Oncology, Sir Run Run Shaw Hospital,College of Medicine,Zhejiang<br />
University, Hangzhou, CHINA<br />
Background: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel<br />
formulation of paclitaxel that does not require solvents such as polyoxyethylated<br />
castor oil and ethanol. Use of <strong>the</strong>se solvents has been associated with toxic response,<br />
including hypersensitivity reactions and prolonged sensory neuropathy. This study<br />
was conducted to evaluate <strong>the</strong> efficacy and safety of combination chemo<strong>the</strong>rapy with<br />
nab-paclitaxel plus oxaliplatin and S-1 as first-line treatment for patients with<br />
advanced gastric cancer.<br />
Patients and methods: Eligible patients (pts) with histologically confirmed<br />
advanced gastric cancer,
Annals of Oncology<br />
Conclusion: The combination of everolimus and capecitabine has a reasonable<br />
toxicity profile and may show significant activity in patients with advanced HCC<br />
pretreated with sorafenib. This combination <strong>the</strong>rapy warrants fur<strong>the</strong>r investigation as<br />
a possible second line treatment for selected patients with HCC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
782TiP REVIEW OF THE MANAGEMENT OF ADVANCED GASTRIC<br />
CANCER; AN EXPERIENCE FROM A LOW RESOURCE<br />
SETTING<br />
K. Beecham 1 , V.D.N.K. Vanderpuye 1 , N.A. Adu-Aryee 2<br />
1 Radio<strong>the</strong>rapy, Korlebu Teaching Hospital, Accra, GHANA, 2 Surgery, Korlebu<br />
Teaching Hospital, Accra, GHANA<br />
Purpose: Adjuvant treatment combines Epirubicin, Cisplatin and 5-FU (ECF).<br />
Replacement of 5FU and Cisplatin with Capecitabine (X) and Oxaliplatin (O) has<br />
shown an efficacy similar to ECF, with improved tolerability and safety. The outcome<br />
of management of advanced gastric cancer at <strong>the</strong> Oncology Unit was assessed, with<br />
emphasis on <strong>the</strong> use of Capecitabine alone or in combination.<br />
Patients & methods: 27 patients adenocarcinoma of <strong>the</strong> stomach between 2004 and<br />
2008 were eligible. Time to disease progression (TTP) as well as tolerability of<br />
treatment was assessed retrospectively.<br />
Results: Median follow up was 12 months (1 to 60 months). No adjuvant treatment<br />
was given in 36%. 26% received concurrent chemoradiation with Capecitabine. 11.1%<br />
received palliative radio<strong>the</strong>rapy only. One patient did not complete radio<strong>the</strong>rapy due<br />
to side effects. 26.6% received Capecitabine alone and combined with Oxaliplatin in<br />
11.1% Grade 3/4 diarrhoea was reported in 7.4%; neuropathy and neutropenia were<br />
seen in 3.7%. Median time to progression in patients who had adjuvant treatment<br />
was 6.4 months (2 to 13 months).<br />
Conclusion: There is a favorable tolerability of Capecitabine used alone or in<br />
combination with radio<strong>the</strong>rapy or o<strong>the</strong>r chemo<strong>the</strong>rapy drugs.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds398 | ix257
abstracts<br />
genitourinary tumors, non-prostate<br />
783O RANDOMIZED PHASE II STUDY OF FIRST-LINE EVEROLIMUS<br />
(EVE) + BEVACIZUMAB (BEV) VERSUS INTERFERON ALFA-2A<br />
(IFN) + BEV IN PATIENTS (PTS) WITH METASTATIC RENAL<br />
CELL CARCINOMA (MRCC): RECORD-2<br />
A. Ravaud 1 , C. Barrios 2 , Ö. Anak 3 , D. Pelov 4 , A. Louveau 5 , B. Alekseev 6 ,<br />
T. M-H 7 , S.S. Agarwala 8 , S. Yalcin 9 , B. Melichar 10<br />
1 Medical Oncology, Bordeaux University, Bordeaux, FRANCE, 2 Department of<br />
Medicine, PUCRS School of Medicine, Porto Alegre, BRAZIL, 3 Oncology Global<br />
Development, Novartis Pharma AG, Basel, SWITZERLAND, 4 Oncology, Novartis<br />
Pharmaceuticals Corporation, Florham Park, NJ, UNITED STATES OF AMERICA,<br />
5 Oncology, Novartis Pharma S.A.S., Paris, FRANCE, 6 Oncourological<br />
Department, Moscow Hertzen Oncology Institute, Moscow, RUSSIAN<br />
FEDERATION, 7 Oncology, OncoCare Cancer Centre, Singapore, SINGAPORE,<br />
8 Cancer Center, St. Luke’s Hospital & Health Network, Bethlehem, PA, UNITED<br />
STATES OF AMERICA, 9 Medical Oncology, Hacettepe University Institute of<br />
Oncology, Ankara, TURKEY, 10 Department of Oncology, Palacky Univeristy<br />
Medical School and Teaching Hospital, Olomouc, CZECH REPUBLIC<br />
Background: Study results demonstrated that IFN augments BEV activity and<br />
improves median PFS in pts with mRCC. Thus, combination BEV + IFN is a<br />
standard first-line treatment option for mRCC. Combining BEV with <strong>the</strong> mTOR<br />
inhibitor EVE may be an efficacious and well-tolerated treatment option. The<br />
open-label, phase II RECORD-2 trial compared first-line EVE + BEV and IFN + BEV<br />
in mRCC. Patients and methods: Therapy-naive pts with clear cell mRCC and prior<br />
nephrectomy were randomized 1:1 to BEV 10 mg/kg IV every 2 weeks with ei<strong>the</strong>r<br />
EVE 10 mg oral daily or IFN (9 MIU SC 3 times/week, if tolerated). Tumour<br />
assessments were every 12 weeks. Primary objective was treatment effect on<br />
progression-free survival (PFS) per central review based on an estimate of <strong>the</strong> chance<br />
of a subsequent phase III trial success (50% threshold for phase II success).<br />
Results: In EVE + BEV (n = 182) and IFN + BEV (n = 183) arms, median age was<br />
60/60 years, 76/72% of pts were men, MSKCC risk was favourable/intermediate/poor<br />
in 36/57/7% and 36/57/7% of pts, and 43/46% of pts had >2 organs involved,<br />
respectively. For EVE + BEV and IFN + BEV, median treatment duration was 8.5/8.3<br />
months, respectively; 23/26% of pts discontinued due to AEs. In EVE + BEV and<br />
IFN + BEV arms, median PFS by central review was 9.3/10.0 months (HRIFN/EVE,<br />
0.91; 95% CI, 0.69-1.19; P =0.485), respectively; probability of subsequent phase III<br />
success was 5.1%. Results of central and local PFS analysis were consistent. Objective<br />
response rate was 27/28% in EVE + BEV and IFN + BEV arms, respectively. Median<br />
overall survival (OS) was not reached in <strong>the</strong> EVE + BEV arm and was 25.9 months<br />
(95% CI: 21.1, 30.2) in <strong>the</strong> IFN + BEV arm. Most frequent AEs (%) were stomatitis<br />
(63), proteinuria (49), diarrhoea (39), hypertension (38), and epistaxis (35) in EVE +<br />
BEV arm and decreased appetite (45), fatigue (41), proteinuria (37), and pyrexia (35)<br />
in IFN + BEV arm.<br />
Conclusions: In RECORD-2, PFS and tolerability were similar for first-line EVE +<br />
BEV and IFN + BEV. Final OS analysis will occur after 2-year follow-up.<br />
Disclosure: A. Ravaud: Alain Ravaud is a member of global, European, and/or<br />
French boards on urological tumors for Pfizer, Novartis, GlaxoSmithKline,<br />
Bayer-Schering, and Dendreon, and has received institutional grant support from<br />
Pfizer, Novartis, and Roche. Ö. Anak: Ozlem Anak is an employee of Novartis<br />
Pharma AG. D. Pelov: Diana Pelov is an employee of Novartis Pharmaceuticals<br />
Corporation. A. Louveau: Anne-Laure Louveau is an employee of Novartis Pharma S.<br />
A.S. T. M-H: Tay M-H is a speaker for an advisory board for Novartis<br />
Pharmaceuticals Corporation. B. Melichar: Bohuslav Melichar has received honoraria<br />
from Novartis and Roche and served on an advisory board for Roche. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
784O CLINICAL ACTIVITY AND SAFETY OF ANTI-PROGRAMMED<br />
DEATH-1 (PD-1) (BMS-936558/MDX-1106/ONO-4538) IN<br />
PATIENTS (PTS) WITH PREVIOUSLY TREATED, METASTATIC<br />
RENAL CELL CARCINOMA (MRCC)<br />
D.F. McDermott 1 , C.G. Drake 2 , M. Sznol 3 , T.K. Choueiri 4 , J.D. Powderly 5 ,<br />
D.C. Smith 6 , J.M. Wigginton 7 , G. Kollia 8 , A. Gupta 9 , M.B. Atkins 10<br />
1 Division of Hematology/Oncology, Beth Israel Deaconess Medical Center,<br />
Boston, MA, UNITED STATES OF AMERICA, 2 Department of Urology, Sidney<br />
Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore,<br />
MD, UNITED STATES OF AMERICA, 3 Section of Medicine Oncology, Yale<br />
Cancer Center, New Haven, CT, UNITED STATES OF AMERICA, 4 Lank Center<br />
for Genitourinary Oncology, Dana-Farber Cancer Institute/Brigham and Women’s<br />
Hospital, Harvard Medical School, Boston, MA, UNITED STATES OF AMERICA,<br />
5 Oncology, Carolina Bio-Oncology Institute, Huntersville, NC, UNITED STATES<br />
OF AMERICA, 6 Department of Internal Medicine, University of Michigan, Ann<br />
Arbor, MI, UNITED STATES OF AMERICA, 7 Discovery Medicine-clinical<br />
Oncology, Bristol-Myers Squibb, Princeton, NJ, UNITED STATES OF AMERICA,<br />
8 Biostatistics and Data Management, Bristol-Myers Squibb, Princeton, NJ,<br />
UNITED STATES OF AMERICA, 9 Discovery Medicine, Immuno-oncology,<br />
Bristol-Myers Squibb, Princeton, NJ, UNITED STATES OF AMERICA, 10 Internal<br />
Medicine, Georgetown Lombardi Comprehensive Cancer Center, Washington<br />
DC, UNITED STATES OF AMERICA<br />
Purpose: BMS-936558 is a fully human monoclonal antibody that blocks <strong>the</strong> PD-1<br />
co-inhibitory receptor expressed by activated T cells. In <strong>the</strong> initial portion of a phase<br />
1 study, BMS-936558 showed promising activity in pts with various solid tumors,<br />
including mRCC. Accrual was expanded to better characterize antitumor, safety, and<br />
dose effects.<br />
Methods: Pts with RCC were treated with BMS-936558 IV q2wk at 10 mg/kg<br />
initially, followed by additional pts at 1 mg/kg. Pts received up to 12 cycles (4 doses/<br />
cycle) of treatment or until unacceptable toxicity, confirmed progressive disease, or<br />
complete response (CR). Clinical activity was assessed by RECIST v1.0.<br />
Results: As of Feb 24, <strong>2012</strong>, 34 mRCC pts had been treated at 1 mg/kg (n = 18) or<br />
10 mg/kg (n = 16). ECOG performance status was 0 in 13 pts and 1 in 21 pts. The<br />
number of prior <strong>the</strong>rapies was 1 (n = 10), 2 (n = 9), or ≥3 (n = 15), and included<br />
prior immuno<strong>the</strong>rapy (n = 20) or antiangiogenic <strong>the</strong>rapy (n = 25); 32/34 pts had<br />
prior nephrectomy. Sites of metastatic disease included lymph node (n = 28), liver<br />
(n = 9), lung (n = 30), and bone (n = 10). Median duration of <strong>the</strong>rapy was 32 wks<br />
(range 4 − 97.3 wks). The incidence of grade 3 − 4 related adverse events was 18%<br />
and included hypophosphatemia (6%), elevated ALT (3%), and cough (3%); <strong>the</strong>re<br />
were no drug-related deaths among mRCC pts. Clinical activity (response or<br />
prolonged stable disease) was observed at both doses (Table). Two pts had a<br />
persistent reduction in target lesion tumor burden in <strong>the</strong> presence of new lesions and<br />
were not categorized as responders. There were responses in all sites of disease.<br />
Conclusions: BMS-936558 is well tolerated and has durable clinical activity in pts<br />
with previously treated, mRCC. Additional long-term follow-up data will be reported.<br />
Dose<br />
(mg/kg)<br />
No.<br />
pts a<br />
ORR<br />
No. pts (%)<br />
[95% CI]<br />
1 17 4 (24)<br />
[7 − 50]<br />
10 16 5 (31)<br />
[11 − 59]*<br />
Annals of Oncology 23 (Supplement 9): ix258–ix293, <strong>2012</strong><br />
doi:10.1093/annonc/mds399<br />
Response<br />
duration<br />
(months)<br />
17.5 + ,<br />
9.2 + , 9.2,<br />
5.6+<br />
22.3 + ,<br />
21.7 + ,<br />
12.9, 12.0,<br />
8.4<br />
SD ≥24 wk<br />
No. pts (%)<br />
[95% CI]<br />
4 (24)<br />
[7 − 50]<br />
5 (31)<br />
[11 − 59]<br />
PFSR at<br />
24 wk (%)<br />
[95% CI]<br />
47 [23 − 71]<br />
67 [43 − 91]<br />
a Response-evaluable pts dosed by 07/01/2011 *1 CR ORR = objective response rate<br />
([{CR + PR} ÷ n] × 100); SD = stable disease; PFSR = progression-free survival rate.<br />
Disclosure: D.F. McDermott: Advisory Role: Bristol-Myers Squibb (myself, Ad board<br />
participation). C.G. Drake: Consultant or Advisory Role: Bristol-Myers Squibb,<br />
Dendreon Inc., and Amplimmune Inc. (myself, compensated). Stock Ownership:<br />
Amplimmune (myself). O<strong>the</strong>r Renumerations: Patents Licensed, Bristol-Myers<br />
Squibb (myself). M. Sznol: Consultant or Advisory Role: Bristol-Myers Squibb<br />
(myself, compensated). Research Funding: Bristol-Myers Squibb (clinical trials<br />
funding, myself). T.K. Choueiri: Consultant or Advisory Role: GlaxoSmithKline,<br />
Aveo, Novartis and Pfizer (myself, compensated). Research Funding: Pfizer (myself).<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
Annals of Oncology<br />
J.D. Powderly: Consultant or Advisory Role: MedicineX and Bristol-Myers Squibb<br />
(myself, compensated). Research Funding: Bristol-Myers Squibb (clinical trials<br />
funding, myself). Honoraria: Bristol-Myers Squibb (ipilimumab speakers bureau,<br />
myself). D.C. Smith: Research Funding: Bristol-Myers Squibb Oncology (myself). J.<br />
M. Wigginton: Employment or Leadership Role: Bristol-Myers Squibb (employment,<br />
myself, compensated). Stock Ownership: Bristol-Myers Squibb (myself). G. Kollia:<br />
Employment or Leadership Role: Bristol-Myers Squibb (employment, myself,<br />
compensated). Stock Ownership: Bristol-Myers Squibb (BMY) (myself). A. Gupta:<br />
Employment or Advisory Role: Bristol-Myers Squibb (employment, myself,<br />
compensated). Stock Ownership: Bristol-Myers Squibb (myself). M.B. Atkins:<br />
Advisory or Consultant Role: Bristol-Myers Squibb, Curetech, and Merck (myself,<br />
compensated).<br />
785O COMPARATIVE ASSESSMENT OF SUNITINIB-ASSOCIATED<br />
ADVERSE EVENTS (AES) AS POTENTIAL BIOMARKERS OF<br />
EFFICACY IN METASTATIC RENAL CELL CARCINOMA<br />
(MRCC)<br />
F. Donskov 1 , M.D. Michaelson 2 , I. Puzanov 3 , M.P. Davis 4 , G.A. Bjarnason 5 ,<br />
R.J. Motzer 6 , X. Lin 7 , D.P. Cohen 7 , R. Wiltshire 8 , B.I. Rini 9<br />
1 Department of Oncology, Aarhus University Hospital, Aarhus, DENMARK,<br />
2 Medical Oncology, Massachusetts General Hospital Cancer Center, Boston,<br />
MA, UNITED STATES OF AMERICA, 3 Division of Hematology-oncology,<br />
Vanderbilt University Medical Center, Nashville, TN, UNITED STATES OF<br />
AMERICA, 4 Medical Oncology, Cleveland Clinic, Cleveland, OH, UNITED<br />
STATES OF AMERICA, 5 Medical Oncology, Sunnybrook Odette Cancer Centre,<br />
Toronto, CANADA, 6 Genitourinary Oncology Service, Memorial Sloan-Kettering<br />
Cancer Center, New York, NY, UNITED STATES OF AMERICA, 7 Reseach and<br />
Development, Pfizer Oncology, La Jolla, CA, UNITED STATES OF AMERICA,<br />
8 Research and Development, Pfizer Oncology, Tadworth, UNITED KINGDOM,<br />
9 Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic Taussig Cancer<br />
Institute, Cleveland, OH, UNITED STATES OF AMERICA<br />
Background: Previous retrospective analyses have separately identified<br />
treatment-associated hypertension (HTN), hand–foot syndrome (HFS), as<strong>the</strong>nia/<br />
fatigue (A/F), neutropenia (N), and thrombocytopenia (T) as potential biomarkers of<br />
sunitinib efficacy in mRCC patients using a pooled database of five clinical trials<br />
(NCT00054886, NCT00077974, NCT00083889, NCT00338884, NCT00137423;<br />
Pfizer). We assessed <strong>the</strong> relative strength and independence of each biomarker in a<br />
combined analysis of <strong>the</strong> same database.<br />
Methods: Data from 770 mRCC patients who received sunitinib 50 mg/d on <strong>the</strong><br />
approved 4-wk-on-2-wk-off schedule (Schedule 4/2; n = 544; 71%) or 37.5 mg/d<br />
continuous daily dosing (n = 226; 29%) were included. Combined multivariate<br />
analysis, repeated using a 12-wk landmark to address potential bias from longer<br />
treatment, was performed (for Schedule 4/2 and both schedules combined). The<br />
following were included as covariates for prediction of PFS and OS: previously<br />
identified prognostic factors; HTN (SBP ≥140 mmHg); N and T (CTCAE grade >1);<br />
and any CTCAE grade HFS and A/F.<br />
Results: HTN, HFS, and A/F remained significant independent biomarkers in<br />
sunitinib-treated mRCC patients on Schedule 4/2, with HTN and HFS supported<br />
by <strong>the</strong> strongest data (table). N and T were not significant in any analyses, possibly<br />
due to a strong correlation of both with HTN and A/F (P < 0.05; Fisher’s exact<br />
test), but not with HFS. Dose reduction, adjusted for time on treatment, was not<br />
associated with clinical outcome. Results were similar with both schedules<br />
combined.<br />
Conclusions: Combined multivariate analyses indicate that HTN and HFS, and to a<br />
lesser degree A/F, may serve as independent biomarkers of sunitinib efficacy in<br />
mRCC patients. Providers who observe <strong>the</strong>se AEs are <strong>the</strong>refore encouraged to<br />
continue sunitinib <strong>the</strong>rapy, managing AEs with standard medical treatment with or<br />
without dose reduction as clinically indicated.<br />
Final multivariate models of associations between AEs and efficacy outcomes for<br />
mRCC patients on Schedule 4/2<br />
Efficacy<br />
endpoint<br />
AE at any time point AE by <strong>the</strong> 12-wk landmark<br />
HR (95% CI) P* HR (95% CI) P*<br />
HTN during treatment<br />
PFS 0.291 (0.220–0.399)
787O EXTERNAL VALIDATION OF THE ASSOCIATION OF<br />
PROGRESSION-FREE SURVIVAL AT 6 MONTHS (PFS6) WITH<br />
OVERALL SURVIVAL AT 12 MONTHS (OS12) IN SECOND-LINE<br />
THERAPY FOR ADVANCED UROTHELIAL CARCINOMA (UC)<br />
G. Sonpavde 1 , B. Maughan 2 , K.M. Boucher 3 , R. Fougeray 4 , T.K. Choueiri 5 ,<br />
G. Niegisch 6 ,Y.Wong 7 , S.S. Sridhar 8 , C.N. Sternberg 9 , J. Bellmunt 10<br />
1 Medical Oncology, Texas Oncology, Baylor College of Medicine, Webster, TX,<br />
UNITED STATES OF AMERICA, 2 Medicine, University of Utah, Salt Lake City, UT,<br />
UNITED STATES OF AMERICA, 3 Biostatistics, University of Utah, Salt Lake City,<br />
UT, UNITED STATES OF AMERICA, 4 Statistics, 5Institut de Recherche Pierre<br />
Fabre, Boulogne, FRANCE, 5 Medical Oncology, Dana Farber Cancer Institute,<br />
Boston, MA, UNITED STATES OF AMERICA, 6 Urologic Oncology, 6 Heinrich<br />
Heine University, Dusseldorf, GERMANY, 7 Medical Oncology, Fox Chase Cancer<br />
Center, Philadelphia, PA, UNITED STATES OF AMERICA, 8 Medical Oncology,<br />
Princess Margaret Hospital, Toronto, ON, CANADA, 9 Medical Oncology, San<br />
Camillo Forlanini Hospital, Rome, ITALY, 10 Medical Oncology, University Hospital<br />
del Mar-IMIM, Barcelona, SPAIN<br />
Background: We hypo<strong>the</strong>sized that PFS at 6 months (PFS6) correlates with OS12<br />
and may be a robust intermediate endpoint for phase II trials of second-line <strong>the</strong>rapy<br />
for advanced UC.<br />
Methods: Ten phase II trials of second-line chemo<strong>the</strong>rapy and/or biologics were<br />
pooled. Progression was defined as tumor progression or death from any cause.<br />
Adjustment of PFS6 and OS12 were performed for variability between trials using<br />
random effects models. The relationship between PFS6 and OS12 was assessed at <strong>the</strong><br />
trial level using Pearson correlation and weighted linear regression. The relationship<br />
between PFS6 and OS12 at <strong>the</strong> individual level was assessed using Pearson chi-square<br />
test with Yates continuity correction. Statistical analyses employed “R” statistical<br />
computing software, version 2.8.0. External validation was conducted in a phase III<br />
trial comparing best supportive care (BSC) with vinflunine plus BSC.<br />
Results: Results from <strong>the</strong> pooled phase II dataset (n = 646) have been reported<br />
(ASCO <strong>2012</strong>): <strong>the</strong> Pearson correlation between trial level PFS6 and OS12 was 0.66<br />
(p = 0.037), and individual level agreement was seen in 82% of patients (kappa =<br />
0.45), Pearson correlation between trial level response and OS12 was 0.37 (p = 0.30)<br />
and individual level agreement was seen in 78% (kappa = 0.36). Of <strong>the</strong> 357 patients<br />
in <strong>the</strong> external validation dataset, 17 had PFS censored before 6 months or OS<br />
censored before 12 months, leaving 340 evaluable patients. Of <strong>the</strong> progression events,<br />
231 were objective progression, 104 were deaths and 5 were alive with PFS > 6<br />
months and OS > 12 months. The PFS6 was 13.25% with BSC and 26.48% with<br />
vinflunine plus BSC. The individual level agreement of PFS6 and OS12 was 81%<br />
(κ= 0.44, p < 0.001) and of response and OS12 was 76% (κ= 0.17, p = 0.0002).<br />
Excluding <strong>the</strong> BSC arm showed an individual level agreement between response<br />
and OS12 of 82% (κ= 0.53, p < 0.0001).<br />
Conclusion: PFS6 is robustly associated with OS12 at <strong>the</strong> trial and individual levels<br />
in <strong>the</strong> setting of second-line <strong>the</strong>rapy for advanced UC. Given <strong>the</strong> suboptimal<br />
association of response and OS12 at <strong>the</strong> trial level, PFS6 may be a more optimal<br />
endpoint to capture <strong>the</strong> durable benefits of agents.<br />
Disclosure: R. Fougeray: Employee of Pierre Fabre. T.K. Choueiri: Research support<br />
from Astrazeneca. Y. Wong: Research support from Imclone. S.S. Sridhar: Research<br />
support from Celgene. J. Bellmunt: Research support to institution from Pierre Fabre.<br />
All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
788O NEOADJUVANT (NACT) AND ADJUVANT CHEMOTHERAPY<br />
(ACT) FOR MUSCLE-INVASIVE BLADDER CANCER: A<br />
POPULATION-BASED OUTCOMES STUDY<br />
C.M. Booth 1 , D.R. Siemens 1 ,G.Li 1 ,Y.Peng 1 , I.F. Tannock 2 , D.M. Berman 1 ,<br />
W. Kong 1 , W.J. Mackillop 1<br />
1 Dept of Oncology, Queen’s University Cancer Research Institute, Kingston, ON,<br />
CANADA, 2 Medical Oncology, Princess Margaret Hospital, Toronto, ON,<br />
CANADA<br />
Background: Utilization of NACT and ACT for bladder cancer in <strong>the</strong> general<br />
population and <strong>the</strong> survival benefit associated with <strong>the</strong>rapy is not well described.<br />
Here we report practice patterns and outcomes associated with NACT/ACT in <strong>the</strong><br />
general population of Ontario, Canada.<br />
Methods: Electronic records of treatment were linked to <strong>the</strong> population-based<br />
Ontario Cancer Registry to identify all patients who underwent cystectomy for<br />
bladder cancer in Ontario 1994–2008. Surgical pathology reports were obtained to<br />
identify cases with muscle-invasive disease. Utilization of NACT/ACT was compared<br />
across 3 study periods: 1994–98, 1999–03, 2004–08. Logistic regression was used to<br />
Annals of Oncology<br />
analyze factors associated with use of NACT/ACT. A Cox model and propensity<br />
score analysis was used to explore <strong>the</strong> association between ACT and survival.<br />
Results: In 1994–2008 4876 patients underwent cystectomy. Surgical pathology<br />
reports were identified for 3429 cases; 2738 had muscle-invasive disease. While use<br />
of NACT did not change over <strong>the</strong> 3 study periods (5%, 3%, 6%; p = 0.004), utilization<br />
of ACT increased with time (16%, 19%, 23%; p = 0.001). In adjusted analyses<br />
younger age and less co-morbidity were associated with greater utilization of NACT/<br />
ACT. T3/T4 tumors (OR 2.1, 95%CI 1.6–2.8), node positive disease (OR 7.2, 95%CI<br />
5.5–9.5), and lymphovascular invasion (OR 1.7, 95%CI 1.2–2.3) were associated with<br />
greater utilization of ACT. While <strong>the</strong>re was no substantial variation in utilization of<br />
NACT across geographic regions (range 3% to 5%), use of ACT varied considerably<br />
(range 12% to 31%). Five year overall (OS) and cancer-specific survival (CSS) for all<br />
muscle-invasive cases was 30% (95%CI 28–31%) and 34% (95%CI 32–36%). In Cox<br />
analysis T3/T4 tumors (HR 1.7, 95%CI 1.6-2.0), node positive disease (HR 1.9, 95%<br />
CI 1.7–2.1), and lymphovascular invasion (HR 1.8, 95%CI 1.6–2.1) were associated<br />
with inferior OS. Utilization of ACT was associated with improved OS (HR 0.70,<br />
95%CI 0.6–0.8) and improved CSS (HR 0.70, 95%CI 0.6–0.8). This result was<br />
consistent in <strong>the</strong> Cox model and propensity score analysis.<br />
Conclusions: Despite accumulating evidence and guidelines, NACT/ACT remains<br />
substantially underutilized in routine clinical practice. Our results suggest that ACT<br />
is associated with a substantial survival benefit in <strong>the</strong> general population.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
789O THE TAXIF II PROTOCOL FINAL RESULTS: A PHASE II TRIAL<br />
OF HIGH-DOSE CHEMOTHERAPY SUPPORTED BY<br />
HAEMATOPOIETIC STEM CELL TRANSPLANTATION IN<br />
PATIENTS WITH DISSEMINATED GERM-CELL TUMORS<br />
FAILING CHEMOTHERAPY AND WITH ADVERSE<br />
PROGNOSTIC FACTORS<br />
F. Selle1 , K. Fizazi2 , P. Biron3 , G. Gravis-Mescam4 , B. Bui5 ,J.Bay6 , A. Flechon3 ,<br />
C. Dubot1 ,A.Caty7 , D. Burcoveanu1 , R. Delva8 , T. de Revel9 , J.M. Miclea10 ,<br />
M. Gaulet11 , E. Horn12 , S. Provent1 , I. Temby1 , I. Brindel10 , J. Khalil1 ,<br />
J. Gligorov1 , J.-P. Lotz7 1 2<br />
Medical Oncology, Hôpital Tenon, Paris, FRANCE, Medical Oncology, Institut<br />
Gustave Roussy, Villejuif, FRANCE, 3 Medical Oncology, Centre Léon Bérard,<br />
Lyon, FRANCE, 4 Medical Oncology, Institut Paoli Calmettes, Marseille, FRANCE,<br />
5 6<br />
Medical Oncology, Institute Bergonie, Bordeaux , FRANCE, Medical Oncology,<br />
Centre Hospitalier Universitaire, Clermont-Ferrand, FRANCE, 7 Medical Oncology,<br />
Centre Oscar Lambret, Lille, FRANCE, 8 Medical Oncology Centre Paul Papin,<br />
Angers, FRANCE, 9 Service d’Hématologie, Hôpital d'Instruction des Armées<br />
Percy, Clamart, FRANCE, 10 Unité de Cytaphérèse et Thérapie Cellulaire et<br />
Département de la Recherche Clinique et du Développement, Hôpital St-Louis,<br />
AP-HP, Paris, FRANCE, 11 3ES-Cegedim Strategic Data, Boulogne, FRANCE,<br />
12<br />
Brown University, Alpert Medical School, Providence, RI, UNITED STATES OF<br />
AMERICA<br />
Background: High-dose chemo<strong>the</strong>rapy (HDCT) has been shown to circumvent<br />
resistance in poor-prognosis germ cell tumors (GCT), mainly for patients whose<br />
relapses occur more than 4 weeks after cisplatin-based CT.<br />
Patients and methods: This multicentric phase II trial was addressed to patients<br />
with poor-prognosis non-refractory GCTs. The main objectives were to determine<br />
<strong>the</strong> complete response rate and to monitor treatment-associated toxicities. Patients<br />
with adverse prognostic factors failing CT were to receive 2 cycles combining<br />
Epirubicin and Paclitaxel (EpiTax), followed by 3 consecutive HDCT [one using a<br />
Paclitaxel/Thiotepa association, 2 using <strong>the</strong> 5-day Ifosfamide-Carboplatine-Etoposide<br />
regimen]. Inclusion criteria included seminomatous GCT in relapse after 2 lines of<br />
CT, non-seminomatous GCT in relapse after 1 or 2 lines, partial remission after<br />
1 line, primary mediastinal GCT in first relapse. Peripheral blood stem cells were<br />
collected after <strong>the</strong> EpiTax cycles.<br />
Results: Between 09/2004 and 12/2007, 45 patients were included: 45 received 1<br />
HDCT, 39 two HDCT, 29 patients received <strong>the</strong> complete protocol. Sixteen patients<br />
did not received <strong>the</strong> entire protocol, 8 (53%) for toxic side effects. Two patients<br />
(4.4%) died of toxicities, 17 (37.7%) of disease progression. For a median follow-up<br />
time of 26 months (4–51 m), <strong>the</strong> final overall response rate was 66,7% (CR, 20,6%).<br />
The median PFS was 16 months (95%CI, 9-NA) and <strong>the</strong> median OS was 32 months<br />
(95%CI, 32–49). The 2-year PFS was a plateau set up at 50% (95%CI, 32-67%) and<br />
<strong>the</strong> 2-year OS was 71% (95%CI, 52–83%).<br />
Conclusion: The TAXIF II protocol was highly effective in non-refractory GCT<br />
patients failing CT.<br />
Disclosure: F. Selle: consultancy for roche and Pharmamar. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
ix260 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
790O GEMCITABINE, OXALIPLATIN, AND PACLITAXEL (GOT) ON<br />
A 2-WEEKLY SCHEDULE IN PATIENTS (PTS) WITH<br />
REFRACTORY GERM CELL CARCINOMA: A PHASE II STUDY<br />
CONDUCTED AT THE UNIVERSITY OF SOUTHERN<br />
CALIFORNIA<br />
D.I. Quinn 1 , O. Hamid 2 , D. Tsao-Wei 3 ,J.Hu 1 , J. Pinski 1 , A. Schuckman 4 ,<br />
S. Daneshmand 4 , S. Groshen 5 , D. Raghavan 6 ,C.Korn 7 , K. Massopust 7 ,<br />
C. Ketchens 7 , A.M. Aparicio 8 , T.B. Dorff 1<br />
1 USC Norris Comprehensive Cancer Center, University of Sou<strong>the</strong>rn California,<br />
Keck School of Medicine, Los Angeles, CA, UNITED STATES OF AMERICA,<br />
2 Neuro-oncology Clinic, The Angeles Clinic and Research Institute, Los Angeles,<br />
CA, UNITED STATES OF AMERICA, 3 Biostatistics, USC Norris Comprehensive<br />
Cancer Center, Los Angeles, CA, UNITED STATES OF AMERICA, 4 Institute of<br />
Urology, Keck School of Medicine, Los Angeles, CA, UNITED STATES OF<br />
AMERICA, 5 Biostatistics, USC Norris Comprehensive Cancer Center, Los<br />
Angeles, CA, UNITED STATES OF AMERICA, 6 Carolinas Healthcare, Levine<br />
Cancer Institute, Charlotte, NC, UNITED STATES OF AMERICA, 7 Division of<br />
Medical Oncology, USC Norris Comprehensive Cancer Center, Los Angeles, CA,<br />
UNITED STATES OF AMERICA, 8 Department of Genitourinary Medical Oncology,<br />
MD Anderson Cancer Center, Houston, TX, UNITED STATES OF AMERICA<br />
Background: Modern <strong>the</strong>rapy for GCT has transformed <strong>the</strong> disease but challenges<br />
remain in managing primary poor risk and refractory cancer.<br />
Methods: Phase II study: 30 men with GCT progression ≤4 wks of a standard<br />
regimen (12) or after salvage (14) or stem cell regimen (3). Growing teratoma<br />
syndrome pts excluded. PS < =2, Age > 16, PD by RECIST/marker criteria. Regimen:<br />
Paclitaxel 170mg/m2/3h; Gemcitabine 800mg/m2/80mins; Oxaliplatin 100mg/m2/<br />
90min, increased to 125mg/m2 in cycle 2 if no major toxicity. Mg2+ & Ca2+ infused<br />
before oxaliplatin. G-CSF was not given prophylactically. The regimen was designed<br />
to maximize oxaliplatin density with full dosing of pts with recovering marrow &<br />
dose escalation for pts with limited toxicity in cycle 1. Retreatment criteria: ANC<br />
≥1000 or 700 with monocytosis, platelets >75K. Pts with marker normalization had<br />
3 fur<strong>the</strong>r cycles. Primary endpoint: Response; 2nd: OS, PFS, toxicity Patient<br />
characterisitcs: Med age 32y, Race: white 41%, Hispanic 48%, Asian 10%, KPS ≥ 90%<br />
66%, Primary site: testis 27, mediastinal 2: Histology: Seminoma: 7% Chorio 10%,<br />
YST 7%, Emb 3%, teratocarcinoma 13%, Undifferentiated 5%, mixed NSGCT 55%.<br />
Prior surgery for primary: 20, met resection 13. Med prior chemo<strong>the</strong>rapy lines: 2<br />
(R 1–7). Med (range) pre-GOT LDH: 173 (109-4504), AFP 22 (1–363002), bHCG<br />
2.4 (2–247040) Endpoints: Median cycles 6 (1–14). Best RECIST response: CR2, PR7,<br />
uPR2, SD 11, PD 5; RR 31% (95%CIs 17-50%). 5 pts (4PR, 1SD) who underwent<br />
definitive surgery after trial <strong>the</strong>rapy were rendered NED. Med FU 28 mos (R 3-81).<br />
Med OS: 16.7 mos (95%CIs 11.9–30.7), med PFS 10.8 (95%CIs 3.0−27.5), 2yr OS<br />
prob: 0.42 + /−0.10. Marker responses: 29% normalized. 7pts (24%) remain alive &<br />
NED >= 1 year. No association between ethnicity and RRor OS.Toxicity: 1pt died:<br />
pneumonia, gr 3/4 neutropenia 17pts, febrile neutropenia 7pt, neuropathy gr1/2:<br />
19 pts, gr3 4pts, gr4 1pt, GI toxicity gr2/3 12 pts.<br />
Conclusion: GOT given 2-wkly for refractory GCT produced high rates of marker &<br />
RECIST response & rendered 5 patients resectable. The median OS of 16.7 mos<br />
compares favorably with 6–13.5 mos in o<strong>the</strong>r series (Oechsle K Eur Urol 60: 850,<br />
2011). ClinicalTrials.gov Identifier: NCT00183820<br />
Disclosure: All authors have declared no conflicts of interest.<br />
791PD MULTIVARIATE ANALYSIS OF CYTOKINES AND<br />
ANGIOGENIC FACTORS (CAFS) AND ESTABLISHED<br />
PROGNOSTIC PARAMETERS IN METASTATIC RENAL<br />
CELL CARCINOMA (MRCC) PATIENTS (PTS) RECEIVING<br />
PAZOPANIB OR PLACEBO<br />
A. Zurita-Saavedra 1 ,Y.Liu 2 ,Y.Lin 2 , H.T. Tran 3 , VEG105192 Team and<br />
investigators 4 , L.N. Pandite 5 , J.V. Heymach 6<br />
1 Dept. of Genitourinary Medical Oncology, The University of Texas M.D.<br />
Anderson Cancer Center, Houston, TX, UNITED STATES OF AMERICA,<br />
2 Oncology Research and Development, GlaxoSmithKline, Philadelphia, PA,<br />
UNITED STATES OF AMERICA, 3 Cancer Medicine, UT MD Anderson Cancer<br />
Center, Houston, TX, UNITED STATES OF AMERICA, 4 VEG105192 Team and<br />
investigators, 5 Clinical Lead, GlaxoSmithKline, Research Triangle Park, NC,<br />
UNITED STATES OF AMERICA, 6 Thoracic/head and Neck Medical Oncology,<br />
MD Anderson Cancer Center, Houston, TX, UNITED STATES OF AMERICA<br />
Background: In mRCC, prognosis is still solely determined based on clinical criteria.<br />
Although multiple candidate biomarkers exist, none has yet been incorporated into<br />
practice. We identified CAFs associated with PFS in mRCC pts with ECOG PS £1<br />
treated in a randomized, placebo-controlled, phase III clinical trial of pazopanib<br />
(Sternberg, JCO 2010, Tran, ASCO 2010 #4522). In this study, we evaluated <strong>the</strong><br />
prognostic significance of <strong>the</strong>se CAFs relative to established clinical parameters.<br />
Methods: Seven candidate CAFs (IL-6, IL-8, VEGF, HGF, TIMP1, osteopontin<br />
[OPN], E-Selectin) in plasma obtained pretreatment, and 5 clinical variables<br />
indicative of poor prognosis (time from diagnosis to treatment
patient preference for P over S, and should be considered in light of <strong>the</strong>ir<br />
comparative efficacy.<br />
Disclosure: D. Cella: Dr. Cella has consulted to GSK and has received research grant<br />
support from GSK. K. Kaiser: Dr. Kaiser has received research grant support from<br />
GSK. J. Beaumont: Ms. Beaumont has received research grant support from GSK. J.<br />
Diaz: Dr. Jose Diaz is a GSK employee and stock owner. L. McCann: Dr. McCann is<br />
a GSK employee and stock owner. F. Mehmud: Dr. Mehmud is a GSK employee and<br />
stock owner. S. Lata: Dr. Lata is a GSK employee and stock owner. P. Bono: Dr.<br />
Bono has received honorarium from GSK and Pfizer. C. Porta: Dr. Porta has acted as<br />
consultant or speaker for GSK, Bayer-Schering, Pfizer, Novartis, Roche, Aveo,<br />
Astellas, Boehringer Ingellheim and Recordat and received research funding from<br />
Novartis and Bayer-Schering. B. Escudier: Dr. Escudier has received honorarium<br />
from GSK, Pfizer, Novartis, Bayer, Aveo, and BMS.<br />
793PD AXITINIB VS SORAFENIB FOR ADVANCED RENAL CELL<br />
CARCINOMA: PHASE III OVERALL SURVIVAL RESULTS AND<br />
ANALYSIS OF PROGNOSTIC FACTORS<br />
R.J. Motzer 1 , B. Escudier 2 , P. Tomczak 3 , S. Negrier 4 , M.E. Gore 5 , J. Tarazi 6 ,<br />
S. Hariharan 7 , B. Rosbrook 6 , S. Kim 6 , B.I. Rini 8<br />
1 Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center,<br />
New York, NY, UNITED STATES OF AMERICA, 2 Service d’Immuno<strong>the</strong>rapie,<br />
Institut Gustave Roussy, Villejuif, FRANCE, 3 Uniwersytet Medyczny, Klinika<br />
Onkologii, Poznań, POLAND, 4 Dept. of Oncology, Centre Léon Bérard, Lyon,<br />
FRANCE, 5 Department of Medicine, Royal Marsden Hospital NHS Foundation<br />
Trust, London, UNITED KINGDOM, 6 Pfizer Oncology, Pfizer Oncology, San<br />
Diego, CA, UNITED STATES OF AMERICA, 7 Pfizer Inc, Pfizer Inc, New York, NY,<br />
UNITED STATES OF AMERICA, 8 Cleveland Clinic Taussig Cancer Institute,<br />
Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, UNITED STATES OF<br />
AMERICA<br />
Purpose: In <strong>the</strong> phase III AXIS trial, axitinib prolonged progression-free survival<br />
(PFS) compared with sorafenib as 2 nd -line <strong>the</strong>rapy for metastatic renal cell carcinoma<br />
(mRCC) (Lancet 2011;378:1931). Mature overall survival (OS) data (as of Nov 1,<br />
2011) are reported.<br />
Methods: 723 patients (pts) with clear cell mRCC, progressive disease after 1<br />
systemic <strong>the</strong>rapy, and Eastern Cooperative Oncology Group performance status<br />
(ECOG PS) 0 or 1 were stratified by ECOG PS and prior <strong>the</strong>rapy and randomised<br />
1:1 to axitinib 5 mg twice daily (BID) or sorafenib 400 mg BID. OS was analysed as a<br />
secondary endpoint based on 425 events and compared using a 1-sided log-rank test<br />
stratified by ECOG PS and prior <strong>the</strong>rapy. Pretreatment prognostic factors were<br />
studied by multivariate analyses. Pts were grouped by diastolic blood pressure (dBP)<br />
on <strong>the</strong>rapy (≥1 dBP measurement ≥90 vs dBP
Annals of Oncology<br />
trial (TIVO-1) comparing TIVO with sorafenib (SOR) in patients (pts) with mRCC<br />
showed superior efficacy to SOR and a favorable safety profile with a low incidence<br />
of off-target adverse events (AEs). Here we provide detailed drug-related AE data<br />
from <strong>the</strong> TIVO-1 trial.<br />
Methods: Pts were randomized 1:1 to TIVO 1.5 mg once daily for 3 weeks (wks)<br />
followed by 1 wk rest, or SOR 400 mg twice daily continuously in a 4-wk cycle. AEs<br />
were recorded from <strong>the</strong> time pts signed <strong>the</strong> informed consent until 30 days after last<br />
dose of study drug. Blood pressure (mm Hg) was measured after a 5-minute rest<br />
period and taken on Days 1 and 15 of Cycle 1, on Day 1 of subsequent cycles, at <strong>the</strong><br />
end-of-treatment visit, and at <strong>the</strong> 30-day follow-up visit. Descriptive statistics of<br />
drug-related AEs are presented.<br />
Results: Pts on <strong>the</strong> TIVO arm (175 [67.6%]) had fewer drug-related AEs than pts on<br />
<strong>the</strong> SOR arm (214 [83.3%]). The most common (≥10%) drug-related AEs and<br />
discontinuations are shown in <strong>the</strong> table.<br />
TIVO (n = 259) n (%) SOR (n = 257) n (%)<br />
AE All Grades Grade ≥3 All Grades Grade ≥3<br />
Hypertension 109 (42.1) 61 (23.6) 79 (30.7) 39 (15.2)<br />
Dysphonia 47 (18.1) – 11 (4.3) –<br />
Diarrhea 47 (18.1) 5 (1.9) 71 (27.6) 15 (5.8)<br />
Hand–foot syndrome 34 (13.1) 5 (1.9) 137 (53.3) 43 (16.7)<br />
Fatigue 28 (10.8) 7 (2.7) 28 (10.9) 7 (2.7)<br />
Alopecia 6 (2.3) – 53 (20.6) –<br />
Discontinuations 11 (4.2) – 14 (5.4) –<br />
Hypertension was <strong>the</strong> most frequent TIVO-related AE but was easily managed with<br />
standard antihypertensives. Fewer pts in <strong>the</strong> TIVO arm had ≥Grade 3 drug-related<br />
AEs than in <strong>the</strong> SOR arm (94 [36.3%] and 131 [51.0%], respectively). Pts in <strong>the</strong><br />
TIVO arm required fewer overall dose reductions than did pts in <strong>the</strong> SOR arm (36<br />
[13.9%] vs 114 [44.4%], respectively). Two deaths in <strong>the</strong> TIVO arm were due to<br />
myocardial infarction; cardiac failure was responsible for 2 deaths in each arm.<br />
Conclusion: Pts on <strong>the</strong> TIVO arm experienced more hypertension and dysphonia,<br />
but less diarrhea, hand-foot syndrome, alopecia and discontinuations than pts on <strong>the</strong><br />
SOR arm. Pts on <strong>the</strong> TIVO arm also had fewer overall dose reductions. These data<br />
demonstrate that TIVO is well-tolerated in pts with mRCC.<br />
Disclosure: T.Q.G. Eisen: Consultancy fee/honorarium: AVEO before trial period,<br />
Bayer Support for travel to mtgs for <strong>the</strong> study or o<strong>the</strong>r purposes: AVEO Board<br />
Membership: AVEO, Bayer (ad boards) Grants/pending: Bayer Payment for lectures,<br />
service on speakers bureau: Bayer. C.N. Sternberg: Consultancy: Astellas. B. Esteves:<br />
AVEO Pharmaceuticals employee with stock options. R.J. Motzer: Consultant: Pfizer<br />
Research Funding: AVEO, GSK, Novartis. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
796PD TIVOZANIB PHARMACOKINETIC (PK)/PHARMACODYNAMIC<br />
(PD) ANALYSIS OF BLOOD PRESSURE (BP) AND SOLUBLE<br />
VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 2<br />
(SVEGFR2) IN PATIENTS WITH ADVANCED RENAL CELL<br />
CARCINOMA (RCC)<br />
D. Nosov 1 , R.J. Motzer 2 , J. Loewy 3 , L. Hodge 3 , B. Esteves 4 , A. Berkenblit 4 ,<br />
W. Yin 5 , K. Dykstra 6 , T.E. Hutson 7 , M. Cotreau 5<br />
1 Clinical Pharmacology and Chemo<strong>the</strong>rapy, N.N. Blokhin Russian Cancer<br />
Research Center, Moscow, RUSSIAN FEDERATION, 2 Genitourinary Oncology<br />
Service, Memorial Sloan-Kettering Cancer Center, New York, NY, UNITED<br />
STATES OF AMERICA, 3 Biostatistics, qPharmetra, Andover, MA, UNITED<br />
STATES OF AMERICA, 4 Clinical Research, AVEO Pharmaceuticals, Cambridge,<br />
MA, UNITED STATES OF AMERICA, 5 Oncology, AVEO Pharmaceuticals, Inc,<br />
Cambridge, MA, UNITED STATES OF AMERICA, 6 qPharmetra, Andover, MA,<br />
UNITED STATES OF AMERICA, 7 GU Center of Excellence Texas Oncology,<br />
Charles A. Sammons Cancer Center / Baylor University Medical Center / Texas<br />
AM Health Science Center College of Medicine, Dallas, TX, UNITED STATES OF<br />
AMERICA<br />
Background: Tivozanib is a potent, selective, long half-life tyrosine kinase inhibitor<br />
of VEGF receptors (VEGFRs) 1, 2, and 3, demonstrating activity against advanced<br />
RCC in Phase (Ph) II–III trials. This analysis explored <strong>the</strong> relationship between<br />
tivozanib PK and BP, as hypertension is a mechanism-based adverse event and a<br />
potential surrogate of response. The relationship between exposure and sVEGFR2<br />
also was explored.<br />
Methods: Pharmacokinetic, BP, and sVEGRF2 data from tivozanib-treated RCC<br />
patients (pts) from a Ph II (n = 21) and a Ph III (n = 259) study were pooled; pts<br />
were treated with 1.5 mg tivozanib daily for 21 days followed by a 7-day rest (28-day<br />
treatment cycle) in each study. A population PK model of tivozanib was constructed<br />
from PK data from Ph I–III studies, to obtain individualized predictions of<br />
steady-state values for Cavg. BP was measured at baseline and on Cycle 1 Day 15<br />
(C1D15), C2D1, and C3D1 in <strong>the</strong> Ph II and Ph III studies, and was binned to <strong>the</strong><br />
nearest 5 mm Hg. Analysis focused on BP shifts in 5 mm Hg increments. Serum<br />
samples for sVEGFR2 (Ph III only) were collected at baseline and on C1D15, C2D1,<br />
and C2D22–28. Models of drug exposure as predictors of longitudinal changes in BP<br />
and/or sVEGFR2 were constructed by non-linear mixed-effects modeling.<br />
Results: Across pts, <strong>the</strong>re was a statistically significant median 5 mm Hg increase in<br />
diastolic BP on C1D15, with similar increases noted on C2D1. There was a<br />
curvilinear decrease in sVEGFR2 with time. An Emax model vs time showed a<br />
half-maximal effect occurring in 19.4 (SE = 1.7) days, and a maximal 53% (%CV =<br />
4%) decrease in sVEGFR2. There was a statistically significant effect of Cavg on<br />
Emax, with <strong>the</strong> magnitude of Emax increasing 6% per 10 ng/mL increase in Cavg.<br />
Conclusion: PK/PD analysis of data from tivozanib Ph II–III studies showed that pts<br />
had a median increase in diastolic BP of 5 mm Hg on C1D15 and C2D1. Levels of<br />
serum sVEGFR2 were found to decrease significantly with time, and <strong>the</strong> effect size<br />
increased with tivozanib exposure. Relationships between exposure, BP, and<br />
sVEGFR2 and outcome are being explored.<br />
Disclosure: R.J. Motzer: Only disclosure is research funding from AVEO Oncology. J.<br />
Loewy: Consulting fee or honoraria from qPharmetra LLC. L. Hodge: Consulting or<br />
honoraria from qPharmetra LLC. B. Esteves: AVEO Pharmaceuticals employee with<br />
stock options. A. Berkenblit: AVEO Pharmaceuticals employee with stock options. W.<br />
Yin: AVEO Pharmaceuticals employee with stock options. K. Dykstra: -Consultancy<br />
fee or honorarium: qPharmetra LLC -Fees for participation in review activities such<br />
as data monitoring boards, statistical analysis, end point committees and <strong>the</strong> like:<br />
qPharmetra LLC. T.E. Hutson: - Consultancy or honoraria: AVEO Pharmaceuticals -<br />
Consultancy: Pfizer, Bayer, GSK, Novartis – Grants, grants pending: Pfizer, Bayer,<br />
GSK, Novartis – Payment for lectures includes service on speakers bureau:Pfizer,<br />
Bayer, GSK, Novartis. M. Cotreau: AVEO Pharmaceuticals employee with stock<br />
options. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
797PD FIRST LINE SUNITINIB IN TYPE I AND II PAPILLARY RENAL<br />
CELL CARCINOMA (PRCC): SUPAP- A PHASE II STUDY OF<br />
THE FRENCH GENITO-URINARY GROUP (GETUG) AND THE<br />
GROUP OF EARLY PHASE TRIALS (GEP)<br />
A. Ravaud 1 , S. Oudard 2 , M. De Fromont 3 , C. Chevreau 4 , G. Gravis 5 , S. Zanetta 6 ,<br />
C. Theodore 7 , M. Jimenez 8 , E. Sevin 9 , B. Escudier 10<br />
1 Oncology Unit, C.H.U. Bordeaux Hopital St. André, Bordeaux, FRANCE,<br />
2 Oncology Department, Georges Pompidou Hospital and Rene Descartes<br />
University, Paris, FRANCE, 3 Pathology, Prado-Pathologie, Marseille, FRANCE,<br />
4 Medical Oncology, Institut Claudius Régaud, Toulouse, FRANCE, 5 Department<br />
of Medical Oncology, Institut Paoli Calmettes, Marseille, FRANCE, 6 Oncology<br />
Department, Centre Georges François Leclerc, Dijon, FRANCE, 7 Medical<br />
Oncology, Hôpital Foch, Suresnes, FRANCE, 8 R&D, Unicancer, Paris, FRANCE,<br />
9 Medical Oncology, Centre François Baclesse, Caen, FRANCE, 10 Service<br />
d’Immuno<strong>the</strong>rapie, Institut Gustave Roussy, Villejuif, FRANCE<br />
Background: Sunitinib has been approved in metastatic clear cell carcinoma due to a<br />
prolonged progression-free survival (PFS). Subgroups analysis of previous studies<br />
hypo<strong>the</strong>sized that sunitinib may be active in PRCC. This is <strong>the</strong> first prospective<br />
clinical trial reported with an anti-angiogenic agent in PRCC, which is an unmet<br />
need.<br />
Methods: SUPAP is a single-arm study using a 2-stage design including 21 patients<br />
(pts) to achieve a 20% ORR and if ≥ 2 pts have an OR, 20 additional pts would be<br />
included. Type I and II PRCC were included separately with an identical design.<br />
Main eligibility criteria included type I and II PRCC confirmed by central<br />
pathological review, PS 0-1, measurable disease, 1st line treatment. Sunitinb was<br />
given at 50mg/d, 4/6 weeks. Primary endpoint was ORR, while safety, PFS and<br />
overall survival (OS) were secondary endpoints.<br />
Results: From 10/07 to 02/11, 15 and 46 pts with type I and II were included,<br />
respectively. The median age was 64 year-old. Fifty-three (87%) pts had a<br />
nephrectomy. PS was 0 on 31 (50%) pts and 1 in 30 pts. Fifty-five (90%) pts had ≥ 1<br />
metastatic site. Using <strong>the</strong> MSKCC scoring system: 12 (19%), 33 (54%) and 9 (14%)<br />
pts were in <strong>the</strong> favorable, intermediate or poor risk group and 7 undetermined. With<br />
a median follow-up of 12.2 months [0.2-46.4], 60 and 61 pts were evaluable for<br />
efficacy and toxicity respectively. The median number of cycles was 4 [1-30] and 23<br />
pts (37.7%) required a dose reduction. In type I PRCC, 2/15 (13%) pts had a partial<br />
response (PR), 10 had a stable disease (SD) with 5 (33%) ≥ 12 weeks. In type II<br />
PRCC, 5/45 (11%) pts had a PR, 25 had a SD with 10 (22%) ≥ 12 weeks and 15 a<br />
progression. The median PFS was 6.6 months [CI 95%: 2.8–14.8] in type I and 5.5<br />
months [CI 95%: 3.8–7.1] in type II. The median overall survival was 17.8 [CI 95%:<br />
5.7–26.1] and 12.4 [CI 95%: 8.2–16] months in type I and II respectively. Toxicity<br />
was similar as in pivotal phase III with sunitinib in metastatic RCC. One patient died<br />
from a pulmonary embolism eventually due to sunitinib.<br />
Conclusion: Sunitinib has a modest activity in PRCC whatever type I or II, but still<br />
represents a treatment option in <strong>the</strong> lack of better <strong>the</strong>rapy.<br />
Disclosure: A. Ravaud: myself ADVISORY ROLE Pfizer Novartis Bayer Schering<br />
GSK Astellas Dendreon Compensated HONORARIA Pfizer Novartis Bayer Schering<br />
Roche GSK Astellas Dendreon OTHER Travel financial support Pfizer Novartis<br />
Institution RESEARCH FUNDING Pfizer Novartis. S. Oudard: Myself ADVISORY<br />
ROLE Pfizer Bayer-Schering Roche GSK Novartis Sanofi Aventis Compensated<br />
HONORARIA Pfizer Bayer-Schering Roche GSK Novartis Sanofi Aventis. B.<br />
Escudier: Honoraria from Pfizer, Novartis, GSK, Bayer, Aveo, BMS. All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds399 | ix263
798PD OPEN-LABEL PHASE II TRIAL OF FIRST-LINE EVEROLIMUS<br />
MONOTHERAPY IN PATIENTS WITH ADVANCED PAPILLARY<br />
RENAL CELL CARCINOMA: RAPTOR INTERIM ANALYSIS<br />
B. Escudier 1 , S. Bracarda 2 , J.P. Maroto 3 , C. Szczylik 4 , P. Nathan 5 , S. Negrier 6 ,<br />
K. Slimane 7 , C. May 8 , C. Porta 9 , V. Grünwald 10<br />
1 Oncology, Institut Gustave Roussy, Villejuif, FRANCE, 2 Medical Oncology,<br />
Ospedale San Donato, Arezzo, ITALY, 3 Medical Oncology, Hospital de la Santa<br />
Creu i Sant Pau, Barcelona, SPAIN, 4 Clinical Oncology, Wojskowy Instytut<br />
Medyczny, Warsaw, POLAND, 5 Cancer Services, Mount Vernon Cancer Centre,<br />
Northwood, UNITED KINGDOM, 6 Oncology, Centre Leon Berard, Lyon,<br />
FRANCE, 7 Oncology, Novartis Pharmaceuticals, Rueil-Malmaison, FRANCE,<br />
8 Oncology, Novartis Pharma GmbH, Nuremberg, GERMANY, 9 Medical<br />
Oncology, IRCCS San Matteo University Hospital Foundation, Pavia, ITALY,<br />
10 Clinic for Hematology, Hemostasis, Oncology, and Stem Cell Transplantation,<br />
Hannover Medical School, Hannover, GERMANY<br />
Background: Treatment options for patients with papillary renal cell carcinoma<br />
(RCC) are limited. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor,<br />
has demonstrated efficacy in clear cell metastatic RCC; mTOR signaling is also<br />
dysregulated in papillary RCC. The ongoing RAPTOR (RAD001 in Advanced<br />
Papillary Tumor Program in Europe; ClinicalTrials.gov, NCT00688753) trial is<br />
evaluating everolimus mono<strong>the</strong>rapy in treatment-naive patients with advanced<br />
papillary RCC. Here, we present <strong>the</strong> results of a preliminary analysis.<br />
Patients and methods: RAPTOR is an open-label, single-arm, multicentre phase II<br />
trial. Adult patients with advanced type I or type II papillary RCC and ECOG<br />
performance status of 0 or 1 were enrolled. Prior systemic <strong>the</strong>rapy for RCC was not<br />
permitted. Patients received oral everolimus 10 mg once daily until disease<br />
progression or unacceptable toxicity. The primary end point is proportion of patients<br />
progression free at 6 months.<br />
Results: At data cut-off (April 11, <strong>2012</strong>), 71 of 92 (77%) enrolled patients were<br />
eligible for analysis according to central pathology review (confirmed papillary renal<br />
cancer); 16 of <strong>the</strong> 92 patients were still on treatment. Most patients were men (73%)<br />
and most were
Annals of Oncology<br />
801P COMPARISON BETWEEN STANDARD AND REDUCED<br />
VOLUME RADIOTHERAPY IN BLADDER PRESERVATION<br />
TRIMODALITY PROTOCOL FOR MUSCLE INVASIVE BLADDER<br />
CANCER PATIENT<br />
W. Arafat, A. Darwish, G. El Hussiny<br />
Clinical Oncology, University of Alexandria, Alexandria, EGYPT<br />
Invasive bladder cancer is <strong>the</strong> most common tumor in Egypt. Preservation protocol<br />
consists of transurethral resection followed by concomitant chemo/ radio<strong>the</strong>rapy. The<br />
induction part of Radio<strong>the</strong>rapy is usually delivered to <strong>the</strong> whole pelvis, The role of<br />
omitting pelvic nodal irradiation has not been addressed before.<br />
Aim: To compare <strong>the</strong> toxicity, pelvic nodal relapse and overall survival of whole<br />
bladder irradiation only to standard technique of whole pelvis irradiation followed by<br />
bladder boost in patients with muscle invasive bladder carcinoma undergoing<br />
bladder preservation protocol.<br />
Material and method: A total of 63 patients with transitional cell carcinoma, stage<br />
T2-3,N0,M0 bladder cancer were subjected to maximal TURB. Then, patients<br />
randomized into two groups: group I (32 patients) to receive whole pelvis<br />
radio<strong>the</strong>rapy 44Gy followed by 20 Gy bladder boost. While Group II (31 patients)<br />
were randomized to receive whole bladder radio<strong>the</strong>rapy alone for a total dose of 64<br />
Gy. In both groups, concomittant cisplatin and paclitaxel were given weekly<br />
throughout <strong>the</strong> whole course of radio<strong>the</strong>rapy where conventional 2 Gy/ fraction were<br />
used. additionally, 4 cycles of Adjuvant cisplatin and paclitaxel were given after <strong>the</strong><br />
end of chemo radio<strong>the</strong>rapy induction course.<br />
Results: Three patients, two in group I and one in group II discontinued due to<br />
grade 3 toxicity. After a median follow up of 2 years, regional relapse occurred in<br />
7.1% of patients in group I and 10.3% in group II. (p = 1). Distant metastases were<br />
detected in 17.9% of patient in group 1 and 13.8% in group II.(p = 0.73). The 2-year<br />
disease free survival was 60% in group I and 63.3% in group II (p = 0.79). The whole<br />
2-years overall survival was 75% in group I and 79.3% in group II (p = 0.689).<br />
Radiation gastrointestinal (GI) Acute toxicity was higher in group I than in group II<br />
(p = 0.001), while late GI radiation toxicity was comparable in both groups.<br />
Conclusion: treating <strong>the</strong> bladder only without elective pelvic nodal irradiation, did not<br />
compromise pelvic control rate, but significantly decreased <strong>the</strong> acute radiation toxicity.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
802P EFFICACY AND PROGNOSTIC FACTORS OF NEOADJUVANT<br />
CHEMOTHERAPY IN RESECTABLE LOCALLY-ADVANCED<br />
MUSCLE-INVASIVE BLADDER CANCER (MIBC) PATIENTS (P)<br />
IN AN OFF-PROTOCOL CLINICAL SETTING<br />
J.L. Cuadra Urteaga 1 , M. Domenech 2 , P. Celiz 1 , J.J. Sánchez 3 , N. Pardo 1 ,<br />
C. Buges 1 , J. Malet 4 , M. Arzoz 5 , J. Areal 5 , A. Font 1<br />
1 Medical Oncology, Catalan Institute of Oncology ICO Badalona Hospital<br />
Germans Trias i Pujol, Medical Oncology, Badalona, SPAIN, 2 Oncology, ALthaia,<br />
Xarxa Assistencial de Manresa, Manresa, SPAIN, 3 Statistics, Autonomous<br />
University of Madrid, Madrid, SPAIN, 4 Urology, ALthaia, Xarxa Assistencial de<br />
Manresa, Manresa, SPAIN, 5 Urology, Hospital Germans Trias i Pujol, Badalona,<br />
SPAIN<br />
Introduction: Although neoadjuvant chemo<strong>the</strong>rapy is a recommended treatment in<br />
MIBC, it has not gained widespread acceptance in clinical practice, due to <strong>the</strong> lack of<br />
predictive markers of efficacy and <strong>the</strong> absence of a standard chemo<strong>the</strong>rapy regimen.<br />
Fur<strong>the</strong>rmore, since few studies have assessed <strong>the</strong> role of neoadjuvant chemo<strong>the</strong>rapy<br />
in an off-protocol setting, <strong>the</strong>re may be doubts about its feasibility.<br />
Material and methods: We retrospectively analyzed 124 p with MIBC treated with<br />
neoadjuvant cisplatin-based chemo<strong>the</strong>rapy at two centers from 1991 to 2010. Clinical<br />
and pathological variables were correlated with survival. All patients were classified<br />
as stage cT2-4N0M0 based on TUR (trans-urethral resection) and CT scan findings<br />
and were candidates for neoadjuvant chemo<strong>the</strong>rapy followed by cystectomy.<br />
Results: 10 p (8%) were cT2N0, 83 p (66%) cT3N0, and 31 p (26%) cT4aN0. 60 p<br />
(48%) were treated with CMV (cisplatin, methotrexate and vinblastine) and 64 p<br />
(52%) with cisplatin/gemcitabine (CG). One patient died from treatment-related<br />
toxicity. A complete resection was performed in 109 p (87%). A significant<br />
pathological response (pR) (pT0-1) was obtained in 60 p (48%). Median survival<br />
(MS) and 5-year (5y) survival were 59 months (m) and 50%, respectively. Median<br />
cancer-specific survival (CSS) was not reached and 5y CSS was 64%. 5y overall<br />
survival was similar (50.3% vs 50.9%) in p treated with CMV or CG. In p with a<br />
significant pR, 5y survival was 77%, while for p who did not respond to<br />
chemo<strong>the</strong>rapy (pT3-4NO or N+), it was 8.3%. Only complete resection (HR:3.36,<br />
P = 0.006) and lymphovascular invasion (LVI) (HR:17.29, P < 0.0001) were significant<br />
in <strong>the</strong> multivariate analysis.<br />
Conclusions: Neoadjuvant chemo<strong>the</strong>rapy followed by cystectomy is feasible in p<br />
with locally-advanced MIBC. Both CMV and CG are active regimens, with 5-y<br />
survival that compares favorably with surgery alone. p responding to neoadjuvant<br />
chemo<strong>the</strong>rapy have an excellent prognosis, while those who do not respond should<br />
be considered for non-cross-resistant adjuvant chemo<strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
803P SELECTIVE BLADDER PRESERVATION BY TRI-MODALITY<br />
THERAPY FOR MUSCLE INVASIVE BLADDER CARCINOMA<br />
A. Darwish 1 , G. Elhussiny 1 ,W.Arafat 2<br />
1 Clinical Oncology, University of Alexandria, Alexandria, EGYPT, 2 Clinical<br />
Oncology, Alexandria International Hospital, Alexandria, EGYPT<br />
Purpose: To access safety, tolerance, local control and survival of transurethral<br />
resection of Bladder tumor (TURB) followed by concomitant cisplatin, paclitaxel and<br />
radiation <strong>the</strong>rapy as selective organ preservation in patients with Muscle Invasive<br />
bladder. Addionally, Surviving and ERCC1 gene expression analysis and response to<br />
treatmentis also studied.<br />
Methods and materials: A total of 63 patients with transional cell carcinoma (TCC),<br />
stage T2–T3, No, Mo bladder carcinoma were enrolled in a protocol of TURP<br />
followed by one daily radio<strong>the</strong>rapy (2Gy/ fraction for a total dose of 44 GY) with<br />
concomitant cis-platin 15mg/m2/ day,d1-3 weekly and paclitaxel 50mg/m2/day,<br />
weekly.Four weeks later, all patients were evaluated by cytoscopy and biopsy. Patients<br />
with complete response proceeded to consolidation Radio<strong>the</strong>rapy (2Gy/fr for a total<br />
20GY with concomitant cisplatin and paclitaxel, while those with recurrent tumor<br />
went on to salavage. Cystectomy. Following consolidation or salvage surgery,<br />
all patients went to complete 4 cycles of cisplatin75mg/m2/ day and paclitaxel<br />
175 mg/day every 21 days. RNA extraction from Biopsy before and after treatment<br />
was analysed for survivin and ERCC1 gene expression using real time PCR.<br />
Results: Three patients could not tolerate <strong>the</strong> treatment and discontinued <strong>the</strong><br />
protocol during <strong>the</strong> induction phase while <strong>the</strong> remaining sixty patients complete <strong>the</strong><br />
induction phase. The complete response after <strong>the</strong> induction phase was 75%. Eleven<br />
percent of <strong>the</strong> complete responders developed superficial relapse with a median time<br />
of relapse of 16 months, while 8.9% developed invasive relapse with a median time of<br />
18 months. 2-year disease for survival was 61.7%. Distant metastases we detected in<br />
15.8% <strong>the</strong> patients. 2year overall survival was 77.2%. RNA was succifully extracted<br />
from 65% of patient, real time PCR for ERCC1 and survivin was done, interpretation<br />
of data will be presented.<br />
Conclusion: Maximal transurethral resection followed by concomitant cis-platin and<br />
paclitaxel, as a bladder preservation <strong>the</strong>rapy, can be considered a valid alternative for<br />
treating selected patients with localized muscle invasive TCC of <strong>the</strong> bladder. ERCC1<br />
and survivn might be a predictive model of treatment response.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
804P PROGNOSTIC STRATIFICATION OF ADVANCED UROTHELIAL<br />
CARCINOMA (UC) RECEIVING SECOND-LINE SYSTEMIC<br />
THERAPY INCLUDING TIME FROM PRIOR CHEMOTHERAPY<br />
(TFPC) AS A PROGNOSTIC FACTOR<br />
G. Sonpavde 1 , G.R. Pond 2 , T.K. Choueiri 3 , R. Fougeray 4 , G. Niegisch 5 ,<br />
Y. Wong 6 , S.S. Sridhar 7 , W.M. Stadler 8 , C.N. Sternberg 9 , J. Bellmunt 10<br />
1 Medical Oncology, Texas Oncology, Baylor College of Medicine, Webster, TX,<br />
UNITED STATES OF AMERICA, 2 Biostatistics, Ontario Clinical Oncology Group<br />
and McMaster University, Hamilton, CANADA, 3 Medical Oncology, Dana Farber<br />
Cancer Institute, Boston, MA, UNITED STATES OF AMERICA, 4 Statistics, Institut<br />
de Recherche Pierre Fabre, Boulogne, FRANCE, 5 Urologic Oncology, Heinrich<br />
Heine University, Dusseldorf, GERMANY, 6 Medical Oncology, Fox Chase Cancer<br />
Center, Philadelphia, PA, UNITED STATES OF AMERICA, 7 Medical Oncology,<br />
Princess Margaret Hospital, Toronto, ON, CANADA, 8 Medical Oncology,<br />
University of Chicago, Chicago, IL, UNITED STATES OF AMERICA, 9 Medical<br />
Oncology, San Camillo Forlanini Hospital, Rome, ITALY, 10 Medical Oncology,<br />
University Hospital del Mar, Barcelona, SPAIN<br />
Background: Prognostic factors for overall survival (OS) in patients receiving<br />
second-line chemo<strong>the</strong>rapy for advanced platinum-pretreated uro<strong>the</strong>lial carcinoma<br />
(UC) include ECOG performance status (PS) >0, hemoglobin (Hb)
Hb, PS and LM. Median PFS for patients with 0, 1, 2 and 3-4 factors (PS > 0, Hb <<br />
10g/dL, LM, TFPC 0, Hb
Annals of Oncology<br />
808P SELECTING PATIENTS FOR HIGH-DOSE INTERLEUKIN-2 ON<br />
THE BASIS OF TUMOUR HISTOLOGY<br />
R. Hawkins 1 , V. Galvis 1 , A. Shablak 1 , A. Spencer-Shaw 1 , F. Thistlethwaite 1 ,<br />
J. Shanks 2 , N. Dalal 2<br />
1 Medical Oncology, The Christie NHS Foundation Trust, Manchester, UNITED<br />
KINGDOM, 2 Pathology, The Christie NHS Foundation Trust, Manchester,<br />
UNITED KINGDOM<br />
Background: High-Dose Interleukin-2 (HD IL2) remains an option for treatment of<br />
metastatic renal cancer. In carefully selected patients, it can produce high rates of<br />
response with many durable remissions (Shablak A et al., J Immuno<strong>the</strong>rapy 2011,<br />
34(1):107–122). There remain uncertainties about <strong>the</strong> optimal way to select patients<br />
for treatment and here we update our approach to selecting patients for HD IL2 and<br />
include <strong>the</strong> analysis of carbonic anhydrase IX(CAIX) expression which has been<br />
previously suggested to correlate with response.<br />
Methods: We present <strong>the</strong> outcomes of 103 patients with “favourable histology” (less<br />
than 10% papillary features and at least one of: >50% alveolar/solid (A/S) or >50%<br />
clear cell features) treated with first-line immuno<strong>the</strong>rapy (including 19 who have<br />
failed prior targeted <strong>the</strong>rapy) with HD-IL2. We examine <strong>the</strong> response rate in relation<br />
to histology and CAIX expression.<br />
Results: Overall <strong>the</strong> response rate was 59/103 (57%) and <strong>the</strong> CR rate is 23/103<br />
(22% - with 4 patients in PR and continuing treatment at <strong>the</strong> time of writing).<br />
Examination of <strong>the</strong> different features in relation to response suggested that <strong>the</strong> most<br />
important features were ≥ 50% A/S pattern as only 1/5 patients who had < 50% A/S<br />
responded and that was not a CR. CAIX staining was only available for 47 patients<br />
but may provide fur<strong>the</strong>r modest benefit in selecting patients for <strong>the</strong>rapy. Certainly,<br />
no patient with < 80% CAIX staining achieved a CR although 3/10 did respond.<br />
In <strong>the</strong> group with >50% A/S pattern and >80% CAIX staining <strong>the</strong> response rate was<br />
22/37 (59%) and <strong>the</strong> CR rate was 9/37(24% with 4 patients in PR and continuing<br />
treatment at <strong>the</strong> time of writing).<br />
Conclusions: These results extend and confirm our previously reported series (of 57<br />
patients) and <strong>the</strong> overall response rate remains around 50% and that, combined with<br />
many durable complete remissions, results in an overall median survival 55 months<br />
(for all 103 patients) with an apparent plateau of 40% long term survivors. HD-IL2<br />
remains an attractive option for carefully selected patients with metastatic clear cell<br />
renal cancer. The most tangible benefit of HD-IL2 is <strong>the</strong> ability to achieve durable<br />
complete remissions and our series suggests <strong>the</strong> optimal histological type in which to<br />
achieve this is patients whose tumour has < 10% papillary features, ≥50% A/S pattern<br />
and expresses ≥80% CAIX.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
809P BEVACIZUMAB (BEV) + LOW-DOSE INTERFERON-a2A (IFN)<br />
FOR FIRST-LINE TREATMENT OF METASTATIC RENAL CELL<br />
CARCINOMA (MRCC): FINAL SAFETY AND EFFICACY DATA<br />
FROM THE PROSPECTIVE BEVLIN STUDY<br />
B. Melichar 1 , S. Bracarda 2 , V. Matveev 3 , A. Kaprin 4 , B. Alekseev 5 ,<br />
R. Janciauskiene 6 , B. Lutiger 7 , M.E. Gore 8 , G. Mickisch 9 , J. Bellmunt 10<br />
1 Oncology, University Hospital Olomouc Palacky University, Faculty of Medicine,<br />
Olomouc, CZECH REPUBLIC, 2 Department of Oncology, Ospedale San Donato<br />
and U.O.C. of Medical Oncology, Arezzo, ITALY, 3 Department of Urology, N.N.<br />
Blokhin Cancer Research Center, Moscow, RUSSIAN FEDERATION,<br />
4 Department of Oncology, Russian Research Centre of Roentgenology and<br />
Radiology, Moscow, RUSSIAN FEDERATION, 5 Department of Oncology,<br />
Research Oncology Institute, Moscow, RUSSIAN FEDERATION, 6 Clinic of<br />
Oncology, Kaunas University of Medicine, Kaunas, LITHUANIA, 7 GPS-MO,<br />
F. Hoffmann-La Roche AG, Basel, SWITZERLAND, 8 Department of Medicine,<br />
Royal Marsden Hospital NHS Foundation Trust, London, UNITED KINGDOM,<br />
9 Department of Urology, Center of Operative Urology Bremen, Bremen,<br />
GERMANY, 10 Department of Medical Oncology, University Hospital del Mar,<br />
Barcelona, SPAIN<br />
Background: In <strong>the</strong> AVOREN trial, first-line BEV + IFN (9 MIU three times in a<br />
week [tiw]) was effective in patients (pts) with mRCC. A retrospective analysis found<br />
that efficacy was maintained and IFN-related toxicity was improved in pts with IFN<br />
dose reduced to 6 or 3 MIU. BEVLiN (MO21609) prospectively assesses <strong>the</strong> safety<br />
and efficacy of BEV with low-dose IFN (3 MIU) in mRCC.<br />
Methods: BEVLiN is an open-label single arm, multinational phase 2 study.<br />
Nephrectomized, treatment-naive pts with clear cell mRCC and favourable/<br />
intermediate Motzer scores were treated with BEV 10mg/kg q2w + IFN 3 MIU tiw<br />
until disease progression. BEVLiN was designed to allow descriptive, cross-trial<br />
comparison with <strong>the</strong> BEV + IFN 9 MIU-treated favourable/intermediate Motzer score<br />
AVOREN subgroup. Primary end points are safety (specific grade [Gr] ≥3<br />
IFN-associated adverse events [AEs]) and progression-free survival (PFS). Secondary<br />
end points are overall survival (OS); overall response rate (ORR); any Gr ≥3, overall,<br />
and serious AEs.<br />
Results: 147 pts were enrolled in BEVLiN. Baseline pt characteristics were similar to<br />
<strong>the</strong> comparator AVOREN subgroup. The median follow-up was 29.4 months. Pts<br />
received a median of 22.5 cycles of BEV (18.0 in <strong>the</strong> AVOREN subgroup). Median<br />
PFS was 15.3 mos (95% CI: 11.7; 18.0) vs 10.5 mos (95% CI: 10.1; 12.9); median OS<br />
was 30.7 mos (95% CI: 25.7; not reached) vs 25.8 mos (95% CI: 22.7; 29.4); and ORR<br />
was 29% vs 36% in BEVLiN and <strong>the</strong> AVOREN subgroup, respectively. The rates of<br />
any-Gr and Gr ≥3 IFN-associated AEs were markedly lower in BEVLiN than in <strong>the</strong><br />
AVOREN subgroup (Table). Overall rates of AEs of special interest were similar<br />
between studies, despite longer BEV duration in BEVLiN.<br />
AE, % (95% CI) BEVLiN n = 146 a AVOREN subgroup n = 283 a<br />
Any Gr Gr ≥3 Any Gr Gr ≥3<br />
Any IFN-related AE 53 (45–62) 10 (6–16) 89 (85–92) 27 (22–32)<br />
· As<strong>the</strong>nia/fatigue 37 (29–45) 10 (5–16) 63 (57–68) 21 (16–26)<br />
· Pyrexia 19 (13–27) 0 (0–2) 45 (39-51) 2 (1–4)<br />
· Nausea 9 (5–15) 1 (0–4) 29 (23–34) 1 (0–3)<br />
· Anorexia 0 (0–2) 0 (0–2) 36 (30–42) 3 (1–5)<br />
Any BEV-related AE of<br />
special interest b<br />
59 (50–67) 23 (17–31) 60 (54–66) 23 (18–28)<br />
a Treated pts. b Includes hypertension, proteinuria, bleeding, and o<strong>the</strong>r AEs.<br />
Conclusions: Use of low-dose IFN with BEV in BEVLiN resulted in a reduction in<br />
IFN-related AEs without compromising efficacy outcomes compared with a control<br />
AVOREN subgroup.<br />
Disclosure: B. Melichar: Dr. Bohuslav Melichar has received honoraria for lectures<br />
from Roche and participated in an advisory board meeting. S. Bracarda: Dr. Sergio<br />
Bracarda is an Advisory Board Member for Novartis, Pfizer, GSK, Bayer, Aveo/<br />
Astellas, Jannsen &Jannsen and Sanofi-Aventis. He has received honoraria for<br />
lectures from Novartis, Sanofi-Aventis and Pfizer. R. Janciauskiene: Dr. Janciauskiene<br />
has been principal investigator in a Hoffmann-La Roche sponsored trial and has<br />
been an invited speaker for Hoffmann-La Roche. B. Lutiger: Beatrix Lutiger is an<br />
employee of F. Hoffmann-La Roche AG. M.E. Gore: Dr. Martin Gore has<br />
participated advisory board meetings and is on <strong>the</strong> speaker’s bureau for Roche. G.<br />
Mickisch: Dr. Gerald Mickisch is a member of <strong>the</strong> BEVLiN Steering Committee. J.<br />
Bellmunt: Dr. Joaquim Bellmunt has participated in an advisory board meeting, and<br />
received a lectures fee from Roche. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
810P TOLERABILITY OF TARGETED AGENTS IN FIRST-LINE<br />
TREATMENT OF METASTATIC RENAL CELL CARCINOMA<br />
(MRCC)<br />
Y. Su 1 , N. Shi 2 , P. Landsman-Blumberg 3 , C. Poehlein 4 , I. Waxman 5<br />
1 Global Health Economics & Outcomes Research, Bristol-Myers Squibb,<br />
Princeton, NJ, UNITED STATES OF AMERICA, 2 Pharma/Biotech, Thomson<br />
Reuters Healthcare, Cambridge, MA, UNITED STATES OF AMERICA,<br />
3 Outcomes Research, Thomson Reuters, Washington DC, UNITED STATES OF<br />
AMERICA, 4 HQ Global Medical Affairs, Immuno-Oncology, Bristol-Myers Squibb,<br />
Princeton, NJ, UNITED STATES OF AMERICA, 5 Oncology, Bristol-Myers Squibb,<br />
Princeton, NJ, UNITED STATES OF AMERICA<br />
Objectives: Between 2005 and 2009, six targeted agents were approved for <strong>the</strong><br />
treatment of mRCC in <strong>the</strong> US. Clinical trials have reported median progression-free<br />
survival (PFS) of up to 11 months for treatment-naive patients. None has<br />
demonstrated an improvement in median overall survival versus ano<strong>the</strong>r targeted<br />
agent. This study aims to determine <strong>the</strong> tolerability of <strong>the</strong>se agents in real-world<br />
practices.<br />
Methods: Adult patients with mRCC diagnosed between Jan 1, 2006 and Dec 31,<br />
2010 were identified from a large commercial insurance claims and Medicare<br />
supplemental database in <strong>the</strong> US. A minimum follow-up of 3 months and ≥1<br />
pharmacy or medical claims on or after metastasis diagnosis date were required for<br />
one of <strong>the</strong> targeted agents: sunitinib (SUN), sorafenib (SOR), pazopanib (PAZ),<br />
everolimus (EVE), temsirolimus (TEM), or bevacizumab with or without interferon<br />
alpha (BEV). Tolerability was measured by rate of dose reduction and duration of<br />
treatment. Median duration of treatment was assessed using <strong>the</strong> Kaplan-Meier<br />
method. Adverse events (AE) were based on diagnosis or treatment indicative of AEs<br />
commonly associated with <strong>the</strong>se agents.<br />
Results: 1,622 patients were identified, of which 1,079 received first-line SUN, 284<br />
SOR, 168 TEM, 40 PAZ, 26 EVE, and 25 BEV. With a median follow up of 13<br />
months, median duration of treatment was <strong>the</strong> longest for PAZ (6.9 mos), followed<br />
by SOR and EVE (both 4.9 mos), SUN (4.8 mos), TEM (3.5 mos) and BEV (1.0<br />
mo). Dose reduction was observed in a higher percentage of patients receiving SUN<br />
(26%) compared to TEM (18.5%), BEV (12.5%), EVE (7.7%), PAZ (7.5%), and SOR<br />
(6%). Claims of AEs were 93%, 86%, 86%, 85%, 80%, and 56% for TEM, SUN, SOR,<br />
EVE, PAZ, and BEV, respectively.<br />
Conclusions: Rates of AEs appear to be high among commonly used first-line<br />
agents, including <strong>the</strong> recently approved PAZ and EVE, and <strong>the</strong>re was substantial<br />
need for dose reduction for <strong>the</strong> most prescribed SUN. Duration of treatment<br />
appeared to be substantially shorter than published PFS values, assuming treatment<br />
until progression for <strong>the</strong> majority of patients. It is important to determine if AEs<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds399 | ix267
may have led to reduced dose and shortened duration of treatment and how costs of<br />
care and patient outcomes might be affected.<br />
Disclosure: Y. Su: Employment and Leadership Role: Bristol-Myers Squibb<br />
(employment, myself, compensated). Stock Ownership: Bristol-Myers Squibb<br />
(myself). P. Landsman-Blumberg: Stock Ownership: Merck & Co., Inc. (myself).<br />
C. Poehlein: Employment and Leadership Role: Bristol-Myers Squibb (employment,<br />
myself, compensated). Stock Ownership: Bristol-Myers Squibb (myself). I. Waxman:<br />
Employment and Leadership Role: Bristol-Myers Squibb (employment, myself,<br />
compensated). Stock Ownership: Bristol-Myers Squibb (myself). All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
811P CLINIC AND HOME BLOOD PRESSURE MEASUREMENTS<br />
ARE RELIABLE FOR GUIDING THERAPY IN PATIENTS WITH<br />
METASTATIC RENAL CELL CARCINOMA RECEIVING<br />
AXITINIB AS FIRST-LINE THERAPY<br />
V. Grünwald 1 , M.N. Fishman 2 , M. Carducci 3 , A. Bair 4 , Y. Chen 4 , S. Kim 4 ,<br />
B.I. Rini 5<br />
1 Clinic for Hematology, Hemostasis, Oncology, Hannover Medical School,<br />
Hannover, GERMANY, 2 Genitourinary Program, H. Lee Moffitt Cancer<br />
CenterUniversity of South Florida, Tampa, FL, UNITED STATES OF AMERICA,<br />
3 Kimmel Cancer Center, Kimmel Cancer Center, Baltimore, MD, UNITED<br />
STATES OF AMERICA, 4 Pfizer Oncology, Pfizer Oncology, San Diego, CA,<br />
UNITED STATES OF AMERICA, 5 Cleveland Clinic Taussig Cancer Institute,<br />
Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, UNITED STATES OF<br />
AMERICA<br />
Background: Axitinib, a potent and selective inhibitor of vascular endo<strong>the</strong>lial growth<br />
factor receptors 1, 2, and 3, is approved in <strong>the</strong> US in patients (pts) with metastatic renal<br />
cell carcinoma (mRCC) who failed 1 prior systemic <strong>the</strong>rapy. Blood pressure (BP)<br />
increases are commonly observed with axitinib. BP measurements are subject to error and<br />
can vary by method employed, eg, home measurements by pts, ambulatory monitoring,<br />
and in-clinic assessments. As part of a phase II study evaluating safety and efficacy of<br />
axitinib for treatment-naïve mRCC, we prospectively characterised and compared BP<br />
measurements from clinic, home, and 24-hr ambulatory BP monitoring (ABPM).<br />
Methods: Clinic BP was obtained at baseline, Days 1 and 15 of <strong>the</strong> first 2 treatment<br />
cycles, and Day 1 of subsequent 28-day cycles. Home BP was obtained by pts twice<br />
daily during <strong>the</strong> treatment period. In a subset of pts, 24-hr ABPM was performed at<br />
baseline and Days 4 and 15.<br />
Results: 213 pts enrolled. Mean age was 61 years; 67% were men. Pooled median<br />
progression-free survival was 14.5 months. No pts had uncontrolled hypertension<br />
(HTN) at study entry. All-grade HTN occurred in 63% and grade 3 in 29%, with no<br />
grade 4 HTN. By 24-hr ABPM, median increases from baseline in systolic BP/<br />
diastolic BP (sBP/dBP) were 10/8 mmHg by Day 4, with modest incremental<br />
increases by Day 15 and stabilisation <strong>the</strong>reafter; changes in BP were generally<br />
consistent at all clock times of day. dBP outcomes were highly consistent between<br />
clinic and home measurements (mean 83 ± 9 vs 83 ± 9 mmHg on Cycle 1 Day 15,<br />
n = 200; 84 ± 11 vs 84 ± 10 mmHg on Cycle 3 Day 1, n = 171). Similarly, dBP<br />
measurements were consistent between clinic and 24-hr ABPM (mean 84 ± 10 vs 84<br />
± 9 mmHg on Cycle 1 Day 15, n = 63). Consistent sBP outcomes were also observed<br />
across various time points and measurement modalities.<br />
Conclusions: BP increased early with axitinib and was generally well-managed. 24-hr<br />
ABPM suggests <strong>the</strong>re is no best time of day to measure BP; ra<strong>the</strong>r, measuring at a<br />
consistent time of day in individual pts would provide <strong>the</strong> most useful data. Results<br />
from clinic and home monitoring appear consistent and both could be reliable in<br />
measuring BP and guiding axitinib <strong>the</strong>rapy.<br />
Disclosure: V. Grünwald: Advisory and honoraria: GSK, Pfizer, Roche, Novartis,<br />
Bayer. Research grant: Pfizer. M.N. Fishman: Dr Fishman has received research<br />
funding, participated in compensated advisory board and promotional presentations<br />
from <strong>the</strong> manufacturer of <strong>the</strong> study drug. M. Carducci: Pfizer DSMB for unrelated<br />
product (compensated). JHU received research funding for conduct of <strong>the</strong> trial. A.<br />
Bair: Employee of and own stock in Pfizer. Y. Chen: Employee of and own stock in<br />
Pfizer. S. Kim: Employee of and own stock in Pfizer. B.I. Rini: Consulting and<br />
research funding from Pfizer.<br />
812P ROLE OF GENETIC VARIANTS IN THE PI3K/AKT/MTOR<br />
PATHWAY IN RENAL CELL CARCINOMA PATIENTS TREATED<br />
WITH EVEROLIMUS- A PILOT STUDY<br />
L. Bodnar 1 , R. Stec 1 , M. Cichowicz 2 , S. Cierniak 3 , M. Smoter 4 ,W.Kozłowski 2 ,<br />
C. Szczylik 1<br />
1 Department of Oncology, Military Institute of Medicine, Warsaw, POLAND,<br />
2 Department of Pathology, Military Institute of Medicine, Warsaw, POLAND,<br />
3 Pathology, Military Institute of Medicine, Warsaw, POLAND, 4 Oncology, Military<br />
Institute of Medicine, Warsaw, POLAND<br />
Background: The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway is<br />
involved in growth regulation, proliferation control and metabolism in renal cell<br />
Annals of Oncology<br />
carcinoma (RCC). In our prospective pilot study, we determined whe<strong>the</strong>r common<br />
genetic variations in <strong>the</strong> AKT/ PI3K, FRAP1 (encoding mTOR) are associated with<br />
clinical outcomes in RCC patients who underwent palliative <strong>the</strong>rapy with everolimus.<br />
Patients and methods: Our pilot study was designed to assess everolimus efficacy in<br />
RCC patients relapsed after TKI inhibitors (sunitinib and/or sorafenib). Patients were<br />
treated with everolimus 10 mg daily orally until disease progression. The genomic<br />
DNA was extracted from formalin-fixed, paraffin-embedded primary tumor RCC<br />
tissues. 12 potentially functional SNPs in 4 key genes (AKT1, AKT2, FRAP1,<br />
PIK3CA) were determined using a real-time PCR genotyping assay and analyzed for<br />
association with response to <strong>the</strong>rapy, progression free survival (PFS) and overall<br />
survival (OS).<br />
Results: Median age of 45 enrolled patients was 62 years (range, 41–78). At a median<br />
follow-up duration of 8,6 months, <strong>the</strong> 6-month PFS rate was 53.3%. Partial response<br />
was observed in 4,4% (2/45) of <strong>the</strong> patients. Median PFS was significantly prolonged<br />
in <strong>the</strong> PIK3CA rs6443624 for <strong>the</strong> CC genotype in comparison to <strong>the</strong> AA/AC<br />
genotype (8.9 months versus 5.5 months, log rank, p= 0.0157). In <strong>the</strong> multivariate<br />
analysis elevated corrected serum calcium and PIK3CA rs6443624 for <strong>the</strong> AA/AC<br />
genotype were unfavorable predictors of PFS (HR 5.25; 95% CI, 1.75–15.75 and HR<br />
3.48; 95%CI, 1.47–8.25, respectively, p < 0.05). 1-year OS rate for patients with<br />
PIK3CA rs6443624 CC and AA/AC genotype was 86% and 51%, respectively (p =<br />
0.0018). In multivariate analysis PIK3CA rs6443624 for <strong>the</strong> AA/AC genotype and<br />
elevated LDH serum level remained significant for OS (HR 18.7; 95% CI,2.70–129.38<br />
and HR 9.7; 95% CI,2.18 – 43.07, respectively; p < 0.05).<br />
Conclusion: These results suggest that PIK3CA rs6443624 genetic variation in PI3K/<br />
AKT/mTOR pathway may modulate clinical outcomes in patients with RCC who<br />
undergo chemo<strong>the</strong>rapy with everolimus. Fur<strong>the</strong>r clinical studies are needed to<br />
confirm <strong>the</strong>se findings.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
813P THE NOVEL CANCER VACCINE, CONSISTING OF<br />
GENETICALLY MODIFIED ALLOGENEIC TUMOR CELLS AND<br />
IMMUNOMODULATOR MGN1601: UPDATED RESULTS OF A<br />
PHASE 1-2 STUDY IN PATIENTS WITH ADVANCED RENAL<br />
CELL CARCINOMA<br />
I.G. Schmidt-Wolf 1 , S. Hauser 2 , S. Weikert 3 , V. Grünwald 4 , M. Schroff 5 ,<br />
M. Schmidt 6 , E. Weith 6 , M. Tschaika 6 , B. Wittig 7<br />
1 Department of Medicine III, Center for Integrated Oncology, University of Bonn,<br />
Bonn, GERMANY, 2 Department of Urology, University of Bonn, Bonn,<br />
GERMANY, 3 Clinic for Urology, Charite, Berlin, GERMANY, 4 Clinic for<br />
Hematology, Hemostaseology, Oncology, Hannover Medical School, Hannover,<br />
GERMANY, 5 Board, Mologen AG, Berlin, GERMANY, 6 Clinical Development,<br />
Mologen AG, Berlin, GERMANY, 7 6Foundation Institute Molecular Biology and<br />
Bioinformatics, Freie Universität Berlin, Berlin, GERMANY<br />
Background: MGN1601 consists of two active pharmaceutical ingredients: genetically<br />
modified allogeneic tumor cells expressing IL-7, GM-CSF, CD80 and CD154 and a<br />
TLR9 agonist, syn<strong>the</strong>tic DNA-based immunomodulator dSLIM®. The first-in-man<br />
phase 1–2 clinical trial (ASET trial) has been conducted in patients with advanced<br />
renal cell carcinoma failed previous <strong>the</strong>rapy lines and without fur<strong>the</strong>r available<br />
standard <strong>the</strong>rapy.<br />
Methods: The ASET study is a multicentric, open, single-arm phase 1-2 clinical<br />
study and consists of <strong>the</strong> treatment, extension and follow up phases. The safety,<br />
efficacy and immunogenicity parameters were evaluated based on clinical and<br />
laboratory assessments, monitoring of patients’ quality of life (QoL) with QLQ-C30,<br />
immunological tests, and central radiological investigations according to RECIST 1.1<br />
as well as immune related Response Criteria.<br />
Results: Ten of nineteen study patients completed <strong>the</strong> treatment per protocol (TPP).<br />
Two patients with disease control after 12-weeks continued treatment in <strong>the</strong><br />
extension phase. One of <strong>the</strong>m is still under <strong>the</strong>rapy showing tumor remission since<br />
48 weeks. The second patient developed radiological PD after 60 weeks of treatment.<br />
Seven patients from <strong>the</strong> TPP population are still alive with stable disease for up to 65<br />
weeks. Evaluation of <strong>the</strong> QoL showed that patients of <strong>the</strong> TPP group have improved<br />
median symptom score from 45.8 to 58.3 in course of treatment. Drug-related AE<br />
included mild fever, edema, exan<strong>the</strong>ma, pruritus, intermittent arthralgia, fatigue, and<br />
moderate soft tissue infection. Local reactions on injection site consisted mostly of<br />
redness up to 50 mm, which were available up to 7 days. The local reactions have no<br />
negative impact on <strong>the</strong> quality of life and daily activities of <strong>the</strong> patients. Six of ten<br />
TPP patients showed significant improvement in <strong>the</strong> immune status in lymphocyte<br />
transformation test.<br />
Conclusions: The allogeneic tumor cell-based cancer vaccine MGN1601 shows<br />
promising efficacy and a favourable safety profile in <strong>the</strong> late stage mRCC patients. A<br />
phase 2 clinical study in mRCC patients with MGN1601 as third-line <strong>the</strong>rapy is<br />
under development.<br />
Disclosure: M. Schroff: Board member of Mologen. M. Schmidt: Mologen employee.<br />
E. Weith: Mologen empoyee. M. Tschaika: Mologen employee. B. Wittig: Member of<br />
Scientific Advisory Board of Mologen. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
ix268 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
814P A PHASE IB CLINICAL TRIAL OF THE MULTITARGETED<br />
KINASE INHIBITOR LENVATINIB (E7080) IN COMBINATION<br />
WITH EVEROLIMUS FOR TREATMENT OF METASTATIC<br />
RENAL CELL CARCINOMA (RCC)<br />
A.M. Molina 1 , T.E. Hutson 2 , J. Larkin 3 , A. Gold 4 , C. Andresen 4 , K. Wood 5 ,<br />
R.J. Motzer 1 , M.D. Michaelson 6<br />
1 Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center,<br />
New York, NY, UNITED STATES OF AMERICA, 2 GU Oncology Program, Baylor<br />
Sammons Cancer Center, Dallas, TX, UNITED STATES OF AMERICA,<br />
3 Department of Medicine, Royal Marsden Hospital, London, UNITED KINGDOM,<br />
4 PCU, Eisai Inc, Woodcliff Lake, NJ, UNITED STATES OF AMERICA, 5 Oncology<br />
Pcu, Eisai Ltd, Hatfield, UNITED KINGDOM, 6 Medical Oncology, Massachusetts<br />
General Hospital Cancer Center, Boston, MA, UNITED STATES OF AMERICA<br />
Background: Lenvatinib (L) is an oral tyrosine kinase inhibitor targeting VEGFR1-3,<br />
FGFR 1-4, RET, KIT, and PDGFβ. Everolimus (E) is an oral mTOR inhibitor<br />
approved for RCC. This Phase (Ph) 1b/2 study investigates <strong>the</strong> combination of L plus<br />
E in RCC patients (pts) (NCT01136733). The Ph 1b component reported here<br />
assessed safety, tolerability, and maximum tolerated dose (MTD). The 3-arm<br />
randomised Ph 2 comparing PFS of L plus E and L alone versus E alone is ongoing.<br />
Methods: Pts with advanced unresectable or metastatic RCC, ECOG PS 0-1, age ≥18<br />
y were eligible for Ph 1b. Pts received L plus E, daily, in 28-day cycles. A standard<br />
3 + 3 dose-escalation design with expansion cohort was used to identify <strong>the</strong> MTD.<br />
Results: 20 pts (M/F: 14/6; median age: 59 y [range 46-72]; median of 2 prior<br />
<strong>the</strong>rapeutic regimens [range 0-5]; 17/20 pts [85%] had received prior anti-VEGF<br />
treatment (tx); 7/20 pts [35%] had also received prior mTOR-targeted tx) were<br />
treated at 3 dose levels of L (12 mg [n = 7]; 18 mg [n = 11]; 24 mg [n = 2]) in<br />
combination with E 5 mg. 4 DLTs were observed: G3 nausea and vomiting (1 pt) and<br />
G2 mucositis (1 pt) at 24 mg; G3 elevated CPK at 18 mg; G3 abdominal pain at 12<br />
mg. The MTD was L 18 mg plus E 5 mg. Median duration of tx was 14.5 wk (range<br />
1-68, 7/20 (35%) pts ongoing). The most common tx-related adverse events (AEs),<br />
all grades were fatigue 45% (G3, 5%); mucosal inflammation 40%; proteinuria 35%<br />
(G3, 10%); diarrhoea 30% (G3, 5%); rash 30%; hypertension 25%; nausea, vomiting<br />
each 25% (each G3 5%); constipation, decreased appetite, epistaxis each 20%. There<br />
was 1 G4 related AE of hypercholesterolemia. PR was observed in 6/18 (33%) pts in<br />
<strong>the</strong> MTD and lower dosing cohorts. Durable stable disease (≥23 wk) or PR were<br />
achieved in 8/16 (50%) pts with postbaseline tumor assessments (and 3 pts ongoing<br />
with SD $10,000. M.D. Michaelson: Dr.<br />
Michaelson discloses institutional research funding from: EISAI, Pfizer, Abbott,<br />
GlaxoSmithKline, Genentech Consultant or advisory role (UNCOMPENSATED):<br />
Pfizer, EISAI. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
815P SUNITINIB (SU) DOSING SCHEDULE AND DATA COLLECTION<br />
TIMEPOINTS: IMPACT ON QUALITY OF LIFE (QOL)<br />
OUTCOMES IN METASTATIC RENAL CELL CARCINOMA<br />
(MRCC)<br />
A. Bushmakin 1 , J.C. Cappelleri 1 , B. Korytowsky 2 , R. Sandin 3 , E. Matczak 4 ,<br />
D. Cella 5<br />
1 Statistics, Pfizer Inc., Groton, CT, UNITED STATES OF AMERICA, 2 Oncology<br />
Health Economics Outcomes Research, Pfizer Global Pharmaceuticals,<br />
New York, NY, UNITED STATES OF AMERICA, 3 Global Health Economics and<br />
Outcomes Research, Pfizer Oncology, Sollentuna, SWEDEN, 4 Oncology, Pfizer,<br />
New York, NY, UNITED STATES OF AMERICA, 5 Medical Social Sciences,<br />
Northwestern University Feinberg School of Medicine, Chicago, IL, UNITED<br />
STATES OF AMERICA<br />
Background: In a randomized phase III trial, SU was associated with superior QoL<br />
compared with interferon-alfa (IFN). Here, we report implications related to <strong>the</strong><br />
timing of collection of QoL data as it relates to SU-approved dosing in mRCC<br />
(4 weeks on treatment, 2 weeks off treatment; Schedule 4/2) and <strong>the</strong> extent to which<br />
such timing affects reported outcomes.<br />
Methods: 750 treatment-naïve patients with mRCC were randomized 1:1 to receive<br />
SU 50 mg orally once daily on Schedule 4/2 or IFN 9 MU subcutaneously thrice<br />
weekly. QoL measures included FACT-G, FKSI-15, FKSI-DRS, EQ-5D, and EQ-VAS.<br />
Higher scores indicated better outcomes (better QoL or fewer symptoms). Patients<br />
completed QoL questionnaires on Days 1 and 28 of each cycle, up to a maximum of<br />
30 cycles. SU data were analyzed to describe how <strong>the</strong> timing of QoL collection may<br />
affect results. Random coefficients mixed-effects models were used.<br />
Results: Data were used from all assessments collected (Days 1 and 28 at every<br />
cycle). The model indicated that QoL results based on Day 28 collection were<br />
consistently and statistically worse (lower QoL scores) than results based on Day 1<br />
(table). Based on a comparison with previously reported between-arm differences<br />
with SU vs. IFN, such variation could potentially diminish or increase <strong>the</strong> observed<br />
treatment effect by 38% to 62%.<br />
Conclusions: To account for overall patient QoL experience on <strong>the</strong>rapy, in this case,<br />
SU on Schedule 4/2, careful consideration must be given to <strong>the</strong> timing of QoL data<br />
collection. For SU in mRCC, QoL data should be collected both on and off treatment<br />
within a cycle. If QoL data are collected at only <strong>the</strong> last or first dose, scores will be<br />
overly negative or positive, respectively. Hence, if QoL data are collected at only a<br />
single timepoint within a cycle, it may not represent <strong>the</strong> full extent of QoL as<br />
experienced by patients on SU and may lead to misinterpretation of <strong>the</strong> true QoL<br />
outcomes.<br />
Model means of QoL endpoints with SU by assessment day<br />
Day 1 Day 28<br />
Difference between<br />
Day 1 and Day 28<br />
(i.e., after (i.e., after Difference<br />
as percentage of<br />
2 weeks 4 weeks between Day<br />
treatment effect*<br />
Endpoint off drug) on drug) 1 and Day 28 P value (SU vs. IFN)<br />
FKSI-15 46.3 44.3 2.0
Results: 1,622 patients were identified. 1,079 received first-line SUN, 284 SOR, 168<br />
TEM, 40 PAZ, 26 EVE, and 25 BEV. With a median follow-up of 13 months, <strong>the</strong><br />
mean healthcare cost PPPM was:<br />
Cost PPPM<br />
1st-line Agent<br />
Total Inpatient O<strong>the</strong>r outpatient mRCC drugs<br />
TEM $15,900 $6,480 $4,959 $3,532<br />
BEV $15,429 $6,529 $3,795 $4,021<br />
EVE $14,519 $3,585 $6,007 $4,063<br />
SUN $14,084 $6,208 $3,834 $2,965<br />
PAZ $12,461 $5,049 $3,895 $2,766<br />
SOR $12,266 $4,759 $3,662 $3,938<br />
Inpatient costs accounted for <strong>the</strong> largest share of total cost. O<strong>the</strong>r outpatient services<br />
and mRCC drug costs were <strong>the</strong> next largest cost drivers. ER and office visits and<br />
o<strong>the</strong>r Rx each averaged less than $500 PPPM. OOP cost averaged $453 PPPM, but<br />
ranged from $380 for EVE to $2,045 for BEV.<br />
Conclusions: Different first-line targeted agents appear to be associated with<br />
different total costs of care in mRCC. Patient characteristics, incidence and severity of<br />
adverse events, rates and duration of response, and choice of subsequent <strong>the</strong>rapies<br />
may all play a role. Fur<strong>the</strong>r characterization of such underlying factors may help<br />
optimize patient care and reduce cost.<br />
Disclosure: Y. Su: Employment or Leadership Role: Bristol-Myers Squibb<br />
(employment, myself, compensated). Stock Ownership: Bristol-Myers Squibb<br />
(myself). P. Landsman-Blumberg: Stock Ownership: Merck & Co., Inc. (myself).<br />
C. Poehlein: Employment or Leadership Role: Bristol-Myers Squibb (employment,<br />
myself, compensated). Stock Ownership: Bristol-Myers Squibb (myself). I. Waxman:<br />
Employment or Leadership Role: Bristol-Myers Squibb (employment, myself,<br />
compensated). Stock Ownership: Bristol-Myers Squibb (myself). All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
817P SORAFENIB IN PATIENTS WITH RENAL CELL CARCINOMA<br />
AND BRAIN, BONE OR LUNG METASTASES: SUBANALYSIS<br />
OF THE NON-INTERVENTIONAL PREDICT STUDY<br />
J. Mardiak 1 ,J.Ma 2 , E. Korbenfeld 3 , M. Zemanova 4 , N. Leonhartsberger 5 ,<br />
K. Stauch 6 , A. Boeckenhoff 7 ,J.Yu 8 , B. Escudier 9 , D. Jäger 10<br />
1 Department of Medical Oncology, National Cancer Institute, Bratislava, SLOVAK<br />
REPUBLIC, 2 Cancer Institute and Hospital, Chinese Academy of Medical<br />
Sciences, Beijing, CHINA, 3 Oncology, Hospital Británico de Buenos Aires,<br />
Buenos Aires, ARGENTINA, 4 First Faculty of Medicine, Charles University,<br />
Prague, CZECH REPUBLIC, 5 Department of Urology, Medical University<br />
Innsbruck, Innsbruck, AUSTRIA, 6 Global Non-interventional Studies, Bayer<br />
HealthCare, Leverkusen, GERMANY, 7 Global Development – Global Clinical<br />
Development, Bayer HealthCare, Wuppertal, GERMANY, 8 Global Medical Affairs,<br />
Bayer HealthCare, Montville, NJ, UNITED STATES OF AMERICA, 9 Department of<br />
Immuno<strong>the</strong>rapy, Institut Gustave Roussy, Villejuif, FRANCE, 10 National Center for<br />
Tumor Diseases, University Medical Center Heidelberg, Heidelberg, GERMANY<br />
Background: Clinical trials in advanced renal cell carcinoma (RCC) tend to exclude<br />
patients (pts) with brain metastases (mets). We report safety and efficacy outcomes<br />
from a subanalysis of PREDICT (NCT 00895674), a large, non-interventional study<br />
of sorafenib in pts with advanced RCC, according to sites of mets.<br />
Methods: Pts were eligible based on a diagnosis of advanced RCC and a decision by<br />
<strong>the</strong> investigator to prescribe sorafenib under compliance of <strong>the</strong> local product label.<br />
Physician assessments of efficacy and tolerability were collected for up to 12 months.<br />
Results: Of <strong>the</strong> efficacy population (n = 2311), 1079 pts (47%) had mets in >1 organ.<br />
Sites included bone (n = 635), brain (n = 113), lung (n = 1639); 750 pts had mets only<br />
in <strong>the</strong> lung (‘lung only’). Baseline characteristics across disease-site subsets were: 69–<br />
Table: 817P<br />
74% male; 73–82% aged 1 site (6.2 months). Median DOT was longest in pts<br />
with lung only mets (9.1 months); in <strong>the</strong> o<strong>the</strong>r subsets it was numerically similar to<br />
overall median DOT (brain, 7.0 months; bone, 6.4 months; lung, 7.5 months).<br />
Sorafenib was generally well tolerated (Table). Serious adverse event rates were<br />
numerically higher in pts with brain mets vs <strong>the</strong> o<strong>the</strong>r subsets, but no<br />
cerebrovascular events were reported.<br />
Conclusions: In pts with RCC treated in clinical practice, sorafenib DOT was >6<br />
months regardless of number or location of metastases, and sorafenib was generally<br />
well tolerated regardless of disease site. Number (%) patients with AEs (safety<br />
population).<br />
Disclosure: J. Mardiak: Jozef Mardiak has received Research Grants from Novartis<br />
and has received honoraria from Pfizer and Pierre Fabre. J. Ma: Jianhui Ma has<br />
received Research Grants from Bayer. M. Zemanova: Milada Zemanova has<br />
received consulting and lecture fees from Glaxo Smith Kline and Roche. N.<br />
Leonhartsberger: Nicolai Leonhartsberger has received honoraria from Bayer,<br />
Pfizer and Roche. K. Stauch: Kathrin Stauch is an employee of Bayer HealthCare<br />
and owns stock in Bayer Pharma AG. A. Boeckenhoff: Annette Boeckenhoff is an<br />
employee of Bayer HealthCare and owns stock in Bayer Pharma AG. J. Yu: Jian<br />
Yu is an employee of Bayer HealthCare. B. Escudier: Bernard Escudier has served<br />
in an advisory role for Pfizer, Novartis, Roche, GSK, Bayer and Aveo, and has<br />
received honoraria from Pfizer, Novartis, Roche, GSK, Bayer and Aveo. D. Jäger:<br />
Dirk Jäger has received honoraria from Bayer, Amgen, Pfizer, Novartis, Roche,<br />
Fresenius Kabi and Hoffmann-La Roche. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
818P PROGRESSION FREE SURVIVAL (PFS) AND OVERALL<br />
SURVIVAL (OS) IN PATIENTS RECEIVING 3 TARGETED<br />
THERAPIES (TTS) FOR METASTATIC RENAL-CELL<br />
CARCINOMA (MRCC)<br />
R. Iacovelli 1 , M. Santoni 2 , G. Di Lorenzo 3 , L. Cerbone 4 , M. Aglietta 5 , C. Masini 6 ,<br />
M.O. Giganti 7 , C. Messina 8 , C.N. Sternberg 9 , G. Procopio 10<br />
1 Department of Radiology, Oncology and Human Pathology, Sapienza University<br />
of Rome, Rome, ITALY, 2 Medical Oncology, Università Politecnica delle Marche,<br />
Ancona, ITALY, 3 Department of Oncology, Cattedra di Oncologia Medica,<br />
Università degli Studi Federico II, Napoli, ITALY, 4 Medical Oncology, San Camillo<br />
and Forlanini Hospital, Rome, ITALY, 5 Div Oncologia ed Ematologia, Fondazione<br />
Piemontese per la Ricerca sul Cancro Onlus, Candiolo, ITALY, 6 Dept. of<br />
Hematology/Oncology, Ospedale Policlinico-Modena, Modena, ITALY, 7 Medical<br />
Oncology, Niguarda Cà Grande Hospital, Milan, ITALY, 8 Medical Oncology,<br />
Ospedali Riuniti di Bergamo, Bergamo, ITALY, 9 Medical Oncology, San Camillo<br />
Forlanini Hospital, Rome, ITALY, 10 Medical Oncology, Fondazione IRCCS –<br />
Istituto Nazionale dei Tumori, Milano, ITALY<br />
Background: In recent years, TTs have improved <strong>the</strong> prognosis of mRCC patients<br />
(pts). Despite a not negligible number of pts received 3 TTs in clinical practice, no<br />
TTs have been evaluated as 3 rd line. Aim of this study is to investigate <strong>the</strong> clinical<br />
outcome in pts who received 3 TTs.<br />
Patients and methods: Pts with clear-cell mRCC who received 3 TTs were included.<br />
A questionnaire was sent to main Italian centers involved in <strong>the</strong> treatment of mRCC.<br />
Demographic data, history of RCC, type and length of first, second and third line<br />
were collected; MSKCC risk class was calculated before starting <strong>the</strong> 1 st and 3 rd lines,<br />
Heng class before <strong>the</strong> 3 rd line. Sequences of class and specific TTs were evaluated:<br />
TKIàTKIàmTOR and TKIàmTORàTKI or sunitinib (SU)-sorafenib(SO)- everolimus<br />
(EV) and SU-EV-SO. Median PFS, OS and Time to Strategy Failure (TTSF: from<br />
start of 1 st to end of 3 rd line) were estimated with <strong>the</strong> Kaplan-Meyer method with<br />
Event<br />
Metastases subsets<br />
Brain (n = 121) Bone (n = 673) Lung, all (n = 1723) Lung, only (n = 779) Overall (n = 2599)<br />
Any AE 77 (63.6) 401 (59.6) 1011 (58.7) 406 (52.1) 1479 (56.9)<br />
Any drug-related AE 58 (47.9) 316 (47.0) 861 (50.0) 366 (47.0) 1240 (47.7)<br />
Any SAE 39 (32.2) 156 (23.2) 297 (17.2) 90 (11.6) 477 (18.4)<br />
Any drug-related SAE 12 (9.9) 42 (6.2) 89 (5.2) 30 (3.9) 140 (5.4)<br />
Most frequent any grade drug-related AEs*<br />
Hand–foot skin reaction 20 (16.5) 106 (15.8) 366 (21.2) 188 (24.1) 520 (20.0)<br />
Diarrhea 19 (15.7) 111 (16.5) 306 (17.8) 114 (14.6) 443 (17.1)<br />
Rash †<br />
Annals of Oncology<br />
8 (6.6) 58 (8.6) 155 (9.0) 65 (8.3) 220 (8.5)<br />
Alopecia 5 (4.1) 36 (5.4) 96 (5.6) 44 (5.7) 145 (5.6)<br />
Decreased appetite 7 (5.8) 24 (3.6) 44 (2.6) 12 (1.5) 76 (2.9)<br />
ix270 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
95% CI and curves were compared with log-rank test. The study had <strong>the</strong> ethical<br />
approval.<br />
Results: 1905 pts were screened and 252 pts (13%) were treated with 3 TTs. The<br />
median age was 60 yrs (range 52–68), 73% were male, 96% underwent nephrectomy<br />
and 38% were metastatic at diagnosis. At 1 st line, <strong>the</strong> Motzer class was good,<br />
intermediate, and poor in 48%, 47% and 5% of pts, respectively. PFS for type and<br />
line of <strong>the</strong>rapy are reported in <strong>the</strong> table below. The TTSF was 36.4 (30.5–42.2) vs.<br />
30.6 (26.5–34.6) mos (p = 0.11), and <strong>the</strong> OS was 52.1 (41.6–62.6) vs. 36.3 (31.2–41.4)<br />
mos (p = 0.01), for TKIàTKIàm-TOR and and TKIàm-TORàTKI, respectively. TTSF<br />
for SU-SO-EV was 36.5 vs. 30.4 mos for SU-EV-SO (p = 0.011). When stratified by<br />
ECOG-PS before 3 rd line or baseline MSKCC, TS maintained its independent<br />
prognostic role (p = 0.002 and p = 0.004, respectively).<br />
Conclusions: Only few patients received 3 lines of TTs. The sequence<br />
sunitinib-sorafenib-everolimus was associated with a better TTSF and OS as<br />
compared to <strong>the</strong> sequence sunitinib-everolimus-sorafenib.<br />
Therapy<br />
1 st line 2 nd line 3 rd line<br />
% PFS % PFS % PFS<br />
Sunitinib 60 10.1 31 11.2 8 14.1<br />
Sorafenib 25 13.1 35 7.7 28 5.2<br />
Pazopanib 2 6.4 0 / 0 /<br />
Bevac. + IFN 11 11.3 0 / 1 4.3<br />
Everolimus 0 / 30 4.7 55 6.9<br />
Temsirolimus 2 5.1 3 5.6 5 2.6<br />
O<strong>the</strong>r 0 / 0 / 3 3.2<br />
TOTAL 100 11.6 100 6.8 100 6.2<br />
Disclosure: All authors have declared no conflicts of interest.<br />
819P IMPLEMENTATION OF TARGETED THERAPY IN DENMARK<br />
FOR PATIENTS WITH METASTATIC RENAL CELL<br />
CARCINOMA: RESULTS FROM THE DANISH RENAL<br />
CANCER GROUP (DARENCA) STUDY-2<br />
A.V. Soerensen 1 , F. Donskov 2 , G.G. Hermann 3 , N.V. Jensen 4 , H. Spliid 5 ,<br />
E.Q. Bergan 6 , K. Fode 2 , P.F. Geertsen 1<br />
1 Department of Oncology, University Hospital of Copenhagen Herlev, Herlev,<br />
DENMARK, 2 Department of Oncology, Aarhus University Hospital, Aarhus,<br />
DENMARK, 3 Department of Urology, University Hospital of Copenhagen<br />
Rigshospitalet, Copenhagen, DENMARK, 4 Department of Oncology, Odense<br />
University Hospital, Odense, DENMARK, 5 Section for Statistics, Informatics and<br />
Ma<strong>the</strong>matical Modelling, Technical University of Denmark, Kongens Lyngby,<br />
DENMARK, 6 Denmark, Pfizer, Ballerup, DENMARK<br />
Background: Treatment options for metastatic renal cell carcinoma (mRCC) have<br />
expanded since <strong>the</strong> introduction of targeted <strong>the</strong>rapies. The impact of <strong>the</strong>se new<br />
treatment options on overall survival in a complete national cohort of patients is<br />
unclear.<br />
Objective: To analyze Overall Survival (OS), Progression Free Survival (PFS) and<br />
Time to Treatment Failure (TTF) in a complete national cohort of patients.<br />
Design, setting and participants: All Danish patients with mRCC starting first line<br />
treatment with immuno<strong>the</strong>rapy, TKIs or mTOR-inhibitors between 2006 and 2010<br />
were included. Baseline and outcome data were collected retrospectively. Untreated<br />
patients referred for treatment were also assessed.<br />
Outcome measurements and statistical analysis: OS, PFS and TTF was calculated<br />
using <strong>the</strong> Kaplan-Meier method. Differences between OS and treatment year were<br />
assessed using <strong>the</strong> log rank test. Differences in distributions were tested with <strong>the</strong><br />
Chi-square test.<br />
Results and limitations: Between 2006 and 2010, a total of 1073 patients were<br />
referred. Of <strong>the</strong>se, 759 patients received first line treatment and 314 received no<br />
systemic treatment. The proportion of treated patients increased from 64% in 2006 to<br />
75% in 2010 (p = 0.02). In 2006 22% received targeted <strong>the</strong>rapy and this increased to<br />
75% in 2010 (p < 0.00001). In 2006 21% of first line patients received second line<br />
treatment compared to 41% in 2010 (p = 0.01). From 2006 to 2010 we observed an<br />
improved median OS from 11.5 to 15.7 months (p = 0.03), improved median PFS<br />
from 4.1 to 5.5 months (p = 0.001) and an improved median TTF from 3.1 to 4.9<br />
months (p = 0.006) for first line treatment. The untreated population of 314 patients<br />
had a median OS of 3.1 months from date of metastatic disease with no significant<br />
change from 2006 to 2010.<br />
Conclusions: In a complete national cohort of patients, implementation of targeted<br />
<strong>the</strong>rapy has resulted in improved treatment options and outcome for patients with<br />
mRCC.<br />
Disclosure: A.V. Soerensen: has received a research grant/funding from Pfizer. F.<br />
Donskov: has received a research grant from Novartis. E.Q. Bergan: Employee of<br />
Pfizer Denmark Aps. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
820P SUNITINIB GLOBAL EXPANDED-ACCESS TRIAL IN<br />
METASTATIC RENAL CELL CARCINOMA (MRCC) – FINAL<br />
RESULTS<br />
M.E. Gore 1 , C. Porta 2 , S. Bracarda 3 , G.A. Bjarnason 4 , S. Oudard 5 , S. Lee 6 ,<br />
L. Crino 7 , T.M. Kim 8 , K. Fly 9 , C. Szczylik 10<br />
1 Department of Medicine, Royal Marsden Hospital NHS Foundation Trust,<br />
London, UNITED KINGDOM, 2 Medical Oncology, IRCCS San Matteo University<br />
Hospital Foundation, Pavia, ITALY, 3 Ospedale San Donato, Medical Oncology<br />
Arezzo, Arezzo, ITALY, 4 Division of Medical Oncology, Sunnybrook Odette<br />
Cancer Centre, Toronto, ON, CANADA, 5 Medical Oncology, Georges Pompidou<br />
Hospital and Rene Descartes University, Paris, FRANCE, 6 Oncology, Seoul<br />
National University Hospital, Seoul, KOREA, 7 Medical Oncology, S. Maria della<br />
Misericordia Hospital, Perugia, ITALY, 8 Medical Oncology, Seoul National<br />
University Hospital, Seoul, KOREA, 9 Oncology, Pfizer Inc., Groton, CT, UNITED<br />
STATES OF AMERICA, 10 Oncology, Military Medical Institute, Warsaw, POLAND<br />
Background: Sunitinib had a manageable safety profile and encouraging efficacy in a<br />
global expanded-access mRCC study (ClinicalTrials.gov, NCT00130897; Pfizer)<br />
initiated prior to regulatory approval, in patients (pts) ineligible for o<strong>the</strong>r trials (Gore<br />
et al, 2009). Here we report final results.<br />
Methods: Pts aged ≥18 yrs with treatment-naïve or previously treated mRCC<br />
received oral sunitinib on <strong>the</strong> approved 50 mg/day 4-wk-on/2-wk-off schedule. Safety<br />
was assessed regularly and tumor measurements were done as per local standard<br />
practice using RECIST-defined response. Analyses included all pts who received ≥1<br />
dose of sunitinib.<br />
Results: 4,577 pts were enrolled. From July 2005 to November 2011, 4,543 pts<br />
received treatment, including poor prognosis pts with brain metastases (7%), Eastern<br />
Cooperative Oncology Group performance status (ECOG PS) ≥2 (14%), non-clear<br />
cell RCC (12%) and age ≥65 yrs (33%). Median treatment duration was 7.5 mths<br />
and median follow-up was 13.6 mths. 4,298 pts (95%) discontinued; reasons included<br />
lack of efficacy (37%), death (20%) and adverse events (AEs; 15%). The most<br />
common treatment-related AEs of any grade were diarrhea (47%), fatigue (40%),<br />
nausea (36%), decreased appetite (31%), mucosal inflammation (29%), stomatitis and<br />
vomiting (both 28%), hand–foot syndrome (HFS; 27%), dysgeusia (25%),<br />
hypertension (24%), thrombocytopenia (23%) and as<strong>the</strong>nia (22%). The most<br />
common treatment-related grade 3/4 AEs were fatigue (9%), thrombocytopenia (8%),<br />
HFS and as<strong>the</strong>nia (both 7%), hypertension and neutropenia (both 6%) and diarrhea<br />
(5%). In 4,219 evaluable pts, <strong>the</strong> objective response rate (ORR) was 16% (n = 660)<br />
with subgroup ORR as follows: baseline brain metastases (30/324 [9%]), ECOG PS<br />
≥2 (32/587 [5%]), non-clear cell RCC (42/505 [8%]), and age ≥65 yrs (195/1,386<br />
[14%]). Overall median progression-free survival was 9.4 mths (95% CI: 8.8, 10.0)<br />
and overall survival was 18.7 mths (95% CI: 17.5, 19.5).<br />
Conclusions: Results from this global expanded-access mRCC trial confirm <strong>the</strong><br />
safety and efficacy of sunitinib in >4,500 pts with wide-ranging disease states in a<br />
real-world setting. The sunitinib AE profile in this broad population was manageable<br />
and consistent with prior trial results.<br />
Disclosure: M.E. Gore: Advisory relationships with Roche, Pfizer, Bristol Myers,<br />
Novartis, GSK, Aveo\\Astellas, Bayer. Honoraria to disclose from Roche, Pfizer,<br />
Bristol Myers, Novartis.C. Porta: Advisory relationship Pfizer Bayer-Schering<br />
Hoffman La Roche GSK Novartis Astellas Boehringer Recordati. Honoraria: Pfizer<br />
Bayer-Schering Hoffman La Roche GSK Novartis Astellas Boehringer Recordati<br />
Research funding Bayer-Schering Novartis. S. Bracarda: Advisory relationship with<br />
Novartis Bayer Schering Pfizer GSK Aveo/Astellas Boheringer-Ingelheim. Honoraria<br />
to disclose from Novartis and Pfizer. G.A. Bjarnason: Advisory relationship with<br />
Pfizer. Honoraria to disclose from Pfizer. Research funding to disclose from Pfizer..<br />
S. Oudard: Advisory relationships: Pfizer, Bayer-Schering, Hoffman La Roche, Glaxo<br />
SmithKline, Novartis Pharma, Sanofi Aventis Honoraria: Pfizer, Bayer-Schering,<br />
Hoffman La Roche, Glaxo SmithKline, Novartis Pharma, Sanofi Aventis. S. Lee:<br />
Advisory relationships with Pfizer, Novartis, Bayer. Honoraria to disclose from<br />
Pfizer, Novartis, Bayer. K. Fly: Employed by Pfizer Inc. as an Oncology Clinician.<br />
Hold Pfizer stock as does an immediate family member. C. Szczylik: Advisory<br />
relationship with Pfizer, GSK, Bayer. Honoraria from Pfizer, GSK, Bayer. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
821P EVEROLIMUS IN PATIENTS WITH METASTATIC RENAL CELL<br />
CARCINOMA WHO PROGRESS AFTER INITIAL VASCULAR<br />
ENDOTHELIAL GROWTH FACTOR RECEPTOR-TYROSINE<br />
KINASE INHIBITOR (VEGFR-TKI) THERAPY: UK RESULTS<br />
FROM THE REACT TRIAL ON BEHALF OF THE UK REACT<br />
INVESTIGATORS<br />
S. Chowdhury 1 , J. Larkin 2<br />
1 Department of Medical Oncology, Guy’s and St. Thomas’ Hospital NHS Trust,<br />
London, UNITED KINGDOM, 2 Department of Medicine, Royal Marsden Hospital,<br />
London, UNITED KINGDOM<br />
Background: The phase III RECORD-1 trial demonstrated clinical benefit of<br />
everolimus in patients with metastatic renal cell carcinoma (mRCC) who had failed<br />
initial VEGFr-TKI <strong>the</strong>rapy. REACT (RAD001 Expanded Access Clinical Trial in<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds399 | ix271
RCC) was designed to address an unmet medical need by providing everolimus to<br />
patients with mRCC prior to regulatory approval. UK results from <strong>the</strong> REACT trial<br />
are reported here.<br />
Methods: REACT was an open-label, international, expanded-access program.<br />
Eligible patients had measurable or nonmeasurable mRCC of any histology, and had<br />
progressed on, or were intolerant of, VEGFr-TKI <strong>the</strong>rapy. Patients received a<br />
once-daily oral 10 mg dose of everolimus. The primary objective of REACT was to<br />
evaluate long-term safety of everolimus. Tumour response was also assessed<br />
according to RECIST.<br />
Results: A total of 120 patients were enrolled in <strong>the</strong> UK, 9% of worldwide<br />
enrolment. Prior sunitinib was received by 76% of patients; only 5.8% of patients<br />
received more than one VEGFr-TKI. Everolimus was received for a median duration<br />
of 21.8 weeks (range, 2.0–59.0), numerically longer than reported overall for REACT<br />
(14.0 weeks; range, 0.1–83.7). Safety findings and tumour responses were consistent<br />
with those observed in <strong>the</strong> global patient population. The most commonly reported<br />
grade 3/4 AEs were anaemia (20.8%), hyperglycaemia (10%), and lower respiratory<br />
tract infection (7.5%). Stomatitis and pneumonitis occurred in 13.3% and 10% of<br />
patients, respectively (all grades); grade 3 events were reported in 6.7% and 3.3% of<br />
patients (no grade 4 events). Investigator-assessed best overall responses were stable<br />
disease in 67 (55.8%) patients and a partial response in 1 patient (0.8%), comparable<br />
with <strong>the</strong> overall population. No complete responses were documented in this trial.<br />
Conclusions: The REACT trial provided everolimus in advance of regulatory<br />
approval and commercial availability to mRCC patients in <strong>the</strong> UK who failed initial<br />
VEGFr-TKI <strong>the</strong>rapy. Everolimus was well tolerated, and safety findings were<br />
consistent with those reported for global REACT.<br />
Disclosure: S. Chowdhury: Consultant or Advisory: Novartis, Pfizer, GSK,<br />
Sanofi-Aventis, Janssen-Cilag, Dendreon. All o<strong>the</strong>r authors have declared no conflicts<br />
of interest.<br />
822P A PHASE I DOSE ESCALATION STUDY INVESTIGATING<br />
DOVITINIB AND EVEROLMUS IN COMBINATION IN<br />
METASTATIC CLEAR CELL RENAL CANCER PATIENTS WHO<br />
HAVE PREVIOUSLY FAILED VEGF TARGETED THERAPY<br />
T.B. Powles 1 , R.J. Jones 2 , S. Crabb 3 , S. Sarker 1 , E. Boleti 4 , J. Shamash 1 ,<br />
N. Sarwar 1 , S. Chowdhury 5<br />
1 QMUL, Barts Cancer Insititute, London, UNITED KINGDOM, 2 Medical<br />
Oncology, Beatson West of Scotland Cancer Centre Gartnavel General Hospital,<br />
Glasgow, UNITED KINGDOM, 3 Oncology, Southampton University, London,<br />
UNITED KINGDOM, 4 Oncology, Royal Free Hospital, London, UNITED<br />
KINGDOM, 5 Oncology, Guys and St Thomas Hospital, London, UNITED<br />
KINGDOM<br />
Introduction: Both dovitinib and everolimus are agents used, or under investigation<br />
in patients with renal cancer refractory to VEGF targeted <strong>the</strong>rapy. It is potentially<br />
attractive to use <strong>the</strong>se agents in combination in patients with VEGF TKI refractory<br />
disease. Toge<strong>the</strong>r <strong>the</strong>y target mTOR, VEGF and FGF-2. The purpose of this study is<br />
to establish a dose for this combination to take forward in randomised trials.<br />
Method: This phase I study (EUDRACT 2010-021250-19) followed a classic dose<br />
escalation 3 + 3 designed. Sequential patients with metastatic clear cell renal cancer,<br />
who had previously failed VEGF tyrosine kinase inhibitors were included. Patients<br />
received fixed doses of drug in each escalating cohort (maximum n = 6) until dose<br />
limiting toxicity (DLT) was reached. DLT included grade 3 toxicity during <strong>the</strong> first<br />
6 weeks of <strong>the</strong>rapy. If 2 episodes of grade 3 or more toxicity occurred in a specific<br />
cohort <strong>the</strong> DLT cohort had been reached. The study has appropriate ethical approval.<br />
Assement of response and progression free survival was by RECIST v1.1<br />
Results: Patients were entered into 2 cohorts before DLT occurred (cohort 0:<br />
dovitinib 200 mg/everolimus 5mg [n = 6]; cohort 1: dovitinib 300 mg/everolimus 5mg<br />
[n = 3]) . DLT in cohort 1 included grade 3 fatigue (2/3) after 2 and 3 week of<br />
<strong>the</strong>rapy. In cohort 0 <strong>the</strong> following toxicity was identified: Lethargy grade 2 3/6 and<br />
3 1/6; Diarrhoea Grade 2 2/6 and 3 0/6 mucositis; grade 2 0/6 and 3 0/6; nausea/<br />
vomiting grade 2 0/6 and 3 1/6, pulmonary fibrosis grade 2 1/6 3 0/6 . Grade 3<br />
toxicity after <strong>the</strong> first 6 weeks of <strong>the</strong>rapy included pulmonary fibrosis 1/6, lipid<br />
abnormalities 2/6. Overall 1 patient (11%) had a partial response to <strong>the</strong>rapy. Of <strong>the</strong><br />
5 patients who did not stop <strong>the</strong>rapy during <strong>the</strong> first 6 weeks due to toxicity,<br />
3 continued for 6 months or more without progression.<br />
Conclusion: The maximum tolerable dose for this combination was dovitinib 200mg<br />
and everolimus 5mg. This dose is being taken forward in an expansion cohort which<br />
will explore efficacy.<br />
Disclosure: T.B. Powles: Novarits Has supplied an educational grant for this project.<br />
Advisroy role for Novratis. S. Chowdhury: Advisory role. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
Annals of Oncology<br />
823P SURVIVAL AMONG ADVANCED RENAL CELL CARCINOMA<br />
(ARCC) PATIENTS WITH >2 PRIOR TARGETED THERAPIES<br />
E. Calvo 1 , R. Casciano 2 , L. Stern 2 , T. Brechenmacher 3 , S. Stergiopoulos 3 ,<br />
J. Coombs 4<br />
1 Start Madrid, Early Clinical Drug Development Unit, Hospital Madrid Norte San<br />
Chinarro Centro Integral Oncologico Clara Campal, Madrid, SPAIN, 2 Global<br />
Outcomes Research and Pricing, Analytica LA-SER, New York, NY, UNITED<br />
STATES OF AMERICA, 3 Oncology, Novartis Pharmaceuticals, East Hanover, NJ,<br />
UNITED STATES OF AMERICA, 4 Global Health Economics and Market Access,<br />
Novartis Oncology, East Hanover, NJ, UNITED STATES OF AMERICA<br />
Background: Despite <strong>the</strong> emergence of VEGFR-TKIs and mTORs in aRCC,<br />
considerable unmet medical needs remain. There are no published guidelines for 3rd<br />
line treatment in aRCC and, despite significant advances, <strong>the</strong>se patients have limited<br />
treatment options. This analysis examines <strong>the</strong> overall survival of patients after<br />
discontinuation from a phase III, randomized, double-blind, placebo-controlled trial<br />
(RECORD-1), who received at least two targeted <strong>the</strong>rapies.<br />
Methods: All patients in RECORD-1 received at least one prior VEGFR-TKI before<br />
randomization to everolimus (EVE) or placebo. Demographics, treatment sequence<br />
and overall survival were reported for patients who discontinued EVE for reasons<br />
o<strong>the</strong>r than death and received additional targeted <strong>the</strong>rapy with ei<strong>the</strong>r sorafenib or<br />
sunitinib.<br />
Results: Of <strong>the</strong> 416 patients in RECORD-1, 274 received EVE, 258 discontinued<br />
EVE for reasons o<strong>the</strong>r than death and approximately one third of those (N = 87)<br />
received sunitinib or sorafenib as additional targeted <strong>the</strong>rapy following EVE (49.4%<br />
sorafenib only, 40.2% sunitinib only and 10.3% both). Baseline patient demographics<br />
at RECORD-1 enrollment are provided in <strong>the</strong> Table. Median time from EVE<br />
discontinuation to additional sunitinib or sorafenib <strong>the</strong>rapy was 0.9 months (mean<br />
1.7, SD 2.5). The median overall survival for patients from start of <strong>the</strong> additional<br />
sunitinib or sorafenib <strong>the</strong>rapy after EVE discontinuation was 13.9 months (95% CI<br />
10.6–17.2 mo).<br />
Baseline Characteristics Patients receiving sorafenib or sunitinib post-EVE<br />
N=87<br />
Male, n (%) 73 (83.9%)<br />
>= 65 years, n (%) 35 (40.2%)<br />
MSKCC Intermediate Risk n (%) 52 (59.8%)<br />
MSKCC Favorable Risk n (%) 29 (33.3%)<br />
KPS— > =90 n (%) 63 (72.4%)<br />
KPS—80 n (%) 20 (23.0%)<br />
Conclusions: In this heavily pre-treated sub-population, following EVE<br />
discontinuation in RECORD-1, some patients experienced meaningful rescue <strong>the</strong>rapy<br />
with a TKI, with a median overall survival of more than a year Clinical trials with<br />
investigational targeted <strong>the</strong>rapies are ongoing, and may provide additional treatment<br />
options.<br />
Disclosure: R. Casciano: Roman Casciano is an employee of Analytica LA-SER,<br />
which received funding for <strong>the</strong> research. L. Stern: Lee Stern is an employee of<br />
Analytica LA-SER, which received funding for <strong>the</strong> research. T. Brechenmacher:<br />
Thomas Brechenmacher is employed by Novartis Pharmaceuticals, which provided<br />
funding for <strong>the</strong> research. S. Stergiopoulos: Sotirios Stergiopoulos is employed by<br />
Novartis Pharmaceuticals, which provided funding for <strong>the</strong> research. J. Coombs: John<br />
Coombs is employed by Novartis Pharmaceuticals, which provided funding for <strong>the</strong><br />
research. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
824P OVERALL SURVIVAL (OS) IN METASTATIC RENAL CELL<br />
CARCINOMA (MRCC) SEQUENTIALLY TREATED WITH<br />
DIFFERENT TARGETED THERAPIES (TTS): RESULTS<br />
FROM A LARGE COHORT OF PATIENTS<br />
G. Procopio 1 , E. Verzoni 1 , I. Testa 1 , R. Iacovelli 2 , E. Garanzini 1 , F.G.M. De Braud 1<br />
1 Medical Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano,<br />
ITALY, 2 Dipartimento di Medicina Sperimentale, Policlinico Umberto I, Roma,<br />
ITALY<br />
Introduction: Targeted Therapies (TTs) have improved survival in patients with<br />
mRCC. However expert opinion on <strong>the</strong> optimal <strong>the</strong>rapeutic strategy is not entirely<br />
shared. This study was performed to assess <strong>the</strong> overall survival (OS) in a consecutive<br />
series of mRCC patients receiving TTs.<br />
ix272 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Methods: Baseline characteristics and outcomes of 336 patients affected by mRCC<br />
receiving TTs were collected from <strong>the</strong> database of IRCCS Istituto Nazionale Tumori<br />
of Milan. The main characteristics of patients were: ECOG PS 0/1/2 186 (55%)/131<br />
(39%)/19 (6%); clear-cell histology 291 (87 %); previous nephrectomy 293 (87%).<br />
According to Motzer criteria 32% of patients showed low risk, 48 % intermediate<br />
and 20% had poor prognosis. Overall, 167 (50%) patients received one TTs, while<br />
116 (34%), 42 (13%) and 11 (3.3%) received 2, 3 and 4 TTs, respectively. Altoge<strong>the</strong>r,<br />
245 (73%) patients received sorafenib (So), 212 (63%) sunitinib (Su), 33 (10%) a<br />
bevacizumab regimen and 73 (22%) o<strong>the</strong>r TTs, including everolimus, temsirolimus<br />
and axitinib. Kaplan Meier curves were used to describe <strong>the</strong> survival of <strong>the</strong>se patients<br />
according to <strong>the</strong> identified prognostic factors. The uni- and multi-variate analyses for<br />
OS were carried out by means of Cox proportional hazard regression analysis.<br />
Results: At a median follow-up of 43 months, 199 patients (57%) had died. The<br />
median OS was 24 months (95%CI: 20.0-27.0) and <strong>the</strong> 5-year OS was 24.6 % (95%<br />
CI: 18.7-30.8). In <strong>the</strong> univariate analyses, <strong>the</strong>re were no significant differences in <strong>the</strong><br />
hazard ratios (HR) for sorafenib followed by sunitinib compared to sunitinib<br />
followed by sorafenib (HRSU−SO / SO-SU = 1.16; 95%CI: 0.57-2.33) or compared with<br />
o<strong>the</strong>r <strong>the</strong>rapies (HR O<strong>the</strong>r sequential th. / SO-SU = 1.21; 95%CI: 0.78-1.88; p = 0.674). In <strong>the</strong><br />
multivariate analysis, in terms of OS no statistical difference was reported as regards<br />
<strong>the</strong> sequence used (Su/So vs So/Su; p > 0.05) or bevacizumab regimen as compared to<br />
Su and/or So used sequentially (p > 0.05). In <strong>the</strong> uni and multivariate analysis ECOG<br />
PS, nephrectomy status, Fuhrman grade and previous cytokines treatments are<br />
independent predictive factors of outcome (p< 0.01).<br />
Conclusions: These efficacy data suggest that TTs improve OS in mRCC without any<br />
statistical difference when using different sequences of TTs. No cross-resistance<br />
between different TTs was documented.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
825P RELATIONSHIP BETWEEN PROGRESSION-FREE (PFS) AND<br />
OVERALL SURVIVAL (OS) IN I-LINE RANDOMIZED CLINICAL<br />
TRIALS (RCT) FOR ADVANCED RENAL CELL CARCINOMA<br />
(RCC): CORRELATION AND POWER ANALYSIS<br />
E. Bria 1 , F. Massari 2 , F. Maines 2 , M. Bonomi 3 , C. Porta 4 , S. Bracarda 5 ,<br />
F. Cognetti 6 , D. Giannarelli 7 , G. Tortora 1 , M. Milella 6<br />
1 Medical Oncology, Azienda Ospedaliera Universitaria Integrata Verona-“Borgo<br />
Roma”, Verona, ITALY, 2 Oncologia Medica, Azienda Ospedaliera Universitaria<br />
Integrata Verona-“Borgo Roma”, Verona, ITALY, 3 Oncologia Medica, Azienda<br />
Ospedaliera Universitaria Integrata Verona, Verona, ITALY, 4 Medical Oncology,<br />
IRCCS San Matteo University Hospital Foundation, Pavia, ITALY, 5 Department of<br />
Oncology, Ospedale San Donato and U.O.C. of Medical Oncology, Arezzo,<br />
ITALY, 6 Divisione di Oncologia Medica A, Istituto Nazionale Tumori Regina Elena,<br />
Roma, ITALY, 7 Medical Oncology, Regina Elena National Cancer Institute, Roma,<br />
ITALY<br />
Purpose: Targeted agents (TA) have become standard 1st-line treatment for<br />
advanced RCC based on evidence of PFS advantage over IFN or placebo.<br />
Retrospective series suggest that PFS may be considered a reliable intermediate<br />
end-point in this setting; however, correlation, surrogacy testing, and validation are<br />
required.<br />
Methods: RCT evaluating <strong>the</strong> efficacy of TA as 1st line targeted treatment for<br />
advanced RCC were considered eligible. PFS/OS Response/Disease Control rates<br />
(ORR, DCR) and Hazard Ratios were extracted from papers/updated presentations.<br />
Correlations between 3-, 6-, 9-, and 12-mo PFS and OS rates according to parametric<br />
(Pearson’s r) and non-parametric (Spearman’s Rho and Kendall’s Tau) coefficients<br />
(with 95% CI) were analyzed to avoid lead-time biases. Regression analysis<br />
(parametric R2) and a power-analysis-model in order to determine patients’ sample<br />
necessary to determine 3%, 5% and 10% OS gain were developed.<br />
Results: Six RCT (4096 patients) were ga<strong>the</strong>red. The best overall correlation between<br />
PFS and OS at concurrent timepoints was found at 9 months. With regard to overall<br />
rates, 3- and 6-months PFS significantly correlated with 9-mo OS, particularly in <strong>the</strong><br />
TA arms (Pearson’s 0.69/P = n.s. and 0.90/p = 0.01; Spearman’s 0.94/p = 0.03 and<br />
0.90/p = 0.04; Tau 0.85/p = 0.02 and 0.82/p = 0.03; respectively). Pearson’s coefficients<br />
for <strong>the</strong> correlation between 3-mo PFS and 6-, and 12-mo OS were 0.70 (p = 0.01)<br />
and 0.67 (p = 0.01), respectively; <strong>the</strong> correlation between 6-mo PFS and 12-mo OS<br />
were significant as well (Pearson 0.74, p = 0.005; Spearman 0.83, p = 0.005; Tau 0.71,<br />
p = 0.001). The regression equation was Y = 0.391861 + 0.4914X [R2 0.44, p(slope) =<br />
0.01]; based on this model, <strong>the</strong> demonstration of a 3-mo PFS absolute difference of<br />
6%, 10% and 21% (corresponding to a 9-mo OS benefit of 3%, 5% and 10%) would<br />
require 2043, 696 and 155 patients, respectively. A significant correlation was found<br />
between DCR and OS.<br />
Conclusions: PFS is an acceptable intermediate end-point for OS in <strong>the</strong> context of<br />
1st line TA treatment of advanced RCC. Individual patient data analysis to verify<br />
Prentice’s criteria would be required for definitive confirmation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
826P DESCRIPTION OF A SUBPOPULATION OF RENAL PATIENTS<br />
WITH LONG-TERM PROGRESSION FREE SURVIVAL (PFS)<br />
WITH SUNITINIB: A SOG_GU EXPERIENCE<br />
E. Esteban 1 , L. Anton-Aparicio 2 , S. Vazquez-Estevez 3 , U. Anido 4 , F.J. Afonso 5 ,<br />
O. Fernandez 6 , M. Lazaro 7 , L. Santomé 8 , M. Ramos Vazquez 9<br />
1 Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, SPAIN,<br />
2 Medical Oncology, Complejo Hospitalario A Coruña, A Coruña, SPAIN,<br />
3 Oncology, Hospital Universitario Lucus Augusti, Lugo, SPAIN, 4 Dept. of Medical<br />
Oncology, Complejo Hospitalario Universitario de Santiagode Compostela<br />
SERGAS, Santiago de Compostela, SPAIN, 5 Medical Oncology, Complejo<br />
Hospitalario Arquitecto Marcide, Ferrol, SPAIN, 6 Medical Oncology, Complexo<br />
Hospitario de Ourense, Ourense, SPAIN, 7 Oncoloxia Médica, Complexo<br />
Hospitalario Universitario de Vigo, Vigo, SPAIN, 8 Medical Oncology, Hospital<br />
Povisa de Vigo, Vigo, SPAIN, 9 Medical Oncology, Centro Oncológico de Galicia,<br />
A Coruña, SPAIN<br />
A multicenter retrospective analysis was performed in patients with metastatic RCC<br />
who achieved long-term progression-free survival (PFS) defined as ≥18 months<br />
during treatment with sunitinib. Forty six patients (87% male) treated with sunitinib<br />
in first (74%) or subsequent lines were included. Median age was 59 years and most<br />
common histology was clear cell (93,5%); 89% had undergone prior nephrectomy,<br />
28.3% were metastatic at diagnosis and 58.7% presented one site of metastasis, 28.3%<br />
two sites and 13% three or more sites. Twelve patients (26%) had bone metastases.<br />
Good, medium and poor prognosis (MKSCC) was presented in 30,4%, 67,4% and<br />
2,2% of patients respectively. Five patients (11%) achieved a complete response (CR),<br />
28 (61%) partial response (PR) and 13 (28.3%) a stable disease with 9 patients<br />
(69.2%) achieving stabilization for ≥25 months. Median duration of response was<br />
22.7 months Median time from diagnosis to sunitinib treatment was 2.23 years and<br />
median duration of <strong>the</strong>rapy was 27 months. At <strong>the</strong> time of analysis 37% were still on<br />
sunitinib. Median time from start Sunitinib until PR and CR was 4.7 and 12.1<br />
months respectively. Median PFS in <strong>the</strong> first line setting was 35.4 months (IC95% =<br />
[27,52-43,28]) and 31.6 months (IC95% = [5,13-58,13]) in subsequent lines. Median<br />
overall survival was not reached at <strong>the</strong> time of analysis. Reasons for discontinuation<br />
were progressive disease (83%), toxicity (10.3%) and death (3.4%). Incidence of<br />
adverse events was as expected, with as<strong>the</strong>nia, hand food syndrome (HFS),<br />
hypertension (HTA) and mucositis as main toxicities. Efficacy results are described<br />
in <strong>the</strong> table. The emergence of drug related toxicities, <strong>the</strong> lack of bone metastasis and<br />
<strong>the</strong> fact of non being metastatic at <strong>the</strong> time of diagnosis were independenly<br />
associated with a trend towards an improvement in PFS (p = NS). A comparison<br />
with a population of Sunitinib refractory patients is already ongoing.<br />
Median PFS Months (p = NS)<br />
With vs. without HTA 44.8 vs. 31.10<br />
With vs. without As<strong>the</strong>nia 35.5 vs. 32.43<br />
with vs. without HFS 44.8 vs. 31<br />
with vs. without Hypothiroidism 47.4 vs. 43.66<br />
with vs. without bone metastasis 31 vs. 37.5<br />
with vs. without metastasis at diagnosis 32.43 vs. 37.50<br />
Disclosure: E. Esteban: Compensated Consultant/Advisory role at PfizerAll o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
827P INTERIM RESULTS OF A PHASE II STUDY OF SUNITINIB<br />
AND LOW DOSE METRONOMIC CYCLOPHOSPHAMIDE IN<br />
ADVANCED RENAL CELL CANCER<br />
M.A. Khattak 1 , K. Edmonds 1 , K. Khabra 2 , A. Sohaib 3 , K. Pennert 2 , L. Pickering 1 ,<br />
M.E. Gore 1 , J. Larkin 1<br />
1 Medical Oncology, Royal Marsden NHS Trust, London, UNITED KINGDOM,<br />
2 Statistics, Royal Marsden NHS Trust, London, UNITED KINGDOM, 3 Radiology,<br />
Royal Marsden NHS Trust, London, UNITED KINGDOM<br />
Introduction: Sunitinib is a standard 1 st line treatment for advanced renal cell<br />
carcinoma (RCC) but 2/3rd of patients do not respond to treatment and <strong>the</strong> 2 weeks<br />
‘off’ treatment is sometimes associated with tumour regrowth and recrudescence of<br />
disease symptoms. Both sunitinib and low dose metronomic cyclophosphamide<br />
(Sun-Cyclo) are anti-angiogenic <strong>the</strong>rapies that act via different pathways. The<br />
possibility <strong>the</strong>refore exists that by combining <strong>the</strong>se two drugs, more complete<br />
blockade of angiogenesis may be achieved.<br />
Aims and objectives: The primary objective of <strong>the</strong> study is to evaluate <strong>the</strong> efficacy<br />
and toxicity of Sun-Cyclo. The primary endpoints are to establish <strong>the</strong> maximum<br />
tolerated dose (MTD) and <strong>the</strong> response rate (RR). The secondary endpoints are to<br />
assess <strong>the</strong> toxicity, progression-free survival (PFS) and overall survival (OS).<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds399 | ix273
Patients and methods: This is a single arm, open label phase 2 study. Treatment<br />
naïve patients with ECOG 0/1 and a histological/cytological diagnosis of RCC, who<br />
were considered suitable for treatment with sunitinib were enrolled into this study.<br />
The study is being conducted in 2 parts. The objective of Stage A is to establish <strong>the</strong><br />
MTD of Sun-Cyclo and evaluate <strong>the</strong> efficacy and toxicity of Sun-Cyclo in a small<br />
cohort (n = 19) of patients. The objective of Stage B is to fur<strong>the</strong>r evaluate efficacy and<br />
toxicity in an expanded population (n = 35). Sun-Cyclo was given as per following<br />
schedule: Sunitinib 50mg OD (4on/2off) and cyclosphosphamide 50mg OD<br />
continuously. We report here <strong>the</strong> interim results of Stage A.<br />
Results: A total of 19 patients have been enrolled into this study out of which 17<br />
were evaluable for analysis. The MTD of Sun-Cyclo was 50mg Sunitinib (4on/2off)<br />
and 50mg Cyclophosphamide. The RR was: partial response 4 (25%), stable disease<br />
10 (62.5%) and progressive disease 2 (12.5%). The median PFS was 11.0m (95% CI<br />
7.9-14.1m) and <strong>the</strong> 1year PFS rate was 46.8%. The commonest grade 3 toxicities were<br />
fatigue (12.5%), neutropaenia (37.5%) and thrombocytopaenia (18.8%). 10 patients<br />
had dose reductions [4 (40%) had 1 dose reduction to 37.5mg and 6 (60%) had 2<br />
dose reductions to 25mg]. 12 patients had treatment delays with a median of 7 days<br />
(range: 2–28).<br />
Conclusion: The combination of Sun-Cyclo was relatively well tolerated. The RR and<br />
PFS with Sun-Cyclo are similar to phase III results with sunitinib alone in RCC.<br />
Disclosure: K. Edmonds: Nil related to this research. K. Khabra: Nil related to this<br />
research. A. Sohaib: Nil related to this research. K. Pennert: Nil related to this<br />
research. L. Pickering: Pfizer: Research funding, honoraria, consultant role. M.E.<br />
Gore: Pfizer, Speaker bureau, advisory board. J. Larkin: Pfizer: Research funding,<br />
honoraria, consultant role. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
828P EVALUATION OF SAFETY, TOLERABILITY AND ACTIVITY OF<br />
TEMSIROLIMUS IN PATIENTS WITH ADVANCED OR<br />
METASTATIC RENAL CELL CARCINOMA (A/MRCC) IN THE<br />
USUAL HEALTH CARE SETTING<br />
U. Mueller 1 , G. Krekeler 1 , L. Bergmann 2 , T. Steiner 3 , D. Kalanovic 1<br />
1 Oncology, Pfizer Pharma GmbH, Berlin, GERMANY, 2 Medical Clinic III,<br />
Universitätsklinikum Frankfurt(Johannes-Wolfgang Goe<strong>the</strong> Institute), Frankfurt am<br />
Main, GERMANY, 3 Urology, Helios Klinikum, Erfurt, GERMANY<br />
Introduction: Temsirolimus (TEMS), an i.v. mTOR inhibitor, is approved in <strong>the</strong> EU<br />
for <strong>the</strong> first-line treatment of patients with a/mRCC who have at least 3 of 6<br />
prognostic risk factors. A pivotal study had demonstrated significantly increased<br />
overall survival with TEMS in poor risk patients compared to <strong>the</strong> former standard<br />
Interferon (10.9 vs. 7.3 mo; p = 0.0078). To better identify <strong>the</strong> safety profile and<br />
efficacy of TEMS during clinical routine, collection of data in a postapproval<br />
non-interventional trial seems to be adequate.<br />
Methods: A registry for a/mRCC patients treated with TEMS was started in<br />
Germany in January 2008 (NCT00700258). Primary objective: evaluation of <strong>the</strong><br />
safety profile of TEMS. Secondary objectives: tolerability and anti-tumor activity of<br />
TEMS; profile of patients; sequence of systemic <strong>the</strong>rapies. Inclusion criteria:<br />
histologically confirmed a/mRCC treated with TEMS and written informed consent<br />
by <strong>the</strong> patient.<br />
Results: 118 active study centers recruited 455 patients from Feb. 2008 to April <strong>2012</strong>.<br />
Preliminary data are available for 430 patients: 68.7% male, median age 68 years,<br />
median Karnofsky index 80%. Histological subtype: 75.3% clear cell, 10.9% papillary<br />
and 2.6% chromophobe RCC. According to modified MSKCC criteria 96.0% of<br />
patients (n = 323) were classified as poor risk and 4.0% as intermediate risk patients.<br />
Adverse events (AE) and serious adverse events (SAE) defined as drug related were<br />
observed in 41.2% and 10.2%, respectively. Skin disorders, fatigue, nausea, diarrhea,<br />
peripheral edema, anemia and dyspnea of any grade were <strong>the</strong> most frequent AEs.<br />
Median progression-free survival for <strong>the</strong> total patient population was 151 days (d),<br />
for <strong>the</strong> subgroup of 1 st line patients 162 d, for patients ≥ 65 yrs 155 d. Median overall<br />
survival for all patients was 381 d.<br />
Conclusions: Patient population in <strong>the</strong> registry represents <strong>the</strong> expected pattern in a/<br />
mRCC regarding distribution of age, sex, and histology. Safety profile and clinical<br />
efficacy of TEMS in <strong>the</strong> usual health care setting confirm <strong>the</strong> phase-III data. In<br />
addition, for patients ≥ 65 years safety and clinical efficacy of TEMS are comparable<br />
to results of <strong>the</strong> overall study population.<br />
Disclosure: U. Mueller: Employment by Pfizer. G. Krekeler: Employment by Pfizer.<br />
L. Bergmann: Advisory boards: Bayer, GSK, Novartis, Pfizer, Roche, Astellas;<br />
Honoraria: Novartis, Pfizer, Roche. D. Kalanovic: Employment by Pfizer. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
829P TUMOUR VASCULAR ENDOTHELIAL GROWTH FACTOR<br />
(VEGF) AND VASCULAR ENDOTHELIAL GROWTH FACTOR<br />
RECEPTORS (VEGFR) POLYMORPHISMS AND CLINICAL<br />
OUTCOME IN ADVANCED RENAL CELL CARCINOMA<br />
PATIENTS RECEIVING FIRST LINE SUNITINIB<br />
M. Bianconi 1 , M. Scartozzi 1 , L. Faloppi 1 , C. Loretelli 1 , L. Burattini 1 , A. Bittoni 1 ,<br />
M. Del Prete 1 , R. Giampieri 1 , R. Montironi 2 , S. Cascinu 1<br />
1 Clinica Di Oncologia Medica, AOU Ospedali Riuniti Ancona Università<br />
Politecnica delle Marche, Ancona, ITALY, 2 Institute of Pathological Anatomy,<br />
Università Pollitecnica delle Marche, Ancona, ITALY<br />
Background: The introduction of novel treatments has radically changed <strong>the</strong><br />
approach to <strong>the</strong> treatment of metastatic renal cell carcinoma (mRCC). Currently<br />
TKIs directed against <strong>the</strong> VEGF pathway are <strong>the</strong> <strong>the</strong>rapeutic strongholds. However,<br />
criteria for treatment selection are largely lacking. In this study we assessed <strong>the</strong> role<br />
of VEGF and VEGFR polymorphisms, in <strong>the</strong> prediction of <strong>the</strong> clinical outcome in<br />
mRCC patients.<br />
Methods: Forty-one formalin-fixed paraffin-embedded tissue blocks from mRCC<br />
patients receiving first-line sunitinib were tested for VEGF-A, VEGF-C and<br />
VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). SNPs results were correlated<br />
with progression free survival (PFS) and overall survival (OS).<br />
Results: Forty-one patients with metastatic renal cell carcinoma were available for<br />
our analysis. All patients received sunitinib as fist-line treatment with standard<br />
schedule, dose reduction was applied in patients with grade 3 and 4 toxicities.<br />
Median PFS was of 8,22 months, while median OS was of 32,13 months. VEGF A<br />
rs833061 polymorphism resulted statistically significant in PFS (17 months for CC +<br />
CT vs 4 months for TT; p = 0,0001) and OS (36 months for CC + CT vs 8 months<br />
for TT; p = 0,0040). VEGF A rs699947 was statistically significant for PFS (17<br />
months for AA + AC vs 4 months for CC; p = 0,0001) and OS (36 months for AA +<br />
AC vs 11 for CC; p = 0,0059). VEGF A rs2010963 was significant in PFS (17 months<br />
for GG vs 5 for GC vs 3 for CC; p = 0,0186). VEGR3 rs6877011 was significant in<br />
PFS (12 months for CC vs 4 for CG; p = 0,0221) and OS (36 months for CC vs 17<br />
for CG; p = 0,0052).<br />
Conclusions: in our analysis patients with TT polymorphism of rs833061, CC<br />
polymorphism rs699947 and CC polymorphism of rs2010963 seem to have a worse<br />
PFS and OS in first line. VEGF-A gene polimorphisms are probably connected with<br />
<strong>the</strong> control of <strong>the</strong> neoangiogenesis, maybe controlling vasculature normalization.<br />
Patients with CG polymorphism of rs6877011 seem equally to have a poor impact of<br />
first line <strong>the</strong>rapy. VEGFR-3 seems to be involved in vessels sprouting and<br />
architecture.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
830P THE PREDICTIVE AND PROGNOSTIC ROLE OF<br />
O6-METHYLGUANINE-DNA METHYLTRANSFERASE (MGMT)<br />
AND TISSUE TRANSGLUTAMINASE-2 (TGASE-2) IN<br />
METASTATIC RENAL CELL CARCINOMA (MRCC) PATIENTS<br />
TREATED WITH SUNITINIB<br />
D. Tunali 1 , B. Sarsık 2 , R. Durusoy 3 ,S.S¸en 2 , E. Gökmen 4<br />
1 Medical Oncology, Ege University Medical School, Izmir, TURKEY, 2 Department<br />
of Pathology, Ege University Medical School, Izmir, TURKEY, 3 Department of<br />
Public Health, Ege University Medical School, Izmir, TURKEY, 4 Department of<br />
Medical Oncology, Ege University Medical School, Izmir, TURKEY<br />
Background: Altough anti-angiogenic drugs are widely used in mRCC, <strong>the</strong> predictive<br />
markers for <strong>the</strong>se agents cannot be well defined yet. MGMT is recently shown to be<br />
anti-angiogenic and responsible for <strong>the</strong> anti-proliferative effect of sunitinib in<br />
glioblastome cell lines. In preclinical studies, MGMT positive cells demonstrate high<br />
sVEGFR-1/VEGFA ratio, increased VEGFR-1 and decreased VEGFR-2.TGase-2 is<br />
known to be responsible for drug resistance, cell proliferation, migration and<br />
angiogenesis. In vitro studies showed that TGase-2 inhibits VHL and this leads to<br />
increase of HIF-1α and IGF-1R.<br />
Objective: To investigate <strong>the</strong> predictive and prognostic role of MGMT and TGase-2<br />
in mRCC patients who were treated with sunitinib.<br />
Methods: We analyzed 82 RCC patients retrospectively. 43 of 82 survive without<br />
recurrence (non-metastatic group), 39 of 82 were already metastatic at <strong>the</strong> diagnosis<br />
or had metastasis during follow up (metastatic group). Expression of MGMT and<br />
TGase-2 proteins were assessed by immunohistochemical (IHC) staining in tissue<br />
samples.In <strong>the</strong> metastatic group, all patients received sunitinib as anti-angiogenic<br />
<strong>the</strong>rapy and <strong>the</strong> overall survival (OS) analysis of <strong>the</strong>se patients were performed<br />
ix274 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
according to time of sunitinib initiation. OS analysis of <strong>the</strong> entire group (metastatic<br />
and non-metastatic) were performed according to <strong>the</strong> time of diagnosis.<br />
Results: In <strong>the</strong> metastatic group (n = 39), <strong>the</strong> ones with low MGMT had median OS<br />
of 30 months while ones with high MGMT had median OS of 47 months (p =<br />
0.498). The ones with low TGase-2 had mean OS of 35.2 months while ones with<br />
high TGase-2 had mean OS of 27.9 months (p = 0.366).In <strong>the</strong> entire group, <strong>the</strong> ones<br />
with low MGMT had mean OS of 115 months while ones with high MGMT had<br />
median OS of 189 months (p = 0.498). The ones with low TGase-2 had mean OS of<br />
212 months while ones with high TGase-2 had mean OS of 133 months (p = 0.281).<br />
Conclusions: Higher MGMT and lower TGase-2 may be predictors of good response<br />
to sunitinib. Independent of <strong>the</strong> treatment, in <strong>the</strong> entire group <strong>the</strong> ones with higher<br />
MGMT and lower TGase-2 have better survival. All <strong>the</strong>se results are not statistically<br />
significant.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
831P A RETROSPECTIVE STUDY OF METASTASECTOMY IN<br />
METASTATIC RENAL CELL CARCINOMA<br />
A. Suder 1 , K. Thillai 2 , S. Rudman 3 , A. Chandra 4 , G. Rottenberg 5 ,<br />
B. Challacombe 6 , G. Kooiman 7 , P. Srinivasan 8 ,T.O’Brien 6 , S. Chowdhury 2<br />
1 Medical Oncology, Guy’s and St Thomas’s NHS Trust, London, UNITED<br />
KINGDOM, 2 Medical Oncology, Guys Hospital, London, UNITED KINGDOM,<br />
3 Medical Oncology Offices, 4th Floor Bermondsey Wing, Guys Hospital, Guys<br />
and St Thomas’s NHS Trust, London, UNITED KINGDOM, 4 Pathology, Guys<br />
Hospital, London, UNITED KINGDOM, 5 Radiology, Guy’s Hospital, London,<br />
UNITED KINGDOM, 6 Urology, Guys and St Thomas’s NHS Trust, London,<br />
UNITED KINGDOM, 7 Urology, Kings College, London, UNITED KINGDOM,<br />
8 Institute of Liver Studies, Kings College, London, UNITED KINGDOM<br />
Introduction: Despite significant advances in <strong>the</strong> systemic <strong>the</strong>rapy for metastatic<br />
renal cell carcinoma (mRCC) long term survival is rare. Systemic VEGF directed<br />
<strong>the</strong>rapy can be toxic and is expensive. Metastatectomy can delay or even completely<br />
avoid systemic <strong>the</strong>rapy. 5-year cancer specific survival rates of up to 73% have been<br />
reported in select patients.<br />
Methods: Patients who underwent metastasectomy for RCC recurrence in our<br />
institution between 2001–2011 were identified through a clinical database that was<br />
cross-referenced with a pathology database and multi-disciplinary team records.<br />
Patient characteristics N= 36 %<br />
Male/Female 25/11 70/30<br />
Median Age (range 44-85) 65 NA<br />
Primary tumour pT2 or less 4 10<br />
Radical nephrectomy 31 97*<br />
Clear cell histology 20 100**<br />
Median time to metastasectomy months (range) 24 5-230<br />
Number of metastases 1 27 77<br />
2-3 7 20<br />
3+ 1 3<br />
Site of metastases Lung 12<br />
Adrenal 7<br />
Bone 4<br />
O<strong>the</strong>r*** 4<br />
Upper GI 2<br />
Liver 2<br />
Minimum Heng risk score at time of metastasectomy Favourable 21<br />
Intermediate 11<br />
Poor 1<br />
Results: *evaluable patients n= 32, **n = 20 *** includes chest wall, ovary, thyroid,<br />
contralateral kidney Median time to first progression from surgery was 21 months<br />
(range 0-50). On progression 17/18 patients had repeat metastasectomy with 10/17<br />
relapsing at a site different to <strong>the</strong> original surgery. To date 11/36 have received<br />
additional <strong>the</strong>rapy including tyrosine kinase inhibitors (n = 7), radio<strong>the</strong>rapy (n = 3)<br />
and interferon (n = 1). Median overall survival from first metastasectomy has not<br />
been reached at mean follow up of 27 months. 27 patients are alive at last follow up<br />
with 14 disease free. Of <strong>the</strong> 13 evaluable patients, none are free from recurrence at 5<br />
years.<br />
Discussion: Despite limitations of retrospective design, selection bias and size, this<br />
data shows that metastasectomy is feasible in selected patients with mRCC. Our<br />
patients included a group with characteristics that have previously been described as<br />
less favourable for resection. Despite this preliminary overall survival data is<br />
encouraging.<br />
Conclusion: Metastatectomy is an important treatment option for selected patients<br />
with metastatic renal cell carcinoma. All patients should be managed in a<br />
multi-disciplinary manner to ensure that patients are considered for metastasectomy<br />
when appropriate.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
832P C-MYC AS A NEW PREDICTIVE BIOMARKER FOR SUNITINIB<br />
IN METASTATIC RENAL CLEAR CELL CARCINOMA<br />
P. Maroto 1 , E. Esteban 2 , E. Fernández-Parra 3 , M.J. Méndez-Vidal 4 ,<br />
M. Domenech 5 , L. León 6 , B. Pérez-Valderrama 7 , V. Calderero 8 ,<br />
J.L. Perez Gracia 9 , F. Algaba 10<br />
1 Dept. of Medical Oncology, Hospital de la Sta. Creu i St. Pau, Barcelona,<br />
SPAIN, 2 Medical Oncology, Hospital Universitario Central de Asturias, Oviedo,<br />
SPAIN, 3 Medical Oncology, Hospital Nuestra Señora de Valme, Seville, SPAIN,<br />
4 Medical Oncology, Hospital Reina Sofía, Cordoba, SPAIN, 5 Oncology, ALthaia,<br />
Xarxa Assistencial de Manresa, Manresa, SPAIN, 6 Medical Oncology, Hospital<br />
General de Santiago, Santiago de Compostela, SPAIN, 7 Medical Oncology,<br />
Hospital Virgen del Rocío, Seville, SPAIN, 8 Medical Oncology, Hospital<br />
Universitario Miguel Servet, Zaragoza, SPAIN, 9 Clinical Oncology, Clinica<br />
Universitaria de Navarra, Pamplona, SPAIN, 10 Medical Oncology, Fundación<br />
Puigvert, Barcelona, SPAIN<br />
Background: Sunitinib is a tyrosin kinase inhibitor with proven efficacy in renal clear<br />
cell carcinoma (RCC). However we still lack properly validated molecular predictors<br />
of response. Two subtypes of sporadic VHL-deficient RCC were proposed based on<br />
HIF1α and HIF2α expression and c-Myc activation. This molecular subclassification<br />
could provide a framework for current targeted <strong>the</strong>rapies. This study aims to explore<br />
<strong>the</strong> predictive value of this molecular signature.<br />
Methods: An observational prospective study involving 10 Spanish Hospitals was<br />
designed to collect formalin-fixed paraffin-embedded primary tumor tissue samples. We<br />
enrolled consecutively attending adults who had a centralized pathologically confirmed<br />
diagnosis of RCC with a clear-cell histology and advanced disease. Eligible patients were<br />
treatment naive and scheduled for sunitinib following routine clinical practice. The<br />
protocol was approved by <strong>the</strong> medical ethics committee of all participating institutions,<br />
and signed informed consent was obtained for all patients. Selected biomarkers were<br />
analyzed by immunohistochemistry following established protocols.<br />
Results: From March 2009 to February 2011, 80 patients were included. At <strong>the</strong> time<br />
of <strong>the</strong> analysis, tumor samples were available for 64 patients and 58 were evaluable<br />
for c-Myc expression. Only 33% (19/58) showed c-Myc immunostainig (any score:<br />
1–3) and 67% (39/58) were negative for c-Myc expression (scored as 0). Both groups<br />
were well balanced and non significant differences in risk prognostic factors were<br />
found. Regarding Sunitinib efficacy, significant differences in PFS were found<br />
between both molecular subgroups. A median PFS of 5.4 months was found in<br />
patients with c-Myc positive primary tumors vs. 11.4 months in patients with c-Myc<br />
negative primary tumors (HR = 2.54, 95%CI (1.28, 5.07), p = 0.0062). Correlation of<br />
c-Myc expression with o<strong>the</strong>r related biomarkers is underway.<br />
Conclusions: Although, this is a small sample and validation is still needed, <strong>the</strong>se<br />
results suggest a promising value for c-Myc immunostaining as a novel tool to<br />
identify those patients with RCC with more probabilities of obtaining benefit with<br />
Sunitinib through an accessible and reproducible technique.This study was supported<br />
by an Independent Investigator Research grant from Pfizer Inc.<br />
Disclosure: P. Maroto: Compensation of consultant/Advisory role at Pfizer. E.<br />
Esteban: Compensation of consultant/Advisory role at Pfizer. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
833P DYNAMIC CHANGES IN PLASMA OSTEOPONTIN AS A<br />
MARKERS OF TUMOR RESPONSE IN METASTATIC RENAL<br />
CELL CARCINOMA (RCC) PATIENTS TREATED WITH<br />
PAZOPANIB<br />
H.T. Tran 1 , Y. Liu 2 ,Y.Lin 2 , A.J. Zurita Saavedra, 3 , K.L. Baker-Neblett 4 ,<br />
VEG105192 Team and investigators 5 , L.N. Pandite 6 , J.V. Heymach 7<br />
1 Cancer Medicine, UT MD Anderson Cancer Center, Houston, TX, UNITED<br />
STATES OF AMERICA, 2 Oncology Research and Development, GlaxoSmithKline,<br />
Philadelphia, PA, UNITED STATES OF AMERICA, 3 Genitourinary Med Oncology<br />
Dept, MD Anderson Cancer Center, Houston, TX, UNITED STATES OF<br />
AMERICA, 4 Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline,<br />
Research Triangle Park, NC, UNITED STATES OF AMERICA, 5 VEG102616<br />
Investigators, patients and team, 6 GlaxoSmithKline, Research Triangle Park, NC,<br />
UNITED STATES OF AMERICA, 7 Thoracic/Head and Neck Medical Oncology,<br />
MD Anderson Cancer Center, Houston, TX, UNITED STATES OF AMERICA<br />
Background: In a Phase II RCC study of pazopanib (VEG102616) a response rate of<br />
34.7% and disease control rate (CR + PR +SD) of 80% were observed (Hutson, JCO<br />
2009. Previously, we reported that elevated levels of E-Selectin, lower levels of IL-6<br />
and HGF were correlated with longer PFS and decrease in tumor shrinkage. Higher<br />
levels of IL-6 and IL-8 correlated with greater tumor burden (Tran ASCO 2010).<br />
IL-8, OPN, HGF and TIMP1 correlated with PFS and IL-6, IL-8 and OPN were<br />
prognostic markers (Yuan GU ASCO 2011, Tran <strong>ESMO</strong> 2011). In this study, we<br />
measured CAF levels at baseline, week 4 and week 12 after inititation of pazopanib<br />
<strong>the</strong>rapy and evaluated for dynamic changes in CAF as potential marker for tumor<br />
response and clinical benefits<br />
Methods: Six candidate CAFs (TIMP1, IL-6, IL-8, HGF, E-Selectin, and OPN) were<br />
measured in 173 patients (pts) whose plasma samples were collected during <strong>the</strong><br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds399 | ix275
treatment at week 4, and week 12 by using Searchlight Protein Array (Aushon). CAF<br />
levels at each time point and changes of CAF levels from baseline at week 4 and<br />
week 12 were correlated with maximum tumor shrinkage (MTS) by linear regression;<br />
PFS by Cox regression; baseline tumor burden using baseline sum of longest tumor<br />
diameter and best response by Spearman.<br />
Results: Decreases in OPN levels from baseline at week 4 (p = 0.030) and week 12<br />
(p = 0.006) show significant correlations with MTS. At week 4, changes in E-Selectin<br />
from baseline was trending (p = 0.053) in correlation with MTS. With PFS, changes<br />
in IL-6 level from baseline at week 12 has near significant correlation with PFS (p =<br />
0.05). E-Selectin has an inverse baseline to week 4 significant correlation with best<br />
response status week 4 (p = 0.0245) but not at week 12.<br />
Conclusion: Decreasing levels of osteopontin from baseline at week 4 and 12<br />
correlated with improved tumor shrinkage; while increase in IL-6 portends shorter<br />
PFS and E-Selectin was inversely correlated with best response status. Additional<br />
investigation is needed to evaluate <strong>the</strong> dynamic changes of CAFs as an approach to<br />
monitor patients while on pazopanib <strong>the</strong>rapy as marker of tumor response.<br />
Disclosure: Y. Liu: Stock ownership: Yes; GSK Membership on an advisory board or<br />
board of directors: No Corporate-sponsored research: No O<strong>the</strong>r substantive<br />
relationships: NoA. Martin: Stock ownership: Yes; GSK Membership on an advisory<br />
board or board of directors: No Corporate-sponsored research: No O<strong>the</strong>r substantive<br />
relationships: NoK.L. Baker-Neblett: Stock ownership: Yes; GSK Membership on an<br />
advisory board or board of directors: No Corporate-sponsored research: No O<strong>the</strong>r<br />
substantive relationships: No. L.N. Pandite: Stock ownership: Yes; GSK Membership<br />
on an advisory board or board of directors: No Corporate-sponsored research: No<br />
O<strong>the</strong>r substantive relationships: No. J.V. Heymach: Stock ownership: No Membership<br />
on an advisory board or board of directors: Yes; GSK Corporate-sponsored research:<br />
Yes; GSK for biomarker analysis. O<strong>the</strong>r substantive relationships: No. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
834P RECIST RESPONSE OF THE PRIMARY LESION IN<br />
METASTATIC RENAL CELL CARCINOMAS TREATED WITH<br />
SUNITINIB: DOES THE PRIMARY LESION HAVE TO BE<br />
REGARDED AS A TARGET LESION?<br />
I. Park 1 , K. Park 1 , S. Park 1 ,Y.Ahn 1 , J. Ahn 1 , H.J. Choi 2 , C. Song 3 , H. Ahn 3 ,<br />
J.H. Hong 3 , J. Lee 1<br />
1 Department of Oncology, Asan Medical Center, University of Ulsan College of<br />
Medicine, Seoul, KOREA, 2 Department of Radiology, Asan Medical Center,<br />
University of Ulsan College of Medicine, Seoul, KOREA, 3 Department of Urology,<br />
Asan Medical Center, University of Ulsan College of Medicine, Seoul, KOREA<br />
Background: There is no consensus on including <strong>the</strong> primary lesion as <strong>the</strong> target<br />
lesion when evaluating <strong>the</strong> response of non-nephrectomized metastatic renal cell<br />
carcinoma (mRCC) patients (pts). We evaluated whe<strong>the</strong>r best overall response<br />
changes by designating primary renal lesions as ei<strong>the</strong>r target or non-target lesions<br />
and assessing response per RECIST in mRCC pts treated with sunitinib. In addition,<br />
we evaluated whe<strong>the</strong>r discordance, if any, leads to a difference in predictive value of<br />
response in terms of time-to-progression (TTP) and overall survival (OS).<br />
Patients and methods: Among pts with histologically confirmed mRCC treated with<br />
sunitinib at Asan Medical Center, pts with an intact primary tumor and at least one<br />
extra-renal measurable lesion were included. To measure <strong>the</strong> influence of including<br />
<strong>the</strong> primary lesion as <strong>the</strong> target lesion, <strong>the</strong> variation of <strong>the</strong> sum of diameters (ΔSOD)<br />
of target lesions and best overall response, assessed from all target lesions and from<br />
metastasis-only target lesions, was documented separately. For examining differences<br />
of two methods in predictive function in estimating TTP and OS, pts were<br />
categorized according to <strong>the</strong>ir best overall responses as responders [complete<br />
response (CR) and partial response (PR)] or non-responders [stable disease (SD) and<br />
progressive disease (PD)] for all target lesions and metastasis-only target lesions,<br />
respectively, and <strong>the</strong>n analyzed for survival.<br />
Results: Forty-one pts were included in this study. Median ΔSOD of <strong>the</strong> primary<br />
lesion and metastatic target lesion were −6.0% (range, −34.0–17.6%), and −18.0%<br />
(range, −100.0–120.0%), respectively. For metastasis-only target lesions, <strong>the</strong> best<br />
overall response of two pts (4.9%) changed from SD to PR. When we categorized pts<br />
into responders and non-responders, response determination using metastasis-only<br />
target lesions resulted in significantly better discrimination of TTP (14.9 vs 4.3<br />
months, P = 0.001) and OS (18.5 vs 9.6 months, P = 0.036) between two groups.<br />
Using all target lesions, both TTP (14.9 vs 5.4 months, P = 0.056) and OS (18.0 vs<br />
10.6 months, P = 0.155) were not statistically significant.<br />
Conclusion: When treating non-nephrectomized mRCC pts, selecting<br />
metastasis-only lesions as target lesions might be better to determine response, which<br />
might be more representative of TTP and OS.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
835P TISSUE MICROARRAY (TMA) AND VHL MUTATIONS AS<br />
PREDICTORS OF OUTCOME IN ADVANCED CLEAR CELL<br />
RENAL CELL CARCINOMA (CCRCC) TREATED WITH FIRS<br />
LINE SUNITINIB<br />
J.F. Rodríguez-Moreno 1 , E. Esteban 2 , M. Morente 3 , I. Alemany 4 ,<br />
D.E. Castellano 5 , A. Gonzalez Del Alba 6 , M. Climent 7 ,<br />
C. Rodriguez-Antona 3 , J. Garcia-Donas 1<br />
1 Medical Oncology, Centro Integral Oncológico Clara Campal, Madrid, SPAIN,<br />
2 Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, SPAIN,<br />
3 Human Genetic, Spanish National Cancer Research Center, Madrid, SPAIN,<br />
4 Medical Oncology, Hospital Universitario Fundacion Alcorcon, Alcorcon, SPAIN,<br />
5 Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, SPAIN,<br />
6 Medical Oncology, Hospital Universitario Son Espases, Palma de Mallorca,<br />
SPAIN, 7 Medical Oncology, Instituto Valenciano de Oncologia, Valencia, SPAIN<br />
Introduction: Sunitinib is a standard treatment for kidney cancer, however in some<br />
patients response is lacking. Molecular predictors of outcome could deeply impact<br />
patient care.<br />
Methods: We conducted an observational, prospective study in 15 institutions<br />
members of <strong>the</strong> Spanish Oncology Genitourinary Group (SOGUG). Inclusion criteria<br />
were patients with confirmed advanced clear cell renal cell carcinoma with no prior<br />
treatment, planned to receive sunitinib according to local practice.From paraffin<br />
embedded tumor samples a Tissue MicroArray (TMA) was constructed and<br />
evaluated independently by two pathologists, also blinded to clinical data. Expression<br />
of Carbonic Anhydrase IX, P-glicoprotein, Vascular Endo<strong>the</strong>lial Growth Factor<br />
(VEGF), VEGF-Receptor 1,2 and 3 (VEGFR1,2 and 3), Platelet-Derived Growth<br />
Factor Receptor (PDGFR-Beta), Hypoxia-Inducible Factor 2 alpha (HIF2α) and Von<br />
Hippel-Lindau protein (pVHL) was assessed. In addition <strong>the</strong> presence of VHL gene<br />
mutations was studied.<br />
Results: 101 patients were recruited from 2007 to 2010. TMA was constructed from<br />
69 tumor samples. In multivariable analysis, HIF2α (HR 0.17 (0.05-0.64) p = 0.0083)<br />
and PDGFRβ (HR 0.042 (0.003-0.70) p = 0.028) overexpression correlated with<br />
progressive disease (PD) as best response. A similar trend in PFS and OS was<br />
observed for HIF-alfa but did not reach statistical significance.Progression free<br />
survival (PFS) was longer in cases with high VEGFR3 expression (HR 0.42<br />
(0.21-0.83) p = 0.013). Interestingly, low levels of this protein strongly correlated<br />
(r = -0.441 P = 0.0003) with <strong>the</strong> presence of a germline SNP (VEGFR3 rs307826) that<br />
has been previously identified as a sunitinib resistance predictor by our group.Finally<br />
overexpression of VEGF (HR 4.6 (1.5-13.6), p= 0.0063), and VEGFR1 (HR 6.2<br />
(1.2-32.2) p = 0.031) were associated with poor overall survival (OS).VHL gene<br />
alterations could only be determined in 30 cases, with 20 (66%) presenting a<br />
pathological mutation. No association with outcome could be established.<br />
Conclusion: Expression of some proteins involved in neoangiogenesis pathway could<br />
play a role in sunitinib sensitivity and resistance. A significant association between<br />
low expression of VEGFR3 and one SNP in such gene, both correlated with poor<br />
outcome, deserves fur<strong>the</strong>r investigation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
836P PROGNOSTIC FACTORS AND VALIDATION OF PROGNOSTIC<br />
NOMOGRAMS IN PATIENTS (PTS) TREATED WITH 3<br />
TARGETED THERAPIES (TTS) FOR METASTATIC RENAL CELL<br />
CARCINOMA (MRCC): RESULTS FROM AN ITALIAN SURVEY<br />
R. Iacovelli 1 , M. Rizzo 2 , V. Lorusso 3 , F. Atzori 4 , P.A. Zucali 5 , C. Sacco 6 ,<br />
F. Boccardo 7 , F. Valduga 8 , F. Massari 9 , G. Procopio 10<br />
1 Department of Radiology, Oncology and Human Pathology, Sapienza University<br />
of Rome, Rome, ITALY, 2 Medical Oncology, Azienda Ospedaliera Antonio<br />
Cardarelli, Naples, ITALY, 3 Medical Oncology Unit, Ospedale Vito Fazzi, Lecce,<br />
ITALY, 4 Medical Oncology, Azienda Ospedaliero Universitaria Cagliari,<br />
Monserrato, ITALY, 5 Department of Oncology, Humanitas Cancer Center IRCCS,<br />
Rozzano, ITALY, 6 Medical Oncology, University Hospital, Udine, ITALY, 7 Dept. of<br />
Medical Oncology B, IRCCS AOU San Martino - IST-Istituto Nazionale per la<br />
Ricerca sul Cancro, Genova, ITALY, 8 Medical Oncology, St Chiara Hospital,<br />
Trento, ITALY, 9 Medical Oncology, Azienda Ospedaliera Universitaria Integrata<br />
Verona-“Borgo Roma”, Verona, ITALY, 10 Medical Oncology, Fondazione IRCCS -<br />
Istituto Nazionale dei Tumori, Milano, ITALY<br />
Background: Outcomes of pts treated with three TTs for mRCC have not been well<br />
characterized. Survival data as well as existing prognostic criteria in this population<br />
were evaluated.<br />
ix276 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Table: 836P<br />
Cleveland Clinic French Heng MSKCC<br />
P Group Pts (%) PFS (mos) p Pts (%) PFS (mos) p Pts (%) PFS (mos) P Pts (%) PFS (mos) p<br />
Good 20 NR ULN; PLT > ULN; Neu > ULN, and<br />
sites of disease >2 had negative prognostic role. Multivariate analysis shows an<br />
independent prognostic role only for ECOG-PS ≥ 2 (HR: 1.8; 95%CI: 1.1–2.8), Hb <<br />
LLN (HR: 1.8; 95%CI: 1.2–2.6) and neu > ULN (HR: 2.1; 95%CI: 1.2–3.8). Pts were<br />
stratified in 3 groups according to <strong>the</strong> presence of none, 1 or ≥2 prognostic factors.<br />
The median OS was 20.3, 13.6 and 7.8 months, respectively (p < 0.0001)<br />
Conclusions: Current nomograms are able to predict survival in patients with mRCC<br />
before <strong>the</strong> 3 rd line with TT. Neutrophils, platelets and ECOG-PS were <strong>the</strong> most<br />
important prognostic factors.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
837P SECOND LINE TREATMENT IN METASTATIC PAPILLARY<br />
RENAL CELL CARCINOMA: RETROSPECTIVE ANALYSIS OF A<br />
48 PATIENTS COHORT<br />
L. Albiges 1 , F. Riet 1 , C. Massard 1 , S. Le Moulec 2 , Y. Loriot 1 , A. Levy 1 , K. Fizazi 1 ,<br />
B. Escudier 1<br />
1 Department of Medical Oncology, Institut Gustave Roussy, Villejuif, FRANCE,<br />
2 Oncology and Radiation Oncology, Hôpital d’Instruction des Armées du<br />
Val-de-Grâce, Paris, FRANCE<br />
Background: Papillary renal cell carcinoma (pRCC) accounts for 10-15% of mRCC.<br />
Although standard VEGF/mTOR inhibitors were retrospectively assessed in this<br />
setting, <strong>the</strong>re is no specific recommendation for this subtype. First line prospective<br />
dedicated studies are to be released shortly. No second line data have been reported<br />
so far.<br />
Material and methods: All pts with metastatic pRCC treated in first line from May<br />
2006 to Nov 2011 at Institut Gustave Roussy, were retrospectively analysed. Clinical<br />
data, prognosis classifications and treatments were assessed; PFS after first and<br />
second line treatments and OS were calculated.<br />
Results: Forty-eight pts with metastatic pRCC were identified. Median age at<br />
diagnosis was 62, sex ratio 41M / 7F. Histological subtypes were type 2 (67%), type I<br />
(10%), and unclassified (23%). Nephrectomy had been performed in 38 pts (78%).<br />
Most pts presented with synchronous metastatic disease (68%). Metastatic sites were<br />
respectively: lung (52%), retroperitoneal LN (44%), mediastinal LN (46%), bone<br />
(25%), liver (23%). Prognostic classification by MSKCC was good in 14, intermediate<br />
in 27 and poor in 4 pts. Median OS was 16.2 months [1-70], 21/48 pts are still alive<br />
with a median follow up of 24 months. A majority of pts (77%) was enrolled in<br />
prospective phase II and III clinical trials as first or second line treatment, o<strong>the</strong>rs<br />
were treated according to guidelines. As first line treatment, pts received: sunitinib<br />
(25), everolimus (19), sorafenib (2), bevacizumab based regimen (2). Median first line<br />
PFS is 8.0 months [1-43]. Thirty-two (73 %) pts received a second line treatment<br />
after first line failure. Second line treatment included VEGFR-TKI (19) including<br />
sunitinib (11), sorafenib (6) and pazopanib (2) or mTOR inhibitor (12). Median<br />
second line PFS is 3.3 months [1-34]. Median PFS is 3.0 months after TKI and 3.7<br />
months after mTOR inhibitors. Noteworthy fourteen patients (29%) received a third<br />
line treatment.<br />
Conclusions: This is <strong>the</strong> first report of second line data in pRCC. Median second<br />
line PFS is 3.3 months, similar for mTOR inhibitors and VEGFR-TKI agents.<br />
Never<strong>the</strong>less PFS post-second line treatment in pRCC is lower than that observed in<br />
clear cell RCC, pointing out <strong>the</strong>ir poorer prognosis and <strong>the</strong> need for biology-driven<br />
dedicated targeted <strong>the</strong>rapy development.<br />
Disclosure: L. Albiges: Laurence Albiges declares Novartis (compensated) and pfizer<br />
(uncompensated) consultant role and honoraria from novartis for o<strong>the</strong>r topic. No<br />
funding or honoraria related to <strong>the</strong> submitted abstract. K. Fizazi: Participation to<br />
advisory boards and/or speaker for: – Amgen – Astrazeneca – Novartis – Sanofi–<br />
Aventis – Keocyt – Ipsen – Janssen – Astellas – BMS – Bayer. B. Escudier:<br />
Consultant: Bayer, Pfizer, Roche, GSK, Aveo Honorario: Bayer, Roche, Pfizer,<br />
Genentech, Novartis, aveo. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
838P EXPRESSION AND CLINICAL IMPORTANCE OF E-CADHERIN,<br />
DYSADHERIN AND CHEMOKINE LIGAND 2 (CCL2) IN RENAL<br />
CELL CARCINOMA (RCC)<br />
U. Demirci 1 , M. Yaman 2 , S. Buyukberber 3 , O. Ekinci 4 , S. Ozkan 5 , U. Coskun 3 ,<br />
M. Benekli 3 , A. Ozet 3 , Ü.E. Bagriacik 2<br />
1 Medical Oncology, Atatürk Education and Research Hospital, Ankara, TURKEY,<br />
2 Immunology, Gazi University Faculty of Medicine, Ankara, TURKEY, 3 Medical<br />
Oncology, Gazi University Faculty of Medicine, Ankara, TURKEY, 4 Pathology,<br />
Gazi University Faculty of Medicine, Ankara, TURKEY, 5 Public Health, Gazi<br />
University Faculty of Medicine, Ankara, TURKEY<br />
Aim: Dysadherin is a cell adhesion molecule that related with aggresiveness and<br />
progression in many cancers. Dysadherin acts role ei<strong>the</strong>r with E-cadherine<br />
dependent or CCL-2 mediated that E-cadherin independent. We studied expression<br />
and clinical importance of dysadherin and e-cadherin as adhesion molecules and<br />
CCL2 in RCC.<br />
Method: Between 2006 and 2010, 38 patients with RCC were evaluated<br />
retrospectively. Median age of <strong>the</strong> patients (27 male, 11 female) was 60 (range, 33–<br />
84). While median tumor size was 5.75 cm (range, 2–30 cm), 13 patients were stage<br />
4, one patient was stage 3, 5 patients were stage 2, 19 patients were stage 1. 15<br />
patients were Fuhrmann grade ¾, 21 patients (55.3%) had capsule invasion, 10<br />
patients (26.3%) had perirenal fat tissue involvement and 4 patients had (10.5%)<br />
renal vein thrombosis. Dysadherin did not express in 10 patients. Low expression<br />
(less than %30) was detected in 25 patients (65.8%), enhanced expression (more than<br />
30%) was detected in 3 patients (%7.9). E-cadherin did not express in 11 patients<br />
(28.9%), low expression was detected in 23 patients (60.5%), moderate-high<br />
expression was detedcted 4 patients (10.6%). CCL2 did not express in 14 patients,<br />
low expression was detected in 7 patients (%18.4), moderate-high expression was<br />
detected in 17 patients (44.3%). Although moderate positive correlation between<br />
dysadherin and CCL2 (r= +0,25, p = 0.49), e-cadherin and CCL2 (r= +0.25, p = 0.33)<br />
were detected, moderate negative correlation between dysadherin and e-cadherin was<br />
detected (r= +0.22, p = 0.66). Moderate negative correlation was detected between<br />
grade of tumor and e-cadherin (r= -0.25, p = 0.49). Median overall survival (OS) was<br />
46.6 months (range, 38.9-54.3), In univariate analysis, stage, grade of tumor, capsule<br />
invasion, tumor thrombosis, perirenal fat tissue involvement were significant<br />
interaction on OS (p < 0.05), however dysadherin, E-cadherin and CCL2 were not<br />
associated with OS (>0.05). Stage and vascular thrombosis were significant on overall<br />
survival in multivariate analysis.<br />
Conclusion: This is <strong>the</strong> first study that evaluated adhesion molecules in RCC and<br />
<strong>the</strong>re is no association <strong>the</strong>se parameters and clinical outcome.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
839P EFFICACY AND SAFETY OF TEMSIROLIMUS IN PATIENTS<br />
WITH METASTATIC RENAL CELL CARCINOMA: RESULTS<br />
FROM THE SPANISH EXPERIENCE<br />
L. Ruiz 1 , E. Esteban 1 , L. León 2 , A. Pinto 3 , C. Suarez 4 , I. Duran 5 , N. Lainez 6 ,<br />
A. Lopez 7 , A. Viqueira 8 , P. Maroto 9<br />
1 Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, SPAIN,<br />
2 Medical Oncology, Hospital General de Santiago, Santiago de Compostela,<br />
SPAIN, 3 Medical Oncology, Hospital Universitario La Paz, Madrid, SPAIN,<br />
4 Oncology, Hospital Vall d’Hebron, Barcelona, SPAIN, 5 Departamento de<br />
Oncologia, Hospital Madrid Norte San ChinarroCentro Integral Oncologico Clara<br />
Campal, Madrid, SPAIN, 6 Medical Oncology, Complejo Hospitalario de Navarra,<br />
Pamplona, SPAIN, 7 CRA, Trial Form Support, Madrid, SPAIN, 8 Oncology, Pfizer,<br />
Madrid, SPAIN, 9 Dept. of Medical Oncology, Hospital de la Sta. Creu i St. Pau,<br />
Barcelona, SPAIN<br />
Temsirolimus (TEM) is an mTOR inhibitor approved for first-line treatment of<br />
patients with poor-prognosis metastatic renal cell carcinoma (RCC). In a phase III<br />
trial TEM showed a statistically significant benefit in overall survival when compared<br />
to interferon-α. Recently, several authors have described that TEM also appears to be<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds399 | ix277
effective in second or fur<strong>the</strong>r lines of treatment. Here we report <strong>the</strong> Spanish<br />
experience with TEM both in first and subsequent lines of treatment.<br />
A retrospective, observational and multicenter study of TEM used following routine<br />
clinical practice in patients with RCC was carried out. Patients treated with TEM<br />
between 2007 and <strong>2012</strong> were included. The objective of <strong>the</strong> study was to analyze <strong>the</strong><br />
efficacy and safety of TEM. A total of 101 patients were included, 70% were male and<br />
<strong>the</strong> median age was 62. According to Motzer Criteria, 13% patients had a favorable<br />
prognosis, 44% an intermediate prognosis and 43% a poor prognosis. Of <strong>the</strong> 101<br />
patients, 53% were treated with TEM in 1st line, 18% in 2nd line, 23% in 3rd line<br />
and 4% in 4th or fur<strong>the</strong>r lines; 23% were patients with non-clear cell RCC and 28%<br />
were non-nephrectomized. Median PFS for all patients was 3 months. The clinical<br />
benefit rate was 59% with an ORR of 17% (all partial responses) and 42% of disease<br />
stabilization. In patients treated in 1st line, median PFS was 3 months, in patients<br />
treated in subsequent lines median PFS were 5, 4 and 1 months in 2nd, 3rd and 4th<br />
line respectively. In non-nephrectomized patients and patients with non-clear RCC<br />
median PFS was 3 months for both subgroups. In terms of tolerability, 79% of <strong>the</strong><br />
patients developed at least one adverse event (AE). Most common AE (all grades)<br />
were anemia (39%), as<strong>the</strong>nia (22%), stomatitis (20%) and rash (15%). TEM appears<br />
to have a modest efficacy and an acceptable toxicity profile in patients with RCC,<br />
both in first and subsequent lines of treatment. TEM seems to achieve similar efficacy<br />
in patient subgroups such as non-nephrectomized patients and patients with<br />
non-clear histologies. Efficacy seems to be consistent with previous reports in second<br />
and third lines of treatment, but seems to be somewhat lower in first line, probably<br />
due to <strong>the</strong> poor-risk profile of <strong>the</strong> patients.<br />
Disclosure: E. Esteban: Compensated advisory/consultant role for Pfizer. A. Lopez:<br />
CRA at TFS working for Pfizer. A. Viqueira: Pfizer Employee. P. Maroto:<br />
Compensated advisory/consultant role for Pfizer. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
840P SEQUENTIAL TARGETED THERAPY FOLLOWING PAZOPANIB<br />
(PZ) IN PATIENTS (PTS) WITH METASTATIC RENAL CELL<br />
CANCER (MRCC): EFFICACY AND TOXICITY<br />
F. Pons Valladares 1 , T.K. Choueiri 2 , T.E. Hutson 3 , T.B. Powles 4 , C. Porta 5 ,<br />
S. Bracarda 6 , M.E. Lampron 2 , L. Cerbone 7 , C.N. Sternberg 7 , J. Bellmunt 1<br />
1 Medical Oncology, University Hospital del Mar, Barcelona, SPAIN, 2 Medical<br />
Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital and<br />
Harvard Medical School, Boston, MA, UNITED STATES OF AMERICA, 3 Gu<br />
Center of Excellence Texas Oncology, Charles A. Sammons Cancer Center /<br />
Baylor University Medical Center / Texas AM Health Science Center College of<br />
Medicine, Dallas, TX, UNITED STATES OF AMERICA, 4 Department of Medical<br />
Oncology, St. Bartholomew’s Hospital, London, UNITED KINGDOM, 5 Oncologia<br />
Medica, Ospedale San Matteo, Pavia, ITALY, 6 Department of Oncology,<br />
Ospedale San Donatoand U.O.C. of Medical Oncology, Arezzo, ITALY, 7 Medical<br />
Oncology, San Camillo and Forlanini Hospital, Rome, ITALY<br />
Background: The optimal sequence for a switch from pazopanib (PZ) to ano<strong>the</strong>r<br />
targeted <strong>the</strong>rapy (VEGF or mTOR inhibitor) is not yet defined. Recent findings<br />
suggest that <strong>the</strong> sequential use of anti-VEGF <strong>the</strong>rapies may provide similar PFS<br />
(Progression Free Survival) benefit than mTOR inhibitors. We embarked on<br />
characterizing <strong>the</strong> clinical outcome to targeted <strong>the</strong>rapies after <strong>the</strong> use of PZ from a<br />
multicenter retrospective study.<br />
Methods: We reviewed <strong>the</strong> records of 36 pts with mRCC from 6 sites in Europe and<br />
US who received ei<strong>the</strong>r a VEGF or an mTOR inhibitor after PZ. Pts and disease<br />
characteristics (demographic data, MSKCC and Heng prognostic score), disease<br />
outcome (objective response, PFS) and toxicity were compared between <strong>the</strong> two<br />
sequential treatment options.<br />
Results: The median age was 62 (range 30–79) and 89% were males, mostly with<br />
clear-cell histology (97.2%) and good or intermediate MSKCC (97%) and Heng<br />
(93%) prognostic score. PZ was given as second line <strong>the</strong>rapy after cytokines (n= 7) or<br />
sunitinib (n = 2) in 25% of pts, and as first line in 75%. Median PFS for PZ<br />
treatment was 9.3 months (mo) (CI 95%: 6,3–12,4 mo). Post- PZ <strong>the</strong>rapies were:<br />
anti-VEGF in 23 patients (sorafenib n = 10, sunitinb n = 3, cediranib n = 4,<br />
cabozantinib n = 3 and bevacizumab n = 3) and mTOR inhibitors in 13 (everolimus<br />
(EV)). Median duration of post-PZ <strong>the</strong>rapy was 6.2 mo in anti-VEGF and 2.6 mo in<br />
EV-treated pts (p = 0.017). Partial Response (PR) was only observed in 2 pts treated<br />
with anti-VEGF agents. Clinical benefit (PR+ Stable Disease) was observed in 80%<br />
and 33% of anti-VEGF and EV treated patients (p = 0.021). The most common<br />
Grade 1-2 adverse events (AE) were as<strong>the</strong>nia (50%), diarrhea (31,8%), Hand-foot<br />
syndrome (27%), rash (22,7%) and stomatitis (13,6%) for <strong>the</strong> anti-VEGF treated<br />
group; and as<strong>the</strong>nia (30,8%), respiratory toxicity (23%) and metabolic alterations<br />
(15,4%) for EV. Grade 3-4 AE occurred in 18% of anti-VEGF and 23% of EV<br />
groups. Median PFS was 7,3 mo for anti-VEGF and 2,4 mo for EV, with a HR of<br />
0,36 (CI 95% 0.16 – 0.81; p = 0.014).<br />
Conclusions: In this retrospective study, anti-VEGF <strong>the</strong>rapy resulted in acceptable<br />
PFS benefit in post-PZ treated patients, and was well tolerated. These findings<br />
support <strong>the</strong> sequential use of an anti-VEGF in post PZ progression. The different<br />
type of anti-VEGF agents in this study is a major limitation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
841P POOLED ANALYSIS OF NON-INTERVENTIONAL STUDIES OF<br />
EVEROLIMUS IN PATIENTS WITH METASTATIC RENAL CELL<br />
CARCINOMA (MRCC) REFRACTORY TO ANTI-VEGF THERAPY<br />
L. Bergmann 1 , U. Kube 2 , L. Albiges 3 , J. Eymard 4 , M. Schmidinger 5 , A. Bamias 6 ,<br />
M. Ktiouet 7 , G. Fischer 8 , D. Xanthaki 9 , G. Guderian 10<br />
1 Tumor Center Rhein-Main, University Hospital Frankfurt, Frankfurt/Main,<br />
GERMANY, 2 Urology, Private practice, Chemnitz, GERMANY, 3 Department of<br />
Medical Oncology, Institut Gustave Roussy, Villejuif, FRANCE, 4 Clinical Research<br />
and Cell Therapy, Institut Jean Godinot, Reims, FRANCE, 5 Department of<br />
Medicine I, Medical University of Vienna, Vienna, AUSTRIA, 6 Department of<br />
Clinical Therapeutics, A<strong>the</strong>ns University, Medical School, A<strong>the</strong>ns, GREECE,<br />
7 Solid Tumors, Novartis Pharma, Paris, FRANCE, 8 Oncology, Novartis Pharma<br />
GmbH, Vienna, AUSTRIA, 9 Oncology, Novartis (Hellas) S.A.C.I., A<strong>the</strong>ns,<br />
GREECE, 10 Solid Tumors and Early Clinical Development, Novartis Pharma<br />
GmbH, Nuremberg, GERMANY<br />
Background: The oral mTOR inhibitor everolimus has demonstrated statistically<br />
significant PFS benefit over placebo in patients with mRCC refractory to 1 or 2<br />
previous VEGFr-tyrosine kinase inhibitors. Here, we report prospective data on<br />
everolimus in routine clinical practice from four European countries after failure of<br />
anti-VEGF <strong>the</strong>rapy.<br />
Patients and methods: Data were pooled from four prospective, non-interventional<br />
studies to evaluate <strong>the</strong> safety and effectiveness of everolimus in Germany, France,<br />
Greece, and Austria.<br />
Results: Data from <strong>the</strong> first 6 months of treatment of 534 patients were pooled for<br />
this analysis. At baseline, median time since diagnosis of RCC was 2.6 years and<br />
median time since diagnosis of first metastasis was 1.8 years. Most patients had<br />
predominantly clear cell mRCC (90%), had previously undergone nephrectomy<br />
(89%), and at initiation of everolimus <strong>the</strong>rapy were of favourable or intermediate<br />
MSKCC risk prognosis (91%). According to investigator’s assessment, 13% of<br />
patients achieved partial response and 56% of patients achieved stable disease.<br />
Overall, 77% of patients reported at least one adverse event (AE) and 22% of patients<br />
reported at least one serious AE. The most common AEs (all grades) were stomatitis<br />
(25%), anaemia (13%), as<strong>the</strong>nia (9%), fatigue (8%), pneumonitis (8%), rash (8%),<br />
diarrhoea (7%), decreased appetite (7%), hypertriglyceridaemia (6%), dyspnoea (6%),<br />
and nausea (6%). The most common serious AEs were stomatitis (3.4%), general<br />
health deterioration (2.2%), anaemia (2.1%), dyspnoea (2.1%), and pneumonitis<br />
(2.1%). A total of 24% of patients discontinued due to AEs. Percentages of patients<br />
with Karnofsky performance status ≥70 were similar at baseline (86%) and at end of<br />
this analysis (80%).<br />
Conclusions: Results of this pooled analysis of European non-interventional studies of<br />
everolimus in patients with mRCC who failed previous anti-VEGF <strong>the</strong>rapy confirm its<br />
safety previously reported in <strong>the</strong> pivotal multi-national RECORD-1 trial and provide<br />
preliminary information about <strong>the</strong> effectiveness of everolimus in routine use. The results<br />
support everolimus as standard of care in VEGF-refractory patients with mRCC.<br />
Disclosure: L. Bergmann: Lothar Bergmann has served on advisory boards for<br />
Novartis, Pfizer, Roche, Astellas, and GlaxoSmithKline and has received honoraria<br />
from Novartis, Pfizer, Roche, and GlaxoSmithKline. L. Albiges: Laurence Albiges is<br />
consultant to Novartis and Pfizer; has received honoraria from Novartis, Bayer, and<br />
Sanofi-Aventis; and has received research funding from Novartis. M. Schmidinger:<br />
Manuela Schmidinger has received honoraria from Pfizer, GlaxoSmithKline,<br />
Novartis, Roche, and Astellas; has served as advisor for Pfizer, Roche,<br />
GlaxoSmithKline, Novartis, and Astellas; and has received research grants from<br />
Pfizer and Roche. M. Ktiouet: Meryem Ktiouet is an employee of Novartis Pharma.<br />
G. Fischer: Gregor Fischer is an employee of Novartis Pharma GmbH. D. Xanthaki:<br />
Despoina Xanthaki is an employee of Novartis (Hellas) S.A.C.I. G. Guderian: Gernot<br />
Guderian is an employee of Novartis Pharma GmbH. All o<strong>the</strong>r authors have declared<br />
no conflicts of interest.<br />
842P BIOMARKERS OF EVEROLIMUS EFFICACY IN PATIENTS WITH<br />
METASTATIC RENAL CELL CARCINOMA (MRCC): ANALYSIS<br />
OF THE PHASE III RECORD-1 TRIAL<br />
S. Oudard 1 , B. Escudier 2 , J. Thompson 3 , V. Grünwald 4 , P.F. Conte 5 ,<br />
S. Bracarda 6 , A. Panneerselvam 7 , S. Gogov 8 , D. Chen 7 , R.J. Motzer 9<br />
1 Oncology Translational Research Unit, Hopital Europeen Georges-Pompidou,<br />
Paris, FRANCE, 2 Immuno<strong>the</strong>rapy Unit, Institut Gustave Roussy, Villejuif, FRANCE,<br />
3 Medical Oncology, Seattle Cancer Care Alliance, Seattle, WA, UNITED STATES<br />
OF AMERICA, 4 Clinic for Hematology, Hemostasis, Oncology, and Stem Cell<br />
Transplantation, Hannover Medical School, Hannover, GERMANY, 5 Oncology,<br />
Universita degli Studi di Modena e Reggio Emilia, Modena, ITALY, 6 Medical<br />
Oncology, Ospedale San Donato, Arezzo, ITALY, 7 Oncology Biometrics and Data<br />
Management, Novartis Pharmaceuticals Corporation, Florham Park, NJ, UNITED<br />
STATES OF AMERICA, 8 Oncology, Novartis Pharma AG, Basel, SWITZERLAND,<br />
9 Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center,<br />
New York, NY, UNITED STATES OF AMERICA<br />
Background: In RECORD-1, everolimus significantly increased median PFS<br />
(primary end point) over placebo in VEGFr-TKI-refractory patients with mRCC. We<br />
ix278 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
investigated angiogenesis pathway molecules, sVEGFR-2, VEGF-A, and bFGF, in<br />
plasma as potential biomarkers of everolimus efficacy in RECORD-1.<br />
Material and methods: Patients received everolimus 10 mg daily (n = 277) or placebo<br />
(n = 139), both with BSC; placebo patients could cross over to everolimus at disease<br />
progression. Pre-dose blood samples were collected on day 1 of <strong>the</strong> first four 28-day<br />
treatment cycles; plasma levels of sVEGFR-2, VEGF-A, and bFGF were assessed<br />
using ELISA. A mixed effects model was used to assess treatment effect over time on<br />
each biomarker. Hazard ratios (HR) for prognostic effects were obtained using log<br />
baseline biomarker values as continuous variables in a stratified Cox proportional<br />
hazards model.<br />
Results: Plasma values for sVEGFR-2, VEGF-A, and bFGF were available for 45/45/<br />
39% of everolimus patients and 50/50/45% of placebo patients. Baseline<br />
characteristics of patients with biomarker data were similar to <strong>the</strong> overall population.<br />
Mean log baseline values for sVEGFR-2, VEGF-A, and bFGF were similar for both<br />
arms; 9.1/5.1/1.6 for everolimus and 9.1/5.2/1.8 for placebo, respectively. Median PFS<br />
was significantly improved with everolimus vs placebo, regardless of baseline levels of<br />
any of <strong>the</strong> biomarkers analyzed (P < .001), suggesting that none of <strong>the</strong>m is predictive<br />
of everolimus efficacy. Lower VEGF-A baseline level (HR, 1.27; 95% CI, 1.03-1.57;<br />
P = .028) was significantly associated with longer PFS in <strong>the</strong> trial population,<br />
suggesting that this biomarker may be prognostic for mRCC. Over <strong>the</strong> time course of<br />
<strong>the</strong> study, a significant everolimus treatment effect over placebo on reducing bFGF<br />
and sVEGFR-2 levels was observed (P = .0095 and P < .001, respectively), but not on<br />
VEGF-A level.<br />
Conclusions: Everolimus provided significant clinical benefit over placebo, regardless<br />
of baseline biomarker levels. However, lower VEGF-A level was seen as a potential<br />
prognostic factor for longer PFS. Plasma levels of bFGF and sVEGFR-2 were<br />
significantly down-regulated from baseline by everolimus treatment.<br />
Disclosure: S. Oudard: Stephane Oudard received honoraria from Bayer, Novartis,<br />
Pfizer, Roche, and Sanofi-Aventis. B. Escudier: Bernard Escudier has received<br />
honorariumfromNovartis,Pfizer,GSK,Aveo,andBayer.J.Thompson:John<br />
Thompson received clinical study support from Novartis. V. Grünwald: Viktor<br />
Grunwald served as consultant to Roche, Bayer, Novartis, Pfizer,<br />
GlaxoSmithKline, and Aveo/Astellas, received honoraria from GlaxoSmithKline,<br />
Novartis, and Pfizer, and received research funding from Pfizer and<br />
GlaxoSmithKline. S. Bracarda: Sergio Bracarda has served as advisor for Pfizer,<br />
Bayer-Schering, GlaxoSmithKline, Novartis, Aveo/Astellas, Boheringer-Ingelheim,<br />
Johnson & Johnson, and Sanofi-Aventis and has received speaker fees from Pfizer,<br />
Novartis,andSanofi-Aventis.A.Panneerselvam:AshokPanneerselvamisan<br />
employee of Novartis Pharmaceuticals Corporation. S. Gogov: Sven Gogov is an<br />
employee of Novartis Pharma AG. D. Chen: David Chen is an employee of<br />
Novartis Pharmaceuticals Corporation. R.J. Motzer: Robert Motzer has received<br />
research funding from Novartis. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
843P AXITINIB (AXI) AND EVEROLIMUS (EVE) IN THE TREATMENT<br />
(TX) OF SUNITINIB-REFRACTORY (SU-R) PATIENTS (PTS)<br />
WITH METASTATIC RENAL CELL CARCINOMA (MRCC):<br />
RESULTS OF A SIMULATED TX COMPARISON (STC)<br />
ANALYSES<br />
I. Proskorovsky 1 , A. Benedict 2 , S. Negrier 3 , J. Larkin 4 , R. Sandin 5 , C. Chen 6<br />
1 Biostatistics, United BioSource Corporation, Dorval, QC, CANADA, 2 Health<br />
Economics, United BioSource Corporation, Budapest, HUNGARY, 3 Medical<br />
Oncology, Comprehensive Cancer Center Leon Berard, Lyon Cedex, FRANCE,<br />
4 Medical and Clinical Oncology, Royal Marsden Hospital London, London,<br />
UNITED KINGDOM, 5 Global Outcomes Research, Pfizer AB, Sollentuna,<br />
SWEDEN, 6 Global Health Outcomes, Pfizer, New York, NY, UNITED STATES OF<br />
AMERICA<br />
Background: Axi is a novel VEGF targeted agent for mRCC pts who failed 1 prior<br />
systemic <strong>the</strong>rapy. <strong>the</strong> The AXIS trial compared axi to sorafenib and showed a<br />
significantly longer PFS in pts treated with axi, including <strong>the</strong> su-r subgroup. No<br />
direct comparison is available between axi and eve but is an important clinical<br />
question. The goal of this analysis was to compare OS and PFS in su-r pts treated<br />
with axi and eve.<br />
Methods: Pts who were su-r and received axi in <strong>the</strong> AXIS trial and eve in<br />
RECORD-1 trial were considered for this analysis. A STC method (Caro et al 2010)<br />
was used to derive OS and PFS curves for a hypo<strong>the</strong>tical cohort of “axi like” pts had<br />
<strong>the</strong>y received eve in <strong>the</strong> AXIS trial. Pt level AXIS data was used to derive predictive<br />
equations for OS and PFS. Parametric survival analysis identified <strong>the</strong> best fitting<br />
distribution and significant predictors of OS and PFS. These equations were<br />
calibrated using pt characteristics and median OS and PFS reported in <strong>the</strong> literature.<br />
Results: 194 axi and 124 eve pts who were su-r were analyzed. While AXIS trial<br />
included only pts that progressed on 1 line of tx, 65% of su-r eve pts had 3 plus<br />
lines of <strong>the</strong>rapy. Some pts were included in <strong>the</strong> eve trial without having<br />
progressed on 1 st line tx. Available pt characteristics were comparable across two<br />
groups, except for difference in MSKCC risk categories (36% vs 17% poor risk pts<br />
in axi and eve respectively), mean duration of prior su (57 vs 44 weeks) and<br />
ECOG score (52% vs 60% with ECOG 0). A log-normal distribution provided <strong>the</strong><br />
best fit for both OS and PFS. MSKCC risk category and duration of prior<br />
sunitinib were significant predictors of OS. The final PFS equation included<br />
MSKCC risk group and age. Estimated median OS and PFS was 15.2 and 5.1<br />
months for axi compared to 10.6 and 3.6 months for eve group respectively.<br />
Estimated difference in mean OS and PFS between axi and eve was 7.6 and 2.6<br />
months.<br />
Conclusion: This analysis suggest that su-r RCC pts treated with axi may have an<br />
improved OS and PFS compared to pts treated with eve. Our analysis could not<br />
account for all differences between trials, such as number of prior <strong>the</strong>rapies, however,<br />
a STC can provide additional comparative context.<br />
Disclosure: I. Proskorovsky: I am an employee of United BioSource Corporation. As<br />
a research consulting organization, it received funding from Pfizer for <strong>the</strong> research<br />
undertaken in this abstract. A. Benedict: I am an employee of United BioSource<br />
Corporation. As a research consulting organization, it received funding from Pfizer<br />
for <strong>the</strong> research undertaken in this abstract. S. Negrier: Dr. Negrier has received<br />
honorariums from Pfizer and Novartis as well as research grants from<br />
GlaxoSmithKline and Roche. J. Larkin: research funding from Pfizer and Novartis,<br />
advisory role to Pfizer, Novartis, GSK, BMS, Aveo. R. Sandin: Employee of Pfizer AB.<br />
Stock or o<strong>the</strong>r ownership interests in Pfizer Inc. C. Chen: Employee and stockholder<br />
of Pfizer only<br />
844P SORAFENIB IN PATIENTS WITH RENAL CELL CARCINOMA<br />
(RCC) AND BASELINE HYPERTENSION OR DIABETES:<br />
SUBANALYSIS OF THE NON-INTERVENTIONAL PREDICT<br />
STUDY<br />
D. Jäger 1 , J. Guo 2 , E. Korbenfeld 3 , M. Zemanova 4 , N. Leonhartsberger 5 ,<br />
K. Stauch 6 , A. Boeckenhoff 7 ,J.Yu 8 , J. Mardiak 9 , B. Escudier 10<br />
1 National Center for Tumor Diseases, University Medical Center Heidelberg,<br />
Heidelberg, GERMANY, 2 Renal Cancer and Melanoma Unit, Peking University<br />
Cancer Hospital and Institute, Beijing, CHINA, 3 Oncology, Hospital Británico de<br />
Buenos Aires, Buenos Aires, ARGENTINA, 4 First Faculty of Medicine, Charles<br />
University, Prague, CZECH REPUBLIC, 5 Department of Urology, Medical<br />
University Innsbruck, Innsbruck, AUSTRIA, 6 Global Non-interventional Studies,<br />
Bayer HealthCare, Leverkusen, GERMANY, 7 Global Development - Global<br />
Clinical Development, Bayer HealthCare, Wuppertal, GERMANY, 8 Global Medical<br />
Affairs, Bayer HealthCare, Montville, NJ, UNITED STATES OF AMERICA,<br />
9 Department of Medical Oncology, National Cancer Institute, Bratislava, SLOVAK<br />
REPUBLIC, 10 Department of Immuno<strong>the</strong>rapy, Institut Gustave Roussy, Villejuif,<br />
FRANCE<br />
Background: Many patients (pts) with advanced RCC have comorbidities<br />
(particularly elderly pts), but pts with comorbidities are often underrepresented in<br />
clinical trials. PREDICT (NCT 00895674) was a large, non-interventional study of<br />
sorafenib (Sor) in pts with advanced RCC in clinical practice. We report findings in<br />
pts with baseline comorbidities.<br />
Methods: Pts diagnosed with advanced RCC and prescribed Sor under compliance<br />
of <strong>the</strong> local product label were eligible. Physician assessments of efficacy and<br />
tolerability were collected for ≤12 months.<br />
Results: The most frequent comorbidities were hypertension (HTN; n = 674)<br />
and diabetes (n = 225); baseline characteristics in <strong>the</strong>se pts (71–73% male, 82–<br />
87% prior nephrectomy, 82–83% clear cell histology) were similar to <strong>the</strong> total<br />
efficacy population (n = 2311; 71% male, 84% prior nephrectomy, 83% clear cell<br />
histology). Pts with HTN (38%; n = 254) and diabetes (38%; n = 85) were more<br />
likely to be aged ≥70 years vs <strong>the</strong> total efficacy population (23%; n = 532).<br />
Median duration of <strong>the</strong>rapy (DOT) in pts with HTN (6.7 months) or diabetes<br />
(7.0 months) was similar to <strong>the</strong> total efficacy population (7.3 months). A<br />
similar trend was seen for all pts aged ≥70 years (median DOT: total efficacy<br />
population, 6.1 months; HTN subset, 6.0 months; diabetes subset, 6.4 months).<br />
Best tumor response per RECIST was similar in <strong>the</strong> total group (complete<br />
response [CR], 2%; partial response [PR], 22%; stable disease [SD], 47%; and<br />
progressive disease [PD], 4%) and comorbid groups (CR, 1–2%; PR, 22–23%;<br />
SD, 43–48%; PD, 4–5%). In general, adverse event (AE) rates were<br />
slightly higher in pts with comorbidities than in <strong>the</strong> total safety population<br />
(Table).<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds399 | ix279
Conclusions: In pts with RCC treated in clinical practice settings, some AE rates<br />
were numerically higher in pts with comorbidities. There were no notable differences<br />
in duration of Sor <strong>the</strong>rapy. Number (%) pts with AEs (safety population)<br />
Comorbidity subset<br />
Hypertension Diabetes<br />
Total<br />
population<br />
Event<br />
(n = 760)<br />
(n = 267) (n = 2599)<br />
Any AE 524 (69.0) 177 (66.3) 1479 (56.9)<br />
Any<br />
drug-related<br />
AE<br />
436 (57.4) 146 (54.7) 1240 (47.7)<br />
Any SAE 191 (25.1) 71 (26.6) 477 (18.4)<br />
Any<br />
drug-related<br />
SAE<br />
59 (7.8) 20 (7.5) 140 (5.4)<br />
Most frequently reported any grade drug-related AEs (preferred term)*<br />
Hand–foot skin<br />
reaction<br />
173 (22.8) 55 (20.6) 520 (20.0)<br />
Diarrhea 177 (23.3) 62 (23.2) 443 (17.1)<br />
Rash †<br />
62 (8.2) 14 (5.2) 220 (8.5)<br />
Alopecia 49 (6.5) 15 (5.6) 145 (5.6)<br />
Hypertension 52 (6.8) 10 (3.8) 110 (4.2)<br />
Nausea 33 (4.3) 15 (5.6) 67 (2.6)<br />
O<strong>the</strong>r AEs in relevant system organ classes<br />
Cardiac<br />
disorders<br />
7 (0.9) 1 (0.4) 16 (0.6)<br />
Renal and<br />
urinary<br />
disorders<br />
7 (0.9) 3 (1.1) 13 (0.5)<br />
Vascular<br />
disorders<br />
(excluding<br />
hypertension)<br />
7 (0.9) 2 (0.7) 15 (0.6)<br />
*Occurring in ≥5% of patients in any subset. † Including rash, rash generalized, rash<br />
ery<strong>the</strong>matous, rash maculo-papular, rash pustular, rash macular, rash pruritic,<br />
exfoliative rash, rash papular. AE, adverse event; SAE, serious adverse event<br />
Disclosure: D. Jäger: Dirk Jäger has received honoraria from Bayer, Amgen, Pfizer,<br />
Novartis, Roche, Fresenius Kabi and Hoffmann-La Roche. M. Zemanova: Milada<br />
Zemanova has received consulting and lecture fees from Glaxo Smith Kline and<br />
Roche. N. Leonhartsberger: Nicolai Leonhartsberger has received honoraria from<br />
Bayer, Pfizer and Roche. K. Stauch: Kathrin Stauch is an employee of Bayer<br />
HealthCare and owns stock in Bayer Pharma AG. A. Boeckenhoff: Annette<br />
Boeckenhoff is an employee of Bayer HealthCare and owns stock in Bayer Pharma<br />
AG. J. Yu: Jian Yu is an employee of Bayer HealthCare. J. Mardiak: Jozef Mardiak<br />
has received Research Grants from Novartis and has received honoraria from Pfizer<br />
and Pierre Fabre. B. Escudier: Bernard Escudier has served in an advisory role for<br />
Pfizer, Novartis, Roche, GSK, Bayer and Aveo, and has received honoraria from<br />
Pfizer, Novartis, Roche, GSK, Bayer and Aveo. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
845P BIOLOGICAL TOXICITY CAN BE A SURROGATE MARKER OF<br />
EFFICACY IN PATIENTS (PTS) TREATED WITH MTOR<br />
INHIBITORS (MTORI) FOR MRCC<br />
M. Jebali 1 , J. Fouque 2 , G. Fargues 2 , A. Jouinot 1 , R.T. Elaidi 3 , S. Oudard 1 ,<br />
J. Medioni 1<br />
1 Medical Oncology, Hopital Europeen Georges-Pompidou, Paris, FRANCE,<br />
2 Pharmacy, Hopital Europeen Georges-Pompidou, Paris, FRANCE, 3 Oncology,<br />
Association pour la Recherche sur les Therapeutiques Innovantes en<br />
Cancerologie, Paris, FRANCE<br />
Background: Biological toxicities of mTORi are well characterized. We investigate<br />
retrospectively if <strong>the</strong>re is a link between biological toxicities and mTORi efficacy.<br />
Patients and methods: Biological toxicities were retrospectively collected in patients<br />
treated with an mTORi (Everolimus [Ev], Temsirolimus [Tem]) for mRCC at <strong>the</strong><br />
European G. Pompidou Hospital in Paris, France between 2007 and 2011. Only pts<br />
having received mTORi for at least 28 days were eligible. Lymphocytes, creatinaemia,<br />
glycaemia, phosphoraemia, liver transaminases, cholesterolaemia, and<br />
Annals of Oncology<br />
triglyceridaemia were recorded with onset date and higher grade (NCI-CTC 3.0).<br />
Time to onset and onset velocity defined as <strong>the</strong> absolute change from baseline (%)<br />
divided by <strong>the</strong> time to onset were calculated for each adverse event. Efficacy was<br />
assessed with time to progression (TTP) from <strong>the</strong> initiation of mTORi until disease<br />
progression/death and objective response according to RECIST criteria 2.0.<br />
Kaplan-Meier estimates with log-rank test were used to compare categorical data and<br />
Cox model for continuous data and hazard ratios.<br />
Results: 75 pts were included. Median age = 56 y (37-86), sex ratio = 4/1 (M/F), pts<br />
on Ev (N = 44)/Tem (N = 31) according to setting: 1st = 2/6, 2nd = 9/11, 3rd = 14/9,<br />
≥4th = 20/4. 10 pts on Ev had a dose reduction. Objective response: PR = 6, SD = 40,<br />
PD = 20. 7 patients discontinued due to toxicity and 2 for personal decision. Median<br />
follow-up time = 22.8 mo. Median TTP = 7.3 mo (95% CI, 4.7-10.8). Hyperglycaemia<br />
and hypophosphoraemia are less important in progressors (P < 0.05). TTP was<br />
significantly associated with onset velocity of lymphocytopaenia (events = 21/44,<br />
HR = 0.98, P = 0.026), hypophosphoraemia (events = 7/11, HR = 0.94, P = 0.044) and<br />
hypertriglyceridaemia (events = 23/33, HR = 1.005, P = 0.023).<br />
Conclusions: Lymphocytopaenia, hyperglycaemia, hypophosphoraemia, and<br />
hypertriglyceridaemia were significantly related to objective response or TTP. These<br />
events, toge<strong>the</strong>r with <strong>the</strong>ir onset velocity, should be prospectively monitored to<br />
investigate <strong>the</strong>ir predictive value for efficacy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
846P MEDICAL OPTIMIZATION OF TORISEL® (MOTOR): A PHASE II<br />
TRIAL OF TEMSIROLIMUS AS SECOND-LINE TREATMENT<br />
FOR ADVANCED RCC BY THE ITALIAN KIDNEY CANCER<br />
GROUP (GIR)<br />
M. Milella 1 , G. Di Lorenzo 2 , A. Felici 1 , M. Aieta 3 ,G.LoRe 4 , C. Boni 5 , E. Aitini 6 ,<br />
E. Villa 7 , S. De Placido 2 , F. Cognetti 1<br />
1 Divisione di Oncologia Medica A, Istituto Nazionale Tumori Regina Elena, Roma,<br />
ITALY, 2 Department of Oncology, Cattedra di Oncologia Medica, Università degli<br />
Studi Federico II, Napoli, ITALY, 3 Medical Oncology, Department of Medical<br />
Oncology, National Institute of Cancer, Rionero in Vulture, Rionero, ITALY,<br />
4 Oncology, Medical Oncology, Pordenone, ITALY, 5 Oncology Dept., Arcispedale<br />
S. Maria NuovaDivisione di Oncologia, Reggio Emilia, ITALY, 6 Med. Oncology &<br />
Hematology Dept., Ospedale C. Poma, Mantova, ITALY, 7 Medical Oncology,<br />
Istituto Scientifico S. Raffaele - IRCCS, Rome, ITALY<br />
Purpose: The mammalian target of rapamycin (mTOR) kinase is a well-established<br />
<strong>the</strong>rapeutic target in renal cell carcinoma (RCC). We explored <strong>the</strong> activity and safety<br />
of Temsirolimus as II-line treatment for advanced RCC pts in a multicenter phase II<br />
trial.<br />
Methodology: in this open-label trial, Temsirolimus (25 mg/wk i.v.) was<br />
administered to advanced RCC pts with documented progression after any I-line<br />
treatment. Primary endpoint was PFS rate at 6 mos. Tumor response was assessed<br />
every 8 wks. Considering a 6-mo PFS rate of 20% unacceptable (p0 = 20%) and a<br />
6-mo PFS rate of 40% (p1 = 40%) of interest, a minimum targeted accrual of 47 pts<br />
in <strong>the</strong> sunitinib-pretreated group was to be pursued in order to reach 90% power at a<br />
significance level of 5%.<br />
Results: From May 2009 to January <strong>2012</strong>, 76 pts were enrolled (median age: 67 yrs,<br />
range: 36-86; M/F: 58/18; ECOG PS 0/1/2: 51/19/6); I-line <strong>the</strong>rapy included sunitinib<br />
(60 pts), bevacizumab (8), sorafenib (3), cytokines (2), or o<strong>the</strong>r (3). With 18/57<br />
evaluable patients free from progression at 6 mos in <strong>the</strong> sunitinib-pretreated group<br />
<strong>the</strong> primary endpoint was met and trial accrual was stopped. Median PFS was 4.0<br />
mos (95% CI: 2.7–5.3) and 4.6 mos (95% CI: 2.8–6.5) in <strong>the</strong> overall (n = 71) and<br />
sunitinib-pretreated (n = 57) populations, respectively; OS in <strong>the</strong> same groups was<br />
13.7 mos (95% CI: 9.1–18.3) and 14.6 mos (95% CI: 8.9-20.3), respectively. Six out of<br />
71 pts (8%) had PR and 33/71 (46%) had SD as <strong>the</strong>ir best response. Toxicity (n = 68)<br />
was mild with G3 anemia, neutropenia and thrombocytopenia in 2, 1, and 1 pts,<br />
respectively; G3 hyperglycemia and G3 hypertriglyceridemia in 2 and 7 pts,<br />
respectively; G4 hypercholesterolemia in 2 pts; G3 stomatitis in 5 pts; G3 as<strong>the</strong>nia in<br />
3 pts; G3-4 pulmonary toxicity in 2 pts; G3 diarrhea in 2 pts; G3 cutaneous rash in 1<br />
pt. Only 1 hypersensitivity reaction occurred during Temsirolimus infusion.<br />
Treatment compliance was good, with
Annals of Oncology<br />
847P CLINICAL EFFICACY OF SUNITINIB AS POST-OPERATIVE<br />
ADJUVANT THERAPY IN PATIENTS WITH HIGH-RISK RENAL<br />
CELL CARCINOMA<br />
X. Zhang 1 , J.Y. Yuan 2 , L. Wang 2 , L. Chen 3 ,J.Pan 4 ,L.Ye 5 , X. Xiao 6 , J. Qiu 7 ,<br />
K. Zhang 8 ,G.Ye 9<br />
1 Urology Department, The General Hospital of <strong>the</strong> People’s Liberation Army,<br />
Beijing, CHINA, 2 Urology Department, Xijin Hospital, <strong>the</strong> Fourth Military Medical<br />
University, Xian, CHINA, 3 Urology Department, 307 Hospital of PLA, Beijing,<br />
CHINA, 4 Urology Department, Southwest Hospital, <strong>the</strong> Third Military Medical<br />
University, Chongqing, CHINA, 5 Urology Department, 304 Hospital of PLA,<br />
Beijing, CHINA, 6 Urology Department, General Hospital of Armed Police Forces,<br />
Beijing, CHINA, 7 Urology Department, Bethune International Peace Hospital of<br />
PLA, Jilin, CHINA, 8 Urology Department, Daping Hospital, <strong>the</strong> Third Military<br />
Medical University, Chongqing, CHINA, 9 Urology Department, Xinqiao Hospital,<br />
<strong>the</strong> Third Military Medical University, Chongqing, CHINA<br />
Objective: To evaluate <strong>the</strong> efficacy and safety of Sunitinib as post-operative adjuvant<br />
<strong>the</strong>rapy in patients with high-risk renal cell carcinoma (RCC).<br />
Methods: A total of 60 patients with resected, histologically confirmed clear cell RCC<br />
were enrolled in this study. Patients received orally Sunitinib ei<strong>the</strong>r at a dose of 50mg<br />
on treatment schedule 4/2 (once daily for 4 weeks followed by 2 weeks off) or at a<br />
dose of 37.5mg once daily for three 6-week cycles from 1 month after surgery.<br />
Results: All 60 patients tolerated Sunitinib treatment well and no patient<br />
discontinued treatment due to adverse events. Most adverse events were grade I to II.<br />
The most frequently reported adverse events were neutropenia (56.7%),<br />
thrombocytopenia (53.3%), leucopenia (48.3%), hand-foot syndrome (46.7%) and<br />
hypertension (36.7%). The most frequently reported grade 3 or 4 toxicities were<br />
thrombocytopenia (25%), neutropenia (15%), hand-foot syndrome (11.7%) and<br />
leucopenia (8.3%). The majority of adverse events occurred within <strong>the</strong> first 1-2 cycles<br />
of Sunitinib treatment, and was ameliorated 1 month after 3 cycles finished. No<br />
irreversible adverse event was observed. As of April 5, <strong>2012</strong>, no recurrence occurred<br />
in patients except one death due to cerebrovascular accident unrelated to treatment,<br />
with both 6-month and 9-month disease-free survival (DFS) rate of 100%.<br />
Conclusion: Myelosuppression occurred less frequently in high-risk RCC patients<br />
treated with Sunitinib as operative adjuvant <strong>the</strong>rapy than in advanced RCC patients,<br />
with a better benefit trend. However, long-term follow-up data are needed to fur<strong>the</strong>r<br />
confirm <strong>the</strong> efficacy of Sunitinib in <strong>the</strong> adjuvant setting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
848P OVERALL SURVIVAL (OS) IN METASTATIC RENAL CELL<br />
CARCINOMA (MRCC): A COMPARISON BETWEEN SORAFENIB<br />
(SO) AND BEST SUPPORTIVE CARE (BSC) AFTER FIRST LINE<br />
TREATMENT WITH SUNITINIB (SU) IN SWEDEN<br />
P. Sandström 1 , R. Sandin 2 , J. Kowalski 3 , T. Wahlgren 4 , M. Jakobsson 4 ,<br />
S. Lundstam 5 , B. Ljungberg 6 , U. Harmenberg 1<br />
1 Department of Oncology-pathology, Karolinska University Hospital and<br />
Karolinska Institutet, Stockholm, SWEDEN, 2 Global Health Economics and<br />
Outcomes Research, Onology, Pfizer AB, Sollentuna, SWEDEN, 3 Department of<br />
Clinical Science, Intervention and Technology, Karolinska University Hospital<br />
Huddinge and Karolinska Institutet, Stockholm, SWEDEN, 4 Oncology, Pfizer AB,<br />
Sollentuna, SWEDEN, 5 Department of Urology, University Hospital, and <strong>the</strong><br />
Sahlgrenska Academy, Go<strong>the</strong>nburg, SWEDEN, 6 Department of Surgical and<br />
Perioperative Sciences, Urology and Andrology, Umeå University, Umeå,<br />
SWEDEN<br />
Background: There is a paucity of efficacy data after first line treatment with SU in<br />
mRCC. This retrospective register study compared OS in patients treated with SO<br />
and BSC after first line treatment with SU in Sweden.<br />
Methods: Three Swedish national health registers were used: <strong>the</strong> Swedish Cancer<br />
register (diagnosis and death), <strong>the</strong> National Patient Register (in-/out-patient data),<br />
and <strong>the</strong> Swedish Prescribed Drug Register. 135 patients identified with mRCC,<br />
diagnosed no later than 2009, were recorded as having received 1st-line treatment<br />
with SU; 59 patients received SO and 76 patients received BSC. Multivariate analysis<br />
was performed using <strong>the</strong> Cox proportional hazards model including estimation of<br />
adjusted OS. The regression model included <strong>the</strong> covariates: age, gender,<br />
nephrectomy, time since diagnosis and metastatic disease, time since mRCC<br />
diagnoses and start of systemic <strong>the</strong>rapy, geographical region, institutional size, and<br />
duration of first line SU treatment. Sensitivity analysis with combinations of<br />
explanatory variables, was performed to test <strong>the</strong> robustness of <strong>the</strong> results.<br />
Results: Patients characteristics differed between <strong>the</strong> SO and BSC patients, but<br />
available information did not indicate a clear advantage in favor of any treatment<br />
arm. OS for patients prescribed with SO was improved compared with OS for BSC<br />
patients. Including all covariates, median adjusted OS was 9,9 vs. 6,6 months,<br />
respectively for patients treated with SO and BSC (HR = 0.652, 95% CI: 0.412, 1.030;<br />
P < 0.067). Sensitivity analysis showed a robust and significant reduction in risk of<br />
death for patients treated with SO; range of 29-42% (HR: 0,58-0,71). In all models,<br />
nephrectomy was independently associated with significantly improved OS. O<strong>the</strong>r<br />
individual covariates were generally not statistically significant, likely due to a low<br />
number of observations.<br />
Conclusion: An improved OS for mRCC patients was seen in patients receiving<br />
SO compared to BSC after first line treatment with SU. Some caution should be<br />
taken with interpreting <strong>the</strong> results as confounding due to unmeasured covariates<br />
may exist.<br />
Disclosure: P. Sandström: Has had an advisory role for Pfizer, Roche, GSK, Novartis,<br />
and Bayer, has received honoraria from Pfizer, Roche, bayer, GSK and Novartis and<br />
has received research funding from Pfizer and Bayer. R. Sandin: Rickard Sandin is an<br />
employee of Pfizer AB and owns Pfizer stock. J. Kowalski: Jan Kowalski is concultant<br />
and received compensation from Pfizer for <strong>the</strong> statistical work for <strong>the</strong> abstract.<br />
T. Wahlgren: Thomas Wahlgren is an employee of Pfizer AB and owns Pfizer stock.<br />
M. Jakobsson: Maria Jakobsson is an employee of Pfizer AB and owns Pfizer stock.<br />
S. Lundstam: Has had an advisory board role for GSK and Bayer, has received<br />
honoraria from Pfizerand GSK, and has received research funding from Pfizer.<br />
B. Ljungberg: Has had an advisory role for Pfizer, GSK, Novartis, Astellas and Bayer,<br />
and has received honoraria from Pfizer, Novartis, GSK and Bayer. U. Harmenberg:<br />
Has had an advisory role for Pfizer, Roche, GSK, Novartis, and Bayer, has received<br />
honoraria from Pfizer, Roche, and Novartis and has received research funding from<br />
Pfizer, GSK and Novartis.<br />
849P SUNITINIB RECHALLANGE IN METASTATIC RENAL CELL<br />
CARCINOMA PATIENTS<br />
K. Nagyivanyi1 , K. Bíró2 , F. Gyergyay2 , Z. Küronya2 , H. Nemeth2 , L. Géczi2 1<br />
Chemo<strong>the</strong>rapy C, National Institute of Oncology, Budapest, HUNGARY,<br />
2<br />
Chemo<strong>the</strong>rapy C and Clinical Pharmacology, National Institute of Oncology,<br />
Budapest, HUNGARY<br />
Background: Sunitinib is an active agent in <strong>the</strong> first line treatment of metastatic clear<br />
cell kidney cancer, based on <strong>the</strong> result of a global phase III study. However, complete<br />
remission is rarely seen and multiply sequential <strong>the</strong>rapies are used in this patient<br />
population. Since options in third line setting are limited, we assessed <strong>the</strong> clinical<br />
activity of sunitinib rechallenge after failure on o<strong>the</strong>r <strong>the</strong>rapies.<br />
Methods: 323 kidney cancer patients were treated with sunitinib from November<br />
2005 to January <strong>2012</strong> in our department. Retrospective data were collected for those<br />
9 patients who we rechallenged with sunitinib failing to at least two previous<br />
<strong>the</strong>rapies, including sunitinib. Patient characteristics, objective response based on<br />
RECIST criteria and progression-free survival (PFS) were analysed. Tumor<br />
assessment was performed every 2nd cycle of sunitinib or every 3 months<br />
Results: Data of 8 men and 1 woman of median age (at sunitinib challenge 59 years,<br />
at sunitinib rechallenge 63 years) with metastatic clear cell cancer of <strong>the</strong> kidney were<br />
analysed. All patients had nephrectomy prior treatment. Initial treatment with<br />
sunitinib was associated with a median progression free survival (PFS) of 13,7<br />
months. Objective response was partial remissions (PR) as best response. At <strong>the</strong> time<br />
of re-exposure patients again showed clinical benefit which was associated with a<br />
median PFS of 6,8 months and consisted of 1 (11%) PR and 5 (55%) disease<br />
stabilizations. PD was seen in 3 (33%) patients.<br />
Conclusions: In sunitinib-responsive patients, re-challenge with sunitinib has been<br />
successful and was well tolerated ei<strong>the</strong>r after an o<strong>the</strong>r TKI or mTOR inhibitor and it<br />
seems to be a valid option as a third line treatment.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
850P GENETIC POLYMORPHISMS AND SUNITINIB TOXICITY IN<br />
METASTATIC RENAL-CELL CARCINOMA<br />
J. Sepulveda Sanchez 1 , C. Farfan 2 , F. Villacampa 3 , G. Velasco 4 , J. Benitez 5 ,<br />
C. Rodriguez 6 , M. Calderon 2 , I. Cañamares 7 , H. Cortes-Funes 1 ,<br />
D.E. Castellano 1<br />
1 Servicio De Oncologia Medica, University Hosptial 12 De Octubre Medical<br />
Oncology, Madrid, SPAIN, 2 Medical Oncology, Hospital Universitario 12 de<br />
Octubre, Madrid, SPAIN, 3 Urology- Urooncology Unit, Hospital Universitario 12<br />
de Octubre, Madrid, SPAIN, 4 Medical Oncology, Hopital 12 de Octubre, Madrid,<br />
SPAIN, 5 Clinical Pharmacology & Pharmacogenetics, University of Extremadura<br />
Medical School & Infanta Cristina University Hospital, Badajoz, SPAIN, 6 Biology,<br />
Centro Nacional de Investigaciones Científicas, Madrid, SPAIN, 7 Pharmacy,<br />
Hospital Universitario 12 de Octubre, Madrid, SPAIN<br />
Background: Sunitinib (SU) is a multi-targeted receptor tyrosine kinase inhibitor<br />
that is approved for <strong>the</strong> treatment of renal cell carcinoma (RCC). However, several<br />
patients ei<strong>the</strong>r do not respond to treatment or <strong>the</strong>y experience significant toxicity.<br />
Our study aims to find genetic markers of toxicity and efficacy using a commercially<br />
available DNA microarray genotyping system.<br />
Methods: 30 patients with newly diagnosed metastatic RCC, from January 2010 to<br />
May 2011, were evaluated prospectively at Hospital 12 de Octubre (Madrid, Spain).<br />
Pts received SU in repeated 6-wk cycles of 50 mg/day (4 wks on followed by 2 wks<br />
off treatment). A total of 92 of single nucleotide polymorphisms (SNPs) in 34 genes<br />
in <strong>the</strong> pharmacokinetic and pharmacodynamic pathways of drugs were analyzed<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds399 | ix281
using Drug inCode ® pharmacogenetic service. SNPs in candidate genes, toge<strong>the</strong>r<br />
with clinical characteristics were tested univariately for association with <strong>the</strong> number<br />
of days of SU treatment until <strong>the</strong> first reduction of dose, PFS and OS.<br />
Results: Complete analysis was possible in 25 pts. Pts with CYP1A2*1/*1. a low<br />
metabolizing genotype, had an increased risk of dose reductions due to toxicity<br />
compare to allele *1F (Median time to dose reduction: 2.33 months Vs NR; p <<br />
0.006). Pts with CYP2C19*1/*1, wild type genotype, had an increased risk of dose<br />
reductions due to toxicity versus o<strong>the</strong>r genotypes (Median time to dose reduction:<br />
2.8 months Vs 9.73 months; P < 0.021). No statistically significant associations were<br />
observed among drug metabolizing genes and PFS or OS.<br />
Catechol-O-methyltransferase (COMT) V158M polymorphism was associated with<br />
PFS and OS (Met/Met carriers median PFS and OS NR; Met/Val pts PFS= 15<br />
months; OS = 17.2 months and Val/Val pts PFS = 3.3 months; OS= 4.4 months;<br />
p = 0.005 for PFS and P = 0.003 for OS).<br />
Conclusions: This preliminary analysis suggests that CYP1A2 and CYP2C19 SNPs<br />
may be associated with toxicity in patients with RCC treated with SU. As CYP1A2<br />
and CYP2C19 activity could be affected by a variety of non-genetic factors, if<br />
confirmed, <strong>the</strong>se results could lead to <strong>the</strong> necessity of controlling toxic and dietary<br />
habits of pts treated with SU. SNPs associated with toxicity and survival in this<br />
preliminary analysis are being validated in an independent cohort of RCC treated<br />
with SU (García-Donas J, et al. Lancet Oncol 2011) and will be presented.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
851P A PHASE IV MULTICENTER STUDY OF THE EFFICACY AND<br />
SAFETY OF SUNITINIB AS FIRST-LINE THERAPY IN CHINESE<br />
PATIENTS WITH METASTATIC RENAL CELL CARCINOMA<br />
(MRCC)<br />
S. Qin 1 , J. Jin 2 , J. Guo 3 , J. Wang 4 , F. Zhou 5 , Y. Huang 6 ,X.Ren 7 ,D.Ye 8 ,<br />
Q. Wang 9 ,S.Pan 10<br />
1 Pla Cancer Center, Nanjing Bayi Hospital, Nanjing, CHINA, 2 Urology, Peking<br />
University First Hospital, Beijing, CHINA, 3 Department of Renal Cancer and<br />
Melanoma, Peking University Cancer Hospital and Institute, Beijing, CHINA,<br />
4 Chinese Academy of Medical Sciences and Peking Union Medical College,<br />
Cancer Hospital/Institute, Beijing, CHINA, 5 Cancer Center, Sun Yat-sen<br />
University, Guangzhou, CHINA, 6 Urology, Shanghai Renji Hospital, Shanghai,<br />
CHINA, 7 Bio<strong>the</strong>rapy, Tianjin Medical University Cancer Institute and Hospital,<br />
Tianjin, CHINA, 8 Urology, Fudan University Shanghai Cancer Center, Shanghai,<br />
CHINA, 9 Global Research and Development, Pfizer, Shanghai, CHINA, 10 Clinical<br />
Statistics, Pfizer, New York, NY, UNITED STATES OF AMERICA<br />
Background: Based on <strong>the</strong> effectiveness and safety profile established in two<br />
single-arm phase II trials and a pivotal phase III trial versus interferon-alfa, sunitinib<br />
is approved worldwide for advanced RCC. Here we report a single-arm, open-label<br />
phase IV study to assess use of sunitinib as first-line <strong>the</strong>rapy in Chinese patients with<br />
mRCC.<br />
Methods: Treatment-naïve patients aged ≥18 yr with ECOG performance status 0/1<br />
and histologically confirmed mRCC received oral sunitinib 50 mg/d on <strong>the</strong> approved<br />
4-wk-on-2-wk-off schedule. Treatment continued until disease progression,<br />
unacceptable toxicity, or consent withdrawal. The primary endpoint was<br />
progression-free survival (PFS). Tumor measurements were performed at screening,<br />
regular intervals, suspected disease progression, to confirm response, and end of<br />
treatment/withdrawal. Safety was assessed regularly using NCI CTCAE version 3.0.<br />
Results: 105 patients received treatment. Mean age was 54.6 yr, 75% were male, and<br />
mean BMI was 23.9 kg/m 2 . The most common site of baseline metastases was <strong>the</strong><br />
lungs (76%). Median (range) number of treatment cycles completed was 8 (0–27).<br />
All patients discontinued treatment; reasons included disease progression/relapse<br />
(63%) and treatment-related AEs (8%). In 105 treated patients, median PFS was 61.7<br />
wk (14.2 mo; 95% CI: 45.1–106.3 wk) and median overall survival (OS) was 133.4 wk<br />
(30.7 mo; lower bound of 95% CI: 94.1 wk). In 103 evaluable patients, objective<br />
response rate (ORR) was 31.1% (95% CI: 22.3–40.9%). Most treatment-emergent AEs<br />
were grade 1/2 severity and <strong>the</strong> most common were hand-foot syndrome (64%),<br />
decreased white blood cell count (52%), fatigue (51%), decreased platelet count<br />
(51%), diarrhea (49%), and decreased appetite (43%). There were no occurrences of<br />
treatment-emergent congestive heart failure, left ventricular dysfunction, or<br />
cardiomyopathy.<br />
Conclusions: With median PFS of 61.7 wk (14.2 mo) and OS of 133.4 wk (30.7 mo),<br />
<strong>the</strong>se results compare favorably with those of <strong>the</strong> phase III trial, while ORR of 31.1%<br />
is comparable. The AE profile is acceptable and generally similar to that in o<strong>the</strong>r<br />
single-agent sunitinib studies and/or in patients with advanced RCC.<br />
Disclosure: Q. Wang: Employed by Pfizer Inc. as a clinician.S. Pan: Employed by<br />
Pfizer Inc. as a Director of Clinical Statistics and holds Pfizer stock. All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
Annals of Oncology<br />
852P PREDICTIVE VALUE OF TIME TO BEST RESPONSE FOR<br />
EFFICACY MTOR INHIBITORS (MTORI) IN METASTATIC<br />
RENAL CELL CARCINOMA (MRCC) PATIENTS (PTS)<br />
R.T. Elaidi 1 , C. Teghom 2 , A. Comte 2 , M. Jebali 2 , J. Fouque 3 , J. Medioni 4 ,<br />
S. Oudard 5<br />
1 Oncology, Hospital G.Pompidou, Paris, FRANCE, 2 Medical Oncology Service,<br />
Hopital European George Pompidou, Paris, FRANCE, 3 Pharmacy, Hopital<br />
Europeen Georges-Pompidou, Paris, FRANCE, 4 Medical Oncology, Georges<br />
Pompidou Hospital and Rene Descartes University, Paris, FRANCE, 5 Medical<br />
Oncology Department, Georges Pompidou Hospital and Rene Descartes<br />
University, Paris, FRANCE<br />
Background: mTORi usually induce stable disease but some patients present with a<br />
rapid objective response. In order to predict early those patients susceptible to<br />
respond to mTORi, we investigated <strong>the</strong> relationship between time to best response<br />
and time to progression.<br />
Methods: Data were retrospectively collected in patients treated with mTORi (Ev:<br />
everolimus, Tem:temsirolimus) for mRCC in 1 st to 4th line setting at <strong>the</strong> European<br />
G. Pompidou Hospital in Paris between 2007 and 2011. Time to best response was<br />
obtained from CT-scan and objective response assessed according to RECIST 2.0.<br />
Efficacy was assessed by time to progression (TTP) from initiation of 1 st mTORi<br />
until disease progression/death. Overall survival (OS) was defined as <strong>the</strong> time from<br />
1 st mTOR to death/last contact. Kaplan-Meier estimates with Log-Rank test were<br />
used for categorical data. Cox model was used for continuous data and hazard ratios<br />
calculation. Only pts having received at least 1 cycle of mTORi were included.<br />
Results: Among <strong>the</strong> 75 pts, 63 presented with a documented response: PR = 6, SD =<br />
40, PD = 17. 12 pts were excluded for mTORi discontinuation due to toxicity before<br />
any response assessment or uncertain date of best response. The 63 eligible pts had a<br />
median age = 61 (range: 28-86), sex ratio = 51/12, Ev/Tem = 37/26. Line setting: 1 st<br />
=7, 2 nd =17, 3 rd =19, 4 th = 17, 5 th = 3. Median follow-up time = 22.8m. Time to<br />
progression= 7.3m (95%CI: [4.3–9.1]). Time to best response: SD = 2.3 (0.7–8.2), PR<br />
= 7.6 (0.7–18.8), PD = 2.1 (0.9–5.0). Time to best response was significantly<br />
associated with TTP (N = 46, 35 events, HR = 0.86, 95% CI [0.76–0.97], p = 0.014),<br />
but also OS (N = 46, 31 events, HR = 0.83, 95% CI [0.70-0.98], p = 0.03]), an early<br />
response leading both to a more rapid progression and being of poor prognosis.<br />
Conclusions: Time to best response was significantly associated to time to<br />
progression and overall survival in pts treated with mTORi for mRCC. Given <strong>the</strong><br />
small sample and <strong>the</strong> rough assessment of RECIST criteria, fur<strong>the</strong>r study is needed<br />
to investigate <strong>the</strong> real value of percentage in tumor decrease at each evaluation and<br />
velocity of response as a more precise predictive marker of efficacy for <strong>the</strong>se drugs.<br />
Disclosure: S. Oudard: Advisory board to disclose: Sanofi Aventis, Bayer, Novartis,<br />
Roche, Pfizer Compensated consultant relatioship to disclose: Novartis, Roche<br />
Honoraria to disclose: Sanofi Aventis, Bayer, Novartis, Roche, PfizerAll o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
853P PRELIMINARY RESULTS OF EARLY ASSESSMENT OF<br />
RESPONSE WITH PERFUSION-CT IN PATIENT WITH<br />
METASTATIC RENAL CELL CARCINOMA TREATED WITH<br />
SUNITINIB<br />
O. Reig Torras 1 , M.C. Sebastia 2 , I. Victoria 1 , B. Paño 3 , M. Campayo 1 ,<br />
C. Nicolau 3 , B. Mellado 1<br />
1 Medical Oncology, Hospital Clinic y Provincial de Barcelona, Barcelona, SPAIN,<br />
2 Radiodiagnóstico, Hospital Clínic de Barcelona, Barcelona, SPAIN, 3 Radiology,<br />
Hospital Clínic de Barcelona, Barcelona, SPAIN<br />
Introduction: The fact that renal cell carcinoma (RCC) is highly dependent of<br />
angiogenesis has allowed <strong>the</strong> development of antiangiogenic drugs (e.g. sunitinib).<br />
The assessment of response was based on Response Evaluation Criteria in Solid<br />
Tumors (RECIST) but in RCC <strong>the</strong>re is no good correlation between response rate<br />
and survival data. So, it is necessary to adopt new image methods that allow a more<br />
accurate assessment of response.<br />
Objectives: To evaluate <strong>the</strong> pattern of response with perfusion-CT one month after<br />
<strong>the</strong> beginning of <strong>the</strong> antiangiogenic treatment and correlate with <strong>the</strong> radiologic<br />
evolution.<br />
Material and methods: Patients (pts) with metastatic RCC and candidates for<br />
sunitinib treatment were selected. A volumetric study (21 cm) with perfusion-CT<br />
(Flash Definition, Siemens, Erlangen, Germany) was done in <strong>the</strong>se patients before<br />
starting <strong>the</strong> treatment, 1 and 4 months after <strong>the</strong> antiangiogenic initiation. We defined<br />
6 types of response patterns based on changes in density (D), perfusion (P) and size<br />
(S) of <strong>the</strong> metastases.<br />
ix282 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Results: From March 2011 to May <strong>2012</strong>, 16 pts were included. The median age was<br />
62 years (43-79), <strong>the</strong> majority of pts had clear cell carcinoma (n = 13, 81.25%) and<br />
good prognosis (n = 14, 87.5%) based on Motzer criteria. We present <strong>the</strong> results of<br />
1-month evaluation: In 12 pts (75%) a decrease of D and P was observed. This<br />
pattern was correlated with a partial response in 8 pts (66.66%). Two pts (16.66%)<br />
had a stable disease and two more pts were lost before 4 months CT. This pattern<br />
was correlated with a partial response in 8 pts (66.66%). Two pts (16.66%) had a<br />
stable disease and two more pts were lost before 4 months CT. The increase of S,<br />
associated with a decrease of P and D, was related to haemorrhagic necrosis and it<br />
should not be confused with disease progression. This pattern was found in only<br />
2 pts (12.5%). In both cases, <strong>the</strong> changes in D and P preceded <strong>the</strong> changes in<br />
S. Stability of D, P and S was found in only one patient (6.25%) who had a papillary<br />
variant of MRC. An increase of D and P was related with disease progression in one<br />
patient (6.25%) and with stability in ano<strong>the</strong>r case (6.25%).<br />
Conclusion: The changes in D and P precede <strong>the</strong> changes in S, and could be<br />
predictive of response to antiangiogenic treatment. Long-term follow-up data and a<br />
larger series will be presented at <strong>the</strong> meeting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
854P SUNITINIB IN ADVANCED RCC: COST-EFFECTIVENESS<br />
EVALUATION BASED ON CLINICAL PRACTICE<br />
M.P. Trojniak 1 , A. Cappetta 2 , A.C. Palozzo 1 , S. Imbevaro 3 , P. Rescigno 3 ,<br />
A. Jirillo 3<br />
1 Pharmacy Department, Istituto Oncologico Veneto IRCCS, Padova, ITALY,<br />
2 Oncologia Medica 1, Istituto Oncologico Veneto IRCCS, Padova, ITALY,<br />
3 Evaluation and Introduction of New Drugs in Cancer Therapy Unit, Istituto<br />
Oncologico Veneto IRCCS, Padova, ITALY<br />
The approval trials have established sunitinib, multi-targeted TKI, a standard<br />
treatment in patients with metastatic RCC. RCTs may fail to show relevant clinical<br />
benefit in wider population and routine use, as certain patient subtypes are<br />
under-represented, notably those with poorer prognostic factors and pretreated. The<br />
data were collected through national registry Onco-AIFA as part of <strong>the</strong> mandatory<br />
surveillance. RCC patients receiving sunitinib once daily, on schedule 4/2, between<br />
2007 and 2011, had been checked prospectively for toxicity, clinical outcomes and<br />
length of treatment. Based on <strong>the</strong> difference in effectiveness in PFS between approval<br />
RCT and clinical practice, a new price adjusted for effectiveness has been calculated.<br />
A total of 106 patients (64 years, M 70/F 36) were reviewed, 77% had prior<br />
nephrectomy and 74% were treatment-naïve. At first evaluation we found 28% partial<br />
responses, 25% stable diseases, 45% progressions and one discontinuation due to<br />
toxicity. The median PFS and OS were 7 and 11.3 months, respectively. Among 79<br />
RCC patients (pts) with metastases (mets) at first diagnosis, 63% had lung mets, 21%<br />
pts had liver mets, 21% had bone mets and 9% had brain mets. Cox regression<br />
model showed in subgroups analysis significantly worse survival prognosis in males,<br />
brain and liver mets, ECOG PS > 1, non-clear cell histology and non prior<br />
nephrectomy. Sorafenib treatment after progression on sunitinib (33% pts) did not<br />
improved OS. Grade 3 thrombocytopenia, neutropenia, mucositis and HFS caused<br />
dosage reductions. Effectiveness adjusted price was 3,87 euro/mg as opposed to <strong>the</strong><br />
ex-factory price of 2,46 euro/mg proportionally to <strong>the</strong> difference of PFS form RCTs<br />
(11 months) and that form clinical practice oncology (7 months). The results show<br />
that sunitinib clinical benefit in RCC patients was gained in selected responders, but<br />
in overall <strong>the</strong> effectiveness was nearly half of that reported in <strong>the</strong> approval RCTs.<br />
Evaluating cost-effectiveness ratio, price should be at least 36% lower than actual<br />
ex-factory price based on net clinical benefit achieved in real life practice.<br />
Post-marketing studies in real life practice are required in order to verify both<br />
effectiveness and safety in general population, testing for external validity of<br />
randomized trials.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
855P EVEROLIMUS-ASSOCIATED NON-INFECTIONS PNEUMONITIS<br />
(NIP) IN KOREAN PATIENTS WITH RENAL CELL CARCINOMA<br />
(RCC)<br />
J. Kim 1 , T.M. Kim 2 , S. Lee 2 , D. Kim 2 ,Y.Kim 2 , D.S. Heo 2<br />
1 Internal Medicine, Seoul Nat’l University Hospital, SEOUL, KOREA, 2 Internal<br />
Medicine, Seoul Nat’l University Hospital, Seoul, KOREA<br />
Background: Everolimus prolonged survival in advanced RCC patients who failed to<br />
VEGF inhibitors. However, nearly 13.5 to 30% of patients experienced NIP.<br />
Although a lower incidence of NIP was observed in Japanese patients from<br />
RECORD-1, <strong>the</strong> actual incidence of everolimus-associated NIP was unknown in<br />
Asian patients. Therefore, this study was undertaken to evaluate<br />
everolimus-associated NIP in Korean RCC patients treated with everolimus.<br />
Patients and methods: Total 36 patients were enrolled at Seoul National University<br />
Hospital including advanced RCC patients who participated in REACT (N = 20) and<br />
in a trial for non-clear cell RCC (N = 16). NIP associated with everolimus was<br />
diagnosed using sequential computed tomography (CT) of <strong>the</strong> chest or<br />
bronchoscopy after an infectious origin and o<strong>the</strong>r causes of radiographic infiltrates<br />
were excluded. Clinico-pathologic findings were compared between NIP and<br />
non-NIP groups. Factors associated with NIP were identified using a binary logistic<br />
regression analysis.<br />
Results: Overall, 10 (27.8%) of 36 RCC patients treated with everolimus developed<br />
NIP that was radiologically proven: ≥ grade 3, 6 (16.7%) patients; and grade 1, 4<br />
(11.1%). Two patients died within 1 week after NIP diagnosis, while 8 recovered<br />
from NIP after cessation of everolimus (N = 4) and steroid use with drug interruption<br />
(N = 4). The mean cumulative dose of everolimus was 1,293 mg (range, 590-2420mg)<br />
at NIP diagnosis. There were no differences in NIP occurrence according to age,<br />
performance status, subtype (clear vs. non-clear), and underlying lung disease (Ps<br />
> .05). However, patients who experienced NIP had a better response (9 of 10<br />
patients) than those without NIP (17 of 26) (P = .015). The response to everolimus<br />
remained predictive of NIP occurrence in multivariate analysis (P = .018).<br />
Conclusion: NIP is relatively common (27.8%) in Korean patients with RCC who<br />
receive everolimus. Response to everolimus is an independent predictor for NIP<br />
development in advanced RCC patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
856P SORAFENIB VERSUS AXITINIB FOR SECOND-LINE<br />
TREATMENT OF SUNITINIB-REFRACTORY PATIENTS WITH<br />
ADVANCED RENAL CELL CARCINOMA (RCC) IN THE UNITED<br />
STATES (US)<br />
I. Ozer-Stillman 1 , R. Keyser 1 , A. Ambavane 1 , P. Cislo 2<br />
1 Health Economics, United BioSource Corp., Lexington, MA, UNITED STATES<br />
OF AMERICA, 2 Global Health Economics and Outcomes Research, Bayer<br />
HealthCare, Montville, NJ, UNITED STATES OF AMERICA<br />
Introduction: A Phase III randomized trial, AXIS, investigated <strong>the</strong> efficacy and safety<br />
of axitinib (Inlyta®) versus sorafenib (Nexavar®), oral targeted <strong>the</strong>rapies licensed in<br />
<strong>the</strong> US for <strong>the</strong> treatment of advanced RCC. The objective of this study was to<br />
conduct an economic evaluation of sorafenib versus axitinib in 2nd-line,<br />
sunitinib-refractory patients with advanced RCC from a US perspective.<br />
Methods: A survival partition model with 3 health states (progression-free,<br />
post-progression and death) was constructed to estimate <strong>the</strong> direct lifetime medical<br />
costs and clinical outcomes for a patient starting in <strong>the</strong> 2nd-line from a US<br />
third-party payer perspective. Patients were apportioned into health states based on<br />
overall survival and progression-free survival Kaplan-Meier curves from <strong>the</strong> AXIS<br />
trial. Patients were assumed to receive cancer medication until progression and best<br />
supportive care <strong>the</strong>reafter. Utility values and medical resource use were based on<br />
literature. Adverse event rates and management were informed by <strong>the</strong> AXIS trial and<br />
clinical expert opinion, respectively. Model outcomes included total costs, life-years<br />
(LYs) and quality-adjusted life-years (QALYs), all discounted at 3% per year.<br />
Probabilistic sensitivity analysis (PSA) evaluated <strong>the</strong> model’s robustness.<br />
Results: Total per-patient costs were estimated to be $127,808 for sorafenib and<br />
$159,800 for axitinib. The cost difference of $31,992 was mainly attributable to<br />
higher cost of axitinib compared to sorafenib. Model results suggested that sorafenib<br />
and axitinib provide similar benefit in terms of LYs and QALYs: sorafenib provided<br />
an average of 1.440 LYs and 1.016 QALYs and axitinib provided an average of 1.423<br />
LYs and 1.015 QALYs per patient. The lower total per-patient cost for sorafenib<br />
versus axitinib finding persisted in <strong>the</strong> PSA, with 95% of iterations resulting in an<br />
incremental cost difference between $9,000 and $63,000.<br />
Conclusions: Results of this modeling study suggest that, for <strong>the</strong> 2nd-line,<br />
sunitinib-refractory patients with advanced RCC in <strong>the</strong> US, treatment with sorafenib<br />
is a less expensive alternative to axitinib that provides similar benefit in terms of LYs<br />
and QALYs.<br />
Disclosure: I. Ozer-Stillman: This research is sponsored by Bayer HealthCareR.<br />
Keyser: This research is sponsored by Bayer HealthCareA. Ambavane: This research<br />
is sponsored by Bayer HealthCareP. Cislo: Employed by Bayer HealthCare<br />
857P PITFALLS OF USING THE COCKCROFT-GAULT FORMULA<br />
WHEN CALCULATING CARBOPLATIN DOSE FOR THE<br />
ADJUVANT TREATMENT OF PATIENTS WITH STAGE I<br />
SEMINOMA<br />
M. Fehr 1 , T. Geldart 2 , H. Sun 3 , P.D. Simmonds 1 , G. Mead 1 , M. Wheater 1 ,<br />
N. Nagaraj 4 , S. Ellis 2 , R. von Moos 5 , R. Cathomas 6<br />
1 Medical Oncology, University Hospital Southampton, Southampton, UNITED<br />
KINGDOM, 2 Medical Oncology, Royal Bournemouth Hospital, Bournemouth,<br />
UNITED KINGDOM, 3 Coordination Center, Swiss Group for Clinical Cancer<br />
research (SAKK), Bern, SWITZERLAND, 4 Nuclear Medicne, University Hospital<br />
Southampton, Southampton, UNITED KINGDOM, 5 Medical Oncology, Kantonal<br />
Hospital Graubünden, Chur, SWITZERLAND, 6 Medizinische Onkologie, Cantonal<br />
Hospital Graub, Chur, SWITZERLAND<br />
Introduction: Single dose Carboplatin (C) AUC7 (7 x glomerular filtration rate<br />
(GFR) mls/min + 25) is a standard adjuvant treatment option for patients with stage<br />
I seminoma. Measuring GFR by a nuclear medicine method represents <strong>the</strong> gold<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds399 | ix283
Table: 857P<br />
standard, but is not available in all centres. 24h urine collection may be prone to<br />
sampling errors. Estimating GFR by <strong>the</strong> Cockroft-Gault formula (CG) is popular<br />
amongst oncologists but data supporting its use in this situation is limited. Reduction<br />
of C dose by 10% in <strong>the</strong> adjuvant treatment of seminoma stage I is associated with a<br />
trend for higher relapse rate.<br />
Methods: Data from 202 consecutive, male patients (median age 39, range 23-68<br />
years) with stage I seminoma with complete documentation of GFR by TC99m<br />
DTPA, serum-creatinine, age, height and weight were evaluated. Actual C doses<br />
(ACD) based on GFR measurement by TC99m DTPA were compared with estimated<br />
C doses (ECD) based on GFR estimation using CG formula. Differences between <strong>the</strong><br />
ACD and ECD were correlated to age and body mass index (BMI) using Fisher’s<br />
Exact test, Pearson correlation and linear regression.<br />
858P ADDITION OF DARBEPOETIN ALFA TO SEQUENTIAL HIGH<br />
DOSE VIP CHEMOTHERAPY FOR PATIENTS WITH ADVANCED<br />
METASTATIC GERM CELL CANCER<br />
J.T. Hartmann 1 , B. Metzner 2 , C. Binder 3 , H. Mergenthaler 4 , O. Rick 5 ,<br />
H.G. Sayer 6 , A. Lorch 7 , W.E. Berdel 8 , C. Bokemeyer 9 , T.C. Gauler 10<br />
1 Medical Oncology, Christian-Albrechts-Universität zu Kiel, Kiel, GERMANY,<br />
2 Abt. Onkologie/haematologie, Klinikum Oldenburg, Oldenburg, GERMANY,<br />
3 Hämatologie und Onkologie, Universitätsmedizin Göttingen, Göttingen,<br />
GERMANY, 4 Klinik F. Onkologie, Klinikum Stuttgart - KatharinenhospitalKlinik<br />
f. Onkologie, Stuttgart, GERMANY, 5 Oncology, Klinik Reinhardshoehe, Bad<br />
Wildungen, GERMANY, 6 Klinik für Innere Medizin II, Universitätsklinikum Jena,<br />
Jena, GERMANY, 7 Urologische Klinik, Universitätsklinikum Düsseldorf,<br />
Düsseldorf, GERMANY, 8 Medizinische Klinik A, Universitaetsklinikum Münster,<br />
Münster, GERMANY, 9 Oncology, Haematology and Bone Marrow<br />
Transplantation, UKE II. Medizinische Klinik und PoliklinikMedizinische Klinik II.,<br />
Hamburg-Eppendorf, GERMANY, 10 Oncology, University Hospital, Essen,<br />
GERMANY<br />
Background: High-dose VIP chemo<strong>the</strong>rapy (HD-VIP) plus ABSCT given as first line<br />
treatment might be a strategy in patients with advanced germ cell tumors (GCT)<br />
with poor prognosis. The objective of <strong>the</strong> trial was to investigate <strong>the</strong> addition of<br />
darbepoetin alfa to HD-VIP in order to reduce anemia/red blood cell (RBC)<br />
transfusions.<br />
Methods: This was a randomized, open-label multicenter phase 2 study conducted in<br />
20 hospitals. Darbepoetin 2,25 mcg/kg weekly or 500 mcg Q3W s.c., started with<br />
HD-VIP (dose level 6), was applied in arm B (arm A: HD-VIP alone). The primary<br />
objective was freedom from blood transfusions (FFT). Secondary objectives included<br />
objective remission rate (ORR) after chemo<strong>the</strong>rapy, 24-mos PFS and OS, median<br />
course of hemoglobin (Hb) levels during 3 HD-VIP cycles as well as drug safety.<br />
Results: Between 7/2003 and 11/2008 108 pts were allocated to <strong>the</strong> study, and 102<br />
were included in <strong>the</strong> intention-to-treat (ITT) analysis. By March <strong>2012</strong>, <strong>the</strong> median<br />
follow-up time after randomization was 62 (range, 3–100) mos for surviving patients.<br />
Localisation of primary was gonadal in 66%, retroperitoneal in 19% and mediastinal<br />
in 14%s. A favourable treatment outcome (CR/NED/PR m-) in conjunction with<br />
secondary surgery (n = 76 pts) was achieved in 58% of pts with no difference between<br />
arms A and B. Overall FFT occurred in 2 pts (4.2%) in arm A and 3 pts (5.6%) in<br />
arm B, and in 23%/15%/15% and 15%/17%/19% of pts during cycles 1-3,<br />
respectively. No differences in baseline Hb, severity of anemia, number of RBC<br />
transfusions and area under <strong>the</strong> curve of Hb levels during HD-VIP was observed. Pts<br />
assigned to darbepoetin had similar treatment toxicity compared to those assigned to<br />
HD-VIP alone. 5-year OS in arm A was 74.0% compared to 63.0% (P = .18) in Arm<br />
B. 5-year DFS was 60.5% in arm A vs 53.1% in Arm B (P = 0.54). Darbepoetin was<br />
generally well tolerated with 2 pts discontinuing treatment due to thrombosis. A<br />
per-protocol (PP) analysis revealed comparable outcomes (OS 74.4 vs 67.5, P = 0.38;<br />
DFS 60.4 vs 58.3, P = 0.70).<br />
Conclusions: Based on ITT and PP analysis, <strong>the</strong> addition of darbepoetin alfa to<br />
HD-VIP compared to HD-VIP alone does not appear to impact FFT, ORR, and<br />
survival in poor prognosis GCT pts (NCT00204633).<br />
Results: 202 patients were included in <strong>the</strong> correlation analysis and 181 patients in<br />
<strong>the</strong> comparison of different subgroups, respectively. Lower BMI and higher age were<br />
significantly associated with lower ECD, Pearson correlation coefficients 0.59 (p <<br />
0.001) and –0.36 (p < 0.001), respectively. Tables show potential under- and<br />
overdosing of C when using CG (ECD expressed as percentage of ACD) in different<br />
age groups (Exact test p = 0.001) and groups with different BMI (Exact test p = 0.026)<br />
Discussion: CG significantly underestimates GFR in leaner and older patients.<br />
According to our data over a third of patients with BMI 20–25 or aged 41–50 would<br />
be at risk for undertreatment if CG were used routinely. Physicans need to be aware<br />
of <strong>the</strong>se limitations when using CG to calculate C dose in patients with stage I<br />
seminoma.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
859P MANAGEMENT OF POST ORCHIDECTOMY STAGE I<br />
CLASSICAL SEMINOMA: 11 YEAR OUTCOME DATA<br />
OF A UK REGIONAL CANCER UNIT<br />
Annals of Oncology<br />
Age (years) 110% ACD BMI (kg/m 2 ) 110% ACD<br />
21-30 n = 29 14% 4 72% 21 14% 4 20-25 n = 60 35% 21 57% 34 8% 5<br />
31-40 n = 84 14% 12 68% 57 18% 15 25-30 n = 81 21% 17 69% 56 10% 8<br />
41-50 n = 68 40% 27 56% 38 4% 3 30-40 n = 33 15% 5 58% 19 27% 9<br />
A.J. McPartlin 1 ,R.Roy 1 , D. Muskett 2 , M. Witkowski 3 , A.J. Birtle 1<br />
1 Oncology, Royal Preston Hospital, Preston, UNITED KINGDOM,<br />
2 Histopathology, East Lancashire Hospitals NHS Trust, blackburn, UNITED<br />
KINGDOM, 3 Pathology, Morcombe bay Hospital Trust, Morcombe Bay,<br />
UNITED KINGDOM<br />
Introduction: Stage I classical seminoma has a 95% 5yr OS. Post-orchidectomy<br />
treatment options include para-aortic radio<strong>the</strong>rapy, single agent carboplatin or active<br />
surveillance. This retrospective study reviewed changing practice and outcomes over a<br />
11 year period in a regional cancer unit.<br />
Patients and methods: 188 consecutive patients seen from January 2000 to<br />
December 2010 were identified. Initial risk factors, treatment received and post<br />
treatment response were recorded and relapse free and overall survival calculated<br />
Results: Adjuvant radio<strong>the</strong>rapy was given to 106 patients (56.4%), adjuvant<br />
chemo<strong>the</strong>rapy to 56 (29.8%) and active surveillance to 26 (13.8%). Five year RFS by<br />
group was 97.2%, 89.9% and 76.9%. Fifteen patients relapsed with one dying despite<br />
third line treatment. Overall CSS was 99.4%. In <strong>the</strong> period before 2005 tumour size<br />
and rete testis invasion was documented in 9% of patients and active surveillance<br />
offered to none. After this time <strong>the</strong> two risk factors were documented in 82% and<br />
surveillance offered to 19.5%. Management and outcome stratified by presence of risk<br />
factor.<br />
Management<br />
Adjuvant<br />
Adjuvant Relapse<br />
Risk factor Surveillance Chemo<strong>the</strong>rapy XRT rate<br />
None<br />
(51 patients)<br />
47.1% 25.6% 27.4% 7.5%<br />
One (24) 22.0% 42.0% 36.0% 14.0%<br />
Two (12) 0% 58.3% 41.7% 12.5%<br />
Conclusion: This review’s outcomes broadly correspond with published data<br />
although with increased incidence of relapse following standard adjuvant<br />
chemo<strong>the</strong>rapy- presumably an artifact of small numbers. Adjuvant treatment<br />
increases 5yr RFS compared to active surveillance but excellent CSS is achieved after<br />
ei<strong>the</strong>r. The vast majority of radio<strong>the</strong>rapy (85%)was offered in <strong>the</strong> first two thirds of<br />
<strong>the</strong> study period and reflects older practice. The absence of risk factors appears to<br />
reduce <strong>the</strong> rate of relapse and should guide treatment decisions. The increasing<br />
awareness of <strong>the</strong> importance of assessing risk factors when deciding on treatment is<br />
reflected in <strong>the</strong>ir improved identification in later patients and <strong>the</strong> increasing use of a<br />
surveillance strategy in those at lower risk of relapse.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix284 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
860P EXPERIENCE WITH FIRST SALVAGE VEIP IN GERM CELL<br />
TUMOR PATIENTS<br />
S. Kumar, I.A. Muazzam, N. Muzaffar, N. Siddqui, K. Das<br />
Medical Oncology, Shaukat Khanum Memorial Cancer Hospital and Reserch<br />
Centre (SKM), Lahore, PAKISTAN<br />
Introduction: Despite cisplatin-etoposide based induction chemo<strong>the</strong>rapy, 20-30% of<br />
germ cell tumor (GCT) patients will require salvage treatment. Cisplatin-ifosfamide<br />
based salvage regimen produces durable remission at <strong>the</strong> cost of severe toxicity. In<br />
this study, we report our experience with first salvage chemo<strong>the</strong>rapy.<br />
Material and methods: Medical records of patients receiving first salvage<br />
chemo<strong>the</strong>rapy with vinblastine 0.11mg/kg iv d1-d2, ifosfamide 1200mg/m2 iv d1-d5<br />
and cisplatin 20mg/m2 iv d1-d5 (VeIP) for GCT was reviewed. Those who continued<br />
to respond were given more than 4 cycles of chemo<strong>the</strong>rapy. Overall response rate<br />
(ORR) was assessed by CT and/or MRI scans using WHO response criteria at <strong>the</strong><br />
completion of chemo<strong>the</strong>rapy.<br />
Results: From April 2006 to April 2011, 350 patients of GCT were treated at Shaukat<br />
Khanum Memorial Cancer Hospital & Research Center, Lahore (Pakistan). Out of<br />
those 350 patients, 34 were treated with VeIP chemo<strong>the</strong>rapy as first salvage for<br />
primary progressive (n = 2) or relapsed (n= 32) GCT (non-seminoma = 30;<br />
seminoma = 4). Thirty three patients were male and only 1 was female. Median age<br />
at <strong>the</strong> time of diagnosis was 26 years (range from 17 to 58) and most (54.3%) had<br />
poor prognostic features according to IGCCC. Median time of relapse after primary<br />
induction chemo<strong>the</strong>rapy was 8.067 months (95% CI 6.491 to 9.642). Median of 4<br />
cycles salvage VeIP were administered (range 1-6 cycles). One patient died during<br />
salvage chemo<strong>the</strong>rapy due to sepsis. Response assessment was possible in 29 patients.<br />
ORR was 31.4% (CR = 6.7% and PR = 30.0%), SD in 26.7% and PD in 36.7%<br />
patients. Surgical resection of residual mass was not possible in any of our patients.<br />
Three patients were fur<strong>the</strong>r treated with radiation <strong>the</strong>rapy. Twenty patients continued<br />
follow up (median 1.93 years; from 0.51 to 4.9) after completion of VeIP. At <strong>the</strong> time<br />
of analysis, 6 patients died and 21 were alive. Median PFS after VeIP was 6.033<br />
months (3.608 to 8.459) while median OS had not yet reached.<br />
Conclusions: VeiP showed radiologic shrinkage of tumor in one-third of our<br />
patients and resulted in reasonably long survival of our high risk relapsed patients.<br />
Our results were comparable with International data.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
861P PERSISTANCE OF CD30 EXPRESSION IN EMBRYONAL<br />
CARCINOMA (EC) CELLS: A RETROSPECTIVE STUDY IN<br />
MULTI-RELAPSED OR CHEMOTHERAPY (CT) REFRACTORY<br />
GERM-CELL TUMOR (GCT)<br />
P. Giannatempo 1 , A. Necchi 2 , M. Colecchia 3 , B. Paolini 3 , N. Nicolai 4 , D. Raggi 2 ,<br />
M. Catanzaro 4 , D. Biasoni 4 , R. Salvioni 4 , A.M. Gianni 1<br />
1 Medical Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan,<br />
ITALY, 2 Medical Oncology/Urology Unit, Fondazione IRCCS – Istituto Nazionale<br />
dei Tumori, Milano, ITALY, 3 Pathology, IRCCS Istituto Nazionale dei Tumori<br />
Milano, Milan, ITALY, 4 Urology, Fondazione IRCCS – Istituto Nazionale dei<br />
Tumori, Milan, ITALY<br />
Background: Despite <strong>the</strong> high rate of long-term surviving patients (pts) with<br />
advanced GCT, a small but invariable proportion of <strong>the</strong>m fail to be cured with<br />
conventional or high-dose CT (HDCT) in <strong>the</strong> salvage setting, followed by surgery.<br />
New drugable targets should be set. CD30 is invariably expressed by untreated EC.<br />
We aimed at evaluating <strong>the</strong> persistence of CD30-positivity after CT, ei<strong>the</strong>r in 1st-line<br />
or in <strong>the</strong> salvage setting.<br />
Methods: We retrieved paraffin-embedded tumor samples and clinical data of all<br />
Institutional pts who had persistence of non-teratoma viable cells after ≥ 1<br />
platinum-based CT for advanced disease. An exclusive or prevalent EC component<br />
was required and assessed by morphology and Oct-3/4 staining. The entire set was<br />
re-assessed for CD30 staining by 2 blinded referral pathologists. CD30-positivity was<br />
defined as a >80% membranous staining with a diffuse moderate-to-strong intensity.<br />
Clinical data included histology of tumor primary, GCT primitivity, treatment setting<br />
and type of surgery.<br />
Results: In <strong>the</strong> time-frame 12/1990-04/<strong>2012</strong>, a total of 245 cases with pure EC or<br />
mixed GCT residuals were treated at our Institute. Among <strong>the</strong>m, 49 (EC: 16; mixed<br />
GCT: 33) had complete data and were suitable tissue for review and re-assessment.<br />
41 pts had retroperitoneal or mediastinal nodes, 18 lung metastases, 3 had ei<strong>the</strong>r<br />
liver, bone or brain mets. 33/49 cases (67%) preserved CD30 positivity. 18/33 (55%)<br />
pts had residual disease after 1st-line CT, 15 (45%) after multiple regimens<br />
(median 3, range 2–5). 2 pts (6%) had undergone HDCT and 4 (12%) were late<br />
relapses. 31 pts (94%) had gonadal primary GCT, 1 had a retroperitoneal and<br />
ano<strong>the</strong>r a mediastinal primary. After a median follow-up of 35 mos (1-249), 16/33<br />
(48%) of CD30+ its are alive compared to 9/16 (56%) of CD30- cases, with a HR<br />
(95%,CI) of 1.93 (0.85–4.37).<br />
Conclusions: Our results on selected relapsed pts suggest that EC samples retained<br />
CD30 expression even in <strong>the</strong> far salvage setting, thus confirming to be a reliable<br />
target for treatment. This may be representative of a significantly larger patient series.<br />
A trend towards a poorer prognosis and shorter survival characterized CD30+ cases.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
862P CONTINUOUS INFUSION BLEOMYCIN IN THE BEP REGIMEN:<br />
A THERAPEUTIC ALTERNATIVE IN THE MANAGEMENT OF<br />
PATIENTS WITH GERM-CELL TUMORS?<br />
C. Helissey 1 , L. Védrine 2 , B. Ceccaldi 2 , A. Houlgatte 3 , H. Mullot 4 ,<br />
O. Bauduceau 1 , C. Chargari 2 , C. Massard 5 , K. Fizazi 6 , S. Le Moulec 7<br />
1 Oncology Radio<strong>the</strong>rapy, HIA Val de Grace, Paris, FRANCE, 2 Oncology and<br />
Radiation Oncology, Hôpital d’Instruction des Armées du Val-de-Grâce, Paris,<br />
FRANCE, 3 Urology, HIA Val de Grace, Paris, FRANCE, 4 Pharmacy, HIA Sainte<br />
Anne, Toulon, FRANCE, 5 Dept. of Medicine, Institut Gustave Roussy, Villejuif<br />
Cedex, FRANCE, 6 Department of Medical Oncology, Institute Gustave Roussy,<br />
Villejuif, FRANCE, 7 Department of Oncology, Val de Grace Hospital, Paris,<br />
FRANCE<br />
Introduction: Germ-cell tumors (GCTs) are highly curable with cisplatin-based<br />
chemo<strong>the</strong>rapy. The BEP chemo<strong>the</strong>rapy (Indianapolis) has become a standard in <strong>the</strong><br />
management of GCT. The aim of this study was to evaluate <strong>the</strong> long-term side effects<br />
of a modified BEP regimen, with of bleomycin as a continuous infusion.<br />
Patients and methods: The military hospital of Val de Grâce has developed a<br />
modified BEP regimen with <strong>the</strong> aim of reducing bleomycin-induced toxicity in<br />
patients with GCTs: bleomycin 15mg/d (d1-5) as an IV continuous injection,<br />
etoposide 100mg/m2 (d1-5) and cisplatin 20mg/m2 (d1-5), repeated every 3 weeks.<br />
Survivors were asked in 2011 to participate to this study on late toxicity, including<br />
assessment of laboratory tests, pulmonary function tests (PFT) and a semen analysis.<br />
Results: Between March 1998 and January 2009, 68 patients with GCTs received first<br />
line chemo<strong>the</strong>rapy with this modified BEP. Distribution of patients’ was as following:<br />
Good prognosis (GP): 42, Intermediate and Poor-prognosis (IPP): 20, stage I with<br />
High risk factors (HP): 6. The median follow-up was 75 months. The 2-years overall<br />
survival was 90%. The relapse rate was 13%. The main immediate adverse events<br />
reported grade III-IV were neutropenia (25%), anemia (1%), thombopenia (1%),<br />
digestive (6%), infection (4%), decreased DLCO (4%) and tromboembolic events<br />
(3%). Thirty four patients were assessable for <strong>the</strong> late toxicity of this regimen (18<br />
patients in GP, 14 patients in IPP and 2 patients in HP).The 5-years overall survival<br />
was 82%. The analysis of late side effects revealed one patient developed a<br />
haematologic malignancy (myelodysplasia).Abnormal PFT was observed in 4<br />
patients, and only 1 patient was clinically symptomatic. In post-treatment analysis,<br />
we evaluated <strong>the</strong> fertility of 30 patients. The fertility was preserved in 22 patients<br />
(73%). Twenty patients have realized a semen analysis after <strong>the</strong> chemo<strong>the</strong>rapy, and<br />
azoospermia was observed in only 3 pts (15%). Among 10 patients remaining,<br />
5 patients had children after <strong>the</strong> treatment.<br />
Conclusion: Using bleomycin as a continuous infusion is feasible and seems to<br />
produce similar results in terms of response rates and overall survival compared to<br />
<strong>the</strong> classic BEP chemo<strong>the</strong>rapy regimen, with a total dose less important than<br />
standard. These results will be compared with those of conventional BEP<br />
Disclosure: All authors have declared no conflicts of interest.<br />
863P MULTI-CYCLE HIGH-DOSE CHEMOTHERAPY WITH TI-CE<br />
REGIMEN FOR PATIENTS WITH RELAPSED/REFRACTORY<br />
GERM CELL TUMORS – A SINGLE INSTITUTION EXPERIENCE<br />
U. De Giorgi 1 , G. Rosti 2 , B. Kopf 1 , C. Ferrario 1 , G. Papiani 3 , R. De Vivo 4 ,<br />
A.L. Gentile 5 , F. Fabbri 1 , M. Bragagni 1 , D. Amadori 1<br />
1 Medical Oncology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura<br />
dei Tumori (I.R.S.T.), Meldola, ITALY, 2 Medical Oncology, Ospedale Civile,<br />
Treviso, ITALY, 3 Medical Oncology, Ospedale Santa Maria delle Croci, Ravenna,<br />
ITALY, 4 Medical Oncology, Ospedale San Bortolo, Vicenza, ITALY, 5 Oncologia –<br />
Asl Teramo, Ospedale Mazzini, Teramo, ITALY<br />
Background: A large international phase III randomized trial (TIGER study) has<br />
been recently planned to compare <strong>the</strong> TI-CE multi-cycle high-dose chemo<strong>the</strong>rapy<br />
(HDCT) with standard chemo<strong>the</strong>rapy as salvage treatment for patients with relapsed<br />
germ cell tumors (GCT), but to date <strong>the</strong>re are no reported experiences with this<br />
regimen o<strong>the</strong>r than <strong>the</strong> phase 2 study from MSKCC (Feldman et al – JCO 2010). We<br />
present preliminary results of our experience with TI-CE in relapsed/refractory GCT<br />
patients.<br />
Methods: From August 2009 to April <strong>2012</strong>, patients with relapsed/refractory GCT<br />
received TI-CE comprising a mobilizing phase with paclitaxel and ifosfamide (TI)<br />
with leukapheresis of peripheral blood progenitor cells (PBPCs), followed by 3<br />
HDCT courses with CE (carboplatin AUC 21 and etoposide 1200 mg/m2), with<br />
PBPC reinfusion. Biosimilar filgrastim (Zarzio®) was used in <strong>the</strong> HDCT phase for all<br />
patients after PBPC reinfusion.<br />
Results: 26 patients (25 males, median age 34) started on TI, but 3 of <strong>the</strong>m did not<br />
receive CE: two had rapidly progressive symptomatic brain metastases, <strong>the</strong> third one<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds399 | ix285
efused HDCT. Of 23 patients, 20 completed <strong>the</strong> TI-CE regimen and are evaluable,<br />
while 3 are still receiving treatment. There were no treatment-related deaths. The<br />
median number of days from <strong>the</strong> start of CE until recovery of neutrophils to 1,000/<br />
mm3 was 14. Twelve (60%) of <strong>the</strong> 20 evaluable patients achieved a complete<br />
remission (CR) (5 clinical CR, 5 pathological CR, 2 surgical CR), 5 had<br />
marker-negative partial remissions lasting 2, 2 + , 2 + , 6+ and 21+ months, and 3<br />
progressed. After a median follow-up of 13 months (range, 2 to 33+), 15 (75%)<br />
evaluable patients are continuously progression-free. Of 4 mediastinal primary<br />
nonseminomatous GCT, 2 achieved a CR (1 sCR and 1 pCR) lasting 7 and 12+<br />
months, respectively.<br />
Conclusions: Our experience confirms that <strong>the</strong> TI-CE regimen is safe and active,<br />
with a response rate and a recovery time of neutrophils after CE similar to that<br />
reported in <strong>the</strong> MSKCC study. Updated results will be presented at <strong>the</strong> meeting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
864P TERATOMA WITH MALIGNANT TRANSFORMATION (TMT) IN<br />
MEN WITH GERM CELL TUMORS (GCTS): RETROSPECTIVE<br />
STUDY OF 26 CASES FROM A SINGLE INSTITUTION<br />
N. Bonnin 1 , H. Boyle 1 , M. Rivoire 2 , C. Bailly 3 ,J.Droz 1 , A. Flechon 1<br />
1 Medical Oncology, Centre Léon Bérard, Lyon Cedex, FRANCE, 2 Surgery,<br />
Centre Léon Bérard, Lyon Cedex, FRANCE, 3 Pathology, Centre Léon Bérard,<br />
Lyon Cedex, FRANCE<br />
Background: GCT is <strong>the</strong> most common solid tumor in young men. TMT is a rare<br />
entity. It occurs in less than 2% of GCTs and is associated with poor prognosis.<br />
Methods: Between Jan 1993 and Jan <strong>2012</strong>, we identified retrospectively all pts with<br />
GCTs with TMT treated at our institution and report here <strong>the</strong>ir characteristics,<br />
treatment and clinical outcome.<br />
Results: Twenty six patients (pts) with TMT were identified. Median age at initial<br />
diagnosis was 26 years (19–48). At initial diagnosis 20 pts had a gonadal primary<br />
(4 stage (sg) I, 8 sg II and 8 sg III) and 6 a primary mediastinal tumor (PMT). Six<br />
pts were classified as good prognosis, 5 as intermediate, 11 as poor according to <strong>the</strong><br />
IGCCCG and 4 unknown. A teratoma component was described in <strong>the</strong> primary<br />
tumor of 22 out of <strong>the</strong> 25 pts with non seminomatous GCT. Only one pt had a pure<br />
seminoma (PMT). Four pts had TMT in <strong>the</strong>ir primary, 9 in resected<br />
post-chemo<strong>the</strong>rapy, residual masses and 13 in a relapse. For <strong>the</strong>se 13 pts, median<br />
time between initial GCT diagnosis and relapse as a TMT was 31.2 months (mo)<br />
(12.0-357.6). Various subtypes of TMT were observed: 10 adenocarcinomas, 4<br />
neuroectodermal tumors, 6 rhadomyosarcomas, 2 leiomyosarcomas, 1 blastema, 1<br />
angiosarcoma and 2 undefined sarcomas. Except 3 pts with sg I disease, all pts<br />
received first line cisplatin-based chemo<strong>the</strong>rapy (CT). Surgery of residual masses was<br />
performed in 20 pts. Nineteen out of <strong>the</strong> 23 pts had initial clinical or surgical<br />
complete response (CR), 2 had a marker positive partial response and 2 had<br />
progressive disease. Iterative surgery for relapse was performed in 9 pts. Eight pts<br />
received CT according to TMT subtype and one achieved CR. With a median<br />
follow-up of 76.8 mo (9.5-369.0), 8 pts have died of disease (DOD), 1 has died of<br />
ano<strong>the</strong>r cause, 2 are alive with disease and 15 alive without disease. Among <strong>the</strong> 8 pts<br />
DOD: 3 pts had PMT, 3 were sg III and 2 sg I; all relapsed and surgery was<br />
incomplete for 4 pts and 1 was inoperable. There was no difference between subtypes<br />
of TMT.<br />
Conclusions: TMT is more frequent in GCTs with extensive disease, PMT and<br />
relapsed disease. Iterative and complete surgical resection is <strong>the</strong> mainstay of<br />
treatment. CT is usually palliative but sometimes gives long responses.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
865P A CYTOKINE AND ANGIOGENIC FACTOR (CAF) ANALYSIS IN<br />
PLASMA IN TESTICULAR GERM CELL TUMOR PATIENTS<br />
M. Mego 1 , D. Cholujova 2 , P. Gronesova 2 , M. Pastorek 2 , V. Miskovska’ 3 ,<br />
J. Obertova 1 , V. Usakova 4 , D. Ondrus 3 , S. Spanik 3 , J. Mardiak 1<br />
1 Medical Oncology, National Cancer Institute, Slovakia, Bratislava, SLOVAK<br />
REPUBLIC, 2 Cancer Immunology, Cancer Research Institute, Slovak Academy of<br />
Sciences, Bratislava, SLOVAK REPUBLIC, 3 Medical Oncology, St. Elisabeth<br />
Cancer Institute, Bratislava, SLOVAK REPUBLIC, 4 Clinical Oncology,<br />
St. Elisabeth Cancer Institute, Bratislava, SLOVAK REPUBLIC<br />
Background: Testicular germ-cell tumours (TGCTs) represent a model for <strong>the</strong> cure<br />
of cancer. None<strong>the</strong>less, a small proportion of patients develop disease recurrence. We<br />
investigated cytokines and angiogenic factors (CAFs) in patients with TGCTs. We<br />
aimed to link <strong>the</strong> CAF profile to PFS and select candidate predictive and prognostic<br />
markers for fur<strong>the</strong>r study.<br />
Methods: In this ongoing translational study, plasma from 55 patients with TGCTs<br />
was collected. The concentrations of 51 plasma CAFs were measured pretreatment<br />
(n = 47) and on day 22 (n = 30) using multiplex bead arrays (Human Group I and II<br />
cytokine panels and TGF beta by Bio-Plex 200 system (Bio-Rad Laboratories,<br />
Hercules, CA). We investigated <strong>the</strong> association between baseline levels of CAFs and<br />
clinico-pathological variables.<br />
Results: We observed elevated level of transforming growths factor beta1 (TGF-b1),<br />
IL-2Ra, CXCL9, CXCL10, IFN-gama, macrophage inflammatory protein-1b<br />
(MIP-1b), and platelet-derived growth factor-BB (PDGF-BB) in seminoma patients<br />
compared to non-seminoma. Patients with poor prognosis according to IGCCCG<br />
have elevated pretreatment level of beta-nerve growth factor (NGF-b) and stromal<br />
cell-derived factor-1 (SDF-1a) compared to patients with good/intermediate<br />
prognosis. Patients with metastatic disease had elevated pretreatment level of stem<br />
cell growth factor beta (SCGF-b) and PDGF-BB compared to patients with stage I<br />
disease.<br />
Conclusions: Using CAF profiling, we revealed differences in subgroups of TGCTs<br />
patients. We suggest that this platform may provide valuable insights into TGCTs<br />
biology, and could be useful in identification of new <strong>the</strong>rapeutic targets.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
866P HIGH-DOSE CHEMOTHERAPY AND AUTOLOGOUS BLOOD<br />
STEM CELL TRANSPLANTATION IN REFRACTORY/<br />
METASTATIC NON-SEMINOMATOUS GERM CELL TUMORS:<br />
GATA SINGLE CENTER RESULTS<br />
N. Karadurmus 1 , A.S. Ataergin 1 , G. Erdem 1 , M. Cakar 1 , I. Barista 2 , T. Turker 3 ,<br />
S. Ozaydin 1 , M. Ozturk 1 , F. Arpaci 1<br />
1 Medical Oncology, Gulhane School of Medicine, Ankara, TURKEY, 2 Medical<br />
Oncology, Hacettepe UniversityFaculty of Medicine, Ankara, TURKEY, 3 Public<br />
Helth, Gulhane School of Medicine, Ankara, TURKEY<br />
Introduction: Some patients with testis cancers do not respond to standard<br />
combination chemo<strong>the</strong>rapy and high-dose chemo<strong>the</strong>rapy (HDC) with autologous<br />
stem cell transplantation (OSCT) as salvage <strong>the</strong>rapy can achieve a complete<br />
remission in <strong>the</strong>se patients.<br />
Materials and methods: 62 patients that received HDC and OSCT between February<br />
1993 – December 2011 were retrospectively evaluated.<br />
Results: Median age was 24 (22-32 years). 56 patients (90.3%) had stage III, 6 (9.6%)<br />
had stage II disease. Histopathologically, embryonal carcinoma (64%), yolk-sac (24%)<br />
and choriocarcinoma (23%) were present. The primary tumor location was testis in<br />
51 patients (82.2%), and 11 patients (17.7%) had extragonadal region origin [6<br />
patients retroperitoneal (9.6%), 5 patients (8.1%) mediastinal]. Evaluation of<br />
metastatic focuses was as follows: liver (n = 20, 32.2%), extrahepatic (bone, lung)<br />
involvement (n = 34, 54.8%) and central nervous system involvement (n = 5, 8.1%).<br />
Six patients with stage II had refractory-high tumor markers and were treated with at<br />
least two different lines of chemo<strong>the</strong>rapy, underwent later HDC and OSCT. Two<br />
patients with stage II and 16 patients with stage III disease underwent fur<strong>the</strong>r<br />
RPLND. HDC included ifosfamide, carboplatin, etoposide. Median follow-up was<br />
39 (6-54) months. Pre-OSCT median AFP, β-HCG and LDH were 176 IU / ml<br />
(4.9-624), 1090 IU / ml (0.6-72000), 346 IU / ml (126–764), respectively; while on<br />
3rd month of OSCT median AFP, β-hCG and LDH were 20 IU / ml (4–54), 4 IU /<br />
ml (0.2-20), 124 IU / ml (102-240), respectively. After HDC, 16 patients (25.8%)<br />
achieved CR, 21 patients (33.8%) had PR, 8 patients (12.9%) had SD and 17 patients<br />
(27.4%) had PD. Three-year OS rate was 41%. The median neutrophil and platelet<br />
engraftment time was 14 days (12–17) and 15 days (13–17). The most important<br />
treatment toxicity was nephrotoxicity (grade 1/2) (11.2%).<br />
Conclusions: OSCT with HDC is an effective and curative treatment option in 26%<br />
of cases of refractory/metastatic germ cell testicular cancers.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
867P EXPERIENCE WITH SINGLE AGENT ADJUVANT<br />
CARBOPLATIN FOR STAGE I SEMINOMA – A<br />
RETROSPECTIVE ANALYSIS<br />
Annals of Oncology<br />
H. Nemeth, Z. Küronya, K. Bíró, I. Bodrogi, L. Géczi<br />
Chemo<strong>the</strong>rapy C and Clinical Pharmacology, National Institute of Oncology,<br />
Budapest, HUNGARY<br />
The cure rate for stage I seminoma is above 99%, and current adjuvant strategies aim<br />
to maintain this favorable result with less <strong>the</strong>rapy related toxicity. Adjuvant<br />
<strong>the</strong>rapeutic options include irradiation of <strong>the</strong> para-aortic lymph nodes, single agent<br />
carboplatin and surveillance. There is an increased risk of relapse in case of tumor<br />
size > 4 cm and rete testis infiltration, so as a risk adapted strategy, to patient with<br />
<strong>the</strong>se risk factors, adjuvant <strong>the</strong>rapy can be advised. We retrospectively analyzed <strong>the</strong><br />
data of our patients, who received adjuvant carboplatin for stage I seminoma in<br />
order to assess <strong>the</strong> safety and efficacy of this treatment. From November 2006 till <strong>the</strong><br />
end of 2011, 275 patients were treated or intended to treat with two courses of<br />
adjuvant carboplatin in <strong>the</strong> dose of area under <strong>the</strong> curve 7 after orchiectomy. One<br />
hundred and thirty two patients (48%) had tumors > 4cm, 131 patients (47.6 %)<br />
had ≤ 4 cm, and we had no data of 12 patients (4.4%). The tumor invaded <strong>the</strong> rete<br />
testis in 103 patients (37.4 %), <strong>the</strong> rete testis was tumor-free in 70 patients (25.4 %)<br />
and data was not available in 102 patients (37.2%). We had data for both risk factors<br />
in 166 patients (60%). Fifty one patients (30.7%) had two risk factors, 72 of <strong>the</strong>m<br />
(43.3%) had one, and 43 patients (26%) had no risk factors. Ten patients received<br />
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Annals of Oncology<br />
only one course of carboplatin. We experienced grade 3 side effects in 4 patients<br />
(vomiting, low platelets, neutropenia, deep vein thrombosis). No toxicity of higher<br />
grade developed. Seven patients relapsed. All relapses occurred in <strong>the</strong> retroperitoneal<br />
lymph nodes. In two patients, <strong>the</strong> retroperitoneal lymph node metastases were<br />
discovered after <strong>the</strong> first cycle of carboplatin, so <strong>the</strong>se cases are not considered real<br />
relapses, but ra<strong>the</strong>r <strong>the</strong> mistake of <strong>the</strong> initial staging. To conclude, single agent<br />
carboplatin proved to be a safe and effective treatment. The risk adapted strategy is<br />
not consistently used in our everyday practice. We aim to improve <strong>the</strong> quality of <strong>the</strong><br />
initial staging to avoid false stage I assessments. We also have to promote <strong>the</strong> more<br />
accurate pathologic examination of <strong>the</strong> specimens to be able to correctly inform <strong>the</strong><br />
patients on <strong>the</strong> risk of relapse and thus enable <strong>the</strong>m to make a fully informed<br />
decision on <strong>the</strong>ir adjuvant treatment.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
868 PROGNOSTIC SIGNIFICANCE OF EPIDERMAL GROWTH<br />
FACTOR RECEPTOR OVEREXPRESSION AND CHROMOSOME<br />
7 POLYSOMY IN CLEAR CELL RENAL CELL CARCINOMA<br />
F. Lumachi 1 , D. Santeufemia 2 , F. Pili 3 , S.M. M. Basso 4 ,G.LoRe 5 , G. Miolo 6 ,<br />
G.B. Chiara 4 , M. Ermani 7 , S. Tumolo 2 , P. Rocca Cossu 3<br />
1 Department of Surgical, Oncological & Gastroenterological Sciences (discog),<br />
University of Padua, School of Medicine, Padova, ITALY, 2 Medical Oncology,<br />
S. Maria degli Angeli Hospital, Pordenone, ITALY, 3 Department of Pathology,<br />
University of Sassari, Sassari, ITALY, 4 Chirurgia 1, S. Maria degli Angeli Hospital,<br />
Pordenone, ITALY, 5 Oncology, Medical Oncology, Pordenone, ITALY, 6 Centro<br />
Riferimento Oncologico (cro), Medical Oncology, Aviano, ITALY, 7 University of<br />
Padua, Department of Neurosciences, Padova, ITALY<br />
Background: Clear cell renal cell carcinoma (ccRCC) is <strong>the</strong> most common<br />
histological subtype of renal cell carcinoma. In patients with ccRCC several<br />
prognostic markers have been suggested, enclosing epidermal growth factor receptor<br />
(EGFR) expression and chromosome 7 polysomy (C7p). Cancer cells addicted to<br />
EGFR bear activated mutations in <strong>the</strong> EGFR gene, and <strong>the</strong>se mutations are useful in<br />
predicting susceptibility of ccRCC to EGFR inhibitors. The aim of this study was to<br />
evaluate <strong>the</strong> prognostic value of EGFR overexpression and C7p.<br />
Patients and methods: Archival specimens, coupled with clinical and survival data<br />
of 34 patients (20 men, 14 women, median age 58, range 42–79 years) who had<br />
undergone radical nephrectomy for ccRCC were analyzed. Immunohistochemistry<br />
and fluorescence in situ hybridization (FISH) specimens were sections of<br />
formalin-fixed paraffin-embedded tissue. EGFR expression was detected as<br />
membranous and cytoplasmic staining of neoplastic cells > 1%, and a ratio between<br />
gene/centromeric signals of more than two was considered to indicate gene<br />
amplification. Mean number of centromeric signals per nucleus was also scored to<br />
evaluate C7p. The log-rank test was used to examine <strong>the</strong> relationship between<br />
gender, EGFR overexpression, C7p and survival. Kaplan-Meyer analysis was<br />
performed to compare parameters with survival.<br />
Results: The age did not differ significantly (p = 0.79) between men and women.<br />
Overall, <strong>the</strong> median survival was 46 months (range 5-150 months). C7p was<br />
observed in 21 (61.8%) cases. The log-rank test showed a significantly (p = 0.01)<br />
shorter survival among men in respect of women. We did not find any relationship<br />
between survival and membranous (p = 0.32) or cytoplasmic (p = 0.51) EGFR<br />
overexpression, while C7p significantly (p = 0.02) correlated with survival. Similarly,<br />
no correlation was found (Cox’s regression) between EGFR overexpression and<br />
survival (R = 0.41, p = 0.21), while <strong>the</strong> relationship with gender (R = 0.87, p < 0.01)<br />
was confirmed.<br />
Conclusions: In our preliminary study, women with ccRCC had an overall better<br />
survival than men. EGFR was not a useful predictor of outcome, while C7p may have<br />
a prognostic significance.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
869 ANGIOGENIC AND SIGNALLING PROTEINS CORRELATE<br />
RESISTANCE AND SEQUENCE OF TREATMENT IN RENAL<br />
CELL CANCER<br />
R. Rosa 1 , V. Damiano 1 , L. Nappi 1 , L. Formisano 1 , F. Massari 2 , A. Scarpa 3 ,<br />
G. Martignoni 4 , R. Bianco 1 , G. Tortora 2<br />
1 Medical Oncology, University Federico II, Napoli, ITALY, 2 Medical Oncology,<br />
Azienda Ospedaliera Universitaria Integrata Verona-“Borgo Roma”, Verona,<br />
ITALY, 3 Patologia e Diagnostica, Universit, Verona, ITALY, 4 Pathology and<br />
Diagnostics, University of Verona, Verona, ITALY<br />
Background: The multi-tyrosine kinases inhibitors and <strong>the</strong> mammalian target of<br />
rapamycin (mTOR) inhibitors have dramatically changed <strong>the</strong> management of<br />
metastatic renal cell carcinoma (RCC). However, a relevant issue in RCC treatment is<br />
still <strong>the</strong> lack of a biological and molecular rationale able to establish <strong>the</strong> most<br />
effective sequence of <strong>the</strong> different <strong>the</strong>rapeutic options available.<br />
Methods: To address this issue, we systematically assessed <strong>the</strong> effect of different<br />
agents, alone and in sequence, on <strong>the</strong> growth, expression and secretion of key<br />
angiogenic and signalling proteins involved in tumor growth and resistance to<br />
treatment, in a panel of human RCC cell lines with different VHL status and in<br />
tumors xenografted in nude mice.<br />
Results: We demonstrated that sunitinib, sorafenib and everolimus are equally active<br />
as single agents in inhibiting cell proliferation, signal transduction and VEGF<br />
secretion, both in vitro and in tumors grown in mice. Pre-treatment of tumor cells<br />
with sunitinib reduced <strong>the</strong> response to subsequent sunitinib and sorafenib but not to<br />
everolimus. Lack by sunitinib of a persistent inhibition of key proteins including<br />
HIF-1, VEGF and MAPK anticipates onset of resistance in xenografted tumors. After<br />
first line sunitinib, second line everolimus was more effective than sorafenib or<br />
sunitinib rechallenge to interfere with critical signalling proteins and VEGF and<br />
Interleukin-8 secretion, translating into an advantage in <strong>the</strong> long-lasting inhibition of<br />
tumor growth and significant prolongation of mice survival.<br />
Conclusions: Our study demonstrates that angiogenic and signalling proteins predict<br />
treatment failure with sunitinib and that <strong>the</strong> use of mTOR inhibitor everolimus in<br />
second line is substantiated by a persistent control of proteins responsible for RCC<br />
growth and resistance to treatment.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
870 COMPLIANCE WITH SUNITINIB TREATMENT IN PATIENTS<br />
WITH RENAL CELL CANCER<br />
A. De Both 1 , V. Kruse 2 , E. De Coene 2 , N. Clottens 3 , A. Somers 3 , S. van Belle 2 ,<br />
L. van Bortel 4 , S. Rottey 2<br />
1 Internal Medicine, University Hospital Ghent, Ghent, BELGIUM, 2 Medical<br />
Oncology, University Hospital Ghent, Ghent, BELGIUM, 3 Pharamcy, University<br />
Hospital Ghent, Ghent, BELGIUM, 4 Clinical Pharamcy, University Hospital Ghent,<br />
Ghent, BELGIUM<br />
Introduction: Sunitinib (SUN) is one of <strong>the</strong> standard treatment options for<br />
metastatic renal cell cancer (mRCC). There are several possible reasons for<br />
non-compliance to <strong>the</strong> prescribed doses: oral intake of <strong>the</strong> drug, side effects and <strong>the</strong><br />
existence of multiple dosage forms. Prescribers are not always aware of this<br />
non-compliance.<br />
Methods: In Belgium SUN can only be delivered by <strong>the</strong> hospital pharmacy. This<br />
allows calculation of <strong>the</strong> used versus <strong>the</strong> prescribed dose. Based on <strong>the</strong>se data, <strong>the</strong><br />
minimum number of non-compliant weeks per patient were calculated.<br />
Results: 34 incident patients were considered, treated in <strong>the</strong> Ghent University<br />
Hospital between 2007–<strong>2012</strong>. The total number of treatment weeks for this patient<br />
group was 1079 (ranging between 1 and 108 weeks). A total of 850 weeks were<br />
suitable for analysis. 14 out of <strong>the</strong>se 34 patients (41.2%) had at least one week in<br />
<strong>the</strong>ir treatment period of non-compliance (insufficient number of pills), with <strong>the</strong><br />
percentage of time of treatment non-compliance in <strong>the</strong>se individual patients ranging<br />
from 2–40 % of <strong>the</strong> total treatment time, <strong>the</strong> average being 19 % of <strong>the</strong> weeks. The<br />
group with one or more weeks of non-compliance were <strong>the</strong> patients with <strong>the</strong> longest<br />
SUN intake: 47.2 versus 20.8 months of intake. On <strong>the</strong> o<strong>the</strong>r hand 5/34 patients<br />
(14.7%) received considerably more pills from <strong>the</strong> pharmacy than <strong>the</strong>ir treatment<br />
regimen warranted.<br />
Conclusions: In our single-center database of patients treated by SUN for mRCC, we<br />
demonstrated that over 40% of <strong>the</strong> patients were possibly non-compliant with <strong>the</strong>ir<br />
prescribed SUN dose. This occurred more frequently in long-term treatment. Given<br />
<strong>the</strong> average non-compliance time in this subgroup (19% of <strong>the</strong> weeks) we can<br />
conclude that this might significantly influence overall survival and response to<br />
treatment. We thus advocate a tighter patient follow-up and a control of drug<br />
prescription and delivery, which could result in detection of non-compliance more<br />
rapidly.<br />
Disclosure: S. Rottey: Advisory board Pfizer, Novartis, Bayer, GSK Research grant<br />
Pfizer, Bayer. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
872 COMPARATIVE EFFICACY OF SUNITINIB VERSUS SORAFENIB<br />
AS THE FIRST-LINE TREATMENT FOR PATIENTS WITH<br />
METASTATIC RENAL CELL CARCINOMA<br />
S.J. Park1 , J. Lee2 , I. Park2 , K. Park2 , J. Ahn2 , D.H. Lee2 , C. Song3 , J.H. Hong3 ,<br />
C. Kim3 , H. Ahn3 1 2<br />
Oncology, Asan Medical Center, Seoul, KOREA, Department of Oncology,<br />
Asan Medical Center, University of Ulsan College of Medicine, Seoul, KOREA,<br />
3<br />
Department of Urology, Asan Medical Center, University of Ulsan College of<br />
Medicine, Seoul, KOREA<br />
Background: Sunitinib has been recommended as <strong>the</strong> primary treatment in <strong>the</strong><br />
patients with metastatic renal cell carcinoma (mRCC) among <strong>the</strong> vascular endo<strong>the</strong>lial<br />
growth factor tyrosine kinase inhibitor (VEGF TKI). However, <strong>the</strong>re are no published<br />
clinical data that compared directly <strong>the</strong> efficacy of targeted agents in <strong>the</strong> first line<br />
setting. This study investigated <strong>the</strong> efficacy and toxicity of sorafenib and sunitinib as<br />
primary treatment for patients with mRCC.<br />
Methods: To compare <strong>the</strong> efficacy and toxicities between sorafenib and sunitinb,<br />
clinical database was used to identify all patients with mRCC treated with VEGF<br />
TKIs in Asan Medical Center from April 2005 to March 2011. Among 304 patients,<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds399 | ix287
we identified 49 and 220 patients who were treated first with sorafenib and sunitinib,<br />
respectively.<br />
Results: The patients in <strong>the</strong> sorafenib group were older than those in <strong>the</strong> sunitinib<br />
group (62 vs 56.5 years, p = 0.019). Disease control rate (DCR) of 71% and 74% were<br />
achieved in sorafenib and sunitinib groups, respectively (p = 0.687). After a median<br />
follow-up duration of 27.6 months, progression free survival (PFS), time to treatment<br />
failure (TTF), and overall survival (OS) were not significantly different between <strong>the</strong><br />
groups (sorafenib vs. sunitinib, PFS 8.6 months vs. 9.9 months, p = 0.948; TTF 6.6<br />
months vs. 7.2 months, p = 0.665; OS; 25.7 months vs. 22.6 months, p = 0.774).<br />
Patients treated with sorafenib required dose reduction due to toxicities less<br />
frequently than those treated with sunitinib (37% vs. 54%, p = 0.034). Haematological<br />
toxicities of grade 3 or 4 were more common in <strong>the</strong> sunitinib group than in <strong>the</strong><br />
sorafenib group (45% vs. 4%, p < 0.001), as was grade 3 or 4 hypertension although<br />
this was not statistically significant (14% vs. 4%, p = 0.066). Age (>60 years), duration<br />
from diagnosis to treatment (
Annals of Oncology<br />
multiple locations. As 1 st line <strong>the</strong>rapy, 24% had cytokine or immuno<strong>the</strong>rapy based<br />
<strong>the</strong>rapies, 52% sunitinib and 17% sorafenib. The duration of 1 st line <strong>the</strong>rapy was 7.0<br />
months in median for all patients (including cytokines) and 7.8 and 13.7 months for<br />
those treated with sunitinib or sorafenib, respectively. 50 patients achieved a second<br />
line <strong>the</strong>rapy prior to everolimus, 22 patients were treated with sorafenib and 26<br />
patients with sunitinib dependent on <strong>the</strong> 1 st line <strong>the</strong>rapy. Most patients treated with<br />
everolimus in 2 nd or 3 rd line <strong>the</strong>rapy had an ECOG of 1 (49.4%) followed by ECOG<br />
0 (39.5%) and ECOG 2 (9.9%). The median duration of treatment with everolimus<br />
was 4.5 months (0.6–22.5), 36% of <strong>the</strong> patients were more than 6 months on<br />
treatment with everolimus. Best response was CR in 2.5%, PR in 12% and SD in 47%<br />
of <strong>the</strong> patients (CBR 61%). Reasons for discontinuation were PD (72%), intolerance<br />
(16%), patients request (6%) and o<strong>the</strong>rs (6%). 77/81 patients (95%) received a fur<strong>the</strong>r<br />
<strong>the</strong>rapy after discontinuation of everolimus. The agents administered beyond<br />
everolimus were sunitinib (29%), sorafenib (29%) and 36% received o<strong>the</strong>r <strong>the</strong>rapies<br />
as temsirolimus, pazopanib or dovitinib. Best reported responses have been CR (1%),<br />
PR (9%), SD (48%) of <strong>the</strong> reported patients. 27 patients received an additional<br />
sequence of <strong>the</strong>rapy (4 th to 5 th line). In summary, <strong>the</strong>se data confirm <strong>the</strong> results of<br />
<strong>the</strong> RECORD-1 trial in clinical practice and demonstrate a clinical benefit of<br />
<strong>the</strong>rapies beyond everolimus. 58% of <strong>the</strong> patients were still alive at time of evaluation.<br />
Disclosure: L. Bergmann: The retrospective analysis was supported by a grant of<br />
Novartis Pharma. The presenter has been an advisor for Novartis Pharma. V.<br />
Grünwald: Advisory board Novartis. S. Weikert: Advisory board Novartis. T.C. Gauler:<br />
Advisary board Novartis. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
876 EFFICACY AND SAFETY OF SEQUENTIAL USAGE OF<br />
EVEROLIMUS IN PATIENTS WITH METASTATIC RENAL CELL<br />
CARCINOMA (MRCC) PREVIOUSLY TREATED WITH<br />
BEVACIZUMAB +/- INTERFERON (INF) THERAPY. RESULTS<br />
FROM THE EUROPEAN AVATOR RETROSPECTIVE STUDY<br />
A. Vuillemin 1 , C. Theodore 2 , L. Jacobasch 3 , J. Schmitz 4 , A. Guillot 5 ,<br />
C. Papandreou 6 , C. Emmanouilides 7 , K. Slimane 8 , M. Ktiouet 8 , T. Nguyen 1<br />
1 Medical Oncology, Hôpital Jean Minjoz, Besançon, FRANCE, 2 Medical<br />
Oncology, HÔPITAL FOCH, Suresnes, FRANCE, 3 Hematology/Oncology, Private<br />
Practice for Hematology/Oncology, Dresden, GERMANY, 4 Hematology/<br />
Oncology, Fachklinik Lindenberg/Ried, Lindenberg, GERMANY, 5 Medical<br />
Oncology, Institut de Cancérologie de la Loire, Saint Priest en Jarez Cedex,<br />
FRANCE, 6 Department of Medical Oncology, University Hospital of Larissa,<br />
Larissa, GREECE, 7 Oncology, Iatriko Diavalkaniko Thessalonikis, Thessaloniki,<br />
GREECE, 8 Oncology, Novartis Pharmaceuticals, Rueil-Malmaison, FRANCE<br />
Background: EVE (Afinitor®) has demonstrated activity in <strong>the</strong> treatment of mRCC<br />
after failure of VEGF-targeted tyrosine kinase inhibitors. However, to this date, <strong>the</strong>re<br />
is no published data evaluating its activity/safety after failure of first line BEV-based<br />
<strong>the</strong>rapy.<br />
Methods: Our non-interventional multicenter international study reports<br />
retrospective data on EVE in routine use. Eligible patients had mRCC; were given<br />
EVE after 1 prior first-line systemic <strong>the</strong>rapy with BEV +/- INF. The data were<br />
provided by each center and centralised. The pts were evaluated for differences in<br />
baseline characteristics and prognostic factors (PFs) validated in mRCC.<br />
Results: Here are <strong>the</strong> results from an interim analysis: 20 sites included 43 pts<br />
between October 2011 and February <strong>2012</strong>. Baseline patient characteristics included<br />
median age of 69 [38–90] years old; 64.3% male; 97.5% with prior nephrectomy.<br />
First-line <strong>the</strong>rapy was BEV + INF in 69% of patients, only BEV for 31%. Prognostic<br />
groups at <strong>the</strong> time of EVE initiation according to Heng (1) and to MSKCC (2) were<br />
respectively: (1): good 25%, intermediate 59.4% and poor prognosis 15.6% and (2)<br />
good 28.1%, intermediate 56.3% and poor 15.6%. Median duration of treatment with<br />
first line <strong>the</strong>rapy was 7.5 months, it was discontinued for disease progression in 61.9<br />
% of pts. Median EVE treatment duration with was 5 [3.0–7.0] months. Median<br />
progression free survival (PFS) has not yet been reached as 15 pts are still receiving<br />
EVE. Overall response rate was 9.5 % and disease stabilization rate was 50%. At least<br />
one adverse event (AE) occurred in 73.8 % of pts with 13 serious AEs. All grade<br />
common AEs were consistent with <strong>the</strong> toxicity profile of EVE with 31% of stomatitis,<br />
16.7% of pneumonitis, 31% of fatigue.<br />
Conclusions: This study provided encouraging results for <strong>the</strong> activity and safety<br />
profile of EVE in second line mRCC setting and warrants fur<strong>the</strong>r investigation after<br />
1 prior first-line <strong>the</strong>rapy with bevacizumab-based regimen. Final results with mature<br />
PFS data and median overall survival from initiation of first-line <strong>the</strong>rapy will be<br />
available in 2013.<br />
Disclosure: A. Vuillemin: Consulting fees : Novartis, Sanofi-Aventis, Ferring Member<br />
of Novartis Advisory board Honorarium study NovartisC. Theodore: Research grant<br />
from Novartis Consulting fees from Novartis Honorarium study NovartisL.<br />
Jacobasch: Honorarium study NovartisA. Guillot: Member of Novartis Advisory<br />
board Speaker at Novartis regional meetings Honorarium study NovartisC.<br />
Papandreou: Participated to advisory boards for NovartisC. Emmanouilides: Research<br />
grants : Novartis, Pfizer, GSKK. Slimane: Novartis employeeM. Ktiouet: Novartis<br />
EmployeeT. Nguyen: Honorarium study NovartisAll o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
877 A REVIEW OF RADIOLOGICAL ASSESSMENT RESPONSE IN<br />
METASTATIC RENAL CELL CARCINOMA TREATED WITH<br />
ANTIANGIOGENIC THERAPY- ARE WE HITTING THE TARGET?<br />
T. Montella 1 , D. Herchenhorn 2<br />
1 INCA, Rio de Janeiro, BRAZIL, 2 Medical Oncology, Brazilian National Cancer<br />
Institute, Rio de Janeiro, BRAZIL<br />
Background: Targeted <strong>the</strong>rapy has changed <strong>the</strong> treatment landsacpe of metastatic<br />
renal cell carcinoma (RCC) in <strong>the</strong> last years. However, despite <strong>the</strong> positive results<br />
with antiangiogenic drugs in <strong>the</strong> treatment of metastatic RCC, <strong>the</strong> evaluation of<br />
response to <strong>the</strong>se <strong>the</strong>rapies remains undefined. This study aimed to review different<br />
proposed radiologic methods used for response evaluation with antiangiogenic agents<br />
in RCC.<br />
Methods: A no systematic literature review using electronic databases PubMed/<br />
MEDLINE, EMBASE, Cochrane Library and LILACS with <strong>the</strong> terms “renal cell<br />
carcinoma”, “response criteria” and “targeted <strong>the</strong>rapy” and its variables.<br />
Results: A total of 53 articles were identified, of which 12 were selected and 41<br />
excluded. After evaluation of <strong>the</strong> references of <strong>the</strong> 12 selected studies, two new<br />
studies were included. The 14 studies were published from August 2009 to October<br />
2011, 11 of <strong>the</strong>m using computed tomography as a method of response evaluation,<br />
one with doppler ultrasound and two o<strong>the</strong>rs with positron emission tomography. A<br />
total of 927 patients were studied. The drugs used for analysis in <strong>the</strong> different studies<br />
were sunitinib, sorafenib, cediranibe, bevacizumab and interferon alpha; but sunitinib<br />
and sorafenib are variously present in all studies. The retrospective design was <strong>the</strong><br />
basis for most of <strong>the</strong> analysis (71%) and endpoints analysed for method comparison<br />
were time to disease progression (TTP) or progression-free survival (PFS). All studies had<br />
RECIST as <strong>the</strong> assessment parameters (control). Proposed new methods of radiographic<br />
response criteria in this context were present in 11 studies (78%). In 3 studies (21%) only<br />
one radiologist reviewed <strong>the</strong> images, in <strong>the</strong> o<strong>the</strong>r at least 2 radiologists participated in <strong>the</strong><br />
evaluation. Most studies evaluated a small number of patients and 8 studies (57%)<br />
included more than one antiangiogenic drugs in its analysis.<br />
Conclusion: Antiangiogenic drugs are considered standard <strong>the</strong>rapy in <strong>the</strong> treatment<br />
of metastatic RCC. Phase III trials are needed to validate <strong>the</strong> best radiological<br />
response criteria in this context, new proposed methods should be incorporated as<br />
secondary end-points in future prospective trials.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
878 THE ROLE OF NEPHRECTOMY IN METASTATIC RENAL CELL<br />
CARCINOMA – A SINGLE CENTRE ANALYSIS<br />
J. Neves 1 , I. Fernandes 2 , J. Ribeiro 2 , D. Macedo 2 , L. Costa 2<br />
1 Faculty of Medicine, University of Lisbon, Lisbon, PORTUGAL, 2 Oncology<br />
Division, Santa Maria Hospital (HSM-CHLN), Lisbon, PORTUGAL<br />
The approval of new <strong>the</strong>rapeutic options has increased <strong>the</strong> survival of metastatic<br />
renal cell carcinoma (mRCC) patients (pts). These drugs were mostly studied in pts<br />
who underwent nephrectomy (Sx) prior to <strong>the</strong> diagnosis of metastatic disease (MD).<br />
Sx is also indicated for pts with MD who are suitable and have good performance<br />
status (PS). The aim of this work is to retrospectively analyse <strong>the</strong> benefit of Sx in <strong>the</strong><br />
pts with mRCC referred to <strong>the</strong> Oncology Division at Santa Maria Hospital from 01/<br />
2006 to 10/2010. Two groups of pts were defined: pts who had Sx and pts who had<br />
no Sx. The first group was fur<strong>the</strong>r divided into pts who had Sx whilst with non-MD<br />
(SxNMD) and pts who did it whilst with MD (SxMD). With significance set at p =<br />
0.05 and <strong>the</strong> aid of IBM® SPSS® Statistics 20, statistical analysis was performed using<br />
descriptive statistics and Fisher’s exact test. Overall survival (OS) - time from<br />
diagnosis of MD to death - was plotted using <strong>the</strong> Kaplan–Meier method and<br />
compared by log-rank test. The population had 44 pts: 72,7% (n = 32) male, 59,1%<br />
(n = 26) under 65 years old, 90,9% (n = 40) with Karnofsky PS (KPS) ≥80 and 59,1%<br />
(n = 26) with clear cell carcinoma. Half were diagnosed with non-MD (NMD) (n =<br />
22) and progressed to MD in a mean of 45,9 months (m). Thirty-eight pts (86,4%)<br />
did medical <strong>the</strong>rapy, of those 86,8% (n = 33) had favourable or intermediate risk<br />
according to <strong>the</strong> Memorial Sloan Kettering Cancer Center (MSKCC) criteria and<br />
86,8% (n = 33) did target <strong>the</strong>rapy. Thirty pts underwent Sx (68,2%) and 14 didn’t<br />
(31,8%). There was no statistical difference between groups regarding gender, age,<br />
KPS, histology, MSKCC risk and medical <strong>the</strong>rapy. The median OS was 14 and 27 m<br />
respectively for <strong>the</strong> no Sx group versus <strong>the</strong> Sx group (p = 0,027). In <strong>the</strong> pts who had<br />
Sx, 21 (70%) were part of <strong>the</strong> SxNMD group and 9 (30%) of <strong>the</strong> SxMD group.<br />
Except for Fuhrman grade (p = 0,022), <strong>the</strong>re was no statistical difference between<br />
groups regarding gender, age, KPS, histology, MSKCC risk and medical <strong>the</strong>rapy. The<br />
median OS for SxNMD had not been reached while <strong>the</strong> median OS for SxMD was<br />
21 m (p = 0,682). In <strong>the</strong> population studied <strong>the</strong>re was no difference in OS curves<br />
between <strong>the</strong> SxNMD group and <strong>the</strong> SxMD group. This suggests that Sx has a<br />
valuable role in pts diagnosed with MD in addition to medical <strong>the</strong>rapy, namely<br />
target <strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds399 | ix289
879 TREATMENT OF PATIENTS WITH METASTATIC KIDNEY<br />
CANCER DURING HAEMODIALYSIS WITH MTOR INHIBITORS<br />
C. Masini 1 , M. Milella 2 , G. Di Lorenzo 3 , A. Onofri 4 , M. Santoni 4 ,V.Prati 5 ,<br />
M. Nicodemo 6 , P.F. Conte 1 , R. Sabbatini 1<br />
1 Dept. of Hematology/oncology, Ospedale Policlinico-Modena, Modena, ITALY,<br />
2 Divisione Di Oncologia Medica A, Istituto Nazionale Tumori Regina Elena, Roma,<br />
ITALY, 3 Genitourinary Cancer Section and Rare-cancer Center, University<br />
Federico II, Napoli, ITALY, 4 Clinica Di Oncologia Medica, AO Ospedali Riuniti,<br />
Università Politecnica delle Marche, Ancona, ITALY, 5 Oncologia Medica A<br />
Direzione Universitaria, Fondazione del Piemonte per l’Oncologia, Istituto per la<br />
Ricerca e la Cura del Cancro, Torino, ITALY, 6 Divisione Di Oncologia, Ospedale<br />
“Sacro Cuore-Don Calabria” Negrar, Verona, ITALY<br />
Background: On <strong>the</strong> basis of a few published data, sunitinib and sorafenib can be<br />
administered safely to patients (pts) with metastatic renal cell carcinoma (mRCC) and<br />
end-stage renal disease on haemodialysis (HD). Aim of this study was to investigate <strong>the</strong><br />
safety and efficacy of temsirolimus and everolimus in pts with mRCC on HD.<br />
Patients and methods: between September 2007 and February <strong>2012</strong>, 13 pts with<br />
mRCC undergoing HD were treated with temsirolimus and everolimus in 6 Italian<br />
Institutions. We retrospectively reviewed <strong>the</strong> medical records of <strong>the</strong>se pts to evaluate <strong>the</strong><br />
doses of mTOR inihibitors administered, <strong>the</strong> tolerability and <strong>the</strong> activity of <strong>the</strong> treatment.<br />
Results: Gender: 9 males/4 females; median age: 63 years (range 47–79). All pts were<br />
undergoing HD, in 7 cases for bilateral nephrectomy; <strong>the</strong> time interval between <strong>the</strong><br />
start of HD and <strong>the</strong> start of mTOR inhibitors treatment was 37 months. Everolimus<br />
was administered at 10 mg daily in 5 pts and at 5 mg in one patient; 7 pts received<br />
temsirolimus at 25 mg weekly. Everolimus was administered as second-line treatment<br />
in 4 pts, as third and fourth-line in two pts; temsirolimus was given as first-line<br />
treatment to 4 pts, as second-line to one patient and as third-line to 2 pts. No<br />
unexpected adverse event (AE) and no grade 4 haematological or<br />
non-haematological toxicity were reported. The most common grade 1–2<br />
non-haematological treatment-related AEs were fatigue (9/13 pts), dyslipidemia (4/13<br />
pts), oral mucositis in 2/13 pts. A grade 3 dyspnea due to interstitial pneumonia led<br />
to treatment discontinuation. The most frequent grade 1–2 haematologic toxicity was<br />
anemia (10/13 pts). None of <strong>the</strong> patients had to change <strong>the</strong> number of dialysis<br />
sessions during mTOR inhibitors treatment. None of <strong>the</strong> pts experienced an objective<br />
response while a disease stabilization was observed in 7 pts. At <strong>the</strong> time of <strong>the</strong><br />
analysis, 7 pts had died due to disease progression. The estimated median<br />
progression-free survival (PFS) of this cohort of pts was 6.1 months.<br />
Conclusions: In this small retrospective series of pts <strong>the</strong> incidence of AEs was as<br />
expected, and a prolonged PFS was observed. The use of temsirolimus and everolimus<br />
is not contraindicated in pts with mRCC and severe renal impairment on HD.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
880 LIVER TOXICITY IN PATIENTS WITH METASTATIC RENAL CELL<br />
CARCINOMA TREATED WITH PAZOPANIB THERAPY<br />
F.L. Lim 1 , J. Shamash 2 , P. Wilson 2 , T. Powles 3<br />
1 Department of Medical Oncology, St. Bartholomew’s Hospital, London,<br />
UNITED KINGDOM, 2 QMUL, Barts Cancer Insititute, London, UNITED<br />
KINGDOM, 3 Barts Cancer Institute, St Bartholomew’s Hospital QMUL, London,<br />
UNITED KINGDOM<br />
Purpose: Pazopanib is a vascular endo<strong>the</strong>lial growth factor receptor, platelet derived<br />
growth factor receptor and c-kit tyrosine kinase inhibitor, used in <strong>the</strong> treatment of<br />
metastatic renal cell carcinoma. It is associated with liver toxicity, although timing<br />
severity management and consequences of this toxicity is not known.<br />
Patients and methods: Sequential patients who were treated with 1 st line pazopanib<br />
for <strong>the</strong>ir metastatic renal cancer were identified from a prospective data base. Four<br />
weekly liver monitoring occurred. Specific protocols for <strong>the</strong> management of grade<br />
1-4 toxicity were followed. Toxicity was graded based on <strong>the</strong> clinical toxicity criteria<br />
(CTC) grading classification. Patients who developed grade 2 or more toxicity had a<br />
structured treatment interruption and dose reduction according to local policy.<br />
Results: 44 patients were identified as having received pazopanib treatment between<br />
2009-<strong>2012</strong>. Fifteen (34%) of whom developed liver toxicity as evidence by a raise in<br />
ei<strong>the</strong>r bilirubin or alkaline transaminase levels (Maximum CTC grade 1 = 4 (27%),<br />
2 = 6 (40%), 3 = 5 (33%), 4= 0 (0%), 5 = 0 (0%). Maximum toxicity occurred a<br />
median 60 days after commencing <strong>the</strong>rapy (range 14 – 83 days). Resolution occurred<br />
in all but 1 patient (grade 1 or less after stopping <strong>the</strong> treatment for a median of 3-21<br />
days. All patients restarted pazopanib. Twelve (80%) of <strong>the</strong>se with a dose reduction.<br />
Recurrence of raised liver function occurred in 4 (27%) patients (grade 1 = 3 (20%)<br />
grade 2 = 1 (7%) rechallanged with pazopainb. One patient died of progression of<br />
disease with a concurrent transaminitis (grade 1). The development of a<br />
transamitinits was associated with increased progression free survival (HR 0.35 95%<br />
CI 0.15 - 0.87 p = 0.024).<br />
Conclusion: Liver toxicity in patients treated with pazopanib occurs in 1/3 of<br />
patients, usually in <strong>the</strong> first 12 weeks of <strong>the</strong>rapy. Management is facilitated by blood<br />
monitoring, temporary cessation of <strong>the</strong>rapy and dose reductions. Transaminitis may<br />
be associated with improved outcomes.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
881 SEQUENTIAL USE OF TREATMENT OPTIONS IN ADVANCED<br />
RENAL-CELL CARCINOMA (RCC): A RETROSPECTIVE<br />
ANALYSIS OF 42 PATIENT CASES<br />
L. Derosa 1 , L. Galli 2 , A. Fontana 1 , E. Biasco 3 , R. Marconcini 1 , C. Cianci 4 ,<br />
A. Farnesi 1 , F. Orlandi 1 , A. Falcone 5<br />
1 Polo Oncologico, Azienda Ospedaliero Universitaria S.Chiara, Pisa, ITALY,<br />
2 Azienda Ospedaliero-universitaria Pisana, Istituto Toscano Tumori, Division of<br />
Medical Oncology, Pisa, ITALY, 3 Azienda Ospedaliero-universitaria Pisana, Istituto<br />
Toscano Tumori, 1Division of Medical Oncology, Pisa, ITALY, 4 Istituto Toscano<br />
Tumori, Azienda Ospedaliero-Universitaria Pisana, Pisa, ITALY, 5 Oncologia,<br />
Trapianti E Nuove Tecnologie In Medicina, Polo Oncologico - Azienda<br />
Ospedaliero-Universitaria Pisana - Istituto Toscano Tumori, Pisa, ITALY<br />
The best sequence of targeted <strong>the</strong>rapy options has not been sufficiently defined and<br />
also <strong>the</strong> significance of Cytokine (Cy) in TKI (Sorafenib-So, Sunitinib-Su) and<br />
mTOR era. The objective of this study was to describe <strong>the</strong> clinical activity of<br />
sequence options in 2nd line treatment.<br />
Methods: Retrospective study of 42 patients receiving TKI or Everolimus (EV)<br />
treatment after progression on first-line <strong>the</strong>rapy. Sequence of systemic targeted treatment<br />
consisted of an Cy-TKI-sequence (n = 20; Cy-So, n = 12; Cy-Su, n = 8), TKI-TKI-sequence<br />
(n=15;Su-So,n=11;So-Su,n=4)oranTKI-EV-sequence(n=7;Su-EV,n=7).We<br />
measured response to treatment (RECIST 1.0). Progression free survival (PFS) and overall<br />
survival (OS) were determined using <strong>the</strong> Kaplan-Meier method.<br />
Results: Sequence treatment groups did not significantly differ by gender, MSKCC<br />
prognostic group, or ECOG PS. Best response to 2nd line <strong>the</strong>rapy included CR (Su:<br />
n = 2, sequential <strong>the</strong>rapy after Cy), PR (So: n = 3, after Cy) and SD (EV: n = 5, after<br />
TKI; TKI: n = 13; So: n = 5 after Cy, Su: n= 3 after So, n= 5 after Cy). The estimated<br />
2nd line PFS was 5.2 months for EV and 5.86 months for So sequential <strong>the</strong>rapy after<br />
Su, 6.56 months for So sequential Cy, 6.7 months for Su sequential <strong>the</strong>rapy after So,<br />
6.54 months for Su sequential Cy. The estimated OS was longer for <strong>the</strong> group of<br />
patients receiving <strong>the</strong> Cy-TKI-sequence (49.87 months; 95% CI:16–26 for <strong>the</strong> group<br />
Cy-So and 40.36 months; 95% CI:16–26 for <strong>the</strong> group Cy-Su) and TKI-EV sequence<br />
(40.72 months; 95%CI:32–48) than for those receiving <strong>the</strong> TKI-TKI sequence So-Su<br />
(33.36 months, 95%CI:21–62) and Su-So (16.32 months, 95%CI:13–37). However,<br />
<strong>the</strong> TKI-TKI group was characterized by a relatively short first-line PFS (6.12 months<br />
of <strong>the</strong> Su-So group to 12.37 So-Su compared to 12.8 months of <strong>the</strong> TKI-EV group)<br />
which may at least in part explain <strong>the</strong> observed OS difference.<br />
Conclusions: Common sequence treatment options may have comparable efficacy in<br />
terms of PFS and response. The observed differences in OS await fur<strong>the</strong>r<br />
confirmation in prospective randomized trials.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
882 USING OF LACTOBACTERIN IN COMBINED TREATMENT OF<br />
SUPERFICIAL URINARY BLADDER CANCER<br />
S. Babakulov 1 , S. Navruzov 2<br />
1 Urology, National Cancer Center of Uzbekistan, Tashkent, UZBEKISTAN,<br />
2 Coloproctology, National Cancer Center of Uzbekistan, Tashkent, UZBEKISTAN<br />
Background: to improve combined treatment results of bladder cancer in<br />
combination with intra-bladder introduction of Lactobacterine. Materials and<br />
methods: During 2010 and 2011 years in National cancer research centre underwent<br />
a course of treatment 50 patients with superficial bladder cancer. Those patients<br />
divided in two groups. Main group 25 patients and control group 25 accordingly. All<br />
patients had morphological confirmed transitional cell carcinoma with histological<br />
differentiation G1-G2. Patients before hospitalization had bacteriological study of<br />
urine. Bacteriological analysis of urine revealed in 14 (28 %) patients presence of - E.<br />
Coli, in 16 (32 %) – S. aureus, in 12 (24%) - Ps. Aeruginosa and in 8 (16%)<br />
Klebsiella. After diagnosing of histological structure of <strong>the</strong> tumor and bladder<br />
microflora patients undergone transurethral resection of tumor. Patients in control<br />
group after TUR took intravisical chemo<strong>the</strong>rapy with doxorubicin 50 mg once in a<br />
week 6 courses. Patients in main group after TUR took intravisical chemo<strong>the</strong>rapy<br />
with doxorubicin 50 mg once in a week 6 courses and instillation of collibacterin.<br />
Treatment regimen was everyday instillation of probiotic collibacterin 20 mg (5<br />
doses) dissolving in 30 ml of 5% glucose solution per day during 5 days. After <strong>the</strong><br />
course patients took 3 mg of dried collibacterin per os during <strong>the</strong> year.<br />
Results: It was detected that side effects of intravisical chemo<strong>the</strong>rapy in <strong>the</strong> form of<br />
bladder disorders in control group was revealed almost in every case. Patients of<br />
main group only 2 of <strong>the</strong>m had insignificant pain during urination. Study of one<br />
year recurrent free survival rate showed that in main group one patient had<br />
recurrence of cancer in 310 th day after surgery. In control group 8 (32%) patients<br />
had recurrence in <strong>the</strong> course of year after operation.<br />
Conclusions: Using of intravisical probiotico<strong>the</strong>rapy in combined treatment of<br />
superficial urinary bladder cancer allows to decrease side effects of chemo<strong>the</strong>rapy and<br />
prolong one year recurrent free survival rate with superficial urinary bladder cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix290 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
883 EXPERIENCE OF ORGAN PRESERVATION IN URINARY<br />
BLADDER<br />
P. Singh, R.R. Prasad<br />
Radiation Oncology, Regional Cancer Centre, Indira Gandhi Institute of Medical<br />
Sciences, Patna, INDIA<br />
Aims: A retrospective analysis to evaluate <strong>the</strong> toxicity profile, protocol completion<br />
rate, tumor response rate, and disease free interval in patients undergoing<br />
chemoradio<strong>the</strong>rapy with muscle-invasive bladder cancer.<br />
Materials and methods: Following transurethral resection of <strong>the</strong> tumor in patients<br />
with Stage T2-T4a bladder cancer, induction chemo<strong>the</strong>rapy with paclitaxel and<br />
cisplatin / gemcitabine and cisplatin was administered for two–three cycles.<br />
Thereafter radio<strong>the</strong>rapy with low dose chemo<strong>the</strong>rapy was administered with weekly<br />
review. Adjuvant chemo<strong>the</strong>rapy based on <strong>the</strong> neoadjuvant protocol was given to all<br />
patients.<br />
Results: Between May 2005 to April 2008 total of 109 patients database were<br />
available for review. Paclitaxel and cisplatin chemo<strong>the</strong>rapy resulted in mildly grater<br />
grade 3-4 acute toxicity, mainly gastrointestinal (25%) as compared with<br />
gemcitabine and cisplatin 17%. Four cycles of adjuvant chemo<strong>the</strong>rapy were<br />
completed per protocol or with minor deviations in 45% of <strong>the</strong> patients in both<br />
<strong>the</strong> arms toge<strong>the</strong>r. Late bladder radiation toxicity was evaluated in 47 patients with<br />
>/ = 2 years of follow-up. Of <strong>the</strong>se 47 patients, 3 experienced self-limited, late<br />
grade 3 bladder toxicity. The post induction complete response rate was 81% and<br />
76% in <strong>the</strong> Paclitaxel and cisplatin group and gemcitabine and cisplatin group<br />
respectively. At a median follow-up of 39.4 months, <strong>the</strong> disease free survival was<br />
69% and 71%, respectively.<br />
Conclusions: Thesefavorabletumorresponserateswithpossibleincreased<br />
bladder preservation rates suggest that this treatment regimen deserves fur<strong>the</strong>r<br />
study.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
884 DOES THE FINDING OF PROSTATIC MALIGNANCY AT RADICAL<br />
CISTECTOMY FOR BLADDER CANCER AFFECT PROGNOSIS?<br />
E. Paze, F. Brusa, L. Ciuffreda, I. Chiappino<br />
Oncologia Medica 1, Azienda Ospedaliera Universitaria S. Giovanni Battista -<br />
Molinette, Torino, ITALY<br />
Radical surgery for muscle invasive male bladder cancer includes prostatectomy. It is<br />
not rare to find incidental prostate carcinoma at histological examination. Whe<strong>the</strong>r<br />
<strong>the</strong> two diseases have any relationship and if this finding may affect survival in this<br />
subset of patients is not well known. We reviewed histological reports in a series of<br />
110 patients who underwent radical cystectomy for bladder cancer and were seen at<br />
our Institution between 2005 and 2009. Prostate tissue was found to harbour<br />
adenocarcinoma in 42 cases, prostatic intraepi<strong>the</strong>lial neoplasia (PIN) in 24 cases and<br />
benign prostatic hyperplasia, prostatitis or normal findings in <strong>the</strong> remaining 44 case.<br />
Incidental prostate adenocarcinomas were between pT1a and pT3b, with Gleason<br />
scores between 5 and 9. High grade PIN was found in 18 patients and low grade in 6<br />
pts. We compared patient and disease characteristics in <strong>the</strong>se 3 groups of patients,<br />
and <strong>the</strong> results are shown in <strong>the</strong> table.<br />
Conclusions: although based on a small number of patients we did not notice any<br />
difference among patients with and without prostatic malignancy undergoing surgery<br />
with curative intent for bladder cancer. 3 and 5 yrs overall survival does not seem to<br />
be different among <strong>the</strong> three groups of patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Table: 884<br />
885 THE EFFICACY OF GEMCITABINE-BASED<br />
CHEMORADIOTHERAPY FOR THE DEFINITIVE TREATMENT OF<br />
LOCALLY-ADVANCED BLADDER CANCER<br />
M. Kurt 1 , H. Ozturk 2 , S. Cetintas 3 , E. Kurt 4 , L. Ozkan 3<br />
1 Radiation Oncology, Uludag University School of Medicine, Bursa, TURKEY,<br />
2 Radiation Oncology, Yunus Emre Hastahanesi, Eskisehir, TURKEY, 3 Radiation<br />
Oncology, Uludag University, Bursa, TURKEY, 4 Medical Oncology, Uludag<br />
University, Bursa, TURKEY<br />
Aim: The aim of <strong>the</strong> present study was to investigate <strong>the</strong> efficacy and <strong>the</strong> tolerability<br />
of gemcitabine-based chemoradio<strong>the</strong>rapy (CRT) for <strong>the</strong> definitive treatment of<br />
locally-advanced bladder cancer.<br />
Methods: Patients with <strong>the</strong> diagnosis of locally-advanced, transitional cell bladder<br />
cancer, who had been treated with gemcitabine-based CRT at <strong>the</strong> Radiation<br />
Oncology department of <strong>the</strong> Uludag University between January 2005 and January<br />
2009, were enrolled in this retrospective analysis. After maximal transurethral<br />
resection of tumor, three-dimensional radio<strong>the</strong>rapy (RT) was administered at an<br />
initial dose of 45 Gy to <strong>the</strong> primary tumor site plus regional lymphatics followed by<br />
a 20 Gy boost to <strong>the</strong> whole bladder with additional 2 cm margins (1.8 Gy daily<br />
fractions, five days a week). All patients received weekly gemcitabine at a dose of 350<br />
mg/m2 on Mondays during <strong>the</strong> course of RT. Response evaluations were performed<br />
every three months by systoscopic examinations and appropriate radiologic studies.<br />
Results: A total of 20 patients were entered into <strong>the</strong> study. There were 18 male and 2<br />
female with a median age of 72 (range: 40–78). The median disease-free survival was<br />
35,0 ± 8,2 months (95% CI: 18,7–51,2), and <strong>the</strong> median overall survival was<br />
37,0 ± 4,4 (95% CI: 28,3–45,7). Acute treatment-related grade ¾ hematologic<br />
toxicities were seen in 4 patients (20%). Although 3 patients (15%) exhibited<br />
grade ½ gastrointestinal toxicities, <strong>the</strong>re were no grade ¾ non-hematologic toxicities.<br />
Conclusion: Gemcitabine-based definitive CRT seems to be effective and tolerable<br />
treatment option for <strong>the</strong> treatment of locally-advanced bladder cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
886 CLINICAL MANAGEMENT OF SMALL-CELL CARCINOMA OF<br />
THE URINARY TRACT(SCCUT): A 10-YEAR SINGLE-CENTER’S<br />
EXPERIENCE<br />
I. Gil-Bazo 1 , E. Castanon Alvarez 1 , L.E. Abella 1 , M.E. Zudaire 1 , A. Castillo 1 ,<br />
E. Arevalo 1 , J.P. Fusco 1 , J.J. Zudaire 2 , R. Martínez-Monge 3 , O.E. Carranza 1<br />
1 Department of Oncology, Clínica Universidad de Navarra, Pamplona, SPAIN,<br />
2 Urology, Clínica Universidad de Navarra, Pamplona, SPAIN, 3 Department of<br />
Radiation Oncology, Clínica Universidad de Navarra, Pamplona, SPAIN<br />
Purpose: This study aimed to review <strong>the</strong> clinical features, <strong>the</strong>rapeutic management<br />
and natural course of patients with small-cell carcinoma of <strong>the</strong> urinary tract<br />
(SCCUT), based on our own clinical experience.<br />
Material and methods: From March 2002 to February <strong>2012</strong> twelve patients were<br />
diagnosed with SCCUT and started treatment at <strong>the</strong> Clínica Universidad de Navarra,<br />
Pamplona (Spain).<br />
Results: The primary tumor site was prostate in 6/12 (50%), urinary bladder in 5/12<br />
(41.7%) and kidney in 1/12 (8.3%) of <strong>the</strong> cases. Overall, 5 patients (41.7%) had<br />
limited disease (LD) and 7 (58.3%) had extensive disease (ED) at <strong>the</strong> time of<br />
diagnosis. Neuron-Specific Enolase (NSE) serum levels were determined in 5 patients<br />
at onset. In all of <strong>the</strong>m, levels over <strong>the</strong> upper-limit were observed. Detailed treatment<br />
information was available in 10 patients, 5 with LD and 5 with ED. LD patients were<br />
treated in a multimodality fashion. After a median follow-up of 26 months, median<br />
progression-free survival (PFS) for patients with LD was 22 months (range 7–40).<br />
No malignancy PIN Adenocarcinoma<br />
Patients age - mean - median<br />
(range)<br />
Bladder cancer: - stage I-II - stage<br />
68 yrs 71 yrs (37-85) 66 yrs 66 yrs (51-82) 70 yrs 70 yrs (57-84)<br />
III-IV 12 pts (27%) 32 pts (73%) 9 pts (38%) 15 pts (63%) 15 pts (36%) 27 pts (64%)<br />
Perioperative treatment for<br />
bladder cancer<br />
5 / 35 pts (4 pts unknown) 9/19 pts (5 pts unknown) 10/39 pts (3 pts unknown)<br />
Perineural and/or lymphovascular<br />
invasion<br />
17/43 pts (1 unknown) 8/24 pts 13/39 pts (3 unknown)<br />
Positive margins after cystectomy 3 pts 5 pts 2 pts<br />
3 yrs overall survival (CI 95%) 41.6% (24.8-58.4%) 77.2% (57.3-97.0%) 65.6% (48.6-82.7%)<br />
5 yrs overall survival (CI 95%) 41.6% (24.8-58.4%) 57.9% (21.9-93.8%) 65.6% (48.6-82.7%)<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds399 | ix291
Median overall survival (OS) was 26 months (range 11–40). Patients showing ED<br />
mostly received palliative chemo<strong>the</strong>rapy. The overall response rate for chemo<strong>the</strong>rapy<br />
in this cohort was 75%; 2/4 achieved a complete response, 1/4 a partial response and<br />
1/4 showed disease stabilization. After a median follow-up of 12 months, <strong>the</strong> median<br />
PFS was 11 months (range 3–14). The median OS was 14 months (range 12–38) for<br />
<strong>the</strong> ED cohort. However, <strong>the</strong> differences observed in PFS and OS between LD and<br />
ED cohorts did not achieve statistical significance. In addition, patients with bladder<br />
SCCUT showed a statistically significant longer PFS (22 months) compared to<br />
patients with a prostatic origin (6 months).<br />
Conclusions: Despite its chemosensitivity, SCCUT showed an aggressive clinical<br />
course and poor prognosis in our series. Bladder origin SCCUT may have a better<br />
prognosis than those from prostate origin. NSE serum levels may help to achieve an<br />
early diagnosis and to provide a proper systemic treatment up-front.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
887 PERI-OPERATIVE CHEMOTHERAPY OR SURVEILLANCE IN<br />
UPPER TRACT UROTHELIAL CANCER (POUT - CRUK/11/027) -<br />
A NEW RANDOMISED CONTROLLED TRIAL TO DEFINE<br />
STANDARD POST-OPERATIVE MANAGEMENT<br />
A.J. Birtle 1 , R. Lewis 2 , J. Chester 3 , J. Donovan 4 , M. Johnson 5 , R.J. Jones 6 ,<br />
R. Kockelbergh 7 , T.B. Powles 8 , E. Jones 9 , E. Hall 2<br />
1 Rosemere Cancer Centre, Lancashire Teaching Hospitals NHS Foundation<br />
Trust, Preston, UNITED KINGDOM, 2 Clinical Trials and Statistics Unit, Institute of<br />
Cancer Research, Surrey, UNITED KINGDOM, 3 Velindre Hospital, Cardiff<br />
University, Cardiff, UNITED KINGDOM, 4 School of Social and Community<br />
Medicine, University of Bristol, Bristol, UNITED KINGDOM, 5 Freeman Hospital,<br />
Newcastle upon tyne hospitals NHS Trust, Newcastle, UNITED KINGDOM,<br />
6 Medical Oncology, Beatson West of Scotland Cancer Centre Gartnavel General<br />
Hospital, Glasgow, UNITED KINGDOM, 7 Department of Urology, University<br />
Hospitals Leicester, Leicester, UNITED KINGDOM, 8 Department of Medical<br />
Oncology, St. Bartholomew’s Hospital, London, UNITED KINGDOM, 9 Clincial<br />
Trials and Statistics Unit, Institute of Cancer Research, Surrey,<br />
UNITED KINGDOM<br />
Background: The POUT trial aims to establish whe<strong>the</strong>r platinum-based combination<br />
chemo<strong>the</strong>rapy is superior to surveillance following nephro-ureterectomy with<br />
curative intent for upper tract transitional cell carcinoma (utTCC).<br />
Methods: We aim to randomise 345 participants world-wide, over a 5-year period.<br />
Previous trials of adjuvant chemo<strong>the</strong>rapy for uro<strong>the</strong>lial cancers suggest that potential<br />
challenges to recruitment include randomisation between “no treatment” vs<br />
chemo<strong>the</strong>rapy with its potential toxicity, and early identification of eligible patients.<br />
To support trial design and <strong>the</strong> development of patient information, we <strong>the</strong>refore<br />
conducted a survey of participating UK centres’ current standard treatment and also<br />
held a dedicated consumer focus group. During <strong>the</strong> trial set up period, additional<br />
sites expressed interest in participating and <strong>the</strong> survey was recirculated; results are<br />
presented here.<br />
Results: 26 of 44 UK centres questioned routinely place utTCC patients on<br />
surveillance following surgery; 18 give chemo<strong>the</strong>rapy if <strong>the</strong> patient is considered fit<br />
enough. The 9 respondents who specified chemo<strong>the</strong>rapy regimens give gemcitabine<br />
and cisplatin or carboplatin, dependent on renal function. All centres discuss patients<br />
pre-operatively in a multi-disciplinary team meeting, but 6 centres do not routinely<br />
discuss patients post-operatively. The consumer group welcomed <strong>the</strong> opportunity for<br />
utTCC patients to participate in research. They approved of <strong>the</strong> proposed<br />
randomisation between surveillance and chemo<strong>the</strong>rapy and supported <strong>the</strong> use of a<br />
two stage pre- and post-operative information giving process.<br />
Conclusions: There is no consensus among UK clinicians regarding optimum<br />
post-operative treatment of muscle invasive utTCC. The POUT trial offers <strong>the</strong><br />
opportunity to standardise post-operative management of utTCC internationally and<br />
is supported by urologists, oncologists and consumer representatives from <strong>the</strong> target<br />
patient population. The trial design incorporates an initial two-year recruitment<br />
optimisation phase which includes qualitative research to inform recruitment<br />
practices.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
888 LAPAROSCOPIC LYMPH NODE RESECTION OF<br />
POST-CHEMOTHERAPY (POST-CHT) RESIDUAL<br />
RETROPERITONEAL (RP) TUMOR MASSES IN PATIENTS WITH<br />
NON-SEMINOMATOUS TESTICULAR GERM-CELL TUMORS<br />
(NSTGCT)<br />
I.G. Sullivan 1 , G. Anguera 1 , C. Arqueros 1 , D. Condori 1 , J. Palou 2 , J.A. Peña 2 ,<br />
H. Villavicencio 2 , P. Maroto 1<br />
1 Medical Oncology, Hospital de Sant Pau, Barcelona, SPAIN, 2 Urology<br />
Department, Fundacio Puigvert, Barcelona, SPAIN<br />
Introduction: Resection of post-CHT residual masses, usually located in<br />
retroperitoneum, is an essential part of <strong>the</strong> management of NSTGCT. Presently,<br />
Annals of Oncology<br />
surgical procedure consists in an open unilateral retroperitoneal lymph node<br />
dissection (RPLND) of a modified template. Laparoscopic procedures have reduced<br />
morbidity compared to open surgery; in addition, limited lymphadenectomies or<br />
resection of essentially <strong>the</strong> residual mass may help to reduce morbidity, although it<br />
might have a higher incidence of local relapses.<br />
Objective: To analyze relapse rate, morbidity and toxicity associated to laparoscopic<br />
RPLND in a series of patients (pts) with NSTGCT of a single tertiary referral center<br />
with surgeons who have extensive experience in post-CHT resection between January<br />
2002 and January <strong>2012</strong>.<br />
Results: Retrospective analysis of 14 pts with a median follow-up of 40 months (m).<br />
Median age at diagnosis was 30 (18-43) years. Pathologic evaluation of <strong>the</strong> testis<br />
tumor revealed mixed NSTGCT with teratomatous elements in 11/14, and pure<br />
teratoma in 1. Embryonal carcinoma was presented in 12/14. Royal Marsden staging<br />
classification was: IIA: 2; IIB: 7; IIC: 2; IIIB: 1; IVB: 1, IVC: 1. All pts received a<br />
median of 4 cycles of BEP and had a complete serum marker response after<br />
induction CHT. RP masses showed a partial response in 8 and stable disease in 6 pts.<br />
Median size of <strong>the</strong> post-CHT retroperitoneum masses was 2,5 cm (1-10). Histologic<br />
examination showed fibrosis or necrosis in 4 (28%) and mature teratoma in 10 (64%)<br />
pts. Toxicity: Median days of hospitalization were 4 (2-9). 5 pts showed decrease of<br />
at least 2 points in hemoglobin, not requiring transfusion support. Chylous ascites<br />
was reported in 1 and an infected RP hematoma in ano<strong>the</strong>r 1 pts. 2 pts developed<br />
ejaculatory dysfunction. Only 1 patient experienced an early relapse (3 m after<br />
RPLND) requiring salvage laparotomy. Pathology of <strong>the</strong> RP mass in this case<br />
reported a growing teratoma. All pts are alive and presently free of disease.<br />
Conclusion: In our series, in a Hospital with long expertise in RP surgery,<br />
laparoscopic RPLND provided a low rate of complications and RP relapses, reducing<br />
morbidity comparing to historical series with open procedures.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
889TiP SUNITINIB TREATMENT OF RENAL ADJUVANT CANCER<br />
(S-TRAC): A RANDOMIZED, DOUBLE-BLIND, PHASE III<br />
STUDY OF SUNITINIB VS. PLACEBO IN SUBJECTS AT HIGH<br />
RISK OF RECURRENT RENAL CELL CARCINOMA (RCC)<br />
A. Ravaud 1 , R.J. Motzer 2 , H. Pandha 3 , M. Staehler 4 , D.J. George 5 , A. Pantuck 6 ,<br />
A. Patel 7 , P. Gerletti 8 , L. Chen 9 , J. Patard 10<br />
1 Medical Oncology, Hôpital Saint André, Bordeux, FRANCE, 2 Genitourinary<br />
Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY,<br />
UNITED STATES OF AMERICA, 3 Postgraduate Medical School, Postgraduate<br />
Medical School, Surrey, UNITED KINGDOM, 4 Department of Urology, University<br />
of Munich, Munich, GERMANY, 5 Oncology, Duke University Medical Center,<br />
Durham, NC, UNITED STATES OF AMERICA, 6 Urology, David Geffen School of<br />
Medicine at UCLA, Los Angeles, CA, UNITED STATES OF AMERICA,<br />
7 Oncology, Whipps Cross University Hospital, Leytonstone, UNITED KINGDOM,<br />
8 Pfizer Oncology Business Unit, Pfizer Italia S.r.l., Milan, ITALY, 9 Biostatistics,<br />
Pfizer, New York, NY, UNITED STATES OF AMERICA, 10 Urology, Paris XI Bicetre<br />
University Hospital, Paris, FRANCE<br />
Background: Surgical resection alone may fail to cure high-risk RCC. Progression to<br />
metastatic recurrence directly relates to tumor size in subjects with clinically localized<br />
RCC, and 25–50% of subjects treated for localized disease eventually experience<br />
recurrence. Sunitinib is an oral, multitargeted tyrosine kinase inhibitor approved in<br />
2006 for <strong>the</strong> treatment of advanced RCC based on robust results from randomized<br />
clinical trials. Sunitinib led to metastatic deposit size reduction in most cases. These<br />
observations provided <strong>the</strong> rationale to investigate sunitinib as an adjuvant<br />
mono<strong>the</strong>rapy in subjects at high risk of recurrence after nephrectomy for clinically<br />
localized RCC.<br />
Methods: In this ongoing prospective, double-blind, placebo-controlled, randomized,<br />
multicenter, phase III study, eligible subjects have histologically confirmed,<br />
predominantly (>50%) clear cell RCC diagnosed by <strong>the</strong> UISS staging system and are<br />
at high risk of recurrence, with no evidence of residual macroscopic disease. Within<br />
12 weeks after nephrectomy, subjects will be randomized 1:1 to oral sunitinib 50 mg/<br />
day on Schedule 4/2 (4 weeks on/2 weeks off) or placebo, for 1 year (9 cycles). Dose<br />
reduction to 37.5 mg/day but not to 25 mg/day is permitted. Subjects will be followed<br />
for disease recurrence every 12 weeks for 1–3 years and every 6 months <strong>the</strong>reafter,<br />
until final analysis. Safety and efficacy data are under review by an independent data<br />
monitoring committee (IDMC). The primary objective is to compare disease-free<br />
survival (DFS) for sunitinib vs. placebo based on independent blinded review. O<strong>the</strong>r<br />
objectives include safety monitoring, overall survival (OS) and health-related quality<br />
of life (EORTC QLQ-C30 and EQ-5D).<br />
Results: 900 subjects were screened and 630 have been randomized (reasons for<br />
screening failures will be presented). The trial is currently ongoing; enrolment closed<br />
worldwide in April 2011, except in China. 615 subjects have completed 1 year of<br />
treatment and are in follow-up for DFS and/or OS. At last review, <strong>the</strong>re were no<br />
unexpected toxicity warnings and <strong>the</strong> IDMC recommended continuing <strong>the</strong> trial.<br />
NCT00375674<br />
Disclosure: A. Ravaud: Advisory relationship with Pfizer, Novartis, Bayer Schering,<br />
GSK, Astellas, Dendreon. Honoraria from Pfizer, Novartis, Bayer Schering, Roche,<br />
GSK, Astellas, Dendreon. Research funding from Pfizer, Novartis. Travel<br />
renumeration from Pfizer and Novartis. R.J. Motzer: Advisory relationship with<br />
ix292 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Pfizer. Research funding from Pfizer. M. Staehler: Advisory relationship with Pfizer.<br />
Honoraria from Pfizer. Research Funding from Pfizer. Expert testimony for Pfizer. D.<br />
J. George: Advisory relationship with Pfizer. Honoraria to disclose from Pfizer.<br />
Research funding from Pfizer. A. Pantuck: Advisory relationship with Pfizer. A. Patel:<br />
Advisory relationship with Pfizer; Global S-TRAC Steering Committee Member.<br />
Travel Reimbursement for Steering Committee Meetings. P. Gerletti: Compensated<br />
employment with Pfizer. Pfizer stock ownership. L. Chen: Compensated employment<br />
with Pfizer. Pfizer stock ownership. J. Patard: Advisory relationship with Pfizer, Bayer<br />
and Novartis. Honoraria from Pfizer, Bayer, Novartis and Baxter. All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
890TiP PHASE II STUDY OF EVEROLIMUS (E) IN REFRACTORY<br />
GERM CELL TUMORS (GCTS)<br />
M. Reckova 1 , M. Mego 1 , D. Svetlovska 2 , V. Miskovska’ 3 , J. Obertova 1 ,<br />
Z. Sycova-Mila 1 , P. Palacka 1 , J. Rajec 1 , S. Liskova 1 , J. Mardiak 1<br />
1 Medical Oncology, National Cancer Institute, Slovakia, Bratislava, SLOVAK<br />
REPUBLIC, 2 Clinical Research, National Cancer Institute, Bratislava, SLOVAK<br />
REPUBLIC, 3 Medical Oncology, St. Elisabeth Cancer Institute, Bratislava,<br />
SLOVAK REPUBLIC<br />
Background: GCTs represent a model for <strong>the</strong> cure of cancer. None<strong>the</strong>less, a small<br />
proportion of patients (pts) develop disease recurrence. Loss of <strong>the</strong> tumor suppressor<br />
gene PTEN (phosphatase and tensin homolog) marks <strong>the</strong> transition from<br />
intratubular germ cell neoplasias (ITGCN) to invasive GCTs. PTEN inactivation is<br />
associated with dysregulation of PI3K/Akt pathway and increased mTOR signalling.<br />
We hypo<strong>the</strong>size that dysregulation of PI3K/Akt pathway due to PTEN inactivation in<br />
GCTs suggests that <strong>the</strong>se pts would have greater benefit from mTOR inhibition.<br />
Methods: In December 2011, National Cancer Institute of Slovakia launched a one<br />
arm, two-staged phase II study aimed to evaluate <strong>the</strong> efficacy and toxicity of<br />
Everolimus (E) in pts with refractory GCTs. The primary objective is to determine<br />
<strong>the</strong> efficacy of E in pts with refractory GCTs. The pts with radiological and/or<br />
serological proof of relapsed GCTs, who were not amenable to be cured by<br />
chemo<strong>the</strong>rapy or surgery and who failed at least two platinum-based regimens or<br />
one platinum regimen in case of platinum-refractory disease or primary mediastinal<br />
non-seminomatous GCTs have been eligible. E has been administered at a dose of<br />
10mg daily until progression or unacceptable toxicity.<br />
Results: From December 2011, 4 patients have been enrolled. Median age of patients<br />
is 28 years. All patients were pretreated with at least 3 cisplatin-based <strong>the</strong>rapy, three<br />
patients were absolute cisplatin refractory, progressed directly on cisplatin-based<br />
<strong>the</strong>rapy. We observed no unexpected toxicity. One patient experienced pneumonitis<br />
grade 3, and dose reduction was needed. One patient progressed early, while three<br />
patients are still on treatment for 1 + , 3+ and 5+ months.<br />
Conclusion: Our preliminary data suggests that, Everolimus is safe and well tolerated<br />
drug in patients with GCT. Efficacy data is warranted.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
891TiP PHASE II STUDY OF DOVITINIB IN FIRST LINE METASTATIC<br />
OR (NON RESECTABLE PRIMARY) ADRENOCORTICAL<br />
CARCINOMA (ACC). SOGUG STUDY 2011-03<br />
S. Hernando 1 , J. Garcia-Donas 2 , M. Climent 3<br />
1 Medical Oncology, Hospital Universitario Fundación Alcorcón, Alcorcón<br />
(Madrid), SPAIN, 2 Madrid, Hospital Madrid Norte San Chinarro Centro Integral<br />
Oncologico Clara Campal, Madrid, SPAIN, 3 Medical Oncology Department,<br />
Instituto Valenciano de Oncologia, Valencia, SPAIN<br />
Background: Dovitinib is a novel targeted <strong>the</strong>rapy, that has proven to inhibit, among<br />
o<strong>the</strong>r tyrosin kinases, <strong>the</strong> fibroblast growth factor receptor (FGFR). Since this<br />
pathway has been proposed to play a major role in ACC, we aim to test <strong>the</strong> clinical<br />
efficacy of dovitinib in this tumor.<br />
Methods: An open label phase II trial has been designed in patients with advanced<br />
non-resectable ACC. The objective will be to obtain at least a 15% response rate<br />
according to RECIST criteria. Taking as a basis <strong>the</strong> two-stage Gehan model, 15<br />
patients would need to be included in <strong>the</strong> first stage to demonstrate a treatment<br />
efficacy of at least 15%. Sample size calculation was done based on <strong>the</strong> following<br />
parameters, probability of Type I error α = 0.05, power of <strong>the</strong> test (1 - β) = 0.8. Main<br />
inclusion criteria are advanced non-resectable disease and no prior <strong>the</strong>rapy (o<strong>the</strong>r<br />
than mitotane). Since this is an extremely unfrequent disease 7 institutions, members<br />
of <strong>the</strong> SOGUG (Spanish Oncology Genitourinary Group), will participate. The active<br />
support of a big collaborative group will guarantee candidate patients to be refereed<br />
to such institutions. So far 6 patients have already been included. Starting January<br />
26th <strong>2012</strong> recruitment is scheduled to last around 12 months. Updated data<br />
regarding population of study and toxicity will be presented at <strong>the</strong> <strong>ESMO</strong> meeting. A<br />
translational research, including whole exome analysis, will be performed in order to<br />
improve our scarce knowledge of ACC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
892TiP PATIENT PREFERENCE FOR TIVOZANIB HYDROCHLORIDE<br />
OR SUNITINIB IN THE TREATMENT OF METASTATIC RENAL<br />
CELL CARCINOMA (MRCC): TAURUS STUDY<br />
B. Escudier 1 , L. Steelman 2 , D. Cesic 2 , A. Berkenblit 2<br />
1 Oncology, Institut Gustave Roussy, Villejuif, FRANCE, 2 Oncology, AVEO<br />
Pharmaceuticals, Cambridge, MA, UNITED STATES OF AMERICA<br />
Purpose: Tivozanib hydrochloride is a potent, selective, long half-life inhibitor of<br />
vascular endo<strong>the</strong>lial growth factor (VEGF) receptors 1, 2, and 3. Inhibition of<br />
VEGF-driven angiogenesis is known to reduce vascularization and tumor growth.<br />
Currently, sunitinib is most commonly used as first-line treatment in patients with<br />
mRCC. Previous Phase II and Phase III studies have demonstrated <strong>the</strong> promising<br />
efficacy and safety of tivozanib in patients with mRCC. The primary objective of this<br />
study is to compare patient preferences for tivozanib or sunitinib. Secondary<br />
objectives include assessing overall safety and tolerability, frequency of dose<br />
modifications, and quality of life in patients treated with tivozanib and sunitinib.<br />
Study design: This Phase II, randomized, double-blind, multinational, crossover study<br />
will compare <strong>the</strong> preference of mRCC patients for tivozanib or sunitinib as treatment<br />
for metastatic disease. Recruitment of 160 patients is planned. Patients will be<br />
randomized to tivozanib 1.5 mg/d for 12 weeks (wks) (Cycle = 3 wks on, 1 wk off) or<br />
sunitinib 50 mg/d for 12 wks (Cycle = 4 wks on, 2 wks off). After a washout period,<br />
patients will cross over to <strong>the</strong> alternate treatment (sunitinib or tivozanib).<br />
Methods: After 12 wks of treatment, tumor response will be assessed using Response<br />
Evaluation Criteria In Solid Tumors (version 1.1). Patients are expected to cross over<br />
to <strong>the</strong> second treatment for 12 wks; however patients with a significant clinical<br />
response (defined as >50% tumor reduction or complete response for<br />
non-measurable disease) will be given <strong>the</strong> option to continue <strong>the</strong> first treatment if<br />
<strong>the</strong>y choose. Patients with Grade 3/4 adverse events may have a dose interruption of<br />
≤2 wks to manage toxicities, after which <strong>the</strong>y may continue at <strong>the</strong> same or reduced<br />
dose; dose reductions to 1.0 mg/d for tivozanib and 37.5 mg/d for sunitinib will be<br />
allowed. After <strong>the</strong> second 12-wk period, patients’ drug preferences, based on a<br />
questionnaire, and <strong>the</strong>ir tumor response will be assessed and reviewed prior to a final<br />
tumor assessment.<br />
Conclusion: The double-blind design of this study will enable comprehensive<br />
assessment of patient preference for tivozanib and sunitinib as treatment for mRCC.<br />
Disclosure: B. Escudier: Board Membership:Pfizer, GSK, Bayer, AVEO, Novartis<br />
Consultancy: Pfizer, GSK, Bayer, Payment for lectures, service on spkrs bureaus:<br />
Pfizer, Novartis Payment for development of educational presentations: Pfizer, GSK,<br />
Bayer, AVEO, Novartis. L. Steelman: Current Employment: AVEO with stock options<br />
Employment: Novartis until 8/11 Employment: ARIAD until 11/09. D. Cesic: AVEO<br />
Pharmaceuticals employee with stock options. A. Berkenblit: AVEO Pharmaceuticals<br />
employee with stock options<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds399 | ix293
abstracts<br />
Genitourinary tumors, prostate<br />
893O SURVIVAL ANALYSIS OF A RANDOMIZED PHASE III TRIAL<br />
COMPARING ANDROGEN DEPRIVATION THERAPY (ADT)<br />
PLUS DOCETAXEL VERSUS ADT ALONE IN<br />
HORMONE-SENSITIVE METASTATIC PROSTATE CANCER<br />
(GETUG-AFU 15/0403)<br />
G. Gravis 1 , K. Fizazi 2 , F. Joly Lobbedez 3 , S. Oudard 4 , F. Priou 5 , I. Latorzeff 6 ,<br />
R. Delva 7 , I. Krakowski 8 , B. Laguerre 9 , F. Rolland 10 , C. Théodore 11 ,<br />
G. Deplanque 12 , J.M. Ferrero 13 , D. Pouessel 14 , L. Mourey 15 , P. Beuzeboc 16 ,<br />
S. Zanetta 17 , B. Esterni 18 , M. Habibian 19 , M. Soulie 20<br />
1 Service d’Oncologie, Institut Paoli Calmettes, Marseille, FRANCE, 2 Department<br />
of Medical Oncology, Institute Gustave Roussy, Villejuif, FRANCE, 3 Service<br />
d’Oncologie Médicale, Centre François Baclesse, Caen, FRANCE, 4 Medical<br />
Oncology Department, Georges Pompidou Hospital and Rene Descartes<br />
University, Paris, FRANCE, 5 Service d’Onco-Hématologie, Centre Hospitalier Les<br />
Oudairies, La Roche-sur-Yon, FRANCE, 6 Service de Radiothérapie, Clinique<br />
Pasteur, Toulouse, FRANCE, 7 Dept. of Medical Oncology, Centre Paul Papin,<br />
Angers, FRANCE, 8 Unité de Soins Oncologiques de Support, Centre Alexis<br />
Vautrin, Vandoeuvre-les-Nancy, FRANCE, 9 Service d’oncologie Médicale, Centre<br />
Eugène Marquis, Rennes, FRANCE, 10 Service d’Oncologie Médicale, Centre<br />
René Gauducheau, Saint-Herblain, FRANCE, 11 Service d’Onco-Hématologie,<br />
Hôpital Foch, Suresnes, FRANCE, 12 Service d’Oncologie, Groupe Hospitalier<br />
Saint Joseph, Paris, FRANCE, 13 Service d’Oncologie Médicale, Centre Antoine<br />
Lacassagne, Nice, FRANCE, 14 Service d’Oncologie Médicale, Centre Val<br />
d’Aurelle-Paul Lamarque, Montpellier, FRANCE, 15 Service d’Oncologie Médicale,<br />
Institut Claudius Régaud, Toulouse, FRANCE, 16 Département d’Oncologie<br />
Médicale, Institut Curie, Paris, FRANCE, 17 Service d’Oncologie Médicale, Centre<br />
Georges François Leclerc, Dijon, FRANCE, 18 Biostatistic, Paoli Calmette,<br />
Marseille, FRANCE, 19 R&D UNICANCER, PARIS Cedex, FRANCE, 20 Chirurgie<br />
Urologique, Centre Hospitalier Universitaire Rangueil, Toulouse, France<br />
Background: Androgen deprivation <strong>the</strong>rapy (ADT) is <strong>the</strong> standard treatment of<br />
hormone-sensitive metastatic prostate cancer (HSMPC). We performed a phase III<br />
multicentre trial to compare ADT alone with ADT plus docetaxel (D) in HNMPC.<br />
Methods: Patients (pts) with HSMPC were randomly assigned to ei<strong>the</strong>r arm A<br />
(ADT + D: 75mg/m q3w, up to 9 cycles) or arm B (ADT). The primary endpoint was<br />
overall survival (OS). The planned number of pts was 378 to detect an improvement<br />
in OS with a hazard ratio (HR) of 0.62, a power of 80% and an alpha risk of 0.05<br />
(two-sided test). Secondary endpoints were biological progression-free survival (PFS)<br />
and clinical PFS. Data on toxicity and quality of life have been previously presented.<br />
Results: From October 2004 to December 2008, 385pts were included. Baseline<br />
characteristics were well balanced between <strong>the</strong> two arms. Median age was 63 years<br />
(43-84), median PSA was 26.4 ng/ml (0.1-11900), Gleason score was ≥ 8 in 57%.<br />
Prognostic classification was as follows: good prognosis (49%), intermediate (29%) and<br />
poor (22%). The majority of pts had metastases at <strong>the</strong> time of diagnosis (72%), 28%<br />
developed metastases after local treatment failure. Median number of D cycles was 8<br />
(range 0-9). The median follow-up was 50 months (mo) [95%CI: 49-54]. At 6 mo, a<br />
higher PSA response (≥ 50%) in arm A (94% vs 85%, p = 0.0096) and a higher PSA<br />
progression (≥ 25%) in arm B (10% vs 1%, p = 0.0015) were observed. Biological PFS was<br />
significantly longer in arm A: 22.9 vs 12.9 mo, HR; 0.72 [95%CI: 0.57-0.91] (p = 0.005).<br />
Clinical PFS was increase in arm A: 23.46 vs 15.44 mo, HR: 0.75 [95CI: 0.59-0.94]<br />
(0.015). OS was not significantly different (median: 58.9 mo in arm A and 54.2 mo in<br />
arm B, HR: 1.01 [95%CI: 0.75-1.36]. The median OS for each prognostic group was 69.1<br />
[95%CI: 60.9-NR], 46.5 [95%CI: 37.7-NR] and 36.6 [95%CI9: 28.5-58.9] mo respectively<br />
in <strong>the</strong> good, intermediate, and poor prognosis groups (p = 0.001), with no difference<br />
between <strong>the</strong> two arms. At <strong>the</strong> cut-off time, 65% of pts from <strong>the</strong> ADT arm had received<br />
docetaxel since <strong>the</strong>y developed castrate-resistant prostate cancer.<br />
Conclusion: Combining docetaxel and ADT improves PFS over ADT alone in pts<br />
with HSMPC. However, no difference in OS was observed between <strong>the</strong> two arms.<br />
Disclosure: G. Gravis: I have expert testimony to disclose: Sanofi Aventis,<br />
uncompensated. K. Fizazi: Participation to advisory boards and speaker for<br />
Sanofi-Aventis. F. Joly Lobbedez: advisory board/board of directors position: Sanofi,<br />
Roche, Pfizer, Novartis, Ferring; compensated consultant relationship: Roche,<br />
Novartis; honoraria: Sanofi, Roche, Pfizer, Novartis, Ferring, Ipsen,Takeda; travel<br />
remuneration: ASCO by Novartis, <strong>ESMO</strong> by Janssen. S. Oudard: I have an advisory<br />
relationship and honoraria to disclose: Pfizer Oncology, Bayer-Schering Pharma,<br />
Hoffman La Roche, Glaxo SmithKline, Novartis Pharma, Sanofi Aventis. D. Pouessel:<br />
Consultant role and honoraria: Sanofi, P. Beuzeboc: Presentations: Avantis, All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
894O ASSOCIATION OF RADIOGRAPHIC PROGRESSION-FREE<br />
SURVIVAL (RPFS) ADAPTED FROM PROSTATE CANCER<br />
WORKING GROUP 2 (PCWG2) CONSENSUS CRITERIA<br />
(APCWG2) WITH OVERALL SURVIVAL (OS) IN PATIENTS (PTS)<br />
WITH METASTATIC CASTRATION-RESISTANT PROSTATE<br />
CANCER (MCRPC): RESULTS FROM COU-AA-302<br />
C.J. Ryan 1 , M. Morris 2 , A. Molina 3 , J.R. Piulats 4 , P. De Souza 5 ,J.Li 6 , T. Kheoh 3 ,<br />
J.S. de Bono 7 , S. Larson 2 , T. Griffin 3 , S. Ma<strong>the</strong>ny 3 , V. Naini 3 , H.I. Scher 2 ,<br />
E. Small 1<br />
1 Helen Diller Family Comprehensive Cancer Center, University of California,<br />
San Francisco, CA, UNITED STATES OF AMERICA, 2 Memorial Sloan-Kettering<br />
Cancer Center, New York, NY, UNITED STATES OF AMERICA, 3 Janssen<br />
Research & Development, Los Angeles, CA, UNITED STATES OF AMERICA,<br />
4 Institut Català d’Oncologia de l’Hospitalet, Barcelona, SPAIN, 5 St. George<br />
Private Hospital, Kogarah, AUSTRALIA, 6 Janssen Research & Development,<br />
Raritan, NJ, UNITED STATES OF AMERICA, 7 The Institute for Cancer Research<br />
and Royal Marsden Hospital, Sutton, UNITED KINGDOM<br />
Background: Imaging data have not been previously rigorously evaluated as an<br />
intermediate marker in mCRPC due to difficulties in interpretation and flare<br />
phenomenon. The APCWG2 is intended to continue treatment until clinically<br />
meaningful progressive disease (PD) occurs. In <strong>the</strong> prospective phase 3 study COU<br />
AA 302, we investigated correlation of OS with a novel rPFS endpoint using<br />
APCWG2 to recognize bone flare and avoid premature discontinuation (DC).<br />
Methods: 1088 pts were randomized 1:1 to abiraterone acetate (AA) + prednisone (P)<br />
or placebo (PL) + P. Scans were obtained q 8 wks during first 24 wks, q 12 wks<br />
<strong>the</strong>reafter. APCWG2-defined PD by bone scan (BS) required confirmation or<br />
persistent lesions depending on timing of first detection of PD. All scans were<br />
investigator reviewed (IR) and blinded central radiologist reviewed (BCRR).<br />
Continuing blinded study medication after radiographic PD in absence of<br />
unequivocal clinical PD was allowed. Association of rPFS to OS was evaluated by<br />
Spearman’s correlation via Clayton copula.<br />
Results: Positive association between rPFS and OS was observed (r = 0.71). 229 pts<br />
(AA 108, PL 121) showed progression (wk 8; ≥ 2 bone lesions [BL]) by BCRR. Of<br />
<strong>the</strong>se, 166 (AA 92, PL 74) did not show PD (follow-up; +≥ 2 BL) (ie, would have<br />
discontinued prematurely by traditional rPFS assessment). Of <strong>the</strong>se, 47 (AA 33, PL<br />
14) showed ↓ BL. There was high consistency between BCRR and IR at interim<br />
analyses (AA, 79%; PL, 76%).<br />
Interim Analysis<br />
(IA) Data Cutoff<br />
Annals of Oncology 23 (Supplement 9): ix294–ix318, <strong>2012</strong><br />
doi:10.1093/annonc/mds400<br />
AA + P<br />
(median,<br />
mos)<br />
PL + P<br />
(median,<br />
mos) HR (95% CI) P<br />
RPFS<br />
BCRR IA1 - Dec 2010 NR 8.3 0.43 (0.35, 0.52)
Annals of Oncology<br />
in Johnson & Johnson, have served as an abiraterone consultant/advisory board<br />
member, and have received consulting fees/grants/travel support fees from Janssen<br />
Research & Development, All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
895O THE IMPACT OF ABIRATERONE ACETATE (AA) THERAPY ON<br />
PATIENT-REPORTED PAIN AND FUNCTIONAL STATUS IN<br />
CHEMOTHERAPY-NAIVE PATIENTS WITH PROGRESSIVE,<br />
METASTATIC CASTRATION-RESISTANT PROSTATE CANCER<br />
(MCRPC)<br />
E. Basch 1 , C.J. Ryan 2 , T. Kheoh 3 , K. Fizazi 4 , C.J. Logo<strong>the</strong>tis 5 , D.E. Rathkopf 6 ,<br />
M.R. Smith 7 , P.N. Mainwaring 8 ,Y.Hao 9 ,T.Griffin 10 ,S.Li 11 , M. Meyers 12 ,<br />
A. Molina 10 , C. Cleeland 13<br />
1 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York,<br />
NY, UNITED STATES OF AMERICA, 2 Department of Medicine (Hematology/<br />
Oncology), UCSF, San Francisco, CA, UNITED STATES OF AMERICA,<br />
3 Biostatistics, Janssen Research & Development, Los Angeles, CA, UNITED<br />
STATES OF AMERICA, 4 Cancer Medicine, Institut Gustave Roussy, Villejuif,<br />
FRANCE, 5 Department of Genitourinary Medical Oncology, The University of<br />
Texas M. D. Anderson Cancer Center, Houston, TX, UNITED STATES OF<br />
AMERICA, 6 Department of Medicine, Memorial Sloan-Kettering Cancer Center,<br />
New York, NY, UNITED STATES OF AMERICA, 7 Department of Genitourinary<br />
Medical Oncology, Massachusetts General Hospital. Boston, MA, UNITED<br />
STATES OF AMERICA, 8 Medical Oncology, Hematology & Oncology Clinics of<br />
Australia, Brisbane, AUSTRALIA, 9 Outcome Research, Janssen Global Services,<br />
Raritan, NJ, UNITED STATES OF AMERICA, 10 Oncology, Janssen Research &<br />
Development, Los Angeles, CA, UNITED STATES OF AMERICA, 11 Biostatistics,<br />
Janssen Research & Development, Spring House, PA, UNITED STATES OF<br />
AMERICA, 12 Oncology, Janssen Research & Development, Raritan, NJ, UNITED<br />
STATES OF AMERICA, 13 Symptom Research, MD Anderson Cancer Center,<br />
Houston, TX, UNITED STATES OF AMERICA<br />
Background: AA is a potent, selective androgen biosyn<strong>the</strong>sis inhibitor. The impact<br />
of AA on pain and functional status was prospectively evaluated as part of a large<br />
phase 3 trial in asymptomatic/mildly symptomatic, progressive, chemo<strong>the</strong>rapy-naïve<br />
mCRPC.<br />
Material and methods: COU-AA-302 is an international, randomized, double-blind<br />
study of AA (1 g daily) + prednisone (P; 5 mg twice daily) versus placebo (PL) + P in<br />
chemo-naïve mCRPC patients (pts) with prior medical/surgical castration and<br />
anti-androgen <strong>the</strong>rapy. Pain and functional status were assessed at baseline and<br />
throughout study treatment using <strong>the</strong> BPI-SF and FACT-P questionnaires,<br />
respectively. For each measure, clinically significant progression/degradation was<br />
evaluated using prespecified definitions.<br />
Results: 546 pts were randomized to AA + P and 542 to PL + P, with<br />
median treatment durations of 13.8 and 8.3 months, respectively. Baseline scores<br />
were similar between arms; at baseline, mean worst pain intensity score was 1.2 and<br />
mean pain interference score was 0.7 in each arm. AA + P significantly delayed<br />
average pain intensity progression, pain interference progression, and degradation<br />
in FACT-P total score and most subscales, except <strong>the</strong> social/family well-being<br />
subscale where <strong>the</strong>re was no difference (Table). A post hoc sensitivity analysis<br />
using a more stringent definition of worst pain intensity progression<br />
(ie, a 2 point worsening at 2 consecutive study visits), showed a significant advantage<br />
of AA + P over PL + P at <strong>the</strong> 25th percentile (median was not reached for this<br />
analysis).<br />
Conclusions: In asymptomatic/minimally symptomatic mCRPC, AA + P delayed<br />
functional decline and progression of pain compared to PL + P alone. The extent of<br />
<strong>the</strong>se benefits, coupled with improvements in o<strong>the</strong>r efficacy end points [Ryan et al<br />
ASCO <strong>2012</strong>], suggests that AA is a suitable <strong>the</strong>rapy option in this setting.<br />
Table: 895O<br />
Disclosure: T. Kheoh is an employee of Janssen R&D and holds stock options of<br />
Johnson & Johnson.K. Fizazi has <strong>the</strong> following conflicts of interest to disclose:<br />
Honoraria: Janssen Consultancy: Janssen, Cougar Biotechnology Speaker/Advisory<br />
Board Participation: Janssen, C.J. Logo<strong>the</strong>tis has received consultancy fees and travel<br />
support from Ortho Biotech and research support from Johnson & Johnson, M.R.<br />
Smith has served as an advisor to Cougar Biotechnology and Johnson & Johnson<br />
and has received research funding from Cougar Biotechnology and Johnson &<br />
Johnson. Y. Hao is an employee of Janssen Global Services and holds stock options<br />
of Johnson & Johnson. T. Griffin is an employee of Janssen R&D and holds stock<br />
options of Johnson & Johnson. S. Li is an employee of Janssen R&D and holds stock<br />
options of Johnson & Johnson. M. Meyers is an employee of Janssen R&D and holds<br />
stock options of Johnson & Johnson. A. Molina is an employee of Janssen R&D and<br />
holds stock options of Johnson & Johnson. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
896O IMPACT OF ENZALUTAMIDE, AN ANDROGEN RECEPTOR<br />
SIGNALING INHIBITOR, ON TIME TO FIRST SKELETAL<br />
RELATED EVENT (SRE) AND PAIN IN THE PHASE 3 AFFIRM<br />
STUDY<br />
K. Fizazi 1 , H.I. Scher 2 , F. Saad 3 , C.N. Sternberg 4 , K. Miller 5 , P. Mulders 6 , K. Chi 7 ,<br />
E. Basch 8 , M. Hirmand 9 , J.S. de Bono 10<br />
1 Department of Cancer Medicine, Institut Gustave Roussy, University of Paris<br />
Sud, Orsay, France, Villejuif, FRANCE, 2 Genitourinary Oncology Service, Sidney<br />
Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering<br />
Cancer Center, New York, NY, USA, New York, NY, UNITED STATES OF<br />
AMERICA, 3 Department of Surgery, University of Montreal Hospital Center,<br />
Montreal, QC, CANADA, 4 Depatment of Medical Oncology, San Camillo Forlanini<br />
Hospital, Rome, ITALY, 5 CC 8: Chirurgische Medizin, Klinik für Urologie, Charité -<br />
Universitätsmedizin Berlin, Berlin, GERMANY, 6 Department of Urology, Radboud<br />
University Nijmegen Medical Centre, Nijmegen, NETHERLANDS, 7 Department of<br />
Experimental Therapeutics, British Columbia Cancer Agency, Vancouver, BC,<br />
CANADA, 8 Departmentgenitourinary Cancer, Memorial Sloan Kettering Cancer<br />
Center, New York, NY, UNITED STATES OF AMERICA, 9 Department of Clinical<br />
Development, Medivation, Inc., San Francisco, CA, UNITED STATES OF<br />
AMERICA, 10 Division of Clinical Studies, The Institute of Cancer Research,<br />
Sutton, UNITED KINGDOM<br />
Background: Enzalutamide-proposed INN (ENZA, MDV3100) inhibits androgen<br />
binding to AR, AR nuclear translocation, and AR association with DNA. The<br />
AFFIRM trial (NCT00974311) demonstrated that ENZA increased survival by 4.8<br />
mo (P
and week 13 BPI-SF Q3 scores), 28% ENZA and 39% placebo pts (P = 0.0018) had<br />
pain progression assessed by pt diaries (increase over baseline in mean pain score).<br />
Median time to pain progression (confirmed increase in FACT-P score of “I have<br />
pain”) was not yet reached vs 13.8 mo for ENZA and placebo (P = 0.0004, HR 0.56).<br />
There was a mean reduction in pain severity (average of 4 severity items of <strong>the</strong><br />
BPI-SF) of 0.65 favoring ENZA (P
Annals of Oncology<br />
899PD ASSOCIATION OF BASELINE CORTICOSTEROID WITH<br />
OUTCOMES IN A MULTIVARIATE ANALYSIS OF THE PHASE<br />
3 AFFIRM STUDY OF ENZALUTAMIDE (ENZA), AN<br />
ANDROGEN RECEPTOR SIGNALING INHIBITOR (ARSI)<br />
H.I. Scher 1 , K. Fizazi 2 , F. Saad 3 , K. Chi 4 , M. Taplin 5 , C.N. Sternberg 6 ,<br />
A.J. Armstrong 7 , M. Hirmand 8 , B. Selby 9 , J.S. de Bono 10<br />
1 Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center,<br />
New York, NY, UNITED STATES OF AMERICA, 2 Department of Cancer<br />
Medicine, Institut Gustave Roussy, University of Paris, Villejuif, FRANCE,<br />
3 Department of Surgery, University of Montreal Hospital Center, Montreal, QC,<br />
CANADA, 4 Oncology, Vancouver Cancer Centre, University of British Columbia,<br />
Vancouver, BC, CANADA, 5 Medical Oncolgy, Dana-Farber Cancer Institution,<br />
Boston, MA, UNITED STATES OF AMERICA, 6 Medical Oncolgy, San Camillo<br />
Forlanini Hospita, Department of Medical Oncology, Roma, ITALY, 7 Medical<br />
Oncology, Duke Comprehensive Cancer Center and <strong>the</strong> Duke Prostate Center,<br />
Durham, NC, UNITED STATES OF AMERICA, 8 Clinical Development, Medivation,<br />
San Francisco, CA, UNITED STATES OF AMERICA, 9 Department of Clinical<br />
Development, Medivation, Inc., San Francisco, CA, UNITED STATES OF<br />
AMERICA, 10 Division of Clinical Studies, Institute of Cancer Research Royal<br />
Marsden Hospital NHS Foundation Trust, Sutton, UNITED KINGDOM<br />
Background: ENZA-proposed INN (MDV3100) increased median survival by 4.8<br />
mo (P
Working Group (PCWG)-2 guidelines recommend time to clinical or radiographic<br />
event endpoints, and discouraged use of endpoints using PSA changes. We<br />
investigated <strong>the</strong> association of progression defined by PCWG-2 guidelines and overall<br />
survival (OS).<br />
Methods: Two trials were analyzed: CS-205, a randomized phase II trial (n = 221)<br />
comparing first-line docetaxel-prednisone (DP) plus AT-101 or placebo, and<br />
SUN-1120 (n = 873), a phase III trial comparing prednisone plus sunitinib (SP) or<br />
placebo (PP) following docetaxel-based chemo<strong>the</strong>rapy. Both trials continued<br />
<strong>the</strong>rapy until progression defined by PCWG-2 criteria and OS was <strong>the</strong> primary<br />
endpoint. OS was derived by <strong>the</strong> Kaplan-Meier method. Cox proportional hazards<br />
regression models were used to estimate <strong>the</strong> effect of progression on OS. Landmark<br />
analyses at 2-month intervals compared patients with prior progression with those<br />
without progression. Sub-analyses compared patients removed from trial for<br />
progression vs. o<strong>the</strong>r reasons and examined <strong>the</strong> association of type of progression<br />
with OS.<br />
Results: Patients who had previously progressed had an increased risk of death.<br />
In CS-205, <strong>the</strong> hazards ratio (HR) ranged from 2.31 to 3.43 between landmark<br />
times of 6 to 12 months and in SUN-1120 HR was 2.75 to 5.21 between<br />
landmark times from 2 to 8 months. Median OS was 5.5 versus 14.4 months in<br />
CS-205 beyond month 6 and 7.1 versus 16.1 months in SUN-1120 beyond<br />
month 2 for those with/without prior progression. The types of progression<br />
associated with OS varied between <strong>the</strong> trials. Patients removed from study due to<br />
progression (excluding death) had a significantly worse OS than those coming off<br />
for o<strong>the</strong>r reasons (HR: 1.90, 95% CI: 1.26-2.87 in CS-205 and HR: 1.23, 95% CI:<br />
1.02-1.48 in SUN-1120).<br />
Conclusions: Progression by PCWG-2 criteria was significantly associated with<br />
decreased OS in patients receiving first-line docetaxel-based chemo<strong>the</strong>rapy or<br />
post-docetaxel <strong>the</strong>rapy. Fur<strong>the</strong>r validation will facilitate <strong>the</strong> employment of PCWG-2<br />
defined progression as an intermediate endpoint.<br />
Disclosure: G. Sonpavde: Research support to institution from Ascenta Therapeutics<br />
and Pfizer, Inc, B.A. Wood: Employee of Ascenta Therapeutics, S. Wang: Employee<br />
of Pfizer, Inc, J. Paolini: Employee of Pfizer, Inc, M. Lechuga: Employee of Pfizer,<br />
Inc, M.R. Smith: Research support to institution from Pfizer, Inc, M.D. Michaelson:<br />
Research support to institution from Pfizer, Inc, All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
902P PREVALENCE OF NON-METASTATIC<br />
CASTRATION-RESISTANT PROSTATE CANCER IN EUROPE<br />
A. Liede 1 , O. Gün<strong>the</strong>r 2 , B. Bennett 3 , S. Wong 3<br />
1 24-2-A, Amgen Inc., Thousand Oaks, CA, UNITED STATES OF AMERICA,<br />
2 Center for Observational Research, Amgen Ltd, Uxbridge, UNITED KINGDOM,<br />
3 Oncosight, Plan A, Inc., Mountain View, CA, UNITED STATES OF AMERICA<br />
Background: Non-metastatic (M0) castration-resistant prostate cancer (CRPC) is a<br />
growing public health burden that has not been adequately quantified. The increased<br />
incidence of prostate cancer (PC) in Europe in <strong>the</strong> last two decades is a result of<br />
widespread prostate-specific antigen (PSA) screening, and associated with declines in<br />
mortality and improved survival as more men are diagnosed with M0 disease. A<br />
proportion of men with M0 PC will receive medical or surgical androgen deprivation<br />
<strong>the</strong>rapy (ADT). Many ADT-treated men eventually relapse to develop M0 CRPC,<br />
characterized by rising PSA without evidence of metastases while on ADT. We report<br />
results of a model to estimate <strong>the</strong> prevalence of M0 CRPC in key populations in<br />
Europe.<br />
Methods: The model uses age-specific incidence and survival data from<br />
population-based national cancer registries to estimate 5-, 10-, and 20-year limited<br />
duration prevalence of PC and M0 PC in each country, each year from 2008 to 2026.<br />
ADT rates for M0 PC by country reported by <strong>the</strong> literature and IMS Oncology<br />
Analyser and disease relapse and progression rates from <strong>the</strong> literature are applied<br />
to estimate prevalence of ADT-treated and M0 CRPC subgroups.<br />
Results: For EU-5 countries (France, Germany, Italy, Spain, and UK), <strong>the</strong> model<br />
projects that 5-year prevalence of PC will increase from approximately 1.0 million in<br />
<strong>2012</strong> to 1.3 million in 2026 as a result of wider adoption of PSA testing and aging of<br />
<strong>the</strong> populations. M0 PC, which comprises about 85% of total PC 5-year prevalence,<br />
will increase from approximately 0.8 million in <strong>2012</strong> to 1.0 million by 2026. In <strong>2012</strong>,<br />
prevalence of M0 CRPC (4-7% of total PC, depending on ADT use in <strong>the</strong> M0<br />
setting) in EU-5 is estimated to reach up to 70,000 with a projected increase to<br />
110,000 patients by 2026.<br />
Conclusion: This model provides <strong>the</strong> first understanding of how many men in<br />
Europe are living with M0 CRPC. Although M0 CRPC represents a small subset of<br />
<strong>the</strong> PC population, <strong>the</strong> model predicts an increase in <strong>the</strong> prevalence of M0 CRPC<br />
over <strong>the</strong> next 14 years. As men with M0 CRPC have an increased risk of developing<br />
metastases (particularly to bone) resulting in a shortened lifespan, <strong>the</strong>se findings<br />
highlight <strong>the</strong> need for clinical trials to establish standards of care for <strong>the</strong>se patients,<br />
and for new <strong>the</strong>rapeutic options.<br />
Disclosure: A. Liede: Employed by and own stock in Amgen Inc. The study was<br />
funded by Amgen Inc.O. Gün<strong>the</strong>r: Employed by Amgen Ltd and own stock in<br />
Amgen. The study was funded by Amgen Inc. B. Bennett: Consultant at Plan A, Inc.<br />
S. Wong: Consultants at Plan A, Inc.<br />
Annals of Oncology<br />
903P IMPROVED SURVIVAL IN PATIENTS WITH METASTATIC<br />
CASTRATION RESISTANT PROSTATE CANCER (MCRPC)<br />
TREATED ON CLINICAL TRIALS<br />
C. Pezaro, A.G. Omlin, D. Mukherji, S. Sandhu, D. Bianchini, A. Mulick Cassidy,<br />
G. Maier, D. Olmos, G. Attard, J.S. de Bono<br />
Prostate Targeted Therapy Group, The Royal Marsden NHS Foundation Trust<br />
and Institute of Cancer Research ICR, Sutton, UNITED KINGDOM<br />
Background: Median overall survival (mOS) in patients (pts) with mCRPC was<br />
13-16 months (m) in <strong>the</strong> pre-docetaxel era. These data, obtained from clinical trials,<br />
were used to construct currently available prognostic nomograms. We hypo<strong>the</strong>sise<br />
that <strong>the</strong>se models no longer reflect survival. Pts and physicians urgently require<br />
updated prognostic data on which to base management decisions.<br />
Methods: Pts with mCRPC treated on Phase I-III and expanded access trials at our<br />
institution were identified and data retrospectively collected. Predicted survival by<br />
Halabi and Smaletz nomograms were compared to calculated survival using<br />
Kaplan-Maier analysis. Cox model multivariate (MV) analysis used variables at<br />
referral, including performance status (PS), Gleason (GS), prostate specific antigen<br />
(PSA), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), hemoglobin (Hb),<br />
visceral disease and albumin.<br />
Results: Between 2003 and 2011, 442 CRPC pts were treated on clinical trials. At<br />
diagnosis median age was 62 years (y; 41.8 – 82.7) and 243 (55.0%) had metastatic<br />
disease. Median interval from diagnosis to CRPC was 2.8y (0.2 – 21.7). At referral<br />
259 pts (58.6%) were chemo<strong>the</strong>rapy-naïve. Halabi and Smaletz models predicted<br />
mOS from referral in chemo-naïve pts of 21m and 17m respectively, however <strong>the</strong><br />
observed mOS was 32m (95%CI 29– 38). Survival from CRPC was 43m (CI 37 – 46)<br />
and 39m (CI 35 - 44) in pre- and post-chemo pts, respectively. In our MV model<br />
using data from 225 evaluable pre-chemo patients, ALP (HR 2.65, p = 0.001), LDH<br />
(HR 2.66, p = 0.018), albumin (HR 0.92, p = 0.002) and PSA (HR 1.31, p = 0.046)<br />
were each prognostic after controlling for o<strong>the</strong>r variables, whereas Hb, PS, GS and<br />
visceral disease did not show a statistically significant effect.<br />
Conclusion: Our pts lived significantly longer than predicted by current nomograms.<br />
This is likely due to development of effective new treatments. MV analysis confirmed<br />
<strong>the</strong> importance of several previously identified prognostic factors. Survival data from<br />
this large cohort of CRPC pts should encourage men considering clinical trial<br />
participation. Previously developed nomograms no longer accurately predict survival.<br />
Disclosure: C. Pezaro: Author is an ICR employee. The ICR has a commercial<br />
interest in Abiraterone and PI3K and AKT inhibitors. D. Mukherji: Author is an ICR<br />
employee. The ICR has a commercial interest in Abiraterone and PI3K and AKT<br />
inhibitors. S. Sandhu: Author is an ICR employee. The ICR has a commercial<br />
interest in Abiraterone and PI3K and AKT inhibitors. A. Mulick Cassidy: Author is<br />
an ICR employee. The ICR has a commercial interest in Abiraterone and PI3K and<br />
AKT inhibitors. G. Maier: Author is an ICR employee. The ICR has a commercial<br />
interest in Abiraterone and PI3K and AKT inhibitors. D. Olmos: Author is an ICR<br />
employee. The ICR has a commercial interest in Abiraterone and PI3K and AKT<br />
inhibitors. G. Attard: Author is an ICR employee. The ICR has a commercial interest<br />
in Abiraterone and PI3K and AKT inhibitors. J.S. de Bono: Author is an ICR<br />
employee. The ICR has a commercial interest in Abiraterone and PI3K and AKT<br />
inhibitors. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
904P THE CHARACTERISTICS OF DIFFERENT PATTERN OF<br />
METASTASES IN PATIENTS WITH CASTRATE RESISTANT<br />
PROSTATE CANCER TREATED WITH TAXOTERE<br />
CHEMOTHERAPY<br />
S. Dixit1 , J. Tito1 , P. Afzal2 1<br />
Oncology, Hull & East Yorkshire NHS Trust, Hull, UNITED KINGDOM,<br />
2<br />
Oncology, Diana Princess of Wales Hospital, Grimsby, Grimsby, UNITED<br />
KINGDOM<br />
Introduction: Many new agents are being tested in patients with castrate resistant<br />
metastatic prostate cancer. Understanding <strong>the</strong> characteristics of different pattern of<br />
metastases and <strong>the</strong>ir responses to taxotere chemo<strong>the</strong>rapy may help in stratifying <strong>the</strong><br />
patients in different prognostic and predictive groups.<br />
Methods: Based on <strong>the</strong> metastases observed on bone scan and CT- scan, before<br />
starting chemo<strong>the</strong>rapy, three metastatic patterns were identified. Metastases<br />
predominantly limited to <strong>the</strong> bones with small volume lymph node metastases (bone<br />
predominant), metastases limited to <strong>the</strong> bones (bones only), and metastases with<br />
bulky lymphadenopathy without bone metastases (lymph nodes only). Median<br />
survival and <strong>the</strong> distribution of known prognostic factors were analysed in <strong>the</strong>se<br />
three groups.<br />
Results: Seventy eight patients with a median age of 70 (Range, 47-86) and a median<br />
PSA of 174 (11-3000) had a median survival of 17 months (95% C.I. 13-20). Factors<br />
associated with statistically significant shorter survival were symptomatic state,<br />
haemoglobin, PSA level, <strong>the</strong> duration of hormone response, and three metastases<br />
pattern. Gleason score and age were not significant. The median survival for three<br />
metastatic pattern, bone predominant (32), bone only (35), and lymph node only<br />
(11) metastases, were 12, 19 and 23 months respectively. The distributions of age,<br />
Gleason score, PSA level before starting chemo<strong>the</strong>rapy, and PSA response were not<br />
ix298 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
significantly different in <strong>the</strong> three metastatic groups. However, patients with bone<br />
predominant metastatic group were symptomatic (not significant), had fewer number<br />
of chemo<strong>the</strong>rapy cycles, and had a lower median Haemoglobin level (significant)<br />
compared with <strong>the</strong> bone only metastases and lymph node only metastases group.<br />
Conclusion: The bone predominant pattern of metastases could be biologically<br />
different disease than <strong>the</strong> bone only and <strong>the</strong> lymph node only (bulky) metastases.<br />
The trials using newer agents stratifying patients based on <strong>the</strong>se metastases pattern<br />
may help in understanding <strong>the</strong> diverse biological behaviour of castrate resistant<br />
prostate cancer.<br />
Disclosure: S. Dixit: Sanofi- aventis has provided an educational grant to conduct<br />
this study. J. Tito: Sanofi aventis provided an educational grant for this study.<br />
P. Afzal: Sanofi -aventis provided an education grant for this study<br />
905P HEALTH CARE COSTS IN PROSTATE CANCER PATIENTS<br />
TREATED WITH DEGARELIX: LOWER COSTS IN<br />
HORMONE-NAïVE PATIENTS IN COMPARISON TO<br />
HORMONALLY PRE-TREATED PATIENTS<br />
J.M. Wolff 1 , M. Gedamke 2<br />
1 Urologische Klinik, Allgemeines Krankenhaus Viersen, Viersen, GERMANY,<br />
2 Urology/Uro-Oncology, Ferring Arzneimittel GmbH, Kiel, GERMANY<br />
Background: Degarelix is a GnRH-antagonist, which is used in <strong>the</strong> treatment of<br />
prostate cancer since 2009. We performed a non-interventional study (NIS) with<br />
prostate cancer (PCA) patients treated routinely with degarelix. This NIS focused on<br />
pharmaco-economic data, health-related quality of life (HRQoL) as well as efficacy<br />
and safety in patients receiving degarelix as first or second line <strong>the</strong>rapy.<br />
Materials: In <strong>the</strong> interim analysis of this ongoing NIS, data from 279 out of 670<br />
PCA-patients treated with degarelix were included. The included cohort reflects<br />
advanced PCA patients (age: 72 years, PSA: 15.8 ng/ml (median)).Testosterone and<br />
PSA values, health-related quality of life (HRQL) and pharmaco-economic data were<br />
collected at baseline, 1, 3, 6, 9 and 12 months. HRQL was assessed by EORTC<br />
QLQ-C30. Pharmaco-economic data included costs for physicians, drugs, hospital,<br />
emergency treatment and o<strong>the</strong>rs.<br />
Results: Treatment costs in hormone-naïve patients treated with degarelix were lower<br />
than in <strong>the</strong> hormonally pre-treated patients. Costs for 12 months were € 3177 for<br />
hormone-naïve patients treated with degarelix in contrast to € 3782 for hormonally<br />
pre-treated patients. As expected <strong>the</strong>re was a marked difference in <strong>the</strong> PSA-decline<br />
between hormone-naïve patients and hormonally pre-treated patients.<br />
Hormone-naïve patients experienced a sharp median decrease in PSA by 80.7%<br />
(n = 116) at month 1. This decline remained stable in 98.7% of <strong>the</strong> patients after one<br />
year. Median PSA reduction was significantly different (p = 0.013) between<br />
hormone-naïve and pre-treated patients. Fur<strong>the</strong>rmore treatment with degarelix<br />
improved HRQL by 16% at one year in metastatic patients. Safety results mirrored<br />
<strong>the</strong> results of previous clinical trials, with x, y and z being <strong>the</strong> most frequent ones.<br />
Conclusions: First line treatment with degarelix was supported by a marked<br />
difference in health care costs between hormone-naïve and pre-treated prostate<br />
cancer patients. As expected, a pronounced difference in <strong>the</strong> PSA-decrease for<br />
hormone-naïve vs. pre-treated patients was seen. However a distinct health-related<br />
quality of life improvement was noted in all patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
906P A PROSTATE CANCER EXPRESSION SIGNATURE TO<br />
PREDICT SURVIVAL BENEFIT OF PRIMARY HORMONE<br />
THERAPY<br />
C. Li 1 , Z. Peng 2 , L. Skoog 2 , M. Hjelm-Eriksson 1 , L. Ährlund-Richter 1 ,<br />
U. Harmenberg 1 , Y. Pawitan 3 , G. Cohn Cedermark 1 , M. Nistér 2 , S. Nilsson 1<br />
1 Clinical Oncology, Karolinska University Hosiptal, Stockholm, SWEDEN,<br />
2 Oncology-Pathology, Karolinska Instiutet, Stockholm, SWEDEN, 3 Medical<br />
Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SWEDEN<br />
Background: At <strong>the</strong> ASCO annual meeting <strong>2012</strong>, we have presented <strong>the</strong><br />
identification of an embryonic stem cell gene predictor (ESCGP) signature in a<br />
cohort of 189 patients with 7-21 years complete survival follow up. The expression<br />
signature is composed of F3, IGFBP3 and VGLL3 and can significantly improve <strong>the</strong><br />
accuracy of survival prediction at <strong>the</strong> time of diagnosis. We fur<strong>the</strong>r hypo<strong>the</strong>size that<br />
measuring stem cell gene expression signature in prostate cancer biopsy samples<br />
taken at <strong>the</strong> time of diagnosis can predict <strong>the</strong> survival benefit of hormone <strong>the</strong>rapy.<br />
Methods: In <strong>the</strong> previous cohort, 139 of <strong>the</strong> 189 patients were primarily treated by<br />
hormone <strong>the</strong>rapy. Of <strong>the</strong>se 139 patients 65 had data of <strong>the</strong> ESCGP signature.<br />
Kaplan-Meier plots were used in <strong>the</strong> survival analysis of this subset of patients.<br />
Results: Of <strong>the</strong> 65 patients, 22 were classified as having high risk, 25 as having<br />
intermediate risk and 18 as having low risk subtype cancers. The obvious overall and<br />
cancer specific survival difference between <strong>the</strong> three subtypes was still maintained<br />
(Kaplan-Meier survival curve, p < 0.001 by log rank test) in <strong>the</strong>se 65 patients. At 8<br />
years after <strong>the</strong> diagnosis, <strong>the</strong> overall survival rate was 0% in patients with <strong>the</strong> high<br />
risk subtype cancer, 16% in patients with <strong>the</strong> intermediate risk subtype cancer and<br />
55.6% in patients with <strong>the</strong> low risk subtype cancer. This obvious survival difference<br />
by <strong>the</strong> ESCGP classification was independent of age, PSA level, tumor grade and<br />
clinical stage.<br />
Conclusions: The expression signature of F3, IGFBP3 and VGLL3 can be accurately<br />
measured in prostate fine needle aspiration samples. If <strong>the</strong> finding is fur<strong>the</strong>r<br />
validated in a large and independent cohort, <strong>the</strong> ESCGP expression signature can be<br />
used to predict <strong>the</strong> survival benefit of primary hormone treatment for patients with<br />
newly diagnosed prostate cancer.<br />
Disclosure: C. Li: Chunde Li is <strong>the</strong> major stock holder of Chundesell Medcals AB.<br />
All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
907P CONFIRMATION OF THE PROGNOSTIC VALUE OF MODELED<br />
PSA CLEARANCE AFTER RADICAL PROSTATECTOMY:<br />
RESULTS OF THE VALIDATION PSAMODEL STUDY<br />
D. Maillet 1 , A. Ruffion 2 ,G.Freyer 3 ,M.Tod 4 , M. Wilbaux 4 , P. Perrin 2 , E. Henin 4 ,<br />
B. You 1<br />
1 Medical Oncology, Lyon-Sud Hospital, Lyon, FRANCE, 2 Urology, Lyon-Sud<br />
Hospital, Lyon, FRANCE, 3 Medical Oncology, Centre Hospitalier Lyon Sud,<br />
Pierre Bénite, FRANCE, 4 EMR3738, University Lyon 01, Lyon, FRANCE<br />
Background: Early predictors of relapse after radical prostatectomy are needed. We<br />
previously showed that ma<strong>the</strong>matical modeling of PSA kinetics during <strong>the</strong> first 50<br />
days after surgery provides a parameter, PSA clearance (CLPSA), which may be an<br />
independent early predictor of relapse [1](You et al; Prostate 2009;69:1325).<br />
Prospective validation of <strong>the</strong>se outcomes was warranted.<br />
Methods: PSAMODEL was a prospective validation study including prostate cancer<br />
patients treated with radical prostatectomy. Modeled individual CLPSA was estimated<br />
with 4 values of PSA centrally measured during <strong>the</strong> first 50 post-operative days,<br />
using <strong>the</strong> bi-compartment model previously reported [1] with NONMEM program.<br />
The prognostic value of modeled CLPSA regarding 3-year biochemical relapse-free<br />
survival (3 y-bRFS) was assessed using survival univariate and multivariate analyses.<br />
Results: Total 119 patients were included in PSAMODEL study. Among <strong>the</strong>m, 13<br />
patients (11%) experienced a relapse after median 6.5 months. Despite high<br />
inter-individual variability, individual PSA decline profiles were well fitted by <strong>the</strong><br />
model. CLPSA, categorized by <strong>the</strong> 0.048 cut-off previously reported [1], was a<br />
significant prognostic factor of 3 y-bRFS using log-rank test (3 y-bRFS: 97% vs 66%,<br />
p = 0.009). Moreover it had independent significant prognostic value when adjusted<br />
on D’Amico score items using multivariate Cox model (p < 0.05).<br />
Conclusion: We confirm modeled CLPSA estimated with 4 PSA values in <strong>the</strong> first 50<br />
days after radical prostactectomy is a prognostic factor of relapse, independently on<br />
d’Amico score. The role of post-operative modeled CLPSA in adjuvant treatment<br />
decision will be assessed. [1] You et al; Prostate 2009;69:1325<br />
Disclosure: All authors have declared no conflicts of interest.<br />
908P PROGNOSTIC VALUE OF FREE TESTOSTERONE (FT) LEVELS<br />
DURING SALVAGE CHEMOTHERAPY WITH CARBOPLATIN<br />
PLUS WEEKLY DOCETAXEL IN METASTATIC CASTRATION-<br />
AND DOCETAXEL-RESISTANT PROSTATE CANCER (MDRPC)<br />
C.W.M. Reuter, M.A. Morgan, M. Fenner, V. Grünwald, A. Ganser<br />
Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover<br />
Medical School, Hannover, GERMANY<br />
Background: Recent data suggest that carboplatin plus weekly docetaxel (DC) is an<br />
effective salvage <strong>the</strong>rapy in DRPC. Carboplatin, docetaxel and steroids all interfere<br />
with testosterone biosyn<strong>the</strong>sis and/or metabolism. In this study <strong>the</strong> impact of DC<br />
treatment on testosterone serum levels was analyzed.<br />
Methods: Docetaxel failure/resistance was defined according to <strong>the</strong> Prostate Cancer<br />
Working Group (PCWG2 2007) criteria. Since February 2005, 71 consecutive DRPC<br />
pts were treated with at least two cycles of carboplatin AUC5 iv for 30 min on day 1<br />
every 4 weeks (q4w), docetaxel at a dose of 35 mg/m iv for one hour on days 1, 8,<br />
(15) plus prednisone 2x5mg/day orally after receiving informed consent until disease<br />
progression or occurrence of intolerable adverse effects. Efficacy measures were done<br />
following PCWG2 recommendations. FT was measured before (n = 44) and during<br />
carboplatin/docetaxel chemo<strong>the</strong>rapy (n = 38).<br />
Results: Response of prostate-specific antigen (PSAR; ≥50% PSA) was observed in<br />
34/71 (47.9%) patients. At <strong>the</strong> time of <strong>the</strong> current analysis <strong>the</strong> median follow-up time<br />
was 14.5 months and 47/71 patients had died. Median progression-free survival<br />
(PFS) for all patients was 6.9 months (CI 95% 4.3, 13.6) and median overall survival<br />
(OS) was 18.0 months (CI 95% 10.4, 25.6). Median FT serum levels were 3.0 pmol/L<br />
before (n = 43) and below <strong>the</strong> RIA detection limit of
atio HR 0.39; CI 0.18, 0.83, p = 0.015) and OS (HR 0.15; CI 0.04, 0.55, p = 0.004).<br />
FT remained statistically prognostic in multivariable analyses. The DC regimen was<br />
reasonably well tolerated, with leukopenia/neutropenia as <strong>the</strong> most common<br />
reversible grade 3/4 toxicity (38.0/35.2%).<br />
Conclusion: These data demonstrate for <strong>the</strong> first time that testosterone is an<br />
important prognostic factor for PFS and OS in mDRPC patients receiving<br />
chemo<strong>the</strong>rapy.<br />
Disclosure: C.W.M. Reuter: Minor consulting fees from Sanofi Aventis, Amgen, V.<br />
Grünwald: Consulting fees from Novartis, All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
909P PREDICTIVE AND PROGNOSTIC ROLES OF BODY MASS<br />
INDEX (BMI) IN DOCETAXEL(D)-TREATED<br />
CASTRATE-RESISTANT PROSTATE CANCER (CRPC)<br />
N. Rozumna-Martynyuk 1 , M.Y. Teo 1 , M.S.N. Mohd Sharial 1 , M. Doherty 1 ,<br />
F. McDonnell 2 ,S.O’Reilly 3 , D.G. Power 3 , R. McDermott 2<br />
1 Dept. of Medical Oncology, AMNCH Adelaide and Meath Hospital, Dublin,<br />
IRELAND, 2 Department of Medical Oncology, Adelaide & Meath Hospital<br />
incorporating National Children’s Hospital, Dublin, IRELAND, 3 Department of<br />
Medical Oncology, Mercy University Hospital, Cork, IRELAND<br />
Introduction: Studies have suggested that overweight and obese patients with early<br />
stage prostate cancer present with lower PSA, higher grade disease and have poorer<br />
outcomes. Data remains limited on <strong>the</strong> influence of BMI on CRPC receiving D. We<br />
previously reported lower pretreatment PSA and rate of PSA response in obese pts<br />
(Teo et al, ASCO GU 2011). With an expanded cohort, we sought to examine <strong>the</strong><br />
influence of BMI on PSA kinetics and CRPC survival.<br />
Methods: Two institutional databases were analysed to identify pts who received D for<br />
CRPC. Demographics and serial PSA levels were extracted. Pts were divided into Group<br />
A, B and C, based on BMI range of ≤25.0, 25.1-29.9 and ≥30 kg/m respectively. PSA<br />
responses and half life were calculated using PCWG2 guidelines. Results were compared<br />
with Mann-Whitney and Fisher’s exact tests. Time to PSA progression (TPP) and<br />
overall survival (OS) were estimated with Kaplan Meier and logrank methods.<br />
Results: 78 pts were identified, with median age of 66 yrs (44-80), median cycles of D<br />
of 7 (1-26), and median BMI of 28.5. Gleason score was evaluable in 75%, with a<br />
median score of 8. The number of pts in each BMI group was 21, 24 and 33,<br />
respectively. Pts in Gp C had significantly lower baseline PSA (table). More pts in Gp C<br />
were PSA non-responders compared to Gp A and B (p = .004). PSA nadir and rates of<br />
PSA reduction >30%, >50% and >90% at 3months were comparable in all groups.<br />
MMMMMedian TPP was 4.2 months in Gp A, 5.2 months in Gp B, and 4.4 months<br />
in Gp C (logrank p = .49). The longest median OS was observed in Gp A at 20 months,<br />
followed by Gp B at 19 months and Gp C at 15 months; <strong>the</strong>se differences were not<br />
statistically significant (p = 0.38). Of 45 pts with treatment details, 24% had dose<br />
reduction and 44% had ≥1 infusion delays. Rates were similar across Gps A to C.<br />
Conclusions: Obese CRPC pts have lower pre-D PSA levels and higher rate of<br />
non-responsive disease. However, BMI does not appear to influence PSA kinetics,<br />
tolerability of D and survival.<br />
BMI (kg/m2) p<br />
≤25 25.1 - 29.9 ≥30<br />
n 21 24 33 NS<br />
Baseline PSA, median ng/mL 131.0 236.6 81.6 0.007<br />
PSA Reduction at 12wks, median % 34.4 47.2 41.4 NS<br />
PSA Nadir as % of Baseline, median 51.1 41.6 39.6 NS<br />
PSA Flare, % 9.5 25.0 14.8 NS<br />
PSA Non-Responders, % 0.0 4.2 25.9 0.004<br />
>30% PSA Reduction at 12wks, % 66.7 79.2 70.4 NS<br />
>50% PSA Reduction at 12wks, % 47.6 62.5 59.3 NS<br />
>90% PSA Reduction at 12wks, % 9.5 29.2 14.8 NS<br />
PSA Half-life, days, median 51.1 41.6 39.6 NS<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Table: 911P<br />
910P MOLECULAR PROFILING OF PERIPHERAL BLOOD IS<br />
ASSOCIATED WITH CIRCULATING TUMOR CELLS (CTCS)<br />
CONTENT AND SURVIVAL IN METASTATIC<br />
CASTRATION-RESISTANT PROSTATE CANCER (MCRPC)<br />
L. Gaba Garcia 1 , M. Marín-Aguilera 1 , J.J. Lozano 2 , A. Tagliapietra 1 , V. Ortega 1 ,<br />
P. Gascón 1 , B. Mellado 1<br />
1 Medical Oncology, Hospital Clinic, Barcelona, SPAIN, 2 Bioinformatics Platform,<br />
Ciberehd, Hospital Clinic, Barcelona, SPAIN<br />
Introduction: Detection of CTCs in peripheral blood has been demonstrated to<br />
correlate with clinical outcome in CRPC. The molecular characterization of <strong>the</strong>se<br />
CTCs is essential for assessing genotypic features of mCRPC and should provide<br />
insights into <strong>the</strong> biology of tumor cell growth, invasion and metastasis.<br />
Objective: To analyze <strong>the</strong> molecular profiling of peripheral blood from mCRPC<br />
patients with known CTC content and to identify those genes that may be related to<br />
<strong>the</strong> number of circulating cells and/or to <strong>the</strong> clinical outcome.<br />
Material and methods: Peripheral blood from mCRPC patients was analyzed for<br />
CTC using <strong>the</strong> CellSearch System. Microarrays analysis was performed by <strong>the</strong><br />
Human Gene 1.1 ST Array (Affymetrix) in samples with varing CTC content. Ten of<br />
<strong>the</strong> most differentially expressed genes between <strong>the</strong> < 5 and ≥ 5 CTCs groups were<br />
validated using reverse transcriptase PCR.<br />
Results: 43 patients were included. The median age was 71 years (42-88), <strong>the</strong><br />
majority of patients had poor prognosis based on Gleason score (n = 22, 51.2%) and<br />
had recieved prior-docetaxel-based chemo<strong>the</strong>rapy (n = 19, 44.2%). The median<br />
number of CTCs per patient sample was 59 (1-889), 23 patients (53.4%) presented <<br />
5 CTCs and 20 patients (46.5%) had ≥ 5 CTCs. Overall survival (OS) in patients with<br />
≥5 CTCs was significantly lower than those with
Annals of Oncology<br />
Conclusions: CTC enumeration by <strong>the</strong> integrated CellSearch® profile kit and LSC<br />
yielded improved CTC recovery compared to <strong>the</strong> standard method. CTC counts<br />
correlated with disease severity and support <strong>the</strong> use of CTCs as predictors of OS. We<br />
will present a comparison of CTC enumeration with a correlation to clinical variables.<br />
Disclosure: V. Melnikova: I am an employee of ApoCell. Y. Zhang: I am an<br />
employee of ApoCell. W. Liu: I am an employee of ApoCell. K. Anderes: I am an<br />
employee of ApoCell. D.W. Davis: I am an employee of ApoCell. All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
912P SERUM CHROMOGRANIN A IN METASTATIC CARCINOMA<br />
PROSTATE - A PROGNOSTIC MARKER FOR HORMONAL<br />
THERAPY<br />
G.S. Bhattacharyya 1 , H. Malhotra 2 , P.M. Parikh 3 , J.K. Singh 4 , G.B. Kanaka 5 ,<br />
S. Basu 6 , M. Singh 4 , J. Biswas 7 , T. Shahid 6 , A.A. Ranade 3<br />
1 Medical Oncology & Hemato-Oncology, FORTIS Hospital, Anandapur, Kolkata,<br />
INDIA, 2 Medicine & Medical Oncology, SMS Hospital, Jaipur, INDIA, 3 Medical<br />
Oncology & Hematology, Indian Co-operative Oncology NetworkICON ARO,<br />
Mumbai, INDIA, 4 Cancer Insuitute, Mahavir Cancer Sansthan, Patna, INDIA,<br />
5 Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, INDIA,<br />
6 Radio<strong>the</strong>rapy, AMRI Hospital, Kolkata, INDIA, 7 Medical Director, Chittaranjan<br />
National Cancer Institute, Kolkata, INDIA<br />
Introduction: Treatment of metastatic carcinoma prostate is hormonal manipulation.<br />
Response to <strong>the</strong> hormone <strong>the</strong>rapy is high but duration is variable. Attempt to<br />
develop a marker has clinical relevance and importance to such activity. Aim 1. To<br />
show that Serum Chromogranin-A (CgA) at baseline can define <strong>the</strong> risk population<br />
of metastatic Ca Prostate 2. Baseline Serum Chromogranin-A (CgA) may be able to<br />
choose patient who may require early non-hormonal interventions.<br />
Method: Study was done in a period of 2005 to 2010. 160 patients of Metastatic Ca<br />
Prostate who had no chemo<strong>the</strong>rapy or hormonal <strong>the</strong>rapy were included. All patients<br />
were staged by Bone Scan, CT scan, and Trans Rectal Ultrasound. Routine<br />
biochemistry was done. Serum Chromogranin-A (CgA) was assayed by<br />
immune-fluorescence microscopy (IFM) and immuno chemiluminometer (ICMA).<br />
PSA was assayed by immuno chemiluminometer (ICMA). Gleason’s score was<br />
obtained from biopsy report. All patients were serially followed up at three monthly<br />
intervals. Statistical analysis, descriptive analysis for population was used. Patients<br />
were stratified on <strong>the</strong> basis of Gleason’s score >7 or 10 or 7 had progressed. 14 patients out of 40 with PSA
We observed tumor responses and prolonged survival. Patients had CRPC and<br />
were chemo<strong>the</strong>rapy-naïve. They received bi-weekly GVAX for a 24 week period<br />
combined with monthly intravenous administrations of ipilimumab. Each cohort<br />
of 3 patients received an escalating dose of ipilimumab at 0·3, 1·0, 3·0 or 5·0 mg/<br />
kg. In an expansion cohort 16 patients were treated with GVAX and 3·0 mg/kg<br />
ipilimumab. Since <strong>the</strong> teratment can be accompanied by side-effects (colitis,<br />
hypophysitis), we looked for lymphoid and myeloid markers as well as antibody<br />
formation. We observed a significantly prolonged OS for patients with high<br />
pre-treatment frequencies of CD4 + CTLA-4 + , CD4 + PD-1 + , or differentiated<br />
CD8+ T cells, or low pre-treatment frequencies of differentiated CD4+ T cells or<br />
CD4 + CD25hiFoxP3+ regulatory T cells. In contrast, increased frequencies of<br />
granulocytic Myeloid-Derived Suppressor Cells and high pre-treatment<br />
frequencies of monocytic CD14 + HLA-DRlo/- MDSC were associated with<br />
reduced OS. Antibody formation against PSMA, NRP2, and PNPO was<br />
associated with prolonged survival and especially when multiple antibodies were<br />
detected.<br />
Conclusions: Toge<strong>the</strong>r <strong>the</strong>se data provide an immune profile to predict clinical<br />
outcome; both pre-treatment CD4+ T-cells as well as antibody formation was<br />
associated with prolonged survival. These potentially biomarkers for patient selection<br />
should be validated in patients treated with ipilimumab.<br />
Disclosure: W.R. Gerritsen: member of advisory board of BMS, K. Hege: former<br />
employee of Cell Genesys, N. Sacks: former employee of Cell Genesys, I. Lowy:<br />
former employee of Medarex, T. Harding: former emloyee of Cell Genesys, A.<br />
van den Eertwegh: member advisory board BMS, T. De Gruijl: educational<br />
grant from Cell Genesys. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
916P C-MYC EXPRESSION IS MODULATED BY STATINS USE AND<br />
IT’S CORRELATED WITH TIME TO PROGRESSION (TTP) IN<br />
MEN WITH LOCALISED PROSTATE CANCER TREATED WITH<br />
RADICAL RADIOTHERAPY<br />
D. Torrejon Castro 1 , I. De Torres 2 , G. Sánchez-Ollé 3 , X. Maldonado 4 ,<br />
R. Morales-Barrera 1 , C. Suarez 1 , C. Valverde Morales 5 , I. Nunez Hernandez 6 ,<br />
J. Morote 7 , J. Carles 1<br />
1 Medical Oncology, Vall d´ Hebron University Hospital, Barcelona, SPAIN,<br />
2 Pathology, Hospital Vall d’Hebron, Barcelona, SPAIN, 3 Oncology, Hospital Vall<br />
d’Hebron, Barcelona, SPAIN, 4 Radio<strong>the</strong>rapy, Vall Hebron Univerity Hospital,<br />
Barcelona, SPAIN, 5 Medical Oncology, Vall Hebron Univerity Hospital, Barcelona,<br />
SPAIN, 6 Oncologia M, Vall d’Hebron University Hospital Institut d’Oncologia,<br />
Barcelona, SPAIN, 7 Urology Department, Hospital Vall d’Hebrón, Barcelona,<br />
SPAIN<br />
Background: Although statins do not affect <strong>the</strong> incidence of prostate cancer (PCa),<br />
its use reduces <strong>the</strong> risk of clinical progression and mortality. The mechanism by<br />
which statins reduce PCa progression is unknown. MYC phosphorylation is a critical<br />
mechanism by which <strong>the</strong> inhibition of HMG-CoA reductase by statins, <strong>the</strong>reby<br />
resulting in MYC dephosphorylation and inactivation, which is essential for <strong>the</strong>ir<br />
anticancer <strong>the</strong>rapeutic effect. The aim of this study was to correlate statins use with<br />
<strong>the</strong> c-MYC levels in PCa patients treated with radical radio<strong>the</strong>rapy (RT) with<br />
concurrent androgen deprivation.<br />
Methods: A total of 85 patients with paraffin-embedded prostate tissue specimens<br />
were investigated immunohistochemically for c-MYC overexpression, diagnosed<br />
with PCa between 2000 and 2005. Clinical and pathological variables were<br />
compared between statin users and non-users and correlates with expression of<br />
c-MYC. Disease-free survival (DFS) and time to progression (TTP) were<br />
analysed.<br />
Results: Mean age was 71 (56-82) years and median follow-up was 75 months.<br />
Three (3.5%), 14 pts (16.5%) and 68 pts (80%) were classified as low, medium<br />
and high risk respectively. Of those, 20 patients (24%) were using statins,<br />
ei<strong>the</strong>r during initial consultation or during follow-up. No statistical differences<br />
were found between treatment groups regarding median age, risk category,<br />
clinical T stage, Gleason score or median radiation dose. Median percentage<br />
value of c-MYC was 20 (5-80) of statin users vs. 35 (5-100) of non-users (p<br />
= 0.057) and elevated c-MYC expression was not significantly associated with<br />
shorterDFS(p=0.5).At<strong>the</strong>timeofanalysis,only13pts(15.3%)had<br />
biochemical relapse (1 low risk, 3 intermediate, and 9 high risk). Statins use<br />
(38%) was significantly associated with improved TTP (55.2 vs. 30.6 months,<br />
p = 0.016).<br />
Conclusions: In our analysis, statins use was associated with a significant<br />
improvement in TTP, in all risk groups. Although no differences in DFS according<br />
cMYC values, <strong>the</strong>re is a tendency towards a lower expression in statins users. Our<br />
findings warrant fur<strong>the</strong>r investigation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
917P METFORMIN IN CHEMOTHERAPY-NAïVE CASTRATION<br />
RESISTANT PROSTATE CANCER (CRPC): A MULTICENTER<br />
PHASE II TRIAL (SAKK 08/09)<br />
C.A. Ro<strong>the</strong>rmundt 1 , R. Cathomas 2 , A. Templeton 1 , R.C. Winterhalder 3 ,<br />
R. Strebel 4 , D. Baertschi 5 , M. Pollak 6 , L. Lui 6 , S. Crowe 7 , S. Gillessen 1<br />
1 Medical Oncology, Kantonsspital St. Gallen, St. Gallen, SWITZERLAND,<br />
2 Medical Oncology, Kantonspital Graubünden, Chur, SWITZERLAND, 3 Medical<br />
Oncology, Luzerner Kantonsspital, Luzern, SWITZERLAND, 4 Urology,<br />
Kantonsspital Chur, Chur, SWITZERLAND, 5 Trial Coordination, SAKK, Bern,<br />
SWITZERLAND, 6 Lady Davis Institute for Medical Research, Jewish General<br />
Hospital, Montreal, QC, CANADA, 7 Statistics, SAKK, Bern, SWITZERLAND<br />
Background: Men with prostate cancer (PC) receiving androgen deprivation <strong>the</strong>rapy<br />
(ADT) are at risk of developing insulin resistance. Hyperinsulinemia causes<br />
activation of insulin-like growth factor (IGF) signalling pathways, promoting<br />
progression of PC. Functional loss of PTEN leads to activation of <strong>the</strong> PI3K pathway,<br />
including Akt kinase and mTOR, critical components of PC cell survival and<br />
oncogenic function of IGF-1. The biguanide metformin is an inexpensive oral drug<br />
used as treatment for diabetes mellitus. Metformin, an activator of AMP-activated<br />
protein kinase, has antiproliferative effects on PC via reduction of systemic insulin<br />
levels and inhibition of mTOR.<br />
Methods: Patients (pts) with CPRC, PSA < 114 ng/ml, PSA-doubling time<br />
(PSA-DT) ≥ 55 days, no prior chemo<strong>the</strong>rapy, and adequate organ function were<br />
eligible. ADT was continued in non-surgically castrated pts. Metformin was<br />
administered continuously at 1000mg bd in 4 week cycles. The primary endpoint was<br />
progression free survival at 12 weeks (PFS12) defined as absence of progression (PSA<br />
increase ≥ 25% above baseline, progression of measurable disease or bone lesions,<br />
clinical progression) or death. Simon’s two-stage optimal design was applied. With<br />
5% significance level and 90% power, 44 evaluable pts were required to test if PFS12<br />
rate ≤ 15% (H0) vs ≥ 35% (H1). If ≥ 11 evaluable pts remain PFS12, <strong>the</strong> trial was<br />
deemed worth of fur<strong>the</strong>r investigation.<br />
Results: 44 pts were enrolled at 10 Swiss centres between 12/2010 and 12/2011.<br />
Median age was 70 (range 48-87) years; median PSA-DT at registration was 89<br />
(range 55-438) days. In total, 186 cycles of metformin were administered; median 4<br />
(range 1-13) cycles. Fourteen pts (31.8%, 95% CI: 18.6%-47.6%) had PFS12.<br />
Confirmed PSA response was seen in 2 pts (4.5%); both of whom had 50% PSA<br />
response. Median PFS was 2.1 (range 0.8-12.5) months. Treatment related adverse<br />
events were generally mild and manageable.<br />
Conclusion: To our knowledge this is <strong>the</strong> first trial reporting on metformin in<br />
CRPC. Metformin shows activity in this disease setting and some pts have prolonged<br />
stabilization of disease. Analysis of insulin and C-peptide levels and correlation to<br />
response will be presented.<br />
Disclosure: S. Gillessen: Advisory boards with honorarium Millennium<br />
Janssen-Cilag Sanofi-Aventis. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
918P PHASE 2 RESULTS FROM A PHASE 1/2 STUDY OF TAK-700<br />
(ORTERONEL), AN ORAL, INVESTIGATIONAL, NONSTEROIDAL<br />
17,20-LYASE INHIBITOR, WITH DOCETAXEL AND<br />
PREDNISONE (DP) IN METASTATIC CASTRATION-RESISTANT<br />
PROSTATE CANCER (MCRPC)<br />
D.P. Petrylak 1 , J.G. Gandhi 2 , W.R. Clark 3 , E.I. Heath 4 , J. Lin 5 , W.K. Oh 6 ,<br />
D.B. Agus 7 , B. Carthon 8 , S. Moran 9 , G. Liu 10<br />
1 Oncology, Columbia University Medical Center, New York, NY, UNITED STATES<br />
OF AMERICA, 2 Oncology and Hematology, Associates in Oncology and<br />
Hematology, Chattanooga, TN, UNITED STATES OF AMERICA, 3 Oncology,<br />
Alaska Clinical Research Center, Anchorage, AK, UNITED STATES OF AMERICA,<br />
4 Oncology, Karmanos Cancer Institute, Detroit, MI, UNITED STATES OF<br />
AMERICA, 5 Medical Oncology, Thomas Jefferson University, Philadelphia, PA,<br />
UNITED STATES OF AMERICA, 6 Oncology, Mt. Sinai Hospital, New York, NY,<br />
UNITED STATES OF AMERICA, 7 Molecular Medicine, University of Sou<strong>the</strong>rn<br />
California, Keck School of Medicine, Beverly Hills, CA, UNITED STATES OF<br />
AMERICA, 8 Hematology, Winship Cancer Institute, Emory University, Atlanta,<br />
GA, UNITED STATES OF AMERICA, 9 Oncology, Millennium Pharmaceuticals,<br />
Inc., Cambridge, MA, UNITED STATES OF AMERICA, 10 Oncology, University of<br />
Wisconsin Carbone Cancer Center, Madison, WI, UNITED STATES OF<br />
AMERICA<br />
Background: The investigational agent TAK-700 (orteronel) is a selective 17,20-lyase<br />
inhibitor that blocks androgen production. Since DP is currently standard<br />
chemo<strong>the</strong>rapy in mCRPC, this phase 1/2 study examined TAK-700 + DP in men<br />
with mCRPC.<br />
Methods: The primary phase 2 objective is tolerability of TAK-700 400 mg BID + D<br />
(75 mg/m q3w) + P (5 mg BID) in castrate men (testosterone [T]
Annals of Oncology<br />
Secondary objectives were PK, PSA response rates after 3 mo, best PSA response at<br />
any time, time to progression of PSA ± radiographic disease, response by RECIST<br />
1.1. D was started on d8 of cycle 1 (28 d); cycles ≥2 = 21 d.<br />
Results: 24 men were treated: median age was 66 yrs (range 53–87), ECOG PS 0/1 (88%/<br />
12%). At baseline, median PSA was 47 ng/mL (4.5–813) and T was 7.2 ng/dL (3.2–13.8).<br />
At data cutoff, 15/24 men remained on study treatment. 22/24 men experienced a<br />
treatment-related AE. 3 men discontinued due to AEs (ALT increase, arthralgia,<br />
pneumonitis). 21 men (88%) had at least 1 Gr ≥3 AE (19 were drug-related).<br />
Drug-related Gr ≥3AEs≥10% were WBC decreased (29%); neutropenia (25%);<br />
decreased neutrophil count (25%); fatigue, and febrile neutropenia (each 13%). The most<br />
common drug-related SAE was febrile neutropenia (13%). As of cutoff, <strong>the</strong>re were no<br />
on-study deaths. At 3 mo, PSA30, PSA50, and PSA90 rates in <strong>the</strong> PSA evaluable<br />
population were 59%, 50%, and 18%, respectively. Best PSA decline (median) was -76%<br />
(n = 22; -99 to +144%). Median T at 3 mo decreased to ≤0.2 ng/dL (0.3–10.6). Best ORR<br />
50% (n = 10; 80% CI: 27,73; partial response in 5 of 10 evaluable men). Median time to<br />
PSA progression was 6.1 mo (95% CI: 4.6, not reached) and median time to radiologic<br />
progression was not reached. The Cmax of DP + TAK-700 was similar to that of DP alone.<br />
Conclusions: TAK-700 400 mg BID + DP appears tolerable and shows<br />
androgen-lowering activity and strong PSA and partial tumor response in mCRPC.<br />
Plasma levels of D administered with TAK-700 + P were similar to published data on<br />
DP without TAK-700.<br />
Disclosure: D.P. Petrylak: Consultant/Advisor: Amgen, Bayer, Pfizer, Ferring,<br />
Millennium, Novartis, Dendreon, Johnson & Johnson, Glaxo Smith Kline Research<br />
funding: Celgene, Dendreon, Sanofi, Pfizer, AstraZenca, Glaxo Smith Kline, Rogosen<br />
institute, Boehringer Ingelheim, W.R. Clark: Investigator for BMS, Millenium, Lily,<br />
Watson, Roll International, Astellas, E.I. Heath: Research funding: Millennium<br />
Pharmaceuticals, Ltd. W.K. Oh: Advisor/consultant: Amgen, Pfizer, Sanofi,<br />
Dendreon, Bellicum, and Medivation, D.B. Agus: Millenium Pharmaceuticals, Inc./<br />
Takeda Advisory Board, S. Moran: Employment: Millennium Pharmaceuticals, Inc.<br />
All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
919P TASQUINIMOD MECHANISM OF ACTION BIOMARKERS:<br />
CORRELATION WITH PFS AND SURVIVAL IN MEN WITH<br />
METASTATIC CASTRATE RESISTANT PROSTATE CANCER<br />
TREATED IN A RANDOMIZED PHASE 2 TRIAL<br />
M. Carducci 1 , A. Armstrong 2 , M. Häggman 3 , W.M. Stadler 4 , J.R. Gingrich 5 ,<br />
V. Assikis 6 , G. Forsberg 7 , A. Olsson 8 , Ö. Nordle 9 , R. Pili 10<br />
1 Kimmel Cancer Center, Baltimore, MD, UNITED STATES OF AMERICA,<br />
2 Divisions of Medical Oncology and Urology, Duke University, Durham, UNITED<br />
STATES OF AMERICA, 3 Urology, University Hospital of Uppsala, Uppsala,<br />
SWEDEN, 4 Medical Oncology, University of Chicago, Chicago, IL, UNITED<br />
STATES OF AMERICA, 5 Urology, University of Pittsburgh, Pittsburgh, PA,<br />
UNITED STATES OF AMERICA, 6 Oncology, Peachtree Hematology and<br />
Oncology, Atlanta, GA, UNITED STATES OF AMERICA, 7 BD, Active Biotech AB,<br />
Lund, SWEDEN, 8 Bioscience, Active Biotech, Lund, SWEDEN, 9 Development,<br />
Active Biotech, Lund, SWEDEN, 10 Oncology, Roswell Park Medical Centre,<br />
Buffalo, NY, UNITED STATES OF AMERICA<br />
Background: Tasquinimod (T) is an oral quinoline-3-carboxamide derivative that<br />
binds to S100A9 and displays immunomodulatory, anti-angiogenic and<br />
anti-metastatic activity. Between Dec 2007 and June 2009, 201 (134 T, 67 Placebo<br />
(P)) men with metastatic castrate resistant prostate cancer (CRPC) were randomized<br />
and received once-daily treatment with 41 P patients crossing over to T after 6<br />
months or disease progression. The primary endpoint to demonstrate an<br />
improvement in PCWG2 criteria-defined progression at 6 months was met (69 vs. 37<br />
% of patients (T/P) were progression free) with PFS of 7.6 vs. 3.3 months (T/P) with<br />
acceptable toxicity (Pili, 2011, J Clin Oncol, 20, 4022.). A trend for survival benefit<br />
(33.4 vs 30.4 mo) was observed and was most pronounced in <strong>the</strong> PCWG2 defined<br />
subpopulation (92 T, 44 P) with bone metastatic disease (34.2 vs 27.1 mo). This<br />
abstract provides exploratory data on biomarkers and <strong>the</strong>rapeutic outcome after<br />
Tasquinimod <strong>the</strong>rapy.<br />
Methods: The biomarkers PSA, LDH, Bone alkaline phosphatase (BAP), VEGF-A,<br />
VEGF-C, thrombospondin-1 (TSP-1), sRAGE and TGF-b were analyzed in serum or<br />
plasma before and during <strong>the</strong>rapy in at least <strong>the</strong> subset of patients with bone<br />
metastatic disease. The influence of each (log2 transformed) biomarker on PFS and<br />
OS was estimated with Cox Regression (SAS, SAS Institute Inc, Cary, NC).<br />
Results: Eight weeks Tasquinimod treatment was associated with an increase (% vs<br />
P) in median circulating levels of VEGF-A (40 %) and TSP-1 (21%) and a decrease<br />
in bone alkaline phosphatase (14 %). An increased ratio (week 8/baseline) was<br />
associated with more rapid progression and shorter survival for TSP-1 (PFS HR =<br />
1.29, p = 0.052; OS HR = 1.25, p= 0.058), VEGF-C (PFS HR = 1.52, p = 0.060 OS HR<br />
= 1.39, p = 0.039) and TGF-b (PFS HR = 1.30, p = 0.091 OS HR = 1.27, p = 0.082).<br />
These changes did not correlate with changes in PSA.<br />
Conclusions: PFS and OS observed after Tasquinimod treatment are encouraging.<br />
Biomarker analysis supports an effect on both immunomodulation as well as angiogenesis.<br />
Changes in <strong>the</strong> levels of TGF-b, TSP-1 or VEGF-C may be markers for treatment benefit.<br />
A controlled phase III study is ongoing in men with bone metastatic CRPC.<br />
Disclosure: M. Carducci: Advisory role Active Biotech, uncompensated,<br />
A. Armstrong: Advisor Active Biotech and Ipsen Research Funding Active Biotech,<br />
M. Häggman: Advisory board Ipsen, G. Forsberg: Employed by Active Biotech<br />
Shareholder in Active Biotech, A. Olsson: Employed by Active Biotech Share holder<br />
Active Biotech, Ö. Nordle: Employed by Active Biotech Shareholder Active Biotech,<br />
R. Pili: Advisor Active Biotech Research funding Active Biotech, All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
920P ARN-509 IN MEN WITH HIGH RISK NON-METASTATIC<br />
CASTRATION-RESISTANT PROSTATE CANCER<br />
M.R. Smith, 1 , E.S. Antonarakis 2 , C.J. Ryan 3 , W. Berry 4 , N.D. Shore 5 , G. Liu 6 ,<br />
J. Alumkal 7 , C. Higano 8 , E. Chow-Maneval 9 , D. Rathkopf 10<br />
1 Genitourinary Cancer Center, Massachusetts General Hospital, Boston, MA,<br />
UNITED STATES OF AMERICA, 2 Sidney Kimmel Comprehensive Cancer Center,<br />
Johns Hopkins University, Baltimore, MD, UNITED STATES OF AMERICA,<br />
3 UCSF Helen Diller Family Comprehensive Cancer Center, University of<br />
California, San Francisco, San Francisco, CA, UNITED STATES OF AMERICA,<br />
4 Oncology, Cancer Centers of North Carolina, Raleigh, NC, UNITED STATES OF<br />
AMERICA, 5 Urology, Carolina Urologic Research Center, Myrtle Beach, SC,<br />
UNITED STATES OF AMERICA, 6 Oncology, University of Wisconsin Carbone<br />
Cancer Center, Madison, WI, UNITED STATES OF AMERICA, 7 Medicine, Oregon<br />
Health & Science University Knight Cancer Institute, Portland, OR, UNITED STATES<br />
OF AMERICA, 8 Seattle Cancer Care Alliance, University of Washington, Seattle,<br />
WA, UNITED STATES OF AMERICA, 9 Clinical Development, Aragon Pharmaceuticals,<br />
San Diego, CA, UNITED STATES OF AMERICA, 10 Medicine, Memorial<br />
Sloan-Kettering Cancer Center, New York, NY, UNITED STATES OF AMERICA<br />
Background: ARN-509 is a novel second-generation anti-androgen that binds<br />
directly to <strong>the</strong> ligand-binding domain of <strong>the</strong> androgen receptor, impairing nuclear<br />
translocation and DNA binding. The Phase II portion of a multicenter Phase I/II<br />
study is evaluating <strong>the</strong> activity of ARN-509 in 3 distinct patient populations of men<br />
with CRPC (high risk non-metastatic CRPC, metastatic treatment-naïve CRPC, and<br />
progressive disease after abiraterone acetate). Preliminary results for <strong>the</strong> cohort of<br />
patients with high-risk non-metastatic CRPC are presented here.<br />
Methods: All patients had CRPC, no radiographic evidence of metastases (pelvic<br />
lymph nodes 2 AEs and no patients<br />
required dose modifications. At 12 weeks, 17/19 patients (89.5%) of patients had a<br />
PSA response. The median decrease in PSA from baseline to week 12 was 83.3%.<br />
Conclusion: In men with high-risk non-metastatic CRPC, ARN-509 is safe and well<br />
tolerated with promising preliminary activity based on high PSA response rates.<br />
Disclosure: E. Chow-Maneval: As an employee of Aragon Pharmaceuticals, I have<br />
stock ownership in Aragon Pharmaceuticals.All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
921P MLN8237 (ALISERTIB), AN INVESTIGATIONAL AURORA A<br />
KINASE (AAK) INHIBITOR, IN PATIENTS WITH ADVANCED<br />
SOLID TUMORS INCLUDING CASTRATION-RESISTANT<br />
PROSTATE CANCER (CRPC) RECEIVING A STANDARD<br />
DOCETAXEL REGIMEN: PRELIMINARY PHASE 1 RESULTS<br />
N.M. Hahn 1 , J. Sarantopoulos 2 , C. Higano 3 , X. Zhou 4 , B. Zhang 5 , E.J. Leonard 4 ,<br />
E. Benaim 6 , J. Graff 7<br />
1 Department of Medicine, Division of Hematology/Oncology, Indiana University<br />
Melvin and Bren Simon Cancer Center, Indianapolis, IN, UNITED STATES OF<br />
AMERICA, 2 Medical Oncology, Institute for Drug Development, Cancer Therapy<br />
Research Center at Universtiy of Texas Health Science Center, San Antonio, TX,<br />
UNITED STATES OF AMERICA, 3 Seattle Cancer Care Alliance, University of<br />
Washington, Seattle, WA, UNITED STATES OF AMERICA, 4 Clinical<br />
Pharmacology, Millennium Pharmaceuticals, Inc., Cambridge, MA, UNITED<br />
STATES OF AMERICA, 5 Biostatistics, Millennium Pharmaceuticals, Inc.,<br />
Cambridge, MA, UNITED STATES OF AMERICA, 6 Clinical Development,<br />
Millennium Pharmaceuticals, Inc., Cambridge, MA, UNITED STATES OF<br />
AMERICA, 7 Medical Oncology, Oregon Health and Science University, Portland,<br />
OR, UNITED STATES OF AMERICA<br />
Background: AAK is a key mitotic regulator overexpressed/amplified in a variety of<br />
tumor types including prostate cancer. MLN8237 is an oral, selective AAK inhibitor.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds400 | ix303
Here we report emerging data from <strong>the</strong> first clinical study of MLN8237 in<br />
combination with docetaxel in pts with solid tumors or CRPC.<br />
Methods: Pts aged ≥18 y with ≤3 prior myelosuppressive chemo<strong>the</strong>rapy regimens<br />
who were candidates for docetaxel received MLN8237 BID (days 1–5 or1–7) in 3 + 3<br />
dosing cohorts plus docetaxel on day 1 in 21-d cycles. Primary objectives were safety/<br />
tolerability and to determine a recommended phase 2 dose/schedule (RP2D);<br />
secondary objectives were pharmacokinetics (PK) and antitumor activity (RECIST<br />
v1.1 and/or PSA response by PCWG2).<br />
Results: 22 pts in 5 dose cohorts received a median of 5 cycles (range 1–17); 9 pts<br />
remain on <strong>the</strong>rapy. Median age was 63 y (36–87), 82% were male, and 14 had CRPC.<br />
8 pts reported dose-limiting toxicities including G4 neutropenia >7 days (n = 5) and<br />
G3/4 febrile neutropenia (n = 3). MTD has not yet been reached. 21 pts reported<br />
drug-related AEs; G ≥ 3 in 20 pts, including neutropenia (86%), leukopenia (27%),<br />
and febrile neutropenia (23%). 11 pts had serious AEs and 3 discontinued due to<br />
AEs. There were 2 on-study deaths (due to disease progression). Steady-state systemic<br />
exposure of MLN8237 increased in an approx. dose proportional manner over 10–<br />
30 mg BID when administered with docetaxel 75 mg/m (n = 18). There was no<br />
consistent effect of MLN8237 dose on docetaxel exposure (n = 19). Of 20<br />
response-evaluable pts, 3 with CRPC achieved PR plus a >50% decrease in PSA and<br />
7 had stable disease including 3 pts who also had a >50% decrease in PSA; 1 pt with<br />
bladder cancer had a PR.<br />
Conclusions: Myelosuppressive G ≥ 3 AEs were common, but 10 of 22 pts remained<br />
on study for ≥6 cycles. PK data from <strong>the</strong> expansion cohort are pending to support<br />
definitive conclusions regarding drug-drug interaction between docetaxel and<br />
MLN8237. Emerging data suggest this combination may have preliminary antitumor<br />
activity in pts with solid tumors/CRPC. Dose escalation/modification is ongoing to<br />
determine RP2D.<br />
Disclosure: N.M. Hahn: Research Support to institution: Merck, Dendreon, Sanofi,<br />
Millennium, Exelexis, Novartis, Bristol-Myers Squibb, Celgene Consultant: Sanofi,<br />
Celgene Speakers Bureau Honoraria: Sanofi, Janssen Biotech, C. Higano: Amgen,<br />
Bayer, Dendreon, GTx, MPI, AZ, Pfizer, Cell Ther., Centocor, Perceptive Inform.,<br />
Sanofi, TEVA, BMS, Aragon, Cell Genesys, Exelixis, Genentech, GSK, ImClone,<br />
OncoGenex, Mediv., Clin. Care Ops, Curatio, Medscape, RBC Capital Mkts Corp.,<br />
Cougar, Endo, X. Zhou: Employment (Millennium Pharmaceuticals, Inc.), B. Zhang:<br />
Employment: Millennium Pharmaceuticals, Inc., E.J. Leonard: Employment<br />
(Millennium Pharmaceuticals, Inc.) Ownership interest (Millennium<br />
Pharmaceuticals, Inc.), E. Benaim: Employment (Millennium Pharmaceuticals, Inc.).<br />
All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
922P A PHASE II STUDY OF SB939 IN PATIENTS (PTS) WITH<br />
CASTRATION RESISTANT PROSTATE CANCER (CRPC)<br />
B.J. Eigl1 , S. North2 , E. Winquist3 , J. Powers4 , J. Good5 , M. Sharma6 , J. Squire5 ,<br />
M. Cox7 , E.A. Eisenhauer8 , K. Chi9 1 2<br />
Oncology, Tom Baker Cancer Centre, Calgary, AB, CANADA, Oncology, Cross<br />
Cancer Institute, Edmonton, AB, CANADA, 3 Medical Oncology, University of<br />
Western Ontario London Regional Cancer Center, London, ON, CANADA,<br />
4 5<br />
Clinical Trials, NCIC Clinical Trials Group, Kingston, ON, CANADA, Pathology<br />
and Molecular Medicine, Queens University, Kingston, ON, CANADA, 6 Urologic<br />
Sciences, The Vancouver Prostate Centre, Vancouver, BC, CANADA, 7 Urologic<br />
Sciences, University of British Columbia, Vancouver, BC, CANADA, 8 Clinical<br />
Trials, Queen’s UniversityNCIC Clinical Trials Group, Kingston, ON, CANADA,<br />
9<br />
Oncology, Vancouver Cancer Centre, University of British Columbia, Vancouver,<br />
BC, CANADA<br />
Background: SB939 is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases<br />
(HDACs). These 3 HDAC classes are highly expressed in CRPC and associated with<br />
poor clinical outcomes. HDAC inhibition abrogates androgen receptor signaling via<br />
inactivation of HSP90, and may have particular relevance in prostate cancer with <strong>the</strong><br />
TMPRSS2-ERG (T2-E) fusion.<br />
Methods: Pts with locally recurrent or metastatic CRPC received SB939 60mg every<br />
o<strong>the</strong>r day 3 times per week x 3 weeks on a 28-day cycle. Primary endpoints were<br />
PSA response rate (RR) (>50% decline from baseline for > 4 weeks) and<br />
progression-free survival (PFS). Secondary endpoints included objective response rate<br />
and duration; overall survival; circulating tumor cell (CTC) enumeration at baseline,<br />
6 and 12 weeks; T2-E fusion analysis; correlative analysis of archival tissue; and<br />
safety. In a 2-stage design, a planned maximum of 29 response evaluable patients<br />
were to be enrolled.<br />
Results: 32 pts were enrolled and have completed study treatment. Median age was<br />
70; 88% of pts had received no prior chemo<strong>the</strong>rapy; and ECOG performance status<br />
was 0/1 in 44%/56%. Bone/lymph node/visceral metastases were present in 91%/75%/<br />
12%. The median number of SB939 cycles administered was 3 (range 1-8). Adverse<br />
events were generally grade 1-2, with 5 pts experiencing one or more grade 3 events<br />
(fatigue (5), vomiting (1), dyspnea (1)). One pt died due to myocardial infarction. A<br />
confirmed PSA response was noted in 2 pts (6%), lasting 3.0 and 9.4 mo. In 16 pts<br />
with measurable disease, <strong>the</strong>re were no objective responses, 7 pts had stable disease<br />
lasting 1.6 to 8.0 months. CTC response (from ≥5 at baseline to 5 at 6 weeks correlated<br />
with PSA progression. Correlative studies to evaluate T2-E from whole blood as well<br />
as T2-E fusion and PTEN deletion status on archival tissue are ongoing.<br />
Annals of Oncology<br />
Conclusion: SB939 is tolerable at <strong>the</strong> dose/schedule given, but does not merit fur<strong>the</strong>r<br />
study as a single agent in CRPC based on PSA RR. Activity was observed in terms of<br />
CTC declines however. Study of SB939 with cytotoxic or AR targeted <strong>the</strong>rapies may<br />
be warranted. Supported by grants from <strong>the</strong> Canadian Cancer Society and <strong>the</strong><br />
Ontario Institute for Cancer Research.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
923P GTX-758, AN ORAL ERα AGONIST, INCREASES SEX<br />
HORMONE BINDING GLOBULIN, REDUCES FREE T AND<br />
DECREASES PSA IN PATIENTS WITH CASTRATION<br />
RESISTANT PROSTATE CANCER<br />
M.S. Steiner, R.P. Taylor, R.H. Getzenberg, M.A. Johnston, M. Hancock, J.<br />
T. Dalton<br />
Medical Affairs, GTx, Inc., Memphis, TN, UNITED STATES OF AMERICA<br />
Introduction & objective: GTx-758 is an oral, selective estrogen receptor α agonist,<br />
which induces sex hormone binding globulin (SHBG) and subsequently reduces free<br />
testosterone (FT) to levels below that achieved with LHRH agonists. Such agonists<br />
represent a distinct class of agents with <strong>the</strong> potential to impact men with advanced<br />
prostate cancer. Herein we report <strong>the</strong> results of a proof of concept trial of GTx-758<br />
in patients who developed castration resistant prostate cancer (CRPC) while on<br />
androgen deprivation <strong>the</strong>rapy (ADT).<br />
Methods: Men (n = 9) receiving ADT and developed CRPC, were enrolled in a Phase<br />
II open label study to 2000 mg GTx-758 daily. Primary endpoint was <strong>the</strong> proportion<br />
of subjects with a ≥ 50% reduction in prostate specific antigen (PSA) from Day<br />
1. Secondary endpoints included serum FT and SHBG. SHBG, FT, and PSA were<br />
assessed at, Days 1, 15, 30, 60, and 90 days.<br />
Results: At enrollment (Day 1) values (n = 9) observed for PSA (38.7 ng/mL ± 52.8),<br />
FT (0.89 pg/mL ± 0.70), and SHBG (53.4± 28.6 nmol/L). Data were available from 7<br />
subjects with at least one on-study assessment for FT and SHBG. By Day 15, 75% (3/<br />
7) and by Day 60, 100% (4/4) of patients had a ≥50% reduction in PSA. Mean<br />
change in FT, at last observation, was -70.4% ± 16.7%. All subjects demonstrated<br />
significant increases in SHBG at day 15 (251 ± 63.1 pmol/L) and end of study (266 ±<br />
73.0 pmol/L), with a mean change at last observation of 429% ± 158%. Although<br />
<strong>the</strong>re were no venous thromboembolic events (VTEs) in this study, a separate study<br />
of GTx-758 for primary ADT in men with advanced prostate cancer was stopped<br />
prematurely due to an increased risk of VTEs, and consequently, this study was<br />
halted as well.<br />
Conclusions: GTx-758 is an oral selective ERα agonist that has demonstrated ability<br />
to increase SHBG more than 4-fold and decrease FT in men with CRPC. Coupled<br />
with <strong>the</strong> observation that 4/4 patients respond with a ≥50% reduction in PSA at day<br />
30, <strong>the</strong>se results suggest that progression of disease, and <strong>the</strong> need for increasingly<br />
toxic <strong>the</strong>rapies, may be delayed in this population. Significantly lower doses of<br />
GTx-758 (100 – 600mg) have also been shown to increase SHBG with a more<br />
favorable safety profile in previous Phase I and II GTx-758 studies. Lower doses of<br />
GTx-758 are being evaluated in an ongoing Phase II trial in men with CRPC.<br />
Disclosure: M.S. Steiner: CEO of GTx and own stock, R.P. Taylor: employee of GTx,<br />
Inc. and own stock in GTx, Inc., R.H. Getzenberg: employee of GTx, Inc., M.A.<br />
Johnston: employee of GTx and own stock, M. Hancock: employee of GTx, Inc. and<br />
own stock in GTx, Inc., J.T. Dalton: employee of GTx, Inc. and own stock in<br />
GTx, Inc.<br />
924P ABIRATERONE IN PATIENTS WITH METASTATIC<br />
CASTRATION-RESISTANT PROSTATE CANCER<br />
PROGRESSING AFTER DOCETAXEL AND MDV3100: A<br />
MULTICENTRE STUDY<br />
D. Bianchini 1 , Y. Loriot 2 , E. Ileana 2 , S. Sandhu 1 , C. Pezaro 1 , L. Albiges 2 ,<br />
G. Attard 1 , K. Fizazi 3 , J.S. de Bono 1 , C. Massard 3<br />
1 Prostate Targeted Therapy Group/ DDU, Royal Marsden Hospital, Sutton,<br />
UNITED KINGDOM, 2 Medical Oncology, Institut de Cancérologie Gustave<br />
Roussy, Villejuif, FRANCE, 3 Department of Medical Oncology, Institute Gustave<br />
Roussy, Villejuif, FRANCE<br />
Background: Androgen receptor signalling remains critically important in metastatic<br />
castration resistant prostate cancer (mCRPC) as confirmed by recent Phase III trials<br />
showing a survival advantage for abiraterone acetate and MDV3100. These novel<br />
inhibitors of androgen biosyn<strong>the</strong>sis and androgen receptor function are anticipated<br />
to be broadly utilized in <strong>the</strong> near future. The antitumor activity of abiraterone in<br />
patients pre-treated with MDV3100 is as yet unknown.<br />
Methods: We investigated <strong>the</strong> activity of abiraterone acetate in patients with mCRPC<br />
who had progressed following treatment with docetaxel and MDV3100. Clinical<br />
data were retrospectively analysed for prostate-specific antigen (PSA) response,<br />
clinical benefit and progression-free survival (PFS). All patients received abiraterone<br />
1000 mg/day plus prednisone 10mg/day.<br />
Results: Thirty-nine patients [median age 70 years: range 52-84, median baseline<br />
PSA 238 ng/mL range: 2-3000, metastatic sites: bone disease in 38 patients (97%),<br />
ix304 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
lymph nodes in 15 patients (38%) and visceral disease in 10 patients (26%)] were<br />
included in <strong>the</strong> analyses. Three patients (8%) attained a PSA response, defined as a<br />
decrease of >50% in PSA, confirmed after ≥ 4 weeks. A fur<strong>the</strong>r six patients (15%)<br />
had a 30% PSA decline. The median PFS was 2.7 months (95% CI: 2.2 -3.9). Six out<br />
of 26 evaluable patients (23%) had a symptomatic response on pain score and<br />
decrease of analgesic consumption. Treatment was well-tolerated. One patient<br />
required discontinuation of abiraterone due to oedema and hypokalemia.<br />
Conclusions: This study indicates that abiraterone has antitumor activity in patients<br />
with mCRPC pretreated with docetaxel and MDV3100. Fur<strong>the</strong>r prospective<br />
evaluation of <strong>the</strong>se agents administered in combination is now warranted (Richards J<br />
et al, Cancer Research <strong>2012</strong>).<br />
Disclosure: C. Pezaro: All authors are ICR employees. The ICR has a commercial<br />
interest in Abiraterone, G. Attard: All authors are ICR employees. The ICR has a<br />
commercial interest in Abiraterone. K. Fizazi: PI and advisory board for Jansen and<br />
Medivation, J.S. de Bono: All authors are ICR employees. The ICR has a commercial<br />
interest in Abiraterone. JS de Bono has served as a paid consultant for J&J,<br />
Sanofi-Aventis, Medivation, Astellas, AstraZeneca, Dendreon, Genentech, Pfizer,<br />
GSK. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
925P CLINICAL ACTIVITY OF ABIRATERONE ACETATE (AA) AFTER<br />
PROGRESSION ON MDV3100 IN PATIENTS WITH<br />
METASTATIC CASTRATION RESISTANT PROSTATE CANCER<br />
(MCRPC)<br />
K. Noonan 1 , S. Ellard 2 , K. Chi 3<br />
1 Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, CANADA,<br />
2 Medical Oncology, BC Cancer Agency - Centre for <strong>the</strong> Sou<strong>the</strong>rn Interior,<br />
Kelowna, BC, CANADA, 3 Oncology, Vancouver Cancer Centre, University of<br />
British Columbia, Vancouver, BC, CANADA<br />
Background: AA improves outcomes in patients with mCRPC through inhibition of<br />
CYP17 and androgen syn<strong>the</strong>sis. Recently MDV3100, an androgen receptor<br />
antagonist has also been shown to improve overall survival from mCRPC in patients<br />
progressing after docetaxel. The optimal sequencing for <strong>the</strong>se agents and whe<strong>the</strong>r<br />
induction of cross-resistance occurs is unknown.<br />
Methods: Multi-centre retrospective review of all patients with mCRPC treated with<br />
AA after progressing on MDV3100.<br />
Results: 25 patients were identified from 3 centres in Canada. Baseline characteristics<br />
at time of AA initiation included a median age of 72 years, metastases in bone,<br />
lymph nodes and lung/liver were present in 88, 44 and 28% respectively, 36% of<br />
patients were on opiates, median hemoglobin was 120 g/L, median alkaline<br />
phosphatase was 144 U/L, and LDH was elevated in 28%. 100% had prior docetaxel<br />
chemo<strong>the</strong>rapy and 0% prior ketoconazole. Median duration of prior MDV3100 was<br />
34 weeks (range 8-95), with 64% (16/25) having had a >30% decline in PSA and 32%<br />
(8/25) having a rising PSA as best response. After AA, 21 patients were evaluable for<br />
response. The median duration of treatment with AA was 12 weeks (range 0-80).<br />
14% (3/21) had a >30% PSA decline. Of <strong>the</strong>se 3 patients, 1 continues to respond at<br />
84 weeks of follow-up, while <strong>the</strong> o<strong>the</strong>r 2 had a time to PSA progression (defined as a<br />
25% increase from nadir and a minimum of 2ug/mL) of 18, and 21 weeks.<br />
Interestingly, <strong>the</strong> 2 patients with PSA responses of 18 and 21 weeks on AA did not<br />
respond to MDV3100. 81% (17/21) had a rising PSA as best response. No objective<br />
responses were observed. Median time to progression (PSA, objective or<br />
symptomatic) on AA was 14.6 weeks [CI 8.8-20.4] and median overall survival was<br />
48.7 weeks.<br />
Conclusions: In this study of patients progressing after MDV3100, treatment with<br />
AA was associated with a modest response rate; however primary resistance to<br />
MDV3100 may not preclude a response to AA. The clinical activity of MDV3100<br />
after progression on AA should also be evaluated to assist in <strong>the</strong> determination of<br />
<strong>the</strong> optimal sequencing of <strong>the</strong>se agents.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
926P SAFETY OF ABIRATERONE ACETATE (AA) IN PATIENTS WITH<br />
CASTRATION RESISTANT PROSTATE CANCER (CRPC) AND<br />
CONCOMITANT CARDIAC RISK<br />
G. Procopio 1 , E. Verzoni 1 , I. Testa 1 , S. Stagni 2 , S. Villa 3 , R. Valdagni 3<br />
, F.G.M. De Braud 1<br />
1 Medical Oncology, Istituto Nazionale dei Tumori di Milano, MILAN, ITALY,<br />
2 Urology, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, ITALY,<br />
3 Radio<strong>the</strong>rapy, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, ITALY<br />
Introduction: Abiraterone acetate (AA) is an inhibitor of extragonadal androgen<br />
biosyn<strong>the</strong>sis that prolongs overall survival in CRPC patients who have received a<br />
chemo<strong>the</strong>rapy including docetaxel. The most common adverse events related to AA<br />
<strong>the</strong>rapy were fluid retention, hypertension, hypokaliemia and cardiac disorders. No<br />
safety data are available in patients with concomitant cardiac disease.<br />
Methods: Metastatic CRPC patients were enrolled in this prospective study if <strong>the</strong>y<br />
were also suffering from a concomitant controlled cardiovascular disease. AA 1000<br />
mg per day and prednisone 5 mg bid were administered orally until grade 3-4<br />
adverse events (AE) or disease progression. The primary endpoint was <strong>the</strong> safety<br />
profile while <strong>the</strong> secondary endpoints were progression-free survival and PSA<br />
response.<br />
Results: From April to September 2011, 46 CRPC patients with concomitant<br />
cardiovascular disorders have been treated with AA. Main patients characteristics<br />
were: median age 71 years (range 57-81); baseline mean PSA value 40 ng/ml<br />
(6.32-995); <strong>the</strong> most common sites of disease were bone (33 pts, 81 %), lung (13 pts,<br />
33%) and liver (6 pts, 15 %). All patients were previously challenged with at least 2<br />
lines of hormone <strong>the</strong>rapy and 1 chemo<strong>the</strong>rapy regimen including docetaxel. The<br />
most common pre-existing cardiac disorders were hypertension 24 (66%),<br />
arrhythmias 4 (12 %), cardiac ischemia 4 (9 %) and conduction irregularity 2 (4 %).<br />
Additionally 10 patients (27 %) had metabolic disorders including dyslipidemia and<br />
hyperglycemia. AA was feasible without inducing grade 3-4 AE nor treatment<br />
modification. The most common grade 1-2 AE were as<strong>the</strong>nia (27%), hypertension<br />
(18%) and fluid retention (28%). After a median time of treatment of 10 months<br />
(range 4-12 months) no dose modifications due to toxicity were required. No efficacy<br />
data are still available.<br />
Conclusions: Treatment with AA was feasible and well tolerated also in patients<br />
suffering from cardiac comorbidities and risk factors for cardiovascular disease.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
927P TIME TO PROGRESSION AND SAFETY RESULTS OF A<br />
NONSPECIFIC CYTOCHROME-P 17 INHIBITOR AFTER<br />
RESPONSE/STABILIZATION TO DOCETAXEL AS A<br />
MAINTENANCE STRATEGY IN METASTATIC<br />
CASTRATATION-RESISTANT PROSTATE CANCER<br />
I. Gil-Bazo1 , E. Arevalo1 , A. Castillo1 , M.E. Zudaire1 , O.E. Carranza1 , J.P. Fusco1 ,<br />
E. Castanon Alvarez1 , L. Zubiri1 , P. Martín1 , I. Gil-Aldea2 1<br />
Department of Oncology, Clínica Universidad de Navarra, Pamplona, SPAIN,<br />
2<br />
Centro de Investigación Biomédica, Complejo Hospitalario de Navarra,<br />
Pamplona, SPAIN<br />
Background: The first-line treatment of metastatic castration-resistant prostate<br />
cancer (mCRPC) consists of docetaxel-based chemo<strong>the</strong>rapy. The median time to<br />
progression (TTP) from chemo<strong>the</strong>rapy initiation is 6-8 months (mo). Ketoconazole<br />
is a nonspecific cytochrome-P 17 inhibitor (CYP17i) that blocks adrenal androgen<br />
syn<strong>the</strong>sis. Low-dose ketoconazole (LDK), (200 mg, t.d.s) has shown interesting<br />
activity in mCRPC after progression to androgen deprivation. The role of a CYP17i<br />
in <strong>the</strong> maintenance setting after response/stabilization to docetaxel has never been<br />
studied.<br />
Methods: Thirty-eight mCRPC patients showing progression to luteinizing-hormone<br />
releasing hormone agonists (LHRHa), maintained LHRHa and received a median of<br />
7 cycles of front-line three-weekly docetaxel (75 mg/m2) plus daily prednisone (10<br />
mg). Twenty out of <strong>the</strong> thirty-eight patients showing no progression to docetaxel<br />
were enrolled. After docetaxel, ten patients were assigned to LDK maintenance<br />
treatment plus prednisone (10 mg/day) and LHRHa, and ten patients received<br />
LHRHa alone. TTP was <strong>the</strong> primary endpoint.<br />
Results: After 33 months follow-up, a median TTP from docetaxel initiation was<br />
11.5 months (IC95%: 6.3-16.6) for maintenance <strong>the</strong>rapy and 9.2 months (IC95%:<br />
8.5-9.9) for <strong>the</strong> control arm p = 0.047). Maintenance treatment was well tolerated<br />
with only one patient experiencing a grade 4 adverse event (non-symptomatic<br />
pulmonary embolism). Grade 1 and 2 as<strong>the</strong>nia and hot flashes worsening were <strong>the</strong><br />
most common toxicities (table).<br />
Conclusions: This is <strong>the</strong> first study testing a CYP17i for maintenance <strong>the</strong>rapy after<br />
response/stabilization to docetaxel. A more than 2 months significant benefit in TTP<br />
with a favorable toxicity profile is observed. A fur<strong>the</strong>r prospective analysis in a larger<br />
series using a CYP17i is warranted.<br />
Toxicity profile of maintenance <strong>the</strong>rapy with a CYP17 inhibitor.<br />
Grade Toxicity 1 2 3 4 5<br />
As<strong>the</strong>nia 3 2 - - -<br />
Diarrhea 1 1 - - -<br />
Hepatotoxicity 1 1 - - -<br />
Hyporexia - 1 - - -<br />
Cephalea 1 - - - -<br />
Hot flashes 1 4 - - -<br />
Fluid Retention 1 2 - - -<br />
Pulmonary embolism - - - 1 -<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds400 | ix305
928P LHRH AGONIST-INDUCED SUPPRESSION OF THE<br />
ANDROGEN SYNTHESIS PATHWAY IN PROSTATE CANCER<br />
J. Pinski, S. Xiong, Q. Wang, S.V. Liu<br />
Division of Medical Oncology, University of Sou<strong>the</strong>rn California Norris<br />
Comprehensive Cancer Center, Los Angeles, CA, UNITED STATES OF<br />
AMERICA<br />
Background: Standard first-line <strong>the</strong>rapy for advanced prostate cancer (PC) includes<br />
<strong>the</strong> use of a luteinizing hormone releasing hormone (LHRH) agonist. While <strong>the</strong><br />
primary site of action for <strong>the</strong>se agents is <strong>the</strong> pituitary-hypothalamic-gonadal axis,<br />
receptors fo LHRH are also present in <strong>the</strong> membrane of PC cells and mediate a<br />
direct anti-tumor effect. The mechanism of this effect has been largely unexplored<br />
and may harbor a context of vulnerability. Previously, we have demonstrated that<br />
luteinizing hormone (LH) increases de novo steroidogenesis in PC cells and silencing<br />
of <strong>the</strong> LH receptor leads to downregulation of steroidogenesis. Here, we examined<br />
<strong>the</strong> impact of LHRH agonists on this process at <strong>the</strong> cellular level.<br />
Methods: LNCaP PC cells were treated with <strong>the</strong> LHRH agonist buserelin for 8 hours<br />
in <strong>the</strong> presence or absence of <strong>the</strong> LHRH antagonist antide. Gene expression of LH<br />
and androgen syn<strong>the</strong>sis enzymes was quantified by real-time polymerase chain<br />
reaction and protein expression was measured with Western blot. Cell proliferation<br />
was assessed in <strong>the</strong>se cells using MTS assays.<br />
Results: The LHRH agonist buserelin significantly suppressed <strong>the</strong> gene expression of<br />
LH and <strong>the</strong> androgen syn<strong>the</strong>sis enzymes AKR1C1, AKR1C2, AKR1C3, CYP11A1<br />
and RDH5 (p < 0.05). Protein expression of LH, AKR1C1, AKR1C3 and CYP17A1<br />
was also inhibited by buserelin treatment (p < 0.05). Buserelin also suppressed<br />
LNCaP cell proliferation in a dose-dependent manner (p < 0.05). The suppressive<br />
effects of buserelin on gene expression, protein expression and cell proliferation were<br />
mitigated by <strong>the</strong> LHRH antagonist antide.<br />
Conclusion: These data implicate <strong>the</strong> LHRH agonist buserelin in <strong>the</strong> direct inhibition<br />
of de novo tumoral steroidogenesis, which may be mediated by suppression of LH.<br />
The LH pathway warrants fur<strong>the</strong>r investigation as a <strong>the</strong>rapeutic target.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
929P LOW-DOSE DETHYLSTILBESTROL IN<br />
CASTRATION-RESISTANT PROSTATE CANCER<br />
A. Sasse 1 , C.L. Nourani 2 , L.O. Reis 3<br />
1 Cevon Centre For Evidences In Oncology, UNICAMP - Universidade Estadual<br />
de Campinas, Campinas, BRAZIL, 2 Oncology, UNICAMP, Campinas, BRAZIL,<br />
3 Urology, UNICAMP, Campinas, BRAZIL<br />
Introduction: The role of sequential lines of hormone <strong>the</strong>rapy in castration-resistant<br />
prostate cancer (CRPC) remains unclear. Currently, <strong>the</strong> standard treatment for<br />
patients with CRPC is chemo<strong>the</strong>rapy. Diethylstilbestrol (DES) is a syn<strong>the</strong>tic estrogen<br />
with anti-tumour properties, which could be effective in <strong>the</strong>se patients, before<br />
chemo<strong>the</strong>rapy. OBJECTIVE: To determine <strong>the</strong> efficacy and safety of low-dose DES in<br />
second-line hormonal <strong>the</strong>rapy for CRPC patients in a single institution.<br />
Methods: Between 2007 and <strong>2012</strong>, a total of 31 patients with metastatic CRPC<br />
received DES 1 mg daily. All patients had progression after central androgenic<br />
suppression and at least one line of androgen antagonists (bicalutamide and/or<br />
flutamide). Central androgenic supression with bilateral orchiectomy or a<br />
gonadotropin-releasing hormone agonist was maintained. Aspirin 100 mg daily was<br />
administered to all patients to minimize risk of thromboembolism. The data of PSA<br />
response (defined as a 50% reduction), progression-free survival (PFS), overall<br />
survival and adverse events were collected and analyzed.<br />
Results: The median age was 76,8 years. The PSA response rate was 55%. After a<br />
median follow up of 22 months, <strong>the</strong> median PFS was 12 months. Only one patient<br />
died at <strong>the</strong> time. The main adverse event was gynecomastia (11/31, 35.4%) and no<br />
thrombotic event was recorded.<br />
Conclusion: Low-dose DES appears to be safe and effective for metastatic CRPC<br />
before initiating chemo<strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
930P WHAT PATIENT GROUPS HAVE SPECIAL BENEFITS USING<br />
THE GNRH-ANTAGONIST DEGARELIX? CONCLUSIONS<br />
BASED ON REAL LIFE DATA FROM A GERMAN REGISTRY<br />
G. Geiges 1 , M. Schulze 1 , M. Gedamke 2<br />
1 Uro-oncology, IQUO, Berlin, GERMANY, 2 Urology/Uro-Oncology, Ferring<br />
Arzneimittel GmbH, Kiel, GERMANY<br />
Introduction and objective: The GnRH-antagonists, especially degarelix, are still<br />
relatively new substances in <strong>the</strong> treatment of prostate cancer. Data on advantages of<br />
this specific approach to ADT is accumulating. It is of interest to understand which<br />
patient groups have a special benefit in using degarelix. We have collected data on<br />
efficacy and safety of degarelix in daily practice in order to compare with data from<br />
clinical studies.<br />
Annals of Oncology<br />
Methods: Data from 421 patients with prostate cancer treated with degarelix were<br />
collected by 93 office based urologists. Previous treatment, concomitant medication,<br />
tumour stage and grade as well as alkaline phosphatase (ALP), prostate volume,<br />
testosterone, PSA and side-effects were documented over a period of up to 2 years or<br />
until completion of <strong>the</strong>rapy.<br />
Results: Tumour stages were documented at baseline as T1 27.9%, T2 22.0%, T3<br />
25.1%, T4 13.1% and Tx 11.5%. Median PSA at baseline was 12.4 ng/mL.<br />
Testosterone was above castration level (>0.5 ng/mL) in 41.7% of patients (pts) with<br />
previous hormone <strong>the</strong>rapy and available testosterone value at inclusion (n = 48). In<br />
14.5% of <strong>the</strong> pts degarelix was used intermittently. Prostate volume measured by<br />
transrectal ultrasound was reduced by 40.8% within 3 months compared to baseline.<br />
For pts in which ALP was measured (n = 61), ALP was suppressed from a median of<br />
639.9 (IU/L) to 108.7 (IU/L) after 2 months and was still suppressed to 78.6 (IU/L)<br />
at month 12. Treatment of pts with prior hormone-<strong>the</strong>rapy resulted in 53.8% in a<br />
stable PSA after 1 year. PSA-reduction to
Annals of Oncology<br />
Has acted as a compensated consultant for Sotio and TEVA, P. Parente: Has<br />
participated in an advisory board for, and has received research funding from,<br />
Sanofi, W.R. Gerritsen: Has acted as a compensated consultant for Algaia<br />
Biomedical Ventures, S. Hitier: Is a Sanofi employee (biostatistician) and owns<br />
shares in Sanofi, A. Heidenreich: Has participated in advisory boards for Sanofi,<br />
Janssen Cilag and Astellas. Has received honoraria from, Sanofi, Astellas, Amgen<br />
and Janssen Cilag, A. Bahl: Has participated in an advisory board for, and<br />
received research funding from Sanofi. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
932P TOLERABILITY OF CABAZITAXEL IN SENIOR ADULTS WITH<br />
METASTATIC CASTRATION-RESISTANT PROSTATE CANCER<br />
(MCRPC) IN EUROPE<br />
A. Heidenreich 1 , S. Bracarda 2 , M. Mason 3 , H. Ozen 4 , L. Sengelov 5 ,<br />
W. Gerritsen 6 , C. Papandreou 7 , S. Fossa 8 , S. Hitier 9 , M. Climent 10<br />
1 Urology, RWTH Aachen University, Aachen, GERMANY, 2 Ospedale San<br />
Donato, Medical Oncology Arezzo, Arezzo, ITALY, 3 Institute of Cancer &<br />
Genetics, Cardiff University, Cardiff, UNITED KINGDOM, 4 Urology, Hacettepe<br />
University Medical Faculty, Ankara, TURKEY, 5 Oncology Department R, Herlev<br />
University Hospital, Herlev, DENMARK, 6 Medical Oncology, University Medical<br />
Center Nijmegen, Nijmegen, NETHERLANDS, 7 Medical Oncology, Larissa<br />
University Hospital, Larissa, GREECE, 8 Medical Oncology, Oslo University<br />
Hospital, Oslo, NORWAY, 9 Statistics, Sanofi, Paris, FRANCE, 10 Medical<br />
Oncology, Instituto Valenciano de Oncologia, Valencia, SPAIN<br />
Background: Cabazitaxel (CBZ), a novel taxane developed to overcome docetaxel<br />
resistance, has been shown to prolong overall survival compared with mitoxantrone<br />
in mCRPC patients (pts) who progressed during or after a docetaxel (D)-based<br />
<strong>the</strong>rapy. Compassionate Use (CUP) and Early-Access (EAP) Programs are allowing<br />
access to <strong>the</strong> drug before its commercial availability. This interim analysis of <strong>the</strong><br />
European part of <strong>the</strong> CUP/EAP focuses on <strong>the</strong> safety profile of CBZ in elderly<br />
population.<br />
Methods: As of September 1 st 2011, 746 pts (range 44-86 years; ≥70 years, n = 325;<br />
Disclosure: S. Oudard: Has acted as an advisor for, and received honoraria from<br />
Pfizer Oncology, Bayer Schering Pharma, Roche, GSK, Novartis and Sanofi, J.S. de<br />
Bono: Has participated in an advisory board and has acted as a consultant for Sanofi.<br />
Has also received honoraria and research funding from Sanofi, M. Özgüroğlu: Has<br />
acted as an advisor and consultant (compensated) for, and has received research<br />
funding from Sanofi, S. Hansen: Has participated in an advisory board for Sanofi, J.<br />
Machiels: Has acted as a consultant to Boehringer Ingelheim (uncompensated) and<br />
has received research funding from Sanofi, G. Gravis: Has acted as an<br />
uncompensated consultant to Sanofi, L. Shen: Is a Sanofi employee (Associate<br />
Director) and owns Sanofi stocks and shares, A.O. Sartor: Has acted as a consultant<br />
for Sanofi. Has also received honoraria and research funding from Sanofi. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
934P EFFICACY AND TOLERABILITY OF TAXANE-BASED<br />
CHEMOTHERAPY IN SENIOR ADULTS WITH METASTATIC<br />
CASTRATION-RESISTANT PROSTATE CANCER (MCRPC):<br />
A PROSPECTIVE INTERNATIONAL REGISTRY<br />
J. Droz 1 , E. Efstathiou 2 , A. Heidenreich 3 , A. Yildirim 4 , P. Cabrera 5 , C. Kim 6 ,<br />
A. Horchani 7 , H. Ozen 8 , J.A. Rinck, Jr 9<br />
1 Medical Oncology, Centre Leon Bérard, Lyon Cedex, FRANCE, 2 Oncology,<br />
University of Texas MD Anderson Cancer Center, Houston, TX, UNITED STATES<br />
OF AMERICA, 3 Urology, RWTH Aachen University, Aachen, GERMANY,<br />
4 Oncology, SB Göztepe Training and Research Hospital, Istanbul, TURKEY,<br />
5 Oncology, Centro Oncologico ISSEMyM, Toluca, MEXICO, 6 Urology, Asan<br />
Medical Center, Seoul, KOREA, 7 Urology, La Rabta Hospital, Tunis, TUNISIA,<br />
8 Urology, Hacettepe University Medical Faculty, Ankara, TURKEY, 9 Medical<br />
Oncology, Hospital A. C. Camargo, Sao Paulo, BRAZIL<br />
Background: Docetaxel every 3 weeks is <strong>the</strong> standard of care in mCRPC, although<br />
o<strong>the</strong>r chemo<strong>the</strong>rapy regimens may be administered. Efficacy and toxicity of taxanes<br />
in older men (70+ y) is poorly documented. Their enrolment in randomized trials is<br />
limited by exclusion criteria related to performance status (PS) and comorbidities.<br />
This prospective international registry evaluates taxane toxicity and efficacy in such<br />
men in real life practice.<br />
Methods: 333 men with mCRPC (median age 76 y) were evaluated. PS, grade 3-4<br />
comorbidities (Cumulative Illness Scoring Rate-Geriatrics), dependence (Activity<br />
Daily Living [ADL], Instrumental ADL [IADL]), nutritional status, primary <strong>the</strong>rapy<br />
received and outcomes (overall survival (OS), progression-free survival (PFS), best<br />
clinical benefit [based on pain, analgesic consumption, PS], PSA response, toxicity)<br />
were collected. Follow-up under <strong>the</strong>rapy was 6 months.<br />
Results: In all, 24.0% had PS ≥2, 13.5% grade 3-4 comorbidities, 21% were<br />
dependent in ≥1 IADL, 15.6% in ≥1 ADL and 12.8% had a weight loss ≥5% within<br />
<strong>the</strong> past 3 months. According to SIOG (International Society of Geriatric Oncology)<br />
algorithm, 65.2% were fit, 13.5% vulnerable, 16.8% frail and 4.5% had terminal<br />
illness. Most men (62.4%) had pain at enrolment. Primary <strong>the</strong>rapy was a taxane in<br />
58% (3-weekly, 84.4%; median, 5 months) and received ano<strong>the</strong>r <strong>the</strong>rapy (hormonal<br />
<strong>the</strong>rapy alone in 23.7%, non-taxane chemo<strong>the</strong>rapy in 10.6%). Clinical characteristics<br />
of men treated by taxanes and o<strong>the</strong>r <strong>the</strong>rapies were comparable at baseline. At 6<br />
months, 91% were still alive with taxanes vs 81% with o<strong>the</strong>r <strong>the</strong>rapies (HR [95% CI]<br />
0.53 [0.30-0.93] p = 0.027). Frail patients showed <strong>the</strong> greatest benefit in OS (83% vs<br />
57%, HR 0.32 [0.11-0.91] p = 0.033). Taxanes also significantly increased PFS (66%<br />
vs 50%, HR 0.55 [0.40-0.76], p < 0.001), best clinical benefit (60% vs 36%, HR 2.05<br />
[1.47-2.85], p < 0.001) and PSA response ≥50% (52.5% vs 37.4%, p = 0.018),<br />
including in frail patients. Main grade 3-4 toxicities with taxanes were fatigue<br />
(17.1%), nausea/vomiting (14%), diarrhoea (8.8%), anaemia (7.8%), nail change<br />
(6.7%) and febrile neutropenia (2.6%).<br />
Conclusions: Taxanes appear <strong>the</strong> most effective first-line <strong>the</strong>rapy in older men with<br />
mCRPC and show an acceptable and manageable toxicity, including in frail patients.<br />
Droz et al. BJU Int 2010; 106: 462-69<br />
Disclosure: J. Droz: Member of Advisory Board on Prostate Cancer- SANOFI, A.<br />
Heidenreich: Advisory relationship for Astellas, Janssen Cilag, Sanofi, Ipsen, Takeda<br />
Honoraria received from Amgen, Astellas, Glaxo, Ipsen, Jansen Cilag, Pfizer, Sanofi,<br />
Takeda. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
935P ORAL METRONOMIC CYCLOPHOSPHAMIDE IN PATIENTS<br />
WITH METASTATIC CASTRATION-RESISTANT PROSTATE<br />
CANCER STRATIFIED BY PRIOR DOCETAXEL THERAPY<br />
R. Barroso-Sousa 1 , A.C.R. Chaves 1 , L.G. Fonseca 1 , G. De Castro, Jr. 2 , C. Dzik 1 ,<br />
P.M. Hoff 1<br />
1 Medical Oncology, ICESP, Sao Paulo, BRAZIL, 2 Medical Oncology, Instituto do<br />
Cancer do Estado de Sao Paulo, Sao Paulo, BRAZIL<br />
Background: Treatment options remain limited for patients (pts) with metastatic<br />
castration-resistant prostate cancer (mCRPC). Here we aimed to investigate <strong>the</strong><br />
Annals of Oncology<br />
efficacy and safety of low-dose oral cyclophosphamide (CTX), an intermittent<br />
metronomic chemo<strong>the</strong>rapy regimen, in pts with mCRPC, previously treated or not<br />
with docetaxel.<br />
Methods: All pts previously diagnosed with mCRPC and treated with CTX 100mg/<br />
day (3 weeks on and 1 week off, every 28 days) plus prednisone 10mg/day between<br />
Oct/2006 and Feb/<strong>2012</strong> at our institution were included in this retrospective analysis.<br />
The primary efficacy endpoint was prostate-specific antigen (PSA) decrease ≥ 50%.<br />
Secondary endpoints were PSA decrease ≥ 30% and toxicity. Kaplan-Meier estimates<br />
were calculated and plotted for time to treatment failure (TTF). Single and<br />
multivariate Cox proportional hazards modeling was used to estimate hazard ratios<br />
with 95% confidence intervals (95% CI).<br />
Results: 51 pts with mCRPC were identified, of which 30 (59%) had been already<br />
treated with docetaxel. The median age was 72 y.o. (56-86) and 27 pts (53%)<br />
were ECOG PS0-1 and 24 pts (47%) PS2-3. Five pts presented with visceral<br />
metastasis (10%) and median PSA 525 ng/dL (12-4099) before treatment. Median<br />
number of previous cytotoxic lines was 1 (0-2). After a median number of cycles<br />
CTX of 3, PSA decrease of ≥50% was achieved in 28.6% and 16.7% of<br />
docetaxel-naive and docetaxel-pretreated pts, respectively ( p= 0.30). Besides, PSA<br />
declines of ≥30% occurred in 38.1% and 30.0% of docetaxel-naive and<br />
docetaxel-pretreated patients, respectively (p= 0.54). Overall, <strong>the</strong> median TTF<br />
was estimated to be 2.4 mo. (95% CI 1.87–3.73). Previously treatment with<br />
docetaxel was not statistically significant to TTF, and <strong>the</strong> median TTF was 2.1<br />
mo. (95% CI 1.6–3.2) for docetaxel-pretreated and 3.4 mo. (95% CI 1.7–5.4) for<br />
docetaxel-naïve patients (HR 1.47; 95% CI 0.78 – 2.74;p=0.22).Ingeneral,oral<br />
CTX was safe and well tolerated and <strong>the</strong> most commonly observed G3-4 AE was<br />
lymphopenia (29%).<br />
Conclusions: Oral metronomic CTX plus prednisone seems to be active and safe in<br />
mCRPC, even in pts previously treated with docetaxel. Its convenient oral<br />
administration, low cost, and acceptable toxicity profile may justify future<br />
investigations of this classic alkylating agent in mCRPC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
936P SAFETY OF CYTOTOXIC CHEMOTHERAPY FOLLOWING<br />
RADIUM-223 CHLORIDE (RA-223) THERAPY IN THE PHASE 3<br />
ALSYMPCA STUDY IN PATIENTS WITH<br />
CASTRATION-RESISTANT PROSTATE CANCER (CRPC) WITH<br />
BONE METASTASES<br />
O. Sartor 1 , R.E. Coleman 2 , S. Nilsson 3 , N. Vogelzang 4 , A. Cross 5 ,C.<br />
G. O’Bryan-Tear 6 , K. Staudacher 6 , J.E. Garcia-Vargas 7 ,J.Zou 8 , C. Parker 9<br />
1 Department of Medicine: Section of Hematology & Medical Oncology and<br />
Department of Urology, Tulane Cancer Center, New Orleans, LA, UNITED<br />
STATES OF AMERICA, 2 Academic Unit of Clinical Oncology, Weston Park<br />
Hospital, Sheffield, UNITED KINGDOM, 3 Radiumhemmet, Karolinska University<br />
Hospital, Stockholm, SWEDEN, 4 Developmental Therapeutics, Comprehensive<br />
Cancer Centers of Nevada, Las Vegas, NV, UNITED STATES OF AMERICA,<br />
5 Biostatistics, PharmaNet, Hemel Hempstead, UNITED KINGDOM, 6 Medical,<br />
Algeta ASA, Oslo, NORWAY, 7 Oncology Global Clinical Programs, Bayer<br />
HealthCare Pharmaceuticals, Montville, NJ, UNITED STATES OF AMERICA,<br />
8 Global Medical Affairs, Bayer HealthCare Pharmaceuticals, Montville, NJ,<br />
UNITED STATES OF AMERICA, 9 Academic Urology, The Royal Marsden NHS<br />
Foundation Trust, Sutton, UNITED KINGDOM<br />
Introduction: Ra-223 is a first-in-class alpha-emitter pharmaceutical that<br />
targets bone metastases with high-energy, extremely short range (
Annals of Oncology<br />
deaths occurred. Prospective studies to evaluate Chemo following Ra-223 are<br />
warranted.<br />
Ra-223 + BSC Placebo + BSC<br />
Parameter<br />
(n = 90)<br />
(n = 54)<br />
Median time to Chemo; days (range) 79.0 (2–667) 64.5 (2–448)<br />
Median duration Chemo; days<br />
(range)<br />
117.5 (1–809) 112.5 (1–863)<br />
Chemo = docetaxel; n (%) 63 (70.0) 39 (72.2)<br />
Docetaxel daily dose (mg); n 22 17<br />
Mean (SD) 97.8 (41.6) 102.7 (46.3)<br />
Median (min-max) 92.5 (35-150) 120.0 (30-165)<br />
Deaths on Chemo; n (%) 13 (14.4) 8 (14.8)<br />
Cause: PC and skeletal mets (± o<strong>the</strong>r<br />
mets)<br />
9 (10.0) 7 (13.0)<br />
PC with o<strong>the</strong>r mets (or mets not<br />
specified)<br />
3 (3.3) 0 (0)<br />
Cerebral hemorrhage due to trauma<br />
Cardiopulmonary failure<br />
1 (1.1) 0 (0) 0 (0) 1 (1.1)<br />
Deaths within 30 days post Chemo;<br />
n (%)<br />
5 (5.6) 2 (3.7)<br />
Cause: PC and skeletal mets<br />
(± o<strong>the</strong>r mets)<br />
3 (3.3) 2 (3.7)<br />
Bronchopneumonia Respiratory<br />
failure + pulmonary edema<br />
1 (1.1) 1 (1.1) 0 (0) 0 (0)<br />
Neutrophils; (Absolute) (x10^9/L) 88 3.6 (0.9-26.0) 47 49 4.6 (1.9-16.4) 30<br />
Baseline, n Median (min-max) 4.4 (0.5-24.4) 41 5.7 (1.6-13.1) 19<br />
Month 2, n Median (min-max) 3.8 (1.3-10.8) 23 4.6 (1.1-8.9) 12<br />
Month 4, n Median (min-max) 3.5 (0.5-6.3) 12 4.7 (1.5-12.2) 7<br />
Month 6, n Median (min-max) 3.5 (1.9-9.4) 13 3.9 (3.0-6.4) 8 4.6<br />
Month 8, n Median (min-max) 3.6 (1.1-8.9) 8 (3.0-8.5) 6 5.6<br />
Month 10, n Median (min-max)<br />
Month 12, n Median (min-max)<br />
5.0 (2.5-7.1) (2.8-8.9)<br />
BSC, best standard of care; Chemo, cytotoxic chemo<strong>the</strong>rapy; mets, metastases; PC,<br />
prostate cancer<br />
Disclosure: O. Sartor: O. Sartor has served in a consultant or advisory role for Algeta<br />
ASA and Bayer. S. Nilsson: S. Nilsson has served in a consultant or advisory role for<br />
Algeta ASA. N. Vogelzang: N. Vogelzang has served in a consultant or advisory role<br />
for and has received grant/research support from Algeta ASA and Bayer. C.G.<br />
O’Bryan-Tear: C.G. O’Bryan-Tear is employed by and has an ownership interest in<br />
Algeta ASA. K. Staudacher: K. Staudacher is employed by and has an ownership<br />
interest in Algeta ASA. J.E. Garcia-Vargas: J. Garcia-Vargas is employed by Bayer<br />
HealthCare Pharmaceuticals. J. Zou: J. Zou is employed by Bayer HealthCare<br />
Pharmaceuticals. C. Parker: C. Parker has served in a consultant or advisory role for<br />
Algeta ASA (uncompensated) and Bayer. All o<strong>the</strong>r authors have declared no conflicts<br />
of interest.<br />
937P DENOSUMAB IN PATIENTS WITH METASTATIC PROSTATE<br />
CANCER PREVIOUSLY TREATED WITH DENOSUMAB OR<br />
ZOLEDRONIC ACID: 2-YEAR OPEN-LABEL EXTENSION<br />
PHASE RESULTS FROM THE PIVOTAL PHASE 3 STUDY<br />
K. Fizazi 1 , J.E. Brown 2 , M. Carducci 3 , N.D. Shore 4 , P. Sieber 5 , F. Kueppers 6 ,<br />
L. Karsh 7 ,R.Wei 8 , C. Goessl 9<br />
1 Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, Villejuif,<br />
FRANCE, 2 Medical Oncology, Cancer Research UK Clinical Centre, Universities<br />
of Leeds/Sheffield, Leeds, UNITED KINGDOM, 3 Kimmel Cancer Center, Sidney<br />
Kimmel Comprehensive Cancer Center, Baltimore, MD, UNITED STATES OF<br />
AMERICA, 4 Urology, Carolina Urologic Research Center, Myrtle Beach, SC,<br />
UNITED STATES OF AMERICA, 5 Urology and Urological Surgery, Urological<br />
Associates of Lancaster, Ltd., Lancaster, PA, UNITED STATES OF AMERICA,<br />
6 Urology, Urology Associates, Christchurch, NEW ZEALAND, 7 Clinical Research<br />
Department, The Urology Center of Colorado, Denver, CO, UNITED STATES OF<br />
AMERICA, 8 Global Biostatistical Science, Amgen Inc., Thousand Oaks, CA,<br />
UNITED STATES OF AMERICA, 9 Clinical Development, Amgen Inc., Thousand<br />
Oaks, CA, UNITED STATES OF AMERICA<br />
Background: In a phase 3, randomized, double-blinded (DB) trial (NCT00321620),<br />
subcutaneous (SC) denosumab prevented skeletal-related events (SRE) more<br />
effectively compared with intravenous (IV) zoledronic acid (ZA) in men with<br />
castration-resistant prostate cancer (CRPC) and bone metastases (Fizazi K et al.,<br />
Lancet 2011). As a result, all patients (pts) remaining on study were offered<br />
open-label (OL) denosumab in a pre-specified 2-year extension phase.<br />
Materials and methods: Pts (n = 1901) with CRPC metastatic to bone received ei<strong>the</strong>r<br />
SC denosumab 120 mg and IV placebo or IV ZA 4 mg (adjusted for renal function)<br />
and SC placebo Q4W in <strong>the</strong> DB treatment phase. OL denosumab Q4W was offered<br />
for up to 2 years to pts remaining on study. Pts declining OL treatment were<br />
followed for survival for up to 2 years after <strong>the</strong>ir last dose of investigational product<br />
in <strong>the</strong> DB treatment phase.<br />
Results: Of 323 pts completing <strong>the</strong> DB phase, 153 (87.4%) who were randomized to<br />
denosumab (here referred to as DD pts) and 128 (86.5%) randomized to ZA (here<br />
referred to as ZD pts) continued in <strong>the</strong> OL phase. Demographics were balanced<br />
between groups. Cumulative median (Q1, Q3) denosumab exposure over <strong>the</strong> entire<br />
study for DD pts was 12.0 (5.6, 21.3) months (range: 0.1 to 67.2 months). Overall,<br />
adverse events (AEs) were comparable between groups (n = 138/147 [93.9%] DD pts;<br />
n = 105/118 [89.0%] ZD pts). Twelve pts in <strong>the</strong> DD group and 7 pts in <strong>the</strong> ZD group<br />
developed osteonecrosis of <strong>the</strong> jaw (ONJ) in <strong>the</strong> OL phase, resulting in a cumulative<br />
ONJ incidence for <strong>the</strong> entire study of 3.8% for DD pts and 2.2% for ZD pts.<br />
Hypocalcemia AEs during <strong>the</strong> OL phase were balanced between groups (n = 8 DD<br />
pts; n = 5 ZD pts). Serious AEs were reported in 78 (53.1%) DD pts and 63 (53.4%)<br />
ZD pts. Median (95% CI) overall survival over <strong>the</strong> entire study was similar<br />
between groups: 19.4 months (17.8 to 21.0) for DD pts, 19.3 months (18.0 to 20.6)<br />
for ZD pts.<br />
Conclusion: This two-year OL extension treatment phase confirmed <strong>the</strong><br />
long-term safety profile of denosumab in pts with prostate cancer metastatic to bone<br />
who received denosumab for up to 5.6 years or who switched from ZA to<br />
denosumab.<br />
Disclosure: K. Fizazi: Consultant/advisor: Amgen, Novartis, J.E. Brown: Advisory<br />
Board Member: Amgen, Novartis, Bristol Myers Squibb Corporate Sponsored<br />
Research: Novartis O<strong>the</strong>r Substantive Relationships: Consultant, Amgen, M.<br />
Carducci: Consultant/advisor: Amgen, N.D. Shore: Consultant/Advisor: Amgen,<br />
Astellas, Bayer, Dendreon, Janssen, Medivation, Sanofi Corporate Sponsored<br />
Research: Amgen, Astellas, Bayer, Dendreon, Janssen, Medivation, Sanofi, Active<br />
Biotech, BMS, Millenium, Oncogenix, Progenics, BN Immuno<strong>the</strong>rapeutics, P. Sieber:<br />
O<strong>the</strong>r substantive relationships: consultant, speaker: Amgen, R. Wei: Employee and<br />
stockholder: Amgen, C. Goessl: Employee and stockholder: Amgen. All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
938P ANDROGEN DEPRIVATION AND RADIATION WITH HELICAL<br />
TOMOTHERAPY TO METASTASES IN PATIENTS WITH<br />
OLIGOMETASTATIC HORMONE - SENSITIVE PROSTATE<br />
CANCER<br />
P. Twardowski 1 ,W.Ye 2 ,S.Pal 1 , C. Arbayo 2 , M. Junqueira 1 , P. Tryon 1 , J. Wong 3<br />
1 Medical Oncology and Experimental Therapuetics, City of Hope Cancer Center,<br />
Duarte, CA, UNITED STATES OF AMERICA, 2 Biostatistics, City of Hope Cancer<br />
Center, Duarte, CA, UNITED STATES OF AMERICA, 3 Radiation Oncology, City of<br />
Hope Cancer Center, Duarte, CA, UNITED STATES OF AMERICA<br />
Background: Metastatic prostate cancer (PC) is treated with androgen deprivation<br />
<strong>the</strong>rapy (ADT) and subsequent treatments are employed only after <strong>the</strong> development<br />
of castration resistance. We hypo<strong>the</strong>sized that treatment of oligometastases with<br />
external beam radiation <strong>the</strong>rapy (EBRT) concurrent with ADT will be feasible and<br />
safe and may provide <strong>the</strong>rapeutic benefit by more effective reduction in <strong>the</strong> tumor<br />
burden.<br />
Methods: Patients (pts) with hormone sensitive PC (HSPC) and 1-5 metastases<br />
(mts) detected by bone scan and CT scan were treated with 36 weeks of LHRH<br />
agonist combined with bicalutamide and EBRT up to 45 Gy to all visible metastatic<br />
sites. Seventeen pts (59%) who had no prior <strong>the</strong>rapy of <strong>the</strong> primary tumor, also<br />
received up to 78 Gy to <strong>the</strong> prostate. Primary objectives were time to treatment<br />
failure (TTF) and toxicity. TTF was calculated from <strong>the</strong> end of <strong>the</strong>rapy until PSA<br />
reached pre-treatment level or 10 (whichever was lower) or radiographic progression<br />
or until ADT was restarted.<br />
Results: Twenty nine pts were treated. Median number of mts was 1. Median<br />
Gleason score was 8 (range 5-10). Median baseline PSA was 11.4 (range 1-74.5).<br />
Twenty one pts (72%) had bone mts, 13 pts (45%) had lymph node (LN) mts and 8<br />
pts (28%) had mts limited to pelvic LNs. Median follow up was 25.7 months (range<br />
13.4-61.4). Grade 3 toxicities included diarrhea (7%), urinary frequency (3%), renal<br />
insufficiency (3%). Twenty five pts (86%) reached PSA nadir of
939P NEOADJUVANT SIPULEUCEL-T IN LOCALIZED PROSTATE<br />
CANCER: EFFECTS ON IMMUNE CELLS WITHIN THE<br />
PROSTATE TUMOR MICROENVIRONMENT<br />
L. Fong1 , V. Weinberg1 , S. Chan1 , J. Corman2 , C. Amling3 , R.A. Stephenson4 ,<br />
J. Simko1 , R.B. Sims5 , P. Carroll1 , E.J. Small1 1<br />
Comprehensive Cancer Center, University of California, San Francisco,<br />
San Francisco, CA, UNITED STATES OF AMERICA, 2 Surgery, Virginia Mason<br />
Medical Center, Seattle, WA, UNITED STATES OF AMERICA, 3 Urology, Oregon<br />
Health & Science University, Portland, OR, UNITED STATES OF AMERICA,<br />
4<br />
Urology, University of Utah, Salt Lake City, UT, UNITED STATES OF AMERICA,<br />
5<br />
Clinical Affairs, Dendreon Corporation, Seattle, WA, UNITED STATES OF<br />
AMERICA<br />
Background: Sipuleucel-T is an FDA-approved autologous cellular immuno<strong>the</strong>rapy<br />
for patients with asymptomatic or minimally symptomatic metastatic castrate<br />
resistant prostate cancer (mCRPC). To date, studies of sipuleucel-T in patients with<br />
mCRPC have studied immune response in peripheral blood. The immune effects of<br />
sipuleucel-T in prostatic cancer tissue are unknown.<br />
Methods: NeoACT (P07-1; NCT00715104) is an open-label, Phase 2 study of<br />
patients with localized prostate cancer who received sipuleucel-T prior to radical<br />
prostatectomy (RP) to examine <strong>the</strong> immunologic effects of treatment on prostate<br />
tissue. Patients received 3 infusions of sipuleucel-T at approximately 2-week intervals,<br />
beginning 6-7 weeks prior to RP, and post-RP are being followed for immune<br />
response. The primary endpoint was <strong>the</strong> change in <strong>the</strong> frequency of lymphocytes<br />
between prostate biopsies (pre-treatment) and RP tissue (post-treatment), as assessed<br />
by immunohistochemistry (IHC).<br />
Results: Of <strong>the</strong> 42 enrolled patients (median age 61 years, all ECOG = 0, Gleason<br />
Sum: ≤6 = 24%, 7 = 43%, ≥8 = 33%), 38 received all 3 pre-RP sipuleucel-T infusions<br />
and were evaluable by IHC. Treatment-related AEs were manageable and transient.<br />
Sipuleucel-T did not appear to affect operative complications, procedure time, or<br />
estimated blood loss. Frequent events (>10% of patients) that occurred ≤1 day after<br />
infusion were fatigue, headache, and myalgia. Significant increases (>3 fold) in<br />
infiltrating CD3 + , CD3 + /CD4 + , and CD3 + /CD8+ T cell populations were<br />
observed at <strong>the</strong> tumor rim (where benign and malignant glands interface), compared<br />
with <strong>the</strong> pretreatment biopsy (all p = 0.0001). CD3 + /CD4 + /FoxP3+ cells were also<br />
increased at <strong>the</strong> tumor rim (∼2-fold; P = 0.005), but represented a small proportion<br />
of <strong>the</strong> observed T cells. This level of T cell infiltration was not seen in a cohort of 12<br />
concurrent cases that did not receive neoadjuvant treatment.<br />
Conclusions: Neoadjuvant sipuleucel-T treatment is associated with an increased<br />
frequency of T cells in <strong>the</strong> prostate at <strong>the</strong> interface of <strong>the</strong> benign and malignant<br />
glands. These data demonstrate that sipuleucel-T can modulate <strong>the</strong> presence of<br />
lymphocytes at prostate cancer tissue in vivo.<br />
Disclosure: L. Fong: Research funding from Dendreon. R.B. Sims: Employee and<br />
stockholder of Dendreon. P. Carroll: Honoraria from Takeda. Research funding from<br />
Myriad and Abbot, E.J. Small: Honoraria from Dendreon. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
940P OVERALL SURVIVAL BENEFIT WITH SIPULEUCEL-T BY<br />
BASELINE PROSTATE-SPECIFIC ANTIGEN (PSA): AN<br />
EXPLORATORY ANALYSIS FROM THREE PHASE 3 TRIALS<br />
P. Kantoff 1 , G. Chodak 2 , R.B. Sims 3 , J.B. Whitmore 4 , P. Schellhammer 5<br />
1 Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, UNITED STATES<br />
OF AMERICA, 2 Oncology, Weiss Memorial Hospital, Chicago, IL, UNITED<br />
STATES OF AMERICA, 3 Clinical Affairs, Dendreon Corporation, Seattle, WA,<br />
UNITED STATES OF AMERICA, 4 Biometrics, Dendreon, Seattle, WA, UNITED<br />
STATES OF AMERICA, 5 Urology, Eastern Virginia Medical School / Urology of<br />
Virginia, Virginia, VA, UNITED STATES OF AMERICA<br />
Introduction and objective: Sipuleucel-T is an autologous cellular immuno<strong>the</strong>rapy<br />
approved for <strong>the</strong> treatment of asymptomatic or minimally symptomatic metastatic<br />
castrate-resistant prostate cancer (mCRPC) based on improved overall survival (OS)<br />
in <strong>the</strong> pivotal phase 3 IMPACT trial (NCT00065442). In a subgroup analysis of<br />
pooled data from three Phase 3 trials of sipuleucel-T in mCRPC, baseline PSA was<br />
found to be <strong>the</strong> most significant predictive factor for OS. To fur<strong>the</strong>r investigate <strong>the</strong><br />
impact of baseline PSA levels on outcomes following sipuleucel-T, we conducted an<br />
exploratory analysis of patients (pts) from three Phase 3 trials.<br />
Methods: The analysis included all 737 randomized pts from three Phase 3 trials<br />
(D9901, D9902A and IMPACT). Pts were categorized by baseline PSA quartile<br />
(Table), as well as by ECOG PS, and median for o<strong>the</strong>r baseline prognostic variables<br />
(i.e. lactate dehydrogenase [LDH], alkaline phosphatase [ALP], and hemoglobin<br />
[Hgb]). Median OS and hazard ratio (HR) were estimated using Kaplan-Meier and<br />
Cox models, respectively.<br />
Results: HR values suggest consistent treatment effect in all subsets, although <strong>the</strong>re is<br />
inadequate power to show statistical significance within each quartile. There was a<br />
trend toward an increased magnitude of treatment benefit in pts with a lower<br />
baseline PSA (Table). Results for o<strong>the</strong>r baseline prognostic variables also suggest a<br />
trend toward greater benefit with better prognostic features. However, results for<br />
baseline Hgb indicated an opposite trend<br />
Conclusions: Although not powered for statistical significance, this analysis supports<br />
a consistent OS benefit with sipuleucel-T across PSA quartiles in patients enrolled in<br />
Phase 3 trials. The greater benefit with lower baseline PSA suggests that pts with less<br />
advanced disease may benefit more from sipuleucel-T.<br />
Baseline PSA (ng/mL)<br />
≤22.3 >22.3– ≤ 49.9 >49.9– ≤ 137.8 >137.8<br />
n<br />
Median OS, mos<br />
184 184 184 183<br />
Sipuleucel-T 41.2 25.9 20.6 15.1<br />
Control 26.7 22.0 14.8 13.5<br />
Difference 14.5 3.9 5.8 1.6<br />
HR; 95% CI 0.48;<br />
0.32–0.73<br />
0.76;<br />
0.53–1.11<br />
Annals of Oncology<br />
0.67;<br />
0.47–0.95<br />
0.88;<br />
0.62–1.25<br />
Disclosure: P. Kantoff: Advisory boards for Dendreon Corporation G. Chodak: Stock<br />
ownership in Amgen; Advisory boards for Dendreon Corporation and Janssen;<br />
Honoraria for Dendreon Corporation and Amgen. R.B. Sims: Stock ownership and<br />
employee of Dendreon Corporation. J.B. Whitmore: Employee of Dendreon<br />
Corporation; Stock ownership in Dendreon Corporation and Amgen, P.<br />
Schellhammer: Honoraria for Dendreon Corporation<br />
941P IMPACT OF SALVAGE THERAPY WITH APC8015F ON THE<br />
OVERALL SURVIVAL (OS) BENEFIT ACHIEVED WITH<br />
SIPULEUCEL-T IN THREE PHASE 3 STUDIES OF<br />
METASTATIC CASTRATE-RESISTANT PROSTATE CANCER<br />
(MCRPC)<br />
D.J. George 1 , L.G. Gomella 2 , T. Devries 3 , J.B. Whitmore 3 , M.W. Frohlich 4 ,<br />
C. Nabhan 5<br />
1 Medicine, Duke University, Durham, NC, UNITED STATES OF AMERICA,<br />
2 Urology, Thomas Jefferson University, Philadelphia, PA, UNITED STATES OF<br />
AMERICA, 3 Biometrics, Dendreon, Seattle, WA, UNITED STATES OF AMERICA,<br />
4 Clinical Affairs, Dendreon Corporation, Seattle, WA, UNITED STATES OF<br />
AMERICA, 5 Hematology and Medical Oncolgoy, Advocate Lu<strong>the</strong>ran General<br />
Hospital, Park Ridge, IL, UNITED STATES OF AMERICA<br />
Background: Sipuleucel-T is an autologous cellular immuno<strong>the</strong>rapy approved for<br />
asymptomatic or minimally symptomatic mCRPC. Three Phase 3 sipuleucel-T trials<br />
(D9901, D9902A, IMPACT) allowed control patients (pts) to receive salvage<br />
treatment with an autologous product derived from previously frozen cells<br />
(APC8015F). We previously reported that APC8015F demonstrated no deleterious<br />
effect. Control pts who received APC8015F had more favorable baseline prognostic<br />
features; however, after adjusting for <strong>the</strong>se imbalances, APC8015F appears to have<br />
prolonged OS in control pts, potentially reducing <strong>the</strong> observed sipuleucel-T<br />
treatment effect. This exploratory integrated analysis estimates <strong>the</strong> OS benefit<br />
conferred by sipuleucel-T, adjusting for APC8015F in control pts.<br />
Methods: A rank-preserving structural failure time (RPSFT) model was used to<br />
estimate control arm OS if treatment with APC8015F had not occurred. This allows<br />
estimation of <strong>the</strong> treatment effect of sipuleucel-T, adjusting for salvage effect.<br />
Results: Median OS from randomization in <strong>the</strong> three pooled trials was 25.4 months<br />
with sipuleucel-T (n = 488) and 21.5 months with control (n = 249). Of <strong>the</strong> control<br />
arm pts, 165 (66.3%) subsequently received APC8015F. Median OS from<br />
randomization in <strong>the</strong> control population was 23.6 months for pts receiving<br />
APC8015F and 12.7 months for those who did not. Using <strong>the</strong> RPSFT model, and<br />
assuming APC8015F was as effective as sipuleucel-T, <strong>the</strong> estimate of median OS for<br />
control pts was 17.3 months, representing an 8.1 month median increase in OS with<br />
sipuleucel-T. Results from extensions of <strong>the</strong> RPSFT model, where APC8015F is<br />
assumed to have less treatment effect than sipuleucel-T, will be presented.<br />
Conclusions: These analyses estimate a median OS benefit for sipuleucel-T between<br />
3.9 and 8.1 months, assuming that APC8015F had ei<strong>the</strong>r no efficacy or comparable<br />
efficacy to sipuleucel-T, respectively. These results suggest a possible greater<br />
treatment effect of sipuleucel-T than was reported in <strong>the</strong> three Phase 3 studies.<br />
Future studies should account for potential crossover treatment bias as this may<br />
diminish estimates of OS benefit.<br />
Disclosure: D.J. George: Consultant, Investigator, or Lecturer for <strong>the</strong> following<br />
companies: Astellas, Bayer, BMS, Dendreon, Exelixis, Genentech/Roche, GSK, Ipsen,<br />
Jansen, Medivation, Novartis, Pfizer, Sanofi, Viamet, L.G. Gomella: Consultant/<br />
Advisor and Clinical Trials for Dendreon, T. Devries: Employee and Stockholder of<br />
Dendreon. J.B. Whitmore: Employee and Stockholder of Dendreon. M.W. Frohlich:<br />
Employee and Stockholder of Dendreon. C. Nabhan: I am on <strong>the</strong> speakers bureau of<br />
Dendreon and have received honoraria for speaking engagements.<br />
ix310 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
942P ANTIGEN PRESENTING CELL (APC) ACTIVATION IN<br />
SIPULEUCEL-T: IS ACTIVATION INCREASED IN EARLIER<br />
PROSTATE CANCER DISEASE STATES?<br />
E.J. Small1 , J.D. Wesley2 , D.I. Quinn3 , C. Higano4 , D. Lin5 , H. Haynes2 ,<br />
F. Stewart6 , J.B. Trager2 , N. Sheikh7 1<br />
Medicine/urology, University of California, San Francisco, San Francisco, CA,<br />
UNITED STATES OF AMERICA, 2 Clinical Immunology, Dendreon, Seattle, WA,<br />
UNITED STATES OF AMERICA, 3 USC Norris Comprehensive Cancer Center,<br />
University of Sou<strong>the</strong>rn California, Keck School of Medicine, Los Angeles, CA,<br />
UNITED STATES OF AMERICA, 4 Seattle Cancer Care Alliance, University of<br />
Washington, Seattle, WA, UNITED STATES OF AMERICA, 5 School of Medicine,<br />
University of Washington, Seattle, WA, UNITED STATES OF AMERICA,<br />
6<br />
Biometrics, Dendreon Corporation, Seattle, WA, UNITED STATES OF AMERICA,<br />
7<br />
Clinical Immunology, Dendreon Corporation, Seattle, WA, UNITED STATES OF<br />
AMERICA<br />
Background: Sipuleucel-T is an autologous cellular immuno<strong>the</strong>rapy approved by <strong>the</strong><br />
US FDA for <strong>the</strong> treatment of asymptomatic or minimally symptomatic metastatic<br />
castrate resistant prostate cancer (mCRPC). In <strong>the</strong> Phase 3 mCRPC trials, APC<br />
activation in <strong>the</strong> sipuleucel-T product correlated with overall survival. In this analysis,<br />
sipuleucel-T product characteristics were compared across a range of disease states.<br />
Methods: Sipuleucel-T product parameters were assessed in 4 trials of <strong>the</strong> following<br />
treatment settings: neoadjuvant, n = 42; serologic progression following local <strong>the</strong>rapy,<br />
n = 12; asymptomatic or minimally symptomatic mCRPC, n = 341; and mCRPC<br />
(asymptomatic and symptomatic), n = 104. Cellular composition and APC activation<br />
(CD54 upregulation) were evaluated for all 3 sipuleucel-T doses; cumulative CD54<br />
upregulation was calculated for each patient. In some studies, cytokines and T cell<br />
and B cell activation markers were assessed during sipuleucel-T manufacture.<br />
Results: Baseline demographics were generally representative of each disease state:<br />
patients in <strong>the</strong> neoadjuvant setting were younger with lower disease burden; those<br />
with mCRPC had <strong>the</strong> highest disease burden and more patients had received prior<br />
chemo<strong>the</strong>rapy. APC activation patterns were similar among trials, with increased<br />
CD54 upregulation at <strong>the</strong> second and third treatment. The median cumulative fold<br />
increase in CD54 upregulation in patients with earlier disease (neoadjuvant: 35.5,<br />
serological progression: 43.5) was significantly greater than in patients with<br />
asymptomatic or minimally symptomatic mCRPC (28.7) and mCRPC (21.8) (p <<br />
0.0001). During sipuleucel-T manufacture, lymphocyte activation and cytokine<br />
profiles were similar across disease states, with consistently enhanced expression at<br />
<strong>the</strong> second and third doses.<br />
Conclusion: The process of manufacturing sipuleucel-T activates APCs in both early<br />
and late disease states, and generates similar T and B cell activation and cytokine<br />
profiles consistent with immunological prime-boost. However, APC activation was<br />
more robust in earlier disease states, raising <strong>the</strong> possibility that patients with less<br />
advanced disease may derive greater benefit.<br />
Disclosure: E.J. Small: Honoraria from Dendreon. J.D. Wesley: Employee and<br />
Stockholder of Dendreon. D.I. Quinn: Consultant/Advisor to Dendreon, Pfizer,<br />
Bayer, Novartis, Genentech, C. Higano: Consultant/advisory role, honoraria, and<br />
research funding from Dendreon, D. Lin: Honoraria from Dendreon. H. Haynes:<br />
Employee and Stockholder of Dendreon. F. Stewart: Employee and Stockholder of<br />
Dendreon. J.B. Trager: Employee and Stockholder of Dendreon. N. Sheikh: Employee<br />
and Stockholder of Dendreon.<br />
943P OPENACT: PHASE 2, OPEN-LABEL STUDY OF SIPULEUCEL-T<br />
IN METASTATIC CASTRATE-RESISTANT PROSTATE CANCER<br />
(MCRPC)<br />
J. Corman 1 , N. Dawson 2 , S. Hall 3 , C. Nabhan 4 , A. Ferrari 5 , A.J. Armstrong 6 ,<br />
M.I. Murdock 7 , F. Stewart 8 , N. Sheikh 9 , D.P. Petrylak 10<br />
1 Surgery, Virginia Mason Medical Center, Seattle, WA, UNITED STATES OF<br />
AMERICA, 2 Medical Oncology, Georgetown University, Washington, WA,<br />
UNITED STATES OF AMERICA, 3 Urology, Mount Sinai School of Medicine,<br />
New York, NY, UNITED STATES OF AMERICA, 4 Hematology and Medical<br />
Oncolgoy, Advocate Lu<strong>the</strong>ran General Hospital, Park Ridge, IL, UNITED STATES<br />
OF AMERICA, 5 Medicine, New York University Cancer Center, New York, NY,<br />
UNITED STATES OF AMERICA, 6 Medical Oncology, Duke Cancer Institute, Duke<br />
University, Durham, NC, UNITED STATES OF AMERICA, 7 Urology, Murdock<br />
Urology Associates, Greenbelt, MD, UNITED STATES OF AMERICA,<br />
8 Biometrics, Dendreon Corporation, Seattle, WA, UNITED STATES OF AMERICA,<br />
9 Clinical Immunology, Dendreon Corporation, Seattle, WA, UNITED STATES OF<br />
AMERICA, 10 Medical Oncology, Columbia University Medical Center, New York,<br />
NY, UNITED STATES OF AMERICA<br />
Background: Sipuleucel-T is an FDA-approved autologous cellular immuno<strong>the</strong>rapy<br />
for <strong>the</strong> treatment of asymptomatic or minimally symptomatic mCRPC. In <strong>the</strong> Phase<br />
3 IMPACT trial, sipuleucel-T showed a 22% reduction in risk of death (p = 0.032)<br />
and a 4.1-month median OS improvement (25.8 vs 21.7 months) compared with<br />
control. OpenACT (P09-1; NCT00901342) is a Phase 2 open-label study to fur<strong>the</strong>r<br />
evaluate <strong>the</strong> safety and immune responses of sipuleucel-T in patients (pts) with<br />
mCRPC.<br />
Methods: Pts received sipuleucel-T at 2-week (wk) intervals for a total of 3 infusions.<br />
Sipuleucel-T is manufactured from autologous PBMCs isolated by leukapheresis at<br />
wks 0, 2 and 4, and activated with PA2024 (a recombinant fusion protein composed<br />
of prostatic acid phosphatase [PAP] linked to GM-CSF). Cell activation is measured<br />
by upregulation of <strong>the</strong> costimulatory molecule CD54. The primary endpoint was to<br />
evaluate <strong>the</strong> magnitude of immune responses to sipuleucel-T treatment.<br />
Results: From October 2009–June 2010, 104 pts were enrolled; 101 pts received ≥1<br />
leukapheresis and 98 pts received ≥1 infusion (safety population). Pts who had<br />
received prior docetaxel (D; 29.3% of enrolled pts) had a higher baseline<br />
prostate-specific antigen (90 vs 40ng/mL) and a greater proportion with a time from<br />
diagnosis of ≥6 years (93.5% vs 68.7%) compared with pts with no prior D exposure.<br />
Consistent with previous studies, CD54 upregulation and post-culture cytokine levels<br />
were significantly greater at wk2 and wk4 compared with wk0 (p < 0.05). At wk 6,<br />
PAP2024 and PAP-specific humoral and T cell proliferative responses were<br />
significantly increased from baseline. Pts without prior exposure to D had higher<br />
CD54 cell counts and total nucleated cell count (TNC) than pts who had received<br />
prior D. The most common AEs were infusion-related: fatigue (30.6%), nausea<br />
(18.4%) and chills (17.3%).<br />
Discussion: Sipuleucel-T generates antigen-specific immune responses in patients<br />
with and without prior D exposure. However, product characteristics suggest that<br />
patients without prior D may generate sip-T products with higher TNC, which has<br />
previously been shown to correlate with prolonged survival, supporting earlier use in<br />
<strong>the</strong> mCRPC treatment paradigm.<br />
Disclosure: J. Corman: On <strong>the</strong> Board of Directors for Benaroya Research Institute<br />
and employee of Virginia Mason Medical Center, N. Dawson: Corporate sponsored<br />
research for Dendreon Corporation, and participation in Speakers Bureau also for<br />
Dendreon Corporation, S. Hall: Corporate sponsored research for Dendreon and<br />
Medivation, C. Nabhan: Participation in corporate sponsored research and speakers<br />
bureau, A. Ferrari: Participation in advisory boards, A.J. Armstrong: Advisory boards<br />
for Bristol Myers Squibb, Bayer, Amgen; sponsored research for Dendreon, Sanofi<br />
Aventis, Medivation, Eli Lilly, Pfizer, Novartis, Janssen Biotech, Kanglaite Active<br />
Biotech/Ipsen; speaker for Dendreon, Sanofi Aventis, Amgen, Pfizer, F. Stewart:<br />
Employee and stock ownership in Dendreon Corporation, N. Sheikh: Employee of<br />
and stock ownership in Dendreon Corporation, D.P. Petrylak: Advisory boards for<br />
Amgen, Bayer, Pfizer, Ferring, Millenium, Novartis, Dendreon, Johnson and<br />
Johnson, GlaxoSmithKline; sponsored research Celgene, Dendreon, Sanofi, Pfizer,<br />
AstraZeneca, GlaxoSmithKline, Rogesen Institute, Boheringer Ingelheim, All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
944P COMPARATIVE EVALUATION OF RADIATION-INDUCED<br />
DAMAGES IN PROSTATE CANCER PATIENTS AFTER<br />
INTRATISSUE RADIATION THERAPY USING I-125 SEEDS<br />
AND EXTERNAL BEAM RADIATION THERAPY<br />
I.N. Boyko, A. Ulyanov, V. Pasov, O. Terekhov<br />
Radiation-Induced Damages, Medical Radiological Research Center of <strong>the</strong> RF<br />
Health and Social Development Ministry, Obninsk, RUSSIAN FEDERATION<br />
Purpose: To compare complications of external beam radiation <strong>the</strong>rapy (EBRT) and<br />
brachy<strong>the</strong>rapy for prostate cancer.<br />
Materials and methods: We performed a comparative evaluation of<br />
radiation-induced damages of <strong>the</strong> small pelvis organs in 46 patients with prostate<br />
cancer. The first group consisted of 24 patients who received EBRT to a total tumor<br />
dose of 65-72 Gy. In <strong>the</strong> second group (22 patients), standard brachy<strong>the</strong>rapy<br />
procedures were carried out.<br />
Results: The patients were distributed according to <strong>the</strong> type of radiation-induced<br />
complications (Table 1). Table 1 Distribution of patients according to <strong>the</strong> type of<br />
radiation-induced complications.<br />
Group No. Cystitis<br />
Bladder<br />
ulcer Rectitis<br />
Rectal<br />
ulcer<br />
Combined damages<br />
(rectitis, rectal<br />
ulcer)<br />
Group 1 (24) 8 (33.3%) 2 (8.3%) 7 (29.2%) 3 (12.5%) 4 (16.7%)<br />
Group 2 (22) 4 (18.2%) 0 13 (59%) 2 (9.1%) 3 (13.7%)<br />
Thus, <strong>the</strong> rate of rectal complications was higher in <strong>the</strong> brachy<strong>the</strong>rapy group<br />
compared with <strong>the</strong> EBRT group. Radiation cystitis occurred more frequently in<br />
patients with bladder lesions of group 1. It is worth noting that <strong>the</strong> severity of<br />
radiation-induced damage appeared to be more marked in group<br />
2. Radiation-induced strictures of <strong>the</strong> posterior urethra were detected in 2 (8.3%)<br />
patients of group 1 and in 5 (22.7%) patients of group 2. More serious complications<br />
associated with functional disturbances of organs (microcystitis, rectovesical fistula,<br />
rectal stricture) occurred only in patients who had undergone external beam<br />
radiation <strong>the</strong>rapy.<br />
Conclusions: Our study suggests that radiation-induced damages of <strong>the</strong> rectum and<br />
posterior urethra occur more often after brachy<strong>the</strong>rapy. EBRT can result in radiation<br />
cystitis. It should be pointed out that EBRT can produce more severe lesions of <strong>the</strong><br />
pelvic organs including complications associated with physical disability.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds400 | ix311
945 BONE TURNOVER MARKERS AND POTENTIAL CORRELATION<br />
WITH OUTCOMES IN PATIENTS WITH GENITOURINARY<br />
CANCER (PROSTATE) AND BONE METASTASIS (RESULTS OF<br />
TUGAMO STUDY)<br />
J. Bellmunt 1 , C. De La Piedra 2 ,A.Gómez Caamaño 3 , M.J. Ribal 4 , F. Vázquez 5 ,<br />
U. Anido 6 , E. Solsona 7 , P. Samper 8 , E. Esteban 9 , J. Morote 10<br />
1 Medical Oncology Department, Hospital del Mar, Barcelona, SPAIN, 2 Clinical<br />
Biochemistry Department, Instituto de Investigación Sanitaria Fundación Jiménez<br />
Díaz, Madrid, SPAIN, 3 Radiation Oncology Department, Complexo Hospitalario<br />
Universitario de Santiago de Compostela, A Coruña, SPAIN, 4 Urology<br />
Department, Hospital Clínic, Barcelona, SPAIN, 5 Urology Department, Hospital<br />
Universitario Virgen de las Nieves, Granada, SPAIN, 6 Oncology Department,<br />
Complexo Hospitalario Universitario de Santiago de Compostela, A Coruña,<br />
SPAIN, 7 Urology Department, Instituto Valenciano de Oncología, Valencia,<br />
SPAIN, 8 Urology Department, Hospital Central de la Defensa Gómez Ulla,<br />
Madrid, SPAIN, 9 Medical Oncology Department, Hospital Universitario Central de<br />
Asturias, Oviedo, SPAIN, 10 Urology Department, Hospital Vall d’Hebrón,<br />
Barcelona, SPAIN<br />
Background: Levels of bone turnover markers (BTM) might be correlated with<br />
outcome in terms of skeletal related events (SRE), disease progression and death. The<br />
aim of this study was to determine <strong>the</strong> possible correlation between BTM, disease<br />
progression, SREs and death in patients with genitourinary cancer and bone<br />
metastases (BM) treated with zoledronic acid (ZA).<br />
Methods: Observational, prospective, multicenter study. Patients with genitourinary<br />
cancer (prostate, renal, bladder) and BM were included. BTM determined were:<br />
carboxiterminal telopeptide of type I collagen (β-CTX) and bone specific alkaline<br />
phosphatase (BALP) by ELISA (immunoenzymatic assay, IDS UK), and<br />
aminoterminal propeptide of type I collagen (P1NP) by automatised assays (Elecsys,<br />
Roche). All BTM were determined at baseline (V0) and every 3 mo of treatment<br />
until Month 18 (V6). All patients started treatment with ZA 4 mg IV every 3-4<br />
weeks at <strong>the</strong> beginning of <strong>the</strong> study.<br />
Results: Data of 168 patients with genitourinary cancer were analyzed. In this work<br />
data of prostate cancer patients (n = 95) are presented. Population basal<br />
characteristics [35 new, without previous treatment (N) / 60 pre-treated, with<br />
anti-hormonal treatment (P)]: mean age (years): 72.1; median time from tumor<br />
diagnosis (months): 7.6 (N) / 11.6 (P); ECOG 0-1: 90% (N) / 87.5% (P). Patients<br />
with pathologic baseline levels were: 47.1% β-CTX, 64.7% BALP and 57.1% P1NP<br />
(N) and 48.3% β-CTX, 80.7% BALP and 60% P1NP (P). After 6 mo.: 28%, 48% and<br />
32% (N) and 32%, 59.4% and 31.3% (P) presented pathologic values of β-CTX,<br />
BALP and P1NP respectively. Normalized levels remained steady throughout 18 mo<br />
follow-up. Reductions from baseline to month 3 in BALP levels correlated with lower<br />
risk of death (p = 0.0219) (Cox regression analysis).<br />
Conclusions: Elevation of baseline BTM levels is frequently present in advanced<br />
prostate cancer with bone metastasis. Addition of AZ to standard systemic <strong>the</strong>rapy<br />
reduces BTM levels, even though in those highly hormone sensitive ones. A<br />
significant association was observed between elevated levels of BALP and death<br />
throughout follow-up.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
946 CABAZITAXEL (CBZ) SHOWS SUPERIOR ANTITUMOR<br />
EFFICACY OVER DOCETAXEL IN A HORMONE-RESISTANT<br />
PROSTATE TUMOR XENOGRAFT MODEL (HID28)<br />
L. Bourré 1 , D. Nicolle 1 , M. Legrier 2 , V. Yvonnet 3 , J. Charpentier 3 , M. Poupon 4 ,<br />
P. Vrignaud 5 , S. Oudard 6 , J-G. Judde 3<br />
1 Contract Research Department, XenTech, Evry, FRANCE, 2 R & D, XenTech,<br />
Evry, FRANCE, 3 XenTech, Evry, FRANCE, 4 Scientific Advisory Board, XenTech,<br />
Fresnes, FRANCE, 5 Translational and Experimental Medicine, Sanofi Oncology,<br />
Vitry-sur-Seine, FRANCE, 6 Medical Oncology Department, Hopital Europeen<br />
Georges Pompidou, Paris, FRANCE<br />
Background: Docetaxel (D) was <strong>the</strong> first cytotoxic treatment demonstrating a<br />
survival benefit in metastatic castration-resistant prostate cancer (mCRPC) patients.<br />
Recently, <strong>the</strong> novel taxane cabazitaxel and <strong>the</strong> CYP17 inhibitor abiraterone acetate<br />
have demonstrated a significant survival benefit in mCRPC patients progressing after<br />
receiving a D-containing regimen. Here we compare <strong>the</strong> antitumour efficacy of D,<br />
cabazitaxel and abiraterone acetate in <strong>the</strong> HID28 hormone-resistant human prostate<br />
carcinoma xenograft.<br />
Methods: HID28 tumour-bearing nude mice received 20 mg/kg of D (IP, Q3W x 2),<br />
cabazitaxel at 15 and 20 mg/kg (IP, Q3W x 2) and abiraterone acetate at 50 mg/kg<br />
(PO, QD x 21). Median tumour growth inhibition (T/C%) was evaluated, as well as<br />
time-course androgen receptor expression (4, 8 and 24 h post-dosing) by western<br />
blot analysis.<br />
Results: D inhibited tumour growth with a T/C% = 16.7% at day 35, 2 partial (PR)<br />
and 1 complete (CR) tumour regressions, and with relapse of all tumours (3/3)<br />
observed at day 42. Cabazitaxel demonstrated dose-dependent efficacy at day 35 with<br />
T/C% = 10.8% and 1.4% for 15 and 20 mg/kg doses, respectively. At a cabazitaxel<br />
dose of 15 mg/kg, 4/10 PR and 3/10 CR were observed, whereas 4/10 PR and 6/10<br />
Annals of Oncology<br />
CR were observed at 20 mg/kg. At day 42, 6/6 tumour relapses were observed at 15<br />
mg/kg, whereas only 3/6 relapses were observed at 20 mg/kg. No anti-tumour activity<br />
was demonstrated with abiraterone acetate as well as no significant decreases in<br />
testosterone levels compared with <strong>the</strong> vehicle group. Tolerability was good for all<br />
treatment groups, with a transitory maximum mean body weight loss of 12%, 6 days<br />
after treatments.Androgen receptor western blot expression analysis after 4, 8 and 24<br />
h post-dosing demonstrated no significant difference between groups and over time.<br />
Conclusions: Cabazitaxel demonstrated superior antitumour efficacy and a similar<br />
tolerability compared with D at equivalent dosing in <strong>the</strong> HID28 hormone-resistant<br />
tumour model. The model did not respond to abiraterone. These results support <strong>the</strong><br />
clinical development of cabazitaxel in first-line treatment of mCRPC patients.This<br />
research was funded by Sanofi.<br />
Disclosure: L. Bourré: Is a Xentech employee, D. Nicolle: Is a Xentech employee,<br />
M. Legrier: Is a Xentech employee, V. Yvonnet: Is a Xentech employee, J.<br />
Charpentier: Is a Xentech employee, M. Poupon: Has acted as an uncompensated<br />
consultant and has provided expert testimony. Is a Xentech employee, P. Vrignaud:<br />
Is a Sanofi employee (Research Investigator) and owns Sanofi stocks and shares, S.<br />
Oudard: Has acted as an advisor for, and received honoraria from Pfizer Oncology,<br />
Bayer Schering Pharma, Roche, GSK, Novartis and Sanofi, J-G. Judde: Is a Xentech<br />
employee.<br />
947 AUGMENTATION OF THE CYTOTOXICITY OF IBANDRONATE<br />
BY Y-27632 IN PROSTATE CANCER CELL LINES<br />
A. Ata 1 , A. Özçimen 2 , H. Kurt 3 , N. Tiftik 4 ,A.Arıcan 5 , K. Büyükafs¸ar 4<br />
1 Dept of Medical Oncology, Mersin State Hospital, Mersin, TURKEY, 2 Biology,<br />
Mersin University Science and Art Faculty, Mersin, TURKEY, 3 Dept of<br />
Pharmacology, Mersin University School of Medicine, Mersin, TURKEY, 4 Dept of<br />
Pharmacology, Mersin University School of Medicine, Mersin, TURKEY, 5 Dept. of<br />
Medical Oncology, Mersin University School of Medicine, Mersin, TURKEY<br />
Background: Bisphosphonates, which have been used for <strong>the</strong> treatment of <strong>the</strong><br />
metastatic bone disease and malignant hypercalcemia due many cancers. These<br />
drugs also inhibit mevalonate pathway that results in <strong>the</strong> reduction of Ras<br />
prenylation, which eventually inhibits tumor growth. Rho/Rho kinase signaling has<br />
a fundamental role in cancer cell proliferation, migration and metastasis. In this<br />
study, we aimed to investigate <strong>the</strong> effects of y-27632 (a Rho-kinase inhibitor) and<br />
ibandronate (a bisphosphonate) and <strong>the</strong>ir combination on cell proliferation in<br />
prostate cell lines.<br />
Methods: The adherent prostate cell line, PC-3, was grown in RPMI-1640<br />
supplemented with 10% fetal bovine serum, 1% L-glutamine, 1% penicillin<br />
(10.000U/ml) and streptomycin (10.000 mg/ml) in a humidified atmosphere<br />
of 5% CO2 at 37 o C for confluency. The cells were seeded in <strong>the</strong> wells of E-plates<br />
(24,000 cells/well) that allowed a real-time-monitoring of <strong>the</strong> cell index reflected<br />
cell growth and proliferation (xCELLigence, Roche). The cell index was evaluated at<br />
<strong>the</strong> different points of time (post-treatment 12, 24, 36, 48, 60 and 72 h) in <strong>the</strong><br />
groups of, y-27632, ibandronate, <strong>the</strong> combination of <strong>the</strong>se drugs and time-course<br />
control.<br />
Results: Both ibandronate alone (10-100 mM) and y-27632 alone (50-100 mM)<br />
markedly decreased cell index. But <strong>the</strong> combination of ibandronate with y-27632<br />
(in differrent concentrations but especially in higher concentrations) resulted in<br />
potentiation of cytotoxicity in prostate cell line.<br />
Conclusions: Rho kinase inhibitors, bisphosphonates and <strong>the</strong>ir combinations may be<br />
used for <strong>the</strong> treatment of prostate cancer in <strong>the</strong> future, according to <strong>the</strong> possible<br />
beneficial results of clinical trials.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
948 ANALYSIS OF THE USA POSTMARKETING SAFETY PROFILE<br />
OF CABAZITAXEL IN THE TREATMENT OF METASTATIC<br />
CASTRATE-RESISTANT PROSTATE CANCER (MCRPC)<br />
PREVIOUSLY TREATED WITH A DOCETAXEL-CONTAINING<br />
TREATMENT REGIMEN<br />
L. Nicacio 1 , P. Raina 2 , R. Sands 3 , S. Neibart 4<br />
1 NA Oncology, Sanofi-Aventis U.S. LLC, Inc., a Sanofi Company, Bridgewater,<br />
NJ, UNITED STATES OF AMERICA, 2 US Pharmacovigilance, sanofi-aventis U.S.<br />
LLC, Inc., a Sanofi Company, Bridgewater, NJ, UNITED STATES OF AMERICA,<br />
3 Global Oncology, sanofi-aventis U.S. LLC, Inc., a Sanofi Company, Cambridge,<br />
MA, UNITED STATES OF AMERICA, 4 Global Pharmacovigilance, sanofi-aventis<br />
U.S. LLC, Inc., a Sanofi Company, Bridgewater, NJ, UNITED STATES OF<br />
AMERICA<br />
Background: Cabazitaxel (Jevtana®) in combination with prednisone was licensed in<br />
<strong>the</strong> United States (USA) in June 2010 for <strong>the</strong> treatment of mCRPC in patients (pts)<br />
previously treated with a docetaxel-containing treatment regimen. We estimate that<br />
over 13,000 patients have since been treated in <strong>the</strong> US. This research analyzes <strong>the</strong><br />
post-marketing safety profile of cabazitaxel based on spontaneously reported<br />
pharmacovigilance (PV) Adverse Events (AEs) in <strong>the</strong> USA. As such reports depend<br />
ix312 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
on voluntary reporting, only a qualitative comparison to <strong>the</strong> safety profile observed<br />
in <strong>the</strong> clinical trial setting is possible.<br />
Methods: Safety information spontaneously reported to Sanofi US PV from June 17,<br />
2010 - March 31, <strong>2012</strong> was reviewed. The most frequently reported AEs are<br />
presented, using MedDRA preferred terms and compared with <strong>the</strong> safety profile<br />
observed in clinical trials.<br />
Results: A total of 692 spontaneously reported AEs were received for 373 US men in<br />
<strong>the</strong> time period indicated, 312 (45%) serious (SAEs) and 380 (55%) non-serious. The<br />
pts were 45 to 88 years old (mean ± SD: 68.6 ± 12) and virtually all with mCRPC.<br />
The most frequently reported hematologic AEs were neutropenia [n = 27; 16 SAEs],<br />
febrile neutropenia [n = 18; 17 SAEs], anemia [n = 9; 4 SAEs] and thrombocytopenia<br />
[n = 7; 3 SAEs]. The most frequently reported non-hematologic AEs included<br />
diarrhea [n = 32; 8 SAEs], fatigue [n = 28; 1 SAEs], hematuria [n = 15; 5 SAEs],<br />
nausea [n = 14; 1 SAEs], vomiting [n = 9; 2 SAEs] and pyrexia [n = 3; 0 SAEs].<br />
Concomitant <strong>the</strong>rapies and co-morbidities were associated with most of <strong>the</strong> cases.<br />
Disease progression was reported as an event in 68 pts with 38 pts reporting<br />
increased PSA levels. A total of 57 deaths were reported: 9 due to disease<br />
progression; 3 pulmonary embolism; 2 chronic obstructive pulmonary disease; 2<br />
febrile neutropenia; 2 sepsis; 2 septic shock; 12 o<strong>the</strong>r causes; and, 25 cause not<br />
specified.<br />
Conclusion: Although subject to <strong>the</strong> limitations of <strong>the</strong> post-marketing voluntary<br />
adverse event reporting system, <strong>the</strong> emerging safety profile of Jevtana is consistent<br />
with that observed in <strong>the</strong> clinical trial setting.<br />
Disclosure: L. Nicacio: I am an employee of Sanofi and own Sanofi stock. P. Raina:<br />
I am an employee of Sanofi and own Sanofi stock. R. Sands: I am an employee of<br />
Sanofi and own Sanofi stock. S. Neibart: I am an employee of Sanofi and own<br />
Sanofi stock.<br />
949 PARAMETRIC EFFECT SIZE ESTIMATES FROM SIPULEUCEL-T<br />
RANDOMIZED TRIALS<br />
B.A. Blumenstein<br />
Trial Architecture Consulting, Washington, DC, UNITED STATES OF AMERICA<br />
Introduction: Median overall survival (OS) difference is frequently used as a<br />
measure of effect size because it is easily understood. O<strong>the</strong>r effect size estimates can<br />
more fully represent <strong>the</strong> OS distribution, and are less subject to local variations.<br />
Analysis of <strong>the</strong> sipuleucel-T D9901 and IMPACT trials using non-parametric<br />
(median) or semi-parametric (hazard ratio [HR]) methods provide 4.5- and<br />
4.1-month estimated median OS differences, respectively, with HRs of 0.586 and<br />
0.752 (not stratified or adjusted). The OS curves from <strong>the</strong>se trials exhibit delayed<br />
separation, suggesting a delayed treatment effect consistent with that shown for<br />
o<strong>the</strong>r immuno<strong>the</strong>rapies. In this research, parametric statistical models are used<br />
to account for delayed effect and obtain alternative effect size estimates from D9901<br />
and IMPACT.<br />
Methods: Parametric models based on <strong>the</strong> Weibull distribution and a modification<br />
of <strong>the</strong> Weibull distribution that allows for delay of effect were applied. These models<br />
require specification of <strong>the</strong> general shape of <strong>the</strong> hazard function.<br />
Results: The table shows <strong>the</strong> original OS and HR estimates in comparison to those<br />
obtained through parametric modeling. D9901 estimates from <strong>the</strong> Weibull model<br />
suggested a larger median OS difference vs <strong>the</strong> original estimates. The OS difference<br />
and <strong>the</strong> HR estimate using <strong>the</strong> delayed effect Weibull model were both indicative of<br />
greater sipuleucel-T effect. For IMPACT, <strong>the</strong> OS difference and HR estimates from<br />
<strong>the</strong> Weibull model indicated greater effect, but to a lesser degree than in D9901. The<br />
delayed effect modified Weibull model for IMPACT did not support a delayed effect.<br />
Discussion: This statistical modeling illustrates alternative methods of obtaining<br />
effect size estimates that may be particularly applicable to clinical trials of cancer<br />
immuno<strong>the</strong>rapies. For <strong>the</strong> sipuleucel-T trials, <strong>the</strong>se models suggest a greater<br />
sipuleucel-T effect than obtained from non-parametric or semi-parametric methods.<br />
Study Estimate Type<br />
D9901 Non-parametric/semi-parametric<br />
Weibull Modified Weibull<br />
IMPACT Non-parametric/semi-parametric<br />
Weibull Modified Weibull<br />
NS, delayed effect not supported *Applicable after delayed efffect<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Median<br />
Difference<br />
(mos) Hazard Ratio<br />
4.5 10.3 6.6 0.586 0.585 0.486*<br />
4.1 4.7 NS 0.752 0.749 NS<br />
950 THE EFFECT OF NEUTROPHIL TO LYMPHOCYTE RATIO (NLR)<br />
PRIOR TO TAXOTERE-BASED CHEMOTHERAPY IN PATIENTS<br />
(PT’S) WITH METASTATIC CASTRATION RESISTANT<br />
PROSTATE CANCER (MCRPC)<br />
A. Sella 1 , T. Sella 2 ,S.Kovel 1<br />
1 Oncology, Asaf Harofeh Medical Center, Beer Jacob, ISRAEL, 2 Oncology,<br />
Sheba Medical Center, Ramat Gan, ISRAEL<br />
Introduction: Increasing evidence supports <strong>the</strong> involvement of systemic<br />
inflammation in cancer development and progression. Neutrophiles/lymphocytes<br />
ration (NLR), a marker of inflammatory response which is associated with poor<br />
outcome in colorectal, gastric, pancreas, hepatocellular, breast, lung and renal cancer<br />
cases. The improved survival with immuno<strong>the</strong>rapy (Provenge) in mCRPC and <strong>the</strong><br />
recent report that high NLR in associated with poor outcome in mCRPC treated with<br />
ketoconazole prompted <strong>the</strong> evaluation of NLR in such pt’s treated with<br />
Taxotere-based chemo<strong>the</strong>rapy.<br />
Methods: During <strong>the</strong> last decade we treated 62 mCRPC pt’s with Taxotere-based<br />
chemo<strong>the</strong>rapy. Blood counts up to 2 month prior to <strong>the</strong>rapy without infection or<br />
steroid treatment are available in 31 pt’s. Statistical analysis was performed with<br />
SPSS17, survival curve was measured with Kaplan-Meyer curve.<br />
Results: Patient’s characteristics: median age-70 (55-82) years, median PSA-95.2<br />
(1.6-2316), median alkaline phosphatase- 123(10.8-1795)U/ml was elevated (> 115<br />
U/ml) in 18 pt’s (58%) and median hemoglobin-12.1(8.4-15.4) with anemia (< 12 gr/<br />
%) in 15 pt’s (48%). Median survival was 15.8 + 2.2 months (mo.) while PSA<br />
response (> 50% decline) occurred in 14 pt’s (45.1%). Eighteen pts (58%) had NLR ><br />
3.0. The two groups were similar in PSA, alkaline phosphatase elevated levels and<br />
PSA response. We observed no difference in survival nor PFS between <strong>the</strong> pt’s with<br />
NLR> 3.0 and NLR < 3.0; 17.1 v.s 13.7 mo. and 5.4 v.s 4.5 mo. respectively. Analysis<br />
according to alkaline phosphatase, hemoglobin levels, elevated PSA and alkaline<br />
phosphatase or PSA response was non-significant.<br />
Conclusions: Unlike o<strong>the</strong>r cancers, elevated NLR in mCRPC treated with<br />
Taxotere-based chemo<strong>the</strong>rapy does not predict worse outcome.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
951 REPONSE TO CABAZITAXEL IN THE POSTCHEMOTHERAPY<br />
SETTING IN CRPC PATIENTS PREVIOUSLY TREATED WITH<br />
DOCETAXEL AND ABIRATERONE ACETATE<br />
L. Albiges 1 , S. Le Moulec 2 , Y. Loriot 1 , M. Gross Goupil 3 , T. De La Motte Rouge 4 ,<br />
A. Guillot 5 , K. Fizazi 6 , C. Massard 7<br />
1 Medical Oncology, Institut de cancérologie Gustave Roussy, Villejuif, FRANCE,<br />
2 Oncologie Medicale, Hopital du Val de Grace Val de Grace, Paris Cedex,<br />
FRANCE, 3 Medical Oncology, Hôpital Saint-André, CHU bordeaux, Bordeaux,<br />
FRANCE, 4 Medical Oncology, Salpétrière Hospital, Paris, FRANCE, 5 Medical<br />
Oncology, Institut de Cancérologie de la Loire, Saint Priest en Jarez Cedex,<br />
FRANCE, 6 Department of Medical Oncology, Institute Gustave Roussy, Villejuif,<br />
FRANCE, 7 SITEP, Institut de Cancérologie Gustave Roussy, Villejuif Cedex,<br />
FRANCE<br />
Background: Cabazitaxel (a tubulin-binding taxane chemo<strong>the</strong>rapy) and Abiraterone<br />
acetate (AA) have recently been approved for patients with metastatic castration<br />
resistant prostate cancer (CRPC) following docetaxel chemo<strong>the</strong>rapy. Recent studies<br />
suggest that taxane also impact AR signalling such as AA, and could explain<br />
cross-resistance between new hormonal manipulations and taxane chemo<strong>the</strong>rapy.<br />
The aim of this study is to evaluate <strong>the</strong> antitumor activity of cabazitaxel in patients<br />
whose disease progresses on AA.<br />
Patients and methods: Eligible pts had metastatic CRPC and progression disease<br />
after docetaxel and AA. All <strong>the</strong> patients received cabazitaxel 20 mg/m2 every 3<br />
weeks + prednisone 5 mg BID. Radiological response by RECIST, PSA response by<br />
PSAWG2 criteria and symptomatic benefit were evaluated.<br />
Results: In <strong>the</strong> 38 pts treated with cabazitaxel, baseline median age was 69 years<br />
(48-81), ECOG PS 0 or 1 in 90% of pts, and median PSA 350 ng/ml (3,75-9150).<br />
Bone, lymph nodes and visceral metastases were present in 30 pts (90%), 5 pts<br />
(15%), and 5 pts (15%) respectively. An average of 4 cycles of cabazitaxel (range 1-9)<br />
were given, 85% patients received granulocyte-colony stimulating factor prophylaxis<br />
from cycle 1, and 15 pts (39%) continue on cabazitaxel at <strong>the</strong> time of safety analysis.<br />
Out of 38 patients, 16 patients stopped before completing <strong>the</strong> full course, 15 of <strong>the</strong>se<br />
patients were due to disease progression. No major toxicities were noticed. Of 32<br />
patients with PSA data available, 18 (56%) pts have had a 50% or greater PSA<br />
decline, 5 pts (15%) have had a partial response.<br />
Conclusion: Cabazitaxel appears active and well tolerated in pts with metastatic<br />
CRPC who are resistant to AA. Our data do not provide any evidence for<br />
cross-resistance between <strong>the</strong>se two agents. Final results will be reported.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds400 | ix313
952 SEQUENTIAL ANDROGEN DEPRIVATION AND<br />
CHEMOTHERAPY IN METASTATIC PROSTATE CANCER:<br />
DISCORDANT RESPONSES IN PILOT STUDY SUGGEST AN<br />
OPPORTUNITY FOR INDIVIDUALIZED THERAPY<br />
R. Tang 1 , C. Piatek 1 , J. Pinski 2 , F. Acosta 1 , C. Korn 1 , D. Raghavan 3 , T.B. Dorff 2 ,<br />
D.I. Quinn 2<br />
1 Medicine, University of Sou<strong>the</strong>rn California, Los Angeles, CA, UNITED STATES<br />
OF AMERICA, 2 USC Norris Comprehensive Cancer Center, University of<br />
Sou<strong>the</strong>rn California, Keck School of Medicine, Los Angeles, CA, UNITED<br />
STATES OF AMERICA, 3 Carolinas Healthcare, Levine Cancer Institute, Charlotte,<br />
NC, UNITED STATES OF AMERICA<br />
Background: CRPC is fatal but with recent better survival based on new agents.<br />
Optimal sequential <strong>the</strong>rapy remains a challenge. We undertook a phase II pilot study<br />
of Mitoxantrone (MTX) followed by docetaxel, estramustine, carboplatin (DEC).<br />
Methods: CRPC pts who progressed on/after MTX were given estramustine 280mg<br />
TID x 5d, docetaxel 60mg/m2, carboplatin AUC = 5 q28 days; ASA & warfarin daily,<br />
max 8 cycles. Endpoints: RR >30% with PSA fall >30% & 30% drop in PSA to MTX or DEC & median OS were: responders to MTX only (n<br />
= 4; 20.3 mos (18.4-25.4)); to docetaxel only (n = 10; 14.6 mos (9.1-43.7); both (n = 5;<br />
28.9 mos (22.7-40.3); nei<strong>the</strong>r (n = 1; 12.3 mos (Fisher’s exact p = 0.3 for response<br />
MTX vs DEC, logrank p = 0.028 for OS). Based on pts ADT PSAn, we found longer<br />
PFS for DEC and MTX with higher PSAn (log-rank p = 0.048 & 0.019) & trend to<br />
better OS on MTX/DEC sequence with PSAn >4 (p = -0.14, med OS 20.1 vs 25.8<br />
months). Fall in Hgb between ADT & start of DEC associated with shorter PFS on<br />
DEC (p = 0.05) with a trend to shorter OS (p = 0.08).<br />
Conclusions: DEC was effective in patients with CRPC given MTX. Pts benefited if<br />
<strong>the</strong>y responded to ei<strong>the</strong>r or both agents but <strong>the</strong>re was limited overlap in response<br />
(25%). High PSA nadir on ADT maybe associated with a longer PFS & OS to<br />
chemo<strong>the</strong>rapy. Biomarkers linked to hormonal & chemo<strong>the</strong>rapy effect for individual<br />
agents in PC could have significant utility. Study with larger cohorts of sequential<br />
<strong>the</strong>rapy is ongoing<br />
Disclosure: All authors have declared no conflicts of interest.<br />
953 CABAZITAXEL IN PATIENTS WITH ADVANCED CRPC AFTER<br />
DOCETAXEL-FAILURE. RESULTS OF EXPANDED PROGRAM<br />
ACCESS (EAP) IN SPAIN: SAFETY AND EFFICACY<br />
D.E. Castellano 1 , L.M. Anton Aparicio 2 , E. Esteban 3 , G. Velasco 1 , Q. Perez 4 ,<br />
A. Sanchez 5 , B. Pérez-Valderrama 6 , N. Batista 7<br />
1 Medical Oncology Department, University Hospital 12 de Octubre, Madrid,<br />
SPAIN, 2 Medical Oncology Department, Complejo Hospitalario A Coruña, A<br />
Coruña, SPAIN, 3 Medical Oncology Department, Hospital Universitario Central<br />
de Asturias, Oviedo, SPAIN, 4 Medical Oncology, Hospital Universitario Central de<br />
Asturias, Oviedo, SPAIN, 5 Medical Oncology Department, Hospital Provincial de<br />
Castellon, Castellon, SPAIN, 6 Medical Oncology, Hospital Virgen del Rocío,<br />
Seville, SPAIN, 7 Medical Oncology Department, Hospital Universitario de<br />
Canarias, Las Palmas, SPAIN<br />
Background: Cabazitaxel is <strong>the</strong> new chemo<strong>the</strong>rapy standard in second line treatment<br />
of metastatic castrate resistant prostate cancer (CPRC) [TROPIC Trial, Lancet 2010].<br />
The aim of this study was to analyze <strong>the</strong> baseline characteristics and outcomes of a<br />
cohort of patients from six Spanish hospitals enrolled in a EAP. (total nº of pts: 138)<br />
Methods: Between 3-2011 and 12-<strong>2012</strong>, 65 mCRPC pts who have progressed on or<br />
after docetaxel-based chemo<strong>the</strong>rapy were treated with Cabazitaxel (25 mg/m2 IV<br />
q3wks plus oral prednisone 10mg daily. All pts had proven histology confirmation of<br />
prostate adenocarcinoma and progressive disease (radiologic and/or rising PSA) at<br />
<strong>the</strong> beginning of <strong>the</strong> treatment.<br />
Results: Median age was 63 years (range 45-83) and ECOG 0-1 in 25%-68%<br />
respectively. Median PSA at baseline was 864 ng/ml. Seventy-eight percent had bone<br />
metastases, 33% lymph nodes metastases and 14% visceral metastases. Previous<br />
<strong>the</strong>rapy was: hormonal, (median 2 lines) and chemo<strong>the</strong>rapy (median 1.6 lines).<br />
Thirty percent (20 pts) had received ketoconazole. Median previous docetaxel dose<br />
was 1029 mg/m2(50-3750). Seventy percent of pts received G-CSF as primary<br />
prophylaxis in any cycle, 24% (16pts) had grade >3 neutropenia and 9% (6 pts) had<br />
febrile neutropenia. O<strong>the</strong>r grade 3 toxicities were: anemia 3pts (4,6%), as<strong>the</strong>nia 5pts<br />
(7,7%), diarrhea 1 pt (1,5%). No toxic death was reported. The PSA decrease ≥50%<br />
Annals of Oncology<br />
was observed in 64% (31pts) and <strong>the</strong> median number of cycles administered was 6 at<br />
last check. Median progression free survival was 4.4 months (2.7-6.1).<br />
Conclusions: Results of this Spanish EAP confirm <strong>the</strong> efficacy and manageable safety<br />
of Cabazitaxel in daily practice. (CGR I would not comment on GCSF as many<br />
countries do not use prophylactic GCSF)<br />
Disclosure: All authors have declared no conflicts of interest.<br />
954 QUALITY OF LIFE OF PATIENTS WITH METASTATIC<br />
CASTRATION-RESISTANT PROSTATE CANCER: RESULTS<br />
FROM AN OBSERVATIONAL STUDY IN 6 EUROPEAN<br />
COUNTRIES<br />
R.N. Dass 1 , P. Hamberg 2 , M. Spencer 1 , P. Wheatley Price 1<br />
1 Hemar (Health Economics, Market Access and Reimbursement), Janssen-Cilag<br />
Ltd, London, UNITED KINGDOM, 2 Internal Medicine, St Franciscus Gasthuis,<br />
Rotterdam, NETHERLANDS<br />
Background: Despite advances in prostate cancer (PC) <strong>the</strong>rapy, treatment options<br />
for metastatic castration-resistant prostate cancer (mCRPC) are limited. However,<br />
studies on health-related quality of life (HRQoL) for mCRPC patients are rare and<br />
although HRQoL is considered as a key outcome of mCRPC treatments, patient<br />
utilities are not measured routinely.<br />
Objective: To assess QoL outcomes in mCRPC patients. Methodology Observational,<br />
cross-sectional, prospective year-long study conducted in 47 centres specialised in PC<br />
treatment in 6 countries: Belgium, France, Germany, Sweden, <strong>the</strong> Ne<strong>the</strong>rlands, and<br />
<strong>the</strong> United Kingdom. Patients with confirmed diagnosis of PC, presenting with<br />
metastatic castration-resistant disease were eligible. At inclusion, clinical and<br />
<strong>the</strong>rapeutic data were collected by physicians, and EQ-5D and FACT-P<br />
questionnaires were completed by patients. Interim results based on 200 patients, of<br />
a target of 900, are presented below.<br />
Results: Mean age was 72.8 years. Mean time since diagnosis of PC was 6.6 years. At<br />
diagnosis, 34.5% of patients had metastases, and 79.2% had a Gleason score ≥ 7. At<br />
inclusion, 34.2% of <strong>the</strong> patients had never been treated with any prior cytotoxic<br />
chemo<strong>the</strong>rapy (CT), 35.3% had been treated with CT in <strong>the</strong> past and 30.5% were<br />
undergoing CT (respective mean times since PC diagnosis: 7.3, 6.4 and 5.7 years).<br />
Mean (SD) EQ-5D single index utility score was 0.7 (0.3). 65.3% of patients had<br />
moderate or extreme pain or discomfort, 53.2% had problems performing daily<br />
activities and 51,3% had mobility problems. Mean (SD) EQ-5D VAS score was 55.7<br />
(22.7). Although not statistically significant (NS), a trend for patients without any<br />
prior CT to have higher mean EQ-5D single index utility and VAS scores, was<br />
observed. Mean (SD) FACT-P total score was 102.8 (24.1) and 107.2 (25.8), 103.2<br />
(23.7) and 98.1 (21.9) respectively in patients without any prior CT, undergoing CT<br />
and treated with CT in <strong>the</strong> past (NS). Subscale scores were: physical well being: 20.3<br />
(6.1), social/family well being: 20.4 (5.4), emotional well being: 16.9 (4.7), functional<br />
well being: 16.0 (6.3) and PC subscale: 29.4 (8.3).<br />
Conclusion: The interim analysis was insufficiently powered to detect a significant<br />
impact of CT on HRQoL in mCRPC patients. The final analysis is expected to<br />
adequately highlight determinants of HRQoL.<br />
Disclosure: R.N. Dass: Janssen Cilag employee, P. Hamberg: Study investigator, M.<br />
Spencer: Janssen Cilag employee, P. Wheatley Price: Janssen Cilag employee<br />
955 SAFETY DATA OF CABAZITAXEL (JEVTANA®) IN PATIENTS<br />
TREATED FOR METASTATIC CASTRATION RESISTANT<br />
PROSTATE CANCER AFTER DOCETAXEL TREATMENT:<br />
RESULTS OF A COHORT OF PATIENTS DURING THE<br />
TEMPORARY AUTHORIZATION FOR USE IN FRANCE (ATU)<br />
N. Houede 1 , J. Eymard 2 , T. Zoubir 3<br />
1 Medical Oncology, Institut Bergonié, Bordeaux, FRANCE, 2 Medical Oncology,<br />
Institut Jean Godinot, Reims Cedex, FRANCE, 3 Médical Oncologie, Sanofi, Paris,<br />
FRANCE<br />
Background: The TROPIC 1 study demonstrated that cabazitaxel (a novel<br />
tubulin-binding taxane drug) improves overall survival of patients (pts) with<br />
metastatic castration resistant prostate cancer (mCRPC) who progressed during or<br />
after docetaxel-based chemo<strong>the</strong>rapy, with a median survival of 15.1 months. Based<br />
on this result, a compassionate-use program has been established to provide pts with<br />
mCRPC with <strong>the</strong> opportunity to receive treatment with cabazitaxel, before licensing<br />
of <strong>the</strong> drug.<br />
Methodology: Temporary Authorization for Use (ATU) of cabazitaxel in France has<br />
been granted before its marketing authorization; all safety data from pts treated<br />
during this period were collected following a specific <strong>the</strong>rapeutic use protocol. All<br />
participating physicians were instructed about <strong>the</strong> molecule and its administration by<br />
a company physician and contacted before <strong>the</strong> first treatment, on day 15 and at <strong>the</strong><br />
end of treatment of each patient to make sure that all G3/4 and serious adverse<br />
events were collected.<br />
Results: We report baseline characteristics and safety data from <strong>the</strong> 184 pts treated in<br />
92 French centers. The median age was 67.2 years (46 - 92), ECOG performance<br />
ix314 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
status was 0-1 for 85% of pts, 88% had bone metastases and 21% had visceral<br />
metastases. All <strong>the</strong> pts had received prior docetaxel, 55% had discontinued for<br />
disease progression; 85% of <strong>the</strong> patients received 1-2 lines of chemo<strong>the</strong>rapy before<br />
cabazitaxel. Patients received a median of 3 cycles of cabazitaxel (1-6). Rates of grade<br />
3-4 hematological toxicities were: neutropenia grade≥ 3 (4%), febrile neutropenia<br />
(3%), all resolved. All grade non-hematological toxicities were: nausea (0.5%),<br />
diarrhea (2.7%) and fatigue (0.5%). No treatment-related death was reported.<br />
Conclusion: The ATU program provides additional safety information on cabazitaxel<br />
in <strong>the</strong> real-life setting; <strong>the</strong>y are consistent with <strong>the</strong> TROPIC study safety results. The<br />
incidence of neutropenia grade≥ 3 (4%) and febrile neutropenia (3%) appears to be<br />
lower than expected from <strong>the</strong> TROPIC trial. Therapeutic use protocols such as <strong>the</strong>se<br />
can be helpful for physicians and pharmacists when new <strong>the</strong>rapies become available.<br />
Proactive education of healthcare givers on AEs management could be considered<br />
when new treatments are introduced. 1 Johann Sebastien de Bono et al; Lancet Vol<br />
376 October 2, 2010.<br />
Disclosure: T. Zoubir: Medical Director of Sanofi France. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
956 HEALTH-RELATED QUALITY OF LIFE (QOL) IN PATIENTS WITH<br />
METASTATIC CASTRATION-RESISTANT PROSTATE CANCER<br />
(MCRPC): CABAZITAXEL EARLY ACCESS PROGRAM (EAP)<br />
INTERIM RESULTS FROM CANADA<br />
F. Saad 1 , E. Winquist 2 , M. Girard 3 , S.S. Sridhar 4<br />
1 Medical Oncology, CHUM, Notre-Dame Hospital, Montreal, QC, CANADA,<br />
2 Medical Oncology, University of Western OntarioLondon Regional Cancer<br />
Center, London, ON, CANADA, 3 Biostatistics, Sanofi Canada, Montreal, QC,<br />
CANADA, 4 Medical Oncology, Princess Margaret Hospital, Toronto, ON,<br />
CANADA<br />
Background: QoL and preference/utility data have not been extensively collected in<br />
post-docetaxel (D) mCRPC. Canada collected EQ-5D-3L data in this setting as part<br />
of <strong>the</strong> single-arm multicenter EAP for Cabazitaxel.<br />
Methods: Between May 2011 and February <strong>2012</strong>, 61 evaluable patients (pts) were<br />
enrolled at 9 centers. EQ–5D-3L data was collected and analyzed at baseline and<br />
after every cycle. EQ-5D health state index (HIS) and visual analog scale (VAS) data<br />
were collected. HIS data were converted into utility values using <strong>the</strong> UK tariff from<br />
Dolan 1997. The relationship between baseline ECOG performance status (PS) and<br />
EQ-5D values (HIS and VAS) across visits was examined.<br />
Results: At time of abstract submission, baseline characteristics and EQ-5D data were<br />
available for 58 pts: median age 65 years, 94% of pts ECOG PS 0 or 1, 85% had bone<br />
metastases, and 45% received at least 6 cycles of cabazitaxel. Significant<br />
improvements (p < 0.05) were noted in <strong>the</strong> EQ-5D pain/discomfort (Pain) domain.<br />
From baseline to cycle 6, <strong>the</strong> percentage of pts reporting “no problem” in Pain<br />
improved from 17% to 30%. O<strong>the</strong>r EQ-5D dimensions (anxiety/depression, mobility,<br />
self-care and usual activities) remained stable over <strong>the</strong> course of treatment. Utility<br />
values (HIS and VAS) remained unchanged during treatment, even after stratifying<br />
by baseline PS. However, stratifying by baseline ECOG PS of 0 or 1, 45% and 36% of<br />
pts improved by a minimally important difference (MID) (Pickard 2007) on <strong>the</strong><br />
EQ-5D VAS and HIS by cycle 6, respectively.<br />
Conclusions: Improvements were seen on <strong>the</strong> EQ-5D in <strong>the</strong> Pain domain, with more<br />
than a third of pts reaching a MID on <strong>the</strong> EQ-5D by cycle 6. Improvements in pain,<br />
a common symptom in mCRPC, directly impact pts’ experience of <strong>the</strong>ir disease. The<br />
poster will present updated data.<br />
Disclosure: F. Saad: Dr Fred Saad sits on <strong>the</strong> advisory board for Sanofi Canada and<br />
has received consultant’s honoraria from Sanofi Canada. He is involved in research<br />
projects with Sanofi Canada. E. Winquist: Dr Eric Winquist has received travel<br />
funding and consultant’s honoraria from Sanofi Canada. He is involved in research<br />
projects with Sanofi Canada, M. Girard: Employee with Sanofi Canada, S.S. Sridhar:<br />
Dr S.S. Sridhar sits on Advisory Boards and receives Research Funding from<br />
Sanofi Canada.<br />
957 WHAT CLINICAL AND NON-CLINICAL FACTORS INFLUENCE<br />
PROSTATE CANCER TREATMENT DECISIONS? A NATIONAL<br />
CLINICAL SURVEY<br />
J.M. Fitzpatrick 1 , L. Sharp 2 , M. De Camargo Cancela 3 , H. Comber 4<br />
1 Surgical Professorial Unit, Mater Misericordiae University HospitalUniversity<br />
College Dublin, Dublin, IRELAND, 2 Research Department, National Cancer<br />
Registry, Ireland, Cork, IRELAND, 3 Reseach Department, National Cancer<br />
Registry, Ireland, Cork, IRELAND, 4 National Cancer Registry, Ireland, Cork,<br />
IRELAND<br />
Background: Prostate cancer treatment remains controversial. Several<br />
population-based studies have revealed strikingly different treatment trends by<br />
patient age, suggesting treatment decisions may be influenced heavily by non-clinical<br />
considerations. To investigate factors considered important by clinicians we surveyed<br />
radio<strong>the</strong>rapists and urologists in Ireland.<br />
Materials and methods: All radio<strong>the</strong>rapists and urologists were asked to complete a<br />
postal questionnaire involving patients scenarios rating 68 comorbid conditions<br />
(from ACE-27) in terms of <strong>the</strong>ir impact on treatment recommendations regarding<br />
radical prostatectomy (RP; urologists), radio<strong>the</strong>rapy (RT; radio<strong>the</strong>rapists) and<br />
androgen deprivation <strong>the</strong>rapy (both). Respondents indicated which of 13<br />
non-medical issues impacted on treatment.<br />
Results: 24 urologists (56%) and 12 radio<strong>the</strong>rapists (46%) responded. Performance<br />
assessment tools were used by more radio<strong>the</strong>rapists than urologists (92% vs 20%).<br />
All urologists and 10 radio<strong>the</strong>rapists prescribed ADT. Conditions rated as having<br />
<strong>the</strong> greatest impact on RP or RT treatment decisions were similar: severe<br />
dementia, acute stroke and recent bypass or amputation for gangrene. Non-clinical<br />
factors with <strong>the</strong> greatest impact were: life expectancy (urologists: 100%;<br />
radio<strong>the</strong>rapists: 100%) and patient’s preference (100%, 92%), followed by age for<br />
urologists (96%) and patient quality-of-life for radio<strong>the</strong>rapists (83%). Conditions<br />
impacting on ADT recommendations were: recent pulmonary embolia, acute stroke<br />
and cirrhosis.<br />
Conclusions: Radio<strong>the</strong>rapists were more heterogeneous than urologists in <strong>the</strong>ir views<br />
on which clinical factors influence treatment decisions. Many conditions which<br />
strongly influence treatment are uncommon in patients, <strong>the</strong>refore unlikely to explain<br />
treatment variations. Our findings confirm clinicians consider non-clinical factors<br />
important, suggesting <strong>the</strong>se may influence treatment independently of comorbid<br />
status or fitness for treatment.<br />
Disclosure: J.M. Fitzpatrick: This study was funded by Sanofi-Aventis, L. Sharp:<br />
This study was funded by Sanofi-Aventis, M. De Camargo Cancela: This study was<br />
funded by Sanofi-Aventis, H. Comber: This study ws funded by Sanofi-Aventis<br />
958 OBSERVATIONAL CROSSOVER STUDY OF CABAZITAXEL AND<br />
ABIRATERONE ACETATE IN METASTATIC<br />
DOCETAXEL-REFRACTORY CASTRATION-RESISTANT<br />
PROSTATE CANCER (MDR-CRPC)<br />
S. Bracarda 1 , M. Sisani 2 , A. Hamzaj 2 , F. Marrocolo 1 , S. Del Buono 1<br />
, V. De Angelis 3<br />
1 Department of Oncology, Ospedale San Donato and U.O.C. of Medical<br />
Oncology, Arezzo, ITALY, 2 Oncology, U.O.C. Medical Oncology, Arezzo, ITALY,<br />
3 Haematology-Oncology, S.C. Medical Oncology. Ospedale S.Maria della<br />
Misericordia, Perugia, ITALY<br />
Purpose: In recent years both cabazitaxel (Cbz) and abiraterone acetate (AA) showed<br />
to be efficacious treatment options for patients with mDR-CRPC. However, no data<br />
exist for patients treated with both <strong>the</strong>se drugs. Aim of our study was to analyze<br />
<strong>the</strong>se data in a real world scenario.<br />
Material and methods: Intention-to-treat (ITT) analysis of activity data deriving<br />
from all consecutive patients with mDR-CRPC treated in our unit with prednisone<br />
plus Cbz, AA or both. Primary end point of <strong>the</strong> study was median Progression Free<br />
Survival (mPFS), evaluated according to Prostate Cancer Working Group 2<br />
(PCWG2) criteria.<br />
Results: Here we report characteristics and activity data of 42 patients, 8 treated with<br />
Cbz, 24 with AA and 10 with both drugs. The median age of our study population<br />
was 70.5 years (range, 55-82), median Gleason Score 8 (4-9) and median ECOG PS 0<br />
(0–3); visceral disease was present in 28 cases (66.7%). The mPFS, according to<br />
Kaplan Meier method (KM), was 4.7 months (m) for patients treated with Cbz, not<br />
reached for cases treated with AA and 6.7 m for cases treated with both agents. Of<br />
<strong>the</strong> 10 patients treated with both drugs, 6 received a sequence Cbz-AA and 4 a<br />
sequence AA-Cbz for an overall median PFS of, respectively, 6.7 and 4.6 m.<br />
Conclusions: In our limited experience, both Cbz and AA confirmed an intriguing<br />
activity in <strong>the</strong> mDR-CRPC setting. Moreover, both drugs seems to be active also in a<br />
sequential use. These data should be verified in large size prospective studies to avoid<br />
potential selection biases.<br />
Disclosure: S. Bracarda: Advisory Board Member for Sanofi-Aventis, Jannsen &<br />
Jannsen. Honoraria (Talks) from Sanofi-Aventis. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
959 PROSTATE CANCER PATIENTS MANAGED BY A<br />
MULTIDISCIPLINARY, MULTIPROFESSIONAL TEAM: IS IT<br />
REALLY FEASIBLE AND EFFECTIVE?<br />
T. Magnani 1 , R. Salvioni 2 , S. Villa 3 , L. Bellardita 1 , N. Nicolai 2 , G. Procopio 4 ,<br />
E. Verzoni 4 , N. Bedini 3 , S. Donegani 1 , R. Valdagni 3<br />
1 Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori,<br />
Milan, ITALY, 2 Urologic Surgery Unit, Fondazione IRCCS Istituto Nazionale dei<br />
Tumori, Milan, ITALY, 3 Radio<strong>the</strong>rapy 1, Fondazione IRCCS Istituto Nazionale dei<br />
Tumori, Milan, ITALY, 4 Medical Oncology, Fondazione IRCCS Istituto Nazionale<br />
dei Tumori, Milano, ITALY<br />
The aim of this abstract is to describe <strong>the</strong> multidisciplinary, multiprofessional<br />
management of prostate cancer (PC) patients activated by <strong>the</strong> Prostate Cancer<br />
Programme at Istituto Nazionale dei Tumori, Milan. PC patients should be better<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds400 | ix315
managed in a multidisciplinary (MD) setting since <strong>the</strong>y have multiple <strong>the</strong>rapeutic<br />
and observational options, depending on <strong>the</strong> risk class. The PC Programme was<br />
established in 2004 as a translational project. A MD team with urologists, radiation<br />
oncologists, medical oncologists, psychologists, palliative care experts, uropathologists<br />
and radiologists was built, diagnostic and <strong>the</strong>rapeutic guidelines were shared and<br />
adopted, a MD clinic was started in March 2005 organized in: Friday clinic:<br />
urologist, radiation oncologist and psychologist (medical oncologist on demand)<br />
examine PC patients synchronously Monday case discussion (CC) to share <strong>the</strong> cases,<br />
check quality and application of guidelines, discuss problematic cases on observation<br />
and complex cases seen monodisciplinarily The MD team became multiprofessional<br />
by including a project manager, a secretary, a data manager and a nurse. Results<br />
2760 MD clinics from March 2005 to March <strong>2012</strong>. The organizational model was<br />
modified to better <strong>the</strong> service. Considering <strong>the</strong> % of low risk PC patients referring to<br />
<strong>the</strong> MD clinic (61% in 2009) and on active surveillance protocols (342 patients in<br />
Feb <strong>2012</strong>), we increased resources to better manage this sub-population. The % of<br />
advanced and metastatic PC patients (5% in 2011) induced to organize <strong>the</strong> lists<br />
according to <strong>the</strong> risk class (medical oncologist on demand). Efficacy of <strong>the</strong> MD clinic<br />
is demonstrated in <strong>the</strong> drug <strong>the</strong>rapies prescribed outside our Institution and<br />
terminated by <strong>the</strong> MD team (11%). Efficacy of <strong>the</strong> CC is demonstrated in <strong>the</strong> % of<br />
indications formulated in <strong>the</strong> MD clinics, changed in <strong>the</strong> following CC (6%)<br />
resulting from quality checks of our own performance.<br />
Conclusions: The MD approach is proving successful. Strategies are agreed on, cases<br />
managed multidisciplinarily, critical issues shared. Psychologists help evaluate<br />
education-related and cultural factors in patients’ decisions. The CC discussion is<br />
fundamental to learn <strong>the</strong> MD working, create a shared know how and approach <strong>the</strong><br />
patient as a subject of care ra<strong>the</strong>r than disease to cure. Thanks to Pro ADAMO and<br />
Fond. Monzino for <strong>the</strong> support<br />
Disclosure: All authors have declared no conflicts of interest.<br />
960 CABAZITAXEL EARLY ACCESS PROGRAM (EAP) - CANADIAN<br />
INTERIM Results: SAFETY, QOL, AND UTILITY VALUES IN<br />
METASTATIC CASTRATION RESISTANT PROSTATE CANCER<br />
(MCRPC)<br />
S.S. Sridhar 1 , E. Winquist 2 , S. Hubay 3 , C. St.-Laurent Thibault 4 , H. Assi 5 ,<br />
S. Berry 6 , E. Levesque 7 , N. Aucoin 8 , P. Czaykowski 9 , F. Saad 10<br />
1 Medical Oncology, Princess Margaret Hospital, Toronto, ON, CANADA,<br />
2 Medical Oncology, University of Western OntarioLondon Regional Cancer<br />
Center, London, ON, CANADA, 3 Medical Oncology, Grand River Regional<br />
Cancer Centre, Kitchener, ON, CANADA, 4 Oncology, Sanofi Inc. Canada,<br />
Montreal, QC, CANADA, 5 Medical Oncology, The Moncton Hospital, Moncton,<br />
NB, CANADA, 6 Medical Oncology, Odette Cancer Centre, Toronto, CANADA,<br />
7 Medical Oncology, CHUQ-L’Hotel-Dieu de Quebec, Quebec City, QC,<br />
CANADA, 8 Medical Oncology, Cité-de-la-Santé Hospital, Laval, QC, CANADA,<br />
9 Medical Oncology, Cancer Care Manitoba, Winnipeg, MB, CANADA, 10 Surgery,<br />
CHUM, Notre-Dame Hospital, Montreal, QC, CANADA<br />
Background: Cabazitaxel/Prednisone (CbzP) improves survival in docetaxel resistant<br />
mCRPC. Canadian investigators collected safety and QoL data for patients (pts)<br />
participating in a global single-arm multicenter EAP.<br />
Methods: Between May 2011 and Feb <strong>2012</strong>, 61 evaluable pts were enrolled at 9<br />
centers. Safety and QoL data were collected at baseline and at each cycle. QoL was<br />
assessed using <strong>the</strong> FACT-P and its subscales, EQ 5D-3L, and ESAS questionnaires.<br />
Utility values were derived from <strong>the</strong> EQ 5D-3L. Present pain intensity (PPI) and<br />
analgesic scores were assessed using <strong>the</strong> McGill-Melzack questionnaire. The change<br />
from baseline QoL in individual patients was analyzed.<br />
Results: At <strong>the</strong> time of analysis, baseline characteristics and safety data were available<br />
for <strong>the</strong> first 33 pts. Median age was 65; 94% were ECOG 0/1; 85% had bone<br />
metastases; and 76% had progressed within 3 months of prior docetaxel. Over half<br />
(56%) received at least 5 cycles of CbzP. Main grade 3+ toxicities were anemia 3%,<br />
leukopenia 3%, and febrile neutropenia 3% (prophylactic and <strong>the</strong>rapeutic G-CSF use<br />
was permitted). Incidence of diarrhea (all grades) was 52%, and grade 3+ diarrhea<br />
was 3%. No treatment related deaths were reported. Preliminary analyses showed<br />
stable QoL and derived utility values over time. A pain subscale of FACT-P, showed<br />
improvements in <strong>the</strong> first 4 cycles; PPI scores improved despite stable analgesic use.<br />
Conclusions: In this EAP, reflecting routine clinical practice, <strong>the</strong> main toxicities of<br />
CbzP were similar to <strong>the</strong> TROPIC trial (neutropenia and diarrhea) emphasizing <strong>the</strong><br />
need for close toxicity monitoring. Preliminary QoL and PPI data support a palliative<br />
benefit of CbzP not reported in TROPIC. Updated data with all evaluable pts and<br />
percentages of pts meeting important response thresholds will be presented.<br />
Disclosure: S.S. Sridhar: Dr. Sridhar has served on <strong>the</strong> advisory board for and is<br />
involved in research projects with Sanofi Aventis Canada. E. Winquist: Dr Winquist<br />
has received travel funding and consultant’s honoraria from Sanofi Canada. He is<br />
involved in research projects with Sanofi Canada. C. St.-Laurent Thibault: Ca<strong>the</strong>rine<br />
Saint-Laurent Thibault is an employee of Sanofi Canada Inc. H. Assi: Membership<br />
on an Advisory board, S. Berry: Membership on an advisory board, N. Aucoin:<br />
Membership on an advisory board, F. Saad: Dr Fred Saad sits on <strong>the</strong> advisory board<br />
Annals of Oncology<br />
for Sanofi Aventis Canada and has received consultant\\’s honoraria from Sanofi<br />
Canada. He is involved in research projects with Sanofi Canada. All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
961 UPDATED ANALYSIS OF A COMBINATION HERBAL<br />
SUPPLEMENT TRIAL IN BIOCHEMICALLY RECURRENT<br />
PROSTATE CANCER<br />
J. Pinski 1 , T.B. Dorff 1 ,D.Hawes 1 , D. Tsao-Wei 1 , D.I. Quinn 1 , A. Goldkorn 1 ,<br />
G. Liskovsky 1 , N. Vogelzang 2 , S. Groshen 3 ,L.Ji 1<br />
1 USC Norris Comprehensive Cancer Center, University of Sou<strong>the</strong>rn California,<br />
Keck School of Medicine, Los Angeles, CA, UNITED STATES OF AMERICA,<br />
2 Oncology, US Oncology Nevada, Las Vegas, NV, UNITED STATES OF<br />
AMERICA, 3 Biostatistics, USC Norris Comprehensive Cancer Center,<br />
Los Angeles, CA, UNITED STATES OF AMERICA<br />
Background: After curative local <strong>the</strong>rapy, thousands of men will experience rising<br />
PSA as an early indicator of recurrent prostate cancer. For <strong>the</strong>se men no standard of<br />
care exists, and concern over serious side effects of androgen deprivation (ADT)<br />
makes delaying ADT common. We tested Prostate Health Cocktail (PHC), which<br />
contains vitamins D & E, saw palmetto, lycopene, green tea and soy extracts, in this<br />
population, to see whe<strong>the</strong>r it could induce PSA declines.<br />
Methods: Eligible men had a rising PSA with doubling time (DT) between 3 and 36<br />
months, with no evidence of metastases on CT and bone scan. Treatment included<br />
PHC 3 capsules PO daily for 4 week cycles for a maximum of 1 year. PSA was<br />
repeated after 1 cycle and <strong>the</strong>n every 2 cycles <strong>the</strong>reafter with imaging only as<br />
clinically indicated; <strong>the</strong> primary endpoint was PSA decline at 12 weeks. PSA<br />
progression was defined as 25% increase above baseline/nadir and absolute increase<br />
of 5 ng/mL or return to baseline. Circulating tumor cells (CTCs) were measured at<br />
baseline and after 3 cycles using parylene membrane filters.<br />
Results: A total of 36 patients were enrolled as of January 31, <strong>2012</strong>; 3 were<br />
retrospectively classified as ineligible and were excluded from all analyses except for<br />
toxicity. The median age was 67 (range 54-85) and baseline PSA was 2.9 ng/mL<br />
(1.1-53.2). The median number of cycles was 8 (1-13). Stable PSA was <strong>the</strong> best<br />
response for 25/27 men assessable at 12 weeks (93%) and 11/33 men (33%) had a<br />
PSA decline (1.1%-49.0% decrease). There was no significant change in testosterone<br />
or DHT during treatment. Circulating tumor cells were detected in some of <strong>the</strong><br />
subjects. One patient had grade 3 transaminitis in <strong>the</strong> setting of alcohol<br />
consumption, o<strong>the</strong>rwise <strong>the</strong> toxicities were limited to grade 1 or 2 and related to <strong>the</strong><br />
gastrointestinal and metabolic/laboratory systems.<br />
Conclusion: PHC demonstrated activity in men with biochemical recurrence,<br />
resulting in PSA declines in about a third of cases, and was not associated with<br />
changes in serum androgens or significant toxicities. For <strong>the</strong> first time, we are<br />
reporting that circulating tumor cells can be detected in men with biochemical<br />
recurrence using filter technology.<br />
Disclosure: J. Pinski: I am a co-owner of OncoNatural Solutions Inc, <strong>the</strong> company<br />
which produces <strong>the</strong> Prostate Heath Coctail (PHC). All o<strong>the</strong>r authors have declared<br />
no conflicts of interest.<br />
962TiP CABAZITAXEL PLUS PREDNISONE (CBZP) IN METASTATIC<br />
CASTRATION-RESISTANT PROSTATE CANCER (MCRPC)<br />
PATIENTS PREVIOUSLY TREATED WITH DOCETAXEL (D):<br />
EFFICACY AND SAFETY RESULTS FROM EARLY-ACCESS<br />
PROGRAM (EAP) SINGLE SITE EXPERIENCE<br />
P. Rescigno 1 ,C.D’Aniello 1 , P. Federico 1 , L. Puglia 1 , A. Petremolo 1 ,<br />
C. Cavaliere 1 , C. Buonerba 1 , S. De Placido 2 , G. Di Lorenzo 1<br />
1 Genitourinary Cancer Section and Rare-cancer Center, University Federico II,<br />
Naples, ITALY, 2 Medical Oncology Department, University Federico II, Naples,<br />
ITALY<br />
Background: In <strong>the</strong> phase 3 TROPIC trial, mCRPC pts previously treated with D<br />
had a significant survival and clinical benefit with CbzP, a new tubulin-binding<br />
taxane, compared with mitoxantrone plus prednisone. The clinical benefits observed<br />
supported a global EAP, allowing pts with mCRPC to have access to Cbz prior to its<br />
commercial availability and providing safety and efficacy data in <strong>the</strong> real life<br />
population. We report <strong>the</strong> safety and efficacy results of 32 consecutive pts treated<br />
with CbzP in a single Italian centre.<br />
Methods: Pts recruited from a single centre between March and December 2011<br />
received Cbz 25mg/m2 IV q21 and prednisone 10 mg daily until disease progression,<br />
unacceptable toxicity, physician/pt decision or death. Biochemical and Tumour<br />
response were assessed before cycle 6 and 12. Pain response was assessed in<br />
symptomatic Pts before each cycle.<br />
Results: 32 pts were analyzed; median age was 67 years (≥ 75 years, 18%); 68.8% of<br />
pts had one previous D regimen and 31.2% ≥ 2 regimens, 93.8% had ECOG PS 0-1;<br />
Median number of CbzP cycles was 8; 43.7% had pain at treatment initiation with a<br />
median PSA value of 85 ng/mL. All pts had bone mets, 68% had visceral disease<br />
ix316 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
(visceral and nodes). The most common Grade 3/4 adverse events (AEs) were<br />
neutropenia (64.5%, 20 Pts) leukopenia (45.2%, 14 Pts), and febrile neutropenia<br />
(9.7%, 3 Pts). G3/4 diarrhoea was reported 3.2%, 1 pt. Pain response was 64.3%.<br />
PSA response 6 cycles (32 Pts)<br />
decline ≥50%<br />
PSA response by Gleason (decline >50%)<br />
53%<br />
GS 4-6 ( 9 Pts) 44%<br />
GS 7 (10 Pts) 60%<br />
GS 8-10 (13 Pts)<br />
PSA response by previous D regimen<br />
54%<br />
1 (17 Pts) 12 (71%)<br />
>1 (15 Pts) 5 (33%)<br />
Tumor Response (RECIST) 22 Pts<br />
PR + SD 19 (86.4%)<br />
PD 3 (13.6%)<br />
Conclusions: Our results indicate a high activity of cabazitaxel in terms of PSA,<br />
tumor and pain responses in all subgroups of pts analysed; cabazitaxel shows globally<br />
a clinically manageable safety profile in daily clinical practice.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
963TiP PHASE I TRIAL OF ASG-5ME IN METASTATIC CASTRATION<br />
RESISTANT PROSTATE CANCER (CRPC)<br />
M. Morris 1 , J. Bruce 2 , L. Reyno 3 , B. Anand 3 , A. Hartford 3 , K. Jelaca-Maxwell 3 ,<br />
J. Lackey 3 , M. Eisenberger 4<br />
1 Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, UNITED<br />
STATES OF AMERICA, 2 Medicine, University of Wisconsin Center for Health<br />
Sciences Medical School UW Carbone Cancer Center, Madison, WI, UNITED<br />
STATES OF AMERICA, 3 Development, Agensys, Santa Monica, CA, UNITED<br />
STATES OF AMERICA, 4 Medicine, Sidney Kimmel Comprehensive Cancer<br />
Center at Johns Hopkins Medical Center, Baltimore, MD, UNITED STATES OF<br />
AMERICA<br />
Background: SLC44A4 is a 710 amino acid protein expressed on prostate, pancreas<br />
and o<strong>the</strong>r cancers. SLC44A4 is found in 95% of primary prostate tumors (75%<br />
express moderate to high levels). ASG-5ME is an antibody drug conjugate (ADC)<br />
comprised of a fully human antibody against SLC44A4, conjugated to <strong>the</strong><br />
microtubule-disrupting agent monomethyl auristatin E. ASG-5ME has<br />
dose-dependent cytotoxic effects in vitro and significant anti-tumor activity in<br />
xenograft models. We report results of a phase I study of ASG-5ME for CRPC,<br />
conducted by <strong>the</strong> Prostate Cancer Clinical Trials Consortium.<br />
Methods: Patients (pts) had progressive metastatic CRPC. Prior chemo<strong>the</strong>rapy was<br />
allowed. Treatment cohorts were 0.3, 0.6, 1.2, 1.8, 2.4, 2.7 and 3.0 mg/kg. ASG-5ME<br />
was given IV q3 weeks. Safety, pharmacokinetic properties, anti-tumor effects,<br />
circulating tumor cell (CTC) enumeration, and CTC molecular profiles were assessed.<br />
Pts were treated until disease progression or unacceptable toxicity. Dose limiting<br />
toxicity (DLT) was defined by cycle 1 toxicity.<br />
Results: 26 pts have been treated (3, 3, 3, 3, 6, 6, and 2 pts per respective cohort).<br />
Mean age was 69.5 (range 56-87), median Gleason score 8 (6-10), mean baseline PSA<br />
82.25 (4.4-1987). Pts received a mean of 3.8 doses (1-12). A DLT occurred at 2.7 mg/<br />
kg: Grade (Gr) 4 neutropenia, Gr 3 constipation and diarrhea. 2 DLTs occurred at 3<br />
mg/kg: one with Gr 3 troponin elevation and <strong>the</strong> second with Gr 3 maculopapular<br />
rash, hypoxia, constipation, and Gr 4 neutropenia. Common Gr 1 and 2 adverse<br />
events included fatigue, anorexia, peripheral neuropathy, dyspnea and nausea. Gr 3<br />
events included: fatigue (2 pts), peripheral neuropathy (1), dyspnea (1) and nausea<br />
(1). Serum concentrations of ASG-5ME decreased multi-exponentially and <strong>the</strong><br />
exposure was dose-proportional. The half-life of <strong>the</strong> ADC was 7.01 days<br />
(range-3.93-15.9, n = 17) after <strong>the</strong> first dose and 11.2 days (range-7.75-19.1 days, n =<br />
10) after <strong>the</strong> last dose. PSA declines of >50% were seen in 3/8 pts treated in <strong>the</strong> last 3<br />
cohorts and one >50% decrease in retroperitoneal nodes.<br />
Conclusions: The maximum tolerated dose (MTD) was exceeded at 3 mg/kg. The<br />
drug appears to have anti-cancer activity above 2.4 mg/kg.<br />
Disclosure: L. Reyno: The author is <strong>the</strong> CMO and Sr Vice President of Agensys, Inc,<br />
B. Anand: The author is a director of Agensys, IncA. Hartford: The author is a<br />
director of Agensys, Inc, K. Jelaca-Maxwell: The author is a paid safety consultant of<br />
Agensys, Inc, J. Lackey: The author is a director of Agensys, Inc. All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
964TiP ARN-509 IN MEN WITH METASTATIC<br />
CASTRATION-RESISTANT PROSTATE CANCER (CRPC)<br />
D. Rathkopf 1 , E.S. Antonarakis 2 , N.D. Shore 3 , R. Tutrone 4 , J. Alumkal 5 ,<br />
C.J. Ryan 6 , M. Saleh 7 , R. Hauke 8 , E. Chow-Maneval 9 , H.I. Scher 1<br />
1 Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, UNITED<br />
STATES OF AMERICA, 2 Sidney Kimmel Comprehensive Cancer Center, Johns<br />
Hopkins University, Baltimore, MD, UNITED STATES OF AMERICA, 3 Urology,<br />
Carolina Urologic Research Center, Myrtle Beach, SC, UNITED STATES OF<br />
AMERICA, 4 Urology, Chesapeake Urology Research Associates, Baltimore, MD,<br />
UNITED STATES OF AMERICA, 5 Medicine, Oregon Health & Science University<br />
Knight Cancer Institute, Portland, OR, UNITED STATES OF AMERICA, 6 Ucsf<br />
Helen Diller Family Comprehensive Cancer Center, University of California,<br />
San Francisco, San Francisco, CA, UNITED STATES OF AMERICA, 7 Medicine,<br />
Georgia Cancer Specialists, Atlanta, GA, UNITED STATES OF AMERICA,<br />
8 Medicine, Nebraska Cancer Specialists, Omaha, NE, UNITED STATES OF<br />
AMERICA, 9 Clinical Development, Aragon Pharmaceuticals, San Diego, CA,<br />
UNITED STATES OF AMERICA<br />
Background: ARN-509 is a novel second-generation anti-androgen that binds<br />
directly to <strong>the</strong> ligand-binding domain of <strong>the</strong> androgen receptor, impairing nuclear<br />
translocation and DNA binding. The Phase II portion of a multicenter Phase I/II<br />
study is evaluating <strong>the</strong> activity of ARN-509 in 3 distinct patient populations of men<br />
with CRPC: 1) non-metastatic treatment-naïve CRPC; 2) mCRPC treatment-naïve<br />
(tx-naïve); and 3) mCRPC abiraterone acetate pre-treated (AA). Preliminary results<br />
for <strong>the</strong> 2 cohorts of patients with metastatic CRPC are presented here.<br />
Methods: All patients had metastatic CRPC with progressive disease based on rising<br />
PSA and/or imaging. No prior chemo<strong>the</strong>rapy for metastatic prostate cancer was<br />
allowed. Patients on <strong>the</strong> AA pre-treated cohort had to have been treated with AA for<br />
at least 6 months. All patients received ARN-509 at <strong>the</strong> recommended Phase II dose<br />
of 240 mg/day (Rathkopf et al, GU ASCO <strong>2012</strong>). The primary endpoint was PSA<br />
response rate at 12 weeks according to <strong>the</strong> Prostate Cancer Working Group 2 Criteria<br />
in each of <strong>the</strong> treatment groups. Secondary endpoints included safety, time to PSA<br />
progression and objective response rates. PSA assessments were collected every 4<br />
weeks and tumor imaging was performed every 16 weeks.<br />
Results: To date, 32 patients have been enrolled: 25 on <strong>the</strong> tx-naïve and 7 on <strong>the</strong><br />
post-AA cohorts, respectively. The combined median age was 67 (range 51-91) and at<br />
baseline, patients presented with ECOG performance status 0 (55%), Gleason Score 8-10<br />
(54%), and median PSA of 14.7 (tx-naïve) and 69.6 (post-AA) ng/mL. All patients<br />
received prior treatment with a LHRH analog with or without a first-generation<br />
anti-androgen. At a median treatment duration of 16 weeks, 4 patients discontinued <strong>the</strong><br />
study due to disease progression, 2 in each cohort. The most common treatment-related<br />
adverse events (AE) were abdominal pain (36%), diarrhea (19%), nausea (16%) and<br />
fatigue (10%). There was only 1 treatment-related Grade 3 AE of abdominal pain. At 12<br />
weeks, <strong>the</strong> PSA response was 91% (tx-naïve) and 60% (post-AA), respectively.<br />
Conclusion: In men with CRPC, ARN-509 is safe and well tolerated with promising<br />
preliminary activity in metastatic, chemo-naïve patients both before and after<br />
treatment with abiraterone.<br />
Disclosure: E. Chow-Maneval: Dr. Chow Maneval is an employee of Aragon and<br />
holds stock in <strong>the</strong> company. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
965TiP A PHASE II STUDY (PERSEUS) OF TWO DOSES OF EMD<br />
525797 (DI17E6) IN PATIENTS (PTS) WITH ASYMPTOMATIC<br />
OR MILDLY SYMPTOMATIC METASTATIC<br />
CASTRATE-RESISTANT PROSTATE CANCER (MCRPC)<br />
K. Miller 1,* , M. Hussain 2,* , G. Mordenti 3 , H. Lannert 4<br />
1 Charité, Department of Urology, Berlin, GERMANY, 2 University of Michigan,<br />
Comprehensive Cancer Center, Ann Arbor, MI, UNITED STATES OF AMERICA,<br />
3 Merck Serono S.A., Global Biostatistics, Geneva, SWITZERLAND, 4 Merck<br />
KGaA, Global Clinical Development Unit Oncology, Darmstadt, GERMANY, * on<br />
behalf of <strong>the</strong> PERSEUS Study Group<br />
Purpose: Expression and function of αv-integrins are deregulated in prostate cancer,<br />
and αv-integrins are thought to play an important role in prostate cancer metastasis.<br />
EMD 525797 (DI17E6) is a humanized monoclonal IgG2 antibody specifically<br />
directed against αv integrin receptors (αvß1, αvß3, αvß5, αvß6, and αvß8). It has<br />
been shown to target tumor cells, <strong>the</strong> tumor’s environment (e.g. osteoclasts and<br />
osteoblasts), as well as angiogenic blood vessels. Previous studies with EMD 525797<br />
have shown a favorable tolerability profile in healthy volunteers and in mCRPC pts.<br />
A phase II trial is investigating <strong>the</strong> anticancer activity of 2 dose levels of EMD<br />
525797 in asymptomatic or mildly symptomatic mCRPC pts.<br />
Methods: Adult pts with CRPC who show radiologic progression of bone lesions<br />
with/without soft tissue lesions within 28 days prior to randomization are eligible for<br />
inclusion. Exclusion criteria are: acute pathologic fracture, spinal cord compression,<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds400 | ix317
or hypercalcemia at screening; prior chemo<strong>the</strong>rapy, biologic, or experimental <strong>the</strong>rapy<br />
for mCRPC; or radio<strong>the</strong>rapy to bone lesions and/or orthopedic surgery for<br />
pathologic fractures. A total of 216 pts receiving standard of care (luteinizing<br />
hormone-releasing hormone [LHRH] antagonists) and bisphosphonate <strong>the</strong>rapy will<br />
be randomized 1:1:1 to receive in a blinded manner placebo, 1500 mg or 750 mg<br />
EMD 525797 (all 1-h intravenous [IV] infusions) on day 1 of every 3-week cycle<br />
until radiographic disease progression (PD). At progression, <strong>the</strong>rapy will be<br />
unblinded and pts in <strong>the</strong> placebo group who show asymptomatic or mildly<br />
symptomatic radiographic confirmed PD can receive open-label <strong>the</strong>rapy with 1500<br />
mg EMD 525797. The primary endpoint is composite progression-free survival,<br />
defined as <strong>the</strong> time (months) from randomization date to first documented sign of<br />
Annals of Oncology<br />
objective radiographic PD or death from any cause. Secondary endpoints include<br />
efficacy (e.g. overall survival and time to progression), safety, <strong>the</strong> pharmacokinetic<br />
profile of EMD 525797, and <strong>the</strong> exploration of a relationship between <strong>the</strong> number of<br />
circulating tumor cells and clinical outcomes. As of April <strong>2012</strong>, 106 pts have entered<br />
<strong>the</strong> trial.<br />
Disclosure: K. Miller: Membership on an advisory board for Merck KGaA,<br />
Darmstadt, Germany, G. Mordenti: Employee of Merck KGaA, Darmstadt,<br />
Germany, H. Lannert: Employee of Merck KGaA, Darmstadt, Germany. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
ix318 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
gynecological cancers<br />
966O BRIVANIB (B) IN ADVANCED OVARIAN CANCER (OC): SUBSET<br />
RESULTS OF A PHASE 2 RANDOMIZED DISCONTINUATION<br />
TRIAL (RDT)<br />
S.B. Kaye 1 , L.L. Siu 2 , J. Jassem 3 , J. Medioni 4 , P. M.M.B. Soetekouw 5 ,<br />
S. Slater 6 , C. M. Rudin 7 , G.K. Schwartz 8 , M. De Jonge 9 ,P.O’Dwyer 10 ,<br />
C. Baudelet 11 , A. Chen 12 , M. J. Ratain 13<br />
1 Royal Marsden Hospital and Institute of Cancer Research, Sutton, UNITED<br />
KINGDOM, 2 Department of Medical Oncology, Princess Margaret Hospital,<br />
Toronto, CANADA, 3 Oncology and Radio<strong>the</strong>rapy, Medical University of Gdansk,<br />
Gdansk, POLAND, 4 Département d’Oncologie Médicale, Hôpital Européen<br />
Georges Pompidou, Paris, FRANCE, 5 Division of Medical Oncology, Maastricht<br />
University Medical Center, Maastricht, NETHERLANDS, 6 Department of Medical<br />
Oncology, Beatson West of Scotland Cancer Center, Glasgow, UNITED<br />
KINGDOM, 7 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins<br />
University, Baltimore, MD, UNITED STATES OF AMERICA, 8 Melanoma and<br />
Sarcoma Service, Memorial Sloan-Kettering Cancer Center, New York, NY,<br />
UNITED STATES OF AMERICA, 9 Department of Medical Oncology, Erasmus<br />
University Medical Center, Rotterdam, NETHERLANDS, 10 Abramson Cancer<br />
Center, University of Pennsylvania, Philadelphia, PA, UNITED STATES OF<br />
AMERICA, 11 Research and Development, Brstol-Myers Squibb, Braine-l’Alleud,<br />
BELGIUM, 12 Research and Development, Bristol-Myers Squibb, Wallingford, CT,<br />
UNITED STATES OF AMERICA, 13 Department of Medicine, University of<br />
Chicago, Chicago, IL, UNITED STATES OF AMERICA<br />
Background: Brivanib (B) is an oral once daily selective dual inhibitor of FGF<br />
and VEGF signaling with preclinical activity against various tumor types. An<br />
RDT assessed B in pts with advanced solid tumors; data showing activity in<br />
sarcoma pts were reported previously, and data for <strong>the</strong> OC pts are presented<br />
here.<br />
Methods: OC pts progressing after previous treatment received open-label B 800 mg<br />
QD for a 12-wk lead-in period and were assessed by CT/MRI. Pts with complete<br />
(CR) or partial response (PR) continued on open-label B, those with progressive<br />
disease (PD) went off study. Pts with stable disease (SD) were randomized 1:1 to B<br />
or placebo (P) until PD or intolerance. Pts with PD on P could crossover to<br />
open-label B. Endpoints included progression-free survival (PFS) in randomized<br />
pts, objective response rate (ORR), disease control rate (DCR = ORR + SD), and<br />
safety.<br />
Results: One hundred twenty-six pts (63% with >3 prior systemic regimens; 88%<br />
FGF2 + by IHC) entered 12-wk lead-in and received B. At wk 12, 12 pts had PR and<br />
43 pts had SD (ORR 10%; DCR 44%). Three of 18 pts pretreated with bevacizumab<br />
(BEV) achieved PR at wk 12. After 12 wks, 49 continued on <strong>the</strong> study, 10 with PR<br />
remained on open-label B; and 39 were randomized to ei<strong>the</strong>r B (n = 19) or P (n =<br />
20). Two pts with PR were randomized in error. Among randomized pts (n = 39),<br />
median PFS was 4 mo for B vs 2 mo for P with HR of 0.54 (90% CI: 0.28-1.03;<br />
p = 0.11). Among randomized FGF2 + pts (n = 36), HR was 0.56 (90% CI:<br />
0.29-1.07; p = 0.14). In <strong>the</strong> randomized phase, 3 additional pts achieved PR<br />
(overall population: 15 PRs; ORR 12%). The most common (≥5%) grade ≥3 AEs<br />
were increased ALT (20%) and AST (14%), fatigue (12%), hyponatremia (9%),<br />
as<strong>the</strong>nia (7%), diarrhea (7%), hypertension (7%), abdominal pain (6%), and<br />
decreased appetite (6%). Discontinuation due to treatment-related AE occurred in<br />
13% of pts.<br />
Conclusions: The observed PFS prolongation with B vs P, ORR and DCR in this<br />
RDT indicate clinical activity of B in pts with heavily pretreated OC, including those<br />
with prior BEV. The high frequency of FGF2 + pts precluded <strong>the</strong> assessment of FGF2<br />
as a predictive biomarker. The safety profile was acceptable. These results support<br />
fur<strong>the</strong>r investigation of B in OC, potentially in pts with prior BEV.<br />
Disclosure: S.B. Kaye: Consultant for Astra Zeneca, Clovis, GSK, J&J, Pfizer Roche<br />
advisory boards Received payment from Roche for development of educational<br />
presentations L. Siu: Received research funding from Bristol-Myers Squibb J.<br />
Jassem: Advisory Board Member for Bristol-Myers Squibb C.M. Rudin:<br />
Consultancy for Oncothyreon P.J. O’Dwyer: Research funding and honorarium<br />
from Bristol-Myers Squibb Company. C. Baudelet: Employment and stock<br />
ownership of Bristol-Myers Squibb Company. A. Chen: Employment and stock<br />
ownership of Bristol-Myers Squibb Company. M.J. Ratain: Research funding<br />
from Bristol-Myers Squibb Company All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
Annals of Oncology 23 (Supplement 9): ix319–ix333, <strong>2012</strong><br />
doi:10.1093/annonc/mds401<br />
967O UPDATED OVERALL SURVIVAL ANALYSIS IN OCEANS, A<br />
RANDOMIZED PHASE 3 TRIAL OF GEMCITABINE (G) +<br />
CARBOPLATIN (C) AND BEVACIZUMAB (BV) OR PLACEBO (PL)<br />
FOLLOWED BY BV OR PL IN PLATINUM-SENSITIVE<br />
RECURRENT EPITHELIAL OVARIAN (ROC), PRIMARY<br />
PERITONEAL (PPC), OR FALLOPIAN TUBE CANCER (FTC)<br />
C. Aghajanian 1 , L.R. Nycum 2 , B. Goff 3 , H. Nguyen 4 , A. Husain 5 , S.V. Blank 6<br />
1 Gynecologic Medical Oncology Service Memorial Sloan-Kettering Cancer<br />
Center New York NY UNITED STATES OF AMERICA, 2 Department of Obstetrics<br />
Gynecology Forsyth Regional Cancer Center Winston-Salem NC UNITED<br />
STATES OF AMERICA, 3 Department of Obstetrics Gynecology University of<br />
Washington School of Medicine Seattle WA UNITED STATES OF AMERICA,<br />
4 Biostatistics Genentech Inc. South San Francisco CA UNITED STATES OF<br />
AMERICA, 5 Avastin Ovarian Cancer Program Genentech Inc. South<br />
San Francisco CA UNITED STATES OF AMERICA, 6 Division of Gynecologic<br />
Oncology NYU School of Medicine New York NY UNITED STATES OF AMERICA<br />
Background: In OCEANS, BV in combination with GC resulted in a statistically<br />
significant and clinically meaningful improvement in PFS in patients (pts) with<br />
platinum-sensitive (Plat-S) ROC (median PFS, 12.4 vs 8.4 months; HR = 0.484;<br />
P < .0001). These results were supported by <strong>the</strong> overall response rate (ORR), duration<br />
of response (DOR), and independent review committee (IRC) analyses. At <strong>the</strong> time<br />
of <strong>the</strong> final PFS analysis, <strong>the</strong> OS data were still not mature. Additional OS updates<br />
have been performed; here we present <strong>the</strong> 3rd interim OS analysis.<br />
Methods: Eligibility criteria included first recurrence of Plat-S OC, PPC, or FTC with<br />
an ECOG PS of 0 or 1, no prior BV or chemo<strong>the</strong>rapy for ROC, and measurable<br />
disease. Pts were randomized 1:1 to arm A: GC (G [1000 mg/m2, days 1 and 8] and<br />
C [AUC 4, day 1], q3w for 6–10 cycles) + concurrent PL (q3w), followed by PL until<br />
disease progression (PD) or unacceptable toxicity; or arm B: GC + concurrent BV<br />
(15 mg/kg q3w), followed by BV until PD or unacceptable toxicity. The primary end<br />
point was investigator-assessed PFS by RECIST. Secondary end points included ORR,<br />
OS, DOR, and safety. The 3rd interim OS analysis was conducted with a data cutoff<br />
date of March 30, <strong>2012</strong>.<br />
Results: As of <strong>the</strong> data cutoff date, 286 events (59% of pts) had occurred. There was no<br />
difference in OS between <strong>the</strong> arms, with an HR of 0.960 (95% CI, 0.760–1.214; log-rank<br />
P = 0.736). With a median follow-up of 42 months, median OS was 33.7 months in <strong>the</strong><br />
GC + PL arm and 33.4 months in <strong>the</strong> GC + BV arm. There was no difference in <strong>the</strong><br />
number of grade 5 treatment-emergent adverse events between arms (1 in each), <strong>the</strong><br />
number of deaths was balanced between arms, and <strong>the</strong> cause of death in <strong>the</strong> majority of<br />
cases was PD in both arms. 89% and 86% of pts received subsequent <strong>the</strong>rapy (including<br />
BV in 39% and 22%) in <strong>the</strong> PL and BV arms, respectively.<br />
Conclusions: These data provide assurance that <strong>the</strong>re is no detriment to OS with<br />
<strong>the</strong> addition of BV in this setting, and supports <strong>the</strong> positive benefit:risk ratio of <strong>the</strong><br />
GC + BV regimen in significantly improving PFS in patients with platinum-sensitive<br />
ROC.<br />
Disclosure: L.R. Nycum: Dr. Nycuum was a member of <strong>the</strong> Avastin-Ovary advisory<br />
board for Genentech for a contract of 1 year. The contract ended <strong>the</strong> end of March<br />
<strong>2012</strong>. H. Nguyen: Hoa Nguyen is an employee of Genentech and owns stock in<br />
Roche. A. Husain: Dr. Husain is an employee of Genentech and holds stock<br />
ownership (Roche). All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
969PD NATURAL HISTORY OF SEROUS OVARIAN CARCINOMA:<br />
HIGH GRADE VERSUS LOW GRADE AND CARCINOMAS<br />
WITH BRCA MUTATIONS<br />
S. Ayers 1 , T.T. Tun 1 , N. Mescallado 1 , A. Wright 1 , D.G.R. Evans 2 , A. Clamp 1 ,<br />
G.C. Jayson 1 , J. Hasan 1<br />
1 Medical Oncology, The Christie NHS Foundation Trust, Manchester, UNITED<br />
KINGDOM, 2 Regional Genetic Service, St Mary’s Hospital, Manchester, UNITED<br />
KINGDOM<br />
Serous carcinomas are <strong>the</strong> commonest histological subtype of epi<strong>the</strong>lial ovarian<br />
cancer (EOC) and associated with BRCA mutations. In this study we analysed<br />
presentation and treatment-related outcomes of patients with high-grade(HGSC) and<br />
low-grade serous carcinomas (LGSC) and <strong>the</strong>ir relationship with BRCA mutations.<br />
Study design: A retrospective cohort study was carried out. Patients diagnosed with<br />
serous ovarian carcinoma from 2005-2010 were identified. A separate database was<br />
accessed to identify BRCA carriers ever treated at <strong>the</strong> Christie Hospital, UK.<br />
Individual patient data was analysed.<br />
Results: 391 patients were identified including 151 with BRCA mutations.<br />
Preliminary data on 303 cases is discussed. Mature data will be presented at <strong>the</strong><br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com<br />
abstracts
meeting. The prevalence of LGSC is low. They present a decade earlier than HGSC<br />
(median age 50 vs 64) and fewer patients have advanced disease at first presentation<br />
(50%). The relapse rate is significantly less than with HGSC (23% vs 64%). Fewer<br />
patients with LGSC maintained platinum-sensitivity at first (15% vs 45%) and<br />
subsequent relapse (4% vs 20%). The median age of ovarian cancer patients with<br />
BRCA mutations was 54. 66% were BRCA1 carriers. The predominant histological<br />
subtype was serous (50%). 25% were poorly differentiated carcinomas. 53% had<br />
FIGO III/IV disease at presentation. At <strong>the</strong> time of analysis over half of patients with<br />
BRCA mutations and HGSC had died compared to 30% with LGSC. BRCA carriers<br />
maintained platinum-sensitivity for a greater period of time and lived longer<br />
compared to patients with sporadic HGSC or LGSC. The median times to<br />
development of platinum-resistance for BRCA carriers, HGSC and LGSC were 139,<br />
79 and 113 weeks respectively. The median overall survival times for <strong>the</strong> three groups<br />
were 367, 159 and 182 weeks respectively. BRCA2 carriers did better than BRCA1<br />
patients. None of <strong>the</strong> LGSC were associated with BRCA mutations.<br />
Conclusion: The presentation and natural history of LGSC is distinct to that of<br />
HGSC. BRCA carriers present at an earlier age and have better survival outcomes<br />
when compared to patients with sporadic serous ovarian carcinoma.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
970PD ANALYSIS OF GENE DOSAGE ABERRATIONS OF ERBB<br />
ONCOGENE FAMILY IN ENDOMETRIAL CANCER<br />
A.M. Supernat 1 , Z. Urban 1 , S. Lapinska-Szumczyk 2 , S. Sawicki 2 , D. Wydra 2 ,A.<br />
J. Zaczek 1<br />
1 Department of Medical Biotechnology, Medical University of Gdansk, Gdansk,<br />
POLAND, 2 Department of Gynaecology, Gynaecological Oncology and<br />
Gynaecological Endocrinology, Medical University of Gdansk, Gdansk, POLAND<br />
Introduction: ERBB (EGFR, epidermal growth factor receptor) family consists of<br />
four tyrosine kinase receptors: ERBB1, ERBB2, ERBB3 and ERBB4, which form a<br />
complex network of interacting signal transduction pathways. Excessive activation of <strong>the</strong><br />
ERBB network, often found in tumors, is associated with rapid growth, proliferation,<br />
cell survival and also poor patient prognosis. Data about <strong>the</strong> importance of ERBB<br />
network in endometrial cancer is scarce. The purpose of this study was to determine<br />
<strong>the</strong> gene dosages of all <strong>the</strong> ERBB genes in endometrial cancer in <strong>the</strong> context of mutual<br />
dependence as well as clinicopathological parameters.<br />
Materials and methods: The study group included 144 premenopausal and<br />
postmenopausal endometrial cancer patients, staged I-IV. Fresh frozen specimens,<br />
derived from primary tumors, were used as material for molecular analysis. Relative<br />
gene dosages of ERBB1, ERBB2, ERBB3 and ERBB4 were assessed by SYBR<br />
Green-based quantitative PCR, using ΔΔCt method.<br />
Results: Gene dosages of individual ERBB genes correlated with each o<strong>the</strong>r.<br />
Particularly strong correlation occurred in case of ERBB2 and ERBB3 (p = 0.002),<br />
ERBB2 and ERBB4 (p T single nucleotide<br />
polymorphism (SNP) within <strong>the</strong> promoter of HMOX1 gene.<br />
Methods: The study included 135 patients (median age, 54 years; 95% CI, 39-69)<br />
with stage I-IV epi<strong>the</strong>lial ovarian cancer who underwent cytoreductive surgery<br />
followed by standard paclitaxel/platinum analogue chemo<strong>the</strong>rapy. Patients DNA was<br />
routinely isolated from <strong>the</strong> peripheral blood and -413A > T SNP was genotyped using<br />
specific SNP Genotyping Assay (Applied Biosystems).<br />
Results: The respective frequencies of -413A > T SNP AA, AT and TT genotypes<br />
within <strong>the</strong> patients’ group were 34.1% (46/135), 46.7% (63/135) and 19.3% (26/135)<br />
Annals of Oncology<br />
and were similar to distribution within <strong>the</strong> general population control group.<br />
Kaplan-Meier analysis has revealed that AA genotype was associated with significantly<br />
longer progression free survival time. The median progression free survival time was<br />
22.2 months in AA harboring patients and 14.5 months in patients with AT + TT<br />
genotype (p = 0.033 by log-rank test). AA genotype was also significantly associated<br />
with longer overall survival time. Three-year overall survival in AA and AT + TT group<br />
was 77.9% and 52.5%, respectively (p = 0.014).<br />
Conclusions: The results of our study show for <strong>the</strong> first time that response to <strong>the</strong><br />
first line treatment and clinical outcome of ovarian cancer patients with standard<br />
paclitaxel/platinum analogue chemo<strong>the</strong>rapy might be associated with functional<br />
-413A > T SNP in <strong>the</strong> HMOX1 gene. This finding may be of practical importance for<br />
prognostication and may suggest that HMOX-1 is a potential target for a supportive<br />
clinical intervention.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
972PD EFFICACY OF PLATINUM PLUS GEMCITABINE (G) IN<br />
PLATINUM-RESISTANT (R) COMPARED TO<br />
PLATINUM-SENSITIVE (S) OVARIAN CANCER: THE ROYAL<br />
MARSDEN EXPERIENCE<br />
A. George 1 , N. Tunariu 2 , N. Wilkinson 3 , S. Gupta 4 , M.E. Gore 5 , S.B. Kaye 6 ,<br />
S. Banerjee 7<br />
1 Dept of Medicine, Royal Marsden NHS Foundation Trust and Institute of Cancer<br />
Research ICR, Sutton, UNITED KINGDOM, 2 Radiology Department, Royal<br />
Marsden NHS Foundation Trust and <strong>the</strong> Institute of Cancer Research ICR,<br />
Sutton, UNITED KINGDOM, 3 Gynaecology Unit, Royal Marsden NHS Foundation<br />
Trust and Institute of Cancer Research ICR, Sutton, UNITED KINGDOM,<br />
4 Statistics Department, Royal Marsden NHS Foundation Trust, London, UNITED<br />
KINGDOM, 5 Department of Medicine, Royal Marsden Hospital NHS Foundation<br />
Trust, London, UNITED KINGDOM, 6 Dept. of Medicine, Institute of Cancer<br />
Research, Sutton, UNITED KINGDOM, 7 Department of Medicine, Royal Marsden<br />
HospitalNHS Foundation Trust, London, UNITED KINGDOM<br />
Background: Carboplatin plus gemcitabine (GC) is approved in S relapsed ovarian<br />
cancer. The likelihood of response to platinum in R relapse (< 6months treatment free<br />
interval) is perceived to be low. Rechallenge with platinum-based chemo<strong>the</strong>rapy is not<br />
routinely used in this setting. However, recent experience suggests that GC should be<br />
considered. Our aims were to assess <strong>the</strong> efficacy of GC in R patients, compare this with<br />
S patients and explore potential factors predicting clinical outcome.<br />
Method: Patients who started GC (C AUC 4 D1, G 800-1000 mg/m 2 D1, D8 q3wk)<br />
for relapsed ovarian, peritoneal or fallopian tube carcinoma between 01/01/10 and<br />
01/04/12 were analysed retrospectively. The primary endpoint was response rate<br />
(RR). Secondary endpoints included GCIG CA125 response and time to progression.<br />
The time between last platinum and first dose of GC (LPGCI) was assessed as a<br />
predictor of response to treatment.<br />
Results: 63 patients (33 S; 29 R; 1 platinum-refractory) were evaluable: age (median,<br />
range) S 57 (34-74), R 58 (34-79); prior lines of chemo<strong>the</strong>rapy (median, range) S 1.5<br />
(1-12), R 3.5 (1-6); 83% high grade serous; 22% BRCA 1/2 germline mutation; 19%<br />
prior PARP inhibitor, 11% received cisplatin due to carboplatin hypersensitivity. The<br />
LPGCIs were (median, range) S 12.3 months (7.0-138), R 11.2 months (2.3-40). The<br />
differences in RR between S and R patients were not statistically significant (RECIST<br />
RR S 74%, R 57% p = 0.17; GCIG CA125 S 79% R 67% p = 0.31). Treatment was<br />
generally well tolerated. However, omission of D8 G on ≥2 cycles was required in<br />
16% due to toxicity (myelosuppression and fatigue). At <strong>the</strong> time of analysis, 78% had<br />
no evidence of disease progression. LPGCI was not predictive of response (p = 0.60,<br />
95% CI 0.97 – 1.04).<br />
Conclusions: The level of activity of GC in R patients is equivalent to that expected<br />
in S patients. This may relate to <strong>the</strong> potential for G to overcome platinum resistance.<br />
The relevance of LPGCI needs to be explored fur<strong>the</strong>r. Fur<strong>the</strong>r clinical outcome<br />
analyses and data on potential predictive factors will be presented. GC should now<br />
be considered a valid option for patients with platinum-resistant ovarian cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
973PD DOSE-DENSE WEEKLY PACLITAXEL AND CARBOPLATIN IS<br />
MORE COST-EFFECTIVE THAN BEVACIZUMAB PLUS<br />
TRIWEEKLY PACLITAXEL AND CARBOPLATIN FOR THE<br />
PRIMARY TREATMENT OF ADVANCED OVARIAN CANCER<br />
K. Harano 1 , T. Shiroiwa 2 , M. Watanabe 3 , K. Suzuki 3 , T. Fukuda 4 , S. Watanabe 3 ,<br />
N. Katsumata 1<br />
1 Department of Medical Oncology, Nippon Medical School Musashikosugi<br />
Hospital, Kawasaki city, JAPAN, 2 Department of Hygiene and Public Health,<br />
Teikyo University School of Medicine, Tokyo, JAPAN, 3 Consulting Division,<br />
Global Health Consulting Japan, Tokyo, JAPAN, 4 Center for Public Health<br />
Informatics, National Institute of Public Health, Saitama, JAPAN<br />
Purpose: To determine whe<strong>the</strong>r dose-dense weekly paclitaxel and carboplatin (ddPC)<br />
is cost effective compared to bevacizumab plus triweekly paclitaxel and carboplatin<br />
(PCB) for <strong>the</strong> primary treatment of advanced ovarian cancer.<br />
ix320 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Methods: A cost-effectiveness analysis compared three treatments: 6 cycles of<br />
paclitaxel and carboplatin (PC), 6 cycles of PC plus bevacizumab followed by 12<br />
cycles of maintenance bevacizumab (PCB), and 6 cycles of dose-dense weekly<br />
paclitaxel and carboplatin (ddPC). Data were taken from reported results of ICON7<br />
(PC and PCB) and JGOG3016 (ddPC). Actual and estimated costs of treatment plus<br />
costs of complications were established for each regimen. Progression-free survival and<br />
rates of complications were estimated based on <strong>the</strong> results of clinical trials. Incremental<br />
cost-effective ratios (ICER) per progression-free life-year saved (PFLYS) were estimated.<br />
Results: The ICER for ddPC was $5,000 per PFLYS compared to PC. For PCB<br />
compared to PC, <strong>the</strong> ICER was $285,000 per PFLYS. When compared<br />
simultaneously, PCB was more costly and less effective than ddPC.<br />
Conclusions: In this model, dose-dense weekly paclitaxel and carboplatin is more<br />
cost effective than PCB for <strong>the</strong> treatment of advanced ovarian cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
974PD A PHASE 1 STUDY OF THE ANTI-ERBB3 ANTIBODY MM-121<br />
IN COMBINATION WITH WEEKLY PACLITAXEL IN PATIENTS<br />
WITH ADVANCED GYNECOLOGICAL AND BREAST CANCERS<br />
J. Liu 1 , R. Patel 2 ,G.Kato 3 , U. Matulonis 1 , V. Moyo 4 , K. Riahi 4 , J. Pearlberg 5 ,<br />
A. Czibere 4 , S. Isakoff 6<br />
1 Gynecology, Dana Farber Cancer Institute, Boston, MA, UNITED STATES OF<br />
AMERICA, 2 Research Department, Comprehensive Blood and Cancer Center,<br />
Bakersfield, CA, UNITED STATES OF AMERICA, 3 Research, Pinnacle Oncology<br />
Hematology, Scottsdale, AZ, UNITED STATES OF AMERICA, 4 Clinical<br />
Development, Merrimack Pharmaceuticals, Cambridge, MA, UNITED STATES<br />
OF AMERICA, 5 Sanofi Oncology, Sanofi, Cambridge, MA, UNITED STATES OF<br />
AMERICA, 6 Department of Hematology and Medical Oncology, Massachusetts<br />
General Hospital, Boston, MA, UNITED STATES OF AMERICA<br />
Background: MM-121 is a fully human monoclonal antibody targeting <strong>the</strong><br />
epidermal growth factor receptor family member ErbB3. ErbB3 has been widely<br />
implicated in driving cancer growth and in <strong>the</strong> development of resistance to<br />
conventional chemo<strong>the</strong>rapies and targeted agents across multiple malignancies.<br />
Single agent weekly paclitaxel is a standard regimen for patients with advanced<br />
gynecological and metastatic breast cancers. Here we present results from an<br />
ongoing Phase 1 study evaluating <strong>the</strong> combination of MM-121 and weekly<br />
paclitaxel.<br />
Methods: A total of 24 patients with ei<strong>the</strong>r platinum resistant ovarian cancer,<br />
metastatic endometrial cancer, or HER2 negative metastatic breast cancer, were<br />
treated in a dose escalation (12 pts) or expansion cohort (12 pts). Patients were<br />
treated until disease progression or intolerable toxicity. Response was assessed every<br />
eight (8) weeks according to RECIST 1.1. In <strong>the</strong> dose-expansion cohorts, pre- and<br />
post-treatment fresh tumor biopsies were obtained from 12 patients to assess ErbB3<br />
signaling status and its potential as a predictive marker for MM-121 response.<br />
Results: To date, 24 patients have been treated with a median follow up of 5.5<br />
months (range 0.8 – 13.1). The median age was 58 years (range 38 – 72), and<br />
patients had received a median of four (range 1 – 11) prior lines of <strong>the</strong>rapy.<br />
Common (>20%) adverse events of any grade included fatigue (62%), peripheral<br />
neuropathy (58%), diarrhea (46%), neutropenia (46%) and rash (38%). Grade 3/4<br />
toxicities included fatigue (17%), peripheral neuropathy (8%), diarrhea (12%),<br />
neutropenia (16%), anemia (4%), abdominal pain (8%), and hypokalemia (4%). 17<br />
(71%) patients were evaluable for response and <strong>the</strong> overall clinical benefit rate, defined<br />
as PR or SD lasting for >4 months, was 71%. 47% achieved a PR and 35% a confirmed<br />
PR with a median duration of response of 4.6 months (range1.7 – 9.6) and 24% had<br />
SD >4 months with a median duration of SD of 5.6 months (range 4.2-12.6). 17%<br />
patients had PD at first assessment and 38% remain on study with a median on-study<br />
time of 10.2 months (range 1.4 – 13.1). Translational analyses exploiting tissue analysis<br />
in combination with in silico modeling are ongoing.<br />
Conclusion: The combination of MM121 and paclitaxel showed activity in metastatic<br />
ovarian and breast cancers.<br />
Disclosure: J. Liu: Joyce Liu is an investigator participating in <strong>the</strong> corporatesponsored<br />
study which is <strong>the</strong> subject of <strong>the</strong> abstract. R. Patel: Ravi Patel is an<br />
investigator participating in <strong>the</strong> corporate-sponsored study which is <strong>the</strong> subject of<br />
<strong>the</strong> abstract. G. Kato: Giraldo Kato is an investigator participating in <strong>the</strong><br />
corporate-sponsored study which is <strong>the</strong> subject of <strong>the</strong> abstract. U. Matulonis: Ursula<br />
Matulonis is an investigator participating in <strong>the</strong> corporate-sponsored study which is <strong>the</strong><br />
subject of <strong>the</strong> abstract. V. Moyo: Victor Moyo is employed by and owns stock in <strong>the</strong><br />
corporate sponsor of this reserach. K. Riahi: Kaveh Riahi is employed by and owns stock<br />
in <strong>the</strong> corporate sponsor of this research. J. Pearlberg: Joseph Pearlberg is employed by<br />
and owns stock in a corporate sponsor of this research. A. Czibere: Akos Czibere is<br />
employed by and owns stock in <strong>the</strong> corporate sponsor of this research. S. Isakoff: Steven<br />
Isakoff is an investigator participating in <strong>the</strong> corporate-sponsored study which is <strong>the</strong><br />
subject of <strong>the</strong> abstract. He has also served as a consulant to Merrimack Pharmaceuticals.<br />
975PD A PHASE 1B STUDY OF AMG 386 PLUS PACLITAXEL AND<br />
CARBOPLATIN IN OVARIAN CANCER PATIENTS<br />
UNDERGOING PRIMARY OR INTERVAL DEBULKING<br />
SURGERY<br />
I.B. Vergote 1 , A. Oaknin Benzaquen 2 , J. Baurain 3 , S. Ananda 4 , S. Wong 5 ,<br />
X. Yang 6 ,B.Wu 7 , Z. Zhong 8 , M. Puhlmann 9 , A. Casado 10<br />
1 Gynecologic Oncology, University Hospital Leuven, Leuven Cancer Institute,<br />
Leuven, BELGIUM, 2 Medical Oncology, Vall d’Habron University Hospital,<br />
Barcelona, SPAIN, 3 Service d’Oncologie Medicale, Universite Catholique de<br />
Louvain, Bruxelles, BELGIUM, 4 Oncology Unit, Royal Women’s Hospital,<br />
Parkville, VIC, AUSTRALIA, 5 Medical Oncology, Western Hospital, Footscray,<br />
VIC, AUSTRALIA, 6 Department of Biostatistics, Amgen Inc., Thousand Oaks,<br />
CA, UNITED STATES OF AMERICA, 7 Department of Pharmacokinetics and Drug<br />
Metabolism, Amgen Inc., Thousand Oaks, CA, UNITED STATES OF AMERICA,<br />
8 Department of Clinical Immunology and Biological Sample Management,<br />
Amgen Inc., Thousand Oaks, CA, UNITED STATES OF AMERICA, 9 Department<br />
of Clinical Development, Amgen Inc., Thousand Oaks, CA, UNITED STATES OF<br />
AMERICA, 10 Medical Oncology, Hospital Clínico San Carlos, Madrid, SPAIN<br />
Background: AMG 386, an investigational peptibody, blocks <strong>the</strong> interaction of<br />
angiopoietin-1 and -2 with <strong>the</strong> Tie2 receptor, <strong>the</strong>reby inhibiting tumor angiogenesis.<br />
We evaluated <strong>the</strong> tolerability of AMG 386 plus paclitaxel and carboplatin in ovarian<br />
cancer patients who had primary or interval debulking surgery (PDS or IDS,<br />
respectively).<br />
Methods: Women (≥ 18 yrs, GOG ≤ 1) with high-risk stage I (grade 3 or aneuploid<br />
grade 1 or 2) or II-IV ovarian cancer received 6 cycles of <strong>the</strong> combination AMG 386<br />
(15 mg/kg IV QW) plus paclitaxel (175 mg/m 2 IV Q3W) and carboplatin (AUC 6 IV<br />
Q3W) followed by AMG 386 maintenance mono<strong>the</strong>rapy up to 18 months. Patients<br />
had PDS; patients with disease stage IIIC or IV had <strong>the</strong> option of planned IDS.<br />
AMG 386 dosing was withheld for > 4 weeks after PDS or before IDS. The primary<br />
endpoint was <strong>the</strong> incidence of dose-limiting toxicities (DLTs), which determined<br />
cohort expansion to n = 25; secondary endpoints included <strong>the</strong> patient incidence of<br />
adverse events (AEs), <strong>the</strong> incidence of anti-AMG 386 antibody formation, and<br />
pharmacokinetics (PK). The current report presents results from <strong>the</strong> study’s<br />
combination <strong>the</strong>rapy phase.<br />
Results: At interim analysis, 27 patients (14 PDS, 13 IDS) were enrolled and<br />
received ≥ 1 dose of AMG 386 plus paclitaxel and carboplatin. No patients<br />
experienced DLTs. The patient incidence of AEs is summarized in <strong>the</strong> table below. 4<br />
of 24 patients developed non-neutralizing binding antibodies; 1 of 26 patients had<br />
pre-existing, non-neutralizing binding antibodies. Coadministration of AMG 386 did<br />
not alter <strong>the</strong> PK of paclitaxel or carboplatin.<br />
AMG 386 +<br />
paclitaxel and carboplatin (n = 27)<br />
Patient incidence of<br />
AEs – n (%)<br />
PDS (n = 14; 52%) IDS (n = 13; 48%)<br />
Patients with any<br />
adverse event<br />
14 (100) 12 (92)<br />
Worst grade ≥ 3 7 (50) 5 (38)<br />
Worst grade ≥ 4 3 (21)* 2 (15)**<br />
Worst grade 5 0 (0) 0 (0)<br />
In ≥ 20% of patients Any Worst grade ≥ 3 Any Worst grade ≥ 3<br />
who had PDS or<br />
IDS<br />
grade<br />
grade<br />
Localized edema 8 (57) 0 (0) 3 (23) 0 (0)<br />
Diarrhea 7 (50) 0 (0) 5 (38) 0 (0)<br />
Nausea 7 (50) 0 (0) 6 (46) 0 (0)<br />
Fatigue 7 (50) 0 (0) 5 (38) 0 (0)<br />
Thrombocytopenia 3 (21) 1 (7) 6 (46) 2 (15)<br />
Decreased appetite 2 (14) 0 (0) 6 (46) 0 (0)<br />
As<strong>the</strong>nia 6 (43) 0 (0) 4 (31) 0 (0)<br />
Neutropenia 5 (36) 4 (29) 3 (23) 2 (15)<br />
Nasopharyngitis 5 (36) 0 (0) 0 (0) 0 (0)<br />
Alopecia 5 (36) 0 (0) 0 (0) 0 (0)<br />
Abdominal<br />
distension<br />
1 (7) 0 (0) 4 (31) 0 (0)<br />
Abdominal pain 2 (14) 0 (0) 4 (31) 0 (0)<br />
Constipation 4 (29) 0 (0) 4 (31) 0 (0)<br />
Peripheral sensory<br />
neuropathy<br />
4 (29) 0 (0) 4 (31) 0 (0)<br />
Hypokalemia 0 (0) 0 (0) 4 (31) 1 (8)<br />
Peripheral<br />
neuropathy<br />
4 (29) 0 (0) 0 (0) 0 (0)<br />
Continued<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds401 | ix321
Table: 975PD Continued<br />
AMG 386 +<br />
paclitaxel and carboplatin (n = 27)<br />
Paras<strong>the</strong>sia 4 (29) 0 (0) 1 (8) 0 (0)<br />
Vomiting 2 (14) 0 (0) 3 (23) 0 (0)<br />
Musculoskeletal pain 2 (14) 0 (0) 3 (23) 0 (0)<br />
Anemia 3 (21) 0 (0) 3 (23) 1 (8)<br />
Mucosal<br />
3 (21) 0 (0) 1 (8) 0 (0)<br />
inflammation<br />
Myalgia 3 (21) 0 (0) 1 (8) 0 (0)<br />
Dizziness 3 (21) 0 (0) 2 (15) 0 (0)<br />
Dysgeusia<br />
Of specific interest<br />
Edema<br />
3 (21) 0 (0) 1 (8) 0 (0)<br />
Generalized 2 (14) 0 (0) 0 (0) 0 (0)<br />
Lymphedema 2 (14) 1 (7) 1 (8) 0 (0)<br />
Female genital tract<br />
fistula<br />
0 (0) 0 (0) 1 (8) 0 (0)<br />
Wound 0 (0) 0 (0) 1 (8) 0 (0)<br />
*Grade 4 AEs were neutropenia (n = 3).<br />
** Grade 4 AEs were neutropenia (n = 1) and thrombocytopenia (n = 1).<br />
Conclusions: Interim results from this Phase 1b study of ovarian cancer patients<br />
undergoing PDS or IDS suggest that AMG 386 at 15 mg/kg IV QW plus paclitaxel<br />
and carboplatin was tolerable. No PK interactions were observed between AMG 386<br />
and paclitaxel or carboplatin.<br />
Disclosure: I.B. Vergote: As is relevant for <strong>the</strong> current drug, I am an advisory board<br />
member for and received funding from Amgen. However, I am also an advisory board<br />
member and received funding from o<strong>the</strong>r companies. J. Baurain: Corporate-sponsored<br />
research: Academic clinical trial run with an Amgen product in squamous skin cancer.<br />
X. Yang: Stock ownership: Amgen I am an employee with Amgen. B. Wu: Stock<br />
ownership: Amgen I am an employee at Amgen. Z. Zhong: Stock ownership: Amgen I<br />
am an employee at Amgen. M. Puhlmann: Stock ownership: Amgen I am an employee<br />
at Amgen. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
976P A SEMI-PROSPECTIVE TRIAL TO DETERMINE THE OUTCOME<br />
OF BORDERLINE OVARIAN TUMOR PATIENTS. RESULTS OF<br />
ROBOT, A STUDY OF THE AGO STUDY GROUP<br />
H. Lueck 1 , N. Ewald-Riegler 2 , N. De Gregorio 3 , A. Reuss 4 , S. Mahner 5 ,<br />
C. Fotopoulou 6 , F. Kommoss 7 , B. Schmalfeldt 8 , S. Hauptmann 9 ,<br />
A. Du Bois 10<br />
1 Gyn Oncol, Gynäkologisch-Onkologische Schwerpunktpraxis Hannover,<br />
Hannover, GERMANY, 2 Klinik für Gynäkologie U. Gynäkologische Onkologie,<br />
HSK Wiesbaden, Wiesbaden, GERMANY, 3 Frauenklinik, Universitätsklinikum Ulm,<br />
Ulm, GERMANY, 4 Studienzentren, Koordinierungszentrum für Klinische Studien,<br />
Marburg, GERMANY, 5 Dept of Gynecology and Gynecologic Oncology,<br />
University Medical Center Hamburg-Eppendorf, Hamburg, GERMANY,<br />
6 Frauenklinik, Charité, Campus Virchow Klinikum, Berlin, GERMANY, 7 Gyn<br />
Tumors, Institut für Pathologie, Mannheim, GERMANY, 8 Frauen- und Poliklinik,<br />
Klinikum rechts der Isar der Technischen Universität, München, GERMANY, 9 Gyn<br />
Tumors, Institut für Pathologie Allgäu-Oberschwaben, Wangen, GERMANY,<br />
10 Klinik für Gynäkologische Onkologie, Kliniken Essen-Mitte, Essen, GERMANY<br />
Background: Borderline ovarian tumors (BOT) are a rare entity, current standard of<br />
care is based on <strong>the</strong> available data of predominantly small retrospective trials.<br />
Therefore we performed a pattern of care study including central pathology review.<br />
Methods: All consecutive patients diagnosed with BOT 1998-2008 in 24 German<br />
institutions were included. Tumor samples were sent for central histopathological<br />
review to experienced pathologists, clinical data were collected and patient follow-up<br />
was updated.<br />
Results: Pathological review was obtained in 1,042 of 1,236 pts resulting in 950<br />
confirmed BOT cases analyzed here. Under- and overdiagnosis occurred in 5.0% and<br />
6.2% of cases. Median age was 49 years; 82% of patients had FIGO stage I disease;<br />
serous type (S-BOT) was diagnosed in 68% and mucinous type (M-BOT) in 31%.<br />
Primary/re-staging surgery led to complete debulking in 92% of pts (residual disease<br />
1.3%, unknown 6.4%). Adjuvant chemo<strong>the</strong>rapy was given to 33 (3.5%) pts only. 166<br />
(17%) underwent fertility preserving surgery and 31 (19%) of <strong>the</strong>se patients had<br />
documented pregnancies <strong>the</strong>reafter. Overall, 74 (7.8%) pts experienced relapse and 43<br />
(4.5%) died, transformation to invasive carcinoma occurred in 30% of <strong>the</strong> relapses.<br />
Inadequate surgical staging, residual tumor, fertility sparing surgery and higher FIGO<br />
stage were associated with shorter progression-free survival. No differences were observed<br />
for laparatomy vs. laparoscopy as initial surgical approach or adjuvant chemo<strong>the</strong>rapy.<br />
Conclusions: To this day, this is <strong>the</strong> largest data set available for this entity.<br />
Prognosis of BOT is good even without adjuvant <strong>the</strong>rapy if correct surgical staging is<br />
performed. Both tumor characteristics and treatment variables had a significant<br />
impact on relapse rate and outcome. In contrast to previous data, transformation to<br />
invasive carcinoma occurred in a significant amount of relapse cases.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
977P PROGNOSTIC FACTORS AFTER CONSERVATIVE TREATMENT<br />
OF A LARGE SERIES OF "STAGE I" SEROUS BORDERLINE<br />
OVARIAN TUMORS<br />
P. Morice 1 , A. Kane 1 , E. Muller 1 , R. Fauvet 2 , S. Gouy 1 , P. Pautier 3 , C. Lhomme 3 ,<br />
E. Darai 4 , P. Duvillard 1 , C. Uzan 1<br />
1 Surgery, Institut Gustave Roussy, Villejuif, FRANCE, 2 Obstetrics Gynecology,<br />
CHU, Amiens, FRANCE, 3 Consultation de Gyn, Institut de Canc, Villejuif Cedex,<br />
FRANCE, 4 Obstetrics & Gynecology, Hopital Tenon, Paris, FRANCE<br />
Objectives: The aim of this study was to evaluate <strong>the</strong> prognostic factors of recurrence<br />
after conservative treatment of a large series of “apparent” stage I serous borderline<br />
ovarian tumors (SBOT).<br />
Methods: A review of 119 patients treated conservatively between 2000 and 2010<br />
with data on <strong>the</strong> follow-up. All pathological slides were reviewed by <strong>the</strong> same expert<br />
pathologist. Prognostic factors of recurrences were studied (age, histologic subtypes,<br />
surgical procedures used … ).<br />
Results: Conservative procedures were: unilateral cystectomy/UC (n = 43; 36%);<br />
unilateral salpingo-oophorectomy/USO (n = 50; 42%); bilateral cystectomy (n = 11;<br />
9%) and USO + CC (n = 15; 13%). Fourteen patients underwent complete peritoneal<br />
staging. Stages distributions were: IA (n = 80; 67%); IB (n = 18; 15%) & IC (n = 21;<br />
18%). Twenty-six patients had bilateral tumors. Respectively 21 (18%) & 13 (11%)<br />
had stromal microinvasion and/or micropapillary pattern. With a median follow-up<br />
of 45 months, 40 (33%) patients recurred (in whom 10 had peritoneal recurrence<br />
under <strong>the</strong> form of non invasive implants during <strong>the</strong> 1 st recurrence). Two of <strong>the</strong>se 40<br />
recurrent patients had evolution in <strong>the</strong> form of invasive recurrence (during <strong>the</strong> 2 nd or<br />
3 rd recurrence): 1 in remaining ovary & 1 in <strong>the</strong> peritoneum. None patient died from<br />
disease. Only 2 prognostic factors of recurrence were identified in multivariate<br />
analysis: <strong>the</strong> young age of <strong>the</strong> patients (< 30 years old) & <strong>the</strong> bilaterality of <strong>the</strong><br />
tumours. None of <strong>the</strong> o<strong>the</strong>rs factors studied had impact on <strong>the</strong> rate of recurrence.<br />
Conclusions: In this series (representing <strong>the</strong> largest series reported of conservative<br />
management of stage I SBOT), <strong>the</strong> risk of recurrence is not related to <strong>the</strong> histologic<br />
patterns of <strong>the</strong> tumor (micropapillary, stromal microinvasion) nor to <strong>the</strong> surgical<br />
procedures used (type of conservative approach, <strong>the</strong> use of staging surgery, <strong>the</strong> use of<br />
laparoscopic approach). The rate of invasive recurrence is very rare in stage I SBOT (2<br />
cases in this series). Young age (< 30 years old) and bilaterality of <strong>the</strong> tumors are risk<br />
factors of recurrence suggesting that improvement of <strong>the</strong> fertility management (before<br />
potential recurrence) should be improved particularly in <strong>the</strong>ses subgroup of patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
978P ROSIA: A SINGLE-ARM STUDY IN MORE THAN 1000<br />
PATIENTS (PTS) RECEIVING FRONT-LINE BEVACIZUMAB<br />
(BEV) + CHEMOTHERAPY (CT) FOR OVARIAN CANCER (OC)<br />
C. Mendiola 1 , I. Davidenko 2 , N. Colombo 3 , J. Korach 4 , F. Selle 5 , P. Gocze 6 ,<br />
E. Chmielowska 7 , P. Pautier 8 , D. Bollag 9 , A.M. Oza 10<br />
1 Medical Oncology Service, University Hosptial 12 De Octubre Medical<br />
Oncology, Madrid, SPAIN, 2 Oncology Dispensary, Krasnodar Regional Clinical<br />
Oncology Center, Krasnodar, RUSSIAN FEDERATION, 3 Gynecologic Oncology<br />
Division, European Institute of Oncology, Milan, ITALY, 4 Gynecology Oncology,<br />
The Chaim Sheba Medical Center, Tel Hashomer, ISRAEL, 5 Medical Oncology,<br />
Hôpital Tenon, Paris, FRANCE, 6 Department of Obstetrics and Gynaecology,<br />
University of Pecs, Pecs, HUNGARY, 7 Oddzial Onkologii, SPZOZ Centrum<br />
Onkologii im. Prof.Lukaszczyka, Bydgoszcz, NAP, POLAND, 8 Hopital de Jour de<br />
Medecine, Institut Gustave Roussy, Villejuif, FRANCE, 9 GPS, F. Hoffmann- La<br />
Roche AG, Basel, SWITZERLAND, 10 Dept. of Medicine, Princess Margaret<br />
Hospital, Toronto, ON, CANADA<br />
Background: BEV significantly improved <strong>the</strong> efficacy of front-line CT for OC in <strong>the</strong><br />
ICON7 and GOG-0218 phase III trials. The global single-arm ROSiA study was<br />
designed to assess <strong>the</strong> safety of BEV-containing <strong>the</strong>rapy, given until progression or<br />
for up to 36 cycles, in <strong>the</strong> context of routine oncology practice.<br />
Methods: Eligible pts have FIGO stage IIb–IV or grade 3 stage I–IIa epi<strong>the</strong>lial<br />
ovarian, fallopian tube or primary peritoneal carcinoma, have received no prior<br />
post-surgical <strong>the</strong>rapy for OC, are aged ≥18 years and have ECOG PS 0–2. Prior<br />
neoadjuvant CT is permitted. Pts with uncontrolled hypertension, clinical signs/<br />
symptoms of GI obstruction, or a history of abdominal fistula, GI perforation or<br />
intra-abdominal abscess within <strong>the</strong> preceding 6 months are ineligible. After definitive<br />
surgery, pts receive BEV 15 mg/kg q3w (or 7.5 mg/kg at <strong>the</strong> investigator’s discretion)<br />
in combination with 4–8 cycles of CT (paclitaxel [175 mg/m 2 d1 q3w or 80 mg/m 2<br />
qw) + q3w carboplatin [AUC 5 or 6]). BEV is continued at <strong>the</strong> same dose as a single<br />
agent until disease progression (PD), unacceptable toxicity or for up to 36 cycles.<br />
The primary objective is to assess safety (CTCAE v4.03). Secondary endpoints<br />
include progression-free survival, overall response rate by RECIST and/or CA-125<br />
response criteria, duration of response and overall survival. The study includes<br />
exploration of potential correlations of plasma, tumour and genetic biomarkers with<br />
BEV efficacy and toxicity.<br />
ix322 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Results: Between Dec 2010 and Apr <strong>2012</strong>, ∼1000 pts were enrolled from 35<br />
countries, predominantly Spain (n = 180), Italy (n = 110) and France (n = 101).<br />
Baseline characteristics were available from 677 pts as of 30 Jan <strong>2012</strong>. Most pts had<br />
stage III/IV OC (stage I/II/III/IV: 7%/11%/60%/18%). The majority (93%) received<br />
paclitaxel q3w and 94% received BEV at a dose of 15 mg/kg; 14% had received prior<br />
neoadjuvant CT. Baseline characteristics from <strong>the</strong> entire population of ∼1000 pts will<br />
be reported, toge<strong>the</strong>r with details of CT and BEV schedules selected.<br />
Conclusions: ROSiA should provide valuable new information on <strong>the</strong> safety of BEV<br />
for up to 36 cycles and in pts who have received neoadjuvant CT, as well as enabling<br />
extensive translational research.<br />
Disclosure: N. Colombo: NC has received honoraria for advisory boards and speaker<br />
engagements from Roche. F. Selle: FS acts as a Consultant for Roche and PharmaMar.<br />
P. Pautier: PP has served on Advisory Boards for Roche and Ipsen. D. Bollag: DB is an<br />
employee and holds stocks in F Hoffmann-La Roche Ltd. A.M. Oza: AO has received<br />
research funding from Roche. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
979P PREDICTIVE AND PROGNOSTIC ROLE OF SURVIVIN AND P53<br />
EXPRESSION IN PATIENTS WITH ADVANCED OVARIAN<br />
CANCER TREATED WITH NEOADJUVANT CHEMOTHERAPY<br />
A. Ga˛ sowska- Bodnar 1 , L. Bodnar 2 , M. Jerzak 3 , G. Wcisło 2 , M. Cichowicz 4 ,<br />
A. Da˛ bek 4 , W. Kozłowski 4 , C. Szczylik 2 , W. Baranowski 1<br />
1 Department of Gynecology and Gyneacology Oncology, MIlitary Institute of<br />
Medicine, Warsaw, POLAND, 2 Department of Oncology, Military Institute of<br />
Medicine, Warsaw, POLAND, 3 Department of Gyneacology and Gyneacology<br />
Oncology, MIlitary Institute of Medicine, Warsaw, POLAND, 4 Department of<br />
Pathology, Military Institute of Medicine, Warsaw, POLAND<br />
Background: Qualification of patients with advanced ovarian cancer (AOC) to<br />
treatment with primary or interval debulking surgery (IDS) is <strong>the</strong> subject of<br />
controversy. The aim of this study was to assess <strong>the</strong> expressions of selected proteins of<br />
apoptosis to <strong>the</strong> effects of neoadjuvant chemo<strong>the</strong>rapy (NAC) in patients with AOC.<br />
Material and methods: We evaluated 60 consecutive patients with AOS (FIGO stage<br />
IIIC-IV) treated with NAC, retrospectively. Formalin-fixed, paraffin-embedded tissue<br />
specimens were immunohistochemically stained for expression of p53 and survivin in<br />
patients given platinum-based NAC undergoing IDS. The expression of survivin was<br />
adopted dichotomization by <strong>the</strong> median expression of <strong>the</strong> protein found total score<br />
(TS) equals 2. For low expression of survivin was TS ≤ 2, while high total score TS> 2<br />
The positive and negative expression of p53 were used to dichotomization study group.<br />
Results: Median age of 60 patients was 60 years. The optimal IDS was achieved in<br />
69.1% (38/55). We observed significant difference in <strong>the</strong> percentage of stained nuclei<br />
(PS, p = 0.0002), <strong>the</strong> intensity of staining (IS, p = 0.0003) and TS (p = 0.0001) by<br />
comparing <strong>the</strong> expression of survivin in tumor tissue taken before and after NAC. The<br />
expression of p53 in tumor tissue before and after NAC was observed and significant<br />
difference was in PS, (p = 0.0424). There were no statistically significant difference in<br />
IS and <strong>the</strong> TS. Expression of survivin and p53 was not related to <strong>the</strong> results of IDS.<br />
Survivin expression was a prognostic factor in AOC patients treated with NAC (p =<br />
0.0484). Expression of survivin and p53 proteins was not a predictor factor in AOC<br />
patients. Adverse factors affecting <strong>the</strong> PFS for AOC patients treated with NAC were:<br />
lack of optimal IDS and <strong>the</strong> lack of an objective response by RECIST criteria<br />
(respectively HR was 3.93 (95% CI, 2.07-7.46, p
physicians in <strong>the</strong> U.S. and Europe. Using historical data, we analyzed projection estimates<br />
up to 2020 across US and EU5 countries by line of <strong>the</strong>rapy and platinum response status.<br />
Results: Projection estimates from 2010 to 2020 by line of <strong>the</strong>rapy varied by country.<br />
Among EU countries, <strong>the</strong> highest number of treated patients was in Germany,<br />
followed by United Kingdom (UK) and Italy. By 2020, <strong>the</strong> percentages of patients that<br />
are platinum sensitive and platinum refractory are expected to increase by about 17%<br />
in <strong>the</strong> US and 9% in <strong>the</strong> EU. Regional variation was observed across Europe with<br />
percentage increase in France being 12%, Germany 6%, Italy 10%, Spain 16% and UK<br />
7%. The table below refers to <strong>the</strong> number of ovarian cancer patients by line of <strong>the</strong>rapy.<br />
Conclusions: Despite ongoing <strong>the</strong>rapeutic efforts, only 44%of patients in US and<br />
65% in EU who receive 1L go on to 2L. This argues for continued efforts to be made<br />
for <strong>the</strong> development of more efficacious treatments for ovarian cancer. Real world<br />
data and disease based registries can help in validating emerging trends in <strong>the</strong>rapy<br />
through providing up to date global projection estimates across line of <strong>the</strong>rapy.<br />
Disclosure: J. Mehta: Employee of Sanofi R. Olivares: Employee of Sanofi O.<br />
Moulard: Employee of Sanofi P. Trask: Employee of Sanofi and owns stock A.<br />
Hamed: Employee of Sanofi.<br />
982P PLATINUM COMBINATION CHEMOTHERAPY VERSUS<br />
PLATINUM MONOTHERAPY IN PLATINUM-SENSITIVE<br />
RECURRENT OVARIAN CANCER: A META-ANALYSIS OF<br />
RANDOMISED TRIALS USING INDIVIDUAL PATIENT DATA<br />
(IPD)<br />
F.A. Raja 1 , N. Counsell 1 , N. Colombo 2 , M.K. Parmar 3 , J. Pfisterer 4 , I.B. Vergote 5 ,<br />
A. Gonzalez Martin 6 , D. Alberts 7 , M. Plante 8 , J.A. Ledermann 1<br />
1 Cancer Research Uk & Ucl Cancer Trials Centre, UCL, London, UNITED<br />
KINGDOM, 2 Gynecologic Oncology Division, European Institute of Oncology,<br />
Milan, ITALY, 3 Cancer Group, Medical Research Council (MRC)MRC Clinical<br />
Trials Unit, London, UNITED KINGDOM, 4 Dept. of Gynecology, St, Solingen,<br />
GERMANY, 5 Obstetrics & Gynaecology, University Hospital Gasthuisberg,<br />
Leuven, BELGIUM, 6 Servicio de Oncologia Medica, MD Anderson Cancer<br />
CenterCenter Espana, Madrid, SPAIN, 7 Oncology, The University of Arizona<br />
Cancer Center, Arizona, UNITED STATES OF AMERICA, 8 Gynecologic Oncology<br />
Service, Centre Hospitalier Universitaire De Québec (chuq), L’hôtel-dieu De<br />
Québec, Laval University, Quebec, CANADA<br />
Objectives: The majority of women with ovarian cancer develop recurrent disease.<br />
For patients with a platinum free interval of > 6months, platinum based<br />
chemo<strong>the</strong>rapy is <strong>the</strong> treatment of choice. The benefit of platinum-based combination<br />
chemo<strong>the</strong>rapy in randomised trials varies and a meta-analysis was performed to gain<br />
more secure information on <strong>the</strong> size of <strong>the</strong> benefit of this treatment.<br />
Methods: we initiated a systematic review to determine whe<strong>the</strong>r combination<br />
chemo<strong>the</strong>rapy is superior to single agent platinum chemo<strong>the</strong>rapy in women with<br />
relapsed platinum-sensitive ovarian cancer. The systematic review and meta-analysis<br />
followed a pre-specified protocol.<br />
Results: A total of five potentially eligible trials that had used combination platinum<br />
chemo<strong>the</strong>rapy versus single agent platinum chemo<strong>the</strong>rapy in women with relapsed<br />
platinum-sensitive ovarian cancer were identified. For one trial adequate contact with<br />
<strong>the</strong> investigators could not be established. Therefore, four trials that randomly<br />
assigned 1,300 (87%) patients were included, with a median follow-up of 36.1<br />
months. OS analyses were based on 865 deaths and demonstrated a statistically<br />
significant benefit of combination platinum chemo<strong>the</strong>rapy on survival (HR, 0.80;<br />
95% CI, 0.64 to 1.00; p = .050). PFS analyses were based on 1,167 events and<br />
demonstrated a highly statistically significant benefit of combination platinum<br />
chemo<strong>the</strong>rapy on progression-free survival (HR, 0.68; 95% CI, 0.57 to 0.81;<br />
p < .00001). There was no evidence of a difference in <strong>the</strong> relative effect of<br />
combination platinum chemo<strong>the</strong>rapy on ei<strong>the</strong>r OS or PFS in patient subgroups<br />
defined by previous paclitaxel treatment, duration of treatment-free interval, or <strong>the</strong><br />
number of previous lines of chemo<strong>the</strong>rapy.<br />
Conclusions: In this IPD meta-analysis we have demonstrated that<br />
combination-platinum chemo<strong>the</strong>rapy significantly improves overall survival and<br />
progression-free survival across all subgroups. This provides <strong>the</strong> strongest evidence to<br />
date of <strong>the</strong> benefit of combination-platinum over single agent platinum.<br />
Disclosure: J.A. Ledermann: Jonathan Ledermann has acted in an advisory role to<br />
Boehringer Ingelheim, Janssen and Roche. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
983P HOSPITAL FOLLOW UP IN OVARIAN CANCER: PHYSICAL<br />
EXAMINATION DOES NOT IMPROVE RELAPSE DETECTION<br />
OR SURVIVAL<br />
S. Chow, S. Ayers, A. Clamp, G.C. Jayson, J. Hasan<br />
Medical Oncology, The Christie NHS Foundation Trust, Manchester, UNITED<br />
KINGDOM<br />
Rationale: There are no trial data that define <strong>the</strong> optimum follow up strategy for<br />
patients with epi<strong>the</strong>lial ovarian cancer (EOC). Relapse is suspected on <strong>the</strong> basis of<br />
symptoms, signs or elevated CA125. The relative merit of each of <strong>the</strong>se is unclear<br />
because of a lack of data on cost-effectiveness and survival benefit. The aim of this<br />
study was to assess <strong>the</strong> utility of follow up procedures in relapse detection and survival.<br />
Study design: A cohort of 429 patients with FIGO stage I-III EOC in remission after<br />
first-line treatment was identified from <strong>the</strong> Christie Hospital ovarian cancer database.<br />
138 patients with recurrent disease were identified in this cohort. Patients were<br />
categorised as having symptomatic relapse, relapse with clinical signs, CA125<br />
elevation or combinations of <strong>the</strong> three. The clinical value of each of <strong>the</strong> three<br />
indicators of relapse and <strong>the</strong>ir effect on survival were analysed.<br />
Results: 41% of relapses were detected by single detection method. In 82% of<br />
patients, relapse was detected from a rising CA125 irrespective of symptoms or<br />
clinical signs. 18% of cases had disease that did not secrete CA125 at relapse. 66%<br />
of patients had symptoms at relapse, and 21% had at least one physical<br />
examination finding suspicious of relapse. A combination of rising CA125 and<br />
symptoms detected majority of relapses (98%) regardless of physical examination<br />
findings. Symptoms only were predictive of relapse in 13% of cases. Physical<br />
examination alone had <strong>the</strong> lowest detection rate of 2% (3/138). None of <strong>the</strong>se<br />
patients were suitable for salvage surgery. CA125 and symptoms detected relapse in<br />
all 18 patients who had salvage surgery. 10/18 had single site relapse. There were<br />
no statistically significant differences in survival between detection methods at 1, 3<br />
and 5 year (p = 0.81).<br />
Conclusion: Physical examination is of limited benefit in <strong>the</strong> follow-up of EOC. It<br />
did not contribute to detection of disease suitable for salvage surgery. CA125 and<br />
symptom history can safely detect relapse in 98% of cases without compromising<br />
survival. This study questions <strong>the</strong> utility of routine hospital follow up in EOC<br />
patients.♦ Decimals rounded to nearest whole number.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
984P CONSERVATIVE SENSITIVITY ANALYSES OF<br />
PROGRESSION-FREE SURVIVAL (PFS) OF TRABECTEDIN<br />
PLUS PEGYLATED LIPOSOMAL DOXORUBICIN (PLD) VS. PLD<br />
ALONE IN PATIENTS WITH RELAPSED OVARIAN CANCER:<br />
OVA-301 STUDY<br />
I. Romero 1 , E. Pujade-Lauraine 2 , A. Tanovic 3 , J. Gómez García 4 ,<br />
A.M. Poveda 1<br />
1 Area Clinica de Oncologia Ginecologica, Fundación Instituto Valenciano de<br />
Oncología, Valencia, SPAIN, 2 Medical Oncology, Hopital Hotel - Dieu, Paris,<br />
FRANCE, 3 Medical Affairs, PharmaMar, Barcelona, SPAIN, 4 Bio Statistics & Data<br />
Management, PharmaMar, Colmenar Viejo, SPAIN<br />
Background: Sensitivity analyses are critical to understanding <strong>the</strong> strength of<br />
conclusions made in <strong>the</strong> primary analysis. A randomised phase III trial OVA-301<br />
compared <strong>the</strong> efficacy of trabectedin 1.1 mg/m 2 in combination with PLD 30 mg/m 2<br />
given every 3 weeks vs. PLD 50 mg/m 2 every 4 weeks in patients with relapsed<br />
ovarian cancer. Primary endpoint was PFS based on independent radiology review<br />
(IRR) per RECIST. Secondary PFS analyses were based on independent oncologist<br />
(IO) and investigator’s assessments (IA).<br />
Methods: Patients were assessed symmetrically every 8 weeks in both arms. To avoid<br />
bias of <strong>the</strong> disease assessment time, two conservative sensitivity analyses of PFS were<br />
performed. Two different conservative analyses considered <strong>the</strong> scheduled date of PFS<br />
evaluation instead of <strong>the</strong> actual date of imaging moving <strong>the</strong> actual date to: #1) <strong>the</strong><br />
last scheduled date of assessment immediately before <strong>the</strong> actual evaluation and to #2)<br />
<strong>the</strong> closest scheduled date before or after <strong>the</strong> actual evaluation.<br />
Results: The treatment effect based on <strong>the</strong> actual dates of assessment in favour of <strong>the</strong><br />
combination arm is maintained across <strong>the</strong> performed sensitivity analyses. Summary<br />
of <strong>the</strong> two sensitivity PFS analyses compared with <strong>the</strong> pre-planned PFS analysis.<br />
Analysis n<br />
Trabectedin +<br />
PLD PLD HR CI 95%<br />
Annals of Oncology<br />
LR test<br />
(p value)<br />
PFS by IR* 645 328 317 0.789 0.646-0.963 0.0190<br />
PFS by IR (#1) 645 328 317 0.813 0.666-0.993 0.0245<br />
PFS by IR (#2) 645 328 317 0.822 0.674-1.004 0.0317<br />
PFS by IO* 671 336 335 0.724 0.599-0.876 0.0008<br />
PFS by IO (#1) 671 336 335 0.749 0.620-0.906 0.0010<br />
PFS by IO (#2) 671 336 335 0.757 0.626-0.916 0.0013<br />
PFS by IA* 672 337 335 0.723 0.608-0.859 0.0002<br />
PFS by IA (#1) 672 337 335 0.742 0.624-0.882 0.0001<br />
PFS by IA (#2) 672 337 335 0.747 0.629-0.888 0.0001<br />
*Main PFS analyses.<br />
#1: Conservative PFS sensitivity analysis; imputation to <strong>the</strong> previous schedule<br />
evaluation.<br />
#2: Sensitivity analysis with imputation to <strong>the</strong> closest scheduled evaluation.<br />
CI, confidence interval; HR, hazard ratio; IA, investigator assessment; IO,<br />
independent oncology review;<br />
IR, independent radiology review; LR, log-rank; PFS, progression-free survival; PLD,<br />
pegylated liposomal doxorubicin.<br />
ix324 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Conclusions: The consistently observed significantly better PFS for <strong>the</strong> trabectedin<br />
combination based on adjusting progression times by moving assessments to<br />
scheduled times added methodological strengths and increased reliability and<br />
interpretability of <strong>the</strong> prior findings of this phase III trial.<br />
Disclosure: A. Tanovic: I am an employee at PharmaMar and stock owner. J. Gómez<br />
García: I am an employee at PharmaMar and stock owner. A.M. Poveda: I received<br />
funding for research from PharmaMar. All o<strong>the</strong>r authors have declared no conflicts<br />
of interest.<br />
985P THE EFFICACY OF TAXANS IN COMBINED TREATMENT OF<br />
OVARIAN CANCER<br />
O.M. Ahmedov, N.S. Yuldasheva, N. Umarova<br />
Gynaecology Department, National Cancer Centre, Tashkent, UZBEKISTAN<br />
Objective: The efficacy of paclitaxel plus carboplatin (TC) or gemcitabine plus<br />
carboplatin (GC) induction regimens with or without paclitaxel consolidation<br />
<strong>the</strong>rapy were assessed in ovarian cancer (OC).<br />
Methods: Patients with stage T2NoMo- T3N1Mo were randomized to ei<strong>the</strong>r GC<br />
(1 group) (gemcitabine 1,000 mg/m 2 ), days 1 and 8, plus carboplatin area under <strong>the</strong><br />
curve [AUC] 5, day 1 and TC (2 group) (paclitaxel 175 mg/m 2 ) plus carboplatin<br />
AUC 6, day 1 every 21 days for up to six-eight cycles. Patients with complete<br />
response were allowed optional consolidation with paclitaxel 135 mg/m 2 every 28<br />
days for ≤ 12 months. Patients without complete response received single-agent<br />
crossover <strong>the</strong>rapy at induction doses/schedules until complete response, disease<br />
progression, or unacceptable toxicity. Disease progression or death in 124 patients<br />
was required to compare induction arms with 80% statistical power for<br />
progression-free survival, <strong>the</strong> primary endpoint.<br />
Results: Randomized induction <strong>the</strong>rapy was received by 230 of 256 patients enrolled;<br />
152 patients with complete response received paclitaxel consolidation whereas 56<br />
patients without complete response received single-agent crossover <strong>the</strong>rapy.<br />
Progression-free survival was similar for GC and TC (median, 19.0 and 21.3 months,<br />
respectively; P = 0.199). Despite high censoring rates (>50%), overall survival was<br />
longer for TC (median, 48.3 versus 43.8 months for GC; P = 0.011). Controlling for<br />
patient characteristics including performance status, residual tumor size, and tumor<br />
stage, <strong>the</strong>re was no statistical difference in a multivariate analysis.<br />
Conclusions: The regiment gemcitabine plus carboplatin does not improve<br />
progression-free survival over paclitaxel plus carboplatin as first-line induction<br />
chemo<strong>the</strong>rapy in ovarian cancer. Although favouring paclitaxel plus carboplatin,<br />
overall survival analyses were limited by <strong>the</strong> study design and high censoring rates.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
986P BEVACIZUMAB PLUS METRONOMIC CYCLOPHOSPHAMIDE<br />
FOR HEAVILY PRETREATED OVARIAN CANCER: A SINGLE<br />
INSTITUTION EXPERIENCE<br />
I. Ghanem, C. Mendiola, A. Diaz, G. Velasco, L. Manso, E. Ciruelos,<br />
R.A. Manneh, S. Hoyos, T. Pascual, H. Cortes-Funes<br />
Medical Oncology, Hopital 12 de Octubre, Madrid, SPAIN<br />
Background: Bevacizumab in combination with chemo<strong>the</strong>rapy has demonstrated<br />
activity for ovarian cancer in first and second lines. The purpose of this study is to<br />
evaluate <strong>the</strong> efficacy and safety of bevacizumab plus metronomic cyclophosphamide<br />
in heavily pretreated ovarian cancer patients<br />
Methods: We reviewed retrospectively 29 patients (p) with recurrent ovarian cancer<br />
treated with bevacizumab 10 mg/Kg IV every 14 days plus oral cyclophosphamide<br />
50 mg daily between January 2007 and January <strong>2012</strong> at a single institution. P<br />
characteristics, tumour features, survival data and adverse events (AE) were collected.<br />
Results: Twenty-nine p with a median age of 59 years old (31-79) and ECOG 1 (0-2)<br />
were analyzed. Fifteen (52%) and 14 (48%) p had stage IV and IIIC respectively<br />
before receiving bevacizumab-cyclophosphamide. The most frequent pathologic<br />
subtype was serous in 22 p (76%). The median of previous lines was 4 (2-9),<br />
including drugs as carboplatin 29p (100%), paclitaxel 29p (100%), pegylated<br />
liposomal doxorubicin 26p (90%), gemcitabine 20p (69%), altretamine 10p (34%),<br />
topotecan 9p (31%) or trabectedine 1p (3%). Twenty-three cases (79%) were<br />
platinum-resistant (progression free interval less than 6 months from last platinum<br />
treatment). The median of cycles administered was 9 (3-67). Twenty-six p were<br />
assessable for CA 125 marker evaluation: 4p (15%) had CA125 normalization, 7p<br />
(27%) partial response (PR), 8p (31%) stable disease (SD) and 7p (27%) progression<br />
disease (PD). The radiologic evaluation was performed in 23 patients: There were 6p<br />
(26%) with PR, 9p (39%) with SD and 8p (35%) with PD. Median progression free<br />
survival (PFS) and overall survival (OS) were 3.7 months and 12.1 months<br />
respectively. P with platinum-resistant disease had significantly worse PFS (3.2m vs<br />
36.0m) p = 0.001 and OS (12m vs not reached) p = 0.009. P with ECOG >1 also had<br />
worse PFS (2.8m vs 4.7m) p = 0.047 and OS (5.4m vs 34.5m) p = 0.011). Severe AE<br />
were G3 arterial hypertension (1p), G3 mucositis (1p), G3 anaemia and G4 digestive<br />
bleeding (1p). No alopecia and neurotoxicity deterioration were observed.<br />
Conclusions: This schedule consisting on bevacizumab plus metronomic<br />
cyclophosphamide shows activity in heavily pre-treated ovarian cancer with a well<br />
toxicity profile<br />
Disclosure: All authors have declared no conflicts of interest.<br />
987P WHOLE ABDOMINOPELVIC RADIOTHERAPY (WAPRT) USING<br />
INTENSITY MODULATED ARC THERAPY (IMAT) AS<br />
PALLIATION FOR PLATINUM-RESISTANT OVARIAN CANCER<br />
A.P. Makar 1 , K. Vandecasteele 2 , P. Tummers 1 ,P.Ost 2 , L. Delrue 3 , S. Van Belle 4 ,<br />
R. Van den Broecke 1 , V. Fonteyne 2 , W. De Never 2 , G. De Meerleer 2<br />
1 Department of Gynaecologic Oncology, University Hospital of Ghent, Ghent,<br />
BELGIUM, 2 Department of Radiation Oncology, University Hospital of Ghent,<br />
Ghent, BELGIUM, 3 Department of Radiology, University Hospital of Ghent,<br />
Ghent, BELGIUM, 4 Department of Medical Oncology, University Hospital of<br />
Ghent, Ghent, BELGIUM<br />
Background and aims: To asses <strong>the</strong> palliative effect of WAPRT using IMAT for<br />
patients with chemo<strong>the</strong>rapy-resistant ovarian cancer.<br />
Methods: Forty-two patients were treated (33Gy; 22 daily fractions). At referral,<br />
median [range] age and Karnofsky performance score (KPS) was 59y [31 -76] and 80<br />
[40-90]. Disease-related symptoms were: intestinal (sub)-obstruction (n = 22), minor<br />
gastro-intestinal symptoms (n = 2), pain (n = 20), ascites (n = 11), and vaginal<br />
bleeding (n = 2). Median [range] CA125 serum level was 421 U/ml [6-13796]. All<br />
patients were heavily pre-treated. The actuarial overall survival (OS) and abdominal<br />
progression free survival (aPFS) were calculated from <strong>the</strong> start, response duration<br />
from <strong>the</strong> end of treatment.<br />
Results: Response rates (completed treatments; n = 30): The median [range] response<br />
duration (all symptoms) was 16 weeks [0-139]. For <strong>the</strong> whole population median<br />
[range] OS and aPFS was 4 months [0-32] and 11 weeks [0-142]. For those patients<br />
who completed treatment median [range] OS and aPFS was 8 months [2-32] and 17<br />
weeks [4-142]. Patients with a KPS ≥70 ended <strong>the</strong> treatment significantly more (p <<br />
0.001), had a better OS (8 vs. 1 month; P < 0.05), aPFS (18 vs 3 weeks; p < 0.001) and<br />
response duration (22 vs 5 weeks p < 0.001). 4)<br />
Conclusion: WAPRT offers important palliation for peritoneal metastasized<br />
/platinum resistant ovarian cancer patients. It can resolve intestinal obstruction for a<br />
substantial period. Carefull patient selection is mandatory (KPS ≥ 70).<br />
Disclosure: All authors have declared no conflicts of interest.<br />
988P HXR9 AND PARP INHIBITION –A NOVEL THERAPEUTIC IN<br />
OVARIAN CANCER<br />
Z. Kelly, H. Pandha, R. Morgan, A. Michael<br />
Institute of Bioscience and Medicine, Department of Microbial and Cellular<br />
Science, University of Surrey, Guildford, UNITED KINGDOM<br />
Background: Ovarian cancer is <strong>the</strong> leading cause of cancer death among all<br />
gynaecological cancers. The majority of patients present with advanced stage disease<br />
having a median survival rate of only 3 years. A major obstacle in <strong>the</strong> treatment of<br />
ovarian cancers is <strong>the</strong> development of resistance to platinum-based <strong>the</strong>rapies. It is<br />
<strong>the</strong>refore essential to introduce new <strong>the</strong>rapeutic approaches. HOX genes are known<br />
to be deregulated in many solid tumours and in ovarian cancer. We have previously<br />
showed that HXR9, which inhibits <strong>the</strong> interaction between HOX and its<br />
down-stream cofactor-PBX induces apoptosis in <strong>the</strong> SKOV-3 epi<strong>the</strong>lial ovarian cell<br />
line. HOXB7 is also known to have a role in DNA double strand break repair<br />
(DSBR). Ano<strong>the</strong>r mechanism of cell death regulation through DNA DSBR is through<br />
inhibition of poly(ADP-ribose) polymerase (PARP). We have <strong>the</strong>refore tested <strong>the</strong><br />
potential synergy between HXR9 and PARP-inhibitors. The objective of this study<br />
was to assess <strong>the</strong> cytotoxicity of HXR9 in cisplatin sensitive and resistant epi<strong>the</strong>lial<br />
ovarian cancer cell lines, and to assess potential synergy with <strong>the</strong> PARP inhibitor,<br />
3-aminobenzamide.<br />
Methods: The MTS cell viability assay was used to show cytotoxicity in <strong>the</strong> ovarian<br />
cancer cell lines SKOV-3, COV-318, TOV-112D, PEO1, PEO4 and TOV-21G after<br />
treatment with HXR9, and in combination with presence PARP inhibitor<br />
3-aminobenzamide. Flow cytometric analysis and <strong>the</strong> caspase-3 assay was used to<br />
evaluate mode of cell death.<br />
Results: HXR9 induced apoptosis in all ovarian cancer cell lines treated compared to<br />
untreated cells with P values < 0.0001 for each of <strong>the</strong> cell lines tested, irrespective of<br />
cisplatin sensitivity status. The combination of HXR9 and 3-aminobenzamide<br />
induced enhanced cell death and showed clear synergy between <strong>the</strong> two drugs. The<br />
apoptosis rate in treated cells was confirmed by <strong>the</strong> capase-3 activity, which was<br />
increased for all cell lines (an average fold increases ranging from 1.3-3.4- compared<br />
to untreated controls).<br />
Conclusion: The combination of HXR9 with PARP inhibitor is synergistic and leads<br />
to enhancement of <strong>the</strong> apoptotic effect in <strong>the</strong> cisplatin-resistant ovarian cancer cell<br />
line SKOV-3. This strategy could potentially lead to a new <strong>the</strong>rapeutic approach for<br />
patients with platinum-resistant ovarian cancer in <strong>the</strong> clinical setting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds401 | ix325
989P PHASE II STUDY OF COMBINATION CHEMOTHERAPY WITH<br />
ORAL S-1 AND OXALIPLATIN (SOX) IN PATIENTS WITH<br />
MUCINOUS ADENOCARCINOMA OF THE OVARY<br />
S. Nishio 1 , M. Shimada 2 , T. Kamura 1 , K. Ishitani 3 , K. Ochiai 4 , N. Takeshima 5 ,<br />
Y. Yokoyama 6 , H. Furumoto 7 , T. Sugiyama 8 , J. Kigawa 2<br />
1 Obstetrics and Gynecology, Kurume University School of Medicine, Kurume,<br />
JAPAN, 2 Obstetrics and Gynecology, Tottori University, Yonago, JAPAN,<br />
3 Obstetrics and Gynecology, Tokyo Women’s Medical University, Tokyo, JAPAN,<br />
4 Obstetrics and Gynecology, Jikei University School of Medicine, Tokyo, JAPAN,<br />
5 Gynecology, Cancer Institute Hospital, Tokyo, JAPAN, 6 Obstetrics and<br />
Gynecology, Hirosaki University Graduate School of Medicine, Hirosaki, JAPAN,<br />
7 Obstetrics and Gynecology, The University of Tokushima Graduate School,<br />
Tokushima, JAPAN, 8 Obstetrics and Gynecology, Iwate Medical University<br />
School of Medicine, Morioka, JAPAN<br />
We previously reported that patients with advanced or recurrent ovarian mucinous<br />
adenocarcinoma (MAC) had poor outcomes. Owing to similar biologic<br />
characteristics, chemo<strong>the</strong>rapy for MAC has been based on standard<br />
chemo<strong>the</strong>rapeutic regimens for colorectal cancer. Our basic studies also showed that<br />
a combination of oxaliplatin (L-OHP) and 5-fluorouracil was effective against MAC<br />
cells. This is <strong>the</strong> first phase II study of combination chemo<strong>the</strong>rapy with oral S-1 and<br />
L-OHP (SOX) in patients with advanced or recurrent MAC. From July 2008 through<br />
December 2011, 40 patients, including 16 with recurrent disease, were enrolled. Two<br />
patients could not receive SOX chemo<strong>the</strong>rapy because <strong>the</strong>ir performance status<br />
suddenly deteriorated after enrollment. L-OHP was administered at a dose of 100<br />
mg/m2 on day 1, and S-1 (80-120 mg/day) was given in 2 divided doses daily for 2<br />
weeks followed by a 1-week rest. This treatment schedule was repeated every 3 weeks<br />
until progressive disease. Tumor responses were evaluated according to <strong>the</strong> Response<br />
Evaluation Criteria in Solid Tumors, and toxicity was assessed with <strong>the</strong> Common<br />
Terminology Criteria for Adverse Events (version 3.0). Central pathological review<br />
(CPR) was also performed. On CPR, primary MAC was diagnosed in 13 patients,<br />
metastatic MAC in 15, endometrioid adenocarcinoma in 7, and o<strong>the</strong>r histological<br />
subtypes in 5. Of <strong>the</strong> 28 patients with a diagnosis of MAC, <strong>the</strong> objective response<br />
rate (RR) as assessed by an independent response review committee was 18%<br />
(complete response: 0, partial response: 5), and <strong>the</strong> disease control rate (CDR),<br />
including 14 patients with stable disease, was 68%. Among <strong>the</strong> 13 patients with<br />
primary MAC, <strong>the</strong> objective RR was 31%. Among <strong>the</strong> 38 patients who received SOX<br />
<strong>the</strong>rapy, 2 discontinued <strong>the</strong> regimen because of toxicity. Grade 3 or 4 hematologic<br />
toxicities were neutropenia (28%), anemia (21%), and thrombocytopenia (10%). The<br />
most common grade 3 or 4 nonhematologic toxicities were anorexia (8%) and<br />
hyponatremia (8%). The present study showed a promising RR and good tolerance,<br />
suggesting that SOX <strong>the</strong>rapy might contribute to prolonging survival.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
990P ERCC1 EXPRESSION AS PREDICTIVE BIOMARKER FOR<br />
PLATINUM CONTAINING CHEMOTHERAPY REGIMENS IN<br />
OVARIAN CARCINOMA<br />
M. Ulker 1 , B.B. Duman 2 , B. Sahin 3 , D. Gumurdulu 4<br />
1 Intenal Medicine, Cukurova University Medical Faculty, Adana, TURKEY,<br />
2 Medical Oncology, Adana Numune Education and Research Hospital, Adana,<br />
TURKEY, 3 Medical Oncology, Cukurova University Medical Faculty, Adana,<br />
TURKEY, 4 Pathology, Cukurova University Medical Faculty, Adana, TURKEY<br />
Background and aims: Platin based chemo<strong>the</strong>rapy regimens are most important<br />
treatment choices for ovarian carcinoma. Significant numbers of patients develop<br />
resistance to platinum combination <strong>the</strong>rapies. We aimed to show <strong>the</strong> role of ERCC1<br />
expression in <strong>the</strong> resistance to <strong>the</strong>rapy in ovarian carcinoma.<br />
Patients and methods: Among all patients treated with platinum containing<br />
chemo<strong>the</strong>rapy regimens, 27 eligible ovarian cancer patients were selected. Tissue<br />
samples were obtained from paraffin blocks and evaluated ERCC1 expression with<br />
immunohistochemical method in <strong>the</strong> pathology department. Expression level 0, 1(+),<br />
2(+) was assessed as low expression, 3(+) was assessed as high expression. The results<br />
were correlated with clinical findings and <strong>the</strong>rapy response. Therapy response was<br />
assessed for RECIST criteria.<br />
Results: In this study 27 patients with pathologically proven ovarian cancer were<br />
enrolled to this study. Sixteen (59%) patients were stage III, and 11(41%) patients<br />
were stage IV. Complete response was determined in 18 (67%) patients, stable disease<br />
was determined in 3 (11%) patients and progressive disease was determined in 6<br />
(22%) patients. Median overall survival was 23 months. Treatment response rates<br />
were 50% in high ERCC1 expression group and 90% in low expression group.<br />
Statistically significant difference was found between two groups (p = 0.04). The<br />
median overall survival was 30 months(95% CI 23-37 months) in low ERCC1<br />
expression group and 15.8 months (95% CI 23-37 months) in high expression group<br />
(p = 0.183).<br />
Conclusion: Some primary tumors and most recurrent tumors develop drug<br />
resistance that lead to treatment failure. High ERCC1 expression levels are associated<br />
with <strong>the</strong> mechanism of cisplatin resistance in ovarian cancer. ERCC1 expression can<br />
be used as a predictive biomarker for <strong>the</strong> platin containing regimens in ovarian<br />
carcinoma.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
991P PATTERNS AND OUTCOMES OF TREATMENT IN ELDERLY<br />
PATIENTS WITH OVARIAN CANCER: A RETROSPECTIVE<br />
MONO-ISTITUTIONAL STUDY<br />
M.O. Nicoletto 1 , L. Furini 1 , M. Dalla Palma 1 , L. Borgato 1 , P. Fiduccia 1 ,<br />
M. Rocchetto 2 , G.B. Nardelli 3 , M.T. Gervasi 4 , V. Zagonel 1<br />
1 Medical Oncology Unit 1, Istituto Oncologico Veneto, Padua, ITALY, 2 School of<br />
Medicine, University of Padua, School of Medicine, Padua, ITALY, 3 Deapartment<br />
of Gynecological Sciences and Human Reproduction, University of Padua,<br />
Padua, ITALY, 4 Ob/Gyn Unit Department for Health of Mo<strong>the</strong>rs and Children,<br />
Azienda Ospedaliera, Padua, ITALY<br />
Introduction: Ovarian cancer incidence is increasing in <strong>the</strong> elderly. We studied<br />
clinical and biological features of ovarian cancer in patients (OCP) aged >or = 70y.<br />
Methods: We conducted a retrospective analysis in 100 elderly OCP observed from<br />
1995 to 2011. We considered overall survival, comorbidities, surgery, hystotype and<br />
grading, chemo<strong>the</strong>rapy (monochemo<strong>the</strong>rapy vs polychemo<strong>the</strong>rapy), response to<br />
treatment, and toxicities.<br />
Results: Median age was 75y (range 70-88y). Most of <strong>the</strong> pts (82%) had advanced<br />
stage at diagnosis (stage III, 70.2%), serous ovarian cancer histotype (67%), and grade<br />
3 (74 pts, 78.7%). Most pts had at least one comorbidity (84%) and more than half<br />
(53.2%) two or more. 29.8% of pts received an optimal debulking ( 5cm) tumour burden at multiple sites, radiological evidence<br />
of serosal disease and half developed bowel obstruction whilst receiving<br />
chemo<strong>the</strong>rapy. Approximately 50% of patients presented with obstructive symptoms,<br />
but 25% presented with erratic bowel habit. Median survival following <strong>the</strong> first<br />
episode of bowel obstruction was 87 days (range 3-1754). Survival was similar<br />
between patients who underwent palliative surgery or chemo<strong>the</strong>rapy (p = 0.89).<br />
Median survival for patients presenting in bowel obstruction with platinum-sensitive<br />
(PS) and platinum-resistant (PR) disease (but not chemonaïve patients) who<br />
proceeded to chemo<strong>the</strong>rapy was prolonged compared with patients unsuitable for<br />
fur<strong>the</strong>r treatment (PS 191 vs. 24 days, p < 0.0001; PR 149 vs. 50 days, p = 0.06). A<br />
feasibility trial investigating <strong>the</strong> efficacy of low residue diet and intravenous<br />
ix326 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
dexamethasone in <strong>the</strong> prevention and treatment of malignant bowel obstruction has<br />
been initiated.<br />
Conclusion: Overall survival in patients with malignant bowel obstruction is poor<br />
with no significant improvement over <strong>the</strong> last decade. Bowel obstruction in patients<br />
with chemonaïve disease represents an aggressive phenotype with poor prognosis.<br />
Judicious selection of patients for surgery and/or chemo<strong>the</strong>rapy can significantly<br />
increase survival.1. <strong>ESMO</strong> Congress 2010, Milan. Poster 987P.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
993P FROM A WEBSITE TO A NATIONAL AND REGIONAL<br />
REFERENCE CENTRE NETWORK: THE FRENCH EXPERIENCE<br />
FOR RARE OVARIAN TUMORS<br />
I. Ray-Coquard 1 , P. Pautier 2 , J. Alexandre 3 , M. Vacher-Lavenu 4 , M. Fabbro 5 ,<br />
A. Floquet 6 , F. Selle 7 , G. Ferron 8 , N. Chiannilkulchai 9 , E. Pujade-Lauraine 3<br />
1 Oncology, Centre Leon Berard, Lyon, FRANCE, 2 Medical Oncology, Institut de<br />
Cancerologie Gustave Roussy, Villejuif, FRANCE, 3 Oncologie Médicale, Hôpital<br />
Hôtel Dieu, Paris, FRANCE, 4 Service D’anatomie et Cytologie Pathologiques,<br />
Hôpital Cochin, Paris, FRANCE, 5 Médecine B2, CRLC Val d’Aurelle, Montpellier,<br />
FRANCE, 6 Oncologie, Institut Bergonié, Bordeaux, FRANCE, 7 Medical Oncology,<br />
Hôpital Tenon, Paris, FRANCE, 8 Médecine - Oncologie, Institut Claudius<br />
Regaud, Toulouse, FRANCE, 9 Hôpital Hôtel Dieu, Arcagy, Paris, FRANCE<br />
Background: Rare ovarian tumors (ROT) represent more than 20% of all ovarian<br />
cancers. Difficulties in histological diagnosis, absence of prognostic factors, evidence is<br />
not available for medical decision. In 2002, <strong>the</strong> GINECO group organized a dedicated<br />
website for sex cords (SCT) and germ cell (GCT) management. At <strong>the</strong> end of 2010,<br />
supported by <strong>the</strong> French NCI, a national network for all ROT was organized with 3<br />
national and 21 regional expert centers (REC). The objectives are to monitor <strong>the</strong><br />
management of ROT and give equal access to expertise (systematic second opinion for<br />
histological diagnosis) and innovative treatments to all patients with ROT.<br />
Methods: The expected incidence of ROT in France is near 1000 new cases per year,<br />
including mostly SCT, GCT, mucinous (MC), clear cell (CCC), carcinosarcoma (CS),<br />
small cell carcinoma and borderline with invasive implants (BLT). A website collecting<br />
all files discussed in <strong>the</strong> REC was generated (www.ovaire-rare.org). The prospective<br />
collection of clinical data, dedicated multidisciplinary staff decision (MS), central<br />
pathological review and patient follow-up were implemented in <strong>the</strong> national database.<br />
Results: In 2011, 712 patients benefited of second opinion & were included by expert<br />
pathologists, representing 71% of expected incident cases. Major discordances<br />
concern 8% of patients. 294 patients gave informed consent & were included in <strong>the</strong><br />
database before initial treatment in 229, (78 % of cases) or at <strong>the</strong> time of <strong>the</strong> first<br />
relapse in 65 (22%) : 85 (29 %) had SCT, 57 GCT, 61 BLT, 26 MC, 20 CCC, 45<br />
o<strong>the</strong>r. 280 (96%) patients cases were discussed in dedicated MS. 18 patients entered a<br />
clinical trial. Virtual tumor banking is on going to develop molecular diagnosis (as<br />
FOXL2 for SCT).<br />
Conclusion: This web-based tool supported by a national network including national<br />
and regional expert centers seems to be an efficient tool for <strong>the</strong> organisation of <strong>the</strong><br />
management of rare ovarian cancer. The present project is under consideration for<br />
an EU project in 5 o<strong>the</strong>r countries interesting to duplicate such organisation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
994P MALIGNANT OVARIAN GERM CELL TUMORS (MOGCT) AT A<br />
TERTIARY CARE SETTING IN PAKISTAN<br />
A. Hannan 1 , N. Siddiqui 2 , F. Badar 2<br />
1 Mediacal Oncology, Shaukat Khanum Memorial Cancer Hospital, Lahore,<br />
PAKISTAN, 2 Medical Oncology, Shaukat Khanum Memorial Cancer Hospital and<br />
Reserch Centre (SKM), Lahore, PAKISTAN<br />
Introduction: Malignant ovarian germ cell tumors (MOGCT) are rare neoplasms.<br />
Little is known about <strong>the</strong>ir behavior in <strong>the</strong> South East Asian populations. Aim of our<br />
study was to evaluate MOGCT patients treated at Shaukat Khanum Memorial Cancer<br />
Hospital and Research Centre, Lahore, Pakistan.<br />
Patients and methods: Of 638 females identified with ovarian cancer at our hospital<br />
from 1994 to 2007, 66 presenting with MOGCT were reviewed retrospectively.<br />
Histology was based on WHO classification. Tumors were staged according to FIGO<br />
system. Data was collected on presenting age, histopathology, stage, alpha-feto<br />
protein (AFP), B-human chorionic gonadotropins (B-hCG) levels, treatment, time to<br />
recurrence (TTR) and overall survival (OS). OS was <strong>the</strong> interval between <strong>the</strong> dates of<br />
diagnosis and last visit / death and TTR was between <strong>the</strong> dates of diagnosis and first<br />
recurrence. OS was determined by <strong>the</strong> Kaplan Meier method. Seven patients were<br />
not included in survival analysis as <strong>the</strong>y were lost to follow up.<br />
Results: Mean presenting age: 18.1 years (6-45). Stage wise distribution (n): Stage 1<br />
(19), II (8), III (21), IV (18). Histology (n): Dysgerminoma (22), malignant teratoma<br />
(16), yolk sac tumor (15), Mixed germ cell (12) and embryonic carcinoma in 1<br />
patient only. AFP levels (n): elevated (29), normal (25) while unknown in 12<br />
patients. B-hCG levels (n): elevated n = 15, normal n = 42 and unknown in 9. Median<br />
follow up time was 48 months (0.2-183). All patients underwent initial surgery, with<br />
20 patients undergoing second look surgeries. Fertility sparing procedures were<br />
performed in 57 % of patients. Thirty four patients (57 %) achieved a complete<br />
remission at <strong>the</strong> end of treatment; while 18 (27.2%) patients did not show a response<br />
to any chemo<strong>the</strong>rapy and had progressive disease. Seven patients relapsed, all within<br />
<strong>the</strong> first 3 years. The TTR was 11.2-32.5 months. Cumulative overall survival: 60<br />
months. 16 (88 %) of stage 1 patients while only 4 (26.6 %) of stage IV patients were<br />
alive at median follow up.<br />
Conclusions: The prognosis of MOGCT appears to be good and results are similar<br />
to what has been seen in <strong>the</strong> west. Fertility sparing surgery was possible in majority<br />
of cases and its feasibility should be explored in this young population of patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
995P DOES PACLITAXEL PLUS CARBOPLATIN (TC) SUBSTITUTE<br />
FOR PACLITAXEL PLUS CISPLATIN (TP) IN CERVICAL<br />
CANCER WITHOUT PRIOR PLATINUM TREATMENT? (SUBSET<br />
ANALYSIS OF JAPAN CLINICAL ONCOLOGY GROUP TRIAL<br />
(JCOG 0505))<br />
H. Tanabe 1 , R. Kitagawa 2 , T. Shibata 3 , M. Saito 1 , S. Takakura 1 , A. Okamoto 1 ,<br />
H. Sasaki 1 , K. Ochiai 1 , H. Yoshikawa 4 , T. Kamura 5<br />
1 Obstetrics and Gynecology, Jikei University School of Medicine, Tokyo, JAPAN,<br />
2 Obstetrics and Gynecology, NTT Medical Center Tokyo, Tokyo, JAPAN,<br />
3 Regulatory Science Section Multi-institutional Clinical Trial Support Center,<br />
National Cancer Center Hospital, Tokyo, JAPAN, 4 Obstetrics and Gynecology,<br />
Tsukuba University, Ibaraki, JAPAN, 5 Obstetrics and Gynecology, Kurume<br />
University School of Medicine, Kurume, JAPAN<br />
Objective: TP is <strong>the</strong> standard regimen for advanced or recurrent cervical cancer.<br />
However, JCOG0505 presented statistically significant non-inferiority of TC to TP in<br />
terms of overall survival (OS), for stage IVB or recurrent cervical cancer in ASCO ‘12<br />
annual meeting. By subset analyses of JCOG0505, we investigated whe<strong>the</strong>r <strong>the</strong><br />
treatment effect of TP or TC is different among some specific subgroups including<br />
<strong>the</strong> one by prior platinum status.<br />
Methods: Patients (Pts) with stage IVB or recurrent cervical cancer; not amenable to<br />
curative <strong>the</strong>rapy; 0-1 prior platinum; no prior taxanes; were randomized with<br />
minimization method to ei<strong>the</strong>r TP (T 135 mg/m 2 24h d1 + P 50 mg/m 2 2h d2) or TC<br />
(T 175 mg/m 2 3h d1 + C AUC5 1h d1), both for maximum 6 cycles every 21 days.<br />
We estimated <strong>the</strong> hazard ratios and 95% confidence intervals in OS among<br />
subgroups (including prior platinum status) for <strong>the</strong> eligible patients, comparing TC<br />
and TP. Each hazard ratio (HR) was estimated by an unstratified Cox regression.<br />
Results: Total 253 pts were enrolled. Median follow-up of all randomized patients is<br />
17.4 months (mo). As was reported before, it was demonstrated that TC was not<br />
inferior to TP for OS (17.5 mo in TC and 18.3 mo in TP, HR 0.99 (non-inferiority<br />
p = 0.032 with a non-inferiority margin 1.29)). Both arms were comparable with<br />
respect to toxicity except for grade 4 neutropenia (45% in TC vs. 75% in TP). In a<br />
subset analysis (n = 244), TP was superior to TC for OS in non-prior platinum group<br />
(n = 117) (13.0 mo in TC and 23.2 mo in TP, HR 1.57 (95% CI:1.06-2.32)). Contrary,<br />
TC tended to show better survival than TP for OS in prior platinum group (n = 127)<br />
(19.0 mo in TC and 16.3 mo in TP, HR 0.69 (95% CI:0.47-1.02)). Fur<strong>the</strong>rmore, TP<br />
tended to be superior to TC for OS in stage IVB (n = 51) (14.8 mo in TC and 25.4<br />
mo in TP, HR 1.50 (95% CI:0.84-2.67)).<br />
Conclusion: Non-inferiority of TC to TP was demonstrated in <strong>the</strong> whole population<br />
of JCOG0505. By <strong>the</strong> subset analyses, however, TP may be still <strong>the</strong> first choice for<br />
patients without prior cisplatin-based treatment such as those with primary stage<br />
IVB cervical cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
996P SHORTER SURVIVAL IN CERVICAL CANCER ASSOCIATION<br />
WITH HIGH EXPRESSION OF NOTCH-1<br />
N.G. Yousif 1 , J. Kamiran 2 , M.G. Yousif 3 , S. Anderson 2 , J. Albaghdadi 2<br />
1 Department of Medicine and Surgery, Box C-320, University of Colorado<br />
Cancer Center Anschutz Cancer Pavilion, Aurora, CO, UNITED STATES OF<br />
AMERICA, 2 Surgery, Colorado University, Aurora, CO, UNITED STATES OF<br />
AMERICA, 3 Biology, Al-Qadysia, IRAQ<br />
Background: Notch1 signaling has been shown to play a key role in carcinogenesis<br />
and progression of various human malignancies. Recent studies have implicated<br />
aberrant Notch signaling in cervical cancers. But, relatively little is known about <strong>the</strong><br />
relation between expression of <strong>the</strong> Notch1 and survival rate in cervical cancer. In this<br />
study, we investigated <strong>the</strong> expression of Notch1 in cervical cancer to determine<br />
whe<strong>the</strong>r <strong>the</strong>y could serve as prognostic predictors.<br />
Materials and methods: The expression of Notch1 was detected in 81 cases of<br />
cervical cancer; immunohistochemistry and Western blot were used to assay <strong>the</strong><br />
expression level of Notch1. The predictive value of this expression for prognosis was<br />
investigated by Kaplan-Meier curves in a multivariate model.<br />
Results: Notch1 factor were intensively stained in cervical cancer<br />
immunohistochemically and expression was significantly increased with age and not<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds401 | ix327
elated with stage, nodal involvement and recurrence. Moreover, expression of<br />
Notch1 showed strong immunoreactive bands in Western blot analysis, survival time<br />
in patients with high Notch1 expression was significantly shorter than that in<br />
patients with low expression (Long rank p value = 0.0175).<br />
Conclusions: High expression of Notch1 is potentially a useful marker for survival in<br />
patients with cervical cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
997P LONGTERM FOLLOW UP OF NEOADJUVANT CHEMOTHERAPY<br />
FOLLOWED BY SURGERY IN LOCALLY ADVANCED<br />
CARCINOMA OF THE CERVIX<br />
R. Majumder 1 , A. Mukhopadhyay 2 , S. Poddar 3 , A.N. Sen 1 , P. Gupta 2<br />
1 Surgical Oncology, Netaji Subhas Chandra BoseCancer Research Institute,<br />
Kolkata, INDIA, 2 Dept. Medical Oncology, Netaji Subhas Chandra BoseCancer<br />
Research Institute, Kolkata, INDIA, 3 Medical Oncology, Netaji Subhas Chandra<br />
BoseCancer Research Institute, Kolkata, INDIA<br />
Purpose: Neoadjuvant chemo<strong>the</strong>rapy in cancer of <strong>the</strong> cervix has been tested for its<br />
efficacy over <strong>the</strong> last two decades. We evaluated <strong>the</strong> outcome of patients treated with<br />
neoadjuvant chemo<strong>the</strong>rapy (NACT) followed by surgery for locally advanced bulky<br />
cancer of cervix.<br />
Methods: From July 2005 to August 2008 we treated 117 patients (median age 47<br />
years, range 38 years to 70 years) of locally advanced or bulky cancer of <strong>the</strong> cervix<br />
(stage IB2 to IIB) at Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata.<br />
The majority of <strong>the</strong> patients were of stage IIB (52%, N = 117). Squamous cell<br />
carcinoma was <strong>the</strong> most common histology (89%). All of <strong>the</strong>m had undergone 2-3<br />
cycles of platin-based chemo<strong>the</strong>rapy (Inj paclitaxel 175mg/m2 + Inj Carboplatin<br />
AUC 5) repeated every 21 days. Response assessment was done 2 weeks after <strong>the</strong> 2nd<br />
cycle. Good responders were taken for surgery and <strong>the</strong> rest were given 1 more cycle.<br />
After <strong>the</strong> 3rd cycle <strong>the</strong>y were assessed and good responders were taken for surgery<br />
and <strong>the</strong> rest were treated with chemoradiation.<br />
Results: The overall response rate was 72.4%. The 5-year overall survival (OS), and<br />
disease-free survival (DFS), were 64.5% and 78%, respectively. DFS was better in<br />
NACT good responders (84% vs 68%, p = 0.04). No difference in survival (OS) was<br />
seen according to tumor size ( 8cm, p = 0.67) or disease stage ( FIGO IB2<br />
vs IIA1 vs IIA2 vs IIB, p = 0.1). Chemo<strong>the</strong>rapy related morbidity was seen in 37%<br />
patients, surgery was delayed due to chemo toxicity in 15% of patients. Wound<br />
healing complication was seen in 26% of patients.<br />
Conclusion: Neoadjuvant chemo<strong>the</strong>rapy followed by surgery is an alternative<br />
treatment option in locally advanced carcinoma of <strong>the</strong> cervix with acceptable<br />
morbidity and should be tested in proper clinical trials against chemoradiation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
998P TO IMPROVE QUALITY OF LIFE OF REPRODUCTIVE AGE<br />
PATIENTS WITH CERVICAL CANCER<br />
V. Navruzova<br />
Oncogynaecology, National Cancer Center of Uzbekistan, Tashkent,<br />
UZBEKISTAN<br />
Background: Currently, <strong>the</strong>re is a steady increase in <strong>the</strong> incidence of cervical cancer,<br />
especially among young women aged 40 – 44. Along with radical treatment, an<br />
important aspect is a quality of life of patients after <strong>the</strong>rapy: 80% of women of<br />
reproductive age after ovarioectomy develop postovarioectomic syndrome, which<br />
includes <strong>the</strong> complex of pathological vegetovascular, neuro-psychiatric and<br />
metabolic-endocrine disturbances. In this connection <strong>the</strong>re is need for a way to<br />
preserve ovarian hormonal activity, so as to ensure <strong>the</strong> quality of life in women of<br />
reproductive age.<br />
Materials and methods: One of <strong>the</strong> methods to preserve ovarian function is to shield<br />
<strong>the</strong>m from radiation zone and it is called transposition. Our study included 189<br />
patients with cervical cancer (CC) T1b-2bN0-1M0 stage (I-III clinical stages) who were<br />
examined and treated at <strong>the</strong> department of Gynecology over 2007 to 2011. 1 st group<br />
comprised 90 (46.7%) patients, who received complex <strong>the</strong>rapy including surgery with<br />
transposition of <strong>the</strong> ovaries. 2 nd group comprised 99 (53.3%) patients, who<br />
underwent surgery without ovarian transposition in <strong>the</strong> complex <strong>the</strong>rapy.<br />
Results: In <strong>the</strong> main group patients complained of hot flushes - 2% (4 patients),<br />
sleep disturbance - 26% (26 patients), sexual dysfunction -19% (23 patients),<br />
sweating - 6% (5 patients), pain in bones - 19% (17 patients), weight gain - 29% (26<br />
patients). In <strong>the</strong> control group <strong>the</strong>re were observed hot flushes - 86% (85 patients),<br />
sleep disturbance - 25% (36 patients), sexual dysfunction - 42% (42 patients ),<br />
sweating - 19% (19 patients), bone pains 29% (29 patients), weight gain 38% (38<br />
patients). This indicates <strong>the</strong> more mild post-operative state of patients with ovarian<br />
transposition, as well as better tolerance of fur<strong>the</strong>r anticancer <strong>the</strong>rapy compared with<br />
<strong>the</strong> control group. The study of history data showed that most of <strong>the</strong> patients<br />
symptoms had manifested within 1 to 3 months (in 48.1% of patients), which<br />
disappeared after appropriate correction.<br />
Annals of Oncology<br />
Conclusion: Transposition of <strong>the</strong> ovaries during treatment for cervical cancer in<br />
women of reproductive age can improve <strong>the</strong> quality of life of patients and reduce <strong>the</strong><br />
terms of social and psychological rehabilitation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
999P MODERN OUTCOMES OF CERVICAL CARCINOMA IN<br />
MOROCCAN WOMEN TREATED WITH CONCURRENT<br />
CHEMORADIOTHERAPY<br />
S. Elmajjaoui 1 , N. Ismaili 2 , K. Hassouni 1 , T. Kebdani 1 , N. Benjaafar 1<br />
1 Radio<strong>the</strong>rapy, National Institute of Oncology, Rabat, MOROCCO, 2 Medical<br />
Oncology, Hassan II Hospital Centre Régional d’Oncologie d’Agadir, Agadir,<br />
MOROCCO<br />
Purpose: To report contemporary outcomes for nonmetastatic cervical cancer in<br />
Morrocan women treated in <strong>the</strong> modern area of concurrent chemoradio<strong>the</strong>rapy<br />
(CCRT).<br />
Methods: we retrospectively reviewed <strong>the</strong> chart of 379 patients with nonmetastatic<br />
invasive cervical carcinoma treated with CCRT between January 2006 and December<br />
2006. Staging was performed on a clinical basis according to <strong>the</strong> FIGO classification.<br />
Chemo<strong>the</strong>rapy was based on weekly cisplatin (40mg /m 2 ). Radiation treatment was<br />
based on external radio<strong>the</strong>rapy at a dose of 46 Gy followed by uterovaginal<br />
brachy<strong>the</strong>rapy or additional radio<strong>the</strong>rapy at a dose of 24 Gy. Overall survival (OS),<br />
event-free survival (EFS) and locoregional recurrence free survival (LRRFS) were<br />
estimated by <strong>the</strong> Kaplan-Meier method. Treatment groups were compared by using<br />
log rank tests. Cox proportional hazard methods were used to determine prognostic<br />
factors for outcomes.<br />
Results: Median age was 49 years (23-79 years). Bleeding was <strong>the</strong> main symptom<br />
(93.4%). Median tumor size was 7cm. About 3.7%, 28.5%, 1.3%, and 42.5% of <strong>the</strong><br />
patients were stages IB2, IIBd, IIIA, and IIIB, respectively. The most predominant<br />
histological type was squamous cell carcinoma (96.4%). Median follow-up was 35<br />
months(range2-78months).Therateofcompleteresponsewas93.9%.OS,EFS<br />
and LRRFS at 5 years were 76%, 56% and 82% respectively. On univariate<br />
analysis, we identified four prognostic factors: <strong>the</strong> stage, influencing OS, EFS and<br />
LRRFS (p < 0.001, p < 0.001 and p < 0.001, respectively); <strong>the</strong> tumor size,<br />
influencing OS and EFS (p = 0.034 and p = 0.019, respectively); <strong>the</strong> lymph node<br />
status (pelvic lymph node and/or para-aortic on imaging), influencing OS and<br />
EFS with trend to significance (p = 0.084 and p = 0.071, respectively). The<br />
anemia, influencing OS, EFS and LRRFS (p = 0.021, p = 0.027, and p = 0.087). On<br />
multivariate analysis, <strong>the</strong> stage was <strong>the</strong> only prognostic factor for OS ( p = 0.002),<br />
EFS and LRRFS.<br />
Conclusion: In Moroccan women with cervical carcinoma, CCRT is an efficient<br />
treatment which achieves a disease control in 93.9% of <strong>the</strong> cases. However, <strong>the</strong><br />
prognosis remains relatively poor due to delayed diagnosis. On univariate analysis,<br />
prognostic factors were <strong>the</strong> stage, tumor size, lymph node involvement, and anemia.<br />
On multivariate analysis <strong>the</strong> stage was <strong>the</strong> only prognostic factor.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1000P NEOADYUVANT CHEMOTHERAPY FOLLOWED BY<br />
CHEMORRADIATION IN LOCALLY-ADVANCED SQUAMOUS<br />
CERVICAL CANCER<br />
M. Vieito Villar 1 , N. Martinez Lago 1 , J.F. Cueva 1 , E. Gonzalez Patiño 2 ,M.<br />
T. Curiel 3 , P. Palacios Ozores 3 , S. Candamio Folgar 3 , N. Salvador Garrido 2 ,<br />
B. Taboada 4 , R. Lopez 1<br />
1 Dept. of Medical Oncology, Complejo Hospitalario Universitario de Santiago de<br />
Compostela SERGAS, Santiago de Compostela, SPAIN, 2 Radiocherapy<br />
Oncology, Hospital Clínico de Santiago de Compostela, Santiago de<br />
Compostela, SPAIN, 3 Medical Oncology, Hospital Clínico de Santiago de<br />
Compostela, Santiago de Compostela, SPAIN, 4 Oncoloxia Radioterápica,<br />
Hospital Clinico Universitario de Santiago, Santiago de Compostela, SPAIN<br />
Introduction: Although <strong>the</strong>re has not been a direct comparison between<br />
neoadjuvant chemo<strong>the</strong>rapy followed by chemor-radiation with <strong>the</strong> standard<br />
treatment of concurrent chemor-radiation, neoadjuvant chemo<strong>the</strong>rapy is active in<br />
squamous cervical cancer.<br />
Material and methods: In this open label 1 arm phase two trial we accrued 19<br />
patients from 2007 to 2011 diagnosed with squamous cervical cancer deemed to be<br />
unresectable and poor candidates to concurrent chemor-radiation. Patients had to<br />
be over 18 years of age, give informed consent, have a PS0-1 and adequate organ<br />
function.They received neoadjuvant chemo<strong>the</strong>rapy with paclitaxel 80mg/m 2 and<br />
cisplatin33mg/m 2 days 1,7,15/28 for two cycles and <strong>the</strong>n external radiation in 1.8<br />
Gy/ fraction with concurrent cisplatin 40mg/m 2 /weekly followed by brachy<strong>the</strong>rapy<br />
in 5-6 applications. After completion of neoadjuvant treatment and after<br />
concurrent chemor-radiation patients were evaluated by RECIST 1,1 criteria for<br />
tumor response with a CT scan and pelvic MNR and data of dose intensity and<br />
toxicity was accrued.<br />
ix328 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Results: Median age at diagnosis was 51 years (27 to 72 years); all <strong>the</strong> patients had<br />
PS1 due to local pain, as<strong>the</strong>nia or genital discharge. Neoadjuvant treatment was<br />
feasible in all patients with manageable toxicities; <strong>the</strong> dose intensity delivered was<br />
97% of <strong>the</strong> preplanned dose. Only 2 episodes of grade III anemia were observed.<br />
In <strong>the</strong> first radiologic evaluation 4 patients had a complete response, 12 had<br />
partial response and 3 disease stabilization. Patients received external<br />
radio<strong>the</strong>rapy in fractions of 1.8 Gy achieving a dose of 66 GY in patients that<br />
could not receive brachy<strong>the</strong>rapy. Mean EQD2C for those who did (68%) was 72<br />
GY. Only 68% of <strong>the</strong> patients received <strong>the</strong> full preplanned concomitant dose due<br />
to toxicity, mainly grade III anemia and diarrhea. In <strong>the</strong> second radiological<br />
evaluation 9 patients had a complete response, 9 partial and only 1 stable disease.<br />
At a mean of 24 months of follow up only 5 patients (26%) thus far have<br />
developed recurrent disease, all of <strong>the</strong> recurrences were simultaneously local as<br />
well as systemic.<br />
Conclusion: Our weekly cisplatin-paclitaxel regimen has been demonstrated to be<br />
feasible and effective in terms of dose delivery, tolerance and radiological responses<br />
without compromising definitive treatment with chemor-radiation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1001P A PHASE II MULTICENTER RANDOMIZED OPEN-LABEL<br />
STUDY OF ORAL STEROID SULPHATASE (STS) INHIBITOR<br />
IROSUSTAT (BN83495) VERSUS MEGESTROL ACETATE (MA)<br />
IN WOMEN WITH ADVANCED/RECURRENT ENDOMETRIAL<br />
CANCER (EC)<br />
P. Pautier 1 , F. Joly Lobbedez 2 , B. Melichar 3 , E. Kutarska 4 , G. Hall 5 , N. Reed 6<br />
1 Medical Department, Institut Gustave-Roussy, Villejuif, FRANCE, 2 Service<br />
d’Oncologie Médicale, Centre François Baclesse, Caen, FRANCE, 3 Oncology,<br />
University Hospital Olomouc Palacky University, Faculty of Medicine, Olomouc,<br />
CZECH REPUBLIC, 4 Oddział Onkologii Ginekologicznej Radioterapii I<br />
Chemioterapii, Centrum Onkologii Ziemi Lubelskiej im. s´ w. Jana z Dukli, Lublin,<br />
POLAND, 5 St James’s Institute of Oncology, St James’s University Hospital,<br />
Leeds, UNITED KINGDOM, 6 Beatson Oncology Centre, Gartnavel General<br />
Hospital, Glasgow, UNITED KINGDOM<br />
Background: Despite <strong>the</strong> progress in <strong>the</strong> diagnosis and <strong>the</strong>rapy of early EC,<br />
advanced (metastatic) or recurrent EC remains an incurable disease. Irosustat (also<br />
known as BN83495, STX64 and 667-coumate) is a selective irreversible STS inhibitor<br />
developed for <strong>the</strong> treatment of hormone-dependent tumors. Objective: A phase II,<br />
randomized, open-label study was designed to explore <strong>the</strong> safety and efficacy of<br />
irosustat as a single agent in advanced/recurrent EC.<br />
Methods: Post-menopausal women with histologically verified estrogen and/or<br />
progesterone receptor-positive EC (defined as ≥10% positive cells in primary tumor<br />
or metastasis), with recurrent/advanced disease, at least one measurable target lesion,<br />
life expectancy ≥6 months, not eligible for surgery or radio<strong>the</strong>rapy and no prior<br />
systemic treatment for EC (except adjuvant chemo<strong>the</strong>rapy if completed ≥1 year<br />
before randomization) were randomized 1:1 to daily oral irosustat 40 mg or MA 160<br />
mg. The primary endpoint was <strong>the</strong> percentage of patients alive without progression<br />
after 6 months of treatment. Blinded central review of responses (evaluated using<br />
RECIST 1.0) was performed. Secondary endpoints included progression-free survival<br />
(PFS), time to progression, overall survival, quality of life and safety.<br />
Results: 73 patients were enrolled in 11 European countries, 36 were randomized to<br />
irosustat and 37 to MA. Median age was 68 years (range 37-85 years).<br />
Treatment-related severe toxicities (grade 3-4) were symptomatic hyponatremia,<br />
as<strong>the</strong>nia, dry skin and worsening of hypertension for irosustat (n = 1) and<br />
pulmonary embolism (n = 3, 1 led to death) and hyperglycemia with MA.<br />
Conclusion: This study demonstrates clinical benefit of hormonal treatment<br />
(irosustat and MA) in selected patients with advanced/recurrent EC with a different<br />
toxicity profile.<br />
Irosustat(n = 36) Megestrol acetate(n = 37)<br />
Alive without progression at<br />
6 months n (%)<br />
13 (36.1) 21 (56.8)<br />
Response (CR + PR) n (%) 4 (11.1) 12 (32.4)<br />
Stable disease n (%) 17 (47.2) 12 (32.4)<br />
Median PFS (weeks)<br />
[90% CI]<br />
16 [9-34] 32 [16-63]<br />
Disclosure: P. Pautier: Author is an advisory board member for Roche and Ipsen. F.<br />
Joly Lobbedez: Author is an advisory board member for Sanofi, Roche, Novartis,<br />
Janssen, Ferring, Pfizer. No conflit of interest with Ipsen or BN83495. N. Reed:<br />
Consultancy fees and lecturing for Novartis, Roche, AZ, Johnson and Johnson,<br />
Otsuka. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1002P THE ROLE OF INTRAVAGINAL BRACHYTHERAPY IN<br />
SURGICALLY-STAGED 1988 FIGO STAGE IC GRADE 3<br />
ENDOMETRIAL CANCER<br />
B. Barney 1 , I.A. Petersen 1 , J.A. Call 1 , A. Gro<strong>the</strong>y 2 , M.G. Haddock 1<br />
1 Radiation Oncology, Mayo Clinic, Rochester, MN, UNITED STATES OF<br />
AMERICA, 2 Medical Oncology, Mayo Clinic, Rochester, MN, UNITED STATES<br />
OF AMERICA<br />
Purpose/objectives: Patients with 1988 International Federation of Gynecology and<br />
Obstetrics (FIGO) Stage IC grade 3 (ICgr3) endometrial cancer (EC) were excluded<br />
or underrepresented on practice-defining intermediate-risk EC trials due to relatively<br />
high rates of occult nodal and/or distant metastasis. Adjuvant <strong>the</strong>rapy<br />
recommendations in this population vary widely, but standard practice is to offer<br />
adjuvant pelvic external beam radio<strong>the</strong>rapy (EBRT) +/- chemo<strong>the</strong>rapy. We report<br />
our single-institution’s experience using adjuvant high-dose rate (HDR) vaginal<br />
brachy<strong>the</strong>rapy (VBT) alone +/- chemo<strong>the</strong>rapy for patients with surgically-staged<br />
1988 FIGO ICgr3 EC.<br />
Methods: From 1998 to 2011, 47 women with FIGO ICgr3 EC underwent TAH/BSO<br />
with pelvic/paraaortic lymph node dissection (median nodes evaluated, 47; range,<br />
5-88) followed by VBT. All VBT was performed using a multi-channel cylinder,<br />
treating <strong>the</strong> entire vaginal mucosa from <strong>the</strong> cuff to within 1-2 cm of urethral meatus<br />
to 21 Gy in 3 fractions. No patient received pelvic EBRT. Twenty-one patients (45%)<br />
also received 3 to 6 cycles of adjuvant platinum-based chemo<strong>the</strong>rapy.<br />
Results: At a median follow-up of 30 months (range, 1 to 127 months), 3 patients<br />
had experienced a vaginal relapse (VR), and <strong>the</strong> 3-year Kaplan-Meier (KM) estimate<br />
of VR was 8%. Rates of isolated pelvic (PR), locoregional (LRR, VR + PR), and<br />
distant relapse (DR) were similarly low, with 3-year estimates of 3, 10, and 14%,<br />
respectively. Estimates for 3-year disease-free (DFS) and overall survival (OS) were 87<br />
and 80%, respectively. On univariate analysis, administration of chemo<strong>the</strong>rapy<br />
significantly correlated with improved DFS (p = 0.03).<br />
Conclusions: Rates of isolated vaginal and pelvic relapse after VBT +/chemo<strong>the</strong>rapy<br />
in <strong>the</strong>se women with surgically-staged 1988 FIGO ICgr3 EC were<br />
comparable to those seen with pelvic EBRT, implying additional radio<strong>the</strong>rapy is<br />
likely unnecessary. Adjuvant platinum-based chemo<strong>the</strong>rapy was associated with<br />
improved disease-free survival. While VBT reduced <strong>the</strong> rate of pelvic relapse, <strong>the</strong><br />
vagina remained <strong>the</strong> most common pelvic site of recurrence.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1003P TREATMENT OUTCOMES AND PROGNOSTIC FACTORS IN<br />
MEXICAN PATIENTS WITH ENDOMETRIAL CARCINOMA:<br />
THE LATIN AMERICAN EXPERIENCE<br />
C. Flores-Balcázar 1 , A. Alvarado-Zermeño 2 , M. Blake-Cerda 2 , A. Mota-García 2 ,<br />
A. Poitevin-Chacón 3 , S. Rosales-Pérez 4 , G. Trejo-Duran 2<br />
1 Radioterapia, Instituto Nacional de Cancerologia, Mexico City, MEXICO,<br />
2 Radioterapia, Instituto Nacional de Cancerelogía, Mexico City, MEXICO,<br />
3 Radioterapia, Hospital Medica Sur, Mexico City, MEXICO, 4 Depto. Radioterapia,<br />
Instituto Mexicano del Seguro Social, Mexico City, MEXICO<br />
Aim: To analyze <strong>the</strong> clinical characteristics and treatment outcomes in patients with<br />
endometrial carcinoma treated in a Latin American institute with emphasis on<br />
patients receiving radio<strong>the</strong>rapy and chemo<strong>the</strong>rapy after surgery.<br />
Methods: A total of 412 patients with endometrial carcinoma admitted to our<br />
hospital between 1999 and 2008 were evaluated retrospectively. The mean age was 55<br />
years (28-87). Two hundred seventy patients received RT following surgery. Stage<br />
distribution was as follows: 221 patients (54%) stage I, 86 patients (21%) stage II, and<br />
103 patients (24.5%) stage III and 2 patients (0.5%) stage IVA.<br />
Results: Overall survival rate was 95% at 2 years, 84% at 5 years and 79% at 10 years.<br />
By <strong>the</strong> end of follow up, 338 patients (82%) were disease-free, and 13 (3%) were alive<br />
with disease. Univariate and multivariate analyses identified age, grade, serosal and<br />
adnexial involvement as significant predictors for overall survival.<br />
Conclusion: The results of our study suggests that early stage, low-grade endometrial<br />
cancer with no risk factors should not receive external beam radio<strong>the</strong>rapy,<br />
intermediate risk patients should receive only vaginal vault brachy<strong>the</strong>rapy and <strong>the</strong><br />
use of chemo<strong>the</strong>rapy with radio<strong>the</strong>rapy for patients high risk and advanced stage<br />
carcinoma <strong>the</strong> addition of radio<strong>the</strong>rapy is associated with a better survival being an<br />
effective <strong>the</strong>rapeutic option. To our knowledge this is <strong>the</strong> largest series exploring <strong>the</strong><br />
characteristics of Mexican patients treated for endometrial carcinoma in literature.<br />
We conclude that adjuvant radio<strong>the</strong>rapy should be considered an integral component<br />
of definitive treatment for women with unfavorable disease as a mean to decrease<br />
mortality and improve patient outcome.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds401 | ix329
1004P CASE CONTROL STUDY ON TWO DIFFERENT<br />
CHEMOTHERAPY REGIMENS IN ADVANCED MIXED<br />
MULLERIAN TUMOURS<br />
M. Mancini 1 , S. Ramondino 1 , R. Di Rocco 1 , M. Ratti 1 , D. Lorusso 1 ,<br />
F. Raspagliesi 2<br />
1 Gynecology Oncology, Fondazione IRCCS National Cancer Institute of Milan,<br />
Milan, ITALY, 2 Department of Gynaecologic Oncology, National Cancer Institute<br />
of Milan, Milan, ITALY<br />
Background: Malignant mixed Mullerian tumours (MMMTs) of <strong>the</strong> uterus and<br />
adnexa represent aggressive gynaecologic malignancies with a high rate of<br />
loco-regional and distant failure. There is no consensus in <strong>the</strong> community about <strong>the</strong><br />
preferred chemo<strong>the</strong>rapy regimen in this population. We evaluated two different<br />
chemo<strong>the</strong>rapy combinations in terms of toxicity and oncologic outcome in patients<br />
with advanced MMMTs.<br />
Methods: Female patients with advanced MMMTs, residual tumor < 1 cm at<br />
cytoreductive surgery, no prior chemo<strong>the</strong>rapy, normal haemopoietic and organ<br />
function were eligible. Chemo<strong>the</strong>rapy was administered according to two different<br />
regimens: Cisplatin 20 mg/mq- Ifosfamide 1500 mg/mq d 1-4 q 21+ Pegfilgrastim<br />
(Group A) and Carboplatin AUC 5-Paclitaxel at 175 mg/m2 day 1 q21 (Group B).<br />
Results: Twenty-four patients (pts) of a median age 64 (49-75) years, performance<br />
status
Annals of Oncology<br />
no postoperative mortality and no excess in morbidity. One patient needed a<br />
re-intervention due to large lymphocoeles. At 3 years OS and DFS were 81% and<br />
91% respectively in <strong>the</strong> wer<strong>the</strong>im group. Non of patients in <strong>the</strong> brachy<strong>the</strong>rapy group<br />
survived 3 years.<br />
Conclusion: Wer<strong>the</strong>im surgery following IMAT ± cisplatin is associated with no<br />
mortality and acceptable morbidity IMAT has low toxicity and is excellent in<br />
rendering irresectable cervical cancer resectable.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1008 THE ROLE OF FUNCTION- SPARING SURGERIES IN PATIENTS<br />
WITH INVASIVE LOCALLY ADVANCED CERVICAL CANCER<br />
V. Navruzova 1 , S. Navruzov 2<br />
1 Oncogynaecology, National Cancer Center of Uzbekistan, Tashkent,<br />
UZBEKISTAN, 2 Administration, National Cancer Center of Uzbekistan, Tashkent,<br />
UZBEKISTAN<br />
Background: The incidence rate among young women leads to <strong>the</strong> necessity of <strong>the</strong><br />
development of new methods and improvement of used surgical, combined and<br />
complex treatment for patients with locally spread cervical cancer (LACC).As a result<br />
of large radical operations, different complications which quite often result in<br />
“qualitative characteristic of life” (physical, functional, psychological and social) with<br />
feasible disability of women are possible. Surgical deprivation of ovarian function<br />
leads to a sharp fall-off of <strong>the</strong> level of sex hormones (first of all, estradiol) in blood.<br />
Patients with bilateral salpingo-oophorectomy, particularly at young age, have<br />
long-term effects of estrogen deficit of more severe character than women with<br />
natural menopause. For patients with invasive and LACC ovarian transposition <strong>the</strong><br />
function- sparing surgery is <strong>the</strong> option in order to exteriorize <strong>the</strong>m from supposed<br />
fields of radiation in patients with invasive and locally advanced cervical cancer.<br />
Material and methods: 156 patients with LACC received complex treatment that<br />
included surgery expansion of extended uterectomy with ovarian transposition at<br />
National Oncological Research Centre of MH of RUz over 2008-<strong>2012</strong> yy. Patients aged<br />
from 23 to 45 yrs. Follow–up period were from 1 month till 3 years. Reproductive age<br />
patients with ovarian transposition had <strong>the</strong> level of sex hormones in blood according<br />
to normal in 94,7% cases after conducted surgery. Estradiol level in patients’ blood was<br />
up to143,6 ng/ml (normal -phase 77-277 ng/ml) in preoperative period.This rate being<br />
up to 140 ng/ml after surgery. After radio<strong>the</strong>rapy <strong>the</strong>se patients’ rate of estradiol level<br />
in blood made up to139 ng/ml. This showed that ovarian function (gonads) is retained<br />
for 80 % of patients after performing of radio<strong>the</strong>rapy.<br />
Conclusions: Our study results showed that <strong>the</strong> conduction of organ-preserving<br />
exposure allows not only to cure <strong>the</strong> malignant process at early stages of its advance<br />
without lowering of <strong>the</strong>rapy effect but also to preserve <strong>the</strong> important functions of<br />
woman body that promote full-fledged medical and social rehabilitation of patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1009 PROGNOSTIC FACTORS AND TREATMENT OF CERVICAL<br />
CANCER (CC) IN ELDERLY<br />
I.Q.S. Caires 1 , R.C.A.D. Lima 1 , R. Barroso-Sousa 1 , E.M.P.D. Andrade 2 ,<br />
J.R.D. Silva 3 , F.B. Sanchez 3 , P.M. Hoff 1 , M. Diz 1<br />
1 Clinical Oncology, Instituto do Câncer do Estado de São Paulo, São Paulo,<br />
BRAZIL, 2 Clinical Medicine, Hospital Agamenon Magalhães, Recife, BRAZIL,<br />
3 Faculdade De Medicina, Universidade de São Paulo, São Paulo, BRAZIL<br />
Background: Cancer diagnostics in <strong>the</strong> elderly is increasing over <strong>the</strong> years. Although<br />
elderly represent less than 10% of CC patients (pts), <strong>the</strong>y usually present more<br />
advanced disease and do’t receive aggressive treatment.<br />
Methods: Retrospective analysis of pts ≥ 70 years old with CC consecutively admitted<br />
at single institution from Aug/2002 up to Feb/<strong>2012</strong>. Primary endpoint was overall<br />
survival (OS). Secondary endpoint was assessment of prognostic factors for OS and<br />
treatment received. Survival was estimated using <strong>the</strong> Kaplan-Meier methods, <strong>the</strong><br />
curves were compared by <strong>the</strong> log-rank test and frequencies with chi-square test.<br />
Results: 70 pts were analyzed (7.5% of all CC pts). Median age was 76 years old<br />
(range, 70-91y). Squamous carcinoma was <strong>the</strong> most common histological type (61<br />
pts, 87.1%), 57 (81.4%) were performance status (PS) 0 or 1 and 37 (52.5%) were<br />
eutrophic (Body Mass Index 18.5- 25 Kg/m 2 ). In terms of initial staging, 14 pts<br />
(20%) were stage I, 30 pts (42.8%) II, 10 pts (14.2%) III, 14 pts (20%) IVa and 2 pts<br />
(2.8%) IVb. Regarding <strong>the</strong> treatment, 32 pts (45.7%) underwent chemoradio<strong>the</strong>rapy<br />
(CRT), 19 pts (27.1%) isolated radio<strong>the</strong>rapy (RT), 12 pts (17.1%) surgery and 7 pts<br />
(10%) best supportive care (BSC). Among CRT pts, 19 (59.3%) completed <strong>the</strong> full<br />
treatment (platinum-based chemo<strong>the</strong>rapy administered for 6 weeks concomitantly<br />
with external radio<strong>the</strong>rapy in <strong>the</strong> pelvis, total dose of 45 Gy, and 4 inserts from 7 to<br />
7.5 Gy of brachy<strong>the</strong>rapy); 16 (50%) received cisplatin and 16 (50%) carboplatin. In a<br />
median follow up of 15.3 mo (range, 0.1- 79.8 mo), mean OS was 79.8 mo for all pts<br />
in this analysis. Hemoglobin level ≥ 10 mg/dL pretreatment correlated with better<br />
mOS (HR 0.10; IC95% 0.02 to 0.42; p = 0.002), while creatinine ≥ 1 mg/dL before <strong>the</strong><br />
treatment (HR 8.1; IC95% 1.87 to 34.88; p = 0.005) was considered risk factor to<br />
mortality. Pts who received QRT, RT had better mOS (HR 0,18; IC 95% 0,06 to 0.54;<br />
p= 0.002). Age, PS, BMI and comorbidities (pneumopathy, cardiopathy, dementia)<br />
did’t correlate with mOS.<br />
Conclusions: CRT is feasible in <strong>the</strong> elderly. Pts submitted to QRT, RT had better<br />
survival than those who did not undergo treatment and age alone can not be used to<br />
decide <strong>the</strong> conduct. Pts at baseline with Hb < 10 mg/dL and kidney disfunction had a<br />
poor prognosis.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1010 A RETROSPECTIVE ANALYSIS OF CERVICAL CANCER<br />
PATIENTS TREATED WITH CARBOPLATIN AND PACLITAXEL<br />
IN FIRST PALLIATIVE LINE AT BRAZILIAN NATIONAL CANCER<br />
INSTITUTE (INCA)<br />
A.H. Ingles Garces 1 , P. Mora 2 , F. Alves 2 , A. Mangia 2 , C. Calazan 2 ,<br />
A. Rodrigues 2 , A. Melo 2<br />
1 Oncologia Clínica, Instituto Nacional do Cancer - INCA 2, Rio de Janeiro,<br />
BRAZIL, 2 Oncologia Clínica, Insituto Nacional do Cancer - INCA 2, Rio de<br />
Janeiro, BRAZIL<br />
Cervical cancer represents a public health problem. Currently, it is <strong>the</strong> second most<br />
common neoplasia worldwide, with approximately 85% of <strong>the</strong> cases in developing<br />
countries. Most of <strong>the</strong> patients presents with advanced disease. The treatment based<br />
on cisplatin and radio<strong>the</strong>rapy is considered standard to patients with locally<br />
advanced cervical cancer, stages IIB to IVA. However, <strong>the</strong> results are not good<br />
enough, especially in stages III e IVA, which shows five-year survival rates of 40 and<br />
15%, respectively. The combination of cisplatin and paclitaxel (CDDP + P) is <strong>the</strong><br />
standard treatment in first palliative line in several oncology institutions. The<br />
replacement of CDDP by carboplatin (C) is regularly done and probably presents less<br />
non-hematologic toxicity; however, <strong>the</strong>re is no data in <strong>the</strong> literature related to <strong>the</strong><br />
specific efficacy and toxicity to <strong>the</strong> combination of C + P in this context. At INCA,<br />
<strong>the</strong> combination of C + P has been <strong>the</strong> standard treatment in first palliative line since<br />
August 2008.<br />
Objectives: To evaluate response rate (RR), progression-free survival (PFS), overall<br />
survival (OS) and toxicity of patients with recurrent or metastatic cervical cancer<br />
treated with C + P.<br />
Material and methods: A retrospective analysis of cervical cancer patients treated<br />
with C + P in first palliative line at INCA, between August 2008 and January 2010.<br />
Results: A total of 154 patients were enrolled in <strong>the</strong> study. The most frequent<br />
histology was squamous carcinoma and 51.3 % of <strong>the</strong> patients were diagnosed as<br />
stages III and IV. 50% of <strong>the</strong> patients received 6 or more cycles of C + P as first<br />
palliative line. Objective responses were documented in 35.1% (5.2% complete<br />
responses plus 29.9 % partial responses). The median PFS and OS was 4.07 (IC95%<br />
2.8 – 5.3) and 8.4 (IC95% 6.2 – 10.7) months respectively. Hematologic toxicity was<br />
<strong>the</strong> most common: Grade 3 and 4 anemia, neutropenia and thrombocytopenia were<br />
42.2%, 18.1% and - 9.1%, respectively.<br />
Conclusion: Indirect comparison with published data of <strong>the</strong> prospective trial using<br />
CDDP + P our results were only slightly different, probably related to differences in<br />
patients clinical and demographics data.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1011 BORDERLINE TUMORS OF THE OVARY: 19 YEARS<br />
EXPERIENCE FROM A TERTIARY CENTER IN SOUTH INDIA<br />
K. Kannan, N. Sridharan, R. Pourrli Neelakantan<br />
Introduction: Borderline tumours of <strong>the</strong> ovary are neoplasms of low malignant<br />
potential (LMP) and constitute 10-15% of all epi<strong>the</strong>lial ovarian cancers. This<br />
retrospective analysis was done to determine <strong>the</strong> outcome of patients with LMP<br />
tumours treated at our institution.<br />
Methods and results: Data was collected from <strong>the</strong> department master records which<br />
were updated at every patient visit. Between 1993 and 2008, 68 patients were<br />
diagnosed with LMP tumours of ovary. The median age at presentation was 39.8<br />
years. Sixty percent of patients were post menopausal. Eight patients presented with<br />
infertility (11.7%). Ascites was present in 50% of patients. Forty nine patients<br />
underwent radical surgery (72%) and 19 patients had fertility sparing surgery (FSS)<br />
(28%). Mucinous tumours were seen in 39 patients (57.3%), serous in 25 patients<br />
(36.7%), Brenner tumour in three (4.4%) and endometroid tumour in one patient<br />
(1.4%). Fifty five patients presented in FIGO stage I (80%) and 13 patients in stage<br />
III (20%). Micropapillary serous tumours were seen in eight patients (11.7%),<br />
invasive peritoneal implants in five patients (7.3%) and microinvasion in four<br />
patients (5.8%). Seven patients underwent chemo<strong>the</strong>rapy post operatively. The<br />
median overall survival (OS) was 178 months and <strong>the</strong> median progression free<br />
survival (PFS) was 175 months. Micropapillary serous tumours, invasive peritoneal<br />
implants, microinvasion, suboptimal surgery and advanced stage were found to be<br />
poor prognostic factors for PFS and OS on univariate analysis. Recurrence was seen<br />
in seven patients of whom five patients died of progressive disease. Eighteen patients<br />
are on follow up and are free from disease. There was no difference in outcome<br />
between patients who underwent radical surgery and FSS (p = 0.11). Seven out of<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds401 | ix331
eight patients who had infertility at diagnosis were able to conceive and deliver<br />
normally after treatment.<br />
Conclusion: Borderline ovarian tumours have an excellent prognosis. Fertility<br />
sparing surgery is a feasible option in <strong>the</strong>se patients and is compatible with a<br />
favourable long term outcome.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1012 THE PROGNOSTIC FACTOR ANALYSIS OF MALIGNANT<br />
MIXED MüLLERIAN TUMOR; BASED ON<br />
CLINICOPATHOLOGIC FACTORS<br />
B. Kang 1 , S. Noh 2 , S. Lee 3<br />
1 Internal Medicine, Yonsei Univ. Severance Hospital, Seoul, KOREA, 2 Pathology,<br />
Yonsei Univ. Severance Hospital, Seoul, KOREA, 3 Department of Internal<br />
Medicine, Yonsei University College of Medicine, Seoul, KOREA<br />
Background: Malignant mixed müllerian tumor (MMMT) is a rare and highly<br />
aggressive malignancy with biphasic pathologic characteristics; epi<strong>the</strong>lial and<br />
mesenchymal components. Until now, its prognosis is still poor and <strong>the</strong>re is no<br />
individualized <strong>the</strong>rapy according to <strong>the</strong> biological characteristics. The aim of this<br />
study was to analyze <strong>the</strong> clincopathological features and identify <strong>the</strong> prognostic<br />
factors which impact <strong>the</strong> survival outcome.<br />
Methods: A retrospective review of patients with MMMT who treated between 1994<br />
and 2011 in our institution was undertaken. The clinical variables such ad age, BMI,<br />
CA-125 at diagnosis, stage, extent of surgery, pathologic findings, adjuvant<br />
chemo<strong>the</strong>rapy and radiation <strong>the</strong>rapy were analyzed. Univariate and multivariate<br />
analysis were done.<br />
Results: The study included 62 patients. The median age was 58 years<br />
(range37.8-79.6). FIGO stages I, II, III, and IV were identified in 38.7%, 4.8%, 32.3%,<br />
and 24.2% respectively. Epi<strong>the</strong>lial dominant, similar, and mesenchymal dominant<br />
pathologic type were 56.3%, 16.7%, and 27.1%. Fifty nine of 62 patients had<br />
undergone hysterectomy and salpingo-oophrectomy and 43 of 62 patients had<br />
lymphadenectomy. Chemo<strong>the</strong>rapy was given to 50 patients (ifosfamide + cisplatin 17,<br />
taxol/taxotere + cisplatin 17, ifosfamide mono 4, o<strong>the</strong>r regimens 14). The pattern of<br />
recurrence was mainly local. Median progression-free- survival after diagnosis is only<br />
13.3months and median overall survival is 18.3months. Adjuvant chemo<strong>the</strong>ray and<br />
radiation <strong>the</strong>rapy had no significant survival benefit. Univariate analysis showed<br />
CA-125 at diagnosis (HR 2.39; p = 0.02), FIGO stage I, II vs III, IV (HR 4.07; p = 0.00),<br />
myometrial invasion depth (HR 0.87; p = 0.05), lymphovascular invasion(HR 2.35; p<br />
= 0.03), and lymphadenectomy (HR 0.37; p = 0.01) had an independent influence on<br />
progression free survival. In multivariate analysis, FIGO stage I, II vs III, IV (p = 0.05)<br />
and lymphadenectomy (p = 0.05) were significant. However, pathologic type and<br />
chemo<strong>the</strong>rapy regimen were not associated with risk of recurrence or death.<br />
Conclusions: According to this study, <strong>the</strong> comprehensive surgical staging is more<br />
important to predict <strong>the</strong> prognosis than its pathologic characteristics. Fur<strong>the</strong>r molecular<br />
studies are needed to find out for breakthrough <strong>the</strong> poor prognosis of MMMT.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1013 PREDICTING FACTORS OF SECONDARY RESECTION AFTER<br />
NEOADJUVANT CHEMOTHERAPY IN LOCALLY ADVANCED<br />
EPITHELIAL OVARIAN CANCERS. A RETROSPECTIVE STUDY<br />
OF 82 CASES<br />
L. Ben Fatma 1 , S. Said 1 , M. Boudagga 1 , M. Hochlef 1 , F. Zairi 1 , H. Khairi 2 ,<br />
O. Gharbi 1 , H. Boussen 3 , S Ben Ahmed 1<br />
1 Medical Oncology, Hopital Farhat Hached, Sousse, 2 Gynecologic Dept, Hopital<br />
Farhat Hached Sousse and, 3 Medical Oncology, Hopital A Mami, Tunis, TUNISIA<br />
Objective: The aims of our study were to assess <strong>the</strong> rate of optimal interval<br />
debulking surgery (IDS) and <strong>the</strong> potential predictors of chemo<strong>the</strong>rapy responsiveness<br />
in patients treated with neoadjuvant chemo<strong>the</strong>rapy(NACT).<br />
Methods: We present a retrospective study including 82 EOC cases (stage IIIC or IV)<br />
collected in <strong>the</strong> medical oncology department of Farhat Hached Hospital-Sousse<br />
(Tunisia) during a period of 9 years (from 2002 to 2010). All patients received<br />
NACT followed by a clinical, radiological and biological assessment.<br />
Results: The mean age of our patients was 54.5 years (27-80 years). Stage IIIC<br />
represented 69.5% of all cases and stage IV 30.5% (8 cases with pleural metastases,<br />
14 cases with liver metastases, and 3 with pleural and liver metastases). CA-125<br />
serum level was normal in only 7 cases. All patients received a mean number of 5<br />
cycles of platinum-based NACT associated with paclitaxel in 78% of cases. Twenty<br />
seven patients achieved complete clinical response (CCR), 28 a partial clinical<br />
response (PCR) and 17 cases have disease progression. In 46/82 pts(56%), serum<br />
CA-125 was normalized after NACT. Ten patients achieved a radiological CR.<br />
Radiological PR was noted in 44 cases, while 19 patients had radiological disease<br />
progression. The rate of secondary resection was 51% (61.4% for stage IIIC and 28%<br />
for stage IV). Thirty one patients (74%) had an optimal IDS. We observed 9<br />
pathological complete responses (pCR). Secondary optimal resection was<br />
significantly correlated to CA-125 serum level at <strong>the</strong> end of NACT (p = 0.001) and<br />
Annals of Oncology<br />
<strong>the</strong> quality of radiological response (CR or PR) (p = 0.001). Overall survival was 28.4<br />
months, significantly better in cases of clinical or radiological complete response<br />
(p = 0.001) and in patients with optimal IDS (p = 0.01). pCR was associated with<br />
higher survival but without significant value (p = 0.08). In multivariate analysis, <strong>the</strong><br />
parameters predicting a prolonged survival were: radiological complete or partial<br />
response (p = 0.05), optimal surgery (p = 0.001) and pCR (p = 0.03).<br />
Conclusion: In initially unresectable EOC, NACT platinum-based chemo<strong>the</strong>rapy<br />
followed by IDS is a <strong>the</strong>rapeutic alternative leading to a higher rate of optimal<br />
surgery with an improvement of survival. Pre-operative CA-125 serum level as well<br />
as <strong>the</strong> radiological response appeared to be good predictors of secondary R0 surgery<br />
and tumor chemosensitivity.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1014 IMPACT OF CHEMOTHERAPY BEYOND THE THIRD LINE IN<br />
PATIENTS WITH RECURRENT EPITHELIAL OVARIAN CANCER<br />
L. Mansi 1 , E. Kalbacher 1 , M. Demarchi 2 , F. Bazan 3 , M. Schneider 4 , A. Vuillemin 5 ,<br />
S. Bernhard 6 , V. Nerich 7 , C. Borg 8 , X. Pivot 9<br />
1 Doubs, Oncology, Besancon, FRANCE, 2 Valencia, Oncology, Valencia, SPAIN,<br />
3 Besancon, Oncology, Besancon, FRANCE, 4 Nice, Oncology, Nice, FRANCE,<br />
5 Medical Oncology, Hôpital Jean Minjoz, Besançon, FRANCE, 6 Department of<br />
Medical Oncology, University Hospital J. Minjoz, Besancon, FRANCE,<br />
7 Pharmacy, Hopital Minjoz, Besançon, FRANCE, 8 Medical Oncology, University<br />
Hospital Besançon, Besançon, FRANCE, 9 Medical Oncology, Hopital Minjoz,<br />
Besançon, FRANCE<br />
Objectives: The goal of this study was to determine <strong>the</strong> benefit in terms of time to<br />
disease control (TDC) achieved by <strong>the</strong> succession of chemo<strong>the</strong>rapy lines beyond <strong>the</strong><br />
third line in patients treated for recurrent epi<strong>the</strong>lial ovarian cancer (EOC). Secondary<br />
objective were to identify patients who benefit from treatments beyond line three,<br />
and overall survival beyond <strong>the</strong> fourth line.<br />
Methods: The cohort of patients was identified from a pharmacy database of<br />
cytotoxic chemo<strong>the</strong>rapy administered between 1992 and 2010 at our regional center.<br />
Among 591 cases of EOC, a total of 122 patients were treated by more than 3 lines<br />
of chemo<strong>the</strong>rapy. The evaluation of benefit obtained by each chemo<strong>the</strong>rapy lines was<br />
based on TDC. Cox proportional hazards model was used to identify factors that<br />
could influence <strong>the</strong> TDC in each line of chemo<strong>the</strong>rapy. Survival data was computed<br />
according to Kaplan-Meier method.<br />
Results: Median OS was 53 months (95% CI, 47 to 67 months), and median OS<br />
after <strong>the</strong> third line was 15,3 months (95% CI, 12 to 20 months). Factors associated<br />
with longer OS after third line were performance status lower than 2 (p = 0.0058), no<br />
hepatic (p = 0.0098) and no pulmonary disease progression (p = 0.0003). Median<br />
durations of TDC was 4.15 (0 – 54.7), 4 (0 – 21.7), 3.34 (0 – 29.6), 4.97 (0 – 29.2),<br />
and 3.13 months (0 – 15), in fourth, fifth, sixth, seventh, eighth line, respectively.<br />
TDC was longer than 6 months in 34% to 40% of patients treated by line 4 to<br />
8. The most important factor influencing TDC length in multivariate analysis<br />
beyond <strong>the</strong> third lines was <strong>the</strong> TDC duration obtained by <strong>the</strong> 2 previous lines of<br />
<strong>the</strong>rapy (p = 0.03).<br />
Conclusion: One can consider that those results might justify <strong>the</strong> administration of<br />
chemo<strong>the</strong>rapy beyond <strong>the</strong> third line, in particular when <strong>the</strong> 2 previous lines are<br />
effective and let a disease control for more than six months.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1015 PROGNOSTIC FACTORS AND TREATMENT OUTCOMES OF<br />
PATIENTS WITH UTERINE LEIOMYOSARCOMA: A<br />
RETROSPECTIVE STUDY OF ANATOLIAN SOCIETY OF<br />
MEDICAL ONCOLOGY<br />
A. Durnali 1 , S. Tokluog˘ lu 2 , N. Ozdemir 3 ,M.I˙nanc 4 , N. Alkis 1 , N. Zengin 3 ,<br />
O.U. Sonmez 1 , M. Kucukoner 5 , M. Ozkan 6 , B. Oksuzoglu 1<br />
1 Department of Medical Oncology, Ankara Dr.A.Y.Oncology Research and<br />
Education Hospital, Ankara, TURKEY, 2 Medical Oncology, Güven Hospital,<br />
Ankara, TURKEY, 3 Medical Oncology, Numune Education and Research<br />
Hospital, Ankara, TURKEY, 4 Department of Medical Oncology, Erciyes University,<br />
Kayseri, TURKEY, 5 Medical Oncology, Dicle University, Diyarbakir, TURKEY,<br />
6 Medical Oncology, Erciyes University Medical FacultyM.Kemal Dedeman,<br />
Oncology Hospital, Kayseri, TURKEY<br />
Background: Uterine leiomyosarcomas are infrequent and aggressive malignancies of<br />
female genital tract.<br />
Methods: Data of 54 uterine leiomyosarcoma patients who were diagnosed and<br />
treated at 4 different centers from November 2000 to October 2010 were analysed<br />
retrospectively.<br />
Results: Mean age was 50.8 years (range 34-72), and 54.9% of patients were<br />
premenapousal. According to last International Federation of Gynecology and<br />
Obstetrics (FIGO) staging system, 26 (48.1%) patients had stage I disease, 14 (25.9%)<br />
stage II, 5 (9.3%) stage III, and 9 (16.7%) stage IV. Of <strong>the</strong> 52 patients who<br />
underwent surgery, 38.4% (20 patients) were given adjuvant chemo<strong>the</strong>rapy, 17.3% (9<br />
ix332 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
patients) adjuvant radio<strong>the</strong>rapy, 23% (12 patients) adjuvant sequential chemo<strong>the</strong>rapy<br />
and radio<strong>the</strong>rapy. Median relapse free survival (RFS) was 19 months. One, 2 and 5<br />
year RFS were 65.2%, 42.6%, 17.2% respectively. Median overall survival (OS) was 56<br />
months, OS after 1, 2, 5 years were 87.7%, 78.7%, 41.9% respectively.<br />
Clinicopathologic parameters that were statistically evaluated included age (
abstracts<br />
head and neck cancer<br />
1016O PHASE 2, RANDOMIZED TRIAL (CONCERT-2) OF<br />
PANITUMUMAB (PMAB) PLUS RADIOTHERAPY (PRT)<br />
COMPARED WITH CHEMORADIOTHERAPY (CRT) IN<br />
PATIENTS (PTS) WITH UNRESECTED, LOCALLY ADVANCED<br />
SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK<br />
(LASCCHN)<br />
J. Giralt 1 , J.M. Trigo 2 , S. Nuyts 3 , E.M. Ozsahin 4 , K. Skladowski 5 , G. Hatoum 6 ,<br />
J. Daisne 7 , A. Zhang 8 , K. Oliner 9 , A. Vanderwalde 10<br />
1 Radiation Oncology, Vall d`Hebron University Hospital, Barcelona, SPAIN,<br />
2 Medical Oncology, Hospital Universitario Virgen de la Victoria, Malaga, SPAIN,<br />
3 Radiation Oncology, University Hospitals Leuven, Leuven, BELGIUM, 4 Radiation<br />
Oncology, Lausanne University Medical Center (Centre Hospitalier Universitaire<br />
Vaudois), Lausanne, SWITZERLAND, 5 Radiation Oncology, Centrum Onkologii<br />
Instytut M. Sklodowskiej-Curie, Gliwice, POLAND, 6 Clinical Biomedical Sciences,<br />
Florida Atlantic University, Lake Worth, FL, UNITED STATES OF AMERICA,<br />
7 Radiation Oncology, Clinique & Maternité Ste-Elisabeth, Namur, BELGIUM,<br />
8 Global Biostatistics, Amgen, Thousand Oaks, CA, UNITED STATES OF<br />
AMERICA, 9 Medical Sciences - Ivd, Amgen, Thousand Oaks, CA, UNITED<br />
STATES OF AMERICA, 10 Oncology Therapeutics, Amgen, Thousand Oaks, CA,<br />
UNITED STATES OF AMERICA<br />
Background: We evaluated <strong>the</strong> safety and efficacy of pmab, a fully human<br />
monoclonal antibody against <strong>the</strong> epidermal growth factor receptor, by comparing<br />
PRT with CRT in pts with LASCCHN.<br />
Methods: Pts with stage III, IVA, or IVB previously untreated LASCCHN of all sites<br />
excluding <strong>the</strong> nasopharynx were randomized 2:3 to open-label CRT or PRT. CRT<br />
included 2 cycles of cisplatin 100 mg/m2 during accelerated fractionation<br />
radio<strong>the</strong>rapy (XRT; 70-72 Gy over 6-6.5 weeks). Pmab included 3 cycles at a dose of<br />
9.0 mg/kg with each cycle administered with XRT. This was an estimation study with<br />
no formal hypo<strong>the</strong>sis testing. The primary endpoint was locoregional control (LRC)<br />
rate at 2 years; key secondary endpoints were progression free survival (PFS), overall<br />
survival (OS), and safety. Preplanned HPV subset analysis (determined by p16<br />
immunohistochemistry) was performed on available samples.<br />
Results: Of 151 treated pts (90 PRT, 61 CRT), 84% were men; median age was 58<br />
years; ECOG PS 0: 64%. Overall, <strong>the</strong> 2-year LRC rate (95% CI) was 51% (40%-62%)<br />
for PRT and 61% (47%-72%) for CRT. For both PFS (hazard ratio [HR] = 1.73 [95%<br />
CI: 1.07-2.81]; p = 0.03) and OS (HR = 1.59 [95% Cl: 0.91-2.79]; p = 0.10), outcomes<br />
favored <strong>the</strong> CRT arm. Of 99 pts with tumors evaluable for HPV, 24% were HPV+. In<br />
75 HPV- tumors, a difference was observed in PFS (HR = 2.04 [95% Cl: 1.05-3.96]; p<br />
= 0.04), with trends also favoring CRT in LRC and OS. Overall, dose intensity was<br />
high for all components of <strong>the</strong>rapy in both arms (median relative dose intensity:<br />
100% for pmab and 99% for cisplatin, median XRT dose: 100% in both arms). Grade<br />
3+ adverse events (AEs) occurred in 85% PRT vs 81% CRT pts. Key differences in<br />
grade 3+ toxicity between arms (PRT, CRT) included skin disorders (which is a<br />
composite of skin-related AEs) (35%, 3%), neutropenia (0%, 13%), and febrile<br />
neutropenia (0%, 8%).<br />
Conclusions: Trends favored <strong>the</strong> CRT arm for <strong>the</strong> primary endpoint (LRC at 2<br />
years), as well as o<strong>the</strong>r measures of efficacy, in this predominantly HPV- LASCCHN<br />
population. Small numbers limit conclusions in <strong>the</strong> HPV+ group. Both PRT and<br />
CRT appeared well tolerated.<br />
Disclosure: G. Hatoum: Advisory Board Member for AmgenK. Oliner: Amgen<br />
stockA. Vanderwalde: Corporate-sponsored research (Amgen), full-time employee of<br />
AmgenAll o<strong>the</strong>r authors have declared no conflicts of interest.<br />
Annals of Oncology 23 (Supplement 9): ix334–ix347, <strong>2012</strong><br />
doi:10.1093/annonc/mds402<br />
1017O PRECLINICAL RATIONAL, SAFETY, AND PRELIMINARY<br />
EFFICACY RESULTS OF WEEKLY EVEROLIMUS,<br />
CARBOPLATIN AND PACLITAXEL AS AN INDUCTION<br />
THERAPY FOR PATIENTS WITH UNRESECTABLE LOCALLY<br />
ADVANCED HEAD & NECK SQUAMOUS CELL CARCINOMA<br />
(CAPRA): A GERCOR-IRC PHASE I/II STUDY<br />
S. Faivre 1 ,C.Dreyer 1 , E. Raymond 1 , J. Fayette 2 , J.P. Delord 3 , M. Gatineau 4 ,<br />
B. Chibaudel 5 , N. Aissat 5 , K. Slimane 6 , C. Le Tourneau 7<br />
1 Oncology Department, Beaujon University Hospital, Clichy, FRANCE, 2 Medical<br />
Oncology, Centre Léon Bérard, LYON, FRANCE, 3 Clinical Resarch Unit, Centre<br />
Claudius-Regaud, Toulouse, FRANCE, 4 Medical Oncology, Hôpital<br />
Saint-Joseph, Paris, FRANCE, 5 Medical Oncology, GERCOR-IRC, Paris,<br />
FRANCE, 6 Oncology, Novartis Pharmaceuticals, Rueil-Malmaison, FRANCE,<br />
7 Department of Medical Oncology, Clinical Trial Unit, Institut Curie, Paris, FRANCE<br />
Background: PI3K/mTOR is a survival pathway that was shown activated in 57-81%<br />
of patients (pts) with head & neck squamous cell carcinoma (HNSCC) and might<br />
drive resistance to cytotoxics.<br />
Methods: We have previously shown synergistic cell-cycle dependent effects between<br />
rapamycin/everolimus and carboplatin, or paclitaxel in HNSCC cells (Aissat 2008).<br />
Based on this preclinical translational rationale, a two-step phase I/II trial was<br />
designed using 9 consecutive weekly (w) cycles of oral everolimus combined with<br />
carboplatin (AUC2) and paclitaxel (60mg/m2) followed by chemoradio<strong>the</strong>rapy in pts<br />
with untreated locally advanced HNSCC.<br />
Results: A total of 27 pts with stage IV HNSCC (median age 58, range 46-84; ECOG<br />
0-2) have been enrolled in this phase I/II study (42 pts scheduled for <strong>the</strong> phase II).<br />
Among <strong>the</strong> 7 pts enrolled in <strong>the</strong> everolimus dose escalation phase I step, 6 pts were<br />
evaluable for safety (3pts at 30 mg/w and 3pts at 50 mg/w). No dose-limiting toxicity<br />
(defined during <strong>the</strong> first 4 weeks of treatment) was reported. Transient asymptomatic<br />
grade 3 neutropenia (3 pts), anemia (3 pts), and thrombocytopenia (1 pt) were observed.<br />
The most frequently reported adverse events were mild to moderate as<strong>the</strong>nia, skin<br />
toxicity, and alopecia. The recommended dose of everolimus for <strong>the</strong> phase II step was 50<br />
mg/w. So far, among pts treated in <strong>the</strong> phase I/II, 11/13 objective responses (1CR, 10 PR,<br />
2SD) were observed in evaluable pts. Interestingly, several major responses (ranging -60<br />
to -80% by RECIST) were observed in large necrotic primary tumors and lymph nodes of<br />
>6cm diameters. Preliminary genetic analysis of tumors showed nei<strong>the</strong>r KRAS, BRAF,<br />
PI3KCA, nor EGFR mutations in tumors responding to this combination.<br />
Conclusions: Weekly 50 mg everolimus combined with carboplatin and paclitaxel<br />
was well tolerated with no DLT, allowing repeated cycles. Major clinical responses in<br />
pts with bulky, locally advanced and necrotic diseases deserve fur<strong>the</strong>r evaluation of<br />
this combination in pts with HNSCC. Updated results will be presented at meeting.<br />
Disclosure: S. Faivre: Novartis, honorarium, compensatedE. Raymond: Novartis,<br />
honorarium, compensatedK. Slimane: Novartis, employment, compensatedAll o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
1018O SAFETY AND EFFICACY OF CISPLATIN PLUS 5-FU AND<br />
CETUXIMAB IN HPV-POSITIVE AND HPV-NEGATIVE<br />
RECURRENT AND/OR METASTATIC SQUAMOUS CELL<br />
CARCINOMA OF THE HEAD AND NECK (R/M SCCHN):<br />
ANALYSIS OF THE PHASE III EXTREME TRIAL<br />
A. Psyrri 1 , L. Licitra 2 , B. De Blas 3 , I. Celik 4 , J.B. Vermorken 5<br />
1 Internal Medicine Propaedeutic, University of A<strong>the</strong>ns Medical School, Attikon<br />
University Hospital, A<strong>the</strong>ns, GREECE, 2 Head & Neck Medical Oncology Unit,<br />
Istituto Nazionale Tumori, Milan, ITALY, 3 Global Clinical Development Unit<br />
Oncology, Merck KGaA, Darmstadt, GERMANY, 4 Global Research & Early<br />
Development, Merck KGaA, Darmstadt, GERMANY, 5 Department of Medical<br />
Oncology, University Hospital Antwerp, Edegem, BELGIUM<br />
Background: Tumor human papillomavirus (HPV) status is a strong predictor of<br />
survival and response to treatment in patients (pts) with early and locally advanced<br />
oropharyngeal cancer, but its effects in R/M SCCHN remain to be clarified. This<br />
retrospective analysis of data from <strong>the</strong> EXTREME trial assessed <strong>the</strong> role of tumor<br />
HPV status in pts with R/M SCCHN receiving cisplatin + 5-FU chemo<strong>the</strong>rapy (CT)<br />
alone or in combination with cetuximab. Material and methods:<br />
Immunohistochemical detection of p16 INK4A was used to determine HPV status:<br />
p16-positive and p16-negative disease is referred to as HPV-positive (HPV+) and<br />
HPV-negative (HPV-) disease, respectively.<br />
Results: 196/222 (88%) pts in <strong>the</strong> CT + cetuximab and 185/220 (84%) pts in <strong>the</strong> CT<br />
arm had tissue evaluable for p16. Of <strong>the</strong>se, 91% and 88%, respectively, had HPVtumors.<br />
Among HPV- pts, CT + cetuximab (n = 178) improved overall survival (OS),<br />
progression-free survival (PFS) and overall response rate (ORR), compared with<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
Annals of Oncology<br />
Table: 1018O: Tumor HPV status: effects on prognosis and efficacy of CT + cetuximab and CT in R/M SCCHN.<br />
Population<br />
CT + cetuximab vs CT<br />
Comparison OS PFS ORR<br />
HPV- (n = 340) Median (months)/rate (%) 9.7 7.3 5.7 3.1 37 17<br />
HR/odds ratio 95% CI p 0.822<br />
0.486<br />
2.753 (1.655–4.579)<br />
(0.647–1.043)<br />
(0.376–0.628)<br />
same CT/RT; Arm B2: 3 cycles of induction TPF followed by CET/RT. A total of 204<br />
deaths (420 ptsincluding <strong>the</strong> 101 randomized in <strong>the</strong> phase II part of <strong>the</strong> study<br />
comparing CT/RT with or w/o induction TPF) were required to detect a HR of death<br />
of 0.675 (A1 + A2 vs. B1 + B2; 2-sided a = 0.05; b = 0.20) and a 10% difference in<br />
G3-4 in-field mucosal toxicity (A1 + B1 vs. A2 + B2).<br />
Results: Accrual was completed (421 pts) in April <strong>2012</strong>. By May <strong>2012</strong>, 348 patients<br />
were evaluable for toxicity during <strong>the</strong> planned concomitant treatments. 82% of pts<br />
were male; median age was 60y; PS of 0 (77.8%) or 1 (22.2%). Stage was III (31%) or<br />
IV (69%). Sites of disease were: oral cavity: 21.7%, oropharynx: 54.8%, hypopharynx:<br />
23.5%. Data on G3-4 in-field toxicity (primary endpoint) and compliance to CT/RT<br />
vs CET/RT are shown in table 1.<br />
CT/RT N<br />
215<br />
CET/RT N<br />
133 p<br />
In-field mucositis Grade 3 Grade 4 37% 4% 35% 2% 0.79 0.45<br />
In-field skin reaction Grade 3 Grade 4 13% 1% 20% 1% 0.07 0.58<br />
RT median dose, Gy (range) 70 (8-70) 70 (14-70) 0.32<br />
RT median duration, weeks (range) 7 (1-13) 8 (1-14) 3days 32% 38% 0.22<br />
RT modification due to acute toxicity 37% 40% 0.58<br />
Conclusions: No advantage for CET/RT over CT/RT were observed regarding G3-4<br />
in-field toxicities and feasibility. Pts are still being followed-up to assess OS. Table 1:<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1021PD MODULATION OF THE PERITUMORAL<br />
MICROENVIRONMENT BY CETUXIMAB: A WINDOW<br />
PRE-OPERATIVE STUDY IN PATIENTS WITH SQUAMOUS<br />
CELL CARCINOMA OF THE HEAD AND NECK (SCCHN)<br />
S. Schmitz 1 , M. Hamoir 2 , H. Reychler 3 , M. Magremanne 3 , B. Weynand 4 ,<br />
R. Lhommel 5 , F. Hanin 5 , D. Rommel 6 , N. Michoux 6 , J.P. Machiels 7<br />
1 Head and Neck Surgery and Medical Oncology, Cliniques Universitaires<br />
Saint-Luc, Brussels, BELGIUM, 2 Head and Neck Surgery, Cliniques<br />
Universitaires St-Luc, Brussels, BELGIUM, 3 Maxillofacial Surgery, Cliniques<br />
Universitaires Saint-Luc, Brussels, BELGIUM, 4 Anatomopathology, Cliniques<br />
Universitaires Saint-Luc, Brussels, BELGIUM, 5 Nuclear Medicine, Cliniques<br />
Universitaires St-Luc, Brussels, BELGIUM, 6 Radiology, Cliniques Universitaires<br />
Saint-Luc, Brussels, BELGIUM, 7 Medical Oncology, Cliniques Universitaires<br />
St. Luc, Brussels, BELGIUM<br />
Background: Only a subset of SCCHN pts benefits from anti-EGFR mAbs. Trials<br />
with pre- and post-<strong>the</strong>rapy tumor biopsies (windows studies) in treatment-naïve<br />
patients are crucial to better characterize <strong>the</strong> molecular pathways involved in<br />
treatment response or resistance.<br />
Methods: Cetuximab (C) (400mg/m2 first wk followed by 250mg/m2/wk) was given<br />
pre-operatively during 2 wks (day -15 until day -1, 3 infusions) before surgery (day<br />
0) to 20 treatment-naïve SCCHN pts selected for primary curative surgery. As<br />
controls, 5 additional pts were included without C treatment but with <strong>the</strong> same<br />
requirements regarding biopsies and imaging. Tumour biopsies, FDG/PET, and CT<br />
were performed at diagnosis and surgery. The aims of <strong>the</strong> study were (i) safety,<br />
(ii) C activity by FDG-PET (Po = 0.10, P1 = 0.35, a = 0.05 and b= 0.10) and (iii)<br />
translational research. We compared pathologic changes in surgical specimens of <strong>the</strong><br />
C group with control specimens and correlated <strong>the</strong>se results with microarray analysis<br />
performed on paired biopsies in <strong>the</strong> C group.<br />
Results: C infusion given 24 hrs before surgery was safe. 90 % had a FDG-PET<br />
partial response (PR) (EORTC guideline) in <strong>the</strong> C group vs 0% in <strong>the</strong> controls. 52%<br />
had a ΔSUVmax decrease of >50%. In surgical specimens we detected modifications<br />
of <strong>the</strong> peritumoral environment. By immunochemistry, we found more fibrosis<br />
arranged in a compact manner in <strong>the</strong> C group than in <strong>the</strong> non-treated samples<br />
(histological score) (p = 0.04). Genome-wide expression analysis (Affymetrix HG<br />
U133 Plus 2.0) of <strong>the</strong> paired biopsies taken in <strong>the</strong> tumor center before and after C<br />
supports this histological observation. Results show a significant increase in<br />
expression (Student’s T test p = 0.02; n = 20) of a previously published stroma<br />
signature (Finak et al., Breast Cancer Res 2006) after C. A trend was also observed<br />
between this stroma signature score and <strong>the</strong> fibrosis histological score.<br />
Conclusions: Pre-operative study with C is safe. Our findings suggest that C induces<br />
quantitative modifications in <strong>the</strong> microenvironment of <strong>the</strong> tumor. We are currently<br />
investigating o<strong>the</strong>r components of <strong>the</strong> peri-tumoral environment (inflammation and<br />
vascularization).<br />
Disclosure: J.P. Machiels: consultant/advisory role: Boehringer IngelheimAll o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
1022PD PHASE II STUDY OF PEMETREXED PLUS CISPLATIN AND<br />
CETUXIMAB IN ADVANCED SQUAMOUS CELL CARCONIMA<br />
OF THE HEAD AND NECK<br />
J.B. Vermorken 1 , T.C. Gauler 2 , J. Stoehlmacher-Williams 3 , A. Dietz 4 , J.M. Lopez-<br />
Picazo 5 , O. Hamid 6 , A.M. Hossain 6 , T. Burkholder 6 , S. Chang 6 , L. Licitra 7<br />
1 Department of Oncology, U.Z.A. University Hospital Antwerp, Edegem, BELGIUM,<br />
2 Oncology, University Hospital, Essen, GERMANY, 3 Oncology, University<br />
Hospital Dresden, Dresden, GERMANY, 4 Oncology, Universitatsklinikum Leipzig,<br />
Leipzig, GERMANY, 5 Oncology, Clinica Universidad de Navarra, Pamplona,<br />
SPAIN, 6 Oncology, Eli Lilly and Company, Indianapolis, IN, UNITED STATES OF<br />
AMERICA, 7 Oncology, Instituto Nazionale Tumori, Milan, ITALY<br />
Background: Patients (pts) with recurrent or metastatic SCCHN have a very poor<br />
prognosis. Platinum-based chemo<strong>the</strong>rapy has long been standard treatment. Adding<br />
cetuximab to cisplatin-based combinations has improved overall survival (OS) and is<br />
currently standard treatment in SCCHN. In a phase III study, pemetrexed has shown<br />
benefit in SCCHN, particularly in performance status (PS) 0-1 pts.<br />
Patients and methods: Pts who had no more than 1 prior systemic <strong>the</strong>rapy for<br />
locally-advanced disease received cetuximab 250 mg/m 2 (loading dose:400 mg/m 2 ),<br />
pemetrexed 500 mg/m 2 , with vitamin supplementation, and cisplatin 75 mg/m 2 day<br />
1, up to 6 cycles. Pts completing at least 4 cycles had <strong>the</strong> option to receive<br />
maintenance with pemetrexed and cetuximab, or mono<strong>the</strong>rapy, if toxicity occurred.<br />
Primary objective was progression-free survival (PFS); secondary objectives were OS,<br />
overall response rate (ORR) and safety. Sixty-five patients were needed to meet an<br />
objective median PFS of 5.5 months (mos.), with 90% power; 2-sided α of 0.05.<br />
Results: Sixty-six Caucasians (53 male), median age of 62 years (42-87) received at least<br />
1 dose of <strong>the</strong>rapy. Nineteen pts had a PS of 0; 47 pts had a PS of 1. Median cycles<br />
received = 5.0 (1-27). Median PFS was 4.4 mos. (95% CI: 3.6, 5.4); median OS was 9.7<br />
mos. (95% CI: 6.5, 13.1). Fifty-eight pts were evaluable for ORR analysis. ORR was 29.3%<br />
(95% CI: 18.1, 42.7); 1 complete response (1.7%); 16 partial responses (27.6%); 20 pts had<br />
stable disease (34.5%). An exploratory subgroup analysis showed larynx tumor pts had<br />
greater improvement in survival than non-larynx pts; median OS = 20.8 mos.(HR = 0.44;<br />
95% CI= 0.20, 0.95); p = 0.032. Drug-related grade 3/4 toxicities included leukopenia<br />
(34.8%), neutropenia (33.4%), fatigue (24.2%), anorexia (12.1%) and hypomagnesemia<br />
(10.6%). There were 5 drug-related deaths (7.6%) on treatment (respiratory failure = 2;<br />
implant site hemorrhage = 1, sepsis = 1; death, not o<strong>the</strong>rwise specified = 1).<br />
Conclusions: Efficacy results were consistent with current standard treatment for<br />
SCCHN, but <strong>the</strong> pre-specified goal of median PFS of 5.5 mos. was not met.<br />
Although toxicities were consistent with <strong>the</strong> safety profiles of this combination, <strong>the</strong>re<br />
were 5 deaths on treatment.<br />
Disclosure: J.B. Vermorken: Dr. Jan B. Vermorken is a member of an advisory board<br />
for Merck-Serono, Amgen, Boehringer-Ingelheim, Genentech and Sanofi-Aventis and<br />
has lectured (compensated) for Merck-Serono, Amgen, Bristol-Byers Squibb and<br />
Sanofi-Aventis.T.C. Gauler: Dr. Gauler is an Advisory board member and received<br />
honoraria from Eli Lilly and Company.J. Stoehlmacher-Williams:<br />
Dr. J. Stoehlmacher-Williams received honoraria for an advisory board and<br />
presentations, travel support and various translational research grants from Eli Lilly<br />
and Company.J.M. Lopez-Picazo: Dr. Lopez-Picazo is an advisory board member for<br />
Eli Lilly and Company.O. Hamid: Dr. Hamid is an employee of Eli Lilly and<br />
Company and has stock ownership.A.M. Hossain: Anwar Hossain is an employee of<br />
Eli Lilly and Company and has stock ownership.T. Burkholder: Tiana Burkholder is<br />
an employee of Eli Lilly and Company and has stock ownership.S. Chang: Dr. Chang<br />
is an employee of Eli Lilly and Company and has stock ownership.L. Licitra: Dr.<br />
Licitra served as an advisory board member and received research sponsorship from<br />
Eli Lilly and Company.All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1023PD TEMSIROLIMUS IS ACTIVE IN REFRACTORY SQUAMOUS<br />
CELL CARCINOMA OF THE HEAD AND NECK (SCCHN)<br />
FAILING PLATINUM-BASED CHEMOTHERAPY AND<br />
CETUXIMAB: EFFICACY AND TOXICITY DATA FROM THE<br />
PHASE II TEMHEAD STUDY<br />
V. Grünwald 1 , U. Keilholz 2 , A. Boehm 3 , O. Guntinas-Lichius 4 , B. Hennemann 5 ,<br />
H.J. Schmoll 6 , P. Ivanyi 1 , A. Zörner 7 , A. Zapf 8 , T.C. Gauler 9<br />
1 Clinic for Hematology, Hemostaseology, Oncology, Hannover Medical School,<br />
Hannover, GERMANY, 2 Hematology & Oncology, Charite, Berlin, GERMANY,<br />
3 Clinic and Policlinic for Ear, Nose and Thorat, Universitätsklinikum Leipzig,<br />
Leipzig, GERMANY, 4 Clinic for Ear, Nose and Throat, Universitätsklinikum Jena,<br />
Jena, GERMANY, 5 Clinic for Heamatology and Medical Oncology, Ev. Be<strong>the</strong>sda-<br />
Johanniter Klinikum GmbH, Duisburg, GERMANY, 6 Dept. Hematology/<br />
Oncology, University of HalleMartin Lu<strong>the</strong>r University Hospital, Halle, GERMANY,<br />
7 Clinical Pharmacology, Medical School Hannover, Hannover, GERMANY,<br />
8 Biostatistics, Medical School Hannover, Hannover, GERMANY, 9 Dept. Int.<br />
Medicine (Cancer Research), University Hospital EssenWestdeutsches<br />
Tumorzentrum, Essen, GERMANY<br />
Background: Prognosis of patients with failure of cisplatin-based 1st line<br />
chemo<strong>the</strong>rapy for recurrent or metastatic SCCHN remains poor. We <strong>the</strong>refore<br />
evaluated temsirolimus after failure of cisplatin and cetuximab in SCCHN.<br />
ix336 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Methods: Patients with progressive SCCHN and failure of platinum-based<br />
chemo<strong>the</strong>rapy and cetuximab were eligible. Patients with loco-regional recurrence as <strong>the</strong><br />
sole lesion had to have a progression free survival (PFS) of at least 6 months from last<br />
<strong>the</strong>rapy. 18 years of age, ECOG 0-2, life expectancy of at least 3 months, and adequate<br />
organ function are key inclusion criteria. Brain metastases were allowed, provided local<br />
<strong>the</strong>rapy has been completed successfully. Tumor assessment was performed every 6<br />
weeks and assessed according to RECIST 1.0. Primary endpoint was <strong>the</strong> progression<br />
free survival rate (PFR) at 12 weeks >20%. Secondary endpoints were time to<br />
progression (TTP), objective response rate (ORR), overall survival and toxicity<br />
(according CTCAE 3.0). 25 mg temsirolimus was given i.v. weekly until progression or<br />
toxicity prevail. PFS, PFR, and OS estimates were calculated by Kaplan-Meier-Curves.<br />
Results: A total of 42 patients entered <strong>the</strong> trial, of whom 40 were eligible. ECOG<br />
performance status of 0/1/2 was found in 7/29/5 pts and missing in 1 patient. Mean<br />
age was 61.6y (range: 42-79y) with male predominance (31 pts; 74%). Progression<br />
free survival rate at 12 weeks was 40% (CI95% 25-55%), TTP was 56 d (CI95%<br />
36-113d), and OS 152d (CI95% 76-256d). Stable disease (SD) was obtained in 19 pts.<br />
(56%), progressive disease (PD) in 10 pts. (29%), 1 pts. was not evaluable for<br />
response, and 10 pts. had missing scans. Treatment with temsirolimus was well<br />
tolerated. Safety data will be presented at <strong>the</strong> meeting.<br />
Conclusions: Temsirolimus reaches its prespecified endpoint with a PFR at 12weeks of<br />
40%. Efficacy data is encouraging and compare to single agent cetuximab activity in<br />
platinum-refractory SCCHN. Fur<strong>the</strong>r studies with this drug in SCCHN are warranted.<br />
Disclosure: V. Grünwald: research funding: Pfizer Advisory Board: Merck KGU.<br />
Keilholz: Research support and honorarium Whyeth / Pfizer.T.C. Gauler:<br />
ADVISORY BOARD: MERCK KG, Pfizer HONORARIA: PfizerAll o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
1025P PLASMATIC EPSTEIN-BARR VIRUS MICRO-RNA -BART-17<br />
IN NASOPHARYNGEAL CARCINOMAS PATIENTS: HIGH<br />
POTENTIAL AS A TUMOR BIOMARKER ASSOCIATED TO EBV<br />
DNA CONCENTRATION<br />
F.R. Ferrand 1 , C. Gourzones 2 , B. Verillaud 2 , E. Saada 3 , P. Lang 4 , V. Schneider 5 ,<br />
C. Amiel 5 , J. Guigay 3 , P. Busson 2<br />
1 Oncologie, Hopital du Val de Grace, Paris Cedex, FRANCE, 2 UMR8126, Institut<br />
Gustave Roussy, Villejuif, FRANCE, 3 Head and Neck Departement, Institut<br />
Gustave Roussy, Villejuif, FRANCE, 4 Medical Oncology, CHU Pitié-Salpetrière,<br />
Paris, FRANCE, 5 Maladies Infectieuses, CHU Tenon, Paris, FRANCE<br />
Background: Because latent Epstein Barr (EBV)-infection is a specific characteristic of<br />
malignant Nasopharyngeal carcinoma (NPC) cells, various molecules of viral origin are<br />
obvious candidate biomarkers. EBV microRNAs are of particular interest because at<br />
least some of <strong>the</strong>se (such as miR-BARTs) deregulate <strong>the</strong> expression of key cellular and<br />
viral genes.<br />
Patients and methods: We performed RT- real-time quantitative PCR targeted on two<br />
cellular miRNAs (has miR16 and 146) and two viral miRNA (ebv-miR BART7 and<br />
17-5p) after RNA extraction on plasma samples from 27 advanced NPC patients,10<br />
patients with advanced head and neck Squamous cell carcinoma and 3 EBV healthy<br />
carriers.<br />
Results: We showed presence of cellular miRNAs in all <strong>the</strong> samples, whereas viral<br />
miRNAs were mostly found in NPC patients plasma samples, with significant<br />
differences for ebv-miR-BART-17 (p = 9,69910 −6 Wilcoxon test) but not for<br />
miR-BART7 and cellular miRNAs. A detection threshold of 0,3 ebv-miR-BART17<br />
copy/plasma µL was specific for NPC diagnosis (ROC curve analysis (AUC= 0,919)<br />
with a sensitivity of 0.9259 and specificity of 0,973) There was no significant<br />
relationship between plasma concentrations of ei<strong>the</strong>r ebv-DNA copy number or viral<br />
and cellular miRNAs and studied clinicopahtological factors.<br />
Conclusion: miR-BART-17 concentrations seem specific of nasopharyngeal<br />
carcinomas and could bring additional information to viral DNA concentrations<br />
especially when DNA is undetectable. Fur<strong>the</strong>r investigations are needed especially in<br />
<strong>the</strong> context of new generation immunoadpative treatment.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1026P EXPRESSION PROFILING OF 21 BIOMOLECULES IN<br />
LOCALLY ADVANCED NASOPHARYNGEAL CARCINOMAS<br />
(LA-NPC) OF CAUCASIAN PATIENTS TREATED WITH<br />
CHEMOTHERAPY OR CHEMO-RADIOTHERAPY (CRT) IN THE<br />
CONTEXT OF A HELLENIC COOPERATIVE ONCOLOGY<br />
GROUP RANDOMIZED TRIAL<br />
M. Bobos 1 , D. Krikelis 1 , G. Karayannopoulou 1 , L. Resiga 2 , S. Chrysafi 1 ,<br />
E. Samantas 1 , D. Andreopoulos 1 , V. Vasiliou 1 , E. Ciuleanu 3 , G. Fountzilas 1<br />
1 Data Office, Hellenic Cooperative Oncology Group (HECOG), A<strong>the</strong>ns, GREECE,<br />
2 Pathology Department, Cancer Institute Ion Chiricuta, Cluj, ROMANIA, 3 Medical<br />
Oncology - Radiation Oncology, Cancer Institute Ion Chiricuta, Cluj, ROMANIA<br />
Introduction: Since scarce data exist on <strong>the</strong> pathogenesis of NPC in Caucasian patients,<br />
we attempted to elucidate <strong>the</strong> responsible molecular pathways in this patient population.<br />
Patients and methods: Formalin-Fixed Paraffin-Embedded tumor tissue samples<br />
from 107 patients, diagnosed with LA-NPC and treated with chemo<strong>the</strong>rapy or CRT,<br />
were analyzed by immunohistochemistry (IHC) for <strong>the</strong> expression of <strong>the</strong> following<br />
proteins: E-cadherin, P-cadherin, Fascin-1, Cyclin D1, COX-2, EGFR, VEGFA,<br />
VEGFC, VEGFR-2, VEGFR-3, ERCC1, p53, p63, Ki67, MAPT, phospho-p44/<br />
42MAPK, PTEN, phospho-Akt, phospho-mTOR, and phospho-GSK3b. EBER status<br />
was assessed by in situ hybridization. The majority of cases were included in tissue<br />
microarray. All stains were performed and assessed centrally by two pathologists. The<br />
median follow-up time was 76.8 (42.3 – 99.2) months.<br />
Results: Biomolecules expressed in >90% of cases were: p53, COX-2, P-cadherin,<br />
EBER, phospho-GSK3b, and Fascin-1. WHO II + III tumors were more frequently<br />
EBER & PTEN positive and VEGFA negative. Advanced age was significantly<br />
associated with positive phospho-GSK3b and ERCC1 expression, male gender with<br />
positive phospho-Akt and phospho-p44/42MAPK, and worse performance status<br />
(PS), 1 or 2, with negative Ki67, ERCC1, PTEN, and phospho-mTOR expression.<br />
Earlier TNM stage was closely associated with p63, MAPT, PTEN, and Cyclin D1<br />
positivity. Univariate Cox regression analysis highlighted Cyclin D1 as a negative<br />
prognostic factor for Disease-Free Survival (DFS) (p = 0.034) and EBER as a positive<br />
one for Overall Survival (OS) (p = 0.048). In multivariate analysis, advanced age and<br />
stage, poor PS, and positive ERCC1 emerged as predictors of worse DFS and OS, as<br />
opposed to positive phospho-mTOR. Clustering analysis defined two<br />
protein-expression groups being predictive of better OS (p = 0.043).<br />
Conclusion: Our study is <strong>the</strong> first to examine <strong>the</strong> activation and interaction of<br />
established biomolecules and signaling pathways in Caucasian NPC patients in an<br />
effort to reveal new <strong>the</strong>rapeutic targets.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1027P PRECLINICAL ANTI-TUMOR ACTIVITY OF XL880 IN<br />
NASOPHARYNGEAL CARCINOMA<br />
M. Xie 1 ,Z.Li 2<br />
1 Medical Oncology, The First Affiliated Hospital of Guangzhou Medical University,<br />
Guangzhou, CHINA, 2 Department of Medical Oncology, Cancer Center of Sun<br />
Yat-Sen University, Guangzhou, CHINA<br />
Background: Outcomes for locoregionally advanced nasopharyngeal carcinoma<br />
(NPC) patients have certainly improved with chemoradiation but eventually local<br />
and distant failure remains a very important clinical problem. An earlier study<br />
showed increased c-Met and VEGFR2 expression in NPC sample compared to<br />
normal nasopharyngeal tissue. XL880 (Foretinib, GSK1363089) is an oral,<br />
ATP-competitive small molecular inhibitor against multiple kinases, in particular<br />
c-Met and VEGFR2 that are involved in tumor cell growth, migration, and<br />
angiogenesis. The objective of this study was to investigate <strong>the</strong> <strong>the</strong>rapeutic potential<br />
of XL880 in NPC.<br />
Methods: Expressions of total and phosphorylated c-Met, VEGFR2, PDGFR, AXL<br />
and Tie-2 were evaluated by western blot in a panel of six NPC cell lines. The effect<br />
of XL880 on NPC cell proliferation was evaluated by Tilter-Glo luminescent Cell<br />
Viability Assay. We fur<strong>the</strong>r studied <strong>the</strong> effect of XL880 on NPC cell cycle and<br />
apoptosis. In vivo activities of XL880 as single agent and in combination with<br />
Cetuximab were investigated in NPC xenografts.<br />
Results: In vitro study showed that XL880 inhibited phosphorylation of both c-Met<br />
and VEGFR2. XL880 repressed <strong>the</strong> growth of both c-Met amplified tumor cells and<br />
endo<strong>the</strong>lial cells stimulated with ei<strong>the</strong>r HGF or VEGF. For <strong>the</strong> most XL880-sensitive<br />
NPC cell line (HK1-LMP1), which harbored <strong>the</strong> highest levels of both c-Met and<br />
VEGFR2, inhibition of cell growth was associated G0/G1 cell cycle arrest as well as<br />
significant downregulation of FAK, Mcl-1 and cyclin D1. XL880 eliminated ∼70% of<br />
tumor vasculature in xenograft models, inhibited tumor growth, and slowed regrowth<br />
of <strong>the</strong> tumor vasculature after drug withdrawal. Importantly, XL880 decreased<br />
invasiveness of primary tumors and reduced metastasis. XL880 in combination with<br />
Cetuximab achieved greater antitumor responses than treatment with ei<strong>the</strong>r agent<br />
alone in NPC xenograft models. Additionally, mRNA levels of EGFR ligands TGF<br />
alpha and Epiregulin were significantly downregulated by XL880 in vivo.<br />
Conclusions: This is <strong>the</strong> first report of preclinical activity of c-Met/VEGFR2 inhibitor<br />
XL880 in NPC. LMP1 (latent membrane protein 1)-positive NPC shows a higher<br />
sensitivity to XL880. Fur<strong>the</strong>r clinical investigation of XL880 is warranted in NPC patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1028P PLASMA EBV DNA CONCENTRATION CORRELATES WITH<br />
FDG PET IN NASOPHARYNGEAL CARCINOMA TREATED<br />
WITH INDUCTION CHEMOTHERAPY<br />
M. Rahal, H. Abdullah, H. Halawani, H. Zagloul, A. Al Buali, A.A. Alfaraj,<br />
H. Abdulkhalek, E.A. Hassan, A. Ahluwalia, F. Medhat<br />
Oncology, King Fahad Specialist Hospital, Dammam, SAUDI ARABIA<br />
Background: While local control rate in locally advanced NPC (LA-NPC)<br />
has improved with concurrent Cisplatin and IMRT, development of distant<br />
metastases remains common in <strong>the</strong>se patients and limits survival. The role of<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds402 | ix337
induction chemo<strong>the</strong>rapy in <strong>the</strong> treatment of LA- NPC is still a matter of debate.<br />
The aim of this retrospective review is to evaluate <strong>the</strong> effect of induction<br />
chemo<strong>the</strong>rapy and to correlate between EBV-DNA concentration and tumor<br />
response by PET-CT.<br />
Methods: Patients with stage III-IVB, WHO II/III received induction chemo<strong>the</strong>rapy<br />
with 2 cycles of TPF : Docetaxel: 75 mg/m2, Cisplatin: 75 mg /m2, 5Fluorouracil:<br />
750 mg / m2 CI for 96 hours followed 3-4 weeks later by concurrent weekly Cisplatin<br />
( 40 mg /m2) and IMRT (GTV:70 Gy over 35 fractions). EBV-DNA quantification<br />
was performed at baseline and repeated before each cycle of TPF. PET scans were<br />
performed at baseline and repeated before IMRT. The max standard uptake values<br />
(SUV) were recorded in <strong>the</strong> primary tumors. Metabolic response was defined as a<br />
decrease in maximum SUV of 35% or more.<br />
Results: 20 patients with LA-NPC (75%Stage IVA/IVB) were reviewed. All but one<br />
completed <strong>the</strong>rapy. Objective response, according to RECIST criteria: CR: 4; PR: 14<br />
NE: 2. Median concentration of EBV-DNA was 11,300 copies /ml (range: 1,184 -<br />
43,000). Post TPF, reduction of EBV-DNA copies by >50% was observed in 83% pts<br />
and 66% achieved complete biochemical response. In <strong>the</strong> FDG-avid tumor pts, <strong>the</strong><br />
median SUV at baseline was 12 (range 10.5 - 17.4); post TPF metabolic response was<br />
observed in 100% and was complete in 33%.All patients with complete biochemical<br />
response had also a complete metabolic response by PET. At 2-year loco-regional<br />
progression free rate is 95% and 2 year overall survival rate is 85%. No recurrence<br />
was seen in complete (biochemical / metabolic) responders.<br />
Conclusion: A negative post induction FDG-PET and complete biochemical<br />
response after TPF are of significant value in LA-NPC and are useful determinant to<br />
predict outcome.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1029P CIRCULATING TUMOR CELLS (CTCS) IN PATIENTS WITH<br />
RECURRENT/METASTATIC HEAD AND NECK SQUAMOUS<br />
CELL CARCINOMA (HNSCC): FREQUENCY, CLINICAL<br />
SIGNIFICANCE AND EGFR EXPRESSION<br />
S. Grisanti 1 , C. Almici 2 , F. Consoli 3 , R. Verardi 2 , M. Buglione 4 , V.D. Ferrari 1 ,<br />
A. Bolzoni-Villaret 5 , P. Nicolai 5 , S.M. Magrini 4 , E. Simoncini 3<br />
1 Medical Oncology, Azienda Spedali Civili, Brescia, ITALY, 2 Lab Manipulation of<br />
Stem Cells, Azienda Spedali Civili, Brescia, ITALY, 3 U.O. Oncologia Medica,<br />
Azienda Spedali Civili, Brescia, ITALY, 4 Radiation Oncology, Università di Brescia,<br />
Brescia, ITALY, 5 Otorhinolaryngology, University of Brescia, Brescia, ITALY<br />
Introduction: Recurrent/metastatic (R/M) HNSCC have a poor prognosis. Palliative<br />
chemo<strong>the</strong>rapy is often used without adequate prognostic and predictive<br />
stratification due to <strong>the</strong> lack of validated predictors in this setting. Fur<strong>the</strong>rmore,<br />
anti-EGFR <strong>the</strong>rapy is used under <strong>the</strong> assumption that more than 80% of <strong>the</strong><br />
primary tumors overexpresses EGFR. CTCs have been identified as prognostic and<br />
predictive indicators in several metastatic cancers. We prospectively studied <strong>the</strong><br />
frequency, clinical significance and EGFR expression of CTCs in pts with R/M<br />
HNSCC.<br />
Patients and methods: Pts with local and/or distant relapse of HNSCC at first<br />
or second relapse were included between January 2009 and December 2011.<br />
CTCs were measured at baseline and at end of treatment or progression. CTCs<br />
analysis was performed with <strong>the</strong> CellSearch® system. The diagnostic performance<br />
of <strong>the</strong> system with squamous cancer cells was tested with cell lines spiking<br />
experiments. The CellSearch® fourth channel was used to analyze EGFR<br />
expression on CTCs.<br />
Results: Fifty-three pts were evaluable for CTCs analysis and clinical response. CTCs<br />
were detected in 14 (26%) pts at baseline and in 22 (41%) pts at any time point.<br />
Median CTCs number was 1 CTC/7.5 mL. CTCs were not associated to any of <strong>the</strong><br />
clinico-pathological variables considered. EGFR was expressed in 45% of<br />
CTC-positive pts. After treatment, CTC numbers decreased, remained stable and<br />
increased in 8%, 54% and 38% of pts, respectively. Baseline CTCs or <strong>the</strong>ir increase<br />
were predictive of stable or progressive disease (p .007). In 42 evaluable pts, baseline<br />
CTCs were prognostic indicators of worse progression-free (PFS) (3 vs 8 months, p<br />
.003) and overall (OS) (5 vs 10 months, p .013) survivals, respectively.<br />
Conclusion: This study demonstrates that: a) low numbers of CTCs are detectable by<br />
CellSearch® in more than 40% of R/M HNSCC pts; b) CTCs at baseline or at any<br />
time point are independent predictors of poor PFS and OS; c) presence of CTCs<br />
during treatment is predictive of chemo-resistant disease; d) EGFR is expressed on<br />
CTCs with a high intra-sample and inter-patient variability. These results encourage<br />
fur<strong>the</strong>r development of CTCs in this setting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1030P INSULIN GROWTH FACTOR RECEPTOR AS A PROGNOSTIC<br />
MARKER IN OPERABLE SQUAMOUS-CELL LARYNGEAL<br />
CANCER<br />
G. Mountzios 1 , I. Kostopoulos 2 , V. Kotoula 3 , S. Levva 4 , E. Fountzilas 4 ,<br />
K. Markou 5 , I. Karasmanis 6 , N. Angouridakis 5 , A. Nikolaou 6 , G. Fountzilas 4<br />
1 Medical Oncology, 251 Airforce General Hospital, A<strong>the</strong>ns, GREECE, 2 Pathology,<br />
Aristotle University of Thessalonikii School of Medicine, Thessaloniki, GREECE,<br />
3 Molecular Biology, Hellenic Foundation for Cancer Research, Thessaloniki,<br />
GREECE, 4 Medical Oncology Clinic Aristotle University of Thessaloniki,<br />
Papageorgiou General Hospital Aristotle University of Thessaloniki, Thessaloniki,<br />
GREECE, 5 Department of Otorhinolaryngology, AHEPA Hospital, Aristotle<br />
University of Thessaloniki School of Medicine, Thessaloniki, GREECE, 6 Ent<br />
Department, “G. Papanikolaou” General Hospital, Thessaloniki, GREECE<br />
Introduction: Prognosis of patients with operable squamous-cell laryngeal cancer is<br />
highly variable and <strong>the</strong>refore potent prognostic biomarkers are warranted. The<br />
Insulin-Growth Factor Receptor (IGFR)-mediated signaling pathway plays a critical<br />
role in laryngeal carcinogenesis.<br />
Patients and methods: We identified all patients with localised TNM stage I-III<br />
laryngeal cancer managed with potentially curative laryngectomy between May 1985<br />
and June 2008. Immunohistochemical (ICH) expression of IGFR1-alpha, IGFR1-beta<br />
and IGFR2 was evaluated using <strong>the</strong> Histo-score (H-score) climax and mRNA levels<br />
of important effectors of <strong>the</strong> IGFR-mediated pathway were assessed, including<br />
IGFR1, IGF-binding protein 3 (IGFBP3), suppressor of cytokine signaling 2 (SOCS2)<br />
and members of <strong>the</strong> MAP-kinase (MA2K1, MAPK9) and phosphatidyl-inositol-3<br />
kinase (PI3KCA, PI3KR1) families. Cox-regression models were applied to assess <strong>the</strong><br />
predictive value of <strong>the</strong> components of <strong>the</strong> IGFR-mediated pathway on disease-free<br />
survival (DFS) and overall survival (OS).<br />
Results: Among 289 eligible patients, 95.8% were male, 95.2% were current or ex<br />
smokers, 75.4% were alcohol abusers, 15.6% had node-positive diease and 32.2% had<br />
received post-operative irradiation. After a median follow-up of 74.5 months, median<br />
DFS was 94.5 months and median OS was 106.3 months. Using <strong>the</strong> median H-score as<br />
<strong>the</strong> pre-defined cut-off value, IGFR1-alpha overexpression was associated with decreased<br />
DFS (p = 0.0538) and OS (p = 0.0157). Increased mRNA levels of MAPK9 were<br />
associated with prolonged DFS (p = 0.0209) and OS (p = 0.0108), as were increased<br />
mRNA levels of PI3KCA, albeit not significantly (p = 0.0723 and 0.0726 for DFS and<br />
OS respectively). In multivariate analysis, IGFR1-alpha overexpression was associated<br />
with a 46.6% increase in <strong>the</strong> probability for relapse (p = 0.0374). Independent predictors<br />
for poor OS included node-positive disease (HR = 2.569, 95%CI: 1.610-4.100, p <<br />
0.0001), subglotic or transglotic location (HR = 1.756, 95%CI: 1.016-3.036, p = 0.0438)<br />
and IGFR1-alpha IHC overexpression (HR = 1.475, 95%CI: 1.000-2.178, p = 0.05).<br />
Conclusion: IGFR1-alpha IHC overexpression may serve as an independent<br />
predictor of relapse and survival in operable laryngeal cancer. Prospective evaluation<br />
of IGFR1-alpha prognostic utility is warranted.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1031P CYCLIN D1, EGFR AND AKT/MTOR SIGNALLING<br />
IN LOCALIZED LARYNGEAL SQUAMOUS CELL<br />
CARCINOMA<br />
Annals of Oncology<br />
D. Dionysopoulos 1 , K. Pavlakis 2 , V. Kotoula 3 , E. Fountzilas 1 , K. Markou 4 ,<br />
I. Karasmanis 5 , N. Angouridakis 6 , A. Nikolaou 7 , K.T. Kalogeras 8 , G. Fountzilas 1<br />
1 Medical Oncology Clinic Aristotle University of Thessaloniki, Papageorgiou<br />
General Hospital Aristotle University of Thessaloniki, Thessaloniki, GREECE,<br />
2 Pathology, National & Kapodistrian University of A<strong>the</strong>ns, A<strong>the</strong>ns, GREECE,<br />
3 Department of Pathology, Aristotle University of Thessaloniki School of<br />
Medicine, Thessaloniki, GREECE, 4 1st Ent Clinic Aristotle University of<br />
Thessaloniki, AHEPA General Hospital, Thessaloniki, GREECE, 5 Ent Department,<br />
Ippokration General Hospital, Thessaloniki, GREECE, 6 Ent Department<br />
Aristotle University of Thessaloniki, Papageorgiou General Hospital,<br />
Thessaloniki, GREECE, 7 Ent Department, Papanikolaou General Hospital,<br />
Thessaloniki, GREECE, 8 Data Office, Hellenic Cooperative Oncology Group,<br />
A<strong>the</strong>ns, GREECE<br />
Introduction: EGFR pathway, Akt/mTOR and Cyclin D1 are activated and interact<br />
in squamous cell head and neck cancer.<br />
Patients and methods: We assessed relative mRNA expression of EGFR, Akt1, 2, 3,<br />
mTOR and cyclin D1, copy number variants of EGFR and CCND1 genes and<br />
immunohistochemical (IHC) expression of EGFR, pAKT308, pAKT473, pmTOR,<br />
PTEN, p53 and cyclin D1 in paraffin-embedded tissue of localized laryngeal<br />
carcinomas.<br />
Results: In 289 patients with T3-4 (77.8%), node-negative (84.1%) tumours of <strong>the</strong><br />
larynx, high EGFR and CCND1 mRNA correlated with never or ex smoking, (p =<br />
0.003) and (p = 0.029) respectively, while low AKT3 correlated with alcohol abuse.<br />
At a median follow-up of 74.5 months, high mTOR RNA was marginally associated<br />
with shorter DFS, HR = 1.54, p = 0.093 and high Akt3 mRNA with shorter OS, HR =<br />
1.49, p = 0.0786 whereas high EGFR IHC expression was associated with shorter DFS<br />
HR = 1.60, p = 0.0311 and OS HR = 1.57, p = 0.056, pAKT308 with shorter OS, HR =<br />
1.003, p = 0.0586 and pAKT473 with shorter DFS HR = 1.004, p = 0.021 and OS HR<br />
ix338 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
= 1.004, p = 0.033, all in univariate analysis. An interaction between mRNA levels of<br />
mTOR and cyclin D1 was found to be associated with shorter DFS, namely at high<br />
mTOR mRNA expression, one unit increase of CCND1 mRNA expression had a<br />
HR = 2.16 and this remained statistically significant in multivariate analysis<br />
(p-value for interaction = 0.0010). In multivariate analysis, node-positive status,<br />
subglottic-transglottic localization, surgery o<strong>the</strong>r than total laryngectomy and mTOR/<br />
cyclin D1 mRNA interaction, were independent predictors of relapse, while<br />
node-positive status, and subglottic-transglottic localization were associated with<br />
higher risk of death.<br />
Conclusions: In laryngeal cancer, an interaction of high mTOR and cyclin D1<br />
mRNA expression is associated with poor patient outcome.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1032P GENOME-WIDE ASSOCIATION STUDY OF BASE OF TONGUE<br />
SQUAMOUS CELL CARCINOMA RISK<br />
G.J. Lourenco1 , B. Carvalho2 , R. Pellegrino3 , L. Khater1 , C.T. Chone1 ,F.<br />
F. Costa 1 , C.S. Passos Lima1 1<br />
Department of Internal Medicine, State University of Campinas, Faculty of<br />
Medical Sciences, Campinas, BRAZIL, 2 Department of Oncology, University of<br />
Cambridge, Computational Biology Group, Cambridge, UNITED KINGDOM,<br />
3<br />
Department of Psychobiology, Federal University of São Paulo, São Paulo,<br />
BRAZIL<br />
Background: Inherited genetic alterations, such as single nucleotide polymorphisms<br />
(SNPs), were described in association with oropharyngeal cancer risk. However,<br />
existing studies have analyzed a limited number of genetic variants. Base of tongue<br />
(BT) squamous cell carcinoma (SCC) is a common tumor of oropharynx; however,<br />
<strong>the</strong> association of SNPs and BTSCC risk is still not clarified and, <strong>the</strong>refore, this was<br />
<strong>the</strong> aim of <strong>the</strong> present study.<br />
Methods: Genomic DNA of 49 BTSCC patients and 49 controls was extracted from<br />
peripheral blood samples using <strong>the</strong> QIamp kit (Qiagen®). Each sample was<br />
genotyped individually using DNA high-resolution microarrays containing 500.568<br />
SNPs (SNP array 5.0, Affymetrix®). Fur<strong>the</strong>r sample processing, including digestion,<br />
adaptor ligation, amplification, fragmentation, labeling, hybridization, washing and<br />
scanning was assayed according to <strong>the</strong> standard protocol. Genotype data were<br />
acquired by genotyping calling of samples using <strong>the</strong> crlmm algorithm provided by<br />
Bioconductor software. The differences between groups were analyzed by <strong>the</strong> logistic<br />
regression model. The SNPs localized in genes of interest were selected by data base<br />
analysis in DAVID and NCBI websites. The validation of selected SNPs was<br />
performed by RT-PCR, using TaqMan® SNP Genotyping Assays (Applied<br />
Biosystems®) in all samples studied.<br />
Results: We observed 6.609 SNPs with distinct frequencies between BTSCC patients<br />
and controls. Fifty-two SNPs (0.8%) were located in coding sequence (CDS), 51<br />
(0.8%) in 3’ and 5’-untranslated regions (UTR), 3.461 (52.4%) in up or downstream<br />
regions (DWS) and 3.045 (46.0%) in introns. Ten SNPs were selected for validation<br />
and eight of <strong>the</strong>m were validated, evidencing those localized in genes related to cell<br />
cycle (3’-UTR: ERP29, rs7114; MCC, rs7033; DWS: LEF1, rs2107028 and rs4245926;<br />
PTCH1, rs16909856 and rs16909859) and transcription process (CDS: IKBKAP,<br />
rs3204145; 3’-UTR: ZNF415, rs3814).<br />
Conclusions: Our preliminary results suggest that SNPs in genes involved in tumor<br />
origin and development may predispose individuals to BTSCC in sou<strong>the</strong>astern Brazil.<br />
However, <strong>the</strong> roles of <strong>the</strong>se SNPs in BTSCC susceptibility should be confirmed by<br />
functional protein studies and validated in larger epidemiological studies from<br />
distinct parts of <strong>the</strong> world. Financial support: FAPESP and FINEP.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1033P HYPOXIA AND METABOLISM GENE EXPRESSION PROFILE<br />
PREDICTS POOR SURVIVAL IN HEAD AND NECK<br />
CARCINOMA<br />
S. Gouerant 1 , S. Mareschal 2 , J.M. Picquenot 3 , A. Berghian 3 , M. Cornic 3 ,<br />
O. Choussy 4 , M. Benard 5 , F. Di Fiore 1 , F. Jardin 2 , F. Clatot 2<br />
1 Medical Oncology, Centre Henri Becquerel, Rouen, FRANCE, 2 Unité INSERM<br />
918, Université de Rouen, Rouen, FRANCE, 3 Pathology, Centre Henri Becquerel,<br />
Rouen, FRANCE, 4 Head and Neck Surgery, CHU Charles Nicolle, Rouen,<br />
FRANCE, 5 Plateforme Primacen, Université de Rouen, Rouen, FRANCE<br />
Background: Despite multimodal treatments combining surgery, radio<strong>the</strong>rapy,<br />
chemo<strong>the</strong>rapy and now targeted <strong>the</strong>rapies, head and neck squamous cell<br />
carcinomas (HNSCC) remain of poor prognosis. Hypoxia being an important<br />
biological characteristics of many HNSCC, we aimed to assess <strong>the</strong> prognostic value of<br />
<strong>the</strong> expression of 42 genes related to hypoxia and metabolism in non metastatic<br />
HNSCC.<br />
Patients and methods: Expression of 42 genes was retrospectively analyzed by high<br />
throughput real-time PCR in 80 patients treated for a non metastatic HNSCC. Fresh<br />
tissue samples were collected at diagnosis. After extraction, RNA quality was<br />
evaluated by an Agilent 2100® Bioanalyzer. After reverse transcription of total RNA,<br />
cDNA were analysed using a 1536 LightCycler®. An unsupervised hierarchical<br />
clustering analysis was performed. Usual prognostic factors and clustering analysis<br />
results were related to overall survival (OS).<br />
Results: Only 61 patients presented suitable quality RNA for gene expression<br />
analysis. With a median follow-up of 39.4 months, 41 patients were alive and 20<br />
were dead of cancer evolution. Among usual prognostic factors, capsular rupture of<br />
involved nodes and lymphovascular invasion were related to poor OS (p = 0.008, p =<br />
0.03, respectively). Gene expression profile distinguished 2 groups. The group 1<br />
composed of 34 patients (7 dead, 27 alive) had a better OS than <strong>the</strong> group 2<br />
composed of 27 patients (13 dead, 14 alive) (2 years OS = 85.3% and 2 years OS =<br />
63.0%, respectively, p = 0.02). The group 1 had frequent overexpression of genes<br />
related to inflammation (SDF1, CXCR4, EP4). The group 2 had frequent<br />
overexpression of genes related to lactate metabolism (LDHA, GLUT1, HK2),<br />
hypoxia (HIF1, BNIP3) or pH regulation (CA9, MCT1). Multivariate analysis based<br />
on <strong>the</strong> usual prognostic factors and <strong>the</strong> clustering analysis confirmed that capsular<br />
rupture, lymphovascular invasion and gene expression profile were related to poor<br />
OS (p = 0.005, p = 0.02, p = 0.003, respectively).<br />
Conclusion: In this cohort, clustering analysis underlined <strong>the</strong> prognostic value of<br />
hypoxia and lactate metabolism gene expression. If confirmed by fur<strong>the</strong>r studies,<br />
tumor metabolism in HNSCC may become a promising target for anticancer drugs.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1034P STUDY ON ASSOCIATION OF POLYMORPHISM OF CYP P<br />
450 2D6 WITH HEAD AND NECK CANCER AND TREATMENT<br />
RESPONSE IN PATIENTS RECEIVING NEOADJUVANT<br />
CHEMOTHERAPY (TPF) FOLLOWED BY CHEMORADIATION<br />
D. Kumar, M.C. Pant, N. Jamal, D. Parmar, S. Kumar, S. Singh, M. Bhatt<br />
Dept. of Radio<strong>the</strong>rapy, VMMC, Safdurjung Hospital, New Delhi, INDIA<br />
Aim of study: 1.To study <strong>the</strong> association of genetic polymorphism in Cyp 2D6 in<br />
patients of locally advanced head and neck cancer. 2. Try to assess a correlation<br />
between this polymorphism & response to treatment. Need of <strong>the</strong> study- To find out<br />
a possible genetic level explanation for <strong>the</strong> different response achieved in patients<br />
with similar histopathology, stage, exposure to carcinogen & ethinicity undergoing<br />
similar treatment.<br />
Material & method: A study comprising of 150 patients & 150 controls was done to<br />
analyse <strong>the</strong> association between polymorphs of Cyp 450 2d6 with Head & neck cancer<br />
and treatment response (TPF- > CTRT). Two cycles of TPF(paclitaxel-175 mg/m2 D1,<br />
cisplatin 35 mg/m2 D2-D3 and 5Fu 1gm/m2 D1-D3 ) were given followed by<br />
radio<strong>the</strong>rapy with concurrent cisplatin (40 mg/m2).The response to <strong>the</strong> treatment was<br />
assessed clinically, radiologically & by laryngoscopy- post treatment .Genotyping of <strong>the</strong><br />
blood samples was done. Analysis of <strong>the</strong> association between genetic polymorphisms<br />
and risk of HNSCC was estimated by calculating crude odds ratio (OR). A p-value of<br />
CT +<br />
RT) is polymorph graded. Our study, thus provides an insight in to <strong>the</strong> concept of<br />
“Right <strong>the</strong>rapy to <strong>the</strong> right patient” & may also explain to <strong>the</strong> fact that why, only<br />
some people are more prone to develop head and neck cancer despite <strong>the</strong> usage of<br />
tobacco,alcohol by so many people.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1035P THE RANDOMIZED STUDY COMPARING THE EFFICACY AND<br />
SAFETY OF RADIO-CHEMOTHERAPY PLUS ADJUVANT<br />
CHEMOTHERAPY (CCRT) VS. NEO-ADJUVANT<br />
CHEMOTHERAPY PLUS RADIO-CHEMOTHERAPY (NAC-RT)<br />
FOR LOCALLY ADVANCED NASOPHARYNGEAL CANCER<br />
S. Chakrabandhu 1 , I. Chitapanarux 1 , R. Jiratrachu 2 , K. Pruegsanusak 2 ,<br />
A. Pinitpatcharalerd 3 , J. Sukhaboon 4 , C. Tovanabutra 5 , A. Srisu<strong>the</strong>p 6 ,<br />
N. Prasongsook 7 , V. Lorvidhaya 1<br />
1 Division of Therapeutic Radiology and Oncology, Chiangmai University,<br />
Chiangmai, THAILAND, 2 Division of Radio<strong>the</strong>rapy, Songklanagarind Hospital,<br />
Songkla, THAILAND, 3 Therapeutic Radiology, Rajavithi Hospital, Bangkok,<br />
THAILAND, 4 Medical Oncology Unit, Lopburi Cancer Center, Lopburi,<br />
THAILAND, 5 Division of Radiation Oncology, Chonburi Cancer Center, Chonburi,<br />
THAILAND, 6 Radiology, Bhumibol Adulyadej RTAF Hospital, Bangkok,<br />
THAILAND, 7 Medical Oncology Unit, Department of Internal Medicine,<br />
Phramongkutklao Hospital, Bangkok, THAILAND<br />
Purpose: Nasopharyngeal carcinoma is radio-chemosensitive. Local control and<br />
survival of patients with advanced disease treated by radio<strong>the</strong>rapy alone remains<br />
unsatisfactory. Chemo<strong>the</strong>rapy has been combined with radio<strong>the</strong>rapy to increase<br />
local-regional control, decrease distant metastasis, and improve survival of <strong>the</strong><br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds402 | ix339
patients. We have developed a randomized trial comparing <strong>the</strong> efficacy and toxicities<br />
of CCRT versus NAC-RT for locally advanced nasopharyngeal cancer.<br />
Patients and methods: A total of 175 patients were included in <strong>the</strong> study. The 87<br />
patients received concurrent radio-chemo<strong>the</strong>rapy daily 70 Gy/7 weeks with cisplatin<br />
100 mg/m 2 q 3 weeks <strong>the</strong>n followed by adjuvant chemo<strong>the</strong>rapy for 3 cycles (q 3<br />
weeks), consisting of cisplatin 80 mg/m 2 on day 1 and 5-FU 1,000 mg/m 2 on day 1-4.<br />
The 88 patients received neoadjuvant chemo<strong>the</strong>rapy for 3 cycles (q 3 weeks)<br />
consisting of docetaxel 75 mg/m 2 on day 1, cisplatin 75 mg/m 2 on day 1, and 5-FU<br />
750 mg/m 2 on days 1- 4 followed by concurrent radio<strong>the</strong>rapy daily 70 Gy/7 weeks<br />
with carboplatin AUC 1.5 weekly for 6 weeks.<br />
Results: The number of patients who completed treatment for <strong>the</strong> CCRT group was<br />
34 (39.1%) and for <strong>the</strong> NAC-RT group was 54 (61.4%). The most common reasons<br />
for study discontinuation were adverse events and patient’s willingness. The grade 3<br />
and 4 treatment-related adverse events were two times higher in <strong>the</strong> CCRT group<br />
(p < 0.06), mostly mucositis / stomatitis and nausea / vomiting. There was no<br />
difference in hematologic adverse events between groups. The 1-year progression-free<br />
survival rate was 91.8% and 89.3% in <strong>the</strong> CCRT and NAC-RT group, respectively.<br />
No evidence of disease at <strong>the</strong> time of this interim analysis was found in 76.5% in <strong>the</strong><br />
CCRT group and 85.2% in <strong>the</strong> NAC-RT group.<br />
Conclusion: Induction chemo<strong>the</strong>rapy with docetaxel / cisplatin and 5-fluoro-uracil<br />
followed by concurrent radio-chemo<strong>the</strong>rapy was tolerable and provided well control<br />
of disease. These interim early results revealed no difference in PFS but less side<br />
effects and increase number of <strong>the</strong> patients with no evidence of disease in <strong>the</strong><br />
NAC-RT arm.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1036P INDUCTION THERAPY WITH CETUXIMAB, DOCETAXEL,<br />
CISPLATIN, AND FLUOROURACIL IN PATIENTS WITH<br />
RESECTABLE NON METASTATIC STAGE III OR IV<br />
SQUAMOUS CELL CARCINOMA OF THE OROPHARYNX. A<br />
GERCOR PHASE II STUDY<br />
B. Chibaudel 1 ,R.Lacave 2 , J. Belloc 3 , A. Banal 4 , S. Albert 5 , F. Chabolle 6 ,<br />
M. Lefevre 7 , P. Soussan 8 , R. Moukoko 9 , J. Lacau Saint Guily 10<br />
1 Department of Medical Oncology, Hôpital Saint Antoine, Paris, FRANCE,<br />
2 Laboratoire d’Histologie et Biologie Tumorale, Hôpital Tenon, PARIS, FRANCE,<br />
3 Oto-Rhino-Laryngologie, Hôpital Simone Veil, Eaubonne, FRANCE, 4 Chirurgie<br />
de la Face et du Cou, Centre René Huguenin, Saint-Cloud, FRANCE,<br />
5 Oto-Rhino-Laryngologie et Chirurgie Cervico-Faciale, Hôpital Bichat Claude<br />
Bernard, Paris, FRANCE, 6 Oto- Rhino-Laryngologie et Chirurgie Cervico-Faciale,<br />
Hôpital Foch, Suresnes, FRANCE, 7 Anatomie et Cyto Pathologie, Hôpital Tenon,<br />
Paris, FRANCE, 8 Virologie, Hôpital Tenon, Paris, FRANCE, 9 Groupe Coopérateur<br />
Multidisciplinaire en Oncologie, GERCOR, Paris, FRANCE, 10 Oto-<br />
Rhino-Laryngologie et Chirurgie Cervico-Faciale, Hôpital Tenon, Paris, FRANCE<br />
Background: Docetaxel/cisplatin/5-FU (TPF) has been reported to be more active<br />
than cisplatin/5-FU in Squamous Cell Carcinoma (SCC) of <strong>the</strong> head and neck (HN).<br />
A clinical Complete Response (CR) rate of 8.5% was achieved after TPF induction<br />
<strong>the</strong>rapy (IT) in patients (pts) with unresectable pharyngolaryngeal SCC (Vermorken<br />
et al, NEJM 2007). EGFR is overexpressed in up to 90% of HN cancers. Cetuximab<br />
(Cet) was active in combination with radio<strong>the</strong>rapy and with cisplatin. The aim of this<br />
multicenter single-arm phase II study was to evaluate Cet with TPF as IT in<br />
oropharyngeal SCC.<br />
Methods: Main inclusion criteria were: previously untreated histologically proven<br />
oropharyngeal SCC, non-metastatic stage III or IV disease (UICC 2002), surgically<br />
resectable, age 18-75 years, ECOG Performance Status (PS) 0-1. Pts received Cet iv<br />
/1-2h (400 mg/m 2 loading dose, <strong>the</strong>n weekly 250 mg/m 2 ) followed by docetaxel iv<br />
75mg/m 2 /1h and cisplatin iv 75mg/m 2 /1h (day 1); and 5-FU iv 750mg/m 2 /day<br />
continuously (days 1-5), every 3 weeks for 3 courses. After completion of IT, <strong>the</strong><br />
treatment of <strong>the</strong> primitive tumor was at <strong>the</strong> investigator’s discretion. The primary<br />
endpoint was <strong>the</strong> clinical and radiological CR of primitive tumor at 3 months.<br />
Correlative studies investigated several EGFR-related biomarkers and HPV analyses<br />
in tumor and blood samples.<br />
Results: Among 42 pts enrolled from 07/2008 to 11/2011 in 9 centers, 41 pts were<br />
treated. The main pts characteristics were: male 81%, mean age 56y, PS0 79%, tonsil<br />
area 88%, stage III/IV 76%/24%. The planned 9 infusions were given in 31 (76%)<br />
pts. A clinical and radiological CR of <strong>the</strong> primitive tumor at 3 months was achieved<br />
in 9 (22%) pts, and a clinical CR in 17 (41%) pts. The most frequent G3-4 toxicities<br />
were: neutropenia (39%), febrile neutropenia (20%), diarrhea (10%), and mucositis<br />
(12%). Any grade acnea-like syndrome was observed in 18 (44%) pts. One toxic<br />
death occurred secondary to chemo-induced colitis with colonic perforation.<br />
Conclusions: The combination of cetuximab with TPF is highly active. A systematic<br />
<strong>the</strong>rapy with granulocyte colony-stimulating factor is necessary to prevent febrile<br />
neutropenia.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
1037P DOCETAXEL, CARBOPLATIN AND FLUORO-URACIL (TCF)<br />
INDUCTION THERAPY IN LOCALLY ADVANCED HEAD AND<br />
NECK SQUAMOUS CELL CARCINOMA (HNSCC) PATIENTS<br />
WITH CONTRAINDICATION FOR CISPLATIN BASED<br />
COMBINATION (TPF)<br />
E. Saada 1 , F.R. Ferrand 1 , M. Fekih 2 , D. Hamdan 1 , F. Janot 1 , S. Temam 2 ,<br />
M. Julieron 1 , A.M. Leridant 1 , A. Schilf 1 , J. Guigay 1<br />
1 Head and Neck Departement, Institut Gustave Roussy, Villejuif, FRANCE, 2 Head<br />
and Neck, Institut Gustave Roussy, Villejuif, FRANCE<br />
Background: TPF regimen is a standard induction combination for fit locally<br />
advanced HNSCC patients (pts). TCF with carboplatin may be an option in frail pts<br />
with contraindication for cisplatin, but data are missing about safety and efficacy of<br />
such an approach.<br />
Method: Retrospective study of monocentric cohort of HNSCC patients treated from<br />
2007 to 2011 with TCF induction regimen at Gustave Roussy Institute. TCF regimen<br />
combined Docetaxel 75mg/m 2 , Carboplatin AUC4, and 5FU: 750 mg/m 2 /day for<br />
5days.<br />
Results: Population included 34 pts, median age 59 years (44-78), all with Charlson<br />
Comorbidity Index score ≥ 2, with oropharynx, hypopharynx, oral cavity, larynx<br />
and paranasal sinuses HNSCC localization (32.3, 23.5, 17.6, 14.7 and 11.8%<br />
respectively). TNM stage were: T1-2 : 4 pts (11.7%), T3-4: 27 pts (79.4%), rTx: 3<br />
pts (8.8%); N0: 8 pts (23.5%), N1: 4 pts (11.8%), N2a-N2b: 6 pts (17.6%), N2c-N3:<br />
13 pts (38.2%); M1: 1 pt (2.9%). TPF contraindications were respiratory disease<br />
(di.) (11 pts: 32.3%), heart di. (6 pts: 17.6%), liver di. (3 pts: 8.8%), alcohol related<br />
neuropathy (3 pts: 8.8%), hearing di. (5 pts: 14.7%), renal di. (5 pts: 14.7%), o<strong>the</strong>r<br />
co-morbidities (3 pts: 8.8%).Patients received 2 to 4 cycles of TCF. GCSF was<br />
delivered in 31 pts (91.2%). Cumulated incidence of Grade 3-4 toxicity was 37.2%,<br />
and one toxic death occurred at C2. Five pts (14.7%) stopped treatment because of<br />
toxicity. RECIST evaluation found complete response in 1 patient (2.9%), partial<br />
response in 23 pts (67.6%), stable disease in 6 pts (17.7%), and progression disease<br />
in 1 pt (2.9%). Subsequent treatment was surgery followed by radio<strong>the</strong>rapy (9 pts,<br />
26.5%), radio<strong>the</strong>rapy or chemoradio<strong>the</strong>rapy (22 pts, 64.7%), chemo<strong>the</strong>rapy (3 pts,<br />
8.8%). Response after RT was: CR: 16 pts (64%), PR: 4 pts (16 %), SD: 3 pts (12<br />
%), PD: 2 pts (8 %). Median recurrence-free survival was 8.7 months, median<br />
overall survival (OS): 22.9 months. Personal history of cancer (HR = 4.6, p = 0.02),<br />
tobacco (HR = 37.5, p = 0.04), alcohol intake (HR = 0.12, p = 0.01), hypertension (<br />
HR = 4.4, p = 0.01), T4 stage ( HR = 0.1, p = 0.02), N2c-N3 stage (HR = 18.5, p =<br />
0.003), BMI < 20 (HR = 9.6, p = 0.02) and lymphopenia (HR = 4.3, p = 0.01) were<br />
associated with OS in multivariate analysis.<br />
Conclusion: TCF induction regimen was manageable and provided objective<br />
responses in 70% of frail HNSCC patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1038P INDUCTION CHEMOTHERAPY WITH DOCETAXEL,<br />
CISPLATIN AND 5-FLUOROURACIL FOLLOWED BY<br />
RADIOTHERAPY WITH CETUXIMAB FOR LOCALLY<br />
ADVANCED SQUAMOUS CELL CARCINOMA OF THE HEAD<br />
AND NECK<br />
F. Keil 1 , E. Selzer 2 , A. Berghold 3 , K. Kapp 4 , A. De Vries 5 , R. Greil 6 , S. Reinisch 7 ,<br />
W. Anderhuber 8 , M. Burian 9 , G.V. Kornek 10<br />
1 Internal Medicine, Hanusch Krankenhaus, Vienna, AUSTRIA, 2 University Clinic of<br />
Radiation Therapy and Radiation Biology, Medical University Vienna, Vienna,<br />
AUSTRIA, 3 Institute for Med. Informatics, Statistics and Documentation, Institute<br />
for Med. Informatics, Statistics and Documentation, Graz, AUSTRIA, 4 Radiation<br />
Therapy - Radiooncology, University Clinic, Graz, AUSTRIA, 5 Radiation Therapy,<br />
LKH Feldkirch, Feldkirch, AUSTRIA, 6 Internal Medicine III, University Hospital<br />
Salzburg, Salzburg, AUSTRIA, 7 Clinical Departement of General Hnc, Medical<br />
University Graz, Graz, AUSTRIA, 8 Departement of HNC, LKH Leoben, Leoben,<br />
AUSTRIA, 9 HNC Departement, Hospital of Barmherzigen Schwestern, Linz,<br />
AUSTRIA, 10 Oncology, Medical University of Vienna, Vienna, AUSTRIA<br />
Purpose: To determine <strong>the</strong> efficacy and feasibility of induction chemo<strong>the</strong>rapy with<br />
docetaxel, cisplatin and 5-fluorouracil followed by radio<strong>the</strong>rapy and cetuximab in<br />
patients with locally advanced head and neck cancer.<br />
Patients and methods: Forty-nine previously untreated patients (median age: 53<br />
years) with local advanced stage III and IV squamous cell carcinoma of <strong>the</strong> head and<br />
neck received three courses of induction chemo<strong>the</strong>rapy consisting of docetaxel 75<br />
mg/m 2 day 1, cisplatin 75 mg/m 2 day 1, and infusional 5-Fluorouracil 750 mg/m 2 /<br />
day on days 1-5 followed by radio<strong>the</strong>rapy plus cetuximab at 250mg/m 2 /week (after<br />
an initial loading dose of 400mg/m 2 ). Patients with an ECOG performance score of 0<br />
or 1 without severe co-morbidities adequate hematopoietic, hepatic, and renal<br />
functions were eligible.<br />
Results: After completion of induction chemo<strong>the</strong>rapy 44 of 49 patients received<br />
radio<strong>the</strong>rapy plus cetuximab. In 45 patients ICT was delivered without delay or dose<br />
ix340 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
reduction and 38 patients received RT at <strong>the</strong> full dose. Three months after <strong>the</strong>rapy<br />
completion tumor response was observed in 33 patients and after 2 years, 25 patients<br />
were in complete remission. Although treatment was accompanied with a rate of<br />
grate 3 and 4 toxicity of 30% during induction chemo<strong>the</strong>rapy and up to 68% during<br />
radio<strong>the</strong>rapy with cetuximab, our treatment seems feasible. Toxicities resolved within<br />
3 months after end of treatment and only two patients became dependent on gastric<br />
feeding tubes after two years, compared to 21 patients during treatment. We lost one<br />
patient because of treatment related toxicity and 73% of <strong>the</strong> 49 included patients<br />
finished treatment without dose reduction or delay of treatment. 2-year<br />
progression-free survival rate was 59% and 2-year overall survival rate was 63%,<br />
respectively.<br />
Conclusion: Concurrent radio<strong>the</strong>rapy plus cetuximab after three courses of<br />
induction chemo<strong>the</strong>rapy was feasible and associated with promising complete<br />
remission, progression-free and overall survival rates. Fur<strong>the</strong>r optimization of dose<br />
and sequence is warranted.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1039P INDUCTION CHEMOTHERAPY USING DOCETAXEL,<br />
CISPLATIN AND FLUOROURACIL (TPF) FOLLOWED BY<br />
CONCOMITANT CHEMORADIOTHERAPY VS THE SAME<br />
CONCOMITANT CHEMORADIOTHERAPY IN PATIENTS WITH<br />
LOCALLY ADVANCED SQUAMOUS CELL CARCINOMA OF<br />
THE HEAD AND NECK (LASCCHN)<br />
W. El-Sadda, I. Abdel Halim, K. Abul Khair, R. Abdel Latif<br />
Clinical Oncology and Nuclear Medicine, Mansoura University Hospital School of<br />
Medicine, Mansoura, EGYPT<br />
Background: Concomitant chemoradio<strong>the</strong>rapy (CCRT) with cisplatin is considered a<br />
standard treatment of LASCCHN. The role of induction chemo<strong>the</strong>rapy (IC) followed<br />
by CCRT remains controversial. Our aim was to compare neoadjuvant chemo<strong>the</strong>rapy<br />
with 3 cycles of TPF followed by CCRT to CCRT alone. The 1ry objective of <strong>the</strong><br />
study was ORR and <strong>the</strong> 2ry objectives were toxicity, PFS and OS.<br />
Patients and methods: Between 2006 & 2008, 100 patients with histologically proven<br />
SCC of <strong>the</strong> Head & Neck (stage IIB-IVA) were enrolled. WHO PS 0-1, with adequate<br />
bone marrow, liver and kidney functions. Fifty patients received 3 cycles of IC<br />
including docetaxel 75 mg/m 2 IV over 1h D1, cisplatin 75mg/m 2 IV over 3h D1 and<br />
5-FU 750 mg/m 2 IV continuous infusion over 24h D1-5 (repeated every 3 wks).<br />
Premedications before and after docetaxel and cisplatin with prophylactic antibiotic<br />
on D5 and G-CSF on D6. This was followed by CCRT in <strong>the</strong> form of radio<strong>the</strong>rapy<br />
using conventional fractionation (2Gy/day, 5 fr/week, total dose of 70Gy) with<br />
concurrent weekly cisplatin 20 mg/m 2 IV (Gp A). In gp B, patients received CCRT<br />
alone. Response was assessed by physical examination, CT scan and endoscopy after<br />
2 cycles, after completion of IC, and 6-8 wks after completion of CCRT.<br />
Results: All patients in both gps had completed <strong>the</strong> treatment schedule and were<br />
evaluable for response, toxicity and survival. The median age was 44.5 years in both<br />
gps (range 27-62). Seventy percent of patients had PS 0, 65 patients had cervical LN<br />
involvement (N 2-3). The ORR after <strong>the</strong> completion of CCRT were 88% & 68% in <strong>the</strong><br />
two groups respectively. Toxicity was manageable in both groups. The main severe<br />
toxicities during IC were G3 alopecia and neutropenia. During CCRT, <strong>the</strong> most<br />
severe side effects in both groups were mucositis and weight loss. The 2-year PFS and<br />
OS rates were 70%, 86% and 75%, 80% respectively.<br />
Conclusion: Induction chemo<strong>the</strong>rapy using TPF followed by CCRT is safe, tolerable<br />
and effective treatment and can significantly improve survival in patients with<br />
LASSCHN.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1040P THE IMPACT OF INDUCTION CHEMOTHERAPY ON<br />
CISPLATION DOSE INTENSITY DURING<br />
CHEMO-RADIOTHERAPY (CTRT) IN OROPHARYNGEAL<br />
SQUAMOUS CELL CANCER (OPC)<br />
R. Granata 1 , P. Bossi 1 , E. Orlandi 2 , L. Locati 1 , C. Bergamini 1 , C. Resteghini 1 ,<br />
T. Ibba 3 , G. Scaramellini 3 , C. Fallai 2 , L. Licitra 1<br />
1 Head & Neck Unit, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano,<br />
ITALY, 2 Radiation Oncology, Fondazione IRCCS Istituto Nazionale Tumori Milano,<br />
Milan, ITALY, 3 Otorhinolaryngology Unit, Fondazione IRCCS Istituto Nazionale<br />
Tumori Milano, Milan, ITALY<br />
Background: Induction (IC) with TPF (Taxotere, Cisplatin, 5-FU) has been<br />
associated with improved outcome in advanced head and neck squamous cell cancer<br />
patients (pts). Full dose of cisplatin (300 mg/m 2 ) during CTRT has been<br />
demonstrated to impact on patients’ outcome. The aim of <strong>the</strong> current study is to<br />
investigate whe<strong>the</strong>r <strong>the</strong> IC could impact on cisplatin dose intensity during CTRT in a<br />
homogeneous population of OPC.<br />
Materials and methods: The study population consisted of 101 pts with stage III-IV<br />
OPC treated from 07/2004 to 12/2011 with IC (n = 53) plus CTRT or CTRT alone<br />
(n= 48). IC consisted of TPF, while weekly 50 mg/m 2 or 3-weekly 100 mg/m 2<br />
cisplatin was administered concurrently with RT (planned chemo<strong>the</strong>rapy dose = 300<br />
mg/m 2 ; planned RT dose = 66-70 Gy, 3DRT or IMRT with a conventional or<br />
accelerated fractionation). Carboplatin substituted cisplatin in case of creatinine<br />
clearance less than 60 mL/min. HPV status, concurrent cisplatin dose intensity and<br />
RT overall treatment time (OTT) were analyzed.<br />
Results: Stage IV pts were 100% in <strong>the</strong> IC group and 83% in CTRT, while HPV<br />
positive OPCs were detected in 58% and 63% of <strong>the</strong> cases respectively. TPF median<br />
number of cycles was 3, with induction cisplatin median dose administered of 200<br />
mg/ m 2 . RT median total dose administered was 70 Gy in both group. Accelerated<br />
fractionated RT was adopted in 65% of CTRT alone group and in 21% of IC group.<br />
Two pts (1 in each group) did not complete CTRT because of cardiovascular events.<br />
Mean and median dose intensity of cisplatin concurrent to RT in <strong>the</strong> IC group was<br />
77.7% and 75% (35%-100%) while in CTRT group was 86% and 91.7% (33%-100%),<br />
with a p value = 0.014. In 11 pts (21%) treated with IC and only in 1 pts (2%)<br />
treated with CTRT alone cisplatin was substituted with carboplatin. No different<br />
cisplatin dose intensity was identified in HPV positive versus HPV negative cases.<br />
Prolonged OTT (longer than 5 days) was observed in two patients in IC group due<br />
to sepsis and severe mucositis as well as in one patient in CTRT group due to<br />
machine failure.<br />
Conclusions: Concurrent cisplatin dose intensity was significantly reduced in pts<br />
receiving IC compared to CTRT alone, irrespective of HPV status. Whe<strong>the</strong>r this has<br />
an impact on <strong>the</strong> results of IC followed by full dose CT/RT has to be clarified.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1041P THE TOLERANCE OF TPF CHEMOTHERAPY REGIME<br />
STANDARD OR MODIFIED IN HEAD NECK CANCER<br />
PATIENTS OVER 65 YEARS OLD<br />
S.M. Ilie 1 , I. Ruginescu 2 , E. Saada 2 , F.R. Ferrand 2 , A. Schilf 2 , F. Janot 2 ,<br />
J. Guigay 2<br />
1 Medical Oncology, Institute of Oncology Bucharest, Fundeni Clinical Hospital<br />
Alexandru Treistoreanu, Bucharest, ROMANIA, 2 Head and Neck Cancer<br />
Treatment, Institute Gustave Roussy, Villejuif, FRANCE<br />
Background: Docetaxel, Cisplatin, 5FU regimen (TPF) has became a standard for<br />
induction chemo<strong>the</strong>rapy in locally advanced squamous cell cancer of head and neck<br />
(SCCHN). However, little is known about tolerance and efficacy of TPF in older<br />
patients Objective of <strong>the</strong> study was to evaluate <strong>the</strong> tolerance of induction<br />
chemo<strong>the</strong>rapy with TPF regimen in SCCHN patients over 65 years, looking for side<br />
effects especially degree 3 and 4.<br />
Materials and methods: retrospective study of <strong>the</strong> database of Head and Neck<br />
Cancer Department of Gustave Roussy Institute between 2006 and 2009: all patients<br />
over 65 years who received a TPF induction chemo<strong>the</strong>rapy were included.<br />
Results: Among 300 patients treated with TPF induction chemo<strong>the</strong>rapy, we found 57<br />
pts over 65 years : 41 (70%)between 65 - 70, 9 (15%)between 70 - 75 and 7 (12%)<br />
over 75. Most of patients received an organ preservation treatment for T3N0-1M0<br />
hypopharynx and larynx cancer (52%) . 30 pts had an impaired nutritional status<br />
and 37(64%) an ACE 27 index superior of 2. 40 pts (70%) accomplished <strong>the</strong>ir planed<br />
cycles but only 37( 65%) received <strong>the</strong> planed doses. 23 pts (41%) presented a grade 3<br />
or 4 hematological or gastrointestinal adverse events and 5 toxic deaths were<br />
observed.<br />
Conclusion: This retrospective study confirms <strong>the</strong> high risk of toxicity of induction<br />
chemo<strong>the</strong>rapy with TPF combination in elderly SCCHN patients that may<br />
compromise <strong>the</strong> postsurgical outcome in patients over 65 years presenting at least<br />
one comorbidity and denutrition. Geriatric assessment is probably useful in this<br />
population to better select candidates to induction chemo<strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1042P SERIAL COMPREHENSIVE GERIATRIC EVALUATION IN<br />
ELDERLY HEAD AND NECK CANCER PATIENTS<br />
UNDERGOING RADIOTHERAPY<br />
P.R. Debruyne 1 , M. Lycke 1 , T. Boterberg 2 , H. Pottel 3 , L. Goethals 1 , N. van den<br />
Noortgate 4 , F. Duprez 2 , S. Rottey 5 , K. Kargar-Samani 6 , L. Pottel 1<br />
1 Campus Loofstraat - Cancer Center, General Hospital Groeninge, Kortrijk,<br />
BELGIUM, 2 Department of Radiation Oncology, Ghent University Hospital,<br />
Ghent, BELGIUM, 3 Department of Biostatistics, Catholic University Leuven<br />
KULAK, Kortrijk, BELGIUM, 4 Department of Geriatrics, Ghent University Hospital,<br />
Ghent, BELGIUM, 5 Department of Medical Oncology, Ghent University Hospital,<br />
Ghent, BELGIUM, 6 Department of Medical Oncology, Centre Hospitalier de<br />
Wallonie Picarde, Tournai, BELGIUM<br />
Background: Elderly head and neck (H&N) cancer patients can present with<br />
significant co-morbidities whilst treatment induces additional morbidity.<br />
Comprehensive geriatric assessment (CGA) has been proposed as a key treatment<br />
approach in elderly cancer patients. We studied <strong>the</strong> feasibility of serial CGA during<br />
radio<strong>the</strong>rapy in this population.<br />
Material and methods: Patients aged ≥ 65 years with primary H&N cancer<br />
undergoing curative radio<strong>the</strong>rapy (with or without systemic treatment), were<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds402 | ix341
evaluated by <strong>the</strong> screening instruments Vulnerable Elders Survey-13 (VES-13) and<br />
G8, and CGA, at baseline and in <strong>the</strong> 4 th week of <strong>the</strong>ir treatment at General Hospital<br />
Groeninge or Ghent University Hospital.<br />
Results: Ninety eligible patients with a median age of 72 (range 65-87) consented.<br />
Patients mostly presented with an advanced stage tumour (67.8%, stage III-IV) of <strong>the</strong><br />
larynx (46.7%) and pharynx (32.2%). Thirteen patients declined assessment in <strong>the</strong> 4 th<br />
week of <strong>the</strong>rapy. Of those patients, one withdrew from fur<strong>the</strong>r study participation,<br />
one died and in two patients, a change of <strong>the</strong>rapeutic intent was indicated. Nine<br />
patients declined because <strong>the</strong>y felt too ill. At baseline, 40.3%, 64.9% and 71.4% of<br />
patients were defined vulnerable, based on respectively VES-13 (cut-off ≥3), G8<br />
(cut-off ≤14) and CGA (defined as impairments in two or more domains).<br />
Significantly more patients were considered vulnerable at week 4 by VES-13 (55.8%,<br />
P < 0.0001), G8 (90.9%, P < 0.0001) and CGA (81.8%, P < 0.05). Patients presented<br />
with deficits in <strong>the</strong> following domains: co-morbidity (CIRS-G), nutrition (MNA),<br />
community functioning (IADL), physical status (Tinetti), self-care (ADL), emotional<br />
wellbeing (GDS) and cognition (MMSE) at both points in time. In addition, <strong>the</strong><br />
incidence of vulnerability in all health domains increased during treatment, with<br />
especially deterioration of nutritional (P < 0.0001), functional (P < 0.0001), mental<br />
(P < 0.01) and emotional (P < 0.01) status.<br />
Conclusion: Serial CGA identifies multidimensional health problems and <strong>the</strong>ir<br />
evolution during radio<strong>the</strong>rapy. It indicates <strong>the</strong> need for re-evaluation of a patient’s<br />
health status and could guide intensive supportive care in elderly patients treated for<br />
H&N cancer. Acknowledgement: Our work is supported by a grant from <strong>the</strong> Belgian<br />
Government, National Cancer Plan (NKP_024_018).<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1043P PHASE II STUDY OF BIWEEKLY DOSE-INTENSE PACLITAXEL<br />
PLUS GEMCITABINE (GEM/TAX) IN PATIENTS WITH<br />
RECURRENT LOCOREGIONAL OR METASTATIC HEAD AND<br />
NECK SQUAMOUS CELL CARCINOMA<br />
A. Sukari1 , M. Salem1 , M. Al-Hajeili1 , J. Jacobs2 , S. Taylo1 ,G.Yoo2 , H. Lin2 ,<br />
L. Heilbrun1 , A. Alousi3 , O. Kucuk4 1<br />
Oncology, Karmanos Cancer Center, Wayne State University, Detroit, MI,<br />
UNITED STATES OF AMERICA, 2 Department of Otolaryngology and Head and<br />
Neck Surgery, Karmanos Cancer Center, Wayne State University, Detroit, MI,<br />
UNITED STATES OF AMERICA, 3 Division of Hematology and Oncolog, MD<br />
Anderson Cancer Center, Houston, TX, UNITED STATES OF AMERICA,<br />
4<br />
Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, UNITED<br />
STATES OF AMERICA<br />
Background: Patients with metastatic head and neck squamous cell carcinoma<br />
(HNSCC) have a poor prognosis, limited treatment options, and median survival of<br />
6 to 9 months. Paclitaxel (TAX) and gemcitabine (GEM) have both shown activity in<br />
HNSCC. The optimal combination, dosing, and scheduling of both drugs is,<br />
however, unknown. Thus, we investigated <strong>the</strong> efficacy and safety of biweekly<br />
dose-intense GEM/TAX in patients with recurrent locoregional or metastatic<br />
HNSCC.<br />
Methods: An open-label, single-institution, single-arm, phase II study was conducted<br />
for patients (pts) who were previously treated with no more than two cytotoxic<br />
regimens. The pts received paclitaxel (150 mg/m 2 IV) and gemcitabine (3000 mg/m 2<br />
IV) on day 1 and 15. The treatments were repeated every 28 days (one cycle), until<br />
disease progression or unacceptable toxicity. The primary end point was response<br />
rate. RECIST-defined response was evaluated every 2 cycles (8 wks) and toxicities<br />
were evaluated after each cycle (4 wks).<br />
Results: Fifty-five pts were enrolled into <strong>the</strong> trial (M: F 42:13, median age (range): 56<br />
years (23-84), performance status 0-2, 48 pts had previous radiation <strong>the</strong>rapy and 39<br />
had previous surgery), 41 of whom were response evaluable. Of <strong>the</strong>se 41 patients,<br />
two pts (4.8%) achieved complete response (CR) and 17 (41.4%) demonstrated a<br />
partial response (PR). Thus, <strong>the</strong> overall response rate was 46%. Thirteen pts (31.7%)<br />
had stable disease (SD), resulting in tumor control in 32 of 41 pts (78% with CR, PR<br />
or SD), whereas 9 pts (21.1%) had disease progression (PD). Among those pts who<br />
achieved objective response or stable disease, <strong>the</strong> median response duration was 5<br />
months and median time to progression was 4 months. Median overall survival (OS)<br />
was 15 months. Myelosuppression was <strong>the</strong> most common adverse event. Grade 3-4<br />
neutropenia and anemia were observed in 5 (12%) and 11 (26%) pts, respectively.<br />
Eight (19%) pts developed grade 3 infection. None of <strong>the</strong>se pts, however, had febrile<br />
neutropenia and <strong>the</strong>re were no treatment-related deaths.<br />
Conclusions: The combination of biweekly dose intense GEM/TAX was tolerable<br />
and active regimen in patients with recurrent locoregional or metastatic HNSCC.<br />
Our findings warrant fur<strong>the</strong>r investigation in a larger patient population.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
1044P PHASE IB TRIAL OF IMO-2055 IN COMBINATION WITH 5-FU,<br />
CISPLATIN AND CETUXIMAB IN 1ST-LINE PTS WITH<br />
RECURRENT/METASTATIC SQUAMOUS CELL CARCINOMA<br />
OF THE HEAD AND NECK (R/M SCCHN)<br />
J.P. Machiels 1 , M.C. Kaminsky 2 , U. Keller 3 , T.H. Brümmendorf 4 , T. Goddemeier 5 ,<br />
U. Forssman 6 , J.P. Delord 7<br />
1 Medical Oncology, Cliniques Universitaires St. Luc, Brussels, BELGIUM,<br />
2 Département d’Oncologie Médicale, Centre Alexis Vautrin, Nancy, FRANCE, 3 III.<br />
Medizinische Klinik, TU München, Munich, GERMANY, 4 Hämatologie und<br />
Onkologie, Universitätsklinikum Aachen, Aachen, GERMANY, 5 Global Clinical<br />
Operations / Global Biostatistics, Merck KGaA, Darmstadt, GERMANY, 6 Global<br />
Clinical Development Unit Oncology, Merck Serono S.A, Geneva,<br />
SWITZERLAND, 7 Clinical Resarch Unit, Centre Claudius-Regaud, Toulouse,<br />
FRANCE<br />
Purpose: IMO-2055 is a toll-like receptor 9 agonist with potential to enhance <strong>the</strong><br />
efficacy of antitumor agents through immune stimulation.<br />
Methods: IMO-2055 was administered to 1st-line pts with R/M SCCHN on days 1, 8<br />
and 15 of each 3-wk cycle in combination with 5-FU, cisplatin and cetuximab.<br />
IMO-2055 doses were to be escalated (3 + 3 design) from dose level (DL) 1 (0.16 mg/<br />
kg) to DL2 (0.32 mg/kg) and DL3 (0.48 mg/kg) if
Annals of Oncology<br />
Results: Globally, 171 pts were considered, 56 in surgical and 115 in CTRT series. In<br />
CTRT series, 40% of <strong>the</strong> pts received induction TPF chemo<strong>the</strong>rapy; in surgical series<br />
57% of <strong>the</strong> pts had extracapsular extension and/or microscopically involved surgical<br />
margins.<br />
Surgical series CTRT series<br />
p16 expression 39% 59%<br />
Stage III 13% 7%<br />
Stage IV 87% 93%<br />
Low risk 20% 20%<br />
Intermediate risk 23% 41%<br />
High risk 57% 39%<br />
Five-year (yr) OS for p16 positive pts was 50% in surgical and 88% in CTRT series,<br />
while for p16 negative was 38% and 49% respectively (p < 0.0001).When stratifying<br />
for risk profile, 5-yr OS of low risk CTRT pts was 100% vs 54% of surgical pts (p =<br />
0.0042) and 5-yr DFS was 93% vs 53% (p = 0.0079); 5-yr OS of intermediate risk<br />
CTRT pts was 76% vs 46% of surgical pts (p = 0.0141) and 5-yr DFS was 79% vs<br />
38% (p = 0.0359). High risk CTRT pts had a 5-yr OS of 51% vs 36% of surgical pts<br />
(p = 0.1902) and a 5-yr DFS of 24% vs 36% (p = 0.6411).<br />
Discussion: In this retrospective analysis, low and intermediate risk OPC pts had a<br />
greater survival benefit when treated with CTRT compared with surgery followed by<br />
RT. Although with <strong>the</strong> limits of different RT techniques and lack of CT in adjunct to<br />
postoperative RT, <strong>the</strong>se data should be considered as hypo<strong>the</strong>sis generating for new<br />
trials design.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1046P ELECTROCHEMOTHERAPY (ECT) WITH BLEOMYCIN AS A<br />
PALLIATIVE TREATMENT OF REGIONAL RELAPSE IN HEAD<br />
AND NECK CANCER (H&NC) PATIENTS (PTS). A PILOT<br />
STUDY<br />
J.J. Grau 1 , M. Caballero 2 , A. Vilalta 3 , I. Victoria 1 , O. Reig 1 , P. Gascon 1 ,<br />
C. Carrera 3 , J. Malvehy 3<br />
1 Medical Oncology, Hospital Clinic y Provincial de Barcelona, Barcelona, SPAIN,<br />
2 Head and Neck Department, Hospital Clinic Barcelona, Barcelona, SPAIN,<br />
3 Dermatology, Hospital Clinic Barcelona, Barcelona, SPAIN<br />
Background: ECT is <strong>the</strong> administration of electrical pulses in <strong>the</strong> tumour during<br />
perfusion of chemo<strong>the</strong>rapy allowing <strong>the</strong> introduction of <strong>the</strong> drug in neoplastic cell.<br />
H&N regional relapse no suitable for local or systemic treatment has a median<br />
survival of 3 months causing local pain and anxiety to <strong>the</strong> pts. We prospecively<br />
analysed antitumoral activity of ECT in regional relapse of H&NC not suitable for<br />
o<strong>the</strong>r <strong>the</strong>rapies.<br />
Methods: Pts with local-regional relapse of H&NC from mucosa (squamous<br />
carcinoma), thyroid gland, salivary gland, cutaneous squamous or cutaneous<br />
melanoma were included. O<strong>the</strong>r inclusion criteria were good general condition, no<br />
history of reaction to Bleomycin, life spectancy of 3 or more months and no<br />
possibility of salvage local surgery. All pts were previously treated with local radiation<br />
and systemic chemo<strong>the</strong>rapy.<br />
Results: Between 2009-2011, 26 ECT courses were performed in 18 consecutive pts<br />
with local relapse of squamous H&NC n = 7(39%); malignant melanoma n = 6(33%);<br />
thyroid carcinoma n = 4(22%); or parotid carcinoma n = 1(6%). Objective responses<br />
were: complete n = 3(17%); partial n = 11(61%); complete plus partial n = 14(78%); or<br />
no response n = 4(22%). The median follow-up was 12 moths, time to progression<br />
was 6 months and overall survival was 9 months for all <strong>the</strong> pts. All responding pts<br />
had a reduction of local pain and anxiety. Mild local pain for few days and skin<br />
necrosis were <strong>the</strong> only side effects.<br />
Conclusions: ECT has a high antitumoral activity in regional relapse of H&NC of<br />
different histologies. This local <strong>the</strong>rapy may have a place in <strong>the</strong> future as palliative<br />
treatment of H&NC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1047P PSYCHOLOGICAL DISTRESS AND QUALITY OF LIFE<br />
EVALUATION IN HEAD AND NECK CANCER: THE ROLE OF<br />
FAMILY CAREGIVER<br />
O. Ostellino 1 , M. Airoldi 1 , M. Garzaro 2 , L. Raimondo 2 , G. Riva 2 , C. Bartoli 2 ,<br />
S. Carnio 1 , G. Fora 1 , C. Giordano 2 , G. Pecorari 2<br />
1 Medical Oncology Division - Medical Oncology Department, San Giovanni<br />
Battista Hospital, Turin, ITALY, 2 1st Ent Division - Physiopathology Department,<br />
University of Turin, Turin, ITALY<br />
Background: Recently <strong>the</strong> figure of family caregiver (FCG) has become a hot<br />
topic and is still largely un-investigated among head and neck cancer patients;<br />
aim of our study was to describe in a more detailed way <strong>the</strong> role of FCG, to<br />
evaluate quality of life (QoL) and psychological distress of FCGs and patients,<br />
and to investigate relationships between FCG’s wellbeing and patient’s QoLand<br />
emotional pattern.<br />
Methods: Sixty couples of patients and <strong>the</strong>ir caregivers were enrolled in this<br />
observational cross-sectional study between April 2007 and May 2011 at 1st ENT<br />
Division, 2th Medical Oncology Division and 2th Radio<strong>the</strong>rapy Division of San<br />
Giovanni Battista Hospital of Turin. Inclusion criteria were: histological diagnosis<br />
of SCC, advanced stage (III-IV), completion of curative treatment and no<br />
evidence of disease at <strong>the</strong> enrolment. Psycho-oncological assessment was<br />
performed using Distress Thermometer (DT), Stay-Trait Anxiety Inventory<br />
Manual in Y1 and Y2 form (STAI Y1-Y2), Beck Depression Inventory (BDI),<br />
Montgomery-Asberg Depression Rating Scale (MDRS), EORTC-QLQ-C30 and<br />
Head and Neck-35 module and Caregiver Quality of Life Index-Cancer<br />
(CQOLC).<br />
Results: Patients state and trait anxiety are 46,7% (STAI Y1 mean value 40,2 ± 10,2;<br />
cut-off 40) and 36,7% (STAI Y2 mean value 36,7 ± 8,2; cut off 40) respectively; self<br />
reported and clinician rated depression are 31,6% (BDI mean value 8,2 ± 5,3; cut-off<br />
9) and 48,3% (MDRS mean value 7,9 ± 5,9; cut-off 6) respectively. FCGs: state and<br />
trait anxiety are 50% (STAI Y1 mean value 42,5 ± 9,9; cut-off 40) and 41,7% (STAI<br />
Y2 mean value 39,1 ± 8,7; cut off 40) respectively; self reported and clinician rated<br />
depression are 28.3% (BDI mean value 7,3 ± 4,7; cut-off 9) and 41.7% (MDRS mean<br />
value 7,6 ± 5,8; cut-off 6) respectively. Data analysis underlined a positive association<br />
among emotional scales of patients and caregivers. Patients’ psychological aspects are<br />
negatively associated with caregivers’ QoL and viceversa.<br />
Conclusions: Anxiety and depression are often present in FCGs and cured HNC<br />
patients. Long term patient’s QoL is <strong>the</strong> result of a frail balance between FCG and<br />
patient emotional and psychological distress. A psychological support for FCG could<br />
improve patient wellbeing.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1048P RADIATION-INDUCED MALIGNANCY FOLLOWING<br />
DEFINITIVE RADIOTHERAPY FOR NASOPHARYNGEAL<br />
CARCINOMA<br />
M. Xi, L. Zhang, M. Liu, Q. Li<br />
Department of Radiation Oncology, Cancer Center, Sun Yat-Sen University,<br />
Guangzhou, CHINA<br />
Purpose: To analyze <strong>the</strong> clinicopathological characteristics, treatment modalities, and<br />
potential prognostic factors of radiation-induced malignancy (RIM) in patients with<br />
nasopharyngeal carcinoma (NPC).<br />
Methods: We reviewed institutional electronic medical records of 39,118 patients<br />
with NPC treated by definitive radio<strong>the</strong>rapy between February 1964 and 2003. A<br />
total of 228 patients with confirmed RIM were included in this study.<br />
Results: The median latency between radio<strong>the</strong>rapy for NPC and <strong>the</strong> diagnosis of<br />
RIM was 9.5 years (range, 3.1 to 30.2 years). Squamous cell carcinoma was <strong>the</strong> most<br />
common histologic type, followed by fibrosarcoma, osteosarcoma, and<br />
adenocarcinoma. Median progression-free survival and overall survival (OS) of <strong>the</strong><br />
216 patients who underwent treatment were 18.7 months (95% CI, 12.8 to 24.5) and<br />
32.0 months (95% CI, 23.8 to 40.1), respectively. Five-year OS rates were 36.9% and<br />
20.2% for carcinoma and sarcoma, respectively (P = 0.004). The 5-year OS rates were<br />
45.4%, 21.8%, and 0% for <strong>the</strong> surgery (140 patients), radio<strong>the</strong>rapy (44 patients), and<br />
chemo<strong>the</strong>rapy (32 patients) groups, respectively (P = 0.000). The independent<br />
prognostic factors associated with improved OS were histologic diagnosis of<br />
carcinoma and complete surgical resection.<br />
Conclusion: Histologic type and treatment modality were <strong>the</strong> significant prognostic<br />
factors for patients with RIM. Complete resection apparently offers <strong>the</strong> best chance<br />
for long-term survival. In select patients with locally advanced and unresectable RIM,<br />
reirradiation should be strongly considered as a curative option.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1049P THE CHANGING ORAL MICROBIAL ECOSYSTEM IN OSCC<br />
FROM DIAGNOSIS TO RADIOTHERAPY<br />
S.W. Ghate 1 , A.T. Sivakumar 2 ,K.Bhat 3 , B.R. Patil 4 , M.V. Muddapur 5<br />
1 Oral Pathology, Hitkarini Dental College and Hospital, Jabalpur, INDIA, 2 Oral<br />
Pathology, S.D.M. College of Dental Sciences & Hospital, Dharwad, INDIA,<br />
3 Microbiology, Maratha Mandal’s Nathajirao G. Halgekar Institute of Dental<br />
Sciences & Research Centre, Belgaum, INDIA, 4 Surgical Oncology, Karnataka<br />
Cancer Treatment and Research Institute, Hubli, INDIA, 5 Statistics, Karnataka<br />
University, Dharwad, INDIA<br />
Purpose: Multiple factors influence <strong>the</strong> oral microflora (OMF) in oral squamous cell<br />
carcinoma (OSCC). These could range from tobacco habits to radio<strong>the</strong>rapy<br />
administered. A preliminary study performed in our hospital revealed <strong>the</strong> differential<br />
support offered by each of <strong>the</strong>se factors on various microbial groups - aerobes,<br />
anaerobes, gram negative anaerobes (GNAB) and Candida.<br />
Method: The study attempts to analyse <strong>the</strong> microbial alteration so as to improve<br />
understanding of <strong>the</strong> possible impact that OMF could create on mucositis and o<strong>the</strong>r<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds402 | ix343
morbidities that radiation would leave behind. Microbial analysis of saliva samples<br />
was done from healthy volunteers (n = 35), tobacco chewers (n = 37) (Age & Sex<br />
matched), OSCC (n = 32) and during radio<strong>the</strong>rapy (n = 31) of <strong>the</strong>se patients (∼ 50%<br />
study samples form a series). Frequency of isolation and mean colony forming units<br />
obtained were subjected to Kruscal - Wallis, Mann - Whitney (unpaired values) and<br />
Wilcoxson - signed rank test (paired values) for comparison.<br />
Results: No isolation of Citrobacter, Enterobacter, Proteus in normal samples and<br />
Corynebacteria, Staphylococcus epidermidis in study samples. Tobacco – induced<br />
change: Among aerobes, E. coli, Citrobacter, Proteus, Klebsiella pneumonia and<br />
Enterobacter increased (p < 0.05), whereas, Streptococcus pneumoniae,<br />
Corynebacteria, Staphylococcus epidermidis, aerobic Streptococci decrease (p < 0.05)<br />
significantly. Amongst <strong>the</strong> anaerobes, anaerobic Streptococci, Prevotella decreased<br />
while Fusobacteria, P. gingivalis increased, but, all non - significantly (p > 0.05).<br />
Tumor - induced change: E. coli, Enterobacter and anaerobic Streptococci,<br />
Fusobacteria, Prevotella (anaerobes & GNAB) significantly increased (p < 0.05).<br />
Radiation – induced change: Among aerobes, Streptococcus pneumoniae,<br />
Staphylococcus epidermidis decreased. Proteus, Klebsiella pneumoniae, Enterobacter,<br />
and amongst anaerobes, Streptococci increased (p < 0.05) significantly. A<br />
non-significant increase was noted in Fusobacteria and P. gingivalis.<br />
Conclusions: The study impresses on <strong>the</strong> rapidly modifying nature of OMF that<br />
accommodates non – residents and increasing proportions of more pathogenic<br />
microorganisms that may contribute to <strong>the</strong> enhanced morbidity.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1050P WHOLE-BODY DIFFUSION MRI AND SKELETAL LESIONS IN<br />
THYROID CANCER: DIAGNOSTIC AND THERAPEUTIC<br />
IMPLICATIONS<br />
L. Locati 1 , R. Granata 1 , P. Potepan 2 , G. Aliberti 3 , E. Civelli 4 , P. Bossi 1 ,<br />
E. Montin 2 , L. Licitra 1<br />
1 Head & Neck Unit, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan,<br />
ITALY, 2 Department of Radiodiagnostic, Fondazione IRCCS - Istituto Nazionale<br />
dei Tumori, Milan, ITALY, 3 Department of Nuclear Medicine, Fondazione IRCCS -<br />
Istituto Nazionale dei Tumori, Milan, ITALY, 4 Department of Diagnostic Imaging<br />
and Radio<strong>the</strong>rapy, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan,<br />
ITALY<br />
Background: Forty-fifty percent of <strong>the</strong> patients with metastatic TC suffer from bone<br />
metastases. 99m Tc scintigraphy is employed to assess bone lesions although it lacks of<br />
accuracy, mostly in lytic lesions of differentiated thyroid cancer (DTC). CT scan has<br />
a sensitivity of 71-100% while data on <strong>the</strong> accuracy of 18 F-FDG-PET/CT are scanty.<br />
MRI captures both bone and bone marrow involvement, more common in medullary<br />
thyroid cancer (MTC). Whole body MRI (WB) and whole-body diffusion<br />
(WB-DWI) are emerging as accurate tools for detection and <strong>the</strong>rapy monitoring of<br />
bone metastases. We investigated <strong>the</strong> role of WB and WB-DWI in bone lesions from<br />
TC i) sensitivity and specificity; ii) evaluation of response during TKIs.<br />
Material and methods: Radiological records of patients with metastatic TC<br />
submitted to WB-DWI at <strong>the</strong> baseline staging were reviewed. For our first purpose,<br />
patients with at least one ano<strong>the</strong>r bone imaging were included. A false-positive was a<br />
positive bone imaging not confirmed by histopathology or/and ano<strong>the</strong>r imaging<br />
technique or by two imaging exams. A false-negative was a negative finding on bone<br />
imaging and a positive one on ano<strong>the</strong>r imaging method plus histopathology or by<br />
two imaging methods. For each imaging modality, sensitivity, specificity and accuracy<br />
were calculated. For <strong>the</strong> secondary aim were considered only patients scanned by<br />
WB-DWI at baseline and during TKIs treatment.<br />
Results: Since 2010, nine MTC (5M/4F) and five DTC (3M/2F) patients were<br />
selected. Results of <strong>the</strong> first aim are listed in <strong>the</strong> table.<br />
WB-DWI Bone scan Bone CT<br />
Number of<br />
exams<br />
14 12 12<br />
True-positive 10 8 8<br />
True-negative 4 4 4<br />
False-positive 0 1 (MTC) 0<br />
False-negative 0 1 (DTC) 1 (MTC)<br />
Sensitivity % 100 88 88<br />
Specificity % 100 80 100<br />
Accuracy % 100 86 92<br />
In five (4 MTC/1 DTC) out eight (62%) true-positive bone scan, WB-DWI<br />
demonstrated a higher number of bone lesions. In three patients (2 MTC/1 DTC),<br />
WB-DWI showed a cystic evolution in <strong>the</strong> responding lesions during TKI (apart<br />
from <strong>the</strong> histotype).<br />
Conclusions: In our hands WB-DWI is <strong>the</strong> best imaging method to identify bone<br />
lesions from TC. It could potentially address unmet clinical and <strong>the</strong>rapeutic needs<br />
for a reliable measure of bone lesion response in this rare tumors.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1706P ANTI-ANDROGEN THERAPY FOR THE PATIENTS WITH<br />
RECURRENT AND/OR METASTATIC SALIVARY DUCT<br />
CARCINOMA EXPRESSING ANDROGEN RECEPTORS: A<br />
RETROSPECTIVE STUDY<br />
Y. Yajima 1 , S. Fujii 2 , T. Kobayashi 1 , H. Ishiki 1 , R. Hayashi 3 , M. Tahara 4<br />
1 Head And Neck Medical Oncology, National Cancer Center Hospital East,<br />
Kashiwa, Chiba, JAPAN, 2 Pathology, National Cancer Center Hospital East,<br />
Kashiwa, Chiba, JAPAN, 3 Head And Neck Surgery, National Cancer Center<br />
Hospital East, Kashiwa, Chiba, JAPAN, 4 Endoscopy & Gi Oncology, National<br />
Cancer Center Hospital East, Kashiwa, Chiba, JAPAN<br />
Background: Salivary duct carcinoma (SDC) is one of <strong>the</strong> WHO classified<br />
histological types of salivary gland tumors (SGT) and consists of less than 10%<br />
among all <strong>the</strong> SGT. SDC is known as highly malignant with its aggressive clinical<br />
course, high rate of recurrence and metastasis and 2-3 years of median survival time.<br />
Up-front <strong>the</strong>rapy is surgery, but treatment option is quite limited when it recurs and/<br />
or metastasis not being suitable for surgical resection. Androgen receptor (AR) is<br />
expressed in about 90% of SDC. Several reports suggest that AR would be a good<br />
candidate for treatment target for this entity.<br />
Patients and methods: We conducted a retrospective analysis in patients with AR<br />
positive, recurrent and/or metastatic SDC treated anti-androgen <strong>the</strong>rapy in our<br />
institution from January 1997 and April <strong>2012</strong>. AR positivity was defined by<br />
immunohistochemistry (AR441, DAKO). Anti-androgen <strong>the</strong>rapy was given as a<br />
single agent LH-RH analogue every four weeks until disease progression or<br />
intolerable adverse events. Responses to anti-androgen <strong>the</strong>rapy were assessed<br />
according to RECIST.<br />
Results: Eight patients were included. All were male. Median age was 57 years (range<br />
40-76). Primary site was parotid gland in 7 and submandibular gland in 1. Initial<br />
clinical stage was II in 2, IVA in 5 and IVC in 1. All patients had received surgery for<br />
SDC prior to anti-androgen <strong>the</strong>rapy. The patterns of relapse were locoregional<br />
recurrence in 4 and distant metastasis in all. Median number of cycles of<br />
anti-androgen <strong>the</strong>rapy was 4 (range 2-10). No serious adverse event was seen. The<br />
best responses were PR in 2 and SD in 3, and median time of response duration was<br />
4.6 months. After progression of anti-androgen <strong>the</strong>rapy, all but one received<br />
chemo<strong>the</strong>rapy included platinum compounds, taxanes and fluorouracil. Median<br />
overall survival time from receiving anti-androgen <strong>the</strong>rapy was 22 months.<br />
Discussion and conclusion: Anti-androgen <strong>the</strong>rapy was well tolerated and<br />
demonstrated promising clinical activity for patients with recurrent and/or metastatic<br />
SDC. This might delay <strong>the</strong> start of chemo<strong>the</strong>rapy and provide survival benefits, and<br />
this approach warrants fur<strong>the</strong>r investigation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1051 INDUCTION CHEMOTHERAPY (CT) WITH DOCETAXEL,<br />
CISPLATIN, AND FLUOROURACIL (TPF) FOLLOWED BY<br />
CONCOMITANT CISPLATIN PLUS RADIOTHERAPY IN<br />
LOCALLY ADVANCED NASOPHARYNGEAL CANCER (NPC)<br />
RESULTS AFTER 03 YEARS<br />
E. Kerboua, N. Lagha, A. Arab, S. Chami, F. Mekki, K. Bouzid<br />
Medical Oncology, Centre Pierre et Marie Curie, Algiers, ALGERIA<br />
Annals of Oncology<br />
Backround: in squamous cell carcinoma of head and neck cancer,TPF induction CT<br />
improved survival over cisplatin and fluorouracil (MR POSNER NEJM, vol 357 oct<br />
2007 ). The main objectif of this study is to evaluate <strong>the</strong> activity and safety of TPF in<br />
patients (pts) with locally advanced NPC followed by concomitant cisplatin plus<br />
radio<strong>the</strong>rapy (cCTRT).<br />
Methods: pts with undifferenciated NPC were enrolled from December 2006 to<br />
December 2010, and received 3 cycles of TPF (docetaxel 75mg/m2 day, and cisplatin<br />
75mg/m2 day 1, plus fluorouracil 750 mg/M2 days 1-5, every 4 wks) with G-CSF days<br />
1-5 post CT. Induction CT was follwed by cCTRT with cisplatin 40 mg/m2/wk and<br />
radio<strong>the</strong>rapy (65-70 gy) starting 4-6 wks after <strong>the</strong> third cycle of induction CT. The<br />
primary endpoint was overall response rate (ORR) after induction CT and after cCTRT.<br />
Secondary end points were toxicity, disease free survival (DFS), and overall survival (OS).<br />
Results: Fourty-two (42) pts with locally advanced NPC have been enrolled (26M/16F).<br />
UICC 1997 classification: n = 9 stage II, n = 10 stage III, n= 23 stage IV (n = 10 IVA; n =<br />
11 IVB). Median age is 37 yrs (range 18-64). Evocative clinical signs are cervical nodes n<br />
= 20, rhinologic n = 13, otologic n = 5, and neurologic n = 4. All pts were evaluated for<br />
safety and 38 for response. TPF was well tolerated with main toxicities grade 3-4 (WHO)<br />
consisting of neutropenia 36%, thrombocytopenia 23%, anemia 18%, diarrhea 6%,and<br />
mucositis 18%. Four pts died from sepsis that was probably treatment-related. ORR was<br />
90% with 71,4% (n = 27) complete response (CR) rate, 23,6% (n = 9) partial response<br />
(PR), and 5,2% (n = 2) stable disease. No pts progressed after induction CT. Main toxicity<br />
during cCTRT was neutropenia grade 3-4 in 9%, mucositis grade 3 in 45% and grade 4<br />
in 4%. Late toxicities were xerostomia grade 3 in 50%. At treatment completion, CR and<br />
PR rates were 79% and 20%; 2 pts had stable disease. At a median follow up of 36<br />
months (7-48), 5% of pts have shown recurrence or progressive disease. DFS and OS<br />
rates at 36 months were 70% and 75%, respectively.<br />
ix344 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Conclusion: TPF followed by cCTRT appears to be an active and feasible regimen<br />
with an acceptable tolerability profile and may be a promising <strong>the</strong>rapeutic option for<br />
pts with high stage NPC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1052 DNA-REPAIR GENE POLYMORPHISMS ASSOCIATED WITH<br />
FAVORABLE CLINICAL OUTCOME FOLLOWING<br />
CETUXIMAB-BASED THERAPY FOR ELDERLY AND<br />
MULTI-MORBID PATIENTS WITH PRIMARY AND RECURRENT<br />
SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK<br />
Y. Chang 1 ,N.Su 1 ,Y.Leu 2 , J. Lee 2 , C. Liu 3 , Y. Chen 4 , H. Chen 4 , I. Fang 5 ,<br />
A. Lo 5 , R. Hsieh 1<br />
1 Hematology and Oncology, Mackay Memorial Hospital, Taipei, TAIWAN,<br />
2 Otolaryngology- Head &neck Surgery, Mackay Memorial Hospital, Taipei,<br />
TAIWAN, 3 Oral and Maxillofacial Surgery, Mackay Memorial Hospital, Taipei,<br />
TAIWAN, 4 Radiology Oncology, Mackay Memorial Hospital, Taipei, TAIWAN,<br />
5 Good Clinical Research Center, Mackay Memorial Hospital, Taipei, TAIWAN<br />
Background: Recent evidences suggest adding cetuximab to standard treatment is an<br />
effective option for recurrent and metastatic head and neck cancers. While<br />
platinum-based chemo<strong>the</strong>rapy is challenging for elderly and multi-morbid patients,<br />
DNA-repair gene polymorphisms may help identifying patients who are more likely<br />
to benefit from <strong>the</strong> regimen.<br />
Methods: Fifty-two patients were retrospectively identified from patients with<br />
treatment-naïve, primary, recurrent, or metastatic squamous cell carcinoma of <strong>the</strong><br />
head and neck, who had received cetuximab-based <strong>the</strong>rapy during 2006 and 2011.<br />
Treatment response, survival, and <strong>the</strong> presence of <strong>the</strong> single nucleotide<br />
polymorphisms, XPD-Asp312Asn, XPD-Lys751Gln, ERCC1-C8092A, and<br />
XRCC1-Arg399Gln, were currently obtained for twelve patients.<br />
Results: Complete or partial remission was observed in all six patients (100%) who<br />
had one or more polymorphic variants, compared to that in three of <strong>the</strong> six patients<br />
(50%) who had only common alleles (one tailed Fisher’s exact test P = 0.091). Annual<br />
overall survival (OS) was 75.0% (median not reached), one-year progression-free<br />
survival (PFS) was 60.0% (median not reached) in <strong>the</strong> patients with any polymorphic<br />
variant, while one-year OS and PFS was 33.3% (median 11.5 months) and 16.7%<br />
(median 3.7 months) in <strong>the</strong> patients with only common alleles (Log-rank P = 0.321<br />
for OS and 0.078 for PFS).<br />
Conclusion: Our preliminary results suggest cetuximab might be an effective and<br />
safe option for elderly and patients with multiple comorbidities, especially for<br />
patients with DNA-repair gene polymorphic variant. Fur<strong>the</strong>r investigation is needed<br />
to validate our findings and adjust for o<strong>the</strong>r prognostic factors.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1053 THE USEFULNESS OF G8 EVALUATION IN THERAPEUTIC<br />
DECISION AND PREDICTION OF TOLERANCE IN LOCALLY<br />
ADVANCED OR METASTATIC SQUAMOUS CELL HEAD AND<br />
NECK CANCER (SCCHN) PATIENTS OLDER THAN 65 YEARS<br />
S.M. Ilie 1 , I. Ruginescu 2 , E. Saada 2 , F.R. Ferrand 2 , A. Schilf 2 , F. Janot 2 ,<br />
J. Guigay 2<br />
1 Medical Oncology, Institute of Oncology Bucharest, Fundeni Clinical Hospital<br />
Alexandru Treistoreanu, Bucharest, ROMANIA, 2 Head and Neck Cancer<br />
Treatment, Institute Gustave Roussy, Villejuif, FRANCE<br />
Background: 2/3 of H&N cancer patients are locally advanced or metastatic and 20%<br />
are older than 65. Those not amenable to radiation or surgery, must be treated<br />
evaluating <strong>the</strong>ir biological age. The current standard is Erbitux based chemo<strong>the</strong>rapy<br />
and <strong>the</strong>re are not enough dates about <strong>the</strong> tolerance for aged pts. G8 was validated<br />
like tool in geriatric oncology but <strong>the</strong> presence of swallowing difficulties and weight<br />
loss in most of HNC patients may alter its usefulness in this population.<br />
Objective: evaluate prospectively <strong>the</strong> G8 score and to report to <strong>the</strong> incidence and<br />
degree of chemo<strong>the</strong>rapy toxicities.<br />
Methods: Prospective study of SCCHN patients over 65 years old, addressed from<br />
January to April <strong>2012</strong> to <strong>the</strong> Department of Head & Neck Cancer of Gustave Roussy<br />
Institute. Parameters studied: G8 score; age, TNM, histology, nutritional status, ACE<br />
-27 index, toxicity of treatment.<br />
Results: We studied 21 patients: 9 pts (42%) less than 70, 4 pts (19%) between<br />
70 -75 and 7 pts (33%) over 75, mostly locally advanced, squamous histological<br />
type; denutrition in 9 pts (42%) 2 over 75 years; 33% had swallowing problems<br />
and 25% loss weight superior of 10% in <strong>the</strong> last 3 months before treatment.<br />
ACE 27 index was over 2 for 18 (85%) patients.We found a G8 score < 14 for 9<br />
(42%), of whom 8 aged over 70 years, 7 with denutrition, 5 with ACE 27 at<br />
3. 16 patients (47%) were treated with Cetuximab based chemo<strong>the</strong>rapy. The<br />
mostly observed toxicities were cutaneous with 3 grade 3 and 1 grade 4, 41%<br />
hematological and g-I from whome only 4 pts (19%) degree 3 or 4. One toxic<br />
death was observed. 12 pts were evaluated and 4 (33%) were in PR, 5 (41%)<br />
were SD and only 3 (25%) were in progression.<br />
Conclusions: this preliminary prospective study demonstrates that G8 score identify<br />
frailty in 42% of elderly SCCHN patients older than 65 years. An adapted tool for<br />
geriatric asessement in SCCHN patients seems necessary.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1055 EFFICACY OF MYOFIBROBLASTS AS AN INDICATOR FOR<br />
INVASION AND NODAL METASTASIS IN OSCC<br />
A.T. Sivakumar 1 ,P.Sowmya 2 , B.M. Jyothi 2 , M.V. Muddapur 3<br />
1 Oral Pathology, SDM College of Dental Sciences & Hospital, Dharwad, INDIA,<br />
2 Oral Pathology, SDM College of Dental Sciences, Dharwad, INDIA, 3 Statistics,<br />
Karnataka University, Dharwad, INDIA<br />
Purpose: Tumour cells work in close coordination with stromal elements from its<br />
stage of initiation to metastasis. Oral squamous cell carcinoma (OSCC) is one of <strong>the</strong><br />
top ten cancers in <strong>the</strong> world with only survival rate of 56%. Myofibroblasts (MF), a<br />
cell that is identified transiently in <strong>the</strong> wounds have also been shown in tumor<br />
stromogenesis in a variety of malignancies. MFs been highlighted for <strong>the</strong>ir<br />
proinvasive role in tumors. These cells remain less explored in OSCC in terms of<br />
invasion and nodal metastasis – Prognosticators.<br />
Method: The study was aimed towards understanding <strong>the</strong> possibility of MF being an<br />
indicator of invasion and nodal metastasis. This was achieved through assessing <strong>the</strong><br />
presence and distribution pattern of MF in OSCC using α-SMA. To improve fur<strong>the</strong>r<br />
our understanding a semiquantative analysis (0= No staining, 1= Focal Positivity, 2 =<br />
Multifocal Positivity) was performed and compared with that from normal mucosa<br />
(NM, number of cases (n) =10), chronic inflammatory lesions (CIL, n= 22), surgical<br />
margins of OSCC patients (SM, n = 24) and pN0, pN+ OSCC samples (n = 56, 28<br />
each). Mann-Whitney test was applied.<br />
Results: No MFs were present in NM and SM. 84% and 32% of OSCC and CIL<br />
showed MFs respectively. Heterogenous pattern (Presence/absence in a location,<br />
Loose/Syncitial arrangements, and Focal/Multifocal distribution) of MFs was seen in<br />
OSCC while <strong>the</strong>y were seen closer to <strong>the</strong> center of <strong>the</strong> lesion away from <strong>the</strong><br />
epi<strong>the</strong>lium in CIL. Lesions reported for longer duration showed MF in CIL. The MFs<br />
were not seen in all <strong>the</strong> invasive fronts. Significant difference in <strong>the</strong> number of MFs<br />
was observed between NM and OSCC (p = 0.00), CIL and SM (p = 0.003), CIL and<br />
SCC (p = 0.00), SM and OSCC (p = 0.00).<br />
Conclusion: MF formation and its retention seems to be influenced by duration<br />
(reactive lesions), and basement membrane invasion with stressed extracellular<br />
matrix (OSCC). Stress-dictated distribution patterns may prove valuable in<br />
distinguishing pN0 and pN+ groups. Smaller incisional biopsies may not be useful in<br />
predicting both invasion and nodal metastasis ei<strong>the</strong>r by quantitation or by<br />
distribution pattern analysis owing to <strong>the</strong> heterogeneity that is displayed.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1056 TREATMENT FAILURE IN HIGH-RISK HEAD AND NECK<br />
CANCER TREATED WITH ADJUVANT CHEMORADIATION<br />
S. Torres, M.T. Marques, M. Ferreira, I. Sargento, E. Netto, J. Oliveira,<br />
M. Roldão, A. Moreira<br />
Medical Oncology, Instituto Portuguès de Oncologia de Lisboa Francisco Gentil,<br />
E.P.E. (IPOLFG EPE), Lisboa, PORTUGAL<br />
Background: Adjuvant chemoradiation (adCRT) is <strong>the</strong> standard of care in<br />
resectable high-risk head and neck squamous cell carcinoma (HNSCC). We<br />
select patients (pts) for adCRT if <strong>the</strong>y are physically fit and have at least 1<br />
major (extra-capsular nodal spread or positive resection margins) and/or 2<br />
minor (pT4, pN2, perineural or vascular invasion) high risk pathological factors.<br />
Loco-regional control and disease-free survival (DFS) are good and <strong>the</strong> toxicities<br />
manageable. The aim of our study was to evaluate <strong>the</strong> patterns of treatment (tt)<br />
failure with this <strong>the</strong>rapy.<br />
Methods: We reviewed <strong>the</strong> charts of all pts with resected high-risk HNSCC treated<br />
with adCRT, from 2007 to 2011. Pts and disease characteristics, compliance to tt,<br />
date and first site of tt failure and disease status at last follow-up (FU) were reviewed.<br />
Overall survival (OS) and DFS were estimated using Kaplan-Meier method.<br />
Results: 221 consecutive pts were included, 93.6% male, median age 52 years. The<br />
incidence of stage IV A−B disease (72.8%) and major high risk pathological features<br />
such as involved surgical margins (50.6%) and extranodal spread of <strong>the</strong> disease<br />
(52.0%) was high. Compliance to tt was good with 94.5% of pts completing at least 2<br />
cycles of chemo<strong>the</strong>rapy. There were no toxic deaths. With a median FU of 18.8<br />
months, 57 pts (25.8%) experienced disease recurrence. Local or regional recurrence<br />
as <strong>the</strong> first site of tt failure occurred in 25 pts (11.3%) and distant metastasis (mets)<br />
occurred in 32 pts (14.5%). The most common site of metastatic disease was <strong>the</strong> lung<br />
(26 pts; 11.7%). Lung recurrence occurred at a median FU of 8 months. Nine pts<br />
(4%) recurred with lung mets less than 6 months after <strong>the</strong> end of adCRT. Five pts<br />
were diagnosed of primary lung cancer during FU. At last FU 175 pts (79.2%) were<br />
alive; 154 (69.9%) in complete remission. The Kaplan-Meier estimates of 3-year OS<br />
and DFS were 68% and 59%, respectively.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds402 | ix345
Conclusions: Through adequate selection of pts and supportive measures, high tt<br />
compliance and manageable toxicity of adCRT are achieved. The observed early<br />
recurrence in a small number of pts, mainly in <strong>the</strong> lung, might suggest that more detailed<br />
pretreatment staging and FU evaluation for early lung disease detection are warranted.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1057 PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS OF<br />
5-FLUOROURACIL IN CHINESE HEAD AND NECK CANCER<br />
(HNC) PATIENTS<br />
L. Zhao 1 ,W.Liu 2 , X. Guo 2 , C. Zhao 2 , Y. Huang 2 ,F.Xu 2 , L. Zhang 2<br />
1 Department of Medical Oncology, Cancer Center of Sun Yat-Sen University,<br />
Guangzhou, CHINA, 2 Medical Oncology, Sun Yat-Sen University Cancer Center,<br />
Guangzhou, CHINA<br />
Background: Pharmacokinetic (PK) variability of 5-fluorouracil (5-FU) has been<br />
demonstrated for +30 years and a significant link between exposure and <strong>the</strong>rapeutic<br />
response has been identified. A maximum tolerated exposure (MTE) from <strong>the</strong> area<br />
under curve (AUC) has been characterized for various regimens and <strong>the</strong>rapeutic dose<br />
management (TDM) has been used to optimize dosing.<br />
Objective: The objective of this study was to characterize <strong>the</strong> PK variability of 5-FU<br />
in <strong>the</strong> Chinese HNC population and examine <strong>the</strong> relationship between AUC, toxicity<br />
and efficacy. The 5-FU MTE in this population was compared with MTE identified<br />
for European HNC patients.<br />
Methods: 89 treatment naïve patients with HNC were administered cisplatin (80mg/<br />
m 2 , d1) and 5-FU (4g/m 2 , 120h IV). Blood samples were collected at steady state<br />
after <strong>the</strong> first 18h of 5-FU infusion. Plasma was analyzed by a 5-FU immunoassay<br />
and AUC was calculated. Relationship between 5-FU AUC and 5-FU related<br />
toxicities was examined. Preliminary efficacy results were evaluated for 5-FU related<br />
toxicity.<br />
Results: The patient 5-FU AUC values varied widely: from 15 to 103 mg · h/L. 33%<br />
of patients were within <strong>the</strong> target range of 25-35 mg· h/L; 18% were below and 49%<br />
were above . Toxicity was recorded for 89 patients. Among <strong>the</strong> 44 patients with AUC<br />
above <strong>the</strong> target range, severe mucositis or mylesupression was experienced by 32<br />
patients. By comparison, among <strong>the</strong> 45 patients within or below target range, only 3<br />
experienced severe toxicities. ROC analysis for 5-FU AUC and severe mucositis<br />
identified a cut-point of 36 mg· h/L (p < 0.0001). These results are listed in <strong>the</strong> table<br />
below.<br />
Incidence of severe mucositis and myelosuppression with 5-FU AUC<br />
AUC ≤35 mghr/L >35 mghr/L<br />
Grade 3 3% 36%<br />
Grade 0 - 2 47% 13%<br />
Conclusion: Results of this study demonstrate wide PK-variability of 5-FU exposure<br />
and a significant relationship between severe toxicity and AUC in HNC cancer<br />
patients. The study confirms that <strong>the</strong> MTE in this population is similar to a<br />
European HNC population treated with cisplatin/5-FU. TDM using <strong>the</strong> target range<br />
of 25-35 mg· h/L may have benefit in lowering toxicity in HNC patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1058 CISPLATIN + VINORELBINE (DDP + VNB) ADMINISTERED IN 60<br />
CASES OF RECURRENT/METASTATIC SALIVARY GLAND<br />
MALIGNANCIES (RMSGM): FINAL REPORT<br />
O. Ostellino 1 , M. Airoldi 1 , M. Garzaro 2 , F. Pedani 1 , L. Raimondo 2 , G. Riva 2 ,<br />
S. Carnio 1 , G. Pecorari 2 , G. Fora 1 , C. Giordano 2<br />
1 Medical Oncology Division - Medical Oncology Department, San Giovanni<br />
Battista Hospital, Turin, ITALY, 2 1st Ent Division - Physiopathology Department,<br />
University of Turin, Turin, ITALY<br />
Background: RMSGM are not amenable to <strong>the</strong> usual treatment with surgery and<br />
post-operative radio<strong>the</strong>rapy. The role of chemo<strong>the</strong>rapy (CT) for RMSGM is palliative<br />
only. VNB showed moderate activity in our experience (Bull Cancer 85:892; 1998)<br />
and in a randomized phase II trial we had demonstrated that <strong>the</strong> DDP + VNB<br />
combination had a better outcome than VNB alone (Cancer 91:541; 2001). In this<br />
abstract we report <strong>the</strong> final results of this combination in 60 cases.<br />
Methods: From April 2001 to February 2009, 60 cases with RMSGM were enrolled.<br />
All patients received <strong>the</strong> following regimen: DDP 80 mg/sm d.1 + VNB 25 mg/sm d.<br />
1,8 every 3 weeks. The study foresees a maximum of 6 cycles.<br />
Results: Patients characteristics were as follows: 35 males (58%) and 25 females<br />
(42%); median age: 56 yrs (range 20-68); median ECOG PS: 1 (0-2); histology:<br />
adenocarcinoma 15 (25%), adenoid cystic ca. 34 (57%), o<strong>the</strong>rs 11 (18%); site of<br />
disease: local 30 (50%), mts +/- local 30 (50%). Forty-two pts received DDP + VNB<br />
as first line CT (70%) while 18 pts (30%) had <strong>the</strong> combination as second-line CT<br />
(30%). After a median of 5 cycles of first line DDP + VNB responses were: 3 CR<br />
(7%), 10 PR (24%), 14 NC (33%) and 15 PD (36%). After a median of 4 cycles of<br />
Annals of Oncology<br />
second line CT responses were: 0 CR; 1 PR (5%), 6 NC (33%) 11 PD (62%). Median<br />
survival: 10 months (3-29) for first line CT; 4 months (1-12) for second line CT.<br />
G3-4 toxicity: neutropenia (20%), anemia (12%), nausea/vomiting (12%), peripheral<br />
toxicity (3%).<br />
Conclusions: DDP + VNB is an effective first line CT in RMSGM; second line CT<br />
has a low palliative activity. Toxicity seems acceptable. This regimen could be<br />
suitable for an integration with new biologic target agents.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1059 ANTI OXIDANT CAPACITY OF CALENDULA OFFICINALIS<br />
FLOWERS EXTRACT AND PREVENTION OF RADIATION<br />
INDUCED OROPHARYNGEAL MUCOSITIS IN PATIENTS WITH<br />
HEAD AND NECK CANCERS: A RANDOMIZED CONTROLLED<br />
CLINICAL STUDY<br />
D. Moslemi 1 , N. Babaee 2 , A. Moghaddamnia 3 , G. Mazdai 4<br />
1 Biochemical, Babol University of Medical Sciences, Babol, IRAN, 2 Department<br />
of Oral Diseases, Babol University of Medical Sciences, Babol, IRAN,<br />
3 Department of Pharmacology, Babol University of Medical Sciences, Babol,<br />
IRAN, 4 Radiation Oncology, Laleh hospital, Tehran, IRAN<br />
To determine <strong>the</strong> effect of Calendula officinalis flower extract mouthwash as gel<br />
formulation on radiation-induced oropharyngeal mucositis (OM) in patients with<br />
head-and-neck cancer. Forty patients with neck and head cancers who were treated<br />
with radio<strong>the</strong>rapy or chemoradio<strong>the</strong>rapy were randomly assigned to receive ei<strong>the</strong>r 2%<br />
calendula extract mouthwash or placebo (20 patients in each group). The subjects<br />
were treated with telecobalt radio<strong>the</strong>rapy at conventional fractionation (2 Gy/fraction,<br />
five fractions weekly, 20–35 fractions within 4–7 weeks). Oropharyngeal mucositis<br />
was evaluated by two doctors (a radiation oncologist and a dentist), using <strong>the</strong> oral<br />
mucositis assessment scale (OMAS). The patients also received concurrent<br />
chemo<strong>the</strong>rapy. Calendula mouthwash significantly decreased <strong>the</strong> intensity of OM<br />
compared to placebo at week 2 (score: 5.5 vs. 6.8, p = 0.019), week 3 (score: 8.25 vs.<br />
10.95, p < 0.0001) and week 6 (score: 11.4 vs. 13.35, p = 0.031). Total antioxidant,<br />
polyphenol and flavonoid contents and quercetin concentration of <strong>the</strong> 1% extract<br />
were 2353.4 ± 56.5 µM, 76.66 ± 23.24, 313.40 ± 6.52 mg/g and 19.41 ± 4.34 mg/l,<br />
respectively. Calendula extract gel could be effective on decreasing <strong>the</strong> intensity of<br />
radio<strong>the</strong>rapy- induced OM during <strong>the</strong> treatment and antioxidant capacitiy may be<br />
partly responsibe for <strong>the</strong> effect.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1060 HORIZONTAL LATERAL THYROIDECTOMY-“THOMAS<br />
TECHNIQUE”A NOVEL SURGICAL APPROACH TO THYROID<br />
NEOPLASMS<br />
T. Varughese<br />
Surgical Oncology and Reconstructive Surgery, Lakeshore Hospital and Reserch<br />
Center, Cochin, INDIA<br />
Background: Kochers’ anterior approach is <strong>the</strong> universal standard for thyroidectomy<br />
but with several complications. Feasibility of horizontal lateral thyroidectomy<br />
(Thomas’ Technique,) based on 3 D volumetric anatomy is a novel concept to<br />
minimize complications to <strong>the</strong> superior, Recurrent Laryngeal nerves, Para thyroids<br />
and vessels which are posterior and lateral. Unique anatomy of platysma,<br />
safeguarding of sub platysmal venous plexus and investing layer of deep fascia in<br />
relation to Cosmetic outcome is highlighted.<br />
Objectives: This feasibility study was designed to avoid all <strong>the</strong> known complications<br />
of thyroidectomy and an unaes<strong>the</strong>tic anterior scar.<br />
Methods: Superior results from <strong>the</strong> pilot study, prompted to extend <strong>the</strong> study for <strong>the</strong><br />
next 2 years.Of 283 subjects thus enrolled, 231 were females and 52 males. 118 had<br />
benign disease out of which 75 were MNGs, 31 adenomas and 9 cysts. Out of 165<br />
Cancers, 160 were differentiated (96papillary, 44 follicular, 20 mixed and 5<br />
medullary).18 had intra thoracic extensions. Using single ipsilateral incision 40 hemi<br />
thyroidectomies, 70 total thyroidectomies of benign and 55 total thyroidectomies of<br />
early cancers were done. Bilateral approach used in 110 cases of carcinomas<br />
requiring bilateral node dissection and for 8 benign cases of bilateral intrathorasic<br />
extensions. Para thyroids were dissected pulverized and injected into<br />
Sternocleidomastoid muscle before dissection if required.<br />
Results: Blood loss was 10-15 ml and hospital stay 24 hrs. There were no nerve<br />
injuries. Parathyroid deficiency was reported in 10/283. 165 thyroidectomies (115<br />
totals) were performed with single lateral incision. Within 6 months scar<br />
disappeared, touch sensations returned to normal. Cosmesis and quality of life were<br />
excellent.<br />
Conclusions: “Horizontal lateral thyroidectomy”–”Thomas technique”, is a novel<br />
method applicable for all thyroid neoplasms. Avoidance of “handling” of <strong>the</strong> gland<br />
upfront, direct vision of nerves, and ligation of vascular pedicles upfront leading to<br />
an avascular gland makes this approach unique and “bloodless”. It facilitates better<br />
lymph adenectomy and is safest for hemi as well as Total thyroidectomy and for<br />
ix346 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
intrathorasic extensions. Complications described in <strong>the</strong> literature are minimised.<br />
Superior cosmetic results compared to Kocher’s technique.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1061TiP FIRST-IN-MAN PHASE I STUDY OF TPCS2A-BASED<br />
PHOTOCHEMICAL INTERNALISATION (PCI) OF<br />
BLEOMYCIN IN LOCALLY RECURRENT OR ADVANCED/<br />
METASTATIC, CUTANEOUS OR SUBCUTANEOUS<br />
MALIGNANCIES<br />
M. Forster, A. Sultan, W. Jerjes, C. Simeon, S. Morley, D. Carnell, C. Hopper<br />
Head and Neck, University College London Hospital, London,<br />
UNITED KINGDOM<br />
Objective: PCI is a novel technique in which chemo<strong>the</strong>rapeutic cytotoxicity is<br />
enhanced with a photosensitiser and light exposure. This dose-escalation study<br />
assessed <strong>the</strong> safety and tolerance of TPCS 2a (tetraphenyl chlorin disulphonic acid,<br />
Amphinex®) in bleomycin PCI, pharmacokinetic profiles, and determined <strong>the</strong><br />
maximum tolerated dose (MTD).<br />
Method: Cohorts of 3 to 6 patients were enrolled and <strong>the</strong> TPCS2a dose escalated by a<br />
pre-specified amount until dose-limiting toxicity (DLT) occurred in at least two<br />
patients (≥33%). Patients received TPCS2a at a starting dose of 0.25mg/kg. Four days<br />
later <strong>the</strong>y received bleomycin (15,000IU/m 2 IV) and after 3 hours red light laser<br />
(652nm) was applied to target lesions for 600 seconds to initiate a <strong>the</strong>rapeutic<br />
response. Patients were followed for 3 months.<br />
Results: Nineteen patients were enrolled: 4 with cutaneous breast cancer, 13<br />
squamous cell carcinoma (SCC) of head and neck and o<strong>the</strong>r regions, 2 o<strong>the</strong>r cancers.<br />
17/19 patients experienced 94 AEs, most commonly pain, photosensitivity and<br />
nausea. Most (83%) were mild or moderate. Fourteen episodes of pain (3 severe)<br />
were treatment-related. Mean patient-reported pain using a VAS scale declined from<br />
4.9 to 1.3 24 hours after treatment. Four patients experienced skin photosensitivity<br />
reactions; 3 were in <strong>the</strong> highest dose cohort. 10/19 patients experienced 15 serious<br />
adverse events: 3 (swelling, and blistering of hands, tongue oedema) were probably<br />
related to treatment. The MTD of TPCS 2a was found to be 1.5mg/kg. At day 28, 11/<br />
16 patients had a complete response (CR) in target lesions, 2 had a partial response<br />
(PR), 2 had stable disease (SD) and 1 had progressive disease (PD). At last visit <strong>the</strong>re<br />
were 8 CRs, 2 PRs, 2 SDs and 2 PDs. During <strong>the</strong> course of <strong>the</strong> study four patients<br />
died (no relation to treatment) and six were withdrawn prematurely.<br />
Conclusion: With appropriate analgesia and anaes<strong>the</strong>sia TPCS 2a-based PCI of<br />
bleomycin was well tolerated in <strong>the</strong>se patients with locally advanced cancer.<br />
Treatment-related AEs were as expected and can be managed. Preliminary<br />
efficacy data are very encouraging and a phase II study in HNSCC has just<br />
begun.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds402 | ix347
abstracts<br />
hematological malignancies<br />
1062O A NATIONWIDE SURVEY OF ADULT T-CELL LEUKEMIA/<br />
LYMPHOMA (ATL) NEWLY DIAGNOSED OVER THE LAST<br />
DECADE IN JAPAN<br />
H. Katsuya 1 , K. Ishitsuka 1 , A. Utsunomiya 2 , S. Hanada 3 , T. Eto 4 , Y. Moriuchi 5 ,<br />
Y. Saburi 6 , T. Yamanaka 7 , J. Suzumiya 8 , K. Tamura 1<br />
1 Department of Medicine, Division of Medical Oncology, Hematology and<br />
Infectious Diseases, Fukuoka University, Fukuoka, JAPAN, 2 Hematology,<br />
Imamura Bun-in Hospital, Kagoshima, JAPAN, 3 Hematology, National Hospital<br />
Organization Kagoshima Medical Center, Kagoshima, JAPAN, 4 Hematology,<br />
Hamanomachi Hospital, Fukuoka, JAPAN, 5 Hematology, Sasebo City General<br />
Hospital, Sasebo, JAPAN, 6 Hematology, Oita Prefectural Hospital, Oita, JAPAN,<br />
7 Research Center for Innovative Oncology, National Cancer Center Hospital East,<br />
Kashiwa, JAPAN, 8 Cancer Center, Shimane University, Izumo, JAPAN<br />
Introduction: ATL is a malignancy of mature T-lymphocytes caused by human<br />
T-lymphotropic virus type I (HTLV-1), and it is classified into 4 clinical subtypes,<br />
i.e. acute, lymphoma, chronic, and smoldering type according to <strong>the</strong> analysis of <strong>the</strong><br />
former nationwide survey performed in late 80’s. During <strong>the</strong> 2 decades after this<br />
analsysis, treatment for ATL has improved, e.g. intensive sequential combination<br />
chemo<strong>the</strong>rapy and allogeneic hematopoietic stem cell transplantation (HSCT). We<br />
<strong>the</strong>refore performed a nationwide survey to know <strong>the</strong> outcome of ATL patients newly<br />
diagnosed during <strong>the</strong> last decade.<br />
Patients and methods: The clinical data was collected retrospectively from <strong>the</strong><br />
medical record of patients who were diagnosed as ATL between 2000 and 2009 in<br />
participating institutions. Approval of this study was obtained from <strong>the</strong> Ethics<br />
Committee and Institutional Review Board of Fukuoka University where <strong>the</strong> central<br />
office is located and at each participating center based on <strong>the</strong>ir institutional policies.<br />
Results: A total of 1552 patients’ survey form was submitted from 81 institutions<br />
across Japan. Fifty-four patients were excluded due to missing data, and <strong>the</strong><br />
remaining 1498 were analyzed. The median survival time (MST) of 897 for acute<br />
type and that of 355 for lymphoma type were 8.3 and 10.6 months, and overall<br />
survival (OS) rates at 5 years were 9% and 13%, respectively. Fifty % of patients had<br />
received CHOP/CHOP-like regimen, 31 % had VCAP-AMP-VECP regimen, and<br />
single agent was used in 6% of <strong>the</strong> patients. The number of patients with allogeneic<br />
HSCT was 227 (46% from a sibling donor and 51% from an unrelated donor), a half<br />
of <strong>the</strong>m were transplanted at first remission. The MST and OS at 5 years from<br />
transplantation were 5 months and 25%, respectively. The MST of 172 for chronic<br />
and that of 74 for smoldering type were 30.3 and 36.7 months, respectively.<br />
Conclusion: The prognosis of acute and lymphoma type was still poor despite <strong>the</strong><br />
recent progress in treatment modalities, and it is of disappointment that <strong>the</strong>ir<br />
<strong>the</strong>rapeutic outcome was not remarkably improved as compared to former survey. It<br />
is also a surprise that <strong>the</strong> prognosis of smoldering type is not good as expected from<br />
<strong>the</strong> previous survey. To note, 25% of patients who underwent transplantation<br />
experienced a long survival, but it should be validated by <strong>the</strong> prospective study.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1063O SEQUENTIAL THERAPY WITH BRENTUXIMAB VEDOTIN IN<br />
NEWLY DIAGNOSED PATIENTS WITH SYSTEMIC<br />
ANAPLASTIC LARGE CELL LYMPHOMA<br />
M. Fanale 1 , R. Advani 2 , N.L. Bartlett 3 , A. Davies 4 , T. Illidge 5 , D.A. Kennedy 6<br />
,A.R. Shustov 7<br />
1 Lymphoma/myeloma, University of Texas, MD Anderson Cancer Center,<br />
Houston, TX, UNITED STATES OF AMERICA, 2 Medicine, Stanford University<br />
Medical Center, Palo Alto, CA, UNITED STATES OF AMERICA, 3 Medicine,<br />
Washington University School of Medicine, St. Louis, MO, UNITED STATES OF<br />
AMERICA, 4 Medical Oncology, University Hospitals Southampton, Southampton,<br />
UNITED KINGDOM, 5 Medical & Human Sciences, University of Manchester<br />
Christie Hospital NHS, Manchester, UNITED KINGDOM, 6 Clinical Affairs, Seattle<br />
Genetics, Inc., Bo<strong>the</strong>ll, WA, UNITED STATES OF AMERICA, 7 Division of<br />
Hematology, University of Washington Medical Center, Seattle, WA, UNITED<br />
STATES OF AMERICA<br />
Brentuximab vedotin (ADCETRIS®) comprises an anti-CD30 antibody conjugated by<br />
a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin<br />
E (MMAE). In a pivotal phase 2 study in patients (pts) with relapsed/refractory<br />
systemic anaplastic large cell lymphoma (sALCL), objective response rate was 86%<br />
Annals of Oncology 23 (Supplement 9): ix348–ix360, <strong>2012</strong><br />
doi:10.1093/annonc/mds403<br />
and median duration of response was 12.6 months. A phase 1, open-label,<br />
multicenter study was implemented to determine <strong>the</strong> safety and activity of sequential<br />
and combination treatment approaches of brentuximab vedotin with CHOP or CH-P<br />
chemo<strong>the</strong>rapy in newly diagnosed pts with CD30-positive mature T- and NK-cell<br />
lymphomas (ClinicalTrials.gov NCT01309789). This abstract presents data from Arm<br />
1 of <strong>the</strong> study, which employs sequential treatment in sALCL pts. Single-agent<br />
brentuximab vedotin (1.8 mg/kg) was administered q3 wks as a 30-minute outpatient<br />
IV infusion for 2 cycles prior to up to 6 cycles of CHOP. Pts in complete or partial<br />
remission (CR, PR) following CHOP were eligible to continue single-agent<br />
brentuximab vedotin up to 16 total cycles. Investigator-evaluated response<br />
assessments utilize <strong>the</strong> Revised Response Criteria for Malignant Lymphoma (Cheson<br />
2007). All 13 pts in Arm 1 had sALCL; 10 had ALK- and 3 had ALK+ disease. 9<br />
were male. Median age was 62 years (range, 23-81). The most common (≥6 pts)<br />
AEs, regardless of severity, were nausea, peripheral sensory neuropathy, and<br />
vomiting. The most common (>1 pt) Grade 3/4 AEs were anemia, fatigue, and<br />
peripheral sensory neuropathy; all have improved or resolved. Thus far, no pts had a<br />
Grade 5 AE or discontinued due to an AE. All 13 pts were evaluable at Cycle 2 and<br />
achieved remission after single-agent brentuximab vedotin (5 CR, 8 PR). Following<br />
CHOP, 10/12 evaluable pts maintained remission (7 CR, 3 PR). 2 pts with PR after<br />
single-agent brentuximab vedotin experienced PD on CHOP treatment. 3 pts have<br />
completed 16 cycles of <strong>the</strong>rapy, all in CR. Sequential <strong>the</strong>rapy with brentuximab<br />
vedotin was generally well tolerated and all pts achieved remission after 2 cycles of<br />
single-agent <strong>the</strong>rapy. The level of activity observed in newly diagnosed pts with this<br />
aggressive lymphoma is promising; a phase 3 randomized study is in development.<br />
Disclosure: M. Fanale: I have acted as a consultant for and served on Advisory Board<br />
for Seattle Genetics, Inc. I have received honoraria and travel expenses from<br />
SeattleGenetics, Inc. Seattle Genetics, Inc. has provided research funding to my<br />
institution.R. Advani: I have served on scientific advisory boards for Seattle Genetics,<br />
Inc., Celgene, and Allos Therapeutics. My institution has received research funding from<br />
Seattle Genetics, Inc., Abbott, Genentech, Pharmacyclic, and Allos Therapeutics.N.L.<br />
Bartlett: I have acted as a consultant to Seattle Genetics, Inc., and have been reimbursed<br />
for travel expenses by Seattle Genetics, Inc. My institution has also received research<br />
funding from Seattle Genetics, Inc.A. Davies: I have served on a scientific advisory<br />
board for Seattle Genetics, Inc. My institution has also received research funding from<br />
Seattle Genetics, Inc.T. Illidge: I have acted as a consultant to Seattle Genetics, Inc. and<br />
Millennium/Takeda. I have received honoraria from Millennium/Takeda. My institution<br />
has received research funding from Seattle Genetics, Inc.D.A. Kennedy: I am an<br />
employee of and have equity ownership in Seattle Genetics, Inc. A.R. Shustov: I have<br />
acted as a consultant to Seattle Genetics, Inc. I have received honoraria from<br />
Millennium. My institution has received research funding from Seattle Genetics, Inc.<br />
1064O IMPACT OF NUMBER OF PREVIOUS TREATMENT LINES<br />
AND PRE-TREATMENT WITH BORTEZOMIB OR<br />
LENALIDOMIDE ON EFFICACY OF<br />
BORTEZOMIB-BENDAMUSTINE-DEXAMETHASONE (BBD) IN<br />
PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE<br />
MYELOMA (MM)<br />
H. Ludwig 1 , H. Kasparu 2 , C. Leitgeb 1 , R. Greil 3 , E. Rauch 1 , W. Linkesch 4 ,<br />
N. Zojer 1 , L. Pour 5 , M. Fillitz 6 , Z. Adam 5<br />
1 1st Department of Medicine, Wilhelminenspital, Wien, AUSTRIA, 2 Department of<br />
Internal Medicine, Hospital Elisabethinen, Linz, AUSTRIA, 3 IIIrd Medical<br />
Department With Hematology and Oncology, Paracelsus Medical University,<br />
Salzburg, AUSTRIA, 4 Hematology, Medical University Graz, Graz, AUSTRIA,<br />
5 Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno,<br />
CZECH REPUBLIC, 6 Internal Medicine III, Hanusch Hospital, Wien, AUSTRIA<br />
Introduction: The number of previous treatment lines and pre-treatment with<br />
Bortezomib (B) or lenalidomide (L) likely impacts <strong>the</strong> efficacy and tolerance of BBD<br />
in r/rMM.<br />
Patients and methods: 71 pts with r/rMM have been enrolled. Median age: 65 yrs<br />
(range 40-86), male/female: 32/39, ISS stage I/II/III: 22, 29, and 20 pts, respectively.<br />
ECOG status 0/I/II: 37, 31, and 3 pts, respectively. Previous treatment lines: 1-2: 44,<br />
3-6: 27 pts, 43 pts had previously been exposed to B and 37 to L. Full data<br />
documentation for response evaluation (≥2 cycles) is available for 65 pts.<br />
Treatment: Benda 70 mg/m2 day 1 + 4, B 1.3 mg/m2 and Dex 20 mg on days 1, 4, 8<br />
and 11, q 4 wks. Planned number of treatment cycles was 8, with discontinuation after 4<br />
cycles in case of no response. K-M survival curves were compared using <strong>the</strong> log-rank test.<br />
Results: After a median follow up of 7.1 mos, myeloma response (ORR: CR-PR) was<br />
noted in 38 (58.5%), CR/nCR in 11 (16.9%), VGPR in 10 (15.4%), PR in 17 (26.2%),<br />
MR in 11 (16.9%), and SD in 16 (24.6%) pts. Median time to response was 77 days.<br />
Tab 1 shows response rates and PFS in pts in regards to number of previous<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
Annals of Oncology<br />
treatment lines and pre-exposure to B, L, and to both B and L. Median OS was not<br />
reached in any of <strong>the</strong> cohorts.<br />
All Pts<br />
1-2<br />
Treatment<br />
lines<br />
3-6<br />
Treatment<br />
lines<br />
Pre-exposure<br />
B L B and L<br />
ORR (%) 58.5% 61% 54% 76% 60% 44%<br />
PFS (mos) 12.2 13.0 7.8 12.2 5.9 6.0<br />
G4 anemia, leucopenia and thrombopenia were reported in < 5%. Incidence of G3-4<br />
infections and GI toxicities was low. G1-2 PNP was documented in 18% of pts at<br />
baseline and remained constant in almost all pts with only 3 developing G3 PNP and 1<br />
G4 PNP. Univariate analysis employing age, FISH ISS, ß2M, LDH, Hb, and<br />
pre-treatment with ei<strong>the</strong>r B or L or both revealed a significant negative correlation<br />
between combined L and B pre-treatment and ORR (p < 0.02), which in multivariate<br />
analysis also proved to be independently associated with ORR (p < 0.02). Conclusio:<br />
The BBD regimen resulted in remarkable response rate and PFS in <strong>the</strong> entire cohort of<br />
pts and in those pre-exposed to B. Pre-treatment with both B and L was associated with<br />
lower response rates and significantly shorter PFS. Median OS was not reached in <strong>the</strong><br />
total cohort or in any of <strong>the</strong> subgroups. The regimen was well tolerated.<br />
Disclosure: H. Ludwig: Received honoraria for speakers bureau from Mundipharma,<br />
Celgene and Janssen-Cilag. Scientific research grants from Mundipharma and<br />
Janssen-Cilag. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1065O COMORBIDITY INDEX IN ELDERLY MYELOMA PATIENTS:<br />
DOES IT AFFECT CLINICAL OUTCOMES?<br />
S. Kim<br />
Medicine, Samsung Medical Center, Seoul, KOREA<br />
Background: Multiple myeloma occurs mainly in elderly patients older than 60-70 years.<br />
Considering high prevalence of comorbid conditions in <strong>the</strong>se age groups, comorbidity<br />
may be an important issue in <strong>the</strong> management of myeloma. However, <strong>the</strong> effect of<br />
comorbidity index on clinical outcome of elderly myeloma patients is not clear, and <strong>the</strong>re<br />
is few data analyzing <strong>the</strong> association between comorbidity and prognosis of myeloma.<br />
Methods: We retrospectively analyzed patient aged ≥ 65 years with symptomatic<br />
myeloma. All patients were newly diagnosed and not eligible for undergoing<br />
autologous stem transplantation. Comorbidity was assessed at <strong>the</strong> time of diagnosis<br />
according to <strong>the</strong> Charlson Comorbidity Index (CCI).<br />
Results: 132 patients were analyzed in this study, and <strong>the</strong>ir median age was 71 years<br />
(range: 65-92 years) and median follow-up duration was 20 months. Approximately a<br />
half of patients (48.5%) had disorders o<strong>the</strong>r than myeloma at diagnosis. Diabetes<br />
mellitus was <strong>the</strong> most frequent comorbid disorder (n = 22, 16.7%). The range of CCI<br />
score was from 0 to 6. Thus, we classified three groups according to <strong>the</strong> value of CCI<br />
score (0, 1-2, 3-6). When overall survival was compared, <strong>the</strong> CCI-based classification<br />
failed to show a significant survival difference (p = 0.456) although <strong>the</strong> median<br />
survival of each group was as follows: 42.6, 34.1, and 25.3month, respectively). Its<br />
relationship with age and performance state was not significant, ei<strong>the</strong>r (p = 0.151,<br />
0.537). In accordance with this, <strong>the</strong> frequency of treatment-related complication was<br />
also similar among <strong>the</strong>m (p = 0.737).<br />
Conclusions: These results suggest that comorbidity does not affect survival and<br />
complications in elderly myeloma patients. Therefore, comorbid disorders may not<br />
become a huddle for deciding active treatment in elderly myeloma patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1066PD OVEREXPRESSION OF ENHANCER OF ZESTE HOMOLOG 2<br />
IS ASSOCIATED WITH CLINICAL OUTCOME IN ACUTE<br />
MYELOID LEUKEMIA PATIENTS<br />
P. Lin 1 ,S.Yeh 2 , L. Bai 2 , C. Lin 2 , C. Chiu 2<br />
1 Medical Genetics and Internal Medicine, Division of Hematology/Oncology, China<br />
Medical University Hospital, Taichung City, TAIWAN, 2 Internal Medicine, Division<br />
of Hematology/Oncology, China Medical University Hospital, Taichung, TAIWAN<br />
Background: Enhancer of zeste homolog 2 (EZH2), a subunit of polycomb repressive<br />
complex 2 functioned as methyltransferase causing trimethylation at lysine-27 of<br />
histone 3, is involved in stem cell regulation and various cancers. It was reported two<br />
faces that both increased expression and mutation/deletion were implicated in cancer<br />
development and progression of different malignancies. For acute myeloid leukemia<br />
(AML), <strong>the</strong> clinical significance of EZH2 was not explored. In this study, we<br />
examined EZH2 expression and mutation and evaluated <strong>the</strong> association between<br />
EZH2 and patient survival.<br />
Methods: A total of 105 patients, who were newly diagnosed as de novo AML and<br />
received intensive chemo<strong>the</strong>rapy between 2004 January and 2010 December, were<br />
retrospectively analyzed. All patients received French-American-British (FAB)<br />
classification, karyotype analyses, immunophenotyping, detection of NPM mutation<br />
and FLT3 internal tandem duplication (FLT3/ITD). The mutation of EZH2 was<br />
identified by direct sequencing. An immunohistochemical analysis of EZH2 was<br />
performed on bone marrow biopsy samples, and overexpression was defined as more<br />
than 50% positive staining among <strong>the</strong> leukemic marrow.<br />
Results: EZH2 overexpression was identified in 57 patients (54.3%), and no<br />
associated with age, gender, FAB classification, karyotype, FLT3/ITD and NPM<br />
mutation. Only two mutations were detected in this cohort. Patients with EZH2<br />
overexpression had a significant shorter median overall survival (OS; 18.5 vs 40.7<br />
months, p = 0.047) as well as a higher trend of relapsed/refractory disease (47.9% vs<br />
66.7%, p = 0.052). Karyotype and FLT3/ITD were also <strong>the</strong> significant prognostic<br />
factors for <strong>the</strong> entire cohort and NPM mutation was a trend of favorable prognostic<br />
factor in intermediate-karyotype patients by univariate analysis. We defined a<br />
prognostic classification based on <strong>the</strong>se four factors that was able to classify patients<br />
into four risk groups showing significant different survivals (median OS: not reached,<br />
not reached, 22.0 and 10.6 months, respectively; p < .0001) and probabilities of<br />
disease relapsed/refractory (p = 0.048).<br />
Conclusion: EZH2 overexpression is a novel poor prognostic biomarker in AML<br />
patients. The current result indicated that EZH2 expression status may be<br />
incorporated into prognostic classification.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1067PD HIGH CO-EXPRESSION OF CD135 AND CD117 PREDICTS<br />
POOR OUTCOME IN ACUTE MYELOID LEUKEMIA: A<br />
PROSPECTIVE STUDY<br />
S.K. Sharawat 1 , R. Gupta 2 , V. Sreenivas 3 , V. Raina 4 , L. Kumar 1 , A. Sharma 1 ,<br />
R. Bakhshi 5 , S. Iqbal 1 , S. Bakhshi 4<br />
1 Medical Oncology, All India Institute of Medical Sciences, New Delhi, INDIA,<br />
2 Lab Oncology, All India Institute of Medical Sciences, New Delhi, INDIA,<br />
3 Biostatistics, All India Institute of Medical Sciences, New Delhi, INDIA, 4 Medical<br />
Oncology, Bhim Rao Ambedkar IRCH, New Delhi, INDIA, 5 University of Delhi,<br />
Rajguru College of Applied Sciences, New Delhi, INDIA<br />
Background: The significance of <strong>the</strong> mutations in FLT3 and c-kit genes in AML has<br />
been well established but <strong>the</strong> role of <strong>the</strong>ir expression is not studied toge<strong>the</strong>r. The aim<br />
of this study was to evaluate clinical significance of FLT3 (CD135) and c-kit<br />
(CD117) co-expression on myeloblasts in AML.<br />
Methods: Five ml peripheral blood/bone marrow from consecutive AML patients at<br />
diagnosis from April 2008 to May 2010 was evaluated by flow-cytometry. CD135 and<br />
CD117 expression was evaluated on dim CD45 positive myeloblasts. Positive<br />
expression was considered as >20% surface antigen expression.<br />
Results: During <strong>the</strong> study period, <strong>the</strong>re were 115 AML patients with median age 16<br />
years and male:female ratio 2.02:1. M2 was <strong>the</strong> most common subtype 57% (66/115)<br />
followed by M4 14% (16/115). Cytogenetically (n = 85) <strong>the</strong>se patients were classified<br />
as good risk in 20 (23%), intermediate risk in 50 (59%) and poor risk in 15 (18%)<br />
patients. Flt3 internal tandem duplication was present in 20 (17%) patients. CD135<br />
was positive in 95 (82%) patients; CD117 was positive in 104 (90%) patients;<br />
co-expression of CD135 and CD117 was observed in 74 (64%) patients. In those<br />
patients who co-expressed CD135 and CD117, <strong>the</strong> median expression was 34.1% of<br />
<strong>the</strong> gated myeloblasts and patients were classified as high co-expression (>/= 34.1%<br />
expression) and low (
anthracyclines in vitro. A favorable impact on <strong>the</strong> dismal clinical course of acute<br />
myeloid leukemia (AML) was suggested (Schlenk et al. ASH 2008). Recently, a phase<br />
I/II trial assessing <strong>the</strong> efficacy and safety of two schedules of Bel in patients unfit for<br />
intensive induction <strong>the</strong>rapy has shown anti-leukemic effect both of Bel alone and in<br />
combination with idarubicin (ClinicalTrials.gov ID: NCT00878722).<br />
We evaluated <strong>the</strong> role of cytogenetic aberrations on response to Bel <strong>the</strong>rapy in 41<br />
patients (pts), of whom cases with intermediate risk cytogenetics in trend responded<br />
better to Bel than patients with high risk cytogenetics (p = 0.14). Five complete<br />
remissions (CR) and 2 partial remissions (PR) were observed in 25 pts (28%) AML<br />
cases with low/intermediate risk cytogenetic aberrations, whereas no CR and 2 PR<br />
were seen in 16 pts (13%) high risk AML cases.<br />
Gene expression profiling based on 13 pts (4 CR + PR and 9 PD) revealed a strong<br />
gene expression pattern associated with <strong>the</strong> response to Bel. MLL, a gene well known<br />
to be involved in epigenetic deregulation, was among <strong>the</strong> top 20 strongest<br />
correlations. Fur<strong>the</strong>rmore, differential expression of TP53 was also of special interest<br />
as histone deacetylases have been shown to modulate p53 transcriptional activity. In<br />
accordance, gene ontology class comparison analysis showed a significant enrichment<br />
of categories associated with epigenetic regulation such as “histone methyltransferase<br />
activity” and “histone deacetylase activity”. In addition, <strong>the</strong> respective gene<br />
expression pattern harbored predictive information as based on an in vitro cell line<br />
derived predictor and a blinded Bel response prediction was feasible.<br />
A trend indicating <strong>the</strong> potential association of Bel response and intermediate risk<br />
cytogenetics AML has been found. High risk AML cases might also benefit from an<br />
epigenetic treatment approach with a HDACi. Fur<strong>the</strong>r randomized studies are<br />
warranted to explore <strong>the</strong> benefit of Bel in pts with AML.<br />
Disclosure: S. Knudsen: MPI EmployeeJ. Tjørnelund: Employment Topotarget. All<br />
o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1069PD PREDICTING RESPONSE RATES OF HIGH GRADE NON<br />
HODGKIN’S LYMPHOMA: A COMPARATIVE STUDY OF<br />
INTERNATIONAL PROGNOSTIC INDEX (IPI) WITH<br />
SUBJECTIVE GLOBAL ASSESSMENT (SGA)<br />
V.S. Ostwal 1 , P. Bagayatkar 2 , P. Pawaskar 1 , R. Thippeswamy 1 , M. Sengar 1 ,<br />
H. Menon 1 , N. Khattry 1 , B. Bagal 1 , R. Nair 1 , M.K. Mallath 3<br />
1 Medical Oncology, Tata Memorial Hospital Centre, Mumbai, INDIA, 2 Medical<br />
Oncology, Tata Memorial Hospital, Mumbai, INDIA, 3 Digestive Diseases, Tata<br />
Memorial Hospital Centre, Mumbai, INDIA<br />
Introduction: Malnutrition is common in patients with cancer and no study has corelated<br />
<strong>the</strong> effect of malnutrition on outcomes of non Hodgkins Lymphoma (NHL)<br />
from India. Besides, <strong>the</strong>re are no studies validating <strong>the</strong> international prognostic index<br />
(IPI) from India. This study was done to compare <strong>the</strong> prognostic abilities of IPI and<br />
subjective global assessment (SGA) for early outcomes in NHL.<br />
Methods: This is a prospective observational study set in <strong>the</strong> lymphoma clinic of<br />
Tata Memorial Hospital, Mumbai between January to December 2010. All patients<br />
were screened for malnutrition at entry using a modified SGA tool. Baseline clinical<br />
factors of prognostic importance including IPI scores were recorded. Univariate and<br />
multivariate comparison were made using SPSS or EpiInfo 2000 software.<br />
Results: There were 401 patients with high grade NHL. The analysis of 389 patients<br />
with all information available showed that <strong>the</strong> IPI scores were low risk, low<br />
intermediate risk, intermediate high risk, high risk in 133 (34.3%), 95 (24.4 %), 91<br />
(23.4%) and 70 (17.9 %) patients respectively. The SGA scores were A, B, and C in<br />
188 (48.6%), 129 (33.2%) and 72 (18.2 %) patients respectively. Early outcomes<br />
included CR in 241 (62.6 %), EFS in 73% and overall survival in 81% patients at<br />
1-year. Univariate analysis revealed that <strong>the</strong> SGA scores were significantly associated<br />
with <strong>the</strong> IPI variables - age, serum LDH, performance status (ECOG), stage (Ann<br />
Arbor), extranodal sites as well as hemoglobin, response rates, one year survival and<br />
disease progression. Multivariate analysis revealed that SGA was a highly significant<br />
independent predictor of all early outcome parameters. Some IPI scores lost<br />
significance in <strong>the</strong> multivariate model.<br />
Conclusions: The SGA is a highly significant and independent predictive biomarker<br />
(for CR) and a prognostic biomarker (for 1-year OS and PFS) with good<br />
discriminative function in patients with NHL.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1070PD RELATIONSHIP BETWEEN PROGRESSION-FREE SURVIVAL<br />
AND OVERALL SURVIVAL IN CHRONIC LYMPHOCYTIC<br />
LEUKEMIA<br />
C. Beauchemin 1 , J.B. Johnston 2 , M. Lapierre 1 , F. Aissa 3 , J. Lachaine 1<br />
1 Faculty of Pharmacy, University of Montreal, Montreal, QC, CANADA, 2 Cancer<br />
Research, Manitoba Institute of Cell Biology, Winnipeg, MB, CANADA, 3 Market<br />
Access and Health Outcome Department, Lundbeck Canada Inc., Montreal, QC,<br />
CANADA<br />
Objectives: Overall survival (OS) represents a universally recognized measure to<br />
evaluate clinical benefits for a new anti-cancer drug. Due to <strong>the</strong> limitations of this<br />
measure of survival, surrogate endpoints are frequently used, such as progression-free<br />
Annals of Oncology<br />
survival (PFS) and time-to-progression (TTP). However, <strong>the</strong> surrogacy of <strong>the</strong>se<br />
endpoints for OS is not validated in all cancer settings. The main objective was to<br />
evaluate <strong>the</strong> relationship between median PFS/TTP and median OS in <strong>the</strong> context of<br />
chronic lymphocytic leukemia (CLL) using a trial-based approach.<br />
Methods: A systematic review of <strong>the</strong> literature was conducted using <strong>the</strong> PICO method:<br />
Population consisted of patients with CLL; Interventions and Comparators (when<br />
applicable) were standard <strong>the</strong>rapies for CLL and Outcomes were median PFS/TTP and<br />
median OS. Two independent reviewers screened titles, abstracts, and full papers for<br />
eligibility, and <strong>the</strong>n extracted data from selected studies. Correlation coefficient was<br />
calculated to assess <strong>the</strong> relationship between median PFS/TTP and median OS.<br />
Subgroup correlation analyses were also conducted according to characteristics of<br />
selected studies such as line of treatment and type of treatment under investigation.<br />
Results: Among <strong>the</strong> 1,263 potentially relevant studies identified by <strong>the</strong> literature<br />
search, 23 articles were included. The mean number of patients included in <strong>the</strong>se<br />
studies was 118 patients (min: 30, max: 724). The median age was 63.0 years and <strong>the</strong><br />
median follow-up period was 33.7 months. On average, median PFS/TTP was 14.0<br />
months (sd =12.4) and median OS was 35.0 months (sd = 31.2). The results of <strong>the</strong><br />
correlation analysis demonstrated that median PFS/TTP is highly correlated with<br />
median OS, with a Spearman’s correlation coefficient of 0.813 (p ≤ 0.001). A<br />
significant correlation between median PFS/TTP and median OS was observed in <strong>the</strong><br />
second-line and subsequent-line <strong>the</strong>rapy, but not in <strong>the</strong> first-line setting.<br />
Conclusion: The present results demonstrate a very strong correlation between<br />
median PFS/TTP and median OS in <strong>the</strong> context of CLL, which reinforce <strong>the</strong><br />
hypo<strong>the</strong>sis that PFS/TTP would be adequate surrogate endpoints for OS in this<br />
cancer setting. These findings would strongly support <strong>the</strong> use of PFS/TTP in <strong>the</strong><br />
appreciation of <strong>the</strong> clinical efficacy of new drugs in CLL.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1071P 3D TELOMERE SIGNATURES OF HODGKIN-CELLS AT<br />
DIAGNOSIS IDENTIFY PATIENTS WITH POOR RESPONSE<br />
TO CONVENTIONAL CHEMOTHERAPY<br />
H. Knecht 1 , N. Kongruttanachok 2 ,B.Sawan 3 , J. Brossard 4 , S. Prévost 5 ,<br />
É. Turcotte 5 , Z. Lichtensztejn 2 , D. Lichtensztejn 2 , S. Mai 2<br />
1 Haematology, CHUS, Sherbrooke, QC, CANADA, 2 MICB, Unversity of<br />
Manitoba, Winnipeg, MB, CANADA, 3 Pathology, CHUS, Sherbrooke, QC,<br />
CANADA, 4 Pediatrics, CHUS, Sherbrooke, QC, CANADA, 5 Medical Imaging,<br />
CHUS, Sherbrooke, QC, CANADA<br />
In classical Hodgkin’s lymphoma (HL) <strong>the</strong> malignant mononuclear Hodgkin (H) and<br />
multinuclear Reed-Sternberg (RS) cells are characterized by a distinct 3D nuclear<br />
telomere organization with shortening of <strong>the</strong> telomere length and <strong>the</strong> formation of<br />
telomeric aggregates. We asked if <strong>the</strong> severity of <strong>the</strong>se telomere changes correlates<br />
with clinical behaviour of <strong>the</strong> disease. We evaluated (mainly prospectively) <strong>the</strong> 3D<br />
telomere organization by quantitative fluorescent in situ hybridization (Q-FISH) on<br />
diagnostic biopsies from 20 patients who were good responders and compared <strong>the</strong>m<br />
with 20 diagnostic biopsies of 11 patients with refractory or relapsing HL (11 initial<br />
biopsies, five confirming progressions and four confirming relapses). The H-cells from<br />
patients with refractory/relapsing disease contained a significantly higher percentage<br />
of very small telomeres (p < 0.05) and telomere aggregates (p < 0.05) compared with<br />
H-cells of patients entering rapid remission. In order to eliminate <strong>the</strong>rapy related<br />
changes of <strong>the</strong> 3D nuclear telomere organization we compared (prior to any<br />
treatment) 10 initial diagnostic biopsies of refractory/relapsing HL with diagnostic<br />
biopsies of 10 patients with ongoing long lasting remission (mean 51 months).<br />
Importantly, <strong>the</strong> differences between both groups were highly significant (p < 0.005)<br />
for very small telomeres and for aggregates (p < 0.02). Since both groups were treated<br />
with standard ABVD chemo<strong>the</strong>rapy, long lasting remission or progression/relapse are<br />
independent of <strong>the</strong> choice of chemo<strong>the</strong>rapy and have to rely on intrinsic factors of <strong>the</strong><br />
tumour cells. Thus, H-cells of refractory/relapsing HL are characterized by a specific<br />
3D telomere signature, i.e. abundant very small telomeres. 3D telomere Q-FISH<br />
identifies <strong>the</strong>se highly aggressive mononuclear H-cells at <strong>the</strong> first diagnostic biopsy<br />
and thus may offer a novel molecular tool to optimize initial treatment.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1072P RECRUIT-TANDAB AFM13 - OVERCOMING LIMITATIONS OF<br />
MONOCLONAL ANTIBODIES IN HODGKIN LYMPHOMA<br />
E. Zhukovsky 1 , M. Ravic 2 , A. Ro<strong>the</strong> 3 , M. Topp 4 , A. Younes 5 , S. Knackmuss 6 ,<br />
U. Reusch 6 , E. Rajkovic 6 ,C.Hucke 2 , M. Little 6<br />
1 Affimed Therapeutics AG, Heidelberg, GERMANY, 2 Clinical Department, Affimed<br />
Therapeutics AG, Heidelberg, GERMANY, 3 Klinikum D.Universität zu Köln Klinik<br />
f. Innere Medizin I, University of Cologne, Cologne, GERMANY, 4 GSLS,<br />
University of Wuerzburg, Med. Klinik und Poliklinik II Immun- und Gen<strong>the</strong>rapie,<br />
Wuerzburg, GERMANY, 5 Department of Lymphoma/Myeloma, University of<br />
Texas M.D. Anderson Cancer Centre, Houston, TX, UNITED STATES OF<br />
AMERICA, 6 Research, Affimed Therapeutics AG, Heidelberg, GERMANY<br />
AFM13 is a RECRUIT-TandAb (CD30xCD16A) for treating Hodgkin Lymphoma by<br />
recruiting NK-cells and macrophages to <strong>the</strong> specific CD30 surface antigen on<br />
ix350 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Reed-Sternberg cells. This redirected immune response leads to potent tumor cell<br />
killing. RECRUIT TandAbs are tetravalent and bispecific, and address key<br />
deficiencies of monoclonal antibodies such as (i) differential binding to V/F allotypes<br />
of CD16A receptor and (ii) non-selective binding to activating CD16A and<br />
non-signalling CD16B receptors. Fur<strong>the</strong>rmore, RECRUIT-TandAbs have significant<br />
advantages over o<strong>the</strong>r antibody fragment technologies such as (i) bivalent binding to<br />
<strong>the</strong> targets and, (ii) longer half-life.<br />
AFM13 binds with high affinity to both CD30 and CD16A and is able to rapidly<br />
induce lysis of CD30+ cells at picomolar concentrations in <strong>the</strong> presence of PBMCs.<br />
Intensive in vitro characterization demonstrated that AFM13 is specific for <strong>the</strong><br />
CD16A receptor, which becomes activated only in <strong>the</strong> presence of tumor cells: <strong>the</strong>re<br />
is no systemic activation of NK-cells in <strong>the</strong> absence of target cells. A robust GMP<br />
production process in mammalian cells and a lyophilized formulation with excellent<br />
stability have been established. Toxicology testing in Cynomolgus monkeys did not<br />
reveal any toxicity. Currently, AFM13 is being investigated in a single arm phase I<br />
dose escalation trial for patients with relapsed and/or refractory Hodgkin Lymphoma<br />
(HL). Patients receive a single cycle of 4 weekly doses, which are escalated in cohorts<br />
of 3 patients at <strong>the</strong> dose levels of 0.01, 0.04, 0.15, 0.5, 1.5, 4.5 and 7.0 mg/kg. Study<br />
objectives are <strong>the</strong> assessment of safety and tolerability, PK, immunogenicity,<br />
antitumor activity, as well as <strong>the</strong> determination of <strong>the</strong> maximum tolerated dose<br />
(MTD) or <strong>the</strong> optimal biological dose (OBD). The safety of <strong>the</strong> MTD or OBD will<br />
be confirmed in fur<strong>the</strong>r patients receiving 2 cycles of AFM13.<br />
AM13 was shown to be safe and well tolerated by highly pre-treated Hodgkin<br />
Lymphoma patients in weekly doses of up to 7.0 mg/kg. Adverse events were<br />
generally mild, with <strong>the</strong> most frequent drug-related event being fever. An objective<br />
response was achieved on <strong>the</strong> dose level 1.5mg/kg. Nine cases of stable disease/minor<br />
response were also observed. In ex vivo assays AFM13 restored impaired cytotoxic<br />
activity of NK cells from HL patients. Preclinical and interim clinical data will be<br />
presented, showing that AFM13 may become a safe and effective targeted <strong>the</strong>rapy for<br />
CD30 positive malignancies.<br />
Disclosures: E. Zhukovsky: The author is <strong>the</strong> employee of Affimed Therapeutics and<br />
<strong>the</strong> member of <strong>the</strong> Management Board, M. Ravic: A consultant to Affimed<br />
Therapeutics and a Chief Medical Officer, M. Topp: Consultant to Affimed, S.<br />
Knackmuss: The coauthor is an employee of <strong>the</strong> company. U. Reusch: The coauthor<br />
is an employee of <strong>the</strong> company. E. Rajkovic: The coauthor is an employee of <strong>the</strong><br />
company. C. Hucke: The co-author is a former employee of Affimed Therapeutics<br />
and currently is a clinical development consultantM. Little: The co-author is a<br />
consultant to Affimed Therapeutics and owns <strong>the</strong> warrants of <strong>the</strong> company.<br />
1073P CONSOLIDATION TREATMENT WITH Y90-IBRITUMOMAB<br />
TIUXETAN AFTER R-CHOP INDUCTION IN HIGH-RISK<br />
PATIENTS WITH FOLLICULAR LYMPHOMA (FL)<br />
(GOTEL-FL1LC): A MULTICENTRIC, PROSPECTIVE STUDY<br />
M. Provencio Pulla 1 , M.A. Cruz Mora 2 , J. Gomez Codina 3 , C. Quero 4 ,<br />
M. Llanos 5 , F.R. Garcia Arroyo 6 , L. De La Cruz 7 , J. Guma 8 , J.R. Delgado 9 ,<br />
A. Rueda 10<br />
1 Medical Oncology, Hospital Universitario Puerta de Hierro Majadahond,<br />
Majadahonda, SPAIN, 2 Medical Oncology, Hospital Virgen de la Salud, Toledo,<br />
SPAIN, 3 Medical Oncology, Hospital Universitari i Polit, Valencia, SPAIN,<br />
4 Radio<strong>the</strong>rapy, Hospital Universitario Virgen de la Victoria, Malaga, SPAIN,<br />
5 Medical Oncology, Hospital Universitario de Canarias, Tenerife, SPAIN, 6 Medical<br />
Oncology, Complejo Hospitalario de Pontevedra, Pontevedra, SPAIN, 7 Medical<br />
Oncology, Hospital Universitario Virgen Macarena, Sevilla, SPAIN, 8 Medical<br />
Oncology, Hospital Universitario San Juan de Reus, Reus, SPAIN, 9 Medical<br />
Oncology, Hospital Universitario Virgen de las Nieves, Granada, SPAIN,<br />
10 Medical Oncology, Hospital Costa del Sol, Marbella, SPAIN<br />
Relapse is <strong>the</strong> main cause of <strong>the</strong>rapeutic failure in FL, which makes it necessary to<br />
investigate strategies that aim to eradicate minimal residual disease. This is why we<br />
set out to evaluate <strong>the</strong> role of consolidation with Y90-Ibritumomab Tiuxetan (RIT)<br />
in high-risk FL patients. As we possessed data making us suspect that prior<br />
treatment with Rituximab could reduce <strong>the</strong> efficacy of RIT, we designed a study with<br />
RIT after 4 cycles of CHOP-R and 2 CHOP, but without R.<br />
Material and Patients: Between April 2008 and April 2010, 30 patients were<br />
included in this trial: 17 male (56.7%) and 13 female (43.3%). Their median age was<br />
54.8 (range, 34-76). 20 (69%) patients had ECOG 0. There were no delays or<br />
reductions in RIT doses.<br />
Results: The objective rate of clinical response was 92.1% (CR + CRi + PR), [CI 95%:<br />
83-100%]. Of <strong>the</strong> 18 patients who presented with partial remission to <strong>the</strong> induction<br />
treatment, 11 (61.1%) had complete CR or remission after <strong>the</strong> consolidation<br />
treatment. There was only one exitus, due to H1N1 viral pneumonia. The most<br />
important G 3/4 toxicity was hematological, with 46% thrombopenia and 56%<br />
neutropenia. None of <strong>the</strong> patients in <strong>the</strong> trial died because of Lymphoma. With<br />
median follow-up of 26 months (12-37), <strong>the</strong> means for disease-free survival or<br />
overall survival were not reached.<br />
Conclusion: The induction procedure with 4 CHOP-R + 2 CHOP prior to consolidation<br />
with RIT gives good response rates and RIT improves CR. This combination is safe and<br />
shows a high activity in both, induction and consolidation procedures.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1074P A RETROSPECTIVE SINGLE CENTRE ANALYSIS OF SAFETY,<br />
TOXICITY AND EFFICACY OF RITUXIMAB (ORIGINAL) AND<br />
ITS BIOSIMILAR IN DIFFUSE LARGE B-CELL LYMPHOMA<br />
PATIENTS TREATED WITH CHEMO-IMMUNOTHERAPY<br />
P.S. Roy 1 , M. Sengar 1 , H. Menon 1 , B. Bagal 1 , N. Khattry 1 , E. Shridhar 2 ,<br />
S. Gujral 2 , S. Laskar 3 , V. Rangarajan, 4 , R. Nair 5<br />
1 Medical Oncology, Tata Memorial Hospital, Mumbai, INDIA, 2 Pathology, Tata<br />
Memorial Hospital, Mumbai, INDIA, 3 Radiation Oncology, Tata Memorial<br />
Hospital, Mumbai, INDIA, 4 Radiology, Tata Memorial Hospital, Mumbai, INDIA,<br />
5 Medical Oncology, Tata Memorial Hospital Centre, Mumbai, INDIA<br />
Background: Rituximab with chemo<strong>the</strong>rapy (CHOP regimen) has been <strong>the</strong> standard<br />
of care for diffuse large B-cell lymphoma (DLBCL). Mab<strong>the</strong>ra® is being used in India<br />
since early 2000. Reditux®, a biosimilar molecule of Rituximab, was developed in<br />
India & approved for use since March 2007. This retrospective audit aims to<br />
compare <strong>the</strong> safety, toxicity and efficacy of Mab<strong>the</strong>ra® with Reditux®.<br />
Methods: Two hundred twenty-three patients aged ≥ 18 years who underwent<br />
treatment from January 2004 to June 2010 were included. All patients received 4-8<br />
cycles of R-CHOP. CT scan of chest & abdomen was done at baseline and within 4<br />
weeks of completion of treatment. Grade 3-4 hematological and non-hematological<br />
toxicities according to CTC version 3.0 were recorded. Response rates [complete<br />
response (CR), partial response (PR)] in both groups were evaluated as per Cheson’s<br />
criteria & compared by Chi-Square test. Overall survival (OS) and progression-free<br />
survival (PFS) were estimated by Kaplan-Meier method & compared by two-sided<br />
log rank test.<br />
Results: One hundred one patients received Mab<strong>the</strong>ra®, 72 received Reditux®. In 17<br />
patients, <strong>the</strong> brand used was unknown and 33 patients received both. Baseline<br />
characteristics such as, age, gender, performance status, stage of disease & revised IPI<br />
score at presentation were similar in both groups. Median number of treatment cycle<br />
received was 6 in each group. Overall response rate (CR + PR) was 88% (Mab<strong>the</strong>ra®)<br />
and 90% (Reditux®). OS at 5 years was 85% (Mab<strong>the</strong>ra®) and 93% (Reditux®); P = 0.13.<br />
PFS at 5 years was 76% (Mab<strong>the</strong>ra®) and 84% (Reditux®); P = 0.44. At a median<br />
follow-up of 35 months (18 to 58 months) treatment related death was seen in 3 in<br />
Mab<strong>the</strong>ra® and 2 in Reditux® group. Grade 3-4 febrile neutropenia was observed in 23%<br />
(Mab<strong>the</strong>ra®) & 20% (Reditux®); grade 3-4 oral mucositis and diarrhea was seen in 25%<br />
(Mab<strong>the</strong>ra®) & 10% (Reditux®). No difference in infusional reactions were observed.<br />
Conclusion: Reditux® is as efficacious as Mab<strong>the</strong>ra® in terms of response rates, OS &<br />
PFS with comparable toxicity. However, randomized prospective trial is needed to<br />
validate <strong>the</strong>se results.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1075P DETECTION OF CAGA EXPRESSION IN GASTRIC<br />
MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA—<br />
BIOLOGIC SIGNIFICANCE AND CLINICAL IMPLICATION<br />
S. Kuo 1 , L. Chen 2 , C. Lin 3 ,M.Wu 4 , P. Hsu 4 , Y. Tzeng 1 , H. Tsai 2 , H. Wang 4 ,<br />
K. Yeh 1 , A. Cheng 1<br />
1 Departments of Oncology, National Taiwan University Hospital, Taipei, TAIWAN,<br />
2 National Institute of Cancer Research, National Health Research Institutes,<br />
Tainan, TAIWAN, 3 Departments of Pathology, National Taiwan University<br />
Hospital, Taipei, TAIWAN, 4 Departments of Internal Medicine, National Taiwan<br />
University Hospital, Taipei, TAIWAN<br />
Background: We recently reported that a direct contact of Helicobacter pylori (HP)<br />
with B cells resulted in CagA translocation into <strong>the</strong> cells (Cancer Res<br />
2010;70:5740-8). The translocated CagA fur<strong>the</strong>r activates extracellular<br />
signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK),<br />
and up-regulates <strong>the</strong> expressions of Bcl-2 and Bcl-xL. In this study, we sought to<br />
verify if CagA exists in <strong>the</strong> malignant B cells of gastric mucosa-associated lymphoid<br />
tissue (MALT) lymphoma.<br />
Methods: Expression of CagA protein, phospho-SHP-2, phospho-ERK,<br />
phospho-p38MAPK, Bcl-2 and Bcl-xL in a series of 26 gastric MALT lymphoma was<br />
determined by immunohistochemistry. Western blot analysis was done to confirm<br />
immunohistochemical detection of CagA and biopsies from non-gastric MALT<br />
lymphoma served as negative controls. The association of CagA expression and <strong>the</strong><br />
tumor response to HP-eradication (HPE) <strong>the</strong>rapy was evaluated in 77 stage IE/IIE1<br />
low-grade gastric MALT lymphoma patients.<br />
Results: The expression of CagA was detected in 35 (45.5%) of 77 patients. CagA<br />
expression was closely associated with <strong>the</strong> expression phospho-SHP-2 (P = .016),<br />
phospho-ERK (P < .001), phospho-p38MAPK (P = 0.014), Bcl-2 (P = 0.009), and<br />
Bcl-xL (P = 0.008). CagA expression was detected in 30 (69.8%) of 43 HP-dependent<br />
cases, and in 5 (14.7%) of 34 HP-independent cases (P < 0.001). Fur<strong>the</strong>rmore,<br />
patients with CagA expression responded to HPE more rapidly than those without<br />
(median time to complete remission, 3.0 months versus 7.0 months, P = 0.032).<br />
Conclusion: CagA protein can be translocated into malignant B cells of MALT<br />
lymphoma. The expression of CagA in lymphoma cells appears to be biologically and<br />
clinically significant.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds403 | ix351
1076P RITUXIMAB PLUS SUBCUTANEOUS CLADRIBINE IN<br />
PATIENTS WITH EXTRANODAL MARGINAL ZONE B-CELL<br />
LYMPHOMA OF THE MUCOSA ASSOCIATED TISSUE<br />
(MALT-LYMPHOMA): A PHASE II STUDY BY THE AGMT<br />
(ARBEITSGEMEINSCHAFT MEDIKAMENTöSE<br />
TUMORTHERAPIE)<br />
M. Troch 1 , B. Kiesewetter 2 , W. Willenbacher 3 , E. Willenbacher 3 , A. Zebisch 4 ,<br />
W. Linkesch 4 , M.A. Fridrik 5 , L. Müllauer 6 , R. Greil 1 , M. Raderer 2<br />
1 Hematology, Medical Onoclogy, Hemostaseology, Infectious Disease,<br />
Rheumatology, Oncologic Center, Paracelsus Medical University of Salzburg,<br />
Salzburg, AUSTRIA, 2 Clinical Oncology and Comprehensive Cancer Center,<br />
Medical University of Vienna, Vienna, AUSTRIA, 3 Hematology and Oncology,<br />
Medical University of Innsbruck, Innsbruck, AUSTRIA, 4 Hemato/Oncology,<br />
Medizinische Universit, Graz, AUSTRIA, 5 Internal Medicine 3, Allgemeines<br />
Krankenhaus Linz, Linz, AUSTRIA, 6 Institute of Pathology, Medical University<br />
of Vienna, Vienna, AUSTRIA<br />
Background: Currently, <strong>the</strong>re is no standard systemic treatment for extranodal<br />
marginal zone B-cell lymphoma of <strong>the</strong> mucosa associated lymphoid tissue<br />
(MALT-lymphoma). Both rituximab (R) and 2-chlorodeoxyadenosine (2CdA) have<br />
shown activity to some extent in this disease, but <strong>the</strong> combination has not been<br />
tested so far. In view of this, we have initiated a phase II study to assess <strong>the</strong> activity<br />
and safety of R/2CdA in patients with MALT-lymphoma.<br />
Patients and methods: Patients with histologically verified MALT-lymphoma were<br />
included in this study. Treatment consisted of R 375 mg/m 2 i.v. day 1 and 2CdA 0.1<br />
mg/kg s.c. days 1 – 4 every 21 days. In case of complete remission (CR) after two<br />
courses, ano<strong>the</strong>r two cycles of <strong>the</strong>rapy were administered, while patients achieving<br />
partial response (PR) or stable disease (SD) were scheduled to receive 6 cycles of<br />
treatment.<br />
Results: Out of 40 evaluable patients (14 female, 26 male), 39 received treatment as<br />
scheduled while one patient died before initiation of <strong>the</strong>rapy and was rated as PD in<br />
<strong>the</strong> intent to treat analysis. Twenty-one patients had gastric lymphoma, while 19<br />
suffered from extragastric MALT-lymphoma (6 lung, 2 salivary gland, 5 ocular<br />
adnexae, 4 intestinal, one breast and one cutaneous lymphoma, respectively). Side<br />
effects were manageable and consisted mainly of hematotoxicity including<br />
leukopenia, lymphopenia, anemia and thrombocytopenia. Twenty-three patients had<br />
a CR (58 %), 9 PR (23%) for an overall reponse rate of 81%, while 5 had SD (13%)<br />
and two progressed during <strong>the</strong>rapy. After a median follow-up of 16.7 months (Inter<br />
Quartile Range; 15.9 – 18.7months), 35 patients are alive (88 %) while four patients<br />
have died (one patient of post-stenotic pneumonia during <strong>the</strong> follow-up period, one<br />
of urosepsis before initiation of <strong>the</strong>rapy, one due to myocardial infarction and one<br />
patient due to lymphoma progression) and one patient withdrew consent and did<br />
not allow fur<strong>the</strong>r follow up.<br />
Conclusion: Our data demonstrate that R plus 2CdA is active and safe in patients<br />
with MALT-lymphoma.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1077P EFFICACY OF THE ANTHRACYCLINE-BASED<br />
CHEMOTHERAPY IN ANGIOIMMUNOBLASTIC T CELL<br />
LYMPHOMA PATIENTS<br />
S. Lee 1 , H. Kim 2 , I. Kim 3 , S.R. Lee 4 , D.S. Kim 5 , C.W. Choi 5 , B.S. Kim 1 ,Y.Park 1<br />
1 Department of Hemato-Oncology, Korea University Medical Center, Anam<br />
Hospital, Seoul, KOREA, 2 Hematooncology, KUMC Anam Hospital, Seoul,<br />
KOREA, 3 Department of Pathology, Korea University Medical Center, Anam<br />
Hospital, Seoul, KOREA, 4 Department of Hemato-Oncology, Korea University<br />
Medical Center, Ansan Hospital, Ansan, Kyong Gi-do, KOREA, 5 Department of<br />
Hemato-Oncology, Korea university Medical Center, Kuro Hospital, Seoul,<br />
KOREA<br />
Background: Peripheral T cell lymphoma (PTCL) is a heterogeneous disease,<br />
composed of five distinctive subtypes. Angioimmunoblastic T-cell lymphoma (AITL)<br />
represents a distinct clinicopathological entity in PTCLs, but <strong>the</strong>re have been limited<br />
data concerning <strong>the</strong> efficacy of treatment for <strong>the</strong> rarity of this disease. Here, we<br />
report <strong>the</strong> efficacy of treatment with anthracycline-based chemo<strong>the</strong>rapy in 49 AITL<br />
patients.<br />
Material and method: A total of 49 patients diagnosed with AITL between April<br />
1994 and October 2011 after <strong>the</strong> histopathological and immunohistochemical review<br />
were analyzed. All patients analyzed were treated with anthracycline-based<br />
chemo<strong>the</strong>rapy. Overall survival (OS) was defined as <strong>the</strong> date of diagnosis to death.<br />
Progression free survival (PFS) was defined as <strong>the</strong> date of diagnosis to <strong>the</strong> first date<br />
of disease progression, relapse, death as a result of any cause, or <strong>the</strong> last date of<br />
follow-up. OS and PFS were analyzed according to <strong>the</strong> Kaplan-Meier methods.<br />
Results: 14 of 49 patients (28.6%) were treated with adriamycin-based chemo<strong>the</strong>rapy<br />
(CHOP), and 35 patients (71.4%) received epirubicin-based chemo<strong>the</strong>rapy (CEOP). 4<br />
patients (8.16%) received high-dose chemo<strong>the</strong>rapy with autologous stem cell<br />
transplantation when <strong>the</strong> disease relapsed. Overall response rate was 69.4%, and<br />
complete remission was shown in 21 patients. (42.9%). 6 cases (12.2%) of <strong>the</strong> AITLs<br />
had progressive disease, and <strong>the</strong> response was not evaluated in 9 cases due to<br />
Annals of Oncology<br />
follow-up loss or early death. Only 2 patients of 49 (4.1%) were related to treatment<br />
related death, defined as death within 28 days after <strong>the</strong> initial day of <strong>the</strong>rapy.<br />
21-month OS rates were 77%, reaching a plateau level around 2 years. 2-year and<br />
5-year PFS rates were 34% and 23%, respectively.<br />
Conclusion: Anthracycline-based chemo<strong>the</strong>rapy could be a choice of chemo<strong>the</strong>rapy<br />
regimen, given <strong>the</strong> acceptable outcome of long term survival. The initial 2-year<br />
survival after initiation of <strong>the</strong> treatment is poor, and fur<strong>the</strong>r analysis is required for<br />
factors associated with <strong>the</strong> initial poor treatment outcome in AITL patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1078P POLYMORPHISMS OF GSTT1 AND GSTM1 GENES IN<br />
DIFFUSE LARGE B CELL LYMPHOMA EGYPTIAN PATIENTS<br />
H.A. Alagizy 1 , E. Essa 2<br />
1 Clinical Oncology Dept., Menofia University, Shebin Elkom, EGYPT, 2 Clinical<br />
Pathology, Menofia University, Shebin Elkom, EGYPT<br />
Background: Evidence, although not so extensive, did show that genetic variations in<br />
glutathione S-transferase (GST) might be associated with risk of developing<br />
lymphoma; overall and/or subtype. Genetic data on <strong>the</strong> contribution of GST genes in<br />
<strong>the</strong> prognosis of lymphomas is scarce even in occupationally exposed populations.<br />
Aim: The study aimed to investigate <strong>the</strong> influence of polymorphisms in GSTM1 and<br />
GSTT1 genes on both <strong>the</strong> risk and prognosis of diffuse large B-cell lymphoma<br />
(DLBCL).<br />
Subjects and methods: The study included 83 newly diagnosed DLBCL patients that<br />
were compared to 89 age and gender matched control subjects.Patient’s stage, LDH,<br />
performance status, extranodal disease and age were assessed and international<br />
prognostic index (IPI) was plotted . Treatment outcome and follow up relapse/<br />
progression and death was done. .GSTM1 and GSTT1 genotyping was performed by<br />
a multiplex PCR protocol.<br />
Results: We found 2.35 fold increase in <strong>the</strong> risk of DLBCL associated with<br />
GSTT1-null genotype (OR = 2.35, 95% CI: 1.02 – 5.40, P = 0.04). Three times<br />
increased risk in individuals with <strong>the</strong> GSTM1/T1-double null genotype (OR3.06, 95%<br />
CI: 1.04 – 8.95, P = 0.03) compared with both GSTM1 and GSTT1 genes undeleted<br />
(wild genotype) was observed. Patients; overall and those with favorable IPI (
Annals of Oncology<br />
developed HCV reactivation by PCR, 2 cases after cycle 6 and 2 within 6 months of<br />
<strong>the</strong>rapy.<br />
Outcome: Complete Remission for uncertain CR was 29/43 (67%). With <strong>the</strong><br />
median follow up of 32 months, The 2 year overall survival was 70% (95%CI<br />
59-81%) and disease free survival was 59% (95% CI 48-70%) with no recorded<br />
treatment related mortality. Dose reduction was required for toxicity in 25% of<br />
all patients.<br />
Conclusion: Rituximab plus CHOP is an effective and marginally tolerable regimen<br />
in <strong>the</strong>rapy of HCV +ve lymphoma patients. Role of prophylactic antiviral <strong>the</strong>rapy has<br />
to be evaluated for those patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1080P ADVERSE PROGNOSTIC IMPACT OF VASCULAR<br />
ENDOTHELIAL GROWTH FACTOR GENE POLYMORPHISM IN<br />
PATIENTS WITH NON-HODGKIN LYMPHOMA<br />
M.H. Han 1 , H. Eom 1 , H. Lee 1 , H. Kim 1 , W.S. Park 1 , S. Kong 2<br />
1 Hematology-Oncology Clinic, National Cancer Center, Goyang-si, Gyeonggi-do,<br />
KOREA, 2 Laboratory Medicine, National Cancer Center, Goyang, KOREA<br />
Vascular endo<strong>the</strong>lial growth factor (VEGF) plays an important role in angiogenesis<br />
and progression of many types of cancer and VEGF expression has been known to<br />
be associated with polymorphism of gene. However, <strong>the</strong> impact of polymorphisms of<br />
<strong>the</strong> VEGF gene on non-Hodgkin lymphoma (NHL) prognosis has not been fully<br />
elucidated. Here we investigated <strong>the</strong> association between VEGF polymorphisms and<br />
prognosis of NHL. The study involved 96 NHL patients treated at <strong>the</strong> National<br />
Cancer Center, Korea. The median patient age was 57 years, and 60 patients (62.5%)<br />
were men. A total of 5 polymorphisms with heterozygous allele were analyzed.<br />
Clinical characteristics (e.g., cell lineage) and international prognostic index (IPI),<br />
including age, performance, LDH, stage and extra-nodal involvement, were evaluated<br />
and related to VEGF polymorphism. Hazard ratios (HRs) were determined in terms<br />
of risk for overall survival using Cox proportional hazard regression analysis. Diffuse<br />
large B cell lymphoma (n = 73) was most common histologic type, and o<strong>the</strong>rs were<br />
as follows: T-cell lymphoma (n = 14), mantle cell lymphoma (n = 6), and Burkitt<br />
lymphoma (n = 3). IPI and stage were predictors for prognosis (p 5 cm)<br />
was presented in 61.4%. Patients received only 2 regimens were 63.7% and 31.8%<br />
had > 2 involved sites. No treatment related toxicity was observed. The overall<br />
response rate was 88.7%; complete response was reached in 59.1% and stable disease<br />
in 6.8%, progressive disease in 4.5% .Median time to local progression was 33<br />
months (95% CI 23.70-42.29), 2 –year local progression free survival was 78%.<br />
Response rate was found to be dependent on age, number of involved sites and<br />
lymph node size but independent on sex, pathological type, number of prior<br />
regimens, LDH level and time since diagnosis.<br />
Conclusion: Short-course-low dose palliative radio<strong>the</strong>rapy (2 x 2 Gy) affords an<br />
attractive option for treatment of relapsed low-grade non-Hodgkin’s lymphoma due<br />
to high response rates. However, <strong>the</strong>se results had to be confirmed in a larger<br />
number of patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1082P VERY HIGH EFFICACY OF CYTARABINE + G-CSF COMPARED<br />
TO CYCLOPHOSPHAMIDE + G-CSF AS HEMATOPOIETIC<br />
STEM CELL MOBILIZATION IN PATIENTS WITH LYMPHOID<br />
MALIGNANCIES REFERRED FOR AUTOLOGOUS<br />
TRANSPLANTATION<br />
T. Kruzel, T. Czerw, M. Sadus-Wojciechowska, J. Najda, M. Glowala-Kosinska,<br />
A. Chwieduk, J. Holowiecki, S. Giebel<br />
Department of Bone Marrow Transplantation, Maria Sklodowska-Curie Memorial<br />
Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, POLAND<br />
High-dose <strong>the</strong>rapy followed by autologous peripheral blood stem cell<br />
transplantation (autoPBSCT) is widely applied in <strong>the</strong> treatment of lymphoid<br />
malignancies. However, a significant proportion of patients fail to mobilize<br />
sufficient number of stem cells. So far, no standards for mobilization have been<br />
elaborated with G-CSF alone or G-CSF in combination with cyclophosphamide<br />
(CTX) being most commonly used regimens.<br />
In this study we evaluated efficacy of mobilization based on cytosine<br />
arabinoside (AraC) 1600 mg/m2 + G-CSF (filgrastim) 5-10 ug/kg. Results of 67<br />
subsequent patients were compared with 45 individuals mobilized with<br />
cyclophosphamide (CTX) (4 g/m2) + G-CSF, according to our preceding standard<br />
protocol. The median age of patients in <strong>the</strong> AraC group was 57 years; <strong>the</strong><br />
indications were: multiple myeloma (MM, n = 37), Hodgkin’s lymphoma (HL, n =<br />
9) and non-Hodgkin lymphoma (n = 21). Patients had previously been treated<br />
with 8 (3-36) cycles of chemo<strong>the</strong>rapy, 2 (1-6) lines of chemo<strong>the</strong>rapy; 33% had<br />
received radio<strong>the</strong>rapy. The characteristics of <strong>the</strong> CTX group were comparable.<br />
All but two patients (97%) treated with AraC reached > 15 CD34 + cells/uL in<br />
peripheral blood, which was required to start leukapheresis, compared to 67% in<br />
<strong>the</strong> CTX + G-CSF cohort (p < 0.0001). Median peak level was 127 (3-780) CD34<br />
+ cells/uL vs. 33 (1-240), respectively (p < 0.0001). After AraC treatment, 65<br />
(97%) patients collected > = 2x10e6 CD34 + cells/kg, required for single<br />
autoPBSCT, while 54 (81%) collected > = 5x10e6 CD34 + cells/kg, needed for<br />
double transplantation. Respective proportions in <strong>the</strong> CTX cohort were 56%<br />
(p < 0.0001) and 42% (p < 0.0001). The total number of harvested CD34 + cells<br />
was 14.9 (2.2-57.2) x10e6/kg for AraC and 5.1 (2-14.3) for CTX (p < 0.0001). The<br />
toxicity related to both regimens was comparable.<br />
We conclude that mobilization based on intermediate doses of AraC + G-CSF is<br />
highly effective allowing adequate CD34+ harvest in almost all patients with<br />
lymphoid malignancies, including heavily pre-treated and elderly individuals. The<br />
level of mobilized CD34+ cells is four times higher compared to commonly used<br />
protocol based on CTX. Hence, AraC + G-CSF may be a preferable option for<br />
predicted poor mobilizers, especially when high number of CD34+ cells is<br />
required for transplantation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1083P PERIPHERAL BLOOD STEM CELL (PBSC) MOBILIZATION<br />
AND ENGRAFTMENT AFTER BRENTUXIMAB VEDOTIN<br />
TREATMENT IN ANAPLASTIC LARGE CELL LYMPHOMA<br />
(ALCL) PATIENTS<br />
A.R. Shustov 1 , J.D. Rosenblatt 2 , D.A. Kennedy 3 , M. Fanale 4<br />
1 Division of Hematology, University of Washington School of Medicine, Seattle,<br />
WA, UNITED STATES OF AMERICA, 2 Hematology-Oncology, University of<br />
Miami, Miami, FL, UNITED STATES OF AMERICA, 3 Clinical Affairs, Seattle<br />
Genetics, Inc., Bo<strong>the</strong>ll, WA, UNITED STATES OF AMERICA, 4 Lymphoma/<br />
Myeloma, University of Texas, MD Anderson Cancer Center, Houston, TX,<br />
UNITED STATES OF AMERICA<br />
Background: Brentuximab vedotin is a CD30-targeted antibody conjugated to <strong>the</strong><br />
microtubule-disrupting agent, monomethyl auristatin E (MMAE), by a<br />
protease-cleavable linker. In a pivotal phase 2 study (ClinicalTrials.<br />
gov NCT00866047), an objective response was achieved in 50 of 58 (86%)<br />
relapsed/refractory ALCL patients (pts) treated with brentuximab vedotin. More<br />
than half of <strong>the</strong> pts achieved a complete remission (CR) (59%), enabling some pts to<br />
subsequently receive a stem cell transplant (SCT) as consolidation. A<br />
retrospective evaluation was performed to characterize PBSC mobilization and<br />
engraftment following brentuximab vedotin treatment (tx).<br />
Methods: Pts received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute<br />
outpatient IV infusion for up to 16 cycles. Antitumor efficacy was based on response<br />
assessments by independent review according to Cheson 2007.<br />
Results: Eight pts received autologous SCT as <strong>the</strong> first <strong>the</strong>rapy after discontinuing tx<br />
with brentuximab vedotin in remission. PBSC collection was completed prior to<br />
initiation of brentuximab vedotin tx in 2 pts, and following brentuximab vedotin tx<br />
in 6 pts. These 6 pts achieved a best clinical response of CR with brentuximab<br />
vedotin tx. After brentuximab vedotin tx, PBSCs were mobilized using<br />
chemomobilization (n = 3 pts), plerixafor (n = 1), and granulocyte colony-stimulating<br />
factor alone (G-CSF) (n = 2). The number of CD34+ cells/kg obtained and <strong>the</strong> days<br />
of collection are shown in <strong>the</strong> table. The CD34 + /kg yield for each pt was greater<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds403 | ix353
than <strong>the</strong> standard target of ≥2.5 x 10 6 , with a median of 7.0 x 10 6 . All pts engrafted,<br />
and <strong>the</strong> median time to engraftment was 10.5 days (range 9–14) for neutrophils and<br />
11.5 days (range 9–13) for platelets. The 100-day mortality rate post SCT was 0%.<br />
Conclusions: Brentuximab vedotin does not appear to have a negative impact on <strong>the</strong><br />
outcome of PBSC mobilization or engraftment in pts receiving high-dose <strong>the</strong>rapy<br />
and auto SCT.<br />
Age Sex<br />
Cycles of<br />
B-V<br />
Mobilization<br />
Regimen<br />
Days<br />
Collected<br />
46 M 4 IE/GCSF 1 46.9<br />
57 F 8 IE/GCSF 2 7.1<br />
61 M 7 plerixafor 4 4.1<br />
41 F 8 GCSF 2 6.9<br />
50 F 8 CED/GCSF 1 28.1<br />
45 F 4 GCSF 2 4.0<br />
IE = ifosfamide, etoposide<br />
CED = cyclophosphamide, etoposide, dexamethasone<br />
CD34+ Cells/kg<br />
(x 10 6 )<br />
Disclosure: A.R. Shustov: I have a consultancy relationship with and have received<br />
research funding from Seattle Genetics, Inc. I have also received honoraria from<br />
Millennium.J.D. Rosenblatt: Seattle Genetics, Inc. has provided research support to<br />
my institution.D.A. Kennedy: I am an employee of and have equity ownership in<br />
Seattle Genetics, Inc.M. Fanale: I have acted as a consultant and served on Advisory<br />
Board for Seattle Genetics, Inc. I have received honoraria and travel expenses from<br />
Seattle Genetics, Inc. Seattle Genetics, Inc. has also provided research funding to my<br />
institution.<br />
1084P AUTOLOGOUS STEM CELL TRANSPLANTATION (HCT) WITH<br />
OR WITHOUT TOTAL BODY IRRADIATION (TBI) IN NEWLY<br />
DIAGNOSED MANTLE CELL LYMPHOMA (MCL) PATIENTS<br />
M. Szymczyk 1 , J. Romejko-Jarosinska 1 , B. Brzeska 1 , W. Osiadacz 1 ,<br />
K. Domanska-Czyz 1 , M. Smorczewska 2 , O. Hermine 3 , M.H. Dreyling 4 ,J.<br />
A. Walewski 1<br />
1 Department of Lymphoid Malignancies, Maria Sklodowska-Curie Institute and<br />
Oncology Centre, Warsaw, POLAND, 2 Radiology Department, Maria<br />
Sklodowska-Curie Institute and Oncology Centre, Warsaw, POLAND,<br />
3 Department of Hematology, Hopital Necker, Paris, FRANCE, 4 Klinikum der<br />
Universität Münchenmedizinische Klinik und Poliklinik III,<br />
Ludwig-Maximilians-Universität München, München, GERMANY<br />
Introduction: MCL is considered incurable due to relapsing course and eventual<br />
resistance despite initial responses to treatment. The 1st line treatment in advanced<br />
disease is immunochemo<strong>the</strong>rapy induction followed by high-dose chemo<strong>the</strong>rapy +/-<br />
TBI and HCT in <strong>the</strong> first complete (CR) or partial remission (PR). The best<br />
conditioning regimen is unknown and <strong>the</strong> TBI role is one of <strong>the</strong> main issues. Very<br />
few retrospective analyses are available.<br />
Methods: We retrospectively evaluated all MCL patients treated 1st line +/- TBI as a<br />
part of myeloablative procedure at <strong>the</strong> Oncology Institute in Warsaw between<br />
1999-2011 with some patients treated in <strong>the</strong> European MCL Network trial for<br />
younger. We analyzed data for 7 women and 26 men, median age 56 years (39-63).<br />
Most (82%) had disease stage III-IV with bone marrow involvement in 64%.<br />
Majority received chemo<strong>the</strong>rapy with rituximab for induction (79%). All received<br />
doxorubicin and 45% cytarabine. 22 had TBI conditioning (TBI group). Most of <strong>the</strong><br />
remaining 11 patients received BEAM (non-TBI group). Before conditioning 18 had<br />
CR (12 before TBI, 6 before conditioning without TBI) and 15 PR (10 before TBI, 5<br />
before conditioning without TBI). There were no statistically significant differences<br />
between groups, including age, sex, disease stage and MIPI. After HCT 27 patients<br />
had CR (18 in TBI, 9 in non-TBI), 6 remained in PR (4 in TBI, 2 in non-TBI).<br />
Median observation time from <strong>the</strong> start of <strong>the</strong>rapy was 50.9 months (6.9-144.8) and<br />
from HCT 49.5 months (0.85-139.7).<br />
Results: After HCT <strong>the</strong> 1, 3 and 5-year overall survival (OS) rates were 96.9%, 89.8%,<br />
75% and <strong>the</strong> progression free survival (PFS) 93.7%, 73.1% and 67.9% respectively. In<br />
bivariate analysis <strong>the</strong> 1, 3 and 5-year OS rates were similar in TBI vs. non-TBI<br />
groups: 95.4% vs. 100%; 90.4% vs. 88.8%; 82.2% vs. 66.7% (p= 0.41). Comparison of<br />
1, 3 and 5-year PFS rates between TBI vs. non-TBI groups: 95.2% vs. 90.9% and<br />
86.6% vs. 47.1% and 78 % vs. 47.1% (p= 0.046) indicated superiority of TBI. In a<br />
multivariate analysis TBI was an independent PFS prognostic factor with relative risk<br />
0.24 (95% CI 0.06–1.02) (p = 0.04).<br />
Conclusion: The results showed PFS advantage of TBI conditioning prior to HCT in<br />
newly diagnosed MCL patients and no OS advantage.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1085P FIRST 100 DAYS OUTCOME OF AUTOLOGOUS<br />
NON-CRYOPRESERVED PERIPHERAL BLOOD STEM CELL<br />
TRANSPLANTS IN MULTIPLE MYELOMA<br />
S. Kayal 1 , V. Raina 1 , A. Sharma 1 , R. Kumar 2 , S. Iqbal 1<br />
1 Dept. of Medical Oncology, All India Institute of Medical Sciences (AIIMS)<br />
Institute Rotary Cancer Hospital, New Delhi, INDIA, 2 Lab Oncology, All India<br />
Institute of Medical Sciences, New Delhi, INDIA<br />
Background: We report <strong>the</strong> outcome of autologous stem cell transplant (ASCT) in<br />
multiple myeloma (MM) after high dose melphalan with peripheral blood stem cell<br />
(PBSC) rescue without cryopreservation in terms of feasibility, safety and 100 day<br />
morbidity and mortality.<br />
Methods: Between Sept 1994 and Feb <strong>2012</strong> a total of 81 patients (56 males, 25<br />
females) were treated with non cryopreserved ASCT, with conditioning regimen of<br />
high dose melphalan 140-200 mg/m 2 given on day-1. PBSC was collected after<br />
G-CSF mobilization with a mean number of leukapheresis of 1.5 (range 1-3) and was<br />
stored at 4 0 C for 1-3 days (median = 2) before reinfusion on day 0. The median<br />
MNC was 3.0 x 10 8 /kg (range 0.99 – 8.07) and CD34 dose was 2.34 x 10 6 /kg (range<br />
0.18 – 7.67).<br />
Results: Median age was 50 years (range 22-65). The median time from diagnosis<br />
to transplant was 12.1 months (range 4.3 - 99.9). Prior to transplant, 67 patients<br />
(83%) had chemosensitive disease (CR, VGPR, PR) and 13(16%) had<br />
chemoresistant (stable, refractory or progressive) disease. Forty five (55%) patients<br />
had an ECOG PS of 0-1. The median score for hematopoietic cell transplant<br />
comorbidity index (HCT-CI) was 0 (range 0-6). The median time to neutrophil<br />
engraftment was 10 days (range 8-27) and platelet engraftment was 14 days<br />
(range 9-38). Febrile neutropenia occurred in 98.7% patients with a clinically<br />
defined focus observed in 14.8%, microbiologically documented infection in 27.1%<br />
and fever of unknown origin in 56.7% cases. Antibiotics were used for a median<br />
of 10 days (range 5-42). Total toxicity score (sum of toxicity grades for all organs<br />
as per Seattle criteria) ranged from 0-13 (median =2) and <strong>the</strong> median length of<br />
hospital stay (LOS) was 18 days (range 12-62). Day 100 mortality was 2.4% (n =<br />
2). Disease status post transplant was CR in 14.8%, VGPR in 60.4% and PR in<br />
11.1% with stable or refractory disease in 8.6%. LOS significantly correlated with<br />
age ≥ 50 yrs and HCT-CI of > 0 (p = 0.028 and 0.007 respectively) but not with<br />
ECOG PS (p = 0.28). Cumulative toxicity score had no significant correlation with<br />
ei<strong>the</strong>r age, HCT-CI or PS.<br />
Conclusion: ASCT in MM using non cryopreserved PBSC graft is safe and effective.<br />
It may be a prudent alternative with potential for wider applicability.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1086P AGGREGATED ANALYSIS OF REPORTED EFFICACY FOR<br />
SALVAGE AUTOLOGOUS STEM-CELL TRANSPLANTATION<br />
FOR MYELOMA<br />
D.P. Smethurst<br />
Medical, Immunoncore Ltd, <strong>Oxford</strong>shire, UNITED KINGDOM<br />
Annals of Oncology<br />
The rate of complete response (CR) achieved soon after autologous stem cell<br />
transplantation (ASCT) is often used as a measure of relative success when<br />
comparing interventions in similar or randomized identical settings. New <strong>the</strong>rapies<br />
are often tried in salvage and rescue settings early on in development and some of<br />
<strong>the</strong>se <strong>the</strong>rapies may electively or necessarily be combined with ASCT also in <strong>the</strong><br />
rescue/salvage setting. Response rates in such settings are anecdotally low however<br />
few studies exist and many variables confound <strong>the</strong>ir understanding not least of which<br />
is <strong>the</strong> small numbers of patients involved.<br />
Methods: A pubmed/medline/googlescholar search strategy along with<br />
hand-searching key haematology and oncology journal archives and key paper<br />
bibliographies was adopted. 13 published cohorts were identified that reported CR as<br />
an outcome from second/salvage ASCT across a total of 1064 patients (table 1).<br />
Reported data that included patients who did not have measurable disease (i.e.<br />
already in CR) going into <strong>the</strong> second transplant were excluded as <strong>the</strong> intent was to<br />
observe salvage ASCT effects in measurable disease. Complete response rate (CR),<br />
Event free survival/Progression free survival (EFS ∼ PFS were considered heuristically<br />
similar) and overall survival (OS) were aggregated. Weighted mean estimates (WME)<br />
of efficacy were derived for each setting adjusted according to <strong>the</strong> number of patients<br />
associated with each CR rate.<br />
Results: The WME CR rate after a second ASCT was calculated to be ∼24%.<br />
Aggregated WME of EFS was 11.2 months and OS 20.8 months.<br />
Conclusions: Complete responses can be expected in approximately 1 in 4 patients<br />
who are selected for clinical trials and given a second transplant for relapsed or<br />
non-responding disease. Variability in reported rates is considerable.CR rate Percent<br />
Number of Patients PFS/EFS months OS months<br />
ix354 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Table: 1086P<br />
CR rate %<br />
Number of<br />
patients<br />
PFS/EFS<br />
Months OS Months<br />
Krishnan 2011 35 295<br />
Olin 2007 5 41 8.5 20.7<br />
N Shah 2011 11 44 12.3 31.7<br />
Simpson 2007 33 45 12.5 30.6<br />
Jiminez 2011 7 81<br />
Mehta 1998 33 42 12.5 32<br />
Qazilbash 2006 21.4 14 6.8 29<br />
Elice 2006 3.8 26 14.8 38.1<br />
Giaccone 2011 17.4 46<br />
Cavo 2007 19.4 103<br />
Sirohi 2002 31.3 94 10.5 15<br />
Rosinol <strong>2012</strong> 11 85<br />
Cook 2011 26 148<br />
Sum 1064<br />
Weighted Average 23.8 11.3 20.8<br />
Disclosure: D.P. Smethurst: Full time employee of Immunocore Ltd. and<br />
Consultant to Adaptimmmune Ltd. Share options in Immunocore Ltd. and<br />
Adaptimmune Ltd.<br />
1087P LEUKOCYTOSIS IN POLYCYTHEMIA VERA AND<br />
SPLENOMEGALY IN ESSENTIAL THROMBOCYTHEMIA ARE<br />
INDEPENDENT RISK FACTORS OF HEMORRHAGE<br />
Y. Chou 1 , J. Gau 1 , J. Liu 1 ,Y.Yu 1 ,J.Pai 2 , L. Hsiao 1 , Y. Hong 1 , C. Liu 1 , P. Chen 1 ,<br />
C. Tzeng 1<br />
1 Department of Medicine, Division of Hematology and Oncology, Taipei Veterans<br />
General Hospital, Taipei, TAIWAN, 2 Department of Medicine, National Yang-Ming<br />
University Hospital, Yilan, TAIWAN<br />
Background: Long term outcomes are generally favorable for patients with<br />
polycy<strong>the</strong>mia vera (PV) or essential thrombocy<strong>the</strong>mia (ET), however, complications<br />
of thrombosis and hemorrhage do cause significant morbidity and mortality.<br />
Methods: Patients diagnosed with PV (n = 101) and ET (n = 146) in a single medical<br />
center from 2001 to 2010 were retrospectively recruited for analysis.<br />
Results: The median overall survival (OS) was 111 months for patients with PV and not<br />
reached for ET (p = 0.872) after a median follow-up period of 36 months. Patients with<br />
PV and ET shared similar hemorrhage-free survival (HFS) (p =0.410). 17.8% of patients<br />
with PV and 18.5% of ET has experienced complications of hemorrhage (p =1.000)<br />
while 9.9% of patients with PV and 14.4% of ET had major bleeding which necessitated<br />
blood transfusion, hospitalizations or caused mortality. Upper gastrointestinal bleeding<br />
was most frequently encountered followed by intracranial hemorrhage (ICH) and<br />
subdural hemorrhage (SDH). Univariate analysis revealed age ≥ 60 years (OR: 4.77, 95%<br />
CI: 1.03-22.15, p = 0.046) and WBC ≥ 16 x10^9/L (OR: 4.15, 95% CI: 1.41-12.24, p =<br />
0.010) as risk factors predicting hemorrhage in PV patients, while for ET patients, <strong>the</strong><br />
risk factors of hemorrhage includes age ≥ 60 years (OR: 3.25, 95% CI: 1.06-10.03, p =<br />
0.040), WBC ≥ 16 x10^9/L (OR: 2.89, 95% CI: 1.15-7.25, p = 0.024), albumin< 4.0 g/dl<br />
(OR: 4.10, 95% CI: 1.67-10.09, p = 0.002), and splenomegaly (OR: 5.19, 95% CI:<br />
1.80-14.95, p = 0.002). Medications for treating or preventing thrombosis and<br />
cytoreductive agents such as aspirin, persantin, antiplatelet, hydroxyurea or anagrelide<br />
demonstrated no elevated risk of hemorrhage of statistical significance. Multivariate<br />
analysis showed that WBC ≥ 16 x 10^9/ L was <strong>the</strong> only significant risk factor of<br />
hemorrhage in PV patients (OR: 3.51, 95% CI: 1.16-10.58, p = 0.026) and splenomegaly<br />
<strong>the</strong> only risk factor in ET patients (OR: 3.54, 95% CI: 1.25-10.00, p = 0.017). The risk<br />
factors of WBC ≥ 16 x10^9/L and splenomegaly also predicted worse HFS for PV and<br />
ET patients, respectively (p = 0.041 for PV and 0.009 for ET, respectively).<br />
Conclusion: Although <strong>the</strong> pathogenic mechanism(s) of hemorrhage behind<br />
leukocytosis in PV and splenomegaly in ET remains elusive, <strong>the</strong> clinical implication<br />
warrants fur<strong>the</strong>r investigation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1088P EFFECT OF 13Q DELETION ON IL-6 PRODUCTION IN<br />
PATIENTS WITH MULTIPLE MYELOMA<br />
T. Yakout 1 , H.A. Azim 2 , N.M. Kassem 2 , R.H. Khalifa 3<br />
1 Medical Oncology, Cairo Oncology Center -CairoCure, Cairo, EGYPT, 2 Clinical<br />
Oncology Department (Nemrock), Faculty of Medicine, Cairo University, Cairo,<br />
EGYPT, 3 Clinical Pathology, Kasr Al-Aini Hospital, Cairo, EGYPT<br />
Background: Numerous studies have shown a correlation between 13q deletion and<br />
poor prognosis in multiple myeloma (MM), but <strong>the</strong> mechanisms are not fully<br />
understood. Earlier studies suggest that this lesion involves large segments or <strong>the</strong><br />
entire long arm involving <strong>the</strong> retinoblastoma (Rb) gene. In myeloma, Rb gene is<br />
believed to downregulate interleukin -6 (IL-6) which plays a central role in <strong>the</strong><br />
pathogenesis of MM. Therefore, it has been hypo<strong>the</strong>sized that loss of Rb gene might<br />
be associated with very high expression of IL-6 and subsequent bad prognosis.<br />
Materials and methods: Forty MM patients and 20 matched controls were included<br />
in this study. Interphase fluorescence in situ hybridization (FISH) analysis was<br />
performed using LSI 13q14-specific probe. Serum levels of IL-6 were determined by<br />
ELISA. All patients received conventional chemo<strong>the</strong>rapy. Refractory patients received<br />
o<strong>the</strong>r <strong>the</strong>rapeutic regimen of Thalidomide or Bortezomib.<br />
Results: Significant increase (p < 0.001) of IL-6 production was recorded in patients<br />
with 13q deletion compared to patients with normal chromosome 13q status .These<br />
patients were also refractory to conventional chemo<strong>the</strong>rapy but showed striking<br />
response to Thalidomide or Bortezomib.<br />
Conclusion: This study suggests that 13q deletions are associated with increased<br />
production of IL-6 in MM and this could be a possible cause of <strong>the</strong> associated bad<br />
prognosis. In addition, <strong>the</strong> results also show <strong>the</strong> potential to improve responses in<br />
patients with refractory MM with <strong>the</strong> introduction of novel <strong>the</strong>rapies.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1089P MALNUTRITION AT DIAGNOSIS INDEPENDENTLY PREDICTS<br />
MORTALITY IN PATIENTS WITH SYSTEMIC<br />
IMMUNOGLOBULIN LIGHT-CHAIN AMYLOIDOSIS (AL)<br />
R. Caccialanza 1 , G. Palladini 2 , C. Klersy 3 , E. Cereda 1 , C. Bonardi 1 , L. Quarleri 1 ,<br />
G. Merlini 2<br />
1 Nutrition and Dietetics Service, Fondazione IRCCS Policlinico San Matteo,<br />
Pavia, ITALY, 2 Amyloidosis Research and Treatment Center, Biotechnology<br />
Research Laboratories, Department of Molecular Medicine, Fondazione IRCCS<br />
Policlinico San Matteo and University of Pavia, Pavia, ITALY, 3 Biometry and<br />
Clinical Epidemiology Service, Fondazione IRCCS Policlinico San Matteo, Pavia,<br />
ITALY<br />
Rationale: We have previously shown that malnutrition is associated with reduced<br />
survival in outpatients with immunoglobulin light-chain amyloidosis (AL). However,<br />
<strong>the</strong>se findings were obtained in a mixed population of treated and untreated patients<br />
with different disease duration and in whom <strong>the</strong> Mayo Clinic cardiac staging system<br />
was not considered. The aim of this study was to investigate <strong>the</strong> prognostic role of<br />
nutritional status of AL patients at diagnosis.<br />
Methods: One hundred and twenty eight consecutive newly diagnosed and<br />
previously untreated patients with AL were enrolled. Anthropometric, biochemical<br />
and clinical variables were measured.<br />
Results: Prevalence of relevant unintentional weight loss (WL; ≥10% in 6 months),<br />
reduced body mass index (BMI;
Patients: From November 2002 to May 2010, 634 patients with CML in any stage of<br />
<strong>the</strong> disease were treated with imatinib at our tertiary cancer research institute.<br />
Among <strong>the</strong>m 274 were female and 221 were of 17 to 50 years age group. We report<br />
information of 8 accidental pregnancies and 10 planned pregnancies involving 18<br />
patients (10 females and 8 males) who conceived while receiving imatinib for <strong>the</strong><br />
treatment of CML.<br />
Observations: Among 10 pregnancies reported in female sufferers <strong>the</strong>re were two<br />
spontaneous and one elective abortion all in unplanned group and seven live births<br />
including one twin. There was one case of hypospadius which could be surgically<br />
corrected. Among <strong>the</strong> eight male patients whose wives conceived four pregnancies<br />
were planned, <strong>the</strong>re was one spontaneous abortion, two elective abortions. The<br />
conceptions resulted in <strong>the</strong> birth of five healthy babies (two females). There was no<br />
o<strong>the</strong>r identifiable congenital anomaly.<br />
Discussion: In <strong>the</strong> patients, who do become pregnant while on treatment, balancing<br />
<strong>the</strong> risk to <strong>the</strong> fetus of continuing imatinib versus <strong>the</strong> risk to <strong>the</strong> mo<strong>the</strong>r of<br />
interrupting treatment remains difficult. From <strong>the</strong> fetal perspective, imatinib should<br />
be discontinued due to <strong>the</strong> potential risk of serious developmental abnormalities;<br />
from <strong>the</strong> maternal perspective also <strong>the</strong>re is chance of drug interruption induced<br />
cytogenetic relapse. In conclusion, exposure to imatinib during pregnancy might<br />
result in an increased risk of serious fetal abnormalities or spontaneous abortion.<br />
Women and men (pregnant wife of male patient) with childbearing potential should<br />
use adequate contraception while taking imatinib.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1091P IMPACT OF NUTRITION ON TREATMENT OUTCOME IN<br />
ACUTE LYMPHOBLASTIC LEUKAEMIA OF CHILDHOOD IN<br />
DEVELOPING COUNTRY<br />
S. Poddar 1 , A. Mukhopadhyay 1 , P. Hor 1 , A. Nandi 1 , P. Gupta 1 ,<br />
S. Mukhopadhyay 2<br />
1 Medical Oncology, Netaji Subhas Chandra Bose Cancer Research Institute,<br />
Kolkata, INDIA, 2 Medical Oncology, Calcutta Hospital Calcutta, West Bengal,<br />
Kolkata, INDIA<br />
Background: All conventional modalities of anti-cancer <strong>the</strong>rapy interfere with<br />
normal nutrition. Therefore, malnutrition is a major problem in children with<br />
cancer. In this study we retrospectively analyzed 500 children suffering from Acute<br />
Lymphoblastic Leukemia (ALL), who were being intensively treated by National<br />
Cancer Institute protocol (MCP 841) during period beginning from August, 1999 to<br />
December, 2011, in a tertiary cancer institute. Our aim was to determine <strong>the</strong><br />
nutritional status at preliminary diagnosis of ALL children and to study <strong>the</strong> influence<br />
of nutrition on complete remission, disease free survival (DFS) and<br />
chemo<strong>the</strong>rapeutic toxicity.<br />
Procedure: The variables studied were height for age (HFA), weight for age (WFA),<br />
mid-arm circumference (MAC), biceps skinfold thickness (BSFT) and serum<br />
albumin levels. The HFA, WFA, MAC and BSFT were taken as normal if <strong>the</strong>y were<br />
between 3rd and 97th percentile curve of <strong>the</strong> growth chart as recommended by <strong>the</strong><br />
Indian Council of Medical Research (ICMR). The albumin level was considered<br />
normal if <strong>the</strong> value was equal to or more than 3g%.<br />
Results: It was observed that 16.8% children were low weight for age and 10.4% were<br />
low height for age during diagnosis. Low WFA (p value 0.001), low HFA (p value<br />
0.0001) and low albumin (p-value 0.0001) were significant in DFS.<br />
Conclusion: We conclude that malnutrition has high impact on ALL prognoses in<br />
developing countries. Major nutritional indicators are HFA, WFA, MAC, BSFT and<br />
serum albumin. Patients with malnutrition have less DFS duration, more chances for<br />
relapse and more <strong>the</strong>rapeutic toxicity when compared to well-nourished children.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1092P COST OF TREATMENT OF ACUTE MYELOID LEUKEMIA –<br />
EXPERIENCES FROM A DEVELOPING COUNTRY<br />
D. Arya 1 , B. Parikh 2 , P.M. Shah 2 , K.M. Patel 2 , S.N. Shukla 2 , A.S. Anand 2 ,<br />
S.S. Talati 2 , S.A. Shah 2 , A.A. Patel 2 , B.B. Parekh 2<br />
1 Medical Oncology, Action Cancer Hospital, Delhi, INDIA, 2 Dept. of Medical and<br />
Pediatric Hemato Oncology, Gujarat Cancer and Research Institute Civil Hospital<br />
Campus, M.P. Shah Cancer Hospital, Ahmedabad, INDIA<br />
Background: Acute Myeloid leukemia (AML) is a difficult disease to treat requiring<br />
specialised induction facilities, doctors, supportive staff and laboratory services. We<br />
try to analyse how <strong>the</strong> cost of diagnosis and treatment combined with socio-cultural<br />
and logistical issues affect treatment delivery and outcomes in AML in developing<br />
countries like India.<br />
Materials and methods: We conducted a retrospective analysis of case records of<br />
adult patients diagnosed with AML between 2009 and 2010 at <strong>the</strong> Gujarat Cancer<br />
and Research Institute, Ahmedabad, India. Patients diagnosed with AML-M3 were<br />
excluded. Data reviewed included epidemiological and demographic details, AML<br />
subtype, cytogenetic anomalies, co morbidities, treatment offered, complications, and<br />
Annals of Oncology<br />
duration of hospital stay. Billing information and o<strong>the</strong>r relevant data were retrieved<br />
from <strong>the</strong> hospital electronic records and analysed.<br />
Results: A total of 76 case records of patients with AML were identified (excluding<br />
AML- M3). Females comprised 51% of all patients. Majority of diagnosed patients<br />
(65%) worked as daily wage labourers. AML-M1 was <strong>the</strong> predominant subtype<br />
(35%). Three % patients expired during initial workup and 27% were offered<br />
supportive care only in view of significant co morbidities, advanced age or poor<br />
performance status. Thirty four % patients refused treatment because of financial,<br />
social or logistical constraints. Only 37 % of all patients received standard 7 + 3<br />
(cytosine arabinoside with daunorubicin) induction treatment. Complication rate<br />
during induction <strong>the</strong>rapy was 71% with induction mortality rate being 8%. Average<br />
stay in hospital was 34 days and cost of remission induction was equivalent of 1000<br />
dollars with nearly 85% of that amount spent for supportive care. Remission rate was<br />
71%, however only 29% patients were disease free at one year. Survival rate at one<br />
year was 61%.<br />
Conclusions: Nearly one third of patients were not candidates for standard treatment<br />
in view of significant co morbidities, advanced age or poor performance status. Only<br />
50% of patients candidate for standard treatment received it with <strong>the</strong> rest refusing <strong>the</strong><br />
same due to financial constraints, expected prolonged hospital stay, lack of social<br />
support and logistical issues.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1093P BCR ABL FUSION PROTEIN DETECTION BY A MODERN<br />
APPROACH: FLUROSCENT IMMUNO BEAD ASSAY<br />
S. Dasgupta 1 , U.K. Ray 1 , A. Mukhopadhyay 2 , J. Basak 1 , S. Mukhopadhyay 1<br />
1 Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute,<br />
Kolkata, INDIA, 2 Dept. Medical Oncology, Netaji Subhas Chandra Bose Cancer<br />
Research Institute, Kolkata, INDIA<br />
Introduction: Chronic Myeloid Leukemia (CML) is probably <strong>the</strong> most extensively<br />
studied human malignancy. CML patients (90-95%) harbor <strong>the</strong> Philadelphia (Ph)<br />
chromosome, a shortened chromosome 22, resulting from a reciprocal<br />
translocation t (9; 22) (q34; q11) between <strong>the</strong> long arms of chromosome 9 and<br />
22, fusion ABL proto-oncogene on chromosome 9 with <strong>the</strong> BCR gene on<br />
chromosome 22. BCR-ABL fusion gene plays a key role in pathogenesis of <strong>the</strong><br />
disease. Approximately 15-30% of adult and 2-5% of childhood ALL and
Annals of Oncology<br />
cardiovascular disease (CVD), by monitoring specific markers of <strong>the</strong> coagulation<br />
profile.<br />
Material and methods: The study comprises 40 patients divided in 2 groups: 20<br />
patients with ET (ET) and 20 patients with ET with CVD associated (ET + CVD).<br />
The patients were tested by determining three factors of coagulation profile: von<br />
Willebrand factor, Protein S and PAI-1, before and after administration of<br />
anticoagulant <strong>the</strong>rapy. Warfarin® was administrated as anticoagulant treatment, in<br />
doses that were adjusted according to <strong>the</strong> INR (International Normalized Ratio)<br />
values.<br />
Results: The level of <strong>the</strong> studied parameters were found significantly modified in<br />
both groups of patients (ET, ET + CVD) (p < 0,001). After <strong>the</strong> administration of<br />
anticoagulant treatment, in <strong>the</strong> first group (ET), it was observed a direct correlation<br />
between <strong>the</strong> treatment and <strong>the</strong> values of investigated parameters; in this group, <strong>the</strong><br />
levels of studied parameters returned close to normal values. This correlation was less<br />
evident in <strong>the</strong> second group of patients (ET + CVD), as <strong>the</strong> monitored values,<br />
although lower than <strong>the</strong> levels at <strong>the</strong> begining of <strong>the</strong> treatement, remained within<br />
pathologic levels.<br />
Conclusions: In ET <strong>the</strong> risk for thrombosis is due to endo<strong>the</strong>lial dysfunction and<br />
changes in prothrombotic circulating factors. The anticoagulant treatment prevents<br />
only partially <strong>the</strong> occurrence of thrombotic events, but does not completely stop it.<br />
In spite of <strong>the</strong> anticoagulant <strong>the</strong>rapy, <strong>the</strong> patients with ET present a high risk for<br />
developing thrombotic complications.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1095 APLASTIC ANEMIA: A SINGLE INSTITUTION EXPERIENCE<br />
M. Almeida 1 , L. Queiroz 1 , N. Domingues 2 , A. Espírito-Santo 2 , I. Oliveira 2 ,<br />
Â. Oliveira 2 , I. Moreira 2 , L. Viterbo 2 , J. Mariz 2<br />
1 Medical Oncology, Hospital de Braga, Braga, PORTUGAL, 2 Onco-Hematologia,<br />
Portuguese Insittute of Oncology - Porto, Porto, PORTUGAL<br />
Background: Aplastic anemia (AA) is an extremely rare disease characterized by<br />
pancytopenia and hypocellular bone marrow (BM). Diagnosis is difficult and requires<br />
high degree of suspicion. Bone marrow transplantation (BMT) and<br />
Immunosuppressive Therapy (IST) are <strong>the</strong> only <strong>the</strong>rapeutic options with a curative<br />
aim.<br />
Objectives: Analysis of clinical and pathological features, <strong>the</strong>rapeutic approach and<br />
overall survival of patients diagnosed with idiopathic AA in IPO-Porto.<br />
Methods: Retrospective analysis of idiopathic AA patients from September/1995 to<br />
October/2011. The overall survival (OS) analysis was performed by Kaplan Meier<br />
method.<br />
Results: During this period, 12 patients were identified with a median age of 31<br />
years (16-49), 75% were younger than 40 years. 50% were female. The main<br />
symptom at diagnosis was as<strong>the</strong>nia (58.3%), followed by ecchymosis (16.7%) and<br />
fever (16.7%). At diagnosis, 33.3% had neutrophil counts less than 1.5x10 9 /L and<br />
41.7% had platelet counts less than 20.0x10 9 /L. All patients had BM cellularity less<br />
than 25%. Only one patient had BMT as 1 st line treatment; this patient is in<br />
complete remission with a follow-up of 15 years. The remaining patients<br />
underwent IST with anti-thymocyte immunoglobulin, cyclosporine and<br />
methylprednisolone; three patients had complete remission but relapsed, with a<br />
disease-free interval of 55 months. As a 2 nd line treatment, three patients received<br />
unrelated BMT and two had complete remission. Of <strong>the</strong> seven patients who<br />
underwent 2 nd line IST, three had complete remission, two underwent BMT on<br />
<strong>the</strong> 3 rd line, and two patients were treated, respectively, with alemtuzumab and<br />
cyclosporine. Patients receiving IST had a median follow-up of 56 months. Three<br />
deaths occurred and OS at 15 years is 70%. Patients with neutrophil counts less<br />
than 1.5x10 9 /L had a lower OS (P = 0.01). There was no secondary myelodysplastic<br />
syndromes or acute leukemias.<br />
Conclusion: BMT is considered to be <strong>the</strong> most appropriate treatment in young<br />
patients with a compatible donor. However, IST is also a valid treatment for those<br />
without a donor, with a good survival.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1096 TREATMENT OF PRIMARY AND THERAPY-RELATED<br />
MYELODYSPLASTIC SYNDROME WITH 5-AZACYTIDINE –<br />
COMPARATIVE RESULTS FROM A SINGLE CENTRE<br />
J.S. Augusto 1 , F. Pierdomenico 2 , S. Barroso 1 , A. Almeida 2<br />
1 Oncology, Hospital Espirito Santo Evora, Evora, PORTUGAL, 2 Haematology,<br />
Instituto Portugues Oncologia Lisboa, Lisbon, PORTUGAL<br />
Introduction: Therapy-related Myelodysplastic Syndrome (tMDS) is a late and rare<br />
complication of chemo<strong>the</strong>rapy, especially that with alkylating agents or<br />
topoisomerase II inhibitors., They are often associated with unfavourable karyotypes,<br />
lower remission rates and shorter survival. PURPOSE: Retrospective analysis of<br />
clinical, analytical and cytogenetic features of patients diagnosed with primary<br />
(pMDS) and tMDS treated with 5-Azacytidine (AZA) between 2005 and 2011 in our<br />
Institute.<br />
Methods: Data was obtained from patient notes and analysed with SPSS.<br />
Results: 48 MDS patients treated with AZA were identified. 43 patients had pMDS,<br />
57% male, median age of 67 years. The IPSS was Intermediate 2 in 42.9% and high<br />
in 40.5%; cytogenetics were normal in 33%, complex in 16.7%. A median of 7<br />
courses (range 1-23) of AZA were administered, 52.4% as 2 nd line <strong>the</strong>rapy. Response<br />
assessment revealed 14.3% complete responses, 31% partial responses and 16.7%<br />
stable disease; best responses were reached after a median of 4 courses (range 2-6).<br />
Progression to secondary AML occurred in 38%; <strong>the</strong> mean survival was 25 months.<br />
Five patients had tMDS: 60% male, median age of 62 years. Previous chemo<strong>the</strong>rapy<br />
included alkylating agents in 100% and topoisomerase II inhibitors in 80%. The<br />
median time to MDS development was 12 years. The IPPS risk was high in 80%; all<br />
with complex cytogenetics. A median of 6 courses of AZA were administered, 60% as<br />
1 st line <strong>the</strong>rapy, with partial response in 40% (4 courses until response) and failure in<br />
60%; 40% developed sAML and <strong>the</strong> mean survival was 12 months. DISCUSSION:<br />
Despite <strong>the</strong> small cohort size, our results were similar to those described in literature.<br />
Even with AZA treatment, tMDS patients had a worse clinical outcome, with shorter<br />
mean survival, compared to pMDS.<br />
Conclusion: tMDS is a rare complication of chemo<strong>the</strong>rapy with a very poor<br />
outcome. Careful review and individualization of chemo<strong>the</strong>rapeutic regimens may<br />
help reduce its incidence.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1097 EXTRANODAL NON-HODGKIN LYMPHOMAS IN A NORTHERN<br />
PORTUGAL INSTITUTION - 2006/2010<br />
L. Queiroz 1 , A.D. Marques 1 , M. Almeida 1 , E. Couto 1 , I. Trindade 2 , C. Portela 1 ,<br />
J. Amorim 1 , T. Macedo 2 , R. Nabiço 1 , H. Marques 1<br />
1 Medical Oncology, Hospital de Braga, Braga, PORTUGAL, 2 Internal Medicine,<br />
Hospital de Braga, Braga, PORTUGAL<br />
Introduction: Non Hodgkin lymphomas (NHL) can arise in nodal or extranodal<br />
lymphoid tissue. In about 20% of cases <strong>the</strong> initial presentation affects <strong>the</strong> extranodal<br />
sites, which characterize <strong>the</strong> primary extranodal NHL (PENL).<br />
Objectives: Analyze <strong>the</strong> clinical and pathological characteristics of patients with<br />
PENL and evaluate prognostic factors.<br />
Material and methods: Retrospective study of 66 patients diagnosed with PENL in<br />
an institution, between January 2006 and December 2010, and clinical-pathological<br />
data collection.<br />
Results: The median age was 63 years (17-87), 52.3% were women and 17% had<br />
ECOG performance status greater than two. The most frequent location was <strong>the</strong><br />
stomach (32.3%) followed by skin and subcutaneous tissue (23.1%). Seventy two<br />
percent were high grade lymphomas and 17% had T phenotype. The most common<br />
histologic type was diffuse large B cells NHL (DLCBL) (55.4%). In 3 (4.6%) cases<br />
<strong>the</strong>re was extranodal secondary attainment. 76.9% of patients had stage I or II at<br />
diagnosis, 29.2% had B symptoms and 23% had increased lactate dehydrogenase<br />
(LDH). The albumin was decreased in 7,7% of <strong>the</strong> cases and <strong>the</strong> β2 microglobulin<br />
levels were increased in 12,3% of patients. Sixty-three percent were in <strong>the</strong> category of<br />
low-risk IPI. Seventy seven percent of patients underwent chemo<strong>the</strong>rapy, 4.6%<br />
primary radio<strong>the</strong>rapy (RT) and 28% adjuvant radio<strong>the</strong>rapy. Seventy two percent of<br />
patients had complete remission and 23,1% were submitted to a second line<br />
treatment. In a median follow-up of 31 months, 13.8% relapsed. The estimated<br />
survival at 50 months was 79%. The high levels of LDH and β2 microglobulin, low<br />
albumin, high IPI and ECOG and extraganglionar secondary involvement constituted<br />
factors of poor prognosis.<br />
Conclusion: This study showed a high prevalence of PENL of gastric and cutaneous<br />
location and of histologic subtype DLCBL. Most patients presented in early stages<br />
and with low IPI prognosis index. The response to primary treatment and <strong>the</strong> overall<br />
survival were high. We identify clinical and biological factors with prognostic value<br />
in univariable analysis.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1098 CRIZOTINIB IN ALK-POSITIVE DIFFUSE LARGE B-CELL<br />
LYMPHOMA: A CASE REPORT<br />
M. Wass, T. Behlendorf, U. Gläser, J. Rüssel, F. Güntsch, K. Jordan, H. Schmoll<br />
Klinik für Innere Medizin IV, Universitätsklinikum Halle (Saale), Halle, GERMANY<br />
Background: Anaplastic lymphoma kinase (ALK)-positive diffuse large B-cell<br />
lymphoma (DLBCL) is a distinct variant of DLBCL characterized by very aggressive<br />
clinical course with an estimated median survival of only 11.0 months. Crizotinib, an<br />
ALK inhibitor, has demonstrated impressive clinical efficacy in patients with<br />
alk-rearranged tumors. The potential role of Crizotinib in ALK-positive DLBCL has<br />
not been established yet.<br />
Case report: A 27-year-old female patient with ALK-positive DLBCL was primary<br />
refractory to 6 cycles of standard chemo<strong>the</strong>rapy with CHOP. She was subsequently<br />
treated with salvage combination chemo<strong>the</strong>rapy regimens including high-dose<br />
chemo<strong>the</strong>rapy with autologous stem-cell transplantation. However, disease followed a<br />
very aggressive course. 6 weeks after transplantation patient presented with right cervical<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds403 | ix357
lymphadenopathy and multiple cutaneous lesions. CT scan revealed additional bilateral<br />
cervical, axillary, mediastinal and abdominal lymphadenopathy and involvement of lung<br />
and liver. LDH levels were exorbitant elevated (233 mmol/l). On an individual base, our<br />
patient received <strong>the</strong> ALK inhibitor Crizotinib 250 mg per os twice daily. No<br />
glucocorticoids or o<strong>the</strong>r drugs with antineoplastic activity were co-administered. Within<br />
72 hours LDH levels were halved (89 mmol/l). On day 8 cervical palpable<br />
lymphadenopathy disappeared. Initial ery<strong>the</strong>matous papular cutaneous lesion decreased<br />
from 4.0 x 2.5 cm to a residual hyperpigmented macule of 1.5 x 2.5 cm. On day 16 LDH<br />
levels were almost within normal limits (6 mmol/l). However, remission was not<br />
sustained and patient developed resistance to Crizotinib. By day 21 after beginning <strong>the</strong><br />
treatment with Crizotinib LDH levels increased again and patient presented with a<br />
swollen left arm due to lymphatic obstruction, detected by CT scan, which showed a<br />
general progressive disease, causing death one month later.<br />
Conclusion: To our knowledge, this is <strong>the</strong> first case which reports sensitivity in<br />
ALK-positive DLBCL to ALK inhibition with Crizotinib. Despite remission duration<br />
was short our results indicate a potential role of ALK in <strong>the</strong> pathogenesis of<br />
ALK-positive DLBCL and suggest ALK inhibition as a potential treatment modality<br />
in <strong>the</strong> <strong>the</strong>rapy of this fatal disease.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1100 LIVER INVOLVEMENT BY LYMPHOMA – INDICATOR OF POOR<br />
RESPONSE AND MORTALITY<br />
S. Kumar, I.A. Muazzam, N. Siddiqui, N. Muzaffar, K. Das, U.E.K. Awan<br />
Medical Oncology, Shaukat Khanum Memorial Cancer Hospital and Reserch<br />
Centre (SKM), Lahore, PAKISTAN<br />
Total = 46 Hodgkin’ Lymphoma (n = 24)<br />
Heptic<br />
(n = 12) Non-hepatic = 12<br />
NonHodgkin’s Lymphoma<br />
(n = 22)<br />
hepatic<br />
(n = 5)<br />
Non-hepatic<br />
(n= 17)<br />
B-symptoms 9 (75%) 9 (75%) 3 (60%) 17 (77%)<br />
Bulky 1 (8%) 1 (8%) 1 (20%) 7 (41%)<br />
CR 8 (67%) 12 (100%) 4 (80%) 11 (64%)<br />
PR 2 (16.5%) 0 (0) 1 (20%) 6 (36%)<br />
PD 2 (16.5%) 0 (0) 0 (0) 0 (0)<br />
ORR = CR + PR 83.5% 100% 100% 100%<br />
Died 4 (33%) 0 (0) 1 (20% ) 6 (36%)<br />
Introduction: Hepatic involvement is more common in Non-Hodgkin’s as compared<br />
to Hodgkin’s Lymphoma (HL) at presentation. It is a poor prognostic feature. We<br />
determined prognosis of our stage IV lymphoma patients who had liver involvement<br />
at baseline.<br />
Material and method: In last 1 year, 70 patients presented in our lymphoma clinic<br />
with stage IV disease. Out of <strong>the</strong>se, 46 had completed <strong>the</strong>ir treatment at <strong>the</strong> time of<br />
analysis. Diagnosis of lymphoma was confirmed on excision or core biopsy of a nodal<br />
site at presentation. PET/CT was done for staging before starting chemo<strong>the</strong>rapy and<br />
response assessment was done after 2-4 cycles of planned chemo<strong>the</strong>rapy. Histologic<br />
evaluation of any residual FDG-avid disease was made in patients who responded to<br />
chemo<strong>the</strong>rapy at all <strong>the</strong> o<strong>the</strong>r sites. Response rate (RR) was calculated by adding<br />
percentage of patients in complete (CR) and partial (PR) remission.<br />
Results: Out of <strong>the</strong>se 46 patients, 24 had HL and intermediate-to-high grade NHL was<br />
diagnosed in 22 patients. Median age at diagnosis was 29.5 years (range 16 to 60).<br />
Secondary liver involvement was found in 17 patients (HL = 12/24; NHL = 5/22). More<br />
NHL patients presented with B-symptoms and bulky disease than HL. Presence of<br />
liver involvement predicted a lower response to initial <strong>the</strong>rapy in patients with HL (RR<br />
83.5%) as compared to NHL (RR 100%). Despite this initial response to treatment,<br />
one-third of advanced stage HL patients died before <strong>the</strong> completion of <strong>the</strong>rapy. Such<br />
relationship was not observed in advanced stage NHL patients (see table).<br />
Conclusion: Despite initial response to treatment, secondary liver involvement at<br />
presentation predicted higher mortality in stage IV HL patients. This effect should be<br />
fur<strong>the</strong>r validated in larger studies.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1101 AN OVERVIEW OF YOUNG CHRONIC LYMPHOCYTIC<br />
LEUKEMIA PATIENTS: A SINGLE CENTRE EXPERIENCE OF<br />
117 CASES FROM NORTHERN INDIA<br />
A. Gogia 1 , A. Sharma 1 , V. Raina 2 , L. Kumar 1 , R. Gupta 3 , R. Kumar 3<br />
1 Medical Oncology, All India Institute of Medical Sciences, New Delhi, INDIA,<br />
2 Dept. of Medical Oncology, All India Institute of Medical Sciences (AIIMS)<br />
Institute Rotary Cancer Hospital, New Delhi, INDIA, 3 Lab Oncology, All India<br />
Institute of Medical Sciences, New Delhi, INDIA<br />
Background: In this study, <strong>the</strong> clinical characteristics, survival, and prognostic factors<br />
of 117 cases of young ( = < 55 years) chronic lymphocytic leukemia (CLL) patients<br />
were analysed at IRCH, AIIMS, a large tertiary care centre of Nor<strong>the</strong>rn India.<br />
Annals of Oncology<br />
Methods: Patients records collected from computer database using ICD code<br />
(C-91.1) between period of 2000-2010 were retrospectively evaluated.<br />
Results: Over a period of 11 years, 285 CLL patients (117 [41.05%] = < 55 years of<br />
age and 168 [58.95%] > 55 years of age) were evaluated. There were similar<br />
distribution of sex, lymphadenopathy, organomegaly, and absolute lymphocyte<br />
count in both groups At diagnosis, younger patients were less incidentally detected<br />
(p < .0001), more B- symptoms (p = 0.001) and advanced Rai stage ( p = 0.021),<br />
than older patients. Response rate and toxicity profile were same in both groups<br />
with chlorambucil and fludarabine based chemo<strong>the</strong>rapy. Overall response rate<br />
(ORR) seen with chlorambucil and fludarabine was 69% and 88% with complete<br />
remission (CR) rate was 3% and 44 % respectively. Richter’s transformation was<br />
significantly higher in younger patients (3.41% v 0.5%; p = 0.001). Median follow<br />
up period was 36 months. Younger and older patients showed a similar overall<br />
median survival but were characterized by a different distribution of causes of<br />
deaths. CLL unrelated deaths predominated in <strong>the</strong> older age group, as one third<br />
of patients have different co-morbities like diabetes, hypertension, coronary artery<br />
disease e.t.c, whereas <strong>the</strong> disease related death were prevalent in <strong>the</strong> younger age<br />
group. Multivariate analysis showed that for young CLL patients, advanced clinical<br />
stage (Rai III and IV) was associated with poor overall survival [HR 2.08 (95% CI<br />
1.19-4.11) p = 0.001].<br />
Conclusion: Forty one percent our CLL population was young. Young CLL patients<br />
presented with more B symptoms and advanced stage (Rai III and IV) than elderly<br />
CLL patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1102 CHRONIC MYELOID LEUKEMIA IN CHILDREN- EXPERIENCE<br />
WITH IMATINIB MESYLATE AT A REGIONAL CANCER<br />
INSTITUTE, BANGALORE, INDIA<br />
K.V. Belathur, L. Appaji, K.C. Lakshmaiah, A.K. B S,, S. Purohith, D.<br />
S. Madhumathi<br />
Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, INDIA<br />
Background: Childhood Philadelphia chromosome-positive (Ph+) CML constitutes<br />
about 3- 5% of <strong>the</strong> total leukemias. Allogeneic stem cell transplantation (SCT) offers<br />
best survival but in view of unaffordability and non availability of suitable donor,<br />
Imatinib Mesylate becomes <strong>the</strong> next best treatment option. The present study was<br />
thus undertaken to evaluate <strong>the</strong> clinical profile, response, survival and adverse effects<br />
of <strong>the</strong> drug.<br />
Methods: This is a retrospective study of Ph + CML in <strong>the</strong> age group of 4-18 yrs, at<br />
Medical & Paediatric Oncology department of our institute.50 patients of CML,<br />
enrolled under <strong>the</strong> Glivec International Patient Assistance Program (GIPAP) between<br />
Jan 2004 to Dec 2011 and started on Imatinib at 340 mg /m2/day were analyzed.<br />
Complete hemogram, liver function tests, bone marrow aspiration studies and<br />
BCR-ABL by RT-PCR were done at intervals as per institution protocol.<br />
Results: Mean age of patients enrolled in <strong>the</strong> study was 12.8 yrs. Mass and pain<br />
abdomen were <strong>the</strong> predominant presentations in 21(42%) and 18(36%) respectively.<br />
One patient each was in accelerated phase and blast crisis. Complete Hematological<br />
Response (CHR) was achieved in 100% with 43 (86%) within 3 months. Complete<br />
cytogenetic response was achieved in 20(40%) with median duration of 14 months<br />
(8-18).13(26%) patients showed Major molecular response with a median of 16<br />
months (6-29) & complete molecular response in 4 (8%) with a median of 21<br />
months(16-22). One out of 4 patients with progressive disease is in blast crisis<br />
waiting for transplantation, 3 are on escalated dose of Imatinib and ei<strong>the</strong>r Cytarabine<br />
or Interferons to maintain CHR. All 4 were negative for Imatinib Mutations. Most<br />
common adverse events were grade 1/2 skin toxicities and weight gain in about 40%<br />
of patients. About 8 (16%) patients had grade2/3 myelosupression which was<br />
manageable. Event free survival and overall survival were 94.4% and 64% at a median<br />
follow up of three years.Sokal score was evaluated with respect to <strong>the</strong> survival<br />
outcome but was not found to be statistically significant.<br />
Conclusions: In view of good response and tolerance, our results reaffirm previously<br />
reported favorable results from various o<strong>the</strong>r centers. Imatinib can be considered as<br />
an alternative to SCT in Pediatric CML population to improve <strong>the</strong> survival and<br />
merits fur<strong>the</strong>r evaluation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1103 COMPLICATIONS OF “VERY HIGH” LEUKOCYTOSIS IN<br />
PEDIATRIC ACUTE LEUKEMIA PATIENTS MANAGED<br />
WITHOUT RASBURICASE AND LEUCOPHERESIS<br />
R.B. Singh, K. Munot, S. Pathania, S. Bakhshi<br />
Dept. of Medical Oncology, All India Institute of Medical Sciences (AIIMS)<br />
Institute Rotary Cancer Hospital, New Delhi, INDIA<br />
Background: Hyperleukocytosis in pediatric leukemias is associated with acute<br />
complications of tumor lysis syndrome (TLS) and leucostasis. In developing<br />
countries, rasburicase is not available and even if available, it may not be affordable<br />
by all patients. Rasburicase became freely available in India in 2010. We evaluated<br />
ix358 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
acute complications pertaining to hyperleukocytosis in pediatric acute leukemia<br />
patients prior to free availability of rasburicase, and without leucopheresis.<br />
Method: Records of pediatric acute leukemia patients and “very high” leucocytosis<br />
(VHL) (WBC > 100,000/mm 3 in AML and > 200,000/mm 3 in ALL) were analyzed.<br />
None of <strong>the</strong>se patients received rasburicase and /or leucopheresis. Patients were<br />
managed with allopurinol and aggressive hydration. Data was analyzed for baseline<br />
presentation, TLS and o<strong>the</strong>r complications pertaining to leucostasis.<br />
Results: Out of 457 pediatric acute leukemia patients from Jun 2003-Dec 2009, <strong>the</strong>re<br />
were 45 (10%) patients with VHL. Median age was 10 years (SD-4.4; range 3-18) and<br />
male: female ratio was 6.5:1. B-ALL, T-ALL and AML constituted 11 (24.4%), 16<br />
(35.5%) and 18 (39.9%) patients respectively. Mean baseline WBC for ALL and AML<br />
patients was 296,500/mm 3 (SD- 104,793; range 200,000-615,220) and 206,300/mm 3<br />
(SD- 110,000; range 106,100-541,900) respectively. Laboratory TLS was seen in 17<br />
(37.7%) patients [ 2 (4.4%) at baseline while 15 (33.3%) patients developed it after<br />
chemo<strong>the</strong>rapy initiation]. Clinical TLS was observed in 6 (13.3%) and renal<br />
dysfunction in 7 (15.5%) patients; none required dialysis. CR was achieved in 32<br />
(71.1%) pts and <strong>the</strong>re were 3 (6.6%) deaths. No relation was seen between laboratory<br />
TLS and baseline features or mortality. Thrombocytopenia below median (
prospective non-interventional study with TEMS in rel/refr MCL-pts was started.<br />
Here we report on interim results of <strong>the</strong> study.<br />
Methods: A registry for rel/refr MCL pts treated with TEMS was started in Germany<br />
in Oct 2009 (NCT00700258). Primary objective: evaluation of <strong>the</strong> safety profile of<br />
TEMS, secondary objectives: tolerability and anti-tumor activity of TEMS, patient’s<br />
profile and <strong>the</strong> sequence of systemic <strong>the</strong>rapies.<br />
Results: 29 pts have been recruited in 12 active centers until Apr <strong>2012</strong>. Baseline<br />
characteristics are available for 23 pts: 69.6% male; median age 72.1 yrs; ECOG PS 0<br />
or 1 in 74%, ECOG PS 2 in 26% of <strong>the</strong> pts; MIPI score: 13.0%, 30.4%, and 56.5% of<br />
<strong>the</strong> pts are classified as low, intermediate and high risk at <strong>the</strong> time of enrollment; Bone<br />
marrow involvement: 47.8% of <strong>the</strong> pts. Median time between diagnosis and start oft<br />
treatment with TEMS is 36 months. The median number of prior <strong>the</strong>rapies is 5 with<br />
65.2% treated in ≥5 th line. Most frequent adverse events are leucopenia, anaemia and<br />
thrombocytopenia. Severe adverse events (drug related) are general, metabolism,<br />
psychiatric disorders and infections (in 2 pts each), thrombocytopenia, leukocytosis,<br />
skin and renal disorder (in 1 pt each). Preliminary efficacy analyses (n = 18) shows a<br />
clinical benefit in 7 pts, PD in 5 pts and 6 pts are not assessable. Median PFS<br />
(assessable pts) is 157 days.<br />
Conclusions: This registry was started to evaluate <strong>the</strong> safety and efficacy of TEMS in<br />
pts with rez/refr MCL in <strong>the</strong> clinical routine. Though <strong>the</strong> here included pts are more<br />
heavily pretreated TEMS shows a predictable, acceptable toxicity and efficacy remains<br />
comparable with phase III-data.<br />
Disclosure: G. Krekeler: Employee of Pfizer Pharma GmbH GermanyC. Herzberg:<br />
Employee of Pfizer Pharma GmbHM.H. Dreyling: Pfizer: Scientific advisory Board,<br />
speaker’s honoraria, support of IITsG. Hess: Research funding and speaker honoraria<br />
from PfizerD. Kalanovic: Employee of Pfizer Pharma GmbH, Germany.<br />
1108TiP DENOSUMAB COMPARED WITH ZOLEDRONIC ACID FOR<br />
PREVENTING SKELETAL COMPLICATIONS IN PATIENTS<br />
WITH MULTIPLE MYELOMA: A RANDOMIZED, PHASE 3,<br />
DOUBLE-BLIND, DOUBLE-DUMMY TRIAL<br />
A. Palumbo 1 , B.G. Durie 2 , N. Raje 3 , R. García Sanz 4 , O. Sezer 5 , K. Shimizu 6 ,<br />
E. Terpos 7 , W. Willenbacher 8 , Y. Qian 9 , A. Balakumaran 10<br />
1 Division of Hematology, University of Torino, A.O.U., Torino, ITALY,<br />
2 Hematology, Cedars-Sinai Outpatient Cancer Center, Los Angeles, CA, UNITED<br />
STATES OF AMERICA, 3 Hematology/Oncology, Massachusetts General Hospital<br />
Cancer Center, Boston, MA, UNITED STATES OF AMERICA, 4 Hematology,<br />
University Hospital of Salamanca, Salamanca, SPAIN, 5 Hematology and<br />
Oncology, University Medical Center Hamburg, Hamburg, GERMANY,<br />
6 Multimodal Therapy For Multiple Myeloma, Aichigakuin University School of<br />
Dentistry, Nagoya, JAPAN, 7 Department of Clinical Therapeutics, University of<br />
A<strong>the</strong>ns School of Medicine, A<strong>the</strong>ns, GREECE, 8 Hematology and Oncology,<br />
Medical University of Innsbruck, Innsbruck, AUSTRIA, 9 Biostatistics, Amgen Inc.,<br />
Thousand Oaks, CA, UNITED STATES OF AMERICA, 10 Global Development,<br />
Amgen Inc., Thousand Oaks, CA, UNITED STATES OF AMERICA<br />
Patients with multiple myeloma (MM) experience osteolytic bone destruction<br />
resulting in skeletal-related events (SREs: pathologic fracture, spinal cord<br />
compression, surgery or radiation to bone). Severity of bone destruction<br />
correlates with significant morbidity and is associated with decreased survival.<br />
Osteoclast activity is enhanced in MM and is primarily regulated by RANK<br />
Annals of Oncology<br />
Ligand (RANKL) and osteoprotegerin. Denosumab is a fully human monoclonal<br />
antibody which binds RANKL, preventing activation of RANK and inhibiting<br />
osteoclast differentiation, activation and survival. Bone resorption and<br />
cancer-induced bone destruction are <strong>the</strong>reby reduced. Denosumab was superior<br />
to zoledronic acid (ZA) in 3 large randomized trials in patients with breast,<br />
prostate, or solid tumors-only analysis. Denosumab is approved for <strong>the</strong><br />
prevention of SREs in patients with bone metastases from solid tumors in many<br />
regions worldwide. The current trial will evaluate <strong>the</strong> efficacy and safety of<br />
denosumab compared with ZA in preventing skeletal complications in patients<br />
with MM. The primary endpoint will determine if denosumab is non-inferior to<br />
ZA in prevention of <strong>the</strong> first on-study SRE. If denosumab is found to be<br />
non-inferior to ZA, superiority in time to first on-study SRE and time to<br />
first-and-subsequent SRE will be assessed as secondary endpoints. Patients will be<br />
randomly assigned 1:1 to receive subcutaneous (SC) denosumab 120 mg and<br />
intravenous (IV) placebo or IV ZA 4 mg and SC placebo every 4 weeks (Q4W).<br />
Randomization will be stratified by planned autologous transplantation (yes/no),<br />
anti-myeloma <strong>the</strong>rapy (novel <strong>the</strong>rapy-based vs non-novel <strong>the</strong>rapy-based), disease<br />
stage (International Staging System 1, 2, or 3), previous SRE (yes/no), and region<br />
(Japan vs o<strong>the</strong>r). Daily supplements of calcium ≥500 mg and vitamin D ≥400<br />
IU will be strongly recommended. Patient screening and enrollment is underway.<br />
In this event-driven study, data cutoff for <strong>the</strong> primary efficacy analysis is planned<br />
for when approximately 800 patients are anticipated to experience an on-study<br />
SRE. The trial is sponsored by Amgen Inc. and registered with ClinicalTrials.gov<br />
(NCT01345019).<br />
Disclosure: A. Palumbo: Advisory Board Member: Celgene and Janssen-Cilag<br />
Honoraria: Celgene, Janssen-Cilag, Bristol-Myers Squibb, Millenium, Merck, Onyx<br />
and Amgen Consultancy: Celgene and Janssen-CilagB.G. Durie: Advisory Board<br />
Member: Celgene Corporation, Millenium Pharmaceuticals, and Onyx<br />
PharmaceuticalsN. Raje: Advisory Board Member: Celgene, Millenium,<br />
Amgen Corporate-sponsored Research: Eli-Lilly, AcetylonR. García Sanz:<br />
Honoraria: Amgen, Jansen Cilag, Celgene, NovartisO. Sezer: Advisory Board<br />
Member: Amgen, JanssenE. Terpos: Advisory Board Member: Amgen,<br />
NovartisW. Willenbacher: Advisory Board Member: AmgenY. Qian: Employee<br />
and Stock Ownership: AmgenA. Balakumaran: Employee and Stock<br />
Ownership: AmgenAll o<strong>the</strong>r authors have declared no conflicts of interest.<br />
ix360 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
melanoma and o<strong>the</strong>r skin tumors<br />
1109O CLINICAL ACTIVITY AND SAFETY OF ANTI-PROGRAMMED<br />
DEATH-1 (PD-1) (BMS-936558/MDX-1106/ONO-4538) IN<br />
PATIENTS (PTS) WITH ADVANCED MELANOMA (MEL)<br />
J. Sosman1 , M. Sznol2 , D.F. McDermott3 , R. Carvajal4 , D.P. Lawrence5 ,<br />
S.L. Topalian6 , J.M. Wigginton7 , G. Kollia8 , A. Gupta9 , F.S. Hodi10 1<br />
Melanoma and Tumor Immuno<strong>the</strong>rapy Program, Vanderbilt University Medical<br />
Center, Nashville, TN, UNITED STATES OF AMERICA, 2 Section of Medicine<br />
Oncology, Yale Cancer Center, New Haven, CT, UNITED STATES OF AMERICA,<br />
3<br />
Biology Therapy Program, Beth Israel Deaconess Medical Center, Boston, MA,<br />
UNITED STATES OF AMERICA, 4 Melanoma-sarcoma Division, Memorial<br />
Sloan-Kettering Cancer Center, New York, NY, UNITED STATES OF AMERICA,<br />
5<br />
Department of Hematology/Oncology, Massachusetts General Hospital Cancer<br />
Center, Boston, MA, UNITED STATES OF AMERICA, 6 Melanoma Program,<br />
Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD,<br />
UNITED STATES OF AMERICA, 7 Discovery Medicine-clinical Oncology,<br />
Bristol-Myers Squibb, Princeton, NJ, UNITED STATES OF AMERICA,<br />
8<br />
Biostatistics and Data Management, Bristol-Myers Squibb, Princeton, NJ,<br />
UNITED STATES OF AMERICA, 9 Discovery Medicine, Immuno-oncology,<br />
Bristol-Myers Squibb, Princeton, NJ, UNITED STATES OF AMERICA,<br />
10<br />
Melanoma Center, Dana-Farber Cancer Institute, Boston, MA, UNITED<br />
STATES OF AMERICA<br />
Purpose: BMS-936558 is a monoclonal antibody that blocks <strong>the</strong> PD-1 co-inhibitory<br />
receptor expressed by activated T cells. This study describes its activity and safety in<br />
pts with previously treated advanced MEL.<br />
Methods: BMS-936558 was administered IV q2wk to pts with various tumors at<br />
0.1 − 10 mg/kg during dose-escalation and/or cohort expansion. Pts received up to<br />
12 cycles (4 doses/cycle) of treatment or until unacceptable toxicity, confirmed<br />
progressive disease, or complete response. Clinical activity was assessed by RECIST<br />
v1.0.<br />
Results: As of Feb 24, <strong>2012</strong>, 104 MEL pts had received BMS-936558 at 0.1 (n = 17),<br />
0.3 (n = 19), 1 (n = 31), 3 (n = 17), or 10 mg/kg (n = 20). ECOG performance status<br />
was 0/1/2 in 63/38/3 pts, respectively. Most pts (67/104) had received prior<br />
immuno<strong>the</strong>rapy (IT); prior anti-CTLA-4, -PD-1, or -PD-L1 was not permitted. The<br />
number of prior <strong>the</strong>rapies was 1 (39%), 2 (35%), or ≥3 (26%). Median <strong>the</strong>rapy<br />
duration was 20 wks (range 2.0 − 121.7 wks). The incidence of grade 3 − 4 related<br />
AEs was 20% and included gastrointestinal (4%), endocrine (2%), and hepatobiliary<br />
disorders (1%). There were no drug-related deaths in MEL pts. Clinical activity<br />
(responses or prolonged stable disease) was observed at all doses (Table). Of <strong>the</strong> 26/<br />
94 (28%) evaluable responders, 19 (73%) are ongoing ranging from 1.9+ to 24.9+<br />
months. For <strong>the</strong> 23 responders followed ≥6 months from first dose on study, 16<br />
(70%) are progression free. ORs occurred in pts with visceral or bone metastases. Six<br />
pts (6%; 95% CI 2 − 13%) had prolonged SD (≥24 wk); 3 pts had a persistent<br />
decrease in target lesion tumor burden in <strong>the</strong> presence of new lesions and were not<br />
categorized as responders.<br />
Conclusions: BMS-936558 had durable clinical benefit in pts with advanced MEL,<br />
including those who had received prior IT. Additional long-term follow-up data will<br />
be reported.<br />
Dose, (mg/kg) No. pts a<br />
ORR,<br />
No. pts (%)<br />
[95% CI]<br />
PFSR at<br />
24 wk (%)<br />
[95% CI]<br />
0.1 14 4 (29) [8 − 58] 40 [13 − 66]<br />
0.3 16 3 (19) [4 − 46] 31 [9 − 54]<br />
1 27 8 (30) [14 − 50] 45 [26 − 65]<br />
3 17 7 (41) [18 − 67]* 55 [30 − 80]<br />
10 20 4 (20) [6 − 44] 30 [9 − 51]<br />
*1 CR a Response-evaluable pts dosed by 7/01/2011 ORR = objective response rate<br />
([{CR + PR} ÷ n] × 100); PFSR = progression-free survival rate.<br />
Disclosure: J. Sosman: Research Funding: Bristol-Myers Squibb (myself). M. Sznol:<br />
Consultant or Advisory Role: Bristol-Myers Squibb (myself, compensated). Research<br />
Funding: Bristol-Myers Squibb (myself, clinical trials funding). D.F. McDermott:<br />
Advisory Board Role: Bristol-Myers Squibb (myself). R. Carvajal: Research Funding:<br />
Annals of Oncology 23 (Supplement 9): ix361–ix375, <strong>2012</strong><br />
doi:10.1093/annonc/mds404<br />
Bristol-Myers Squibb (myself). S.L. Topalian: Consultant or Advisory Role:<br />
Bristol-Myers Squibb (myself, immediate family member, uncompensated). Research<br />
Funding: Bristol-Myers Squibb (myself). J.M. Wigginton: Employment or Leadership<br />
Position: Bristol-Myers Squibb (myself, employment, compensated). Stock<br />
Ownership: Bristol-Myers Squibb (myself). G. Kollia: Employment or Leadership<br />
Role: Bristol-Myers Squibb (employment, myself, compensated). Stock Ownership:<br />
Bristol-Myers Squibb/BMY stocks (myself). A. Gupta: Employment or Leadership<br />
Role: Bristol-Myers Squibb (employment, myself, compensated). Stock Ownership:<br />
Bristol-Myers Squibb (myself). F.S. Hodi: Consultant or Advisory Role: Bristol-Myers<br />
Squibb (myself, uncompensated). Research Funding: Bristol-Myers Squibb (myself).<br />
All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1110O IMMUNOGENICITY AND SAFETY OF THE PRAME CANCER<br />
IMMUNOTHERAPEUTIC IN METASTATIC MELANOMA:<br />
PHASE I/II DOSE ESCALATION STUDY<br />
R. Gutzmer 1 , L. Rivoltini 2 , E. Levchenko 3 , A. Testori 4 , J. Utikal 5 , P.A. Ascierto 6 ,<br />
B. Salaun 7 , N. Vanhoutte 8 , M. Gillet 9 , V. Brichard 10<br />
1 Dermatology and Allergy, Hannover Medical School, Hannover, GERMANY,<br />
2 Unit of Immuno<strong>the</strong>rapy of Human Tumors, Fondazione IRCCS Istituto Nazionale<br />
dei Tumori, Milan, ITALY, 3 Thoracic Oncology, Petrov Research Institution of<br />
Oncology, St. Petersburg, RUSSIAN FEDERATION, 4 Melanoma Division,<br />
European Institute Of Oncology, Milan, ITALY, 5 Skin Cancer Unit, German<br />
Cancer Research Center, Heidelberg, Germany and Department of Dermatology,<br />
Venereology and Allergology, University Medical Center Mannheim,<br />
Ruprecht-Karl University of Heidelberg, Mannheim, Germany, German Cancer<br />
Research Center, Mannheim, GERMANY, 6 Melanoma, Cancer Immuno<strong>the</strong>rapy<br />
and Innovative Therapies, Istituto Nazionale Tumori Fondazione “G. Pascale”,<br />
Napoli, ITALY, 7 R&D DAP Cancer, GlaxoSmithKline Biologicals, Rixensart,<br />
BELGIUM, 8 Immuno<strong>the</strong>rapeutics, GlaxoSmithKline Biologicals, Rixensart,<br />
BELGIUM, 9 Global Vaccine Development, GlaxoSmithKline Biologicals,<br />
Rixensart, BELGIUM, 10 Immuno<strong>the</strong>rapeutics Bu, GlaxoSmithKline Biologicals,<br />
Rixensart, BELGIUM<br />
Introduction: Patients (pts) with metastatic melanoma have a poor prognosis. The<br />
PRAME tumor antigen, expressed at high frequency in different cancers and at lower<br />
levels in a limited number of normal cells, offers an attractive target for active<br />
immunization. This open-label, dose-escalation phase I/II study aimed at<br />
determining <strong>the</strong> optimal dose of PRAME immuno<strong>the</strong>rapeutic (PRAME recombinant<br />
protein (recPRAME) with AS15 immunostimulant) by evaluating its safety and<br />
immunogenicity in pts with advanced melanoma.<br />
Methods: Pts with stage IV PRAME-positive melanoma were enrolled to 3<br />
consecutive cohorts to receive up to 24 injections of recPRAME (20 µg, 100 µg, and<br />
500 µg) with AS15 (fixed dose) over approximately 4 years. Adverse events (AEs),<br />
including pre-defined dose-limiting toxicity (DLT), were recorded throughout <strong>the</strong><br />
study. The anti-PRAME humoral and cellular responses were evaluated post-dose 4<br />
by ELISA and flow cytometry (PRAME-specific T-cells producing both IFNγ and<br />
TNFα), respectively.<br />
Results: 66 pts were treated in <strong>the</strong> study (20 pts received 20 µg recPRAME, 24 pts<br />
received 100 µg recPRAME and 22 pts received 500 µg recPRAME). AEs considered<br />
by <strong>the</strong> investigator to be causally related were mostly grade 1/2, 2 pts reported grade<br />
3 AEs, and 1 serious AE causally related to PRAME administration was reported. 2<br />
DLTs were recorded in 2 pts (cohorts 2 and 3; post-dose 6 and 8) but no maximum<br />
tolerated dose was reached. Humoral and cellular immunological results are shown in<br />
table 1. No cellular response for CD8+ T-cells was detected.<br />
Conclusions: PRAME cancer immuno<strong>the</strong>rapeutic was well-tolerated and induced<br />
similar humoral and cellular responses in all 3 cohorts. Based on <strong>the</strong>se results, a<br />
phase II was initiated to fur<strong>the</strong>r evaluate <strong>the</strong> clinical activity, safety and<br />
immunogenicity of <strong>the</strong> PRAME immuno<strong>the</strong>rapeutic containing 500 µg recPRAME.<br />
Immunogenicity post-dose 4 (ATP population).<br />
Cohort (recPRAME dose) 1 (20 µg) 2 (100 µg) 3 (500 µg)<br />
Humoral responders, n/N* 13/13 13/13 17/17<br />
CD4+ T-cell responders, n/N* (%) 7/9 (78%) 7/11 (64%) 11/15 (73%)<br />
CD8+ T-cell responders, n/N* (%) 0/8 (0%) 0/9 (0%) 0/8 (0%)<br />
number of patients enrolled into each group; * number of patients with pre and<br />
post-vaccination results; n, number of responders; ATP, according-to-protocol<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com<br />
abstracts
Funding: GSK Biologicals<br />
Disclosure: R. Gutzmer: Roche Pharma, BMS, GSK, Novartis, MSD/Essex, Celgene,<br />
Lilly, EISAI, Astra-Zeneca, Vical, Cytavis, Centocor, Genta, SwedishOrphan,<br />
Philogen, Amgen, Almirall-Hermal, Merck Serono (Clin. studies, Research, Lectures,<br />
Advisory honoraria, Meetings). L. Rivoltini: Participation to one single GSK Advisory<br />
Board on MEK/BRAF inhibitors in Melanoma. A. Testori: I declare to have a<br />
consultant or advisory relationship with Bristol Meyers Squibb, AMGEN,<br />
GlaxoSmithKline advisory boards and I received honoraria from <strong>the</strong>m. I have o<strong>the</strong>r<br />
remuneration to disclose: travel expenses refunded by Oncovision and IGEA. J.<br />
Utikal: I dońt have any financial interest in products or processes involved in this<br />
research abstract. I dońt own GSK stocks. I served as a member on an advisory of<br />
GSK and Roche in <strong>the</strong> past time. P.A. Ascierto: Consultant for MSD; Advisory role<br />
for BMS, MSD, Roche-Genetech, GSK, Amgen, Celgene, Medimmune, Novartis;<br />
received honoraria from BMS, MSD, and Roche-Genentech. B. Salaun: Currently<br />
employed by GSK Biologicals as a scientist. N. Vanhoutte: Employee of GSK<br />
Biologicals. M. Gillet: Employee of GSK Biologicals. V. Brichard: GSK employee.<br />
All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1111PD EXPANDED ACCESS STUDY OF ADVANCED BCC PATIENTS<br />
TREATED WITH THE HEDGEHOG-PATHWAY INHIBITOR<br />
VISMODEGIB<br />
G.J. Weiss1 ,A.Oro2 , A.L.S. Chang3 , J.A. Solomon4 , P.M. LoRusso5 , O. Hamid6 ,<br />
D.M. Chen7 , E. McKenna7 , S. Feng7 , J.D. Hainsworth8 1<br />
Virginia G. Piper Cancer Center Clinical Trials, Scottsdale Healthcare,<br />
Scottsdale, AZ, UNITED STATES OF AMERICA, 2 Department of Dermatology,<br />
Stanford University School of Medicine, Stanford, CA, UNITED STATES OF<br />
AMERICA, 3 Department of Dermatology, Stanford University School of Medicine,<br />
Redwood City, CA, UNITED STATES OF AMERICA, 4 Clinical Research,<br />
Ameriderm Research, Ormond Beach, FL, UNITED STATES OF AMERICA,<br />
5<br />
Research Administration, Karmanos Cancer Institute, Detroit, MI, UNITED<br />
STATES OF AMERICA, 6 Melanoma Center, The Angeles Clinic and Research<br />
Institute, Los Angeles, CA, UNITED STATES OF AMERICA, 7 Medical Affairs,<br />
Genentech, South San Francisco, CA, UNITED STATES OF AMERICA,<br />
8<br />
Oncology Research, Sarah Cannon Research Institute, Nashville, TN, UNITED<br />
STATES OF AMERICA<br />
Background: Patients (pts) with advanced basal cell carcinoma (aBCC; disease that<br />
is locally advanced [laBCC] or metastatic [mBCC]) have limited <strong>the</strong>rapeutic<br />
alternatives. The Hedgehog signaling pathway is a key driver in <strong>the</strong> pathogenesis of<br />
BCC. In a pivotal Phase II study, vismodegib (Erivedge)—a first-in-class<br />
small-molecule inhibitor of Hedgehog pathway signaling—demonstrated significant<br />
clinical activity in aBCC with an acceptable safety profile. This US-only expanded<br />
access study initiated prior to FDA approval, provided vismodegib for aBCC pts and<br />
fur<strong>the</strong>r characterized its safety profile and clinical activity.<br />
Methods: Pts with histologically confirmed mBCC or laBCC inappropriate for, or<br />
recurring after surgery or radio<strong>the</strong>rapy, received daily oral vismodegib 150 mg until<br />
disease progression or intolerable toxicity. Interim data for <strong>the</strong> first 96 pts, enrolled<br />
Jul 2010–Nov 2011, are summarized; final results will be presented at <strong>the</strong> meeting.<br />
Results: Of 96 pts (52 laBCC, 44 mBCC), 74% were male; median age was 63 (28–<br />
100) years. Median disease duration from diagnosis was 3.6 (0.02–53.2) years. Prior<br />
treatments included surgery (92%) and radio<strong>the</strong>rapy (51%). Pts received vismodegib<br />
for a median of 4.3 (0.6–16.1) months (median follow-up [f-u] 4.7 [0.6–16.1]<br />
months). Treatment-emergent adverse events (AEs) of any grade in ≥15% pts were:<br />
muscle spasms (60.4%), dysgeusia (55.2%), alopecia (45.8%), diarrhea (17.7%),<br />
nausea (17.7%), and fatigue (17.7%), with median times to first event of 30, 36, 84,<br />
27, 25, and 22 days, respectively. No serious AEs related to vismodegib were<br />
reported. Discontinuations (n = 26) were due to disease progression (n = 14), AEs<br />
(n = 3), death (n = 1), lost to f-u (n = 1), physician (n = 1) or subject decision (n = 5),<br />
or o<strong>the</strong>r (n = 1). Of 69 evaluable patients with RECIST-measurable disease, <strong>the</strong><br />
investigator-assessed response rate was 20/40 (50%; 95% CI 34–66%) for laBCC and<br />
10/29 (34%; 95% CI 18–54%) for mBCC. 16 pts (40%) with laBCC and 14 (48%)<br />
with mBCC had stable disease.<br />
Conclusions: Incidence and severity of AEs and clinical activity reported in this<br />
analysis are similar to those reported in <strong>the</strong> pivotal study in pts with aBCC.<br />
Vismodegib is an effective treatment option for aBCC pts.<br />
Disclosure: G.J. Weiss: Speaker’s bureau: Genentech, Pfizer Funding to my<br />
institution: Genentech, Novartis, Eli Lilly, Infinity. A. Oro: Trial funding: Genentech,<br />
Novartis, Infinity. A.L.S. Chang: Studies sponsored: Genentech, Novartis, Infinity,<br />
NuSkin, Galderma. J.A. Solomon: Advisory Committee/Group: GenentechP.M.<br />
LoRusso: Research funding: Genentech Advisory Board: Genentech Speakers’ Bureau:<br />
Genentech. O. Hamid: Consulting fee: Genentech Speaker bureau: BMS, Lilly,<br />
Genentech, Dendreon Research fee: GSK, Roche, merck, ArQule, Morphotek, EISAI,<br />
Lilly, BMS, Millenium. D.M. Chen: Employee: Genentech Shareholder: Genentech. E.<br />
McKenna: Employee: Genentech Shareholder: Genentech. S. Feng: Employee:<br />
Genentech Shareholder: Genentech. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
1112PD EFFICACY AND SAFETY OF THE HEDGEHOG PATHWAY<br />
INHIBITOR VISMODEGIB IN PATIENTS WITH ADVANCED<br />
BASAL CELL CARCINOMA (BCC): 12-MONTH ERIVANCE<br />
BCC STUDY UPDATE<br />
A. Sekulic 1 , M.R. Migden 2 , A. Oro 3 , K. Lewis 4 , J.D. Hainsworth 5 ,S.Yoo 6 ,<br />
L. Dirix 7 , J. Hou 8 , H. Yue 8 , A. Hauschild 9<br />
1 Dermatology Department, Mayo Clinic, Scottsdale, AZ, UNITED STATES OF<br />
AMERICA, 2 University of Texas, MD Anderson Cancer Center, Houston,<br />
Houston, TX, UNITED STATES OF AMERICA, 3 Department of Dermatology,<br />
Stanford University School of Medicine, Stanford, CA, UNITED STATES OF<br />
AMERICA, 4 Cutaneous Oncology, University of Colorado Cancer Center, Denver,<br />
CO, UNITED STATES OF AMERICA, 5 Oncology Research, Sarah Cannon<br />
Research Institute, Nashville, TN, UNITED STATES OF AMERICA, 6 Department<br />
of Dermatology, Northwestern University, Evanston, IL, UNITED STATES OF<br />
AMERICA, 7 Clinical Trials Oncology, Sint Augustinus Hospital, Antwerp,<br />
BELGIUM, 8 Product Development Clinical Oncology, Genentech Inc., South<br />
San Francisco, CA, UNITED STATES OF AMERICA, 9 Klinik für Dermatologie,<br />
Venerologie und Allergologie, Universitätsklinikum Schleswig-Holstein, Kiel,<br />
GERMANY<br />
Background: Vismodegib (Erivedge, GDC-0449) is a first-in-class small-molecule<br />
inhibitor of <strong>the</strong> Hedgehog signaling pathway, which is implicated in <strong>the</strong> pathogenesis<br />
of BCC. ERIVANCE BCC is <strong>the</strong> pivotal trial of vismodegib for treatment of locally<br />
advanced (laBCC) and metastatic BCC (mBCC) patients (pts) for whom <strong>the</strong>re are no<br />
o<strong>the</strong>r effective <strong>the</strong>rapies. The study met its primary endpoint of overall response rate<br />
by independent review (Dirix, <strong>ESMO</strong> 2011 LBA#1). On behalf of <strong>the</strong> ERIVANCE<br />
BCC investigators, we present <strong>the</strong> previously unreported updated<br />
investigator-assessed (I-A) efficacy and safety endpoints as of Nov 28, 2011<br />
(additional 12 months of follow-up).<br />
Methods: In this multicenter, nonrandomized 2-cohort study, pts with histologically<br />
confirmed laBCC (deemed inoperable or for whom surgery would be significantly<br />
disfiguring) or mBCC with RECIST-measurable disease, received 150 mg oral<br />
vismodegib daily.<br />
Results: 104 pts (71 laBCC/33 mBCC) enrolled at 31 global sites. I-A efficacy<br />
endpoints were:<br />
Parameter<br />
Overall Response Rate<br />
(ORR), n (%)<br />
[95% CI]<br />
Median Duration of<br />
Response (DOR),<br />
months [95% CI]<br />
Median Progression-free<br />
Survival (PFS),<br />
months [95% CI]<br />
Median Overall Survival<br />
(OS), months [95%<br />
CI]<br />
Nov 26, 2010 Data Cut Nov 28, 2011 Data Cut<br />
mBCC<br />
(n = 33)<br />
15 (45.5)<br />
[28.1–62.2]<br />
(n = 15)<br />
12.9<br />
[5.6–12.9]<br />
9.2<br />
[7.4–NE]<br />
laBCC<br />
(n = 63)<br />
38 (60.3)<br />
[47.2–71.7]<br />
(n = 38)<br />
7.6<br />
[7.4–NE]<br />
11.3<br />
[9.5–16.8]<br />
mBCC<br />
(n = 33)<br />
16 (48.5)<br />
[30.8–66.2]<br />
(n = 16)<br />
14.7<br />
[5.6–NE]<br />
9.3<br />
[7.4–16.6]<br />
NA NA 24.1<br />
[14.3–NE]<br />
Annals of Oncology<br />
laBCC<br />
(n = 63)<br />
38 (60.3)<br />
[47.2–71.7]<br />
(n = 38)<br />
NE<br />
[9.0–NE]<br />
12.9<br />
[10.2–NE]<br />
NE<br />
[NE–NE]<br />
With a median follow-up of 22.3 months, 1- and 2-year survival rates were 78%<br />
(95% CI 63.6–92.4%) and 60% (95% CI 42.6–78.1%), for mBCC and 93.1% (95% CI<br />
86.6–99.6%) and 85% (95% CI 75.6–94.7%), for laBCC. Adverse events (AEs) in<br />
>30% of pts were muscle spasms, alopecia, dysgeusia, weight decrease, fatigue,<br />
nausea, and amenorrhea (in 2/6 female nonmenopausal pts). Serious AEs were<br />
reported in 33 pts (32%), compared with 26 (25%) in Nov 2010.<br />
Conclusions: This 12-month update of I-A efficacy and safety data from <strong>the</strong><br />
ERIVANCE BCC study confirms <strong>the</strong> significant clinical benefit of vismodegib in<br />
laBCC and mBCC reported at primary analysis. Median DOR and PFS increased<br />
numerically with fur<strong>the</strong>r follow-up. The AE profile was consistent with <strong>the</strong> prior data<br />
cut. Following approval of vismodegib by <strong>the</strong> FDA, <strong>the</strong>se data fur<strong>the</strong>r support<br />
vismodegib as an effective treatment option for pts with advanced BCC.<br />
Disclosure: A. Sekulic: Speaker bureau: Genentech/Roche. M.R. Migden: Advisory<br />
board: Genentech. A. Oro: Grant: Genentech, Novartis, Infinity. K. Lewis: Grant:<br />
Genentech Consulting fee/honoria: Genentech. J. Hou: Employee: Genentech<br />
Shareholder: Genentech. H. Yue: Employee: Genentech Shareholder: Genentech. A.<br />
Hauschild: Consult/honoraria:Roche, AZ, Biovex, BMS, Boehringer-Ingelheim,<br />
Celgene, Eisai, GSK, IGEA, Merck/MSD, Novartis,SOBI Reviews:Roche Spker bureau:<br />
Roche, AZ, Biovex, BMS, Boehringer-Ingelheim, Celgene, Eisai, GSK, IGEA, Merck/<br />
MSD, Novartis,SOBI. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
ix362 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
1113PD THE MELANOMA RISK LOCI AS DETERMINANTS<br />
OF MELANOMA PROGNOSIS<br />
J. Rendleman 1 , S. Shang 2 , C. Brocia 3 ,M.Ma 4 , R. Shapiro 4 , R. Berman 4 ,<br />
A. Pavlick 4 , Y. Shao 2 , I. Osman 4 , T. Kirchhoff 3<br />
1 Cancer Institute, NYU Medical Center, New York, NY, UNITED STATES OF<br />
AMERICA, 2 Division of Biostatistics, NYU Medical Center, New York, NY,<br />
UNITED STATES OF AMERICA, 3 Division of Epidemiology, Nyu Cancer Institute,<br />
NYU Medical Center, New York, NY, UNITED STATES OF AMERICA,<br />
4 Dermatology, NYU Medical Center, New York, NY, UNITED STATES OF AMERICA<br />
Background: Genetic risk factors of human cancer emerge as promising markers of<br />
clinical outcome. Recent melanoma genome-wide scans (GWAS) have identified loci<br />
associated with disease risk, nevi or UV/pigmentation, but prognostic potential of <strong>the</strong>se<br />
variants is yet to be determined. In this study, we performed <strong>the</strong> first-to-date systematic<br />
evaluation of <strong>the</strong> association between established melanoma risk loci and progression.<br />
Methods: 891 melanoma patients prospectively accrued and followed up at NYU<br />
Medical Center were studied. We examined <strong>the</strong> association of 108 melanoma<br />
susceptibility single nucleotide polymorphisms (SNPs), selected or imputed from recent<br />
GWAS on melanoma, nevi or pigmentation, with recurrence-free survival (RFS) and<br />
overall survival (OS). The genotyping was performed using Sequenom I-plex. Univariate<br />
and multivariate Cox PH model were used to test association between each SNP and<br />
RFS and OS. Multivariate adjustments included age at diagnosis, gender, tumor stage,<br />
histological subtype, thickness, ulceration status, and mitotic index. ROC curves were<br />
used to measure utility of SNPs in predicting 3-year recurrence.<br />
Results: Strong associations were observed from <strong>the</strong> multivariate analysis for<br />
rs7538876 (RCC2) with RFS (HR = 1.48, 95% CI 1.20 – 1.83, p = 0.0002) and<br />
rs9960018 (DLGAP1) with both RFS and OS (HR = 1.43, 95% CI = 1.07-1.91, p =<br />
0.0159, HR = 1.52, 95% CI = 1.09-2.22, p = 0.0138, respectively). Subgroup analyses<br />
for ulceration and tumor thickness have identified several SNPs which show<br />
associations for RFS and OS among <strong>the</strong>se different groups. In addition, we identified<br />
<strong>the</strong> classifiers rs7538876 and rs9960018, that when combined with stage and<br />
histological type, achieve a higher area under <strong>the</strong> ROC curve (AUC = 84%),<br />
compared to <strong>the</strong> baseline (AUC = 78%), in predicting 3-year recurrence.<br />
Conclusions: Our data revealed associations between specific melanoma<br />
susceptibility variants and worse disease outcome. The strength of associations<br />
observed for rs7538876 and rs9960018 suggest biological implication of <strong>the</strong>se loci in<br />
melanoma recurrence. The observed predictive patterns of associated variants with<br />
clinical outcome provide <strong>the</strong> evidence for <strong>the</strong> potential utilization of genetic markers<br />
in melanoma prognostication.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1114PD SKIN-TEST INFILTRATING LYMPHOCYTES PREDICT<br />
CLINICAL OUTCOME OF DENDRITIC CELL BASED<br />
VACCINATION IN METASTATIC MELANOMA<br />
K. Bol1 , E. Aarntzen1 , W.R. Gerritsen1 , G. Schreibelt2 , J. Jacobs1 ,<br />
W.J. Lesterhuis1 , M. van Rossum3 , C.J.A. Punt4 , C. Figdor2 , J. De Vries2 1<br />
Medical Oncology/tumorimmunology Lab, Radboud University Nijmegen<br />
Medical Centre, Nijmegen, NETHERLANDS, 2 Tumorimmunology Lab, Radboud<br />
University Nijmegen Medical Center, Nijmegen, NETHERLANDS, 3 Dematology,<br />
Radboud University Nijmegen Medical Center, Nijmegen, NETHERLANDS,<br />
4<br />
Department of Medical Oncology, Academic Medical Center, Amsterdam,<br />
NETHERLANDS<br />
Introduction: The identification of responding patients early during treatment would<br />
greatly improve <strong>the</strong> efficacy of novel and costly immuno<strong>the</strong>rapies. Bioassays which<br />
accurately link preceding immune responses to clinical outcome are <strong>the</strong>refore needed.<br />
The mainstay of immuno<strong>the</strong>rapy is to induce, enhance or sustain TAA-specific effector<br />
T cell immunity. Consequently, evaluation of <strong>the</strong> migratory-, antigen recognition-, as<br />
well as <strong>the</strong> effector function of tumor-specific cellular responses is critical.<br />
Methods: A large cohort of metastatic melanoma patients (n = 91) enrolled in dendritic<br />
cell (DC)-based vaccination protocols was retrospectively analyzed for overall survival<br />
(OS) in relation to skin-test infiltrating lymphocyte (SKIL) cultures characteristics.<br />
Increasingly stringent criteria were defined identify long-term survivors.<br />
Results: The presence of TAA-specific CD8 + T cells (criterion I: detection by<br />
tetrameric MHC-peptide complexes) in SKIL cultures associated with improved OS;<br />
14.1 versus 10.9 months, p = 0.055. Fur<strong>the</strong>r analyses showed that <strong>the</strong> presence of<br />
multiple specificities was highly predictive for long-term survival. Tumor recognition<br />
by TAA-specific CD8+ T cells on peptide level (detected by specific production of<br />
Thelper 1 (Th1) cytokines (criterion II; e.g. IFNg and/or IL-2) or cytotoxicity and no<br />
Thelper 2 (Th2) cytokines) was strongly associated with improved OS; 14.2 versus<br />
10.2 months, p = 0.003. Recognition of naturally processed antigen by specific<br />
production of Th1 cytokines or cytotoxicity and no Th2 cytokines ((criterion III),<br />
maximized <strong>the</strong> accuracy of <strong>the</strong> test; 24.1 versus 9.9 months, p = 0.001.<br />
Conclusion: Our results demonstrate that analyzing SKIL cultures is a solid bioassay<br />
to predict overall survival in metastatic melanoma patients. This bioassay is simple,<br />
feasible and integrates multiple aspects of cellular functions needed for effective<br />
immune responses.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1115PD A PHASE 2 RANDOMIZED STUDY OF RAMUCIRUMAB (IMC<br />
1121B; RAM) WITH OR WITHOUT DACARBAZINE (DTIC)<br />
IN PATIENTS (PTS) WITH METASTATIC MELANOMA (MM)<br />
(CP12-0604/NCT00533702)<br />
R. Carvajal 1 , J. Thompson 2 , M. Gordon 3 , K. Lewis 4 , A. Pavlick 5 , J. Wolchok 1 ,<br />
P. Rojas 6 , J. Schwartz 7 , A. Bedikian 8<br />
1 Melanoma-Sarcoma Division, Memorial Sloan-Kettering Cancer Center,<br />
New York, NY, UNITED STATES OF AMERICA, 2 Medical L Oncology, Seattle<br />
Cancer Care Alliance, Seattle, UNITED STATES OF AMERICA, 3 Pinnacle<br />
Oncology Hematology, Oncology Research Associates, Scottsdale, AZ, UNITED<br />
STATES OF AMERICA, 4 Medical Oncology, University of Colorado Denver,<br />
Aurora, CO, UNITED STATES OF AMERICA, 5 Hematology-Oncology, New York<br />
University, New York, NY, UNITED STATES OF AMERICA, 6 Biostatistics, ImClone<br />
Systems, Bridgewater, NJ, UNITED STATES OF AMERICA, 7 Medical, ImClone<br />
Systems, Bridgewater, NJ, UNITED STATES OF AMERICA, 8 Melanoma Medical<br />
Oncology, MD Anderson Cancer Center, Houston, UNITED STATES OF AMERICA<br />
Background: Vascular endo<strong>the</strong>lial growth factor (VEGF)-mediated angiogenesis<br />
contributes to MM pathogenesis. RAM is a fully human IgG1 recombinant monoclonal<br />
antibody that inhibits VEGF receptor-2 (VEGFR-2) ligand binding and signaling. We<br />
investigated RAM alone and in combination with DTIC in chemo<strong>the</strong>rapy-naïve MM pts.<br />
Methods: Eligible pts had stage IV cutaneous MM, ECOG PS 0-1, adequate<br />
hematologic, hepatic, and renal function. Therapy (Rx) in Arm A: RAM (10 mg/kg)<br />
+ DTIC (1000 mg/m 2 ); Arm B: RAM (10 mg/kg). Rx was every (q) 3 weeks (wk);<br />
tumor assessments were q6 wk. The primary endpoint was progression-free survival<br />
(PFS); o<strong>the</strong>r endpoints were safety, response, overall survival (OS).<br />
Results: 106 pts were randomized; 102 received study Rx. Arm A (n = 52) median<br />
(medn) age was 63, 71% male, 37% had elevated LDH, 23% stage M1c. Arm B (n =<br />
50) medn age was 62, 76% male, 38% had elevated LDH, 36% stage M1c. Medn PFS<br />
was 2.6 months (m) Arm A and 1.7m Arm B; 6m PFS rates were 31% and 18%; 12m<br />
PFS rates were 24% and 16% on Arms A and B, respectively. There were 9 (17%)<br />
partial responses (PR) & 19 (37%) with stable disease (SD); 2 (4%) PR & 21(42%)<br />
SD on Arms A and B, respectively. Medn OS was 8.7m Arm A; 11m Arm<br />
B. Nonhematologic adverse events (AEs) considered at least possibly related to RAM<br />
included fatigue (50%; 4% Grade [G] ≥3), hypertension ([HTN] 21%; 15% G ≥3),<br />
infusion-related reactions ([IRR] 8%; 0 G ≥3), proteinuria ([PU] 8%; 4% G ≥ 3),<br />
headache ([HA] 10%; 2% G ≥3) on Arm A; fatigue (30%; 2% G ≥3), HTN (22%;<br />
14% G ≥3), IRR (14%; 6% G ≥3), PU (12%; 2% G ≥3), HA (20%; 0 G ≥3) on Arm<br />
B. IRR incidence was reduced following a recommendation for premedication after<br />
37 pts received initial Rx. Hematologic AEs were neutropenia ([NP] 33%; 19% G<br />
≥3), thrombocytopenia ([TP] 39%; 15% G ≥3), and anaemia ([A]14%; 4% G ≥3) on<br />
Arm A; NP (0%), TP (6%; 0 G ≥3) and A (2%; 0 G ≥3) on Arm B.<br />
Conclusions: RAM alone or in combination with DTIC was associated with<br />
acceptable incidence of AEs in MM. Clinical activity was modest on both arms.<br />
Although <strong>the</strong> study was not powered for definitive comparison between treatment<br />
arms, PFS appeared greater in Arm A. Biomarker analysis is ongoing.<br />
Disclosure: R. Carvajal: Cosulting, Novartis - money paid to me Consulting,<br />
Morphotek - money paid to me Grants, NIH/NCI - money paid to me Grants,<br />
FDA - money paid to me Grants, ASCO - money paid to me. J. Thompson: ImClone<br />
provided funding to <strong>the</strong> University of Washington to support this research. K. Lewis:<br />
Research Funding - ImClone. J. Wolchok: Consultant - Bristol Myers Squibb; Merck;<br />
GlaxoSmithKline Research support - Bristol Myers Squibb and GlaxoSmithKline. P.<br />
Rojas: I am an employee of Lilly and own Lilly stock. J. Schwartz: I am an employee<br />
of Lilly and own Lilly stock. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1116PD FIVE-YEAR SURVIVAL RATES FOR PATIENTS (PTS) WITH<br />
METASTATIC MELANOMA (MM) TREATED WITH<br />
IPILIMUMAB (IPI) IN PHASE II TRIALS<br />
C. Lebbe1 , J.S. Weber2 , M. Maio3 , B. Neyns4 , K. Harmankaya5 , K. Chin6 ,<br />
D. Opatt McDowell7 , L. Cykowski8 , M.B. McHenry9 , J.D. Wolchok10 1 2<br />
Saint-Louis Hospital, APHP University, Paris, FRANCE, Interdisciplinary<br />
Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, FL,<br />
UNITED STATES OF AMERICA, 3 Department of Oncology, Azienda Ospedaliera<br />
Senese - Medical Oncology and Immuno<strong>the</strong>rapy Unit, Siena, ITALY, 4 Medical<br />
Oncology, Vrije Universiteit Brussel, Brussels, BELGIUM, 5 Department of General<br />
Clinical Dermatology, Medical University of Vienna, Vienna, AUSTRIA, 6 Global<br />
Clinical Research - Oncology, Bristol-Myers Squibb, Wallingford, CT, UNITED<br />
STATES OF AMERICA, 7 Global Medical, Bristol-Myers Squibb, Lawrenceville,<br />
NJ, UNITED STATES OF AMERICA, 8 Global Clinical Operations, Bristol-Myers<br />
Squibb, Wallingford, CT, UNITED STATES OF AMERICA, 9 Global Biometrics<br />
Sciences, Bristol-Myers Squibb, Wallingford, CT, UNITED STATES OF AMERICA,<br />
10<br />
Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, UNITED<br />
STATES OF AMERICA<br />
Purpose: Two phase III, randomized trials showed statistically significant<br />
improvement in overall survival (OS) in MM pts treated with IPI and data from<br />
phase II/III studies of IPI suggest <strong>the</strong> potential for prolonged survival (beyond 4 yrs)<br />
in some pts with MM. Three phase I/II studies conducted at NCI demonstrated 5-yr<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds404 | ix363
survival rates of 13-25% (Prieto et al, CCR, <strong>2012</strong>). Evaluation of <strong>the</strong> long-term<br />
survival benefit of IPI for MM pts from 3 additional completed phase II studies<br />
continues and we now report 5-yr survival data.<br />
Methods: Trials included: (1) CA184-008, a single-arm study of IPI at 10 mg/kg in<br />
previously treated pts; (2) CA184-022, a dose-ranging study of IPI at 0.3, 3, or 10<br />
mg/kg in previously treated pts with crossover from lower doses to 10 mg/kg allowed<br />
upon disease progression; and (3) CA184-007, a study of IPI at 10 mg/kg +/prophylactic<br />
budesonide in treatment-naive and previously treated pts. IPI was given<br />
q 3 wks x 4 (induction); eligible pts could receive reinduction or maintenance IPI q<br />
12 wks from Week 24. The analysis reports OS with updated last known alive date or<br />
death based on data collected through March <strong>2012</strong>. Safety data for <strong>the</strong>se trials have<br />
been previously published.<br />
Results: Survival rates at 5 yrs ranged from 12-28% in pretreated pts and 38-50% in<br />
treatment-naive pts. The table summarizes median OS, previously reported yearly<br />
survival rates, and current 5-yr survival rates.<br />
Trial N<br />
IPI dose<br />
(mg/kg)<br />
Median<br />
OS,<br />
months<br />
OS rate, %<br />
1-yr 2-yr 3-yr 4-yr 5-yr<br />
008 155* 10 10.2 47.2 32.8 23.3 19.7 18.2<br />
022 72* 10 11.4 48.6 29.8 24.8 21.5 21.5<br />
72* 3 8.7 39.3 24.2 19.7 18.2 16.5<br />
73* 0.3 8.6 39.6 18.4 13.8 13.8 12.3<br />
007 57 (total) 10 + placebo 19.3 62.4 41.8 34.4 32.0 32.0<br />
32 †<br />
30.5 71.4 56.6 42.5 37.7 37.7<br />
25* 14.8 50.8 24.2 24.2 24.2 24.2<br />
58 (total) 10 + 17.7 55.9 41.1 38.7 36.2 36.2<br />
21 budesonide<br />
†<br />
45.0 65.9 57.7 57.7 49.5 49.5<br />
37* 8.5 49.9 31.6 28.4 28.4 28.4<br />
*Previously treated; †Treatment naive.<br />
Conclusions: Across studies, 5 yr OS rates appear similar to those at 4 years,<br />
suggesting that IPI mono<strong>the</strong>rapy may result in prolonged survival in some pts with<br />
MM. Fur<strong>the</strong>r research and analyses are needed to identify <strong>the</strong> pt population with<br />
MM most likely to achieve long term survival benefit from IPI <strong>the</strong>rapy.<br />
Disclosure: C. Lebbe: Participation to BMS Advisory Boards. J.S. Weber: For BMS,<br />
only honoraria less than 10K dollars and advisory role in Ad Boards. M. Maio: Paid<br />
Advisor in Boards from BMS and Roche. B. Neyns: No conflict of interest to report<br />
with regards to this abstract. K. Harmankaya: With Regards to conflict of interest in<br />
this abstract, unpaid investigator on this study. K. Chin: Employed by BMS; Stock<br />
ownership. D. Opatt McDowell: Employed by BMS; Stock ownership. L. Cykowski:<br />
Employed by BMS; Stock ownership. M.B. McHenry: Employed by BMS, Stock<br />
OwnershipJ.D. Wolchok: I am a consultant to Bristol-Myers Squibb, Merck and<br />
Glaxo SmithKline. I receive research funding from Bristol-Myers Squibb.<br />
1117PD LONG TERM SURVIVAL AND IMMUNOLOGICAL<br />
CORRELATES IN METASTATIC MELANOMA TREATED<br />
WITH IPILIMUMAB AT 10 MGS WITHIN AN EXPANDED<br />
ACCESS PROGRAM<br />
A.M. Di Giacomo 1 , L. Calabrò 1 , R. Danielli 1 , I. Pesce 1 , E. Fonsatti 1 , E. Bertocci 1 ,<br />
D. Giannarelli 2 , M. Biagioli 3 , M. Altomonte 1 , M. Maio 1<br />
1 Department of Oncology, Medical Oncology and Immuno<strong>the</strong>rapy,University<br />
Hospital of Siena, Siena, ITALY, 2 Medical Oncology, Regina Elena National<br />
Cancer Institute, Roma, ITALY, 3 Department of Medicine, Dermatology, University<br />
Hospital of Siena, Siena, ITALY<br />
Background: Ipilimumab (IPI) has shown long lasting responses in metastatic<br />
melanoma (MM) patients (pts) in phase II/III trials (Hodi et al., NEJM 2010; Robert<br />
et al. NEJM 2011; Prieto et al., CCR <strong>2012</strong>). We have previously reported a significant<br />
clinical efficacy of IPI in 27 heavily pre-treated MM pts enrolled within <strong>the</strong> 10 mgs<br />
expanded access program (EAP) available at <strong>the</strong> University Hospital of Siena; one<br />
and 2-years survival were 34.8% and 23.5%, respectively (Di Giacomo, et al. CII,<br />
2010). In spite of its clinical efficacy, no definitive predictive markers of response<br />
have been identified yet. We report here <strong>the</strong> survival follow-up of this cohort of MM<br />
pts and preliminary data on immunological correlates.<br />
Methods: Twenty-seven pts with stage III (2) or IV (25) MM, progressing to a<br />
median of 3 (1-5) systemic <strong>the</strong>rapies, were treated according to <strong>the</strong> EAP with IPI at<br />
10 mg/Kg i.v. given at weeks (wks) 1, 4, 7, 10 during <strong>the</strong> induction phase, and every<br />
12 wks from W24 in <strong>the</strong> maintenance phase. Peripheral blood mononuclear cells<br />
were collected from 17 pts at baseline, W7, W12 and W24 and analyzed by flow<br />
cytometry for ICOS expression on both CD4 and CD8+ T cells. The ratio between<br />
absolute blood neutrophils (N) and lymphocytes (L) count was determined at<br />
baseline, W4, W7 and W10 for 27, 27, 24 and 23 pts, respectively.<br />
Results: With a median follow-up of 9.6 months <strong>the</strong> median OS was 9.6 months<br />
(95% CI: 4.2-16.1; range: 3.1-51.2; three and 4-years survival rates were 20.9%, with 5<br />
long-term survivors (>4 yrs). A significant (p < 0.05) increase in <strong>the</strong> percentage and<br />
absolute number of CD4 + ICOS+ and CD8 + ICOS+ circulating T cells was observed<br />
Annals of Oncology<br />
from W7 on. Compared to baseline, pts with a fold increase in CD4 + ICOS+ and<br />
CD8 + ICOS+ T cells higher than 4 at W7 and W12 experienced a clinical benefit<br />
(SD, PR and CR). Pts with a N/L ratio lower than median at W7 and W10 had a<br />
significantly better survival.<br />
Conclusions: ipi can induce long-term survivals in heavily pre-treated MM pts.<br />
Circulating ICOS+ T cells and N/L ratio in <strong>the</strong> course of treatment with ipi may<br />
represent predictive markers of clinical effectiveness in <strong>the</strong> daily practice.<br />
Disclosure: M. Maio: Advisory Board and Honoraria from Bristol-Myers Squibb and<br />
Roche. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1118PD MULTIPLE PRIMARY MELANOMAS FROM SAME PATIENTS<br />
PRESENT DISCREPANT SOMATIC ALTERATIONS IN MAIN<br />
CANDIDATE GENES<br />
M. Colombino 1 , M. Sini 1 , V. De Giorgi 2 , A. Lissia 3 , D. Massi 4 , C. Rubino 5 ,<br />
A. Cossu 3 , F. Ayala 6 , P.A. Ascierto 6 , G. Palmieri 1<br />
1 Unit of Cancer Genetics, Institute of Biomolecular Chemistry, CNR, Sassari,<br />
ITALY, 2 Department of Dermatology, University of Florence, Florence, ITALY,<br />
3 Institute of Pathology, University of Sassari, Sassari, ITALY, 4 Institute of<br />
Pathology, University of Florence, Florence, ITALY, 5 Plastic Surgery, University of<br />
Sassari, Sassari, ITALY, 6 Melanoma, National Tumor Institute Fondazione<br />
Pascale, Naples, ITALY<br />
Background: A series of patients with multiple primary melanoma (MPM) were<br />
screened for <strong>the</strong> involvement of <strong>the</strong> key-regulator genes in susceptibility (CDKN2A)<br />
and pathogenesis (BRAF, cKIT, CyclinD1) of such a disease.<br />
Methods: Genomic DNA from peripheral blood of 63 MPM patients (54 cases with<br />
two primary melanomas, 8 with three, and 1 with four) were screened for germline<br />
mutations in p16 CDKN2A and p14 CDKN2A genes by automated DNA sequencing.<br />
Melanoma families were identified according to standardized criteria: 9 (14%)<br />
patients were classified as familial cases. Paired synchronous and/or asynchronous<br />
MPM tissues (N = 100) from same patients (N = 46) were analyzed for somatic<br />
mutations in BRAF gene and FISH-based amplifications in cKIT and CyclynD1<br />
genes.<br />
Results: Overall, 6 (10%) different CDKN2A germline mutations were identified: 5<br />
inp16 CDKN2A and 1 inp14 CDKN2A . The age of onset was significantly lower and <strong>the</strong><br />
number of primary melanomas higher in patients with mutations. CDKN2A<br />
mutations were significantly more frequent in patients with familial history of<br />
melanoma (5/9; 56%) compared with patients without (1/54; 2%) (P < 0.001), and in<br />
patients with more than two melanomas (3/9; 33%) compared with patients with<br />
only two melanomas (3/54; 6%) (P = 0.012). The debated A148T polymorphism was<br />
found at low level (2/54; 4%) in our series. Regarding genetic alterations at somatic<br />
level, BRAF mutations were identified in 36/100 (36%) primary melanoma tissues,<br />
whereas amplification of cKIT and CyclinD1 genes was observed in 2/88 (2%) and<br />
10/88 (11%) analyzed tissue samples, respectively. Considering all types of genetic<br />
events, paired samples presented a poorly consistent distribution of somatic<br />
alterations in same patients (52% consistency).<br />
Conclusions: Coexistence of MPM and familial recurrence of melanoma as well as<br />
<strong>the</strong> presence of more than two melanomas seem to be strong indications to address<br />
patients to CDKN2A mutational screening. The low consistency in genetic patterns<br />
of primary tumors from <strong>the</strong> same patients provide additional evidence that<br />
pathogenetic mechanisms of melanomagenesis are heterogeneous and molecularly<br />
different cell types may be generated in multiple primary melanoma.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1119P ASSOCIATION OF GENETIC POLYMORPHISMS IN TUMOR<br />
SUPPRESSORS, ERP29 AND PTCH1, AND DNA<br />
TRANSCRIPTION FACTORS, IKBKAP AND ZNF415, WITH<br />
CUTANEOUS MELANOMA RISK<br />
E.F.D. Costa, G.J. Lourenço, C. Oliveira, J.A. Rinck-Junior, A.M. Moraes,<br />
G.A.S. Nogueira, C.S.P. Lima<br />
Clinical Medical, State University of Campinas, Campinas, BRAZIL<br />
Introduction: Recently, we found that genetic single nucleotide polymorphisms<br />
(SNPs) in tumor suppressors ERP29 c.293A > G, PTCH1 g.79755C > T and g.79456C<br />
> T, and in genes of DNA transcription IKBKAP p.Cys1072Ser and ZNF415 c.443A<br />
> G, alter <strong>the</strong> oropharynx cancer risk. The study was conducted using high resolution<br />
DNA microarrays genotyping (SNP 5.0 array, Affymetrix®) and <strong>the</strong> quantities and<br />
functions of <strong>the</strong> proteins encoded by distinct alleles are being examined by our<br />
research group. Objective: To investigate <strong>the</strong> influence of <strong>the</strong> referred SNPs in <strong>the</strong><br />
risk of cutaneous melanoma (CM).<br />
Materials and methods: Genomic DNA from 153 CM patients and 153 controls<br />
were analyzed by TaqMan® genotyping assays. The differences between groups were<br />
analyzed by <strong>the</strong> logistic regression model. Power analysis (PA) was used to verify <strong>the</strong><br />
effect of sample size on <strong>the</strong> results obtained in <strong>the</strong> study.<br />
ix364 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Results: The frequencies of ERP29 c.293AA + PTCH1 g.79755CC (95.0 vs 80.1%,<br />
P= 0.006; PA= 86%), ERP29 c.293AA + PTCH1 g.79456CC (94.9 vs 79.4%, P= 0.005;<br />
PA= 88%), ERP29 c.293AA + ZNF415 c.443GG (56.2 vs 31.6%, P= 0.01; PA= 84%)<br />
combined genotypes were more common in patients than in controls. Individuals with<br />
<strong>the</strong> referred genotypes were under a 4.3 (95%CI: 1.61-13.43), 4.3 (95%CI: 1.63-13.49),<br />
and 3.05 (95%CI: 1.29-7.53) fold increased risk for CM than o<strong>the</strong>rs. In addition, <strong>the</strong><br />
frequencies of ERP29 c.293AA + PTCH1 g.79456CC + IKBKAP p.1072CysCys (98.5 vs<br />
83.3%, P= 0.01; PA= 86%), ERP29 c.293AA + PTCH1 g.79456CC + ZNF415 c.443GG<br />
(85.7 vs 44.1%, P= 0.004; PA= 96%) combined genotypes were also higher in patients<br />
than in controls. Individuals with <strong>the</strong> referred genotypes were under a 13.5 (95%CI:<br />
2.47-252.3) and 8.05 (95%CI: 2.21-39.24) fold increased risks for CM than o<strong>the</strong>rs.<br />
Conclusions: Our data present for <strong>the</strong> first time that: 1) ERP29 c.293A > G, PTCH1<br />
g.79755C > T and g.79456C > T, IKBKAP p.Cys1072Ser, and ZNF415 c.443A > G<br />
SNPs are important inherited risk factors for CM and; 2) healthy individuals with<br />
<strong>the</strong>se SNPs should receive recommendation to avoid sunlight exposition and should<br />
be frequently evaluated by a dermatologist to perform an early diagnosis of <strong>the</strong><br />
tumor. Financial support: FAPESP and FINEP.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1120P TIME TREND INFLUENCE OF SOCIECONOMIC STATUS<br />
ON SURVIVAL, BRESLOW THICKNESS, TIME FROM ONSET<br />
OF SYMPTOMS AND SURGICAL RESECTION IN STAGE I-II<br />
PRIMARY CUTANEOUS MELANOMA<br />
M. Mandala 1 , G. Imberti 2 , D. Piazzalunga 3 , R. Labianca 1 , G. Lucisano 4 ,<br />
B. Merelli 1 , S. Mosconi 1 , L. Marchesi 2 , A. Gianatti 5 , C. Tondini 1<br />
1 Oncology and Haematology, Ospedali Riuniti di Bergamo, Bergamo, ITALY,<br />
2 Dermatology, Ospedali Riuniti Bergamo, Bergamo, ITALY, 3 Surgical Oncology,<br />
Ospedali Riuniti Bergamo, Bergamo, ITALY, 4 Epidemiology, Mario Negri Sud,<br />
Santa Maria Imbaro, ITALY, 5 Pathology, Ospedali Riuniti Bergamo, Bergamo,<br />
ITALY<br />
Objective: To investigate <strong>the</strong> time trend influence of socioeconomic status (SES) on<br />
Breslow thickness (BT) and survival in patients (pts) with stage I-II primary<br />
cutaneous melanoma (PCM).<br />
Patients and methods: Pathologic and sociodemographic characteristics of<br />
prospectively collected, consecutive pts diagnosed with PCM between November 1,<br />
1998, and July 31, 2009 were evaluated. We categorized SES into 3 levels: low<br />
(manual employees with primary education level), middle (non-manual employees<br />
with middle education level), and high (professionals, executives with tertiary<br />
education). We divided <strong>the</strong> representative years between 2000 and 2009 into three<br />
four-year (table 1). In <strong>the</strong> multilvariate analysis models <strong>the</strong> following variables were<br />
tested: SES, marital status, sex and age.<br />
Results: A total of 1274 available pts were analyzed. Overall a progressive decrease of<br />
BT was observed (table 1). In <strong>the</strong> first four year period gender and age correlated with<br />
BT and ulceration [m vs f OR (95%CI): 1.66 (1.10-1.52) and (>60 vs G, PTCH1 G.79755C > T<br />
AND PTCH1 G.79456C > T POLYMORPHISMS WITH<br />
INHERITED RISK OF CUTANEOUS MELANOMA<br />
G.A.S. Nogueira, G.J. Lourenço, C. Oliveira, J.A. Rinck-Junior, E.F.D. Costa,<br />
A.M. Moraes, C.S.P. Lima<br />
Clinical Medical, University of Campinas, Campinas, BRAZIL<br />
Background: Recently we found that SNPs alter <strong>the</strong> oropharynx carcinoma risk in<br />
tumor suppressor MCC c.*5077A > G, PTCH1 g.79755C > T, and PTCH1 g.79456C ><br />
T. This study was conducted using high-resolution large-scale DNA microarray<br />
genotyping (5.0 SNP array, Affymetrix ®), and <strong>the</strong> quantities and functions of <strong>the</strong><br />
proteins encoded by distinct alleles of <strong>the</strong> polymorphisms are being examined by our<br />
research group. Objective: We aimed to verify whe<strong>the</strong>r <strong>the</strong> different genotypes of<br />
polymorphisms in MCC c.*5077A > G, PTCH1 g.79755C > T, and PTCH1 g.79456C<br />
> T alter <strong>the</strong> CM susceptibility.<br />
Materials and methods: Genomic DNA of 149 CM patients and 153 controls was<br />
analyzed by TaqMan genotyping (Applied Biosystems®). Statistical significance of<br />
differences between groups was calculated by using chi-square (χ2) and Fisher’s exact<br />
tests. Power analysis (PA) was used to verify <strong>the</strong> effect of sample size on <strong>the</strong> results<br />
obtained in <strong>the</strong> study.<br />
Results: Samples from patients with MC and controls were in Hardy-Weinberg<br />
equilibrium for MCC and PTCH1 loci. Similar frequencies of MCC and PTCH1<br />
genotypes were observed in patients and controls. Individuals with distinct isolated<br />
genotypes of <strong>the</strong> genes were under similar risks for CM. The frequencies of <strong>the</strong><br />
combined genotypes MCC 5077AA + PTCH1 79755CC (90.4% versus 72.3%, P=<br />
0.004; PA: 99.0%), MCC 5077AA + PTCH1 79456CC (89 0% versus 71.6%, P= 0.008;<br />
PA: 98.0%), and MCC 5077AA + PTCH1 79755CC + PTCH1 79456CC (91.3% versus<br />
76.1%, P= 0.004; PA: 99.0%) were higher in patients than in controls. Individuals<br />
with <strong>the</strong>se genotypes were at 4.44 (CI95%: 1.68 – 13.17), 3.60 (CI95%: 1.45 – .87),<br />
and 4.70 (CI95%: 1.75 – 14.63)-fold increased risks for CM than o<strong>the</strong>rs, respectively.<br />
Conclusion: Our results suggest that combined MCC and PTCH1 polymorphisms<br />
are an important inherited risk factor for CM. We believe that healthy carriers with<br />
<strong>the</strong>se genotypes deserve recommendations for protecting <strong>the</strong>ir skin from <strong>the</strong> harmful<br />
effects of UV rays to prevent tumor disease and periodic follow-up with <strong>the</strong><br />
dermatologist for early tumor diagnosis. Financial support: State of São Paulo<br />
Research Foundation (FAPESP) and Research and Project Financing (FINEP)<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1122P INHERITED ABNORMALITIES IN GENES THAT DURING THE<br />
APOPTOSIS PROCESS AND CUTANEOUS MELANOMA RISK<br />
C. Oliveira 1 , J.A. Rinck-Junior 1 , G.J. Lourenço 1 , M.L. Cintra 2 , A.M. Moraes 1 ,<br />
C.S.P. Lima 1<br />
1 Department of Internal Medicine, State University of Campinas, Distrito de<br />
Barão Geraldo, Campinas, São Paulo, Brazil, BRAZIL, 2 Department of<br />
Pathology, State University of Campinas, Distrito de Barão Geraldo, Campinas,<br />
São Paulo, Brazil, BRAZIL<br />
Background: P53 (guardian of <strong>the</strong> genome), MDM2 (p53 inhibitor), BCL2<br />
(anti-apoptotic) and BAX (proapoptotic) genes remove cells damaged by ultraviolet<br />
(UV) rays of sunlight and, <strong>the</strong>refore, are related to <strong>the</strong> origin of cutaneous melanoma<br />
(CM). All <strong>the</strong>se genes are polymorphic in humans. The Arg wild allele of <strong>the</strong> P53<br />
Arg72Pro polymorphism is more efficient than <strong>the</strong> variant Pro allele at inducing<br />
apoptosis. The variant G and A alleles of MDM2 T309G and <strong>the</strong> BCL2 C (-948) A<br />
polymorphisms, and <strong>the</strong> variant A allele of <strong>the</strong> BAX G(-248)A polymorphism are<br />
related to higher and lower expressions of <strong>the</strong> encoded proteins, respectively, than <strong>the</strong>ir<br />
wild T, C and G alleles. This study aimed to clarify <strong>the</strong> roles of <strong>the</strong> above-mentioned<br />
genetic polymorphisms in <strong>the</strong> risk and clinical manifestation of <strong>the</strong> tumor.<br />
Material and methods: In this case-control study, genomic DNA from peripheral<br />
blood of 150 consecutive CM patients (75 males and 75 females, 138 Caucasians and 12<br />
non-Caucasians aged 20-89 years) and 150 healthy subjects, matched by age, gender and<br />
race, was analyzed by polymerase chain reaction followed by enzymatic digestion.<br />
Results: The frequencies of <strong>the</strong> P53 ArgArg and <strong>the</strong> BCL2 AA genotypes were higher in<br />
patients than in controls (58.7% versus 44.7%, P= 0.01) and (28.0% versus 15.3%, P=<br />
0.004), respectively. Carriers of <strong>the</strong>se genotypes had a 1.86 and 2.87-fold increased risk for<br />
CM than those with <strong>the</strong> remaining genotypes, respectively. Excesses of <strong>the</strong> P53 ArgArg<br />
plus BCL2 AA and P53 ArgArg plus BAX AA were seen in patients when compared to<br />
controls (36.1% versus 16.9%, P= 0.002) and (29.5% versus 15.3%, P= 0.008). Carriers of<br />
<strong>the</strong>se genotypes had a 3.43 and 2.71-fold increased risk for CM than o<strong>the</strong>rs, respectively.<br />
Conclusions: The data suggest that P53 Arg72Pro, BCL2 C(-248)A and BAX G<br />
(-248)A polymorphisms, alone or combined, alter <strong>the</strong> risk for CM in our region. We<br />
believe that carriers of specific genotypes of <strong>the</strong> above-mentioned genes should<br />
receive additional recommendation to avoid exposition to sunlight, in addition to<br />
frequently being evaluated by a dermatologist for early disease diagnosis. Financial<br />
support: (FAPESP)<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1123P BRAF-V600 AND C-KIT MUTATION ANALYSIS IN<br />
CYTOLOGYCAL SAMPLES FROM METASTATIC MELANOMA<br />
T. Labiano 1 , M.D. Lozano 1 , J.I. Echeveste 1 , M. Montañana 1 , M.F. Sanmamed 2 ,<br />
E. Castanon Alvarez 2 , N. Gómez 1 , A. Gurpide 2 , M.A. Idoate 1 , S. Martin Algarra 3<br />
1 Pathology, University of Navarra, Pamplona, SPAIN, 2 Medical Oncology, Clinica<br />
Universitaria de Navarra, Pamplona, SPAIN, 3 Medical Oncology, Clinica<br />
Universidad de Navarra, Pamplona, SPAIN<br />
Background: Vemurafenib is approved for <strong>the</strong> first-line treatment of BRAF-V600E+<br />
metastatic melanoma (MM). Also, preliminary clinical experience with imatinib in<br />
MM patients with gene amplification or activating mutations of c-KIT, have shown<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds404 | ix365
high response rates and prolonged progression free survival. These results emphasise<br />
<strong>the</strong> importance of molecular information, even in those cases in which <strong>the</strong> diagnosis<br />
is made on small samples obtained through minimally invasive approaches. Cytology<br />
is an accurate and cost-effective tool for <strong>the</strong> diagnosis of MM and cytological smears<br />
are occasionally <strong>the</strong> only samples available from <strong>the</strong>se patients.<br />
Methods: We have studied BRAF and c-KIT mutations in 62 cytological samples<br />
from MM patients. Preliminary results of 56 cases (32 men (58%) and 23 women<br />
(42%); median age 52 years) are included in this abstract. Diagnosis was made on<br />
fine needle aspiration in 41 cases, imprints in 10, direct eye touch in 1, a smear from<br />
cellular culture in 1, and pleural and peritoneal fluid in 3. To assure tissue quality,<br />
DNA was extracted directly from Papanicolau stained smears on which cytological<br />
diagnosis was made. BRAF and c-KIT mutations were analysed by PCR and direct<br />
sequencing using an ABI PRISM TM 310XL.<br />
Results: BRAF mutations was found in 30 cases (53.5%): V600E mutation in 26<br />
(86,7%) and V600K in 4 (13,3%). c-KIT mutations were studied in 18 cases. L576P<br />
mutation was present in 1 patient with liver metastasis from acral melanoma<br />
(5.56%). BRAF status did not correlated with primary melanoma histology, age at<br />
diagnosis, disease free survival, brain metastases rate and overall survival.<br />
Conclusions: The frequency of activating mutations in BRAF is 53.5% in this series.<br />
V600E is <strong>the</strong> most commonly observed mutations, but V600K appears in 13.3% of<br />
<strong>the</strong> cases. c-KIT mutations incidence is low (5.56%). Mutational analysis of BRAF<br />
and c-KIT using cytological samples from patients with metastatic melanoma is<br />
feasible and can be used to extend <strong>the</strong> benefits of targeted <strong>the</strong>rapy to those patients<br />
from which biopsies are not available. Updated results will be presented.<br />
Disclosure: S. Martin Algarra: Participation in Advisory Boards of Roche. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
1124P AN OPEN-LABEL, MULTICENTRE SAFETY STUDY<br />
OF VEMURAFENIB IN PATIENTS WITH METASTATIC<br />
MELANOMA<br />
C. Blank 1 , M. Del Vecchio 2 , P.A. Ascierto 3 , P. Queirolo 4 , A. Hauschild 5 ,<br />
A. Arance 6 ,M.Brown 7 , L. Mitchell 8 , L. Veronese 8 , J. Larkin 9<br />
1 Immunology, The Ne<strong>the</strong>rlands Cancer Institute Antoni van Leeuwenhoek<br />
Hospital, Amsterdam, NETHERLANDS, 2 Department of Medical Oncology,<br />
Instituto Nazionale dei Tumori, Milan, ITALY, 3 Unit of Medical Oncology and<br />
Innovative Therapy, Istituto Nazionale Tumori Fondazione G. Pascale, Naples,<br />
ITALY, 4 National Institute for Cancer Research, San Martino Hospital, Genova,<br />
ITALY, 5 Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum<br />
Schleswig-Holstein, Kiel, GERMANY, 6 Medical Oncology, Hospital Clinic,<br />
Barcelona, SPAIN, 7 Oncology, Royal Adelaide Hospital Cancer Centre, Adelaide,<br />
AUSTRALIA, 8 F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, 9 Department<br />
of Medicine, Royal Marsden Hospital, London, UNITED KINGDOM<br />
Background: Vemurafenib, a BRAF inhibitor, is associated with improved<br />
progression-free survival and overall survival in patients (pts) with BRAF V600 -mutant<br />
metastatic melanoma (mM). Here we present findings from a safety study of<br />
vemurafenib in pts with unresectable Stage IIIC/IV BRAF V600 -positive mM.<br />
Methods: Pts with untreated or previously treated Stage IIIC/IV BRAF V600<br />
mutation-positive (cobas® 4800 BRAF V600 Mutation Test) melanoma were enrolled.<br />
Pts received continuous oral vemurafenib 960 mg bid. Primary study endpoint was<br />
safety; efficacy (RECIST V 1.1) was a secondary endpoint.<br />
Results: Of 5273 screened pts (Mar 2011–Feb <strong>2012</strong>), 2353 (45%) were enrolled and<br />
2096 received ≥1dose of vemurafenib. Median age was 54 (16–95 years), 56% were<br />
male. Median time since first mM diagnosis was 6.4 months. Most pts were Stage IV<br />
(84%); 47.1% M1c, 2% Stage IIIC (stage not reported for 14% of pts). At baseline,<br />
87% of pts had ECOG PS 0/1, 11% ECOG PS ≥2; 24% had brain metastases and<br />
37% had elevated LDH. Most pts had received prior systemic <strong>the</strong>rapy (60%)<br />
including ipilimumab (10%), MEK and BRAF inhibitors (3%). At data cut-off (29<br />
Feb <strong>2012</strong>), median treatment duration was 3.1 months (10%) of any grade were arthralgia (30.7%), rash (25.6%),<br />
fatigue (19.6%), alopecia (15.6%), nausea (15%) and photosensitivity (11%), and were<br />
similar irrespective of brain metastases and ECOG PS. AEs caused treatment<br />
interruption in 492 (23.5%) pts. Of 774 pts (37%) who discontinued treatment, most<br />
withdrew due to progressive disease (71%) or death (14%) but 6% had AEs (most<br />
commonly general physical deterioration). Tumour assessments at Week 8 of<br />
treatment were available for 1356/2096 (65%) pts; 60% of pts achieved a CR or PR;<br />
31% had SD.<br />
Conclusions: In a setting representative of routine clinical practice, vemurafenib is<br />
well tolerated and both safety profile and activity resemble <strong>the</strong> Phase I–III data,<br />
although this analysis is limited by <strong>the</strong> study duration.<br />
Disclosure: C. Blank: Financial disclosure: Roche global steering committee, Roche<br />
NL presentations, conference travel, Novartis NL: conference travel, advisory board;<br />
MedImmune: research grant; BMS: advisory board, clinical research funding. M. Del<br />
Vecchio: Consultant or Advisory Role: Merck/Schering-Plough (U); Research<br />
Funding: Celgene, Novartis, Roche. P.A. Ascierto: Consultant for MSD; Advisory role<br />
for BMS, MSD, Roche-Genetech, GSK, Amgen, Celgene, Medimmune, Novartis;<br />
Annals of Oncology<br />
received honoraria from BMS, MSD, and Roche-Genentech. P. Queirolo: Advisory<br />
Board of Bristol Myers Squibb, Roche-Genentech, GSK, MSD and received honoraria<br />
from Brystol Myers Squibb and Roche-Genentech. A. Hauschild: Honoraria for adboard<br />
membership, and payments for lectures/speakers bureaus from Amgen,<br />
AstraZenica, Biovex, BMS, Boehringer, Ingelheim, Celgene, Eisai, GSK, IGEA, Lilly,<br />
Medac, MelaSciences, MSD?Merck, Novartis, Roche Pharma, SOBI, Vical, Janssen. A.<br />
Arance: Steering committee of this safety study (Roche). M. Brown: Membership<br />
of a Roche Melanoma Advisory Board. L. Mitchell: Full-time employee at<br />
F. Hoffmann-la-RocheL. Veronese: Full-time employee at F. Hoffmann-la-Roche.<br />
All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1125P OPEN-LABEL PILOT STUDY OF VEMURAFENIB IN<br />
PREVIOUSLY TREATED METASTATIC MELANOMA (MM)<br />
PATIENTS (PTS) WITH SYMPTOMATIC BRAIN METASTASES<br />
(BM)<br />
R. Dummer 1 , S. Goldinger 2 , C. Turtschi 2 , N. Eggmann 2 , O. Michielin 3 ,<br />
L. Mitchell 4 , L. Veronese 4 , P.R. Hilfiker 5 , J.D. Rinderknecht 2<br />
1 Department of Dermatology, Universitätsspital Zürich, Zürich, SWITZERLAND,<br />
2 Department of Dermatology, University Hospital of Zurich, Zurich,<br />
SWITZERLAND, 3 Melanoma Clinic, Multidisciplinary Oncology Center, Lausanne,<br />
SWITZERLAND, 4 F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, 5 Radiology,<br />
MRI Bethanien, Zurich, SWITZERLAND<br />
Background: The BRAF inhibitor vemurafenib has shown high response rates and<br />
improved progression-free and overall survival in mM harbouring V600-mutated<br />
BRAF. BMs are often observed with mM and indicate a poor prognosis. The aim of<br />
this preliminary investigation is to determine <strong>the</strong> feasibility of vemurafenib <strong>the</strong>rapy<br />
in mM with BM.<br />
Methods: 24 evaluable pts with BRAF V600 mutation positive (cobas® 4800 BRAF V600<br />
Mutation Test) mM and BMs, requiring corticosteroids for symptom control, were<br />
enrolled (Nov 2010–Nov 2011). Pts received twice-daily vemurafenib 960 mg. Primary<br />
endpoint is safety; secondary endpoint is best overall response rate (RECIST v1.1).<br />
Results: All pts were white, median age 47 (24–70) years. Median baseline number of<br />
BMs was 3.5 (1–20). Median time since BM diagnosis was 3.2 (0–64) months. O<strong>the</strong>r<br />
lesion sites included skin, lung, liver, bone, lymph nodes, colon/large intestine,<br />
stomach, breast and adrenal. All pts had prior treatment for BM: radio<strong>the</strong>rapy 83%<br />
(58% whole brain, 25% precision), 2 pts had surgery and 83% of pts had systemic<br />
<strong>the</strong>rapy. As of clinical data cut-off (15 Dec 2011), median treatment duration was<br />
117 (3–304) days. 9 pts are ongoing; 15 (63%) discontinued treatment because of<br />
progression of disease (PD), 8 of whom died because of PD. 22 pts (92%) reported<br />
≥1 adverse event (AE), which were mainly mild or moderate. Most common AEs<br />
were arthralgia (33%), photosensitivity (21%) and seizures (20%, pre-existing). 3 pts<br />
reported 1 of each of <strong>the</strong> following grade 3 AEs: epilepsy, cutaneous squamous cell<br />
carcinoma (cuSCC), increased amylase, elevated γ-glutamyltransferase and ileus with<br />
perforation. Overall, cuSCC occurred in 3 pts (12.5%), skin papilloma in 3 pts<br />
(12.5%) and keratoacanthoma in 1 pt (4.2%). 7/24 pts (29%) had a confirmed partial<br />
response: 9 pts (38%) had stable disease, 3 (12%) PD and 5 (21%) were not evaluable<br />
for response. Median duration of response was 3.8 (0.8–4.7) months.<br />
Conclusions: Vemurafenib <strong>the</strong>rapy is feasible in advanced melanoma patients with<br />
symptomatic BM. Interpretation of efficacy is currently limited because of a short<br />
follow-up time, but <strong>the</strong>re are strong indications of vemurafenib activity in BM.<br />
Disclosure: R. Dummer: Research funding: Astra Zeneca, Novartis, Cephalon, MSD,<br />
Transgene, BMS, Roche, GlaxoSmithKline, Bayer. Ad-board: Astra Zeneca, Novartis,<br />
Cephalon, MSD, Transgene, Genta, Bayer, Roche, BMS, GSK, Spirig. L. Mitchell:<br />
Full-time employee of F. Hoffmann-la-Roche. L. Veronese: Full time employee at<br />
F. Hoffmann-la-Roche. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1126P PHASE II STUDY OF IPILIMUMAB PLUS TEMOZOLOMIDE<br />
IN PATIENTS WITH METASTATIC MELANOMA<br />
S. Patel 1 , R. Bassett 2 ,W.Hwu 1 , K. Kim 1 , N. Papadopoulos 1 ,P.Hwu 1 ,<br />
A. Bedikian 1<br />
1 Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, TX,<br />
UNITED STATES OF AMERICA, 2 Biostatistics, MD Anderson Cancer Center,<br />
Houston, TX, UNITED STATES OF AMERICA<br />
Background: Ipilimumab (Ipi) alters <strong>the</strong> immune system balance by inhibiting <strong>the</strong><br />
suppression of T-cell function. In two Phase III trials, Ipi has shown an overall<br />
survival benefit alone and in combination with dacarbazine in previously treated and<br />
treatment-naïve patients (pts) with metastatic melanoma (MM), respectively. We<br />
performed a single-institution, Phase II clinical trial of Ipi plus temozolomide (Tem)<br />
in pts with MM.<br />
Methods: Pts between <strong>the</strong> ages of 18 and 75 with previously untreated unresectable<br />
Stage III or Stage IV MM and an ECOG Performance Status (PS) of 0 to 1 were<br />
enrolled in a Phase II trial of Ipi plus Tem. Induction phase consisted of Ipi 10mg/kg<br />
intravenous on Day 1 and oral Tem 200 mg/m 2 on Days 1 – 4 every 3 weeks for 4<br />
doses. Maintenance consisted of Ipi 10 mg/kg intravenous on Day 1 starting week 12<br />
and repeated every 12 weeks and oral Tem 200 mg/m 2 on Days 1 – 5 starting week<br />
ix366 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
12 and repeated every 4 weeks until disease progression or unacceptable toxicity<br />
occurred. The primary endpoint was progression-free survival (PFS) rate at 6<br />
months. Responses were evaluated using immune-related response criteria.<br />
Results: Sixty-four pts were enrolled and received at least one dose of study drug. All<br />
pts were included in <strong>the</strong> analysis. With a median follow-up of 51 weeks, <strong>the</strong> PFS rate<br />
at 6 months was 45%, exceeding <strong>the</strong> proposed rate of 30%, and <strong>the</strong> median PFS was<br />
22 weeks. There were 10 (15.6%) confirmed complete responses and 10 (15.6%)<br />
confirmed partial responses. To date, median overall survival has not been reached.<br />
Among many variables including age, gender, ECOG PS, and stage, <strong>the</strong>re was a<br />
statistically significant difference in PFS in <strong>the</strong> group of patients with bone metastasis<br />
and those without bone metastasis.<br />
Conclusion: At a median follow-up of 51 weeks, <strong>the</strong> overall response rate in this<br />
study is 31%. Ipi at 10 mg/kg in combination with Tem given in an induction<br />
followed by maintenance fashion is safe, well-tolerated, and efficacious in MM. The<br />
primary endpoint of 6-month PFS has been reached and exceeded.<br />
Factors Associated with PFS<br />
No. of Pts<br />
Median PFS<br />
(weeks)<br />
Univariate<br />
P-Value<br />
Hazard<br />
Ratio 95% CI<br />
Bone Mets<br />
No 57 24 — 1.00 —<br />
Yes 7 12 0.01 2.73 1.20 – 6.20<br />
Disclosure: S. Patel: Research funding from Bristol-Myers Squibb. W. Hwu: Research<br />
funding from Merck Research funding from Bristol-Myers Squibb. K. Kim: Research<br />
funding from Bristol-Myers Squibb Advisory board, honoraria from Bristol-Myers<br />
Squibb. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1127P FOUR-YEAR SURVIVAL UPDATE FOR METASTATIC<br />
MELANOMA (MM) PATIENTS (PTS) TREATED WITH<br />
IPILIMUMAB (IPI) + DACARBAZINE (DTIC) ON PHASE 3<br />
STUDY CA184-024<br />
M. Maio 1 , I. Bondarenko 2 , C. Robert 3 , L. Thomas 4 , C. Garbe 5 , A. Testori 6 ,<br />
S. Francis 7 , K. Chin 8 , J. Wolchok 9<br />
1 Department of Oncology, Azienda Ospedaliera Senese - Medical Oncology and<br />
Immuno<strong>the</strong>rapy Unit, Siena, ITALY, 2 Department of Oncology, Radiodiagnosis<br />
and Radioth, Dnipropetrovsk Municipal Clinical Hospital #4, Dnepropetrovsk,<br />
UKRAINE, 3 Melanoma Unit, Institute Gustave Roussy, Villejuif, FRANCE,<br />
4 Department of Dermatology, Lyon 1 University Centre Hospitalier Lyon Sud,<br />
Villeurbanne, FRANCE, 5 Oncology, University Medical Center, Tuebingen,<br />
GERMANY, 6 Melanoma Division, European Institute of Oncology, Milan, ITALY,<br />
7 Global Biometrics Sciences, Bristol-Myers Squibb, Braine-l’Alleud, BELGIUM,<br />
8 Global Clinical Research - Oncology, Bristol-Myers Squibb, Wallingford, CT,<br />
UNITED STATES OF AMERICA, 9 Melanoma-sarcoma Division, Memorial<br />
Sloan-Kettering Cancer Center, New York, NY, UNITED STATES OF AMERICA<br />
Background: Data from clinical trials suggest a long-term survival effect (beyond 4<br />
yrs) of IPI <strong>the</strong>rapy in some pts with MM. An analysis of 177 pts from 3 phase I/II<br />
IPI studies conducted at NCI demonstrated 5-yr survival rates of 13-25% (Prieto,<br />
et al., CCR <strong>2012</strong>). In o<strong>the</strong>r phase II trials, IPI mono<strong>the</strong>rapy was associated with<br />
long-term survival of 4+ yrs in some pts with MM (Wolchok, et al., 2011 PIM). IPI<br />
in combination with DTIC in previously untreated MM patients significantly<br />
improved OS in phase III study CA184-024 (Robert, et al, NEJM 2011). Safety data<br />
from study 024 has been previously published. Here we report 4-yr survival data<br />
from study 024, <strong>the</strong> longest IPI survival follow-up from a phase III study.<br />
Methods: Pts with treatment-naive MM were randomized to receive ei<strong>the</strong>r IPI (10<br />
mg/kg) + DTIC (850 mg/m 2 ) or placebo + DTIC (850 mg/m 2 ) given at Wks 1, 4, 7,<br />
10 followed by DTIC q 3 wks through Wk 22. Pts with stable disease or better <strong>the</strong>n<br />
received IPI or placebo q 12 wks as maintenance. This analysis reports OS with<br />
updated last known alive date or death date based on data collected through April<br />
<strong>2012</strong>.<br />
Results: The table summarizes median OS, previously reported survival<br />
rates at 1, 2, and 3 years, and current analyses for 4-year survival rates by treatment<br />
group.<br />
Table: 1127P<br />
Treatment<br />
group<br />
Median OS,<br />
months<br />
[95% CI]<br />
Overall survival rate, % [95% CI]<br />
Conclusions: The 4-year survival rates observed in an extended follow-up of a<br />
completed phase III trial suggests that IPI 10 mg/kg in combination with DTIC<br />
continues to demonstrate a survival benefit compared to <strong>the</strong> control arm. The<br />
continued survival of some patients at 4 yrs suggests that prolonged survival may<br />
indeed be obtained in some pts with treatment-naive MM. This observation of<br />
long-term survival benefit in a phase III RCT is consistent with observations from<br />
phase I/II studies of IPI in patients with advanced melanoma.<br />
Disclosure: M. Maio: Paid advisor in boards from BMS and Roche. C. Robert:<br />
Consultant for BMS, GSK, Roche and Novartis. C. Garbe: I received honoraria and<br />
research funding from BMS. S. Francis: Employed by BMS. K. Chin: Employed by<br />
BMS and have Stock ownership. J. Wolchok: I am a consultant to BMS, Merck and<br />
GSK. I receive rsearch funding from BMS. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
1128P THE EUROPEAN IPILIMUMAB EXPANDED ACCESS<br />
PROGRAMME (EAP): EFFICACY AND SAFETY DATA FROM<br />
THE ITALIAN COHORT OF PATIENTS WITH PRETREATED,<br />
ADVANCED MELANOMA<br />
P.A. Ascierto 1 , V. Chiarion Sileni 2 , M. Del Vecchio 3 , M. Altomonte 4 , F. De Galitiis 5 ,<br />
L. Ridolfi 6 , F. Cognetti 7 , A. Testori 8 , M.G. Bernengo 9 , P. Queirolo 10<br />
1 Unit of Medical Oncology and Innovative Therapy, Istituto Nazionale Tumori di<br />
Napoli, Napoli, ITALY, 2 U.O. Oncologia Medica, Istituto Oncologico Veneto<br />
IOV-IRCCS, Padova, ITALY, 3 Department of Medical Oncology, Fondazione<br />
IRCCS Istituto Nazionale dei Tumori Milan, Milan, ITALY, 4 Department of<br />
Oncology, Azienda Ospedaliera Senese - Medical Oncology and Immuno<strong>the</strong>rapy<br />
Unit, Siena, ITALY, 5 Department of Oncology, Dermopathic Institute of <strong>the</strong><br />
Immaculate IDI-IRCCS, Rome, ITALY, 6 Medical Oncology, Scientific Institute of<br />
Romagna for <strong>the</strong> Study and Treatment of Cancer (IRST), Meldola, ITALY,<br />
7 Division Medical Oncology A, Istituto Regina Elena, Roma, ITALY, 8 Melanoma<br />
Division, Eurpean Institute of Oncology, Milan, ITALY, 9 Institute of Dermatology,<br />
University Hospital St John <strong>the</strong> Baptist, Turin, ITALY, 10 National Institute for<br />
Cancer Research, San Martino Hospital, Genoa, ITALY<br />
Purpose: Ipilimumab was <strong>the</strong> first agent approved for <strong>the</strong> treatment of unresectable<br />
or metastatic melanoma that showed an overall survival benefit in a randomised<br />
phase III trial. Here, we evaluate <strong>the</strong> safety and efficacy of ipilimumab treatment<br />
outside of clinical trials in patients enrolled in <strong>the</strong> EAP in Italy.<br />
Methods: Ipilimumab was available upon physician request for patients aged ≥16<br />
years with unresectable stage III/stage IV melanoma who had ei<strong>the</strong>r failed systemic<br />
<strong>the</strong>rapy or were intolerant to ≥1 systemic treatment and for whom no o<strong>the</strong>r<br />
<strong>the</strong>rapeutic option was available. Ipilimumab 3 mg/kg was administered<br />
intravenously every 3 weeks for 4 doses. Tumour assessments were conducted at<br />
baseline and after completion of induction <strong>the</strong>rapy using immune-related response<br />
criteria. Patients were monitored for adverse events (AEs), including immune-related<br />
AEs, within 3 to 4 days of each ipilimumab dose using Common Terminology<br />
Criteria for Adverse Events v.3.0.<br />
Results: In total, 848 Italian patients participated in <strong>the</strong> EAP from June 2010 to<br />
April <strong>2012</strong> across 53 centres. Of <strong>the</strong>se 848 patients, data are currently available for<br />
563 patients. With a median follow-up of 3 months, <strong>the</strong> disease control rate among<br />
468 evaluable patients was 31.4%, including 7 patients with a complete response, 51<br />
with a partial response and 89 with stable disease. As of April <strong>2012</strong>, median<br />
progression-free survival and overall survival were 3.1 months and 6.2 months,<br />
respectively, with 1-year survival rate of 34%. In total, 50.1% patients reported an AE<br />
of any grade, most of which were drug-related (36.2%). Grade 3/4 AEs were reported<br />
by 18.5% patients and considered drug-related in 8.5%. Eleven patients discontinued<br />
treatment due to toxicity. AEs were generally reversible with treatment as per<br />
protocol-specific guidelines. Complete data on all 848 patients, with longer<br />
follow-up, will be presented.<br />
Conclusions: Ipilimumab is a feasible treatment option for pretreated patients who<br />
progressed on, or were unable to tolerate previous <strong>the</strong>rapies. Many patients<br />
experienced durable disease control.<br />
Disclosure: P.A. Ascierto: PA has served as a consultant for Merck Sharp & Dohme,<br />
and as an advisor to Bristol-Myers Squibb (BMS), Merck Sharp & Dohme, Roche,<br />
GlaxoSmithKline, Amgen, Celgene, Medimmune and Novartis. He has received<br />
honoraria from BMS, Merck Sharp & Dohme and Roche. V. Chiarion Sileni: Vanna<br />
Chiaron Sileni has acted as an advisor for Bristol-Myers Squibb, Roche,<br />
1-year 2-year 3-year 4-year<br />
IPI + DTIC N = 250 11.2 [9.4-13.6] 47.5% [41.2–53.8] 28.8% [23.2–34.6] 21.2% [16.1–26.5] 19.0% [14.2 - 24.2]<br />
Placebo + DTIC N = 252 9.1 [7.8-10.5] 36.4% [30.4–42.4] 17.8% [13.2–22.6] 12.1% [8.1–16.3] 9.6% [6.1 - 13.5]<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds404 | ix367
GlaxoSmithKline, Merck Sharp & Dohme and Schering-Plough. M.G. Bernengo:<br />
Maria Grazia Bernengo has acted as an advisor to Bristol-Myers Squibb, Novartis<br />
and Pfizer. P. Queirolo: Paola Queirolo has acted as an advisor for Roche,<br />
GlaxoSmithKline, Bristol-Myers Squibb and Schering-Plough and received honoraria<br />
from Bristol-Myers Squibb and Roche. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
1129P IPILIMUMAB (IPI) EXPANDED ACCESS PROGRAM (EAP) FOR<br />
PATIENTS (PTS) WITH STAGE III/IV MELANOMA: SAFETY<br />
DATA BY SUBGROUPS<br />
D. Lawrence 1 , D.F. McDermott 2 , O. Hamid 3 , J.S. Weber 4 , J.D. Wolchok 5 ,<br />
J. Richards 6 , A. Amin 7 , K. Bennett 8 , A. Balogh 9 , F.S. Hodi 10<br />
1 Department of Medicine, Massachusetts General Hospital Cancer Center,<br />
Boston, MA, UNITED STATES OF AMERICA, 2 Division of Hematology/Oncology,<br />
Beth Israel Deaconess Medical Center, Boston, MA, UNITED STATES OF<br />
AMERICA, 3 Neuro-oncology Clinic, The Angeles Clinic and Research Institute,<br />
Los Angeles, CA, UNITED STATES OF AMERICA, 4 Department of Oncology,<br />
H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, FL, UNITED<br />
STATES OF AMERICA, 5 Medicine, Memorial Sloan-Kettering Cancer Center,<br />
New York, NY, UNITED STATES OF AMERICA, 6 Oncology Hematology,<br />
Oncology Specialists SC, Parkridge, IL, UNITED STATES OF AMERICA, 7 Levine<br />
Cancer Institute, Carolinas Medical Center, Charlotte, NC, UNITED STATES OF<br />
AMERICA, 8 Global Medical, Bristol-Myers Squibb, Plainsboro, NJ, UNITED<br />
STATES OF AMERICA, 9 Global Biometrics Sciences, Bristol-Myers Squibb,<br />
Brain-l’Alleud, BELGIUM, 10 Melanoma Center, Dana-Farber Cancer Institute,<br />
Boston, MA, UNITED STATES OF AMERICA<br />
Background: Treatment protocol CA184-045, a component of <strong>the</strong> EAP, provides a<br />
large safety database for IPI. Study 045 included pts with disease characteristics<br />
typically excluded from registrational clinical trials such as ECOG PS of 2,<br />
asymptomatic brain metastases (BM) and primary ocular (OM) and mucosal (MM)<br />
melanoma. We now report safety data by subgroups for pts treated in <strong>the</strong> US at 3<br />
mg/kg from March 2010 through July 2011.<br />
Methods: Eligible pts had unresectable Stage III or IV melanoma that progressed on<br />
at least 1 systemic <strong>the</strong>rapy and had no alternate treatment options. Treatment<br />
algorithms were used for identification and management of immune-related adverse<br />
events (AEs). During induction, pts received 3 mg/kg IPI iv q 3 wks up to 4 doses.<br />
All AEs and on-study deaths were collected. This analysis includes events through 70<br />
days post last induction dose.<br />
Results: 2017 pts were included in this analysis; 96% were Stage IV and 92% were<br />
ECOG 0-1. Median number of doses during induction was 4, except 3 for BM. Data<br />
from pts < 65 or ≥ 65 yrs and those with BM, OM, MM, or all o<strong>the</strong>rs are<br />
summarized.<br />
Disclosure: D.F. McDermott: BMS advisory board participantO. Hamid: Speaker for<br />
BMS - Reimbursed Clinic reimbursed for work done on research trials. J.S. Weber:<br />
BMS only honoraria less thank 10K dollars and advisory role in ad boards. J.D.<br />
Wolchok: I am a consultant to BMS, Merck and GSK. I receive research funding<br />
from BMS. J. Richards: Consultant and speaker for BMS. A. Amin: Participated in<br />
<strong>the</strong> BMS speaker’s bureau and advisory board during <strong>the</strong> last 2 years; unpaid<br />
investigator on EAP. K. Bennett: Employed by BMS; Stock Ownership. A. Balogh:<br />
Employed by BMS. F.S. Hodi: Nonpaid consultant and received clinical trial support<br />
from BMS. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
Table: 1129P<br />
1130P EFFICACY AND SAFETY OF IPILIMUMAB IN PATIENTS WITH<br />
PRETREATED, MUCOSAL MELANOMA: EXPERIENCE FROM<br />
ITALIAN CLINICS PARTICIPATING IN THE EUROPEAN<br />
EXPANDED ACCESS PROGRAMME (EAP)<br />
M. Del Vecchio 1 , E. Simeone 2 , V. Chiarion Sileni 3 , C. Nuzzo 4 , G. Rinaldi 5 ,<br />
A. Testori 6 , F. De Galitiis 7 , P. Queirolo 8 , R. Marconcini 9 , M. Maio 10<br />
1 Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan,<br />
ITALY, 2 Fondazione Pascale, Instituto Nazional per lo Studio, Napoli, ITALY,<br />
3 Medical Oncology II, Istituto Oncologico Veneto IRCCS, Padova, ITALY,<br />
4 Department of Medical Oncology, Regina Elena National Cancer Institute,<br />
Rome, ITALY, 5 Discipliniche Chirurgiche ed Oncologiche, Azienda Ospedaliera<br />
UniversitariaPoliclinico Paolo Giaccone, Palermo, ITALY, 6 Melanoma Muscle<br />
Cutaneous Sarcoma Division, European Institute of Oncology, Milan, ITALY,<br />
7 Department of Oncology, Dermopathic Institute of <strong>the</strong> Immaculate IDI-IRCCS,<br />
Rome, ITALY, 8 National Institute for Cancer Research, San Martino Hospital,<br />
Genova, ITALY, 9 Department of Oncology, University Hospital Pisa “ Ga<strong>the</strong>red<br />
Hospitals of Santa Clara”, Pisa, ITALY, 10 Department of Oncology, Medical<br />
Oncology and Immuno<strong>the</strong>rapy,University Hospital of Siena, Siena, ITALY<br />
Purpose: Mucosal melanoma is an extremely rare and aggressive malignancy<br />
associated with a poor prognosis. Because of its rarity and <strong>the</strong> challenges associated<br />
with each anatomical location, mucosal melanoma often remains undetected until it<br />
is at an advanced stage, when effective treatment options are limited. The EAP<br />
provided an opportunity to assess <strong>the</strong> activity and safety of ipilimumab in patients<br />
with mucosal melanoma outside of controlled clinical trials from <strong>the</strong> EAP in Italy.<br />
Methods: Ipilimumab was available upon physician request for patients aged ≥16<br />
years with stage III (unresectable) or stage IV skin, ocular or mucosal melanoma,<br />
who had failed or did not tolerate previous treatments and for whom no <strong>the</strong>rapeutic<br />
option was available. Patients were treated with ipilimumab 3 mg/kg every 3 weeks<br />
for 4 doses. Tumour assessments were conducted at baseline and after completion of<br />
induction <strong>the</strong>rapy using immune-related response criteria. Patients were monitored<br />
for adverse events (AEs), including immune-related AEs, within 3 to 4 days of each<br />
scheduled visit using Common Terminology Criteria for Adverse Events v.3.0.<br />
Results: Of 848 Italian patients participating in <strong>the</strong> EAP, 70 (8.2%) had mucosal<br />
melanoma. Of <strong>the</strong>se, data are available for 50 patients. With a median follow-up of<br />
2.5 months, <strong>the</strong> disease control rate among 39 evaluable patients was 23.1%,<br />
including one patient with a complete response, two patients with a partial response<br />
and six with stable disease. As of April <strong>2012</strong>, median progression-free survival and<br />
overall survival among patients with mucosal melanoma were 3.9 months and 6.2<br />
months, respectively. In total, 40.0% patients reported an AE of any grade, most of<br />
which were drug-related (32.0%). Grade 3/4 AEs were reported by 18.0% patients<br />
and considered drug-related in 12.0%. AEs were generally manageable and most<br />
resolved with treatment as per protocol-specific guidelines.<br />
Conclusions: Results from <strong>the</strong> EAP suggest that ipilimumab is active in some<br />
patients with mucosal melanoma and warrants fur<strong>the</strong>r investigation in prospective<br />
clinical trials.<br />
Disclosure: E. Simeone: Ester Simeone has received honoraria from Bristol-Myers<br />
Squibb. V. Chiarion Sileni: Vanna Chiaron Sileni has acted as an advisor for<br />
Bristol-Myers Squibb, Roche, GlaxoSmithKline, Merck Sharp & Dohme and<br />
Schering-Plough. P. Queirolo: Paola Queirolo has acted as an advisor for Roche,<br />
GlaxoSmithKline, Bristol-Myers Squibb and Schering-Plough and received honoraria<br />
from Bristol-Myers Squibb and Roche. M. Maio: Michele Maio has acted as an<br />
advisor for Bristol-Myers Squibb and Roche. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
Age Group Melanoma Sub-type<br />
Annals of Oncology<br />
Total N = 2017 < 65 yrs n = 1250 ≥ 65 yrs n = 767 BM** n = 686 OM** n = 118 MM** n = 112 All o<strong>the</strong>rs n = 1150<br />
Demographics, % Males < 65 yrs Received<br />
all 4 induction doses<br />
64 62 59 61 – 58 69 – 60 67 72 49 50 63 59 51 58 53 65 57 65<br />
Discontinuations, % Disease progression<br />
Study drug toxicity Adverse event<br />
Study terminated ‡ 93* 49 4 2 92* 52 3 1 93* 46 6 3 94* 56 4 3 93* 55 3 2 98* 55 5 2 92* 45 4 1<br />
O<strong>the</strong>r<br />
21 17<br />
20 16<br />
22 16<br />
16 15 22 11 25 11<br />
23 19<br />
Select Grade 3/4 drug-related AEs, % 3 3 0.3
Annals of Oncology<br />
1131P EFFICACY AND SAFETY OF IPILIMUMAB REINDUCTION<br />
THERAPY PATIENTS WITH PRETREATED ADVANCED<br />
MELANOMA PARTICIPATING IN AN EXPANDED ACCESS<br />
PROGRAMME (EAP) IN ITALY<br />
J. Pigozzo 1 , L. Calabrò 2 , P.A. Ascierto 3 , F. De Galitiis 4 , P.F. Ferrucci 5 ,<br />
P. Queirolo 6 , M.G. Bernengo 7 , M. Aglietta 8 , M. Mandala 9 , M. Del Vecchio 10<br />
1 U.o.oncologia Medica, Istituto Oncologico Veneto IOV-IRCCS, Padova, ITALY,<br />
2 Department of Oncology, Medical Oncology and Immuno<strong>the</strong>rapy,University<br />
Hospital of Siena, Siena, ITALY, 3 Unit of Medical Oncoloty and Innovative<br />
Therapy, Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, ITALY,<br />
4 Department of Oncology, Dermopathic Institute of <strong>the</strong> Immaculate IDI-IRCCS,<br />
Rome, ITALY, 5 Melanoma and Sarcoma, Istituto Europeo di Oncologia, Milano,<br />
ITALY, 6 National Institute for Cancer Research, San Martino Hospital, Genova,<br />
ITALY, 7 Institute of Dermatology, University Hospital St John <strong>the</strong> Baptist, Turin,<br />
ITALY, 8 Div Oncologia ed Ematologia, Fondazione Piemontese per la Ricerca sul<br />
Cancro Onlus, Candiolo, ITALY, 9 Oncology and Haematology, Ospedali Riuniti di<br />
Bergamo, Bergamo, ITALY, 10 Department of Medical Oncology, National Cancer<br />
Institute, Milan, ITALY<br />
Purpose: In <strong>the</strong> registrational phase III trial of ipilimumab, patients who progressed<br />
after initially responding to ipilimumab treatment could subsequently receive<br />
additional ipilimumab <strong>the</strong>rapy with <strong>the</strong> same treatment regimen (reinduction). Here,<br />
we describe efficacy and safety data from <strong>the</strong> Italian subgroup of patients in <strong>the</strong> EAP<br />
who received reinduction with ipilimumab outside of a clinical trial setting.<br />
Methods: Ipilimumab was available upon physician request for patients aged ≥16<br />
years with life-threatening, unresectable stage III/IV melanoma who failed or did not<br />
tolerate previous treatments and for whom no <strong>the</strong>rapeutic option was available.<br />
Induction <strong>the</strong>rapy with ipilimumab was 3 mg/kg every 3 weeks for 4 doses. Patients<br />
who progressed after stable disease (SD) lasting ≥3 months or an initial partial<br />
response (PR) or complete response (CR) were eligible for reinduction <strong>the</strong>rapy at <strong>the</strong><br />
same dose/schedule. Tumour assessments were conducted at baseline and after<br />
completion of induction <strong>the</strong>rapy using immune-related response criteria. Patients<br />
were monitored for adverse events (AEs), including immune-related AEs, within 3 to<br />
4 days of each ipilimumab dose using Common Terminology Criteria for Adverse<br />
Events v.3.0.<br />
Results: Of 848 patients participating in <strong>the</strong> EAP in Italy, 59 received reinduction<br />
treatment. After a median follow-up of 10 months, <strong>the</strong> disease control rate among 26<br />
reinduced patients with data available was 100%; comprising nine patients with a PR<br />
and 17 with SD. Overall, only two reinduced patients died as a result of disease<br />
progression, after 11 and 13 months. As of April <strong>2012</strong>, median overall survival for<br />
patients that received reinduction <strong>the</strong>rapy had not yet been reached. In total, 57%<br />
patients reported grade 1/2 AEs. Grade 3/4 AEs were reported by 15% patients, but<br />
were only considered drug-related in one patient. AEs were generally reversible with<br />
treatment as per protocol-specific guidelines.<br />
Conclusions: Considering available data, reinduction with ipilimumab resulted in<br />
durable objective responses and/or stable disease. No new types of toxicities occurred<br />
during reinduction and most events were mild-to-moderate.<br />
Disclosure: P.A. Ascierto: PA has served as a consultant for Merck Sharp & Dohme,<br />
and as an advisor to Bristol-Myers Squibb (BMS), Merck Sharp & Dohme, Roche,<br />
GlaxoSmithKline, Amgen, Celgene, Medimmune and Novartis. He has received<br />
honoraria from BMS, Merck Sharp & Dohme and Roche. P. Queirolo: Paola Queirolo<br />
has acted as an advisor for Roche, GlaxoSmithKline, Bristol-Myers Squibb and<br />
Schering-Plough and received honoraria from Bristol-Myers Squibb and Roche. M.G.<br />
Bernengo: Maria Grazia Bernengo has acted as an advisor to Bristol-Myers Squibb,<br />
Novartis and Pfizer. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1132P EFFICACY AND SAFETY DATA FROM PATIENTS WITH<br />
ADVANCED MELANOMA AND BRAIN METASTASES<br />
PARTICIPATING IN THE EUROPEAN IPILIMUMAB<br />
EXPANDED ACCESS PROGRAMME (EAP) IN ITALY<br />
P. Queirolo 1 , E. Simeone 2 , F. De Galitiis 3 , L. Di Guardo 4 , A.M. Di Giacomo 5 ,<br />
R. Marconcini 6 , V. Ferraresi 7 , F. De Rosa 8 , M. Guida 9 , S. Stragliotto 10<br />
1 National Institute for Cancer Research, San Martino Hospital, Genova, ITALY,<br />
2 Fondazione Pascale, Instituto Nazional per lo Studio, Napoli, ITALY,<br />
3 Department of Oncology, Dermopathic Institute of <strong>the</strong> Immaculate IDI-IRCCS,<br />
Rome, ITALY, 4 Department of Medical Oncology, National Cancer Institute,<br />
Milan, ITALY, 5 Medical Oncology and Immuno<strong>the</strong>rapy, University Hospital of<br />
Siena, Siena, ITALY, 6 Department of Oncology, University Hospital Pisa<br />
“Ga<strong>the</strong>red Hospitals of Santa Clara”, Pisa, ITALY, 7 Department of Medical<br />
Oncology, Regina Elena National Cancer Institute, Rome, ITALY, 8 Medical<br />
Oncology, Scientific Institute of Romagna for <strong>the</strong> Study and Treatment of Cancer<br />
(IRST), Meldola, ITALY, 9 Medical Oncology, National Institute of Cancer, Bari,<br />
ITALY, 10 Medical Oncology II, Istituto Oncologico Veneto IRCCS, Padova, ITALY<br />
Purpose: Patients with melanoma brain metastases have a very poor prognosis and<br />
are usually excluded from melanoma clinical trials. The EAP provided an<br />
opportunity to evaluate <strong>the</strong> feasibility of ipilimumab treatment in this patient<br />
population outside of a controlled clinical trial in Italy.<br />
Methods: Ipilimumab was available upon physician request for patients aged ≥16<br />
years with unresectable stage III /IV melanoma, including those with asymptomatic<br />
brain metastases, who had ei<strong>the</strong>r failed systemic <strong>the</strong>rapy or were intolerant to ≥1<br />
systemic treatment. Induction <strong>the</strong>rapy with ipilimumab was 3 mg/kg every 3 weeks<br />
for 4 doses. Tumour assessments were conducted at baseline and after completion of<br />
induction <strong>the</strong>rapy using immune-related response criteria. Patients were monitored<br />
for adverse events (AEs), including immune-related AEs, within 3 to 4 days of each<br />
ipilimumab dose using Common Terminology Criteria for Adverse Events v.3.0.<br />
Results: Of 848 patients with advanced melanoma participating in <strong>the</strong> EAP in Italy,<br />
144 (17%) had asymptomatic brain metastasis. Of <strong>the</strong>se, data are available for 84<br />
patients. With a median follow-up of 3 months, <strong>the</strong> disease control rate among 74<br />
evaluable patients was 16.2%, comprising four patients with a partial response and<br />
eight with stable disease. As of April <strong>2012</strong>, median progression-free survival and<br />
overall survival among patients with brain metastases were 2.5 months and 3.8<br />
months, respectively. In total, 50.0% patients reported an AE of any grade, most of<br />
which were drug-related (40.5%). Grade 3/4 AEs were reported by 28.5% patients<br />
and considered drug-related in 15.5%. The most common grade 3/4 drug-related<br />
adverse events were diarrhoea (n = 3; 3.6%) and liver dysfunction (n = 3; 3.6%). AEs<br />
were generally reversible with treatment as per protocol-specific guidelines.<br />
Conclusions: Ipilimumab shows activity in patients with advanced melanoma<br />
metastatic to brain, with safety results consistent to what has been previously<br />
reported for ipilimumab.<br />
Disclosure: P. Queirolo: Paola Queirolo has acted as an advisor for Roche,<br />
GlaxoSmithKline, Bristol-Myers Squibb and Schering-Plough and received honoraria<br />
from Bristol-Myers Squibb and Roche. E. Simeone: Ester Simeone has received<br />
honoraria from Bristol-Myers Squibb. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
1133P EFFICACY AND SAFETY OF IPILIMUMAB IN PATIENTS WITH<br />
PRETREATED, OCULAR MELANOMA: EXPERIENCE FROM<br />
ITALIAN CLINICS PARTICIPATING IN THE EUROPEAN<br />
EXPANDED ACCESS PROGRAMME (EAP)<br />
M. Maio 1 , V. Chairion Sileni 2 , L. Pilla 3 , S.V.L. Nicoletti 4 , L. Di Guardo 5 ,<br />
P. Queirolo 6 , F. De Galitiis 7 , M. Mandala 8 , M. Guida 9 , P.A. Ascierto 10<br />
1 Istituto Toscano Tumori, University Hospital of Siena, Siena, ITALY, 2 Department<br />
of Oncology, Oncology Institute of Veneto, Padova, ITALY, 3 Department of<br />
Oncology, San Raffaele Hospital, Milan, ITALY, 4 Department of Medical<br />
Oncology, Scientific Institute of Romagna for <strong>the</strong> Study and Treatment of Cancer<br />
(IRST), Meldola, ITALY, 5 Department of Medical Oncology, National Cancer<br />
Institute, Milan, ITALY, 6 National Institute for Cancer Research, San Martino<br />
Hospital, Genoa, ITALY, 7 Oncology, IDI-IRCCS, Rome, ITALY, 8 Oncology and<br />
Haematology, Ospedali Riuniti di Bergamo, Bergamo, ITALY, 9 Medical Oncology,<br />
National Institute of Cancer, Bari, ITALY, 10 Unit of Medical Oncology and<br />
Innovative Therapy, Istituto Nazionale Tumori Fondazione G. Pascale, Napoli,<br />
ITALY<br />
Purpose: Ocular melanoma is a rare malignancy with an incidence of 5.3–10.9 cases<br />
per million per year (Papastefanou and Cohen; J Skin Cancer 2011). Currently, <strong>the</strong><br />
treatment of metastatic ocular melanoma is limited by <strong>the</strong> lack of an effective<br />
systemic <strong>the</strong>rapy. The EAP provided an opportunity to assess <strong>the</strong> activity and safety<br />
of ipilimumab in patients with ocular melanoma outside of a controlled clinical trial<br />
in patients from <strong>the</strong> EAP in Italy.<br />
Methods: Ipilimumab was available upon physician request for patients aged ≥16<br />
years with stage III (unresectable) or stage IV skin, ocular or mucosal melanoma,<br />
who had failed or did not tolerate previous treatments and for whom no <strong>the</strong>rapeutic<br />
option was available. Patients were treated with ipilimumab 3 mg/kg every 3 weeks<br />
for 4 doses. Tumour assessments were conducted at baseline and after completion of<br />
induction <strong>the</strong>rapy using immune-related response criteria. Patients were monitored<br />
for adverse events (AEs), including immune-related AEs, within 3 to 4 days of each<br />
scheduled visit using Common Terminology Criteria for Adverse Events v.3.0.<br />
Results: Of 848 Italian patients participating in <strong>the</strong> EAP, 83 (9.8%) had ocular<br />
melanoma. Of <strong>the</strong>se 83 patients, 55 have data available. With a median follow-up of<br />
3 months, <strong>the</strong> disease control rate among 46 evaluable patients was 34.8%, including<br />
3 patients with a partial response and 13 with stable disease. As of April <strong>2012</strong>,<br />
median progression-free survival and overall survival among patients with ocular<br />
melanoma were 2.9 months and 5.9 months, respectively. In total, 63.6% patients<br />
reported an AE of any grade, most of which were drug-related (47.3%). Grade 3/4<br />
AEs, which were reported by 20.0% patients, were only considered drug-related in<br />
5.4%. AEs were generally manageable and most resolved with treatment as per<br />
protocol-specific guidelines.<br />
Conclusions: Safety and early efficacy results are similar to experience in o<strong>the</strong>r<br />
melanoma populations, thus suggesting that treatment of ocular melanoma with<br />
ipilimumab warrants fur<strong>the</strong>r investigation in prospective clinical trials.<br />
Disclosure: M. Maio: Michele Maio has acted as an advisor for Bristol-Myers Squibb<br />
and Roche. V. Chairion Sileni: Vanna Chiaron Sileni has acted as an advisor for<br />
Bristol-Myers Squibb, Roche, GlaxoSmithKline, Merck Sharp & Dohme and<br />
Schering-Plough. P. Queirolo: Paola Queirolo has acted as an advisor for Roche,<br />
GlaxoSmithKline, Bristol-Myers Squibb and Schering-Plough and received honoraria<br />
from Bristol-Myers Squibb and Roche. P.A. Ascierto: PA has served as a consultant/<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds404 | ix369
advisor for Merck Sharp & Dohme, and as an advisor to Bristol-Myers Squibb<br />
(BMS), Roche, GlaxoSmithKline, Amgen, Celgene, Medimmune and Novartis. He<br />
has received honoraria from BMS, Merck Sharp & Dohme and Roche. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
1134P LONG-TERM SURVIVAL OF PATIENTS WITH ADVANCED<br />
MELANOMA TREATED SECOND LINE WITH IPILIMUMAB<br />
D. Lee 1 , L. Pericleous 2 , M. Lebmeier 2 , B. Winn 1 , A. Batty 1 , T. Nikoglou 2<br />
1 Health Economics, BresMed, Sheffield, UNITED KINGDOM, 2 Health Economics<br />
and Outcomes, Bristol Myers Squibb, Uxbridge, UNITED KINGDOM<br />
Objective: To estimate <strong>the</strong> long-term survival of patients with advanced melanoma<br />
treated second-line with ipilimumab 3 mg/kg compared to no active treatment (best<br />
supportive care [BSC]).<br />
Methods: At <strong>the</strong> end of <strong>the</strong> Phase III trial (MDX010-20) 17% of patients receiving<br />
ipilimumab were alive compared to 4% of those receiving GP100: median follow up<br />
28 months, maximum 55 months. Trial data were used to model survival beyond <strong>the</strong><br />
trial period. GP100 has been shown to have no impact on survival (within<br />
MDX010-20 and a mixed treatment comparison). GP100 arm data were used to<br />
model survival of patients receiving BSC. Two groups were seen: Patients who<br />
experience <strong>the</strong>rapy benefit and enter a stable period leading to a gradual plateau of<br />
<strong>the</strong> KM curve; Patients whose immune systems do not respond quickly and die<br />
causing an initial steep drop in <strong>the</strong> KM curve Standard modelling techniques did not<br />
fit <strong>the</strong> available data well and underestimated <strong>the</strong> durable response of<br />
immuno<strong>the</strong>rapy. Around 18 months <strong>the</strong> mortality hazard was shown to change in<br />
<strong>the</strong> ipilimumab arm meaning that different methods were required to predict survival<br />
before and after this time. We estimated long-term survival as follows: · ≤18 Months<br />
Kaplan-Meier data was used, mimicking survival within <strong>the</strong> trial · >18 Months - 5<br />
years (representing <strong>the</strong> maximum data available from MDX-010-20) a standard<br />
parametric curve was fitted to <strong>the</strong> data · >5 years 15 year registry data from Balch<br />
et al (2001) for Stage IV melanoma and background mortality were used to estimate<br />
long-term survival.<br />
Results: Using <strong>the</strong> three-part approach reduced <strong>the</strong> mean absolute error (MAE)<br />
associated with <strong>the</strong> curve fits. Those selected having an MAE of 0.003 (0.004 for<br />
long-term survivors) on <strong>the</strong> ipilimumab arm, and 0.008 (0.012 for long-term<br />
survivors) on <strong>the</strong> BSC arm. This compares to a MAE at least 7 x higher (0.06) for<br />
standard parametric curves. For BSC patients, <strong>the</strong> model predicts mean survival of<br />
1.2 years whereas those taking ipilimumab are expected to survive for a mean of 3.7<br />
years. This is due to more patients remaining alive beyond 5-years, after which death<br />
from melanoma is less likely.<br />
Conclusion: Treatment with ipilimumab provides a substantial increase in survival<br />
over BSC in <strong>the</strong> second-line treatment of advanced melanoma.<br />
Disclosure: D. Lee: Funding for <strong>the</strong> analysis conducted was provided to BresMed by<br />
BMS. I have not received any personal funding and do not have any personal interest<br />
in BMS or any competitor products. L. Pericleous: I have worked for BMS. O<strong>the</strong>r<br />
than this I have not received any personal funding and do not have any personal<br />
interest in BMS or any competitor products. M. Lebmeier: I work for BMS. O<strong>the</strong>r<br />
than this I have not received any personal funding and do not have any personal<br />
interest in BMS or any competitor products. B. Winn: Funding for <strong>the</strong> analysis<br />
conducted was provided to BresMed by BMS. I have not received any personal<br />
funding and do not have any personal interest in BMS or any competitor products.<br />
A. Batty: Funding for <strong>the</strong> analysis conducted was provided to BresMed by BMS. I<br />
have not received any personal funding and do not have any personal interest in<br />
BMS or any competitor products. T. Nikoglou: I work for BMS. O<strong>the</strong>r than this I<br />
have not received any personal funding and do not have any personal interest in<br />
BMS or any competitor products.<br />
1135P SEQUENTIAL COMBINATION OF LOW DOSE<br />
CHEMO-MODULATING TEMOZOLOMIDE WITH<br />
FOTEMUSTINE IN METASTATIC MELANOMA (MM). A PHASE<br />
II STUDY<br />
M. Guida 1 , A. Cramarossa 2 , P. Petrillo 1 , A. Albano 1 , S. Pisconti 3 , M. Aieta 4 ,<br />
M. Traversa 2 , R. Ridolfi 5 , G. Colucci 1<br />
1 Medical Oncology, National Cancer Research Centre, Bari, ITALY, 2 Radiology,<br />
National Cancer Research Centre, Bari, ITALY, 3 Medical Oncology, Ospedale<br />
Civile, Taranto, ITALY, 4 Medical Oncology, Department of Medical Oncology,<br />
National Institute of Cancer, Rionero in Vulture, ITALY, 5 Medical Oncology,<br />
Immuno<strong>the</strong>rapy Unit, National Cancer Institute of Romagna (IRST), Meldola,<br />
ITALY<br />
Background and purpose: MM is a chemoresistant cancer with poor prognosis.<br />
Fur<strong>the</strong>r progress is likely to come from novel targeted antiBRAF <strong>the</strong>rapy, available<br />
for about 50% of pts, and from immuno<strong>the</strong>rapeutic agents such as <strong>the</strong> mAb<br />
Annals of Oncology<br />
ipilimumab, at present available only in some countries. Preclinical and clinical<br />
experiences support <strong>the</strong> concept that continuous exposure to an alkilating agent can<br />
effectively deplete cells of <strong>the</strong> DNA repair enzyme O6-methylguanine DNA<br />
methyltransferare, <strong>the</strong> primary mechanism of tumor resistance to chemo<strong>the</strong>rapeutic<br />
agents like nitrosurea analogs. Our study was finalized to verify this hypo<strong>the</strong>sis using<br />
a sequential combination of low dose chemo-modulating TMZ and FM. Primary<br />
endpoints were safety and tumor response evaluation.<br />
Methods: 53 consecutive MM pts were enrolled in <strong>the</strong> study. The majority of <strong>the</strong>m<br />
(80%) were enrolled before <strong>the</strong> targeted <strong>the</strong>rapy. The main characteristics included:<br />
median age 56 years (21-79); ECOG PS 1 (0–2); number of disease sites: 1 in 30%, 2<br />
in 27%, >2 in 43%; M status: M1a 9%, M1b 21%, M1c 70% with 5 pts having brain<br />
metastases. The following schedule was used: oral TMZ 100 mg/m2 d 1 and 2; FM iv<br />
100 mg/m2 d 2, 4 h after TMZ. The regimen was repeated every 3 weeks for a<br />
maximum total of 9 cycles. Tumour assessments were conducted at baseline and<br />
<strong>the</strong>n every 3 cycles.<br />
Results: 52 pts are evaluable for toxicity and 51 for clinical assessment (1 withdrew<br />
consent prior to starting treatment; 2 early). The median number of treatment cycles<br />
administered was 7 (range 2-9). There were 13 (25%) responses (1 CR and 9 PRs)<br />
with a median duration of 7 months, and 12 (23%) stable disease. Median<br />
progression-free survival was 6 months and median overall survival 11+ months<br />
(range 2-35+ months). Drug-related toxicities ≥ grade 3 included thrombocytopenia<br />
(10%), neutropenia (6%), anemia (2%), and hepatopathy (2%). Approximately 75%<br />
of pts were treated without dose reduction. Two patients (4%) discontinued <strong>the</strong>rapy<br />
because of toxicities.<br />
Conclusions: sequential low dose TMZ and FM demonstrated a high activity in our<br />
patient population with an acceptable toxicity. This schedule could <strong>the</strong>refore<br />
represent a good alternative for patients not eligible for targeted <strong>the</strong>rapy or in whom<br />
previous targeted <strong>the</strong>rapies failed. The study of <strong>the</strong> correlation between MGMT level<br />
and clinical outcomes is ongoing.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1136P 18F-FDG-PET/CT IMAGING AS SURVIVAL PREDICTOR<br />
IN PATIENTS WITH METASTATIC UVEAL MELANOMA<br />
A. Rodriguez-Vida 1 , E. Muñoz 2 , M. Ochoa de Olza 1 , S. Rossi 3 , C. Gamez 3 ,<br />
J.M. Caminal 4 , J. Perez 1 , J. Cortes 2 , J.M. Piulats 1<br />
1 Medical Oncology, Institut Catala d’Oncologia L’Hospitalet, L’Hospitalet de<br />
Llobregat, SPAIN, 2 Medical Oncology, Hospital Valle de Hebron, Barcelona,<br />
SPAIN, 3 Nuclear Medicine, Hospital Universitario de Bellvitge, L’Hospitalet de<br />
Llobregat, SPAIN, 4 Ophthalmology, Hospital Universitario de Bellvitge,<br />
L’Hospitalet de Llobregat, SPAIN<br />
Aims: To correlate metabolic activity by 18 F-FDG-PET/CT with survival in uveal<br />
melanoma patients with liver metastases (LM).<br />
Methods: We undertook a retrospective study of 34 patients with uveal melanoma<br />
and LM who underwent a 18 F-FDG-PET/CT at <strong>the</strong> time of metastatic diagnosis.<br />
Metabolic activity of LM was measured by standardized uptake value (SUV) and by<br />
grouping in 18 F-FDG-PET-negative (lower or same metabolic activity in LM than in<br />
normal liver parenchyma (NLP) comparing to 18 F-FDG-PET-positive (higher<br />
metabolic activity in LM than in NLP). These measures were correlated with overall<br />
survival (OS).<br />
Results: Patients were treated in 2 institutions between 2004-2010. There were 19<br />
women and 15 men. Median age was 62 years (30-84). Median follow-up was 16.7<br />
months. Treatment of primary tumor was: 15 enucleation (44.1%), 3 resection (8.8%)<br />
and 16 brachy<strong>the</strong>rapy (47.1%). LM were diagnosed on screening protocol and<br />
histologically confirmed if possible (85.3%). Median major diameter of LM was 20<br />
mm (9-130). Median maximum SUV of LM was 8.7 (2-25). 18 F-FDG-PET/CT was<br />
negative for metabolic activity in 6 patients and positive in 28 patients. All 6 patients<br />
with negative 18 F-FDG-PET/CT were histologically confirmed. Metastatic disease<br />
treatments were: chemo<strong>the</strong>rapy (27 patients), liver surgery (9 patients), liver<br />
stereotactic radio<strong>the</strong>rapy (2 patients), liver radiofrequency ablation (1 patient).<br />
Median OS was 18.8 months (CI 95% 7.2-30.4). Median OS was significantly higher<br />
(p = 0.001) in patients with 18 F-FDG-PET-negative (median not reached) than in<br />
patients with 18 F-FDG-PET-positive (15.1 months, CI 95% 11.5-18.7). Assessed as a<br />
continuous variable, maximum SUV in <strong>the</strong> liver was correlated with OS (p = 0.002,<br />
HR 1.1, CI 95% 1.03-1.2). Maximum SUV greater than 5 was related with poor<br />
prognosis (p = 0.025). Major diameter of LM in 18 F-FDG-PET/CT was significantly<br />
correlated with OS (p < 0.001). LM greater than 20 mm were related with poor<br />
prognosis (p < 0.001). By multivariate analysis, major diameter of LM (p < 0.001)<br />
and 18 F-FDG-PET/CT status (p = 0.001) remained significant survival predictors.<br />
Conclusion: Metabolically 18 F-FDG-PET-negative liver metastases correlated with<br />
better OS in patients with metastatic uveal melanoma.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix370 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
1137P IMMUNO-CHEMOABLATION OF METASTATIC MELANOMA<br />
WITH INTRALESIONAL ROSE BENGAL<br />
S.S. Agarwala 1 , J.F. Thompson 2 , B.M. Smi<strong>the</strong>rs 3 , M. Ross 4 , B.J. Coventry 5 ,<br />
D.R. Minor 6 , C.R. Scoggins 7 , E. Wachter 8<br />
1 Cancer Center, St. Luke’s Hospital & Health Network, Bethlehem, UNITED<br />
STATES OF AMERICA, 2 Surgery, Melanoma Institute, Sydney, AUSTRALIA,<br />
3 Surgery, Princess Alexandra Hospital, Woolloongabba, AUSTRALIA, 4 Surgery,<br />
MD Anderson, Houston, UNITED STATES OF AMERICA, 5 Surgery, Royal<br />
Adelaide Hospital, Adelaide, AUSTRALIA, 6 Medical Oncology, California Pacific<br />
Medical Center, San Francisco, UNITED STATES OF AMERICA, 7 Surgery,<br />
University of Louisville, Louisville, UNITED STATES OF AMERICA, 8 Drug<br />
Development, Provectus Pharmaceuticals, Knoxville, UNITED STATES OF<br />
AMERICA<br />
Intralesional rose bengal (PV-10) is being investigated for treatment of solid tumors,<br />
where it may elicit selective chemoablation of injected lesions and a tumor-specific,<br />
immune-mediated bystander response in untreated bystander lesions. In phase 1<br />
testing in 20 subjects with AJCC Stage III-IV melanoma, single-dose treatment with<br />
PV-10 was well tolerated, producing a durable objective response (OR) at 12-24<br />
weeks in 40% of subjects (20% CR + 20% PR by modified RECIST) and locoregional<br />
disease control (CR + PR + SD) in 75% of subjects; 15% of subjects achieved an OR<br />
in bystander lesions, which strongly correlated with response of <strong>the</strong>ir injected lesions.<br />
Phase 2 testing in 80 subjects with Stage III-IV metastatic melanoma (median age<br />
70.0 yrs, range 33-97) commenced at 7 centers in Australia and <strong>the</strong> USA in October<br />
2007 with final clinical evaluation completed in May 2010 (Clinical Trials ID<br />
NCT00521053). In this study, subjects could receive up to four courses of PV-10 to<br />
up to 20 cutaneous or subcutaneous lesions (median 2 courses, range 1-4).<br />
Preliminary study data was presented at SMR 2010 in Sydney, Australia, and showed<br />
that treatments were well tolerated, with adverse events predominantly mild to<br />
moderate, locoregional and transient, with no grade 4 or 5 AEs attributed to PV-10.<br />
Preliminary evaluation also showed robust response, with 24% of subjects achieving a<br />
CR, 25% PR and 22% SD of <strong>the</strong>ir target lesions. Additionally, 24% of 38 subjects<br />
with evaluable, untreated bystander lesions achieved CR in <strong>the</strong>ir bystander lesions,<br />
along with 13% PR and 18% SD. As observed in phase 1, response of bystander<br />
lesions strongly correlated with response of injected lesions. Final efficacy data will be<br />
presented, including response rate and time-to-event (progression free survival and<br />
overall survival). These data demonstrate that <strong>the</strong> safety and efficacy profile of PV-10<br />
compares favorably with available and emerging treatment options for this patient<br />
population, and serve as <strong>the</strong> basis for phase 3 testing of PV-10 in Stage III patients<br />
with recurrent, in-transit or satellite metastases. A randomized controlled trial to<br />
assess PFS against standard care is expected to commence in <strong>the</strong> second half of <strong>2012</strong><br />
at centers in Australia, <strong>the</strong> USA and <strong>the</strong> EU.<br />
Disclosure: S.S. Agarwala: Provectus Pharmaceuticals: advisory board,<br />
corporate-sponsored research. J.F. Thompson: Provectus Pharmaceuticals:<br />
advisory board, corporate-sponsored research. B.M. Smi<strong>the</strong>rs: Provectus<br />
Pharmaceuticals: corporate-sponsored research. M. Ross: Provectus<br />
Pharmaceuticals: advisory board, corporate-sponsored research. B.J. Coventry:<br />
Provectus Pharmaceuticals: corporate-sponsored research. D.R. Minor: Provectus<br />
Pharmaceuticals: corporate-sponsored research. C.R. Scoggins: Provectus<br />
Pharmaceuticals: advisory board, corporate-sponsored research. E. Wachter:<br />
Employee of sponsoring company, stock holder<br />
1138P CHEMOTHERPAY AND DENDRITIC CELL VACCINE IN<br />
PATIENT WITH METASTATIC MELANOMA: PHASE II<br />
PROSPECTIVE RANDOMIZED TRIAL<br />
I.V. Samoylenko 1 , T.N. Zabotina 2 , I.N. Mikhaylova 1 , G.Z. Chkadua 3 ,O.<br />
V. Korotkova 2 , K. Baryshnikov 1 , L.V. Demidov 1<br />
1 Tumor Bio<strong>the</strong>rapy, N.N Blokhin Russian Cancer Research Center, Moscow,<br />
RUSSIAN FEDERATION, 2 Laboratory of Clinical Immunology, N.N Blokhin<br />
Russian Cancer Research Center, Moscow, RUSSIAN FEDERATION,<br />
3 Laboratory of Experimental Diagnostics and Tumor Bio<strong>the</strong>rapy, N.N Blokhin<br />
Russian Cancer Research Center, Moscow, RUSSIAN FEDERATION<br />
Introduction: We performed a vaccine trial in metastatic melanoma patients with a<br />
stable disease course.<br />
Aim: Primary end point was 6-month progression-free survival; secondary end<br />
points included overall survival, progression free survival, immunological parameters.<br />
Patients and methods: Inclusion criteria were morphologically proven metastatic<br />
melanoma, ECOG status 0-2, LDH level
or cutaneous melanoma. A survival update was performed on 31 March 2011.<br />
CS-PHP melphalan 3.0 mg/kg ideal body weight was infused into <strong>the</strong> hepatic artery<br />
over 30 min with concurrent extracorporeal filtration for 60 min. Up to 6 treatments<br />
were given every 4–8 wks. In <strong>the</strong> BAC group, crossover to CS-PHP melphalan was<br />
permitted after hepatic disease progression. The primary endpoint was<br />
investigator-assessed hepatic progression-free survival (hPFS). An exploratory<br />
post-hoc analysis of pts who crossed from BAC to CS-PHP vs. BAC-only pts was<br />
also performed.<br />
Results: 93 pts were randomized to CS-PHP (n = 44) or BAC (n = 49). After hepatic<br />
disease progression, 28 pts crossed over to CS-PHP. Results are shown in <strong>the</strong> Table.<br />
The most common grade 3/4 toxicities in CS-PHP pts (n = 40) were hematological<br />
peri-procedural thrombocytopenia (73%) and anemia (55%) and post-procedural<br />
(beyond day 4 post-treatment) neutropenia (93%) or thrombocytopenia (83%). The<br />
safety profile in crossover pts was similar to that in pts randomized to CS-PHP<br />
melphalan.<br />
Conclusions: CS-PHP melphalan significantly prolonged hPFS compared with BAC<br />
in pts with liver-dominant metastatic melanoma, <strong>the</strong>reby meeting <strong>the</strong> primary study<br />
objective. Efficacy was similar after hepatic disease progression in BAC-CS-PHP<br />
crossover pts as in those randomized initially to CS-PHP.<br />
Median<br />
hPFS, Hazard ratio Median Hazard ratio<br />
Treatment group n mo (95% CI) OS, mo (95% CI)<br />
CS-PHP 44 8.0 0.35 (0.23-0.54) 9.8 1.08 (0.69-1.68)<br />
BAC 49 1.6 P < 0.0001 9.9 NS<br />
BAC only 21 1.6 0.32 4.1 0.33<br />
BAC →<br />
CS-PHP crossover<br />
28 8.8 15.3<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1142P THE CONCORDANCE OF HER2 STATUS IN PRIMARY<br />
AND METASTATIC SITES OF EXTRAMAMMARY PAGET’S<br />
DISEASE<br />
R. Tanaka 1 , Y. Sasajima 2 , H. Tsuda 2 , K. Namikawa 1 , A. Tsutsumida 1 ,<br />
N. Yamazaki 1<br />
1 Division of Dermatologic Oncology, National Cancer Center Hospital, Tokyo,<br />
JAPAN, 2 Pathology and Clinical Laboratory Division, National Cancer Center<br />
Hospital, Tokyo, JAPAN<br />
Background: HER2-targeted <strong>the</strong>rapies have been introduced to treat breast and<br />
stomach cancers that show HER2 protein overexpression and/or HER2 gene<br />
amplification. However, <strong>the</strong> HER2 status of primary tumors and <strong>the</strong>ir corresponding<br />
metastatic sites is shown to be heterogeneous in less than 20% of cases. In<br />
extramammary Paget’s disease (EMPD), HER2 protein overexpression and gene<br />
amplification has been shown to occur in 5-80% of cases; however, knowledge<br />
regarding <strong>the</strong> concordance of HER2 status in primary and metastatic sites of EMPD<br />
is limited. The aim of this study was to clarify <strong>the</strong> concordance rate of HER2 status<br />
in <strong>the</strong> primary tumors and metastatic sites of EMPD.<br />
Methods: Twenty-six tissue blocks of primary tumors and corresponding lymph<br />
node metastases were subjected to an immunohistochemistry (IHC) analysis. The<br />
IHC scores were classified into four groups (0 to 3+) according to <strong>the</strong> American<br />
Society of Clinical Oncology/College of American Pathologists Guidelines (2007).<br />
When <strong>the</strong> primary tumors and lymph node metastases showed IHC scores of ei<strong>the</strong>r<br />
2+ or 3 + , <strong>the</strong> presence of HER2 gene amplification was examined using<br />
fluorescence in situ hybridization (FISH) and dual-colored in situ hybridization<br />
(DISH).<br />
Results: mmunohistochemically, 27% (7/26) of <strong>the</strong> primary tumors and 38% (10/26)<br />
of <strong>the</strong> lymph node metastases showed IHC scores of ei<strong>the</strong>r 2+ or 3+. When HER2<br />
protein overexpression was classified as being ei<strong>the</strong>r positive (2 + , 3+) or negative (0,<br />
1+), <strong>the</strong> concordance rate of <strong>the</strong> HER2 status of <strong>the</strong> primary tumors and<br />
corresponding lymph node metastases was 85% (22/26). The presence of HER2 gene<br />
amplification was examined in six primary tumors and 10 metastatic sites. HER2<br />
gene was amplified in a total of seven cases (27%): four cases in both <strong>the</strong> primary<br />
and metastatic sites, two cases in <strong>the</strong> metastatic sites only and one case in <strong>the</strong><br />
primary site only.<br />
Conclusion: Good concordance of HER2 protein overexpression and gene<br />
amplification status was seen in <strong>the</strong> primary tumors and corresponding lymph node<br />
metastases of patients with EMPD. Fur<strong>the</strong>rmore, <strong>the</strong> HER2 gene was found to be<br />
always amplified in cases with an IHC score of 3+ and in two cases with an IHC<br />
score of 2+ in <strong>the</strong> lymph node metastases, which is suitable to be targeted for<br />
<strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
1143P A COMPARISON OF GENERAL POPULATION AND PATIENT<br />
UTILITY VALUES FOR ADVANCED MELANOMA<br />
A. Batty 1 , B. Winn 1 , L. Pericleous 2 ,D.Rowen 3 , D. Lee 1 , T. Nikoglou 2<br />
1 Health Economics, BresMed, Sheffield, UNITED KINGDOM, 2 Health Economics<br />
and Outcomes, Bristol Myers Squibb, Uxbridge, UNITED KINGDOM, 3 School of<br />
Health and Related Research, University of Sheffield, Sheffield, UNITED<br />
KINGDOM<br />
Background: Health-related quality of life (HRQL) is a fundamental part of health<br />
technology assessment. Utility values are vital because <strong>the</strong>y can be used as preference<br />
weights and allow <strong>the</strong> calculation of HRQL benefits. The objective of this study was<br />
to compare utilities calculated for patients with advanced melanoma in <strong>the</strong> Phase III<br />
clinical trial for ipilimumab (MDX010-20) using a generic and a condition-specific<br />
preference-based measure to utilities produced by vignettes for advanced melanoma.<br />
A secondary objective was to determine how different analyses might be used most<br />
appropriately within cost-effectiveness modelling.<br />
Methods: The trial utilities were generated using <strong>the</strong> condition-specific EORTC-8D<br />
(1,190 observations) and generic SF-6D (1,157 observations) preference-based<br />
measures. Progression-status and time-to-death analyses were conducted on <strong>the</strong><br />
patient-level data and <strong>the</strong> predictive abilities were compared. Patient-level results<br />
were compared to <strong>the</strong> utilities derived for progression status using vignettes valued<br />
by <strong>the</strong> general population.<br />
Results: On disease progression, vignette-generated utilities showed a greater<br />
decrease (0.77 to 0.59) than ei<strong>the</strong>r <strong>the</strong> generic SF-6D (0.64 to 0.619) or<br />
condition-specific EORTC-8D (0.801 to 0.763). SF-6D and EORTC-8D showed a<br />
large decrease in utility in <strong>the</strong> 180 days prior to death (from 0.826 to 0.628 and from<br />
0.655 to 0.505, respectively). Compared to progression status, time to death showed a<br />
lower Root Mean Squared Error and higher R2 when used to predict patient utility.<br />
Conclusion: Practitioners should carefully analyse patient level utility data prior to<br />
constructing economic models as standard measures, such as progression status,<br />
may not fully capture <strong>the</strong> patient experience. Similarly, where vignettes are valued<br />
to represent health states in an economic model, <strong>the</strong>ir applicability to <strong>the</strong> disease<br />
and patient population should be carefully scrutinised. The use of standard<br />
progression based cost-effectiveness modelling techniques may not be appropriate<br />
for this disease. Consequently, <strong>the</strong>re are implications for <strong>the</strong> analysis of utility<br />
information in future studies and <strong>the</strong> methods of cost-effectiveness modelling used<br />
for cancer treatments.<br />
Disclosure: A. Batty: BresMed were funded by BMS to conduct <strong>the</strong> analysis<br />
presented within this paper. O<strong>the</strong>r than this I have not received any personal<br />
funding and do not have any personal interest in BMS or any competitor products.<br />
B. Winn: BresMed were funded by BMS to conduct <strong>the</strong> analysis presented within<br />
this paper. O<strong>the</strong>r than this I have not received any personal funding and do not<br />
have any personal interest in BMS or any competitor products. L. Pericleous: I have<br />
worked for BMS. O<strong>the</strong>r than this I have not received any personal funding and do<br />
not have any personal interest in BMS or any competitor products. D. Lee:<br />
BresMed were funded by BMS to conduct <strong>the</strong> analysis presented within this paper.<br />
O<strong>the</strong>r than this I have not received any personal funding and do not have any<br />
personal interest in BMS or any competitor products. T. Nikoglou: I work for BMS.<br />
O<strong>the</strong>r than this I have not received any personal funding and do not have any<br />
personal interest in BMS or any competitor products. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
1144 CETUXIMAB IN METASTATIC SQUAMOUS CELL CANCER<br />
OF THE SKIN: A CASE SERIES<br />
K. Conen 1 , N. Fischer 2 , G.F. Hofbauer 3 , B. Shafaeddin-Schreve 3 ,<br />
R. Win<strong>the</strong>rhalder 4 , C. Rochlitz 5 , A. Zippelius 1<br />
1 Medical Oncology, University Hospital Basel, Basel, SWITZERLAND, 2 Medical<br />
Oncology, Kantonsspital Winterthur, Winterthur, SWITZERLAND,<br />
3 Dermatologische Klinik, Universitätsspital Zürich, Zürich, SWITZERLAND,<br />
4 Medical Oncology, Kantonsspital Luzern, Luzern, SWITZERLAND, 5 Medical<br />
Onkology, University Hospital Basel, Basel, SWITZERLAND<br />
Background: Treatment of metastatic squamous cell cancer of <strong>the</strong> skin (SCCS) is<br />
challenging. Only few <strong>the</strong>rapeutic options including cisplatin-based combinations are<br />
currently available. In a recently published phase II trial, cetuximab, a monoclonal<br />
antibody against <strong>the</strong> epidermal growth factor receptor (EGRF), has demonstrated a<br />
promising clinical activity with an overall 69% disease control rate (DCR) and 28%<br />
response rate (RR) in patients with unresectable SCCS. Whe<strong>the</strong>r this treatment is<br />
also effective in metastatic SCCS is unclear.<br />
Purpose: To summarize <strong>the</strong> efficacy of cetuximab at any line in a series of patients<br />
with metastatic SCCS.<br />
Patients and methods: We performed a retrospective analysis of six patients from<br />
four centres in Switzerland. We collected standard baseline data by reviewing <strong>the</strong><br />
ix372 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
patients’ records. Endpoints were DCR at 4-8 weeks, 12-14 weeks and 20-36 weeks of<br />
treatment. In addition, we evaluated <strong>the</strong> treatment-related toxicity.<br />
Results: The median age of <strong>the</strong> patients was 67 years. A total of 10 cycles in median<br />
were applied (range 1-21). The DCR was 67% (4 of 6 patients) at 4-8 weeks, 50% (3<br />
of 6 patients) at 12-14 weeks, and 33% (2 of 6 patients) at 20-26 weeks (Table 1).<br />
One patient showed a complete response (CR) after 4 weeks of treatment and is still<br />
in remission since <strong>the</strong>n. Death due to sepsis occurred in one patient. 83% (5 of 6<br />
patients) developed Grade I-III acne-like rash around week 3 of treatment. All<br />
patients who had <strong>the</strong>ir disease controlled at 4-8 weeks showed an acne-like rash<br />
(4 of 6 patients), 1 patient had a rash without disease control.<br />
Conclusions: Cetuximab treatment in patients with metastatic SCCS achieved an<br />
overall DCR of 57% at 4-8 weeks of treatment. 1 of 6 patients had a CR. These data<br />
suggest that cetuximab may be effective in this setting.<br />
Response and disease control rates.<br />
Response at 4-8 weeks 12-14 weeks 20-36 weeks<br />
Variable No % No % No %<br />
Complete response 1 17 1 17 1 17<br />
Partial response 3 50 1 17 1 17<br />
Stable disease 0 0 1 17 0 0<br />
Progressive disease 2 33 1 17 1 17<br />
Disease control rate 67 50 33<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1145 SENSITIVE DETECTION OF BRAF MUTATIONS USING<br />
MUTANT-ENRICHED PCR AND REVERSE-HYBRIDIZATION<br />
TESTSTRIPS<br />
M. Novy, G. Kriegshäuser, B. Rauscher, C. Oberkanins<br />
Research - Development, ViennaLab Diagnostics GmbH, Vienna, AUSTRIA<br />
Background: BRAF plays a key role in growth factor receptor induced signalling<br />
pathways. Somatic BRAF mutations are involved in oncogenesis and are found in<br />
various types of tumors, including colorectal, thyroid and skin cancer. Activating<br />
BRAF mutations confer resistance to anti-EGFR monoclonal antibody <strong>the</strong>rapy.<br />
Moreover mutated BRAF is a prominent target of <strong>the</strong> drug vemurafenib.<br />
Materials and methods: We have developed a reverse-hybridization StripAssay<br />
detecting nine BRAF mutations: c.1799T > C (V600A), c.1799_1800TG > AT<br />
(V600D), c.1799T > A (V600E), c.1799_1800TG > AA (V600E), c.1799T > G<br />
(V600G), c.1798_1799GT > AA (V600K), c.1798G > A (V600M), c.1798_1799GT ><br />
AG (V600R) and c.1801A > G (K601E). The test is based on mutant-enrichted PCR<br />
in <strong>the</strong> presence of a BRAF wild-type suppressor, followed by hybridization of PCR<br />
products to teststrips presenting a parallel array of allele-specific oligonucleotide<br />
probes. Bound sequences are visualized using streptavidin-alkaline phosphatase<br />
conjungate and colour substrates. The hybridization and detection steps can be<br />
carried out fully automated using commercially available instrumentation.<br />
Results: Plasmid clones served as reference DNA templates to control for specificity.<br />
StripAssay performance was evaluated on genomic DNA obtained from cultured cell<br />
lines and formalin-fixed paraffine-embedded (FFPE) tissue. Using normal DNA<br />
spiked with serial dilutions of DNA from <strong>the</strong> BRAF-mutant tumor cell lines HT29 or<br />
IGR-1, <strong>the</strong> mutations c.1799T > A (V600E) and c.1798_1799GT > AA (V600K) were<br />
shown to be detectable at a level of 1%.<br />
Conclusions: The simultaneous detection of nine different mutations with high<br />
sensitivity will make <strong>the</strong> StripAssay a very useful tool for <strong>the</strong> assessment of <strong>the</strong> BRAF<br />
mutation status of cancer patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1146 INTER- AND INTRA- TUMOR HETEROGENEITY OF SOMATIC<br />
BRAF MUTATIONS IN MELANOMA<br />
S. Murray 1 , H. Linardou 2 , F. Siannis 3 , D. Bafaloukos 2<br />
1 Oncology, GeneKor SA, A<strong>the</strong>ns, GREECE, 2 1st Department of Medical<br />
Oncology, Metropolitan Hospital, A<strong>the</strong>ns, GREECE, 3 Department of<br />
Ma<strong>the</strong>matics, University of A<strong>the</strong>ns, A<strong>the</strong>ns, GREECE<br />
Background: Somatic mutations of BRAF are correlated with improved outcomes in<br />
patients with Melanoma treated with <strong>the</strong> anti-BRAF tyrosine kinase inhibitor<br />
Vemurafenib (PLX4032). Heterogeneity of patient responses to Vemurafenib in<br />
patients harboring BRAF mutations has questioned <strong>the</strong> stability of concordance<br />
between and within tumors. We conducted a systematic search of <strong>the</strong> literature to<br />
assess such status.<br />
Methods: Using a broad search string including “BRAF”, “RAS”, “Melanoma”,<br />
“Cancer” and associated synonyms from inception through to 23/12/2011 in<br />
MEDLINE (PubMed) we identified articles providing information on Melanoma<br />
patients pertaining to concordance between synchronous (intra-) tumors; between<br />
primary and metastasis; and within (inter-) tumor heterogeneity. Data extraction was<br />
conducted by two investigators. Predictive values of testing for <strong>the</strong> presence of BRAF<br />
(True positive) and ‘no detectable mutation’ (True negative) were assessed and 95%<br />
confidence intervals calculated. Positive and Negative Predictive Values are presented<br />
(PPV, NPV).<br />
Results: Sixteen articles presented for synchronous, 13 for meta-synchronous, and 7<br />
for retesting (intra-tumoral analysis). Data indicates that <strong>the</strong>re is a significant level<br />
of dis-concordance: a) between synchronous tumors (PPV = 0.70 [0.59-0.79],<br />
NPV = 0.46 [0.35-0.56]); b) between meta-synchronous tumors (primary versus<br />
metastasis (PPV = 0.68 [0.54-0.80], NPV = 0.45 [0.32-0.58]); and within (intra-)<br />
tumors (PPV = 0.56 [0.49-0.69], NPV = 0.40 [0.29-0.52]).<br />
Conclusions: Repetitive data sets indicated heterogeneity of BRAF genotype status<br />
between synchronous, meta-synchronous tumors, and also at <strong>the</strong> intra-tumoral<br />
level. PPV and NPV were worryingly high and outside of acceptable limits.<br />
Approximately 30% of patients may have dis-concordance in <strong>the</strong>ir BRAF reporting<br />
status. No obvious technical errors were identified to explain <strong>the</strong>se differences.<br />
Several studies are now indicating that tumor heterogeneity may affect several<br />
cancer types, and this may impact on biomarker driven stratification. More data is<br />
eagerly awaited<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1147 BRAF MUTATIONS ARE FREQUENT IN MALIGNANT<br />
MELANOMA IN ISRAELI POPULATION AND PREDICTS POOR<br />
RESPONSE TO BIOCHEMOTHERAPY<br />
I. Lazarev, A. Yakobson, S. Ariad<br />
Department of Oncology, Soroka Medical Center, Beer-Sheva, ISRAEL<br />
Introduction: Malignant melanoma is a highly-aggressive form of skin cancer.<br />
Lesions developing in non-chronically sun-damaged skin are associated with frequent<br />
activating mutations in BRAF with substitution of valine for glutamic acid at position<br />
600 (BRAF V600E ). The prognostic significance of BRAF mutation in patients with<br />
metastatic melanoma (MM) treated with chemobio<strong>the</strong>rapy is uncertain.<br />
Patients and methods: We studied <strong>the</strong> prognostic significance of BRAF mutation in<br />
69 patients with MM treated with chemobio<strong>the</strong>rapy at <strong>the</strong> Soroka Medical Center,<br />
Beer Chemobio<strong>the</strong>rapy consisted of BCNU, DTIC, cisplatin, IL-2, alpha-interferon,<br />
GM-CSF, cimetidine, and tamoxifen. Samples were micro-dissected at <strong>the</strong> molecular<br />
lab, Hacarmel hospital, and subjected to high-resolution melting analysis using<br />
primers flanking codon 600 in <strong>the</strong> BRAF gene. All abnormal high-resolution melting<br />
traces were subjected to bidirectional DNA sequencing.<br />
Results: Mean age-55 years (range 25-80); Gender-male/female–41/28; Ulceration–<br />
30/54; Site of primary lesion: limbs/head/neck/trunk/retina/mucous membranes–12/<br />
13/0/14/2/3; Depth: T1/T2/T3/T4/undetermined-3/8/24/16/4; Lymph node biopsy–<br />
32/54; Lymph node involvement: none/micrometastases/metastases–14/2/16. BRAF<br />
mutation–42/69 (61%). BRAF mutation correlated with poor response to treatment<br />
(P = 0.056), but had no effect on disease-free interval (DFI). DFI was affected only by<br />
nodal stage (P = 0.026). In Cox multivariate analysis only male gender was associated<br />
with worse prognosis (P = 0.03), while BRAF mutation showed a trend towards worse<br />
prognosis (P = 0.169).<br />
Conclusions: BRAF mutation in patients with MM treated with chemobio<strong>the</strong>rapy<br />
may predict poor response to treatment.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1148 SAFETY AND EFFICACY OF IPILIMUMAB 10 MG/KG AMONG<br />
PATIENTS WITH ADVANCED MELANOMA FROM ITALY<br />
ENROLLED IN A EUROPEAN COMPASSIONATE USE<br />
PROGRAM<br />
M. Maio 1 , P. Queirolo 2 , A. Testori 3 , M. Altomonte 1 , M. Maur 4 , E. Bajetta 5 ,P.<br />
A. Ascierto 6 , V. Chiarion Sileni 7 , A.M. Di Giacomo 1 , R. Ridolfi 8<br />
1 Department of Oncology, Azienda Ospedaliera Senese - Medical Oncology and<br />
Immuno<strong>the</strong>rapy Unit, Siena, ITALY, 2 Department of Oncology, National Institute<br />
for Cancer Research - Genova, Genova, ITALY, 3 Melanoma Muscle Cutaneous<br />
Sarcoma Division, European Institute of Oncology, Milan, ITALY, 4 Dept. of<br />
Hematology/Oncology, Ospedale Policlinico-Modena, Modena, ITALY, 5 Medical<br />
Oncology, Istituto di Oncologia del Policlinico di Monza, Monza, ITALY, 6 Unit of<br />
Medical Oncology and Innovative Therapy, Istituto Nazionale Tumori Fondazione<br />
G. Pascale, Napoli, ITALY, 7 U.O.Oncologia Medica, Istituto Oncologico Veneto<br />
IOV-IRCCS, Padova, ITALY, 8 Immunoterapia e Terapia Cellulare Somatica,<br />
IRCCS-IRST Meldola, Meldola (FC), ITALY<br />
Purpose: Clinical studies of ipilimumab have shown improved survival and durable<br />
tumour responses across a spectrum of doses and schedules. Here, we evaluate <strong>the</strong><br />
use of ipilimumab 10 mg/kg outside of clinical trials, in a setting similar to daily<br />
practice.<br />
Methods: Ipilimumab was available upon physician request for patients (pts) aged<br />
≥16 years with unresectable stage III/stage IV melanoma who had ei<strong>the</strong>r failed<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds404 | ix373
systemic <strong>the</strong>rapy or were intolerant to ≥1 systemic treatment and for whom no o<strong>the</strong>r<br />
<strong>the</strong>rapeutic option was available. Induction <strong>the</strong>rapy with ipilimumab 10 mg/kg was<br />
given on Week (wk) 1, 4, 7 and 10 with tumour assessments conducted at baseline,<br />
wk 12 and q 12 wks <strong>the</strong>reafter using modified World Health Organization criteria.<br />
Maintenance <strong>the</strong>rapy with ipilimumab was available q 12 wks from wk 24 for pts<br />
with evidence of clinical benefit. Pts were monitored for adverse events (AEs) using<br />
Common Terminology Criteria for Adverse Events v.3.0.<br />
Results: In total, 74 pts, including 11 with brain metastasis, received ≥1 dose of<br />
ipilimumab and were eligible for analysis. Of <strong>the</strong>se, 43 (58.1%) completed <strong>the</strong><br />
induction phase and 26 (35.1%) received maintenance <strong>the</strong>rapy (median of 2 cycles;<br />
range: 1–13). The disease control rate was 32%, including 3 pts (4%) with a complete<br />
response, 6 (9%) with a partial response, and 13 (19%) with stable disease. Median<br />
progression-free survival (PFS) and overall survival (OS) was 3 months (mo) (95%<br />
CI: 2.3–3.7) and 7 mo (95% CI: 5.3–8.7), respectively. For pts with brain metastases,<br />
PFS and OS were 3 mo (95% CI: 2.4–3.6) and 4 mo (95% CI: 2.4–5.6). The 3-yr<br />
survival rate was 16.6%, with 11 long survivors pts (>3 yrs). Overall, 45 pts (61%)<br />
reported an AE of any grade; most commonly pruritis and diarrhoea. Eight grade 3/4<br />
AEs were reported, including diarrhoea (n = 2), pain (including epigastric; n = 3) and<br />
one case each of fever, increased liver enzymes and pancytopenia. Most AEs were<br />
manageable through adherence to protocol-specific guidelines.<br />
Conclusions: Ipilimumab is a feasible treatment option for pts who progressed on,<br />
or were unable to tolerate previous <strong>the</strong>rapies, with approximately one-third of pts<br />
achieving disease control and a long-term survival benefit.<br />
Disclosure: M. Maio: Advisory board and honoraria from: BMS and Roche.<br />
P. Queirolo: Paola Queirolo served on Advisory Board of Bristol Myers Squibb,<br />
Roche-Genentech, GSK, MSD and received honoraria from Brystol Myers Squibb<br />
and Roche-Genentech. A. Testori: I have a consultant or advisory relationship to<br />
disclose ( BMS, GSK, AMGEM advisory boards); I have honoraria to disclose (from<br />
above mentioned advisory boards); I have o<strong>the</strong>r remuneration to discloure ( travel<br />
expenses from oncovision and Igea). P.A. Ascierto: Consultant or advisory<br />
relationship for: Brystol Myers - Squibb Merck Roche GSK Amgen. Honoraria to<br />
disclose from BMS, Merck, Roche. V. Chiarion Sileni: Advisory Board and/or<br />
Honoraria from: BMS MSD Shering & Plough Roche GSK. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
1149 IPILIMUMAB FOR ADVANCED MELANOMA IN AN EXPANDED<br />
ACCESS PROGRAMME (EAP): OCULAR, MUCOSAL AND<br />
ACRAL SUBTYPE UK EXPERIENCE<br />
H. Shaw 1 , J. Larkin 2 , P. Corrie 3 , S. Ellis 4 , J. Nobes 5 , E. Marshall 6 , S. Kumar 7 ,<br />
S. Danson 8 , R. Plummer 9 , P. Nathan 1<br />
1 Cancer Services, Mount Vernon Cancer Centre, Northwood, UNITED<br />
KINGDOM, 2 Department of Medicine, Royal Marsden Hospital, London, UNITED<br />
KINGDOM, 3 Oncology Centre, Cambridge University Hospitals NHS Foundation<br />
Trust, Cambridge, UNITED KINGDOM, 4 Department of Oncology, Southampton<br />
General Hospital, Southampton, UNITED KINGDOM, 5 Department of Medicine,<br />
Norfolk and Norwich University Hospital, Norwich, UNITED KINGDOM,<br />
6 Oncology, Clatterbridge Centre for Oncology, Liverpool, UNITED KINGDOM,<br />
7 Department of Oncology, Velindre Cancer Centre, CARDIFF, UNITED<br />
KINGDOM, 8 Department of Oncology, Weston Park Hospital, SHEFFIELD,<br />
UNITED KINGDOM, 9 Medical Oncology, Nor<strong>the</strong>rn Institute for Cancer Research,<br />
University of Newcastle upon Tyne, Newcastle, UNITED KINGDOM<br />
Background: Ipilimumab (Ipi) is a fully human monoclonal antibody against<br />
CTLA-4 which acts to promote an anti-tumour immune response. Previous phase III<br />
randomised controlled trials showing improved overall survival (OS) in metastatic or<br />
unresectable cutaneous melanoma excluded those of ocular (OM) or mucosal<br />
(MuM) origin and provided no data for acral melanoma (AM). These patients (pts)<br />
were permitted Ipi treatment in <strong>the</strong> setting of <strong>the</strong> EAP. Participating UK centres were<br />
asked to report data relating to <strong>the</strong> outcome of Ipi treatment in pts with rare<br />
melanoma types.<br />
Methods: Patients with unresectable stage III/IV disease were treated within <strong>the</strong> Ipi<br />
EAP protocol at an induction dose of 3mg/kg for up to 4 cycles. RECIST criteria<br />
were used for response assessment at baseline, 12 weeks and every 12 weeks<br />
<strong>the</strong>reafter. Documentation of adverse events (AEs) and immune-related AEs (ir-AEs)<br />
was according to CTCAE v3.0.<br />
Results: 27 pts; 18 ocular (66%), 5 acral (19%) and 4 mucosal (15%); received at least<br />
one cycle of Ipi across 8 UK centres. All had previously received one or more lines of<br />
<strong>the</strong>rapy for <strong>the</strong>ir disease. Two pts (40%) with AM had a partial response (PR), with a<br />
median duration of response of 22 wks (range: 20-24).One pt (25%) with MuM and<br />
3 pts (17%) with OM had stable disease (SD), with a fur<strong>the</strong>r OM pt demonstrating a<br />
mixed response. The median progression free survival (PFS) was 12 wks for <strong>the</strong><br />
single MuM case and 14.5 wks (range: 6-64) in OM. 5 episodes of G3 ir-AEs were<br />
reported in 4 pts (3 colitis, 2 hepatitis), and 2 G3/4 AEs of fatigue. These resolved on<br />
steroid <strong>the</strong>rapy.<br />
Conclusion: Partial responses were seen in metastatic acral but not mucosal or<br />
ocular melanoma in this setting. Given <strong>the</strong> small sample size it is difficult to<br />
accurately interpret outcome data. Activity of ipilimumab in rare melanoma subtypes<br />
needs to be assessed in prospective studies.<br />
Annals of Oncology<br />
Disclosure: J. Larkin: I have received honoraria from BMS. P. Corrie: I have<br />
undertaken consultancy work and advisory Boards for BMS. J. Nobes: I have been<br />
sponsored by BMS to attend conferences. E. Marshall: I have received previous<br />
honoraria for serving on an advisory board for BMS. S. Kumar: I have served on <strong>the</strong><br />
advisory board for BMS. R. Plummer: I have received honoraria for advisory boards<br />
to BMS. P. Nathan: I have received compensation for advisory board and speakers<br />
panel from BMS. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1150 SPANISH MELANOMA MULTIDISCIPLINARY GROUP (GEM)<br />
EXPERIENCE WITH IPILIMUMAB (IPI) IN THE EXPANDED<br />
ACCESS PROGRAMME (EAP)<br />
S. Martin Algarra 1 , L. Alonso 2 , J. Valdivia 3 , A. Garcia Castaño 4 , V. Escrig 5 ,<br />
P. Mut 6 , A. Ballesteros 7 , T. Puertolas 8 , E. Ortega 9 , A. Berrocal 10<br />
1 Oncology, Clinica Universitaria de Navarra, Pamplona, SPAIN, 2 Medical<br />
Oncology, Hospital Clínico Victoria, Málaga, SPAIN, 3 Medical Oncology, Hospital<br />
Virgen de las Nieves, Granada, SPAIN, 4 Hospitalmedical Oncology, Hospital<br />
Marqués de Valdecilla, Santander, SPAIN, 5 Medical Oncology, Hospital Clínico<br />
Valencia, Valencia, SPAIN, 6 Medical Oncology, Hospital Son Llazer Mallorca,<br />
Mallorca, SPAIN, 7 Medical Oncology, Hospital Universitario La Princesa, Madrid,<br />
SPAIN, 8 Medical Oncology, Hospital Miguel Servet, Zaragoza, SPAIN, 9 Medical<br />
Oncology, Hospital Armau de Villanova, Lérida, SPAIN, 10 Medical Oncology,<br />
Hospital General Universitario, Valencia, SPAIN<br />
Objective: Retrospective review of <strong>the</strong> IPI-EAP experience in Spain.<br />
Patients and methods: Demographics were provided by BMS. Response (R), survival<br />
(S) and toxicity (T) were collected from a questionnaire (Q) distributed by <strong>the</strong> GEM<br />
to EAP treating physicians. IPI dose was 3mg/kg q 3w x 4. Patients (pts) progressing<br />
after objective R were eligible for reinduction.<br />
Results: 355 EAP requests result in 288 treated pts. Median age: 59y (24-83); Male<br />
57%; Stage: IVa 28.8%, IVb 20%, IVc 51.2%; CNS metastases (mts) 15%, liver 37%,<br />
lung 21%. ECOG (PS): 0 48%, 1 41%, 2 11%; Prior treatment (thx): chemo<strong>the</strong>rapy<br />
(chx) 94%, immuno<strong>the</strong>rapy 37%, radio<strong>the</strong>rapy 28%. At <strong>the</strong> time of this report,<br />
information from 138 treated pts (48%), collected using <strong>the</strong> GEM Q, was available<br />
for a preliminary analysis Median age: 58y (24-81); Male 57.2%; CNS mts 18.8%,<br />
Liver 47.1%. >2 metastatic sites: 53.6%. PS 0-1: 81.8%. Prior adjuvant thx: 44.9% pts<br />
(79% high dose interferon). All except 2 pts, received chx (34.8% >1 line). Median<br />
time from metastases to 1st dose of IPI was 11.2 months (m). 60.9% pts completed 4<br />
doses of IPI. Reinduction was requested for 17 pts (12.1%) and 8 received 4 cycles<br />
(5.8%). Discontinuation was due to death or progression (P) in 87% and T in 3.7%.<br />
R was evaluable in 129 pts: CR: 2 (1.4%); PR: 23 (16.6%) including 11 (7.9%) with<br />
initial P and delayed PR; SD: 18 (13%); P: 86 (62.3%). Of <strong>the</strong> 9 non-evaluable pts, 6<br />
just finished thx and 3 were still on IPI. Reinduction was done in 13 pts, 8 received 4<br />
doses: 2 pts with prior PR achieved a new PR, 3 with prior PR had SD, and 3 with<br />
prior SD progressed. Median S: 6,1 m (95% CI:125.3-272.6); 1y S: 32.9%; 18 m S:<br />
28.8%. Prognostic factors for S were baseline lymphocytes >1000/ml (p = 0.0008) and<br />
LDH >1.5xULN (p = 0.003) T was mild. Skin: grade (G) I 21.7%, GII 3.6%; liver: GI<br />
5.8%, GII 1.4%, GIII 2.2%; diarrhoea: GI 14.5%, GII 3.6%, GIII-IV 1.7%. 9 pts had<br />
GIII-IV T.<br />
Conclusions: IPI can be safely used by trained oncologists in a non-clinical trial<br />
setting. In this series, activity and T profile in is similar to <strong>the</strong> phase III data.<br />
Although this preliminary analysis is limited by its numbers (
Annals of Oncology<br />
mg/kg, for 4 cycles. We have focused on patients aged 70 or more years with<br />
previously treated, advanced melanoma.<br />
Results: Information on 30 patients is available. Median age was 75 years (70-81),<br />
53.3% were males. Liver and CNS metastases were respectively present in 26.7% and<br />
13.3% of <strong>the</strong> patients; 53.3% had 3 or more metastatic sites, and 51.7% had elevated<br />
LDH. Performance status (ECOG) was 0-1 in 93.3%. Up to 26.7% of <strong>the</strong> patients had<br />
received previous adjuvant treatment, which consisted of high dose interferon in<br />
75%. All patients had received previous first line chemo<strong>the</strong>rapy, including 26.7% with<br />
2 or more lines. Medium time from <strong>the</strong> diagnosis of metastatic disease to <strong>the</strong> first<br />
dose of IPI was 14.2 months. A total of 76.7% of <strong>the</strong> patients completed <strong>the</strong> 4<br />
intended doses of IPI. Main reasons for early discontinuation were death or<br />
progression in all patients, with no patient discontinuing due to toxicity. Responses<br />
were evaluable in 26 patients: PR: 6 (20%) -including 3 (10%) with a delayed PR<br />
after an initial PD; SD: 3 (10%), and PD: 17 (56.7%). Out of <strong>the</strong> 4 non-evaluable<br />
patients, 3 had just completed treatment and 1 was still on <strong>the</strong>rapy at <strong>the</strong> time of <strong>the</strong><br />
data collection. So far, reinduction treatment has not been offered to any patient.<br />
Estimated median survival (Kaplan -Meier) is 180 days (5.9 months) (95% CI<br />
119.7-240.2). One year survival rate is 21%. Prognostic factors of survival at baseline<br />
were peripheral blood lymphocytes > 1000 /mL (p = 0.005) and LDH > 1.5 X ULN<br />
(p = 0.027) The reported toxicity per patient has been mild: skin: 23.3% grade I and<br />
13.3% grade II; liver 6.7% grade I; and diarrhea 6.7% grade I, 3.3% grade III-IV. Only<br />
4 patients experienced toxicity grade III to IV.<br />
Conclusions: Ipilimumab efficacy in older patients, when it is used outside a clinical<br />
trial setting, is in line to published phase III data. There is no increase in toxicity,<br />
making this treatment a valid option for older patients with previously treated<br />
metastatic melanoma.<br />
Disclosure: J.A. Lopez Martin: Participation in Avisory Boards of BMS and speaker<br />
in educational activities of BMS. A. Berrocal: Participation in Advisory Boards and<br />
speaker in educational activities sponsored by BMS. All o<strong>the</strong>r authors have declared<br />
no conflicts of interest.<br />
1152 IPILIMUAMB TREATMENT AFTER ELECTROCHEMOTHERAPY<br />
COULD BE AN EFFECTIVE SEQUENTIAL COMBINATION<br />
APPROACH<br />
E. Simeone 1 , L. Benedetto 2 , G. Gentilcore 1 , C. Caracò 1 , G. Di Monta 2 ,<br />
U. Marone 1 , A.M. Grimaldi 1 , S. Mori 1 , N. Mozzillo 2 , P.A. Ascierto 1<br />
1 Oncology, National Cancer Institute, Naples, ITALY, 2 Surgical Oncology,<br />
National Cancer Institute, Naples, ITALY<br />
Backgroud: Electrochemo<strong>the</strong>rapy (ECT) has shown to be effective as local treatment<br />
of disseminated superficial melanoma, but <strong>the</strong>re is a lack of evidence of its potential<br />
systemic effect. Potential immunologic changes due to ECT could have an impact on<br />
metastatic lesions but this hasn’t been demonstrated yet. Combining ECT with new<br />
drugs, like ipilimumab (ipi), could be a new <strong>the</strong>rapeutic strategy. T-regulatory cells<br />
(T-Reg) are immunosuppressive lymphocytes whose role during ipi <strong>the</strong>rapy has still<br />
to be clarified. Our previous experience showed a reduction of T-reg cells in patients<br />
responder to ipi.<br />
Patients and methods: 20 patients with advanced melanoma (8 at stage IIIc and 12<br />
IV M1c) underwent ECT with bleomycine. 5 patients were treated with ECT and no<br />
fur<strong>the</strong>r <strong>the</strong>rapies, while 15 pts were treated with ECT first and <strong>the</strong>n, after<br />
progression, with ipi at 3 mg/kg for 4 cycles. We collected PBMC of <strong>the</strong>se patients.<br />
Blood draw was performed at ECT day 0-1-15-30 and during follow-up, while during<br />
ipi <strong>the</strong>rapy, at each cycle (week 4-7-10) and at every tumor evaluation (every 12<br />
weeks).<br />
Results: 5/20 (25%) patients, all at stage IIIc, had performed only ECT and showed a<br />
good local response (2 CR and 3 PR). No variation of T-Reg was detected after ECT<br />
treatment with median value of 0.40 % (range 0.40-2.6 %). 15/20 (75%) patients had<br />
a low local response and developed visceral progression after ECT without significant<br />
reduction of T-Reg levels. The median T-reg value was of 0.7 (range 0.50-2.6%)<br />
During ipi treatment, we found a decrease of T-Reg of 0.10% per cycle. This result<br />
was consistent with our previous evidence in patients treated with ipi in Italian EAP.<br />
Moreover, 3/15 patients (20%) showed local CR and 2 of <strong>the</strong>m also systemic PR<br />
lasting at 12.1 months of follow- up, with a median T-Reg value of 0.10%. 8/15<br />
(53%) had both local and systemic SD with a median TTP of 7.9 months and a<br />
median T-Reg of 0.30%. 4/15 (27%) developed a local and distant progression and<br />
we found a small decrease with median T-Reg of 1.8%.<br />
Conclusion: ECT followed by ipi in patients with metastatic melanoma, may be<br />
more effective than ECT and ipi alone. This combination may represent a new<br />
option. Anyway, fur<strong>the</strong>r studies are necessary to verify <strong>the</strong>se data.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1153 PACLITAXEL/CARBOPLATIN CHEMOTHERAPY AS SALVAGE<br />
TREATMENT IN METASTATIC MELANOMA: IS<br />
NON-CUTANEOUS MELANOMA DIFFERENT?<br />
W. Chang 1 , J. Lee 1 , S.J. Lee 1 , S. Park 1 , M.K. Choi 1 , J.Y. Hong 1 , Y.S. Kim 1 ,<br />
C.H. Maeng 2 , S. Kim 1<br />
1 Medicine, Samsung Medical Center, Seoul, KOREA, 2 Hematology-Oncology,<br />
Samsung Medical Center, SEOUL, KOREA<br />
Background: There is limited data on salvage chemo<strong>the</strong>rapy for metastatic,<br />
non-cutaneous melanoma after failure to dacarbazine-based chemo<strong>the</strong>rapy. Given <strong>the</strong><br />
high incidence of non-cutaneous melanoma in Korea, we focused on <strong>the</strong> treatment<br />
outcome of paclitaxel/carboplatin as salvage chemo<strong>the</strong>rapy in noncutaneous<br />
metastatic melanoma.<br />
Patients and methods: We retrospectively analyzed patients with metastatic<br />
melanoma who underwent paclitaxel and carboplatin (PC) chemo<strong>the</strong>rapy as<br />
salvage treatment at Samsung Medical Center (SMC) between February 2009<br />
and February <strong>2012</strong>. The treatment schedule is as follows: intravenous paclitaxel<br />
175 mg/m 2 plus intravenous carboplatin at area under curve 5 (AUC 5) on day 1 of a<br />
21-day interval. Overall response rate, overall and progression free survival were<br />
calculated.<br />
Results: Thirty two patients (median age: 54 years, range 24 – 72 years) were treated<br />
with PC as salvage chemo<strong>the</strong>rapy. All patients were pretreated and had previously<br />
received a median of 2 systemic <strong>the</strong>rapies. With respect to primary site, 10 patients<br />
(31.3%) had cutaneous melanoma, 8 (25%) had acral melanoma, 10 (31.3%) had<br />
mucosal melanoma, 2 (6.3%) had ocular melanoma. Of 32 patients, 7 patients<br />
achieved partial response (PR) (21.9%) and 11 patients were stable disease (34.4%).<br />
Median progression free survival (PFS) was 2.53 months for all patients. PFS was 4.3<br />
months for patients controlled disease (partial response and stable disease) compared<br />
to 1.37 months for patients with progressive disease (p = 0.0001). Median overall<br />
survival was 5.2 months without a significant difference between noncutaneous and<br />
cutaneous metastatic melanoma group (p =0.75).<br />
Conclusion: PC chemo<strong>the</strong>rapy seems to be a reasonable <strong>the</strong>rapeutic option in<br />
heavily pretreated metastatic melanoma patients. Especially, this combination<br />
chemo<strong>the</strong>rapy appears to have definite and clinically meaningful activity when used<br />
as salvage <strong>the</strong>rapy in metastatic melanoma including non-cutaneous melanoma.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds404 | ix375
abstracts<br />
neuroendocrine tumors and cup<br />
1154O THE VEGF PATHWAY IN PATIENTS WITH PANCREATIC<br />
NEUROENDOCRINE TUMORS: EFFICACY OF EVEROLIMUS<br />
BY BASELINE MARKER LEVEL, AND PROGNOSTIC AND<br />
PREDICTIVE EFFECT ANALYSES FROM RADIANT-3<br />
J.C. Yao 1 , M. Shah 2 , A. Panneerselvam 3 , S. Stergiopoulos 4 , D. Chen 5 , T. Ito 6 ,<br />
M. Pavel 7<br />
1 Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX,<br />
UNITED STATES OF AMERICA, 2 Medical Oncology, Ohio State University,<br />
Columbus, OH, UNITED STATES OF AMERICA, 3 Oncology Biometrics and Data,<br />
Novartis Pharmaceuticals Corporation, East Hanover, NJ, UNITED STATES OF<br />
AMERICA, 4 Oncology, Novartis Pharmaceuticals, East Hanover, NJ, UNITED<br />
STATES OF AMERICA, 5 Oncology Biometrics and Data, Novartis<br />
Pharmaceuticals Corporation, Florham Park, NJ, UNITED STATES OF AMERICA,<br />
6 Medicine and Bioregulatory Science, National Cancer Center Hospital, Tokyo,<br />
JAPAN, 7 Dept of Gastroenterology & Hepatology, Charité Universitätsmedizin<br />
Berlin, Berlin, GERMANY<br />
Background: RADIANT-3 was a phase III study investigating <strong>the</strong> effect of <strong>the</strong><br />
mammalian target of rapamycin inhibitor everolimus on progression-free survival<br />
(PFS) in patients with advanced pancreatic neuroendocrine tumors (pNET; Yao<br />
et al, NEJM, 2011). Everolimus significantly improved PFS compared with<br />
placebo (11 vs 4.6 months, P < .001). Here we investigate <strong>the</strong> predictive and<br />
prognostic effect of soluble VEGF pathway biomarkers among patients treated in<br />
this study.<br />
Methods: Baseline plasma levels of VEGF-A, PlGF, sVEGFR1, and sVEGFR2<br />
were determined by ELISA using multiplexed MSD platform. The optimal cutoffs<br />
for <strong>the</strong>se markers were explored using <strong>the</strong> “survival tree analysis” method.<br />
Interaction of treatment and baseline marker status (< or ≥ cutoff) was analyzed<br />
using a Cox proportional hazards model to assess predictive effects of <strong>the</strong>se<br />
markers. P values and hazard ratios for prognostic effects were obtained using<br />
stratified log rank test and Cox proportional hazards model, stratified by<br />
treatment.<br />
Results: PFS was significantly improved to a similar extent in patients receiving<br />
everolimus compared with patients who received placebo, regardless of baseline<br />
levels of markers (P < .001, all analyses; Table), suggesting that none of <strong>the</strong>se<br />
markers are associated with <strong>the</strong> efficacy of everolimus in patients with pNET.<br />
However, significantly longer PFS was seen in those with lower VEGF-A, PlGF,<br />
and sVEGFR1 levels, suggesting <strong>the</strong>se three markers are prognostic in pNET<br />
(Table).<br />
Conclusions: These exploratory analyses demonstrated consistent everolimus efficacy<br />
in all patients with advanced pNET irrespective of <strong>the</strong>ir baseline VEGF pathway<br />
biomarker levels. However, levels of VEGF-A, PlGP, and sVEGFR1 are potential<br />
prognostic factors for pNET.<br />
Marker<br />
Cutoff<br />
(pg/mL)<br />
Median PFS<br />
Annals of Oncology<br />
1156O RAMSETE: A SINGLE-ARM, MULTICENTER, SINGLE-STAGE<br />
PHASE II TRIAL OF RAD001 (EVEROLIMUS) IN ADVANCED<br />
AND METASTATIC SILENT NEURO-ENDOCRINE TUMOURS<br />
IN EUROPE: ANALYSIS BY TUMOR ORIGIN<br />
M. Pavel 1 , B. Wiedenmann 1 , J. Capdevila 2 , J.W. Valle 3 , W.W. De Herder 4 ,<br />
C. Metzer 5 , R. Salazar 6 , D. Horsch 7 , K. Oberg 8<br />
1 Dept of Gastroenterology & Hepatology, Charité Universitätsmedizin Berlin,<br />
Berlin, GERMANY, 2 Medical Oncology, Hospital Vall d’Hebrón, Barcelona,<br />
SPAIN, 3 Medical Oncology, The Christie NHS Foundation Trust, Manchester,<br />
UNITED KINGDOM, 4 Endocrine Oncology, Erasmus University Medical Center,<br />
Rotterdam, NETHERLANDS, 5 Internal Medicine and Clinical Chemistry,<br />
Ruprecht-Karls-Universitat Heidelberg Medizinische Klinik und Poliklinik,<br />
Heidelberg, GERMANY, 6 Medical Oncology, ICO Hospital Duran i Reynals,<br />
Barcelona, SPAIN, 7 Gastroenterology and Endocrinology, ChA Klinik für Innere<br />
Medizin, Bad Berka, GERMANY, 8 Endocrine Oncology Unit, Dept of Medicine,<br />
Uppsala University, Uppsala, SWEDEN<br />
Background: Everolimus is an oral inhibitor of <strong>the</strong> mammalian target of<br />
rapamycin and approved for treatment of advanced pancreatic neuroendocrine<br />
tumors (pNET). Its efficacy in nonsyndromic, nonpancreatic NET is unknown.<br />
Here we report a secondary exploratory post hoc analysis by tumor origin of <strong>the</strong><br />
RAMSETE trial.<br />
Methods: RAMSETE include patients (pts) with advanced, progressive,<br />
nonsyndromic, nonpancreatic NET who received everolimus (10 mg/day)<br />
mono<strong>the</strong>rapy. Primary endpoint was objective response rate (per RECIST v1.0) by<br />
central radiologic review. Secondary endpoints included progression-free survival<br />
(PFS).<br />
Results: Database lock was Dec 1, 2011, and included 73 pts with median everolimus<br />
treatment of 193 days. In <strong>the</strong> total population, <strong>the</strong> best response was stable disease<br />
(55%) with a median PFS of 185 days (95% CI: 158-255). 22 (30.1%) pts had<br />
primary tumor origin in <strong>the</strong> lung, thymus, bronchus, or mediastinum; 34 (46.6%) pts<br />
had primary tumor origin o<strong>the</strong>r than <strong>the</strong> lung, bronchus, or mediastinum (<strong>the</strong><br />
largest subsets included small bowel/ileum [n = 16], rectum [n = 4], and caecum [n =<br />
2]); and 17 (23.3%) pts had unknown primary tumor origin. Tumor characteristics<br />
and efficacy by tumor origin site are detailed in <strong>the</strong> Table. Everolimus was associated<br />
with a high proportion of stable disease along with a favorable PFS in pts with<br />
nonsydromic, nonpancreatic NET.<br />
Conclusions: These results provide evidence that everolimus may be effective in<br />
nonsyndromic, nonpancreatic NET with diverse tumor origin sites and in pts with<br />
high tumor grade. These data support previous results from phase III trials that<br />
indicate everolimus is effective in pancreatic NET (RADIANT-3) and in NET<br />
associated with carcinoid syndrome (RADIANT-2).<br />
Characteristic and<br />
Endpoint<br />
Lung, thymic, bronchial,<br />
mediastinal (n = 22)<br />
O<strong>the</strong>r than<br />
lung (n = 34)<br />
Unknown<br />
(n = 17)<br />
Well differentiated, % 40.9 97.0 82.3<br />
Moderately<br />
differentiated, %<br />
59.0 2.9 17.6<br />
Ki67 >10%, % 62.5 42.8 50.0<br />
Stable disease, % 63.2 42.9 69.2<br />
Progressive disease, % 36.8 57.1 30.8<br />
Median PFS, days<br />
(95% CI)<br />
189 (84–321) 174 (118–245) 316 (126–337)<br />
Disclosure: M. Pavel: Honoraria for presentations and participation in advisory<br />
board meetings for Novartis, Ipsen, Pfizer; Research grant from Novartis. B.<br />
Wiedenmann: Honoraria from and consultancy with Novartis, Ipsen, Pfizer, and<br />
Lexicon. J.W. Valle: Consultant/advisory relationship with Novartis; Honoraria from<br />
Novartis. W.W. De Herder: Consultant/advisory relationship with Novartis;<br />
Honoraria from Novartis. R. Salazar: Research funding from Novartis; Honoraria from<br />
Novartis. D. Horsch: Consultant or advisory role with Pfizer, Novartis, and IPSEN;<br />
honoraria from Pfizer and Novartis; research funding from Novartis, Ipsen, MDS,<br />
Nordion, Covidien, Eckart and Ziegler. K. Oberg: Consultant/advisory relationship with<br />
Novartis; Honoraria from Novartis. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
1157O PAZONET: A PHASE II TRIAL OF PAZOPANIB AS A<br />
SEQUENCING TREATMENT IN PROGRESSIVE METASTATIC<br />
NEUROENDOCRINE TUMORS (NETS) PATIENTS (PTS), ON<br />
BEHALF OF THE SPANISH TASK FORCE FOR NETS (GETNE)<br />
E. Grande 1 , D. Castellano 2 , R. García-Carbonero 3 , A. Teulé 4 , I. Durán 5 ,<br />
J. Fuster 6 , I. Sevilla 7 , P. Escudero 8 , J. Sastre 9 , O. Casanovas 10 , L. Ortega 11 ,<br />
J. Earl 12 , J.J. Díez 13 , G. de Velasco 2 , F. Longo 1 , A. Navarro 14 , V. Pachón 1 ,<br />
A. Carrato 1 , R. Salazar 4 , J. Capdevila 14<br />
1 Medical Oncology Department, Ramon y Cajal University Hospital, Madrid,<br />
SPAIN, 2 Medical Oncology Department, Doce de Octubre University Hospital,<br />
Madrid, SPAIN, 3 Medical Oncology Department, Virgen del Rocío University<br />
Hospital, Seville, SPAIN, 4 Medical Oncology Department, Catalan Institute of<br />
Oncology, Barcelona, SPAIN, 5 Medical Oncology Department, Centro Integral de<br />
Oncología Clara Campal, Madrid, SPAIN, 6 Medical Oncology Department, Som<br />
Espases Hospital, Mallorca, SPAIN, 7 Medical Oncology Department, Virgen de la<br />
Victoria University Hospital, Malaga, SPAIN, 8 Medical Oncology Department,<br />
Hospital Clínico Universitario Lozano Blesa, Zaragoza, SPAIN, 9 Medical<br />
Oncology Department, Hospital Clínico San Carlos, Madrid, SPAIN, 10 Tumor<br />
Angiogenesis Group, Translational Research Laboratory, Catalan Institute of<br />
Oncology, Barcelona, SPAIN, 11 Pathology Department, Hospital Clínico San<br />
Carlos, Madrid, SPAIN, 12 Medical Oncology Laboratory, Ramon y Cajal<br />
University Hospital, Madrid, SPAIN, 13 Endocrinology Department, Ramón y Cajal<br />
University Hospital, Madrid, SPAIN, 14 Medical Oncology Department, Vall<br />
D’Hebrón University Hospital, Barcelona, SPAIN<br />
Background: Pazopanib is an oral tyrosine kinase inhibitor of <strong>the</strong> VEGFR, PDGFR<br />
and KIT with demonstrated clinical activity in NETs. The aims of our study were to<br />
assess efficacy, safety and potential predictive biomarkers of pazopanib in pts with<br />
NETs who may have received previous antiangiogenic or mTOR inhibitor treatment.<br />
Methods: All pts had pancreatic or extra-pancreatic metastatic NET disease<br />
documented as progressive. Pazopanib 800 mg was given daily until disease<br />
progression (DP) or unacceptable toxicity. Primary endpoint was Clinical Benefit<br />
Rate (CBR) at 6 months (m) defined as Complete Response (CR) plus Partial<br />
Response (PR) plus Stable Disease (SD) by RECIST-V-1.0. Optimal two-stage Simon<br />
design was utilized with H1 and H0 set at 70 % and 50 % respectively, Kaplan-Meier<br />
estimates were used for <strong>the</strong> analysis of time-to-event variables: 95% CI.<br />
Results: 41 evaluable pts for response per protocol. 53.7% males, mean age 59.2 ±<br />
10.3 years. At 6 months, 3 pts had PR (7.36%), 32 SD (78.0%), and 6 DP (14.6%),<br />
thus <strong>the</strong> CBR was 85.4%. Global median PFS 48,3 (13.9-82.7) weeks (w). By<br />
subgroups, CBR at 6 m and median PFS were 100% and 25.7 w in pts with no<br />
previous targeted <strong>the</strong>rapy (9 pts), 88.9% and 48.3 w in pts with previous mTOR<br />
inhibitors (9 pts), 83.3% and 50.3 w in pts with previous antiangiogenics (16 pts)<br />
and 71.4% and 20.6 w in pts with previous antiangiogenics and mTOR inhibitors (7<br />
pts) respectively. The sum of <strong>the</strong> longest diameter of target lesions had a decrease ><br />
10% in 32.5 % of pts (37.5% without previous biological treatment, 22.2 % with<br />
previous mTOR inhibitor, 31.3% with prior multitarget inhibitor, and 42.9% with<br />
previous multitarget and mTOR, p = 0.506). Most frequent toxicities at of any grade<br />
were: as<strong>the</strong>nia (75%), diarrhoea (63%), nausea (42%). Translational studies on<br />
angiogenesis and inmunohistochemistry biomarkers and CTCs are ongoing.<br />
Conclusions: Pazopanib 800 mg daily has promising activity in advanced NET<br />
regardless of previous treatment with o<strong>the</strong>r targeted <strong>the</strong>rapies. This trial suggests <strong>the</strong><br />
role that treatment sequencing with novel targeted agents may have in NETs.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1158P KI-67 INDEX VARIABILITY IN NEUROENDOCRINE TUMORS<br />
J. Craig 1 , M. Cheung 2 ,C.Law 3 , S. Singh 1<br />
1 Medical Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre,<br />
Toronto, ON, CANADA, 2 Hematology, Odette Cancer Centre, Sunnybrook<br />
Health Sciences Centre, Toronto, ON, CANADA, 3 Surgical Oncology, Odette<br />
Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, CANADA<br />
Introduction: The Ki-67 labeling index is now well recognized as an integral factor<br />
in <strong>the</strong> identification and treatment of neuroendocrine tumors (NETs) from both a<br />
prognosis and treatment perspective. In 2010, <strong>the</strong> WHO endorsed a grading system<br />
of NETs dividing tumors into G1 (Ki-67 <br />
20%) classes. Previous studies have associated higher Ki-67 scores with greater<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds405 | ix377
morbidity, with G3 tumors behaving particularly aggressively, often requiring<br />
cytotoxic chemo<strong>the</strong>rapy. Currently Ki-67 is determined from a single biopsy in a<br />
majority of cases. Little is known about <strong>the</strong> variability of <strong>the</strong> Ki-67 labeling index<br />
during <strong>the</strong> disease course or between primary and metastatic deposits, and <strong>the</strong>re are<br />
no consensus guidelines on taking multiple biopsy specimens throughout <strong>the</strong> disease<br />
course. AIMS: To compare Ki-67 labeling among multiple biopsy samples in<br />
individual patients to examine for variability.<br />
Methods: The Sunnybrook Odette NETs database (n = 327) was retrospectively<br />
reviewed for patients with a confirmed diagnosis of NET and multiple ( > = 2) biopsy<br />
or surgical pathologic specimens, ei<strong>the</strong>r at variable times in <strong>the</strong>ir disease course or<br />
biopsies of both <strong>the</strong> primary and metastasis. All but 2 cases were reviewed by our<br />
expert local neuroendocrine pathologist. Changes in WHO classification between<br />
multiple specimens in individual patients were determined.<br />
Results: 43 patients were identified for inclusion in <strong>the</strong> analysis. 39 patients had<br />
pathology on <strong>the</strong>ir primary tumor as well as a metastatic focus, while 4 had<br />
pathology on multiple metastatic foci only. 16/43 patients (37.2%) were identified<br />
who had enough variability between Ki-67 indices resulting in differing WHO<br />
classification grades. Twelve cases of 43 (27.9%) resulted in a second sample that<br />
increased <strong>the</strong> WHO grade by at least one level. Seven of 43 (16.3%) resulted in a new<br />
WHO classification of G3.<br />
Conclusions: The Ki67 labeling index in neuroendocrine tumors may change<br />
throughout <strong>the</strong> disease course, may differ between primary tumor and metastases,<br />
and may behave more aggressively later in <strong>the</strong> disease. Given <strong>the</strong> reliance on this<br />
index for management decisions, multiple biopsies of both <strong>the</strong> primary and<br />
metastatic tumor as well as through <strong>the</strong> disease course may be required to effectively<br />
treat <strong>the</strong>se heterogeneous malignancies.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1159P A PHASE II TRIAL OF BEVACIZUMAB COMBINED WITH<br />
CHEMOTHERAPY IN PATIENTS WITH METASTATIC<br />
WELL-DIFFERENTIATED DUODENO-PANCREATIC<br />
ENDOCRINE TUMORS (BETTER STUDY)<br />
J. Seitz 1 , D. Smith 2 ,D.O’Toole 3 , C. Lepère 4 , C. Dromain 5 , A. Gorana 6 , E. Mitry 7 ,<br />
M.P. Ducreux 8<br />
1 Oncologie Digestive, Hôpital de la Timone, Marseille, FRANCE, 2 Oncologie<br />
Digestive, Hôpital Saint André, Bordeaux, FRANCE,<br />
3 Gastroentérologie-Pancréatologie, Hôpital Beaujon, Clichy, FRANCE,<br />
4 Hépato-Gastro Entérologie et Oncologie Digestive, Hôpital Européen Georges<br />
Pompidou, Paris, FRANCE, 5 Radiodiagnostic, Institut Gustave Roussy, Villejuif,<br />
FRANCE, 6 Pharmacovigilance, Laboratoires Roche, Boulogne-Billancourt,<br />
FRANCE, 7 Oncologie Médicale, Institut Curie, Paris, FRANCE, 8 Oncologie<br />
Digestive, Institut de Cancérologie Gustave Roussy, Villejuif, FRANCE<br />
Background: We assessed bevacizumab (Bv), a monoclonal antibody targeting<br />
VEGF, in combination with chemo<strong>the</strong>rapy in duodeno-pancreatic NET, in a<br />
multicenter, open-label, non-randomized, two-group phase II trial. Demographics<br />
and primary endpoint (PFS) will be presented at ASCO <strong>2012</strong> (abstract # 4036). Here<br />
we emphasize on response centralized review, PP analysis and safety data.<br />
Methods: Patients (pts) with progressive, metastatic, well-differentiated<br />
duodeno-pancreatic NET (WHO 2000), ECOG PS ≤2 and Ki 67 index < 15% were<br />
treated with Bv (7.5 mg/kg IV on day 1, every 3 weeks) and 5-FU (400 mg/m 2 /d)/<br />
Streptozocin (500 mg/m 2 /d IV, d1-5/ every 42 days), during 6 months and up to 24<br />
months. Efficacy, safety and quality of life were assessed.<br />
Results: In <strong>the</strong> ITT population (n = 34), 22 (64.7%) pts were men, median age 55.3<br />
years (37.0-77.6), ECOG-PS was 0/1 in 33 pts (97.1%). Ki-67 proliferative index was<br />
between 3 - 15% in 75.0% of pts. After a maximum of 24 months of follow-up per<br />
patient, median PFS assessed by investigators was 23.7 months [95%CI: 13.1; not<br />
reached] based on 18 events. Centralized review of tumor control rate was 100% (n=<br />
33; 1 missing) including partial response in 17 (51.5%) pts and stable disease in 16<br />
(48.5%) pts; similarly to investigators assessments. Survival rate at 24 months was<br />
88%. Median OS was not reached. All efficacy results were comparable in <strong>the</strong> ITT<br />
and PP populations. All patients experienced at least one adverse event (AE). CTC<br />
grade 3/4 AEs occurred in 23 (67.6%) of pts, mainly digestive 5 (14.7%) pts<br />
(abdominal pain, 4 pts). G3/4 AEs of special interest to BV were hypertension in 7<br />
(20.6%) pts and thromboembolism in 3 (8.8%), all venous. No grade 3/4 proteinuria<br />
was observed. Five patients died (4 of disease progression and 1 of thromboembolic<br />
event).<br />
Conclusions: Efficacy results of Bv and 5-FU/stz, a novel approach in<br />
duodeno-pancreatic NET, are encouraging. The toxicity profile of <strong>the</strong> combination of<br />
Bv with streptozocin is acceptable and did not induce any unexpected events. These<br />
results warrant to be confirmed in a phase III study.<br />
Disclosure: M.P. Ducreux: Consultant: Roche, Merck Serono Honoraries: Roche,<br />
Merck Serono, Amgen, Bayer, Fresenus, Pfizer, Sanofi Clinical research project:<br />
Pfizer, Chugai, Merck Serono. J. Seitz: Consultant: Keocyt Honoraries: Roche, Pfizer.<br />
C. Dromain: Consultant: Roche Honoraries: Roche. A. Gorana: Employment: Roche.<br />
E. Mitry: Honoraries: Roche. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
1160P A PHASE II TRIAL OF BEVACIZUMAB WITH CAPECITABINE<br />
IN PROGRESSIVE, METASTATIC WELL-DIFFERENTIATED<br />
DIGESTIVE ENDOCRINE TUMORS (BETTER STUDY)<br />
T.A. Walter 1 , E. Baudin 2 , J.E. Kurtz 3 , P. Ruszniewski 4 , L. Bengrine-Lefevre 5 ,<br />
G. Cadiot 6 , S. Dominguez-Tinajero 7 , S. Kraemer 8 , M.P. Ducreux 9 , E. Mitry 10<br />
1 Oncologie Médicale, Hôpital Edouard Herriot, Lyon, FRANCE, 2 Oncologie,<br />
Institut Gustave Roussy, Villejuif, FRANCE, 3 Oncologie et Hématologie, Hôpitaux<br />
Universitaires, Strasbourg, FRANCE, 4 Gastro-Entérologie, Hôpital Beaujon,<br />
Clichy, FRANCE, 5 Oncologie Médicale, Hôpital Saint-Antoine, Paris, FRANCE,<br />
6 Gastro-Entérologie et Hépatologie, Hôpital Robert Debré, Reims, FRANCE,<br />
7 Oncologie - Pathologie Digestive, Centre Oscar Lambret, Lille, FRANCE,<br />
8 Biostatistique, Laboratoires Roche, Boulogne-Billancourt, FRANCE, 9 Oncologie<br />
Digestive, Institut de Cancérologie Gustave Roussy, Villejuif, FRANCE,<br />
10 Oncologie Médicale, Institut Curie, Paris, FRANCE<br />
Background: We assessed bevacizumab (Bv), a monoclonal antibody directed against<br />
VEGF, combined with capecitabine (CAP) in neuroendocrine digestive tumors<br />
(NET) known to be highly vascularized neoplasms Demographics and primary<br />
endpoint (PFS) will be presented at ASCO <strong>2012</strong> (abstract#4071). Here we emphasize<br />
on response (central review), PP analysis and safety data.<br />
Methods: BETTER is a multicenter, open-label, non-randomized, two-group phase II<br />
trial. Patients (pts) with progressive, metastatic well-differentiated digestive tract<br />
endocrine tumors (WHO 2000 classification), ECOG-PS ≤2, Ki 67 index < 15%, no<br />
prior systemic chemo<strong>the</strong>rapy were treated with Bv (7.5 mg/m 2 on d1/3 weeks) and<br />
CAP (1000 mg/m 2 twice daily, orally d1-14, resumed on day 22). Pts were treated for<br />
≤6 months, up to 24 months. Efficacy (PFS, overall survival [OS], response rate),<br />
safety and quality of life were assessed.<br />
Results: In <strong>the</strong> ITT population (n = 49), 26 (53.1%) pts were men; median age 60.3<br />
years (41.2-82.3); ECOG-PS was 0/1 in 46 (93.9%) pts. Primary tumor site was<br />
mainly small intestine 40 (81.6%) pts. Ki-67 proliferative index was 0-2% in 17<br />
(35.4%) pts and 3-14% in 31 (64.6%). After a maximum of 24 months of follow-up<br />
per patient, median PFS assessed by investigators was 23.4 months [95%CI: 13.2; not<br />
reached] based on 26 events. Centrally reviewed tumor control rate was 93.8% (n =<br />
45) including partial response in 6 (12.5%) pts and stable disease in 39 (81.3%) pts<br />
(1 missing and 3 not evaluable), comparable to investigators assessment. Survival rate<br />
at 24 months was 85%. Median OS was not reached. All efficacy results were similar<br />
in <strong>the</strong> ITT and PP populations. CTC grade 3/4 Adverse Events (AEs) occurred in 41<br />
(83.7%) pts, mainly digestive 14 (28.6%) pts. Main G3/4 AE of special interest to BV<br />
was hypertension in 15 (30.6%) pts. Eight patients died: 3 of disease progression, 2 of<br />
AEs (stroke, peritonitis) and 3 for o<strong>the</strong>r reasons (Parkinson disease, liver<br />
transplantation/septicemia, cardiac arrest).<br />
Conclusions: In this phase II study assessing Bv and CAP in a chemo<strong>the</strong>rapy<br />
resistant tumor; such encouraging results suggest that this combination may become<br />
a good alternative in <strong>the</strong> treatment of ileal NET.<br />
Disclosure: E. Mitry: Honoraries: Roche. E. Baudin: Honoraries: Scientific committee<br />
of BETTER Trial. P. Ruszniewski: Consultant: Ipsen, Novartis, Pfizer Honoraries:<br />
Ipsen, Novartis, Pfizer. Clinical research project: Ipsen, Novartis, Pfizer. G. Cadiot:<br />
Honoraries: Novartis, Ipsen, Pfizer O<strong>the</strong>r financing (please detail): Novartis, Ipsen,<br />
Pfizer. S. Kraemer: Employment: Roche. M.P. Ducreux: Consultant: Roche, Merck<br />
Serono Honoraries: Roche, Merck Serono, Amgen, Bayer, Fresenus, Pfizer, Sanofi<br />
Clinical research project: Pfizer, Chugai, Merck Serono. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
1161P TREATMENT OF ADVANCED NEUROENDOCRINE TUMOURS:<br />
FINAL RESULTS OF THE UKINETS AND NCRI RANDOMISED<br />
PHASE 2 NET01 TRIAL<br />
T. Meyer 1 , M. Caplin 2 , N. Reed 3 , W. Qian 4 , S. Lao-Sirieix 4 , G. Armstrong 4 ,<br />
J. Valle 5 , D. Tablot 6 , D. Cunningham 7 , P. Corrie 8<br />
1 Ucl Cancer Institute, University College London, London, UNITED KINGDOM,<br />
2 Royal Free Hampstead Nhs Trust, Royal Free Hampstead NHS Trust, London,<br />
UNITED KINGDOM, 3 Beatson Oncology Centre, Gartnavel General Hospital,<br />
Glasgow, UNITED KINGDOM, 4 Cambridge Cancer Trials Centre, Cambridge<br />
University Hospitals NHS foundation Trust, Cambridge, UNITED KINGDOM,<br />
5 Histopathology, The Christie NHS Foundation Trust, Manchester, UNITED<br />
KINGDOM, 6 Cancer Medicine, University of <strong>Oxford</strong>, <strong>Oxford</strong>, UNITED KINGDOM,<br />
7 The Royal Marsden, The Royal Marsden, London, UNITED KINGDOM,<br />
8 Oncology Centre, Cambridge University Hospitals NHS Foundation Trust,<br />
Cambridge, UNITED KINGDOM<br />
Background: Chemo<strong>the</strong>rapy is widely used for advanced, unresectable<br />
neuroendocine tumours (NETs) but only four randomised trials are published. The<br />
first combined streptozocin (strep) and 5fluorouracil (5FU), reporting 63% response<br />
rate (RR), but subsequent retrospective studies had lower RRs (6-45%). Cisplatin has<br />
been combined with strep + 5FU in a retrospective study with promising activity in<br />
ix378 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
NETs and capecitabine (cap) has been effectively substituted for 5FU in many<br />
tumours. The NET01 trial was designed to investigate whe<strong>the</strong>r cap + strep ± cisplatin<br />
warrant fur<strong>the</strong>r evaluation.<br />
Methods: Patients (pts) with histologically confirmed, unresectable, advanced and/or<br />
metastatic NETs of foregut, pancreatic or unknown primary site were randomised<br />
(1:1) to 6 cycles of 3-weekly cap 625 mg/m 2 po bd daily (D1-21), strep 1.0g/m 2 IV<br />
(D1), with cisplatin 70mg/m 2 IV (D1) (Cap-strep-cist) or without (Cap-strep). The<br />
primary outcome measure was RR using RECIST criteria. 84 pts were required to test<br />
a RR of 60% with a significance level of 5% and 80% power in each arm.<br />
Central pathology review and 10% of central radiology review were performed.<br />
Results: 86 pts (58% male, median age 59 years) were randomised (44 Cap-strep, 42<br />
Cap-strep-cist) with primary site – foregut 20%, pancreatic 48% and unknown 33%.<br />
The grade was low 12 (17%), intermediate 43 (62%) and high 14 (20%). Baseline<br />
characteristics were balanced between <strong>the</strong> 2 arms. 59% Cap-strep and 33%<br />
Cap-strep-cist pts received ≥6 cycles. 18 Cap-strep and 26 Cap-strep-cist pts<br />
experienced grade ≥3 toxicities. Outcome results are summarised in <strong>the</strong> table.<br />
Cap-strep-cist Cap-strep<br />
Response PR SD PD n = 38 13% 61% 26% n = 40 8% 73% 20%<br />
PFS No. progressions/deaths,<br />
n(%) Median (mo)<br />
n = 42 35 (83%) 9.7 n = 44 34 (77%) 10.2<br />
OS No. deaths, n(%) Median<br />
(mo)<br />
n = 42 22 (52%) 27.5 n = 44 25 (57%) 26.7<br />
Conclusions: The novel Cap-strep ± cisplatin regimens were associated with overall<br />
disease control and survival durations consistent with published studies. Cap-strep<br />
was better tolerated than Cap-strep-cist. Fur<strong>the</strong>r prospective randomised trials are<br />
needed to determine optimal NET chemo<strong>the</strong>rapy.<br />
Disclosure: D. Cunningham: Research Funding: Amgen, Roche. Astra Zeneca Expert<br />
testimony: Amgen (Uncompensated) Honoraria: None Advisory: Amgen Roche<br />
(Uncompensated). All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1162P PHASE 1 STUDY OF EVEROLIMUS COMBINED WITH<br />
LUTETIUM-177 OCTREOTATE RADIOPEPTIDE THERAPY OF<br />
ADVANCED LOW-GRADE NEUROENDOCRINE TUMOURS<br />
P. Claringbold 1 , J.H. Turner 2<br />
1 Oncology, Fremantle Hospital and Health Service, Fremantle, WA, AUSTRALIA,<br />
2 Nuclear Medicine, Fremantle Hospital, Fremantle, WA, AUSTRALIA<br />
Background: Recent clinical trials of mTOR inhibitors have shown benefit from<br />
everolimus treatment of advanced low-grade neuroendocrine tumours (NETs).<br />
Targeting of NET somatostatin receptors with radiopeptides is ano<strong>the</strong>r effective<br />
<strong>the</strong>rapeutic option. This phase I study investigates <strong>the</strong> safety of combining<br />
everolimus with lutetium-177 octreotate.<br />
Methods: Patients with biopsy proven low-grade NETs (Ki 67 index < 5%), positive<br />
on gallium 68-octreotate PET scan were studied. All patients received fixed dose 7.8<br />
GBq lutetium-177 octreotate each 8 weeks for 4 cycles, combined with everolimus.<br />
Successive cohorts received escalating doses of everolimus in groupings of 5, 7.5 and<br />
10 mg given as a daily oral dose for <strong>the</strong> 24 weeks of radiopeptide <strong>the</strong>rapy. Dose<br />
limiting toxicities were established by standard NCI common toxicity criteria<br />
(CTCAE v 4.03).<br />
Results: Eleven patients have been treated, 4 patients at <strong>the</strong> 5 mg everolimus dose<br />
level and 3 each at <strong>the</strong> 7.5 mg and 10 mg levels. Full dose lutetium-177 octreotate<br />
for 4 cycles was possible in 6 of 7 patients in cohorts 1 and 2, whilst only 1 of<br />
3 patients completed all cycles at <strong>the</strong> 10 mg dose level. Patients at 5 mg and 7.5<br />
mg doses of everolimus received 85% of <strong>the</strong> total planned dosage over 24 weeks.<br />
All patients required dose reduction or complete cessation of everolimus at <strong>the</strong><br />
10 mg level because of unacceptable toxicities. The commonest reasons for dose<br />
reductions in cohorts 1 and 2 were grade 2 or 3 neutropenia and<br />
thrombocytopenia. Unexpected reversible grade 2 nephrotoxicity caused significant<br />
reductions in creatinine clearance levels of 40-50% baseline in 2 of 3 patients in<br />
<strong>the</strong> 10 mg cohort, not seen in <strong>the</strong> lower dose levels. Tumour responses have been<br />
observed at each dose level.<br />
Conclusion: Everolimus can be combined safely with lutetium-177 octreotate to treat<br />
low-grade NETs. Toxicities were observed at all dosage levels of everolimus but<br />
appear manageable and reversible. The maximum tolerated dose (MTD) of<br />
everolimus was 7.5 mg daily in combination with 7.8 GBq lutetium-177 octreotate in<br />
a 4 cycle course over 24 weeks.<br />
Disclosure: P. Claringbold: Dr Claringbold has acted on an advisory panel and<br />
received financial support from Novartis Pharmaceuticals. J.H. Turner: Dr Turner<br />
has acted on an advisory panel and received financial support from Novartis<br />
Pharmaceuticals.<br />
1163P RESPONSE EVALUATION USING RECIST AND CHOI<br />
CRITERIA IN PATIENTS WITH WELL-DIFFERENTIATED<br />
PANCREATIC NEUROENDOCRINE TUMORS (PNET)<br />
TREATED WITH SUNITINIB OR EVEROLIMUS<br />
C. Dreyer 1 , O. Hentic 2 , M. Zappa 3 , P. Hammel 2 , M. Bouattour 1 , C. Mateescu 1 ,<br />
S. Faivre 1 , P. Ruszniewski 2 , E. Raymond 4<br />
1 Oncology Department, Beaujon University Hospital, Clichy, FRANCE,<br />
2 Gastroenterology, Beaujon, Clichy, FRANCE, 3 Radiology, Beaujon, Clichy,<br />
FRANCE, 4 Department of Medical Oncology, Beaujon University Hospital, Clichy,<br />
FRANCE<br />
Background: Despite low response rate by RECIST, sunitinib and everolimus<br />
improved <strong>the</strong> progression-free survival of patients (pts) with well-differentiated<br />
pNET in two large phase III controlled trials. RECIST being a poor surrogate<br />
endpoint for PFS, this study aimed evaluating <strong>the</strong> value of CHOI criteria in PNET<br />
pts.<br />
Methods: Data for this analysis were collected from pts with well-differentiated<br />
PNET treated consecutively with sunitinib or everolimus in our center between<br />
10-2006 and 11-2010. All pts had tumor progression within 12 months (m) prior to<br />
treatment. Pts were considered evaluable if CT-scans were performed within 6 weeks<br />
prior treatment and
pts. Poorly differentiated endocrine carcinoma (PDEC). Age (median) 54 a. (r<br />
18-84). Primary Location: small intestine 40, pancreas 26 pts. Appendix 9 pts.,<br />
Stomach 8, rectum 6, unknown 6, colon 4, and esophagus 1 pte. Metastatic disease<br />
76 pts., Localized disease in 24 pts. The expression of SSTR was: Subtype 2 (positive<br />
80 pts.) and subtype 5 (positive 46 pts.). Ki 67 was less than or equal to 2% in 36<br />
pts., between 3 and 15%, 49 pts. and more than 15% in 12 pts. 26/100 pts. had<br />
functioning tumors. The analysis included 55 pts. with SSTR 2 / 5 pos. Ki 67 less<br />
than or equal to 2% (Group 1), 38 pts. with SSTR 2 / 5 pos and Ki 67 more than 2%<br />
(Group 2), 5 pts. with SSTR 2 / 5 neg. Ki 67 less than or equal to 2% (Group 3) and<br />
2 pts. with SSTR 2 / 5 neg and Ki 67 more than 2% (Group 4). Univariate analysis<br />
showed significant differences for <strong>the</strong> expression of SSTR 2 (p. 009), and Ki 67<br />
(p. 001). Survival was higher in Group 1 versus Group 2, median OS was 97 months<br />
vs 49 months, and 36 to 23 months, in groups 3 and 4 respectively (p. 0001).<br />
Conclusions: In this population of pts with GEP-NET we could identify a subgroup<br />
of better prognosis associated with expression of SSTR 2 / 5 and Ki 67 less than or<br />
equal to 2%. The assessment of SSTR 2 and 5 in tissue, and proliferative index are<br />
useful tools for evaluating prognosis in this setting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1165P EFFICACY AND SAFETY OF SOMATULINE AUTOGEL IN<br />
COMBINATION WITH MOLECULAR TARGETED THERAPIES<br />
(MTT) IN NEUROENDOCRINE TUMORS (NETS)<br />
J. Capdevila 1 , I. Sevilla 2 , V. Alonso 3 , L. Anton-Aparicio 4 , P. Jimenez Fonseca 5 ,<br />
E. Grande 6 , J.J. Reina 7 , J.L. Manzano 8 , J. Alonso-Jara 9 , P. García Alfonso 10<br />
1 Medical Oncology, Vall d’Hebron University Hospital, Barcelona, SPAIN,<br />
2 Medical Oncology, Virgen de la Victoria University Hospital, Malaga, SPAIN,<br />
3 Medical Oncology, Miguel Servet University Hospital, Zaragoza, SPAIN,<br />
4 Medical Oncology, Complejo Hospitalario A Coruña, A Coruña, SPAIN, 5 Medical<br />
Oncology, Hospital Universitario Central de Asturias, Oviedo, SPAIN, 6 Medical<br />
Oncology, Ramon y Cajal University Hospital, Madrid, SPAIN, 7 Medical<br />
Oncology, Virgen de la Macarena University Hospital, Sevilla, SPAIN, 8 Medical<br />
Oncology, ICO Hospital Germans Trias i Pujol, Barcelona, SPAIN, 9 Medical<br />
Oncology, Virgen de la Arrixaca University Hospital, Murcia, SPAIN, 10 Medical<br />
Oncology, Gregorio Marañón University Hospital, Madrid, SPAIN<br />
Background: Analysis of <strong>the</strong> mechanisms of action of somatostatin analogs (SSAs)<br />
and mTOR inhibitors or multiple tyrosine kinase inhibitors have suggested that <strong>the</strong>y<br />
may provide synergistic effects when used in combination for <strong>the</strong> treatment of<br />
patients with NETs.<br />
Methods: This is a Spanish Multicenter cohort of patients (pts) with NETs treated<br />
with <strong>the</strong> SSAs lanreotide (LAN) and MTTs at 35 Spanish Medical Oncology<br />
Departments. The data of 159 combined treatments (133 pts) was retrospectively<br />
collected in order to evaluate <strong>the</strong> efficacy and safety of such combinations out of trials.<br />
Results: 133 pts (52,6% Male) with a mean age of 59,4 years; ECOG 0/1/2/3: 34%/<br />
49%/16%/1%; Lung/Pancreas/Gastrointestinal//Unknown(UK)origin: 9%/48% /32%/<br />
11%; G1/G2/G3/UK: 41%/32%/1%/26%; Non Functioning/ Functioning (69%/31%)<br />
received treatment with MTT + LAN for synergistic antiproliferative purpose in 85%<br />
of <strong>the</strong> cases, hormonal control (13,5%) or both objectives (1,5%). 115 pts received<br />
just one and 18 pts received between 2 (12 pts) and 5 (1 pt) combination treatments.<br />
LAN was administrated in combination with everolimus (46%), sunitinib (38%),<br />
bevazucimab (6%), sorafenib (5%) and pazopanib (5%). The reported toxicity was<br />
determined by <strong>the</strong> MTT profile with no significant additional severe adverse events<br />
related to <strong>the</strong> combination with LAN. The median progression-free survival (mPFS)<br />
for <strong>the</strong> two main groups was 31.9 months for those pts who received LAN and<br />
sunitinib (n = 50) and 21.9 months for those pts who received LAN and everolimus<br />
(n = 56).<br />
Conclusions: The combination of LAN and MTT treatments, mainly everolimus and<br />
sunitinib, is widely used in clinical practice without unexpected toxicities. Although<br />
studies are not directly comparable mPFS observed in <strong>the</strong> two main groups were<br />
higher than data showed by phase III studies with sunitinib, everolimus or SSAs<br />
alone raising <strong>the</strong> hypo<strong>the</strong>sis of enhanced antitumor efficacy combining SSAs and<br />
MTT that should be confirmed in randomized prospective clinical trials.<br />
Tumor Response (%)<br />
Nº PD SD PR CR Not evaluated<br />
61 Sunit +LAN 4.9 68.9 14.8 1.6 9.8<br />
73 Evero +LAN 12.3 67.0 15.1 0 5.5<br />
9 Bevac +LAN 0 88.9 11.1 0 0<br />
8 Soraf +LAN 0 100.0 0 0 0<br />
8 Pazop +LAN 12.5 75.0 12.5 0 0<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
1166P AWARENESS OF THE CLINICAL PRESENTATION AND<br />
DIAGNOSIS OF NEUROENDOCRINE TUMOURS IN AN<br />
AUSTRALIAN GENERAL PHYSICIAN POPULATION<br />
J.C. Leyden<br />
Anaes<strong>the</strong>sia, Royal North Shore Hospital, St Leonards, NSW, AUSTRALIA<br />
Background: Neuroendocrine Tumours (NETs) are a rare group of malignancies<br />
where <strong>the</strong> correct diagnosis is often delayed for many years resulting in local and<br />
distant spread of <strong>the</strong> disease and mean 5 year survival rate of 30%. The diagnosis<br />
of NETs is challanging and requires <strong>the</strong> expertise of many medical specialists and<br />
diagnostic modalities. The General Physician (GP) is pivotal for early recognition,<br />
referral and management of this disease. The Unicorn Foundation, Australia’s only<br />
charity directed to NET patient support, advocacy and research conducted a<br />
survey of Australian Physicians to determine knowledge of NETs. A secondary<br />
objective of <strong>the</strong> survey was to raise awareness of <strong>the</strong> disease in a broad medical<br />
population.<br />
Methods: 9952 registered medical practitioners received an introductory email<br />
requesting participation in <strong>the</strong> online “NET Awareness Survey”. The questions were<br />
presented as ‘best answer’ multiple choice format with <strong>the</strong> ability to choose ‘not sure’<br />
as an option. 26 questions covering basic NET epidemiology, clinical pathology and<br />
presentation, diagnosis and referral pattern were included.<br />
Results: The survey was open from July 2011 until December 2011. A population of<br />
9552 registered medical practitioners received <strong>the</strong> email; 38% (3630) ‘opened’ <strong>the</strong><br />
email and 7% (655) completed <strong>the</strong> survey. Of <strong>the</strong> survey respondants, 65% (425)<br />
were General Physicians. The results of <strong>the</strong> survey indicated a lack of awareness/<br />
knowledge regarding NET epidemiology; pathology; spectrum of disease (including<br />
metastatic potential) and use of Chromogranin A as a biomarker of <strong>the</strong> disease. The<br />
majority of <strong>the</strong> respondants acknowledged <strong>the</strong> difficulties of diagnosis; <strong>the</strong> myriad<br />
presenting symptoms and association of NETs with familial syndromes.<br />
Conclusion: The survey results showed that a significant proportion of General<br />
Physicians had minimal knowledge of Neuroendocrine Tumours (NETs) and <strong>the</strong>ir<br />
behaviour and <strong>the</strong>re was a general misunderstanding of appropriate investigations to<br />
facilitate diagnosis. Improved awareness of <strong>the</strong> NETs and investigative strategies to<br />
improve diagnosis are needed amongst medical practitioners especially those in<br />
general practice.<br />
Disclosure: J.C. Leyden: This research project has been supported by unrestricted<br />
educational grant from Novartis Oncology, Ipsen Pharmaceutical and Pfizer<br />
Pharmaceutical.<br />
1167P NEUROENDOCRINE TUMORS: A REVIEW OF THE<br />
SUNNYBROOK ODETTE CANCER CENTRE DATABASE<br />
J. Craig 1 , M. Cheung 2 ,C.Law 3 , S. Singh 4<br />
1 Medical Oncology, Sunnybrook Odette Cancer Center, Toronto, ON, CANADA,<br />
2 Hematology, Odette Cancer Centre, Sunnybrook Health Sciences Centre,<br />
Toronto, ON, CANADA, 3 Surgical Oncology, Odette Cancer Centre, Sunnybrook<br />
Health Sciences Centre, Toronto, ON, CANADA, 4 Medical Oncology, Odette<br />
Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, CANADA<br />
Background: Neuroendocrine tumors (NETs) are an uncommon and heterogeneous<br />
group of malignancies. A number of reviews have been published attempting to<br />
better identify factors of important prognostic significance in predicting overall<br />
survival, however <strong>the</strong>se studies are often limited by small sample size and were<br />
published before new <strong>the</strong>rapy options came into widespread use. AIMS: We reviewed<br />
our experience at our NETs multidisciplinary reference centre in <strong>the</strong> management of<br />
NETs to attempt to identify important patient and tumor characteristics associated<br />
with improved overall survival.<br />
Methods: The Sunnybrook Odette Cancer Centre NETs Database was retrospectively<br />
reviewed. All patients with a pathologically confirmed diagnosis of NET were<br />
included in <strong>the</strong> analysis. Patient characteristics, tumor markers and pathology,<br />
treatment, and response to treatment were recorded. Univariate and multivariate<br />
Cox-regression analyses were performed.<br />
Results: A total of 327 patients were included in <strong>the</strong> analysis. Mean age at presentation<br />
was 55.6 years. A total of 159 (48.6%) patients were male. The most common primary<br />
site was small bowel (34.3%), followed by pancreas (21.1%) and large bowel/rectum/<br />
anus (11.9%). In univariate analysis, factors associated with improved overall survival<br />
included local/regional disease at presentation (p < 0.001), lower Ki67 index<br />
(p < 0.001), normal chromogranin A at presentation (p = 0.008), urinary<br />
5-Hydroxyindoleacetic acid drop following treatment (p = 0.024), symptom response to<br />
treatment (p < 0.001), surgery on <strong>the</strong> primary tumor (p < 0.001), surgery on metastases<br />
(p = 0.003), having multiple surgeries (p < 0.001), and treatment with long-acting<br />
somatostatin (LAS) (p = 0.029). In multivariate analysis, treatment with LAS (p <<br />
0.001, HR 0.141, 95%CI 0.064-0.31) and having multiple surgeries (p = 0.045, HR<br />
0.591, CI 0.354-0.988) were shown to be independent predictors of improved overall<br />
survival.<br />
ix380 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Conclusions: Treatment with long-acting somatostatin and having multiple surgeries<br />
were shown to be independent predictors of improved overall survival in NETs. This<br />
data fur<strong>the</strong>r supports <strong>the</strong> use of aggressive medical and surgical intervention in a<br />
multi-modal approach for advanced NETs. This may be best achieved in <strong>the</strong> setting<br />
of NETs multidisciplinary reference centres.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1168P DOES SPECIALIST CENTRE HISTOPATHOLOGY REVIEW<br />
OF GASTROINTESTINAL NEUROENDOCRINE TUMOURS<br />
AFFECT CLINICAL MANAGEMENT?<br />
S.C. Bowen Jones, L. Foster, J. Valle, W. Mansoor, R. Hubner, B. Chakrabarty<br />
Histopathology, The Christie NHS Foundation Trust, Manchester,<br />
UNITED KINGDOM<br />
Introduction: Gastroenteropancreatic Neuroendocrine Tumours (GEP NET) are<br />
uncommon tumours occurring at all sites within <strong>the</strong> gastrointestinal tract. The<br />
behaviour of <strong>the</strong>se tumours is difficult to predict and <strong>the</strong>y have been subject to<br />
numerous changes in classification and grading systems. In <strong>the</strong> UK <strong>the</strong> National<br />
Institute for Clinical Excellence recommends centralised histopathology review of<br />
<strong>the</strong>se tumours by a member of <strong>the</strong> NET tumour board. We aimed to determine <strong>the</strong><br />
frequency of discrepancies between local and central histopathology that could<br />
impact clinical management.<br />
Methods: We identified 86 cases of suspected GEP NET referred for specialist<br />
histopathology review at <strong>the</strong> regional network centre from January 2010 to April<br />
<strong>2012</strong>. Cases were identified by a SnoMed search for cases coded under various<br />
endocrine tumour designations and by cross referencing with patient lists from<br />
multidisciplinary team meetings. Details of <strong>the</strong> local and network centre pathology<br />
reports were compared. The reports were also judged for compliance with <strong>the</strong> UK<br />
Royal College of Pathologists minimum dataset.<br />
Results: There was complete diagnostic agreement in 54 cases (63%). Discrepancies<br />
occurred in <strong>the</strong> remaining 32 cases (37%), including, 18 differences in grade or<br />
proliferation index score (21%), 16 differences in nomenclature (19%), 6 differences<br />
in stage (7%) and 5 differences in assessment of perineural or vascular invasion (6%).<br />
In 9 cases (10%) an original diagnosis of endocrine tumour was changed to a<br />
different type of tumour without endocrine differentiation or vice versa following<br />
review. Twenty-six of <strong>the</strong> overall discrepancies (30% of <strong>the</strong> total cases) had <strong>the</strong><br />
potential to meaningfully impact on clinical management. In addition, nei<strong>the</strong>r<br />
tumour grade nor proliferation index were recorded in 15 local pathology reports<br />
(17%), which would necessitate additional pathological analysis prior to clinical<br />
decision making. There was full adherence to <strong>the</strong> minimum dataset in only 19 cases<br />
(42% of resections).<br />
Conclusions: This study highlights <strong>the</strong> importance of specialist centre histopathology<br />
review of GEP NET to ensure <strong>the</strong>se patients receive <strong>the</strong> appropriate clinical<br />
management.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1169P NOVEL INFLAMMATION-BASED PROGNOSTIC<br />
DETERMINANTS IN PATIENTS WITH CARCINOMA<br />
OF UNKNOWN PRIMARY<br />
Z. Mohamed, D.J. Pinato, R. Sharma<br />
Division of Experimental Medicine, Imperial College London, Hammersmith<br />
Hospital, Hammersmith, UNITED KINGDOM<br />
Background: Carcinomas of unknown primary (CUP) incorporate tumours with<br />
heterogeneous biology and invariably poor prognosis. There is a lack of validated<br />
prognostic indices in this context. The presence of a cancer related systemic<br />
inflammatory reaction is both pathogenic and prognostic in advanced cancer. We<br />
aimed to assess whe<strong>the</strong>r a panel of inflammatory indices including <strong>the</strong><br />
modified-Glasgow Prognostic Score (mGPS), neutrophil/lymphocyte ratio (NLR) and<br />
platelet/lymphocyte ratio (PLR) could predict prognosis and response to <strong>the</strong>rapy in<br />
CUP.<br />
Methods: Consecutive patients diagnosed with histologically proven CUP at <strong>the</strong><br />
Imperial College oncology unit (1996-2011) were considered. Demographic,<br />
treatment, disease status and bloods were collected. The effect of candidate<br />
prognostic factors on overall survival (OS) was determined using Kaplan-Meier<br />
curves followed by multivariate Cox regression analysis. Normalisation of <strong>the</strong> NLR<br />
following 1 cycle of epirubicin cisplatin and capecitabine (ECX) chemo<strong>the</strong>rapy was<br />
tested for its impact on OS in a subgroup of patients receiving ECX chemo<strong>the</strong>rapy<br />
(n = 14).<br />
Results: 60 patients were included: median age 61 (range: 33-86); 51% men; median<br />
OS 5.9 months (0.7-42.9); 88% had metastasatic disease. On univariate analysis NLR<br />
> 5 (p = 0.009) and mGPS (p = 0.027) correlated with OS, unlike PLR > 300 (p = 0.5).<br />
Multivariate analysis confirmed mGPS (Hazard Ratio (HR); 1.52, 95%CI 1.0-2.3 p =<br />
0.029) and NLR > 5 (HR 2.02 95%CI 1.0-4.1, p = 0.043) as independent predictors of<br />
OS. NLR normalisation post 1 cycle of ECX was associated with improved OS (8.6<br />
months vs 4.6 months, p = 0.014). Results from an independent validation set will be<br />
presented.<br />
Conclusion: Inflammatory indices are independent prognostic predictors in patients<br />
with CUP. Additionally, correction of NLR appears to reflect successful disease<br />
modulating effects of chemo<strong>the</strong>rapy and may be used to predict survival benefit from<br />
treatment. External validation of <strong>the</strong>se scores is ongoing.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1170P PROGNOSTIC AND PREDICTIVE SIGNIFICANCE OF<br />
PHARMACOGENETIC ANALYSIS IN PATIENTS WITH<br />
CARCINOMAS OF UNKNOWN PRIMARY (CAUP)<br />
C. Papadaki 1 , G. Pen<strong>the</strong>roudakis 2 , A. Cervantes Ruiperez 3 , E. Lagoudaki 4 ,<br />
D. Petrakis 2 , J. Souglakos 5 , E.R. Braun 6 , V. Georgoulias 7 , D. Mavroudis 5 ,<br />
N. Pavlidis 8<br />
1 Laboratory of Tumor Cell Biology, School of Medicine, University of Crete,<br />
Heraklion, GREECE, 2 Medical Oncology, University General Hospital of Ioannina,<br />
Ioannina, GREECE, 3 Serv. Hematologia y Oncologia Medica, Hospital Clinico<br />
Universitario de Valencia, Valencia, SPAIN, 4 Laboratory of Pathology, School of<br />
Medicine, University of Crete, Heraklion, GREECE, 5 Medical Oncology, University<br />
General Hospital of Heraklion, Crete, GREECE, 6 Hematology and Medical<br />
Oncology, INCLIVA University of Valencia, Valencia, SPAIN, 7 Medical Oncology,<br />
University Hospital of Heraklion, Heraklion, GREECE, 8 Dept. Medical Oncology,<br />
University of Ioannina, Ioannina, GREECE<br />
Purpose: To investigate <strong>the</strong> prognostic/predictive significance of <strong>the</strong> expression of<br />
BRCA1, ERCC1, RRM1, TOPO-I, TOPO-IIa, TOPO-IIb, TXR1 TYMS and HIF1a<br />
mRNA in patients with Carcinomas of Unknown Primary (CaUP).<br />
Material and methods: Ninety-three patients with CaUP and available tumoral<br />
samples diagnosed in three institutions were included in <strong>the</strong> study. The mRNA levels<br />
of <strong>the</strong> target genes were determined by quantitative real-time PCR from<br />
microdissected cells derived from patients’ tumoral specimens. β-actin and PGK1<br />
were used as reference genes.<br />
Results: Successful amplification of at least one gene was achieved in all samples.<br />
BRCA1, ERCC1, HIF1a and TXR1 were amplified in all samples, while RRM1,<br />
TOPO-I, TOPO-IIa, TOPO-IIb were amplified in 88 samples and TYMS in 86 of<br />
<strong>the</strong>m. Patients’ characteristics were: median age 68 (28-84) years; 53 (57%) males;<br />
ECOG-PS 0 in 23 (25%), 1 in 33 (35%) and ≥ 2 in 37 (40%) patients. The<br />
histological type was: 47 (50%) adenocarcinomas, 18 (19%) squamous cell<br />
carcinomas, 14 (15%) undifferentiated carcinomas, 8 (9%) carcinomas with<br />
neuroendocrine features and 6 (6%) clear cell carcinomas. Forty-one (47%)<br />
patients received a platinum analog as 1 st line treatment, while 21 (24%) were<br />
treated with taxane-based chemo<strong>the</strong>rapy. Patients with high ERCC1 mRNA levels<br />
presented increased median overall survival compared with those with low<br />
ERCC1 expression (mOS: 16.5 versus 8.3 months; p = 0.034). Also, high<br />
compared to low expression of TXR1 or TOPO-I was significantly correlated with<br />
decreased survival (4.5 months vs. 22.6 months; p = 0.015 and 5.9 months vs.<br />
16.5 months; p = 0.042, respectively). A statistical trend for increased survival was<br />
also observed in patients with low HIF1a expression (p = 0.07), while <strong>the</strong><br />
expression of <strong>the</strong> o<strong>the</strong>r genes did not show significant prognostic correlation. No<br />
predictive significance of any gene was observed in patients treated with a<br />
platinum analog.<br />
Conclusions: The ERCC1, TXR1, TOPO-IA and HIF1a expression may be used as<br />
prognostic markers in patients with CaUP. The predictive significance of <strong>the</strong>se genes<br />
was not confirmed in <strong>the</strong> small subgroup of patients treated with platinum analogs.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1171P THE IMPACT OF PERFORMANCE STATUS AT DIAGNOSIS<br />
ON PROGRESSION-FREE SURVIVAL AFTER SECOND-LINE<br />
CHEMOTHERAPY IN UNFAVORABLE-RISK CANCER OF<br />
UNKNOWN PRIMARY PATIENTS<br />
T. Shimoi, E. Sasaki, M. Kudo, T. Shimoyama, Y. Omuro, R. Okamoto,<br />
Y. Maeda, T. Sasaki<br />
Chemo<strong>the</strong>rapy, Cancer and Infectious Diseases Center Komagome Hospital,<br />
Bunkyo-ku, Tokyo, JAPAN<br />
Introduction: Cancer of unknown primary (CUP) patients classified as an<br />
unfavorable-risk group generally have a poor prognosis. Moreover, <strong>the</strong>re are no<br />
well-defined studies of <strong>the</strong> efficacy of second-line chemo<strong>the</strong>rapy in unfavorable-risk<br />
CUP patients. Unfavorable-risk CUP patients who had second-line chemo<strong>the</strong>rapy<br />
were retrospectively reviewed, and <strong>the</strong> characteristics predictive of better<br />
progression-free survival (PFS) after second-line chemo<strong>the</strong>rapy were examined.<br />
Methods: A total of 117 CUP patients was diagnosed in our hospital between May<br />
2002 and April <strong>2012</strong>, and 97 patients had more than first-line chemo<strong>the</strong>rapy. A total<br />
of 34 patients (46% of unfavorable-risk patients) received second-line chemo<strong>the</strong>rapy.<br />
Results: Among 34 patients, <strong>the</strong>re were 21 female patients (62%). The median age<br />
was 60 (range, 39–74) years. The majority of patients had PS 1 (75%).<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds405 | ix381
Adenocarcinoma was present in 25 patients. The median number of primary<br />
metastatic sites was 2.5 (range, 1–8) sites, with 3 (range, 1–9) metastatic sites before<br />
second-line chemo<strong>the</strong>rapy. For <strong>the</strong> first-line chemo<strong>the</strong>rapy regimen, 28 patients (82%)<br />
had a platinum-based combination regimen. For second-line chemo<strong>the</strong>rapy, 12 patients<br />
received platinum-based combination chemo<strong>the</strong>rapy, 12 patients had non-platinum-based<br />
combination chemo<strong>the</strong>rapy, and 10 patients had non-platinum-based mono<strong>the</strong>rapy.<br />
Response to second-line chemo<strong>the</strong>rapy; 7 (21%) patients showed an objective partial<br />
response, and 16 (47%) showed stable disease. The median overall survival in 34<br />
unfavorable-risk CUP patients who could receive second-line chemo<strong>the</strong>rapy was 46<br />
months (median survival time not reached). The median PFS after second-line<br />
chemo<strong>the</strong>rapy was 1.8 (range, 0.23–25) months. Multivariate Cox analysis showed that PS<br />
0 or 1 relative to PS 2 at initial diagnosis was related to better PFS (Hazard Ratio, 0.033;<br />
95% confidence interval, 0.00053-0.61) (p = 0.022).<br />
Conclusion: The results of this retrospective study showed that 21% of<br />
unfavorable-risk patients responded to second-line chemo<strong>the</strong>rapy. The data suggest<br />
that PS 0 or 1 may be associated with better PFS after second-line chemo<strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1172 LONG ACTING OCTREOTIDE IN PTS WITH DISSEMINATED<br />
NEUROENDOCRINE TUMORS<br />
A. Markovich, G. Emelianova, V. Gorbounova, V. Bruzgin, N. Orel<br />
Dept. of Chemo<strong>the</strong>rapy, N.N. Blokhin Russian Cancer Research Center of Ramn,<br />
Moscow, RUSSIAN FEDERATION<br />
Objectives: To evaluate <strong>the</strong> effectiveness of long acting octreotide at <strong>the</strong> doses 30 -<br />
40 mg per month in heavily pretreated pts (pts) with disseminated neuroendocrine<br />
tumors (NET).<br />
Annals of Oncology<br />
Patients and methods: 31 pts with disseminated NET, progressing on different<br />
treatment regimens. We used long acting octreotide: Sandostatin-LAR,<br />
Octreotide-Depo, Octreotide-LONG. Origin of <strong>the</strong> tumor were: pancreas (3 pts,<br />
9.7%), intestines (15 pts, 48.4%), lung (1 pt, 3.2%), kidney (1 pt, 3.2%), or unknown<br />
(11 pts, 35.5%).Tumor grades were as follows: G1 - 8 (25.8%), G2 - 14 (45.2%), G3<br />
-1 (3.2%), unknown - 8 (25.8%). Isolated liver metastases were found in 15 pts<br />
(48.4%). 12 pts (38.7%) had liver metastases in combination with o<strong>the</strong>r sites of<br />
involvement. Carcinoid syndrome along with high levels of serum chromogranin A,<br />
serotonin and 5-OIAA were present in 29 pts (93.5%). Initially, 29 pts received long<br />
acting octreotide 20 mg for an average of 20 months (range, 3-60). The reasons for<br />
dose escalation were disease progression in 19 pts (61.3%), increase in markers and<br />
lack of control of carcinoid syndrome in 12 pts (38.7%). In 18 pts (58%) <strong>the</strong> dose<br />
was 30 mg, in 13 pts (42%) — 40 mg. 14 pts received long acting octreotide only<br />
(45.1%), 6 pts (19.4%) — in combination with α-interferon, 11 pts (35.5%) - in<br />
combination with chemo<strong>the</strong>rapy.<br />
Results: In 14 pts receiving long acting octreotide only, objective responses were not<br />
observed; 11pts (78.6%) had stable disease (SD), 3 pts (21.4 %) progressed. Median<br />
time to progression was not reached. The pts were followed for a median of 13.5<br />
months. 5 pts (35.7%) are still receiving <strong>the</strong> treatment after 20 months. In <strong>the</strong> total<br />
group PR (partial response) was observed in 1 pts (3.2%), receiving octreotide with<br />
chemo<strong>the</strong>rapy, SD — in 25 pts (80.7%), PD — in 5 pts (16.1%). Control of tumor<br />
growth was achieved in 83.9% of cases, <strong>the</strong>se pts got a biochemical response and<br />
obtained symptom relief. In <strong>the</strong> total group <strong>the</strong> median time to progression was 18<br />
months. Median survival was not reached. Tolerability of long-acting octreotide in a<br />
dose of 30-40 mg was satisfactory for all pts.<br />
Conclusion: long acting octreotide at doses of 30-40 mg, alone or in combination<br />
with o<strong>the</strong>r types of drug treatment, controls <strong>the</strong> growth of disseminated tumors in<br />
most pts progressing on a lower dose, and has a good tolerability.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix382 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
new diagnostics<br />
1173P A HIGHLY SENSITIVE IMMUNOHISTOCHEMICAL ASSAY TO<br />
DETECT BRAF V600E MUTATIONS IN PATIENTS WITH<br />
COLORECTAL CANCER<br />
J. Desai 1 ,F.Day 2 , A. Muranyi 3 , S. Singh 3 , K. Shanmugam 3 , T. Grogan 3 ,<br />
P. Gibbs 4 , D. Williams 2 , O. Sieber 2 , P. Waring 5<br />
1 Medical Oncology, Ludwig Institute for Cancer Research, Royal Melbourne<br />
Hospital, Peter MacCallum Cancer Centre, Parkville, AUSTRALIA, 2 LCCI, Ludwig<br />
Institute for Cancer Research, Parkville, AUSTRALIA, 3 Ventana, Ventana Medical<br />
Systems, Tucson, AZ, UNITED STATES OF AMERICA, 4 LCCI, Ludwig Institute<br />
for Cancer Research, Royal Melbourne Hospital, Parkville, VIC, AUSTRALIA,<br />
5 Pathology, University of Melbourne, Parkville, AUSTRALIA<br />
Background: The BRAF V600E mutation is a well-validated negative prognostic<br />
biomarker in metastatic colorectal cancer (mCRC), and is a highly attractive drug<br />
target. Barriers to <strong>the</strong> development of agents targeting BRAF V600E in mCRC are<br />
<strong>the</strong> low rate of mutations (approximately 10%) and reliance on to sequencing-based<br />
technologies, which are not routinely available outside of large cancer centres. A<br />
simple immunohistochemistry (IHC) test, more suited to routine pathology practice,<br />
would provide much broader access to patient (pt) identification, and would also<br />
enable studies of tumor heterogeneity. Aims: To validate an IHC-based method of<br />
detecting <strong>the</strong> BRAF V600E mutation in a large cohort of community-based CRC<br />
patients.<br />
Methods: Tissue microarrays, comprising matched normal and tumor paraffin<br />
embedded tissue samples obtained from colectomy specimens from a community<br />
cohort of 505 pts with stage I–IV CRC, were tested with 2 antibodies (Ab): pBR for<br />
total BRAF and VE1 for BRAF V600E, using <strong>the</strong> Ventana UltraView and OptiView<br />
kits, respectively. IHC was assessed independently by 2 blinded pathologists, and<br />
results compared to BRAF V600E status determined by Sanger sequencing (SS). pBR<br />
negative samples were considered non - evaluable. Nine discordant cases were<br />
re-tested with a BRAF V600E SNaPshot assay.<br />
Results: Demographic features were evenly matched. SS was evaluable in 504/505;<br />
IHC in 477/505; with both evaluable in 476/505 pts. 56/476 (11.8%) pts had V600E<br />
mutations detected by SS, 65/476 (13.7%) by IHC. The positive predictive value was<br />
84.6% (55/65). 1 pt was negative by IHC and positive on SS and SNaPshot; resulting<br />
in a negative predictive value of 99.8% (410/411 cases). There was 100% concordance<br />
between SS and SNaPshot. Fur<strong>the</strong>r validation is ongoing, and outcome data will be<br />
available at <strong>the</strong> time of presentation.<br />
Conclusions: We have conducted a comprehensive analytical and clinical validation<br />
and feasibility analysis of an IHC-based method to detect <strong>the</strong> BRAF V600E mutation<br />
in a large community-based population of pts with CRC. Shown to be highly<br />
sensitive, we are planning to adopt this approach as our initial screening step in an<br />
upcoming prospective combination trial targeting BRAF V600E in pts with mCRC.<br />
Disclosure: J. Desai: Research Support: Roche, Ventana Medical Systems,<br />
A. Muranyi: Employee: Ventana Medical Systems, K. Shanmugam: Employee and<br />
Shareholder, Ventana Medical Systems, T. Grogan: Shareholder and Chief Scientific<br />
Officer, Ventana Medical Systems, P. Gibbs: Research Support, Ventana Medical<br />
Systems, P. Waring: Research Support: Ventana Medical Systems, All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
1174P DIAGNOSTIC AND PROGNOSTIC SIGNIFICANCE OF THE<br />
ALTERNATIVELY SPLICED ACTN4 VARIANT IN HIGH-GRADE<br />
NEUROENDOCRINE PULMONARY TUMOURS<br />
A. Miyanaga 1 , K. Honda 1 , K. Tsuta 1 , M. Masuda 1 , H. Tsuda 2 , H. Asamura 3 ,<br />
A. Gemma 4 , T. Yamada 1<br />
1 Division of Chemo<strong>the</strong>rapy and Clinical Research, National Cancer Center<br />
Research Institute, Tokyo, JAPAN, 2 Pathology and Clinical Laboratory Division,<br />
National Cancer Center Hospital, Tokyo, JAPAN, 3 Division of Thoracic Surgery,<br />
National Cancer Center Hospital, Tokyo, JAPAN, 4 Internal Medicine, Nippon<br />
Medical School, Tokyo, JAPAN<br />
Background: High-grade neuroendocrine tumours (HGNTs) of <strong>the</strong> lung manifest a<br />
wide spectrum of clinical behaviour, but no method of predicting <strong>the</strong>ir outcome has<br />
been established.<br />
Materials and methods: We newly established a monoclonal antibody specifically<br />
recognizing <strong>the</strong> product of <strong>the</strong> alternatively spliced ACTN4 transcript (namely,<br />
variant actinin-4), and used it to examine <strong>the</strong> expression of variant actinin-4<br />
Annals of Oncology 23 (Supplement 9): ix383–ix384, <strong>2012</strong><br />
doi:10.1093/annonc/mds406<br />
immunohistochemically in a total of 609 surgical specimens of various histological<br />
subtypes of lung cancer.<br />
Results: Variant actinin-4 was expressed in 55% (96/176) of HGNTs, but in only<br />
0.8% (3/378) of non-neuroendocrine lung cancers. Expression of variant actinin-4<br />
was significantly associated with unfavorable overall survival in HGNT patients<br />
(P = 0.00021, log-rank test). Multivariate analysis using <strong>the</strong> Cox proportional hazards<br />
model showed that expression of variant actinin-4 was <strong>the</strong> most significant<br />
independent negative predictor of survival in HGNT patients (hazard ratio, 2.18;<br />
P = 0.000714) after <strong>the</strong> presence of lymph node metastasis (hazard ratio, 2.30;<br />
P = 0.00012).<br />
Conclusions: Expression of variant actinin-4 is an independent prognostic factor for<br />
patients with HGNTs. This protein has high affinity for filamentous actin polymers<br />
and likely promotes aggressive behaviour of cancer cells. The present clinical findings<br />
clearly support this notion.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1175P CLINICAL FEASIBILITY STUDY OF A NOVEL<br />
CYTOMETRY-BASED SYSTEM FOR THE DETECTION OF<br />
CIRCULATING TUMOR CELLS IN PATIENTS WITH LUNG<br />
CANCER<br />
Y. Koh 1 , M. Watanabe 1 , T. Sawada 2 , Y. Uehara 2 , Y. Fujimura 3 , T. Tamura 4 ,<br />
F. Koizumi 2<br />
1 Division of Drug Discovery and Development, Shizuoka Cancer Center,<br />
Sunto-gun, JAPAN, 2 Shien-Lab, National Cancer Center Hospital, Tokyo,<br />
JAPAN, 3 R&D, On-Chip Biotechnologies Co., Ltd, Koganei, JAPAN, 4 Division of<br />
Thoracic Oncology, National Cancer Center Hospital, Tokyo, JAPAN<br />
Background: The presence and number of circulating tumor cells (CTCs) in <strong>the</strong><br />
peripheral blood of solid tumor patients are predictive of clinical outcome. To date<br />
<strong>the</strong> CellSearch system has been <strong>the</strong> only FDA-cleared CTCs enumeration system for<br />
advanced breast, prostate and colon cancers. However, low prevalence of CTCs and<br />
lack of capability as an application platform for molecular analysis have limited <strong>the</strong><br />
use of CTCs in <strong>the</strong> clinic. To overcome <strong>the</strong>se shortcomings, innovative and emerging<br />
technologies with easier access to fur<strong>the</strong>r molecular analysis are under development<br />
worldwide.<br />
Methods: We have developed a flow cytometry-based CTCs detection system<br />
independent of EpCAM expression level of tumor cells with cytokeratin and<br />
vimentin-staining after <strong>the</strong> depletion of CD45-expressing cells. In a preclinical study,<br />
various cancer cell lines were spiked into blood from healthy donors and <strong>the</strong><br />
sensitivity in detection was evaluated at two different sites (Shizuoka Cancer Center<br />
and National Cancer Center Tokyo). Then clinical feasibility study was conducted in<br />
patients with lung cancer.<br />
Results: Enumeration of <strong>the</strong> spiked cancer cells (10 to 1000 cells in 4 ml of blood)<br />
was linear, with a recovery rate of over 90%. A significantly higher recovery rate was<br />
observed with our system (90 to 102%) than that with CellSearch system (0%)<br />
particularly when EpCAM-negative PC-14 non-small lung cancer cells were spiked<br />
in, suggesting a superior sensitivity of our system in capturing EpCAM-negative<br />
tumor cells. In 22 blood samples from lung cancer patients, CTCs were detected with<br />
numbers ranging from 0 to 16 CTCs (median, 6.5) per 4 ml of blood with our<br />
system and in 72.7% (17/23) of <strong>the</strong> patients, 4 CTCs or more per 4 ml of blood were<br />
detected. On <strong>the</strong> o<strong>the</strong>r hand with CellSearch system, 2 CTCs or more per 7.5 ml of<br />
blood were detected in only 27% of <strong>the</strong> patients.<br />
Conclusions: The preclinical study and <strong>the</strong> results of <strong>the</strong> clinical feasibility study<br />
suggested superior sensitivity of our flow cytometry-based detection method than<br />
CellSearch system. Cell sorting device under development will be combined with this<br />
system for isolation and collection of CTCs for molecular analysis with<br />
next-generation sequencing.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1176P EBUS-TBNA GIVES ADEQUATE TISSUE INFORMATION ON<br />
CELL TYPE IN LUNG CANCER<br />
M.K. Wong, M.S. Ip, D.C. Lam, J.C.M. Ho<br />
Medicine, Queen Mary Hospital, Hong Kong, HONG KONG<br />
Introduction: In formulating systemic treatment in patients with advanced stage<br />
lung cancer, it is now considered imperative to know <strong>the</strong> cell type such as squamous<br />
carcinoma, adenocarcinoma and large cell carcinoma as chemo<strong>the</strong>rapeutic agents<br />
would be tailored to treat different cell type.<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com<br />
abstracts
Method: Endobronchial ultrasound guided transbronchial needle aspiration<br />
(EBUS-TBNA)was performed under local anaes<strong>the</strong>sia in patients presented with<br />
mediastinal abnormality suspected of or confirmed lung cancer for diagnosis and<br />
staging purpose. Once malignancy was confirmed from <strong>the</strong> pathological materials,<br />
exact cell type, origin of tumour, differentiation were recorded. In <strong>the</strong> later phase of<br />
<strong>the</strong> study period, molecular profiling was also deployed to confirm <strong>the</strong> EGFR<br />
mutation and ALK translocation status.<br />
Results: Over <strong>the</strong> study period of 4 years and 4 months, <strong>the</strong>re were 269 EBUS-TBNA<br />
performed in 258 patients. Of <strong>the</strong> 209 patients confirmed having malignancy as <strong>the</strong>ir<br />
final diagnosis, EBUS-TBNA was able to detect extrathoracic malignancy in<br />
23 (11.0%) and primary lung cancer in 133 (63.6%). Among those 133 patients<br />
confirmed having primary lung cancer, 116 (87.2%) had exact cell type delineated.<br />
For those 40 patients who had molecular profiling performed, patients with adequate<br />
tissue for EGFR mutation and/or ALK translocation were obtained in 38 (95.0%). Of<br />
<strong>the</strong> 157 patients confirmed to have malignancy by EBUS-TBNA, only 22 (14%) had<br />
revealed NSCLC without knowing <strong>the</strong> exact cell type, differentiation of <strong>the</strong> tumour,<br />
EGFR status or primary origin of <strong>the</strong> tumour. In <strong>the</strong> 220 patients with final<br />
diagnosis of malignancy, <strong>the</strong> sensitivity was 89.0% and negative predictive value was<br />
65.0%<br />
Conclusion: EBUS-TBNA is effective in subtyping of tumour cells and molecular<br />
profiling in patients with lung cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1177P VARIATIONS OF DISCORDANCE OF THE CLINICAL TNM<br />
STAGE WITH THE PATHOLOGICAL TNM STAGE BETWEEN<br />
JAPANESE DESIGNATED CANCER HOSPITALS<br />
F. Nakamura 1 , T. Higashi 2 , Y. Emori 3 , H. Nishimoto 3<br />
1 Healthcare Epidemiology, Kyoto University Graduate School of Medicine and<br />
Public Health, Kyoto, JAPAN, 2 Department of Public Health/Health Policy, The<br />
University of Tokyo Graduate School of Medicine, Tokyo, JAPAN, 3 Cancer<br />
Surveillance Division, National Cancer Center, Tokyo, JAPAN<br />
Introduction: Previous studies showed that TNM stages that were clinically<br />
determined before surgery were not often concordant with pathological TNM stages.<br />
However, no previous studies have examined variations of discordance of <strong>the</strong> clinical<br />
TNM stage with <strong>the</strong> pathological TNM stage among hospitals. We aimed to examine<br />
<strong>the</strong> discordance of <strong>the</strong> clinical and pathological stages among Japanese designated<br />
cancer hospitals using compiled data from <strong>the</strong> hospital-based cancer registry<br />
submitted from 286 designated cancer care hospitals in Japan.<br />
Methods: The registry data had UICC TNM stages before and after surgery for<br />
stomach, colorectal, lung and breast cancer patients treated in <strong>the</strong>se hospitals. We<br />
excluded patients who received adjuvant chemo<strong>the</strong>rapy or radio<strong>the</strong>rapy, patients who<br />
received care from facilities with less than 10 patients, male breast cancer and<br />
patients whose stages were unknown from <strong>the</strong> analysis. We also calculated<br />
discordance of stages that could have <strong>the</strong>oretically resulted in changes in surgical<br />
procedures or treatment choice. Discordance was also calculated after excluding stage<br />
IV patients as sensitivity analysis.<br />
Results: In total, 145,726 patients (38,692 stomach, 47,304 colorectal, 19,643 lung<br />
and 40,096 breast cancer patients) were included in <strong>the</strong> analysis. Patients’ mean age<br />
and clinical TNM stage varied across hospitals. The facility-level discordance between<br />
clinical and pathological stages ranged from 4% to 52% in stomach cancer, 3% to<br />
Annals of Oncology<br />
57% in colorectal cancer, 0% to 50% in lung cancer and 1% to 45% in breast cancer.<br />
TNM stages before surgery were lower than after surgery in more than half of <strong>the</strong><br />
cases. The multi-level logistic regression model showed that variance in facilities<br />
existed after adjustment for age, sex and clinical TNM stage. Discordance of stages<br />
that could lead to changes in <strong>the</strong> surgical procedures or treatment choice ranged<br />
from 4% to 58% in stomach cancer, 4% to 63% in colorectal cancer, 0% to 5% in<br />
lung cancer, and 5% to 52% in breast cancer. Sensitivity analysis yielded similar<br />
results.<br />
Conclusion: We can confirm variations of discordance of TNM stages before and<br />
after surgery.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1178TiP PROSPECTIVE EVALUATION OF PLANAR BONE<br />
SCINTIGRAPHY, SPECT/CT, 18F NAF PET/CT AND WHOLE<br />
BODY 1.5T MRI FOR DETECTION OF BONE METASTASES<br />
IN HIGH RISK BREAST AND PROSTATE CANCER PATIENTS<br />
A.K. Kuisma 1 , I. Jambor 2 , R. Huovinen 1 , M. Sandell 2<br />
1 Oncology and Radio<strong>the</strong>rapy, University Hospital of Turku, Turku, FINLAND,<br />
2 Radiology, University Hospital of Turku, Turku, FINLAND<br />
Purpose: The aim of <strong>the</strong> study was to compare <strong>the</strong> diagnostic accuracy of 99mTc<br />
methylene-diphosphonate planar bone scintigraphy (99mTc-MDP BS), 99mTc<br />
methylene-diphosphonate single photon emission tomography/computed<br />
tomography (99mTc-MDP SPECT/CT), 18F NaF positron emission tomography/<br />
computed tomography (PET/CT) and whole body 1.5 Tesla magnetic resonance<br />
imaging (1.5T MRI) for <strong>the</strong> detection of bone metastases in high risk breast and<br />
prostate cancer patients.<br />
Materials and methods: Twenty breast cancer patients and eight prostate cancer<br />
patients at high risk of bone metastases prospectively underwent 99mTc-MDP BS,<br />
99mTc-MDP SPECT/CT, 18F NaF PET/CT and whole body 1.5T MRI using spine<br />
and surface coils. Four independent reviewers interpreted each individual modality<br />
without <strong>the</strong> knowledge of o<strong>the</strong>r imaging findings. The final metastatic status was<br />
based on <strong>the</strong> consensus reading of all imaging modalities. The findings were<br />
compared on patient and region basis. In <strong>the</strong> region based analysis, <strong>the</strong> skeleton was<br />
divided into five regions.<br />
Results: Based on <strong>the</strong> consensus reading, 13 (46%) patients and 42 (30%) regions<br />
had presence of bone metastases while 15 patients and 98 regions were free of bone<br />
metastases. 99mTc-MDP BS was false negative in four patients. In <strong>the</strong> patient/region<br />
based analysis, <strong>the</strong> sensitivity for 99mTc-MDP BS, 99mTc-MDP SPECT/CT, 18F<br />
NaF PET/CT and whole body 1.5T MRI was 69%/44%, 77%/76%, 92%/90% and<br />
77%/71%, respectively, while <strong>the</strong> accuracy was 86%/82%, 89%/92%, 96%/97% and<br />
86%/91%, respectively.<br />
Conclusions: 99mTc-MDP SPECT/CT, 18F NaF PET/CT and whole body MRI<br />
including diffusion weighted imaging demonstrated higher sensitivity and accuracy in<br />
detection of bone metastasis compared to planar bone scintigraphy. Observed<br />
difference between imaging modalities might potentially affect <strong>the</strong> patient<br />
management. Clinical relevance statement: 99mTc-MDP SPECT/CT, 18F NaF PET/<br />
CT and whole body MRI including diffusion weighted imaging showed higher<br />
sensitivity for detecting bone metastases in high risk breast and prostate cancer<br />
patients to planar bone scintigraphy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix384 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
non-small cell lung cancer, early stage<br />
1179O THE EUROPEAN THORACIC ONCOLOGY PLATFORM<br />
LUNGSCAPE PROJECT: A WAY TO BRIDGE NON-SMALL<br />
CELL LUNG CANCER MOLECULAR CHARACTERISTICS<br />
AND CLINICAL DATA<br />
S. Peters 1 , O. Dafni 2 , L. Bubendorf 3 , P. Meldgaard 4 ,K.O’Byrne 5 , A. Wrona 6 ,<br />
W. Weder 7 , M. Canela 8 , S. Malatesta 9 , J. Vansteenkiste 10 , A-M. Dingemans 11 ,<br />
M. Nicolson 12 , S. Savic 13 , P. Baas 14 , R. Peck 15 ,S.Lu 16 ,E.Smit 17 ,<br />
E. Jantus-Lewintre 18 , R. Rosell 19 , R.A. Stahel 20<br />
1 Multidisciplinary Oncology Center, Lausanne Cancer Center, Centre Hospitalier<br />
Universitaire Vaudois, Lausanne, SWITZERLAND, 2 Frontier Science<br />
Foundation-Hellas, A<strong>the</strong>ns, GREECE, 3 Division of Cytology, Institute for<br />
Pathology, University Hospital Basel, Basel, SWITZERLAND, 4 Department of<br />
Oncology, Aarhus University Hospital, Aarhus, DENMARK, 5 HOPE Directorate,<br />
St James’s Hospital, Dublin, IRELAND, 6 Department of Oncology and<br />
Radio<strong>the</strong>rapy, Medical University of Gdansk, Gdansk, POLAND, 7 Division of<br />
Thoracic Surgery, University Hospital Zurich, Zurich, SWITZERLAND, 8 Surgery,<br />
Vall d’Hebron University Hospital, Barcelona, SPAIN, 9 Anatomia Patologica,<br />
Ospedale Clinicizzato, Chieti, ITALY, 10 Respiratory Oncology, University Hospital<br />
Leuven, Leuven, BELGIUM, 11 Pulmonology, Maastricht University Medical<br />
Centre, Maastricht, NETHERLANDS, 12 Medical Oncology, Aberdeen Royal<br />
Infirmary, Aberdeen, UNITED KINGDOM, 13 Pathology, Institute for Pathology,<br />
University Hospital Basel, Basel, SWITZERLAND, 14 Department of Thoracic<br />
Oncology, The Ne<strong>the</strong>rlands Cancer Institute, Amsterdam, NETHERLANDS,<br />
15 University Hospital South Manchester and The Christie NHS Foundation Trust,<br />
Manchester, UNITED KINGDOM, 16 Shanghai Lung Tumor Clinic Center,<br />
Shanghai Chest Hospital, Shanghai, CHINA, 17 Pulmonology, Vrije Universiteit<br />
Medical Center, Amsterdam, NETHERLANDS, 18 Fundación para la Investigación<br />
del Hospital General Universitario de Valencia, Valencia, SPAIN, 19 Medical<br />
Oncology Service, Catalan Institute of Oncology, Badalona (Barcelona), SPAIN,<br />
20 Clinic of Oncology, University Hospital Zurich, Zurich, SWITZERLAND<br />
Background: The Lungscape project aims at building a virtual biobank to facilitate<br />
an international high-quality analysis of large numbers of tumors for molecular<br />
alterations linked to clinical and biological characteristics captured in <strong>the</strong> iBiobank.<br />
Methods: Retrospective radically resected stage I-III non-small cell lung cancer cases<br />
from 15 ETOP centers, with mandatory comprehensive clinical annotations<br />
including at least 2 years of FU have been reviewed and captured.<br />
Results: This first set of 1614 cases was enriched in adenocarcinoma (61.8%), with<br />
28.8% of squamous and 4.9% of large cell histologies. Median age is 65 yrs, 37.6%<br />
are women, and respectively 13.9%, 33.5% and 49.6% are never, current and former<br />
smokers. Stage distribution is: IA 23.7%, IB 25.8%, IIA 16.4%, IIB 11.6%, IIIA 20.8%,<br />
IIIB 1.7%. At last FU, 52.8% of patients were still alive, with a median FU of 5.3 yrs.<br />
PFS<br />
No. of<br />
patients 5 years (95% C.I.)<br />
Median (mos)<br />
(95% C.I.)<br />
TOTAL 1614 46 (43.3, 48.6) 49.0 ( 43.9, 55.2)<br />
Stage Ia 382 64.5 (59.1, 60.5) NR<br />
Ib 417 55.4 (50.3, 60.5) 78.0<br />
IIa 264 44.8 (38.4, 51.3) 46.9<br />
IIb 187 39.2 (31.6, 46.8) 33.7<br />
IIIa 335 20.0 (15.2, 24.8) 17.5<br />
IIIb 28 11.9 (0.0, 25.3) 10.1<br />
OS 1614 52.0 (49.3, 54.7) 64.2 (57.3, 76.9)<br />
Stage Ia 382 70.0 (64.9, 75.2) NR<br />
Ib 417 60.6 (55.5, 65.7) NR<br />
IIa 264 50.5 (43.8, 57.1) 62.2<br />
IIb 187 43.7 (36.0, 51.4) 43.3<br />
IIIa 335 29.3 (23.9, 34.7) 29.0<br />
IIIb 28 10.3 (0.0, 27.1) 20.2<br />
Conclusion: This is <strong>the</strong> first large-scale series based on 7th TNM classification<br />
reporting on OS and PFS in <strong>the</strong> context of European standards of care. These data<br />
confirm <strong>the</strong> discriminative capacity of <strong>the</strong> 7 th TNM with a potentially somewhat<br />
superior outcome. Histologies o<strong>the</strong>r than adenocarcinoma are currently actively<br />
being captured. Complete data including PFS and TTP - never reported before - as<br />
well as OS based on <strong>the</strong> expected 2400 patients correlated to stage, gender, smoking<br />
status, histology and age will be provided. This complete clinical dataset will be<br />
Annals of Oncology 23 (Supplement 9): ix385–ix388, <strong>2012</strong><br />
doi:10.1093/annonc/mds407<br />
invaluable to investigate <strong>the</strong> impact of molecular characteristics on outcome. It will<br />
allow building future hypo<strong>the</strong>sis for prospective evaluation of new treatment<br />
strategies and help in <strong>the</strong> development of a molecularly refined TNM.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1180PD EXPRESSION OF HYPOXIA-INDUCED FACTOR 1α AND<br />
GLUCOSE TRANSPORTER 1 CORRELATES WITH<br />
[18F]-FLUORO-2-DEOXY-GLUCOSE UPTAKE ON<br />
POSITRON EMISSION TOMOGRAPHY AND TUMOR<br />
AGGRESSIVENESS IN DIFFERENT HISTOLOGIC SUBTYPES<br />
OF LUNG ADENOCARCINOMAS<br />
Y. Miyata, T. Furukawa, Y. Tsutani, T. Mimae, K. Misumi, T. Yoshiya, Y. Ibuki,<br />
M. Okada<br />
Surgical Oncology, Hiroshima University, Hiroshima, JAPAN<br />
Background: High maximal standardized uptake values (SUVmax) on<br />
[18F]-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) are<br />
associated with inferior survival in lung adenocarcinoma. However, <strong>the</strong> exact<br />
mechanisms are unknown. Here, we investigated <strong>the</strong> biological mechanisms<br />
underlying FDG uptake in different subtypes of adenocarcimomas.<br />
Methods: This retrospective study included 287 patients with adenocarcinoma (166<br />
with Stage IA). The patients underwent systematic tumor resection at Hiroshima<br />
University Hospital from January 2007 to December 2011, at <strong>the</strong> latest, 4 weeks after<br />
FDG-PET. The SUVmax values for primary lesions were calculated based on FDG<br />
uptake. Tumors were subdivided according to each morphologic growth pattern. The<br />
expression of hypoxia-inducible factor 1α (HIF1α) and glucose transporter 1 (GLUT1)<br />
was evaluated in 70 patients with 147 histologic subtypes using immunostaining.<br />
Results: There were significant differences in SUVmax and disease-free survival<br />
(DFS) among different histologic subtypes. Mean SUVmax and 5-year DFS were 0.90<br />
and 100% in is situ (n = 41), 1.1 and 100% in minimally invasive (n = 5), 1.8 and<br />
94.3% in lepidic (n = 66), 3.9 and 75.2% in papillary (n = 136), 5.4 and 91.7% in<br />
acinar (n = 26), and 7.6 and 71.6% in solid (n = 13) predominant subtypes. HIF1α<br />
and GLUT1, and GLUT1 and SUVmax were significantly correlated (p < 0.001 for<br />
both) in adenocarcinoma. Moreover, <strong>the</strong> expressions of HIF1α and GLUT1<br />
correlated with various clinicopathological factors relating to malignancy, such as<br />
pathological stage (I vs. II + III; p = 0.014), lymph node metastasis (p = 0.037),<br />
pleural invasion (p = 0.0093), lymphatic invasion (p < 0.001), and venous invasion<br />
(p < 0.001). GLUT1 and SUVmax were jointly associated with DFS (p = 0.0098 and<br />
p < 0.001, respectively in adenocarcinoma). There were significant differences in<br />
HIF1α and GLUT1 expression among different histologic subtypes. Mean HIF1α and<br />
GLUT1score were 0 and 0.15 in is situ (n = 13), 0.03 and 0.11 in lepidic (n = 36),<br />
0.19 and 1.0 in papillary (n = 52), 0.47 and 1.2 in acinar (n = 34), 0.11 and 1.6 in<br />
micropapillary (n = 9), and 2.3 and 3.0 in solid (n = 3) subtypes.<br />
Conclusions: In different histologic subtypes of lung adenocarcinomas,<br />
HIF1α-induced GLUT1 expression might explain high FDG uptake on PET and<br />
correlate with poor prognosis.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1181PD RANDOMIZED PHASE II STUDY OF ADJUVANT<br />
CHEMOTHERAPY WITH S-1 VERSUS CDDP + S-1 IN<br />
RESECTED STAGE II-IIIA NON-SMALL-CELL LUNG<br />
CANCER (WJOG4107)<br />
H. Yoshioka1 , Y. Iwamoto2 , S. Ito3 , T. Yamanaka4 , H. Tada5 , M. Yoshimura6 ,<br />
I. Okamoto7 , I. Yoshino8 , K. Nakagawa7 , Y. Nakanishi9 1 2<br />
Respiratory Medicine, Kurashiki Central Hospital, Kurashiki, JAPAN, Medical<br />
Oncology, Hiroshima City Hospital, Hiroshima, JAPAN, 3 Department of Thoracic<br />
Surgery, Aichi Cancer Center Hospital, Nagoya, JAPAN, 4 Clinical Research<br />
Center, National Cancer Research Center, East Hospital, Kashiwa, JAPAN,<br />
5<br />
General Thoracic Surgery, Osaka City General Hospital, Osaka, JAPAN,<br />
6 7<br />
Thoracic Surgery, Hyogo Cancer Center, Akashi, JAPAN, Medical Oncology,<br />
Kinki University School of Medicine, Osakasayama, JAPAN, 8 General Thoracic<br />
Surgery, Chiba University Graduate School of Medicine, Chiba, JAPAN,<br />
9<br />
Research Institute for Diseases of The Chest, Kyushu University Hospital,<br />
Fukuoka, JAPAN<br />
Background: Postoperative cisplatin doublet chemo<strong>the</strong>rapy benefits patients with<br />
completely resected stage II-IIIA non-small-cell lung cancer (NSCLC). S-1 is an oral<br />
fluorinated pyrimidine formulation that combines tegafur (FT), 5-chloro-2,<br />
4-dihydroxypyridine (CDHP), and potassium oxonate in a molar ratio of 1:0.4:1 and<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com<br />
abstracts
widely used by single agent or platinum doublet for advanced NSCLC in Japan. This<br />
phase II trial assessed <strong>the</strong> efficacy and safety of S-1 and cisplatin plus S-1 for<br />
adjuvant chemo<strong>the</strong>rapy.<br />
Methods: From September 2007 to Dec 2009, 200 patients with completely resected<br />
stage II and IIIA (exclude multi-station N2 cases) NSCLC were randomized to<br />
receive ei<strong>the</strong>r oral S-1 (40 mg/m2 twice per day) for consecutive 2 weeks repeated<br />
every 3 weeks for 1 year or cisplatin (60 mg/m2 day1) plus oral S-1 (40 mg/m2 twice<br />
per day) for consecutive 2 weeks repeated every 3 weeks for 4 cycles within 8 weeks<br />
after surgery. Main inclusion criteria were no prior chemo<strong>the</strong>rapy or radio<strong>the</strong>rapy,<br />
ECOG PS 0-1, an age of less than 75 years, and an adequate organ function.<br />
Stratification factors included histology, stage and institutions. Primary endpoint was<br />
relapse free survival rate on 2 years and secondary endpoints were overall survival<br />
(OS) and toxicity.<br />
Results: Patient demographics were well balanced between <strong>the</strong> arms in terms of<br />
sex, age, histologic type and stage. 52.6% of patients in S-1 arm and 76.7% in<br />
cisplatin plus S-1 arm were completed planned administration. Relapse free<br />
survival rate on 2 years was 65.6% (95% confidence interval, 55.3-74.0%) in <strong>the</strong><br />
S-1 arm and 58.1% (95% confidence interval, 47.7-67.2%) in <strong>the</strong> cisplatin plus S-1<br />
arm. OS were not matured in <strong>the</strong> both arms. Though <strong>the</strong> rates of leukopenia or<br />
neutropenia of grade 3/4, febrile neutropenia, nausea, and vomiting were more<br />
frequent in <strong>the</strong> cisplatin plus S-1 arm, <strong>the</strong>re were no treatment related deaths in<br />
<strong>the</strong> both groups.<br />
Conclusion: Both S-1 mono<strong>the</strong>rapy and cisplatin plus S-1 are feasible as adjuvant<br />
chemo<strong>the</strong>rapy for completed resected NSCLC.<br />
Disclosure: I. Yoshino: Research Funds from Taiho Pharmaceutical Co. and Chugai<br />
Pharmaceutical Co.All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1182P IMMUNOGENICITY AND SAFETY OF THE PRAME CANCER<br />
IMMUNOTHERAPEUTIC IN NON-SMALL CELL LUNG<br />
CANCER (NSCLC): PHASE I DOSE ESCALATION STUDY<br />
J. Pujol 1 ,T.DePas 2 , A. Rittmeyer 3 , B. Kubisa 4 , E. Vallieres 5 , E. Levchenko 6 ,<br />
B. Salaun 7 , N. Vanhoutte 8 , M. Debois 8 , V. Brichard 9<br />
1 Thoracic Oncologic Unit, Montpellier Academic Hospital, Hospital Arnaud De<br />
Villeneuve, Montpellier, Montpellier, FRANCE, 2 Medical Oncology, European<br />
Institute of Oncology, Milan, ITALY, 3 Lungenfachklinik Immenhausen,<br />
Lungenfachklinik Immenhausen, Immenhausen, GERMANY, 4 Thoracic Surgery,<br />
Pomeranian Medical University, Szczecin, POLAND, 5 Thoracic Oncology,<br />
Swedish Cancer Institute, Seattle, WA, UNITED STATES OF AMERICA, 6 Thoracic<br />
Oncology, Petrov Research Institution of Oncology, St. Petersburg, RUSSIAN<br />
FEDERATION, 7 R&D DAP Cancer, GlaxoSmithKline Biologicals, Rixensart,<br />
BELGIUM, 8 Immuno<strong>the</strong>rapeutics, GlaxoSmithKline Biologicals, Rixensart,<br />
BELGIUM, 9 Immuno<strong>the</strong>rapeutics BU, GlaxoSmithKline Biologicals, Rixensart,<br />
BELGIUM<br />
Introduction: Adjuvant chemo<strong>the</strong>rapy (CT) is <strong>the</strong> standard treatment for stage II–<br />
IIIA NSCLC, but is debated for stage IB. As not all patients (pts) are eligible for CT<br />
and many of <strong>the</strong>m relapse, alternative <strong>the</strong>rapies are needed. The PRAME tumor<br />
antigen, expressed frequently in NSCLC and at lower levels in few normal cells, offers<br />
an attractive target for active immunization. Moreover, while most NSCLC tumors<br />
expressing <strong>the</strong> antigen MAGE-A3 are PRAME positive, 45% of PRAME-expressing<br />
NSCLC do not express MAGE-A3. This dose-escalation phase I open study aimed at<br />
determining <strong>the</strong> optimal dose of <strong>the</strong> PRAME cancer immuno<strong>the</strong>rapeutic (PRAME<br />
recombinant protein (recPRAME) with AS15 immunostimulant) by evaluating its<br />
safety and immunogenicity in NSCLC pts.<br />
Methods: Pts with PRAME-positive resected stage IB-IIIA NSCLC were enrolled in 3<br />
consecutive cohorts to receive up to 13 injections of recPRAME (20 µg, 100 µg, and<br />
500 µg) with AS15 (fixed dose) over approximately 2 years. Adverse events (AEs),<br />
including pre-defined dose-limiting toxicity (DLT), were recorded throughout <strong>the</strong><br />
study. The anti-PRAME humoral and cellular responses were assessed post-dose 4 by<br />
ELISA and flow cytometry (PRAME-specific T-cells producing both IFNγ and<br />
TNFα), respectively.<br />
Results: 60 pts were treated in <strong>the</strong> study (18, 18, 24 pts received 20, 100, 500 µg<br />
recPRAME, respectively). AEs were mostly grade 1/2. No grade 3/4 AEs considered<br />
by <strong>the</strong> investigator to be causally related were reported. One grade 2 serious AE<br />
causally related to PRAME administration was reported. No DLTs were reported.<br />
Immunogenicity results are shown in <strong>the</strong> table.<br />
Conclusions: The PRAME cancer immuno<strong>the</strong>rapeutic was well-tolerated and elicited<br />
similar humoral responses in all 3 cohorts. A trend for an increased cellular response<br />
was observed with increasing dose of recPRAME. Thus, <strong>the</strong> highest dose was selected<br />
for fur<strong>the</strong>r clinical development.<br />
Immunogenicity post-dose 4 (ATP population).<br />
Annals of Oncology<br />
Cohort (recPRAME dose) 1 (20 µg) 2 (100 µg) 3 (500 µg)<br />
Humoral responders, n/N* 10/10 11/11 19/19<br />
CD4+ T-cell responders, n/N* (%) 3/9 (33%) 6/10 (60%) 12/15 (80%)<br />
CD8+ T-cell responders, n/N* (%) 0/8 (0%) 0/10 (0%) 0/13 (0%)<br />
N, number of patients enrolled into each group; * number of patients with pre and<br />
post-vaccination results; n, number of responders; ATP, according-to-protocol<br />
Funding: GSK Biologicals<br />
Disclosure: J. Pujol: Honorarium study coordination as only conflict of interest. B.<br />
Kubisa: I am <strong>the</strong> Principal Investigator of this study at my institution. E. Vallieres: I<br />
am a consultant for GLAXOSMITHKLINE BIOLOGICALS and a member of <strong>the</strong><br />
PRAME NSCLC Global Development Advisory Board. B. Salaun: Currently<br />
employed by GSK Vaccines as a scientist. N. Vanhoutte: Employee of<br />
GlaxoSmithKline Biologicals. M. Debois: Employee of GlaxoSmithKline Biologicals.<br />
V. Brichard: GSK employee. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1183P USE OF ADJUVANT CHEMOTHERAPY (CT) AND<br />
RADIOTHERAPY (RT) IN INCOMPLETELY RESECTED (R1)<br />
EARLY STAGE NON-SMALL CELL LUNG CANCER (NSCLC): A<br />
EUROPEAN SURVEY CONDUCTED BY THE EUROPEAN<br />
SOCIETY FOR MEDICAL ONCOLOGY (<strong>ESMO</strong>) YOUNG<br />
ONCOLOGISTS COMMITTEE<br />
R. Califano, on behalf of <strong>the</strong> Young Oncologists Committee of <strong>the</strong> European<br />
Society for Medical Oncology<br />
Department of Medical Oncology, The Christie NHS Foundation Trust &<br />
University Hospital of South Manchester NHS Foundation Trust, Manchester,<br />
UNITED KINGDOM<br />
Background: Early stage NSCLC is potentially curable with radical surgery.<br />
Cisplatin-based adjuvant CT improves survival and is recommended in <strong>the</strong> <strong>ESMO</strong><br />
guidelines for stage II-III completely resected NSCLC. There is limited evidence to<br />
guide <strong>the</strong> use of adjuvant CT and RT in incompletely resected (R1) early stage NSCLC.<br />
Design and objective: A European survey of oncologists treating lung cancer was<br />
conducted to evaluate <strong>the</strong> use of adjuvant CT and RT for R1-resected NSCLC and to<br />
identify factors influencing treatment decisions. Demographics were collected and<br />
outcomes such as clinical stage, regimens, cycles planned, radio<strong>the</strong>rapy site,<br />
multidisciplinary management and discussion about inconclusive evidence with <strong>the</strong><br />
patient were analyzed. Logistic regression model was used to detect statistical association<br />
and to estimate Odds Ratio; Cochrane-Armitage test was used to detect trend.<br />
Results: 768 surveys were collected from 41 European countries between January to<br />
April <strong>2012</strong>. 82.9% of participants were medical oncologists; 49.3% <strong>ESMO</strong> members;<br />
37.1% based in a University Hospital; 32.6% practicing oncology for more than 15<br />
years and 81.4% active in research. 91.4% of participants prescribed adjuvant CT.<br />
Prescription according to stage: IA/IB/IIA/IIB/IIIA = 13.3%/44.8%/83.9%/90.5%/<br />
94.5%, respectively. Most common CT regimens were: Cisplatin/Vinorelbine (81.2%),<br />
Cisplatin/Gemcitabine (42.9%), Carboplatin/Vinorelbine (31.6%), Carboplatin/<br />
Paclitaxel (31%) and Carboplatin/Gemcitabine (26.7%). Number of cycles planned: 3/<br />
4/6 = 7.5%/78.1%/14.5%, respectively. 85% discussed limited clinical evidence with<br />
<strong>the</strong> patient. 48.3% of participants prescribed adjuvant RT. Among <strong>the</strong>se, RT to <strong>the</strong><br />
surgical bed and for pN2 disease was prescribed by 85.1% and 84.8%, respectively.<br />
Most common RT regimens for surgical bed: 60 Gy in 30 fractions (Fx) (45.6%), 54<br />
Gy in 27-30 Fx (29.6%), 50 Gy in 20 Fx (23.4%) and 52.5 Gy in 20 Fx (3.6%). Most<br />
common RT regimens for pN2 disease: 60 Gy in 30 Fx (35.2%), 54 Gy in 27-30 Fx<br />
(34.1%), 50 Gy in 20 Fx (24.1%) and 50 Gy in 25 Fx (4.8%).<br />
Conclusions: This European survey indicates that adjuvant CT and RT for<br />
incompletely resected (R1) NSCLC are commonly used in clinical practice despite<br />
limited evidence. Prospective trials for R1-resected NSCLC are necessary to clarify<br />
optimal management.<br />
Acknowledgments: <strong>ESMO</strong> Young Oncologists Committee: R. Califano, The Christie<br />
NHS Foundation Trust, Manchester, United Kingdom; E. Martinelli, Second<br />
University of Naples, Naples, Italy; V. Guarneri, University of Modena and Reggio<br />
Emilia, Modena, Italy; S. Banerjee, Royal Marsden Hospital, London, United<br />
Kingdom; D. Olmos Hidalgo, National Cancer research Centre (CNIO), Madrid,<br />
Spain; S. Postel-Vinay, Institute of Cancer Research ICR, London, United Kingdom;<br />
K. Jordan, University Hospital of Halle, Halle, Germany; M. Karamouzis, School of<br />
Medicine, University of A<strong>the</strong>ns, A<strong>the</strong>ns, Greece; K. Kamposioras, University Hospital<br />
of Larissa, Larissa, Greece; M. Preusser, Medical University of Vienna, Vienna,<br />
Austria; E. de Azambuja, Institute Jules Bordet, Brussels, Belgium; M. Hutka, Royal<br />
Marsden Hospital, London, United Kingdom.<br />
ix386 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Medical Statistics: V. Torri, Istituto di Ricerche Farmacologiche “Mario Negri”,<br />
Milan, Italy; L. Porcu, Istituto di Ricerche Farmacologiche “Mario Negri”, Milan,<br />
Italy<br />
<strong>ESMO</strong> project management team: K. Fumasoli, L. Kristoffersen, M. Cogo,<br />
Viganello-Lugano, Switzerland<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1184P PROGNOSTIC FACTORS IN EARLY STAGE NON-SMALL CELL<br />
LUNG CANCER (NSCLC): THE IMPORTANCE OF NUMBER OF<br />
RESECTED LYMPH NODES AND VASCULAR INVASION<br />
M. Caramanti 1 , R. Berardi 1 , A. Santinelli 2 , A. Brunelli 3 , A. Savini 1 , P. Mazzanti 1 ,<br />
C. Pompili 3 , M. Salati 3 , C. Pierantoni 1 , S. Cascinu 4<br />
1 Clinica di Oncologia Medica, AOU Ospedali Riuniti Ancona Università<br />
Politecnica delle Marche, Ancona, ITALY, 2 Anatomia Patologica, AOU Ospedali<br />
Riuniti Ancona Università Politecnica delle Marche, Ancona, ITALY, 3 Thoracic<br />
Surgery, AOU Ospedali Riuniti Ancona, Ancona, ITALY, 4 Dipartimento di<br />
Medicina Clinica e Biotecnologie A, University of Ancona, Ancona, ITALY<br />
Introduction: Despite an appropriate surgical treatment, half of early-stage NSCLC<br />
patients will die due to lung cancer. The number of resected lymph-nodes and<br />
vascular invasion have proved to be a prognostic factor in o<strong>the</strong>r solid tumors, as well<br />
as breast and colorectal cancer. Here we evaluate <strong>the</strong>ir prognostic impact in <strong>the</strong><br />
largest mono-centric series of resected NSCLC patients.<br />
Methods: Clinical and pathological characteristics and prognostic outcomes of 439<br />
consecutive patients undergoing radical surgical resection for NSCLC at our<br />
Institution were evaluated.<br />
Results: The multivariate analysis showed that number of resected lymph nodes,<br />
vascular invasion and sex had a prognostic impact on overall survival. The optimal<br />
cut-off number of lymph nodes with <strong>the</strong> highest sensitivity and specificity for<br />
estimating <strong>the</strong> outcome was set at 10 after Receiver Operating Characteristics (ROC)<br />
curve analysis. Removing 10 lymph nodes in our study represents a cut-off with a<br />
significant prognostic impact particularly in resected stage II NSCLC.<br />
Conclusions: Similarly to o<strong>the</strong>r cancer types (i.e. colorectal cancer), our results suggest<br />
that an adequate classification of NSCLC should always include an adequate lymph<br />
nodes clearance, particularly in stage II NSCLC. Again vascular invasion resulted an<br />
independent prognostic factors for overall survival (H.R. 0.82, CI 0.68-0.96, p = 0.042).<br />
Therefore <strong>the</strong> number of resected lymph nodes, toge<strong>the</strong>r with vascular invasion, may<br />
also drive <strong>the</strong> selection of NSCLC patients for adjuvant treatment.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1185P PROGNOSTIC ROLE OF ERBB FAMILY RECEPTORS, MYC<br />
AND MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) IN<br />
PATIENTS WITH EARLY-STAGE NON SMALL-CELL LUNG<br />
CANCER<br />
V. Ludovini 1 , G. Bellezza 2 , F. Bianconi 3 , R. Chiari 1 , C. Bennati 1 , F.R. Tofanetti 1 ,<br />
J. Vannucci 4 , F. Puma 4 , A. Sidoni 2 , L. Crinò 1<br />
1 Medical Oncology Division, S. Maria della Misericordia Hospital, Perugia, ITALY,<br />
2 University of Perugia, Institute of Pathological Anatomy and Histology, University<br />
of Perugia, Perugia, Italy, Perugia, ITALY, 3 Department of Surgical and Medical<br />
Specialties & Public Health, University of Perugia, Perugia, ITALY, 4 Department of<br />
Thoracic Surgery, University of Perugia, Perugia, ITALY<br />
Background: EGFR deregulation has been extensively studied in non small-cell lung<br />
cancer (NSCLC), but <strong>the</strong> expression and <strong>the</strong> role of o<strong>the</strong>r ErbB receptors and <strong>the</strong>ir<br />
downstream signal transductions remains still unclear. MYC and MAPK are key<br />
downstream components of <strong>the</strong> EGFR pathway and have significant roles in cell<br />
survival, proliferation, and growth. This study evaluates <strong>the</strong> prognostic role of EGFR,<br />
ErbB2, ErbB3, ErbB4, MYC and MAPK by immunohistochemistry (IHC) in early<br />
stage NSCLC.<br />
Methods: One-hundred nine NSCLC patients were evaluated: median age was 67<br />
years (range 40–84); Male/Female: 93/16; squamous (SCC)/adenocarcinoma (ADC)/<br />
BAC/o<strong>the</strong>r: 52/36/3/18; smoker/never smoker:100/9, and stage I/II/III:67/17/25. IHC<br />
results were evaluated by two independent observers and <strong>the</strong> tumors with ≥10%<br />
positive cells were classified positive, fur<strong>the</strong>r confirmed by Receiver Operating<br />
Characteristic (ROC) analysis. Kaplan-Meier estimates of survival and time to<br />
recurrence were calculated for clinical and biologic variables using Cox model for<br />
multivariate analysis.<br />
Results: EGFR was expressed in 55.9%, ErbB2 in 24.7% ErbB3 in 33.9%, ErbB4 in<br />
27.5%, Myc in 23.8% and MAPK in 27.5 % of patients, respectively. EGFR and<br />
ErbB3 were associated with SCC (p < 0.0001 and p = 0.004, respectively) whereas<br />
ErbB2 and MYC with ADC (p = 0.004 and p < 0.0001, respectively). EGFR and<br />
ErbB3 were significantly associated (p = 0.003), as well as MAPK and ErbB4<br />
(p = 0.02). At a median follow-up of 75 months <strong>the</strong> contemporary over-expression of<br />
EGFR, ErbB2 and MAPK was associated with shorter disease free survival (DFS)<br />
(HR = 5.4, p = 0.002) and overall survival (OS) (HR = 8.9, p < 0.0001). At multivariate<br />
analysis adjusting for stage, <strong>the</strong> co-expression of EGFR, ErbB2 and MAPK was an<br />
independent predictor for worse DFS and OS (HR = 5.7, p = 0.004; HR = 8.67,<br />
p < 0.001, respectively).<br />
Conclusions: Our results suggest that in early stage NSCLC <strong>the</strong> co-expression of<br />
EGFR, ErbB2 and MAPK predicted a worse prognosis. Such features may have<br />
important implications for future targeted <strong>the</strong>rapies. We thank Italian Association for<br />
Cancer Research (AIRC) for supporting <strong>the</strong> study.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1186P GENE AMPLIFICATION OF ACTN4 IN LUNG CANCER: A<br />
NOVEL PROGNOSTIC INDICATOR FOR STAGE I<br />
ADENOCARCINOMA OF THE LUNG<br />
K. Honda 1 , R. Noro 2 , N. Miura 1 , K. Tsuta 3 , G. Ishii 4 , H. Tsuda 3 , A. Gennma 2 ,<br />
H. Asamura 5 , K. Nagai 6 , T. Yamada 1<br />
1 Division of Chemo<strong>the</strong>rapy and Clinical Research, National Cancer Center<br />
Research Institute, Tokyo, JAPAN, 2 Department of Internal Medicine, Division of<br />
Pulmonary Medicine, Infectious Diseases and Oncology, Nippon Medical School,<br />
Tokyo, JAPAN, 3 Pathology and Clinical Laboratory Division, National Cancer<br />
Center Hospital, Tokyo, JAPAN, 4 Department of Pathology, National Cancer<br />
Center Hospital East, Kashiwa, JAPAN, 5 Division of Thoracic Surgery, National<br />
Cancer Center Hospital, Tokyo, JAPAN, 6 Department of Thoracic Oncology,<br />
National Cancer Center Hospital East, Kashiwa, JAPAN<br />
Background: Even if detected at an early stage, a substantial number of lung cancers<br />
relapse after surgery. Patients with such tumors are likely to benefit from adjuvant<br />
<strong>the</strong>rapy, but methods for identifying such patients have yet to be established.<br />
Methods: We retrospectively analyzed multiple cohorts totaling 1744 patients who<br />
underwent resection of lung adenocarcinoma. Expression of actinin-4 protein in<br />
tumors was evaluated immunohistochemically, and copy numbers of <strong>the</strong> actinin-4<br />
(ACTN4) gene were determined by fluorescence in situ hybridization.<br />
Results: Amplification of <strong>the</strong> ACTN4 gene correlated significantly with smoking<br />
history (P = 0.02), pathological stage (P = 0.002), and histological differentiation<br />
(P < 0.001, chi-squared test). Overall survival was significantly worse for patients with<br />
stage I lung adenocarcinoma harboring ACTN4 gene amplification than for those<br />
with tumors showing no such gene amplification (P < 0.001, log-rank test).<br />
Multivariate analysis revealed ACTN4 gene amplification in stage I lung<br />
adenocarcinoma as an independent factor associated with higher risk of death<br />
(hazard ratio, 6.78; 95% confidence interval, 2.59-17.7; P < 0.001, Cox regression<br />
analysis). The 5-year survival rate of patients with stage I lung adenocarcinoma<br />
showing increased actinin-4 protein expression and ACTN4 gene amplification was<br />
58%, compared to 87% for patients with tumors lacking gene amplification and 95%<br />
for patients with tumors lacking actinin-4 protein expression. The former group<br />
showed significantly worse overall survival than ei<strong>the</strong>r of <strong>the</strong> latter (P < 0.001).<br />
Conclusions: Amplification of <strong>the</strong> actinin-4 gene defines a subset of stage I lung<br />
adenocarcinoma with distinctly poor outcomes.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1187P THE ROLE OF MUTATIONS OF EGFR, K-RAS, EML4-ALK,<br />
AND B-RAF GENES IN RESECTED PATHOLOGICAL STAGE I<br />
LUNG ADENOCARCINOMA<br />
G. Toyokawa 1 , T. Ohba 1 , K. Sugio 2 , Y. Morodomi 1 , T. Takenaka 1 ,<br />
M. Yamaguchi 1 , F. Hirai 1 , K. Taguchi 3 , T. Seto 1 , Y. Ichinose 2<br />
1 Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka,<br />
JAPAN, 2 Department of Thoracic Oncology, Clinical Research Institute, National<br />
Kyushu Cancer Center, Fukuoka, JAPAN, 3 Clinical Research Center, National<br />
Kyushu Cancer Center, Fukuoka, JAPAN<br />
Background: The mutations of EGFR, K-ras, EML4-ALK and B-RAF genes are an<br />
early event during oncogenesis of NSCLC. This study retrospectively assessed <strong>the</strong><br />
mutations of <strong>the</strong>se genes and <strong>the</strong>ir clinical significance in resected adenocacinomas.<br />
Methods: A total of 256 patients with resected stage I lung adenocarcinoma were<br />
retrospectively included in this study. The mutations of EGFR and K-ras were determined<br />
using PCR-based fragment analysis and direct sequencing. The EML4-ALK fusion gene<br />
was assayed by immunohistochemistry and multiplex RT-PCR. The mutation of B-RAF<br />
gene was determined using direct sequencing. The DFS for prognostic value and <strong>the</strong> OS<br />
for predictive value of treatment after recurrence were evaluated.<br />
Results: In 256 tumors, <strong>the</strong> mutations of EGFR, K-ras, EML4-ALK, and B-RAF<br />
genes were detected in 114 (44.5%), 14 (5.5%), 7 (2.7%), and 3 (1.2%). One patient<br />
with <strong>the</strong> EML4-ALK fusion gene harbored <strong>the</strong> mutation of EGFR, and double<br />
mutations of EGFR and B-RAF were also observed in one patient. The incidence of<br />
EGFR mutations was significantly higher in females than males (41.2% vs. 54.4%, p<br />
< 0.05). The incidence of K-ras mutations was higher in males than females and<br />
older patients than younger patients (not significant). The EML4-ALK fusion gene<br />
was detected in younger patients (4.2 vs. 0%). The DFS and OS of K-ras mutant<br />
group were significantly inferior than those of EGFR mutant group, EML4-ALK<br />
fusion gene group, and wild-type group. Twenty-four of 41 patients with recurrent<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds407 | ix387
disease after surgery were treated by EGFR-TKI and 17 patients were treated by o<strong>the</strong>r<br />
cytotoxic agents. In <strong>the</strong> patients treated by EGFR-TKI, <strong>the</strong> MST in patients with<br />
EGFR mutation (n = 15) was 53.4 months, which was significantly superior than that<br />
in patients without EGFR mutation (n = 9) of 20.1 months. In patients treated by<br />
cytotoxic agents, <strong>the</strong>re was no difference in OS between EGFR-mutation positive and<br />
negative groups. Six of 7 patients with EML4-ALK fusion gene are alive without<br />
recurrent disease. However, <strong>the</strong> evaluation of prognostic value of EML4-ALK and<br />
B-RAF was difficult because of <strong>the</strong> small number of patient with mutation.<br />
Conclusion: In patients with stage I adenocarcinoma, <strong>the</strong> mutation of K-ras gene<br />
was a poor prognostic factor for recurrence, and <strong>the</strong> mutation of EGFR was a<br />
predictive factor for EGFR-TKI treatment after recurrence.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1188P EXAMINATION OF PATHOLOGICAL STAGE IB NON-SMALL<br />
CELL LUNG CANCER—ADEQUACY OF PLEURAL<br />
INFILTRATION ASSESSMENT<br />
R. Nakahara 1 , H. Suzuki 1 , S. Igarashi 2 , H. Matsuguma 1<br />
1 Division of Thoracic Surgery, Tochigi Cancer Center, Utsunomiya, JAPAN,<br />
2 Division of Pathology, Tochigi Cancer Center, Utsunomiya, JAPAN<br />
Background: In January 2010, <strong>the</strong> TNM classification of lung cancer was revised<br />
(7th version). The T factor was more closely divided, and lung cancer with 3 cm or<br />
less in greatest dimension and infiltration of visceral pleura was classified as <strong>the</strong> T2a<br />
group.<br />
Purpose: We examined whe<strong>the</strong>r <strong>the</strong> evaluation of visceral pleural infiltration in <strong>the</strong><br />
new TNM classification is appropriate.<br />
Methods: Among patients with non-small cell lung cancer who underwent radical<br />
surgery in our hospital between October 1986 and December 2006, pathological T1<br />
to T3N0M0 tumors were detected in 625. Of <strong>the</strong>se, we performed survival analysis in<br />
197 with T2aN0M0 (stage IB) tumors using gender, age, pleural infiltration (p),<br />
lymph vessel invasion (ly), and vascular infiltration (v) as prognostic factors.<br />
Fur<strong>the</strong>rmore, <strong>the</strong> stage-IB patients were divided into 3 groups based on <strong>the</strong> tumor<br />
diameter (s) and visceral pleural infiltration (p): Group A: s ≤ 3 cm, p1,2 (n = 49),<br />
Group B: 3 cm < s ≤ 5 cm, p0 (n = 101), and Group C: 3 cm < s ≤ 5 cm, p1,2 (n = 47).<br />
We compared <strong>the</strong> survival rate among <strong>the</strong> 3 groups, and investigated differences from<br />
<strong>the</strong> survival rates in <strong>the</strong> IA to IIB groups.<br />
Results: Concerning <strong>the</strong> clinical background of <strong>the</strong> 197 stage-IB patients, <strong>the</strong> mean<br />
age was 68 years (37 to 87), and <strong>the</strong> number of males was 128 (65%). The number of<br />
patients with adenocarcinoma was 125 (63%), and that of patients with squamous<br />
cell carcinoma was 61 (31%). Univariate analysis showed that advanced age, male<br />
gender, p(+), and v(+) were significant prognostic factors. On multivariate analysis,<br />
age (p = 0.0002) and p factor (p = 0.0007) alone were regarded as independent<br />
prognostic factors. The 5-year survival rates in Groups A, B, and C were 61, 82, and<br />
57%, respectively. There were significant differences between Groups A and B<br />
(p = 0.0074), as well as between Groups B and C (p = 0.0058). In <strong>the</strong> p(+) factor<br />
group, <strong>the</strong> prognosis was significantly less favorable than in <strong>the</strong> p(-) factor group.<br />
The survival rates in Groups A and C were similar to <strong>the</strong> 5-year survival rate in<br />
T2bN0M0 (stage IIA) patients (64%).<br />
Discussion: In this study, p(+) patients showed an unfavorable prognosis regardless<br />
of <strong>the</strong> tumor diameter. When selecting <strong>the</strong> T factor, it should be evaluated as higher<br />
in p(+) patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1189P IMPACT OF ADENOCARCINOMA VERSUS<br />
SQUAMOUS-CELL-CARCINOMA HISTOLOGY ON SURVIVAL<br />
OF RESECTED STAGE I-II NON-SMALL CELL LUNG CANCER<br />
(NSCLC) IN A COHORT OF 509 PATIENTS<br />
J. Bosch-Barrera 1 , X. Baldo 2 , M. Rubio 2 , M. Buxó 3 , L. Vilardell 3 , R. Porta 1 ,<br />
E. Marmol 2 , N. Basté 1 , A. Izquierdo 1 , F. Sebastian 2<br />
1 Oncology, Catalan Institute of Oncology, Girona, SPAIN, 2 Thoracic Surgery,<br />
Hospital Universitari de Girona Dr. Josep Trueta, Girona, SPAIN, 3 Epidemiology<br />
Unit and Cancer Registry of Girona, Oncology Planning, Department of Health,<br />
Girona Biomedical Research Institute, Girona, SPAIN<br />
Annals of Oncology<br />
Background: Histology is a prognostic and predictor of <strong>the</strong> response factor in<br />
advanced non-small cell lung cancer (NSCLC). Adenocarcinoma (ADC) has a better<br />
prognosis in advanced NSCLC whereas it is considered that resected patients (pts)<br />
with squamous-cell-carcinoma (SqCC) have a better outcome. We have analyzed our<br />
experience of resected stage I-II NSCLC pts to determine <strong>the</strong> impact of ADC vs<br />
SqCC histology in this setting.<br />
Methods: From 1996 to 2010, 289 stage I pts and 220 stage II pts were treated by<br />
surgery. Chemo<strong>the</strong>rapy (CT) was administered in 19 (6.6%) pts with stage I disease<br />
and 94 (42.7%) pts with stage II disease. Overall survival (OS) and cause-specific<br />
survival (CSS) curves were estimated by Kaplan-Meier analysis and differences were<br />
assessed with <strong>the</strong> log-rank test or <strong>the</strong> Peto and Peto modification of <strong>the</strong><br />
Gehan-Wilcoxon test.<br />
Results: Most pts (92.9%) were men. Median age was 68 years and mean follow-up<br />
was 37.4 months. Median OS for pts with stage I NSCLC was 68 mo (IC 95: 55-123)<br />
for ADC and 55 mo (IC 95: 47-67) for SqCC (p = 0.0604) with an estimated OS at 5<br />
years of 54.1% vs 48%. Median CSS were not achieved in <strong>the</strong> two histology groups,<br />
with an estimated CSS at 5 years of 78.3% for ADC versus 71.5% for SqCC (p = 0.<br />
626). For pts in stage II disease, <strong>the</strong> median OS was 31 mo (IC 95: 21-45) for ADC<br />
and 24 mo (IC 95: 18-34) for SqCC (p = 0.515) with an estimated OS at 5 years of<br />
20.5% vs 29.6%. Median CSS were 45 mo (IC 95: 31-NA) for ADC and 93 mo (IC<br />
95: 39-NA) for SqCC (p = 0.462), with an estimated CSS at 5 years of 44.8% vs<br />
54.3%.<br />
Conclusions: A trend for better OS of ADC was observed in stage I compared to<br />
SqCC but it disappeared for CSS. Thus, no statistically significant differences in OS<br />
nor CSS were observed in resected stage I-II NSCLC patients between ADC vs SqCC<br />
histology.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1190P SPECIFICITIES OF LUNG CANCER IN NEVER-SMOKING<br />
WOMEN<br />
J. Mazieres 1 , I. Rouquette 1 , B. Lepage 1 , J. Milia 1 , P. Validire 2 , P. Hofman 3 ,<br />
M. Beau-Faller 4 , L. Brouchet 1 , P. Fouret 5<br />
1 Thoracic Oncology, CHU Toulouse - Hôpital Larrey, toulouse, FRANCE,<br />
2 Pathology, Institut Mutualiste Montsouris, Paris, FRANCE, 3 Pathology, CHU<br />
Nice, Nice, FRANCE, 4 Pathology, CHU Strasbourg, Strasbourg, FRANCE,<br />
5 Pathologie, APHP-La Salpetrière, PAris, FRANCE<br />
Introduction: Based on epidemiological, clinical, and preclinical data, lung<br />
carcinogenesis can be distinctive in women. No clear data is available to help us<br />
understand <strong>the</strong> high rate of tobacco-independent lung cancer in women. We<br />
hypo<strong>the</strong>size that genetic events or hormonal factors might be partly involved in <strong>the</strong>se<br />
tobacco-independent lung cancers.<br />
Method: We thus aimed to compare clinical, pathological and biological<br />
characteristics of lung cancer in two cohorts of smoking and never smoking women.<br />
A population of 140 women (63 never-smokers and 77 former or current smokers)<br />
carrying adenocarcinoma issued from our centre and a national collection has been<br />
included in this study.<br />
Results: The non-smoking population was characterized by a higher age (67yrs<br />
vs 58.7, p < 0.0001) and a higher frequency of a lepidic component (60.3% vs<br />
37.7 %, p = 0.008) than <strong>the</strong> smoking patients. We observed a differential genetic<br />
alteration repartition in women according to <strong>the</strong>ir tobacco status: 50.8% of<br />
never-smokers displayed EGFR mutation vs. 10.4% of smokers (p < 0.001). At<br />
<strong>the</strong> opposite KRas mutation was more frequently mutated in smokers (33.8%)<br />
than in never-smokers (9.5%, p = 0.001). We also observed a higher percentage<br />
of ERα (p = 0.03 by using <strong>the</strong> breast cancer score) and ERβ expression (p = 0.02)<br />
for non-smoking patients compared with smoking ones. We found no significant<br />
differences for progesterone receptors. Lastly ER expression was correlated with<br />
EGFR mutation.<br />
Conclusion: This study suggests that lung cancer occurring in never-smoking<br />
women is more frequently associated with EGFR mutation and ER expression,<br />
with a correlation between both markers. These findings underline <strong>the</strong> possibility<br />
of <strong>the</strong>rapy in non-smoking-women targeting both hormonal factors and genetic<br />
abnormalities.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix388 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
non-small cell lung cancer, locally<br />
advanced<br />
1191PD CLINICAL ACTIVITY OF CRIZOTINIB IN PATIENTS WITH<br />
ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC)<br />
HARBORING ROS1 GENE REARRANGEMENT<br />
S.I. Ou 1 , D.R. Camidge 2 , J. Engelman 3 , J. Clark 4 ,L.Tye 5 , K. Wilner 6 ,<br />
P. Stephenson 6 , M. Varella-Garcia 7 ,A.Iafrate 4 , A.T. Shaw 4<br />
1 Cancer Centre, Chao Family Centre, Irvine, CA, UNITED STATES OF AMERICA,<br />
2 School of Medicine, University of Colorado, Denver, UNITED STATES OF<br />
AMERICA, 3 Cancer Research, Massachusetts General Hospital, Charlestown,<br />
MA, UNITED STATES OF AMERICA, 4 Cancer Center, Massachusetts General<br />
Hospital, Boston, UNITED STATES OF AMERICA, 5 Oncology, Pfizer, CA,<br />
UNITED STATES OF AMERICA, 6 Chapel Hill, Rho, Inc., NC, UNITED STATES OF<br />
AMERICA, 7 School of Medicine, University of Colorado, CO, UNITED STATES<br />
OF AMERICA<br />
Background: Chromosomal rearrangements in <strong>the</strong> receptor tyrosine kinase (RTK)<br />
ROS1 define a new molecular subset of NSCLC. ALK inhibitors can inhibit ROS1<br />
kinase activity in cell lines. We examined <strong>the</strong> efficacy and safety of crizotinib, a small<br />
molecule inhibitor of two o<strong>the</strong>r RTKs, MET and ALK, in patients with advanced,<br />
ROS1-rearranged NSCLC.<br />
Methods: Patients with advanced NSCLC harboring ROS1 rearrangement, as<br />
determined using a break-apart FISH assay, were recruited into an expansion cohort<br />
of <strong>the</strong> original phase 1 study of crizotinib. Patients were treated with crizotinib at <strong>the</strong><br />
standard oral dose of 250 mg BID. The objective response rate (ORR) was<br />
determined based on RECIST v1.0. The disease control rate (DCR; stable disease<br />
[SD] + partial response [PR] + complete response [CR]) was evaluated at weeks<br />
8 and 16.<br />
Results: At <strong>the</strong> time of data cut-off on April 19, <strong>2012</strong>, 15 patients with ROS1 NSCLC<br />
had received crizotinib and 14 were evaluable for response. The median age was 54<br />
years (range 31–72). Fourteen patients were never-smokers and all had<br />
adenocarcinoma histology. All patients were confirmed negative for ALK<br />
rearrangement. The median number of prior treatments was 1 (range 0–6). The first<br />
ROS1 patient received crizotinib on October 19, 2010. To date, <strong>the</strong> ORR is 57%<br />
(8/14; 95% CI 28.9–82.3), with 7 PR and 1 CR. There were 4 SD, one of which was<br />
unconfirmed as PR at <strong>the</strong> time of data cut-off. The DCR at 8 weeks was 79% (11/14).<br />
Median duration of treatment was 25.7 weeks (range 0.1 + to 65.3 + ), and 12 patients<br />
continue on study. The pharmacokinetics, antitumor activity and safety profile of<br />
crizotinib in this group of patients were similar to those observed in patients with<br />
ALK-positive NSCLC.<br />
Conclusions: Crizotinib is associated with clinically significant antitumor activity in<br />
patients with ROS1 NSCLC. Similar to ALK, ROS1 rearrangement defines ano<strong>the</strong>r<br />
unique molecular subset of NSCLC patients for whom crizotinib <strong>the</strong>rapy may be<br />
highly effective. Importantly, this study represents <strong>the</strong> first clinical investigation of<br />
ROS1 as a driver mutation and <strong>the</strong>rapeutic target in cancer.<br />
Disclosure: S.I. Ou: Advisory role: Pfizer, Genentech. Compensated Honoraria:<br />
Pfizer, Genentech, Lilly. Myself Research funding: Pfizer. Myself (institution). D.R.<br />
Camidge: Advisory role: Pfizer. Myself. Honoraria: Pfizer. Myself. L. Tye:<br />
Employment: Pfizer. Clinician. Myself. Stock Ownership; Pfizer. Myself. K. Wilner:<br />
Emplyement: Pfizer. Senior Director. Myself. Compensated. Stock ownership: Pfizer.<br />
Myself. M. Varella-Garcia: Honoraria: Abbott Molecular. Myself. funding for <strong>the</strong> trial<br />
provided by NIH - yes. A.T. Shaw: Advisory role: Pfizer, Ariad, Chugai, Novartis,<br />
Daiichi-sankyo. Myself. Compensated Research funding: Astra Zeneca, Novartis.<br />
Myself. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1192PD LACE-BIO POOLED ANALYSIS OF THE PROGNOSTIC AND<br />
PREDICTIVE VALUE OF TP53 MUTATIONS IN COMPLETELY<br />
RESECTED NON SMALL CELL LUNG CANCER (NSCLC)<br />
P. Hainaut 1 ,X.Ma 2 , B. Lacas 3 , M. Tsao 4 , J. Douillard 5 , V. Rousseau 6 ,<br />
A. Dunant 6 , L. Seymour 7 , M. Filipits 8 , S. Graziano 9<br />
1 Research, International Prevention Research Institute, Lyon, FRANCE, 2 Jinan<br />
Central Hospital, Shandong University, Jinan, CHINA, 3 Meta-Analysis Unit,<br />
Institut Gustave-Roussy, Villejuif, FRANCE, 4 Hematology and Oncology, Princess<br />
Margaret Hospital, Toronto, CANADA, 5 Medical Oncology, Centre René<br />
Gauducheau, Saint-Herblain, FRANCE, 6 Biostatistics, Institut Gustave Roussy,<br />
Villejuif, FRANCE, 7 NCIC Clinical Trials Group, Queen’s University, Kingston,<br />
CANADA, 8 Medicine, Medical University of Vienna, Vienna, AUSTRIA,<br />
Annals of Oncology 23 (Supplement 9): ix389–ix399, <strong>2012</strong><br />
doi:10.1093/annonc/mds408<br />
9 Hematology and Internal Medicine, SUNY Upstate Medical University Hospital,<br />
Syracuse, UNITED STATES OF AMERICA, on behalf of <strong>the</strong> LACE-Bio Study<br />
Group<br />
Background: Mutations in <strong>the</strong> Tumour Suppressor Gene TP53 occur in about 50%<br />
of Stage II-III NSCLC. However, prognostic and predictive value of survival after<br />
adjuvant <strong>the</strong>rapy not defined. We report here on <strong>the</strong> pooled analysis of 4<br />
randomized trials of platinum-based Adjuvant ChemoTherapy (ACT) or observation.<br />
Methods: Trials included IALT, JBR10, CALGB-9633 and ANITA. Mutations in<br />
exons 5-8 of TP53 (encompassing hotspots and over 90% of known mutations) were<br />
detected by PCR/sequencing in DNA extracted from formalin-fixed<br />
paraffin-embedded NSCLC. Mutations were classified into 3 structure/function<br />
groups: non-missense; missense outside DNA Binding Notifs (missense non-DBM);<br />
missense DBM. Main endpoint was overall survival (OS). Hazard ratio (HR) and<br />
95% confidence interval (CI) were estimated with a Cox model stratified on trial and<br />
adjusted on gender, age and clinico-pathological variables.<br />
Results: 1209 NSCLC patients (pts) (5.5 years median follow-up) were analysed.<br />
Mutations were detected in 434 pts (36%; IALT: 42%; JBR10: 28%; CALGB-9633:<br />
39%; ANITA: 30%). Mutant TP53 had a borderline significant prognostic effect (HR<br />
for OS, mutation vs. wild-type (WT): 1.19; CI [1.00-1.41]; p = 0.05). Missense<br />
non-DBM mutations, likely to alter p53 protein structure, had a marginally worse<br />
prognostic effect (HR for OS, missense non-DBM vs. WT: 1.38; CI [1.08-1.75]), but<br />
effects in <strong>the</strong> 3 function groups were not significantly different (p = 0.23). Among pts<br />
with WT TP53, OS was better in <strong>the</strong> ACT group (HR for OS, ACT vs. no ACT: 0.77;<br />
CI [0.62-0.96]; p = 0.02), whereas ACT had no effect among pts with mutation.<br />
Conversely, in <strong>the</strong> ACT group, OS was significantly shorter in pts with TP53<br />
mutation than in WT pts (HR for OS, Mutant vs. WT TP53: 1.39; CI [1.09-1.77]; p<br />
= 0.008), whereas TP53 had no prognostic effect in <strong>the</strong> control group. The ACT effect<br />
in <strong>the</strong> mutated and WT groups and <strong>the</strong> prognostic effect in <strong>the</strong> ACT and control<br />
groups were not different (interaction test p = 0.07).<br />
Conclusion: TP53 mutation status had a borderline prognostic effect and was not<br />
predictive of adjuvant chemo<strong>the</strong>rapy effect on OS in NSCLC. Supported by French<br />
Ligue against Cancer (LNCC) and by unrestricted grant from Sanofi Aventis. XM<br />
was supported by a fellowship from International Agency for Research on Cancer<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1193P ONCOGENIC DRIVER MUTATIONS IN CHINESE NON-SMALL<br />
CELL LUNG CANCER (NSCLC)<br />
J. He 1 , H. Yang 2 , Q. Deng 3 ,P.He 2 , J. Jiang 1 , M. Zhao 2 ,X.Gu 4 , L. Zheng 5 ,<br />
H. Pang 1 , J.X. Zhou 6<br />
1 Thoracic Surgery, The First Affiliated Hospital of Guangzhou Medical University,<br />
Guangzhou, CHINA, 2 Thoracic Oncology, The First Affiliated Hospital of<br />
Guangzhou Medical University, Guangzhou, CHINA, 3 The Center for Translational<br />
Medicine, The First Affiliated Hospital of Guangzhou Medical University,<br />
Guangzhou, CHINA, 4 Pathology, The First Affiliated Hospital of Guangzhou<br />
Medical University, Guangzhou, CHINA, 5 The Center for Translational Medicine,<br />
Xiamen University, Xiamen, CHINA, 6 Pathology, Ningbo University School of<br />
Medicine, Ningbo, CHINA<br />
Background: Oncogenic driver mutations are responsible for both <strong>the</strong> initiation and<br />
maintenance of cancers including NSCLC. Elucidation of driver mutation occurrence<br />
in NSCLC and its relationship with clinical outcome are imperative to personalized<br />
treatment of NSCLC.<br />
Methods: Tumor tissues from a total of 488 Chinese NSCLC patients at various<br />
stages were enrolled in this retrospective study. Mutations were assessed using<br />
amplification-refractory mutation system (ADx-ARMSTM)-PCR and verified using<br />
direct sequencing. ERCC1 levels were measured using immunohistochemistry<br />
method. The relationship between tumor gene mutation status and patient’s<br />
disease-free survival (DFS) was analyzed.<br />
Results: Of <strong>the</strong> 488 NSCLC tumors, 28 had EML4-ALK fusions (5.7%). Female<br />
(10.38%), young age (
stage IIIA NSCLC, EML4-ALK fusion-positive patients had poorer DFS than those<br />
EML4-ALK fusion-negative patients (P = 0.0057). Moreover, multivariate Cox<br />
proportional hazard analysis indicated that in stage IIIA NSCLC EML4-ALK fusion<br />
was <strong>the</strong> only significant predictor for poor DFS (HR = 4.4, 95% CI 2.0-9.7, P < 0.001).<br />
We fur<strong>the</strong>r found that ERCC1 was highly expressed in EML4-ALK fusion-positive<br />
tumors.<br />
Conclusion: Oncogenic driver mutations define molecular subsets of Chinese<br />
NSCLC patients with distinct clinicopathological characteristics. EML4-ALK fusion<br />
might be a significant prognostic biomarker for locally advanced stage NSCLC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1194P TISSUE AND SERUM BIOMARKER RESULTS FROM THE<br />
PHASE II INNOVATIONS STUDY IN NON-SMALL CELL LUNG<br />
CANCER (NSCLC)<br />
N. Reinmuth 1 , S.J. Scherer 2 , R. Penzel 3 , P. Schnabel 4 , M. Meister 1 ,<br />
J. Kiemle-Kallee 5 , A. Reuss 6 , J.R. Fischer 7 , M. Wolf 8 , M. Thomas 1<br />
1 Department of Thoracic Oncology, Thoraxklinik Heidelberg, University of<br />
Heidelberg, Heidelberg, GERMANY, 2 Pharma Development Department,<br />
F. Hoffmann-La Roche Ltd/Genentech, San Francisco, CA, UNITED STATES OF<br />
AMERICA, 3 Institute of Pathology, University of Heidelberg, Heidelberg,<br />
GERMANY, 4 Department of Pathology, University of Heidelberg, Section for<br />
Thoracic Pathology, Heidelberg, GERMANY, 5 Pharma AG, Roch Pharma AG,<br />
Grenzach, GERMANY, 6 Coordinating Center for Clinical Trials, Phillips-University<br />
Marburg, Marburg, GERMANY, 7 Department of Medical Oncology, Klinik<br />
Löwenstein, Löwenstein, GERMANY, 8 Division of Haematology and Oncology,<br />
Klinikum Kassel, Kassel, GERMANY<br />
Background: The phase II INNOVATIONS study was a randomised trial of 224<br />
patients (pts) with advanced non-squamous NSCLC who received 1 st -line treatment<br />
with ei<strong>the</strong>r erlotinib (E) plus bevacizumab (B) or cisplatin (P) plus gemcitabine (G)<br />
plus B. PGB was superior to EB for progression-free survival (PFS). Pts with EGFR<br />
mutation-positive NSCLC were most likely to benefit from EB [1]. This abstract<br />
reports exploratory analyses from <strong>the</strong> optional biomarker (BM) sub-study for a<br />
number of candidate BMs commonly examined in previous NSCLC bevacizumab<br />
trials.<br />
Methods: Tissue (t) markers were determined by immunohistochemistry H-score.<br />
Serum (s) markers were analysed on day 0 and 43 using a novel protein array/ELISA.<br />
Median baseline values were used to dichotomise pts (low vs high BM) and to<br />
correlate BMs with PFS/overall survival (OS) (Cox model). Analyses were not<br />
adjusted for multiple testing.<br />
Results: BM population represented 88% of <strong>the</strong> intent-to-treat population; baseline<br />
characteristics were well balanced. Tissue (n = 198) and serum samples (day 0, n =<br />
184; day 43, n = 151) were provided for BM analysis. Soluble VEGFA was not<br />
assessed; only serum samples were available. Serum analyses: PFS was longer for <strong>the</strong><br />
BM population with low baseline IL8 and FLT4 (HR = 0.55, p < 0.05 and HR = 0.50,<br />
p < 0.05, respectively); <strong>the</strong> trend was consistent in EB and PGB treatment arms.<br />
Similar results were seen for day 43 analyses (PFS/OS). Low baseline FLT1 was<br />
associated with longer PFS in PGB pts (HR = 0.53, p < 0.05). Low ICAM levels were<br />
associated with better clinical outcomes (PGB arm). Tissue analyses: None of <strong>the</strong><br />
three tumour markers tested showed significant association with PFS/OS (p > 0.05).<br />
Significant correlations (p < 0.05) were observed between tumour and serum<br />
markers: tVEGFR1 and tVEGFR2/tVEGF; tVEGFR2 and tVEGF; sFLT1 and sTie2;<br />
sKDR and sICAM; sFLT4 and sICAM.<br />
Conclusion: Several serum baseline candidate BMs showed a statistically significant<br />
correlation with OS/PFS, in particular FLT4/IL8. The choice of treatment partner<br />
(E/PG) for bevacizumab may influence <strong>the</strong> value of BMs. Fur<strong>the</strong>r examination of <strong>the</strong><br />
data from this and o<strong>the</strong>r bevacizumab trials may provide greater insight. [1] Thomas<br />
et al. J Clin Oncol 2011;29:7504<br />
Disclosure: N. Reinmuth: Advisory Board, Lilly Corporate sponsored research, F.<br />
Hoffmann-La Roche Ltd. S.J. Scherer: Currently employed by Roche/Genentech. J.<br />
Kiemle-Kallee: Currently employed by Roche. M. Thomas: Attended advisory boards<br />
for Roche and Lilly. Received research funding from Roche and Lilly. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
1195P DETECTION OF ANAPLASTIC LYMPHOMA KINASE (ALK)<br />
GENE REARRANGEMENT IN NON-SMALL CELL LUNG<br />
CANCER (NSCLC): A GLANCE AT “BORDERLINE” CASES<br />
M. von Laffert 1 , E. Berg 1 , D. Lenze 1 , P. Lohneis 1 , M. Hummel 1 , M. Dietel 2<br />
1 Institue of Pathology Charité, Charite Berlin Mitte, Berlin, GERMANY, 2 Surgical<br />
Pathology, Charité, Humboldt-Universität zu Berlin, Berlin, GERMANY<br />
Background: Lung cancer is <strong>the</strong> leading cause of cancer related mortality in men<br />
and women. In ∼5% [range: 0.9-13] of NSCLC a genomic EML4-ALK fusion has<br />
been described, showing <strong>the</strong>rapeutically sensitivity for ALK-inhibitors. Although<br />
much has been reported about clinical and histological data of this NSCLC subtype<br />
(young patients, non-smokers, solid/mucinous adenocarcinomas), <strong>the</strong> parameters for<br />
Annals of Oncology<br />
FISH-based (e.g. threshold of positive cells, signal distance) diagnosis vary among <strong>the</strong><br />
different studies.<br />
Material and methods: We performed retrospective screening (tissue microarray<br />
based) of 488 NSCLC (336 adenocarcinomas, 152 squamous cell carcinomas) for<br />
ALK-expression (IHC-intensity: 0-3) using immunohistochemistry (Novocastra) and<br />
ALK-breaks using FISH (Abbott, ALK break-apart with positivity if split signals or<br />
single red signals were detectable in ≥15% per 100 cells). The evaluation of <strong>the</strong> IHC<br />
and FISH data was performed independent from each o<strong>the</strong>r. Since various thresholds<br />
for ALK-break positivity have been reported in <strong>the</strong> literature, special attention was<br />
given to cases with ALK-breaks in <strong>the</strong> range of 12%-20%.<br />
Results: 95.7% (467/488) of <strong>the</strong> cases were ALK-break-negative (
Annals of Oncology<br />
harboring EGFR activating mutations. However, almost all patients eventually acquire<br />
resistance to EGFR-TKIs within several years. The major mechanisms of acquired<br />
resistance including 2 nd mutation of T790M and amplification of MET have been<br />
identified. However, <strong>the</strong> mechanisms of o<strong>the</strong>r resistance remain unclear. In this<br />
study, we established novel erlotinib-resistant NSCLC cells and examined <strong>the</strong>ir<br />
resistant mechanisms.<br />
Methods: NSCLC HCC827 cells have an EGFR Exon 19 deletion and gene<br />
amplification and are highly sensitive to erlotinib. The resistant cells were established<br />
by continuously exposing HCC827 cells to 0.1, 1 or 10 µM of erlotinib in 96 well<br />
plates for three months. The resistant mechanisms were determined by direct<br />
sequence analysis and EGFR FISH analysis.<br />
Results: The fourteen and three resistant cells were established by 0.1 µM and 1 µM<br />
of erlotinib exposure, respectively. No resistant cells appeared in <strong>the</strong> wells of 10 µM<br />
of erlotinib. The IC50 values of <strong>the</strong>se resistant cells were more than 25-fold higher<br />
than that of parental cells. No 2 nd mutation of T790M was detected in any of <strong>the</strong><br />
resistant cells and MET gene amplification was detected in only one resistant cells.<br />
Instead, we found that 13/17 resistant cells were dominated by EGFR not amplified<br />
cells and one of resistant cells B10 consisted of more than 99.9% of EGFR not<br />
amplified cells, and that <strong>the</strong> parental cells consisted of only 2.5% of EGFR not<br />
amplified cells and 97.5% of EGFR amplified cells. EGFR not amplified clone 4D8<br />
isolated from parental cells and showed resistance to erlotinib comparable to <strong>the</strong><br />
resistant cells B10. Fur<strong>the</strong>rmore, we found that EGFR not amplified cells were<br />
constantly emerged from EGFR amplified clone isolated from parental cells under<br />
normal cell culture condition.<br />
Conclusion: Loss of amplified EGFR gene with mutation causes acquired resistance<br />
in HCC827 cells when exposed to relatively low concentration of erlotinib while high<br />
concentration of erlotinib deprives HCC827 cells of <strong>the</strong> chance of emergence of<br />
resistant cells.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1198P A RANDOMIZED PHASE (PH) 2 STUDY WITH EXPLORATORY<br />
BIOMARKER ANALYSIS OF FICLATUZUMAB (F) A<br />
HUMANIZED HEPATOCYTE GROWTH FACTOR (HGF)<br />
INHIBITORY MAB IN COMBINATION WITH GEFITINIB (G)<br />
VERSUS G IN ASIAN PATIENTS (PTS) WITH LUNG<br />
ADENOCARCINOMA (LA)<br />
T.S.K. Mok 1 , K. Park 2 , S.L. Geater 3 , S. Agarwal 4 , M. Han 5 , M. Credi 4 ,<br />
K. McKee 6 , N. Kuriyama 7 , W. Slichenmyer 4 , E.H. Tan 8<br />
1 Department of Clinical Oncology, Chinese University of Hong Kong Prince of<br />
Wales Hospital, Shatin, Hong Kong, CHINA, 2 Division of Hematology/Oncology,<br />
Department of Medicine, Sungkyunkwan University, School of Medicine, Seoul,<br />
KOREA, 3 Oncology, Prince of Songkla University Faculty of Medicine, Songkla,<br />
THAILAND, 4 Clinical Research, AVEO Pharmaceuticals, Inc, Cambridge, MA,<br />
UNITED STATES OF AMERICA, 5 Preclinical Development, AVEO<br />
Pharmaceuticals, Inc, Cambridge, MA, UNITED STATES OF AMERICA, 6 Clinical<br />
Operations, AVEO Pharmaceuticals, Inc, Cambridge, MA, UNITED STATES OF<br />
AMERICA, 7 Biostatistics, AVEO Pharmaceuticals, Inc, Cambridge, MA, UNITED<br />
STATES OF AMERICA, 8 Medical Oncology, National Cancer Institute, Singapore,<br />
SINGAPORE<br />
Background: HGF/cMet pathway activation has been implicated in EGFR TKI<br />
resistance in LA. F is an HGF IgG1 inhibitory MAb that prevents cMet receptor<br />
activation by blocking its only known ligand, HGF. This study compared FG with G<br />
in treatment naïve pts with high incidence of sensitizing EGFR mutation (SM + ),<br />
and explored o<strong>the</strong>r biomarkers.<br />
Methods: This was a multicenter, open-label, randomized Ph 2 Study in Asian pts<br />
with LA. Pts received ei<strong>the</strong>r G (250 mg daily) or F (20 mg/kg IV q 2 wks) plus G<br />
(250 mg daily). Pts on G were allowed to cross over to FG upon disease<br />
progression. Primary endpoint was ORR. The secondary endpoints included PFS<br />
and correlation of biomarkers with clinical activity. Biomarker analysis included<br />
EGFR mutation status, cMet and HGF expression, EGFR and cMet gene copy<br />
number.<br />
Results: 188 pts were randomized, 94 (19M/75F) to FG or G, respectively; mean<br />
age (FG: 59, G: 60) yrs; ECOG-PS was balanced between arms. Tumor tissue<br />
samples were analyzed from 144 of 188 subjects. Table 1 shows efficacy by<br />
biomarker subset and includes results for overall population. Notable difference<br />
was seen in low cMet group, ORR (41 v 22%) and mPFS (7.3 v 2.8 m), favoring<br />
FG. The difference can be mostly attributed to <strong>the</strong> SM + /cMet low subset ORR<br />
(70 v 44%) and mPFS (11.0 v 5.5 m) favoring FG. The low cMet group may<br />
identify a subgroup in SM + that had worse outcome by G (mPFS 5.5 v 7.4 m in<br />
SM + overall) and benefited from FG treatment (11.0 m). There is also a trend in<br />
OS favoring FG in several biomarker subsets. FG demonstrated a manageable<br />
toxicity profile.<br />
Conclusions: FG was well tolerated and showed clinical activity in biomarker subsets.<br />
However, <strong>the</strong> study results did not reach statistical significance. FG appears to<br />
improve treatment outcome in a subset of pts with SM + and low cMet expression.<br />
These observations warrant fur<strong>the</strong>r evaluation.<br />
FG G<br />
N PFS, m ORR,% N PFS, m ORR,%<br />
Overall Population 94 5.6 43 94 4.7 40<br />
Biomarker Subset N PFS, m ORR,% N PFS, m ORR,%<br />
SM + 33 9.2 58 38 7.4 61<br />
SM- 24 1.8 25 30 1.9 10<br />
cMet Low 22 7.3 41 23 2.8 22<br />
cMet High 34 7.4 44 44 5.5 30<br />
SM + /cMet Low 10 11.0 70 9 5.5 44<br />
SM-/cMet Low 9 1.3 0 13 2.3 0<br />
Disclosure: S. Agarwal: Employed by AVEO Pharmaceuticals, Inc. Involved in <strong>the</strong><br />
design, execution, data analysis, and interpretation, of this trial. M. Han: Employed<br />
by AVEO Pharmaceuticals, Inc. Involved in <strong>the</strong> design, execution, data analysis, and<br />
interpretation, of this trial. K. McKee: Employed by AVEO Pharmaceuticals, Inc.<br />
Involved in <strong>the</strong> design, execution, data analysis, and interpretation, of this trial. M.<br />
Credi: Employed by AVEO Pharmaceuticals, Inc. Involved in <strong>the</strong> design, execution,<br />
data analysis, and interpretation, of this trial. N. Kuriyama: Employed by AVEO<br />
Pharmaceuticals, Inc. Involved in <strong>the</strong> design, execution, data analysis, and<br />
interpretation, of this trial. W. Slichenmyer: Employed by AVEO Pharmaceuticals,<br />
Inc. Involved in <strong>the</strong> design, execution, data analysis, and interpretation, of this trial.<br />
All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1199P A RANDOMISED PHASE II STUDY OF CETUXIMAB (C) IN<br />
COMBINATION WITH TWO CISPLATIN-BASED CONCURRENT<br />
CHEMORADIOTHERAPY REGIMENS IN PATIENTS (PTS) WITH<br />
STAGE III NON-SMALL CELL LUNG CANCER (NSCLC). FINAL<br />
RESULTS OF THE GFPC 08-03 TRIAL<br />
L. Greillier 1 , I. Martel-Lafay 2 , D. Arpin 3 , N. Pourel 4 , S. Chabaud 5 , R. Lamy 6 ,<br />
A. Madroszyk 7 , P. Fournel 8<br />
1 Multidisciplinary Oncology & Therapeutic Innovations, Aix-Marseille Univ,<br />
Assistance Publique-Hôpitaux de Marseille, Marseille, FRANCE, 2 Radio<strong>the</strong>rapy,<br />
Centre Leon Berard, Lyon, FRANCE, 3 Pulmonology, Centre Hospitalier de<br />
Macon, Macon, FRANCE, 4 Radio<strong>the</strong>rapy, Institut Sainte Ca<strong>the</strong>rine, Avignon,<br />
FRANCE, 5 UBET, Centre Leon Berard, Lyon, FRANCE, 6 Pulmonology, Centre<br />
Hospitalier de Bretagne Sud, Lorient, FRANCE, 7 Medical Oncology, Institut Paoli<br />
Calmettes, Marseille, FRANCE, 8 Département d’Oncologie Médicale, Institut de<br />
Cancérologie Lucien Neuwirth, Saint-Priest en Jarez, FRANCE<br />
Background: This non-comparative randomised trial (EUDRACT 2008-005013-21)<br />
aimed to assess <strong>the</strong> feasibility of combining cetuximab (C) with cisplatin (P) + vinorelbine<br />
(V) + radio<strong>the</strong>rapy (R) or with P + etoposide (E) + R in selected stage IIIA/B NSCLC PTS.<br />
Methods: Eligibility criteria included age
1200P CONCOMITANT CHEMORADIATION GIVES SIGNIFICANT<br />
SURVIVAL AND HRQOL BENEFITS IN PATIENTS WITH<br />
LOCALLY ADVANCED STAGE III NON SMALL CELL LUNG<br />
CANCER (NSCLC) NOT ELIGIBLE FOR RADICAL<br />
TREATMENT: A RANDOMIZED TRIAL BY THE NORWEGIAN<br />
LUNG CANCER STUDY GROUP<br />
H.H. Strøm 1 , S. Sundstrøm 2 , N. Helbekkmo 3 , R. Bremnes 3 , U. Aasebø 4<br />
1 Medical Department, Helgelands Hospital, Sandnessjøen, NORWAY,<br />
2 Oncology, St.Olavs Hospital, Trondheim, NORWAY, 3 Oncology, University<br />
Hospital of Nor<strong>the</strong>rn Norway, Tromsø, NORWAY, 4 Medical, University Hospital of<br />
Nor<strong>the</strong>rn Norway, Tromsø, NORWAY<br />
Background: In patients with locally advanced, inoperable NSCLC and negative<br />
prognostic factors, treatment will be of palliative intent. Platinum-based<br />
chemo<strong>the</strong>rapy and thoracic radiation are both well documented, but <strong>the</strong> role of<br />
chemoradiation has not been established. Objective: Will concomitant radio- and<br />
chemo<strong>the</strong>rapy (chemoradiation), when compared to chemo<strong>the</strong>rapy alone, be superior<br />
with respect to survival and health-related quality of life (HRQOL) in patients with<br />
incurable NSCLC stage III (negative prognostic factors)?<br />
Methods: Stage III NSCLC patients, not eligible for curative radio<strong>the</strong>rapy due to<br />
tumor size ≥ 8 cm or performance status 2 or weight loss ≥ 10 % during <strong>the</strong> last 6<br />
months, were randomized to receive ei<strong>the</strong>r chemoradiation or chemo<strong>the</strong>rapy alone.<br />
Chemo<strong>the</strong>rapy consisted of 4 cycles of carboplatin iv day 1 and vinorelbine po day 1<br />
and 8, with 3-week intervals. Patients in <strong>the</strong> chemoradiation arm also received<br />
radio<strong>the</strong>rapy with fractionation 42 Gy/2.8 Gy, starting at <strong>the</strong> 2nd chemo course. The<br />
primary endpoint was overall survival. Secondary endpoints were HRQOL and<br />
toxicity.<br />
Results: 191 patients from 25 Norwegian hospitals were randomized from Nov 2006<br />
until Nov 2011, when enrollment was terminated due to slow accrual. Median age<br />
was 67 years and 20% had PS 2. In <strong>the</strong> chemo<strong>the</strong>rapy versus <strong>the</strong> concomitant arm,<br />
<strong>the</strong> median overall survival was 9.7 and 13.3 months, respectively (p < 0.01).1-year<br />
survival 31.9 % and 51.1%, respectively (p < 0.01). Following a minor decline in<br />
global QOL during treatment, patients in <strong>the</strong> chemoradiation arm improved over <strong>the</strong><br />
subsequent months, while those in <strong>the</strong> chemo<strong>the</strong>rapy only arm reported gradual<br />
deterioration. In <strong>the</strong> chemoradiation arm, <strong>the</strong>re were more hospital admissions<br />
related to side effects (p < 0.01) as 31.5 % of <strong>the</strong>se patients reported esophagitis grade<br />
3, but none grade 4.<br />
Conclusions: Of <strong>the</strong> 2 investigated treatment regimens; chemoradiation was superior<br />
to chemo<strong>the</strong>rapy alone with respect to both survival and global HRQOL, at <strong>the</strong><br />
expense of more hospital admissions due to toxicity.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1201P 18F-FDG-PET RESPONSE DURING THE SECOND WEEK OF<br />
CONCURRENT OR SEQUENTIAL CHEMO-RADIOTHERAPY<br />
SIGNIFICANTLY CORRELATES WITH 2-YEAR SURVIVAL IN<br />
NSCLC PATIENTS<br />
W. van Elmpt 1 , M. Öllers 1 , A.C. Dingemans 2 , P. Lambin 1 , D. De Ruysscher 1<br />
1 Department of Radiation Oncology (Maastro), GROW, Maastricht University<br />
Medical Centre, Maastricht, NETHERLANDS, 2 Pulmonology, Maastricht<br />
University Medical Center (MUMC), Maastricht, NETHERLANDS<br />
Purpose/Objective: Assessment early during <strong>the</strong> course of treatment could identify<br />
prognostic groups, allowing treatment individualisation at a time when <strong>the</strong>rapy<br />
changes are possible and before major toxicity occurred. We hypo<strong>the</strong>sised that<br />
FDG-PET/CT imaging during <strong>the</strong> second week of chemo-radio<strong>the</strong>rapy would<br />
correlate with 2-year overall survival (OS).<br />
Methods: We performed FDG-PET/CT imaging at two time points: One 4D PET/<br />
CT was performed prior to <strong>the</strong> start of radio<strong>the</strong>rapy, and a second 4D PET/CT<br />
during <strong>the</strong> second week of radio<strong>the</strong>rapy, sequential or concurrently with<br />
cisplatin-vinorelbine. In total 34 consecutive patients with NSCLC were successfully<br />
imaged. Images were analysed both for CT-based characteristics (volume of <strong>the</strong><br />
primary tumour and, if present, involved lymph nodes), PET characteristics included<br />
<strong>the</strong> average, maximum and peak SUV (SUVmean, SUVmax, SUVpeak, resp.). The<br />
difference in <strong>the</strong>se parameters between both time points were correlated to <strong>the</strong> 2-year<br />
overall survival.<br />
Results: The change in FDG-uptake (SUVmean) of <strong>the</strong> primary tumour was<br />
significantly different (p = 0.007) between <strong>the</strong> group surviving more than 2 years<br />
(-20.2 ± 20.5%) compared to <strong>the</strong> group not surviving two years ( + 2.1 ± 21.9%).<br />
Using <strong>the</strong> EORTC criteria for partial response (decrease in signal of 15%), a<br />
sensitivity of 63% and a specificity of 93% in this population was found that<br />
separated <strong>the</strong> survival curves (p = 0.001). CT-based early response parameters were<br />
not associated with prediction of survival.<br />
Conclusions: Decrease in FDG-uptake already in <strong>the</strong> second week of (chemo-)<br />
radio<strong>the</strong>rapy is correlated with overall survival in NSCLC. This opens avenues for<br />
individualized and optimized treatment based on early treatment response analysis.<br />
A prospective trial including 120 patients has just been terminated.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1202P OUTCOMES OF AGGRESSIVE CONCURRENT<br />
CHEMOTHERAPY IN SEPTUAGENARIANS WITH STAGE IIIB<br />
NON-SMALL CELL LUNG CARCINOMA<br />
E. Topkan 1 , C. Parlak 1 , S. Topuk 1 , O. Ozyilkan 2<br />
1 Department of Radiation Oncology, Baskent University Adana Medical Faculty,<br />
Adana, TURKEY, 2 Medical Oncology, Baskent University Faculty of<br />
MedicineAdana Uygulama Ve Arastirma Mer., Adana, TURKEY<br />
Background: Aim of <strong>the</strong> study was to retrospectively assess <strong>the</strong> feasibility of radical<br />
chemoradio<strong>the</strong>rapy in terms of tolerability and survival outcomes in medically fit 71<br />
to 79 years old stage IIIB NSCLC patients.<br />
Materials and methods: From <strong>the</strong> hospital records, 78 medically fit, septuagenerians<br />
with stage IIIB lung carcinoma were evaluated. Patients should have performance of<br />
ECOG 0-1, body mass index of ≥20kg/m 2 , and weight loss of
Annals of Oncology<br />
Results: Out of <strong>the</strong> 230 patients, 227 were eligible for analysis. With a median FU of<br />
23 months <strong>the</strong> median PFS was 15 months (95% CI 12-21 months), and a 2 years<br />
overall survival of 55% (95% CI 48%-64%). At <strong>the</strong> time of analysis 134 PFS events<br />
had occurred. The primary factors associated with PFS were tumor volume and SCC,<br />
with <strong>the</strong> pairwise interactions between SCC and both gender and histology also being<br />
potentially important. A full Cox regression model including <strong>the</strong> interactions and a<br />
reduced model only including only SCC and tumor volume were constructed. In<br />
both models a difference in PFS at 24 months of roughly 40% was observed between<br />
<strong>the</strong> high-and low risk groups.<br />
Conclusion: A model prognostic for PFS using SCC and tumor volume, was<br />
developed that identified stage II-III patients at high risk for progressive disease after<br />
CCRT. Validation of this model is ongoing.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1204P PHASE III STUDY COMPARING SECOND- AND<br />
THIRD-GENERATION REGIMENS WITH CONCURRENT<br />
THORACIC RADIOTHERAPY IN UNRESECTABLE STAGE III<br />
NON-SMALL CELL LUNG CANCER: AN ADDITIONAL<br />
ANALYSIS BY THE HISTOLOGICAL TYPE IN THE<br />
WJTOG0105 STUDY<br />
M. Satouchi 1 , Y. Chiba 2 , N. Yamamoto 3 , Y. Nishimura 4 , K. Tsujino 5 , Y. Fujisaka 6 ,<br />
S. Kudoh 7 , T. Hida 8 , S. Atagi 9 , K. Nakagawa 6<br />
1 Thoracic Oncology, Hyogo Cancer Center, Hyogo, JAPAN, 2 Clinical Reserch<br />
Center, Kinki University, Osakasayama, JAPAN, 3 Thoracic Oncology, Shizuoka<br />
Cancer Center, Shizuoka, JAPAN, 4 Radiation Oncology, Kinki University Faculty<br />
of Medicine, Osakasayama, JAPAN, 5 Radiation Oncology, Hyogo Cancer center,<br />
Akashi, JAPAN, 6 Medical Oncology, Kinki University Fuculty of Medicine, Osaka,<br />
JAPAN, 7 Respiratory Medicine, Osaka City University, Osaka, JAPAN, 8 Thoracic<br />
Oncology, Aichi Cancer Center, Nagoya, JAPAN, 9 Thoracic Oncology,<br />
Kinki-chuo Chest Medical Center, Osaka, JAPAN<br />
Background: The WJTOG0105 study was conducted to compare third-generation<br />
regimen (irinotecan/carboplatin [IC], paclitaxel/carboplatin [PC]) and<br />
second-generation regimen (mitomycin/vindesine/cisplatin [MVP]) with concurrent<br />
thoracic radio<strong>the</strong>rapy (TRT) in patients with unresectable stage III non-small-cell<br />
lung cancer (J Clin Oncol. 2010; 28: 3739-45). We conducted an additional analysis<br />
by <strong>the</strong> histological type (Squamous [Sq] vs. Non-squamous [Non-sq]) to closely<br />
examine differences of efficacy between more frequent radiosensitizing doses and<br />
systemic doses of chemo<strong>the</strong>rapy.<br />
Materials and methods: Patients received <strong>the</strong> following treatments: MVP, mitomycin<br />
(8 mg/m2 on day 1, 29), vindesine (3 mg/m2 on day 1, 8, 29, 36), and cisplatin (80<br />
mg/m2 on day 1, 29) with concurrent TRT (60 Gy), followed by 2 courses of MVP;<br />
IC, weekly irinotecan (20 mg/m2)/carboplatin (AUC 2) for 6 weeks with concurrent<br />
TRT (60 Gy), followed by 2 courses of irinotecan (50 mg/m2)/carboplatin (AUC 5);<br />
PC, weekly paclitaxel (40 mg/m2)/carboplatin (AUC 2) for 6 weeks with concurrent<br />
TRT (60 Gy), followed by 2 courses of paclitaxel (200 mg/m2)/carboplatin (AUC 5).<br />
Overall survival (OS), progression free survival (PFS), and patterns of initial failure<br />
were compared by <strong>the</strong> histological type.<br />
Results: The median OS and PFS were 20.3, 9.0 months in Sq and 20.5, 8.1 months<br />
in Non-sq. The Hazard ratio (HR) for OS and PFS in Non-sq were 0.996 (P = 0.973)<br />
and 1.199 (P = 0.079). Although <strong>the</strong>re was no statistically significant difference<br />
between Sq and Non-sq, <strong>the</strong> out-field recurrence rate in Non-sq (51.1%) was higher<br />
than Sq (26.1%) and <strong>the</strong> PFS in Sq tended to be longer than Non-sq. The efficacy of<br />
PC was compared with MVP in each histological type. For Sq, <strong>the</strong> median OS and<br />
PFS were 22.0, 10.4 months in PC and 19.7, 9.3 months in MVP. The HR for OS<br />
and PFS in PC were 0.957 (P = 0.822) and 0.871 (P = 0.459). For Non-sq, <strong>the</strong> median<br />
OS and PFS were 21.3, 8.1 months in PC and 21.8, 7.6 months in MVP. The HR for<br />
OS and PFS in PC were 1.083 (P = 0.662) and 0.996 (P = 0.984). Therefore no<br />
statistically significant difference was found between PC and MVP in each<br />
histological type. Fur<strong>the</strong>rmore, <strong>the</strong> patterns of initial failure were similar between PC<br />
and MVP.<br />
Conclusion: Weekly PC with concurrent TRT showed similar efficacy to MVP with<br />
concurrent TRT, with no relation to <strong>the</strong> histological type.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Table: 1205P<br />
1205P PHASE II STUDY OF TWO ERIBULIN REGIMENS IN<br />
COMBINATION WITH ERLOTINIB IN PATIENTS (PTS) WITH<br />
PREVIOUSLY TREATED ADVANCED NON-SMALL CELL LUNG<br />
CANCER (NSCLC)<br />
S.L. Geater 1 , N. Ianotti 2 , S. Thongprasert 3 , A. Spira 4 , D. Smith 4 , V. Lee 5 ,<br />
W-T. Lim 6 , P. Gopalakrishna 7 , C. Reynolds 8 , T.S.K. Mok 9<br />
1 Medical Oncology, Songklanagarind Hospital, Hatyai Songkhla, THAILAND,<br />
2 Medical Oncology, Hematology Oncology Associates, Port Saint Lucie, FL,<br />
UNITED STATES OF AMERICA, 3 Department of Medicine, Maharaj Nakorn<br />
Chiang Mai Hospital, Faculty of Medicine, Chiangmai, THAILAND, 4 Medical<br />
Oncology, US Oncology Research, Houston, TX, UNITED STATES OF<br />
AMERICA, 5 Medical Oncology, Queen Mary Hospital, Hong Kong, Hong Kong,<br />
CHINA, 6 Medical Oncology, National Cancer Centre, Singapore, SINGAPORE,<br />
7 Medical Oncology, Eisai Ltd, Hatfield, UNITED KINGDOM, 8 Oncology, Ocala<br />
Oncology Center and US Oncology Research, Houston, TX, UNITED STATES<br />
OF AMERICA, 9 Clinical Oncology, Chinese University of Hong Kong, Hong Kong,<br />
CHINA<br />
Background: Eribulin, a microtubule dynamics inhibitor, is approved for pts with<br />
locally advanced/metastatic breast cancer that progressed after ≥2 chemo<strong>the</strong>rapeutic<br />
regimens for advanced disease. Prior <strong>the</strong>rapy should have included an anthracycline<br />
and taxane unless not suitable. This randomized, multicenter study compared<br />
efficacy and tolerability of two eribulin regimens administered sequentially with<br />
erlotinib in pts with advanced NSCLC to establish an optimal dosing schedule.<br />
Methods: Pts (ECOG ≤2; ≥1 prior anti-cancer <strong>the</strong>rapy for advanced NSCLC<br />
including ≥1 platinum-based <strong>the</strong>rapy) received 2.0 mg/m 2 eribulin mesilate (2-5 min<br />
IV) on Day (D) 1 and 150 mg oral erlotinib on D2-16 (21D cycle), or 1.4 mg/m 2<br />
eribulin mesilate on D1 and D8 and 150 mg erlotinib on D15-28 (28D cycle).<br />
Primary endpoint was objective response rate (ORR); secondary endpoints were<br />
progression-free survival (PFS), overall survival (OS), disease control rate (DCR),<br />
safety, pharmacokinetics and biomarker (BM) assessment.<br />
Results: 123 pts were treated (63 pts 21D cycle, 60 pts 28D cycle). Median age was<br />
63 years (range 35-87), 53.7% male, 75.6% smokers, 65.9% stage IV disease and<br />
91.1% ≥2 prior <strong>the</strong>rapy for advanced NSCLC. ORR was 12.7% (21D) and 16.7%<br />
(28D); o<strong>the</strong>r efficacy parameters were also greater with <strong>the</strong> 28D cycle. Concomitant<br />
administration of erlotinib did not affect eribulin exposure and was well tolerated<br />
with no unexpected toxicities. BM analysis supported overall results.<br />
Conclusions: Both regimens were associated with moderate activity in this heavily<br />
pre-treated population. The 28D regimen appears to have greater activity and less<br />
toxicity than <strong>the</strong> 21D.<br />
Disclosure: S. Thongprasert: The author declares <strong>the</strong> following conflicts of interest:<br />
consultant/advisory role (Novartis/Pfizer/Eli Lilly), honoraria (AstraZeneca/Roche),<br />
and research funding (Novartis/Pfizer/Roche). D. Smith: The author declares <strong>the</strong><br />
following conflicts of interest: research funding (Eisai). P. Gopalakrishna: The author<br />
declares <strong>the</strong> following conflicts of interest: employee (Eisai Ltd. C. Reynolds: The<br />
author declares <strong>the</strong> following conflicts of interest: honoraria/speakers bureau (Eisai).<br />
T.S.K. Mok: Consultant/advisory role (AstraZeneca /Pfizer/Eli Lilly/Roche/Merck<br />
Serono/Eisai/BMS/BeiGene/AVEO/Taiho/BI), honoraria (AstraZeneca/Roche Pfizer/<br />
Eli Lilly/ Merck Serono/Eisai/BMS/BeiGene/AVEO /Taiho/BI), research funding<br />
(AstraZeneca). All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1206P PEMETREXED (PEM) COMBINATION THERAPY WITH<br />
CARBOPLATIN (CB) FOLLOWED BY PEM MAINTENANCE IN<br />
JAPANESE PATIENTS (PTS) WITH NONSQUAMOUS<br />
NON-SMALL CELL LUNG CANCER (NSCLC): SUBGROUP<br />
ANALYSIS OF ELDERLY PTS<br />
N. Nogami 1 , R. Sekiguchi 2 , S. Enatsu 2 , K. Nakagawa 3 , T. Tamura 4<br />
1 Dept of Thoracic Oncology, NHO Shikoku Cancer Center, Matsuyama, JAPAN,<br />
2 Development Center of Excellence, Eli Lilly Japan K.K., Kobe, JAPAN, 3 Medical<br />
Oncology, Kinki University School of Medicine, Osaka, JAPAN, 4 Division of<br />
Internal Medicine and Thoracic Oncology, National Cancer Center Hospital,<br />
Tokyo, JAPAN<br />
Objectives: This subgroup analysis evaluated <strong>the</strong> efficacy and safety of Pem<br />
combination <strong>the</strong>rapy with Cb followed by Pem maintenance in Japanese elderly<br />
NSCLC pts.<br />
21D 28D<br />
Median no. cycles (range) Pts completing ≥6 cycles, % 3 (1-31) 36.5 4 (1-23) 36.7<br />
ORR a Partial response (PR) b Stable disease (SD) b DCR<br />
(Complete response + PR + SD) a<br />
12.7 (5.6, 23.5) 8 (12.7) 22 (34.9) 47.6 (34.9, 60.6) 16.7(8.3, 28.5 ) 10 (16.7) 28 (46.7) 63.3 (49.9, 75.4)<br />
PFS c OS c<br />
3.5 (1.9, 4.7) 7.6 (6.3,12.1) 3.8 (3.3, 5.5) 8.5 (6.2,13.1)<br />
Adverse events of interest (grade ≥3), % Diarrhea Neutropenia<br />
Peripheral neuropathy Rash<br />
6.3 44.4 3.2 6.3 1.7 38.3 0 1.6<br />
a % (95% CI) b n (%) c median, months (95% CI).<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds408 | ix393
Patients and methods: The study was a multicenter, prospective post-marketing<br />
study which assessed <strong>the</strong> safety and efficacy of Cb AUC 6 and Pem 500 mg/m 2 on<br />
Day 1 of each 21-day cycle for 4 cycles as induction <strong>the</strong>rapy followed by Pem<br />
maintenance <strong>the</strong>rapy. For this subgroup analysis 109 advanced nonsquamous<br />
NSCLC pts with good PS (ECOG 0-1) were grouped by age (elderly: ≥70 years,<br />
younger: 60years (22% vs 9%, p > 0.05).<br />
Histology also significantly effected <strong>the</strong> development of brain metastasis (43.2% in<br />
adenocarcinoma, 16.4% in epidermoid carcinoma, p = 0.004). On multivariate<br />
analysis, only age was found to be significant prognostic factor (p = 0.01)<br />
Conclusion: Age and histology significantly effects development of brain metastasis<br />
in locally advanced NSCLC. Younger age was <strong>the</strong> only significant variable for brain<br />
metastasis.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1208 ANAPLASTIC LYMPHOMA KINASE (ALK) GENE<br />
REARRANGEMENT IN NON-SMALL CELL LUNG CANCER<br />
(NSCLC): RESULTS OF THE FIRST INTERN ROUND ROBIN<br />
PANEL TESTING (8 INSTITUTES FROM GERMANY AND<br />
SWITZERLAND)<br />
M. von Laffert 1 , P. Schirmacher 2 , H. Kreipe 3 , R. Büttner 4 , I. Petersen 5 ,<br />
W. Jochum 6 , M. Dietel 7 , M. Hummel 1<br />
1 Institute of Pathology Charité, Charite Berlin Mitte, Berlin, GERMANY,<br />
2 Pathology, University of Heidelberg, Heidelberg, GERMANY, 3 Pathology, MHH<br />
(University of Hannover), Hannover, GERMANY, 4 Pathology, University of<br />
Cologne, Köln, GERMANY, 5 Pathology, University of Jena, Jena, GERMANY,<br />
6 Pathology, Kantonspital St Gallen, St.Gallen, SWITZERLAND, 7 Surgical<br />
Pathology, Charité, Humboldt-Universität zu Berlin, Berlin, GERMANY<br />
Background: The reliable identification of NSCLC patients with breaks in <strong>the</strong> gene<br />
of <strong>the</strong> anaplastic lymphoma kinase (ALK) is crucial for <strong>the</strong> induction of <strong>the</strong>rapy with<br />
Annals of Oncology<br />
inhibitors (e.g. Crizotinib) against <strong>the</strong> ALK activity. The implementation of round<br />
robin tests is essential to certificate institutes of pathology which are capable to<br />
perform ALK-testing with high reliability.<br />
Material and methods: Tissue microarrays consisting of 10 NSCLC cases (all<br />
adenocarcinomas; 3 cores for each case) were independently tested for<br />
ALK-expression by immunohistochemistry (IHC) and genomic ALK-breaks by FISH<br />
in 8 institutes of pathology (listed authors on behalf of <strong>the</strong> group: Universities of<br />
Berlin, Heidelberg, Hannover, Köln, München, Jena, St. Gallen and Wiesbaden). 5<br />
cases were ALK-break positive (one case with a low percentage of ALK-break positive<br />
cells; 20%) whereas <strong>the</strong> remaining 5 cases were clearly ALK-break negative as<br />
determined by blinded testing independently performed in Berlin and Heidelberg.<br />
RT-PCR was carried out to confirm <strong>the</strong> presence of an EML4-ALK fusion in <strong>the</strong><br />
ALK-break positive cases.<br />
Results: All 8 participants identified <strong>the</strong> 5 ALK-break negative cases correctly (IHC<br />
and FISH) and 4 of <strong>the</strong> FISH-positive cases were detected by all but one of <strong>the</strong><br />
participants (FISH). The remaining ALK-break positive case with a low number of<br />
affected tumour cells was scored negative by 3 of <strong>the</strong> 8 participants. IHC for <strong>the</strong><br />
detection of ALK-expression revealed heterogeneous results in <strong>the</strong> ALK-break<br />
positive cases whereas ALK-break negative cases were consistently scored negative by<br />
all participants.<br />
Conclusion: Our round robin test for ALK-testing demonstrates that<br />
unequivocal ALK-break negative NSCLC cases were consistently scored negative<br />
by all participants by means of FISH and IHC. In contrast ALK-IHC<br />
(ALK-expression) with currently available antibodies clearly failed to detect all<br />
ALK-translocation positive lung cancers. Thus, application and validation of<br />
more reliable ALK-antibodies is required before IHC screening can be<br />
recommended. ALK-break positivity appears to be reliably detectable (FISH) in<br />
cases with a high percentage of affected tumour cells. Cases with low numbers<br />
of ALK-break positive tumour cells (between 15% and 20%) remain a<br />
diagnostic challenge.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1209 DETECTING EGFR MUTATION AND ITS LIGANDS<br />
EXPRESSION IN ADVANCED NON-SMALL CELL LUNG<br />
CANCER PATIENTS<br />
S. Wang 1 , X. Han 2 ,J.Li 1 ,X.Hu 1 , X. Wang 1 , L. Gui 1 , L. Zhao 1 , Y. Sun 1 ,Y.Shi 1<br />
1 Medical Oncology, Cancer Hospital-China Academy of Medical Sciences Chao<br />
Yang District CAMS and PUMC, Beijing, CHINA, 2 Clinical Laboratory, Cancer<br />
Institute/Hospital, Chinese Academy of Medical Sciences & Peking Union<br />
Medical College, Beijing, CHINA<br />
Background: Epidermal growth factor receptor (EGFR) mutations testing for<br />
advanced non–small cell lung cancer (NSCLC) patients were found to be predictive<br />
of response to EGFR tyrosine kinase inhibitor (TKI). The aim of our study was to<br />
explore whe<strong>the</strong>r expression levels of ligands of EGFR measured in plasma were<br />
predictive of response to EGFR-TKIs.<br />
Methods: 134 cases of formalin-fixed and paraffin-embedded tumor tissues and<br />
paired plasma from advanced NSCLC patients treated by EGFR-TKIs were collected,<br />
EGFR mutations were assessed by Scorpions and ARMS using real time PCR.<br />
Amphiregulin, transforming growth factor-alpha (TGFa) and TGFb were assessed<br />
using enzyme-linked immune-sorbent assay (Elisa). We evaluated <strong>the</strong> relationship<br />
between <strong>the</strong> EGFR mutation status, concentrations of ligands and response to<br />
EGFR-TKIs <strong>the</strong>rapy.<br />
Results: 68 (50.7%) of 134 advanced NSCLC patients were detected EGFR somatic<br />
mutations. The effect of EGFR-TKIs treatment on progression-free survival (PFS)<br />
and overall survival (OS) showed a significant difference by EGFR mutation<br />
(p 0.05, respectively). EGFR mutation rate was found to be higher in women than<br />
in men (p < 0.05), and <strong>the</strong>re was no difference between mutation rates with o<strong>the</strong>r<br />
clinical characteristics. Also, <strong>the</strong>re was no difference between expression levels of<br />
ligands with clinical characteristics.<br />
Conclusions: EGFR somatic mutations appear to occur frequently in China,<br />
Scorpions and ARMS technology is a sensitive method to detect EGFR mutation and<br />
is suitable for screening patients who would like to accept EGFR-TKIs <strong>the</strong>rapy.<br />
Ligands of EGFR measured in plasma could not be predictive of response to<br />
EGFR-TKIs <strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix394 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
1210 LONG-TERM EFFICACY AND SAFETY OF L-BLP25 VACCINE<br />
IN A MULTI-CENTRE OPEN-LABEL STUDY OF PATIENTS<br />
WITH UNRESECTABLE STAGE III NSCLC<br />
C. Butts 1 , R.N. Murray 2 , C.J. Smith 3 , P.M. Ellis 4 , K. Jasas 5 , A. Maksymiuk 6 ,<br />
G. Goss 7 , M. Falk 8 , A.H. Loos 9 , D. Soulières 10<br />
1 Department of Oncology, Cross Cancer Institute, Edmonton, AB, CANADA,<br />
2 Department of Medical Oncology, Vancouver Cancer Centre, Vancouver, BC,<br />
CANADA, 3 Department of Oncology, Tom Baker Cancer Centre, Calgary,<br />
CANADA, 4 Department of Oncology, Juravinski Cancer Centre, Hamilton, ON,<br />
CANADA, 5 Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA,<br />
AUSTRALIA, 6 Department of Oncology, CancerCare Manitoba, Winnipeg, MB,<br />
CANADA, 7 Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, ON,<br />
CANADA, 8 Global Clinical Development Unit, Merck KGaA, Darmstadt,<br />
GERMANY, 9 Global Biostatistics / Oncology, Merck KGaA, Darmstadt,<br />
GERMANY, 10 Departement of Medicine, CHUM Hôpital Notre-Dame, Montreal,<br />
QC, CANADA<br />
Introduction: L-BLP25 (Stimuvax®) is an antigen-specific cancer immuno<strong>the</strong>rapeutic<br />
agent targeting <strong>the</strong> mucin 1 tumour-associated antigen. Phase IIb data suggest<br />
prolonged overall survival with L-BLP25 when administered after completion of<br />
chemoradio<strong>the</strong>rapy for locally advanced non-small-cell lung cancer (NSCLC;<br />
non-significant). This study was initiated in April 2005 to obtain safety data when<br />
modifications of <strong>the</strong> adjuvant component of <strong>the</strong> immuno<strong>the</strong>rapeutic were performed.<br />
Here we report an updated analysis of long-term data based on <strong>the</strong> cut-off date 18<br />
May 2011.<br />
Methods: The primary objective of this open-label phase II study was to evaluate <strong>the</strong><br />
safety of <strong>the</strong> new formulation of L-BLP25 in patients with unresectable stage IIIA/B<br />
NSCLC, with a secondary objective of assessment of survival time. Following<br />
completion of initial chemoradio<strong>the</strong>rapy, patients with stage III NSCLC received<br />
treatment with L-BLP25 starting with weekly injections over 8 weeks, followed by<br />
injections given every 6 weeks from week 13 onwards until disease progression. A<br />
single low dose of intravenous cyclophosphamide 300 mg/m 2 (maximum 600 mg)<br />
was given 3 days before first vaccination.<br />
Results: Twenty-two patients were enrolled. After a median follow-up of 70.3<br />
months (median treatment duration 9.9 months [range, 1–73]), median survival time<br />
was 51.9 months (95%CI, 17.5, not estimable [NE]) and median progression-free<br />
survival was 31.4 months (95%CI, 5.7, NE). Five-year survival was 50% (95%CI, 29–<br />
71%); previously reported 1- and 2-year survival rates, 82% (95%CI, 66–98%) and<br />
64% (95%CI, 44–84%), respectively. Four patients survived more than 72 months.<br />
Safety findings were consistent with previous reports; adverse events (AEs) consisted<br />
mainly of fatigue (59%), injection-site reactions (55%) and mild-to-moderate<br />
influenza-like illness. Two serious treatment-emergent AEs were assessed as being<br />
treatment-related: cholecystitis and pneumonia.<br />
Conclusions: Long-term follow-up of this small patient population provides<br />
encouraging survival data for L-BLP25 maintenance <strong>the</strong>rapy in stage III NSCLC.<br />
Long-term safety data were consistent with previous reports and did not reveal any<br />
new safety issues.<br />
Disclosure: C. Butts: Charles Butts has provided consultancy and served on Speakers’<br />
Bureaux for Merck Serono. A. Maksymiuk: Andrew Maksymiuk has some stock<br />
shares in Merck Canada (
months (95% CI:13-25). The PFS and OS at 1/2 years were 59%/38% and 85%/46%<br />
respectively. A total of 43 cycles of D-C induction chemo<strong>the</strong>rapy were given; main<br />
toxicities (NCI-CTC 3.0) per p Grade (g) 1-2/3-4 (%) were as follows: neutropenia<br />
2.3/13.9; anemia 13.9/0; nausea/vomiting 23.2/2.3; diarrhea 25.5/2.3; febrile<br />
neutropenia, 2 p. Main toxicities per p in CChRT (D-C doses: 147, 3.4 per p; mean<br />
doses RT: 63,4 Gys) were g1-2/3 (%): neutropenia 25.5/6.9; anemia 43.9/0; nausea/<br />
vomiting 18.6/0; fatigue 37.2/4.6; esophagitis 46.5/2.3 and pneumonitis 39.5/0; <strong>the</strong>re<br />
were three episodes of hospitalization: febrile neutropenia, 2 p and g3 esophagitis,<br />
1p.<br />
Conclusions: CChRT with bi-weekly Docetaxel and Cisplatin and thoracic<br />
radio<strong>the</strong>rapy is a feasible treatment option for inoperable locally advanced stage III<br />
NSCLC, showing good clinical efficacy and tolerability with promising survival.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1213 ACUTE TOXICITY OF FULL-DOSE CISPLATIN-ETOPOSIDE<br />
CONCURRENTLY WITH HIGH-DOSE HYPOFRACTIONATED<br />
CHEST RADIOTHERAPY FOR STAGE III NON-SMALL CELL<br />
LUNG CANCER: SUBSET ANALYSIS OF NON-RANDOMISED<br />
PATIENTS IN THE PET-BOOST PHASE II TRIAL<br />
(NCT01024829)<br />
D. De Ruysscher 1 , W. van Elmpt 1 , R. Wanders 1 , A. van Baardwijk 1 ,A.<br />
C. Dingemans 3 , B. Reymen 1 , G. Bootsma 4 , P. Lambin 2 , J. Sonke 5 ,<br />
J. Belderbos 5<br />
1 Maastro Clinic, Maastricht University Medical Center (MUMC), Maastricht,<br />
NETHERLANDS, 2 Department of Radiation Oncology (maastro), Grow,<br />
Maastricht University Medical Centre, Maastricht, NETHERLANDS,<br />
3 Pulmonology, Maastricht University Medical Center (MUMC), Maastricht,<br />
NETHERLANDS, 4 Pulmonology, Atrium Medical Center Heerlen, Heerlen,<br />
NETHERLANDS, 5 Radiation Oncology, Ne<strong>the</strong>rlands Cancer Institute,<br />
Amsterdam, NETHERLANDS<br />
Background: Full-dose concurrent platinum-based doublet chemo<strong>the</strong>rapy and 2 Gy/<br />
day radio<strong>the</strong>rapy is <strong>the</strong> first choice treatment for most patients with stage III NSCLC.<br />
No prospective data are available on <strong>the</strong> acute toxicity of full-dose chemo<strong>the</strong>rapy and<br />
high-dose hypofractionated accelerated radio<strong>the</strong>rapy. Here we report on a subset of<br />
patients included in <strong>the</strong> PET-boost trial that could not be randomised because dose<br />
escalation to <strong>the</strong> primary tumour over 72 Gy/ 24 fractions was not possible because<br />
of OAR constraints.<br />
Methods: Patients received cisplatin 80 mg/m2 on day 1 and etoposide 100 mg/m2<br />
on days 1-3 every 21 days for a total of three cycles. At day 1 of <strong>the</strong> second<br />
chemo<strong>the</strong>rapy cycle, radio<strong>the</strong>rapy to <strong>the</strong> primary tumour and <strong>the</strong> involved lymph<br />
nodes was delivered (66 Gy /24 QD fractions of 2.75 Gy). Toxicity was evaluated<br />
weekly and scored according to CTCAE3.0. We considered <strong>the</strong> treatment safe when<br />
at maximum 5/12 developed G3 acute toxicity, reversible in at least 4/5 within 8<br />
weeks post-<strong>the</strong>rapy.<br />
Results: 12 patients, 10 males, 2 females, mean age 66.9 years with stage III NSCLC<br />
were included. Mean PTV dose: 64.9 Gy. Mean fractions: 23.6. Mean OTT: 32.6 days.<br />
Mean MLD: 19.2 Gy, mean mean oesophageal dose 30.7 Gy, mean max oesophageal<br />
dose 60.4 Gy. Median follow-up: 9.9 months (range 3.3-15.1). G2 dyspnea: 1 (8.3 %).<br />
Maximal oesophagitis: G1: 2 (16.7 %), G2: 6 (50.0 %), G3: 4 (33.3 %), all recovering<br />
to G0 within 6 weeks post-treatment.<br />
Conclusions: Full-dose cisplatin-etoposide was safely combined with high-dose<br />
hypofractionated accelerated radio<strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1214 A PHASE II CLINICAL TRIAL OF TUMOR TREATING FIELD<br />
(TTF) THERAPY CONCOMITANT TO PEMETREXED FOR<br />
ADVANCED NON-SMALL CELL (NSCLC) LUNG CANCER<br />
M. Pless 1 , D. Betticher 2 , C. Droege 3 , M. Salzberg 4 , R. von Moos 5<br />
1 Tumorcenter, Kantonsspital Winterthur, Winterthur, SWITZERLAND, 2 Medical<br />
Oncology, Fribourg Cantonal Hospital, Fribourg, SWITZERLAND, 3 Medical<br />
Oncology, Spital Maennedorf, Maennedorf, SWITZERLAND, 4 Medical Affairs,<br />
Medpace Inc., Cincinatti, UNITED STATES OF AMERICA, 5 Medizinische<br />
Onkologie und H, Cantonal Hospital Graub, Chur, SWITZERLAND<br />
Background: TTF <strong>the</strong>rapy is a novel, non-invasive treatment modality for solid<br />
tumors recently approved by FDA for recurrent GBM. It uses intermediate frequency<br />
alternating electric fields to inhibit tumor growth, by mitotic spindle and plasma<br />
membrane integrity disruption during cytokinesis. Pemetrexed is a folate<br />
antimetabolite used as a first/second line and as a maintenance <strong>the</strong>rapy for<br />
non-squamous NSCLC patients. Preclinical studies in NSCLC models demonstrated<br />
that TTF <strong>the</strong>rapy and pemetrexed had additive efficacy, with no increase in toxicity.<br />
The current trial tested TTF <strong>the</strong>rapy concomitant to pemetrexed in NSCLC patients.<br />
Methods: A single arm, multi-center, prospective trial was performed in 42 stage<br />
IIIB (with pleural effusion) and IV NSCLC patients, following progression after at<br />
least one prior chemo<strong>the</strong>rapy. Patients received continuous 150 KHz TTF <strong>the</strong>rapy<br />
Annals of Oncology<br />
(12 h/day) using <strong>the</strong> NovoTTF-100L system (NovoCure, Israel), concomitant to<br />
pemetrexed (Alimta, Eli Lilly) q3w, until progression. Pemetrexed was in use for<br />
squamous histology when <strong>the</strong> study opened.<br />
Results: The trial included 35 patients with non-squamous histology and 7 patients<br />
with squamous histology. TTF Therapy was well tolerated by all patients enrolled in <strong>the</strong><br />
trial, with high compliance (11 h/day). No TTF-related adverse events were reported<br />
apart from dermatitis caused by <strong>the</strong> application of transducer arrays. Median<br />
progression free survival was 22.7 and 10.3 weeks for non-squamous and squamous<br />
histology, respectively. Seven patients who initially had in-field-only disease (including<br />
squamous histology) had distant metastases before progressing in-field. Median overall<br />
survival was 12.4 and 13.8 months for nonsquamous and squamous histology,<br />
respectively. One- and two- year-survival was 53% and 27%, respectively.<br />
Conclusions: TTF <strong>the</strong>rapy concomitant to pemetrexed was well tolerated and safe<br />
for patients with advanced NSCLC, of all histologies. Efficacy indices are<br />
promising, in view of <strong>the</strong> poor outcome previously reported for similar<br />
populations. This first clinical trial involving TTF as a treatment for NSCLC<br />
patients suggests that it should be fur<strong>the</strong>r studied in larger clinical trials for<br />
squamous and nonsquamous NSCLC<br />
Disclosure: M. Salzberg: Medpace Inc. is a contracted Contract Research Organization<br />
(CRO) for Novocure Ltd. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1215 PHASE I TRIAL OF COMBINATION CHEMOTHERAPY OF<br />
PEMETREXED PLUS CISPLATIN AND CONCURRENT<br />
THORACIC RADIOTHERAPY IN PATIENTS WITH LOCALLY<br />
ADVANCED NON-SQUAMOUS NON-SMALL-CELL LUNG<br />
CANCER: POST-HOC ANALYSIS FOR SURVIVAL AND<br />
RECURRENT SITES<br />
S. Niho 1 , H. Nokihara 2 , K. Nihei 3 , T. Akimoto 3 , M. Sumi 4 , Y. Ito 4 , I. Sekine 2 ,<br />
K. Kubota 1 ,Y.Ohe 1 , T. Tamura 2<br />
1 Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa,<br />
JAPAN, 2 Division of Thoracic Oncology, National Cancer Center Hospital, Tokyo,<br />
JAPAN, 3 Division of Radiation Oncology, National Cancer Center Hospital East,<br />
Kashiwa, JAPAN, 4 Division of Radiation Oncology, National Cancer Center<br />
Hospital, Tokyo, JAPAN<br />
Background: Combination chemo<strong>the</strong>rapy of pemetrexed (PEM) plus cisplatin<br />
(CDDP) is established as a standard treatment for advanced non-squamous<br />
(Non-Sq) non-small-cell lung cancer (NSCLC). PEM has radiosensitizing potential<br />
when evaluated in vitro in combination with platinum-containing compounds and<br />
radiation. Our previous phase I trial demonstrated that combination chemo<strong>the</strong>rapy<br />
of PEM plus CDDP with concurrent thoracic radio<strong>the</strong>rapy (TRT) at a total dose of<br />
66Gy was well tolerated in patients with locally advanced Non-Sq NSCLC, and <strong>the</strong><br />
response rate was 83% (The European Multidisciplinary Cancer Congress 2011,<br />
#9060). We conducted a post-hoc analysis of progression-free survival (PFS) and<br />
recurrent sites in those patients who were enrolled in <strong>the</strong> phase I trial.<br />
Methods: Patients received PEM 500mg/m2 plus CDDP 75mg/m2 on day 1 of a 21-day<br />
interval for 3 cycles and concurrent TRT of 60Gy (n = 6) or 66Gy (n = 12) followed by<br />
consolidation PEM 500mg/m2 of a 21-day interval for 3 cycles. We reviewed <strong>the</strong> medial<br />
records to collect data on progression, recurrent sites, late toxicity and survival.<br />
Results: Between November 2008 and December 2010, 20 patients were enrolled in<br />
this study, and 18 patients received <strong>the</strong> protocol treatment. No late radiation<br />
morbidity was observed. 12 patients had progressed, and recurrence included distant<br />
metastases (n = 7), local (n = 7) (in <strong>the</strong> radiation field (n = 6), out of <strong>the</strong> radiation<br />
field (n = 2), and both (n = 1)), and local plus distant sites (n = 2). Median PFS was<br />
10.5 months (95% confidence interval: 8.7-12.3), and 2-year PFS rate was 32%.<br />
Median follow-up time for censored cases was 21.8 months (range: 17.2-35.6<br />
months). Overall survival data will be presented.<br />
Conclusions: Median PFS in our study was comparable with that in historical<br />
controls of chemoradio<strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1216 CT BASED QUANTIFICATION OF RADIATION INDUCED LUNG<br />
DAMAGE (RILD) AND THE INTERACTION WITH<br />
CHEMOTHERAPY AND CETUXIMAB<br />
H. Sharifi 1 , W. van Elmpt 1 , R. Vandendries 1 , A.C. Dingemans 2 , M. Das 3 ,<br />
G. Nalbantov 1 , M. Oellers 1 , P. Lambin 1 , J. Belderbos 4 , D. De Ruysscher 1<br />
1 Department of Radiation Oncology (Maastro Clinic), GROW - School for<br />
Oncology and Developmental Biology, Maastricht University Medical Centre,<br />
Maastricht, NETHERLANDS, 2 Pulmonology, Maastricht University Medical Center<br />
(MUMC), Maastricht, NETHERLANDS, 3 Radiology, Maastricht University Medical<br />
Center (MUMC),GROW - School for Oncology and Developmental Biology,<br />
Maastricht University Medical Centre, Maastricht, NETHERLANDS, 4 Radiation<br />
Oncology, Ne<strong>the</strong>rlands Cancer Institute, Amsterdam, NETHERLANDS<br />
Purpose: Radiation-induced lung damage (RILD) is one of <strong>the</strong> most important<br />
dose-limiting toxicities in <strong>the</strong> treatment of lung cancer patients. Prediction models<br />
ix396 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
are still unsatisfactory, partly because dyspnea as an endpoint is influenced by<br />
many o<strong>the</strong>r parameters than RILD and is difficult to quantify. Interactions<br />
between drugs and radio<strong>the</strong>rapy (RT) are thus difficult to assess. We <strong>the</strong>refore<br />
evaluated RILD more objectively, quantitatively and on a continuous scale<br />
measuring <strong>the</strong> changes of lung density per voxel before and after chemo-RT and<br />
with or without cetuximab.<br />
Methods: CT scans from 55 stage III NSCLC patients were evaluated. Deformable<br />
registration was used to register <strong>the</strong> 3 month follow-up scans to <strong>the</strong> baseline<br />
scans. Changes in CT density in <strong>the</strong> lungs were correlated to <strong>the</strong> RT dose<br />
delivered in every part (i.e. voxel) of <strong>the</strong> lungs. Four different treatments were<br />
included: sequential chemo-RT (N = 9), concurrent chemo-RT (N = 17), concurrent<br />
chemo–RT with cetuximab (N = 19) from phase I trial (NCT00522886) and<br />
patients from <strong>the</strong> randomized phase II PET-boost trial (NCT01024829) receiving a<br />
higher radiation dose per fraction than <strong>the</strong> o<strong>the</strong>r groups (2.75 Gy) (N = 10).<br />
Patients with an increase of over 0.5 Hounsfield Units (HU) per Gy dose in each<br />
voxel of <strong>the</strong> lungs were considered as ‘responders’, i.e. showing susceptibility for<br />
RILD.<br />
Results: Patients received a mean dose of 64.14 Gy(range 55-86 Gy) to <strong>the</strong> tumor,<br />
with a standard deviation of 11.3. The number of responders in patients treated in<br />
cetuximab was 16/19 (85%), in <strong>the</strong> concurrent chemo-RT group 11/16 (69 %), 7/10<br />
(70 %) in <strong>the</strong> PET-boost patients and 4/9 (56 %) in <strong>the</strong> sequential chemo-RT group.<br />
The average increase in density was 2.6 HU per Gy for responders and 0.01 HU per<br />
Gy for non-responders.<br />
Conclusion: CT density changes allow quantitative non-invasive assessment of RILD,<br />
giving complementary information to clinical endpoints. Large individual variability<br />
in <strong>the</strong> susceptibility for RILD could be shown by CT as well as treatment modality<br />
related differences.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1217 MODIFIED FRACTIONATION RADIOTHERAPY VERSUS<br />
CONVENTIONAL RADIOTHERAPY FOR UNRESECTED<br />
NON-SMALL CELL LUNG CANCER PATIENTS: A<br />
COST-EFFECTIVENESS ANALYSIS<br />
D. De Ruysscher 1 , B.L.T. Ramaekers 2 , M.A. Joore 3 , B. Lueza 4 , J. Bonastre 4 ,<br />
A. Mauguen 4 , J. Pignon 4 , C. Le Pechoux 5 , J.P. Grutters 2 , on behalf of The<br />
Mar-LC Collaborative Group 4<br />
1 Department of Radiation Oncology (Maastro Clinic), GROW - School for<br />
Oncology and Developmental Biology, Maastricht University Medical Centre,<br />
Maastricht, NETHERLANDS, 2 Department of Health Services Research (HSR),<br />
Caphri - School for Public Health and Primary Care, Maastricht University,<br />
Maastricht, NETHERLANDS, 3 Clinical Epidemiology and Medical Technology<br />
Assessment (KEMTA), Maastricht University, Maastricht, NETHERLANDS,<br />
4 Biostatistics and Epidemiology, Institut de Cancérologie Gustave-Roussy,<br />
Villejuif, FRANCE, 5 Medical Oncology, Institut Gustave Roussy, Villejuif, FRANCE<br />
Background: Modified fractionation radio<strong>the</strong>rapy (RT), delivering multiple fractions<br />
per day or shortening <strong>the</strong> overall treatment time, improves overall survival for<br />
non-small cell lung cancer (NSCLC) patients over conventional fractionation RT<br />
(CRT). However, its cost-effectiveness is unknown. Objective: To examine and<br />
compare <strong>the</strong> cost-effectiveness of different modified RT schemes and CRT in <strong>the</strong><br />
curative treatment of unresected NSCLC patients.<br />
Methods: A probabilistic Markov model was developed based on individual patient<br />
data from <strong>the</strong> Meta-Analysis of Radio<strong>the</strong>rapy in Lung Cancer (MAR-LC) with 10<br />
randomized trials (N = 2000). Costs (Dutch healthcare perspective), quality-adjusted<br />
life years (QALYs) and net monetary benefits (NMB) were compared between 2<br />
accelerated RT schemes (very accelerated (VART) and moderately accelerated<br />
(MART)), 2 hyperfractionated RT schemes (using an identical total treatment dose<br />
as CRT (HRT I ) and higher total treatment dose as CRT (HRT H )) and CRT. The<br />
NMB was calculated by multiplying <strong>the</strong> number of QALYs by <strong>the</strong> ceiling ratio (what<br />
society is willing to pay per QALY) of €80,000 per QALY and subtracting <strong>the</strong> total<br />
costs. The treatment strategy with <strong>the</strong> highest NMB can be considered as <strong>the</strong> most<br />
cost-effective treatment.<br />
Results: All modified fractionations were more effective and costly than CRT (1.179<br />
QALYs, €24,341). VART and MART were most effective (1.360 and 1.383 QALYs)<br />
and costed €25,735 and €26,194 respectively. HRT I and HRT H yielded less QALYs<br />
than <strong>the</strong> accelerated schemes (1.327 and 1.202 QALYs), and costed €26,187 and<br />
€29,688 respectively. MART had <strong>the</strong> highest NMB (€84,427; 95%CI<br />
€41,708-€139,698) and was thus <strong>the</strong> most cost-effective treatment followed by VART<br />
(€83,071; CI €69,785-€97,619). CRT had <strong>the</strong> second lowest NMB (€69,997; CI<br />
€59,684-€80,786). Uncertainty was considerable: MART had <strong>the</strong> highest probability<br />
of being cost-effective (43%), followed by VART (31%), HRT I (24%), HRT H (2%)<br />
and finally CRT (0%).<br />
Conclusion: Implementing accelerated RT is almost certainly more efficient than<br />
current practice (CRT) and should be recommended as standard RT for <strong>the</strong> curative<br />
treatment of unresected NSCLC patients.<br />
Disclosure: J. Pignon: Unrestricted grants from Roche for a meta-analysis of<br />
bevacizumab in advanced NSCLC. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
1218 PROSPECTIVE, SINGLE-ARM, POST-MARKETING CLINICAL<br />
STUDY OF PEMETREXED (PEM) AND CARBOPLATIN<br />
COMBINATION FOLLOWED BY MAINTENANCE PEM IN<br />
CHEMO-NAïVE JAPANESE PATIENTS WITH NON-SQUAMOUS<br />
NON-SMALL CELL LUNG CANCER (NSCLC): 24 MONTH<br />
FOLLOW-UP OS RESULTS<br />
K. Hotta 1 , K. Kiura 1 , K. Kubota 2 , H. Yoshizawa 3 , S. Enatsu 4 , R. Sekiguchi 4 ,<br />
K. Nakagawa 5 , T. Tamura 2<br />
1 Department of Respiratory Medicine, Okayama University Hospital, Okayama,<br />
JAPAN, 2 Division of Internal Medicine and Thoracic Oncology, National Cancer<br />
Center Hospital, Tokyo, JAPAN, 3 Bioscience Medical Research Center, Niigata<br />
University Medical and Dental Hospital, Niigata-City, JAPAN, 4 Development<br />
Center of Excellence, Eli Lilly Japan K.K., Kobe, JAPAN, 5 Medical Oncology,<br />
Kinki University School of Medicine, Osaka, JAPAN<br />
Background: Platinum doublet chemo<strong>the</strong>rapy is standard first-line treatment for<br />
advanced NSCLC, however, fur<strong>the</strong>r studies are required to establish <strong>the</strong> effectiveness<br />
of maintenance <strong>the</strong>rapy. The aim of this study was to evaluate <strong>the</strong> efficacy and safety<br />
of Pem/Carboplatin (Cb) followed by Pem in Japanese patients (pts) with advanced<br />
non-squamous NSCLC. This study is sponsored by Eli Lilly Japan K.K.<br />
(ClinicalTrials.gov: NCT01020786).<br />
Patients and methods: Pts were chemo-naïve with unresectable stage IIIB, IV or<br />
postoperative recurrent non-squamous NSCLC, and a PS (ECOG) of 0-1. Pts<br />
received Cb AUC 6 and Pem 500 mg/m 2 on Day 1 of each 21-day cycle for 4 cycles<br />
as induction <strong>the</strong>rapy. Pts who achieved non-PD at <strong>the</strong> end of <strong>the</strong> 4-cycle induction<br />
<strong>the</strong>rapy could continue Pem as maintenance <strong>the</strong>rapy until PD. The primary endpoint<br />
was PFS, and it was assumed that <strong>the</strong> threshold and <strong>the</strong> expected values for <strong>the</strong><br />
median PFS were 5 and 7 months, respectively.<br />
Results: A total of 111 pts were enrolled. Of <strong>the</strong> 109 treated pts, 75 pts (69%)<br />
completed induction <strong>the</strong>rapy and 60 pts (55%) entered maintenance <strong>the</strong>rapy; 15 pts<br />
(14%) discontinued in <strong>the</strong> 4th cycle due to PD (8 pts), AE (4 pts), and investigator<br />
or subject decision (3 pts). Pts (n = 109): median age 63 years, stage IV/o<strong>the</strong>rs (66%/<br />
34%), PS 0/1 (34%/66%), EGFR-mutant/wild-type/unknown (22%/58%/20%).<br />
Among <strong>the</strong> 109 pts, 38 pts (35%) achieved PR, 41 pts (38%) SD, and 21 pts (19%)<br />
PD. Median PFS and MST from enrollment was 5.6 months (95% CI: 4.3, 7.2) and<br />
20.2 months (95% CI: 16.7, incalculable), respectively. The MST for EGFR (-) pts<br />
was 19.4 months; MST could not be calculated for EGER ( + ) pts (17 pts [71%]<br />
censored). The most common Gr 3/4 toxicities in <strong>the</strong> induction and maintenance<br />
phases were neutropenia (57%), thrombocytopenia (41%), anemia (31%), whereas Gr<br />
3 febrile neutropenia occurred in 1 pt without any regimen-related deaths.<br />
Conclusions: PFS as <strong>the</strong> primary endpoint was not better than expected, but o<strong>the</strong>r<br />
endpoints seemed favorable. Hematologic toxicities were frequently observed.<br />
Updated data including MST will be presented at <strong>the</strong> congress.<br />
Disclosure: S. Enatsu: An employee of Eli Lilly Japan K.K. R. Sekiguchi: An<br />
employee of Eli Lilly Japan K.K. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
1219 COST-UTILITY ANALYSIS OF MAINTENANCE THERAPY WITH<br />
EITHER GEMCITABINE OR ERLOTINIB VERSUS<br />
OBSERVATION WITH PREDEFINED SECOND-LINE<br />
TREATMENT AFTER CISPLATIN-GEMCITABINE INDUCTION<br />
CHEMOTHERAPY IN ADVANCED NSCLC: IFCT-GFPC<br />
0502-ECO PHASE III STUDY<br />
I. Borget 1 , M. Perol 2 , D. Perol 3 , A. Lavole 4 , L. Greillier 5 , R. Gervais 6 , G. Zalcman 7 ,<br />
S. Chabaud 8 , A. Vergnenegre 9 , C. Chouaid 10<br />
1 Biostatistics and Epidemiology, institut Gustave Roussy, Villejuif, FRANCE,<br />
2 Medical Oncology, Centre L, Lyon Cedex, FRANCE, 3 Biostatistics Unit, Centre<br />
L, Lyon Cedex, FRANCE, 4 Pneumology, Hopital Tenon, Paris, FRANCE,<br />
5 Multidisciplinary Oncology & Therapeutic Innovations, Aix-Marseille Univ,<br />
Assistance Publique-Hôpitaux de Marseille, Marseille, FRANCE, 6 Pneumology,<br />
Centre François Baclesse, Caen, FRANCE, 7 Service de Pneumologie, C.H.U. de<br />
Caen, Caen Cedex, FRANCE, 8 UBET, Centre Leon Berard, Lyon, FRANCE,<br />
9 Service de Pneumologie, Hopital du CluzeauCHU Dupuytren, Limoges Cedex,<br />
FRANCE, 10 Pulmonology, Hopital Saint-Antoine, Paris, FRANCE<br />
Rationale: The IFCT–GFPC 0502 phase III reported prolongation of progression-free<br />
survival with maintenance with ei<strong>the</strong>r gemcitabine or erlotinib versus observation<br />
after cisplatin-gemcitabine chemo<strong>the</strong>rapy in advanced NSCLC. Their incremental<br />
cost-effectiveness ratio (ICER) was assessed in global population and in pre specified<br />
sub-groups.<br />
Methods: A cost-utility analysis was performed to evaluate ICER of maintenance<br />
<strong>the</strong>rapy with ei<strong>the</strong>r gemcitabine or erlotinib, compared to observation. Direct<br />
medical costs (drugs costs, hospitalization, examinations, second-line treatments and<br />
palliative costs) were prospectively collected per patient alongside <strong>the</strong> trial, until<br />
death, from <strong>the</strong> third party payer perspective. Utility were extracted from literature.<br />
Sensitivity analyses were performed.<br />
Results: ICER for maintenance <strong>the</strong>rapy with gemcitabine and erlotinib were<br />
respectively 76 625 and 184 733 €/quality-adjusted life years (QALY). Gemcitabine<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds408 | ix397
maintenance <strong>the</strong>rapy had favourable ICER in patients with PS = 0 (52 213 €/QALY),<br />
in responders to induction chemo<strong>the</strong>rapy (64 296 €/QALY) and in patients with<br />
adenocarcinoma (62 292 €/QALY); erlotinib had favourable ICER if PS = 0 (94 908<br />
€/QALY), in patients with adenocarcinoma (97 160 €/QALY) and objective response<br />
to induction (101,186 €/QALY), but it is not cost-effective in patients with PS = 1,<br />
o<strong>the</strong>r histology or if stable disease.<br />
Conclusion: Gemcitabine and erlotinib maintenance <strong>the</strong>rapy have acceptable ICER<br />
but with wide variation, function of histology, PS and response to <strong>the</strong> first line<br />
chemo<strong>the</strong>rapy.<br />
Disclosure: I. Borget: Honoraria from Roche for set up a class in health economy<br />
(no relation with <strong>the</strong> present study). M. Perol: consultant or advisory board with<br />
Roche, Lilly (myself) Honoraria from Lilly, Roche, Pfizer, Boehringer Ingelheim<br />
(myself) Research funding from Lilly, Roche (myself). D. Perol: Honoraria : Roche<br />
(myself). G. Zalcman: Honoraria from Lilly, Roche Research funding from Lilly,<br />
Roche. A. Vergnenegre: honoraria and research funding from Roche. C. Chouaid:<br />
Honoraria from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffman la<br />
Roche, Astra Zeneka, Sanofi Aventis, Lilly, Novartis and Amgen Research funding<br />
from AstraZeneca, Lilly, Novartis and Amgen. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
1220 DOUBLET VERSUS SINGLE CYTOTOXIC AGENT AS<br />
FIRST-LINE TREATMENT FOR ELDERLY PATIENTS WITH<br />
ADVANCED NON-SMALL-CELL LUNG CANCER: A<br />
SYSTEMATIC REVIEW AND META-ANALYSIS<br />
W. Qi 1 , Y. Yao 2 , Z. Shen 2 ,A.He 2 ,F.Lin 2<br />
1 Oncology, The Sixth People Hospital, Shanghai Jiao Tong University, Shanghai,<br />
CHINA, 2 Dept. of Oncology, The Sixth People’s Hospital Shanghai Jiaotong<br />
University, Shanghai, CHINA<br />
The standard treatment for elderly patients with advanced non-small cell lung cancer<br />
(NSCLC) is still debated. As a result, we performed a meta-analysis of all<br />
randomized controlled trials comparing <strong>the</strong> efficacy of doublet versus single<br />
third-generation cytotoxic agent in <strong>the</strong> elderly patients with advanced NSCLC.<br />
Finally, eight eligible trials involved 2108 patients were identified. The intention to<br />
treatment (ITT) analysis demonstrated that doublet <strong>the</strong>rapy significantly improved<br />
OS (HR0.85 95%CI 0.72-1.00, p = 0.048), PFS (HR 0.72, 95%CI 0.55-0.93, p = 0.012),<br />
1-year SR (RR 1.18, 95%CI 1.02-1.36, p = 0.027) and ORR (RR1.65,95%CI 1.36-1.99,<br />
p = 0.000), compared with single cytotoxic agent. Sub-group analysis also favored<br />
platinum-based doublet <strong>the</strong>rapy in terms of OS, PFS/TTP, 1-year SR and ORR.<br />
Though gemcitabine-based doublet significantly increased ORR compared with<br />
single agent (RR1.51, 95%CI 1.21-1.87, p = 0.000), it did not translate into increase in<br />
survival benefits in terms of OS, PFS and 1-year SR. More incidences of grade 3 or 4<br />
hematologic toxicities were observed in doublet <strong>the</strong>rapy group. With respect to grade<br />
3 or 4 non-hematologic toxicities, equivalent frequencies were found between groups<br />
excluding more incidence of neutrotoxicity in doublet <strong>the</strong>rapy group. Our data<br />
indicated that doublet <strong>the</strong>rapy was superior to single third-generation cytotoxic agent<br />
for elder patients with advanced NSCLC. The optimal drug dosage and treatment<br />
schedule of platinum-based doublet should be investigated in future prospective<br />
clinical trials. Gemcitabine-based doublet could be considered for elderly patients<br />
who were not suitable for platinum-based chemo<strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1221 WEEKLY PACLITAXEL VERSUS THE STANDARD 3-WEEKLY<br />
SCHEDULE IN PATIENTS WITH NON-SMALL CELL LUNG<br />
CANCER<br />
I. Abdel Halim 1 , M. El-Ashry 2 , W. El-Sadda 1 , S. Temraz 1<br />
1 Clinical Oncology & Nuclear Medicine, Mansoura University Hospital School of<br />
Medicine, Mansoura, EGYPT, 2 Clinical Oncology, Mansoura University<br />
HospitalSchool of Medicine, Mansoura, EGYPT<br />
Background: Paclitaxel is one of <strong>the</strong> active drugs in non-small cell lung cancer<br />
(NSCLC). Weekly paclitaxel seems less toxic and more effective compared to<br />
paclitaxel every three weeks (possibly because of <strong>the</strong> proapoptotic and angiogenic<br />
activity) <strong>the</strong> dose intensity is quiet higher with tolerable toxicities. The purpose of<br />
<strong>the</strong> study is to compare <strong>the</strong> efficacy of weekly paclitaxel to <strong>the</strong> every three weeks<br />
schedule in terms of response, toxicity profile, PFS and OS. Patients<br />
Methods: Between Sep 2007 & Sep 2009, eighty patients were enrolled in <strong>the</strong> study,<br />
40 in each group. Eligibility criteria were chemo-naiive patients, stage III & IV<br />
histologically proven NSCLC, WHO PS 0-1, adequate bone marrow, kidney & liver<br />
functions. Patients were randomized for 6-8 cycles of ei<strong>the</strong>r weekly paclitaxel 80 mg/<br />
m 2 D1,8,15 (1 hour IV infusion) and paraplatin AUC = 5 D1 (30 min IV infusion )<br />
every 4 weeks (Group A) or paclitaxel 175 mg/m 2 and paraplatin AUC = 5 every 3<br />
weeks (Group B). Prophylactic growth factor support was allowed if indicated in<br />
Group B. Response was assessed every 2 cycles, patients who showed objective<br />
response (CR, PR, or SD) had continued to 8 cycles.<br />
Results: All patients were evaluable for response, toxicity, and survival. The median<br />
age was 56 years (range 42-64) in both groups. Median WHO PS 1. Male to female<br />
Annals of Oncology<br />
ratio was 4:1. Stage III 60% & 62.5%, stage IV 40% & 37.5% in groups A & B<br />
respectively. The overall response rates ware 60% (CR 10%, PR 50%) & 40% (CR 5%,<br />
PR 35%) in groups A & B respectively. No grade IV toxicities were observed in ei<strong>the</strong>r<br />
group. In group A & B; grade II anemia occurred in 15 & 25% of patients, grade III<br />
neutropenia was noted in 10 & 30% of patients, and grade II neuropathy occurred in<br />
10 & 50% of patients in group A & B respectively. Median time to progression and<br />
median survival were 10 & 7 months and 14 & 11 months respectively.<br />
Conclusion: Weekly paclitaxel is more effective than <strong>the</strong> every 3 weeks<br />
administration in <strong>the</strong> treatment of advanced NSCLC with higher RR, TTP, OS and<br />
better toxicity profile.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1222 ERLOTINIB IN SECOND AND THIRD LINE THERAPY IN<br />
ADVANCED NSCLC (STAGE IIIB AND IV), RELATION WITH<br />
CHEMOTHERAPY AND SCHEDULE OF ADMINISTRATION<br />
(A RETROSPECTIVE STUDY)<br />
A. Grigorescu, I. Turtoi, S.E. Boeru<br />
Medical Oncology, Institute of Oncology Bucharest, Bucharest, ROMANIA<br />
Background: Is now very well known that Erlotinib (E) has an impact in progression<br />
free survival and in some study in overall survival in second or third line <strong>the</strong>rapy for<br />
advanced non small -cell lung cancer (NSCLC). Aims of <strong>the</strong> study: This study try to<br />
provide data which sustain <strong>the</strong> use of E in second and third line and <strong>the</strong> fact that<br />
mono-chemo<strong>the</strong>rapy could be active and after treatment with E for some patients<br />
(Pt) with advanced NSCLC. In addition we try to find data supporting <strong>the</strong> use of E<br />
for senior adults.<br />
Materials and method: The data from 90 case report forms of Ps with Stage IIIB<br />
and IV NSCLC treated with E in Institute of Oncology Bucharest between March<br />
2010 and March <strong>2012</strong> were analyzed regarding clinical benefit, survival and relation<br />
with mono- chemo<strong>the</strong>rapy in second or third line. In particular we purposed to<br />
point out <strong>the</strong> benefit of senior adults treated with E and <strong>the</strong> possible benefit of<br />
chemo<strong>the</strong>rapy with a single agent after failure of treatment with E. Main symptoms<br />
were evaluated by Edmonton scale. Statistical analysis was perform by Caplan Meyer<br />
curve and X2 test.<br />
Results: 86 Pt were valuable, 17 with stage IIIB and 69 stage IV. The overall survival<br />
for <strong>the</strong> Pt included in this study was 17 month. The survival in second line <strong>the</strong>rapy<br />
with E was 7 month (CI: 3.6 – 10.3) and <strong>the</strong> survival after third line chemo<strong>the</strong>rapy<br />
was 3 month (CI:2.1-3.8). On <strong>the</strong> whole <strong>the</strong> clinical benefit was 90% of Pt. The<br />
response rate for chemo<strong>the</strong>rapy in third line after E was 8% but symptomatic benefit<br />
was in 15% of Pt. As a function of waiting time to receive E in second line it was a<br />
higher response rate in Ps who received E without waiting time, toxicity of E was<br />
represented by rash grade I 80%, diarrhea 10%, dizziness 3%, ocular dysfunctions<br />
2%. Grade III of toxicity was observed only in 3% of patients. Toxicity for senior<br />
adults treated by E. was similar with younger Pt.<br />
Conclusions: Despite <strong>the</strong> limits of a retrospective study we can conclude that E is<br />
useful in second and third line treatment for advanced lung cancer, chemo<strong>the</strong>rapy<br />
could have benefit in third line after E, and senior adults have about <strong>the</strong> some<br />
response and benefit from E. Toxicity was reduced for all Pt treated with E.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1223 HYPERBARIC OXYGENATION AND EP (CISPLATIN AND<br />
ETOPOSIDE) CHEMOTHERAPY IN TREATMENT OF PATIENTS<br />
WITH ADVANCED NON SMALL CELLS LUNG CANCER<br />
(NSCLC)<br />
M.V. Kopp 1 , I.A. Koroleva 1 , S.V. Kozlov 2 , L.V. Shaplygin 3 , M.E. Popova 1 ,<br />
J.G. Kutyreva 1<br />
1 Chemo<strong>the</strong>rapy, Samara Regional Clinical Oncology Dispensary, Samara,<br />
RUSSIAN FEDERATION, 2 Oncological, Samara State Medical University,<br />
Samara, RUSSIAN FEDERATION, 3 Samara Oncology Center, Samara, RUSSIAN<br />
FEDERATION<br />
Background: By <strong>the</strong> time of diagnosis more than 75% of all lung cancer patients<br />
have locally advanced or metastatic process. According to WHO, at different stages<br />
of treatment to 80% of lung cancer patients need chemo<strong>the</strong>rapy. Malignant neoplasm<br />
lead to <strong>the</strong> development of tissue oxygen deficiency or directly related to acute or<br />
chronic hypoxia. Hypoxia of normal tissue is one of <strong>the</strong> reasons of chronic anemia<br />
in patients with advanced NSCLC. We conducted an analysis of toxicity of<br />
chemo<strong>the</strong>rapy in patients with advanced NSCLC by means of chemo<strong>the</strong>rapy<br />
concurrently with hyperbaric oxygenation.<br />
Materials and methods: Between October 2010 and March <strong>2012</strong> 63 patients with<br />
advanced NSCLC were treated with EP chemo<strong>the</strong>rapy regimen (Cisplatin 75mg/m2<br />
on day 1 + Etoposide 120mg/m2 in 1, 3, 5 days). Cycles repeated every 21 days. We<br />
used two hyperbaric pressure chamber: BLKS 303MK and BLKS-307 Khrunichev.<br />
Hyperbaric oxygenation procedures are held under pressure 1.3 atm for 40 minutes,<br />
1 time a day every day for 5 consecutive days. All <strong>the</strong> patients were divided into 2<br />
groups. 28 patients received chemo<strong>the</strong>rapy only. 35 patients received chemo<strong>the</strong>rapy<br />
ix398 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
simultaneously with hyperbaric oxygen <strong>the</strong>rapy. Patients were not given any<br />
prophylaxis of neutropenia. Toxicity was evaluated with Common Toxicity Criteria,<br />
Version 3.0.<br />
Results: Grade 2 anemia was reported in 29% patients treated with chemo<strong>the</strong>rapy<br />
and hyperbaric oxygenation and in 43% patients treated with chemo<strong>the</strong>rapy only.<br />
The beneficial effect of hyperbaric oxygenation was also demonstrated by a quick<br />
recovery of hemoglobin level than in control. We evaluated <strong>the</strong> dose intensity of<br />
chemo<strong>the</strong>rapy. Dose reductions and increased periods between cycles of<br />
chemo<strong>the</strong>rapy are associated with poor outcomes of chemo<strong>the</strong>rapy. Dose intensity in<br />
patients received chemo<strong>the</strong>rapy with hyperbaric oxygenation was 91%, but in <strong>the</strong><br />
group of chemo<strong>the</strong>rapy only dose intensity was 79%. We did not observed any<br />
specific side effects of hyperbaric oxygenation.<br />
Conclusions: The results show that hyperbaric oxygenation procedures with<br />
<strong>the</strong> chemo<strong>the</strong>rapy n reduced grade of anemia in patients with advanced<br />
NSCLC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds408 | ix399
abstracts<br />
non-small cell lung cancer, metastatic<br />
1225O A RANDOMIZED PHASE 2 STUDY OF ERLOTINIB PLUS<br />
PEMETREXED VS ERLOTINIB OR PEMETREXED ALONE AS<br />
SECOND-LINE TREATMENT FOR NEVER-SMOKER<br />
PATIENTS WITH NON-SQUAMOUS ADVANCED NON-SMALL<br />
CELL LUNG CANCER (NSCLC)<br />
D.H. Lee 1 , J.S. Lee 1 , S.W. Kim 1 , J. Rodrigues Pereira 2 , B. Han 3 , X.Q. Song 4 ,<br />
J. Wang 5 , H-K. Kim 6 , T. P. Sahoo 7 , R. Digumarti 8 , X. Wang 9 , S. Altug 10 ,<br />
M. Orlando 11<br />
1 Asan Medical Center, Seoul, KOREA, 2 Grupo de Assistencia Médica, Sao<br />
Paulo, BRAZIL, 3 Shanghai Chest Hospital, Shanghai, CHINA, 4 Affiliated Cancer<br />
Hospital of Guangxi Medical University, Nan Ning, CHINA, 5 Beijing Tumor<br />
Hospital, Beijing, CHINA, 6 St. Vincent Hospital, Suwon, KOREA, 7 Chirayu<br />
Medical College and Hospital, Bhopal, INDIA, 8 Nizam’s Institute of Medical<br />
Sciences, Hyderabad, INDIA, 9 Eli Lilly and Company, Shanghai, CHINA, 10 Eli Lilly<br />
and Company, Istanbul, TURKEY, 11 Eli Lilly and Company, Buenos Aires,<br />
ARGENTINA<br />
Background: Erlotinib (E) and Pemetrexed (P) are approved second-line treatments<br />
in patients (pts) with relapsed NSCLC and may be effective in combination. This<br />
randomized phase 2 study compared <strong>the</strong> efficacy and safety of E + P vs ei<strong>the</strong>r agent<br />
alone, as second-line treatment in never-smoker pts with advanced non-squamous<br />
NSCLC.<br />
Methods: From Nov 2007 to Jul 2010, never-smoker NSCLC, ECOG Performance<br />
Status (PS) ≤2 pts who had failed 1 prior chemo<strong>the</strong>rapy regimen were enrolled<br />
and randomized to ei<strong>the</strong>r: E 150 mg daily, P 500 mg/m 2 day 1, or P 500 mg/m 2<br />
day 1 plus E 150 mg daily on days 2 to 14 of a 21-day cycle, continued until<br />
discontinuation criteria were met. The primary endpoint of progression-free<br />
survival (PFS) was analyzed using a sequential approach. A multivariate Cox<br />
model was used to perform a global comparison across <strong>the</strong> 3 arms with pairwise<br />
comparisons between treatments using contrasts within <strong>the</strong> model. If <strong>the</strong> global<br />
null hypo<strong>the</strong>sis was rejected at a 2-sided 0.2 significance level (SL), <strong>the</strong>n 2<br />
pairwise comparisons of E + P vs E or P were conducted. Statistical significance<br />
was claimed if both pairwise and global null hypo<strong>the</strong>ses were rejected at a<br />
2-sided 0.05 SL.<br />
Results: A total of 240 non-squamous pts (Male, 34.6%; East Asian, 55.4%; ECOG<br />
PS 0-1, 92.9%) were included. A statistically significant difference in PFS was found<br />
across <strong>the</strong> 3 arms (global p = 0.003), with E + P significantly better than both single<br />
agents (HR (95% CI) for E + P vs E was 0.57 (0.40, 0.81), p = 0.002; for E + P vs P<br />
was 0.58 (0.39, 0.85), p = 0.005). Median PFS (95% CI) was 7.4 months (4.4, 12.9) in<br />
E + P, 3.8 (2.7, 6.3) in E and 4.4 (3.0, 6.0) in P. Safety analyses showed a higher<br />
number of pts with ≥1 TEAE with CTCAE grade 3/4 toxicity in E + P (n = 45;<br />
60.0%) than in P (n = 10; 28.9%) or E (n = 22; 12.0%), <strong>the</strong> majority being<br />
neutropenia, anemia, rash and diarrhea.<br />
Conclusions: Erlotinib + Pemetrexed significantly improved PFS compared to ei<strong>the</strong>r<br />
agent alone in this clinically selected population. E + P had more toxicity, but was<br />
clinically manageable. Fur<strong>the</strong>r analysis of <strong>the</strong> EGFR mutational status will help to<br />
understand and predict which pts will benefit most from this approach.<br />
Disclosure: X. Wang: I am employee of Eli Lilly and Company. S. Altug: I am<br />
employee of, and hold stock/stock options in, Eli Lilly and Company. M. Orlando: “I<br />
Annals of Oncology 23 (Supplement 9): ix400–ix446, <strong>2012</strong><br />
doi:10.1093/annonc/mds409<br />
am employed by and hold stock in Eli Lilly & Company”. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
1226O BIOMARKER ANALYSES AND OVERALL SURVIVAL (OS)<br />
FROM THE RANDOMIZED, PLACEBO-CONTROLLED, PHASE<br />
3, FASTACT-2 STUDY OF INTERCALATED ERLOTINIB WITH<br />
FIRST-LINE CHEMOTHERAPY IN ADVANCED<br />
NON-SMALL-CELL LUNG CANCER (NSCLC)<br />
T.S.K. Mok 1 , J.S. Lee 2 , L. Zhang 3 ,C.Yu 4 , S. Thongprasert 5 , G.E.I. Ladrera 6 ,<br />
V. Srimuninnimit 7 , M.I. Truman 8 , B. Klughammer 9 ,Y.Wu 10<br />
1 Department of Clinical Oncology, Chinese University of Hong Kong, Prince of<br />
Wales Hospital, Hong Kong, HONG KONG, 2 Research Institute and Hospital,<br />
National Cancer Center, Goyang, KOREA, DEMOCRATIC PEOPLE’S REPUBLIC<br />
OF, 3 Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou,<br />
CHINA, 4 Department of Internal Medicine, National Taiwan University Hospital,<br />
Taipei, TAIWAN, 5 Faculty of Medicine, Chiang Mai University, Chiang Mai,<br />
THAILAND, 6 Department of Pulmonary Medicine, Lung Center of <strong>the</strong> Philippines,<br />
Quezon City, PHILIPPINES, 7 Department of Medicine, Siriraj Hospital, Mahidol<br />
University, Bangkok, THAILAND, 8 Department of Biometrics, F. Hoffmann-La<br />
Roche Ltd., Sydney, AUSTRALIA, 9 Pharmaceutical Division, F. Hoffmann-La<br />
Roche Ltd., Basel, SWITZERLAND, 10 Guangdong Lung Cancer Institute,<br />
Guangdong General Hospital & Guangdong Academy of Medical Sciences,<br />
Guangzhou, CHINA<br />
Background: FASTACT-2 is a randomized, placebo-controlled, phase 3 study in<br />
first-line advanced NSCLC, which met its primary endpoint of significantly<br />
prolonged PFS with intercalated erlotinib and chemo<strong>the</strong>rapy: median 7.6 vs 6.0<br />
months; HR = 0.57; p < 0.0001 (Mok et al. ASCO <strong>2012</strong>). We report OS results and<br />
correlations of biomarkers with PFS for this study.<br />
Methods: Patients (pts) with untreated stage IIIB/IV NSCLC and ECOG PS 0/1<br />
received up to 6 cycles of gemcitabine (1,250 mg/m 2 on d1 & 8) plus platinum<br />
(carboplatin AUC = 5 or cisplatin 75 mg/m 2 on d1) q4w, with ei<strong>the</strong>r intercalated<br />
erlotinib (150 mg/day on d15–28; GC-E; n = 226) or placebo (GC-P; n = 225). Pts<br />
without progression received maintenance erlotinib or placebo until progression,<br />
unacceptable toxicity or death. Provision of tumour samples was encouraged;<br />
tests were conducted at a central laboratory and prioritized as follows: EGFR<br />
mutation; KRAS mutation (both by PCR-based test [COBAS]); ERCC1 expression<br />
by immunohistochemistry (IHC; median cut-off); EGFR gene copy number by<br />
fluorescence in-situ hybridization (FISH); and EGFR IHC.<br />
Results: OS data are not fully mature yet (45.1% and 52.4% of pts in GC-E and<br />
GC-P arms with event, respectively, in Oct 2011), but a trend towards prolonged OS<br />
with GC-E vs GC-P was observed: HR = 0.78 (95% CI 0.60–1.02); p = 0.0686; median<br />
18.3 vs 14.9 months. Updated OS data with June <strong>2012</strong> cut-off will be presented. A<br />
total of 283/451 pts (62.7%) provided samples for biomarker analyses. The table<br />
shows correlations with PFS for <strong>the</strong> overall biomarker populations and <strong>the</strong> EGFR<br />
wild-type (WT) subgroup.<br />
Conclusions: As expected, <strong>the</strong> EGFR mutation-positive (Mut+) subgroup had <strong>the</strong><br />
strongest PFS benefit with intercalated erlotinib and first-line chemo<strong>the</strong>rapy. ERCC1<br />
IHC+ status was also associated with longer PFS with GC-E vs GC-P, even in pts<br />
with known EGFR WT status.<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
Annals of Oncology<br />
Biomarker subgroup<br />
HR for PFS<br />
(95% CI)<br />
Median PFS<br />
with GC-E vs<br />
GC-P, months p-value<br />
EGFR Mut+ (n = 97) 0.21 (0.12–0.35) 15.6 vs 6.9
Ingelheim, GSK Biologicals (compensated). Received honoraria from all <strong>the</strong> above.<br />
Research funding from AstraZeneca. J. O’Connell: Employed by Pfizer as Senior<br />
Director. Holds Pfizer stock. S. Ou: Advisory relationship with Pfizer and Genentech<br />
(compensated). Honoraria from Pfizer, Genentech and Eli Lilly. Research funding<br />
from Pfizer. I. Taylor: Employed by Pfizer as a Senior Director. Holds Pfizer stock.<br />
H. Zhang: Employed by Pfizer as a Senior Manager. Holds Pfizer stock.<br />
1229PD LUX-LUNG 3: SYMPTOM AND HEALTH-RELATED QUALITY<br />
OF LIFE RESULTS FROM A RANDOMIZED PHASE III STUDY<br />
IN 1ST-LINE ADVANCED NSCLC PATIENTS HARBOURING<br />
EGFR MUTATIONS<br />
L.V. Sequist 1 , M. Schuler 2 , N. Yamamoto 3 , K.J. O’Byrne 4 , V. Hirsh 5 , T.S.<br />
K. Mok 6 , J. Lungershausen 7 , M. Shahidi 8 , M. Palmer 9 , J.C. Yang 10<br />
1 Medicine, Massachusetts General Hospital, Boston, MA, UNITED STATES OF<br />
AMERICA, 2 Medicine, West German Cancer Center, University Duisburg-Essen,<br />
Essen, GERMANY, 3 Thoracic Oncology, Shizuoka Cancer Center, Shizuoka,<br />
JAPAN, 4 Oncology, St James’s Hospital, Dublin, IRELAND, 5 Oncology, McGill<br />
University Health Centre, Montreal, QC, CANADA, 6 Department of Clinical<br />
Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong, CHINA,<br />
7 Health Economics, Boehringer Ingelheim, Ingelheim, GERMANY, 8 Clinical<br />
Research / Management, Boehringer Ingelheim, Bracknell, UNITED KINGDOM,<br />
9 Statistics, Keele University, Keele, UNITED KINGDOM, 10 Oncology, National<br />
Taiwan University Hospital, Taipei, TAIWAN<br />
Background: Afatinib (A) is an oral, irreversible ErbB family blocker. LUX-Lung 3<br />
compared A with cisplatin/pemetrexed (CP) in patients with EGFR mutation positive<br />
lung adenocarcinoma. The primary analysis demonstrated significant improvement<br />
in progression-free survival (PFS), with a median PFS of 11.1 months for A and 6.9<br />
months for CP (HR = 0.58, p = 0.0004). Here, we present patient-reported<br />
Health-related Quality of Life (HRQoL) data.<br />
Methods: 345 patients were randomized (2:1) to receive A or CP. Symptoms and<br />
HRQoL were measured using EORTC questionnaires (QLQ-C30/LC13) at baseline<br />
and q3w until progression. Changes of ≥10 points were considered clinically<br />
significant. Analyses of cough, dyspnoea and pain symptoms were pre-specified.<br />
Time to deterioration (1st 10-point worsening from baseline) was analyzed using a<br />
stratified log rank test. Percentage improved/worsened by ≥10 points or stable was<br />
determined. Mean scores over time were estimated using longitudinal (mixed-effects<br />
growth curve) models.<br />
Results: Compliance with questionnaires was >85% over time and all patients had<br />
low baseline symptom burden. Compared to CP, <strong>the</strong>rapy with A significantly delayed<br />
time to deterioration for cough (HR = 0.60; p = 0.0072) and dyspnoea (HR = 0.68; p<br />
= 0.0145); results for pain trended toward A (HR = 0.82; p = 0.1913). A higher<br />
proportion of A-treated patients had ≥10 point improvements in cough (67% vs<br />
60%; p = 0.2444), dyspnoea (64% vs 50%; p = 0.0103) and pain (59% vs 48%; p =<br />
0.0513), compared to CP, particularly among patients with baseline symptoms. Mean<br />
scores over time for cough and dyspnoea also significantly favoured A. Consistent<br />
with <strong>the</strong> safety profile of A, a higher proportion of A-treated patients had significant<br />
worsening of symptoms of diarrhoea, sore mouth and dysphagia compared to CP.<br />
Reported fatigue, nausea, and vomiting were significantly worse on CP. Overall,<br />
<strong>the</strong>rapy with A improved global HRQoL, physical, role and cognitive functioning<br />
compared to CP (p < 0.05).<br />
Conclusion: In LUX-Lung 3, prolongation of PFS on A was associated with<br />
significant HRQoL improvement and delay of deterioration of lung cancer-related<br />
symptoms compared to CP.<br />
Disclosure: L.V. Sequist: Paid consultancy/advisory relationship with: Boehringer<br />
Ingelheim, Daiichi-Sankyo, Merrimack, Clovis and Celgene; Research funding from:<br />
Boehringer Ingelheim. M. Schuler: Paid consultancy/advisory relationship with:<br />
Boehringer Ingelheim; Research funding from: Boehringer Ingelheim; Travel support<br />
from: Lilly. K.J. O’Byrne: Paid consultancy/advisory relationship with: Boehringer<br />
Ingelheim, Lilly Oncology; Honoraria from Boehringer Ingelheim, Lilly Oncology;<br />
Research funding from Boehringer Ingelheim; O<strong>the</strong>r remuneration from Boehringer<br />
Ingelheim, Lilly Oncology. V. Hirsh: Honoraria from <strong>the</strong> Boehringer Ingelheim<br />
Advisory Board. T.S.K. Mok: Paid consultancy/advisory relationship with and<br />
honoraria from: AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, BeiGene,<br />
AVEO, Pfizer, Taiko, Boehringer Ingelheim; Research funding from: AstraZeneca. J.<br />
Lungershausen: Employee of Boehringer Ingelheim. M. Shahidi: Employee of<br />
Boehringer Ingelheim. M. Palmer: Consulting fee, honorarium, travel support, fees<br />
for reviews, and payment for writing or reviewing <strong>the</strong> manuscript via N Zero 1 Ltd;<br />
Board membership of N Zero 1 Ltd and consultancy, travel/accommodation/meeting<br />
costs unrelated to activities listed. J.C. Yang: James Chih-Hsin Yang has received<br />
honorarium for speech and advisory roles from Astrazeneca, Roche, Pfizer, OSI. He<br />
was <strong>the</strong> advisor for Boehringer Ingelheim and Eli Lilly without payment. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
1230PD UPDATED RESULTS OF A GLOBAL PHASE II STUDY WITH<br />
CRIZOTINIB IN ADVANCED ALK-POSITIVE NON-SMALL<br />
CELL LUNG CANCER (NSCLC)<br />
D. Kim 1 , M. Ahn 2 ,P.Yang 3 , X. Liu 4 ,T.DePas 5 , L. Crinò 6 , S. Lanzalone 7 ,<br />
A. Polli 7 , A. Shaw 8<br />
1 Internal Medicine, Seoul National University Hospital, Seoul, KOREA, 2 Division of<br />
Hematology/Oncology, Department of Medicine, Sungkyunkwan University<br />
School of Medicine Samsung Medical Center, Seoul, KOREA, 3 Department of<br />
Internal Medicine, National Taiwan University College of Medicine, Taipei,<br />
TAIWAN, 4 Cancer Center, 307 Hospital of <strong>the</strong> Academy of Military Medical<br />
Sciences, Beijing, CHINA, 5 Medical Oncology Unit of Respiratory Tract and<br />
Sarcomas, European Institute of Oncology, Milano, ITALY, 6 Department of<br />
Medical Oncology, Ospedale Santa Maria della Misericordia, Perugia, ITALY,<br />
7 Oncology, Pfizer, Milano, ITALY, 8 Hematology/Oncology, Department of<br />
Medicine, Massachusetts General Hospital, Boston, MA, UNITED STATES OF<br />
AMERICA<br />
Background: Anaplastic lymphoma kinase (ALK) is a known oncogenic driver in<br />
NSCLC, and approximately 5% of patients harbor ALK gene rearrangements.<br />
Crizotinib is a first-in-class, selective small-molecule ALK inhibitor with<br />
demonstrated clinical activity in ALK-positive NSCLC. PROFILE 1005 is a global,<br />
multicenter, open-label, single-arm phase II study evaluating <strong>the</strong> safety and<br />
efficacy of crizotinib in previously treated patients with ALK-positive advanced<br />
NSCLC.<br />
Methods: Crizotinib 250 mg was administered BID to patients with ALK-positive<br />
advanced NSCLC who had received ≥1 chemo<strong>the</strong>rapy for locally advanced/<br />
metastatic disease, including those with treated brain metastases. Most patients had<br />
centrally confirmed ALK-positivity by break-apart fluorescence in-situ hybridization,<br />
defined as ≥15% of tumor cells with split signals. Disease response was evaluated by<br />
RECIST 1.1 every 6 weeks.<br />
Results: As of January <strong>2012</strong>, 901 patients had been dosed. The first 261 patients<br />
who had enrolled and started crizotinib by February 2011, with a median<br />
duration of treatment of 48 weeks, were considered to be <strong>the</strong> mature population.<br />
Demographic, exposure, and efficacy results in both <strong>the</strong> overall and mature<br />
populations are provided in <strong>the</strong> table. Among all 901 patients, 15% discontinued<br />
treatment due to adverse events (AEs) and 10% had a dose reduction due to an<br />
AE. The most frequent AEs of any cause were vision disorder (54%), nausea<br />
(51%), diarrhea (44%), vomiting (44%), and constipation (37%), which were<br />
mostly grade 1/2.<br />
Conclusions: Crizotinib demonstrated a high response rate that was durable, with a<br />
median progression-free survival of 8.1 months. Crizotinib has a favorable tolerability<br />
profile. These findings continue to provide strong evidence for crizotinib as a<br />
standard of care for advanced ALK-positive NSCLC.<br />
Overall population Mature population<br />
Total no. of patients, n 901 261<br />
Response-evaluable patients, n 803 259<br />
Demographics:<br />
Median age, years<br />
Male/female, %<br />
ECOG PS 0/1, %<br />
Annals of Oncology<br />
53<br />
52<br />
43/57<br />
46/54<br />
82<br />
83<br />
Adenocarcinoma, %<br />
92<br />
94<br />
Duration of treatment (weeks), median<br />
(range)<br />
20 (
Annals of Oncology<br />
1231PD IMPACT OF CRIZOTINIB TREATMENT ON<br />
PATIENT-REPORTED SYMPTOMS AND QUALITY OF LIFE<br />
(QOL) IN ADVANCED ALK-POSITIVE NON-SMALL CELL<br />
LUNG CANCER (NSCLC)<br />
F.H. Blackhall 1 , T.L. Evans 2 , J. Han 3 , R. Salgia 4 , D. Moro-Sibilot 5 , S. Gettinger 6 ,<br />
L. Crino 7 , K. Wilner 8 , A. Reisman 9 ,S.Iyer 10<br />
1 Medical Oncology, The Christie NHS Foundation Trust, Manchester, UNITED<br />
KINGDOM, 2 Medical Oncology, University of Philadelphia, Philadelphia, PA,<br />
UNITED STATES OF AMERICA, 3 Center for Lung Cancer, National Cancer<br />
Center, Goyang, KOREA, 4 Department of Medicine, Section of Hematology/<br />
Oncology, University of Chicago, Chicago, IL, UNITED STATES OF AMERICA,<br />
5 Department of Lung Cancer, CHU De Grenoble - Hôpital A. Michalon,<br />
Grenoble, FRANCE, 6 Thoracic Oncology, Yale University School of Medicine,<br />
New Haven, CT, UNITED STATES OF AMERICA, 7 Medical Oncology, S. Maria<br />
della Misericordia Hospital, Perugia, ITALY, 8 Reseach and Development, Pfizer<br />
Oncology, La Jolla, CA, UNITED STATES OF AMERICA, 9 Medical Oncology,<br />
Pfizer Inc, New York, NY, UNITED STATES OF AMERICA, 10 Medical Oncology,<br />
Pfizer Oncology, New York, NY, UNITED STATES OF AMERICA<br />
Background: Crizotinib is a potent, selective, ATP-competitive ALK inhibitor<br />
demonstrating a high response rate in advanced ALK-positive NSCLC. The effect of<br />
crizotinib on patient-reported symptoms, functioning and QOL from PROFILE 1005<br />
is presented.<br />
Methods: PROFILE 1005 is an ongoing global, multicenter, open-label, single-arm,<br />
phase II study evaluating <strong>the</strong> safety and efficacy of crizotinib (250 mg BID in 3-week<br />
cycles) in previously treated patients with advanced ALK-positive NSCLC.<br />
Patient-reported outcomes (PROs) were assessed as secondary endpoints using <strong>the</strong><br />
European Organisation for Research and Treatment of Cancer questionnaire<br />
(EORTC-QLQ-C30) and lung cancer module (QLQ-LC13) at baseline, Day 1 of each<br />
cycle and at end of treatment. Functioning, symptoms and global QOL were assessed<br />
and scored on scales of 0–100. Higher scores indicate higher symptom severity or<br />
higher functioning/QOL. Change from baseline was assessed for statistical and<br />
clinical significance (defined as ≥10-point change from baseline).<br />
Results: As of Jan <strong>2012</strong>, 901 patients were evaluable for safety and 797 (88%) of<br />
<strong>the</strong>se patients had completed <strong>the</strong> entire questionnaire at baseline. The majority of<br />
patients was female (57%), never smokers (66%), and had adenocarcinoma (92%),<br />
with a median age of 52 years. A clinically meaningful (≥10-point) improvement<br />
from baseline was observed early and maintained in patient-reported symptoms of<br />
cough (Cycle 2 onwards), pain (Cycles 2 to 19), dyspnea from QLQ–C30 (Cycles 3<br />
to 19), pain in chest (Cycles 3 to 20 except for Cycle 18), pain in arm and shoulder<br />
(Cycles 3 to 16) and fatigue (Cycles 4 to 21). Clinically significant deterioration was<br />
observed for constipation (Cycles 2 and 3) and diarrhea (Cycle 2 to 6, 9 and 10).<br />
Clinically meaningful improvements were observed for physical functioning (Cycle 8<br />
and 9), role functioning (Cycles 9 and 10), social functioning (Cycles 4 to 15, except<br />
Cycle 12) and global QOL (Cycles 3 to 15, except Cycle 11).<br />
Conclusion: Treatment with crizotinib in pretreated patients with advanced<br />
ALK-positive NSCLC showed an overall positive impact on patient-reported lung<br />
cancer symptoms and global QOL.<br />
Disclosure: F.H. Blackhall: Advisory relationship with Pfizer. Honoraraia, research<br />
funding and o<strong>the</strong>r remuneration received from Pfizer. D. Moro-Sibilot: Honoraria<br />
received from Pfizer. K. Wilner: Employed by Pfizer as a Senior Director and has<br />
stock ownership with Pfizer. A. Reisman: Employed by Pfizer and has stock<br />
ownership with Pfizer. S. Iyer: Employed as a Director (Global Outcomes Research)<br />
by Pfizer. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1232PD LUNG CANCER HARBORING HER2 MUTATION:<br />
EPIDEMIOLOGICAL CHARACTERISTICS AND<br />
THERAPEUTIC PERSPECTIVES<br />
J. Mazieres 1 , S. Peters 2 , A. Cortot 3 , B. Besse 4 , F. Barlesi 5 , M. Beau-Faller 6 ,<br />
T. Urban 7 , D. Moro-Sibilot 8 , J. Milia 1 , O. Gautschi 9<br />
1 Department of Pneumology, CHU Toulouse - Hôpital Larrey, Toulouse,<br />
FRANCE, 2 Oncology, Centre Hospitalier Universitaire Vaudois - CHUV,<br />
Lausanne, SWITZERLAND, 3 Pneumology, CHU Lille, Lille, FRANCE, 4 Thoracic<br />
Group, INSERM U981, Institut Gustave Roussy, Villejuif, FRANCE, 5 Service<br />
d’Oncologie Multidisciplinaire et Innovations Thérapeutique, Hôpital Nord,<br />
Marseille, FRANCE, 6 Hôpitaux Universitaires de Strasbourg et INSERM U682<br />
Hôpital De Hautepierre Laboratoire de Biochimie et de Biologie Moléculaire,<br />
Strasbourg Cedex, E/M Laboratoire de Biochimiee et de Biologie Moléculaire,<br />
Hôpitaux Universitaires de Strasbourg et INSERM U682 Hôpital de Hautepierre,<br />
Strasbourg, FRANCE, 7 Oncology Department, CHU Anger, Anger, FRANCE,<br />
8 Cancérologie, Hôpital A. Michallon - CHU Grenoble, Grenoble, FRANCE,<br />
9 Medizinsiche Onkologie, Luzerner Kantonsspital, Luzern, SWITZERLAND<br />
Introduction: HER2 oncogene is a member of <strong>the</strong> EGFR family, encoding a<br />
transmembrane receptor that drives and regulates cell proliferation. HER2 mutations<br />
are identified in about 2% of non small cell lung cancer (NSCLC), mainly located in<br />
exon 20, and appear to be critical for lung cancer carcinogenesis. Very scarce data<br />
are available to define a clinical profile of <strong>the</strong> patients harboring HER2 mutated<br />
NSCLC. We aimed to study clinicopathological characteristics and <strong>the</strong>rapeutic<br />
outcomes of patients harboring HER2 mutation in a large European series.<br />
Results: We retrospectively identified 46 NSCLC patients diagnosed with HER2 exon<br />
20 mutation. HER2 mutation was mainly exclusive as only one concomitant KRas<br />
mutation was described. Our population was characterized by a median age of 60 yr<br />
(31 to 86 yr), a high proportion of women (30 vs. 16 men, 65%), and of never<br />
smokers (24, 52%). All tumors were adenocarcinomas (two with lepidic features).<br />
Half of <strong>the</strong> patients had stage IV disease at <strong>the</strong> time of diagnosis. HER2 targeted<br />
treatment was delivered after conventional chemo<strong>the</strong>rapy. A total of 20 anti-Her2<br />
treatments were evaluable. We observed 4 progressive diseases, 7 disease stabilizations<br />
and 9 partial responses according to RECIST 1.1 (overall response rate ORR = 45%;<br />
disease control rate DCR = 80%). Specifically, we observed a DCR of 92% for<br />
trastuzumab-based <strong>the</strong>rapies (n = 14), 100 % for afatinib (n = 3) but no response to<br />
lapatinib (n = 2) and to a multiTKI (n = 1). Median survival was of 68.2 months and<br />
22.9 months for respectively early stage and stage IV patients.<br />
Conclusion: This study, <strong>the</strong> largest to date dedicated to HER2 mutated NSCLC,<br />
reinforces <strong>the</strong> importance of an HER2 screening strategy in lung adenocarcinomas.<br />
HER2-targeted drugs should be tested fur<strong>the</strong>r, ideally within large collaborative<br />
clinical trials.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1233PD EFFICACY AND PATIENT (PT)-REPORTED OUTCOMES<br />
(PROS) WITH SELUMETINIB (AZD6244, ARRY-142866;<br />
SEL) + DOCETAXEL (DOC) IN KRAS-MUTANT ADVANCED<br />
NON-SMALL CELL LUNG CANCER (NSCLC): A<br />
RANDOMIZED, PHASE II TRIAL<br />
P.A. Janne 1 , A.T. Shaw 2 , J.R. Pereira 3 , G. Jeannin 4 , J.F. Vansteenkiste 5 ,<br />
C. Barrios 6 , F.A. Franke 7 , L. Grinsted 8 , I. Smith 8 , L. Crino 9<br />
1 Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, MA,<br />
UNITED STATES OF AMERICA, 2 Hematology/Oncology, Massachusetts General<br />
Hospital, Boston, MA, UNITED STATES OF AMERICA, 3 Depto de Pneumologia,<br />
Grupo de Assistencia Médica, Sao Paulo, BRAZIL, 4 Service de Pneumologie,<br />
Hôpital Gabriel Montpied, Clermont- Ferrand, FRANCE, 5 Respiratory Oncology<br />
Unit (Pulmonology), University Hospital Gasthuisberg, Leuven, BELGIUM,<br />
6 Oncology, Hospital Sao Lucas da PUC de Porto Alegre, Porto Alegre, BRAZIL,<br />
7 Cacon, Hospital de Caridade de Ljui, Ljui, BRAZIL, 8 Oncology, Astra Zeneca,<br />
Alderley Park, UNITED KINGDOM, 9 Department of Oncology, Hospital Santa<br />
Maria della Misericordia, Perugia, ITALY<br />
Objectives: This randomized, double-blind, placebo (PBO)-controlled, phase II trial<br />
evaluated <strong>the</strong> efficacy and safety of SEL + DOC as second-line treatment for pts with<br />
KRAS-mutant advanced NSCLC. Assessment of <strong>the</strong> prevalence, severity, and change<br />
over time of lung cancer symptoms was an exploratory objective.<br />
Methods: Pts with stage IIIB-IV, second-line KRAS-mutant advanced NSCLC,<br />
received iv DOC 75mg/m 2 , and po SEL 75mg or PBO BD. PROs were assessed using<br />
<strong>the</strong> Lung Cancer-Specific Symptom Questionnaire (LSSQ), which includes <strong>the</strong> Lung<br />
Cancer Subscale (LCS) plus items relating to symptoms and functional activities<br />
from <strong>the</strong> FACT-L. Pts completed <strong>the</strong> questionnaire on Day 1, and every 3 weeks<br />
until discontinuation from study treatment, and at discontinuation.<br />
Results: 422 pts were screened across 67 centers in 12 countries; 87 were randomized<br />
(SEL + DOC, 44; PBO + DOC, 43). Baseline characteristics were reasonably balanced.<br />
OS was longer for SEL + DOC vs PBO + DOC (9.4 vs 5.2 mo), but not statistically<br />
significant (HR 0.80; 80% CI 0.56–1.14) and hazards were non-proportional. All<br />
secondary endpoints, including response rate (37% vs 0%; p < 0.0001) and PFS (5.3<br />
vs 2.1 mo; HR 0.58; 80% CI 0.42–0.79), were significantly improved for SEL + DOC<br />
vs PBO + DOC. Most frequent grade 3/4 AEs were neutropenia and febrile<br />
neutropenia. Compliance for completion of <strong>the</strong> LSSQ at baseline and at least 1<br />
follow-up visit was 85.5%. There was a numerical improvement in <strong>the</strong> change from<br />
baseline in <strong>the</strong> LSSQ scores with SEL + DOC compared with PBO + DOC,<br />
throughout <strong>the</strong> assessment period. In a post-hoc analysis, <strong>the</strong> % pts with a clinically<br />
meaningful improvement in LCS score was greater for SEL + DOC (44%) than PBO<br />
+ DOC (24%; OR 2.50; 80% CI 1.34–4.77; 1-sided p = 0.029). The time to<br />
deterioration of LCS score was also in favor of SEL + DOC (HR 0.33; 80% CI 0.22–<br />
0.49; 1-sided p = 0.0002).<br />
Conclusions: This is <strong>the</strong> first prospective study to demonstrate a clinical benefit of<br />
targeted <strong>the</strong>rapy (SEL + DOC) for pts with KRAS-mutant cancer of any type. In a<br />
post-hoc analysis, more pts experienced clinically meaningful improvements in lung<br />
cancer symptoms with SEL + DOC than PBO + DOC.<br />
Disclosure: P.A. Janne: I have served as a consultant to Astra Zeneca and have been<br />
compensated. A.T. Shaw: Research funding from Astra Zeneca and funding for costs<br />
of clinical trials. J.F. Vansteenkiste: Dr. Vansteenkiste is <strong>the</strong> holder of <strong>the</strong> Astra<br />
Zeneca Chair in personalized lung cancer care which provides research funding. L.<br />
Grinsted: Lynda Grinsted is an employee of Astra Zeneca and receives stock shares. I.<br />
Smith: Ian Smith is an employee of Astra Zeneca and receives stock. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds409 | ix403
1234PD RANDOMIZED PHASE III TRIAL OF S-1 PLUS CISPLATIN<br />
VERSUS DOCETAXEL PLUS CISPLATIN FOR ADVANCED<br />
NON-SMALL-CELL LUNG CANCER (TCOG0701)<br />
H. Sakai 1 , A. Gemma 2 , K. Kubota 2 , M. Nishio 3 , H. Okamoto 4 , A. Inoue 5 ,<br />
H. Isobe 6 , K. Kobayashi 7 , M. Takeuchi 8 , S. Kudoh 9<br />
1 Thoracic Oncology, Saitama Cancer Center, Saitama, JAPAN, 2 Internal<br />
Medicine, Nippon Medical School, Tokyo, JAPAN, 3 Thoracic Oncology Center,<br />
The Cancer Institute Hospital of Japanese Foundation for Cancer Research,<br />
Tokyo, JAPAN, 4 Department of Respiratory Medicine, Yokohama Municipal<br />
Citizen’s Hospital, Yokohama, JAPAN, 5 Department of Respiratory Medicine,<br />
Tohoku University, Sendai, JAPAN, 6 Clinical Oncology, KKR Sapporo Medical<br />
Center, Sapporo, JAPAN, 7 Respiratory Medicine, Saitama International Medical<br />
Center, Saitama, JAPAN, 8 Biostatistics and Pharmaceutical Medicine, Kitasato<br />
University School of Pharmacy, Tokyo, JAPAN, 9 Respiratory Medicine, Fukujuji<br />
Hospital, Tokyo, JAPAN<br />
Background: Quality of life (QOL) should be an explicit priority throughout <strong>the</strong><br />
course of care for patients with advanced non-small-cell lung cancer (NSCLC).<br />
Docetaxel plus cisplatin (DP) is <strong>the</strong> only third-generation regimen that has<br />
demonstrated statistically significant improvements in overall survival and QOL by a<br />
head-to-head comparison with a second-generation regimen (vindesine plus<br />
cisplatin) in patients with advanced NSCLC. S-1 plus cisplatin (SP) has shown<br />
activity and good tolerability in phase II settings.<br />
Method: Patients with previously untreated stage IIIB or IV NSCLC, an ECOG PS of<br />
0-1 and adequate organ functions were randomly assigned to receive ei<strong>the</strong>r oral S-1<br />
80 mg/m 2 /day (40 mg/m 2 b.i.d.) on days 1 to 21 plus cisplatin 60 mg/m 2 on day 8<br />
every 5 weeks or docetaxel 60 mg/m 2 on day 1 plus cisplatin 80 mg/m 2 on day 1<br />
every 3 weeks, both up to 6 cycles. The primary endpoint was overall survival (OS).<br />
A non-inferiority study design was employed; <strong>the</strong> upper confidence interval (CI)<br />
limit of <strong>the</strong> hazard ratio (HR) was
Annals of Oncology<br />
1236PD TUMOUR BIOMARKER AND PLASMA TIME COURSE DATA<br />
FROM ABIGAIL, A PHASE II STUDY OF 1ST-LINE<br />
BEVACIZUMAB + CHEMOTHERAPY IN ADVANCED<br />
NON-SQUAMOUS NON-SMALL-CELL LUNG CANCER<br />
(NS-NSCLC)<br />
M. Reck 1 , V.A. Gorbunova 2 , E. Juhasz 3 , B. Szima 4 , S. Orlov 5 ,C.Yu 6 ,<br />
C. Pallaud 7 , S.J. Scherer 8 , V. Archer 9 , T.S.K. Mok 10<br />
1 Department of Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf,<br />
GERMANY, 2 Department of Chemo<strong>the</strong>rapy, Russian Research Oncology Center<br />
n.a. N. N. Blokhin Russian Cancer Research Center, Moscow, RUSSIAN<br />
FEDERATION, 3 Pulmonology Department XIV, Országos Korányi TBC és<br />
Pulmonologiai Intézet, Budapest, HUNGARY, 4 Department of Oncoradiology,<br />
Markusovszky Hospital, Szomba<strong>the</strong>ly, HUNGARY, 5 Laboratory of Thoracic<br />
Oncology, St Petersburg State Medical University, St Petersburg, RUSSIAN<br />
FEDERATION, 6 Department of Internal Medicine, National Taiwan University<br />
Hospital, Taipei, TAIWAN, 7 Pharma Development Oncology Department,<br />
F. Hoffmann-La Roche Ltd., Basel, SWITZERLAND, 8 Pharma Development<br />
Department, Genentech, San Francisco, CA, UNITED STATES OF AMERICA,<br />
9 Clinical Development (oncology), Roche Products Ltd., Welwyn Garden City,<br />
UNITED KINGDOM, 10 Department of Clinical Oncology, Chinese University of<br />
Hong Kong, Prince of Wales Hospital, Hong Kong, HONG KONG<br />
Background: BO21015 (NCT00700180) is a phase II, randomized, multicentre study<br />
exploring correlation between biomarkers (BMs) and best overall response (BOR) to<br />
bevacizumab with carboplatin/gemcitabine (CG) or carboplatin/paclitaxel (CP) in<br />
chemonaïve patients with advanced/recurrent NSCLC. Efficacy, safety and correlation<br />
of 7 baseline (BL) plasma BM (bFGF, E-selectin, ICAM, PLGF, VEGFA, VEGFR-1<br />
and VEGFR-2) with BOR and progression-free survival (PFS) have been reported. 1<br />
This abstract presents BM analysis for tumour tissue, plasma time course and clinical<br />
outcome.<br />
Methods: 303 eligible patients were randomized 1:1 to receive bevacizumab 7.5 mg/<br />
kg or 15 mg/kg until disease progression (PD) or unacceptable toxicity (with 6 cycles<br />
of CG or CP, at investigators’ discretion). Consented patients provided blood 1 and<br />
tumour samples for BM analysis. Pre-specified exploratory analyses examined<br />
correlation between BL plasma BM and overall survival (OS) and changes in plasma<br />
BM levels from BL to PD, cycles 2, 4 and 6. Plasma BM levels were measured by<br />
ELISA. IHC analyses of 5 tumour BMs (VEGFR-1, MVD, VEGFA, VEGFR-2 and<br />
NRP1) were assessed for correlation with BOR, PFS and OS, and with BL plasma<br />
BM levels.<br />
Results: \Fur<strong>the</strong>r exploratory analyses adjusting for BL prognostic factors and<br />
accounting for multiple testing showed a correlation of high BL VEGFA levels<br />
( 3 median) with shorter OS (n = 280; 19.8 vs 11.1 mos; p = 0.0042). No o<strong>the</strong>r<br />
BL plasma BMs correlated with OS. No significant changes in plasma BM<br />
levels were seen between baseline and PD, and/or cycles 2, 4 or 6 for any of<br />
<strong>the</strong> BMs. The only correlation between tumour and plasma markers was for<br />
tumour VEGFR1 expression and VEGFA plasma BL (p = 0.025, 0.26). No<br />
significant correlation was seen between tumour BM level and BOR, PFS or<br />
OS.<br />
Conclusions: Exploratory analysis showed high plasma BL VEGFA significantly<br />
correlated with shorter OS, consistent with previously reported data on PFS. No<br />
o<strong>the</strong>r BL plasma BMs correlated with OS. BL plasma VEGFA levels correlated with<br />
tumour VEGFR1 expression. None of <strong>the</strong> investigated tumour BMs significantly<br />
correlated with clinical outcome. 1 Mok et al. <strong>ESMO</strong> 2011<br />
Disclosure: M. Reck: Attended advisory boards for Roche, Lilly, BMS, AstraZeneca<br />
and Daiichi Sankyo. Received honoraria for lectures from Roche, Lilly, Daiichi<br />
Sankyo and AstraZeneca. V.A. Gorbunova: Attended advisory boards with Novartis<br />
and Pfizer. Honoraria for lectures from Roche and Bayer. B. Szima: Received<br />
funding for research. C. Yu: Attended advisory boards for Roche, AstraZeneca,<br />
Pfizer and Takeda. C. Pallaud: Owns stock in Roche. Currently employed by Roche.<br />
S.J. Scherer: Currrently employed by Roche/Genentech. V. Archer: Currently<br />
employed by Roche. T.S.K. Mok: Advisory boards: AstraZeneca, Roche, Eli Lilly,<br />
Merck Serono, Eisai, BMS, BeiGene, AVEO, Pfizer, Taiho, BI, GSK Biologicals. On<br />
<strong>the</strong> IASLC board of directors. Received research funding from AstraZeneca.<br />
Employed by The Chinese Uinversity of Hong Kong. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
1237PD CLINICAL ACTIVITY AND SAFETY OF ANTI-PROGRAMMED<br />
DEATH-1 (PD-1) (BMS-936558/MDX-1106/ONO-4538) IN<br />
PATIENTS (PTS) WITH ADVANCED NON-SMALL CELL LUNG<br />
CANCER (NSCLC)<br />
S. Gettinger 1 , L. Horn 2 , S.J. Antonia 3 , D. Spigel 4 , L. Gandhi 5 , L.V. Sequist 6 ,J.<br />
M. Wigginton 7 , G. Kollia 8 , A. Gupta 9 , J.R. Brahmer 10<br />
1 Thoracic Oncology, Yale University School of Medicine, New Haven, CT,<br />
UNITED STATES OF AMERICA, 2 Thoracic Oncology Program, Vanderbilt-Ingram<br />
Cancer Center, Nashville, TN, UNITED STATES OF AMERICA, 3 Thoracic<br />
Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL,<br />
UNITED STATES OF AMERICA, 4 Oncology, Sarah Cannon Research Institute/<br />
Tennessee Oncology PLLC, Nashville, TN, UNITED STATES OF AMERICA,<br />
5 Oncology, Dana-Farber Cancer Institute, Boston, MA, UNITED STATES OF<br />
AMERICA, 6 Oncology, Massachusetts General Hospital Cancer Center, Boston,<br />
MA, UNITED STATES OF AMERICA, 7 Discovery Medicine-Clinical Oncology,<br />
Bristol-Myers Squibb, Princeton, NJ, UNITED STATES OF AMERICA,<br />
8 Biostatistics and Data Management, Bristol-Myers Squibb, Princeton, NJ,<br />
UNITED STATES OF AMERICA, 9 Discovery Medicine, Immuno-Oncology,<br />
Bristol-Myers Squibb, Princeton, NJ, UNITED STATES OF AMERICA,<br />
10 Melanoma Program, Sidney Kimmel Cancer Center at Johns Hopkins<br />
University, Baltimore, MD, UNITED STATES OF AMERICA<br />
Purpose: BMS-936558 is a fully human monoclonal antibody that blocks <strong>the</strong> PD-1<br />
co-inhibitory receptor expressed by activated T cells. We report here <strong>the</strong> activity and<br />
safety of BMS-936558 in pretreated pts with advanced NSCLC, a tumor not<br />
previously considered responsive to immuno<strong>the</strong>rapy.<br />
Methods: BMS-936558 was administered IV q2wk to pts with various solid tumors<br />
at 1 − 10 mg/kg during dose escalation and/or cohort expansion. Pts with advanced<br />
NSCLC previously treated with at least 1 prior line of <strong>the</strong>rapy were eligible. Pts<br />
received up to 12 cycles (4 doses/cycle) of treatment or until unacceptable toxicity,<br />
confirmed progressive disease, or complete response. Clinical activity was assessed by<br />
RECIST v1.0.<br />
Results: As of Feb 24, <strong>2012</strong>, 122 NSCLC pts had received BMS-936558 at 1 (n = 31),<br />
3 (n = 33), or 10 mg/kg (n = 58). ECOG performance status was ≤1 for 117/122 pts;<br />
67/122 pts had received ≥3 prior <strong>the</strong>rapies. Median duration of <strong>the</strong>rapy was 12<br />
weeks (range 2 − 101.3 wks). Common drug-related AEs in NSCLC pts were fatigue<br />
(18%), decreased appetite (10%), anemia (8%), and nausea (7%). The incidence of<br />
grade 3–4 related AEs was 8%. There were 2 drug-related deaths from pneumonitis.<br />
Of 76 evaluable pts, 14 had a partial response (PR) (Table); all 14 were treated ≥24<br />
wk, and 8 had responses of ≥24 wk. 5 Five pts had stable disease (SD) lasting ≥24<br />
wk. Additionally, 3 pts had a persistent decrease in target lesion tumor burden in <strong>the</strong><br />
presence of new lesions and were not categorized as responders.<br />
Conclusions: BMS-936558 had an acceptable risk: benefit profile in previously<br />
treated, advanced NSCLC. Activity in squamous NSCLC was particularly intriguing.<br />
Additional long-term follow-up data will be reported.<br />
Dose, mg/kg No. pts a<br />
ORR,<br />
No. pts (%)<br />
[95% CI]<br />
PFSR at<br />
24 wks, %<br />
[95% CI]<br />
1 18 1 (6) [0.1 − 27] 16 [0 − 34]<br />
3 19 6 (32) [13 − 57] 41 [18 − 64]<br />
10 39 7 (18) [8 − 34] 24 [11 − 38]<br />
All 76 b<br />
14 (18) [11 − 29] 26 [16 − 36]<br />
All–Nonsquamous 56 7 (13) [5 − 24] 22 [11 − 34]<br />
All–Squamous 18 6 (33) [13 − 59] 33 [12 − 55]<br />
a Response-evaluable pts dosed by 07/01/2011 b Includes 2 pts with unknown<br />
histology, 1 with PR ORR = objective response rate ([{CR + PR} ÷ n] × 100); PFSR =<br />
progression-free survival rate<br />
Disclosure: L. Horn: Consultant or Advisory Role: OSI/Astellas (myself,<br />
uncompensated). D. Spigel: Consultant or Advisory Role: Bristol-Myers Squibb<br />
(myself, uncompensated). L.V. Sequist: Consultant or Advisory Role: Clovis, Celgene,<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds409 | ix405
GlaxoSmithKline (myself, compensated); Daiichi-Sankyo, Merrimack (myself,<br />
uncompensated). J.M. Wigginton: Employment or Leadership Role: Bristol-Myers<br />
Squibb (employment, myself, compensated). Stock Ownership: Bristol-Myers Squibb<br />
(myself). G. Kollia: Employment or Leadership Role: Bristol-Myers Squibb<br />
(employment, myself, compensated). Stock Ownership: Bristol-Myers Squibb<br />
(myself). A. Gupta: Employment or Leadership Role: Bristol-Myers Squibb<br />
(employment, myself, compensated). Stock Ownership: Bristol-Myers Squibb<br />
(myself). All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1238PD ACTIVE SPECIFIC IMMUNOTHERAPY WITH<br />
RACOTUMOMAB IN THE TREATMENT OF ADVANCED<br />
A. Macías 1 , S. Alfonso 2 , E. Santiesteban 3 , C. Viada 1 , I. Mendoza 4 , P.P. Guerra 4 ,<br />
R.E. Gómez 5 , M.L. Ardigo 5 , A.M. Vázquez 1 , R. Pérez 1<br />
1 Clinical Department, Center of Molecular Immunology, Havana, CUBA,<br />
2 Oncology Unit, University Hospital “Celestino Hernánez Robau”, Las Villas,<br />
CUBA, 3 Oncology Unit, Hospital “José Ramón Tabranes”, Matanzas, CUBA,<br />
4 Project Management and Monitoring, National Clinical Trial Coordinator Center,<br />
Havana, CUBA, 5 Clinical Research, Elea Laboratories, Buenos Aires, ARGENTINA<br />
Background: Gangliosides, especially NeuGc-GM3, are an attractive target for cancer<br />
immuno<strong>the</strong>rapy. They do not express in normal human cells but are overexpressed<br />
in several solid tumors including NSCLC and are involved in tumor development<br />
and growth. Racotumomab is <strong>the</strong>rapeutic vaccine which induces a cellular and<br />
humoral immune response against NeuGc-GM3 expressed in tumors. Phase I and II<br />
trials in melanoma, breast and lung cancer have shown <strong>the</strong> low toxicity and high<br />
immunogenicity of racotumomab.<br />
Methods: Multicenter, randomized, placebo controlled, double blind clinical trial in<br />
patients with advanced (IIIB and IV) NSCLC who had an ECOG status ≤ 2 and had<br />
achieved partial or complete response or disease stabilization after completion of<br />
onco-specific treatment. 176 patients were randomized 1:1 to placebo or<br />
racotumomab. Initially 1 dose was administered every 14 days (induction period, 5<br />
doses in total), followed by 1 dose every 28 days (maintenance period) until patient<br />
refusal or worsening of ECOG status.<br />
Results: Safety: The most common adverse events were expected mild reactions at <strong>the</strong><br />
injection site (pain and itching). No differences were observed between both groups.<br />
Overall Survival (OS): Intent to Treat Analysis (ITT): Survival since inclusion was 15.7<br />
months (mean) and 8.3 months (median) in <strong>the</strong> racotumomab arm and 10.6 months<br />
(mean) and 6.3 months (median) in <strong>the</strong> placebo arm (log rank test, p= 0.02). OS rate<br />
(%) at 12 and 24 months was 38 % and 17 % in <strong>the</strong> racotumomab arm and 24 % and<br />
7 % in <strong>the</strong> placebo arm. Per Protocol Population Analysis (PPP): Includes patients<br />
who received ≥ 5 doses of racotumomab/ placebo (135/174 patients, 77% of <strong>the</strong> patient<br />
population). Survival since inclusion was 18.9 months (mean) and 10.9 (median) in<br />
<strong>the</strong> racotumomab arm and 11.4 months (mean) and 6.9 months (median) in <strong>the</strong><br />
placebo arm (log rank test, p= 0.002). OS rate (%) at 12 and 24 months: 48 % and 22<br />
% in <strong>the</strong> racotumomab arm and 28 % and 8 % in <strong>the</strong> lacebo arm.<br />
Conclusions: Immunization with racotumomab is safe. There is an OS benefit for<br />
racotumomab, both in <strong>the</strong> ITT and PPP analyses. Survival benefit appears to be<br />
increased when <strong>the</strong> patient’s clinical condition allows completion of <strong>the</strong> induction<br />
period of vaccination.<br />
Disclosure: R.E. Gómez: Is a full time employee at Elea Laboratories. M.L. Ardigo: Is a full<br />
time employee at Elea Laboratories. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1239P CLINICAL GENOTYPING AND EFFICACY OUTCOMES:<br />
EXPLORATORY BIOMARKER DATA FROM THE PHASE II<br />
ABIGAIL STUDY OF 1ST-LINE BEVACIZUMAB +<br />
CHEMOTHERAPY IN NON-SQUAMOUS NON-SMALL-CELL<br />
LUNG CANCER (NS-NSCLC)<br />
C. Pallaud 1 , M. Reck 2 , E. Juhasz 3 , B. Szima 4 ,C.Yu 5 , O. Burdaeva 6 , S. Orlov 7 ,<br />
S.J. Scherer 8 , V. Archer 9 , T.S.K. Mok 10<br />
1 Pharma Development Oncology Department, F. Hoffmann-La Roche Ltd, Basel,<br />
SWITZERLAND, 2 Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf,<br />
GERMANY, 3 Pulmonology Department Xiv, Országos Korányi TBC és<br />
Pulmonológiai Intézet, Budapest, HUNGARY, 4 Pulmonology Department,<br />
Markusovszky Hospital Oncoradiology, Szomba<strong>the</strong>ly, HUNGARY, 5 Department of<br />
Internal Medicine, National Taiwan University Hospital, Taipei, TAIWAN,<br />
6 Chemo<strong>the</strong>rapy Department, Arkhangelsk Regional Oncology Center,<br />
Arkhangelsk, RUSSIAN FEDERATION, 7 Laboratory of Thoracic Oncology, St<br />
Petersburg State Medical University, St. Petersburg, RUSSIAN FEDERATION,<br />
8 Pharma Development Department, Genentech, San Francisco, CA, UNITED<br />
STATES OF AMERICA, 9 Clinical Development (oncology), Roche Products Ltd.,<br />
Welwyn Garden City, UNITED KINGDOM, 10 Department of Clinical Oncology,<br />
Chinese University of Hong Kong Prince of Wales Hospital, Shatin, Hong Kong, CHINA<br />
Background: ABIGAIL (BO21015; NCT00700180) is a phase II, randomized,<br />
multicentre study exploring correlation between biomarkers (BMs) and best overall<br />
response (BOR) to bevacizumab with carboplatin/gemcitabine (CG) or carboplatin/<br />
paclitaxel (CP) in chemonaïve patients with advanced/recurrent ns-NSCLC.<br />
Annals of Oncology<br />
ABIGAIL efficacy, safety and plasma baseline results have been reported. This<br />
abstract presents exploratory clinical genotyping data from this study.<br />
Methods: 303 patients with untreated advanced/recurrent ns-NSCLC were<br />
randomized 1:1 to receive bevacizumab 7.5 mg/kg or 15 mg/kg until progression or<br />
unacceptable toxicity (with 6 cycles of CG or CP). Patients who consented provided<br />
blood and tumour samples for BM analysis. Exploratory analyses were conducted to<br />
assess whe<strong>the</strong>r genetic variants in <strong>the</strong> VEGFA pathway may act as biomarkers for<br />
efficacy and safety. Here we report data from DNA analysis for 12 single-nucleotide<br />
polymorphisms (SNPs) across 3 genes: VEGFA (5 SNPs), VEGFR-1 (3 SNPs) and<br />
VEGFR-2 (4 SNPs). SNPs were identified using specific individual genotyping assays.<br />
Results: VEGFA: c. + 405/c.-634 (CG), VEGFA: c.-460T > C; c. -1498T > C (CT) and<br />
VEGFA: c.-2578 C > A (AC) were all associated with >50% higher odds of<br />
responding to treatment. VEGFR-1 rs9554316 (GT) was associated with >30% higher<br />
risk of progression and >40% higher risk of death. VEGF: c. + 936 C > T (CT) was<br />
associated with higher incidence of hypertension. When p-values were adjusted for<br />
treatment and prognostic factors, no SNPs were associated with significantly higher<br />
risk of hypertension.<br />
Conclusions: One SNP was associated with increased risk of progression/death, while<br />
3 o<strong>the</strong>rs were associated with increased BOR. However, adjustment for multiple<br />
testing would no longer result in statistically significant p-values. SNPs analysed in<br />
this study have been previously reported as showing potential predictive value in<br />
o<strong>the</strong>r studies: VEGFA SNPs in breast cancer (E2100) and NSCLC (E4599); VEGFR1<br />
SNP in pancreatic cancer (AVITA). More exploratory analyses from this and o<strong>the</strong>r<br />
trials of bevacizumab may provide fur<strong>the</strong>r insight.<br />
Disclosure: C. Pallaud: Own stock in and currently employed by F. Hoffmann-La<br />
Roche Ltd. M. Reck: Attended advisory boards for Roche, Lilly, BMS, AstraZeneca<br />
and Daiichi Sankyo. Received honoraria for lectures from Roche, Lilly, Daiichi<br />
Sankyo and AstraZeneca. B. Szima: Received funding for research. C. Yu: Attended<br />
advisory boards for Roche, AstraZeneca, Takeda and Pfizer. S.J. Scherer: Currently<br />
employed by Roche/Genentech. V. Archer: Currently employed by Roche. T.S.K.<br />
Mok: Attended advisory boards for AstraZeneca, Roche, Eli Lilly, Merck Serono,<br />
Eisai, BMS, BeiGene, AVEO, Pfizer, Taiho, BI and GSK Biologicals. On <strong>the</strong> IASLC<br />
board of directors. Received research funding from AstraZeneca. All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
1240P CIRCULATING ENDOTHELIAL CELLS (CEC), CIRCULATING<br />
ENDOTHELIAL PROGENITORS (CEP) AND CIRCULATING<br />
TUMOUR CELLS (CTC) AS MARKERS FOR RESPONSE TO<br />
BEVACIZUMAB/CARBOPLATIN/PACLITAXEL (B + CP) OR<br />
BEVACIZUMAB/ERLOTINIB (B + E) IN ADVANCED<br />
NON-SQUAMOUS NON-SMALL-CELL LUNG CANCER<br />
(NS-NSCLC)<br />
F. Farace 1 , S. Le Moulec 2 , J. Mazieres 3 , H. Senellart 4 , E. Dansin 5 ,<br />
A. Madroszyk 6 , X. Quantin 7 , H. Berard 8 , B. Besse 9<br />
1 Laboratory of Translational Research, Institut Gustave Roussy, Villejuif, FRANCE,<br />
2 Department of Oncology, Hôpital d’Instruction des Armées du Val-de-Grâce,<br />
Paris, FRANCE, 3 Department of Thoracic Oncology, Hôpital De Larrey, Toulouse,<br />
FRANCE, 4 Department of Medical Oncology, Institut de Cancérologie de l’Ouest<br />
Site René Gauducheau, Nantes, FRANCE, 5 Department of Medical of Oncology,<br />
CLCC Oscar Lambret, Lille, FRANCE, 6 Department of Medical Oncology, Institut<br />
Paoli Calmettes, Marseille, FRANCE, 7 Department of Thoracic Oncology, Hôpital<br />
Arnaud de Villeneuve, CHU de Montpellier, Montpellier, FRANCE, 8 Department<br />
of Pnuemology, Hôpital d’Instruction des Armées Sainte Anne, Toulon, FRANCE,<br />
9 Departement of Medicine, Institute Gustave Roussy, Villejuif, FRANCE<br />
Background: The phase II, open-label BRAIN study (ML21823; NCT00800202) is<br />
<strong>the</strong> first to assess <strong>the</strong> efficacy/safety of bevacizumab combined with chemo<strong>the</strong>rapy in<br />
patients (pts) with ns-NSCLC and untreated CNS metastases. Investigation of CEC,<br />
CEP or CTC levels as potential markers of response to bevacizumab was undertaken.<br />
Methods: In <strong>the</strong> B + CP arm, blood samples were taken before treatment on day 1<br />
(d1) of cycle 1 (C1) (and 6 hrs after [C1 + 6h] treatment at one centre only), and on<br />
d1 of C2 and C3, i.e. 4 samples in total. Samples were taken for <strong>the</strong> B + E arm on d1<br />
of C1, C2 and C3 (3 samples total). CEC and CTC levels were measured with<br />
CellSearch (Immunicon, Veridex). CEP were measured using four-colour flow<br />
cytometry after enrichment of progenitor cells using Miltenyi Biotec EPC<br />
enumeration and enrichment kit. Cut-offs were 15 cells/4mL for CEC, 2 cells/7.5mL<br />
for CTC and median for CEP. Relation between marker levels and 6-month<br />
progression-free rate (PFR) and best overall response (BOR) was examined.<br />
Results: CEC and CTC were analysed in 69/91 (76%) pts, and CEP in 32/91 (35%)<br />
pts; baseline (BL) characteristics were similar to <strong>the</strong> overall population. CEC, CTC<br />
and CEP were detected at BL in 94%, 94% and 100% of <strong>the</strong>se pts. In <strong>the</strong> B + CP<br />
group, CEC levels were increased at C1 + 6h, possibly reflecting <strong>the</strong> antivascular effect<br />
of chemo<strong>the</strong>rapy. Fur<strong>the</strong>rmore, in <strong>the</strong> B + CP group, pts with higher BL CTC and no<br />
peak in CEC levels at C1 + 6h progressed at 6 months. Analysis of association of<br />
markers with BOR and PFR for <strong>the</strong> two regimens is ongoing.<br />
Conclusions: Measuring CEC, CTC and CEP is feasible in NSCLC. Detailed analyses<br />
will be presented. The clinical value of <strong>the</strong>se markers for predicting response to<br />
bevacizumab in advanced ns-NSCLC patients warrants fur<strong>the</strong>r investigation.<br />
ix406 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
CEC (cells/4mL)<br />
Median (range)<br />
C1<br />
cells/4mL<br />
C1 + 6h<br />
cells/4mL change<br />
from BL<br />
C2<br />
cells/4mL change<br />
from BL<br />
C3<br />
cells/4mL change<br />
from BL<br />
CTC (cells/7.5mL)<br />
n (%)<br />
C1<br />
< 2 cells/7.5mL<br />
≥ 2 cells/7.5mL<br />
C2<br />
< 2 cells/7.5mL<br />
≥ 2 cells/7.5mL<br />
C3<br />
< 2 cells/7.5mL<br />
≥ 2 cells/7.5mL<br />
CEP (133+ CEP/<br />
1000 CD34+)<br />
Median (range)<br />
B + CP B + E<br />
Progression/death at 6<br />
Progression/death at 6 months months<br />
No<br />
(n = 28)<br />
(n = 27)<br />
24 (4–464)<br />
(n = 9)<br />
104 (12–632) 36<br />
(-336–72)<br />
(n = 24)<br />
24 (8–308)<br />
(n = 23)<br />
0 (-376–268)<br />
(n = 26)<br />
34 (0–228)<br />
(n = 25)<br />
4 (-440–208)<br />
No<br />
(n = 28)<br />
(n = 28)<br />
24 (85.7%)<br />
4 (14.3%)<br />
(n = 24)<br />
21 (87.5%)<br />
3 (12.5%)<br />
(n = 25)<br />
22 (88.0%)<br />
3 (12.0%)<br />
No<br />
(n = 12)<br />
C1 (n = 12)<br />
1.8 (0.0–4.3)<br />
C1 + 6h (n = 8)<br />
1.5 (0.0–7.8)<br />
C2 (n = 12)<br />
0.3 (0.0–5.8)<br />
C3 (n = 12)<br />
1.2 (0.0–8.7)<br />
Yes<br />
(n = 19)<br />
(n = 18)<br />
32 (0–184)<br />
(n = 7)<br />
28 (0–120) -16<br />
(-172–100)<br />
(n = 15)<br />
20 (0–216)<br />
(n = 14)<br />
-4 (-176–196)<br />
(n = 10)<br />
30 (0–464)<br />
(n = 10)<br />
10 (-172–444)<br />
Yes<br />
(n = 19)<br />
(n = 17)<br />
8 (47.1%)<br />
9 (52.9%)<br />
(n = 16)<br />
10 (62.5%)<br />
6 (37.5%)<br />
(n = 11)<br />
7 (63.6%)<br />
4 (36.4%)<br />
Yes<br />
(n = 9)<br />
(n = 9)<br />
1.6 (0.0–5.9)<br />
(n = 6)<br />
0.0 (0.0–0.5)<br />
(n = 7)<br />
0.0 (0.0–3.3)<br />
(n = 4)<br />
0.0 (0.0–1.5)<br />
No<br />
(n = 13)<br />
(n = 12)<br />
28 (8–<br />
108)<br />
– –<br />
(n = 12)<br />
34 (4–<br />
180)<br />
(n = 11)<br />
-4 (-72–<br />
160)<br />
(n = 11)<br />
28 (0–76)<br />
(n = 10)<br />
0 (-100–<br />
52)<br />
Yes<br />
(n = 8)<br />
(n = 8)<br />
44 (4–96)<br />
(n = 8)<br />
34 (0–<br />
356)<br />
(n = 8)<br />
-4 (-76–<br />
316)<br />
(n = 7)<br />
76 (0–<br />
244)<br />
(n = 7)<br />
28 (-20–<br />
No<br />
192)<br />
Yes<br />
(n = 13) (n = 8)<br />
(n = 12) (n = 8)<br />
10 7 (87.5%)<br />
(83.3%)<br />
2 (16.7%)<br />
1 (12.5%)<br />
(n = 11) (n = 8)<br />
9 (81.8%) 5 (62.5%)<br />
2 (18.2%) 3 (37.5%)<br />
(n = 12) (n = 6)<br />
12 (100%) 4 (66.7%)<br />
0 (0%) 2 (33.3%)<br />
No Yes<br />
(n = 7) (n = 4)<br />
(n = 7)<br />
0.0 (0.0–<br />
2.1)<br />
– –<br />
(n = 6)<br />
0.4 (0.0–<br />
3.2)<br />
(n = 7)<br />
0.7 (0.0–<br />
3.7)<br />
(n = 4)<br />
5.0 (0.2–<br />
7.1)<br />
(n = 4)<br />
0.3 (0.0–<br />
1.1)<br />
(n = 3)<br />
1.8 (0.0–<br />
3.4)<br />
Disclosure: H. Senellart: Financial Interest: Advisory Board. E. Dansin: Attended<br />
advisory boards for Roche, Lilly and Boehringer-Ingelheim. B. Besse: Received<br />
research grants from Roche. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1241P A PLASMA PROTEOMIC SIGNATURE PREDICTS OUTCOMES<br />
IN A PHASE 3 STUDY OF GEMCITABINE (G) + CISPLATIN (C)<br />
± SORAFENIB IN FIRST LINE STAGE IIIB OR IV NSCLC<br />
J.F. Vansteenkiste 1 , L. Paz-Ares 2 , T.Q.G. Eisen 3 , D. Heigener 4 , W. Eberhardt 5 ,<br />
M. Thomas 6 , C. Zhou 7 , A. Santoro 8 , C. Lathia 9 , H. Roder 10<br />
1 Respiratory Oncology Unit (Pulmonology), University Hospital Gasthuisberg,<br />
Leuven, BELGIUM, 2 Instituto de Investigaciones Biomédicas de Sevilla,<br />
University Hospital Virgen del Rocío, Seville, SPAIN, 3 Oncology, University of<br />
CambridgeAddenbrooke’s Hospital, Cambridge, UNITED KINGDOM, 4 Medical<br />
Oncology, Krankenhaus Großhansdorf, Grosshansdorf, GERMANY, 5 Department<br />
of Medical Oncology, West German Cancer Center, University Hospital Essen,<br />
Essen, GERMANY, 6 Department of Thoracic Oncology, University of Heidelberg,<br />
Heidelberg, GERMANY, 7 Lung Cancer Institute, Shanghai Pulmonary Hospital,<br />
Shanghai, CHINA, 8 Medical Oncology, Istituto Clinico Humanitas, Rozzano,<br />
ITALY, 9 Clinical Sciences, Bayer HealthCare Pharmaceuticals, Montville, NJ,<br />
UNITED STATES OF AMERICA, 10 Research and Development, Biodesix, Inc,<br />
Boulder, CO, UNITED STATES OF AMERICA<br />
Introduction: Previously presented results from NExUS, a Phase 3 study of sorafenib<br />
in combination with G + C (GC) vs placebo + GC in first line NSCLC patients, showed<br />
no improvement in overall survival (OS) and a small statistically significant<br />
improvement in progression free survival (PFS) for sorafenib + GC. VeriStrat® (V),<br />
a proteomic test using Matrix Assisted Laser Desorption/Ionization Time of Flight<br />
Mass Spectrometry (MALDI-TOF MS), was used in <strong>the</strong> present study to classify<br />
baseline plasma samples from NExUS patients into V Good (VG) and V Poor<br />
(VP) categories based on a pre-specified 8-peak mass spectral signature. The<br />
overall objective was to determine if V status was predictive of sorafenib + GC<br />
clinical activity.<br />
Methods: Patients with Stage IIIB or IV NSCLC, ECOG PS = 0 or 1, were<br />
randomized 1:1 to receive G (1250 mg/m 2 on Days 1 and 8) and C (75 mg/m 2 on<br />
Day 1) for up to six 21-day cycles, in combination with sorafenib 400 mg bid or<br />
placebo. V status was determined for 403 of 774 non-squamous patients. Analyses<br />
were performed blinded to clinical outcomes. PFS was compared between treatment<br />
arms within VP and VG groups. Hazard ratios (HR) and Kaplan-Meier curves were<br />
evaluated and multivariate analyses performed.<br />
Results: Consistent with previous reports, approximately 30% of subjects had VP<br />
status. PFS and HRs in treatment arms in patients with and without assigned V<br />
status were similar. VG status was associated with a longer PFS in placebo + GC<br />
patients (HR = 0.51, log-rank p
1243P IDENTIFICATION OF MICRORNA (MIRNA) SIGNATURES FOR<br />
RESPONSE AND SURVIVAL IN NON-SMALL CELL LUNG<br />
CANCER (NSCLC) PATIENTS (PTS) TREATED WITH<br />
CISPLATIN-VINORELBINE (CV): A ELCWP STUDY<br />
I. Cstoth 1 , T. Berghmans 1 , L. Willems 2 , M. Paesmans 3 , L. Ameye 3 , J. Lafitte 4 ,<br />
A. Scherpereel 4 , A. Cortot 4 , C. Mascaux 1 , J. Sculier 5<br />
1 Thoracic Oncology, Institut Jules Bordet, Brussels, BELGIUM, 2 Molecular and<br />
Cellular Biology Laboratory, Gemboux Agro-Bio Tech, Gembloux, BELGIUM,<br />
3 Data Centre, Institute Jules Bordet, Brussels, BELGIUM, 4 Pneumology, CHU<br />
Lille, Lille, FRANCE, 5 Intensive Care and Thoracic Oncology, Institut Jules<br />
Bordet, Brussels, BELGIUM<br />
Background: Clinical variables, like stage and performance status (PS), have<br />
predictive and prognostic values in advanced NSCLC pts treated with chemo<strong>the</strong>rapy,<br />
but not on an individual basis. As a secondary aim of a prospective study, we<br />
assessed <strong>the</strong> predictive (for response) and prognostic (for survival) values of miRNA<br />
expression in NSCLC pts treated by C (60 mg/m 2 D1) and V (25 mg/m 2 , D1 + 8) in<br />
1 st line chemo<strong>the</strong>rapy.<br />
Methods: During <strong>the</strong> diagnostic bronchoscopy, a tumour biopsy was lysed into<br />
Tripure Isolation Reagent (Roche Diagnostics) on ice, snap frozen and stored at -80°<br />
C. miRNA expression was assessed using TaqMan Low Density Arrays (756 human<br />
miR panel, Applied Biosystems) and normalized using <strong>the</strong> delta delta CT method to<br />
RNU48 (SNORD48) CT value for every sample. Survival was measured from <strong>the</strong><br />
registration date and response by WHO criteria.<br />
Results: From 180 pts screened between 04/2009 and 11/2011, 38 pts were eligible<br />
including 27 males, 26 pts with Karnofsky PS of 80-100, 20 adenocarcinomas and 30<br />
stage IV. Sixteen partial responses (43%) were observed. After stepwise selection, a<br />
two miRNA (miR-149 and miR-375) predictive signature for response to CV (AUC<br />
0.90, sensitivity 88%, negative predictive value 89%) which was related to<br />
progression-free survival (medians 12 and 17 months (ms), respectively, p = 0.047).<br />
Using a linear combination of <strong>the</strong> miRNA CT values with Cox’s regression<br />
coefficients as weights, a prognostic score for survival including 4 miRNA (miR-200c,<br />
miR-424, miR-29c and miR-124) was identified. The signature distinguished pts with<br />
good (n = 18) and poor (n = 20) prognosis with median survival of 47.3 months<br />
(95% CI 29.8-52.4) and 15.5 months (95% CI 9.1-22.8), respectively (p C SNP, 3R G > C SNP) and<br />
methylenetetrahydrofolate reductase (MTHFR) (C677T, A1298C). Progression-free<br />
survival (PFS) and overall survival (OS) were evaluated according to each genotype.<br />
Results: 103 patients with stage III-IV NSCLC (47% adenocarcinoma, 41%<br />
squamous cell carcinoma, 12% NOS) receiving platinum-based chemo<strong>the</strong>rapy were<br />
eligible (14 patients with stage I-II were excluded). The median PFS was significantly<br />
longer in patients with C/T or T/T genotypes in codon 118 in ERCC1: 13 months<br />
(m) and 10 m, respectively, as compared to 6 m for <strong>the</strong> C/C patients (p = 0.034).<br />
Patients with ERCC1 C/T or T/T genotypes had a trend to longer median OS (20 m)<br />
than those C/C (10.5 m; p = 0.1). Subgroup analysis revealed that ERCC1 C/T or T/T<br />
genotypes were associated with increased PFS in male (p = 0.005), smokers (p =<br />
Annals of Oncology<br />
0.036) and age
Annals of Oncology<br />
1246P RANDOMISED PHASE II STUDY OF AXITINIB OR<br />
BEVACIZUMAB COMBINED WITH PACLITAXEL/<br />
CARBOPLATIN (PAC/CARB) AS FIRST-LINE THERAPY FOR<br />
PATIENTS (PTS) WITH ADVANCED NON–SMALL CELL LUNG<br />
CANCER (NSCLC)<br />
C. Twelves 1 , E. Chmielowska 2 ,L.Havel 3 , S. Popat 4 , A. Swieboda-Sadlej 5 ,<br />
P. Sawrycki 6 , P. Bycott 7 , A. Niethammer 8 , P. De Besi 9 , J.H. Schiller 10<br />
1 Clinical Cancer Research Groups, Leeds Institute of Molecular Medicine & St<br />
James’s Institute of Oncology, Leeds, UNITED KINGDOM, 2 Onkologii, Oddzial<br />
Kliniczny Onkologii Centrum Onkologii Bydgoszcz, Bydgoszcz, POLAND,<br />
3 Pneumology- Budinova 2, Fakultni Nemocnice Na Bulovce, Phaha, CZECH<br />
REPUBLIC, 4 Department of Medicine, Royal Marsden HospitalNHS Foundation<br />
Trust, London, UNITED KINGDOM, 5 Oncology, Samodzielny Publiczny Centralny<br />
Szpital Kliniczny, Warsaw, POLAND, 6 Oddzial Chemioterapii Nowotworow,<br />
Wojewodzki Szpital Zespolony, Torun, POLAND, 7 Biostatistics, Pfizer Oncology,<br />
San Diego, UNITED STATES OF AMERICA, 8 Pfizer Global Research and<br />
Development, Pfizer Oncology, San Diego, UNITED STATES OF AMERICA, 9 Clinical<br />
Oncology, Pfizer Italia Srl, Milano, ITALY, 10 Hematology/Oncology, University of<br />
Texas Southwestern Medical Center, Dallas, UNITED STATES OF AMERICA<br />
Background: Axitinib is a potent and selective second-generation inhibitor of<br />
vascular endo<strong>the</strong>lial growth factor receptors 1, 2, and 3, with promising single-agent<br />
activity in advanced NSCLC. This study evaluated <strong>the</strong> efficacy and safety of axitinib<br />
+ pac/carb vs bevacizumab + pac/carb in advanced non-squamous NSCLC.<br />
Methods: Pts with stage IIIB with pleural effusion or stage IV non-squamous<br />
NSCLC without prior systemic <strong>the</strong>rapy (except adjuvant <strong>the</strong>rapy >12 mo prior to<br />
enrolment) were stratified by prior adjuvant <strong>the</strong>rapy and gender, and randomised 1:1<br />
to receive axitinib (5 mg twice daily) or bevacizumab (15 mg/kg every 3 wks [q3w])<br />
plus pac/carb (200mg/m 2 /AUC 6 mg/mL x min q3w). The primary endpoint was<br />
progression-free survival (PFS).<br />
Results: Pt baseline characteristics in <strong>the</strong> axitinib (n = 58) and bevacizumab (n = 60)<br />
arms were well balanced: 38% were female, 31% vs 30% were current smokers,<br />
respectively. Median PFS (95% confidence interval [CI]) was 5.7 mo (4.1–7.5) in <strong>the</strong><br />
axitinib vs 6.1 mo (4.2–8.7) in <strong>the</strong> bevacizumab arms (hazard ratio [HR] 1.09, 95% CI<br />
0.68–1.76; 1-sided stratified P = 0.64). Median overall survival (95% CI) was 10.6 mo (7.5–<br />
16.4) and 13.3 mo (10.4–17.6), respectively, in <strong>the</strong> axitinib vs bevacizumab arms (HR<br />
1.12, 95% CI 0.74–1.69; 1-sided stratified P = 0.70). Objective response rates (95% CI)<br />
were 29.3% (18.1–42.7) and 43.3% (30.6–56.8) and duration of response was 4.4 and 7.0<br />
mo for <strong>the</strong> axitinib and bevacizumab arms, respectively. Common treatment-emergent<br />
all-causality adverse events (AEs) with axitinib + pac/carb vs bevacizumab + pac/carb,<br />
respectively, were diarrhoea (47% vs 34%), alopecia (36% vs 46%), hypertension (43% vs<br />
42%), decreased appetite (43% vs 22%), fatigue (34% vs 39%), nausea (36% vs 32%), and<br />
neutropenia (31% vs 27%). Neutropenia was <strong>the</strong> most common grade 3/4 AE in both<br />
treatment arms. More pts in <strong>the</strong> axitinib arm discontinued treatment due to AEs than in<br />
<strong>the</strong> bevacizumab arm (41% vs 31%, respectively).<br />
Conclusions: Axitinib + pac/carb did not improve efficacy compared with bevacizumab<br />
+ pac/carb, and was less well tolerated in pts with advanced non-squamous NSCLC.<br />
Disclosure: C. Twelves: I am an advisor/board member for Pfizer and Genentech/<br />
Roche, received honorarium from Pfizer, and honorarium from Speaker’s Bureau<br />
from Genentech/Roche. S. Popat: I am a consult for Roche and Pfizer and received<br />
honoraria from Roche and Pfizer. P. Bycott: I am a full-time employee of Pfizer Inc<br />
and own Pfizer stocks. A. Niethammer: I am a full-time employee of Pfizer and own<br />
Pfizer stocks. P. De Besi: I am a conusltat for Pfizer Italia Srl. J.H. Schiller: I am a<br />
consultant for Pfizer and Genentech and received grants/research support from<br />
Pfizer and Genentech. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1247P RANDOMISED PHASE II TRIAL OF ORAL VINORELBINE (N)<br />
AND CISPLATIN (P) OR PEMETREXED AND C (PC) IN FIRST<br />
LINE ADVANCED NON SQUAMOUS (NSCC) NON SMALL<br />
CELL LUNG CANCER (NSCLC) PATIENTS (PTS).<br />
NAVOTRIAL01: FINAL RESULTS<br />
E.H. Tan 1 ,L.Havel 2 , M.J. Krzakowski 3 , J. Kollmeier 4 , R. Gervais 5 , E. Dansin 6 ,<br />
M. Serke 7 , S. Malassé 8 , F. Biville-Hedouin 9 , J. Bennouna 10<br />
1 Medical Oncology, National Cancer Institute, Singapore, SINGAPORE,<br />
2 Pneumology- Budinova 2, Fakultni Nemocnice Na Bulovce, Phaha, CZECH<br />
REPUBLIC, 3 Lung & Thoracic Tumors Dept, MSC Memorial Cancer Centre and<br />
Institute Maria Sklodowska Curie, Warsaw, POLAND, 4 Oncology/pneumology,<br />
Helios Clinic Emil von Behring, Berlin, GERMANY, 5 Pneumology, Centre François<br />
Baclesse, Caen, FRANCE, 6 Pneumology, Centre Oscar Lambret, Lille, FRANCE,<br />
7 Pneumology, Lungenklinik Hemerdes Deutschen<br />
Gemeinschafts-Diakonieverbandes GmbH, Hemer, GERMANY, 8 Statistical<br />
Department, Institut de Recherche Pierre Fabre, Boulogne Billancourt, FRANCE,<br />
9 Medical Affairs Oncology, Institute de Recherche Pierre Fabre, Boulogne<br />
Billancourt Cedex, FRANCE, 10 Oncology/ Pneumology, Institut de Cancerologie<br />
de l’Ouest-site René Gauducheau, Nantes, FRANCE<br />
Background: Individualized treatments in NSCLC are now based on molecular<br />
and/or histological data. This randomized trial (2/1) was set up to assess <strong>the</strong><br />
efficacy of NC compared to PC for pts with nSCC. The primary end-point was<br />
disease control rate (DCR) including overall response rate (ORR) and stable<br />
disease (SD).<br />
Methods: Pts received N60-80 mg/m 2 D1, D8 + C80 mg/m 2 D1 or P500 mg/m 2 +<br />
C75 mg/m 2 D1 for 4 cycles q3w; pts with DCR received single agent continuation<br />
maintenance (CM) until progression or toxicity.<br />
Results: From 10/09 to 02/11, 151 pts were treated with NC or PC.<br />
ITT = 151<br />
NC<br />
n = 100<br />
PC<br />
n=51<br />
Male/Stage IV (%) 62.0/87.0 64.7/88.2<br />
Median age (y, range) 61.0 (38.4-75.1) 63.8 (40.3-75.5)<br />
Combination: (%) ITT(95% CI)<br />
DCR 75.0 (65.3-83.1) 74.5 (60.4-85.7)<br />
ORR 21.0 (13.5-30.3) 23.5 (12.8-37.5)<br />
Combination + CM:(%) ITT (95% CI) n= 53 n = 33<br />
DCR 75 (65.3-83.1) 76.5 (62.5-87.2)<br />
ORR 24 (16.0-33.6) 31.4 (19.1-45.9)<br />
Median PFS ITT (m,range) 4.2 (3.6-4.7) 4.2 (3.2-5.6)<br />
PFS ITT at 6/12/18m (%) 33.0/10.3/5.5 27.5/7.4/2.5<br />
Median OS ITT (m,range) 10.6 (7.8-12.1) 10.8 (7.0-14.5)<br />
Related toxicities G3/4 (%pts) NC/PC during Combination: anemia 9.0(G3)/8.2,<br />
leucopenia 26.0/10.2, neutropenia 44.0/18.3, febrile neutro 2.0/2.0, thrombocytopenia<br />
0/6.1, fatigue(G3) 7.0/3.9, hyperglycemia 4.0/7.8, nausea(G3) 5.0/0, vomiting(G3) 7.0/<br />
2.0, stomatitis(G3) 0/2.0, pneumonia(G3) 0/2.0, deep vein thrombosis(G3) 0/2.0,<br />
pulmonary embolism(G4) 0/2.0. During Maintenance: anemia 5.0/4.1, leucopenia<br />
2.0/10.2, neutropenia 11.0/20.4, febrile neutro 3.8/0, fatigue (G3) 3.8/0, stomatitis<br />
(G3) 1.9/ 3.0, pain 3.8/6.0, Respiratory disorders 0/4.0, deep vein thrombosis (G3)0/<br />
2.0. Deaths potentially related to CT 2/1.<br />
Conclusions: NC and PC had similar efficacy. In <strong>the</strong> present economic context, <strong>the</strong><br />
acquisition cost of <strong>the</strong> two platinum based doublets should be considered in <strong>the</strong><br />
treatment decision making of pts with advanced nSCC NSCLC.<br />
Disclosure: S. Malassé: Statistician of <strong>the</strong> study Employment for <strong>the</strong> sponsor. F.<br />
Biville-Hedouin: Medical Project Manager of <strong>the</strong> study Employment for <strong>the</strong> sponsor.<br />
All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1249P FINAL RESULTS OF A RANDOMIZED, DOUBLE-BLIND<br />
PHASE II STUDY TO COMPARE NITROGLYCERIN (N) PLUS<br />
ORAL VINORELBINE (NVBO) PLUS CISPLATIN (C) WITH<br />
PLACEBO (P) PLUS NVBO PLUS C IN PATIENTS (PTS) WITH<br />
STAGE IIIB/IV NON-SMALL CELL LUNG CANCER (NSCLC)<br />
M. Reck 1 , A. Meyer 2 , D. Hartwigsen 3 , C. Schaeper 4 , R. Skock-Lober 5 , A. Bier 6 ,<br />
G. Huebner 7 , U. Gereke 8 , C. Rose 9 , C.P. Held 10<br />
1 Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, GERMANY, 2 Klinik<br />
Fuer Pneumologie, Kliniken Maria Hilf Moenchengladbach, Moenchengladbach,<br />
GERMANY, 3 Medizinische Klinik I, Malteser Krankenhaus St. Franziskus -<br />
Hospital Flensburg, Flensburg, GERMANY, 4 Klinik fuer Innere Medizin B,<br />
Universitaetsmedizin Greifswald, Greifswald, GERMANY, 5 Klinik fuer<br />
Pneumologie, Helios Klinikum Schwerin, Schwerin, GERMANY, 6 Zentrum fuer<br />
Innere Medizin, Abteilung fuer Pneumologie, Universitaetsklinikum Rostock,<br />
Rostock, GERMANY, 7 Klinik Oldenburg, Klinik fuer Innere Medizin, Sana Kliniken<br />
Ostholstein, Oldenburg, GERMANY, 8 Klinik fuer Haematologie und Onkologie,<br />
Hanse-Klinikum Stralsund, Stralsund, GERMANY, 9 Onkologie, Pierre Fabre<br />
Pharma GmbH, Freiburg, GERMANY, 10 Clinical Science, GMIHO mbH, Berlin,<br />
GERMANY<br />
Background: Yasuda (JCO 2006) reported increased ORR, TTP and OS when adding<br />
N to <strong>the</strong> combination of i.v. vinorelbine (NVBiv) + C in pts with stage IIIB/IV<br />
NSCLC probably due to better drug delivery based on changed vascular tonus.<br />
NVBo and NVBiv have comparable efficacy with a more convenient administration<br />
of <strong>the</strong> oral form. Main study objective was <strong>the</strong> confirmation of <strong>the</strong> Asian results in a<br />
Caucasian population.<br />
Methods: In <strong>the</strong> experimental arm pts received N 25 mg D-3 to D2 + NVBo (60) 80<br />
mg/m 2 D1, D8 + C 80 mg/m 2 D1, q3w; in <strong>the</strong> control arm pts received P D-3 to D2<br />
+ NVBo (60) 80 mg/m 2 D1, D8 + C 80 mg/m 2 D1, q3w. Treatment continued until<br />
PD, unacceptable toxicity (tox) or pts wish to discontinue treatment. The primary<br />
endpoint was ORR, secondary endpoints included OS, PFS and safety. To show an<br />
ORR-increase from 40 to 70% with a power of 0.80 and a two-side alpha of 0.05 <strong>the</strong><br />
planned sample size was 100 pts.<br />
Results: From 10/07 to 05/10, 68 pts were randomised to <strong>the</strong> N-arm (35 pts) or<br />
P-arm (33 pts). 66 pts were treated (N-arm: 34 pts, P-arm: 32 pts). The study was<br />
stopped prematurely due to lack of recruitment.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds409 | ix409
N-arm<br />
n=34<br />
P-arm<br />
n=32<br />
All<br />
n=66<br />
Male (%) 76.5 68.8 72.7<br />
Median age<br />
(y, range)<br />
63.0 (36-82) 62.5 (33-73) 62.5 (33-82)<br />
Median Karnofsky<br />
(%, range)<br />
90 (70-100) 90 (70-100) 90 (70-100)<br />
Smoker (%)<br />
non/former/current<br />
8.8/41.2/50.0 15.6/40.6/43.8 12.1/40.9/47.0<br />
Squamous/adeno (%) 55.9/44.1 46.9/34.4 51.5/39.4<br />
IIIB/IV/local relapse (%) 32.4/64.7/2.7 34.4/65.6/0 33.3/65.2/1.5<br />
Median N cycles<br />
(n, range)<br />
4.5 (1-8) 4.0 (1-6) 4.0 (1-8)<br />
ORR ITT (%)<br />
35.3 18.8 27.3<br />
95%CI<br />
(19.7-53.5)<br />
p = 0.171<br />
(7.2-36.4)<br />
ORR eval (%)<br />
37.5 22.2 30.5<br />
95%CI (n = 32/27/59)<br />
(21.1-56.3)<br />
p = 0.262<br />
(8.6-42.3)<br />
DCR ITT (%) 61.8 53.1 57.6<br />
Median TTP (mo) 4.7 5.0 4.8<br />
Median OS (mo) 11.0 12.1 11.5<br />
Tox G3-4 >5% (%pts): N-arm: neutropenia 32.3, leucopenia 20.6, anemia 14.7, nausea<br />
8.8 (G3), fatigue 5.9 (G3), pneumonia 5.9 (G3). P-arm: neutropenia 43.8, leucopenia<br />
25.0, fatigue 9.4 (G3), nausea 9.4 (G3), anemia 6.3, vomiting 6.3. 1 case of febrile<br />
neutropenia G3 (N-arm). 2 deaths potentially related to chemo<strong>the</strong>rapy (1 per arm).<br />
Conclusions: The oral formulation of Vinorelbine + C achieved in both arms a high<br />
level of efficacy (all pts: ORR 27.3, DCR 57.6, TTP 4.8, OS 11.5). Despite <strong>the</strong><br />
premature discontinuation and low sample size per group, <strong>the</strong> results seem to<br />
confirm previous data reported in Asian patients, with an ORR numerically higher in<br />
<strong>the</strong> N-arm but without significance.<br />
Disclosure: M. Reck: Honoraria for lectures: Lilly, Roche, AstraZeneca,<br />
Daiichi-Sankyo Advisory Board: Lilly, Roche, AstraZeneca, Daiichi-Sankyo, BMS,<br />
Pfizer, Genentech. C. Rose: Employed by Pierre Fabre Pharma GmbH. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
1250P DISRUPT: A RANDOMIZED PHASE 2 TRIAL OF OMBRABULIN<br />
(AVE8062) COMBINED WITH A TAXANE-PLATINUM REGIMEN<br />
IN THE FIRST-LINE TREATMENT OF METASTATIC<br />
NON-SMALL CELL LUNG CANCER (NSCLC)<br />
J. von Pawel 1 , V. Gorbounova 2 , M. Reck 3 , D. Kowalski 4 , A. Allard 5 , M. Chadjaa 6 ,<br />
A. Rey 6 , J. Bennouna 7 , F. Grossi On Behalf of The Disrupt Investigators 8<br />
1 Department of Medicine III, Asklepios Fachkliniken, Muenchen, GERMANY,<br />
2 Oncology, Cancer Research Centre, Moscow, RUSSIAN FEDERATION,<br />
3 Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, GERMANY,<br />
4 Oncology, Maria Sklodowska-Curie Memorial Cancer Centre, Warsaw,<br />
POLAND, 5 Bio Stats, Sanofi, Chilly-Mazarin, FRANCE, 6 Clinical, Sanofi,<br />
Vitry-sur-Seine, FRANCE, 7 Medical Oncology, Institut de Cancérologie de<br />
l’Ouest, Herblain, FRANCE, 8 Lung Cancer Unit, National Institute for Cancer<br />
Research, Genova, ITALY<br />
Introduction: Ombrabulin is a vascular disrupting agent and analogue of<br />
combretastatin A4 that damages established tumor vasculature, which causes tumor<br />
necrosis and regression. DISRUPT (NCT01263886) evaluated whe<strong>the</strong>r adding<br />
ombrabulin to a taxane-platinum doublet in <strong>the</strong> first-line setting improves outcomes<br />
in patients with metastatic NSCLC.<br />
Methods: Patients (≥18 yrs of age, ECOG PS 0–1, stage IV) were randomized 1:1 to<br />
ei<strong>the</strong>r ombrabulin 35 mg/m 2 or placebo (Pbo) on day 1 followed by a taxane-platinum<br />
regimen on day 2 (docetaxel 75 mg/m 2 + cisplatin 75 mg/m 2 or paclitaxel 200 mg/m 2<br />
+ carboplatin AUC 6), every 3 weeks. Randomization was stratified by histology<br />
(squamous/nonsquamous) and taxane-platinum regimen. Treatment was continued<br />
up to 6 cycles, or until unacceptable toxicity, disease progression, or consent<br />
withdrawal. The primary endpoint was progression-free survival (PFS) (stratified<br />
log-rank analysis; one-sided significance level 0.2). The study had 92% power to detect<br />
a 33% risk reduction in <strong>the</strong> hazard rate for progression (HR 0.67). Secondary<br />
endpoints included overall survival (OS), response rate (RR), and safety.<br />
Results: From February 2011 to January <strong>2012</strong>, a total of 176 patients were<br />
randomized (n = 88 in each group). Groups were balanced in terms of baseline<br />
characteristics. Overall, <strong>the</strong> median age was 62 yrs (range, 32 – 84), 76% were male,<br />
66% were nonsquamous and 34% squamous, 52% received paclitaxel-carboplatin and<br />
48% docetaxel-cisplatin. PFS was analyzed after 124 events (61 ombrabulin; 63 Pbo);<br />
median follow-up was 8 months. PFS was not significantly improved in <strong>the</strong><br />
ombrabulin group versus Pbo (median 5.7 vs 5.5 months, respectively; HR 0.95; 60%<br />
CI 0.81–1.11; one-sided p = 0.39). Overall RR were similar (ombrabulin 32%; Pbo<br />
31%). Median OS was 11.0 months in both arms. Safety profiles were comparable;<br />
rates of grade 3-4 adverse events were 57% for ombrabulin and 52% for Pbo.<br />
Annals of Oncology<br />
Conclusions: This randomized phase 2 trial of ombrabulin combined with a<br />
platinum-taxane regimen did not meet <strong>the</strong> primary endpoint of improving PFS<br />
compared with Pbo in <strong>the</strong> first-line treatment of metastatic NSCLC. Study sponsored<br />
by Sanofi.<br />
Disclosure: J. von Pawel: Member of Sanofi Steering Committee. V. Gorbounova:<br />
Member of advisory board: Novartis and Pfizer Honoraria for lectures: Hoffman La<br />
Roche. M. Reck: Ad board membership: Lilly, Hoffmann-La Roche, Daiichi-Sankyo,<br />
Pfizer, AstraZeneca, BMS Honoraria for lectures: Lilly, Hoffmann-La Roche,<br />
Daiichi-Sankyo, AstraZeneca. A. Allard: Sanofi employee. M. Chadjaa: Sanofi employee<br />
and stock holder. A. Rey: Sanofi employee and stock held. J. Bennouna: Advisory<br />
board: Sanofi-Aventis. F. Grossi On Behalf of The Disrupt Investigators: Membership<br />
on advisory board: Sanofi. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1251P FRONT-LINE CHEMOTHERAPY WITH OR WITHOUT<br />
NGR-HTNF IN NON-SMALL CELL LUNG CANCER (NSCLC)<br />
V. Gregorc 1 , N. Zilembo 2 , F. Grossi 3 ,T.DePas 4 , F. Pietrantonio 2 , M. Giovannini 4 ,<br />
G. Rossoni 1 , A. Bulotta 1 , A. Lambiase 5 , C. Bordignon 5<br />
1 Oncologia, IRCCS San Raffaele, Milano, ITALY, 2 Department of Oncology,<br />
IRCCS Fondazione Istituto Nazionale dei Tumori, Milan, ITALY, 3 Lung Cancer<br />
Unit, Istituto Nazionale per la Ricerca sul Cancro, Genoa, ITALY, 4 Unit of<br />
Respiratory Tract and Sarcomas, Istituto Europeo di Oncologia, Milan, ITALY,<br />
5 Clinical Development, MolMed, Milan, ITALY<br />
Background: NGR-hTNF (asn-gly-arg-human tumor necrosis factor) is a selective<br />
vascular targeting agent able to improve intratumoral chemo<strong>the</strong>rapy uptake.<br />
Methods: After stratification by histology (nonsquamous or squamous) and PS (0 or<br />
1), previously untreated patients (pts) with advanced NSCLC were randomly<br />
assigned to receive cisplatin 80 mg/m 2 /d1 plus ei<strong>the</strong>r pemetrexed 500 mg/m 2 /d1<br />
(nonsquamous) or gemcitabine 1,250 mg/m 2 /d1 + 8 (squamous) q3w for 6 cycles<br />
with (arm A) or without (arm B) NGR-hTNF 0.8 µg/m 2 /d1 q3w given until<br />
progression. Progression-free survival (PFS) was primary endpoint of this phase 2<br />
trial (β = 20%, α = 20%, n = 102). Secondary endpoints included adverse events (AEs),<br />
overall survival (OS), and response rate (RR).<br />
Results: Baseline characteristics in arm A (n = 61) v B (n = 58): median age 62 v 63<br />
years; male 36 v 38; PS of 1 22 v 22; squamous 17 v 16; nonsmokers 19 v 14; EGFR<br />
mutations 5 v 5. For <strong>the</strong> nonsquamous stratum, 295 cycles were given in A (mean<br />
6.9; range 1-18) and 192 in B (4.8; 1-6), while for <strong>the</strong> squamous stratum, 95 in A<br />
(6.3; 1-24) and 49 in B (3.5; 1-6). The rates of grade 3 to 4 AEs were comparable in<br />
arm A v B: neutropenia 14% v 17% and fatigue 7% v 11%. Nei<strong>the</strong>r grade 3 to 4 AEs<br />
related to NGR-hTNF nor bleeding in pts with squamous histology were noted. With<br />
a median follow-up of 16.4 months for all pts, median PFS was 5.8 v 5.6 months,<br />
1-year OS rate was 58% v 56%, and RR was 25% v 21% in arm A v B, respectively.<br />
For <strong>the</strong> nonsquamous stratum, trends toward higher 6-month PFS rates for arm A v<br />
B were noted in pts with PS 1 (65% v 33%), nonsmoking history (59% v 33%),<br />
younger age (64% v 30%), and EGFR mutations (75% v 25%). Similarly, in <strong>the</strong>se pts<br />
<strong>the</strong> 1-year OS rates were: PS 1 (60% v 56%), nonsmoking history (77% v 65%),<br />
younger age (75% v 63%), and EGFR mutations (100% v 50%). For <strong>the</strong> squamous<br />
stratum, median PFS was 5.6 v 4.3 months (HR = 0.71) and median OS was 14.2 v<br />
10.2 months (HR = 0.54) for arm A v B, respectively. In <strong>the</strong>se pts, RR was 36% for<br />
arm A and 23% for arm B, while median changes from baseline in target tumor size<br />
after 2, 4, and 6 cycles were -27%, -39%, and -33%, respectively for arm A, and -18%,<br />
-22%, and -14%, respectively for arm B.<br />
Conclusion: NGR-hTNF can be safely given with standard chemo<strong>the</strong>rapy and may<br />
have <strong>the</strong>rapeutic potential in squamous NSCLC<br />
Disclosure: A. Lambiase: Employment - MolMed. C. Bordignon: Employment -<br />
MolMed. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1252P ACTIVITY OF AFATINIB IN UNCOMMON EPIDERMAL<br />
GROWTH FACTOR RECEPTOR (EGFR) MUTATIONS IN<br />
LUX-LUNG 3, A PHASE III TRIAL OF AFATINIB OR<br />
CISPLATIN/PEMETREXED IN EGFR MUTATION-POSITIVE<br />
LUNG CANCER<br />
J.C. Yang 1 , M. Schuler 2 , N. Yamamoto 3 , K.J. O’Byrne 4 , V. Hirsh 5 , T.S.K. Mok 6 ,<br />
D. Massey 7 , V. Zazulina 8 , M. Shahidi 8 , L.V. Sequist 9<br />
1 Oncology, National Taiwan University Hospital, Taipei, TAIWAN, 2 Medicine, West<br />
German Cancer Center, University Duisburg-Essen, Essen, GERMANY,<br />
3 Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, JAPAN, 4 Oncology, St<br />
James’s Hospital, Dublin, IRELAND, 5 Oncology, McGill University Health Centre,<br />
Montreal, QC, CANADA, 6 Clinical Oncology, The Chinese University of Hong<br />
Kong, Hong Kong, CHINA, 7 Statistics, Boehringer Ingelheim, Bracknell, UNITED<br />
KINGDOM, 8 Clinical Research / Management, Boehringer Ingelheim, Bracknell,<br />
UNITED KINGDOM, 9 Medicine, Massachusetts General Hospital, Boston, MA,<br />
UNITED STATES OF AMERICA<br />
Background: Afatinib (A) is an irreversible ErbB family blocker of EGFR (ErbB1),<br />
HER2 (ErbB2) and ErbB4 with in vitro activity against activating and resistant EGFR<br />
mutations. LUX-Lung 3 demonstrated superiority of A vs cisplatin/pemetrexed (CP)<br />
ix410 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
in 345 treatment-naive pts with EGFR mutation-positive NSCLC; median<br />
progression-free survival (PFS) 11.1 vs 6.9 mo, HR 0.58, p = 0.0004 (ITT cohort) and<br />
13.6 vs 6.9 mo, HR = 0.47, p < 0.0001 for pts with common (Del19/L858R) mutations<br />
(n = 308). Here we present data from pts with uncommon EGFR mutations, detected<br />
by central EGFR screening assay (Theracreen29).<br />
Methods: All pts (n = 345) were stratified according to mutation (Del19, L858R,<br />
o<strong>the</strong>r) and randomized 2:1 to oral A 40 mg daily or IV CP (75 mg/m 2 + 500 mg/m 2<br />
q21 days up to 6 cycles) until progression. O<strong>the</strong>r mutations were categorized into 5<br />
groups: T790M, G719X, S768I, exon 20 insertions, L861Q; <strong>the</strong> first 3 groups<br />
included double mutant pts. PFS, best overall response and tumour shrinkage by<br />
independent review were described per pt within <strong>the</strong>se 5 groups.<br />
Results: Uncommon mutations comprised 10.7% (n = 37, A: 26, CP: 11) of <strong>the</strong> trial<br />
population. Breakdown into <strong>the</strong> 5 groups was: de novo T790M (A:11, CP:2), exon 20<br />
insertions (A:6, CP:3), G719X (A:3, CP:3), L861Q (A:3, CP:3), S768I (A:3, CP:0).<br />
Baseline imbalances between <strong>the</strong> A and CP arms were noted for smoking status<br />
(never smoker 65% vs 82%, respectively) and presence of brain (27% vs 0%) and<br />
liver metastases (27% vs 18%). Of 32 pts with target lesions, 19/23 on A and 8/9 on<br />
CP had measurable shrinkage. The small size of <strong>the</strong> uncommon mutation cohort, its<br />
molecular heterogeneity and numeric imbalances within genetic subgroups limited<br />
formal statistical analyses. Tumour response and prolonged PFS were noted in<br />
A-treated pts with L858R + T790M (1PR, 11.0 mo; 3SD, 9.6+ mo, 8.5 mo and 6.7<br />
mo); L861Q (1SD, 8.3 mo); G719X (1PR, 10.8 mo); S768I + L858R (1PR, 13.8+ mo);<br />
S768I (1PR, 19.2+ mo).<br />
Conclusions: RECIST responses and prolonged disease control were observed in pts<br />
with most types of uncommon EGFR mutations. The efficacy of A in uncommon<br />
EGFR mutations should be explored in larger cohorts in future studies.<br />
Disclosure: J.C. Yang: James Chih-Hsin Yang has received honorarium for speech<br />
and advisory roles from Astrazeneca, Roche, Pfizer, OSI. He was <strong>the</strong> advisor for<br />
Boehringer Ingelheim and Eli Lilly without payment. M. Schuler: Paid consultancy/<br />
advisory relationship with: Boehringer Ingelheim; Research funding from: Boehringer<br />
Ingelheim; Travel support from: Lilly. K.J. O’Byrne: Paid consultancy/advisory<br />
relationship with: Boehringer Ingelheim, Lilly Oncology; Honoraria from Boehringer<br />
Ingelheim, Lilly Oncology; Research funding from Boehringer Ingelheim; O<strong>the</strong>r<br />
remuneration from Boehringer Ingelheim, Lilly Oncology. V. Hirsh: Honoraria from<br />
<strong>the</strong> Boehringer Ingelheim Advisory Board. T.S.K. Mok: Paid consultancy/advisory<br />
relationship with and honoraria from: AstraZeneca, Roche, Eli Lilly, Merck Serono,<br />
Eisai, BMS, BeiGene, AVEO, Pfizer, Taiko, Boehringer Ingelheim; Research funding<br />
from: AstraZeneca. D. Massey: Employee of Boehringer Ingelheim. V. Zazulina:<br />
Employee of Boehringer Ingelheim. M. Shahidi: Employee of Boehringer Ingelheim.<br />
L.V. Sequist: Paid consultancy/advisory relationship with: Boehringer Ingelheim,<br />
Daiichi-Sankyo, Merrimack, Clovis and Celgene; Research funding from: Boehringer<br />
Ingelheim. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1253P DOES GEFITINIB RE-CHALLENGE OR TREATMENT BEYOND<br />
PROGRESSION (TBP) PROLONG SURVIVAL OF NSCLC<br />
PATIENTS? - REAL WORLD EVIDENCE FROM GEFITINIB<br />
TREATMENT RESPONDERS<br />
Y. Namba 1 , F. Imamura 2 , S. Morita 3 , M. Mori 1 , K. Komuta 4 , T. Kijima 5 ,<br />
Y. Nakazawa 1 , S. Yokota 1 , S. Yamamoto 4 , A. Kumanogoh 5<br />
1 Department of Thoracic Oncology, National Hospital Organization Toneyama<br />
National Hospital, Toyonaka, JAPAN, 2 Department of Thoracic Oncology, Osaka<br />
Medical Center for Cancer and Cardiovascular Diseases, Osaka, JAPAN,<br />
3 Biostatistics and Epidemiology, Yokohama City University Medical Center,<br />
Yokohama, JAPAN, 4 Department of Thoracic Oncology, Osaka Police Hospital,<br />
Osaka-City, JAPAN, 5 Department of Thoracic Oncology, Osaka University<br />
Graduate School of Medicine, Suita, JAPAN<br />
Background: After gefitinib was approved in July 2002, several patients have<br />
experienced long-term survival in <strong>the</strong> clinical setting. However, it is not yet clear<br />
which factor of treatment strategy is contributing to <strong>the</strong> long-term survival.<br />
Methods: We extracted information from medical records of advanced NSCLC<br />
patients with <strong>the</strong> following inclusion criteria: 1) Japanese patients who were<br />
diagnosed by October 2010 and treated with gefitinib after July 2002. 2) Performance<br />
status (PS) 0-2. 3) PR, CR, or long SD (6 months or more) by gefitinib. 4) Patients<br />
who had not received curative surgical operation or radiation <strong>the</strong>rapy. The primary<br />
objective was to evaluate <strong>the</strong> effects of treatment histories on Overall Survival (OS).<br />
We also conducted a “Dynamic Treatment Regimen Analysis (DTRA)” to identify<br />
<strong>the</strong> key treatment strategy contributing to long-term survival. DTRA included<br />
baseline clinical factors (sex, age, stage, histology, PS, smoking) and time-dependent<br />
clinical factors (PS, pretreatment).<br />
Results: A total of 335 NSCLC patient details were extracted. The mean age was 64.8<br />
years and 90.3% had adenocarcinoma histology. Sixty five patients experienced<br />
gefitinib re-challenge and 93 patients experienced gefitinib Treatment Beyond<br />
Progression (TBP). There was a statistical difference in OS between gefitinib<br />
re-challenge group and non re-challenge group (median OS was 1272 days vs 774<br />
days; p < 0.001), Comparison of gefitinib TBP group and non TBP group also<br />
showed statistical difference (median OS was 1016 days vs 797 days; p = 0.035). Next,<br />
a cox regression model to investigate potential factors showed that “gefitinib<br />
re-challenge” was a factor which significantly contributed to long-term OS (HR:<br />
0.515, 95%CI: 0.363-0.731; p = 0.0002) whereas “gefitinib TBP“ was not (HR: 0.787,<br />
95%CI: 0.571-1.084; p = 0.1427). We confirmed this result using DTRA, The DTRA<br />
strongly supported <strong>the</strong> significant contribution of <strong>the</strong> gefitinib re-challenge treatment<br />
strategy to longer OS time.<br />
Conclusion: This retrospective cohort that gefitinib re-administration may have a<br />
significant impact on OS in long surviving patients who experienced response to<br />
gefitinib.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1254P POOLED ANALYSIS OF CLINICAL OUTCOMES FOR<br />
PATIENTS WITH EGFR MUTATIONS IN NON-SMALL-CELL<br />
LUNG CANCER: AN UPDATE<br />
L. Paz-Ares 1 , D. Soulières 2 , B. Klughammer 3 , I. Bara 4 , J. Moecks 5 , T.S.K. Mok 6<br />
1 Oncology Service, Hospital Universtario Virgen del Rocío, Seville, SPAIN,<br />
2 Haematology and Medical Oncology, Centre Hospitalier de l’Université de<br />
Montréal, Montréal, CANADA, 3 Pharmaceutical Division, F. Hoffmann-La Roche<br />
Ltd., Basel, SWITZERLAND, 4 Global Medical Affairs Oncology, F. Hoffmann-La<br />
Roche Ltd., Basel, SWITZERLAND, 5 Bioma<strong>the</strong>matics, BIOMCON GmbH,<br />
Mannheim, GERMANY, 6 Department of Clinical Oncology, Chinese University of<br />
Hong Kong Prince of Wales Hospital, Shatin, Hong Kong, CHINA<br />
Background: In 2010, <strong>the</strong> results of a pooled analysis examining <strong>the</strong> correlation of<br />
EGFR mutations with clinical outcome were reported [1]; EGFR TKIs appeared to be<br />
<strong>the</strong> most effective treatment for EGFR mutation-positive NSCLC. Since this report,<br />
more trials (including large controlled phase III studies) have been published, doubling<br />
<strong>the</strong> number of eligible patients. An updated analysis was carried out to provide a<br />
comprehensive dataset assessing <strong>the</strong> treatment of EGFR mutation-positive NSCLC.<br />
Methods: Congress reports and papers reporting progression-free survival (PFS)<br />
for EGFR mutation-positive NSCLC treated with chemo<strong>the</strong>rapy, erlotinib or<br />
gefitinib (phase II/III studies/retrospective analyses) were identified in a literature<br />
search and checked for duplication. Most papers report high level results e.g.<br />
median PFS. Calculations were based on simplifying assumptions to allow for<br />
pooling of results and to obtain an accuracy estimate (surrogate for confidence<br />
intervals). The pooled median PFS, MPFS(all), was estimated by a study-size N (i)<br />
weighted average: MPFS(all)= 1/N(all)∑N(i)MPFS(i). The potential for publication<br />
bias was assessed using funnel plots. Permutation testing will be carried out. For<br />
full methodology see [1].<br />
Results: Data were included from 20 chemo<strong>the</strong>rapy studies (n = 984; updated from n<br />
= 375 [1]), 27 erlotinib studies (n = 735; from n = 365 [1]), and 56 gefitinib studies<br />
(n = 1843; from n = 1069 [1]). Longer PFS was seen with both EGFR TKIs compared<br />
with chemo<strong>the</strong>rapy across treatment lines (Table).<br />
Conclusion: In <strong>the</strong> past three years, several important studies have examined EGFR<br />
TKI <strong>the</strong>rapy in patients with EGFR mutation-positive NSCLC. This updated dataset<br />
provides a comprehensive picture of treatment outcomes in this patient subset,<br />
confirming that this subgroup derives a greater benefit from EGFR TKIs than from<br />
conventional chemo<strong>the</strong>rapy, especially when administered as first line. [1] Paz-Ares J<br />
Cell Mol Med 2010<br />
Pooled median PFS (95% accuracy interval) for patients with EGFR<br />
mutation-positive tumours<br />
Single-agent erlotinib<br />
All lines of <strong>the</strong>rapy (n = 735) 12.4 months (11.6–13.4)<br />
*Predominantly first-line (n = 354) 12.0 months (10.8–13.3)<br />
Single-agent gefitinib<br />
All lines of <strong>the</strong>rapy (n = 1843) 9.3 months (8.9–9.8)<br />
*Predominantly first-line (n = 716) 9.7 months (9.0–10.5)<br />
Chemo<strong>the</strong>rapy (may be single- or multiple-agent<br />
treatment)<br />
All lines of <strong>the</strong>rapy (n = 984) 5.6 months (5.3–6.0)<br />
*Predominantly first-line (n = 868) 5.8 months (5.5–6.2)<br />
*Predominantly first-line is ≥90% of patients treated in first-line setting<br />
Disclosure: L. Paz-Ares: Advisory board: Roche. D. Soulières: Advisory board:<br />
Roche, Boehringer Ingelheim. B. Klughammer: Stock ownership: F. Hoffmann-La<br />
Roche Ltd Employed by F. Hoffmann-La Roche Ltd. I. Bara: Employed by<br />
F. Hoffmann-La Roche Ltd. J. Moecks: Corporate sponsored research in<br />
bioma<strong>the</strong>matics for Roche in several fields Former employee of F. Hoffmann-La<br />
Roche Ltd. T.S.K. Mok: Advisory board:AstraZeneca, Roche, Eli Lilly, Merck Serono,<br />
Eisai, BMS, BeiGene, AVEO, Pfizer, Taiho, BI, GSK Biologicals On <strong>the</strong> Board of<br />
Directos for IASLC Corporate sponsored research for AstraZeneca Employed by The<br />
Chinese University of Hong Kong<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds409 | ix411
1255P POPULATION BASED EVALUATION OF CHEMOTHERAPY<br />
USE AFTER FIRST LINE GEFITINIB IN EPIDERMAL GROWTH<br />
FACTOR RECEPTOR (EGFR) MUTATION POSITIVE<br />
ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC)<br />
C. Mariano 1 , I. Bosdet 2 , D. Ionescu 3 , A. Karsan 3 , S. Sun 1 , N. Murray 1 ,<br />
B. Melosky 1 , J. Laskin 1 ,C.Ho 1<br />
1 Medical Oncology, British Columbia Cancer Agency, vancouver, BC, CANADA,<br />
2 Cancer Genetics, British Columbia Cancer Agency, Vancouver, CANADA,<br />
3 Pathology, British Columbia Cancer Agency, vancouver, CANADA<br />
Introduction: The IPASS trial demonstrated superior progression free survival for<br />
Asian, light/never smoking, advanced, adenocarcinoma patients treated with first line<br />
Gefitinib compared to carboplatin/paclitaxel, of which 59% of those tested were<br />
EGFR mutation positive (MUT+). In IPASS 39% of Gefitinib treated patients went<br />
on to receive platin based <strong>the</strong>rapy. We hypo<strong>the</strong>size that in a population-based setting<br />
fewer patients receive second line platin based chemo<strong>the</strong>rapy.<br />
Methods: The Iressa Alliance Program provided standardized EGFR mutation testing<br />
and appropriate access to Gefitinib to all patients in British Columbia (population<br />
4.5 million) with advanced, non squamous NSCLC. EGFR mutation testing was<br />
limited to <strong>the</strong> most common mutations; exon 19 and 21. We retrospectively analyzed<br />
clinical, pathologic and outcomes for all patients tested in this program between<br />
March 2010 and June 2011.<br />
Results: A total of 548 patients were referred for testing and 107 (19%) patients were<br />
MUT+. Baseline characteristics of MUT- and MUT + ; median age 67/65, male 41%/<br />
31%, Asian 15%/51%, never smoker 21%/58%, stage IV 80%/91%. Overall survival was<br />
10.9 versus 14.9 months (p < 0.0001). In MUT + patients treated with first line<br />
Gefitinib average duration of <strong>the</strong>rapy was 312 days. 5% of patients had a CR, 43% PR,<br />
34% SD, 5% PD with 12% not evaluable. 23% of patients continued on Gefitinib after<br />
radiographic progression. 51 Gefitinib treated patients progressed at <strong>the</strong> time of<br />
analysis; 15% of patients received Gefitinib only, 33% platin based doublet, 10% o<strong>the</strong>r<br />
chemo<strong>the</strong>rapy and 42% no fur<strong>the</strong>r treatment. Five patients received 3rd line <strong>the</strong>rapy.<br />
Conclusions: This North American population based study shows similar efficacy of<br />
Gefitinib in MUT+ patients compared to <strong>the</strong> IPASS trial. Clinicians often continued<br />
Gefitinib past progression, likely due to ongoing clinical benefit. Contrary to our<br />
hypo<strong>the</strong>sis, delivery of second line chemo<strong>the</strong>rapy was feasible in a significant<br />
proportion of Gefitinib treated patients, similar to results seen in clinical trials. MUT<br />
+ patients have a better prognosis and this may contribute to <strong>the</strong>ir ability to receive<br />
fur<strong>the</strong>r <strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1256P LONG-TERM SURVIVORS IN NON-SMALL CELL LUNG<br />
CANCER (NSCLC) PATIENTS WITH EPIDERMAL GROWTH<br />
FACTOR RECEPTOR (EGFR) MUTATIONS: DATA FROM A<br />
RANDOMIZED PHASE III STUDY COMPARING GEFITINIB<br />
WITH CARBOPLATIN PLUS PACLITAXEL (NEJ002)<br />
Y. Minegishi 1 , K. Kobayashi 2 , M. Maemondo 3 , A. Inoue 4 , S. Sugawara 5 ,<br />
S. Oizumi 6 , K. Hagiwara 7 , T. Nukiwa 8 , S. Morita 9 , A. Gemma 10<br />
1 Internal Medicine, Division of Pulmonary Medicine, Infectious Diseases, and<br />
Oncology, Nippon Medical School, Tokyo, JAPAN, 2 Respiratory Medicine,<br />
Saitama International Medical Center, Saitama, JAPAN, 3 Department of<br />
Respiratory Medicine, Miyagi Cancer Center, Natori, JAPAN, 4 Department of<br />
Respiratory Medicine, Tohoku University, Sendai, JAPAN, 5 Department of<br />
Respiratory Medicine, Sendai Kousei Hospital, Sendai, JAPAN, 6 First<br />
Department of Medicine, Hokkaido University School of Medicine, Sapporo,<br />
JAPAN, 7 Department of Respiratory Medicine, Saitama Medical University,<br />
Saitama, JAPAN, 8 Medical Commisioner, South Miyagi Medical Center, Miyagi,<br />
JAPAN, 9 Biostatistics and Epidemiology, Yokohama City University Medical<br />
Center, Yokohama, JAPAN, 10 Internal Medicine, Nippon Medical School, Tokyo,<br />
JAPAN<br />
Background: In <strong>the</strong> NEJ002 study comparing first-line gefitinib to a<br />
standard-chemo<strong>the</strong>rapy of carboplatin plus paclitaxel for advanced NSCLC patients<br />
with tumors harboring sensitive EGFR mutations, progression-free survival was<br />
significantly longer in <strong>the</strong> gefitinib group compared with <strong>the</strong> standard-chemo<strong>the</strong>rapy<br />
group. However, as 98% of <strong>the</strong> patients in whom first-line carboplatin-paclitaxel<br />
failed crossed over to gefitinib <strong>the</strong>rapy, <strong>the</strong> overall survival was similar between <strong>the</strong><br />
two groups. The 2.5-year survival rate of both groups in NEJ002 were very good at<br />
about 50%. In order to clarify <strong>the</strong> factors which contribute to <strong>the</strong> long-term survival<br />
of NSCLC patients with mutated EGFR, we evaluated any correlation between<br />
demographic factors and overall survival outcome in 230 patients enrolled in<br />
NEJ002.<br />
Methods: The analysis was performed independently from our previous reports. A<br />
total of 226 patients who received EGFR-tyrosine kinase inhibitors (TKI) and had<br />
survival confirmation were analyzed. Fourteen factors were evaluated using <strong>the</strong><br />
cause-specific survival, and uni- and multi-variate analyses were conducted by Cox’s<br />
proportional hazard model.<br />
Results: Four prognostic factors were identified by univariate analysis: base-line<br />
performance status (PS), existence of <strong>the</strong> distant metastasis, response to<br />
Annals of Oncology<br />
standard-chemo<strong>the</strong>rapy and EGFR-TKI (P < 0.05). There were no significant<br />
differences among age, sex, smoking status, histologic type, clinical stage, EGFR<br />
mutation type and <strong>the</strong> assigned treatment groups. Three independent prognostic<br />
factors were identified by multivariate analysis: PS 1 [hazard ratio 1.64: 95% CI<br />
1.14-2.36] and stable disease or progressive disease as response to<br />
standard-chemo<strong>the</strong>rapy [HR 2.29 : 95% CI 1.31-4.02] and to EGFR-TKI [HR 3.18 :<br />
95% CI 2.01-4.00].<br />
Conclusion: Base-line PS, responses to standard chemo<strong>the</strong>rapy and response to<br />
EGFR-TKI were significant factors on <strong>the</strong> prognosis of NSCLC with sensitive EGFR<br />
mutations. Using updated survival data, a logistic regression analysis for long<br />
survivors (more than 3 years) will be presented.<br />
Disclosure: A. Inoue: I was paid lecture fees from AstraZeneca. S. Oizumi: I was paid<br />
an honorarium (AstraZeneca). K. Hagiwara: I was paid honoraria from AstraZeneca.<br />
A. Gemma: I (my department) received grant for basic research by AstraZeneca as a<br />
chief of department. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1257P INFLUENCE OF SMOKING STATUS ON RESPONSE TO EGFR<br />
TKI – A RETROSPECTIVE ANALYSIS OF REFLEX EGFR<br />
MUTATION TESTING IN ASIAN PATIENTS WITH ADVANCED<br />
LUNG ADENOCARCINOMAS<br />
A. Jain 1 , S.L. Koo 1 , K.S. Chan 2 , Q.S. Ng 1 , N.M. Chau 1 , M.K. Ang 1 , L. Oon 2 ,W.<br />
T. Lim 1 , E.H. Tan 1 , D.S.W. Tan 3<br />
1 Department of Medical Oncology, National Cancer Centre Singapore,<br />
Singapore, SINGAPORE, 2 Department of Pathology, Singapore General Hospital,<br />
Singapore, SINGAPORE, 3 Department of Medical Oncology, National Cancer<br />
Center, Singapore, SINGAPORE<br />
Introduction: Although <strong>the</strong> role of EGFR mutations (mt) is established in predicting<br />
response to EGFR TKI, <strong>the</strong>re is little data on <strong>the</strong> impact of smoking on mt subtypes<br />
and treatment outcomes. We hypo<strong>the</strong>sized that mt spectra differ between<br />
never-smokers (NS) and those with a smoking history (ex-smokers or current<br />
smokers) (SM), and that SM may have poorer outcomes to EGFR TKI.<br />
Methods: All cases that had undergone reflex EGFR mt testing between 6/10 – 3/12<br />
were reviewed for smoking status, performance status, patient demographics and type<br />
of EGFR mt. In patients who were treated with EGFR TKI, progression free survival<br />
(PFS) and 1-year overall survival (OS) was determined.<br />
Results: 742 patients (M:F 384:358) were identified of which 342 (46.1%) were EGFR<br />
mt+. Majority were females 64.6% (n = 221, S:NS 15:197) while males comprised<br />
35.4% (n = 121, S:NS 54:66). Mts in order of frequency: Exon (Ex) 19 deletions (del)<br />
(52.3%), L858R 33.9%, Ex 20 insertion (ins)/duplication (4.9%), G719X (4.1%),<br />
L861Q (1.8%), T790M (1.2%), and Exon 19 ins (0.3%). In patients with known<br />
smoking status and mt status, (n = 332), median age was 63 years in both NS (n =<br />
261) and SM (n = 71). There was no significant difference in location of mt (Ex 18,<br />
19, 20 and 21, p= 0.991), or <strong>the</strong> type of mt (Ex19 deletions vs. point mutations, p =<br />
0.723). When we reviewed <strong>the</strong> clinical outcomes of 127 TKI naïve patients (NS n =<br />
103, SM n = 24) receiving gefitinib or erlotinib mono<strong>the</strong>rapy with at least 6 months<br />
of follow up, median PFS was 11.9 months (m)and OS at 1 year was 75.3%. In<br />
subgroup analysis, PFS for NS vs. SM was 11.9 m and 14.7 m (p = 0.855) and 1 year<br />
OS 75.3% vs. 65.7% (p = 0.683).<br />
Conclusion: EGFR mutations occur in 46% of patients in Singapore, of which<br />
one-fifth of patients had significant smoking history. Contrary to our hypo<strong>the</strong>sis, <strong>the</strong><br />
EGFR mt spectra and clinical outcomes is similar in NS vs. SM underscoring <strong>the</strong><br />
importance of reflex testing in a population where mt prevalence is high.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1258P GEFITINIB (G) AND PEMETREXED (PEM) AS A FIRST LINE<br />
TREATMENT IN PATIENTS WITH EGFR MUTANT ADVANCED<br />
NON-SMALL CELL LUNG CANCER (NSCLC): A PHASE II<br />
STUDY<br />
N. Yoshimura 1 , K. Matsuura 1 , S. Mitsuoka 1 , K. Asai 1 , Y. Tochino 1 , T. Kimura 1 ,<br />
M. Nakai 1 , Y. Mitsukawa 2 , K. Hirata 1 , S. Kudoh 1<br />
1 Department of Respiratory Medicine, Osaka City University Medical School,<br />
Osaka, JAPAN, 2 Pharmaceutical Department, Osaka City University Hospital,<br />
Osaka, JAPAN<br />
Background: G is <strong>the</strong> key drug for patient (pts) with NSCLC harboring mutations of<br />
EGFR as a first line treatment. However, <strong>the</strong>y have disease progression in most cases.<br />
PEM and G are reported to have a schedule-depended cytotoxic synergism.<br />
Objectives: We evaluated <strong>the</strong> efficacy and safety of G and PEM as a first line<br />
chemo<strong>the</strong>rapy in pts with NSCLC harboring mutations of EGFR.<br />
Methods: Eligibilities were histologically or cytologically proven non-squamous<br />
NSCLC with EGFR active mutation, chemo<strong>the</strong>rapy naïve, measurable lesion, ECOG<br />
PS0-1, adequate organ function, life expectancy longer than 12 weeks and written<br />
informed consent. G (250mg/body) was administered on days 2-16 and PEM<br />
(500mg/m2) was administered on day 1. This combination was repeated every 3<br />
weeks until progressive disease (PD). Primary endpoint was overall response rate<br />
ix412 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
(ORR) and secondary endpoints were toxicities, disease control rate (DCR),<br />
progression free survival (PFS), and overall survival (OS). The planed sample size<br />
was 26 pts.<br />
Results: From March 2010 to May <strong>2012</strong>, 20 pts were enrolled and eligible: males/<br />
females 10/10; median age 66 (range 59-75); PS 0/2 2/18; stage III/IV 1/19; adeno/<br />
o<strong>the</strong>rs 20/0. Nineteen pts were eligible for efficacy and toxicity; a total of 226 cycles<br />
(median 12 cycles, range 1-27) was given. Major grade 3/4 toxicities were<br />
neutropenia, leucopenia, liver dysfunction and infection, respectively. There was no<br />
treatment-related death. ORR was 68.8%, and DCR was 100%. Median PFS is 18.2<br />
months and median OS is not reached.<br />
Conclusions: This combination showed longer median PFS and acceptable toxicity.<br />
Randomized trial of PEM + G compare with G alone is warranted.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1259P GEFITINIB FOR NON-SMALL CELL LUNG CANCER (NSCLC)<br />
WITH MINOR EGFR MUTATIONS: A RETROSPECTIVE STUDY<br />
FROM THE NORTH EAST JAPAN STUDY GROUP (NEJ)<br />
S. Watanabe 1 , H. Yoshizawa 1 , M. Maemondo 2 , A. Inoue 3 , S. Sugawara 4 ,<br />
H. Isobe 5 , M. Harada 6 , Y. Ishii 7 , K. Hagiwara 8 , K. Kobayashi 9<br />
1 Bioscience Madecal Research Center, Niigata University Medical and Dental<br />
Hospital, Niigata-City, JAPAN, 2 Department of Respiratory Medicine, Miyagi<br />
Cancer Center, Natori, JAPAN, 3 Department of Respiratory Medicine, Tohoku<br />
University, Sendai, JAPAN, 4 Department of Respiratory Medicine, Sendai Kousei<br />
Hospital, Sendai, JAPAN, 5 Clinical Oncology, KKR Sapporo Medical Center,<br />
Sapporo, JAPAN, 6 Department of Pulmonary Disease, National Hospital<br />
Organization Hokkaido Cancer Center, Sapporo, JAPAN, 7 Department of<br />
Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University School<br />
of Medicine, Mibu, JAPAN, 8 Department of Respiratory Medicine, Saitama<br />
Medical University, Saitama, JAPAN, 9 Respiratory Medicine, Saitama<br />
International Medical Center, Saitama, JAPAN<br />
Background: In NSCLC, <strong>the</strong> sensitive mutations of epidermal growth factor receptor<br />
(EGFR), such as exon 19 deletion and L858R point mutation, are predictors of<br />
response to EGFR tyrosine kinase inhibitors (TKIs). However, it is still uncertain<br />
whe<strong>the</strong>r minor EGFR mutations are associated with sensitivity to EGFR-TKIs.<br />
Materials and methods: Retrospective review of 221 EGFR mutated (exon 19<br />
deletion, L858R, G719X and L861Q) patients who were treated with gefitinib in a<br />
NEJ002 study was performed. We identified 7 patients with G719X and 3 patients<br />
with L861Q.<br />
Results: Among 10 patients harboring minor EGFR mutations (G719X or L861Q), 5<br />
patients were treated with gefitinib as <strong>the</strong> 1st line treatment, and 5 patients were<br />
treated with carboplatin/paclitaxel as <strong>the</strong> 1st line chemo<strong>the</strong>rapy, and <strong>the</strong>n received<br />
gefitinib as <strong>the</strong> 2nd line treatment. Only 2 patients showed PR, 4 achieved SD, and 4<br />
had PD with gefitinib treatment. The overall response rate was 20% and <strong>the</strong> disease<br />
control rate was 60%. The overall survival (OS) from enrollment was significantly<br />
shorter in patients with minor mutations (median OS, 12 months (95% CI, 5.8 -<br />
30.5)) compared to patients with 19 deletion or L858R (median OS, 28 months (95%<br />
CI, 24.1 – 33.2), P = 0.0057). Tendency of longer progression free survival and OS<br />
were observed in minor EGFR mutation patients who received carboplatin/paclitaxel<br />
as <strong>the</strong> 1st line treatment (median PFS, 5.3 months (95% CI, 3.7 – 8.9) and median<br />
OS, 22.8 months (95% CI, 9.9 – 41.8)) compared to those who were treated with<br />
gefitinib as <strong>the</strong> 1st line treatment (median PFS, 2.2 months (95% CI, 0.5 – 10.6), P =<br />
0.997 and median OS, 11.9 months (95% CI, 5.8 – 22.6), P = 0.1021).<br />
Conclusions: Our results indicate that NSCLC patients with G719X or L861Q minor<br />
EGFR mutations are less responsive to gefitinib than those with 19 deletion or<br />
L858R.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1260P A PHASE II STUDY OF ERLOTINIB AS FIRST-LINE<br />
TREATMENT IN JAPANESE ADVANCED NSCLC PATIENTS<br />
HARBORING EGFR MUTATIONS<br />
A. Horiike 1 , M. Nishio 1 , K. Goto 2 , N. Yamamoto 3 , K. Chikamori 4 ,<br />
M. Maemondo 5 , T. Hida 6 , N. Katakami 7 , T. Tamura 3<br />
1 Thoracic Oncology Center, The Cancer Institute Hospital of Japanese<br />
Foundation for Cancer Research, Koto-ku, Tokyo, JAPAN, 2 Division of Thoracic<br />
Oncology, National Cancer Center Hospital East, Kashiwa, JAPAN, 3 Division of<br />
Internal Medicine and Thoracic Oncology, National Cancer Center Hospital,<br />
Chuo-ku, Tokyo, JAPAN, 4 Oncology Medicine, National Hospital Organization,<br />
Yamaguchi - Ube Medical Center, Ube, JAPAN, 5 Department of Respiratory<br />
Medicine, Miyagi Cancer Center, Natori, JAPAN, 6 Department of Thoracic<br />
Oncology, Aichi Cancer Center Hospital, Nagoya, JAPAN, 7 Integrated Oncology,<br />
Institute of Biomedical Research and Innovation Hospital, Kobe, JAPAN<br />
Background: Several studies of EGFR TKIs have shown a benefit in response and<br />
progression-free survival (PFS) for NSCLC patients harboring EGFR mutations in<br />
<strong>the</strong> first-line setting. This is <strong>the</strong> first prospective study to investigate erlotinib for <strong>the</strong><br />
first-line treatment of NSCLC patients harboring EGFR mutations in Japanese<br />
patients.<br />
Methods: We undertook <strong>the</strong> single-arm phase II study at 25 centers. Eligible patients<br />
were adults (over 20 years) with advanced or recurrent NSCLC harboring EGFR<br />
mutations (Exon 19 deletions (19del) or Exon 21 L858R mutation) with no prior<br />
chemo<strong>the</strong>rapy for NSCLC. The primary endpoint was progression-free survival (PFS)<br />
and safety. Secondary endpoints were overall response rate (ORR), disease control<br />
rate (DCR), overall survival (OS), and response duration.<br />
Results: Between April 8 and October 6 2010, 103 patients were enrolled. All<br />
patients were administered erlotinib and included in <strong>the</strong> safety analysis. One<br />
patient was excluded from efficacy analysis, because of <strong>the</strong> deviation of GCP. Thus<br />
102 patients were analyzed in <strong>the</strong> efficacy analysis. At Data cut-off (Sep 1, 2011),<br />
median PFS assessed by Independent Review Committee was 11.8 months [95 %<br />
CI 9.7- not reached]. The updated median PFS incorporated with follow up<br />
assessments will be obtained in August <strong>2012</strong>. The most common adverse events<br />
were rash and diarrhea in 82.5 % and 80.6 % respectively, with Grade 3 was 13.6<br />
% and 1.0 % respectively, and <strong>the</strong>re were no Grade 4/5 rash and diarrhea. Six<br />
treatment-related ILD like events were reported by investigators, and of which two<br />
were fatal. ORR was 78.4 %, DCR was 95.1 %, and response duration was 11.1<br />
months [95 %CI 9.4- not reached], OS data is immature at this time (only ten<br />
deaths events). Median PFS in 50 patients with 19del was 12.5 months, in 50<br />
patients with L858R was 11.0 months, and two patients with L858R/T790M was<br />
3.8months.<br />
Conclusion: This study showed a promising efficacy and safety profile of erlotinib in<br />
Japanese advanced NSCLC patients harboring EGFR mutations.<br />
Disclosure: A. Horiike: Corprate-sponsored research: Chugai, Pfizer, Merck,<br />
KyowaKirin, Taiho, Eisai, Novartis, AMGEN. M. Nishio: Corporate-sponsored<br />
research: Chugai, Eli Lillly, Pfizer, DiichiSankyo, KyowaKirin, Taiho, Eisai, Novartis.<br />
Lecture fees: Chugai. K. Goto: Corporate-sponsored research: Chugai, Pfizer,<br />
KyowaKirin, Taiho, Eisai, Merckserono, Boehringer Ingelheim Lecture fees: Chugai,<br />
Taiho, Ono. N. Yamamoto: Corporate-sponsored research: Chugai, Pfizer,<br />
KyowaKirin. K. Chikamori: Corporate-sponsored research: Chugai, Taiho, Nippon<br />
Kayaku Lecture fees: Eli Lilly. M. Maemondo: Corporate-sponsored research: Chugai,<br />
Taiho, Janssen Lecture fees: Chugai, Eli Lilly. T. Hida: Corporate-sponsored research:<br />
Chugai, Eli Lilly, Bayer, Pfizer, DaiichiSankyo, KyowaKirin, Taiho, Boehringer<br />
Ingelheim, Merck, Aventis. N. Katakami: Corporate-sponsored research: Chugai,<br />
Pfizer, Kyowakirin, Ono, Janssen, Merckserono, Boehringer Ingelheim,<br />
Dainipponsumitomo, Eisai, Shionogi. T. Tamura: Corporate-sponsored research:<br />
Chugai, DaiichiSankyo, Boehringer Ingelheim, Abbott, Eisai, Bristol-Myers Squib,<br />
KyowaKirin Lecture fees: Taiho, Eli Lilly, Chugai<br />
1261P ERLOTINIB AS NEOADJUVANT TREATMENT IN PATIENTS<br />
WITH IIIA-N2 NON-SMALL CELL LUNG CANCER(NSCLC)<br />
WITH ACTIVATING EPIDERMAL GROWTH FACTOR<br />
RECEPTOR (EGFR) MUTATION (NCT01217619, ESTERN)<br />
B. Han, L. Xiong, R. Li, J. Sun, Y. Lou, Y. Zhang<br />
Department of Pulmonary Medicine, Shanghai Chest Hospital affiliated to<br />
Shanghai Jiaotong University, Shanghai, CHINA<br />
Background: Patients with stage IIIA N2 NSCLC have poor outcomes with 5-year<br />
survival rate of approximately 15% after treatment with surgical resection or<br />
chemo-radio<strong>the</strong>rapy. Tyrosine kinase inhibitor mono<strong>the</strong>rapy have been demonstrated<br />
a significant improvement in tumor response rate and progression free survival as <strong>the</strong><br />
first line treatment for metastatic NSCLC patients with activating EGFR mutation.<br />
The objective of this trial is to explore <strong>the</strong> efficacy and safety profile of erlotinib as<br />
neoadjuvant treatment in patients of stage IIIA-N2 NSCLC with activating EGFR<br />
mutation.<br />
Material and methods: This is a single arm, one center, phase II study of erlotinib<br />
as neoadjuvant treatment in patients with Endobronchial Ultrasound (EBUS)<br />
confirmed stage IIIA-N2 NSCLC with activating EGFR mutation in exon 19 or 21.<br />
The primary endpoint is to evaluate radical resection rate. A total of 44 patients will<br />
be enrolled. Major inclusion criteria: IIIA-N2 NSCLC Patients with pathologically<br />
confirmed ipsilateral mediastinal metastasis by EBUS. The biopsy specimen shows<br />
activating EGFR mutation in exon 19 or 21.<br />
Treatment schedule: All <strong>the</strong> recruitment patients will be treated by erlotinib 150mg<br />
orally per day for 56 days for neoadjuvant period. Patients will be assessed by Chest<br />
CT for <strong>the</strong> efficacy evaluation in day 29 and right after day 56. All <strong>the</strong> post-operative<br />
patients will receive standard adjuvant treatment which will be decided by <strong>the</strong><br />
investigator.<br />
Current enrollment: 48 patients have been screened, and 7 patients met <strong>the</strong><br />
inclusion criteria and were enrolled. 2 patients are still on neoadjuvant treatment, 5<br />
patients have completed <strong>the</strong> neoadjuvant <strong>the</strong>rapy, and RECIST evaluation showed<br />
partial response in 2 patients, disease progression in 2 patients, and disease stable in<br />
1 patient. Due to active hepatitis and technical infeasibility, 2 patients with PR didn’t<br />
receive surgery, only one SD patient received R0 surgery.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds409 | ix413
1262P DISTINCT SPREAD OF EGFR MUTATED PULMONARY<br />
ADENOCARCINOMAS<br />
D. Shin 1 , S.Y. Kwon 2 , C.H. Kim 1 , S.H. Yang 1 , I.I. Na 1<br />
1 Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological<br />
and Medical Sciences, Seoul, KOREA, 2 Hospice and Palliative Care Team, Korea<br />
Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences,<br />
Seoul, KOREA<br />
Introduction: Our aim in this study was to explore <strong>the</strong> potential association of<br />
epidermal growth factor receptor (EGFR) with characteristics of tumor spread in<br />
patients with pulmonary adenocarcinoma. Clinical implication of EGFR mutational<br />
status on brain metastasis was also evaluated in surgically treated patients.<br />
Methods: We analyzed clinical data on 317 patients who were tested for EGFR<br />
mutation and who underwent brain MRI at diagnosis between October 2005 and<br />
December 2011. The relationship between EGFR mutation status and clinical factors<br />
were analyzed. Initial metastatic disease was stratified according to brain metastases<br />
and <strong>the</strong>ir association with EGFR mutations was evaluated using multinomial logistic<br />
regression.<br />
Results: Of <strong>the</strong> 317 patients, 139 patients (43.85%) harbored EGFR mutations. EGFR<br />
mutations was more commonly found in patients with early nodal stage (71.9 %<br />
versus 28.1%, adjusted odds ratio [OR] = 1.90, p = 0.030) and distant metastases<br />
(54.0% versus 46.0%, adjusted OR = 2.05, p = 0.011). Fur<strong>the</strong>r analysis showed that<br />
EGFR mutations were more likely to be detected in brain metastases (64.7% versus<br />
35.3%, p = 0.005), whereas <strong>the</strong>ir association with noncranial metastases was not<br />
significant (55.4% versus 44.6%, p = 0.960). In addition, survival analysis of 133<br />
patients treated with surgical resection showed that EGFR mutation status was a poor<br />
prognostic factor for brain metastasis (HR = 5.94, 95% CI = 1.08-16.28, p = 0.039)<br />
after adjustment of pathologic N stage.<br />
Conclusions: In this study, EGFR mutation status was significantly associated with<br />
early nodal and distant metastasis, in <strong>the</strong> patients with pulmonary adenocarcinoma.<br />
The current study also suggests <strong>the</strong> preference of brain metastases in mutant EGFR<br />
tumors at initial presentation and after curative resection.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1263P IMPACT OF EPIDERMAL GROWTH FACTOR<br />
RECEPTOR-TYROSINE KINASE INHIBITOR TREATMENT IN<br />
ADVANCED NON-SMALL CELL LUNG CANCER: A<br />
META-ANALYSIS<br />
C.K. Lee 1 , C. Brown 2 , R. Gralla 3 , V. Hirsh 4 , A. Inoue 5 , V. Gebski 6 , C.J. Yang 7<br />
1 NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, AUSTRALIA,<br />
2 Clinical Trials, NHMRC Clinical Trials Centre, University of Sydney, Sydney,<br />
AUSTRALIA, 3 Department of Medicine, Hofstra University School of Medicine,<br />
New York, UNITED STATES OF AMERICA, 4 Oncology, McGill University Health<br />
Centre, Montreal, QC, CANADA, 5 Department of Respiratory Medicine, Tohoku<br />
University, Sendai, JAPAN, 6 Biostatistics and Research Methodology, NHMRC<br />
Clinical Trials Centre, University of Sydney, Sydney, AUSTRALIA, 7 Department of<br />
Oncology, National Taiwan University Hospital, Taipei, TAIWAN<br />
Background: Previous meta-analyses have reported that epidermal growth factor<br />
receptor (EGFR)-tyrosine kinase inhibitor (TKI) improves progression-free<br />
survival (PFS) in patients with advanced non-small cell lung cancer (NSCLC)<br />
harbouring EGFR mutation. We examined <strong>the</strong> influence of EGFR-TKI on PFS<br />
and overall survival (OS) in those with (EGFR+) and without mutation<br />
(EGFR-).<br />
Methods: We included published and unpublished randomised trials of advanced<br />
NSCLC that compared EGFR-TKI mono<strong>the</strong>rapy or combination EGFR-TKI<br />
chemo<strong>the</strong>rapy with chemo<strong>the</strong>rapy or placebo. We used published hazard ratios (HR)<br />
if available, or derived treatment estimates from o<strong>the</strong>r survival data. We investigated<br />
treatment effects in different treatment settings and trial regimens.<br />
Results: We identified 20 eligible trials investigating EGFR-TKI in front-line (n = 12),<br />
second or subsequent (n = 5), and maintenance (n = 3) treatment, with EGFR status<br />
known in 3198 (23%) patients. Overall, HR for EGFR-TKI over control for PFS were<br />
(EGFR+) 0.37 (95% CI, 0.32 to 0.42; p < 0.001) and (EGFR-) 1.02 (95% CI, 0.93 to<br />
1.12; p = 0.67). EGFR mutation is predictive of PFS benefit with EGFR-TKI in all<br />
settings: front-line HR (EGFR+) 0.39, p < 0.005, HR (EGFR-) 1.07, p = 0.27,<br />
interaction p < 0.001; second or subsequent lines HR (EGFR+) 0.38, p = 0.01, HR<br />
(EGFR-) 1.22, p = 0.07, interaction P = 0.003; maintenance HR (EGFR+) 0.15, p <<br />
0.001, HR (EGFR-) 0.81, p = 0.02, interaction p = 0.02. There was no difference in OS<br />
for patients treated with EGFR-TKI or control in <strong>the</strong>se subgroups of patients: HR<br />
(EGFR+) 0.95, p = 0.21; HR (EGFR-) 0.95; p = 0.29.<br />
Conclusions: In this meta-analysis, treatment with EGFR-TKI was found to<br />
significantly delay disease progression in EGFR+ patients; however, no impact on<br />
OS was identified. EGFR mutation is a predictive biomarker of PFS benefit<br />
with EGFR-TKI treatment in all settings. These findings support assessment for<br />
Annals of Oncology<br />
EGFR mutation before initiation of EGFR-TKI treatment and that EGFR-TKI<br />
should be considered as front-line <strong>the</strong>rapy in EGFR+ patients with advanced<br />
NSCLC.<br />
Disclosure: R. Gralla: Consultant or advisory role for Boehringer Ingelheim. V.<br />
Hirsh: Advisory role for Boehringer Ingelheim. A. Inoue: Received lecture fees and<br />
research grants from AstraZeneca. C.J. Yang: Advisory roles for Boehringer<br />
Ingelheim, AstraZeneca, Roche and OSI, and have received honoraria from<br />
AstraZeneca, Roche and OSI. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
1264P CLINICOPATHOLOGIC FEATURES OF NEVER-SMOKING<br />
WOMEN LUNG CANCER (WLC): A REVIEW FROM THE<br />
SPANISH WORLD07 DATABASE<br />
J. De Castro 1 , D. Isla Casado 2 , M. Provencio Pulla 3 , M. Majem Tarruella 4 ,<br />
N. Vinolas Segarra 5 , E. Felip 6 , A. Artal-Cortes 7 , R. García-Campelo 8 ,<br />
M. Domine 9 , P. Garrido Lopez 10<br />
1 Medical Oncology, Hospital Universitario La Paz, Madrid, SPAIN, 2 Oncology<br />
Service, Hospital Clínico Universitario Lozano Blesa, Zaragoza, SPAIN, 3 Medical<br />
Oncology, Hospital Universitario Puerta de Hierro Majadahond, Majadahonda,<br />
SPAIN, 4 Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona,<br />
SPAIN, 5 Medical Oncology, Hospital Clinic y Provincial de Barcelona, Barcelona,<br />
SPAIN, 6 Oncologia Médica, Vall d’Hebron University Hospital Institut<br />
d’Oncologia, Barcelona, SPAIN, 7 Servicio de Oncologia Medica, Hospital Miguel<br />
Servet, Zaragoza, SPAIN, 8 Medical Oncology, Complexo Hospitalario<br />
Universitario de A Coruña, La Coruña, SPAIN, 9 Oncology, Fundación Jiménez<br />
Díaz, Madrid, SPAIN, 10 Medical Oncology, Hospital Ramon y Cajal, Madrid,<br />
SPAIN<br />
Background: Lung cancer in never-smoker appears to be a distinct entity from lung<br />
cancer in smoker, with specific molecular characteristics and potential different<br />
treatment. Several factors like hormonal, environmental, genetic, pre-existing lung<br />
diseases, and virus, may play etiologic roles, and an in-depth understanding of <strong>the</strong>m<br />
is needed. So, new clinicopathologic aspects of never-smoking WLC should be very<br />
important to know <strong>the</strong> biology of this tumoral disease.<br />
Methods: Information has been extracted from WORLD07 database, a prospective,<br />
from 32 Spanish centers, epidemiologic female-specific lung cancer e-database<br />
performed by ICAPEM, an association to research WLC.<br />
Results: From October 2007 to October 2011, 539 newly diagnosed never-smoking<br />
WLC were included in World07 database (39.3% of 1371 patients(p). P<br />
characteristics are: median age 71.1 years(y) (range: 22-91). Previous history of<br />
cancer (%): 13(breast, lung, cervix: 41.4,5.7,2.9). Gynecological features: median age<br />
of menarche 13y, Postmenopausal 88.9%, median age of menopause 49y. Median age<br />
of first child 26.4y Children: 91.2% (median: 2.3). Oral contraceptive: 11.9%. HRT:<br />
5.2%. Tobacco exposure: Second-hand smokers: 40%, work-exposure 17.1%,<br />
home-exposure 88.8%. Obesity: 16.3%. Familiar history of cancer: 39.9% (lung cancer<br />
29.8%).Lung cancer histology (%): adenocarcinoma/BAC/squamous/large cell/SCLC/<br />
o<strong>the</strong>rs: 69.2/6.8/5.7/5.0/3.8/3.8. EGFR mutated p (268 p analized): 55.5%, exon 19/<br />
20/21(%): 61.1/7.4/36.9. TNM NSCLC I/II/III/IV (%): 14/3.3/19.8/60.3. Treatment:<br />
EGFR-TKI in p harboring EGFR mutations stage IV (1 st -/2 nd -line)(%): 51.7/15.4;<br />
stage IV NSCLC(1 st -line)(%): platinum-based chemo<strong>the</strong>rapy 42.5, combinations with<br />
bevacizumab 2.9. Overall survival: median 27 months (m), 1/2-y(%) 74.8/55.2; stage<br />
IV NSCLC: median 20.5m, 1/2-y(%) 67/46; EGFR mutated p: median 27.3m, 1/2-y<br />
(%) 75/54.3.<br />
Conclusions: Never-smoking WLC represents 39% of Spanish World07 database.<br />
The high incidence of adenocarcinoma histology (69.2%) and EGFR mutated tumors<br />
suggests a different clinical and genetic profiling and recommend a different<br />
treatment approach for this group of patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1265P IS THERE A BENEFIT ON SURVIVAL OF TYROSINE-KINASE<br />
INHIBITORS VERSUS CHEMOTHERAPY IN FIRST LINE IN<br />
MUTATED EGFR PATIENTS WITH ADVANCED NON-SMALL<br />
CELL CANCER (NSCLC)? A META-ANALYSIS<br />
G. Des Guetz 1 , B. Uzzan 2 , K. Chouahnia 1 , P. Nicolas 2 , L. Zelek 1 , M. Pailler 1 ,<br />
J. Morère 1<br />
1 Oncology, Hôpital Avicenne, Bobigny, FRANCE, 2 Pharmacology, Hôpital<br />
Avicenne, Bobigny, FRANCE<br />
Background: Tyrosine-Kinase Inhibitors (TKIs) markedly improve Progression<br />
Free Survival (PFS) of advanced NSCLC patients mutated for Epidermal Growth<br />
Factor Receptor (EGFR). Results on Overall Survival (OS) are more questionable.<br />
Therefore, we performed a publication-based meta-analysis to fur<strong>the</strong>r assess this<br />
issue.<br />
ix414 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Methods: We did a PubMed query using keywords simultaneously (lung neoplasm,<br />
TKI, EGFR mutation, survival). We also searched for relevant abstracts in<br />
proceedings of ASCO, <strong>ESMO</strong>, WCLC annual meetings. We cross-checked all<br />
references from all articles. Only phase III randomized controlled trials comparing<br />
TKI and chemo<strong>the</strong>rapy were included. We used EasyMA software.<br />
Results: The 6 eligible studies included 2223 patients (516 males, 1688 females,<br />
mostly Asian, median age 60 years, 2155 adenocarcinomas (97 %), 996 mutated<br />
tumors, 389 stage IIIB, 1572 Stage IV (71 %), 1989 never smokers (89.5 %). Four<br />
studies assessed gefitinib, 2 erlotinib. Chemo<strong>the</strong>rapies were doublets including a<br />
platinum salt. Four studies included only mutated patients. Compared to<br />
chemo<strong>the</strong>rapy, EGFR TKIs significantly improved PFS (HR = 0.39, 95 % CI<br />
0.28-0.53, random effect model). Conversely, OS was similar among patients who<br />
first received TKI or chemo<strong>the</strong>rapy (HR = 1.00, CI 0.83-1.22, fixed effect model). PFS<br />
was significantly worse among non mutated patients in <strong>the</strong> 2 studies including both<br />
mutated and wild-type EGFR patients, whereas OS was unchanged. Concerning<br />
side-effects, rash, diarrhoea and interstitial lung disease were significantly more<br />
frequent after TKI (RRs 5.00; 2.40 and 6.07). As expected, fatigue (RR 0.41), nausea/<br />
vomiting (0.19) and haematological disorders were all significantly more frequent<br />
after chemo<strong>the</strong>rapy (RRs for neutropenia, thrombocytopenia and anaemia 0.08; 0.18<br />
and 0.26).<br />
Conclusions: The major discrepancy between a markedly improved PFS and a<br />
similar OS after TKI compared with chemo<strong>the</strong>rapy could be related to <strong>the</strong> high level<br />
of crossing-over between <strong>the</strong> 2 groups. We found no detrimental effect on OS of<br />
TKIs among wild-type patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1266P RETROSPECTIVE STUDY OF CLINICOPATHOLOGIC<br />
FACTORS ASSOCIATED WITH ALK REARRANGEMENT AND<br />
SURVIVAL OUTCOME IN CHINESE PATIENTS (PTS) WITH<br />
NSCLC<br />
X. Zhang 1 , C. Blanckmeister 2 , Y. Cheng 3 ,D.Wu 4 , J. Yang 1 , H. Tian 1 , J. Chen 5 ,<br />
Z. Xie 1 ,H.Yan 1 ,Y.Wu 6<br />
1 Guangdong General Hospital, Guangdong Academy of Medical Sciences,<br />
Guangdong Lung Cancer Institute,, Guangdong, CHINA, 2 Pfizer, New York, NY,<br />
UNITED STATES OF AMERICA, 3 Oncology, Jiling Province Tumor Hospital, Jilin,<br />
CHINA, 4 Jilin Provincial Cancer Hospital, Jilin Province, CHINA, 5 Pfizer China<br />
Medical Affairs, Shanghai, CHINA, 6 Guangdong Lung Cancer Institute,<br />
Guangdong General Hospital (GGH) & Guangdong Academy of Medical<br />
Sciences, Guangzhou, CHINA<br />
Background: We tested 400 NSCLC pts for ALK, EGFR and KRAS status and<br />
correlated clinical factors with ALK status and overall survival (OS).<br />
Methods: ALK status was assessed with RACE-PCR, IHC and FISH; EGFR and<br />
KRAS status were assessed by direct DNA sequencing. OS was estimated by <strong>the</strong><br />
Kaplan-Meier method.<br />
Results: Consecutive, unselected cases from sou<strong>the</strong>rn (n = 294) and nor<strong>the</strong>rn (n =<br />
106) China were tested; 31 (7.7%), 105 (26.2%) and 33 (8.2%) pts were ALK + ,<br />
EGFR+ and KRAS + , respectively. ALK and EGFR aberrations were largely exclusive<br />
(P = 0.009); 2 cases were ALK + /EGFR+. ALK+ status was associated with female sex<br />
(P = 0.023), non/light-smoking (P = 0.001) and adenocarcinoma (P = 0.017), and was<br />
more prevalent in sou<strong>the</strong>rn (9.2%; 27/294) than nor<strong>the</strong>rn (3.8%; 4/106) pts. The<br />
ALK fusion partner was EML4 in all 31 cases; predominantly variants V1–3 (90.3%,<br />
28/31). In 326 modeled pts, female sex (HR = 2.84; P = 0.022), wild type EGFR (HR<br />
= 15.87; P = 0.001), non/light-smoking (HR = 3.95; P = 0.021) and adenocarcinoma<br />
(HR = 4.12; P = 0.031) were associated with ALK+. In 187 cases evaluated by IHC<br />
and RACE-PCR, IHC sensitivity was 100% (19/19; [5 IHC + ; 10 IHC + +; 4 IHC + +<br />
+ ]) and specificity was 79.8% (134/168). All 19 ALK+ cases by RACE-PCR were also<br />
ALK+ by FISH. In <strong>the</strong> first 303 pts, <strong>the</strong>re were no significant OS differences between<br />
ALK + , EGFR + , KRAS+ and triple-negative pts, between ALK+ and ALK– pts, or<br />
between ALK+ cases matched with non-TKI-treated controls balanced for disease<br />
stage, sex, histology and EGFR/KRAS status. In ALK+ pts, non/light-smoking status<br />
(P = 0.016) and prior surgery (P = 0.024) were associated with increased OS by<br />
log-rank test. In a Cox model, disease stage (P ≤ 0.001 for both stage I and II), and<br />
surgical treatment (P = 0.001) were prognostic for OS.<br />
Conclusion: ALK fusion prevalence was 7.7% overall, and was higher in sou<strong>the</strong>rn<br />
pts. ALK+ was associated with non/light-smoking, adenocarcinoma and female sex.<br />
ALK fusion variants were mostly V1–3, which may inform RT-PCR screening. IHC<br />
for ALK protein and FISH for ALK rearrangement may be useful for patient<br />
selection. ALK+ was not a favorable prognostic factor, although disease stage and<br />
smoking history may influence OS in ALK+ NSCLC.<br />
Disclosure: C. Blanckmeister: Employment: Pfizer. Myself. Compensated. Stock<br />
ownership: Pfizer. Myself. J. Chen: Employment: Senior Medical Affairs Therapeutic<br />
Area Manager. Pfizer. Myself. Compensated. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
1267P A LARGE RETROSPECTIVE ANALYSIS OF PEMETREXED<br />
(PEM) ACTIVITY IN PATIENTS (PTS) WITH ALK-POSITIVE<br />
(ALK+) NON-SMALL CELL LUNG CANCER (NSCLC) PRIOR TO<br />
CRIZOTINIB (CRIZ) TREATMENT<br />
G. Scagliotti1 , D.W. Kim2 , A.T. Shaw3 , S.I. Ou4 , G.J. Riely5 , S. Gettinger6 ,<br />
B. Besse7 , K. Wilner8 ,Y.Tang8 , C.H. Bartlett9 1 2<br />
S. Luigi Hospital, University of Turin, Turin, ITALY, Department of Internal<br />
Medicine, Seoul National University Hospital, Seoul, KOREA, 3 Cancer Center,<br />
Massachusetts General Hospital, Boston, MA, UNITED STATES OF AMERICA,<br />
4<br />
Cancer Centre, University of California at Irvine, Irvine, CA, UNITED STATES OF<br />
AMERICA, 5 Medical Oncology, Memorial Sloan-Kettering Cancer Center,<br />
New York, NY, UNITED STATES OF AMERICA, 6 Thoracic Oncology, Yale<br />
University School of Medicine, New Haven, CT, UNITED STATES OF AMERICA,<br />
7 8<br />
Department of Medicine, Institute Gustave Roussy, Villejuif, FRANCE, Reseach<br />
and Development, Pfizer Oncology, La Jolla, CA, UNITED STATES OF AMERICA,<br />
9<br />
Medical Oncology, Pfizer Oncology, New York, NY, UNITED STATES OF<br />
AMERICA<br />
Background: Retrospective small cohort studies evaluating multiple lines of <strong>the</strong>rapy<br />
suggest ALK+ NSCLC may be particularly sensitive to PEM treatment.<br />
Methods: PROFILE 1005 (NCT00932451; Pfizer) is a large phase 2 multinational,<br />
single-arm study of CRIZ in previously treated ALK+ NSCLC. We retrospectively<br />
assessed best overall response rate (ORR) and time to progression (TTP; 1st dose to<br />
objective progression) in pts who received PEM-based regimens prior to CRIZ in <strong>the</strong><br />
1st-line (1L) and 2nd-line (2L) settings. ORR to CRIZ post-PEM-based regimens was<br />
assessed.<br />
Results: Of <strong>the</strong> 901 ALK+ pts enrolled as of Jan <strong>2012</strong>, 711 (79%) received prior PEM<br />
(single-agent or combination; any line advanced/metastatic) with an ORR to PEM of<br />
19%. Pts who received 1L PEM combinations (n = 308) were predominately of young<br />
age (median 53 y, 82%
1268P VISUAL DISTURBANCES IN PATIENTS (PTS) WITH<br />
ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE<br />
ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC)<br />
TREATED WITH CRIZOTINIB<br />
B. Besse 1 , R. Salgia 2 , B. Solomon 3 , A. Shaw 4 , D. Kim 5 , R. Schachar 6 ,<br />
K. Wilner 7 , A. Reisman 8 , C.H. Bartlett 9 ,S.Iyer 10<br />
1 Dept. of Medicine, Institut de Cancérologie Gustave Roussy, Villejuif Cedex,<br />
FRANCE, 2 Department of Medicine, Section of Hematology/Oncology, University<br />
of Chicago, Chicago, IL, UNITED STATES OF AMERICA, 3 Oncology, Peter<br />
MacCallum Cancer Centre, Melbourne, VIC, AUSTRALIA, 4 Hematology/<br />
Oncology, Department of Medicine, Massachusetts General Hospital, Boston,<br />
MA, UNITED STATES OF AMERICA, 5 Oncology, Seoul National University<br />
Hospital, Seoul, KOREA, 6 Specialty Care, Pfizer, La Jolla, CA, UNITED STATES<br />
OF AMERICA, 7 Reseach and Development, Pfizer Oncology, La Jolla, CA,<br />
UNITED STATES OF AMERICA, 8 Statistics, Pfizer Inc., New York, NY, UNITED<br />
STATES OF AMERICA, 9 Oncology, Pfizer, New York, NY, UNITED STATES OF<br />
AMERICA, 10 Global Outcomes Research, Pfizer Oncology, New York, NY,<br />
UNITED STATES OF AMERICA<br />
Background: Crizotinib is a potent, small-molecule ALK inhibitor with a high<br />
response rate in advanced ALK-positive NSCLC. In early phase studies, patients (pts)<br />
commonly reported mild visual disturbances. Here we characterize such visual effects<br />
with objective and subjective measures in an ongoing phase II study (PROFILE 1005).<br />
Methods: Previously treated pts with advanced ALK-positive NSCLC received<br />
crizotinib 250 mg BID. Ophthalmological examinations, comprising best corrected<br />
visual acuity (BCVA), biomicroscopy, and fundoscopy, were performed at screening<br />
and after a visual effect event was reported, except for a subset of pts in France,<br />
where examinations were done every 4 cycles. In addition, on day 1 of each cycle, pts<br />
completed <strong>the</strong> Visual Symptom Assessment Questionnaire (VSAQ) that assessed <strong>the</strong><br />
presence, frequency, timing, duration, and severity of visual effects and <strong>the</strong>ir impact<br />
on activities of daily living (ADL).<br />
Results: As of Jan <strong>2012</strong>, 901 pts had enrolled in PROFILE 1005; 21 − 27% were<br />
evaluable for ophthalmological examinations (visual acuity: 193/901; biomicroscopy:<br />
239/901; fundoscopy: 239/901). There were no changes in BCVA, conjunctiva, cornea,<br />
anterior chamber, iris, lens, or fundus attributable to crizotinib. The most frequently<br />
reported ophthalmological finding was worsening of cataracts (right eye: 9%; left eye:<br />
10%), which was not attributed to crizotinib. Visual effects as identified by <strong>the</strong> VSAQ<br />
were reported by 65% of pts (405/622) at cycle 2 (C2), 58% at C3 (323/558), 55% at C4<br />
(287/519), and 50% at C5 (247/495). The most common were appearance of flashing<br />
lights, streamers/strings/floaters, and overlapping shadows. Most pts reported each<br />
event as lasting ≤1 min (C2: 63%; C3: 68%; C4: 72%; C5: 75%), occurring mostly in<br />
<strong>the</strong> morning (46–59%) and/or evening (70–74%). The majority of pts reported that<br />
visual effects were not at all or a little bo<strong>the</strong>rsome, with no or minimal impact on<br />
ADL. Similar results were observed in <strong>the</strong> French pt subset.<br />
Conclusions: There were no objective ophthalmological changes associated with <strong>the</strong><br />
visual effects on crizotinib. Pt-reported visual effects were frequent, but transient,<br />
with no or minimal impact on ADL.<br />
Disclosure: B. Besse: Research funding: Pfizer. B. Solomon: Compensated advisory<br />
relationship: Pfizer. Research funding: Pfizer. A. Shaw: Compensated advisory<br />
relationship: Pfizer, Ariad, Chugai, Novartis, and Daiichi-Sankyo. Research<br />
funding: AstraZeneca and Novartis. D. Kim: Compensated advisory relationship:<br />
Pfizer. Honoraria: Pfizer. R. Schachar: Compensated employment: Pfizer. Stock<br />
ownership: Pfizer. K. Wilner: Compensated employment: Pfizer. Stock ownership:<br />
Pfizer. A. Reisman: Compensated employment: Pfizer. Stock ownership: Pfizer. C.<br />
H. Bartlett: Compensated employment: Pfizer. Stock ownership: Pfizer. S. Iyer:<br />
Compensated employment: Pfizer. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
1269P FINAL OVERALL SURVIVAL AND UPDATED BIOMARKER<br />
ANALYSIS RESULTS FROM THE RANDOMIZED PHASE III<br />
ICOGEN TRIAL<br />
S. Yan 1 , S. Yuankai 1 ,Z.Li 2 , L. Xiaoqing 3 , C. Zhou 4 ,Z.Li 5 , W. Dong 6 , L. Qiang 7 ,<br />
S. Qin 8 , Z. Shucai 9<br />
1 Oncology, Cancer Hospital,Chinese Academy of Medical Science, Beijing,<br />
CHINA, 2 Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, CHINA,<br />
3 Oncology, 307 Hospital, Academy of Military Medical Science, Beijing, CHINA,<br />
4 Lung Cancer Institute, Shanghai Pulmonary Hospital, Shanghai, CHINA,<br />
5 Respiratory, Peking Union Medical College Hospital, Beijng, CHINA, 6 Oncology,<br />
Daping Hospital & Research Institute of Surgeryof <strong>the</strong> Third Military Medical<br />
University, Chongqing, CHINA, 7 Respiratory, Changhai Hospital of <strong>the</strong> Second<br />
Military Medical University, Shanghai, CHINA, 8 Oncology, The 81 Hospital of <strong>the</strong><br />
Chinese People’s Liberation Army, Nanjing, CHINA, 9 Oncology, Beijing Chest<br />
Hospital, Capital Medical University, Beijing, CHINA<br />
Purpose: A total of 399 pretreated patients with advanced NSCLC were randomly<br />
assigned to receive gefitinib or icotinib in <strong>the</strong> phase III ICOGEN trial, <strong>the</strong> results of<br />
Annals of Oncology<br />
primary endpoint-PFS has been reported previously. This report presents updated<br />
efficacy and biomarker analysis results to determine <strong>the</strong> relationship between EGFR<br />
mutation and clinical outcomes.<br />
Methods: EGFR mutation was evaluated by Scorpion ARMS (QIAGEN, n = 152).<br />
Overall survival was analyzed by survival analysis at 82% matutity.<br />
Results: Median OS was 13.3 months for icotinib and 13.9 months for gefitinib<br />
(hazard ratio [HR] = 0.90; 95% CI, 0.79 to 1.02; P = .109). EGFR mutation rate was<br />
43% for icotinib group and 59% for gefitinib group. Compared to wild type patients,<br />
patients with EGFR mutation had longer PFS (median, 6.2m vs. 2.3m; P = .0000) as<br />
well as OS (median, 20.5m vs. 7.7m; P = .0000). There was no significant difference<br />
of PFS or OS between two treatment groups in EGFR mutation-positive (median<br />
PFS, 7.8m vs. 5.3m for icotinib and gefitinib groups, respectively, P =.3162; median<br />
OS, 20.9m vs. 20.2m for icotinib and gefitinib groups, respectively, P =.7611.) or in<br />
EGFR mutation-negative (median PFS, 2.3m vs. 2.2m for icotinib and gefitinib<br />
groups, respectively, P =.1531; median OS, 7.8m vs. 6.9m for icotinib and gefitinib<br />
groups, respectively, P =.7885.) subgroups.<br />
Conclusion: There was no statistically significant difference between icotinib and<br />
gefitinib in all patients or EGFR mutated patients. This suggests icotinib can<br />
provide similar overall survival to gefitinib. The EGFR mutation status is <strong>the</strong><br />
strongest predictor in identifying which patients will be likely to benifit from<br />
icotinib.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1270P MUTACT: AN OBSERVATIONAL STUDY OF EGFR MUTATION<br />
STATUS AND MANAGEMENT OF PATIENTS WITH<br />
NON-SMALL CELL LUNG CANCER (NSCLC)<br />
ADENOCARCINOMA<br />
P. Souquet 1 , P. Fournel 2 , C. Locher 3 , J.C. Sabourin 4 , E. Garcia 5 , M. Licour 5 ,<br />
N. Karam 5<br />
1 Département d’Oncologie Thoracique, Hospices Civils de Lyon, Pierre Bénite,<br />
Lyon, FRANCE, 2 Département d’Oncologie Médicale, Institut de Cancérologie<br />
Lucien Neuwirth, Saint-Priest en Jarez, FRANCE, 3 Service Pneumologie, Centre<br />
Hospitalier de Meaux, Meaux, FRANCE, 4 Service de Pathologie, CHU Charles<br />
Nicolle, Rouen, FRANCE, 5 Medical Department, AstraZeneca, Rueil-Malmaison,<br />
FRANCE<br />
Background: Certain mutations in <strong>the</strong> EGFR gene predict sensitivity to EGFR<br />
tyrosine kinase inhibitors (TKIs) in advanced NSCLC, and are more common in<br />
adenocarcinoma than o<strong>the</strong>r histologies. When this study was planned,<br />
epidemiological data on EGFR mutations were mostly derived from Asian studies.<br />
MUTACT aims to determine <strong>the</strong> frequency of EGFR mutation positive (EGFR M+)<br />
cases in a cohort of French patients with NSCLC adenocarcinoma, and <strong>the</strong> clinical<br />
outcomes of patients with EGFR M+ disease.<br />
Methods: All patients ≥18 years old with NSCLC adenocarcinoma and a planned<br />
EGFR mutation test were eligible for this observational study (NCT01167972,<br />
AstraZeneca sponsored). Demographics, disease characteristics and EGFR mutation<br />
status were recorded for all patients. Follow-up for treatment decisions and clinical<br />
outcomes for patients with EGFR M+ disease is ongoing.<br />
Results: Between Sept 2010 and Aug 2011, 1382 patients were enrolled at 76<br />
sites in France. Baseline characteristics were: male (57%), Caucasian (95%) and<br />
stage IV disease (79%), including more smokers (38%) than never-smokers (30%)<br />
or ex-smokers (29%). EGFR M + /M-/non-evaluable (Mx) disease rates were<br />
respectively 20.6%, 76.1% and 3.3%. Most samples were analysed by direct<br />
sequencing (69%) using primary tumour tissue (77%), with a median turnover<br />
time of 12 days. Patients with EGFR M+ disease were mostly female (67%) and<br />
never-smokers (70%). As expected, <strong>the</strong> majority of mutations were detected at<br />
exons 19 (54%) and 21 (37%), but mutations were also found at exons 18 (3%)<br />
and 20 (7%). Overall, 1% patients had mutations conferring decreased sensitivity<br />
to EGFR TKIs (exon 20). At inclusion, 633 patients (46%) were in 1 st line<br />
treatment (o<strong>the</strong>rs had surgery or were in 2 nd /3 rd line). Of <strong>the</strong> 283 patients with<br />
EGFR M+ disease, 186 (66%) were in 1 st line treatment at inclusion; 158 (84%)<br />
of <strong>the</strong>se received EGFR TKI.<br />
Conclusions: MUTACT provides a large epidemiological database of predominantly<br />
Caucasian patients with NSCLC. More females and never-smokers than expected in<br />
an adenocarcinoma population were included, resulting in a high EGFR M+ rate.<br />
EGFR TKIs were <strong>the</strong> most common 1 st line treatment in patients with EGFR M+<br />
disease.<br />
Disclosure: P. Souquet: P-J Souquet is currently conducting research sponsored<br />
by AstraZeneca. He has also participated in several boards with AstraZeneca<br />
and has received fundings from AstraZeneca. J.C. Sabourin: J-C Sabourin is a<br />
member of a scientific board for AstraZeneca and has received funding for<br />
research from AstraZeneca. E. Garcia: E Garcia is an employee of AstraZeneca.<br />
M. Licour: M Licour is an employee of AstraZeneca. N. Karam: N Karam is an<br />
employee of AstraZeneca. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
ix416 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
1271P ANALYSIS OF PFS AND OS FROM THE SATURN STUDY<br />
ACCORDING TO EGFR IHC STATUS USING THE H-SCORE<br />
READING METHOD<br />
J. Mazières 1 , W. Brugger 2 , F. Cappuzzo 3 , P. Middel 4 , A. Frosch 5 , I. Bara 6 ,<br />
G. Klingelschmitt 7 , B. Klughammer 8<br />
1 Thoracic Oncology Unit, Larrey Hospital, Toulouse, FRANCE, 2 Haematology/<br />
Oncology, Schwarzwald-Baar Klinikum, University of Freiburg,<br />
Villingen-Schwenningen, GERMANY, 3 Oncology, Istituto Toscano Tumori,<br />
Livorno, ITALY, 4 Department of Pathology, Targos Advance AG, Kassel,<br />
GERMANY, 5 Department of Pathology, Göttingen University Hospital, Gottingen,<br />
GERMANY, 6 Global Medical Affairs Oncology, F. Hoffmann-La Roche Ltd, Basel,<br />
SWITZERLAND, 7 MDBB Biometrics, F. Hoffmann-La Roche Ltd, Basel,<br />
SWITZERLAND, 8 Department of Biomarkers, F. Hoffmann-La Roche Ltd, Basel,<br />
SWITZERLAND<br />
Background: In <strong>the</strong> phase III SATURN study, maintenance erlotinib significantly<br />
prolonged progression-free survival (PFS) vs placebo in patients (pts) with advanced<br />
non-small-cell lung cancer (NSCLC) and non-progressive disease after first-line<br />
chemo<strong>the</strong>rapy (Cappuzzo et al, Lancet Oncol 2010). Epidermal growth factor<br />
receptor (EGFR) expression analysis by immunohistochemistry (IHC) found no<br />
significant difference in PFS (p = 0.63) or overall survival (OS; p = 0.52) with<br />
erlotinib by EGFR IHC status (Brugger et al, J Clin Oncol 2011). Recently, Pirker at<br />
al. (Lancet Oncol <strong>2012</strong>) presented data on EGFR expression as a predictor of OS for<br />
first-line chemo<strong>the</strong>rapy plus cetuximab in <strong>the</strong> phase III FLEX study, using a novel<br />
method (H-score) to assign EGFR IHC status. We used this method to reassess<br />
samples from <strong>the</strong> SATURN study.<br />
Methods: The H-score method assigns an IHC score to each pt on a continuous<br />
scale of 0–300, based on <strong>the</strong> percentage of cells at different staining intensities<br />
(Pirker et al, Lancet Oncol <strong>2012</strong>). As per this method, <strong>the</strong> outcome-based<br />
discriminatory threshold IHC H-score for our analysis was set at 200 and existing<br />
samples were re-read and classed as low (H-score
MERCK SERONO: Advisor, speaker in symposia, research grant PFIZER: Advisor<br />
ROCHE/GENENTECH: Advisor, speaker in symposia. R. Pirker: The author declares<br />
<strong>the</strong> following: Honoraria for Advisory Board and speaker’s fee from AstraZeneca,<br />
Boehringer Ingelheim, Merck Serono and Roche. K.J. O’Byrne: The author declares:<br />
Payment from Merck Serono in relation to a protocol writing committee and<br />
advisory boards and travel costs in related to attendance. Honoraria from Merck<br />
Serono associated with presentation of data at satellite/company symposia. K.M.<br />
Kerr: Keith Kerr has acted on Advisory Boards and has received speaker’s fees from<br />
Merck Serono. He has had similar roles with Astra Zeneca, Roche, Eli Lilly, Daichi<br />
Sankyo, Pfizer, Boeringher Ingelheim and Glaxo Smith Klein. S. Störkel: The author<br />
has been involved in sponsored research by Merck KGaA. I. Celik: The author is an<br />
employee of Merck KGaA. A. von Heydebreck: Teh author is an employee of Merck<br />
KGaA and declares stock ownership in this company. F.A. Shepherd: Honorarium<br />
from Merck KGaA for presentation at Scientific, Industry-sponsored Satellite<br />
Symposium. Provided compensated consultation services to Merck KGaA.<br />
1273P T790M RESISTANT MUTATION IN PLASMA OF ACQUIRED<br />
RESISTANT EGFR MUTATED NON SMALL CELL LUNG<br />
CANCER (NSCLC) PATIENTS - THE TARZO TRIAL<br />
(NCT00503971)<br />
N. Reguart 1 , E. Nadal 2 , M.A. Molina 3 , E. Carcereny 4 , C. Queralt 4 , A. Insa Molla 5 ,<br />
I. Aguirre 6 , M. Taron 7 , D. Isla Casado 8 , R. Rosell 9<br />
1 Medical Oncology, Hospital Clinic Barcelona, BARCELONA, SPAIN, 2 Medical<br />
Oncology, Hospital Duran i Reynals (ICO), Barcelona, SPAIN, 3 Laboratoy of<br />
Biology Department, Pangaea Biotech, USP Dexeus University Institute,<br />
Barcelona, SPAIN, 4 Medical Oncology Service, Hospital Germans Trias i Pujol<br />
(ICO), Badalona, SPAIN, 5 Medical Hematology and Oncology, Hospital Clinico<br />
Universitario de Valencia, Valencia, SPAIN, 6 Medical Oncology, Hospital<br />
Germans Trias i Pujol, Barcelona, SPAIN, 7 Medical Oncology, Hospital Germans<br />
Trias i Pujol (ICO), Barcelona, SPAIN, 8 Oncology Service, Hospital Clínico<br />
Universitario Lozano Blesa, Zaragoza, SPAIN, 9 Medical Oncology, Hospital<br />
Germans Trias i Pujol (ICO)Oncology, Badalona, SPAIN<br />
Background: EGFR-mutant NSCLC patients (pts) ultimately overcome resistant to<br />
tyrosine kinase inhibitors (TKIs). Among resistant mechanisms secondary EGFR<br />
T790M is <strong>the</strong> most frequent and account 50% of tumors. Previous data suggest that<br />
tumors with acquired T790M at post-progression biopsy specimen may have a more<br />
favorable prognosis and indolent progression. However, tumor re-biopsies at<br />
progression sites are scare in NSCLC patients and blood samples are a non-invasive<br />
method that may help to identify resistant mechanisms.<br />
Material and methods: Pts with advanced NSCLC harboring EGFR mutations (Exon<br />
19 and 21) and acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) were<br />
eligible. All patients where included in a phase II trial (TARZO) and treated with<br />
erlotinib 150 mg PO daily plus oral vorinostat 400 mg QD on days 1–7 and 15–21 in<br />
a 28-day cycle. Blood samples were required at study entry. We aim to determine <strong>the</strong><br />
feasibility and incidence of T790M resistant mutation from plasma DNA from<br />
patients by mutation from cell free circulating DNA from patients using a 5 0 nuclease<br />
PCR assay (TaqMan assay) with a FAM MGB-labeled probe for <strong>the</strong> wild-type and a<br />
VIC MGB-labeled probe for <strong>the</strong> mutant sequence in <strong>the</strong> presence of a protein<br />
nucleic acid (PNA) clamp, which was designed to inhibit <strong>the</strong> amplification of <strong>the</strong><br />
wild-type allele (Pangaea Biotech SL patent).<br />
Results: Twenty-five pts were included in <strong>the</strong> trial. From those, nineteen plasma<br />
specimens were obtained and used for DNA extraction. Overall T790M resistant<br />
mutation was detected from plasma DNA in 36.8% of <strong>the</strong> samples (7/19). There were<br />
no differences according patient characteristics (gender/ECOG-PS, smoking habits,<br />
number of previous treatments) or type of sensitizing mutation in tissue (Exon 19,<br />
L858R) and <strong>the</strong> presence of T790M. Median time to progression (TTP) and survival<br />
(OS) for <strong>the</strong> entire cohort was 2.4 months (IC 95% 1.2-3.6) and 13.2 months (IC<br />
95% 2.23-26.9 months). Median TTP and OS were 2.4 vs 1.8 (p 0.076) and 13.7 vs<br />
3.7 (p 0.095) in patients without and with T790M respectively.<br />
Conclusions: T790M mutation is a common feature of resistant acquired EGFR<br />
mutated NSCLC patients and can be detected using plasma DNA.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1274P ALK AND EGFR MUTATION ANALYSIS IN A PHASE II TRIAL<br />
OF CISPLATIN/PEMETREXED IN JAPANESE PATIENTS WITH<br />
ADVANCED NON-SQUAMOUS NON-SMALL CELL LUNG<br />
CANCER<br />
N. Yanagitani 1 , K. Kaburaki 1 , F. Ohyanagi 1 , K. Kudo 1 , A. Horiike 1 , N. Motoi 2 ,<br />
K. Takeuchi 2 , Y. Ishikawa 2 , T. Horai 1 , M. Nishio 1<br />
1 Thoracic Oncology Center, Cancer Institute Hospital, Japanese Foundation for<br />
Cancer Research, Tokyo, JAPAN, 2 Pathology, Cancer Institute Hospital,<br />
Japanese Foundation for Cancer Research, Tokyo, JAPAN<br />
Background: Recently, ethnic differences and genotypes such as EGFR mutation or<br />
fusion gene (ALK translocation) are important factors in non-small cell lung cancer<br />
(NSCLC) treatment. Pemetrexed (P)/cisplatin (C) is one of <strong>the</strong> standard treatments<br />
Annals of Oncology<br />
for advanced non-squamous (Nsq) NSCLC. However, <strong>the</strong> efficacy of <strong>the</strong> CP regimen<br />
has not been well examined in Japanese Nsq NSCLC patients; fur<strong>the</strong>rmore, <strong>the</strong><br />
difference in efficacy between genotypes was not thoroughly examined. Therefore, <strong>the</strong><br />
present study was conducted to evaluate <strong>the</strong> efficacy of <strong>the</strong> CP regimen in Japanese<br />
Nsq NSCLC patients, and to determine whe<strong>the</strong>r EGFR mutation and ALK<br />
translocation impacted <strong>the</strong> treatment.<br />
Methods: This study was conducted from May 2009 to December 2010. Patients<br />
were eligible for this study if <strong>the</strong>y had histologically or cytologically confirmed<br />
recurrent or metastatic Nsq NSCLC previously untreated with chemo<strong>the</strong>rapy, an<br />
ECOG performance status of 0 or 1, life expectancy of more than 12 weeks, and<br />
adequate organ function. Patients received C (75 mg/m2) plus P (500 mg/m2) on day<br />
1 every 3 weeks. Of <strong>the</strong> 50 patients initially enrolled, 49 were evaluated, and 43<br />
tumor samples were available for analysis. Most patients were male (80%), and 80%<br />
of <strong>the</strong> patients had adenocarcinoma. The primary endpoint was <strong>the</strong> response rate<br />
that was evaluated. according to RECIST. EGFR mutation was examined using<br />
PCR-based methods, and <strong>the</strong> ALK fusion protein was examined using a highly<br />
sensitive IHC method in <strong>the</strong> available tumor specimens.<br />
Results: The objective response rate and disease control rate in all patients were<br />
44.9% and 79.6%, respectively. The median progression-free survival was 4.4 months,<br />
and <strong>the</strong> 1-year survival was 73.5%. Toxicities were mild; no new toxicity profile was<br />
identified. Among <strong>the</strong> 43 samples, <strong>the</strong> following mutations were identified: 9 EGFRm<br />
(21%), 5 ALK (12%), and 29 wild-type (67%). Objective response was observed in 6<br />
(66.7%) EGFRm, 2 (40%) ALK (+), and 13 (44.8%) wild-type mutations.<br />
Conclusion: Although <strong>the</strong> CP regimen demonstrates consistent efficacy in Japanese<br />
Nsq NSCLC patients, EGFR mutation and ALK translocation may have impacted<br />
this treatment.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1275P UPDATED SAFETY AND QUALITY OF LIFE (QOL) RESULTS<br />
OF PARAMOUNT STUDY: MAINTENANCE PEMETREXED<br />
(PEM) PLUS BEST SUPPORTIVE CARE (BSC) VS PLACEBO<br />
(PBO) PLUS BSC IMMEDIATELY FOLLOWING INDUCTION<br />
TREATMENT WITH PEM PLUS CISPLATIN (CP) FOR<br />
ADVANCED NONSQUAMOUS NON-SMALL CELL LUNG<br />
CANCER (NS-NSCLC)<br />
J. Pujol 1 , L. Paz-Ares 2 , M. Dediu 3 , M. Thomas 4 , P. Bidoli 5 , J. Corral 2 ,<br />
N. Chouaki 6 , C.M. Visseren-Grul 7 , A. Zimmermann 8 , C. Gridelli 9<br />
1 Thoracic Oncologic Unit, Montpellier Academic Hospital, Hospital Arnaud de<br />
Villeneuve, Montpellier, Montpellier, FRANCE, 2 Medical Oncology, Hospital<br />
Universitario Virgen del Rocío, Seville, SPAIN, 3 Medical Oncology, Institute of<br />
Oncology Bucharest, Fundeni Clinical Hospital Alexandru Treistoreanu,<br />
Bucharest, ROMANIA, 4 Department of Thoracic Oncology, University of<br />
Heidelberg, Thoraxklinik Heidelberg, GERMANY, 5 Medical Oncology, Azienda<br />
Ospedaliera S. Gerardo U.O. Oncologia Medica, Monza, ITALY, 6 Medical<br />
Department, Eli Lilly, Paris, FRANCE, 7 Oncology Europe, Eli Lilly, RA Houten,<br />
NETHERLANDS, 8 Oncology, Eli Lilly and Company, Indianapolis, IN, UNITED<br />
STATES OF AMERICA, 9 Medical Oncology, UO Oncologia Medica “S.G. Moscati<br />
Hospital”, Avellino, ITALY<br />
Objectives: The PARAMOUNT trial showed that continuation maintenance <strong>the</strong>rapy<br />
with pem after induction <strong>the</strong>rapy with pem plus CP significantly reduced <strong>the</strong> risk of<br />
disease progression (HR = 0.62) and death (HR = 0.78) in patients (pts) with<br />
advanced NS-NSCLC. The purpose of this abstract is to present <strong>the</strong> updated safety<br />
and patients’ QoL results from <strong>the</strong> continuation maintenance treatment of <strong>the</strong><br />
PARAMOUNT trial.<br />
Methods: In this phase III, randomized, double-blind, PBO-controlled study, 939 pts<br />
were treated with pem (500 mg/m 2 ) plus CP (75 mg/m 2 ) on day 1 of four 21-day<br />
cycles. Patients (n = 539) who had not progressed and had an Eastern Cooperative<br />
Oncology Group performance status (PS) of 0/1, were randomized (2:1; stratified for<br />
PS, induction response, and disease stage) to maintenance pem (500 mg/m 2 ,day1)<br />
plus BSC (n = 359) or PBO plus BSC (n = 180) until disease progression. All pts<br />
received vitamin B 12, folic acid, and dexamethasone. All randomized pts were<br />
qualified for <strong>the</strong> maintenance phase safety analyses, which included summaries of<br />
<strong>the</strong> incidence of adverse events by maximum Common Terminology Criteria<br />
Adverse Events, version 3, grade. All enrolled patients that had provided baseline and<br />
at least 1 subsequent measurement for EuroQol 5-dimensional (EQ-5D) scale were<br />
included in <strong>the</strong> analysis of patient-reported outcomes.<br />
Results: Safety and <strong>the</strong> QoL analyses in <strong>the</strong> continuation maintenance <strong>the</strong>rapy will<br />
be presented.<br />
Conclusions: The long-term and low-grade toxicities of continuation maintenance<br />
<strong>the</strong>rapy with pem will be discussed.<br />
Disclosure: C.M. Visseren-Grul: Employed by and own stock in Eli Lilly and<br />
Company. L. Paz-Ares: I have advisory board relationship and honararia to disclose<br />
with Eli Lilly and Company, Bayer, Roche, Pfizer. I. M. Dediu: Advisory Board - Eli<br />
Lilly and Company. M. Thomas: Advisory Board - Eli Lilly and Company Corporate<br />
Sponsored Trial - Eli Lilly and Company. N. Chouaki: Employed by and own stock<br />
in Eli Lilly and Company. A. Zimmermann: Employed by and own stock in Eli Lilly<br />
and Company. J. Pujol: Advisory Board - Eli Lilly and Company. C. Gridelli:<br />
ix418 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Advisory Board, corporate-sponsored research, and honoraria/speaker bureau with<br />
Eli Lilly and Company. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1276P SECOND-LINE ERLOTINIB THERAPY IN ELDERLY PATIENTS<br />
WITH ADVANCED NON-SMALL-CELL LUNG CANCER:<br />
IFCT-0501 RANDOMISED, PHASE 3 TRIAL<br />
E. Quoix 1 , V. Westeel 2 , J. Oster 3 , E. Pichon 4 , J. Dauba 5 , D. Debieuvre 6 ,<br />
L. Baudrin 7 , F. Morin 8 , B. Milleron 9 , G. Zalcman 10<br />
1 Pneumologie, HUS, Strasbourg, FRANCE, 2 Pneumologie, CHU, Besançon,<br />
FRANCE, 3 Pneumologie, CH, Colmar, FRANCE, 4 Pneumologie, CHU, Tours,<br />
FRANCE, 5 Pneumologie, CH, Mont-de-Marsan, FRANCE, 6 Pneumology, General<br />
Hospital, Mulhouse, FRANCE, 7 Biostatistics, IFCT, Paris, FRANCE, 8 IFCT,<br />
PARIS, FRANCE, 9 Pneumologie, AP-HP Hôpital Tenon, PARIS, FRANCE,<br />
10 Pneumologie, CHU, Caen, FRANCE<br />
Background: The IFCT-0501 randomised, phase 3 trial showed a significant survival<br />
benefit for <strong>the</strong> experimental arm using carboplatin-weekly paclitaxel doublet<br />
chemo<strong>the</strong>rapy (Arm B) over vinorelbine or gemcitabine mono<strong>the</strong>rapy (Arm A), in<br />
elderly patients with advanced NSCLC (Quoix et al, Lancet 2011; 378:1079-88). In<br />
case of progression or toxicity, second-line (2nd) treatment with erlotinib was<br />
administered in both arms. Here we report <strong>the</strong> results of this 2nd-line <strong>the</strong>rapy.<br />
Methods: Patients aged 70 to 89 years, with locally advanced or metastatic NSCLC,<br />
received erlotinib 150 mg daily as 2nd-line treatment until disease progression or<br />
excessive toxicity.<br />
Results: Among 443 patients who completed first-line chemo<strong>the</strong>rapy, 292 received<br />
2nd-line erlotinib, at <strong>the</strong> same proportion in both arms (A: 64%, B: 67%, p = 0.46).<br />
Median duration of erlotinib treatment was not different according to first-line<br />
treatment arm, 2.01 and 2.24 months for arm A and arm B, respectively. Ability to<br />
receive 2nd-line treatment was significantly associated with performance status (0-1<br />
vs. 2-3), weight loss (≤5% vs. >5%), MMS (≤23 vs. >23) and ADL ( 80), sex or histology (squamous vs.<br />
non squamous). Response evaluated after 2 months of erlotinib was: CR: 1 (0,35%),<br />
PR : 25 (8,77%) and SD : 63 (22,1%). From <strong>the</strong> Day 1 of erlotinib administration,<br />
median overall survival was 4 and 6.8 months in arm A and B, respectively, with a<br />
1-yr survival rate of 26.4% and 33.7%, respectively (p = 0.08). Progression-Free<br />
Survival was 2.2 and 2.6 months, respectively (p = 0.36). Grade 3/4/5 toxicity was<br />
19.9/1/0%.<br />
Conclusions: In elderly patients with advanced NSCLC, administration of 2nd-line<br />
erlotinib is feasible, well tolerated, with a response rate comparable to that observed<br />
in previous trials, and maintained <strong>the</strong> survival advantage obtained with first-line<br />
carboplatin-weekly paclitaxel (NCT002598415).<br />
Disclosure: E. Quoix: Travel grants for meetings : lilly roche Advisory board : Lilly,<br />
Roche Grants for <strong>the</strong> study given to IFCT: BMS, pierre Fabre, Roche. V. Westeel:<br />
stock ownership: No membership on an advisory board or board of directors: roche,<br />
Lilly corporate-sponsored research: Roche o<strong>the</strong>r substantive relationships: Roche,<br />
Lilly, AstraZeneca, Boehringer Ingelheim. B. Milleron: stock ownership: No<br />
membership on an advisory board or board of directors: Yes Lilly, Roche<br />
corporate-sponsored research: No o<strong>the</strong>r substantive relationships: travel grants from<br />
Lilly and Roche. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1277P COMPARATIVE EFFICACY AND SAFETY OF ERLOTINIB IN<br />
NON-SMALL CELL LUNG CANCER (NSCLC) OF SQUAMOUS<br />
CELL AND ADENOCARCINOMA HISTOLOGY IN THE PHASE<br />
III NCIC CTG BR.21 AND SATURN (BO18192) TRIALS<br />
S. Wojtowicz-Praga 1 , L. Leon 2<br />
1 Biooncology, Medical Affairs, Genentech, Inc., South San Francisco, CA,<br />
UNITED STATES OF AMERICA, 2 Biostatistics, Genentech, Inc., South<br />
San Francisco, CA, UNITED STATES OF AMERICA<br />
Background: Tumors of squamous cell (SC) histology are present in 25–30% of lung<br />
cancer patients (pts), and are more frequent in pts with a history of smoking.<br />
Erlotinib is an oral EGFR TKI shown to prolong progression-free survival (PFS)<br />
compared with placebo in first-line (1L) maintenance (SATURN; Cappuzzo, Lancet<br />
Oncol 2010) and second- or third-line (2L/3L) NSCLC settings (BR-21; Shepherd,<br />
NEJM 2005). Data from <strong>the</strong>se pivotal studies were retrospectively analyzed to<br />
compare outcomes for pts with tumors of SC histology with those of pts diagnosed<br />
with adenocarcinomas (AD).<br />
Methods: BR.21 randomized ECOG PS 0–3 pts with advanced NSCLC who<br />
progressed after 1L or 2L chemo<strong>the</strong>rapy 2:1 to erlotinib (150 mg daily) or placebo.<br />
SATURN randomized ECOG PS 0–1 pts with advanced NSCLC who did not<br />
progress after 1L chemo<strong>the</strong>rapy 1:1 to maintenance <strong>the</strong>rapy with erlotinib (150 mg<br />
daily) or placebo. PFS and overall survival (OS) were estimated using Kaplan-Meier<br />
methods. Hazard ratios (HRs) were calculated using Cox regression analysis.<br />
Results: 587 and 763 pts were evaluable in BR.21 and SATURN, respectively. A<br />
higher percentage of SC pts were smokers (current or ex-) and males versus AD pts<br />
in both studies. Most o<strong>the</strong>r baseline characteristics were similar between histology<br />
groups within each study. Efficacy and safety outcomes are shown (Table). In an<br />
interaction model analyzing for differential treatment effects on survival by SC and<br />
AD histology, P-values were >0.65 and >0.45 for PFS and OS in BR.21, respectively,<br />
and >0.2 for PFS in SATURN, providing no evidence for a statistically significant<br />
differential effect.<br />
Conclusions: Analyses of data from two large pivotal trials associated erlotinib<br />
treatment with significant survival benefit in both SC and AD histology subgroups,<br />
supporting its efficacy in pts with SC NSCLC in <strong>the</strong> 1L maintenance, 2L, and 3L<br />
settings.<br />
Measure<br />
BR.21 (N = 587)<br />
Grade 3–5 adverse events, n (%)<br />
Placebo arm Erlotinib arm HR (95% CI)<br />
AD (n = 365) 75 (63) 148 (60) –<br />
SCC<br />
Median PFS, mo<br />
56 (72) 109 (76) –<br />
AD 1.84 2.37 0.62 (0.49–0.79)<br />
SCC<br />
Median OS, mo<br />
1.81 2.27 0.48 (0.35–0.67)<br />
AD 5.36 7.75 0.76 (0.58–0.98)<br />
SCC<br />
SATURN (N = 763)<br />
Grade 3–5 adverse events, n (%)<br />
3.58 5.57 0.60 (0.44–0.82)<br />
AD (n = 403) 27 (14) 59 (29) –<br />
SCC (n = 360)<br />
Median PFS, mo<br />
23 (12) 41 (25) –<br />
AD 2.60 2.83 0.63 (0.51–0.78)<br />
SCC 2.60 3.02 0.77 (0.61–0.96)<br />
Disclosure: S. Wojtowicz-Praga: Dr. Wojtowicz-Praga is an employee of and holds<br />
stock options in Roche/Genentech. L. Leon: Dr. Leon is an employee of and holds<br />
stock options in Roche/Genentech.<br />
1278P CUMULATIVE EXPOSURE (EXP) TO BEVACIZUMAB (BV)<br />
MAINTENANCE AFTER INDUCTION THERAPY AND<br />
SURVIVAL IN ADVANCED NON-SMALL CELL LUNG CANCER<br />
(NSCLC): A TIME-DEPENDENT ANALYSIS FROM THE SAIL<br />
(MO19390) STUDY<br />
N. Thatcher 1 , P. Garrido Lopez 2 , N. Pavlakis 3 , J. Laskin 4 , E. Dansin 5 ,<br />
F. Griesinger 6 , L. Leon 7 , D. Dalal 8 , P. Perez-Moreno 9 , L. Crino 10<br />
1 Department of Medical Oncology, University of Manchester, Manchester,<br />
UNITED KINGDOM, 2 Medical Oncology, Hospital Ramon y Cajal, Madrid,<br />
SPAIN, 3 Medical Oncology, Royal North Shore Hospital, St Leonards,<br />
AUSTRALIA, 4 Medical Oncology, BC Cancer Agency, Vancouver, CANADA,<br />
5 Département De Cancérologie Générale, CLCC Oscar Lambret, Lille Cedex,<br />
FRANCE, 6 Klinik für Hämatologie und Onkologie, Pius-Hospital Oldenburg,<br />
Oldenburg, GERMANY, 7 Biostatistics, Genentech, Inc., South San Francisco,<br />
CA, UNITED STATES OF AMERICA, 8 US Medical Affairs, Genentech, Inc., South<br />
San Francisco, CA, UNITED STATES OF AMERICA, 9 Pharmaceuticals Division,<br />
Gpsmo, F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, 10 Department of<br />
Oncology, Hospital Santa Maria della Misericordia, Perugia, ITALY<br />
Background: Exploratory analyses from randomized and observational studies have<br />
shown that continuation BV until progressive disease (PD) is associated with<br />
prolonged overall survival (OS) in advanced NSCLC. We evaluated <strong>the</strong> correlation<br />
between cumulative exp to post-induction phase (post-IP) BV and OS in patients<br />
(pts) with NSCLC.<br />
Methods: The multinational phase 4 SAiL study enrolled advanced NSCLC pts<br />
receiving BV with 1st-line chemo<strong>the</strong>rapy (CT). Pts who began BV and CT<br />
simultaneously and did not have PD after completing 12–18 weeks (4–6 cycles) of<br />
CT were included for analysis. OS was measured from <strong>the</strong> end of each pt’s BV+CT<br />
IP. BV exp, over follow-up, was defined as <strong>the</strong> cumulative days of post-IP BV<br />
treatment (tx). A time-dependent Cox regression model was fitted to assess <strong>the</strong> effect<br />
of cumulative post-IP BV exp on OS, while controlling for potential time-dependent<br />
and -fixed confounders. A landmark sensitivity analysis compared OS in pts in <strong>the</strong><br />
analysis population who did and did not continue BV after IP.<br />
Results: Of 2212 pts in SAiL, 1625 NSCLC pts were alive and without PD through<br />
IP tx. Baseline characteristics (n = 1625) were: 58% male, 13% ≥70 y, 32% never<br />
smokers, and 4% ECOG PS ≥2. 1047 (64%) pts received post-IP BV. Baseline and<br />
end-of-IP characteristics were generally similar between pts receiving post-IP BV or<br />
no post-IP BV within <strong>the</strong> landmark period. Across follow-up, <strong>the</strong> hazard ratios<br />
(HRs) for OS decreased by ∼7% (range, 5%–9%) with each additional 21-day interval<br />
of cumulative exp (Table). Landmark sensitivity analyses also support that post-IP<br />
BV was associated with longer OS (post-IP BV vs no post-IP BV; HR, 0.74; 95% CI,<br />
0.64–0.85).<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds409 | ix419
Conclusions: These data from SAiL along with previously presented data from<br />
ARIES suggest that cumulative exp to post-IP BV is associated with incremental<br />
increases in OS for NSCLC pts.<br />
Cumulative<br />
post-IP BV cycles a<br />
No. of pts who received cumulative<br />
cycles of post-IP BV continuously b<br />
HR (95% confidence<br />
interval) for OS<br />
1 1006 0.91 (0.89–0.93)<br />
2 884 0.82 (0.79–0.86)<br />
3 758 0.75 (0.70–0.80)<br />
4 643 0.68 (0.62–0.74)<br />
5 530 0.62 (0.55–0.69)<br />
6 447 0.56 (0.49–0.64)<br />
7 370 0.51 (0.44–0.59)<br />
8 315 0.46 (0.39–0.55)<br />
a A cycle is approximately 21 days of post-IP cumulative exp. b Eg, n = 530 pts were<br />
continuously dosed through day 105 (cycle 5) after IP.<br />
Disclosure: N. Thatcher: Dr. Thatcher is a member of <strong>the</strong> Roche advisory board and<br />
has received speaker fees from Roche. P. Garrido Lopez: Dr. Garrido Lopez is a<br />
member of <strong>the</strong> Roche advisory board. N. Pavlakis: Dr. Pavlakis has received speaker<br />
honoraria and travel grants from Roche, and has participated in Roche Advisory<br />
Boards. J. Laskin: Dr. Laskin is a member of <strong>the</strong> Canadian National Ad Board for<br />
lung cancer for Astra Zeneca, BI, and Eli Lilly and has received research funding<br />
from Roche, Boehringer-Ingelheim, and Eli Lilly. E. Dansin: Dr. Dansin is a member<br />
of <strong>the</strong> Roche advisory board. F. Griesinger: Dr. Griesinger is a member of national<br />
and international advisory boards of Roche and has received honoraria for<br />
presentations at meetings. L. Leon: Dr. Leon is an employee of and holds stock<br />
options in Roche/Genentech. D. Dalal: Dr. Dalal is an employee of and holds stock<br />
options in Roche/Genentech. P. Perez-Moreno: Dr. Perez-Moreno is an employee of<br />
and holds stock options in F. Hoffman LaRoche. L. Crino: Dr. Crino received<br />
honorarium from Roche as a speaker in a scientific symposium.<br />
1279P CUMULATIVE EXPOSURE TO BEVACIZUMAB (BV) AFTER<br />
DISEASE PROGRESSION (PD) CORRELATES WITH SURVIVAL<br />
IN NON-SMALL CELL LUNG CANCER (NSCLC): A<br />
TIME-DEPENDENT ANALYSIS OF THE ARIES<br />
OBSERVATIONAL COHORT STUDY<br />
T.J. Lynch 1 , M. Jahanzeb 2 , D.R. Spigel 3 , A. Wozniak 4 , L. Leon 5 , S. Fish 5 ,E.<br />
D. Flick 6 , D. Dalal 6 , M.P. Kosty 7<br />
1 Yale School of Medicine, Yale Comprehensive Cancer Center, New Haven,<br />
UNITED STATES OF AMERICA, 2 University of Miami, Miller School of Medicine,<br />
Sylvester Comprehensive Cancer Center, Deerfield Beach, FL, UNITED STATES<br />
OF AMERICA, 3 Lung Cancer Research Program, Sarah Cannon Research<br />
Institute, Nashville, TN, UNITED STATES OF AMERICA, 4 Department of<br />
Hematology-Oncology, Wayne State University, Detroit, MI, UNITED STATES OF<br />
AMERICA, 5 Biostatistics, Genentech, Inc., South San Francisco, CA, UNITED<br />
STATES OF AMERICA, 6 Us Medical Affairs, Genentech, Inc., South<br />
San Francisco, CA, UNITED STATES OF AMERICA, 7 Department of Oncology,<br />
Scripps Clinic, La Jolla, CA, UNITED STATES OF AMERICA<br />
Background: Duration of BV use appears to contribute to treatment (tx) efficacy in<br />
some cancers (eg, CRC, ovarian). A phase 3 mCRC trial met its 1° endpoint of<br />
improved postprogression overall survival (ppOS) when continuing BV with<br />
chemo<strong>the</strong>rapy (CT) into 2nd-line (2L) tx. A phase 2 study showed a trend for OS<br />
benefit when adding BV to CT in BV-naive 2L NSCLC (HR 0.71; 95% CI 0.41–1.21)<br />
(Herbst JCO 2007). This analysis evaluated whe<strong>the</strong>r BV exposure (exp) after PD<br />
correlates with ppOS in NSCLC.<br />
Methods: ARIES 1st-line (1L) BV-treated NSCLC patients (pts) who survived 1st PD<br />
were included. ppOS equaled <strong>the</strong> time from 1st PD to any-cause death. BV exp, over<br />
follow-up, equaled <strong>the</strong> cumulative days of BV from 1st PD. A time-dependent Cox<br />
regression model was fitted to assess <strong>the</strong> effect of cumulative BV exp on ppOS, while<br />
controlling for potential time-dependent and -fixed confounders. A landmark<br />
sensitivity analysis, also adjusting for confounders, compared ppOS in pts treated<br />
with BV beyond PD (BBP) and pts treated o<strong>the</strong>rwise (No BBP) ≤30 days after PD.<br />
Results: As of 09/2011, of 1967 enrolled 1L pts, 1461 (74%) had 1st PD.<br />
Characteristics (n = 1461) were: 48% had 1st PD within 6 mos, 52% male, 31% ≥70<br />
y, 13% never smokers, and 13% ECOG status ≥2. The median ppOS for all pts with<br />
1st PD was 6 mos (95% CI 5.6–6.7). Among pts with any BV tx, <strong>the</strong> mean<br />
cumulative BV exp was 116 days (range, 2–1140). Across follow-up, <strong>the</strong> HRs for<br />
ppOS decreased by ∼4% for each additional 21-day interval of cumulative exp<br />
(Table). Cumulative BV duration was associated with improved ppOS (P < .0001).<br />
The landmark analysis also showed that BBP was independently associated with<br />
higher ppOS (BBP vs No BBP; HR, 0.75; 95% CI, 0.65–0.86).<br />
Conclusions: This analysis suggests that cumulative exp to BV after 1st PD may<br />
correspond with incremental increases in ppOS for NSCLC pts, and supports <strong>the</strong><br />
conduct of <strong>the</strong> phase 3 AvaALL trial.<br />
Cycle a<br />
No. of pts who received<br />
cumulative cycles of BV<br />
continuously b<br />
Hazard ratio<br />
(HR) for ppOS<br />
Annals of Oncology<br />
95% confidence<br />
interval (CI)<br />
1 229 0.959 0.941–0.978<br />
2 159 0.920 0.885–0.956<br />
3 118 0.883 0.833–0.935<br />
4 84 0.847 0.784–0.914<br />
5 72 0.812 0.738–0.894<br />
6 55 0.779 0.694–0.874<br />
7 41 0.747 0.653–0.855<br />
8 32 0.717 0.614–0.836<br />
a A cycle is calculated as 21 days of cumulative exposure after PD. b Eg, n = 55 patients<br />
were continuously dosed through approximately day 126 (cycle 6) after PD.<br />
Disclosure: T.J. Lynch: Dr. Lynch is on <strong>the</strong> Infinity Pharmaceuticals board of<br />
directors, consults for Merck, Boehringer-Ingleheim and Astex, and holds a patent<br />
on EGFR testing from Partners Healthcare. M. Jahanzeb: Dr. Jahanzeb is a<br />
consultant/advisor for Genentech. D.R. Spigel: Dr. Spigel is an unpaid advisor/<br />
consultant to Genentech. A. Wozniak: Dr. Wozniak has received honoraria and<br />
research support from Genentech and research funding from Eli Lilly. L. Leon: Dr.<br />
Leon is an employee of and holds stock options in Roche/Genentech. S. Fish: Dr.<br />
Fish is an employee of and holds stock options in Roche/Genentech. E.D. Flick: Dr.<br />
Flick is an employee of and holds stock options in Roche/Genentech. D. Dalal: Dr.<br />
Dalal is an employee of and holds stock options in Roche/Genentech. M.P. Kosty:<br />
Dr. Kosty has participated in <strong>the</strong> Genentech Speakers’ Bureau.<br />
1280P A PHASE II STUDY OF ERLOTINIB MONOTHERPAY IN<br />
PREVIOUSLY TREATED ADVANCED NON-SMALL CELL LUNG<br />
CANCER (NSCLC) WITHOUT EGFR GENE MUTATION WHO<br />
HAVE NEVER/LIGHT SMOKING HISTORY: NEJ006/<br />
TCOG0903<br />
M. Maemondo 1 , Y. Ishii 2 , Y. Demura 3 , K. Okudera 4 , K. Takamura 5 ,<br />
N. Morikawa 6 , M. Harada 7 , O. Ishimoto 8 , K. Kobayashi 9 , Y. Saijo 10<br />
1 Respiratory Medicine, Miyagi Cancer Center, Natori, JAPAN, 2 Pulmonary<br />
Medicine and Clinical Immmunolog, Dokkyo Medical University School of<br />
medicine, Tochigi, JAPAN, 3 Respiratory Medicine, Ishikawa Prefectural Central<br />
Hospital, Kanazawa, JAPAN, 4 Respiratory Medicine, Hirosaki Central Hospital,<br />
Hirosaki, JAPAN, 5 Respiratory Medicine, Obihiro-Kousei General Hospital,<br />
Obihiro, JAPAN, 6 Medical Oncology, Tohoku Kousei-Nenkin Hospital, Sendai,<br />
JAPAN, 7 Respiratory Medicine, National Hospital Organization Hokkaido Cancer<br />
Center, Sapporo, JAPAN, 8 Respiratory Medicine, Sendai Kosei Hospital, Sendai,<br />
JAPAN, 9 Respiratory Medicine, Saitama International Medical Center, Saitama,<br />
JAPAN, 10 Medical Oncology, Niigata University Graduate School of Medical and<br />
Dental Sciences, Nigata, JAPAN<br />
Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors<br />
(TKIs) have dramatically improved clinical outcome in NSCLC harboring EGFR<br />
gene mutation. On <strong>the</strong> o<strong>the</strong>r hand, survival benefit from erlotinib was revealed even<br />
in <strong>the</strong> NSCLC patients with wild type (wt) EGFR gene by subset analyses of several<br />
phase III trials. Additionally, smoking status was identified as one of predictive<br />
factors of erlotinib efficacy. This study aimed to evaluate <strong>the</strong> efficacy of erlotinib in<br />
Japanese NSCLC patients with wt-EGFR and to find a biomarker that predicts <strong>the</strong><br />
efficacy of erlotinib except EGFR gene mutation.<br />
Methods: The primary endpoint was an objective response rate. Secondary endpoints<br />
included disease control rate, overall survival, safety, and a biomarker finding.<br />
Advanced NSCLC patients without EGFR gene mutation who had received one to<br />
three prior chemo<strong>the</strong>rapy regimens and who had never or light smoked were eligible<br />
in this study. EGFR gene status was evaluated by <strong>the</strong> PNA-LNA PCR clamp method.<br />
Erlotinib was administered daily (150mg/day) until disease progression or<br />
unacceptable toxicities.<br />
Results: Forty seven patients were enrolled between March 2010 and November<br />
2011. One patient was excluded for evaluation because having activating EGFR<br />
mutation. Efficacy and safety were evaluated among 46 patients. Best responses were<br />
PR 7 (15.2%), SD 12 (26.1%), PD 26 (46.4%), and NE 1 (2.2%). Response rate and<br />
disease control rate were 15.2% (95%CI: 4.9-25.5%) and 41.3 % (95%CI 27.1-55.5%)<br />
respectively. Median PFS were 1.5 months and 5 (11%) cases received erlotinib for<br />
more than 6 months. Grade 3 or 4 adverse events were anorexia (4), skin rash (2),<br />
neutropenia (1), leukopenia (1), anemia (2), elevation of AST/ALT (1), rectal ulcer<br />
(1), and cerebral infarction (1).Two patients suffered grade 3 interstitial lung disease.<br />
Conclusion: This is <strong>the</strong> first report to evaluate erlotinib efficacy in NSCLC selected<br />
by EGFR mutation negative and smoking status. This study elucidated that erlotinib<br />
has appreciable effect on some EGFR-wild cases without severe toxicities. Finding of<br />
predictive marker became more important. Biomarker analysis is ongoing.<br />
Disclosure: M. Maemondo: M. Maemondo received honoraria for lecture fees from<br />
Chugai. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
ix420 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
1281P MAINTENANCE THERAPY FOR NONSQUAMOUS<br />
NON-SMALL CELL LUNG CANCER (NSQNSCLC):<br />
PATIENT-REPORTED SYMPTOMS, PERFORMANCE STATUS<br />
(PS) AND EFFICACY<br />
C. Obasaju 1 , L. Bowman 2 , P. Wang 1 , W. Shen 3 , K.B. Winfree 2 , E.N. Smyth 2 ,<br />
M. Boye 2 , W. John 1 , C.P. Belani 4<br />
1 Oncology, Eli Lilly and Company, Indianapolis, IN, UNITED STATES OF<br />
AMERICA, 2 Global Health Outcomes, Eli Lilly and Company, Indianapolis, IN,<br />
UNITED STATES OF AMERICA, 3 Global Statistics, Eli Lilly and Company,<br />
Indianapolis, IN, UNITED STATES OF AMERICA, 4 Cancer Institute, Penn State<br />
Milton S. Hershey Medical Center, Hershey, PA, UNITED STATES OF AMERICA<br />
Purpose: Ciuleanu et al. (2009) showed that pemetrexed (Pem) maintenance <strong>the</strong>rapy<br />
is well-tolerated and offers significantly superior overall survival (OS) and<br />
progression-free survival (PFS) versus (vs) placebo (pbo) in patients (pts) with<br />
advanced nsqNSCLC. This retrospective analysis assessed <strong>the</strong> effect of maintenance<br />
<strong>the</strong>rapy on OS and PFS by baseline patient-reported symptom burden and PS.<br />
Methods: Data from 481 nonsquamous pts were analyzed. Symptom burden of 464<br />
pts was captured with baseline values of <strong>the</strong> Lung Cancer Symptom Scale (LCSS),<br />
which includes 6 disease-specific symptom items (anorexia, fatigue, cough, dyspnea,<br />
pain, hemoptysis), each ranging from 0 (no symptoms) to 100 (worst symptoms).<br />
Average symptom burden index (ASBI) is <strong>the</strong> mean of <strong>the</strong> 6 items. Symptom<br />
subgroups were defined by ASBI: low symptom burden (LSB; ASBI < 25) and high<br />
symptom burden (HSB; ASBI ≥ 25). Multivariate Cox models were used to evaluate<br />
<strong>the</strong> maintenance treatment effect within ASBI subgroups adjusting for 9<br />
demographic/clinical (DC) factors, including ECOG PS and stage of disease.<br />
Similarly, maintenance treatment effects within PS 0, 1 subgroups were evaluated.<br />
Results: Controlling for PS and o<strong>the</strong>r DC factors, pts with LSB (n = 333) and HSB<br />
(n = 131) who received maintenance <strong>the</strong>rapy had improved PFS vs pbo: 5.1 vs 2.4<br />
months [mos] (hazard ratio [HR] 0.49, p < 0.001) for LSB and 3.7 vs 2.8 mos (HR<br />
0.50, p = 0.003) for HSB. LSB pts had improved OS vs pbo (median OS 17.5 vs 11.0<br />
mos, HR 0.63, p = 0.001), but HSB pts did not (median OS 11.8 vs 10.6 mos, HR<br />
1.02, p = 0.92). PS was associated with patient-reported symptoms. PS 0 pts had<br />
lower mean LCSS scores than PS 1 pts for fatigue, pain, and ASBI (each p < 0.05). PS<br />
subgroup results are similar to <strong>the</strong> symptom-burden analysis: improved PFS in PS 0,<br />
1 pts and improved OS in PS 0 pts.<br />
Conclusion: NsqNSCLC pts with LSB and HSB at <strong>the</strong> end of induction <strong>the</strong>rapy<br />
experienced significant improvements in PFS with Pem maintenance <strong>the</strong>rapy. This<br />
translated into improved OS for LSB pts. These data suggest that maintenance<br />
<strong>the</strong>rapy, ra<strong>the</strong>r than a break in treatment or “chemo holiday,” is an appropriate<br />
treatment strategy for nsqNSCLC pts at successful completion of induction <strong>the</strong>rapy.<br />
Disclosure: C. Obasaju: Employed by and own stock in Eli Lilly and Company. L.<br />
Bowman: Employed by and own stock in Eli Lilly and Company. P. Wang: Employed by<br />
and own stock in Eli Lilly and Comany. W. Shen: Employed by and own stock in Eli Lilly<br />
and Company. K.B. Winfree: Employed by and own stock in Eli Lilly and Company. E.N.<br />
Smyth: Employed by and own stock in Eli Lilly and Company. M. Boye: Employed by<br />
and own stock in Eli Lilly and Company. W. John: Employed by and own stock in Eli<br />
Lilly and Company. C.P. Belani: Served on advisory board for Eli Lilly and Company<br />
1282P TOPICAL: RANDOMIZED PHASE III TRIAL OF ERLOTINIB<br />
COMPARED WITH PLACEBO IN PATIENTS WITH ADVANCED<br />
NON–SMALL CELL LUNG CANCER (NSCLC) UNSUITABLE<br />
FOR FIRST-LINE CHEMOTHERAPY: UPDATED ANALYSIS<br />
S. Lee 1 , S. Upadhyay 2 , C. Lewanski 3 , S. Falk 4 , G. Skailes 5 , E. Marshall 6 ,<br />
Y. Ngai 7 , R. Rudd 7 , A. Hackshaw 7 , C. Boshoff 1<br />
1 Oncology, University College London (UCL) Hospitals & UCL Cancer Institute,<br />
London, UNITED KINGDOM, 2 Oncology, Scunthorpe General Hospital,<br />
Scunthorpe, UNITED KINGDOM, 3 Oncology, Charing Cross Hospital, London,<br />
UNITED KINGDOM, 4 Oncology, Yeovil District Hospital, Yeovil, UNITED<br />
KINGDOM, 5 Oncology, Royal Lancaster Infirmary, Blackpool, UNITED<br />
KINGDOM, 6 Oncology, Clatterbridge Centre for Oncology, Liverpool, UNITED<br />
KINGDOM, 7 Cancer Research Uk & Ucl Cancer Trials Centre, UCL Cancer<br />
Institute, London, UNITED KINGDOM<br />
Background: Despite <strong>the</strong> recommendation to treat advanced NSCLC with<br />
platinum-based chemo<strong>the</strong>rapy, <strong>the</strong> majority of <strong>the</strong>se pts receive only active<br />
supportive care (ASC) because of poor performance or multiple co-morbidities. We<br />
previously showed that erlotinib significantly improved PFS in such patients, but<br />
with an enhanced OS and PFS effect in female pts. Here, we report mature OS data<br />
including <strong>the</strong> association of first-cycle rash (FCR).<br />
Methods: 670 pts with stage IIIB/IV NSCLC (ECOG PS 2/3 or PS 0/1 with multiple<br />
co-morbidities unsuitable for chemo<strong>the</strong>rapy) were randomized to receive placebo (n =<br />
320) or erlotinib 150 mg/day (n = 350) and ASC until disease progression/toxicity. OS,<br />
PFS, adverse events, and QoL were examined. Pre-specified subgroup analyses included<br />
erlotinib-rash ≤28 days of starting treatment (FCR), and EGFR where available.<br />
Results: Baseline characteristics were well balanced in <strong>the</strong>se predominantly elderly<br />
NSCLC pts (median = 77 yrs, range 42-91). Among all pts, <strong>the</strong> hazard ratios (HRs)<br />
were 0.94 (95% CI 0.81-1.10, P = 0.46) for OS. Pts receiving erlotinib had a better<br />
PFS, HR = 0.83 (95% CI 0.71-0.97, P = 0.02). 59% of pts on erlotinib developed FCR.<br />
FCR was <strong>the</strong> only independent factor predictive of OS (HR = 0.17; P = 0.02) in a<br />
multivariate analysis containing rash, age, gender, histology, ECOG score and stage.<br />
There was a benefit for both OS (HR = 0.76, 95% CI 0.63-0.92, P = 0.01) and PFS<br />
(HR = 0.66, CI 0.54-0.80, P < 0.01), compared to placebo. The benefits were seen in<br />
all <strong>the</strong> subgps including those with <strong>the</strong> worst PS score (ECOG 3); OS HR = 0.58 and<br />
PFS HR = 0.41 & stage IV; OS HR = 0.66 and PFS = 0.56. The OS medians (months)<br />
were 6.2 (erlotinib-rash), 2.9 (no rash) and 4.1 (placebo). Continuous erlotinib,<br />
without rash, appeared to be associated with worse OS in some subgroups (e.g.<br />
males, ECOG 3). Results for EGFR and KRAS mutations are available on 390 pts. 7%<br />
(27/390) of pts had activating EGFR mutation; <strong>the</strong> benefits of erlotinib were seen<br />
regardless of EGFR status. KRAS mutations (19%, 73/390) were nei<strong>the</strong>r prognostic<br />
nor predictive of erlotinib benefit. Grade 3/4 diarrhea was more common with<br />
erlotinib (8.4% vs. 1.3%, p < 0.001); o<strong>the</strong>r adverse events were similar between<br />
groups.<br />
Conclusions: Erlotinib prolongs PFS and OS in patients with advanced NSCLC<br />
considered unsuitable for chemo<strong>the</strong>rapy, but only if <strong>the</strong>y develop FCR.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1283P A COMPARATIVE STUDY OF EPIDERMAL GROWTH FACTOR<br />
RECEPTOR TYROSINE KINASE INHIBITOR IN TREATMENT<br />
OF PATIENTS WITH BRAIN METASTASIS FROM NON-SMALL<br />
CELL LUNG CANCER<br />
L. Zhang 1 , L. Cai 2 , J. Zhu 1<br />
1 Thoracic Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, CHINA,<br />
2 Radio-Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, CHINA<br />
Purpose: Brain metastasis (BM) presents 20-25% of patients with non-small cell lung<br />
cancer (NSCLC). Whole brain radiation <strong>the</strong>rapy (WBRT) was considered as a<br />
standard <strong>the</strong>rapy along with stereotactic radiosurgery (SRS), or surgical resection<br />
(SR) or chemo<strong>the</strong>rapy (CXT). Median survival time ranged from 6.5-10 months for<br />
conventional <strong>the</strong>rapy. In this study, we purposed to compare <strong>the</strong> outcomes of<br />
conventional <strong>the</strong>rapy (CVT) combined with or without epidermal growth factor<br />
receptor tyrosine kinase inhibitor (EGFR-TKI) in <strong>the</strong> treatment for patients with BM<br />
from NSCLC.<br />
Methods: A total of 275 NSCLC patients with BM were treated sequentially between<br />
Jan, 1999 and Nov, 2011 according to our institutional protocol. Of <strong>the</strong>se 275<br />
patients, 97 (35%) underwent EGFR-TKI combined with CVT (TKI + CVT), and 178<br />
(65%) underwent CVT. All patients received WBRT. Both treatment groups were<br />
similar with regard to age, sex, smoking status, histological subtype, number and size<br />
of BM lesions, extracranial lesions and intracranial symptoms.<br />
Results: Median overall survivals (MOS), median progress free survivals (MPFS),<br />
median progress free survivals of intracranial lesions (MPFSI) and median progress<br />
free survivals of extracranial lesions (MPFSE) were 28.2 (95% CI:22.3-34.1) and 13.7<br />
(95% CI:11.4-15.9) months, 10.9 (95% CI:8.4-13.4) and 6.7 (95%CI:5.1-8.4) months,<br />
18.7 (95%CI: 12.6-24.8) and 10.3 (95%CI:8.4-12.3) months, 11.1(95%CI:9.1-13.1) and<br />
7.9 (95%CI:6.2-9.5) months for TKI + CTV and CTV groups, respectively. With TKI<br />
+ CVT group, improved outcome was found to be significantly associated with no<br />
lymph node metastasis (P = 0.001) and adverse drug reaction (ADR) (P = 0.001) for<br />
MOS, MPFS, MPFSI and MPFSE. With CVT group, improved MOS was found to be<br />
associated with age
NSCLC diagnosis and time of BM diagnosis were estimated using Kaplan-Meier<br />
method. Association between delayed WBRT, after at least 2 cycles of chemo<strong>the</strong>rapy<br />
(CT) or not, and death was evaluated using multivariable Cox proportional hazards<br />
model adjusted for gender, histology, smoking status and RPA score.<br />
Results: We included 175 consecutive pts: 61% were male, median age was 57 years<br />
[range = 27-79]. 68% had adenocarcinoma, 15% were never smoked. At first diagnosis of<br />
NSCLC, <strong>the</strong> TNM 2009 stage was mainly IV (68%) and III (21%). 42 % of BM were<br />
synchronous and 36% pts had no extracranial metastasis. The number of BM was: one<br />
in 34%, and more than three lesions in 41%. Karnofsky index was >= 70% in 79% of<br />
pts. The RPA class was good-I in 13 pts and poor-III in 37 pts. Radical surgery was<br />
performed in 23 pts (16%) while 8 pts (4.6%) received SRS. 70% had CT with a median<br />
nbr of 1 line [0-6], 31% were treated with anti EGFR <strong>the</strong>rapy. Median OS from NSCLC<br />
diagnosis was 18 (95%CI = [15;20]) months. Median OS from BM diagnosis was 9m<br />
(95%CI = [7.6;10.6]) for <strong>the</strong> whole population, 43 m for RPA class I, 10 m for class II<br />
and 2 m for class III. In 26% of <strong>the</strong> pts, WBRT was delayed and delayed WBRT was not<br />
associated with survival in multivariable analysis (HR = 1.24 95%CI.0.85-1.80).<br />
Conclusions: Our results suggest that in NSCLC with BM, RPA class II could be<br />
easily treated with systemic <strong>the</strong>rapy, with <strong>the</strong>n long survival, selected RPA class III<br />
may benefit WBRT and systemic treatment. ALK and EGFR status will be presented.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1285P BIWEEKLY CARBOPLATIN AND PACLITAXEL AS FIRST-LINE<br />
THERAPY FOR ELDERLY ADVANCED NON-SMALL CELL<br />
LUNG CANCER PATIENTS (PHASE II STUDY)<br />
I. Kota, K. Soejima, K. Naoki, H. Yasuda, H. Terai, A. Daisuke, K. Ohgino,<br />
S. Yoda, S. Ikemura, T. Betsuyaku<br />
Respiratory Medicine, Keio University School of Medicine, Tokyo, JAPAN<br />
Background: Incidence of elderly patients with advanced non-small cell lung cancer<br />
(NSCLC) is increasing, however <strong>the</strong> treatment for elderly patients is still waiting for <strong>the</strong><br />
best answer. Although several studies had suggested <strong>the</strong> advantage of chemo<strong>the</strong>rapy with<br />
platinum doublet for elderly patients with advanced NSCLC (e.g. Quoix E, et al., The<br />
Lancet 378, 2011), <strong>the</strong> application of platinum doublet to <strong>the</strong> elderly is still controversial.<br />
To evaluate <strong>the</strong> efficacy and tolerability of combination chemo<strong>the</strong>rapy with biweekly<br />
carboplatin (CBDCA) and paclitaxel (PTX) for elderly patients with advanced NSCLC,<br />
we conducted a multicenter non-randomized open label phase II trial.<br />
Methods: Eligibility criteria were as follows; histologically proven NSCLC, aged 70<br />
years and older, ECOG Performance Status (PS) of 0 to 2, clinical stage IIIB and IV,<br />
chemo<strong>the</strong>rapy naïve, and adequate organ function. Patients received CBDCA (AUC<br />
= 2.5) and PTX (90 mg/m2) on day 1 and 15 every 4-week for up to 6 cycles, until<br />
disease progression or intolerable toxicity. The primary endpoint was ORR, and <strong>the</strong><br />
secondary endpoints were PFS, OS and tolerability.<br />
Results: 60 patients (median age 78 years old, range 70-85) were enrolled. 45 patients<br />
were male and 45 were stage IV. PS 0/1/2 were 26/30/4, respectively. The median<br />
number of treatment cycle was 3 (1-6). CR/PR/SD/PD were 0/28.9/37.8/33.3% as <strong>the</strong><br />
best response, giving an ORR of 28.9 % and DCR of 66.7%. Median PFS and OS<br />
were 5.3 month (95% CI: 3.1-7.5) and 26.7 month (95% CI: 18.2-35.1), respectively.<br />
Grade 3/4 hematological toxicities were neutropenia (27%), leucopenia (15%) and<br />
anemia (8%). Grade 3 non-hematological toxicities were infusion reaction (2%),<br />
anorexia (2%), infection (10%), thrombosis (2%), fatigue (3%), diarrhea (2%) and<br />
gastrointestinal bleeding (3%). Although no grade 4 non-hematological toxicity was<br />
observed, one patient died probably due to treatment-related interstitial pneumonitis.<br />
The adverse events were relatively mild and manageable.<br />
Conclusions: The combination of biweekly CBDCA (AUC = 2.5) and PTX<br />
(90 mg/m2) was effective and well tolerated for elderly patients with advanced<br />
NSCLC. (This study was registered at UMIN 000001328)<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1286P A PHASE II STUDY OF PEMETREXED IN<br />
CHEMOTHERAPY-NAïVE ELDERLY PATIENTS WITH<br />
ADVANCED NON-SQUAMOUS NON-SMALL-CELL LUNG<br />
CANCER: HANSHIN ONCOLOGY GROUP 003<br />
M. Iwasaku 1 , Y. Hattori 2 , S. Morita 3 , H. Yoshioka 1 , K. Otsuka 4 , N. Katakami 5 ,<br />
S. Fujita 5 , S. Yokota 6 , F. Imamura 7 , S. Negoro 8<br />
1 Respiratory Medicine, Kurashiki Central Hospital, Kurashiki, JAPAN,<br />
2 Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, JAPAN,<br />
3 Biostatistics and Epidemiology, Yokohama City University Medical Center,<br />
Yokohama, JAPAN, 4 Division of Respiratory Medicine, Kobe City Medical Center<br />
General Hospital, Kobe, JAPAN, 5 Integrated Oncology, Institute of Biomedical<br />
Research and Innovation Hospital, Kobe, JAPAN, 6 Department of Thoracic<br />
Oncology, National Hospital Organization Toneyama National Hospital, Toyonaka,<br />
JAPAN, 7 Department of Thoracic Oncology, Osaka Medical Center for Cancer<br />
and Cardiovascular Diseases, Osaka, JAPAN, 8 Thoracic Oncology, Hyogo<br />
Cancer Center, Akashi, JAPAN<br />
Background: Single-agent chemo<strong>the</strong>rapy (ie, doxetaxel, gemcitabine or vinorelbine)<br />
is one of <strong>the</strong> standard treatments for elderly patients with advanced NSCLC.<br />
Annals of Oncology<br />
Pemetrexed has clinically equivalent efficacy, but with less toxicity compared to<br />
doxetaxel in <strong>the</strong> second line setting of patients with advanced NSCLC. We conducted<br />
a phase II trial to evaluate <strong>the</strong> efficacy and safety of frontline pemetrexed in elderly<br />
patients with advanced non-squamous (non-Sq) NSCLC.<br />
Methods: In this multicenter phase II trial, we recruited elderly patients with non-Sq<br />
NSCLC. Eligibility criteria were as follows: chemonaïve; locally advanced or<br />
metastatic non-Sq NSCLC; age 75 or older; ECOG performance status 0-1; adequate<br />
organ function. Patients received pemetrexed (500 mg/m2) intravenously on day 1<br />
every 3 weeks until disease progression had been confirmed. The primary endpoint<br />
was response rate (RR). The secondary endpoints included progression free survival<br />
(PFS), overall survival (OS), disease control rate (DCR) and safety. The planned<br />
sample size was 45 patients.<br />
Results: Between August 2009 and July 2011, 47 patients were enrolled. Median age<br />
was 79 years (range: 75-91), 57% (20/47) were male, 36% (17/47) had never smoked,<br />
85% (40/47) had adenocarcinoma, 72% (34/47) had stage IV and 41% (16/39) had<br />
EGFR tyrosine kinase activating mutation. Median number of cycles was 4 (1 to 15).<br />
RR was 13.3% (95%CI: 5.1, 26.8), DCR was 66.7% (95%CI: 51.0, 80.0), PFS was 4.9<br />
months (95%CI: 3.0, 6.2 months), median OS was not reached. The most frequent<br />
treatment-related AEs were anemia, fatigue, hypocalcemia, mostly grade1/2.<br />
Treatment-related Grade 3/4 AEs were reported in 17.8% of patients (mostly<br />
neutropenia and fatigue). No treatment-related death occurred.<br />
Conclusions: The efficacy and limited side effects of pemetrexed are promising in<br />
elderly patients with non-Sq NSCLC.<br />
Disclosure: S. Negoro: HONORARIA: Lily. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
1287P FINAL RESULTS OF A PHASE 2, OPEN-LABEL STUDY OF<br />
RAMUCIRUMAB (IMC-1121B; RAM), AN IGG1 MAB<br />
TARGETING VEGFR-2, WITH PACLITAXEL AND<br />
CARBOPLATIN AS FIRST-LINE THERAPY IN PATIENTS (PTS)<br />
WITH STAGE IIIB/IV NON-SMALL CELL LUNG CANCER<br />
(NSCLC) (NCT00735696)<br />
D.R. Camidge 1 , R.C. Doebele 1 , M. Ballas 2 , T. Jahan 3 , M. Haigentz 4 ,<br />
D. Hoffman 5 , J. Spicer 6 , H. West 7 , S. Yurasov 8 , A.C. Mita 9<br />
1 Oncology, University of Colorado Cancer Center, Aurora, CO, UNITED STATES<br />
OF AMERICA, 2 Oncology, New York University Langone School of Medicine,<br />
New York, NY, UNITED STATES OF AMERICA, 3 Division of Hematology/<br />
Oncology, University of California - San Francisco, San Francisco, CA, UNITED<br />
STATES OF AMERICA, 4 Department of Medicine (oncology), Albert Einstein<br />
College of Medicine/Montefiore Medical Center, Bronx, NY, UNITED STATES OF<br />
AMERICA, 5 Oncology/hematology, Tower Hematology Oncology Medical Group,<br />
Beverly Hills, CA, UNITED STATES OF AMERICA, 6 Department, King’s College<br />
School of Medicine and Guy’s Hospital, London, UNITED KINGDOM, 7 Oncology<br />
- Medical, Swedish Cancer Institute, Seattle, WA, UNITED STATES OF<br />
AMERICA, 8 Medical, ImClone Systems, Bridgewater, NJ, UNITED STATES OF<br />
AMERICA, 9 Oncology, University of Texas Health Sciences Center, San Antonio,<br />
TX, UNITED STATES OF AMERICA<br />
Background: VEGF-mediated angiogenesis contributes to NSCLC pathogenesis.<br />
RAM is a recombinant human mAb that binds <strong>the</strong> extracellular domain of <strong>the</strong><br />
vascular endo<strong>the</strong>lial growth factor receptor-2 (VEGFR-2) and inhibits cancer growth<br />
in diverse preclinical models.<br />
Methods: Pts with advanced NSCLC (Stage IIIb not suitable for locoregional <strong>the</strong>rapy<br />
or Stage IV) were eligible. Squamous histology and treated brain metastases were<br />
allowed. Exclusion criteria included prior bevacizumab, blood vessel invasion,<br />
intratumor cavitation, and recent gross hemoptysis. Pts received RAM 10 mg/kg,<br />
paclitaxel 200 mg/m 2 , and carboplatin AUC = 6 on Day 1 of a 3-week cycle for up to<br />
6 cycles, followed by maintenance RAM. The primary endpoint was PFS at 6 months<br />
(m); secondary/exploratory endpoints were safety, ORR, OS rate at 1 year, PK/PD<br />
profiles, and immunogenicity.<br />
Results: 40 pts were treated (15M:25F; median age 60; 39 nonsquamous / 1<br />
squamous); all have discontinued. 39 pts were evaluable for response. 22 of 40<br />
treated pts had an objective response (1 CR, 21 PR; ORR = 55%). 14 pts had a best<br />
response of SD. Median PFS was 7.85 m (95% CI: 5.49 m-9.86 m), and <strong>the</strong> PFS rate<br />
at 6 m was 62.5% (90% CI: 48.3%-75.3%); <strong>the</strong> 1-year survival rate was 74.6% (95%<br />
CI: 57.9%-85.4%). 34 of 40 pts (85%) reported an AE at least possibly related to<br />
RAM; <strong>the</strong> most common related AEs were fatigue (53%), peripheral neuropathy<br />
(33%), nausea (28%), myalgia (23%), and epistaxis (23%). Related AEs of Gr ≥ 3<br />
were reported for 15 pts; <strong>the</strong> most common were neutropenia (5 pts),<br />
thrombocytopenia (4 pts), fatigue, febrile neutropenia (3 pts each), peripheral<br />
neuropathy and pulmonary embolism (2 pts each). There were 5 pts with a total of 6<br />
Gr 4 related events: febrile neutropenia, pulmonary embolism (2 pts each),<br />
neutropenia and thrombocytopenia (1 pt each).<br />
Conclusions: RAM in combination with paclitaxel and carboplatin shows promising<br />
efficacy based on <strong>the</strong> overall disease control rate (CR + PR + SD) reaching 90% and<br />
PFS rate at 6 m of 62.5%, and is well tolerated by patients with NSCLC.<br />
Disclosure: D.R. Camidge: I have received research funding from Eli Lilly and<br />
Company and honoraria from ImClone Systems. R.C. Doebele: Research Funding:<br />
ImClone Systems, Eli Lilly & Co., Pfizer Inc. Honoraria: Boehringer Ingelheim,<br />
ix422 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Abbott Laboratories, Pfizer Inc Stock: Ariad (
1291P PHASE I/II DOSE-FINDING STUDY OF CRIZOTINIB (CRIZ) IN<br />
COMBINATION WITH ERLOTINIB (E) IN PATIENTS (PTS)<br />
WITH ADVANCED NON-SMALL CELL LUNG CANCER<br />
(NSCLC)<br />
S.I. Ou 1 , R. Govindan 2 , K. Eaton 3 , A. Argiris 4 , G. Otterson 5 , F. Robert 6 ,<br />
N. Brega 7 , T. Usari 7 ,W.Tan 8 , M. Gutierrez 9<br />
1 Chao Family Comprehensive Cancer Center, University of California at Irvine,<br />
Orange, CA, UNITED STATES OF AMERICA, 2 Medical Oncology, Washington<br />
University School of Medicine, St. Louis, MO, UNITED STATES OF AMERICA,<br />
3 Thoracic/head and Neck Oncology, Ùniversity of Washington/Seattle Cancer<br />
care Alliance, Seattle, WA, UNITED STATES OF AMERICA, 4 Oncology, University<br />
of Texas Health Sciences Center, San Antonio, TX, UNITED STATES OF<br />
AMERICA, 5 Comprehensive Cancer Center, The Ohio State University,<br />
Columbus, OH, UNITED STATES OF AMERICA, 6 Comprehensive Cancer Center,<br />
University of Alabama at Birmingham, Birmingham, AL, UNITED STATES OF<br />
AMERICA, 7 Oncology, Pfizer Italia, Milan, ITALY, 8 Oncology, Pfizer, San Diego,<br />
CA, UNITED STATES OF AMERICA, 9 John Theurer Cancer Center, Hackensack<br />
University Medical Center, Hackensack, NJ, UNITED STATES OF AMERICA<br />
Background: c-Met expression is common in NSCLC tumors and has been<br />
implicated in <strong>the</strong> development of resistance to EGFR inhibitors. Criz is an ALK and<br />
MET/HGF receptor tyrosine kinase inhibitor (TKI). In pre-clinical studies,<br />
combining criz with an EGFR inhibitor enhanced anti-tumor activity in NSCLC cell<br />
lines that were sensitive or resistant to EGFR inhibition. The phase I portion of a<br />
phase I/II study (A8081002; NCT00965731) investigated <strong>the</strong> combination of E<br />
(EGFR TKI) and criz in pts with advanced NSCLC.<br />
Methods: Pts had advanced NSCLC, 1 or 2 prior chemo<strong>the</strong>rapy regimens, and no<br />
previous MET-directed <strong>the</strong>rapy. Endpoints included maximum tolerated dose (MTD)<br />
determination, safety, and pharmacokinetics (PK). Pts received E 100 mg QD for ≥7<br />
days before adding criz 150 or 200 mg BID (150 + 100 and 200 + 100, respectively).<br />
Results: As of March 15th <strong>2012</strong>, 27 pts had started <strong>the</strong>rapy. Median (range) duration<br />
of combination <strong>the</strong>rapy in 150 + 100 (n = 19) was 7 weeks (0.1–28.0); for 200 + 100 (n<br />
= 7) was 6.9 weeks (1.9–77.6). Five pts had dose-limiting toxicities (grade [G] 2 and<br />
unable to receive at least 80% of <strong>the</strong> planned dose or ≥G3), all of which resolved: 3 pts<br />
at 150 + 100, G2 vomiting, G2 esophagitis and dysphagia, G3 diarrhea and<br />
dehydration; and at 200 + 100, G3 dry eye (1 pt) and G3 esophagitis (1 pt). Most pts<br />
(96%) experienced treatment-related adverse events (TRAEs), mainly of G1 or 2<br />
severity. Common TRAEs were diarrhea (73%), rash (62%) and fatigue (46%). Six pts<br />
discontinued <strong>the</strong>rapy due to TRAEs (150 + 100: G3 diarrhea, G3 dehydration, and G1<br />
hyponatremia in 1 pt, G2 as<strong>the</strong>nia, G2 vomiting, G2 esophagitis, n = 1 each; 200 + 100:<br />
G3 dry eyes, G1 esophagitis, n = 1 each). One partial response (200 + 100; duration 73<br />
weeks) and 9 stable diseases (n = 7 150 + 100, n = 2 200 + 100; duration 8–62 weeks)<br />
were observed overall. Co-administration of both doses of criz with E increased E AUC<br />
by 1.8 fold; criz PK parameters appeared to be unaffected. Plasma exposure to E 100<br />
mg QD with criz was comparable to 150 mg QD from historical data.<br />
Conclusions: E plus criz at <strong>the</strong> MTD was well tolerated, with no unexpected AEs,<br />
and showed signs of activity in a pre-treated population. E 100 mg QD plus criz 150<br />
mg BID was defined as MTD.<br />
Disclosure: S.I. Ou: Advisory relationship with Pfizer and Genentech (both<br />
compensated). Received honoraria from Pfizer, Genentech and Lilly. Research funding<br />
from Pfizer. K. Eaton: Research funding from Pfizer. A. Argiris: Advisory relationship<br />
with Pfizer. Received honoraria from Pfizer. Research funding from Pfizer. G.<br />
Otterson: Received honoraria from Genentech and Abraxis/Celgene. Research funding<br />
from Genentech, Abraxis/Celgene, Pfizer, Tragara, Amgen, Pharmacyclics, OSI and<br />
GSK. F. Robert: Research funding to <strong>the</strong> University of Alabama at Birmingham. N.<br />
Brega: Employed by Pfizer as a Director. Hold Pfizer stock. T. Usari: Employed by<br />
Pfizer as a statistician. Holds Pfizer stock. W. Tan: Èmployed by Pfizer. Holds Pfizer<br />
stock. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1292P PHASE II TRIAL OF AFATINIB AS A THIRD-LINE TREATMENT<br />
FOR KOREAN PATIENTS (PTS) WITH WILD-TYPE<br />
EPIDERMAL GROWTH FACTOR RECEPTOR (WTEGFR)<br />
STAGE IIIB/IV LUNG ADENOCARCINOMA<br />
M.A. Ahn 1 , S. Kim 2 , B. Cho 3 , J.S. Ahn 1 , D.H. Lee 2 , J. Sun 4 , D. Massey 5 ,<br />
M. Kim 6 ,Y.Shi 7 , K. Park 1<br />
1 Division of Hematology/Oncology, Department of Medicine, Sungkyunkwan<br />
University, School of Medicine, Seoul, KOREA, 2 Division of Oncology,<br />
Department of Internal Medicine, University of Ulsan, College of Medicine, Seoul,<br />
KOREA, 3 Division of Oncology, Department of Internal Medicine, Yonsei<br />
University, College of Medicine, Seoul, KOREA, 4 Division of Haematology/<br />
Oncology, Department of Medicine, Sungkyunkwan University, School of<br />
Medicine, Seoul, KOREA, 5 Statistics, Boehringer Ingelheim, Bracknell, UNITED<br />
KINGDOM, 6 Medical Affairs, Boehringer Ingelheim, Seoul, KOREA, 7 Medical<br />
Affairs, Boehringer Ingelheim, Beijing, CHINA<br />
Background: EGFR inhibition benefits not only pts with mutated (mut) EGFR<br />
non-small cell lung cancer (NSCLC), but also pts with wtEGFR. Afatinib (BIBW<br />
Annals of Oncology<br />
2992), an irreversible ErbB Family Blocker, has shown activity in heavily pretreated<br />
pts with mutEGFR NSCLC. This Phase II trial evaluated <strong>the</strong> efficacy of afatinib in pts<br />
with advanced wtEGFR NSCLC as third-line <strong>the</strong>rapy at 3 Korean institutions.<br />
Methods: Eligible pts had Stage IIIB/IV or recurrent wtEGFR (by local lab) lung<br />
adenocarcinoma with measurable disease, ECOG PS 0–2 and had failed 2 lines of<br />
chemo<strong>the</strong>rapy (1–2 platinum-containing regimens). Prior treatment with anti-EGFR<br />
agents was not permitted. Pts received oral afatinib 40 mg/day until disease<br />
progression or occurrence of intolerable adverse events (AEs). The primary endpoint<br />
was confirmed objective tumour response rate (complete response [CR] + partial<br />
response [PR]) by RECIST 1.1; secondary endpoints included disease control rate<br />
(DCR = CR + PR + stable disease [SD]), progression-free survival (PFS), and safety<br />
profile.<br />
Results: Forty-two pts received afatinib, but 4 pts were excluded from efficacy analyses<br />
because mutEGFR NSCLC was confirmed by central lab. Baseline pt characteristics<br />
were median age of 58.0 years, 79% male, 67% current/ex-smokers. Median treatment<br />
time with afatinib was 4.1 weeks (wks) (range 1.4–54.4 wks); 2 pts (1 pt with<br />
mutEGFR and 1 pt with wtEGFR) were still receiving afatinib at <strong>the</strong> time of analysis.<br />
No CRs or PRs were reported. DCR was 24% (9/38 pts) and <strong>the</strong> median duration of<br />
disease control was 19.3 wks (range 11.6–28.0 wks). Median PFS was 4.1 wks (95% CI:<br />
3.9, 8.0). The most frequently reported AEs (mainly Grade 1 or 2) were rash (76%),<br />
diarrhoea (62%), and decreased appetite (43%). AEs led to dose reduction in 6 pts<br />
(14%) and discontinuation in 7 pts (17%). No treatment-related deaths were reported.<br />
Conclusions: A proportion of heavily pretreated patients with wtEGFR NSCLC<br />
derived benefit from afatinib; fur<strong>the</strong>r investigation will be planned including<br />
potential o<strong>the</strong>r biomarkers. Afatinib was tolerable as third-line treatment, with AEs<br />
that were manageable and consistent with <strong>the</strong> known safety profile.<br />
Disclosure: B. Cho: Lecture fees from Merck and AstraZeneca; consulting fees from<br />
Merck. D. Massey: Employee of Boehringer-Ingelheim. M. Kim: Employee of<br />
Boehringer-Ingelheim. Y. Shi: Employee of Boehringer-Ingelheim. K. Park: Advisor/<br />
Consultant for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sereno, Pfizer,<br />
Roche; Steering Committee for AMGEN, Kyowa Kirin. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
1293P FINAL RESULTS OF A JAPANESE PHASE 1 TRIAL<br />
EVALUATING A C-MET INHIBITOR TIVANTINIB IN<br />
COMBINATION WITH AN EGFR INHIBITOR ERLOTINIB IN<br />
ADVANCED/METASTATIC NON-SMALL CELL LUNG CANCER<br />
(ARQ 197-003/005 STUDY)<br />
N. Yamamoto 1 , H. Murakami 1 , T. Takahashi 1 , H. Hayashi 2 , Y. Fujisaka 3 ,<br />
T. Hirashima 4 , K. Takeda 5 , M. Satouchi 6 , K. Nakagawa 2<br />
1 Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, JAPAN, 2 Medical<br />
Oncology, Kinki University School of Medicine, Osaka, JAPAN, 3 Medical<br />
Oncology, Kinki University Fuculty of Medicine, Osaka, JAPAN, 4 Department of<br />
Thoracic Malignancy, Osaka Prefectural Medical Center for Respiratory and<br />
Allergic diseases, Osaka, JAPAN, 5 Clinical Oncology, Osaka City General<br />
Hospital, Osaka, JAPAN, 6 Thoracic Oncology, Hyogo Cancer Center, Hyogo,<br />
JAPAN<br />
Background: Tivantinib (formerly ARQ 197) is a selective, oral, non-ATP-competitive,<br />
small-molecule inhibitor of c-MET, and is metabolized by CYP2C19 and moderately by<br />
CYP3A4. A Japanese phase 1 study testing tivantinib as a single agent demonstrated that<br />
<strong>the</strong> major dose-limiting toxicity was neutropenia, and that <strong>the</strong> recommended doses were<br />
360 mg bid for CYP2C19 extensive metabolizers (EMs) and 240 mg bid for poor<br />
metabolizers (PMs). A Western phase 2 study showed a prolonged progression free<br />
survival in metastatic NSCLC patients treated with tivantinib in combination with an<br />
EGFR inhibitor erlotinib, which is mainly metabolized by CYP3A4. Here we evaluate<br />
<strong>the</strong> safety and tolerability of tivantinib in combination with erlotinib, in Japanese EMs<br />
and PMs (ARQ 197-003 /005), respectively.<br />
Methods: Heavily pretreated patients with advanced or metastatic NSCLC received<br />
tivantinib as a single agent for single dose analysis on day 1, and <strong>the</strong>reafter, started a<br />
repeating dose of tivantinib and erlotinib combination until progression or<br />
unacceptable toxicity. Tivantinib was separately escalated in EMs and PMs, up to <strong>the</strong><br />
dose respective doses recommended by <strong>the</strong> previous single agent phase 1. Erlotinib<br />
was administered at 150 mg/day for all patients.<br />
Results: A total of 25 patients (16 EMs, 9 PMs) were treated. Tivantinib, when<br />
combined with erlotinib, was well tolerated up to 360 mg bid for EMs and 240 mg<br />
bid for PMs. Rash, dry skin, diarrhea, and nausea were <strong>the</strong> treatment emergent<br />
adverse events (TEAEs) observed in >25% of all patients. Grade ≥3 neutropenia was<br />
observed in 2 PMs (8% in all patients) throughout <strong>the</strong> studies, and <strong>the</strong> rate was not<br />
largely different from <strong>the</strong> previous phase 1 study. Drug-drug interaction was not<br />
observed in tivantinib metabolism in combination with erlotinib. All patients were<br />
evaluable for response; 3 PRs and 10 SD.<br />
Conclusion: Tivantinib at <strong>the</strong> recommended dose in single agent phase 1 could be<br />
combined with erlotinib without accelerating tivantinib-related AE, or significantly<br />
changing <strong>the</strong> pharmacokinetics. A pivotal phase 3 trial is currently underway in<br />
Asian non-squamous NSCLC with wild-type EGFR, to evaluate <strong>the</strong> OS-prolongation<br />
by <strong>the</strong> combination over erlotinib alone.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix424 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
1294P DEFINITIVE THORACIC CHEMORADIOTHERAPY IN<br />
NON-SMALL CELL LUNG CANCER PATIENTS WITH<br />
SOLITARY BRAIN METASTASIS<br />
C. Parlak 1 , O.C. Guler 1 , O. Ozyilkan 2<br />
1 Department of Radiation Oncology, Baskent University Adana Medical Faculty,<br />
Adana, TURKEY, 2 Medical Oncology, Baskent University Faculty of<br />
MedicineAdana Uygulama Ve Arastirma Mer., Adana, TURKEY<br />
Background: The aim of <strong>the</strong> study was to evaluate <strong>the</strong> impact of definitive thoracic<br />
chemoradio<strong>the</strong>rapy on outcomes in non-small cell lung cancer (NSCLC) patients<br />
with solitary brain metastasis.<br />
Materials and methods: Fifty four medically fit NSCLC patients with isolated BM<br />
were retrospectively evaluated. Patients were staged with PET-CT besides<br />
conventional staging tools. TRT to a total dose of 66 Gy in 2 Gy fx was delivered<br />
with 2 cycles of concomitant cisplatin –based chemo<strong>the</strong>rapy (CT) following surgery<br />
+ 30 Gy whole-brain RT (WBRT) (n:18), 30 Gy WBRT + 15 Gy boost (n:22), or 30<br />
Gy WBRT + stereotactic radiosurgery (SRS) (n:14) for <strong>the</strong>ir BM. Response evaluation<br />
was done according to EORTC RECIST criteria<br />
Results: Pretreatment patients characteristics were as given in Table 1. Overall <strong>the</strong><br />
treatment was well-tolerated and all patients received planned TRT and 2 cycles of<br />
CT. At a median follow up of 15.2 months (4.4-42.3), median overall, locoregional<br />
progression free and progression free survivals were 12.2, 8.5 and 5.9 months.<br />
Univariate analyses revealed that patients receiving WBRT + SRS for BM (P < 0.001),<br />
performance status of ECOG 0-1 (P < 0.001), older than median age of 50 (p:0.031)<br />
no weight loss (p:0.001) had better survival. Multivariate analysis based on <strong>the</strong>se<br />
factors demonstrated that all factors except age retained <strong>the</strong>ir independent prognostic<br />
values (p
Network utilization of WBCGF in <strong>the</strong> metastatic setting to determine current<br />
practice and associated costs in this palliative chemo<strong>the</strong>rapy setting.<br />
Methods: We retrospectively identified metastatic NSCLC patients between 7/2006<br />
and 6/2011 using <strong>the</strong> US Oncology Network EHR database (iKnowMed).<br />
Secondary diagnoses and clinical trials were excluded. Chemo<strong>the</strong>rapy and WBCGF<br />
utilization was determined by <strong>the</strong> number of patients assigned to a 1st or 2nd+ (and<br />
beyond) line of <strong>the</strong>rapy (LOT) during <strong>the</strong> study period.<br />
Results: During this timeframe, 10,374 patients (female: 44%; median age 67)<br />
diagnosed with metastatic NSCLC were identified. Of <strong>the</strong>se, 3284 patients received<br />
WBCGF with chemo<strong>the</strong>rapy; where, 2825 patients (33%) were administered 1st LOT<br />
and 459 patients (27%) were administered 2nd+ LOT. When reviewing <strong>the</strong><br />
chemo<strong>the</strong>rapy regimens assigned (regardless of WBCGF administration), <strong>the</strong> most<br />
commonly utilized regimens were: Carboplatin + Paclitaxel +/- Bevacizumab,<br />
Pemetrexed containing regimens, Docetaxel containing regimens, Gemcitabine<br />
containing regimens, and Vinorelbine. The average estimated cost for <strong>the</strong>se<br />
chemo<strong>the</strong>rapy regimens (Medicare Allowable 1Q<strong>2012</strong>) is $2589/cycle; <strong>the</strong> average<br />
estimated cost of WBCGF usage in <strong>the</strong> metastatic setting was $1889/dose (Medicare<br />
Allowable 1Q<strong>2012</strong>).<br />
Conclusion: The American Society of Clinical Oncology has recently identified two<br />
opportunities to reduce <strong>the</strong> cost of care without adversely affecting outcomes (i.e.,<br />
ineffective chemo<strong>the</strong>rapy at <strong>the</strong> end of life; <strong>the</strong> use of WBCGF in palliative<br />
chemo<strong>the</strong>rapy where dose reduction is an option). These intersect in this study of<br />
NSCLC. These data indicate <strong>the</strong>re is an opportunity to address 40% of <strong>the</strong> drug costs<br />
of NSCLC by <strong>the</strong> judicious use of protocols using dose reduction as a strategy.<br />
Disclosure: J.R. Hoverman: I am a medical director for Innovent Oncology. R.<br />
Beveridge: I am EVP, Medical Director for McKesson Specialty Health. All o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
1298P ANALYSIS OF ERLOTINIB-RELATED SKIN TOXICITIES FROM<br />
JAPANESE POST-MARKETING SURVEILLANCE<br />
(POLARSTAR) IN 9,909 NON-SMALL-CELL LUNG CANCER<br />
(NSCLC) PATIENTS (PTS)<br />
Y. Kiyohara 1 , N. Yamazaki 2 , A. Seki 3 , M. Fukuoka 4<br />
1 Dermatology Division, Shizuoka Cancer Center, Nagaizumi, Shizuoka, JAPAN,<br />
2 Department of Dermatologic Oncology, National Cancer Center Hospital, Tsukiji,<br />
Chuo-ku, Tokyo, JAPAN, 3 Pharmacovigilance Department, CHUGAI<br />
PHARMACEUTICAL CO., LTD., Muromach, Chuo-ku, Tokyo, JAPAN, 4 Medical<br />
Oncology, Izumi Municipal HospitalCancer Center, Izumi City, JAPAN<br />
Background: Skin toxicities (rash) are <strong>the</strong> most common adverse reaction associated<br />
with erlotinib. Most cases of rash are mild or moderate using appropriate rash<br />
management (RM). RM is very important for keeping good QOL during erlotinib<br />
treatment. Though steroids are commonly used as RM, <strong>the</strong> precise efficacy and <strong>the</strong><br />
appropriate way of administration have not yet been fully established. Establishment<br />
of appropriate management of rash is necessary to continue erlotinib treatment for<br />
obtaining maximum benefit. In this surveillance, we analyzed RM in clinical practice<br />
from 9,909 NSCLC pts.<br />
Methods: From Dec 2007 to Oct 2009, all recurrent/advanced NSCLC pts in Japan<br />
treated with erlotinib were enrolled into this surveillance. The observation period was<br />
12 months and all adverse events were collected. Erlotinib related rash, interventions<br />
for <strong>the</strong> symptoms and outcomes of <strong>the</strong> interventions were analyzed.<br />
Results: A total of 9,909 pts were evaluated. Rash was occurred in 67.4 % (6,674) pts.<br />
Grade 1 / 2 / 3 of rash was observed (26.8 %, 32.4 %, and 7.2 %). Frequency and <strong>the</strong><br />
median time to onset from erlotinib administration to per each acneiform rash, dry<br />
skin, and paronychia were 60.9 %, 9.0 days, 7.4 %, 16.0 days, and 6.6 %, 34.0 days,<br />
respectively. The most common RM was steroids in 75.0 % of acneiform rash. In <strong>the</strong><br />
patients who were treated with steroids for <strong>the</strong>ir acneiform rash, more than 75 % of<br />
<strong>the</strong>m started steroids within 4 days from onset date. Median time from steroids start<br />
to recovery in pts whose steroids were started after 0-1 days / 2-6 days / 7-13 days /<br />
14-20 days/ 21 days or later from rash observed were 35.0 days / 39.0 days/ 40.0<br />
days/ 64.0 days/ 103.5 days, respectively. In <strong>the</strong> patients who are initiated from<br />
medium potency of steroids for <strong>the</strong>ir rash, 32.4 % pts are required to change stronger<br />
potency steroids, and median time to recovery of <strong>the</strong>m was 71.5 days. On <strong>the</strong><br />
o<strong>the</strong>rhand, Median time to recovery from rash onset was 40.0 days in <strong>the</strong> pts who<br />
were initiated with steroids of strong or strongest potency.<br />
Conclusion: Earlier initiation of management for rash with more than strong topical<br />
steroids achieves faster improvement.<br />
Disclosure: Y. Kiyohara: Chugai, Takeda, Merck Serono,Bristol-Myers Squibb,<br />
GlaxoSmithKline:advisory board. N. Yamazaki: Chugai, Takeda, Merck Serono,<br />
Bristol-Myers Squibb, GlaxoSmithKline: advisory board, Chugai: corporate-sponsored<br />
research. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1299P PHASE II STUDY OF BEVACIZUMAB IN COMBINATION WITH<br />
1ST-LINE CHEMOTHERAPY OR 2ND-LINE ERLOTINIB IN<br />
NON-SQUAMOUS NSCLC (NS-NSCLC) PATIENTS WITH<br />
ASYMPTOMATIC UNTREATED BRAIN METASTASES<br />
(ML21823)<br />
B. Besse 1 , S. Le Moulec 2 , H. Senellart 3 , J. Mazieres 4 , F. Barlesi 5 , E. Dansin 6 ,<br />
G. Robinot 7 , M. Perol 8 , D. Moro-Sibilot 9 , J. Soria 10<br />
1 Department of Medicine, Institut Gustave Roussy, Villejuif, FRANCE,<br />
2 Department of Oncology, Hôpital d’Instruction des Armées du Val-de-Grâce,<br />
Paris, FRANCE, 3 Department of Medical Oncology, Institut de Cancérologie de<br />
l’Quest, Site René Gauducheau, Nantes, FRANCE, 4 Department of Thoracic<br />
Oncology, Hôpital de Larrey, Toulouse, FRANCE, 5 Service d’Oncologie<br />
Multidisciplinaire et Innovations Thérapeutique, Aix Marseille University,<br />
Assistance Publique Hôpitaux de Marseille, Marseille, FRANCE, 6 Department of<br />
Medical Oncology, CLCC OSCAR Lambret, Lille, FRANCE, 7 Institut De<br />
Cancerologie, Centre Hospitalier Universitaire, Brest, FRANCE, 8 Department of<br />
Medical Oncology, Hôpital de la Croix-Rousse, Lyon, FRANCE, 9 Thoracic<br />
Oncology Unit, Hôpital A. Michalon, Grenoble, FRANCE, 10 Department of<br />
Cancer Medicine, Institut Gustave Roussy, Villejuif, FRANCE<br />
Background: Brain metastases (BM) occur in up to 56% of pts with advanced cancer<br />
and are no longer a contraindication to bevacizumab treatment based on safety data.<br />
The non-comparative phase II BRAIN trial (NCT00800202) is <strong>the</strong> first study to<br />
assess <strong>the</strong> efficacy/safety of bevacizumab in combination with systemic treatments in<br />
ns-NSCLC pts with untreated BM.<br />
Methods: Eligible pts (stage IV ns-NSCLC; PS 0–1; untreated, asymptomatic BM;<br />
ineligible for surgery/radiosurgery) received: arm A (n = 67),1 st -line bevacizumab<br />
(15mg/kg q3w until progression/unacceptable toxicity) plus carboplatin (AUC 6<br />
q3w, ≤6 cycles) and paclitaxel (200mg/m 2 q3w, ≤6 cycles) (B + CP); or arm B (n<br />
= 24), bevacizumab (as above) plus erlotinib (150mg/day until progression/<br />
unacceptable toxicity) (B + E) in 2 nd line. Primary endpoint: 6-month<br />
progression-free survival (PFS) by treatment arm. Secondary endpoints: response<br />
rate (RR; RECIST v1.1), overall survival (OS) and safety. The trial could be halted<br />
if <strong>the</strong> incidence of brain haemorrhage (ICH) was >3 in B + CP or >2 in B + E. All<br />
sites of disease were assessed every 6 weeks including mandatory MRI for BM<br />
assessment.<br />
Results: Pt baseline characteristics and outcomes are shown (Table). Efficacy: <strong>the</strong><br />
observed 6-month PFS was 56.5% (B + CP) and 58.0% (B + E). Safety: ICH frequency<br />
comparable to previously published data in a similar pt population (B + CP, n = 1<br />
grade 1; B + E, n = 0). Grade 3–5 adverse events of special interest (AESI) were seen<br />
in 19.4% (B + CP) and 20.8% (B + E) of pts. No erlotinib-related grade 3–5 AESIs<br />
were seen. There were 3 AEs leading to death (1 epilepsy, B + CP; 1 hypertensive<br />
encephalopathy, 1 ischaemic stroke, B + E).<br />
Conclusion: Bevacizumab with 1 st -line chemo<strong>the</strong>rapy or 2 nd -line erlotinib<br />
demonstrated efficacy and acceptable safety in pts with ns-NSCLC with<br />
asymptomatic untreated brain metastases when compared to historical controls.<br />
Baseline characteristics and clinical outcomes for patients in <strong>the</strong> BRAIN study.<br />
B+CP B+E<br />
n=67 n=24<br />
Baseline characteristics<br />
Gender, n (%) Male 46 (68.7) 11 (45.8)<br />
Female 21 (31.3) 13 (54.2)<br />
Median age, years (range) 61.0 (40–79) 54.0 (34–70)<br />
ECOG performance<br />
status, n (%)<br />
0 37 (55.2) 13 (54.2)<br />
1 30 (44.8) 11 (45.8)<br />
WHO histology, n (%) Adenocarcinoma 59 (88.1) 23 (95.8)<br />
Large-cell carcinoma 8 (11.9) 1 (4.2)<br />
Recurrence, n (%) No 61 (91.0) 13 (54.2<br />
Yes 6 (9.0) 11 (45.8)<br />
Clinical outcomes (95% CI)<br />
6-month PFS, % 56.5 (43.8–67.4) 58.0 (36.0–74.8)<br />
Median PFS, months 6.7 (5.7–7.1) 6.3 (2.5–8.4)<br />
Median OS, months 15.1 (11.8–NR) 13.6 (7.5–26.3)<br />
12-month OS, % 62.8 (49.7–73.4) 50.7 (28.7–69.0)<br />
18-month OS % 41.1 (27.4–54.3) 40.5 (20.2–60.0)<br />
Overall RR, % 62.7 (50.0, 74.2) 12.5 (2.7, 32.4)<br />
RR, % Intracranial metastases 61.2 (48.5–72.9) 20.8 (7.1–42.2)<br />
Extracranial metastases 64.2 (51.5–75.5) 12.5 (2.7–32.4)<br />
NR = not reached<br />
Annals of Oncology<br />
ix426 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Disclosure: B. Besse: Received grants from Roche. H. Senellart: Attended advisory<br />
boards. F. Barlesi: Attended adivsory boards for Roche. Received research funding<br />
from Roche. E. Dansin: Attended advisory boards for Roche, Lilly and<br />
Boehringer-Ingelheim. M. Perol: Attended advisory boards for Roche, Pfizer, Lilly<br />
and Boehringer-Ingelheim. D. Moro-Sibilot: Attended adivsory boards for Roche,<br />
Pfizer and Lilly. Received reserarch funding from Roche, Pfizer, Lilly, Astra Zeneca<br />
and BIF. Substantive Relationships with Roche, Pfizer, Lilly, Astra Zeneca and BIF. J.<br />
Soria: Attended Roche Advisory board. All o<strong>the</strong>r authors have declared no conflicts<br />
of interest.<br />
1300P HIGH EXPRESSION OF BAP1 IS BIOMARKER OF BETTER<br />
PROGNOSTIC IN ADVANCED NON-SMALL CELL LUNG<br />
CANCER PATIENTS<br />
Y. Zuo 1 , Z. Shen 2<br />
1 Department of Respiration Medicine, Lianshui People’s Hospital, Lianshui,<br />
Jiangsu, CHINA, 2 Department of Oncology, Shanghai 6 th People’s Hospital,<br />
Shanghai Jiao Tong University, Shanghai, CHINA<br />
Background: Non small cell lung cancer (NSCLC) is <strong>the</strong> leading worldwide source of<br />
cancer-related deaths. Although some drugs targeting EGFR mutations were<br />
developed, most of advanced NSCLC is still incurable. New targets for anticancer<br />
drugs are demanded. BRCA1-associated protein-1 (BAP1) is a component of <strong>the</strong><br />
ubiquitin proteasome system (UPS). The UPS has emerged as a potential target for<br />
anticancer drugs. The expression of BAP1 protein in patients with NSCLC has not<br />
been reported to date.<br />
Methods: Here, we assessed BAP1 expression by Western blot in 103 cases patients<br />
with advanced NSCLC to investigate <strong>the</strong> impact of BAP1 on survival.<br />
Results: Our data revealed 49 (47.5%) patients were classified as high expression of<br />
BAP1. Squamous cell carcinomas were more likely to be BAP1 high expressers<br />
compared to adenocarcinomas (55.8% vs. 32.3%, p= 0.001). High BAP1 expression<br />
was associated with lymph node metastasis (p= 0.008) as well as remote metastasis<br />
(p= 0.012) and was not associated with o<strong>the</strong>r clinical or pathological characteristics.<br />
In Kaplan-Meier survival analysis showed that patients with high BAP1 expression<br />
had a longer median survival compared to low expressers (23.2 vs. 14.7 months, p=<br />
0.021) especially in <strong>the</strong> subset of squamous tumors (27.3 vs. 13.1 months, p= 0.013).<br />
Multivariate analysisrevealed that high BAP1expression was an independent lower<br />
risk for all 103 patients (HR = 0.61, 95% CI 0.32-0.71, p = 0.003).<br />
Conclusions: BAP1 may be a useful prognostic factor of NSCLC patients and<br />
potential target for anticancer drugs.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1301P FINAL ANALYSIS OF RANDOMIZED PHASE II TRIAL OF<br />
CARBOPLATIN COMBINED WITH WEEKLY PACLITAXEL (CP)<br />
AND DOCETAXEL ALONE (D) IN ELDERLY PATIENTS (PTS)<br />
WITH ADVANCED NON-SMALL CELL LUNG CANCER<br />
(NSCLC): NJLCG 0801<br />
T. Harada 1 , M. Maemondo 2 , S. Sugawara 3 , A. Inoue 4 , K. Usui 5 , M. Ando 6 ,<br />
N. Morikawa 7 , Y. Mori 8 , A. Gemma 9 , T. Nukiwa 10<br />
1 Center for Respiratory Diseases, Hokkaido Social Insurance Hospital, Sapporo,<br />
JAPAN, 2 Department of Respiratory Medicine, Miyagi Cancer Center, Natori,<br />
JAPAN, 3 Department of Respiratory Medicine, Sendai Kousei Hospital, Sendai,<br />
JAPAN, 4 Department of Respiratory Medicine, Tohoku University, Sendai,<br />
JAPAN, 5 Division of Respirology, NTT Medical Center Tokyo, Tokyo, JAPAN,<br />
6 Division of Internal Medicine, Tsuboi Cancer Center Hospital, Kooriyama,<br />
JAPAN, 7 Department of Medical Oncology, Tohoku Kosei Nenkin Hospital,<br />
Sendai, JAPAN, 8 Division of Respiratory Medicine, Iwate Prefectural Central<br />
Hospital, Morioka, JAPAN, 9 Internal Medicine, Nippon Medical School, Tokyo,<br />
JAPAN, 10 President, South Miyagi Medical Center, Miyagi, JAPAN<br />
Background: Standard first-line chemo<strong>the</strong>rapy for elderly NSCLC pts has been<br />
considered as a mono<strong>the</strong>rapy with vinorelbine or gemcitabine. D has been<br />
considered as an alternative option for this population in Japan (WJTOG9904, JCO<br />
2006). Meanwhile, we have shown <strong>the</strong> high efficacy of CP for elderly pts<br />
(NJLCG0403, Ann Oncol 2010). Thus we compared <strong>the</strong> two regimens to select a<br />
proper candidate for future phase III trial.<br />
Methods: Eligible pts were aged 70 years or older with newly diagnosed stage IIIB/IV<br />
NSCLC; ECOG performance status 0-1; adequate organ function; written informed<br />
consent. Pts were randomized to receive carboplatin (AUC 6) on day 1 and paclitaxel<br />
(70mg/m2 on day 1, 8, and 15) every 4 weeks or D (60mg/m2 on day 1) every 3<br />
weeks. The primary endpoint was overall response rate (ORR), and secondary<br />
endpoints were progression-free survival (PFS), overall survival, and toxicity profile.<br />
Assuming that ORR of 40% would be potential usefulness while ORR of 20% would<br />
be <strong>the</strong> lower limit of interest, 40 pts in each arm were required if expect 10% loss to<br />
follow up.<br />
Results: Between July 2006 and September 2010, 84 pts were enrolled and 41 pts in<br />
CP arm and 42 pts in D arm were eligible (median age, 76 years; 75% male; 72%<br />
stage IV). Median treatment cycle was 4 in each arm (CP, range 1-6; D, range 1-8).<br />
ORRs were 54% (95%CI: 39-69%) and 24% (95%CI: 11-37%) in <strong>the</strong> CP and D arm,<br />
respectively. With a median follow-up of 27.6 months, median PFS were 6.6 and 3.5<br />
months in <strong>the</strong> CP and D arm, respectively (P = 0.0005) and median survival time<br />
were 14.3 and 13.8 months in <strong>the</strong> CP and D arm, respectively (P = 0.24). Grade 3 or<br />
severer toxicities were as follows: neutropenia (CP, 56% and D, 79%), anemia (CP,<br />
15% and D, 7%), thrombocytopenia (CP, 10% and D, 0%), infection (CP, 20% and<br />
D, 25%). One treatment-related death due to neutropenia, pneumonia, and lethal<br />
arrhythmia occurred in D arm.<br />
Conclusions: The platinum doublet CP achieved higher activity with less toxicity<br />
profile for elderly pts with advanced NSCLC compared to mono<strong>the</strong>rapy with D. The<br />
superiority of CP to <strong>the</strong> mono<strong>the</strong>rapy in this trial is consistent with results of recent<br />
IFCT-0501 trial (Lancet 2011).<br />
Disclosure: M. Maemondo: Makoto Maemondo receives honoraria from Sanofi. S.<br />
Sugawara: Shunichi Sugawara receives honoraria from Sanofi. A. Inoue: Akira Inoue<br />
receives honoraria from Sanofi. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
1302P CLINICAL IMPACT OF PRESENCE AND TYPE OF KRAS<br />
MUTATION IN A POPULATION OF EGFR WILD TYPE (WT)<br />
ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC)<br />
PATIENTS (PTS) TREATED WITH PLATINUM-BASED<br />
CHEMOTHERAPY: A RETROSPECTIVE ANALYSIS<br />
G. Metro 1 , S. Duranti 1 , V. De Angelis 1 , R. Chiari 1 , C. Bennati 1 , M.F. Currà 1 ,<br />
D. Giannarelli 2 , V. Ludovini 1 , V. Minotti 1 , L. Crinò 1<br />
1 Medical Oncology, Santa Maria della Misericordia Hospital, Perugia, ITALY,<br />
2 Medical Oncology, Regina Elena National Cancer Institute, Roma, ITALY<br />
Background: In this retrospective analysis we assessed whe<strong>the</strong>r KRAS mutation<br />
would affect <strong>the</strong> clinical outcome of EGFR WT advanced NSCLC pts treated with a<br />
first-line platinum-based chemo<strong>the</strong>rapy. Moreover, <strong>the</strong> effect of specific mutant<br />
KRAS was evaluated.<br />
Methods: One hundred and ninety-five EGFR WT, advanced NSCLC pts were<br />
included in <strong>the</strong> analysis. Study pts were treated at <strong>the</strong> Medical Oncology of <strong>the</strong><br />
Perugia Hospital from Jan 2005 to March <strong>2012</strong>. EGFR (exons 18 to 21) and KRAS<br />
(codons 12, 13 and 61) genes were amplified by nested PCR and sequenced in both<br />
sense and antisense directions.<br />
Results: Median age was 60 years (29-81); 181 pts (92.8%) were PS 0 or 1; 155 pts<br />
(79.4%) belonged to <strong>the</strong> non-squamous subtype and 39 pts (20.0%) were<br />
never-smokers. Treatment was as follows: platinum + a third generation agent in 103<br />
pts (52.8%); platinum + pemetrexed in 81 pts (41.6%); platinum-based doublet +<br />
bevacizumab in 11 pts (5.6%). Seventy-five pts (38.4%) were KRAS mutant (MUT),<br />
of which 60 pts at codon 12 (COD 12 MUT), 12 pts at codon 13 (COD 13 MUT)<br />
and 3 pts at codon 61 (COD 61 MUT). The most common amino acid changes<br />
found were: Gly12Cys (29 pts), Gly12Val (11 pts) and Gly13Cys (10 pts). In <strong>the</strong><br />
whole study population, 69 pts (35.3%) responded to treatment and 62 pts (31.7%)<br />
achieved stable disease, for a disease control rate of 67.0%. At a median follow-up of<br />
14 months (2-102), median progression-free survival (PFS) and overall survival (OS)<br />
were 6.2 and 21.6 months, respectively. When analyzed according to KRAS mutation<br />
status, a significantly shorter PFS was noted for <strong>the</strong> EGFR WT/KRAS MUT<br />
subgroup (n = 75) compared with <strong>the</strong> EGFR WT/KRAS WT population (n = 120)<br />
[5.1 vs 6.6 months, respectively, P = 0.02; HR = 1.43 (95% CI, 1.05 to 1.95)].<br />
Similarly, a significant difference was observed between <strong>the</strong> two groups in terms of<br />
OS [13.7 vs 26.1 months, respectively, P = 0.02; HR = 1.56 (95% CI, 1.06 to 2.30)]. In<br />
<strong>the</strong> EGFR WT/KRAS MUT subrgoup, OS for COD 12 MUT, COD 13 MUT and<br />
COD 61 MUT was 17.2, 10.2 and 8.0 months, respectively, P = 0.17. Multivariate<br />
analysis for PFS and OS confirmed that KRAS mutation was an independent<br />
predictor of poorer oucome.<br />
Conclusions: EGFR WT/KRAS MUT pts appear to experience a less favorable<br />
prognosis compared with <strong>the</strong> EGFR WT/KRAS WT genotype, with a significant<br />
difference in clinical outcome according to <strong>the</strong> mutant codon of KRAS.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds409 | ix427
1303P COST EFFECTIVENESS OF PEMETREXED/CISPLATIN (PEM/<br />
CIS) IN THE TREATMENT OF ADVANCED, NON-SQUAMOUS,<br />
NON-SMALL CELL LUNG CANCER (NSQNSCLC) PATIENTS<br />
K.B. Winfree 1 , M. Shah 2 , P. Peterson 3 , S. Gruschkus 2 , M. Eaddy 2 , M. Green 2<br />
1 Global Health Outcomes Oncology, Eli Lilly and Company, Indianapolis, UNITED<br />
STATES OF AMERICA, 2 Oncology, Xcenda AmerisourceBergen Consulting<br />
Services, Palm Harbor, FL, UNITED STATES OF AMERICA, 3 Oncology Statistics,<br />
Eli Lilly and Company, Indianapolis, IN, UNITED STATES OF AMERICA<br />
Purpose: Pem/cis is indicated for 1 st line <strong>the</strong>rapy in patients (pts) with advanced,<br />
nsqNSCLC. Data from community practices provide an opportunity to evaluate <strong>the</strong><br />
cost effectiveness (CE) of Pem/cis relative to o<strong>the</strong>r 1 st line regimens.<br />
Methods: Advanced nsqNSCLC pts receiving 1 st line <strong>the</strong>rapy with Pem/cis,<br />
carboplatin/paclitaxel + bevacizumab (C/P + B), or carboplatin/paclitaxel (C/P) from<br />
2006–2009 were identified through EMRs of 20 large US community oncology<br />
practices. Pts were matched by stage, ECOG performance status (PS), gender, age,<br />
and index year. Progression-free survival (PFS)/overall survival (OS) were calculated<br />
and treatment effect was assessed via Kaplan-Meier and Cox regression analyses.<br />
Costs included chemo<strong>the</strong>rapy, supportive care, and medical services. To evaluate CE,<br />
differences in costs/survival were calculated. Bootstrapping was used to estimate 95%<br />
confidence intervals (CIs) for mean differences and probability of falling within<br />
quadrants of CE plane.<br />
Results: Each comparison had 78 matched pairs. Mean age was 64.1, 59.0% were<br />
male and 78.2% had PS = 0/1. Median PFS for pts treated with Pem/cis (128 days)<br />
was significantly longer than those treated with C/P + B (112 days; P = 0.007) or C/P<br />
(105 days; P = 0.004). Pts treated with Pem/cis had higher median OS, however not<br />
significant. Analyses of costs/PFS and costs/OS revealed greater effectiveness with less<br />
cost for Pem/cis compared to C/P + B (Tables).<br />
Conclusions: Pts treated with Pem/cis experienced a significant PFS benefit and a<br />
trending OS benefit compared to C/P + B and C/P pts. Compared to C/P + B, Pem/<br />
cis yielded greater effectiveness with less cost.<br />
Pem/cis vs C/P + B Pem/cis vs C/P<br />
Mean D OS (95% CI) 30 days (-44.0, 98.6) 57 days (-8.4, 134.6)<br />
Mean D Cost (95% CI)<br />
Probability Pem/cis is<br />
-$18,216 (-$33,306, -$3,889) $25,111 ($9,987, $30,627)<br />
less costly, more effective 83.7% 0%<br />
more costly, more<br />
effective<br />
1.0% 95.8%<br />
Pem/cis vs C/P + B Pem/cis vs C/P<br />
Mean D PFS (95% CI) 15 days (-53.3, 82.3) 39 days (-23.5, 99.7)<br />
Mean D Cost (95% CI)<br />
Probability Pem/cis is<br />
-$17,603 (-$27,547, -$2,817 ) $25,583 ($15,601, $38,741)<br />
less costly, more effective 63.4% 0%<br />
more costly, more<br />
effective<br />
1.2% 89.4%<br />
Disclosure: K.B. Winfree: I am an employee of and have stock ownership in Eli<br />
Lilly and Company. M. Shah: Eli Lilly and Company sponsored this research<br />
study. P. Peterson: I am an employee of and have stock ownership in Eli Lilly and<br />
Company. S. Gruschkus: Eli Lilly and Company sposored this research study. M.<br />
Eaddy: Eli Lilly and Company sposored this research study. M. Green: On 3/16/12<br />
I served as moderator for a Lilly Global Adv Board per my employment with<br />
Xcenda. Consistent with Lilly rules, <strong>the</strong> payments made to Xcenda for services<br />
will appear on <strong>the</strong> Lilly website delineating payments to physicians for services to<br />
Lilly.<br />
Annals of Oncology<br />
1304P CHARACTERISTICS OF 982 LUNG CANCER PATIENTS IN<br />
SERBIA ACCORDING TO THE WHO/IASLC CLASSIFICATION<br />
OF LUNG CANCERS AND SUBSEQUENT TREATMENT –<br />
AVATAR EPIDEMIOLOGY STUDY<br />
D. Jovanovic 1 , N. Secen 2 , Z. Murtezani 3 , M. Rancic 4 , V. Kacar-Kukric 1 ,<br />
M. Velinovic 1 , A. Tepavac 5 , E. Budisin 5 , Z.G. Andric 3 , N. Vukobradovic Djoric 6<br />
1 Institute of Lung Diseases, Clinical Center of Serbia, Belgrade, SERBIA, 2 Clinic<br />
for Pulmonary Oncology - Department for Chemo<strong>the</strong>rapy, Institute for Pulmonary<br />
Diseases of Vojvodina, Sremska Kamenica, SERBIA, 3 Medical Oncology, KBC<br />
Bezanijska Kosa, Belgrade, SERBIA, 4 Clinic for Pulmonary Diseases - Knez Selo,<br />
Clinical Center Nis, Nis, SERBIA, 5 Clinic for Pulmonary Oncology, Institute for<br />
Pulmonary Diseases of Vojvodina, Sremska Kamenica, SERBIA, 6 Medical,<br />
Roche, Belgrade, SERBIA<br />
Introduction/background: The purpose of this prospective study, conducted over 3<br />
months period, was to analyse demographic and clinicopathological features of lung<br />
cancer patients in Serbia, and subsequent treatment approach as well.<br />
Material and methods: The data on lung cancer patients were collected based on<br />
specific questionnaire at 4 major centers in Serbia. An analysis of demographic and<br />
clinical/ histological features with subsequent treatment was performed in 982<br />
patients (aged over 19 years).<br />
Results: Male to female ratio 709 (72%): 273 (28%), 46% aged < 60 years. Majority<br />
were current smokers (68%) and ex-smokers (21%), 11% non-smokers. NSCLC was<br />
diagnosed in 80% (789), and SCLC in 19 %. Among NSCLC patients, 71.6 % had<br />
stage IIIb and IV. Most common histological subtype was adenocarcinoma (46%),<br />
squamous cell carcinoma - 44%, large cell - 4% and <strong>the</strong> rest NOS and rare subtypes.<br />
Neodjuvant <strong>the</strong>rapy was applied in 8%, 19% were operated: 64% of <strong>the</strong>m recieved<br />
adjuvant chemo<strong>the</strong>rapy. Most common adjuvant regimens were PE (65%) and<br />
platinum/gemcitabine (20%). First line chemo<strong>the</strong>rapy was applied in 91% of stage<br />
IIIb and IV NSCLC patients: platinum/etoposide-51% and platinum/<br />
gemcitabine-45% were most frequently applied. ECOG PS 0 and 1, was noted in<br />
92%. Second line chemo<strong>the</strong>rapy was given to 27% of patients who recieved 1st line<br />
<strong>the</strong>rapy. Most common 2nd line regimens were platinum/gemcitabine (35%),<br />
platinum/taxanes (18%), platinum/vinorelbine (13%) and taxanes mono<strong>the</strong>rapy<br />
(12.5%). Only 8% recieved pemetrexed or erlotinib. Almost all 2nd line treated<br />
patients (93%) had good ECOG PS: 0 and 1. Third line chemo<strong>the</strong>rapy was applied in<br />
22% of those who recieved 2nd line.<br />
Conclusions: This is <strong>the</strong> largest series of lung cancer patients in Serbia, analized by<br />
both, patient characteristics and <strong>the</strong>rapy regimens. Compared with previous similar<br />
analysis from 2009, it can be concluded <strong>the</strong> number of NSCLC patients is increasing,<br />
especially in stage IIIb and IV (1.5% per year). Adenocarcinoma rate is also<br />
increasing (41% in 2009 vs 45% in 2011). Regarding treatment, we can conclude<br />
<strong>the</strong>re is no major progress in treatment options in Serbia.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1305P FACTORS PREDICTING BRAIN METASTASES IN PATIENTS<br />
WITH NON-SMALL CELL LUNG CANCER<br />
S. Hsiao 1 , C. Chung 1 , H.E. Liu 2<br />
1 Division of Pulmonary Medicine, Department of Internal Medicine, Taipei<br />
Medical University Hospital, Taipei, Taipei, TAIWAN, 2 Division of Hematolgy and<br />
Oncology, Department of Internal Medicine, Department of Medicine, Wanfang<br />
Hospital, Taipei Medical University, Taipei, TAIWAN<br />
Purpose: Brain metastases (BM), a common complication of non-small cell lung cancer<br />
(NSCLC), usually lead to a poor prognosis. Recent advances in BM <strong>the</strong>rapy modesly<br />
prolong <strong>the</strong> survival after BM diagnosis in a subset of patients. Selection of treatment<br />
modalities for BM is based largely on <strong>the</strong> number of BM, BM-related symptoms and<br />
patient’s functional performance status. Therfore, early dection of BM in high-risk<br />
patients is crucial. In this study, we sough to elucidate <strong>the</strong> factors predicting BM.<br />
Methods and patients: Medical records of patients with stage 1-4 NSCLC were<br />
retrospectively reviewed for <strong>the</strong> period between January 2006 and December 2011<br />
under <strong>the</strong> approval of <strong>the</strong> joint institutional review board. Clinical demographic data,<br />
ix428 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
histology, stage of disease, presence of BM, survial were collected and analyzed. A<br />
multivariate logistic regression model was used to identiy <strong>the</strong> predictors of BM.<br />
Results: Among 596 NSCLC patients with a mean follow-up time of 12.5± 12.5<br />
months and a mortality rate of 62% at <strong>the</strong> last follow up, 187 (31%) experienced BM<br />
during <strong>the</strong>ir disease course. The accumulative incidence of BM was higher in patients<br />
with adenocarcinoma (ADC) than those with squamous cell carcinoma (SCC) (36% vs<br />
13%, p < 0.001). On multivatiate analysis, female, age < 60 years, ADC and stage 3b/4<br />
were significantly associated with BM (OR = 1.67, 95% CI = 1.06-2.63, p = 0.025, and<br />
OR = 1.89, 95% CI = 1.28-2.78, p = 0.001, and OR = 2.67, 95% CI = 1.35-5.26, p =<br />
0.017, and OR = 3.94, 95% CI = 2.15-7.13, p < 0.001, respectively). The incidence of<br />
BM in stage 3b/4 NSCLC patients was 36% and varied from 14% to 59% in patients<br />
with or without identified risk facotrs. Specifically, ADC patients with age less than 60<br />
years were more likely to experience BM than <strong>the</strong> elder with SCC (OR = 5.46, 95% CI<br />
= 2.79-10.71, p < 0.001). Additionally, prolonged survial after diagnosis of lung cancer<br />
heightened <strong>the</strong> risk of BM; its incidence was 42%, 54% and 64% in patients who<br />
survived longer than 3, 12 and 24 moths, respectively.<br />
Conclusion: We find that gender, age and histological subtype are independent<br />
factors predicting BM in NSCLC patients and suggest identification of patients at<br />
high risks for BM might help detect BM earlier and facilitate <strong>the</strong> design of clinical<br />
trials aming at <strong>the</strong> prevention of BM.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1306P INITIAL REPORT OF COHORT STUDY IN PATIENTS WITH<br />
NON-SMALL-CELL LUNG CANCER (NSCLC) WHO WERE<br />
TREATED WITH 1ST-LINE PLATINUM-BASED<br />
CHEMOTHERAPY (SAPPHIRE STUDY)<br />
Y. Naito 1 , K. Kishi 2 ,K.Yoh 3 , Y. Goto 4 , Y. Ohashi 5 , H. Kunitoh 6<br />
1 Dept. of Hematology and Medical Oncology, National Cancer Center Hospital<br />
East, Kashiwa, JAPAN, 2 Dept. of Respiratory Medicine, Toranomon Hospital,<br />
Tokyo, JAPAN, 3 Division of Thoracic Oncology, National Cancer Center Hospital<br />
East, Kashiwa, JAPAN, 4 Department of Respiratory Medicine, Graduate School<br />
of Medicine, University of Tokyo, Tokyo, JAPAN, 5 Department of Biostatistics,<br />
School of Public Health, University of Tokyo, Tokyo, JAPAN, 6 Department of<br />
Respiratory Medicine, Mitsui Memorial Hospital, Tokyo, JAPAN<br />
Background: Although 2nd-line chemo<strong>the</strong>rapy comprises <strong>the</strong> standard of care for<br />
NSCLC, not every patient could receive one. How many and why did <strong>the</strong>y miss <strong>the</strong><br />
opportunity are not fully investigated.<br />
Methods: We prospectively registered consecutive patients with NSCLC treated with<br />
platinum-based 1st-line <strong>the</strong>rapy from April 2010 to September 2011 from 30<br />
institutions in Japan. Baseline characteristics, regimens and responses for <strong>the</strong> 1st-line<br />
<strong>the</strong>rapy, whe<strong>the</strong>r <strong>the</strong> patients received 2nd-line chemo<strong>the</strong>rapy or not, and if not<br />
treated, <strong>the</strong> reason was recorded. This study was supported by <strong>the</strong> Public Health<br />
Research Center Foundation CSPOR.<br />
Results: A total of 866 patients were registered. Patient characteristics were: median<br />
age, 65 (24 - 80); female patients, 27.5%; ECOG PS 0 or 1, 91.6%; adenocarcinoma,<br />
69.6%; squamous cell carcinoma, 20.1%; never smoker, 20.1%; EGFR activating<br />
mutation positive, 10.2%. Maintenance chemo<strong>the</strong>rapy was administered to 28.9%<br />
(131 / 454) of patients whose disease did not progress during <strong>the</strong> course of 1st-line<br />
chemo<strong>the</strong>rapy. Among 592 patients with at least 6 months of follow-up, 193 were<br />
excluded (129 PD during <strong>the</strong> course of 1st-line chemo<strong>the</strong>rapy, 20 ongoing 1st-line<br />
chemo<strong>the</strong>rapy, and 44 o<strong>the</strong>rs). The remaining 399 patients were analyzed with regard<br />
to administration of 2nd-line chemo<strong>the</strong>rapy. A total of 135 patients (33.8%) did not<br />
receive 2nd-line chemo<strong>the</strong>rapy, and <strong>the</strong> reasons were: without disease progression, 42<br />
(31.1%); declined PS, 55 (40.7%); patient refusal, 20 (14.8%); death of any cause, 5<br />
(3.7%). Therefore, approximately 20% of patients missed <strong>the</strong>ir opportunity to receive<br />
appropriate 2nd-line chemo<strong>the</strong>rapy during follow-up period after completion of<br />
effective 1st-line <strong>the</strong>rapy.<br />
Conclusion: This is <strong>the</strong> largest prospective observational study exploring <strong>the</strong><br />
proportion and <strong>the</strong> reasons for NSCLC patients not receiving 2nd-line<br />
chemo<strong>the</strong>rapies. Fur<strong>the</strong>r investigations to identify predictive factors for ‘missing <strong>the</strong><br />
opportunity for 2nd-line chemo<strong>the</strong>rapy’ are underway.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1307P EFFECTIVENESS OF ERLOTINIB TREATMENT IN K-RAS<br />
WILD TYPE LUNG ADENOCARCINOMAS –RESULTS OF A<br />
HUNGARIAN OBSERVATIONAL COHORT STUDY (MOTIVATE)<br />
G. Ostoros 1 , V. Sárosi 2 , G. Losonczy 3 , J. Strausz 4 , E. Tolnay 5 , L. Molnár 6<br />
1 Department VIII, National Korányi Institute of Pulmonology, Budapest,<br />
HUNGARY, 2 1st Department of Internal Medicine Pulmonology Department,<br />
University of Pécs, Pécs, HUNGARY, 3 Department of Pulmonology, Semmelweis<br />
University, Budapest, HUNGARY, 4 Department Vi., National Korányi Institute of<br />
Pulmonology, Budapest, HUNGARY, 5 2nd Department, Pest County Institution<br />
of Pulmonology, Törökbálint, HUNGARY, 6 Pulmonology Department, Borsod<br />
County Szent Ferenc Hospital, Miskolc, HUNGARY<br />
Background: Erlotinib as a targeted <strong>the</strong>rapy is a highly potent inhibitor of epidermal<br />
growth factor receptor tyrosine-kinase activity. K-RAS mutations are found in<br />
25-35% of lung adenocarcinomas, and <strong>the</strong>se mutations may be predictive of<br />
resistance to treatment with erlotinib. The aim of our analysis was to investigate<br />
prospectively <strong>the</strong> efficacy and safety of second and third line erlotinib treatment in<br />
advanced lung adenocarcinoma excluding <strong>the</strong> K-RAS mutation positive cases.<br />
Materials and methods: This observational study was conducted in 27 Hungarian<br />
sites. Enrolled patients were treated with erlotinib. Analyzed patients have<br />
histologically or cytologically verified, advanced (IIIB/IV), K-RAS (codon-12,<br />
codon-13) mutation negative lung adenocarcinoma, refractory to at least one prior<br />
chemo<strong>the</strong>rapy. Primary endpoint was progression-free survival. Secondary endpoints<br />
were best tumor response rate according to RECIST, overall survival and safety.<br />
Results: 327 patients’ data were analyzed, who were enrolled between February 2008<br />
and December 2010. The study closure date was 31. December 2011. Baseline<br />
patients’ characteristics: median age: 60,3 years; male: 50,2%; stage: III/B: 31,1%, IV:<br />
68,9%; smoking status: former/current/never smoker: 39,1/28,8/31,9%. ECOG PS: 0/<br />
1/2/3: 35,9/51,8/11/1,2%. Best tumor response: CR/PR/SD/PD were achieved: 0,9/<br />
16,2/41,9/24,5 % of all patients. The disease control rate was 70,48% in patients for<br />
whom <strong>the</strong> best response data were available . The median progression-free survival<br />
(PFS) was 3.27 months. The median overall survival was 14,1 months. For ECOG PS<br />
0-1 patients, <strong>the</strong> median OS was 16,1 months and <strong>the</strong> median PFS was 3,47 months,<br />
while median OS of 2.5 and median PFS of 1,9 months were detected for ECOG PS<br />
2-3 patients.<br />
Conclusions: Our results confirm <strong>the</strong> favorable efficacy of erlotinib in K-RAS<br />
mutation negative lung adenocarcinoma with an OS of 14,1 months in this real-life<br />
setting. A remarkable, 16.1 months median OS was identified in patients with ECOG<br />
PS 0-1 receiving erlotinib.<br />
Disclosure: G. Ostoros: corporate-sponsored research: investigator in<br />
company-sponsored (Roche) trials. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
1308P PKM2 EXPRESSION MAY PREDICT CHEMOSENSITIVITY TO<br />
CISPLATIN-BASED CHEMOTHERAPY IN METASTATIC<br />
NON-SMALL CELL LUNG CANCER (NSCLC)<br />
C. Papadaki 1 , M. Sfakianaki 1 , E. Lagoudaki 2 , G. Giagkas 1 , E. Tsakalaki 1 ,<br />
M. Trypaki 1 , S. Pontikakis 1 , A. Koulouridi 1 , V. Georgoulias 3 , I. Souglakos 4<br />
1 Laboratory of Tumor Cell Biology, School of Medicine, University of Crete,<br />
Heraklion, GREECE, 2 Laboratory of Pathology, School of Medicine, University of<br />
Crete, Heraklion, GREECE, 3 Medical Oncology, University Hospital of Heraklion,<br />
Heraklion, GREECE, 4 Medical Oncology, University General Hospital of Heraklion,<br />
Heraklion, GREECE<br />
Background: Tumor cells have been shown to express exclusively <strong>the</strong> embryonic M2<br />
isoform of pyruvate kinase (PKM2). Overexpression of PKM2 has been correlated<br />
with cisplatin resistance in cell lines and xenograft models. We evaluated <strong>the</strong><br />
predictive significance of PKM2 in patients with stage IV NSCLC.<br />
Methods: PKM2 mRNA expression was analysed by RT-qPCR in microdissected<br />
FFPE primary tumors from 305 NSCLC patients (148 as training set and 157 as<br />
experimental set) treated with front-line cisplatin-based chemo<strong>the</strong>rapy and 85<br />
patients treated with a non-platinum doublet (as validation set).<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds409 | ix429
Results: The patients’ characteristics were all typical for metastatic NSCLC (median<br />
age 61 years, 86% males, 64% adenocarcinomas and 28% squamous cell carcinomas,<br />
ECOG PS 0-1: 83%). PKM2 was successfully amplified in all specimens. Progression<br />
Free Survival (PFS) was significantly lower in patients with overexpression of PKM2<br />
(4.9 vs. 6.4 months for high and low expression, respectively, p = 0.028) in <strong>the</strong><br />
training set and <strong>the</strong> results were confirmed in <strong>the</strong> experimental set (3.7 vs. 5.9<br />
months, p = 0.006). Similarly, median overall survival (mOS) was significantly<br />
decreased in patients with upregulation of PKM2 in both sets: 10.1 vs 17.0 months in<br />
<strong>the</strong> training set (p = 0.01) and 8.3 vs 16.8 months in <strong>the</strong> experimental sets (p =<br />
0.003), for high and low expression, respectively. In contrast, <strong>the</strong>re was no statistical<br />
difference in terms of PFS (5.6 vs. 5.9 months, p = 0.431) and mOS (9.8 vs. 10.1<br />
months, p = 0.512) between low and high PKM2 expression in <strong>the</strong> validation group.<br />
Multivariate analysis revealed that PKM2 high mRNA expression could be emerged<br />
as an independent factor associated with decreased PFS (training set: HR = 1.6, p =<br />
0.02; experimental set: HR = 2.1, p = 0.013) and mOS (training set: HR = 1.9, p = 0.02;<br />
experimental set: HR = 2.6, p = 0.001), but not in <strong>the</strong> validation set (PFS: HR = 1.1, p<br />
= 0.627; mOS: HR = 0.96, p = 0.495).<br />
Conclusions: These results indicate that <strong>the</strong> PKM2 mRNA expression may be used<br />
as a predictive factor for sensitivity to cisplatin-based chemo<strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1309P ROLE OF THE HEDGEHOG PATHWAY IN MEDIATING<br />
RESISTANCE TO ANTI-EGFR TYROSINE KINASE INHIBITORS<br />
IN NON SMALL CELL LUNG CANCER<br />
F. Morgillo, C.M. Della Corte, G. Martini, A. Manzo, V. Gambardella,<br />
D. Vitagliano, E. Martinelli, T. Troiani, F. Ciardiello<br />
Medical Oncology, Second University of Naples, Napoles, ITALY<br />
In recent years, <strong>the</strong> management of non small lung cancer (NSCLC) has been<br />
moving towards molecular-guided treatment, and <strong>the</strong> best example of this new<br />
approach is <strong>the</strong> use of EGFR tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib.<br />
The clinical benefit observed with EGFR-TKIs in NSCLC is limited to a subset of<br />
patients, and <strong>the</strong> development of resistance, even in responders, is sooner or later<br />
observed. Several studies have provided new insights into <strong>the</strong> molecular basis of<br />
EGFR inhibitors resistance. Recently our group demonstrated <strong>the</strong> acquisition of a<br />
mesenchymal phenotype in an in vitro model of NSCLC cell lines with acquired<br />
resistance to anti-EGFR TKIs. Among <strong>the</strong> various molecular pathways, <strong>the</strong> Hedgehog<br />
(Hh) signaling pathway has emerged as an important mediator of carcinogenesis and<br />
cancer metastases. The objective of this research is to investigate <strong>the</strong> role of Hh<br />
signaling pathway in human NSCLC cell models of constitutive or acquired<br />
resistance to EGFR-TKIs. To investigate <strong>the</strong> expression profile of Hh signalling<br />
components in our panel of sensitive and resistant NSCLC cell lines, we performed<br />
analysis of mRNA and protein levels of Shh, Gli1 and Smo by using semiquantitative<br />
PCR and Western blot analysis. The experiment showed a strong expression of sonic<br />
Hh and Gli1 in NSCLC cell lines resistant to EGFR TKIs. In addition, PTCH mRNA<br />
levels resulted increased in TKI-resistant cell lines. This is of relevance, because<br />
PTCH gene itself is a target gene of Gli1 transcriptional activity and its levels<br />
indicates an activation of Hh signalling in such cells. Treatment with cyclopamine, a<br />
Smo inhibitor, strongly inhibited <strong>the</strong> proliferation of resistant NSCLC cell lines.<br />
Fur<strong>the</strong>rmore, treatment with cyclopamine blocked <strong>the</strong> invasive and migratory<br />
behavior of resistant cells. Of interest, <strong>the</strong> inhibition of Smo and Hh signaling<br />
pathway was accompanied by an inhibition of MET and MAPK phosphorylation.<br />
Our study should provide <strong>the</strong> opportunity to better understand <strong>the</strong> role of HH<br />
pathway in mediating resistance to anti-EGFR TKIs and to design new strategies to<br />
be easily transferred into clinical practice.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1310P PROGNOSTIC IMPACT OF SERUM CYFRA 21-1 IN<br />
ADVANCED LUNG ADENOCARCINOMA<br />
A. Ono 1 , T. Takahashi 1 , H. Akamatsu 1 , T. Taira 1 , T. Shukuya 1 , H. Kenmotsu 1 ,<br />
T. Naito 1 , H. Murakami 1 , M. Endo 2 , N. Yamamoto 1<br />
1 Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, JAPAN,<br />
2 Division of Diagnostic Radiology, Shizuoka Cancer Center, Shizuoka, JAPAN<br />
Background: Serum CYFRA 21-1 is one of <strong>the</strong> most important serum markers<br />
in diagnosing non-small cell lung cancer (NSCLC), especially squamous-cell<br />
carcinoma. It is not known whe<strong>the</strong>r pretreatment serum CYFRA 21-1 values<br />
(PCV) have prognostic implications in advanced lung adenocarcinoma. The aim<br />
of this study was to evaluate <strong>the</strong> prognostic implications of PCV in advanced<br />
lung adenocarcinoma.<br />
Material and methods: Out of 424 newly diagnosed lung cancer patients (pts) at our<br />
institution during <strong>the</strong> period April 2008- June 2010, we retrospectively reviewed 284<br />
consecutive pts who were diagnosed with advanced lung adenocarcinoma and had<br />
been treated with systemic chemo<strong>the</strong>rapy. Survival was estimated using <strong>the</strong><br />
Kaplan-Meier method. A log-rank test was performed to test <strong>the</strong> significance of<br />
differences in <strong>the</strong> overall survival among <strong>the</strong> groups. A multivariate analysis using <strong>the</strong><br />
Annals of Oncology<br />
Cox proportional hazards model was used to establish <strong>the</strong> association between<br />
various prognostic factors and survival.<br />
Results: One hundred twenty one pts (43%) had activating EGFR mutations (Mt+)<br />
and 163 pts (57%) had EGFR wild type (Mt-). The median follow-up time was 29.7<br />
months (range: 2.8- 75.7 months). In univariate analysis, gender (male/ female),<br />
ECOG performance status (PS) (0-2/ 3-4), PCV (< 2.2ng/ml, > 2.2ng/ml), EGFR<br />
mutation (Mt + / Mt-), and smoking history (yes/ no) were favorable prognostic<br />
factors (p= 0.01, p< 0.0001, p< 0.0001, p< 0.0001, p= 0.0008 respectively), but not<br />
age ([< 70, > 70], p = 0.67). A Cox’s multivariate analysis showed that PCV (< 2.2ng/<br />
ml) was significantly associated with prolonged survival (p< 0.0001, hazard ratio:<br />
0.38, 95% CI 0.32-0.63), when adjusted by PS (p< 0.0001), EGFR mutation status<br />
(p< 0.0001), gender (p= 0.37), and smoking history (p= 0.11). Fur<strong>the</strong>rmore, patients<br />
with Mt+ and CYFRA < 2.2ng/ml (n= 70) had a better prognosis than those with Mt<br />
+ and CYFRA > 2.2ng/ml (n= 48) (median survival time [MST]: 52.4 vs. 21.0<br />
months, p< 0.0001), and those with Mt- and CYFRA < 2.2ng/ml (n= 78) had a better<br />
prognosis than Mt- and CYFRA > 2.2ng/ml (n = 86) (MST: 24.1 vs. 10.2 months,<br />
p
Annals of Oncology<br />
Methods: The presence and relative quantity of two ALK exon spanning transcript<br />
targets located before (ALK-5’) and after (ALK-3’) <strong>the</strong> translocation breakpoints of<br />
this gene were assessed with qRT-PCR in 198 NSCLC RNA samples from paraffin<br />
tissues upon stringent intra- and inter-run assay performance validation. ALK<br />
mRNA expression was compared with ALK gene status assessed with FISH. Patients<br />
had been treated in <strong>the</strong> adjuvant and/or 1 st line setting. None of <strong>the</strong>m received<br />
crizotinib.<br />
Results: Four patterns of ALK mRNA expression emerged: tumors negative for both<br />
transcripts (85/198, 42.9%) or positive for both (56/198, 28.3%), which were<br />
considered as close to normal (ALK-N); and, ALK-5’ positive only (34/198, 17.2%)<br />
or ALK-3’ positive only (23/198, 11.6%), which were termed as aberrant (ALK-A).<br />
ALK translocation was observed in 9/124 cases (7.3%). ALK copies >2.2 were noticed<br />
in 40 cases (32.3%) with >6 copies in 26 cases (21%) and overall complex gene gain<br />
patterns. ALK mRNA was unrelated to ALK translocation, but ALK-3’ was associated<br />
with increased ALK gene copies (p = 0.017). ALK-A was more common in stage<br />
IIIB-IV tumors, while ALK mRNA and gene copy gains were not associated with<br />
gender, smoking and histology. ALK gene status was not associated with patient<br />
outcome. In comparison to patients with tumors expressing ALK-N, those with<br />
ALK-A had a significantly shorter overall survival (OS, median 29.3 vs. 13.1 months,<br />
CI95% 19.1-39.6 vs. 5.4-20.9, p = 0.0007). The same unfavorable impact of ALK-N<br />
vs. ALK-A was observed on stage IIIB-IV patient OS (median 17.5 vs. 11 months,<br />
CI95% 9.1-26.0 vs. 6.6-15.3, p = 0.0050).<br />
Conclusions: ALK gene status and mRNA expression seem to suffer a complex<br />
pathology in NSCLC. When expressed, ALK mRNA may be fragmented, possibly<br />
due to currently unknown genomic alterations. Aberrant ALK mRNA expression<br />
appears to have an unfavorable prognostic impact on NSCLC patient outcome; its<br />
role on NSCLC biology merits fur<strong>the</strong>r evaluation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1313 PROGNOSTIC SIGNIFICANCE OF EGFR, HER-2, CEA ON<br />
CIRCULATINGTUMOUR CELLS (CTCS) IN PATIENTS WITH<br />
METASTATIC NON-SMALL-CELL LUNG CANCER (MNSCLC)<br />
C. Loretelli 1 , E. Galizia 2 , M. Scartozzi 1 , R. Giampieri 1 , D. Gagliardini 1 ,<br />
C. Brugiati 1 , S. Cascinu 1 , R. Cellerino 1<br />
1 Clinica di Oncologia Medica, AOU Ospedali Riuniti Ancona Università<br />
Politecnica delle Marche, Ancona, ITALY, 2 Oncologia Medica, Ospedale “E.<br />
Profili”, Fabriano, ITALY<br />
Purpose: We aimed to assess <strong>the</strong> role of CTCs in providing prognostic information<br />
of mNSCLC patients receiving chemo<strong>the</strong>rapy.<br />
Patients and methods: In this single-center prospective study, blood samples for<br />
CTCs analysis were obtained from patients with previously untreated mNSCLC.<br />
CTCs were measured using an epi<strong>the</strong>lial cell adhesion molecule-based<br />
immunomagnetic technique. Immunomagnetic bead enrichment for cells expressing<br />
epi<strong>the</strong>lial cell adhesion molecule (EpCAM) was performed, followed by multi-marker<br />
quantitative real-time PCR of a panel of marker genes: EGFR, HER-2, CEA.<br />
Results: We analysed 45 patients with mNSCLC: 24 adenocarcinoma, 8 squamous<br />
cell carcinoma and 13 poorly differentiated. EGFR, HER-2 and CEA expression<br />
were found in CTCs of respectively 12, 5 and 11 patients. Globally, 31 patients<br />
(68.9%) progressed during treatment, whereas disease control (i.e. patients with<br />
partial/complete response or stable disease) was achieved in 14 patients (31.1%).<br />
EGFR expression was detected in 11/31 patients with disease progression (35.5%)<br />
and in only 1 out of 14 patients with disease controlled (7.1%) (p 0.07). HER-2<br />
expression was detected in 3/31 patients with disease progression (9.7%) and in 2/<br />
14 patients with disease controlled (14.3%) (p 0.64). CEA expression was detected<br />
in 10/31 patients with disease progression (32.3%) and in 1/14 patients with<br />
disease controlled (7.1%) (p 0.13). Only EGFR expression in CTCs showed a<br />
correlation with clinical outcome, expressed by progression free survival (PFS).<br />
Patients with and without EGFR expression in CTCs were homogeneous for<br />
clinical characteristics. PFS was 2.8 v 2.3 months (p 0.03) respectively for patients<br />
without and with EGFR expression.<br />
Conclusion: CTCs are detectable in patients with mNSCLC and could show novel<br />
prognostic factor for this disease. Fur<strong>the</strong>r validation is warranted before routine<br />
clinical application.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1314 ASSESSMENT OF THE PREDICTIVE/ PROGNOSTIC VALUE OF<br />
THE MYELOID-DERIVED SUPPRESSOR CELLS (MDSC) AND<br />
REGULATORY T CELLS (TREGS) IN NON-SMALL CELL LUNG<br />
CANCER (NSCLC). PRELIMINARY RESULTS<br />
E.K. Vetsika 1 , E. Skalidaki 1 , A. Koutoulaki 1 , D. Mavroudis 2 , V. Georgoulias 2 ,<br />
A. Kotsakis 2<br />
1 Laboratory of Tumor Cell Biology, University of Crete, School of Medicine,<br />
Heraklion, GREECE, 2 Medical Oncology, University Hospital of Heraklion,<br />
Heraklion, GREECE<br />
Background: The circulating MDSCs and Tregs in cancer patients suppress immune<br />
system. This study is investigating <strong>the</strong> expression of <strong>the</strong> MDSCs and Tregs in <strong>the</strong><br />
peripheral blood of NSCLC patients and <strong>the</strong>ir correlation with <strong>the</strong> clinical outcome<br />
of <strong>the</strong> 1 st line chemo<strong>the</strong>rapy.<br />
Methods: 62 chemo<strong>the</strong>rapy naive patients (57 males) with stage IIIB/ IV NSCLC<br />
have been enrolled in this study, so far; median age 67. Peripheral blood was<br />
collected prior to treatment. 19 healthy, aged-matched donors (12 males) were used<br />
as controls. The distinct MDSC subpopulations [A (monocytic):<br />
CD11b + CD14 + CD15 − CD33 + CD13 + IL-4R + Lin low/- HLA-DR − ; B (monocytic):<br />
CD11b + CD14 + CD15 + CD33 + CD13 + IL-4R + Lin low/- HLA-DR − and C (granulocytic):<br />
CD11b + CD14 − CD15 + CD33 + CD13 + IL-4R + )], CD4 + Tregs (CD4 + CD25 +high<br />
CD127 low FoxP3 + CD39 + CD13 + ) and CD8 + Tregs (CD3 + CD8 + CD25 +<br />
CD45RO + CD13 + CCR7 + FoxP3 + CD39 + ) were determined by using flow cytometry. A<br />
comparison of <strong>the</strong> overall survival (OS) and <strong>the</strong> progression-free survival (PFS)<br />
according to <strong>the</strong> frequency of <strong>the</strong> MDSC and Tregs was performed (high expression<br />
defined as <strong>the</strong> percentage of cells above <strong>the</strong> 75% percentile of <strong>the</strong> controls).<br />
Results: The levels of Tregs prior to treatment did not differ from <strong>the</strong> controls’.<br />
Patients with progression (PD) during <strong>the</strong> 1 st line treatment had significantly<br />
elevated percentage of CD4 + (24.6 ± 8.5) and CD8 + (0.7± 0.2) Tregs at baseline<br />
compared to those with no PD (3.7± 1.8, p = 0.04; 0.1± 0.05, p= 0.03, respectively).<br />
In contrast, MDSCs were significantly increased (A: 3.8 ±0.7; Β: 2.5 ± 0.5 and C: 10.8<br />
± 2.3) in patients compared to controls (0.8 ± 0.4, p = 0.001; 0.5 ± 0.2, p= 0.01, and<br />
2.7 ± 1.3, p= 0.05, respectively) but that difference was not associated with response<br />
to treatment. Patients with normal CD8 + Tregs levels at baseline had higher OS and<br />
PFS compared to those with high levels (13.2 mo vs 7.9 mo, p= 0.02 and 13.1 mo vs<br />
3.7 mo, p= 0.003, respectively).<br />
Conclusion: The MDSCs are elevated in NSCLC. The increased expression of CD4 +<br />
και CD8 + Tregs negatively correlated with <strong>the</strong> treatment outcome, indicating that<br />
CD4 + and CD8 + Tregs could be a potential predictive/prognostic biomarker. The<br />
study is still opened to accrual and more mature data will be presented at <strong>the</strong><br />
meeting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1315 CYTOLOGY SAMPLES (S) FOR EGFR AND KRAS MUTATION<br />
(MUT) TESTING IN NON-SMALL-CELL LUNG CANCER<br />
(NSCLC).EXPERIENCE FROM A SINGLE INSTITUTION<br />
T. Moran Bueno1 , E. Castella Fernandez2 , M. Tierno Garcia1 ,C.<br />
Buges Sanchez1 , C. Queralt Herrero1 , M. Perez Cano1 , D. Naranjo Hans2 ,F.<br />
Andreo Garcia3 , L. Capdevila Riera1 , R. Rosell1 1<br />
Medical Oncology Department, Catalan Institute of Oncology Badalona,<br />
Hospital Universitari Germans Trias i Pujol, Badalona, SPAIN, 2 Pathology<br />
Department, Hospital Universitari Germans Trias i Pujol, Badalona, SPAIN,<br />
3<br />
Pulmonology Department, Hospital Universitari Germans Trias i Pujol, Badalona,<br />
SPAIN<br />
Background: Targeted <strong>the</strong>rapy has yielded impressive clinical outcomes in advanced<br />
NSCLC. For molecular testing, cytology samples are not commonly used since <strong>the</strong><br />
tumor content is less likely to be adequate. At ICO-Badalona, Hospital Germans<br />
Trias i Pujol we have used cytology specimens when biopsies are not available. We<br />
describe <strong>the</strong> general results when using cytology specimens in NSCLC to detect<br />
EGFR and KRAS mut.<br />
Methods: From January 2007 to February <strong>2012</strong>, 227 cytology samples from patients<br />
with NSCLC were collected at <strong>the</strong> Department of Pathology as cell blocks or fresh<br />
specimens extended over an appropriate slide (MembraneSlide 1.0 PEN, Zeiss®).<br />
Tumor cells (8-150) were captured by laser microdissection. DNA sequencing for<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds409 | ix431
EGFR mut at exons 18, 19, 21, and KRAS mut at codons 12 and 13 and allelic<br />
discrimination technique for EGFR mut at exon 20 were performed at Molecular<br />
Biology Laboratory (ICO-Badalona).<br />
Results: EGFR mut were tested in 227 s. The overall output was 86.3% (15 not<br />
evaluable, 8 insufficient tissue, 4 no tumor cells, 4 not done). EGFR mut were<br />
detected in 8.81% (20/227). KRAS mut were tested in 41 s with results in 33, 80.5%<br />
(2 not evaluable, 3 insufficient tumor cells 1 no tumor and 2 not done). KRAS mut<br />
were positive in 14.6% (6/41). The output for cell block was 83.3% (124/148) and<br />
testing was not possible in 24 s (11 not evaluable, 6 insufficient tumor cells, 4 not<br />
tumor and 3 not done). The output for fresh specimens was 91.1% (72/79) and was<br />
not possible in 7 s (4 not evaluable, 2 insufficient tumor cells and 1 not done).<br />
Conclusions: Our results support <strong>the</strong> use of cytology samples for EGFR and<br />
KRAS molecular testing in NSCLC when biopsy specimens are not available.<br />
Both fresh specimens and cytology blocks have been used and are suitable for<br />
molecular testing.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1316 FEASIBILITY AND USEFULNESS OF DETERMINING EGFR AND<br />
KRAS MUTATIONS IN CYTOLOGICAL SAMPLES AND CNB OF<br />
NSCLC USING AN AUTOMATED REAL-TIME PCR SYSTEM<br />
M.D. Lozano 1 , T. Labiano 1 , M. Montañana 1 , J.I. Echeveste 1 , A. Gurpide 2 , J.L.<br />
Pérez - Gracia 2 , F. Shieh 3 , T. Ramos 4 , J. Zulueta 5 , S. Martin Algarra 2<br />
1 Pathology, University of Navarra, Pamplona, SPAIN, 2 Clinical Oncology, Clinica<br />
Universitaria de Navarra, Pamplona, SPAIN, 3 Roche Molecular System, Roche<br />
Molecular System, Pleasanton, UNITED STATES OF AMERICA, 4 Roche<br />
Diagnostics, Barcelona, SPAIN, 5 Pulmonary Medicine, Clinica Universidad de<br />
Navarra, Pamplona, SPAIN<br />
Background: EGFR and KRAS gene mutations guide treatment selection in<br />
non-small cell lung cancer (NSCLC) patients. About 70%-80% of <strong>the</strong>se patients are<br />
diagnosed at advanced stage, and mutational analysis has to be performed in small<br />
samples: core needle biopsy (CNB) and fine needle aspiration (FNA) cytology.<br />
Cobas® EGFR Mutation Test has been CE-IVD marked for <strong>the</strong> detection of 41<br />
mutations in formalin-fixed-paraffin-embedded (FFPE) NSCLC specimens. No<br />
validation studies have been performed using cytological samples. Determining <strong>the</strong><br />
feasibility of cobas® test on such samples is an important step to extend <strong>the</strong> benefits<br />
of molecular targeted <strong>the</strong>rapy.<br />
Methods: EGFR and KRAS mutations were studied in 64 non-selected samples from<br />
NSCLC patients: 31 CNB and 33 FNA. DNA was extracted directly from stained<br />
smears in FNA samples and from 4-micron sections in CNB. All samples contained<br />
at least 50% of tumor cells. All cases were studied using <strong>the</strong> cobas® test, and FNA<br />
samples were also analyzed by direct sequencing. DNA was extracted using <strong>the</strong><br />
cobas® DNA Sample Preparation Kit. DNA concentration and DNA ratio of sample<br />
absorbance at 260/280nm (A260/280) were registered. U Mann Whitney test was<br />
used.<br />
Results: CNB diagnosis was: 23 SqCC, 6 AC, 1 BAC, and 1 NSCLC-NOS. FNA<br />
diagnosis was: 26 AC, 3 SqCC, 1 BAC, 1 LCC, and 2 NSCLC-NOS. Mean DNA<br />
concentration from CNB was 23.07ng/ul ± 20.99, and from FNA samples 12.41ng/ul<br />
± 20.04 (p < 0.001). However A260/280 was 1.61 ± 0.26 and 1.71 ± 0.55 respectively<br />
(p = 0.666). Mutational analysis results from all 31 CNB and from 19 FNA cases are<br />
shown in Table 1. Sanger sequencing in all FNA cases rendered concordant results.<br />
Updated results will be presented.<br />
FNA CNB<br />
EGFR WT 6 28<br />
EXON 19 DEL 2 1<br />
EXON 20 INS 0 1<br />
INVALID 1 1<br />
KRAS WT 9 26<br />
12/13<br />
MUTATED<br />
9 4<br />
INVALID 1 1<br />
Conclusions: Assessment of EGFR and KRAS mutations in FNA and CNB samples<br />
using cobas® EGFR and KRAS test is feasible and reliable. Quality of DNA (A260/<br />
280) using cobas® DNA Sample Preparation Kit in FNA samples is similar to those<br />
from CNB. Molecular results from FNA samples using cobas® test and direct<br />
sequencing are concordant, though cobas® tests are simpler, faster and easier to use.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
1318 FREQUENCY AND SPECTRUM OF EGFR MUTATIONS IN<br />
MOROCCAN LUNG ADENOCARCINOMA PATIENTS<br />
I. Elghissassi 1 , H. Inrhaoun 2 , A. Boukir 2 , Y. Bensouda 2 , H. Mrabti 1 , H. Errihani 1<br />
1 Medical Oncology, Institut National d’Oncologie Sidi Mohamed Ben Abdellah,<br />
Rabat, MOROCCO, 2 Medical Oncology, National Institute of Oncology, Rabat,<br />
MOROCCO<br />
Background: EGFR mutations reported in lung cancer are potential <strong>the</strong>rapeutic<br />
targets leading to improved response with tyrosine kinase inhibitors (TKI). The<br />
frequency of EGFR mutations is ethnicity-dependent with a higher proportion in<br />
Asian populations (30%) than in Caucasians (10-15%). Fur<strong>the</strong>rmore, exon 19<br />
mutation is associated with better response to EGFR-TKI compared to exon 21<br />
mutation. The aim of this study was to report <strong>the</strong> frequency and spectrum of<br />
EGFR mutations in unselected group of Moroccan lung adenocarcinoma<br />
patients.<br />
Methods: We summarized <strong>the</strong> result of <strong>the</strong> EGFR mutation analysis in exons 18-21<br />
for 83 patients performed from November 2010 to march <strong>2012</strong> in three laboratories<br />
in Rabat. Mutation detection techniques were PCR amplification and sequencing.<br />
Only Moroccan lung adenocarcinoma patients were included.<br />
Results: The overall frequency of <strong>the</strong> EGFR mutation was 22%. It was more frequent<br />
in female patients (58%) than in male ones (5%). Mutations were mainly detected in<br />
<strong>the</strong> exon 19 (67%) followed by exon 21 (17%) and exon 20 (11%), while that in <strong>the</strong><br />
exon 18 was rare (5%).<br />
Conclusion: Some one fifth of Moroccan lung adenocarcinoma tumors harbor EGFR<br />
mutations. This mutation frequency is higher than that found in Caucasians but<br />
lower than in Asian population. The high rate of exon 19 mutation in Moroccan<br />
population may result in a higher frequency of response to TKI<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1319 THE ROLE OF EPITHELIAL-MESENCHYMAL TRANSITION AND<br />
IGF-1R EXPRESSION IN PREDICTION OF GEFITINIB ACTIVITY<br />
AS THE SECOND-LINE TREATMENT FOR ADVANCED<br />
NON-SMALL CELL LUNG CANCER<br />
W. Zhang, B. Chen<br />
Oncology, Guangzhou General Hospital of Guangzhou Military Command,<br />
Guangzhou, Guangzhou, CHINA<br />
We retrospectively analyzed <strong>the</strong> relationship of EMT, IGF-1R and gefitinib efficacy in<br />
53 NSCLC patients who accepted gefitinib as <strong>the</strong> second-line treatment. Compared<br />
with EMT (+), EMT (-) showed a higher ORR in both EGFR mutation subgroup<br />
(50.0% vs. 28.6%) and EGFR wild-type subgroup (20.0% vs. 4.5%), and a longer<br />
MST in EGFR wild-type subgroup (6 months vs. 3 months, P = 0.014). IGF-1R (-)<br />
showed a higher ORR tendency than IGF-1R (+) in EGFR mutation patients (54.6%<br />
vs. 30.0%) and EGFR wild-type patients (18.2% vs. 4.8%). EMT and IGF-1R are<br />
correlated with <strong>the</strong> efficacy of gefitinib as <strong>the</strong> second-line <strong>the</strong>rapy for NSCLC,<br />
especially in patients with wild- type EGFR. (This work is supported by grants from<br />
<strong>the</strong> National Foundation of Natural Science, China. No. 81172225, No. 81101821 and<br />
No. 81000819)<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1320 PERIODIC MEASUREMENT OF N-TELOPEPTIDES OF TYPE I<br />
COLLOGEN IN SERUM (SNTX) FOR EARLY DIAGNOSIS OF<br />
BONE METASTASIS IN PATIENTS WITH LUNG CANCER<br />
H. Daga 1 , M. Tamiya 2 , S. Tokunaga 3 , K. Taira 3 , H. Okada 3 , H. Suzuki 2 ,<br />
N. Okamoto 2 , N. Morishita 2 , T. Hirashima 2 , K. Takeda 3<br />
1 Department of Clinical Oncology, Osaka City General Hospital, Osaka, JAPAN,<br />
2 Thoracic Malignancy, Osaka Prefectural Hospital Organization Osaka Prefectural<br />
Medical Center for Respiratory and Allergic Diseases, Habikino-City, JAPAN,<br />
3 Clinical Oncology, Osaka City General Hospital, Osaka, JAPAN<br />
Background: The bone resorption biomarker sNTx has been previously shown to<br />
add value as an aid in <strong>the</strong> diagnosis of bone metastasis in patients with lung cancer.<br />
The objective of this prospective study was to determine if periodic sNTx<br />
measurements could lead to early diagnosis of bone metastasis in patients with lung<br />
cancer.<br />
Methods: Patients with newly diagnosed organ-confined lung cancer were enrolled.<br />
sNTx values were determined once each month using <strong>the</strong> OSTEOMARK TM serum<br />
NTx assay (Alere Medical). The presence or absence of bone metastasis was<br />
determined by monthly physical examination and by bone scintigraphy every 3<br />
ix432 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
months for 12 months. All patients were required to provide written informed<br />
consent.<br />
Results: Forty patients were enrolled between June and December 2010. One patient<br />
withdrew early and was excluded from analysis. The mean +/- 1 SD baseline level of<br />
sNTx was 17.5 +/- 4.4 nM BCE/L. Five patients developed bone metastasis (as<br />
characterized by bone scintigraphy) during <strong>the</strong> study period. The level of sNTx in<br />
subjects with bone metastasis was slightly increased (21.6 +/- 3.2 nM BCE/L),<br />
however, in <strong>the</strong>se patients, <strong>the</strong>re was no statistically significant difference between<br />
sNTx values at baseline (18.2 +/- 4.2 nM BCE/L) and when metastasis was<br />
diagnosed. (p = 0.176). When a cut-off value of sNTx was set to 22.0 nM BCE/L, <strong>the</strong><br />
sensitivity and <strong>the</strong> specificity of detection of bone metastasis were 80.0% and 41.2%,<br />
respectively. Using this cut-off, <strong>the</strong> elevation of sNTx could predict bone metastasis<br />
at least one month before diagnosis by bone scintigraphy in all 5 patients, however,<br />
<strong>the</strong> specificity was relatively low for clinical implementation. Additionally, <strong>the</strong><br />
sensitivity and <strong>the</strong> specificity of early detection of systematic spread of disease<br />
(including bone metastasis) were 70.6% and 45.5%, respectively.<br />
Conclusions: Periodic determination of sNTx in patients with organ confined lung<br />
cancer did not provide sufficient specificity for it to be used for <strong>the</strong> early diagnosis of<br />
bone metastasis or disease progression.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1321 USEFULNESS OF SERIAL MEASUREMENT OF SERUM<br />
N-TELOPEPTIDES OF TYPE I COLLOGEN (NTX) IN PATIENTS<br />
WITH LUNG CANCER WHO DEVELOPED BONE METASTASIS:<br />
A PROSPECTIVE STUDY<br />
M. Tamiya 1 , S. Tokunaga 2 , H. Okada 2 , K. Taira 2 , H. Daga 3 , N. Morishita 4 ,<br />
H. Suzuki 4 , N. Okamoto 4 , K. Takeda 2 , T. Hirashima 1<br />
1 Department of Thoracic Malignancy, Osaka Prefectural Medical Center for<br />
Respiratory and Allergic Diseases, Osaka, JAPAN, 2 Clinical Oncology, Osaka City<br />
General Hospital, Osaka, JAPAN, 3 Department of Clinical Oncology, Osaka City<br />
General Hospital, Osaka, JAPAN, 4 Thoracic Malignancy, Osaka Prefectural<br />
Hospital Organization Osaka Prefectural Medical Center for Respiratory and<br />
Allergic Diseases, Habikino-City, JAPAN<br />
Background: The bone resorption biomarkers urinary NTx (uNTx) and serum NTx<br />
(sNTx) have been shown to aid in <strong>the</strong> diagnosis of bone metastasis in patients with<br />
lung cancer. Patients with metastatic bone disease from lung cancer (MBDLC) are<br />
often treated with zoledronic acid. Zoledronic acid reduces <strong>the</strong> levels of bone<br />
resorption biomarkers and also <strong>the</strong> risk of skeletal adverse events in patients with<br />
MBDLC. We studied <strong>the</strong> effects of treatments including zoledronic acid on levels of<br />
sNTx during disease progression.<br />
Methods: Patients with MBDLC at <strong>the</strong> initial diagnosis were entered to this study.<br />
sNTx was measured once a month using <strong>the</strong> sNTx assay OSTEOMARK TM serum<br />
NTx (Alere Medical). MBDLC was characterized by monthly physical examination<br />
and by bone scintigraphy every 3 months for 12 months. All patients were required<br />
to provide written informed consent.<br />
Results: Twenty patients were enrolled between June and December 2010. The mean<br />
+/- 1 SD of <strong>the</strong> sNTx concentrations was 19.8 +/- 5.8 nM BCE/L at baseline. In <strong>the</strong><br />
16 patients receiving zoledronic acid, <strong>the</strong> levels of sNTx showed a significant decrease<br />
in <strong>the</strong> first month of treatment (baseline: 21.3 +/- 5.5 nM BCE/L; one month later:<br />
13.6 +/- 2.7 nM BCE/L; p < 0.01). During follow-up period, 12 of <strong>the</strong> patients treated<br />
with zoledronic acid experienced worsening MBDLC or had died from lung cancer,<br />
and <strong>the</strong>re were statistically significant differences in <strong>the</strong> levels of sNTx at baseline<br />
(19.7 +/- 4.47 nM BCE/L), at <strong>the</strong> lowest levels after <strong>the</strong> administration of zoledronic<br />
acid (11.5 +/- 2.73 nM BCE/L) and at <strong>the</strong> point of measurable disease progression or<br />
death (13.0 +/- 2.07 nM BCE/L).<br />
Conclusions: Serial measurements of sNTx in patients with MBDLC treated with<br />
zoledronic acid might predict disease progression of bone metastasis. Administration<br />
of zoledronic acid significantly decreased <strong>the</strong> level of sNTx from baseline within one<br />
month and maintained <strong>the</strong> level of sNTx lower than baseline during study periods.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1322 PREDICTIVE BIOMARKERS IN NSCLC PATIENTS TREATED<br />
WITH ERLOTINIB AFTER CHEMOTHERAPY: EGFR<br />
EXPRESSION OR MUTATIONS?<br />
A. Inno 1 , E. Maci 1 , M. Martini 2 , V. Arena 2 , V.P. Di Noia 1 , G. Schinzari 1 ,L.<br />
M. Larocca 2 , A. Cassano 1 , C. Pozzo 1 , C. Barone 1<br />
1 Oncologia Medica, Università Cattolica del Sacro Cuore, Roma, ITALY, 2 Istituto<br />
di Patologia, Università Cattolica del Sacro Cuore, Roma, ITALY<br />
Introduction: Retrospective subgroup analysis from randomized trials did not show<br />
a significant association between activating EGFR mutations and benefit from<br />
erlotinib in patients with NSCLC previously treated with chemo<strong>the</strong>rapy, so whe<strong>the</strong>r<br />
EGFR mutational status should be used as a tool to select patients for erlotinib in <strong>the</strong><br />
second-line setting is debatable. Novel predictive biomarkers would be helpful to<br />
choose <strong>the</strong> most appropriate <strong>the</strong>rapeutic strategy.<br />
Methods: We correlated retrospectively <strong>the</strong> mutational status of EGFR and KRAS<br />
and also <strong>the</strong> IHC expression of EGFR, cMET, IGF1R and HER2, with <strong>the</strong> outcome<br />
of 51 patients with metastatic NSCLC treated with erlotinib as second or third-line at<br />
our institution from 2009 to <strong>2012</strong>.<br />
Results: EGFR and KRAS activating mutations were mutually exclusive and were<br />
found in 5 and 7 patients. IHC score for EGFR, IGF1R, cMET and HER2 was 3+ in<br />
11, 8, 7 and 1 patients, respectively. RR was 20% and 13% and PFS was 9 and 2<br />
months for EGFR mutant and wt patients, respectively, but <strong>the</strong> difference was not<br />
statistically significant. Similarly, KRAS mutational status did not significantly affect<br />
<strong>the</strong> outcome, although none of KRAS mutant patients achieved an objective response.<br />
RR and PFS were not related to IGF1R and cMET expression. Nine out of 11 patients<br />
(81.8%) with EGFR overexpression responded to treatment, compared with 13 out of<br />
40 patients (32.5%) with a lower EGFR level. EGFR overexpression was also associated<br />
with a longer PFS (8 vs 2 months, p = 0.05). Interestingly, in our study <strong>the</strong> outcome of<br />
patients was not affected by gender, performance status, histology or smoking history.<br />
Conclusion: cMET and IGF1R were not related to <strong>the</strong> efficacy of erlotinib as second<br />
or third-line treatment for metastatic NSCLC patients. No conclusions can be drawn<br />
about HER2 since only one case of overexpression was found. EGFR mutations are<br />
associated with a longer PFS, even if not significantly. The IHC expression of EGFR<br />
seems to be predictive of a better outcome, whereas KRAS mutations may represent a<br />
mechanism of resistance. Given <strong>the</strong> retrospective nature of our study, however, those<br />
findings should be confirmed within prospective clinical trials.<br />
Disclosure: A. Inno: Speaker at educational meetings sponsored by Merk-Serono and<br />
Amgen. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1323 STUDY OF THE SAFETY AND EFFICACY OF EPIDERMAL<br />
GROWTH FACTOR RECEPTOR TYROSINE KINASE<br />
INHIBITORS IN 97 PATIENTS WITH EPIDERMAL GROWTH<br />
FACTOR RECEPTOR MUTATION-POSITIVE NON-SMALL CELL<br />
LUNG CANCER<br />
M. Ishibashi 1 , K. Ogawa 1 , S. Motizuki 1 , S. Hanada 1 , H. Uruga 1 , H. Takaya 1 ,<br />
A. Miyamoto 1 , N. Morokawa 1 , T. Fujii 2 , K. Kishi 1<br />
1 Dept. of Respiratory Medicine, Toranomon Hospital, Tokyo, JAPAN, 2 Pathology,<br />
Troranomon Hospital, Tokyo, JAPAN<br />
Background: Recent phase 3 trials have demonstrated that first-line epidermal<br />
growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) improved <strong>the</strong><br />
progression-free survival (PFS) in good performance status (PS) patients with<br />
non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. We<br />
aimed to study <strong>the</strong> safety and efficacy of EGFR TKIs in patients with activating<br />
EGFR mutation-positive NSCLC in a normal clinical setting.<br />
Materials and methods: Between August 2006 and October 2011, 487 patients with<br />
NSCLC were examined for EGFR mutations by <strong>the</strong> peptide nucleic acid–locked<br />
nucleic acid polymerase chain reaction clamp method at Toranomon Hospital. One<br />
hundred and forty-two patients were tested positive for EGFR mutations: 82 patients<br />
had exon 19 deletions and 60 patients had L858R mutations in exon 21. Of <strong>the</strong>se 142<br />
patients, EGFR TKIs were administered in 97 patients (51 men and 46 women, with<br />
a median age of 68 years). We retrospectively studied <strong>the</strong> clinical data to determine<br />
<strong>the</strong> efficacy and toxicity of EGFR TKIs that were administered to <strong>the</strong>se patients. The<br />
overall survival and PFS from <strong>the</strong> start date of EGFR TKI <strong>the</strong>rapy were calculated<br />
using <strong>the</strong> Kaplan–Meier method.<br />
Results: Thirty-one patients were aged 75 or more. Fourteen patients had a poor PS of<br />
3 or 4 and 57 patients had previously undergone chemo<strong>the</strong>rapy. Gefitinib was<br />
administered to 76 patients, erlotinib to 56 patients, and both drugs to 35 patients. The<br />
response rate was 49%. The median PFS was 10.6 months and <strong>the</strong> median survival<br />
time was 26.4 months. The following grade 3 or 4 toxicities were observed: skin rash<br />
(n = 6), increased aminotransferase levels (n = 4), and interstitial lung disease (n = 6).<br />
Conclusion: Although patients who are elderly, those with poor PS, and those who had<br />
previously undergone chemo<strong>the</strong>rapy were included in this study, EGFR TKIs for 97<br />
patients with EGFR mutation-positive NSCLC in clinical practice showed a median PFS<br />
of 10.6 months and a median survival time of 26.4 months without treatment-related<br />
death. The results of this study were consistent with those of <strong>the</strong> recent phase 3 trials.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1324 ANALYSIS OF EML4-ALK POSITIVE NON-SMALL CELL LUNG<br />
CANCER WITH ADVANCED STAGE<br />
J. Park 1 , C. Kondo 1 , J. Shimizu 2 , Y. Horio 1 , K. Yoshida 1 , Y. Yatabe 3 ,<br />
T. Mitsudomi 4 , T. Hida 1<br />
1 Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya,<br />
JAPAN, 2 Thoracic Oncology, Aichi Cancer Center, Nagoya, JAPAN,<br />
3 Department of Pathology and Molecular Diagnostics, Aichi Cancer Center,<br />
Nagoya, JAPAN, 4 Department of Thoracic Surgery, Kinki University Faculty of<br />
Medicine, Sayama, JAPAN<br />
Background: The purpose of this study is to investigate <strong>the</strong> clinical characteristics<br />
and <strong>the</strong> efficacy of <strong>the</strong> cytotoxic chemo<strong>the</strong>rapy in <strong>the</strong> first and second line setting in<br />
EML4-ALK positive NSCLC with advanced stage.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds409 | ix433
Methods: EML4-ALK fusion was screened with RT-PCR and<br />
immunohistochemistry. When positive results were obtained with ei<strong>the</strong>r<br />
method, gene rearrangement of ALK was confirmed with fluorescent in-situ<br />
hybridization. Clinical features and <strong>the</strong> efficacy of chemo<strong>the</strong>rapy were evaluated<br />
retrospectively.<br />
Results: We evaluated 20 EML4-ALK positive patients with advanced stage.<br />
Seventeen (85%) of 20 had stage IV disease. Nine cases were male, and 11 were<br />
female. The mean ages were 46.3 years (range26-79). Most of <strong>the</strong>ir CT findings<br />
demonstrated mass or nodule in primary sites, while 2 cases showed air-space<br />
consolidation. In patients with stage IV <strong>the</strong> most common sites of metastasis at <strong>the</strong><br />
first onset were bone (47.0%), followed by pleura (35.2%), liver (29.4%), and lung<br />
(23.5%). In 13 cases of which were evaluable in <strong>the</strong> first line setting, 7 (53.8%) had a<br />
partial response (PR), 4 (30.8%) had stable disease (SD), and 2 (15.4%) had<br />
progressive disease (PD). Among 10 evaluable cases in <strong>the</strong> second line setting, 2<br />
(20%) had a PR, 5 (50%) had SD, and 3 had PD (30%). Two patients who had a PR<br />
were both treated by oral ALK inhibitor (crizotinib). One case had no response to<br />
crizotinib. Within <strong>the</strong> 7 patients who were treated by cytotoxic agents, none had<br />
marked clinical response. Five patients (71.4%) had SD, 2 patients had PD (28.6%)<br />
on single cytotoxic drug.<br />
Conclusions: Our study suggests that <strong>the</strong> EML4-ALK positive patients may show<br />
relatively favorable response to cytotoxic drug in <strong>the</strong> first line setting, but low<br />
response in <strong>the</strong> second line setting. These data could be helpful for fur<strong>the</strong>r clinical<br />
trials including EML4-ALK patients.<br />
Disclosure: T. Mitsudomi: Dr. Mitsudomi has received lecture fees from<br />
AstraZeneca and Chugai, and he is a member of advisory boards of Pfizer<br />
and Boehringer-Ingelheim. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
1325 FIRST-LINE GEFITINIB TREATMENT FOR ELDERLY PATIENTS<br />
WITH NON-SMALL CELL LUNG CANCER HARBORING EGFR<br />
MUTATION: MULTICENTER PHASE II TRIAL CJLSG0901<br />
K. Takahashi 1 , H. Saito 1 , M. Yamamoto 2 , E. Kojima 3 , T. Yokoyama 4 , Y. Sugino 5 ,<br />
T. Kimura 6 , T. Ogasawara 7 , R. Suzuki 8 , Y. Hasegawa 9<br />
1 Respiratory Medicine, Aichi Cancer Center Aichi Hospital, Okazaki, JAPAN,<br />
2 Respiratory Medicine, Nagoya Ekisaikai Hospital, Nagoya, JAPAN, 3 Respiratory<br />
Medicine, Komaki Municipal Hospital, Komaki, JAPAN, 4 Respiratory Medicine,<br />
Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, JAPAN, 5 Respiratory<br />
Medicine, Toyota Memorial Hospital, Toyota, JAPAN, 6 Respiratory Medicine and<br />
Allergy, Tosei General Hospital, Seto, JAPAN, 7 Respiratory Medicine,<br />
NagoyaDaini Red Cross Hospital, Nagoya, JAPAN, 8 Respiratory Medicine,<br />
Toyohashi Municipal Hospital, Toyohashi, JAPAN, 9 Respiratory Medicine,<br />
Nagoya University Graduate School of Medicine, Nagoya, JAPAN<br />
Background: Recently, <strong>the</strong> elderly population of lung cancer patients is increasing<br />
worldwide. Although first-line Gefitinib is one of <strong>the</strong> standard treatments for<br />
advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor<br />
receptor (EGFR) mutation, few data have been reported on elderly patients. Thus, we<br />
conducted a phase II trial to evaluate <strong>the</strong> efficacy and safety of first-line gefitinib<br />
<strong>the</strong>rapy for this specific population.<br />
Methods: Chemo<strong>the</strong>rapy-naïve patients aged 70 years or older and diagnosed with<br />
stage IIIB or IV (including recurrent non-small cell lung cancer) harboring ei<strong>the</strong>r<br />
exon 19 deletion or L858R point mutation were enrolled and treated with oral<br />
gefitinib 250 mg daily until disease progression or unacceptable toxicity occurred.<br />
The primary endpoint was response rate. Quality of life was also assessed<br />
prospectively.<br />
Results: Twenty patients were enrolled between June 2009 and March 2011. The<br />
median age was 79.5 years (range: 72-90). All <strong>the</strong> patients had adenocarcinoma, 12<br />
patients had exon 19 deletion, and 8 had L858R mutation. Overall response rate was<br />
70% (95% CI, 46 - 88%), and <strong>the</strong> disease control rate was 90% (95% CI, 68 - 99%).<br />
The median progression-free survival was 10.8 months. The median overall survival<br />
time has not been reached. The most common adverse events were rash and liver<br />
dysfunction, and grade 1 interstitial lung disease developed in one patient. No<br />
treatment-related death was observed. The scores of <strong>the</strong> Functional Assessment of<br />
Cancer Therapy-Lung Cancer Subscale (FACT-LCS) improved significantly four<br />
weeks after <strong>the</strong> initiation of gefitinib and maintained a favorable tendency during <strong>the</strong><br />
12 weeks of treatment.<br />
Conclusion: First-line gefitinib <strong>the</strong>rapy for elderly patients with NSCLC harboring<br />
EGFR mutation demonstrated a good response rate, quality of life, and tolerance.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
1326 PHASE II TRIAL OF CARBOPLATIN AND PEMETREXED AS<br />
FIRST-LINE CHEMOTHERAPY FOR NON-SQUAMOUS<br />
NON-SMALL CELL LUNG CANCER AND CORRELATION<br />
BETWEEN THE EFFICACY/TOXICITY AND GENETIC<br />
POLYMORPHISMS ASSOCIATED WITH PEMETREXED<br />
METABOLISM: HOKKAIDO LUNG CANCER CLINICAL STUDY<br />
GROUP TRIAL (HOT) 0902<br />
Y. Fujita 1 , H. Yokouchi 2 , S. Fujiuchi 1 , T. Harada 3 , M. Harada 4 , K. Takamura 5 ,<br />
S. Oizumi 6 , H. Isobe 7 , H. Akita 8 , M. Nishimura 6<br />
1 Department of Respiratory Medicine, National Hospital Organization Asahikawa<br />
Medical Center, Asahikawa, JAPAN, 2 Department of Pulmonary Medicine,<br />
Fukushima Medical University Hospital, Fukushima, JAPAN, 3 Center for<br />
Respiratory Diseases, Hokkaido Social Insurance Hospital, Sapporo, JAPAN,<br />
4 Department of Pulmonary Disease, National Hospital Organization Hokkaido<br />
Cancer Center, Sapporo, JAPAN, 5 First Department of Medicine, Hokkaido P.W.<br />
F.A.C Obihiro-Kosei General Hospital, Obihiro, JAPAN, 6 First Department of<br />
Medicine, Hokkaido University School of Medicine, Sapporo, JAPAN,<br />
7 Department of Medical Oncology and Respiratory Medicine, KKR Sapporo<br />
Medical Center, Sapporo, JAPAN, 8 Department of Medical Oncology, Hokkaido<br />
University Graduate School of Medicine, Sapporo, JAPAN<br />
Background: The importance of biomarkers is increasing in individualized treatment<br />
strategy for cancer patients (pts). We evaluated <strong>the</strong> efficacy and safety of carboplatin<br />
(CBDCA) and pemetrexed (PEM) in Japanese pts with non-squamous non-small cell lung<br />
cancer (NSCLC), and single nucleotide polymorphisms (SNPs) associated with PEM<br />
metabolism were also analyzed to investigate <strong>the</strong>ir relationship with efficacy or toxicity.<br />
Patients and methods: Eligible pts had a performance status 0 or 1, aged from 20 to<br />
74 years, chemo<strong>the</strong>rapy-naïve stage IIIB/IV non-squamous NSCLC, and adequate<br />
organ function. Pts received CBDCA at a dose targeting an area under <strong>the</strong><br />
concentration-time curve of 5 and 500 mg/m 2 PEM every 3 weeks. More than 3<br />
cycles was considered as completion of treatment. Peripheral blood was drawn for<br />
SNPs analyses of thymidylate synthase gene (TS) and methylenetetrahydrofolate<br />
reductase gene (MTHFR) in pts with consent for <strong>the</strong> biomarker study.<br />
Results: Forty-one pts (28 men, 13 women; median age 63 years, range 43 - 73),<br />
with 39 adenocarcinomas and 2 large cell carcinomas, were enrolled and SNPs were<br />
analyzed in 37 pts. The median follow-up time was 16.1 months and <strong>the</strong> median<br />
number of treatment cycle was 4 (range 1 - 6). The completion rate was 80.5% (33<br />
pts). All pts were assessable for response; <strong>the</strong> overall response rate (RR) was 36.6%<br />
and disease control rate (DCR) was 85.4%. Median progression-free survival (PFS)<br />
and overall survival (OS) were 4.6 months (138 days: 95%C.I.; 107-168) and 16.1<br />
months (483 days: 95%C.I.; 180-786), respectively. Grade 3 or 4 hematologic<br />
toxicities included anemia (34.1%), neutropenia (29.3%), leukopenia (19.5%) and<br />
thrombocytopenia (17.1%). Grade 3 or 4 non-hematologic toxicities included<br />
anorexia (7.3%) and nausea (4.9%). No treatment-related death was observed.<br />
Although <strong>the</strong> SNPs had no relation to PFS, OS, RR nor hematologic toxicity, <strong>the</strong><br />
variable number of tandem repeat (VNTR) of <strong>the</strong> TS significantly correlated with<br />
anemia (p = 0.047) and thrombocytopenia (p = 0.038).<br />
Conclusion: The efficacy of this regimen seems even better than previously reported,<br />
and with acceptable toxicities. VNTR of <strong>the</strong> TS has <strong>the</strong> possibility of being a<br />
predictive factor of anemia and thrombocytopenia for this regimen.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1327 A PHASE II TRIAL OF CISPLATIN-DOCETAXEL-BEVACIZMAB<br />
INDUCTION CHEMOTHERAPY FOLLOWED BY BEVACIZMAB<br />
AND PEMETREXED MAINTENANCE THERAPY IN PATIENTS<br />
WITH NONSQUAMOUS CELL LUNG CARCINOMA: OKAYAMA<br />
LUNG CANCER STUDY GROUP TRIAL 0903<br />
A. Nishiyama 1 , H. Yoshioka 1 , K. Kunimasa 1 , K. Hotta 2 , N. Nogami 3 , T. Kozuki 4 ,<br />
S. Harita 5 , N. Takigawa 6 , M. Tanimoto 2 , K. Kiura 2<br />
1 Respiratory, Kurashiki Central Hospital, Kurashiki, JAPAN, 2 Department of<br />
Respiratory Medicine, Okayama University Hospital, Okayama, JAPAN,<br />
3 Respiratory, NHO Shikoku Cancer Center, Matsuyama, JAPAN, 4 Dept of<br />
Thoracic Oncology, NHO Shikoku Cancer Center, Matsuyama, JAPAN,<br />
5 Respiratory, Chugoku Central Hospital, Hukuyama, JAPAN, 6 Internal Medicine,<br />
Kawasaki-Hospital, Okayama, JAPAN<br />
Background: Addition of bevacizmab (BEV) to platinum-based doublet yields a<br />
significant but only modest survival advantage. Recently, in <strong>the</strong> PARAMOUNT trial<br />
ix434 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
pemetrexed (PEM) maintenance <strong>the</strong>rapy produced a high magnitude of PFS<br />
improvement. The OLCSG 0903 phase 2 trial investigated efficacy and safety of cisplatin<br />
(CDDP)-docetaxel (DOC)-BEV induction <strong>the</strong>rapy followed by BEV-PEM maintenance<br />
<strong>the</strong>rapy in patients with advanced nonsquamous non-small cell lung carcinoma.<br />
Methods: In this trial, 40 patients with good PS (0 or 1) participated in <strong>the</strong> induction<br />
phase, specified as four cycles of induction CDDP (80 mg/m 2 ), DOC (60 mg/m 2 ) and<br />
BEV (15 mg/kg) on day 1 of a 21-day cycle. Patients who had not progressed during<br />
CDDP-DOC-BEV induction received maintenance BEV (15 mg/kg) and PEM (500<br />
mg/m 2 ) on day 1 of a 21-day cycle until disease progression. The primary endpoint<br />
was PFS, and <strong>the</strong> secondary endpoints included toxicity, OS and response rate.<br />
Results: Patient characteristics were as follows: median age: 62 years; 78% male;<br />
100% Japanese; 30% PS 0; 73% stage IV; and 70% adenocarcinoma. At <strong>the</strong> time of<br />
this analysis, 23pts (58%) discontinued <strong>the</strong> treatment, and <strong>the</strong> proportion of<br />
discontinuations to AEs was 35% (8/23). The principal toxicity was<br />
myelosuppression (grade 4 hematological: 20 patients [50%]), and grade 3/4 febrile<br />
neutropenia was observed in 10 (25%) despite no treatment-related deaths. The<br />
objective response rate and disease control rate (% patients with CR/PR/SD) was<br />
82.5% and 97.5%, respectively. The median PFS time was 10.2 months, and <strong>the</strong><br />
6-month PFS rate was 63.2% (95% confidence interval: 44.9-76.9 %).<br />
Conclusions: CDDP-DOC-BEV followed by BEV-PEM maintenance seems an<br />
effective and moderately tolerated treatment for patients with advanced<br />
nonsquamous non-small cell lung carcinoma.<br />
Disclosure: K. Hotta: Eli Lilly Japan sanofi-aventis Chugai Pharmaceutical Co. Ltd<br />
Nippon Kayaku. N. Takigawa: Eli Lilly Japan sanofi-aventis Chugai Pharmaceutical<br />
Co. Ltd. K. Kiura: Eli Lilly Japan sanofi-aventis Chugai Pharmaceutical Co. Ltd<br />
Nippon Kayaku. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1328 META-ANALYSIS OF RELATIONSHIP BETWEEN SKIN RASH<br />
AND OUTCOME IN NON-SMALL-CELL LUNG CANCER<br />
(NSCLC) PATIENTS TREATED WITH ERLOTINIB (E) AND<br />
GEFITINIB (G)<br />
K.F. Borgonovo, F. Petrelli, M. Cabiddu, M. Ghilardi, M. Cremonesi, F. Maspero,<br />
S. Barni<br />
Medical Oncology Division, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio,<br />
ITALY<br />
Introduction: Dermatological toxicity in <strong>the</strong> form of acneiform rash is a common<br />
event in NSCLC patients being treated with anti-EGFR TKIs. An association between<br />
clinical benefit by EGFR-targeted <strong>the</strong>rapy and development of this form of skin<br />
toxicity has been noted. The objective of this meta-analysis was to assess <strong>the</strong> predictive<br />
value of skin rash for outcome in patients with NSCLC treated with E or G.<br />
Materials and methods: Prospective clinical trials or retrospective case series with<br />
reported survival (OS), progression (PFS/TTP) and response rate (RR) as a function<br />
of skin rash were serched in PubMed until January <strong>2012</strong>. The selected studies have to<br />
include adult patients with histologically confirmed NSCLC treated with G or E,<br />
alone or in combination with o<strong>the</strong>r approved agents. Hazard ratios with 95%<br />
confidence intervals (HRs) for PFS/TTP and OS and risk ratios (RRs) for response<br />
rate in patients with rash were pooled in a meta-analysis.<br />
Results: Twenty-four publications were included in this meta-analysis (17<br />
prospective trials and 7 retrospective case series) for a total of 3032 patients. For <strong>the</strong><br />
primary endpoint (OS) <strong>the</strong> occurrence of skin rash was significantly associated with<br />
reduced risk of death in patients treated with E or G (HR 0.30, p 3 14/7;<br />
non-smoker/smoker: 13/8, with EGFR mutations/without EGFR mutations – 12/9.<br />
Results: Median PFS was 7 months overall, ORR was 75% (9/12, 8 partial responses,<br />
1 complete response) and <strong>the</strong> MoS was not reached in patients with EGFR<br />
mutations. Median PFS was 2 months overall, no objective responses and <strong>the</strong> MoS<br />
was 4 months in patients without EGFR mutations. Differences are statistically<br />
significent in ORR and PFS (p < 0.05).<br />
Conclusions: EGFR TKIs showed high effectiveness and good disease control in<br />
patients with brain metastases from NSCLC with EGFR mutations.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1331 COMPARISON OF SURVIVAL IN PATIENTS WITH ADVANCED<br />
LUNG ADENOCARCINOMA TREATED BEFORE AND AFTER<br />
GEFITINIB APPROVAL IN CHINA<br />
Y. Shi 1 ,Y.Liu 1 , X. Hao 1 ,J.Li 1 ,X.Hu 1 , Y. Wang 1 , Z. Wang 2 , H. Wang 1 , X. Han 1 ,<br />
X. Zhang 1<br />
1 Oncology, Cancer Hospital-China Academy of Medical Sciences, Beijing,<br />
CHINA, 2 Medical Oncology, Cancer Hospital-Chao Yang District BeijingCAMS<br />
and PUMC, Beijing, CHINA<br />
Objective: This study compared <strong>the</strong> overall survival (OS) between advanced lung<br />
adenocarcinoma patients of before and after gefitinib approval in China.<br />
Methods: The clinical data of 558 advanced lung adenocarcinoma patients who ever<br />
received palliative chemo<strong>the</strong>rapy were reviewed retrospectively. According to a<br />
matched-pair case-control study design, 255 patients of before gefitinib approval who<br />
only received palliative chemo<strong>the</strong>rapy and 255 patients of after gefitinib approval<br />
who received gefitinib treatment were matched by age, sex and smoking history.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds409 | ix435
Results: The median survival time (MST) of 510 advanced lung adenocarcinoma<br />
patients from <strong>the</strong> date of first-line palliative <strong>the</strong>rapy was 22.8 months. MST was<br />
significantly longer among <strong>the</strong> patients treated with gefitinib after gefitinib approval<br />
compared with <strong>the</strong> patients treated before gefitinib approval (33.5 vs. 14.1months, p <<br />
0.001). Multivariate analysis showed that <strong>the</strong> independent prognostic factors to<br />
significantly improve OS of 510 patients included gefitinib treatment (hazard ratio<br />
0.175, P
Annals of Oncology<br />
received docetaxel (75mg/m2 IV), cisplatin (80 mg/m2 IV) and bevacizumab (15 mg/<br />
kg IV) in cycles of 21 days. Patients did not receive maintenance bevacizumab.<br />
Results: All patients were eligible for response. Complete and partial responses were<br />
achieved in two (4,2%) and 14 (29.2%) patients, respectively [overall response rate:<br />
33,3%; 95% CI = (20.0%-46.7%)] whereas stable disease was documented in 14<br />
patients. The median PFS was 4, 4 months (95% CI: 1,32-7,48) and <strong>the</strong> median OS<br />
13,27 (95% CI: 9,72-16,81). Treatment-related grade 3 or 4 hematologic adverse<br />
events were leucopenia, neutropenia, and anemia in 8,4%, 18,7% and 2,1% of <strong>the</strong><br />
patients, respectively. Three (6,3%) patients developed grade 2-4 febrile neutropenia<br />
and one (2.1%) patient (2,1%) died because of sepsis due to bowel perforation.<br />
Conclusions: The DCV regimen is an active regimen with manageable toxicity when<br />
administered as front line treatment in patients with advanced non-squamous<br />
NSCLC and merits to be fur<strong>the</strong>r investigated.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1336 CLINICAL MODES OF EGFR TYROSINE KINASE INHIBITOR<br />
FAILURE AND SUBSEQUENT MANAGEMENT IN ADVANCED<br />
NON-SMALL CELL LUNG CANCER<br />
H. Chen, J. Yang, H. Yan, X. Zhang, Z. Wu, Y. Wu<br />
Guangdong Lung Cancer Institute, Guangdong General Hospital (GGH) &<br />
Guangdong Academy of Medical Sciences, Guangzhou, CHINA<br />
Context: The diversity of epidermal growth factor receptor (EGFR) tyrosine kinase<br />
inhibitor (TKI) failure in advanced non-small cell lung cancer (NSCLC) has been<br />
reported sporadically, but <strong>the</strong>re is no published overview of EGFR-TKI failure<br />
modes, which could hinder <strong>the</strong> appropriate management for patients with distinct<br />
failure modes.<br />
Objectives: This study mainly aimed to classify <strong>the</strong> diversity of TKI failure, and to<br />
investigate <strong>the</strong> usefulness of clinical modes in subsequent management and<br />
prognosis.<br />
Patients and methods: The retrospective study accrued 227 Chinese advanced<br />
NSCLC patients with EGFR-TKI failure. One-hundred and twenty consecutive<br />
clinical trial patients were enrolled as <strong>the</strong> training set to establish a clinical model<br />
based on clinical factors. Ano<strong>the</strong>r 107 routine patients were enrolled as <strong>the</strong> validating<br />
set according to a Bayes discriminant analysis. EGFR mutations and c-MET<br />
amplification were analyzed. Kaplan–Meier survival analysis was used to test <strong>the</strong><br />
differences of prognosis and subsequent management in clinical modes.<br />
Results: The duration of disease control, symptom improvement, and evolution of<br />
tumor burden were verified as feasible grouping variables. A correct grouping rate<br />
achieved 84.1%. The cohort was classified into three groups, as follows: 130 patients<br />
with dramatic progression, 42 with gradual progression, and 55 with local<br />
progression. Progression-free survivals (PFSs) for <strong>the</strong> dramatic progression, gradual<br />
progression, and local progression groups were 9.3, 12.9, and 9.2 months,<br />
respectively (P =0.007). Overall survivals for <strong>the</strong> groups (OSs) were 17.1, 39.4, and<br />
23.1 months, respectively (P
enefit from sustained EGFR blockade during subsequent salvage <strong>the</strong>rapy is unclear.<br />
LUX-Lung 5 is an international, multicenter phase III trial studying <strong>the</strong> efficacy of<br />
BIBW2992 (Afatinib®, A), an irreversible erbB family blocker, in NSCLC pts<br />
progressing after treatment with ctx and E or G irrespective of <strong>the</strong>ir EGFR mutation<br />
status. Here we report <strong>the</strong> outcome of NSCLC pts treated within LUX-Lung 5 at a<br />
single center in relation to EGFR and KRAS mutation status.<br />
Methods: Pts with stage IV (UICC 7) NSCLC progressing after ctx and E or G were<br />
enrolled into LUX-Lung 5. In part A of <strong>the</strong> study pts received A (starting dose 50<br />
mg/d) until progression. In part B pts with clinical benefit ≥12 wks were randomized<br />
between A plus weekly paclitaxel vs investigator’s choice mono ctx. Following<br />
microdissection, tumor DNA was extracted and analyzed by PCR and Sanger<br />
sequencing.<br />
Results: Between May 2010 and February 2011 39 pts (20 f, 19 m; median age 61<br />
y, 38-83 y) were enrolled at <strong>the</strong> West German Cancer Center. Median number of<br />
pretreatments was 3 (1-8) including E or G. So far, tumor biopsies were retrieved<br />
from 25 pts (64%). Somatic EGFR mutations were detected in 11 pts (44% of<br />
analyzed tumors, 28% of entire cohort), whereas 14 pts (56%/36%) exhibited<br />
EGFR wild type (wt) sequences. EGFR mutation status remains unknown in 14<br />
pts (36%). KRAS mutation analysis was performed in 20 pts (51% of entire<br />
cohort) and 4 mutations were observed (20%/10%), 3 in EGFR wt and one in an<br />
EGFR mutant tumor. Median survival time from initiation of A was 432 d in<br />
EGFR mutant pts, 189 d in EGFR wt pts, and 255 d in KRAS mutant pts.<br />
Median survival time of pts with unknown EGFR mutation status was 191<br />
d. Safety of A was manageable.<br />
Conclusions: A can achieve disease control in heavily pretreated NSCLC pts. Pts<br />
with EGFR mutant tumors experience prolonged survival as compared to EGFR wt<br />
tumors (HR 0.29; 95% CI 0.07–0.64; p = 0.0058). This argues for sustained tumor<br />
dependency on EGFR signaling despite progression after E or G.<br />
Disclosure: J. Köhler: J. Köhler received financial support from Boehringer<br />
Ingelheim for writing a review article. T.C. Gauler: T.C. Gauler is principle<br />
investigator of <strong>the</strong> BI1200.43 trial testing Afatinib in HNSCC. D. Theegarten:<br />
D. Theegarten is member of <strong>the</strong> Lilly Advisory Board. W. Eberhardt: W. Eberhardt<br />
received honoraries for advisory board functions from Boehringer Ingelheim, Astra<br />
Zeneca, Roche, OSi Pharmaceuticals, Pfizer and honoraries for lectures from<br />
Boehringer Ingelheim, Astra Zeneca, Roche and Pfizer. M. Schuler: M. Schuler<br />
received research funding from Boehringer Ingelheim and travel support from Lilly.<br />
All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1340 PHASE II STUDY OF ERLOTINIB IN JAPANESE PATIENTS<br />
WITH PRETREATED EGFR MUTATION POSITIVE NON-SMALL<br />
CELL LUNG CANCER:LUNG ONCOLOGY GROUP IN KYUSHU,<br />
JAPAN (LOGIK0803)<br />
K. Takayama1 , Y. Nakanishi1 , S. Kawakami2 , K. Saruwatari3 , K. Yamada4 ,<br />
R. Morinaga5 , N. Aragane6 , S. Nagata7 , J. Kishimoto8 , Y. Ichinose9 1<br />
Research Institute for Diseases of The Chest, Kyushu University, Fukuoka,<br />
JAPAN, 2 Respirology, Kyushu Kosei-Nenkin Hospital, Kitakyusyu, JAPAN,<br />
3 4<br />
Respiratory Medicine, Kumamoto University, Kumamoto, JAPAN, Division of<br />
Respirology, Kurume University, Kurume, JAPAN, 5 Medical Oncology, Oita<br />
University Faculty of Medicine, Oita, JAPAN, 6 Blood and Lung and Tumor<br />
Instituite, Saga University, Saga, JAPAN, 7 Respiratory Medicine, University of<br />
Occupational and Environmental Health, Kitakyusyu, JAPAN, 8 Center for Clinical<br />
and Translational Research, Kyushu University Hospital, Fukuoka, JAPAN,<br />
9<br />
Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka,<br />
JAPAN<br />
Background: Erlotinib has been reported to be useful for treating EGFR<br />
mutation-positive (EGFR-mt) non-small cell lung cancer (NSCLC) (OPTIMAL<br />
<strong>ESMO</strong> 2010, EURTAC Lancet Oncol. <strong>2012</strong>). However, its usefulness had not been<br />
investigated in Japanese patients. Hence, we conducted a multicenter phase II study<br />
to investigate <strong>the</strong> efficacy and safety of erlotinib in Japanese patients with pretreated<br />
EGFR-mt NSCLC.<br />
Methods: Erlotinib, 150 mg/day, was orally administered daily to patients with<br />
pretreated EGFR-mt (exon 19/21) NSCLC who had not been treated with<br />
EGFR-TKIs. The primary endpoint was objective response rate (ORR), and <strong>the</strong><br />
secondary endpoints were disease control rate (DCR), progression-free survival<br />
(PFS), and safety.<br />
Results: Between April 2009 and January 2011, 26 patients were enrolled from 15<br />
participating centers. The patient characteristics were as follows: median age, 68 years<br />
(51 to 79); men/women, 11/15; adenocarcinoma/o<strong>the</strong>rs, 24/2; nonsmoking/smoking,<br />
20/6; ECOG PS 0/1/2, 16/8/2; exon 19/21, 19/7; and 2nd/3rd line <strong>the</strong>rapy, 25/1. The<br />
antitumor effect was as follows: PR, 14 patients; SD, 7 patients; PD, 4 patients; NE, 1<br />
patient; ORR, 54%; and DCR, 81%. The ORR and DCR according to <strong>the</strong> EGFR<br />
status were 47.4%/71.4% (exon 19/21, p = 0.3913) and 73.7%/100% (p = 0.2782),<br />
respectively. The PFS was 9.3 months (range, 0.9 to 19.2 mo). Major adverse drug<br />
reactions were rash (96%) and hepatic function disorder (40%); most episodes were<br />
grade 2 or less, and all were tolerable. No patients developed interstitial lung disease,<br />
and <strong>the</strong>re were no treatment-related deaths.<br />
Conclusion: In this study, <strong>the</strong> usefulness of erlotinib was investigated prospectively<br />
in Japanese patients with pretreated EGFR-mt NSCLC for <strong>the</strong> first time, and this<br />
Annals of Oncology<br />
drug was shown to be effective and tolerable. At this congress, we will report <strong>the</strong><br />
study results including <strong>the</strong> ORR and PFS according to <strong>the</strong> patient characteristics.<br />
Disclosure: Y. Nakanishi: From Chugai Pharmaceutical, I received 7500 Euro as<br />
honoraria on 2011, and 22000 Euro on 2010 and 70000 Euro on 2011 as research<br />
grant. Y. Ichinose: I have research funding with Chugai Pharmaceutical company. All<br />
o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1341 DOCETAXEL REGIMEN AS SECOND-LINE TREATMENT FOR<br />
PRETREATED ADVANCED NSCLC PATIENTS - A<br />
LARGE-SCALE, MULTICENTER, UNCONTROLLED, REGISTRY<br />
STUDY IN CHINA<br />
S. Lu 1 , Y.L. Wu 2 , Y.Z. Wang 3 , X. Song 4 , L.Q. Jia 5 , G.Y. Chen 6 ,T.Sun 7 ,K.<br />
H. Lu 8 , M. Ouyang 9 , H. Zhao 10<br />
1 Shanghai Lung Tumor Clinical Center, Shanghai Chest Hospital, Shanghai,<br />
CHINA, 2 Department of Clinical Oncology, Guangdong General Hospital (GGH)<br />
& Guangdong Academy of Medical Sciences, guangzhou, CHINA, 3 Department<br />
of Medical Oncology, Peking Union Medical College Hospital, Beijing, CHINA,<br />
4 2nd Department of Respiratory Diseases, Shanxi Cancer Hospital, Taiyuan,<br />
CHINA, 5 Oncology Department of Integrative Medicine, China Janpan Friendship<br />
Hospital, Beijing, CHINA, 6 Department of Medical Oncology, Heilongjiang Cancer<br />
Hospital, Harbin, CHINA, 7 Department of Medical Oncology, Liaoning Cancer<br />
Hospital, Shenyang, CHINA, 8 Department of Medical Oncology, Jiangsu<br />
Province Hospital, Nanjing, CHINA, 9 Department of Thoracic Surgery, The First<br />
Affiliated Hospital of Guangzhou Medical University, Guangzhou, CHINA,<br />
10 Department of Medical Oncology, The 301 Military Hospital, Beijing, CHINA<br />
Background: Docetaxel has been approved as a second-line <strong>the</strong>rapy for advanced<br />
non-small cell lung cancer (NSCLC) patients. The objective of this study is to<br />
provide real-world data of docetaxel regimen as second-line treatment in Chinese<br />
NSCLC patients through comparing <strong>the</strong> efficacy, toxicities and <strong>the</strong>rapeutic schema.<br />
Methods: 1220 advanced NSCLC patients who had received docetaxel regimen as<br />
second-line treatment from nationwide 47 clinical centers in China from April 2009 to<br />
October 2010 were analyzed. The primary end point was overall survival (OS).<br />
Progression-free survival (PFS), response, toxicities and <strong>the</strong>rapeutic models of docetaxel<br />
were assessed as secondary end points. Survival analysis was evaluated by Kaplan-Meier<br />
method. Single factor analysis and <strong>the</strong> COX regression model were performed to<br />
analyze <strong>the</strong> relationship between <strong>the</strong> influential factors and <strong>the</strong> prognosis of disease.<br />
Results: Docetaxel as second-line treatment for NSCLC associated with high<br />
response rate (RR) of 29.7%, median PFS of 8.2 months, median OS of 16.1 months.<br />
TNM staging (IV vs non-IV, P = 0.0270) and docetaxel regimen (docetaxel-based<br />
combinations vs docetaxel alone, P < 0.0001) were <strong>the</strong> prognostic factors for <strong>the</strong><br />
studied group. The hematologic toxicity was <strong>the</strong> main adverse effect for docetaxel<br />
regimen. The most common grade III/IV adverse events were febrile neutropenia<br />
(4.3%), leucopenia (9.3%), neutropenia (11.6%), thrombocytopenia (0.6%), anemia<br />
(0.3%), nausea (1.6%), vomiting (1.6%), and alopecia (5.2%) in <strong>the</strong> total group. 608<br />
(608/1220, 49.8%) patients were treated with docetaxel alone, and 612 (612/1220,<br />
50.2%) with docetaxel-based combinations. Compared with docetaxel alone regimen,<br />
docetaxel-based combinations better prolonged <strong>the</strong> PFS (9.0m vs 7.1m, P < 0.0001)<br />
and OS (20.6m vs 14.3m, P < 0.0001) for advanced NSCLC. The toxicity of<br />
combination <strong>the</strong>rapy was significantly higher in terms of hematologic (P = 0.0197)<br />
and non-hematologic adverse events (P = 0.0322) compared with docetaxel alone.<br />
Conclusions: Docetaxel as a second-line treatment provides better PFS and OS for<br />
Chinese NSCLC patients. The hematologic toxicity is <strong>the</strong> main adverse effect for<br />
docetaxel regimen. Owing to <strong>the</strong> limitation of registry study, fur<strong>the</strong>r studies are<br />
warranted to confirm <strong>the</strong>se findings.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1342 ERLOTINIB (ERL) VERSUS PEMETREXED (MTA) AS<br />
SECOND-LINE TREATMENT FOR NON-SQUAMOUS<br />
NON-SMALL CELL LUNG CANCER (NSNSCLC): EFFICACY<br />
AND SAFETY DATA<br />
J. Zugazagoitia 1 , J. Puente 1 , S. Hernandez 2 , J.L. Gonzalez-Larriba 1 , J. Sanz 2 ,<br />
A. Manzano 1 , E. Diaz-Rubio 1<br />
1 Medical Oncology, Hospital Clinico San Carlos, Madrid, SPAIN, 2 Anatomic<br />
Pathology, Hospital Clinico San Carlos, Madrid, SPAIN<br />
Background: A recently published study shows that ERL and chemo<strong>the</strong>rapy (MTA/<br />
docetaxel) offer similar efficacy outcomes in pretreated patients (p) with advanced<br />
NSCLC, and a direct comparison of ERL versus MTA in a prospective, randomized<br />
phase III trial also shows equivalent efficacy. However, both studies were conducted<br />
before <strong>the</strong> treatment-by-histology interaction effect was observed for MTA and p<br />
were not prospectively selected based on histology. Moreover, both studies included p<br />
considered optimal candidates for randomized trials, not always representative of <strong>the</strong><br />
entire patient population.<br />
Material and methods: P with advanced nsNSCLC treated with ERL (150 mg/d p.o.)<br />
or MTA (500 mg/m2 on d1, every 3 weeks) as 2nd-line treatment were included in<br />
<strong>the</strong> study. This single-centre, retrospective, observational study was conducted to<br />
ix438 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
compare <strong>the</strong> efficacy and safety of ERL versus MTA in non-selected p with nsNSCLC<br />
who have progressed after 1st-line chemo<strong>the</strong>rapy in a clinical practice scenario.<br />
Results: From 2006-2011, 67 p fulfill eligibility criteria, ERL (n = 32) and MTA (n =<br />
35). Baseline characteristics ERL/MTA: median age 67/65 yrs.; male 69/80%; smokers<br />
34/40%; PS ≥ 2 22/26%; adenocarcinoma 91/71%; stage IV 81 /77%; EGFR mutation<br />
positive 19/3%. No difference in terms of OS, 8.9 m (ERL) vs 7.1 months (MTA) (p<br />
= 0.551). Statistically significant differences were recorded for PFS, 3.5 (ERL) and 2.3<br />
months (MTA) (p = 0.02) and a relative reduction in risk of progression of 53.5 %<br />
for ERL vs MTA (p = 0.005). SLP differences remained statistically significant when<br />
adjusting for EGFR mutation status, histology, prior response to 1st-line treatment<br />
and location of metastatic sites. OS showed a non-statistically significant difference<br />
after adjusting for each variable. The DCR was 40.6% in <strong>the</strong> ERL and 31.4 % in <strong>the</strong><br />
MTA arm (p = 0.46). There was more grade 3-4 hematologic toxicity, anemia (8.5%),<br />
thrombopenia (11.4 %) and neutropenia (5.71%), in <strong>the</strong> MTA arm, and skin rash<br />
(9.3%) and diarrhea (6.2%) in <strong>the</strong> ERL arm.<br />
Conclusions: These results in real-life setting suggest that ERL offers similar efficacy<br />
outcomes as MTA for p with nsNSCLC, with less and easier manageable toxicity.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1343 MULTICENTER SURVEY FOR MANAGEMENT BEYOND<br />
PROGRESSION DISEASE WITH GEFITINIB IN NON-SMALL<br />
CELL LUNG CANCER<br />
T. Sawa 1 , Y. Futamura 1 , J. Shindoh 2 , Y. Ohno 3 , S. Shigeki Satoh 4 ,O.<br />
Osamu Taguchi 5 , M. Morise 6 , Y. Hasegawa 7<br />
1 Cancer Center, Gifu Municipal Hospital, Gifu, JAPAN, 2 Respiratory Medicine,<br />
Ogaki Municipal Hospital, Ogaki, JAPAN, 3 Respiratory Medicine, Gifu University,<br />
Gifu, JAPAN, 4 Medical Oncology, Nagoya City University, Nagoya, JAPAN,<br />
5 Respiratory Medicine, Mie University, Tsu, JAPAN, 6 Respiratory Medicine,<br />
Nagoya University, Nagoya, JAPAN, 7 Respiratory Medicine, Nagoya University<br />
Graduate School of Medicine, Nagoya, JAPAN<br />
Purpose: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is<br />
effective in patients with activating EGFR mutations, and median time to progression<br />
in such patients is generally up to 12 months. Usually, treatment with EGFR-TKI is<br />
terminated when disease progression ( PD) is confirmed, while acute exacerbation<br />
after <strong>the</strong> withdrawal of EGFR-TKI has been reported. To investigate current clinical<br />
management beyond PD with gefitinib, multicenter survey was conducted in Japan.<br />
Objective: All patients with EGFR mutation-positive non-small cell lung lancer<br />
confirmed PD in <strong>the</strong> treatment of gefitinib in 2010, were included in this survey to<br />
evaluate patients characteristics, progression free survival and overall survival with<br />
gefitinib, selection of regimen beyond PD, and response rate.<br />
Result: From <strong>the</strong> six participating institute, 64 cases (median age 69 years old, exon19<br />
in 37 cases, exon18 in 25 cases, ano<strong>the</strong>r type in 4 cases respectively) had been enrolled.<br />
Gefitinib has been used as first line in 35 cases, as second line in 25 cases, as 3rd line<br />
or more in 6 cases. Progression free survival was 13 months, and overall survival was<br />
33 months. In PFS and OS, <strong>the</strong>re is no difference between first line and second line use<br />
with gefitinib. Response rate shows good efficacy in patients with good performance<br />
status. Beyond PD, gefitinib administration was continued in 9 cases (including<br />
additional combined <strong>the</strong>rapy in 4 cases), and erlotinib was switched in 15 cases while<br />
platinum doublet in 2 cases, ano<strong>the</strong>r mono<strong>the</strong>rapy in 19 cases respectively. Response<br />
rate was shown 22.2% in gefitinib, 26.7% in erlotinib even beyond PD.<br />
Conclusion: In <strong>the</strong> patients with active EGFR mutation, it is confirmed that<br />
antitumor effectiveness is recognized in patients who continues to be treated under<br />
EGFR-TKI after progression of gefitinib.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1344 IS CHANGE TO ANOTHER TREATMENT IMMEDIATELY AFTER<br />
FAILURE OF GEFITINIB RECOMMENDED IN PATIENTS<br />
HARBORING ACTIVATING EPIDERMAL GROWTH FACTOR<br />
RECEPTOR MUTATIONS?<br />
K. Asami1 , T. Okuma2 , T. Hirashima3 , M. Kawahara4 , T. Kawaguchi5 , K. Okishio5 ,<br />
N. Omachi6 , N. Takeuchi1 1 2<br />
Clinical Oncology, Kinki-chuo Chest Medical Center, Sakai, JAPAN, Radiology,<br />
Kinki-chuo Chest Medical Center, Sakai, JAPAN, 3 Department of Thoracic<br />
Malignancy, Osaka Prefectural Medical Center for Respiratory and Allergic<br />
Diseases, Osaka, JAPAN, 4 Clinical Oncology, Federation of National Public<br />
Service Personnel Mutual Aid Associations, Otemae Hospital, Osaka, JAPAN,<br />
5<br />
Internal Medicine, Kinki-Chuo Chest Medical Center, Sakai-City, JAPAN,<br />
6<br />
Internal Medicine, National Hospital Organization Kinki-Chuo Chest Medical<br />
Center, Sakai, JAPAN<br />
Background: Gefitinib is an effective agent for use in treating patients suffering from<br />
non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor<br />
(EGFR) mutations. However, no optimal strategies have been established for treating<br />
<strong>the</strong>se patients after gefitinib fails. Here, we conducted a retrospective study to assess<br />
<strong>the</strong> survival benefit of continued gefitinib treatment in <strong>the</strong>se cases.<br />
Patients and methods: We analyzed gefitinib responders with activating EGFR<br />
mutations who developed progressive disease (PD) during <strong>the</strong> course of <strong>the</strong>rapy.<br />
Prognostic variables were analyzed using a Cox proportional-hazards model.<br />
Results: Among <strong>the</strong> 146 patients retrospectively reviewed, exon-19 deletion<br />
mutations and L858R point mutations were detected in 78 and 68 patients,<br />
respectively. Median survival time after PD confirmation was 14.9 months (95%<br />
confidence interval [CI]: 7.9-21.9), and <strong>the</strong> median duration of continued gefitinib<br />
<strong>the</strong>rapy beyond PD was 3.4 months. Statistical analysis showed that good<br />
performance status (0-1) (hazard ratio [HR]: 0.7), progression of previously evaluated<br />
lesion (HR: 0.6), and at least 3 months of continued treatment (HR: 0.4) were<br />
independent prognostic factors.<br />
Conclusion: Continuation of gefitinib beyond PD is an effective optional treatment<br />
in EGFR-mutated patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1345 POST-PROGRESSION SURVIVAL AFTER ERLOTINIB<br />
TREATMENT IN PATIENTS WITH ADVANCED NSCLC<br />
M.P. Trojniak 1 , A.C. Palozzo 1 , S. Imbevaro 2 , P. Rescigno 2 , D. Pastorelli 3 ,<br />
A. Jirillo 2<br />
1 Pharmacy Department, Istituto Oncologico Veneto, IRCCS, Padova, ITALY,<br />
2 Evaluation and Introduction of New Drugs in Cancer Therapy Unit, Istituto<br />
Oncologico Veneto IRCCS, Padova, ITALY, 3 Medical Oncology II, Istituto<br />
Oncologico Veneto IOV-IRCCS, Padova, ITALY<br />
Erlotinib is a potent inhibitor of epidermal growth factor receptor tyrosin-kinase<br />
activity and its efficacy has been demonstrated for <strong>the</strong> treatment of advanced NSCLC<br />
in large randomized trials. A prospective observational study was run, using<br />
institutional data collected through web-based National Oncology registry, from<br />
December 2006 to May 2011. The patients with non-small cell lung cancer,<br />
unselected for EGFR mutation/amplification and after at least one line<br />
chemo<strong>the</strong>rapy, were treated with erlotinib (150 mg/day orally) until disease<br />
progression. Every patient was checked prospectively for toxicity, clinical outcomes,<br />
previous line treatments, length of treatment and for treatments following erlotinb<br />
using hospital databases. In overall study population (130 patients), <strong>the</strong> median Time<br />
to Progression (TTP) and Overall Survival (OS) were 2.4 and 4.4 months,<br />
respectively and 1-year survival rate was 25%. 4 patients achieved partial response<br />
and 23 patients achieved stable disease, making <strong>the</strong> disease control rate 21%. Grade<br />
1-2 rash and diarrhoea were <strong>the</strong> most frequent adverse events. The subgroups<br />
analysis showed significantly improved OS for patients with chemo<strong>the</strong>rapy<br />
post-erlotinib (pemetrexed, docetaxel) compared to those with no chemo<strong>the</strong>rapy<br />
post-erlotinib, 12.7 months and 3.0 months (p < 0.0001), respectively. The main<br />
prognostic factors, such as age, sex, histology, ECOG performance status, smoking<br />
status, treatment line and <strong>the</strong> median time to relapse of previous line treatments were<br />
equally distributed between <strong>the</strong>se two subgroups. The data of EGFR mutation and<br />
EGFR FISH positive status were available for 21% of <strong>the</strong> patients, however we did<br />
not find a significant association between EGRF expression and treatment response<br />
in both groups. This evaluation has revealed significantly better survival with<br />
chemo<strong>the</strong>rapy post-erlotinib regardless of <strong>the</strong> EGFR expression, giving evidence of<br />
o<strong>the</strong>r existing mechanisms. The post-marketing studies in real life practice are<br />
needed in order to verify both effectiveness and safety in general population, testing<br />
for external validity of <strong>the</strong> randomized trials. The post-progression survival<br />
assessment may be crucial to determine real clinical impact of investigational drug in<br />
combination with o<strong>the</strong>r treatments as it usually lacks in <strong>the</strong> approval RCTs.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1346 ERLOTINIB ROLE IN PRETREATED EGFR WILD TYPE<br />
CAUCASIAN PATIENTS: A RETROSPECTIVE OBSERVATIONAL<br />
STUDY<br />
B. Gori, E. Del Signore, A. Fulvi, S. Ricciardi, M.R. Migliorino, R. Belli, S. Condò,<br />
S. De Santis, A.M. Colacchi, F. De Marinis<br />
1st Oncological Pulmonary Unit, San Camillo High Specialization Hospital, Rome,<br />
ITALY<br />
Introduction: Erlotinib in UE was approved in unselected A-NSCLC patients (pts)<br />
(2nd/3rd line and switch maintenance) and in EGFR mutated pts.<br />
Methods: We conducted a retrospective mono-institutional observational study (Jan<br />
2007- May <strong>2012</strong>) of Caucasian pts with A-NSCLC, all EGFR wild-type (WT), who<br />
received erlotinib in 2nd, 3rd, 4th, 5th line of <strong>the</strong>rapy.191 pts with pretreated<br />
A-NSCLC were evaluated, including 108 (57%) treated with erlotinib as 2nd line and<br />
83 (43%) as 3rd/4th/5th line. All pts were considered for survival, analyzing some<br />
different clinical characteristics for pts in 2nd line. All pts received a CT scan<br />
evaluation every two months of treatment.<br />
Results: Of 108 pts who received erlotinib in 2nd line <strong>the</strong> median PFS was 8,4 weeks<br />
(wks) with an Overall Survival(OS) of 16,8 wks, of which 59 pts (55%) with ECOG<br />
PS 1 had mPFS of 12,6 wks and mOS of 21 wks, compared with 49 pts (45%) with<br />
PS 2-3 who had 4,2 wks of mPFS and 8,4 wks of mOS. Selecting pts according to<br />
clinical prognostic/predictive factors we obtained different groups: <strong>the</strong> best one was<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds409 | ix439
epresented by 19 pts (32%) female, adenocarcinoma, PS1, never/former smokers<br />
with a mPFS of 25,2 wks and mOS of 37,8 wks against <strong>the</strong> worst one defined by 7<br />
pts (12%) male, squamous, current smokers with mPFS of 8,4 wks and mOS of 16,8<br />
wks. In subsequent lines of <strong>the</strong>rapy where <strong>the</strong> mPFS of 83 pts (43%) was 8.4 wks<br />
with a mOS of 21.0 wks, <strong>the</strong> PS played a decisive role: PS 1 63 pts (76%) showed<br />
respectively 12,6 wks and 25,2 wks of mPFS and mOS respect of 4,2 wks and 8,4 wks<br />
of 20 pts (24%) with PS 2-3.<br />
Conclusions: 90% of <strong>the</strong> Caucasian patients do not express <strong>the</strong> EGFR mutation,<br />
estimated to date in no more than 50-60% of patients diagnosed with A-NSCLC.<br />
Erlotinib is a standard treatment in 2nd / 3rd line, without adequate studies<br />
comparing with chemo<strong>the</strong>rapy in wild-type population. This retrospective analysis,<br />
original for <strong>the</strong> assessment of EGFR mutational status and for <strong>the</strong> large number of<br />
cases, confirms <strong>the</strong> predictive/prognostic role of <strong>the</strong> PS 1 for <strong>the</strong> WT EGFR pts treated<br />
with erlotinib across all <strong>the</strong> lines ( p = .0001), limiting <strong>the</strong> advantage in <strong>the</strong> PS 2/3.<br />
Moreover, <strong>the</strong> results of <strong>the</strong> 2nd line shows that it is possible to identify a group of WT<br />
pts with positive predictive characteristics (PS 1, ADC, never / former smokers,<br />
female) to receive a greater benefit in survival (p= .03) with <strong>the</strong> use of erlotinib.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1347 EGFR-TYROSINE KINASE INHIBITOR TREATMENT BEYOND<br />
PROGRESSION IN LONG-TERM RESPONDERS TO ERLOTINIB<br />
IN ADVANCED NON-SMALL CELL LUNG CANCER:<br />
RELEVANCE OF EGFR MUTATION STATUS<br />
M. Faehling 1 , R. Eckert 2 , T. Kamp 3 , J. Sträter 4 , G. Ott 5 , W. Spengler 6<br />
1 Klinik für Kardiologie und Pneumologie, Klinikum Esslingen, Esslingen,<br />
GERMANY, 2 Oncology Group Practice, Wendlingen, GERMANY, 3 Oncology,<br />
Oncology Group Practice, Wendlingen, GERMANY, 4 Pathologie, Institut für<br />
Pathologie, Esslingen, GERMANY, 5 Pathology, Robert Bosch Krankenhaus,<br />
Stuttgart, GERMANY, 6 Medizinische Klinik II, Universitätsklinik Tübingen,<br />
Tübingen, GERMANY<br />
Introduction: Some patients with advanced NSCLC show prolonged disease<br />
stabilization on treatment with an EGFR-tyrosine kinase inhibitor (TKI) such as<br />
erlotinib. It is not clear how to treat patients who progress after prolonged response<br />
to erlotinib. We hypo<strong>the</strong>sized that TKI <strong>the</strong>rapy beyond progression with added<br />
chemo<strong>the</strong>rapy, radio<strong>the</strong>rapy or best supportive care may improve survival.<br />
Patients and methods: We retrospectively analyzed all NSCLC patients treated with<br />
erlotinib at our institutions since 2004 who progressed after at least stable disease on<br />
erlotinib for at least six months. The first 16 patients did not receive fur<strong>the</strong>r TKI<br />
treatment after progression (controls). The following 25 patients were treated with<br />
TKI beyond progression (TKI patients). Overall survival (OS) was analyzed for <strong>the</strong><br />
whole population, a case-control analysis of pairs matched for gender, smoking<br />
status, histology, best response to first TKI <strong>the</strong>rapy, and <strong>the</strong>rapy line. Fur<strong>the</strong>rmore,<br />
OS of patients with known EGFR-mutation status (n = 24) and those treated with<br />
pemetrexed (n = 21) is reported.<br />
Results: Treatment with TKI and chemo<strong>the</strong>rapy was well tolerated. TKI-patients had<br />
a significantly longer OS from progression on TKI (case control: median 14.5 vs. 2.0<br />
months, HR 0.154) and longer OS from diagnosis of lung cancer (case control:<br />
median 54.5 vs. 28.3 months, HR 0.474). Patients with an activating EGFR mutation<br />
had prolonged survival compared with patients without an activating EGFR<br />
mutation. However, both in patients with and without an activating EGFR mutation,<br />
patients treated with erlotinib beyond progression had a longer survival.<br />
Conclusions: In our case-control analysis in long-term erlotinib responders,<br />
treatment with TKI beyond progression in addition to chemo<strong>the</strong>rapy or radio<strong>the</strong>rapy<br />
was feasible and lead to prolonged overall survival. A prolonged survival with<br />
erlotinib beyond progression was observed in both EGFR-mutation positive and<br />
negative long-term responders to erlotinib.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1348 EFFICACY OF CHEMOTHERAPY (CHT) BEYOND TYROSINE<br />
KINASES INHIBITORS (TKI) IN ADVANCED NON SMALL CELL<br />
LUNG CANCER (NSCLC) PATIENTS (PTS) UNSELECTED FOR<br />
EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) MUTATION<br />
P. Trenta 1 , R. Iacovelli 1 , A. Palazzo 1 , D. Pellegrino 2 , C. Mosillo 2 , F. Rubini 2 ,<br />
A. Prete 2 , V. Magri 2 , A. De Benedetto 2 , E. Cortesi 2<br />
1 Department of Radiology, Oncology and Human Pathology, Sapienza University<br />
of Rome, Rome, ITALY, 2 Department of Radiology, Oncology and Human<br />
Pathology, Policlinico Umberto I, Rome, ITALY<br />
Background: After failure of a second or third line <strong>the</strong>rapy with TKI, many<br />
clinicians offer to <strong>the</strong>ir advanced NSCLC pts a new line of cht, even if <strong>the</strong>re are no<br />
perspective trials that support this choice. We report our experience about cytotoxic<br />
treatment administered after a target <strong>the</strong>rapy with Erlotinb or Gefitinib in pts with<br />
unknown EGFR mutational status or EGFR wild type.<br />
Patients and methods: Since January 2003 to December 2011, 84 pts received TKI<br />
in second or third line and after progression 34 of <strong>the</strong>m were treated with at least<br />
one subsequent line of cht. We collected response data, analyzed overall survival<br />
Annals of Oncology<br />
(OS) and progression free survival (PFS) of cht beyond TKI with Kaplan-Meier<br />
method and correlated <strong>the</strong>m with Disease Control (DC) and PFS of first line cht and<br />
TKI using log-rank test.<br />
Results: 29 out of 34 pts received cht as third and 5 pts as forth line treatment. 67,6<br />
% of pts received a mono<strong>the</strong>rapy, while 32,4% a combination treatment, platinum<br />
based in 7 cases. A response rate (RR) of 20,5% and a DC rate of 52,9% were<br />
registered. Median OS post-TKI and PFS were 13 (95% C.I. 6,36-19,63) and 3<br />
months (mos) (95% C.I 0,5-5,5) respectively. OS of pts who obtained DC during TKI<br />
was 18,2 mos compared to 5,7 mos of pts not responder to target treatment (p =<br />
0,019). At univariate analysis good PS(≤1) after TKI (p = 0,022), DC (p = 0,025) and<br />
PFS > 6 mos with first line cht(p = 0,002) were found to be <strong>the</strong> only predictive<br />
factors of a better PFS with post-TKI cht. At multivariate analysis only <strong>the</strong> PFS > 6<br />
mos with first line cht was confirmed as an independent predictive factor of better<br />
PFS in post-TKI setting (p = 0,05). Age more or less than 65 years (p = 0,7) use of<br />
combination (p = 0,84) and platinum-based <strong>the</strong>rapy (p = 0,75) seems not to improve<br />
survival outcome and DC of cht beyond TKI.<br />
Conclusions: DC with TKI identify a good prognostic group of pts. Good and<br />
prolonged response (> 6 mos) to <strong>the</strong> first line cht and a PS ≤1 are useful predictive<br />
factors to select pts who could benefit from receiving a cytotoxic treatment after<br />
target agents failure. Aggressive cht strategies do not seem to produce a real<br />
advantage in this setting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1349 SORAFENIB IN ADVANCED NON-SMALL-CELL LUNG<br />
CANCER: A RETROSPECTIVE ANALYSIS OF PATIENTS IN<br />
PROGRESSION AFTER TWO OR MORE LINES OF THERAPY<br />
S. Vazquez-Estevez 1 , S. Varela 2 , B. Campos 2 , R. Garcia-Campelo 3 , E. Alvarez 2 ,<br />
G. Quintero 2 , L. Anton-Aparicio 4 , J.R. Mel 2<br />
1 Oncology, Hospital Universitario Lucus Augusti, Lugo, SPAIN, 2 Oncoloxia<br />
Médica, Hospital Universitario Lucus Augusti de Lugo, Lugo, SPAIN, 3 Oncology,<br />
Complejo Hospitalario Universitario A Coruña, A Coruña, SPAIN, 4 Medical<br />
Oncology, Complejo Hospitalario A Coruña, A Coruña, SPAIN<br />
Background: Sorafenib (SOR) is a potent inhibitor of c-Raf, b-Raf VEGFR-1/2/3 and<br />
PDGFR-β. In NSCLC, proliferative signaling through <strong>the</strong> Ras/Raf/MEK/ERK pathway is<br />
often activated from K-ras mutations. Their efficacy as mono<strong>the</strong>rapy for treating advanced<br />
NSCLC has been demonstrated in several trials. In <strong>the</strong>m, SOR improved <strong>the</strong> rate of disease<br />
stabilization in patients who had previously been treated with chemo<strong>the</strong>rapy. Our<br />
objective is to confirm <strong>the</strong> clinical and safety results in daily clinical activity.<br />
Methods: Between October 2008 and December 2011, 16 Caucasian patients with<br />
metastatic NSCLC and measurable disease were treated after having received two or<br />
more prior lines of <strong>the</strong>rapy for metastatic disease.SOR was administered at a starting<br />
dose of 400 mg bid continuously in 28-day cycles.The primary end-point was<br />
Progression Free Survival (PFS). The secondary end-points were Overall Survival<br />
(OS) and Response Rate (RR).<br />
Results: Median age was 59 years (40-86). 100% patients were PS (ECOG) 0/1 (5/11,<br />
31/69%). Most were males (n = 10, 62%). The predominant histologic type was<br />
adenocarcinoma (n = 10, 62%). Thirteen (81%) patients were in stage IV at diagnosis.<br />
The predominant metastatic sites were lung (n = 9, 56%), lymph nodes, (n = 6, 38%),<br />
pleura (n =3, 19%) and bone (n = 3, 19%) Patients received a median of 3 (range: 2<br />
to 4) treatment lines prior to <strong>the</strong> SOR regimen; Eleven (68.8%) patients received at<br />
least 3 treatment lines before SOR. The median duration of <strong>the</strong> SOR regimen was<br />
114 days (9-247).Median PFS and median OS were 2.8 and 3.3 months, respectively.<br />
After administration of SOR, 2 patients (13%) had a partial response and 5 (33%)<br />
had stable disease. The toxicity profile was mild. Adverse events CTC G3/4 were<br />
dyspnea (n = 4, 25%), skin toxicity (n = 1, 6%) and vomiting (n = 1, 6%). In 1 case,<br />
treatment was interrupted by non-hematological toxicity.<br />
Conclusions: Patients with advanced NSCLC receiving SOR after two or more lines of<br />
<strong>the</strong>rapy got a 2.8 and 3.3 months median PFS and OS, respectively, with a 46% Disease<br />
Control Rate and with an acceptable safety profile. While still waiting for <strong>the</strong> results of<br />
ongoing trials, SOR is active and safe in this widely treated patient population.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1350 METASTATIC NSCLC OUTCOMES AT A SINGLE CANADIAN<br />
INSTITUTION OVER A DECADE<br />
S. Otsuka, W. Boland, D. Hao, D. Morris, D.G. Bebb<br />
Oncology, Tom Baker Cancer Centre/University of Calgary, Calgary, AB,<br />
CANADA<br />
Background: In <strong>the</strong> past 10 years, <strong>the</strong> standard of care in non small cell lung cancer<br />
has seen <strong>the</strong> adoption of several less toxic and better tolerated <strong>the</strong>rapies, allowing a<br />
greater proportion of metastatic patients <strong>the</strong> opportunity to receive 2 nd and even 3 rd<br />
line treatment. We investigated whe<strong>the</strong>r this improvement in <strong>the</strong> number of available<br />
<strong>the</strong>rapies for metastatic NSCLC had any bearing on overall patient survival, by<br />
retrospectively analyzing patients diagnosed in 1999, 2004 and 2009 at our centre.<br />
Methods: Demographic details, clinical variables and outcome data were ga<strong>the</strong>red<br />
retrospectively via chart review, on NSCLC patients diagnosed at <strong>the</strong> Tom Baker<br />
ix440 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Cancer Centre (TBCC) in 1999, 2004 and 2009 (Glans-Look Lung Cancer Database).<br />
All patients were restaged according to <strong>the</strong> new 7th Edition of <strong>the</strong> American Joint<br />
Committee on Cancer TNM system for NSCLC staging. Survival was analyzed using<br />
<strong>the</strong> Kaplan-Meier method and differences measured by a log rank test.<br />
Results: 807 patients were included in <strong>the</strong> analysis (649 who were stage IV at<br />
diagnosis, 158 who recurred with metastatic disease). Of <strong>the</strong>se patients, 22.1%<br />
received palliative systemic <strong>the</strong>rapy (18.9% in 1999, 23.0% in 2004 and 23.1% in<br />
2009). During this time, <strong>the</strong> proportion of patients who received 2 or more lines of<br />
treatment almost doubled (6.9% in 1999, 9.0% in 2004 and 12.7% in 2009). In<br />
addition, <strong>the</strong>re was a trend towards increasing median overall survival (MOS) of<br />
systemically treated patients over 1999-2009, from 10.8 months (95% CI: 8.4-13.3) in<br />
1999 to 14.7 months (95%CI: 9.6-14.4) in 2009 (p = 0.2).<br />
Conclusions: Our analysis suggests that <strong>the</strong>re is an increasing proportion of metastatic<br />
NSCLC patients being treated systemically at our centre, specifically, <strong>the</strong> proportion of<br />
patients being treated with two or more lines of systemic <strong>the</strong>rapy has increased over<br />
<strong>the</strong> decade from 1999-2009. This study also suggests a trend toward an increased MOS<br />
for systemically treated patients diagnosed in 2009 compared to those diagnosed in<br />
1999. However, <strong>the</strong> vast majority of patients (>3/4) are still not being treated with<br />
systemic <strong>the</strong>rapy, despite <strong>the</strong> increase in available <strong>the</strong>rapies now compared to a decade<br />
ago. The reasons for this are not clear but may include poor ECOG performance<br />
status, rapid decline, sub-optimal referral pathways and rural residence.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1351 DOES ELIGIBILITY FOR BEVACIZUMAB (BV) LEAD TO<br />
SELECTION BIAS?<br />
Y. Takagi 1 , A. Toriihara 2 , Y. Hosomi 1 , Y. Nakahara 1 , M. Akahane 1 , Y. Okuma 1 ,<br />
M. Iguchi 1 , T. Okamura 1 , M. Shibuya 1<br />
1 Department of Thoracic Oncology and Respiratory Medicine, Tokyo<br />
Metropolitan Cancer and Infectious Diseases Center Komagome Hospital,<br />
Tokyo, JAPAN, 2 Department of Radiology, Tokyo Medical and Dental University,<br />
Tokyo, JAPAN<br />
Background: Eligibility is often narrowed in clinical trials of targeted drugs<br />
because of specific adverse effects. Modified eligibility criteria can affect endpoints<br />
such as overall survival independently of <strong>the</strong> actual effect of an investigational<br />
drug.<br />
Methods: Patients with stage IIIB/IV, non-squamous non-small cell lung cancer<br />
(NSCLC) who started chemo<strong>the</strong>rapy from 2005 to 2009 were reviewed.<br />
Bevacizumab (BV) was first used to treat lung cancer at our institution in 2010.<br />
We divided patients into BV-eligible (A) and -ineligible (B) groups. To estimate<br />
survival, Kaplan-Meier curves were calculated and compared between <strong>the</strong> groups<br />
using <strong>the</strong> log-rank test. We also examined <strong>the</strong> prognostic impact of age, gender,<br />
M factor, performance status (PS), use of platinum in first-line chemo<strong>the</strong>rapy,<br />
history of hemoptysis, major blood vessel invasion (MVI) by <strong>the</strong> tumor and<br />
clinically significant cardiovascular disease upon overall survival using <strong>the</strong> Cox<br />
proportional hazards model. A radiologist who was blinded to <strong>the</strong> clinical<br />
outcomes evaluated MVI. All tests were two sided with a significance level of<br />
0.05.<br />
Results: Among 576 patients with lung cancer who undergone chemo<strong>the</strong>rapy at<br />
our department, 283 of <strong>the</strong>m had stage IIIB/IV non-squamous NSCLC. After<br />
excluding 15 patients with indications for combined chemoradio<strong>the</strong>rapy and 22<br />
with PS 3/4, <strong>the</strong> eligibility of 246 patients for BV was finally evaluated.<br />
Eighty-nine patients were considered ineligible for BV (cohort B), based on one or<br />
more of a history of hemoptysis (N = 32), MVI (N = 64) and cardiovascular<br />
disease (N = 13). Eligibility could not be determined in ten patients and <strong>the</strong><br />
remaining 147 patients were classified into cohort A. Overall survival was<br />
significantly better in cohort A (median, 14.9 months) than in cohort B (median,<br />
8.6 months; hazard ratio, 0.55; 95%CI, 0.42-0.74; P < .0001). Multivariate analysis<br />
indicated that gender, PS, a history of hemoptysis and MVI are significant<br />
prognostic factors.<br />
Conclusion: Eligibility for BV itself is a powerful prognostic factor for patients with<br />
non-squamous NSCLC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1352 CLINICAL PROFILE AND PATTERNS OF PROGRESSION (PD)<br />
OF PATIENTS (PTS) WITH ADVANCED NON-SQUAMOUS<br />
NON-SMALL CELL LUNG CANCER (NSNSCLC) TREATED<br />
WITH FIRST LINE BEVACIZUMAB (B): AVVA STUDY<br />
J. De Castro 1 , J.M. Garcia-Bueno 2 , M. Domine 3 , S. Saura 4 , R. Garcia-Gomez 5 ,<br />
M. Sereno 6 , O. Juan 7 , E. Pujol 8 , B. Rubio 9 , M. Cobo 10<br />
1 Medical Oncology, Hospital Universitario La Paz, Madrid, SPAIN, 2 Oncology<br />
Deparment, Hospital General de Albacete, Albacete, SPAIN, 3 Oncology,<br />
Fundacion Jeminez DiazClin Nstra Senora de la Concepcion, Madrid, SPAIN,<br />
4 Medical Oncology, Hospital Universitario Dr. Negrin, Las Palmas de Gran<br />
Canaria, SPAIN, 5 Medical Oncology, Hospital General Universitario Gregorio<br />
Marañon, Madrid, SPAIN, 6 Medical Oncology, Hospital Infanta Sofia, Madrid,<br />
SPAIN, 7 Medical Oncology, Hospital Arnau de Vilanova, Valencia, SPAIN,<br />
8 Medical Oncology, Hospital Santa Barbara, Soria, SPAIN, 9 Medical Oncology,<br />
Centro Integral Oncológico Clara Campal, Madrid, SPAIN, 10 Medical Oncology,<br />
Hospital Regional Universitario Carlos Haya, Malaga, SPAIN<br />
Background: B in combination with platinum doublets prolongs survival and delays<br />
PD in chemo-naïve pts with advanced nsNSCLC and its safety profile has been<br />
widely described in clinical trials. In this study we aim to evaluate <strong>the</strong> behavior,<br />
clinical profile and patterns of PD of real-life nsNSCLC pts treated with B in 44<br />
Spanish institutions.<br />
Methods: AVVA is a multicenter, epidemiological study to define <strong>the</strong> clinical profile<br />
(gender, age, PS, histology, stage, comorbidities, tumor load, Tx, response and<br />
tolerability) and describe <strong>the</strong> patterns of PD. Pts diagnosed with advanced nsNSCLC<br />
and evidence of PD after treatment (Tx) with standard chemo<strong>the</strong>rapy (CT) plus B<br />
up to 6 cycles followed by maintenance B were included.<br />
Results: Data of 158 pts are presented. Clinical profile was: median age 58 years<br />
(range 34-79); male 65%; stage IV 91%; adenocarcinoma 77%; ECOG PS 0/1/ ≥ 2<br />
(%): 35/56/9; never/current/former smokers (%): 23/40/37. 64% of pts presented<br />
relevant concomitant disease at baseline (27% cardiovascular disease, 24% pulmonary<br />
disease). Tx received: B plus carboplatin-doublet/cisplatin-doublet/o<strong>the</strong>r (%) 70/25/5.<br />
Median no. of cycles for CT/B: 6/9. Patterns of PD: 44% presented high tumor load<br />
(tumor diameter ≥55mm and ≥5 lesions); 97% of pts presented intra-thoracic<br />
disease, 53% presented extra-thoracic disease and 13% only pulmonary disease. High<br />
tumor load was associated with extra-thoracic disease (p < 0.05). ORR was 53% (95%<br />
CI: 45-61) and disease control rate was 85%. Best response was achieved after a<br />
median of 4 cycles (range 1-16). ECOG 0/1 at PD (%): 15/50. Median PFS was 7.7<br />
months (95% CI: 7.3-8.1). No differences were found in ORR or PFS according to<br />
tumor load and intra/extra-thoracic disease. Grade 3/4 toxicities were: venous<br />
thrombosis (3.2%/0), proteinuria (0.6%/0), hemoptysis (0.6%/0), pulmonary<br />
embolism (0/0.6%) and mucositis (0.6%/0).<br />
Conclusions: B was effective in this real-life patients’ population, irrespective of<br />
tumor load and location of <strong>the</strong> disease. These results confirm <strong>the</strong> well-established<br />
safety profile and <strong>the</strong> efficacy of B as frontline Tx in nsNSCLC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1353 PHASE II TRIAL OF BEVACIZUMAB PLUS DOCETAXEL IN<br />
PATIENTS WITH PREVIOUSLY TREATED NON-SQUAMOUS<br />
NON-SMALL CELL LUNG CANCER<br />
F. Ohyanagi, K. Kudo, N. Yanagitani, A. Horiike, T. Horai, M. Nishio<br />
Thoracic Oncology Center, Cancer Institute Hospital, Japanese Foundation for<br />
Cancer Research, Tokyo, JAPAN<br />
Background: The additional effects of bevacizumab (B) as a first line chemo<strong>the</strong>rapy<br />
for non-squamous (Nsq) non-small cell lung cancer (NSCLC) have been established.<br />
However, its efficacy as a second line or higher chemo<strong>the</strong>rapeutic agent is not<br />
sufficiently investigated. Docetaxel (D) is a standard second line <strong>the</strong>rapy for NSCLC,<br />
and <strong>the</strong> synergistic effects of a combination of D and B (D + B) have been<br />
demonstrated in preclinical models. Therefore, this phase II study evaluated <strong>the</strong><br />
efficacy and safety of D + B in patients with previously treated Nsq NSCLC.<br />
Methods: Patients with histologically or cytologically confirmed Nsq NSCLC (20–74<br />
years) with an Eastern Cooperative Oncology Group performance status (PS) of 0-2<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds409 | ix441
and at least one prior course of chemo<strong>the</strong>rapy were eligible for <strong>the</strong> study. Patients<br />
were treated with D (60 mg/m 2 ) and B (15 mg/kg) on day 1, which was repeated<br />
every 3 weeks until progressive disease (PD) or unacceptable toxicity occurred. The<br />
primary endpoint was <strong>the</strong> response rate (RR).<br />
Results: Between May 2010 and July 2011, 28 patients were enrolled in <strong>the</strong> study (16<br />
males/12 females; median age, 65 years; PS, 0/1/2: 19/9/0; adeno/o<strong>the</strong>r: 22/6; number<br />
of prior chemo<strong>the</strong>rapy regimens, 1/2/3/4/5: 16/5/2/1/4). Of <strong>the</strong>se, 28 patients were<br />
included in <strong>the</strong> analysis of toxicities and 27 were evaluated for <strong>the</strong>ir response. An<br />
objective response was observed in 18 patients (partial response, 18; stable disease, 8;<br />
PD, 1). RR and disease control rate were 66.7% and 96%, respectively. After a<br />
median follow-up of 15.7 months, <strong>the</strong> median progression-free survival was 7.2<br />
months and median overall survival was 16.7 months. The main toxicity observed<br />
was myelosuppression (grade 3/4 neutropenia, 85.7%; febrile neutropenia, 21%). Mild<br />
nonhematological toxicity with minimal bleeding was also observed.<br />
Conclusions: A combination of D and B was highly active in patients with<br />
previously treated Nsq NSCLC; fur<strong>the</strong>r study is warrented.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1354 PHASE II TRIAL OF SINGLE-AGENT PEMETREXED IN<br />
CHEMONAIVE ELDERLY PATIENTS WITH ADVANCED<br />
NON-SMALL-CELL LUNG CANCER (NSCLC) AND ITS<br />
ACCRUAL RATE IN A COMMUNITY-BASED CLINICAL TRIAL<br />
GROUP: LCEN1001<br />
N. Seki 1 , T. Yokoyama 2 , K. Kishi 3 , T. Takao 4 , I. Tsujino 5 , N. Takahashi 5 ,<br />
H. Yoshifumi 5 , S. Maho 6 , S. Morita 6 , K. Eguchi 1<br />
1 Division of Medical Oncology, Department of Internal Medicine, Teikyo University<br />
School of Medicine, Tokyo, JAPAN, 2 Department of Respiratory Medicine, Kyorin<br />
University Hospital, Tokyo, JAPAN, 3 Dept. of Respiratory Medicine, Toranomon<br />
Hospital, Tokyo, JAPAN, 4 Division of Respiratory Medicine, Itabachi Chuo<br />
Medical Center, Itabashi, JAPAN, 5 Respiratory Medicine, Nihon University School<br />
of Medicine, Tokyo, JAPAN, 6 Biostatistics and Epidemiology, Yokohama City<br />
University Medical Center, Yokohama, JAPAN<br />
Background: Optimal treatment for elderly patients with advanced NSCLC has been<br />
under investigation. This study evaluated <strong>the</strong> safety and efficacy of single-agent<br />
pemetrexed for elderly patients with advanced NSCLC. Moreover, <strong>the</strong> reasons that<br />
prevented accrual and <strong>the</strong> preferential regimen for such patients in a<br />
community-based group were investigated.<br />
Patients and methods: Chemonaive elderly (≥ 70 years) patients with stage IIIB/IV<br />
non-squamous NSCLC received 500 mg/m2 of pemetrexed (day 1, every 3 weeks) for<br />
4-6 cycles. As a QOL assessment, FACT-L lung cancer symptom subscale and<br />
Comprehensive Geriatric Assessment were also evaluated. Moreover, clinical trial<br />
enrollment decisions were noted.<br />
Results: From May 2010 to October 2011, 193 consecutive patients were diagnosed<br />
as chemonaive elderly (≥ 70 years) patients with stage IIIB/IV non-squamous<br />
NSCLC. Among <strong>the</strong>m, 25 patients were enrolled in phase II trial. Characteristics<br />
were m/f, 19/6; median age, 78 years (range 70-89); PS 0/1/2, 6/18/1; stage IIIB/IV, 6/<br />
19. After a median of 4 cycles of pemetrexed, <strong>the</strong> ORR and DCR were 16.0% and<br />
68.0%, respectively. Fur<strong>the</strong>rmore, <strong>the</strong> median PFS was 126.0 days and <strong>the</strong> median OS<br />
was not reached. Grade 3/4 hematologic toxicity consisted of leukopenia (20%),<br />
neutropenia (24%), thrombocytopenia (4%), and anemia (12%), whereas grade 3/4<br />
nonhematologic toxicity consisted of nausea (4%), anorexia (12%), fatigue (8%),<br />
pneumonitits (G3, 8%), febrile neutropenia (0%), and treatment-related death (0%).<br />
Among 168 patients who were not enrolled in <strong>the</strong> trial, 83 and 85 patients were<br />
eligible and ineligible, respectively. Therefore, <strong>the</strong> accrual rate was 25 (23.1%) of 108<br />
eligible patients and 25 (13.0%) of total 193 patients, whereas ineligible rate was 85<br />
(44.0%) of total 193 patients. The most common reason for not participating in <strong>the</strong><br />
trial despite appropriate eligibility was <strong>the</strong> preference of platinum doublet<br />
chemo<strong>the</strong>rapy (57.8%), whereas <strong>the</strong> most common treatment choice for ineligible<br />
patients was best supportive care (67.1%).<br />
Conclusions: Single-agent pemetrexed has shown moderate activity and is well<br />
tolerated as first-line treatment for advanced NSCLC in elderly patients. However, in<br />
our community-based clinical trial group, platinum doublet chemo<strong>the</strong>rapy was <strong>the</strong><br />
preferential regimen for such patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
1355 ERYTHROCYTE MEAN CORPUSCULAR VOLUME CHANGE<br />
DURING PEMETREXED TREATMENT IN ADVANCED NON<br />
SMALL CELL LUNG CANCER PATIENTS<br />
S. Buti 1 , P. Bordi 1 , M. Tiseo 2 , S. Panni 3 , S. Novello 4 , E. Bria 5 , S.G. Rapetti 6 ,<br />
S. Pilotto 7 , R. Camisa 1 , A. Ardizzoni 1<br />
1 Oncologia Medica, Azienda Ospedaliero-Universitaria di Parma, Parma, ITALY,<br />
2 Oncologia Medica, Azienda Ospedaliera di Parma, Parma, ITALY, 3 Oncologia,<br />
Azienda Istituti Ospitalieri di Cremona, Cremona, ITALY, 4 Department of Clinical<br />
and Biological Sciences - Thoracic Oncology Unit, Azienda<br />
Ospedaliero-Universitaria ASOU San Luigi Gonzaga, Orbassano (TO), ITALY,<br />
5 Medical Oncology, Azienda Ospedaliera Universitaria Integrata Verona - “Borgo<br />
Roma”, Verona, ITALY, 6 Department of Clinical and Biological Sciences -<br />
Thoracic Oncology Unit, Azienda Ospedaliero-Universitaria ASOU San Luigi<br />
Gonzaga, Orbassano, ITALY, 7 Medical Oncology, Azienda Ospedaliera<br />
Universitaria Integrata Verona-”Borgo Roma”, Verona, ITALY<br />
Introduction: Pemetrexed (Pem) has been approved for <strong>the</strong> treatment of advanced<br />
non small cell lung cancer (NSCLC) non-squamous histology, both as 1° and 2° line<br />
<strong>the</strong>rapy with or without platinum compounds, respectively. Pem is an antimetabolite<br />
drug, that inhibits enzymes involved in nucleotides bio-syn<strong>the</strong>sis arresting cancer<br />
cells cycle. Literature data show <strong>the</strong> effect of antimetabolities on increment of<br />
erythrocyte mean corpuscolar volume (MCV) in cancer patients (pts) treated with<br />
capecitabine and, recently, a positive correlation between increased MCV and<br />
response to capecitabine-based <strong>the</strong>rapy has emerged [Arslan et al, Tumori 2011;<br />
Dellapasqua et al, Breast <strong>2012</strong>]. The aim of this study was <strong>the</strong> evaluation of <strong>the</strong><br />
impact of Pem on MCV change and its possible correlation with disease control rate<br />
(overall response + stable disease rate) (DCR), progression free survival (PFS) and<br />
overall survival (OS) in NSCLC pts.<br />
Methods: A retrospective collection of clinical and laboratory data (including basal<br />
MCV and maximum MCV occurred during Pem <strong>the</strong>rapy) in 165 advanced NSCLC<br />
pts treated with Pem from 4 Italian centres was performed.<br />
Results: Pts characteristics: 59% men, median age 64 years (range 36-83), 58%<br />
ECOG PS 0, 90% stage IV and 10% stage IIIB (according 6 th TNM), 87%<br />
adenocarcinoma histotype, 74% current or ex-smokers, 59% as 1° line, 41% as ≥ 2°<br />
line, 68% in combination with a platinum compound, median cycle 4 (range 1-29).<br />
All pts received vitamin B 12 and folic acid supplementation. Mean MCV significantly<br />
increased from basal (89.6 fl) to “during treatment” (94.8 fl), with mean ΔMCV = 5.2<br />
fl (t test for paired data, p < 0.0001). The median time from <strong>the</strong>rapy start to<br />
maximum MCV was 2.3 months (mos). DCR was 84% and 62% [χ 2 test, p = 0.002],<br />
median PFS was 6.9 [CI95% 5.7-8.1] and 3.6 [CI95% 1.9-5.3] mos [p = 0.0019], and<br />
median OS was 16.0 [CI95% 7.9-24.1] and 10.8 [CI95% 9.0-12.6] mos [p = 0.0346],<br />
in ΔMCV > 5 fl (n = 68) and in ΔMCV ≤ 5 fl (n = 97) pts, respectively.<br />
Conclusion: Pem induces significant increase of erythrocyte MCV. ΔMCV > 5 fl on<br />
Pem <strong>the</strong>rapy appears to be correlated with better DCR, PFS and OS. These data<br />
should be related to a decreased metabolism of Pem and subsequent increased drug<br />
exposure in pts who develop higher ΔMCV during treatment. A larger prospective<br />
evaluation could be useful to better clarify <strong>the</strong>se findings.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1356 PHASE II STUDY OF PEMETREXED IN ELDERLY (≥75)<br />
NON-SQUAMOUS NON-SMALL-CELL LUNG CANCER: KYOTO<br />
THORACIC ONCOLOGY RESEARCH GROUP TRIAL 0901<br />
Y.H. Kim 1 , M. Hirabayashi 2 , S. Kosaka 3 , J. Nikaidoh 2 , Y. Yamamoto 3 ,<br />
M. Shimada 2 , T. Toyazaki 3 , H. Nagai 1 , M. Mishima 1<br />
1 Respiratory Medicine, Kyoto University-Graduate school of medicine, Kyoto,<br />
JAPAN, 2 Respiratory Medicine, Hyogo Prefectural Amagasaki Hospital,<br />
Amagasaki, JAPAN, 3 Thoracic Surgery, Shimane Prefectural Central Hospital,<br />
Izumo, JAPAN<br />
Background: Single-agent chemo<strong>the</strong>rapy with non-platinum agents, such as<br />
vinorelbine, gemcitabine, and docetaxel (DOC), is considered to be a standard<br />
<strong>the</strong>rapeutic option for elderly non-small-cell lung cancer (NSCLC). Previous<br />
randomized trials have reproducibly demonstrated that pemetrexed (PEM) is more<br />
effective for non-squamous NSCLC, in contrast to be less effective for squamous cell<br />
lung cancer. In addition, although in second-line setting, subgroup analysis of <strong>the</strong><br />
ix442 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
phase III study comparing PEM with DOC suggested that PEM was superior to<br />
DOC in <strong>the</strong> elderly population (≥70) in terms of both efficacy and toxicity.<br />
Patients and methods: This was a single-arm phase II study of PEM in elderly<br />
(≥75) Japanese patients with chemo-naive advanced non-squamous NSCLC.<br />
Patients received four cycles of PEM (500 mg/m 2 ) every 3 weeks. The primary<br />
endpoint was <strong>the</strong> response rate, and secondary endpoints were safety and<br />
survival.<br />
Results: Twenty-eight patients were enrolled between January 2010 and April <strong>2012</strong>.<br />
Patient characteristics were as follows: male/female: 14/14; median age: 77 yr (75-88);<br />
histology, Ad/La: 27/1; disease stage, IIIB/IV: 6/22; PS, 0/1: 7/21. Five patients were<br />
still under protocol treatment, and 23 patients were evaluable for both safety and<br />
efficacy. There were 0 CR, 7 PR, 10 SD, 5 PD, and 1 NE. Response rate and disease<br />
control rate were 30.4% and 73.9%, respectively. Median treatment cycles were four.<br />
Grade 3/4 toxicity rates were 21.7% for leukocytopenia, 26.1% for neutropenia, 4.3%<br />
for anemia, 8.7% for thrombocytopenia, and 8.7% for nausea/vomiting, respectively.<br />
Four patients required G-CSF treatment, but no patients required blood transfusion.<br />
There were no treatment-related deaths.<br />
Conclusions: PEM was safe and effective in elderly (≥75) Japanese patients with nonsquamous<br />
NSCLC. Final results, including survival data, will be presented at <strong>the</strong> meeting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1357 VERY ELDERLY INOPERABLE NSCLC PATIENTS ABOVE 75<br />
YEARS COMPARED TO YOUNGER PATIENTS: EQUAL<br />
ACTIVITY OF PLATINUM-BASED DOUBLET CHEMOTHERAPY<br />
BUT HIGHER TOXICITY<br />
J.N. Jakobsen, S. Wallerek, S.A. Jensen, J.B. Sorensen<br />
Department of Oncology, Rigshospitalet, Copenhagen University Hospital,<br />
Copenhagen, DENMARK<br />
Purpose: Tolerability and activity of platinum-based doublet chemo<strong>the</strong>rapy was<br />
examined in very elderly inoperable NSCLC patients aged >75 years and compared<br />
to younger patients.<br />
Patients and methods: Chemo<strong>the</strong>rapy naïve inoperable NSCLC patients aged > 18<br />
years with no upper age limit received Carboplatin AUC 5 and Vinorelbine (VNB)<br />
25 mg/m2 day 1 and VNB 80 mg/m2 orally day 8 q 3 weeks for maximum 6 courses<br />
without g-csf. They were divided in group A being 70 years, group B 70-75 years,<br />
and group C > 75 years.<br />
Results: A total of 135 patients received 530 treatment courses (group A 70 patients,<br />
group B 40 patients, and group C 25 patients). There were no differences in<br />
pre-treatment characteristics such as gender, histologic subtype, performance status,<br />
weight loss, or stage. The median age (with range), and frequencies of performance<br />
status 2, stage IV, and subsequent 2nd line chemo<strong>the</strong>rapy were in group A 59.8 years<br />
(36-69), 23%, 69%, and 39%, in group B 72.3 years (70-75), 25%, 60%, and 23%, and<br />
in group C 78.0 years (76-84), 20%, 60%, and 12%, respectively. The frequencies of<br />
grade 4 and grade 3 and 4 leucopenia were 32% and 48% in group C and 6% and<br />
23% in group A, respectively (p = 0.001, p = 0.018) and <strong>the</strong> frequency of febrile<br />
neutropenia in C (20%) and in A (7%) (p = 0.072). There were no toxic deaths.<br />
Response rates for groups A, B, and C were 33%, 34%, and 44% and median<br />
survivals (with range) were 35 weeks (1-336), 42 weeks (0-104+), and 58+ weeks<br />
(7-296), respectively (not significant). Median times to progression were 19, 29, and<br />
16 weeks, respectively.<br />
Conclusions: Very elderly patients aged > 75 years could receive similar number<br />
of treatment courses as younger patients and with similar level of toxicity except<br />
for leucopenia and febrile neutropenia, which were more frequent in <strong>the</strong> very<br />
elderly compared to <strong>the</strong> younger groups. The activity of Carboplatin and<br />
Vinorelbine was statistically similar between age groups, though with a<br />
remarkable trend towards higher disease control rate (NC + PR + CR) among <strong>the</strong><br />
elderly and very elderly. Platinum-based doublet chemo<strong>the</strong>rapy is feasible and<br />
highly active in very elderly NSCLC patients but require close hematologic<br />
monitoring. The use of bone marrow stimulating treatment may be considered to<br />
diminish toxicity in this population.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1358 OUTCOMES FOR ELDERLY, ADVANCED–STAGE NON-SMALL<br />
CELL LUNG CANCER (NSCLC) PATIENTS TREATED WITH<br />
AMRUBICIN (AMR) AS THIRD-LINE OR FOURTH-LINE<br />
CHEMOTHERAPY: ANALYSIS OF HOKKAIDO LUNG CANCER<br />
CLINICAL STUDY GROUP TRIAL (HOT) 0901<br />
S. Oizumi 1 , T. Harada 2 , K. Takamura 3 , S. Sugawara 4 , M. Maemondo 5 , Y. Fujita 6 ,<br />
I. Kinoshita 7 , H. Dosaka-Akita 7 , H. Isobe 8 , M. Nishimura 9<br />
1 First Department of Medicine, Hokkaido University School of Medicine,<br />
Sapporo, JAPAN, 2 Center for Respiratory Disease, Hokkaido Social Insurance<br />
Hospital, Sapporo, JAPAN, 3 First Department of Medicine, Obihiro-Kosei<br />
General Hospital, Obihiro, JAPAN, 4 Department of Respiratory Medicine, Sendai<br />
Kousei Hospital, Sendai, JAPAN, 5 Department of Respiratory Medicine, Miyagi<br />
Cancer Center, Natori, JAPAN, 6 Department of Respiratory Medicine, National<br />
Hospital Organization Asahikawa Medical Center, Asahikawa, JAPAN,<br />
7 Department of Medical Oncology, Hokkaido University Graduate School of<br />
Medicine, Sapporo, JAPAN, 8 Department of Medical Oncology and Respiratory<br />
Medicine, KKR Sapporo Medical Center, Sapporo, JAPAN, 9 First Department of<br />
Medicine, Hokkaido university School of Medicine, Sapporo, JAPAN<br />
Background: HOT0901 trial evaluated <strong>the</strong> efficacy and safety of AMR,<br />
third-generation syn<strong>the</strong>tic anthracycline agent, for NSCLC patients as third-line or<br />
fourth-line chemo<strong>the</strong>rapy. We conducted a subset analysis of HOT0901 to determine<br />
<strong>the</strong> outcome for elderly patients.<br />
Methods: Eligible patients had a performance status 0 to 2, failure of second-line or<br />
third-line chemo<strong>the</strong>rapy, and adequate organ function. Patients received AMR 35 mg/m 2<br />
intravenously on days 1-3 every 3 weeks. The primary endpoint was disease control rate<br />
(DCR: CR + PR + SD). Secondary endpoints were overall survival (OS), progression-free<br />
survival (PFS), response rate (CR + PR), and toxicity profile. Elderly patients were defined<br />
as those at least 70 years of age at <strong>the</strong> time of enrollment. The efficacy and safety data for<br />
AMR <strong>the</strong>rapy was compared between <strong>the</strong> elderly and younger patients (< 70 years).<br />
Results: There were 14 elderly and 27 younger patients in this study. Elderly patients<br />
accounted for 34% of <strong>the</strong> study cohort. Clinical characteristics such as PS or histologic<br />
subtypes were similar between <strong>the</strong> groups. The median number of treatment cycles was<br />
3 in elderly and 2 in younger patients. The overall response rate and DCR were 14.3%<br />
and 71.4% in elderly patients and 7.4% and 55.5% in younger patients, respectively (p =<br />
0.42 and 0.26). Median PFS was 3.6 and 2.4 months (p = 0.70), whereas median survival<br />
time was 11.3 and 13.9 months (p = 0.67) in elderly and younger patients. The most<br />
common grade 3/4 toxicity was neutropenia (64.3 vs. 70.4%); overall, <strong>the</strong>re was no major<br />
difference in <strong>the</strong> incidence of hematological and nonhematological toxicities between <strong>the</strong><br />
groups. No treatment-related death was observed in this study.<br />
Conclusion: Third-line or fourth-line AMR yielded <strong>the</strong> similar efficacy and toxicity<br />
profiles between elderly and younger NSCLC patients. Data from this post-hoc analysis<br />
encourage prospective evaluation of potential benefit of AMR in elderly NSCLC patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1359 MULTI-CENTER OBSERVATIONAL STUDY ON THE DIAGNOSIS<br />
OF NON-SMALL CELL LUNG CANCER BONE METASTASIS<br />
AND THE EFFICACY AND SAFETY OF BISPHOSPHATES<br />
TREATMENT (C-TONG 0801)<br />
Y. Wu 1 ,Z.Li 2 , C. Zhou 3 , L. Shun 4 , Y. Zhang 5 , M. Hou 6 , W. Liu 7 , J. Wang 8 ,<br />
G. Chen 9 , Y. Zhou 10<br />
1 Department of Clinical Oncology, Guangdong General Hospital (GGH) &<br />
Guangdong Academy of Medical Sciences, Guangzhou, CHINA, 2 Oncology, Sun<br />
Yat-Sen University Cancer Center, Guangzhou, CHINA, 3 Lung Cancer Institute,<br />
Shanghai Pulmonary Hospital, Shanghai, CHINA, 4 Shanghai Lung Cancer<br />
Clinical Center, Shanghai Chest Hospital, Shanghai, CHINA, 5 Oncology, Zhejiang<br />
Cancer Hospital, Hangzhou, CHINA, 6 Oncology, West China Hospital, Chengdu,<br />
CHINA, 7 Oncology, Xijing Hospital, Xi’an, CHINA, 8 Oncology, Beijing Cancer<br />
Hospital, Beijing, CHINA, 9 Oncology, Heilongjiang Cancer Hospital, Harbin,<br />
CHINA, 10 Oncology, Henan Provincal Hospital, Zhengzhou, CHINA<br />
Objective: To study <strong>the</strong> current status of <strong>the</strong> NSCLC bone metastasis (BM) in China,<br />
including <strong>the</strong> diagnosis, NTX parameters, and <strong>the</strong> efficacy and safety of<br />
bisphosphates (BP) treatment.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds409 | ix443
Methods: NSCLC patients with radiographic verification of BM were treated with<br />
at least one kind of BPs in this prospective observational study. NTX, SRE<br />
incidence and adverse event (AE) data were collected at baseline and every 3<br />
months after treatment. Treatment continued at least until death. NTX levels<br />
were characterized as normal (N; = 50 nmol/<br />
mmol).<br />
Results: By <strong>the</strong> time of this analysis, 580 patients were enrolled into this study with<br />
<strong>the</strong> median follow-up of 6.1 months. There were 566 patients with baseline NTX<br />
results. Most patients (86.7%) had BM diagnosed using of CT containing method.<br />
The E baseline NTX patients were 374 (66.6%). Patients with multiple BM (459 pts,<br />
81.2%) had significantly higher NTX baseline level than those with single BM (108.9<br />
vs 67.3 nmol/mmol, p = 0.0003). The OS was 23.2 months. The overall SRE was<br />
22.2%, and <strong>the</strong> annual SRE was 3.4 times/person/year. Patients with E baseline NTX<br />
had trend of earlier onset of SRE (<strong>the</strong> median time to first SRE: 1.2 vs 1.6 months, p<br />
= 0.179) and shorter OS (20.6 vs not reached, months), especially after 15 months.<br />
The frequency of adverse events was 17.1%, study drug related AE was 7.1%, and<br />
serious AE was 2.6%. There were no significant changes in serum creatinine levels<br />
before and after bisphosphate <strong>the</strong>rapy. No cases of osteonecrosis of <strong>the</strong> jaw (ONJ)<br />
were observed. Zoledronic Acid-related AE was observed in 37 cases (7.7%), and SAE<br />
was observed in 14 cases (2.9%).<br />
Conclusion: NSCLC bone metastasis is a relatively common and serious clinical<br />
problem in Chinese patients, which were most frequently identified by CT. Baseline<br />
NTX level has significant negative impact on SRE. Prolonged bisphosphate <strong>the</strong>rapy<br />
could help reduce SRE with acceptable safety profiles.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1360 RETROSPECTIVE STUDY OF RADIOLOGICAL FINDINGS OF<br />
PULMONARY EMBOLISMS (PE) IN PATIENTS (PTS) WITH<br />
ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC)<br />
E. Capelletto 1 , S. Novello 1 , F. Solitro 2 , L. Focaraccio 1 , M. Giaj Levra 1 ,S.<br />
G. Rapetti 1 , T. Vavala 1 , J. Menis 3 , A. Veltri 2 , G.V. Scagliotti 1<br />
1 Department of Clinical and Biological Sciences - Thoracic Oncology Unit,<br />
Azienda Ospedaliero-Universitaria ASOU San Luigi Gonzaga, Orbassano, ITALY,<br />
2 Department of Radiology, Azienda Ospedaliero-Universitaria ASOU San Luigi<br />
Gonzaga, Orbassano, ITALY, Orbassano, ITALY, 3 Department of Medical<br />
Oncology, University Hospital Santa Maria della Misericordia, Udine, ITALY<br />
Introduction: Venous thromboembolism (VTE) is one of <strong>the</strong> leading cause of death<br />
for cancer pts, with an incidence of 1 event per 110-120 patients, mainly within <strong>the</strong><br />
first year from diagnosis. Cancer pts with VTE show a 2.2-fold increase in mortality<br />
and lung cancer is <strong>the</strong> second tumor type with <strong>the</strong> highest incidence of VTE.<br />
Considering that chemo<strong>the</strong>rapy is associated with a 6 times increased risk of VTE<br />
and that biological agents, especially antiangiogenetic compounds, cause an<br />
additional risk, <strong>the</strong> aim of <strong>the</strong> study is to evaluate, with a radiological retrospective<br />
evaluation, <strong>the</strong> real incidence of PE in selected cohorts of advanced NSCLC patients<br />
and <strong>the</strong> impact of PE on survival.<br />
Materials and methods: This retrospective monocentric study enrolled 141 advanced<br />
NSCLC pts, diagnosed between June 2007 and June 2008 (cohort 1), and between<br />
January 2010 and December 2010 (cohort 2). Pts were mostly men, with a median<br />
age of 63 years, performance status of 0 and a prevalence of comorbidities<br />
predisposing to VTE of 42.0% and 70.0% in first and second cohort, respectively.<br />
74.1% and 43.3% of pts received biological agents in first and second cohort; 39.5%<br />
and 21.7% antiangiogenetic agents.<br />
Results: Retrospective review of 460 contrast-enhanced multidetector computed<br />
tomography studies showed a prevalence of PE of 13.6% in <strong>the</strong> first cohort and of<br />
15.0% in <strong>the</strong> second one. Survival analysis didn’t show any statistically significant<br />
differences in terms of OS and TTP in <strong>the</strong> first cohort. In <strong>the</strong> second cohort, Kaplan<br />
Meier curves showed a significantly difference in terms of TTP in favor of pts who<br />
never developed PE, p-value = 0.003. Similar results were observed considering as<br />
stratification factors <strong>the</strong> use of biological agents, p-value = 0.007, and of<br />
antiangiogenic agents, p-value = 0.010.<br />
Conclusion: The higher incidence of PE in <strong>the</strong> second cohort, despite a lower<br />
exposure to biological and antiangiogenic agents, could be related to a greater<br />
thrombogenic action of <strong>the</strong>se drugs, but also a higher prevalence of comorbidities<br />
predisposing to VTE. Descriptive analysis was confirmed by survival data, underlining<br />
<strong>the</strong> need of fur<strong>the</strong>r studies to clarify <strong>the</strong> role of predisposing factors for PE.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1361 RISK OF KIDNEY FAILURE IN PATIENTS WITH NON-SMALL<br />
CELL LUNG CANCER (NSCLC) TREATED WITH PEMETREXED<br />
P. Kongsted, A. Mellemgaard<br />
Oncology, Herlev University Hospital, Herlev, DENMARK<br />
Annals of Oncology<br />
Background: Pemetrexed is effective as both first and later lines of chemo<strong>the</strong>rapy for<br />
non-squamous NSCLC. In first-line pemetrexed is used in combination with cis- or<br />
carboplatin. In progressive or relapsing disease after platinum based combination<br />
chemo<strong>the</strong>rapy it is used as a single-drug. Drug elimination is mainly renal. A few<br />
case-reports have described acute renal failure during treatment with pemetrexed.<br />
Aim: To determine <strong>the</strong> incidence rate of acute renal failure in patients treated with<br />
ei<strong>the</strong>r single agent pemetrexed or combination <strong>the</strong>rapy, evaluate reversibility of possible<br />
renal failure and to identify possible risk-factors for developing acute renal failure.<br />
Material and methods: A total of 54 consecutive patients receiving single agent<br />
pemetrexed and 55 consecutive patients receiving combination platin and<br />
pemetrexed were included. Patients were treated between 2008 and 2011. 9 patients<br />
did not receive treatment and were excluded. Pretreatment and all subsequent<br />
creatinine levels were registered. Acute renal failure was defined according to <strong>the</strong><br />
RIFLE-criteria as a more than 50 % rise in pretreatment creatinine level within 30<br />
days of latest pemetrexed infusion.<br />
Results: Fourteen percent in <strong>the</strong> single agent group and 8 % in <strong>the</strong> combination<br />
chemo<strong>the</strong>rapy group developed acute renal failure (non significant,<br />
Chi-Squared-Test). Of <strong>the</strong>se 11 patients, 3 (27 %) regained pretreatment values of<br />
creatinine. In <strong>the</strong> remaining 8 cases, 5 (63 %) had persistent or progressive renal<br />
failure (2 in <strong>the</strong> combination group and 3 in <strong>the</strong> single agent group). Three patients<br />
died shortly after established renal failure (2 in <strong>the</strong> single agent group and 1 in <strong>the</strong><br />
combination group). No patients were treated with dialysis. Age, sex, disease stage,<br />
performance status, pretreatment creatinine values, number of treatment cycles and<br />
co-morbidity were unrelated to development of kidney failure.<br />
Conclusion: Out of 100 patients treated with pemetrexed, 11 % developed acute<br />
renal failure. In <strong>the</strong> majority of cases, kidney failure was irreversible. We were unable<br />
to identify pretreatment factors predictive of kidney injury. Fur<strong>the</strong>r studies are<br />
warranted to address causality between pemetrexed treatment and acute renal failure.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1362TiP A PHASE II STUDY OF SORAFENIB MONOTHERAPY IN THE<br />
PATIENTS WITH ADVANCED OR RECURRENT<br />
NON-SMALL-CELL LUNG CANCER AFTER FAILURE OF<br />
EGFR-TKI (CTONG0805)<br />
Q. Zhou 1 , C. Zhou 2 , G. Chen 3 , Y. Cheng 4 , C. Huang 5 , L. Zhang 6 , Y-L Wu 1<br />
1 Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong<br />
Academy of Medical Sciences, Guangzhou, CHINA, 2 Lung Cancer Institute,<br />
Shanghai Pulmonary Hospital, Shanghai, CHINA, , 3 Haerbing Medical University<br />
Affiliated Tumor Hospital, Haerbing, CHINA, 4 Jiling Province Tumor Hospital, Jilin,<br />
CHINA, 5 Fujian Province Tumor Hospital, Fujian, CHINA, 6 Sun Yat-Sen University<br />
Cancer Center, Guangzhou, CHINA<br />
Background: Sorafenib is a multikinase inhibitor with antitumor and anti-angiogenic<br />
activity. This study was designed to evaluate <strong>the</strong> efficacy and tolerability of sorafenib<br />
mono<strong>the</strong>rapy for patients with advanced lung adenocarcinoma previously treated<br />
with EGFR tyrosine-kinase inhibitors.<br />
Methods: A phase II, single arm clinical trial (NCT00922584) was conducted in 6<br />
centers in China. Patients with stage IIIB or IV adenocarcinoma, ECOG score of 0-2,<br />
no more than 1 previous chemo<strong>the</strong>rapy regimen with 1 prior EGFR-TKI treatment<br />
failure, or, with K-ras mutation were enrolled. Patients received oral sorafenib 400mg<br />
bid continuously until disease progression or intolerable toxicity.<br />
Results: Between Dec 2008 and Jun 2010, 65 patients were enrolled and 64 could be<br />
analyzed. The median time of sorafenib administrated was 3.7 months (range, 0.23 -<br />
14months). The median follow-up time was 5.5 months (range, 0.3 – 30.6months).<br />
The primary endpoint disease control rate (DCR) was 32.8%, including 2 (3.2%)<br />
partial responses and 19 (29.7%) patients with stable disease (lasting more than 3<br />
months), which did not meet <strong>the</strong> predefined statistical hypo<strong>the</strong>sis of 38.4%. However,<br />
<strong>the</strong> secondary endpoint including median PFS and OS were improved compared<br />
with history data (pemetrexed1, EGFR TKIs2-3), 3.7 months (95%CI:3.5 ∼ 3.9) and<br />
7.4months (95%CI:5.7 ∼ 9.2) respectively. Logistic and COX regression analysis<br />
showed no correlation between DCR or survival results with age, gender, smoking<br />
status, PS, and o<strong>the</strong>r clinical factors. The most common toxicity was hand foot skin<br />
ix444 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
reaction (HFSR) (71.9%), and <strong>the</strong> incidence at 4weeks, 8weeks,12weeks was<br />
64.1%,45.3% and 37.5% respectively, showing a decline of HFSR incidence along<br />
with <strong>the</strong> time of <strong>the</strong>rapy . 21.9% of patients occurred ≥grade 2 o<strong>the</strong>r dermatologic<br />
reactions o<strong>the</strong>r than HFSR, followed by diarrhea (26.2%), hypertension (15.4%) .<br />
Dose interruptions due to toxicity happened in 19 patients (29.2%).<br />
Conclusion: Sorafenib mono<strong>the</strong>rapy has encouraging efficacy improving PFS and OS<br />
with tolerable toxicity as second or third line treatment in patients with advanced<br />
lung adenocarcinoma, who have failed prior chemo<strong>the</strong>rapy and EGFR-TKI<br />
treatment. Fur<strong>the</strong>r randomized studies are needed to confirm <strong>the</strong> clinical benefit of<br />
sorafenib in such patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1364TiP A RANDOMIZED, PHASE II, MULTICENTER,<br />
DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF<br />
ONARTUZUMAB (METMAB) WITH EITHER BEVACIZUMAB +<br />
PLATINUM + PACLITAXEL OR PEMETREXED + PLATINUM<br />
AS FIRST-LINE TREATMENT FOR PATIENTS (PTS) WITH<br />
STAGE IIIB OR IV NON-SQUAMOUS NON-SMALL CELL<br />
LUNG CANCER (NSCLC)<br />
H. Wakelee 1 ,W.Yu 2 , K. Rittweger 3 , V.E. Paton 2<br />
1 Thoracic Oncology, Stanford University Cancer Center, Stanford, CA, UNITED<br />
STATES OF AMERICA, 2 Oncology, Genentech Inc, South San Francisco, CA,<br />
UNITED STATES OF AMERICA, 3 Oncology, Hoffman-La Roche, Nutley, NJ,<br />
UNITED STATES OF AMERICA<br />
Background: Dysregulation of <strong>the</strong> HGF/Met pathway has been associated with<br />
tumorigenesis in many malignancies, including NSCLC. Onartuzumab (MetMAb) is<br />
a recombinant, humanized, monovalent monoclonal antibody directed against Met.<br />
In a phase Ia/Ib study, onartuzumab (+/- bevacizumab) was well tolerated in pts with<br />
advanced solid tumors (Moss et al. Ann Oncol 2010;21(Suppl. 8):Abstr. 504P). In a<br />
phase II study of pts with previously treated NSCLC, onartuzumab + erlotinib was<br />
associated with a significant benefit in PFS (HR 0.53; p = 0.04) and OS (HR 0.37; p =<br />
0.002) compared with erlotinib alone in pts with Met IHC diagnostic-positive<br />
(Met-positive) tumors (Spigel et al. J Clin Oncol 2011;29(Suppl.):Abstr. 7505). Pts<br />
with Met-negative tumors who received onartuzumab + erlotinib reported worse<br />
outcomes compared with erlotinib alone (PFS HR 1.82, p = 0.05; OS HR 1.78, p =<br />
0.16). An interaction between onartuzumab and erlotinib could explain this outcome<br />
and <strong>the</strong>refore may not be seen in this study with chemo<strong>the</strong>rapy. The most<br />
commonly reported adverse events associated with onartuzumab are peripheral<br />
edema and fatigue. An early safety review is planned for this study.<br />
Methods: In this study <strong>the</strong> treating physician will assign appropriate chemo<strong>the</strong>rapy<br />
for each pt (Cohort 1: bevacizumab + platinum + paclitaxel; Cohort 2: pemetrexed +<br />
platinum). Eligible pts within cohorts will be stratified by Met IHC status (positive vs<br />
negative) and randomized (1:1) to receive 4 cycles of chemo<strong>the</strong>rapy + onartuzumab<br />
or placebo. Thereafter, pts without disease progression may continue to receive<br />
placebo or onartuzumab (+ cohort-assigned chemo<strong>the</strong>rapy, without platinum or<br />
paclitaxel) until disease progression, unacceptable toxicity, or death. The co-primary<br />
endpoints are PFS in all pts and by Met status. Secondary endpoints include OS,<br />
ORR, safety, and PK. Approximately 260 pts will be randomized until 130 pts with<br />
Met-positive NSCLC are enrolled. This study is open for accrual; fur<strong>the</strong>r details can<br />
be found on ClinicalTrials.gov (NCT01496742).<br />
Disclosure: H. Wakelee: Dr. Wakelee reports an uncompensated consultancy/<br />
advisory relationship with Genentech-Roche. Dr Wakelee receives research funding<br />
(through Stanford University) from Genentech-Roche. W. Yu: Dr Yu is a full-time<br />
employee of Genentech, Inc. and minor stockholder of Hoffmann-La Roche, Inc. K.<br />
Rittweger: Mrs Rittweger is a full-time employee of Hoffmann-La Roche, Inc. V.E.<br />
Paton: Dr Paton is a full-time employee of Genentech, Inc. and minor stockholder of<br />
Hoffmann-La Roche, Inc.<br />
1365TiP A RANDOMIZED, PHASE II, MULTICENTER,<br />
DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF<br />
ONARTUZUMAB (METMAB) IN COMBINATION WITH<br />
PACLITAXEL + CISPLATIN (OR CARBOPLATIN) AS<br />
FIRST-LINE TREATMENT FOR PATIENTS (PTS) WITH<br />
STAGE IIIB OR IV SQUAMOUS NON-SMALL CELL LUNG<br />
CANCER (NSCLC)<br />
F.R. Hirsch1 , D. Gandara2 , R. Govindan3 , V.E. Paton4 ,W.Yu4 1<br />
Department of Medicine, University of Colorado Denver, Denver, CO, UNITED<br />
STATES OF AMERICA, 2 Thoracic Oncolology Program, UC Davis Cancer Center,<br />
Sacramento, CA, UNITED STATES OF AMERICA, 3 Oncology, Washington<br />
University School of Medicine, St. Louis, MO, UNITED STATES OF AMERICA,<br />
4<br />
Oncology, Genentech Inc, South San Francisco, CA, UNITED STATES OF<br />
AMERICA<br />
Background: Dysregulation of <strong>the</strong> HGF/Met pathway has been associated with<br />
tumorigenesis in many malignancies, including NSCLC. Onartuzumab (MetMAb) is<br />
a recombinant, humanized, monovalent monoclonal antibody directed against Met.<br />
By binding to <strong>the</strong> extracellular domain of Met, onartuzumab selectively blocks<br />
ligand binding and subsequent activation by HGF. Current data support a strategy<br />
of combining onartuzumab with numerous chemo<strong>the</strong>rapies and targeted agents<br />
(bevacizumab, erlotinib). In a phase Ia/Ib study, onartuzumab (mono<strong>the</strong>rapy and in<br />
combination with bevacizumab) was shown to be well tolerated in pts with<br />
advanced solid tumors (Moss et al. Ann Oncol 2010;21(Suppl. 8):Abstr. 504P). A<br />
phase II study of onartuzumab in combination with erlotinib in pts with previously<br />
treated NSCLC reported a significant benefit in PFS (HR 0.53; p = 0.04) and OS<br />
(HR 0.37; p = 0.002) in pts with Met-positive (Met IHC diagnostic positive) tumors<br />
(Spigel et al. J Clin Oncol 2011;29 (Suppl.):Abstr. 7505). Pts with Met-negative<br />
tumors who received onartuzumab + erlotinib reported worse outcomes compared<br />
with erlotinib alone (PFS HR 1.82; p = 0.05; OS HR 1.78; p = 0.16). The most<br />
commonly reported adverse events associated with onartuzumab are peripheral<br />
edema and fatigue.<br />
Methods: In this phase II study, pts with squamous NSCLC are randomized (1:1) to<br />
receive 4 cycles of paclitaxel, cisplatin (or carboplatin) and ei<strong>the</strong>r placebo or<br />
onartuzumab. Pts without disease progression may continue to receive placebo or<br />
onartuzumab as maintenance <strong>the</strong>rapy until disease progression, unacceptable toxicity,<br />
or death. The primary study endpoint is PFS in all pts. PFS by Met IHC diagnostic<br />
status (Met positive vs Met negative) will also be analyzed. Secondary endpoints<br />
include OS, ORR, safety, and PK. A minimum of 110 pts will be randomized to<br />
achieve 55 pts with Met-positive squamous NSCLC. A maximum of 55 pts with<br />
Met-negative squamous NSCLC will be enrolled. This study is open for accrual;<br />
fur<strong>the</strong>r details can be found on ClinicalTrials.gov (NCT01519804).<br />
Disclosure: F.R. Hirsch: Advisory relationship: Genentech-Roche,<br />
Boehringer-Ingelheim, Pfizer, Merck-Serono, Bristol-Myers Squibb. Research<br />
funding (through University of Colorado): Imclone-Lilly, Celgene, Morphotek.<br />
Board of Directors: IASLC. D. Gandara: Dr. Gandara reports a consultant/advisory<br />
relationship with Genentech, Inc. He also receives research funding from<br />
Genentech, Inc. R. Govindan: Dr. Govindan reports a consultant/advisory<br />
relationship with Bristol-Myers Squibb, Boehringer-Ingelheim, Astra Zeneca, Pfizer,<br />
Genentech, Inc. and GlaxoSmithKline. V.E. Paton: Dr Paton is a full-time employee<br />
of Genentech, Inc. and minor stockholder of Hoffmann-La Roche, Inc. W. Yu: Dr<br />
Yu is a full-time employee of Genentech, Inc. and minor stockholder of<br />
Hoffmann-La Roche, Inc.<br />
1366TiP PHASE II STUDY OF ERLOTINIB FOR PREVIOUSLY<br />
TREATED NON-SMALL CELL LUNG CANCER PATIENTS<br />
WITHOUT EPIDERMAL GROWTH FACTOR RECEPTOR<br />
MUTATION: CENTRAL JAPAN LUNG STUDY GROUP<br />
(CJLSG) 0903 TRIAL<br />
M. Morise 1 , H. Taniguchi 2 , H. Saka 3 , J. Shindoh 4 , R. Suzuki 5 , E. Kojima 6 ,<br />
T. Hase 1 , M. Kondo 1 , H. Saito 7 , Y. Hasegawa 1<br />
1 Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya,<br />
JAPAN, 2 Department of Respiratory Medicine and Allergy, Tosei General<br />
Hospital, Seto, JAPAN, 3 Medical Oncology & Respiratory Medicine, National<br />
Hospital Organization Nagoya Medical Center, Nagoya, JAPAN, 4 Respiratory<br />
Medicine, Ogaki Municipal Hospital, Ogaki, JAPAN, 5 Respiratory Medicine,<br />
Toyohashi Municipal Hospital, Toyohashi, JAPAN, 6 Respiratory Medicine, Komaki<br />
Municipal Hospital, Komaki, JAPAN, 7 Respiratory Medicine, Aichi Cancer Center<br />
Aichi Hospital, Okazaki, JAPAN<br />
Background: Erlotinib has been shown moderate activity for previously treated<br />
non-small cell lung cancer (NSCLC) patients with wild-type epidermal growth<br />
factor receptor (EGFR). However, <strong>the</strong> sensitivity of methods for detection of EGFR<br />
mutations can influence <strong>the</strong> efficacy of erlotinib. Moreover, it is controversial about<br />
association between K-ras mutations and erlotinib resistance in EGFR wild-type<br />
NSCLC. Here, we conducted a phase II study of erlotinib for previously treated<br />
NSCLC patients without EGFR mutation screened by PNA-LNA PCR clamp<br />
methods, which is known to be highly sensitive method for <strong>the</strong> detection of EGFR<br />
mutations. Fur<strong>the</strong>rmore, we have planned exploratory reanalysis of EGFR mutation<br />
status and screening of K-ras mutation status by <strong>the</strong> Scorpion Arms method which<br />
is also highly sensitive method among patients whose samples are available for<br />
analysis.<br />
Patients and methods: Major eligibility criteria were advanced NSCLC with<br />
EGFR-wild type (gene analysis by PNA-LNA PCR clamp method), previously treated<br />
with one or two chemo<strong>the</strong>rapy, and ECOG performance status (PS) of 0-2. Oral<br />
erlotinib 150mg was given daily until progression or unacceptable toxicity. The<br />
primary objective of <strong>the</strong> study was objective response rate. Secondary objectives were<br />
tolerability, progression-free survival, overall survival, verification of <strong>the</strong> concordance<br />
of EGFR mutation detection between <strong>the</strong> PNA-LNA PCR clamp method and<br />
Scorpion ARMS method, and screening K-ras mutation status by Scorpion ARMS<br />
methods. As of April <strong>2012</strong>, enrollment of 55 patients has been completed. The study<br />
is in progress and we are planning data cut-off for efficacy and safety analysis in<br />
August <strong>2012</strong>. (Unique trial Number; UMIN000002692)<br />
Disclosure: H. Taniguchi: Hiroyuki Taniguchi has served as a member of advisory<br />
boards for Boehringer-Ingelheim, Chugai-Pharma, Shionogi & Co. Ltd. H. Saito:<br />
Hiroshi Saito received research funding from Chugai Pharmaceuticals. Y. Hasegawa:<br />
Yoshinori Hasegawa received research funding from Chugai Pharmaceuticals. All<br />
o<strong>the</strong>r authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds409 | ix445
1367TiP LONG-TERM ERLOTINIB THERAPY IN PATIENTS WITH<br />
ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC):<br />
INTERIM ANALYSIS OF BASELINE CHARACTERISTICS<br />
C. Chouaid 1 , R. Gervais 2 , C. Locher 3 , D. Moro-Sibilot 4 , B. Commenges 5 ,<br />
S. Chenoufi 5<br />
1 APHP, Pneumologie, APHP, Paris, FRANCE, 2 Oncologie, CAC, Caen, FRANCE,<br />
3 Pneumologie, Meaux, Meaux, FRANCE, 4 Pneumologie, CHU Grenoble,<br />
Grenoble, FRANCE, 5 France, Roche, Neuilly, FRANCE<br />
Background: Erlotinib has been shown to improve outcomes in patients with<br />
recurrent or progressive NSCLC after platinum based chemo<strong>the</strong>rapy. In this clinical<br />
setting, some patients derived long-term benefits from erlotinib treatment with at<br />
least 9 months of Progression Free Survival (PFS). The aim of this<br />
non-interventional prospective study was to analyze <strong>the</strong> clinical characteristics of<br />
<strong>the</strong>se patients. A secondary objective was to evaluate erlotinib long-term safety.<br />
Patients and methods: Patients with advanced NSCLC with recurrent or progressive<br />
NSCLC after platinum based chemo<strong>the</strong>rapy treated for at least 9 months by erlotinib<br />
and followed for at least 24 months have been included prospectively. Patients’<br />
demographics, clinical and histological characteristics, treatments received before<br />
erlotinib initiation, data related to erlotinib <strong>the</strong>rapy (line of treatment, dosage,<br />
duration of treatment, tolerability), median PFS, objective response rate, overall<br />
survival, safety and quality of life data were recorded.<br />
Results: Between June 2010 and June 2011, 205 patients have been included in 76<br />
French institutions. Patients’ characteristics were: mean age, 67.4 ± 10.1 years;<br />
Caucasian, 96.5%; ECOG performance status (PS) 0/1/2/3, 39.3/54.6/4.6/1.5 (%);<br />
male, 42.9%; current/former/never smokers, 5.9/45.6/39.2 (%); adenocarcinoma,<br />
82.2%; stage IV/IIIB, 83.3/16.7 (%). Among 42 patients tested, 50% presented<br />
activating epidermal growth factor receptor (EGFR) mutation. Erlotinib was<br />
administered as first/second/third line treatment in 20.5/50.7/22.4 (%) of patients.<br />
Since treatment initiation, most frequent reported grade 3/4 toxicities were folliculitis<br />
(8.8%) and diarrhea (4.4%).<br />
Conclusion: These are, to our knowledge, <strong>the</strong> first data reported prospectively of<br />
long-responders with advanced NSCLC treated with erlotinib. The long-term benefit<br />
of erlotinib according to <strong>the</strong> results of this interim analysis seems to be more marked<br />
in patients with adenocarcinoma, good PS and never or former smokers. O<strong>the</strong>rwise<br />
<strong>the</strong> benefit seems to be independent of gender. Erlotinib was well tolerated without<br />
life-threatening toxicities.<br />
Disclosure: C. Chouaid: In <strong>the</strong> past 5 years, I received fees for attending scientific<br />
meetings, speaking, organizing research from AstraZeneca, Boehringer Ingelheim,<br />
GlaxoSmithKline, Hoffman la Roche, Astra Zeneka, Sanofi Aventis, Lilly, Novartis<br />
and Amgen. R. Gervais: In <strong>the</strong> past 5 years, Radj Gervais received fees for attending<br />
scientific meetings, speaking, organizing research or consulting from AstraZeneca,<br />
Hoffman la Roche, Astra Zeneka, Sanofi Aventis, Lilly, Novartis and Amgen.<br />
C. Locher: In <strong>the</strong> past 5 years, Chrystel Locher received fees for attending scientific<br />
meetings, speaking, organizing research or consulting from AstraZeneca, Hoffman la<br />
Roche, Astra Zeneka, Sanofi Aventis, Lilly, Novartis and Amgen. D. Moro-Sibilot: In<br />
<strong>the</strong> past 5 years, Denis Moro Sibilot received fees for attending scientific meetings,<br />
organizing research or consulting from AstraZeneca, Boehringer Ingelheim, Hoffman<br />
la Roche, Astra Zeneka, Sanofi Aventis, Lilly, Novartis and Amgen. B. Commenges:<br />
Commenges B is employed by Roche France. S. Chenoufi: Chennoufi S is employed<br />
by Roche France<br />
1368TiP RADIOTHERAPY WITH OR WITHOUT CONCOMITANT<br />
TEMOZOLOMIDE FOR BRAIN METASTASES OF<br />
NON-SMALL CELL LUNG CANCER<br />
M. Rajer, M. Vrankar, V. Kovac, M. Zwitter<br />
Radio<strong>the</strong>rapy, Institute of Oncology Ljubljana, Ljubljana, SLOVENIA<br />
Annals of Oncology<br />
Introduction: Brain metastases from solid tumours are <strong>the</strong> most common CNS<br />
neoplasm, and non-small cell lung cancer is <strong>the</strong>ir single most common origin. The<br />
standard <strong>the</strong>rapeutic option for multiple lesions is palliative radio<strong>the</strong>rapy, which<br />
while able to offer an efficient palliation of symptoms cannot prolong life.<br />
Chemo<strong>the</strong>rapy has a limited role in <strong>the</strong> treatment of CNS neoplasms, almost<br />
exclusively in primary neoplasms. Standard chemo<strong>the</strong>rapy for non-small cell lung<br />
cancer is not very useful in treatment of brain metastases. In some trials<br />
temozolomide, an alkylating agent used in treatment of gliomas, has shown some<br />
efficacy, while <strong>the</strong> combination of temozolomide and radio<strong>the</strong>rapy has not yet proven<br />
its value.<br />
Patients and methods: Patients with cytologically or histologically confirmed<br />
non-small cell lung cancer in performance status of 2 or better, brain metastases not<br />
amenable to local treatment (ei<strong>the</strong>r surgery or SRS) and with adequate<br />
haematological and biochemistry function are randomized between ei<strong>the</strong>r<br />
radio<strong>the</strong>rapy or concomitant chemo-radio<strong>the</strong>rapy with temozolomide. Radio<strong>the</strong>rapy<br />
is given in dose 35 Gy in 14 fractions and temozolomide in dose 75 mg per m2 from<br />
day 1 to 14 of radio<strong>the</strong>rapy including any eventual breaks. Standard haematologic<br />
and biochemistry tests are performed weekly. Response to treatment is assessed using<br />
CT/MRI, symptom relief and TTP/OS.<br />
Results: Currently, recruitment is still on-going, but an interim analysis was<br />
performed. Until now 20 patients were included. All patients had stage IV lung<br />
cancer with radiologically proven brain metastases. Median age was 55,8 (40-67<br />
years) and 7 were males. 12 patients received concomitant temozolomide. The main<br />
toxicity was haematologic. Although <strong>the</strong> number of patients is still small, <strong>the</strong><br />
difference in survival seems to indicate <strong>the</strong>re might be a connection between<br />
concomitant temozolomide use and longer survival.<br />
Conclusions: Chemo-radio<strong>the</strong>rapy with temozolomide for non-small cell lung cancer<br />
brain metastases seems to be a feasible treatment option, pending fur<strong>the</strong>r evaluation.<br />
However, toxicity despite a lower cumulative dose is more pronounced than in<br />
primary CNS neoplasms and treatment should not be given outside clinical trials<br />
with cautious patient selection.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix446 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
oncology and public health<br />
1369P RISK OF MAJOR BLEEDING IN CANCER PATIENTS<br />
RECEIVING CHEMOTHERAPY<br />
J.H. Zong 1 , L. Eckert 2 , L. Zhang 1 , W.S. Dai 1 , A.T. Cohen 3 , G.H. Lyman 4<br />
1 Global Pharmacovigilance and Epidemiology, Sanofi R&D, Bridgewater, NJ,<br />
UNITED STATES OF AMERICA, 2 Global Evidence Value and Development,<br />
Sanofi, Chilly-Mazarin, FRANCE, 3 Vascular Medicine, Department of Vascular<br />
Surgery, King’s College Hospital, London, UNITED KINGDOM, 4 Medicine, Duke<br />
University, Durham, NC, UNITED STATES OF AMERICA<br />
Cancer patients receiving chemo<strong>the</strong>rapy are at increased risk of venous<br />
thromboembolism (VTE). The presence of cancer and anticoagulant use are risk<br />
factors for bleeding, yet data on bleeding risk are limited in <strong>the</strong>se patients. This<br />
analysis evaluated <strong>the</strong> risk of major bleeding in cancer patients receiving<br />
chemo<strong>the</strong>rapy using a US claims database. This retrospective cohort study used <strong>the</strong><br />
MarketScan® databases, a nationwide database containing data from about 100 payers<br />
and covering > 30 million patients annually. Adult cancer patients receiving<br />
chemo<strong>the</strong>rapy within 6 months of cancer diagnosis between January 2004 and<br />
December 2010 were included. Cancers of interest were: lung, colon/rectum,<br />
pancreas, bladder, stomach, and ovary. The index date was <strong>the</strong> first date of<br />
chemo<strong>the</strong>rapy. Patients were followed until <strong>the</strong> earliest of: 1) first diagnosis of major<br />
bleeding; 2) termination of enrolment in <strong>the</strong> health plan; 3) end of study. The<br />
primary outcome was <strong>the</strong> first occurrence of major bleeding, based on selected<br />
ICD-9-CM/CPT codes, following chemo<strong>the</strong>rapy initiation. Of 74,575 patients<br />
identified, exclusion of those with prior history of bleeding at baseline (∼5%)<br />
resulted in 70,822 patients included in <strong>the</strong> analysis. Mean age was 62 years, 37%<br />
were ≥ 65 years, and 52% were male. Average time of follow up and chemo<strong>the</strong>rapy<br />
were 14.3 and 8.6 months, respectively; 6% had a history of VTE within 6 months<br />
prior to <strong>the</strong> index date. Major bleeding occurred in 5.8% of patients and <strong>the</strong><br />
incidence rate for all cancers combined was 4.9 per 100 person-year (PY) and 10.5,<br />
9.3, 6.2, 4.3, 3.6, and 3.3/100 PY for pancreatic, stomach, lung, bladder, colon/<br />
rectum, and ovarian cancer, respectively. Approximately 14% of patients (N = 10,456)<br />
developed VTE after chemo<strong>the</strong>rapy initiation (> half in <strong>the</strong> first 3 months of<br />
chemo<strong>the</strong>rapy treatment). Of <strong>the</strong>se, 7.8% experienced major bleeding with incidence<br />
rates ranging from 5.9-17.7/100 PY after VTE. Major bleeding incidence in cancer<br />
patients receiving chemo<strong>the</strong>rapy varies by cancer type with <strong>the</strong> highest rates in<br />
patients with upper gastrointestinal cancer. Compared to <strong>the</strong> overall cohort, major<br />
bleeding risk was higher in cancer patients who developed VTE.<br />
Disclosure: J.H. Zong: Employee of Sanofi. L. Eckert: Employee of Sanofi. L. Zhang:<br />
Employee of Sanofi. W.S. Dai: Employee of Sanofi. A.T. Cohen: Consult: Astellas,<br />
Table: 1370P<br />
Drug Type Cancer Type<br />
PFS in RCT<br />
(months)<br />
PFS in Clinical Practice<br />
Oncology (months)<br />
AZ, Bayer, BI, BMS, Daiichi, GSK, J&J, Mitsubishi, Pfizer, Portola, Sanofi, S-P;<br />
ResFund: AZ, Bayer, BI, BMS, Daiichi, GSK, J&J, Pfizer, Sanofi, S-P;<br />
BoardSpeakerAdvis comm: Bayer, BI, BMS, Daiichi, GSK, J&J, Mitsubishi, Pfizer,<br />
Sanofi. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1370P A NEW PROPOSAL OF DRUG PRICING BASED ON VALUE<br />
FOR EFFECTIVENESS IN REAL PRACTICE ONCOLOGY<br />
A. Jirillo 1 , M.P. Trojniak 2 , S. Imbevaro 1 , P. Rescigno 1 , D. Pastorelli 3 ,<br />
A.C. Palozzo 2<br />
1 Evaluation and Introduction of New Drugs in Cancer Therapy Unit, Istituto<br />
Oncologico Veneto, IRCCS, Padova, ITALY, 2 Pharmacy Department, Istituto<br />
Oncologico Veneto, IRCCS, Padova, ITALY, 3 Medical Oncology II, Istituto<br />
Oncologico Veneto IOV-IRCCS, Padova, ITALY<br />
In Europe pricing of new drugs is assessed directly by member countries<br />
contracting with pharmaceutical companies. Health technology evaluation is based<br />
on efficacy/safety results in approval RCTs and scarce resource allocation. Since<br />
clinical outcomes in wider population are more variable and conditions less<br />
selected, <strong>the</strong> clinical outcomes may result changed. The real cost benefit value<br />
should be revised once effectiveness data from clinical practice is available. The<br />
clinical data were collected from web-based national oncology registry Onco-AIFA,<br />
as part of mandatory surveillance. The observational study was performed on 724<br />
advanced cancer patients treated with high novel oncology drugs. The median<br />
follow up was 67 months form May 2006 to December 2011. Approval RCTs of<br />
seven selected drugs were reviewed. The comparison was performed between<br />
survival outcomes achieved from RCT and those from our setting (see table).<br />
Progression free survival is a valuable indicator for efficacy/effectiveness assessment .<br />
Based on <strong>the</strong> difference in benefit in PFS, a new price adjusted for effectiveness was<br />
proposed. The post-marketing evaluation showed that in all analysed drugs <strong>the</strong> PFS<br />
from clinical practice was shorter in comparison to RCTs outcomes. As a result <strong>the</strong><br />
real price value should be revised taking into account <strong>the</strong> difference of clinical<br />
response. The calculated effectiveness adjusted price is ex-factory price, expressed in<br />
euro per 1 mg, proportional to <strong>the</strong> difference of PFS form RCTs and that from<br />
clinical practice.<br />
The post marketing study allows for assessment of response outcomes in<br />
real life practice in order to verify both effectiveness and safety in general<br />
population testing external validity of <strong>the</strong> randomized trials. This kind of<br />
assessment lacks in approval RCTs, fur<strong>the</strong>r emphasizing <strong>the</strong> importance of<br />
observational investigations in clinical practice. The price should be based on net<br />
clinical benefits achieved in real life practice as more appropriate in evaluating<br />
cost-benefit balance.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Ex-factory<br />
(euro /1mg)<br />
Effectiveness Ajusted<br />
Price (euro /1mg)<br />
Sorafenib Kidney 5,5 3,2 0,16 0,09 44%<br />
Sorafenib Liver 5,5 3,0 0,16 0,09 44%<br />
Erlotinib NSCLC 2,2 2,0 0,48 0,44 8%<br />
Sunitinib Kidney 11,0 7,0 3,87 2,46 36%<br />
Cetuximab Colorectal 4,1 3,0 2,08 1,52 27%<br />
Pemetrexed Lung adenoca 2,9 1,8 3,02 1,87 38%<br />
Bevacizumab Colorectal 10,6 6,3 3,36 2,00 40%<br />
Bevacizumab Breast 11,8 7,9 3,36 2,25 33%<br />
Panitumumab Colorectal 2,0 1,9 4,22 4,01 5%<br />
1372P HEALTH RESOURCE UTILISATION (HRU) IN EUROPE<br />
ASSOCIATED WITH SKELETAL-RELATED EVENTS (SRES):<br />
RESULTS FROM A RETROSPECTIVE STUDY<br />
J. Body 1 , J. Pereira 2 , H. Sleeboom 3 , N. Maniadakis 4 , E. Terpos 5 , J. Finek 6 ,<br />
O. Gun<strong>the</strong>r 7 , G. Hechmati 8 , T. Mossman 9 , R. von Moos 10<br />
1 Medicine, Centre Hospitalier Universitaire BrugmannUniversit, Brussels,<br />
BELGIUM, 2 National School of Public Health, Universidade NOVA de Lisboa,<br />
Lisbon, PORTUGAL, 3 Department of General Internal Medicine, HAGA Hospital,<br />
The Hague, NETHERLANDS, 4 Department of Health Services Management,<br />
National School of Public Health, A<strong>the</strong>ns, GREECE, 5 Department of Clinical<br />
Therapeutics, University of A<strong>the</strong>ns School of Medicine, Alexandra University<br />
Annals of Oncology 23 (Supplement 9): ix447–ix461, <strong>2012</strong><br />
doi:10.1093/annonc/mds410<br />
Difference in<br />
priceDiscount proposal<br />
Hospital, A<strong>the</strong>ns, GREECE, 6 Comprehensive Cancer Department, University<br />
Hospital, Plzen, CZECH REPUBLIC, 7 Centre for Observational Research, Amgen<br />
Ltd., Uxbridge, UNITED KINGDOM, 8 Health Economics, Amgen (Europe) GmbH,<br />
Zug, SWITZERLAND, 9 Biostatistics, Contractor Amgen Ltd., Cambridge,<br />
UNITED KINGDOM, 10 Medizinische Onkologie und H, Cantonal Hospital Graub,<br />
Chur, SWITZERLAND<br />
Objectives: To evaluate European HRU associated with SREs (radiation to bone<br />
[RB], surgery to bone [SB], pathologic fracture [PF], spinal cord compression<br />
[SCC]).<br />
Methods: Eligible patients (bone metastases from breast/lung/prostate cancer or<br />
multiple myeloma, with an index SRE [defined as an SRE preceded by an SRE-free<br />
period of at least 6.5 months] between July 2004 and July 2009) were enrolled from<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com<br />
abstracts
Austria, Czech Republic, Finland, Greece, Poland, Portugal, Sweden and Switzerland<br />
(Study:20090146). HRU data were ga<strong>the</strong>red from baseline (pre-index SRE period:<br />
3-month period, beginning 3.5 months pre-index SRE) and post-index SRE period<br />
(14-day diagnosis period pre-index SRE to 3 months post-SRE). We present mean<br />
(bootstrapped 95% confidence interval [CI]) change in HRU from baseline per index<br />
SRE for pooled country data.<br />
Results: The Table presents <strong>the</strong> mean change from baseline in HRU per index SRE for<br />
<strong>the</strong> pooled data from <strong>the</strong> 8 European countries included in this study. An increase was<br />
observed in all HRU types following <strong>the</strong> index SRE. Change in overall HRU was<br />
predominantly driven by increases in <strong>the</strong> duration of inpatient stays, with a mean<br />
increase of between 7.81 and 22.21 days depending on SRE type. Substantial increases<br />
were also seen in <strong>the</strong> number of procedures and <strong>the</strong> number of outpatient visits, with<br />
mean increases from 5.85 to 9.58 and from 2.58 to 4.24, respectively. Of <strong>the</strong> index<br />
SREs, SCC was associated with <strong>the</strong> greatest increase in HRU burden for <strong>the</strong> following<br />
HRU types: duration of inpatient stays, emergency room (ER) visits, and procedures.<br />
Conclusions: Overall, SREs are associated with substantial HRU burden. The largest<br />
increases in HRU burden were seen following SCC.<br />
Mean (95% CI) change from baseline in HRU according to index SRE type (full<br />
analysis set).<br />
SRE<br />
HRU type RB n = 482 SB n = 99 PF – long<br />
bone<br />
n = 118<br />
Inpatient 0.52 1.48 1.23<br />
PF – o<strong>the</strong>r<br />
n = 241<br />
SCC n = 82<br />
0.80 1.33<br />
stays (0.41, 0.62) (1.24, 1.72) (1.02, 1.44) (0.65, 0.95) (1.01, 1.65)<br />
Duration of 7.81 18.81 20.92 12.27 22.21<br />
inpatient (6.53, 9.09) (15.31, (16.90, (9.71, 14.84) (16.88,<br />
stays<br />
22.31) 24.94)<br />
27.54)<br />
Outpatient 4.24 2.65 2.58 3.96 4.06<br />
visits (3.67, 4.80) (1.52, 3.78) (1.70, 3.46) (3.22, 4.71) (2.65, 5.47)<br />
ER visits 0.10 0.18 0.30 0.22 0.45<br />
(0.03, 0.17) (0.03, 0.33) (0.17, 0.42) (0.12, 0.33) (0.27, 0.64)<br />
Procedures 8.51 6.36 6.10 5.85 9.58<br />
(7.84, 9.18) (4.83, 7.90) (4.80, 7.40) (5.03, 6.67) (7.82, 11.35)<br />
Disclosure: J. Body: Consultant for Amgen, Bayer, Novartis. Lectures for Amgen and<br />
Novartis. J. Pereira: Honorarium from Amgen. H. Sleeboom: Ad Board Novartis and<br />
Amgen, speaking honoraria Amgen. N. Maniadakis: Received honoraria and<br />
corporate sponsored research from Amgen Hellas. E. Terpos: Honorarium from<br />
Amgen. J. Finek: Consultant for GSK, Amgen, Bayer, Novartis and Roche. Lectures<br />
for Amgen, Novartis, Roche and Pfizer. O. Gun<strong>the</strong>r: Employee of Amgen, holds<br />
Amgen stock. G. Hechmati: Employee of Amgen and holds Amgen stock. T.<br />
Mossman: Contractor of Amgen. R. von Moos: Receive research grants and speaker<br />
honoraria from Amgen and Roche. Participate in Ad Boards for Amgen, Roche and<br />
Novartis<br />
1373P ECONOMIC BURDEN OF COSTLY CANCER DRUGS IN A<br />
HEALTHCARE SERVICE<br />
M. Blanco Villalba, A. Pini, G. Streich, E. Molinas, J.R. Puyol, M.P. Bramajo, E.<br />
J. Batagelj<br />
Oncology, Centro Medico Austral OMI, Buenos Aires, ARGENTINA<br />
Background: The equitable access to medical treatment accordingly to individual<br />
needs is an important issue to discuss taking into account that resources are limited.<br />
In this study we describe <strong>the</strong> incidence of costly cancer drugs in a healthcare service<br />
with 200000 affiliates from Buenos Aires city, from January 2010 to December 2011<br />
and compare both years. We also calculate <strong>the</strong> total annual cost of expensive drug<br />
treatment and identify <strong>the</strong> highest cost drugs used.<br />
Material and methods: Retrospective study Source: clinical history and files from<br />
patients on anticancer treatment from January 2010 to December 2011 and drug<br />
costs information from <strong>the</strong> accounting department.<br />
Results: During <strong>the</strong> year 2010, 3% of <strong>the</strong> total cancer patients (906) received costly<br />
cancer treatment. The most used <strong>the</strong>rapies were: Rituximab (39.2%), Trastuzumab<br />
(25%). Bevacizumab (10%).The total annual cost was $ 563188 of which 37.7% was<br />
for breast cancer, 30.3 % was for haematological cancer and 20.17% was for<br />
colorectal cancer. The mean annual cost per patient was $20113. During <strong>the</strong> year<br />
2011, 4, 5% of <strong>the</strong> total cancer patients (1135) received costly cancer treatment. The<br />
most used <strong>the</strong>rapies were: Trastuzumab (54%).Rituximab (18%), Bevacizumab (8%).<br />
The total annual cost was $947873 of which 61.6% was for breast cancer, 13.3 % was<br />
for haematological cancer and 8.78% was for colorectal cancer. The mean annual<br />
cost per patient was $18957.<br />
Conclusion: The results of this analysis provide useful information to health care<br />
providers and decision makers in understanding <strong>the</strong> economic burden of cancer.<br />
Annals of Oncology<br />
Additionally, this cost information will greatly assist in determining <strong>the</strong><br />
cost-effectiveness of new technologies and early detection systems. In order to<br />
warrant adequate access to <strong>the</strong>se expensive treatments we need to generate a model<br />
of health coverage enhancing participation of all parts.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1374P ADVANCING CLINICAL ONCOLOGY PRACTICE IN<br />
DEVELOPING COUNTRIES: INTEGRATING RESEARCH<br />
INFORMATICS FOR CONTINUOUS PROCESS IMPROVEMENT<br />
A.S. Alfaar, M. Kamal, O. Hassanain, M. Sabry, S. Ezzat, S. Abouelnaga<br />
Research Department, Children’s Cancer Hospital Egypt, Cairo, EGYPT<br />
In developing countries, Clinical Research is considered a luxurious interest with<br />
lower priority.Ongoing studies show considerable gap in responses between<br />
developed countries where most research is conducted and developing countries<br />
where most of needy population is located. We demonstrate a case where practice<br />
was improved in a multi-disciplinary cancer center through setting <strong>the</strong> institution<br />
vision and objectives to be patient centered, research focused and outcome oriented.<br />
Since <strong>the</strong> development of <strong>the</strong> Protocol Monitoring unit and <strong>the</strong> Research<br />
Department, a monitoring process has been established which identified violations<br />
and deviations from <strong>the</strong> developed clinical protocols with a continuous feedback to<br />
<strong>the</strong> attending treatment and research teams i.e treating each treatment regimen as a<br />
research protocol.<br />
This process proved effective and necessitated developing tools for providing<br />
more comprehensive treatment roadmaps and tracking patients’ treatment<br />
milestones. Ano<strong>the</strong>r advantage of applying <strong>the</strong> system is <strong>the</strong> improvement of medical<br />
team conduct knowing that <strong>the</strong>ir performance is being reviewed in what’s known as<br />
Hawthorne Effect. With <strong>the</strong> establishment of first research informatics unit in <strong>the</strong><br />
region Monitoring process became live web-based activity where performance<br />
and survival can be monitored instantaneously. The customized treatment protocols<br />
were developed through identifying key evidence-based practices, integrating it<br />
with research questions and local clinical expertise. Cooperation with international<br />
centers like St. Jude Children’s Research hospital and Dana Farber Cancer Institute<br />
as well as Children’s Hospital-Boston has supported our transition into an<br />
international center through benchmarking and training.<br />
Conclusion: Within five years we’ve developed a model example for<br />
developing countries to improve clinical practice through integrating research<br />
methods and informatics. Dealing with all treatment regimens as research<br />
protocol with <strong>the</strong> integration of audit and feedback approach in <strong>the</strong> treatment<br />
process definitely improves treatment outcome most specifically at poorly established<br />
settings.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1375P CANCER AWARENESS PROGRAMMES IN URBAN AND<br />
SEMI-URBAN POPULATIONS OF WEST BENGAL, INDIA<br />
P. Das 1 , J. Basak 2 , C.K. Bose 3 , A. Mukhopadhyay 4 , S. Mukhopadhyay 1<br />
1 Dept of Molecular Biology, Netaji Subhash Chandra Bose Cancer Research<br />
Institute, Kolkata, INDIA, 2 Molecular Biology, Netaji Subhash Chandra Bose<br />
Cancer Research Institute, Kolkata, INDIA, 3 Clinical Reseach, Netaji Subhas<br />
Chandra Bose Cancer Research Institute, Kolkata, INDIA, 4 Dept. Medical<br />
Oncology, Netaji Subhas Chandra BoseCancer Research Institute, Kolkata,<br />
INDIA<br />
Background: Of <strong>the</strong> current world estimate of 9 million new cancer cases diagnosed<br />
each year, India contributes 7l akhs new cases every year with an overall count of 20<br />
lakhs. Of <strong>the</strong>se, 2.3 lakhs cancer (33%) are obesity and life style related.<br />
Objectives: Our non-government cancer control program aims to educate <strong>the</strong><br />
urban and semi-urban population in and around <strong>the</strong> outskirts of <strong>the</strong> city of Kolkata<br />
about <strong>the</strong> perils of cancer and its symptoms. Ultimately it aspires to create public<br />
awareness regarding <strong>the</strong> inter-relation between obesity, cancer and lifestyle<br />
modification, thus informing <strong>the</strong>m about <strong>the</strong> benefits of minor lifestyle changes in<br />
preventing cancer.<br />
Methods: A 5 year (Jan‘06–Dec’11), bi-monthly awareness program was conducted<br />
by NCRI in Kolkata and its immediate outskirts targeting <strong>the</strong> urban and semi-urban<br />
population. Main concerns were oral, breast and cervical cancers detected by oral<br />
examination, self breast inspection, Pap Smear test followed by collecting patient<br />
history and lifestyle factors including dietary fat-caloric & tobacco intake, alcohol<br />
consumption, and weight of <strong>the</strong> subject which might act as a pre-determinant<br />
disease markers. Positive screening results stage-specific planning of treatment and/or<br />
palliative care at our institute.<br />
Results: Enthusiastic public participation (app.85%) including women was observed.<br />
Out of 46,000 screened individuals, cancer was detected in 3840 (8%) cases, of which<br />
ix448 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
58% were female and 42% were male. Incidence of breast cancer in female were<br />
predominant (29.99%), followed by cervical carcinoma (23.99%). Tobacco habits<br />
predominated among 80% of males and 20% of females. Hence oral cancer was <strong>the</strong><br />
most common (35.98%) amongst men, followed by lung cancer (29.98 %).<br />
Conclusion: The results showed a strong association of overweight and obesity with<br />
cancer in this group primarily due to life style, dietary and smoking habits. Hence<br />
some minor lifestyle choices which encompasses dietary restriction of calorie/fat<br />
intake and avoiding animal protein especially red meat, cessation of tobacco and<br />
alcohol intake, exercising and maintaining an ideal body-mass index, healthy body<br />
weight and composition through a diet rich in fruits and green vegetables reduces <strong>the</strong><br />
risk of cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1376P NEXT GENERATION CANCER REGISTRY; OPPORTUNITIES<br />
OF WEB 3.0 AND PHYSICIAN PERSPECTIVE<br />
A.S. Alfaar, M. Kamal, M. Sabry<br />
Research Department, Children’s Cancer Hospital Egypt, Cairo, EGYPT<br />
Background: Cancer registry is a systematic data collection about cancer incidents.<br />
They are ei<strong>the</strong>r population based or hospital based (also known as center based)<br />
cancer registries. Population-based cancer registries can help in building hypo<strong>the</strong>ses<br />
about cancer shared risk factors in contrast with hospital-based registries which focus<br />
more on improving quality of <strong>the</strong>rapy. Standardizing documentation and<br />
communication methods fosters collaboration between different regional institutes for<br />
building a national cancer registry. In our study we aim at demonstrating how recent<br />
Web 3.0 technologies can help cancer registries.<br />
Material and methods: We started by studying <strong>the</strong> available information technology<br />
resources by qualified researchers who work on analyzing clinical research needs.<br />
We’ve developed a system analysis after studying paper and computer-based cancer<br />
registries. Starting from this set of recommendations we started to match needs and<br />
available technologies. Development took place in adherence to international<br />
standards of medical documentation and communication. Implementation and<br />
Evaluation phases were conducted with assistance of o<strong>the</strong>r clinical researchers,<br />
research nurses and cancer registrars.<br />
Results: The analysis phase stated that cancer registries can be improved using<br />
interoperability, semantic and visual data entry, client & server side-validation,<br />
real-time analysis, rich presentation, tagging, social integration, data mining and<br />
artificial intelligence technologies that are offered by current Internet era.<br />
. Delivery for mobile phones with intelligent validation and interpretation facilitated<br />
<strong>the</strong> portability of <strong>the</strong> system. Integration with knowledge bases added a decision<br />
support property to cancer registry with providing real-time reports and diagrams<br />
plotted over demographic maps. Usability was enhanced by providing user-friendly<br />
interfaces.<br />
Conclusions: Cancer registries have potential stunning future by gaining benefit<br />
from <strong>the</strong> recent web technologies. Research on improving cancer information systems<br />
should go hand in hand with continuous internet revolution.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1377P BURDEN OF SKELETAL-RELATED EVENTS (SRES) IN<br />
PATIENTS (PTS) WITH SOLID TUMORS: RESULTS OF THE<br />
STARS OBSERVATIONAL STUDY IN THE US VS EU<br />
I. Duran 1 , A. Mahmood 2 , H. Hoefeler 3 , H. Ghazal 4 , D. Lueftner 5 , M. Fink 6 ,<br />
A. Bahl 7 , G. Hechmati 8 ,R.Wei 9 , C. Atchison 10<br />
1 Departamento de Oncologia, Hospital Madrid Norte San ChinarroCentro<br />
Integral Oncologico Clara Campal, Madrid, SPAIN, 2 Cancer Specialists of South<br />
Texas, Corpus Christi Cancer Center, Corpus Christi, TX, UNITED STATES OF<br />
AMERICA, 3 Forschungszentrum Ruhr, Klifocenter, Witten, GERMANY,<br />
4 Oncology, Kentucky Cancer Clinic, Hazard, KY, UNITED STATES OF AMERICA,<br />
5 Oncology, Universitätsmedizin Berlin, Berlin, GERMANY, 6 Oncology, Orange<br />
Coast Memorial Medical Center, Fountain Valley, CA, UNITED STATES OF<br />
AMERICA, 7 Clinical Oncology, Bristol Haematology and Oncology Centre, Bristol,<br />
UNITED KINGDOM, 8 International Health Economics, Amgen (Europe) GmbH,<br />
Zug, SWITZERLAND, 9 Global Biostatistical Science, Amgen, Inc., Thousand<br />
Oaks, CA, UNITED STATES OF AMERICA, 10 Global Health Economics, Amgen,<br />
Inc., Thousand Oaks, CA, UNITED STATES OF AMERICA<br />
Background: The STARS study was a prospective, multicenter, international,<br />
observational study designed to measure <strong>the</strong> burden of SREs (radiation or surgery to<br />
bone, pathologic fracture, or spinal cord compression) in pts with advanced cancer<br />
and bone metastases. Here we report results in pts with solid tumors by geographical<br />
region for US vs EU (Germany, United Kingdom, Spain, and Italy).<br />
Methods: This analysis included pts with bone metastases secondary to breast,<br />
prostate, or lung cancer and ≥1 SRE in <strong>the</strong> 97 days before enrollment (05/08 – 05/<br />
10). Data on SREs and health resource utilization (HRU), including inpatient stays,<br />
outpatient visits, emergency room visits, nursing home/long-term care facility stays,<br />
home health visits, procedures, and certain medications, were collected<br />
retrospectively for <strong>the</strong> 97 days before enrollment and prospectively for up to 21<br />
months. Investigators were responsible for attributing HRU to each SRE.<br />
Results: US = 190 pts with 354 SREs; EU = 478 pts with 893 SREs. Baseline<br />
demographics and disease characteristics were similar for US and EU. Inpatient stays<br />
were more frequent in EU compared with US, and <strong>the</strong> length of stay was longer in<br />
EU (table). Outpatient visits were more frequent in US vs EU, while emergency room<br />
visits were similar between regions. Nearly every SRE was associated with a<br />
procedure in both regions; however, <strong>the</strong> number of procedures per SRE was higher in<br />
US, which was in part due to a much greater number of external beam radiation<br />
procedures per SRE in US likely reflecting standard use of multi-fraction radiation.<br />
Slightly more pts were receiving bisphosphonates at/before enrollment in US<br />
compared with EU, and pts in US received IV bisphosphonates sooner than in EU.<br />
Conclusion: The HRU burden of SREs was substantial in both US and EU. Some<br />
regional differences were observed, particularly with respect to hospitalization, length<br />
of stay, and time to receipt of IV bisphosphonates.<br />
HRU US (n = 354)* EU (n = 893)*<br />
Inpatient Stays (IS) Proportion of SREs with IS<br />
Number/SRE<br />
14.7% 29.5%<br />
Mean 0.18 0.32<br />
Median Length of Stay (days) 0.0 0.0<br />
Mean 10.6 19.9<br />
Median 7.0 17.0<br />
Outpatient Visits (OV) Proportion of SREs<br />
with OV Number/SRE<br />
88.1% 74.1%<br />
Mean 9.1 4.8<br />
Median 9.0 2.0<br />
Emergency Room Visits (ERV) Proportion of<br />
SREs with ERV Number/SRE<br />
4.0% 4.1%<br />
Mean 0.05 0.04<br />
Median 0.0 0.0<br />
Inpatient/Outpatient Procedures (P)<br />
Proportion of SREs with P Number/SRE<br />
95.5% 96.4%<br />
Mean 11.3 6.9<br />
Median 12.0 5.0<br />
Bisphosphate (BP) Use Proportion of pts<br />
receiving oral or IV BP<br />
70.0% 63.0%<br />
at or before enrollment Time from diagnosis of<br />
bone metastasis to first IV BP use (months),<br />
median**<br />
1.8 6.7<br />
*n = number of SREs; **Kaplan-Meier estimate<br />
Disclosure: I. Duran: Advisory Board Member, Amgen. A. Bahl: Advisory Board<br />
member Amgen, Novartis. G. Hechmati: Employee of Amgen and owns Amgen<br />
stock. R. Wei: Employee of Amgen and owns Amgen stock. C. Atchison: Employee<br />
of Amgen and owns Amgen stock. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
1378P STATISTICAL CONSIDERATION OF BIASES IN<br />
PROGRESSION-FREE SURVIVAL (PFS) RESULTING FROM<br />
DIFFERENCES IN IMAGING SCHEDULES<br />
T. Tanase 1 , C. Hamada 2 , H. Fujii 3 , N. Nakayama 4 , T. Denda 5 , T. Takayama 6 ,<br />
T. Yoshino 7 , A. Ohtsu 7<br />
1 Data Science, Taiho Pharmaceutical Co., Ltd, Tokyo, JAPAN, 2 Faculty of<br />
Engineering, Tokyo University of Science, Tokyo, JAPAN, 3 Division of Clinical<br />
Oncology, Jichi Medical University, Tochigi, JAPAN, 4 Department of<br />
Gastroenterology, Kanagawa Cancer Center, Kanagawa, JAPAN, 5 Department<br />
of Gastroenterology, Chiba Cancer Center, Chiba, JAPAN, 6 Department of<br />
Gastroenterology and Oncology, University of Tokushima Graduate School,<br />
Tokushima, JAPAN, 7 Department of Gastroenterology & Gi Oncology, National<br />
Cancer Center Hospital East, Chiba, JAPAN<br />
Backgroud: In <strong>the</strong> three PIII trials for metastatic colorectal cancer (mCRC) patients<br />
who are refractory to standard chemo<strong>the</strong>rapy: NCIC CTG CO.17 (NEJM<br />
2007;357:2040-8), 20020408 (JCO 2007;25:1658-65), and CORRECT (<strong>2012</strong><br />
ASCO-GI, #LBA 385) trial, <strong>the</strong> median PFS (mPFS) were similar and <strong>the</strong> early part<br />
of PFS curves overlapped between treatment groups regardless of significance.<br />
Generally, experimental treatments can potentially have biomarkers in such cases.<br />
However, we consider that <strong>the</strong> scheduling of imaging tests affects PFS evaluations.<br />
Material and methods: We simulated PFS computationally under <strong>the</strong> assumptions<br />
for mCRC patients in first (L1), second (L2), and third line (L3) as “True<br />
Parameters” in <strong>the</strong> following table (show L3 only). In addition, we assumed that <strong>the</strong><br />
probability of unscheduled progression was 0 and 20%, and <strong>the</strong> imaging schedules<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds410 | ix449
were every 6 weeks (wk) (S1), every 8 wk (S2), and 4, 8, 12 and every 8 wk <strong>the</strong>reafter<br />
(S3), sample size was 250 patients in each group. S3 is <strong>the</strong> same schedule plan as in<br />
<strong>the</strong> TAS-102 PII trial (2011 ECCO, #6005).<br />
Results: The following table shows <strong>the</strong> simulation results assumed that a probability<br />
of unscheduled progression is 0%. Simulated mPFSs were similar between <strong>the</strong><br />
schedules in each treatment group of L1 and L2, but not in <strong>the</strong> control group of L3.<br />
Simulated hazard ratios (HRs) were almost <strong>the</strong> same regardless of <strong>the</strong> schedules in all<br />
lines. The difference of mPFSs between schedules in <strong>the</strong> control group of L3<br />
depended on <strong>the</strong> timing of first evaluation. The simulated mPFSs in L3S2 were<br />
similar to results of <strong>the</strong> above three PIII trials, and those in L3S3 were similar to<br />
results of TAS-102 PII trial. The simulation results assumed <strong>the</strong> proportion of<br />
unscheduled progression of 20% were similar to that of 0%.<br />
Setting True<br />
Paremeters Simulation Results<br />
mTTP, MST<br />
Mean of HR<br />
(mo) Mean of mPFS (mo)<br />
E C E C<br />
L3S1 2, 6 1, 4.5 1.9 [1.5, 2.6] 1.4 [1.4, 1.4] 0.58 [0.49, 0.67]<br />
L3S2 1.9 [1.9, 2.0] 1.8 [1.8, 1.9] 0.59 [0.50, 0.69]<br />
L3S3 1.9 [1.8, 1.9] 1.0 [1.0, 1.1] 0.57 [0.48, 0.65]<br />
TTP: Time To Progression, E: Experimental Group, C: Control Group, [ ]: 2.5 and<br />
97.5% percentiles.<br />
Conclusion: The HR in PFS is a more important indicator than mPFS regardless of<br />
<strong>the</strong> timing of <strong>the</strong> first evaluation of tumor response in patients with mCRC in <strong>the</strong><br />
later line. These idea might be applicable for mCRC as well as o<strong>the</strong>r cancers.<br />
Disclosure: T. Tanase: Employed by, and own stock in, Taiho Pharmaceutical. C.<br />
Hamada: Taiho pharmaceutical. H. Fujii: Chugai Pharmaceutical, Bristol-Myers<br />
Squibb, Sanofi-Aventis, Novartis Pharma, GlaxoSmithKline, Eisai, Yakult Honsha,<br />
Takeda Pharmaceutical, Shionogi, Taiho Pharmaceutical, Ono Pharmaceutical,<br />
Takeda Bio Development Center. N. Nakayama: merck serono, Takeda<br />
pharmaceutical. T. Denda: Taiho Pharmaceutical, Pfizer, Yakult Honsha, Daiichi<br />
Sankyo. T. Yoshino: Consulting fee from Takeda; honoraria from Chugai, Takeda,<br />
Yakult, Bristol-Myers Squibb, and MerkSerono; research funding from Daiichi<br />
Sankyo, Taiho, Bayer, and ImClone. A. Ohtsu: Employment position in Bayer, and<br />
consulting fee from Takeda, Daiichi Sankyo, Novartis, Chugai,and Taiho; honoraria<br />
from Takeda, Daiichi Sankyo, Taiho, GlaxoSmithKline, Pfizer, Yakult, MerkSerono,<br />
and Bristol-Myers Squibb. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1379P MOLECULAR THERAPEUTICS IN HEAD AND NECK<br />
SQUAMOUS CELL CARCINOMA: A SYSTEMATIC REVIEW OF<br />
COST-EFFECTIVENESS ANALYSES<br />
R. Zaim 1 , W.K. Redekop 2 , G.A.M.S. van Dongen 3 ,R.DeBree 3 , C.A.<br />
Uyl-De Groot 2<br />
1 Institute for Medical Technology Assessment Office J5-51, Erasmus University,<br />
Rotterdam, NETHERLANDS, 2 Institute for Medical Technology Assessment,<br />
Erasmus University, Rotterdam, NETHERLANDS, 3 Department of<br />
Otolaryngology/Head and Neck Surgery, VU University Medical Center,<br />
Amsterdam, NETHERLANDS<br />
Background: The focus of locally advanced (LA) and recurrent and/or metastatic (R/<br />
M) squamous cell carcinoma of <strong>the</strong> head and neck (SCCHN) <strong>the</strong>rapy has recently<br />
shifted to <strong>the</strong> molecular level. Although <strong>the</strong> clinical effectiveness of novel <strong>the</strong>rapeutics<br />
has been discussed extensively, <strong>the</strong> experience with cost-effectiveness analyses (CEAs)<br />
of targeted agents is limited. The objective of this study was to systematically review<br />
CEAs of molecular <strong>the</strong>rapeutics in LA and R/M SCCHN.<br />
Methods: A systematic literature review was performed focusing on CEAs of<br />
molecularly targeted <strong>the</strong>rapeutics in LA and R/M SCCHN using MEDLINE,<br />
EMBASE, NHS Economic Evaluation Database (NHS EED) and <strong>the</strong> Tufts CEA<br />
Registry. Studies were screened according to a priori eligibility criteria. Two<br />
independent reviewers appraised <strong>the</strong> studies using published criteria by Philips et al.<br />
to assess <strong>the</strong> quality and methodology of decision analytic models.<br />
Results: A total of four studies and eight CEAs met <strong>the</strong> inclusion criteria. All CEAs<br />
were conducted from <strong>the</strong> perspective of <strong>the</strong> health care sector. Country-specific costs<br />
were applied. Efficacy data for LA and R/M patients were obtained by <strong>the</strong> Bonner<br />
(Bonner et al.) and <strong>the</strong> EXTREME (Vermorken et al.) trials, respectively. Lifetime<br />
horizon and discounting were considered. The incremental cost-effectiveness ratios of<br />
combination <strong>the</strong>rapy with cetuximab ranged from likely to be cost-effective in LA<br />
patients (€8,135-€30,691/quality-adjusted life year (QALY) gained) to unlikely to be<br />
cost-effective in R/M patients (€158,060/QALY gained). The most influential variable<br />
was <strong>the</strong> cost of cetuximab. Critical assessment of <strong>the</strong> CEAs revealed that decision<br />
analytic models varied in quality and methodology. Type of sensitivity analysis,<br />
justification of preferred methods, transparency and credibility were key areas in<br />
which differences were evident.<br />
Annals of Oncology<br />
Conclusions: Well-performed CEAs suggest that cetuximab may provide good value<br />
for money in LA SCCHN patients. Critical review of existing CEAs helps to improve<br />
<strong>the</strong> quality of forthcoming studies. Future research in LA and R/M SCCHN should<br />
explore <strong>the</strong> optimal role of molecularly targeted agents in daily practice.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1380P THE QUALITY OF SAMPLE SIZE CALCULATION (SSC)<br />
REPORTING IN CANCER CLINICAL TRIALS<br />
G.M. Bariani 1 , A.C.R.C. Ferrari 1 , P.M. Hoff 1 ,R.Arai 1 , M. Precivale 2 ,<br />
R.P. Riechelmann 1<br />
1 Medical Oncology, Instituto do Cancer do Estado de Sao Paulo, Sao Paulo,<br />
BRAZIL, 2 Statistics, PGS Statistics, Sao Paulo, BRAZIL<br />
Background: SSC is a pivotal step in clinical trial concept and design. It determines<br />
<strong>the</strong> chance of detecting a significant result, ensures appropriate power, and helps<br />
sponsors to allocate adequate resources into trials. Here we describe <strong>the</strong> frequency<br />
with which randomized cancer clinical trials (RCT) report <strong>the</strong> data required for SSC.<br />
Methods: We systematically searched for phase III RCT published in top clinical<br />
oncology journals which were accompanied by editorials from Jan 2008 to Oct 2011.<br />
We assumed that RCT discussed by editorialists were clinically important. Two<br />
blinded investigators extracted data on SSC. Table 1 describes <strong>the</strong> information<br />
required for SSC according to variable type used for primary endpoint.<br />
Results: 140 out of 150 RCT were eligible. Median sample size was 596 subjects<br />
(50-40,000) per RCT. In 65.7% of RCT, <strong>the</strong> number of enrolled subjects was at least<br />
90% of <strong>the</strong> planned sample size. The primary endpoint was a categorical variable in<br />
10.0%, continuous in 27.9%, and time-to-event in 62.1%. In general, 80.7% reported<br />
a planned sample size, 57.9% described <strong>the</strong>ir null hypo<strong>the</strong>sis (H0), with 20.7% giving<br />
a scientific rationale for H0. 57.9% informed <strong>the</strong>ir alternative hypo<strong>the</strong>sis (H1). Alpha<br />
(α) and beta (β) errors were explicit in 92.9% and 90.7%, respectively. Expected<br />
difference between arms was reported in 88.6%. Only 2.9% of RCT provided all<br />
information for proper SSC (required and optional, Table). Excluding “optional<br />
information”, SSC could be reproducible in 18.6% of RCT.<br />
Conclusion: Regardless of <strong>the</strong> CONSORT 2010 statement, <strong>the</strong> quality of SSC<br />
reporting in phase III cancer RCT seems inadequate. This may compromise future<br />
study designs, pooling of data and interpretation of results. Lack of transparency in<br />
SSC reporting may also have ethical implications.<br />
Information necessary for SSC<br />
Variable Type Required information Optional information<br />
Categorical H1<br />
Dropout rate<br />
H0<br />
Statistical test used for SSC<br />
Expected difference between Scientific rationale for H0<br />
arms (delta)<br />
α and β errors<br />
and H1<br />
Continuous H1<br />
H0<br />
Delta<br />
Standard deviation for both<br />
arms<br />
α and β errors<br />
Same as above<br />
Time-to-event H1<br />
H0<br />
Delta (hazard ratio)<br />
Length of recruitment<br />
Length of follow up for each<br />
patient<br />
α and β errors<br />
Same as above<br />
Disclosure: G.M. Bariani: Travel expenses covered: Novartis, Roche. A.C.R.C. Ferrari:<br />
Travel expenses covered: Roche. R.P. Riechelmann: Honoraria (Roche, Merk Serono,<br />
Novartis and Bayer). Consultancy (Novartis and Merck Serono). Travel to scientific<br />
meetings (Roche, Merk Serono, Novartis e Bayer). All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
1381P PERCEPTIONS OF CLINICAL TRIALS IN ASIAN CANCER<br />
PATIENTS: A COMPREHENSIVE SURVEY IN A KOREAN<br />
TERTIARY HOSPITAL<br />
S.J. Lee 1 , L.C. Park 2 , J. Lee 1 , S. Kim 3 , S. Kim 1 , W. Chang 1 , Y.S. Park 1<br />
1 Medicine, Samsung Medical Center, Seoul, KOREA, 2 Internal Medicine, Kosin<br />
University Gospel Hospital, Busan, KOREA, 3 Biostatistics Team, Samsung<br />
Medical Center, Seoul, KOREA<br />
Background: In <strong>the</strong> past few years, <strong>the</strong> number of clinical trials has increased rapidly<br />
in East Asia, especially for cancer types such as gastric and hepatobiliary cancer that<br />
ix450 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
are prevalent in Asian populations. However, <strong>the</strong> actual degree of understanding or<br />
perceptions of clinical trials by cancer patients in East Asian countries have seldom<br />
been studied.<br />
Methods: Between July 1st 2011 and November 30th 2011, we conducted a<br />
prospective study to survey cancer patients regarding <strong>the</strong>ir awareness of, and<br />
willingness to participate in, a clinical trial. The questionnaire consisted of 21<br />
questions based on an Index of Clinical Trial Understanding. Patients with<br />
gastrointestinal/hepatobiliary cancer who visited <strong>the</strong> Hematology-Oncology<br />
outpatient clinic at Samsung Medical Center (SMC) and who signed an informed<br />
consent form were enrolled. The survey was conducted by a well-trained research<br />
nurse and <strong>the</strong> data were statistically analyzed at <strong>the</strong> biostatistics core at SMC.<br />
Results: In this survey study, 1,000 patients were asked to participate and 675<br />
patients consented to participate (67.5%). The awareness of clinical trials was<br />
substantially higher in patients who had a higher level of education (p < 0.001), were<br />
married (p = 0.004), and had a higher economic status (p = 0.001). Willingness to<br />
participate in a clinical trial was not significantly increased by higher level of<br />
education (p = 0.286), marital status (p = 0.685), or economic status (p = 0.310). The<br />
most common source for acquisition of clinical trial knowledge was attending<br />
physicians (52.0%) followed by mass media (36.6%), o<strong>the</strong>r patients (6.39%), <strong>the</strong><br />
internet (3.3%), and o<strong>the</strong>r sources (1.5%). The most influential factors for patient’s<br />
willingness to participate were physician’s opinion (N = 181, 26.8%), limited<br />
treatment options (N = 178, 26.4%), and expectations of effectiveness of new<br />
anti-cancer drugs (N = 142, 21.0%). Patients were likely to refuse to participate in a<br />
clinical trial due to unverified treatment modality (N = 320, 47.4%) and negativity<br />
toward clinical trials (N = 193, 28.6%).<br />
Conclusions: We surveyed a large patient cohort to specifically inquire about<br />
willingness to participate in, and awareness of, clinical trials in patients with<br />
Asian-prevalent cancer types. Fur<strong>the</strong>r correlative analyses with diverse variables will<br />
be presented at <strong>the</strong> meeting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1382P AWARENESS AND UNDERSTANDING OF STRATIFIED/<br />
PERSONALIZED MEDICINE IN PATIENTS TREATED FOR<br />
CANCER: A MULTINATIONAL SURVEY<br />
S. Tejpar 1 , T. Teague 2 , J. Lake 3 , J. Tabernero 4 , J.F. Vansteenkiste 5 , S. Vlassak 6 ,<br />
F. Ciardiello 7<br />
1 Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, BELGIUM,<br />
2 Global Business Intelligence, Oncology, Merck KGaA, Darmstadt, GERMANY,<br />
3 Vivian Road, Mile End, London, UNITED KINGDOM, 4 Medical Oncology<br />
Department, Vall d’Hebron University Hospital, Barcelona, SPAIN, 5 Respiratory<br />
Oncology Unit (Pulmonology), University Hospital Gasthuisberg, Leuven,<br />
BELGIUM, 6 Global Clinical Development Unit-oncology, Merck KGaA,<br />
Darmstadt, GERMANY, 7 Division of Medical Oncology, Department of<br />
Experimental and Clinical Medicine and Surgery "F. Magrassi and A. Lanzara",<br />
Second University of Naples, Naples, ITALY<br />
Background: The identification of biomarkers predictive for <strong>the</strong> efficacy of targeted<br />
anticancer agents allows for <strong>the</strong> tailoring of treatment to maximize patient (pt)<br />
benefit and outcomes. It is important that information about <strong>the</strong> potential for <strong>the</strong><br />
personalization of anticancer <strong>the</strong>rapy is available to pts so that <strong>the</strong>y are fully<br />
informed about treatment and biomarker screening options. The current survey<br />
assessed pt awareness and understanding of <strong>the</strong>se issues.<br />
Methods: Pts with a diagnosis of late-stage breast cancer (BC), stage III/IV<br />
non-small cell lung cancer (NSCLC) or metastatic colorectal cancer (mCRC) within<br />
<strong>the</strong> previous 5 years were eligible. Participating physicians or pt organizations in<br />
seven countries (Argentina, China, France, Germany, Italy, Spain and <strong>the</strong> UK)<br />
identified potentially suitable pts and invited <strong>the</strong>m to take part. Written informed<br />
consent was obtained from all pts, with those confirmed as eligible <strong>the</strong>n completing<br />
a telephone-based questionnaire.<br />
Results: Questionnaires were completed by 811 pts: 164 previously diagnosed with<br />
BC; 157 with NSCLC and 490 with mCRC. Of those interviewed: 260/811 pts (32%)<br />
thought that <strong>the</strong>re was no method of testing to determine which cancer treatments<br />
might work (or work better) in certain people, while 430/811 pts (53%) thought that<br />
such testing might be possible (62% of pts with BC, 48% with NSCLC and 52% with<br />
mCRC). Most pts (532/811, 66%) were willing to delay treatment if that helped select<br />
<strong>the</strong> most effective drug, 286/532 (54%) of those, by more than two weeks, and most<br />
(557/811, 69%) were willing to undergo a tumor re-biopsy as part of any such<br />
treatment selection process. Almost all pts (737/811, 91%) would allow a hospital to<br />
retain a tumor sample for future research. The internet was cited as a useful source<br />
of information regarding disease and treatment options by 192/811 pts (24%).<br />
Conclusions: Pts are generally willing to participate in biomarker test procedures to<br />
facilitate <strong>the</strong> personalization of <strong>the</strong>ir treatment. There is considerable scope for<br />
physicians and support groups to better inform pts that not all cancers are <strong>the</strong> same<br />
and that new tests may be able to identify which treatments will work most<br />
effectively for <strong>the</strong>m.<br />
Disclosure: S. Tejpar: The author declares research and speakers’ bureau funding<br />
from Merck Serono. T. Teague: The author is an employee of Merck KGaA. J.<br />
Tabernero: The author declares: Consultant or Advisory Role (compensated) :<br />
Amgen, Bristol-Myers Squibb, Genentech, Merck KGaA, Millennium, Novartis,<br />
Onyx, Pfizer, Roche and Sanofi Honoraria: Amgen, Merck KGaA, Novartis, Roche<br />
and Sanofi. S. Vlassak: I am an employee for Merck Serono in <strong>the</strong> medical<br />
department. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1383P WHEN DOES PERSONALIZED CANCER THERAPY<br />
RESEARCH PROVIDE POSITIVE RETURN ON INVESTMENT<br />
IN EUROPE?<br />
H.J. Conter 1 , D. Conter 2 , R.A. Wolff 3<br />
1 Cancer Medicine, UT M.D. Anderson Cancer Center, Houston, TX, UNITED<br />
STATES OF AMERICA, 2 Philisophy, Huron College, London, ON, CANADA,<br />
3 Gastrointestinal Medical Oncology, UT M.D. Anderson Cancer Center, Houston,<br />
TX, UNITED STATES OF AMERICA<br />
Background: Personalized cancer <strong>the</strong>rapies targeting pre-specified genetic mutations<br />
currently benefits only subsets of patients. Developing <strong>the</strong> technologies and supporting<br />
<strong>the</strong> research to identify new targets and treatments requires a significant monetary<br />
outlay. How much money should <strong>the</strong> European public invest in such research?<br />
Methods: Since current investment should be less than or equal to <strong>the</strong><br />
net-present-value (NPV) of <strong>the</strong> future health gains achieved, <strong>the</strong> marginal benefit<br />
gained from a new drug can be estimated by calculating <strong>the</strong> difference between <strong>the</strong><br />
incremental cost-effectiveness ratio (ICER) and <strong>the</strong> willingness-to-pay (WTP) for <strong>the</strong><br />
increase in health by society. We calculated <strong>the</strong> NPV of <strong>the</strong> future development for new<br />
drugs with similar characteristics to crizotinib, a prototypic personalized cancer <strong>the</strong>rapy.<br />
Sensitivity analyses were performed to assess <strong>the</strong> influence of WTP thresholds, time<br />
horizon of return, and size of treatable population. Systematic reviews of PubMed and<br />
EMBASE were employed to determine <strong>the</strong> current range of ICERs for approved<br />
small-molecule inhibitors and monoclonal antibodies, and WTP thresholds. European<br />
cancer statistics were used to estimate <strong>the</strong> size of population who may benefit.<br />
Results: Of 1576 titles, 104 abstracts and manuscripts were included in <strong>the</strong> final<br />
analysis. The median ICER for targeted <strong>the</strong>rapies was €45,000 (range,<br />
€10,000-€163,000), and median WTP was €50,000 (range, €12,000-€152,000). With a<br />
development time horizon of 8 years, €840 million in research funding provides<br />
positive societal returns for new pharmaceuticals bought at a marginal value of<br />
greater than €5,000. Doubling <strong>the</strong> time horizon reduces <strong>the</strong> NPV of current research<br />
by €230 million. If current-generation personalized <strong>the</strong>rapies are dominated by newer<br />
technologies earlier than predicted, halving <strong>the</strong>ir market-life as an example, only<br />
€500 million in public investment would be worthwhile. The NPV of research was<br />
highly sensitive to changes in <strong>the</strong> estimated size of <strong>the</strong> treatable population. Focusing<br />
on drug development for breast, lung, and colon cancer only, may yield a NPV for<br />
research of €1.34 billion.<br />
Conclusion: Regional differences in cancer incidence and WTP for new <strong>the</strong>rapeutics<br />
should be formally incorporated into research funding decisions to ensure optimal<br />
resource allocation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1384P ARE THERE DIFFERENCES IN PATIENT CHARACTERISTICS<br />
AND TREATMENT PATTERNS BY TREATMENT SETTING?<br />
C. Reyes 1 , S. Dacosta Byfield 2 , A. Small 3<br />
1 Health Outcomes & Payer Support US Medical Affairs, Genentech,<br />
San Francisco, CA, UNITED STATES OF AMERICA, 2 HEOR - Observational<br />
Reserach, OptumInsight, Eden Prairie, MN, UNITED STATES OF AMERICA,<br />
3 Oncology, Outcomes Research, Us Meidcal Affairs, Genentech, San Francisco,<br />
CA, UNITED STATES OF AMERICA<br />
Background: Few studies have examined whe<strong>the</strong>r differences in treatment and<br />
outcomes exist among cancer patients by <strong>the</strong> setting where care is delivered. This<br />
study investigates differences in demographics, treatment patterns and health care<br />
resource use among non-Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic<br />
Leukemia (CLL) patients receiving rituximab (R) or R+ chemo<strong>the</strong>rapy based on site<br />
of care: office/clinic (OC) vs. hospital outpatient (HO).<br />
Methods: Patients ≥18 years with evidence of NHL or CLL diagnoses codes at least<br />
30 days apart and received ≥2 R claims from Jan 2007 to Mar 2011 were identified<br />
from a large US commercial insurance claims database. Patients were required to be<br />
enrolled in <strong>the</strong> health plan for at least 6 months before and after <strong>the</strong> index date (date<br />
of first R claim). The follow-up period was <strong>the</strong> date of <strong>the</strong> first infusion to 30 days<br />
after <strong>the</strong> last infusion prior to a gap of ≥7 months. Patients with evidence of<br />
multiple cancers or receipt of R at both sites of care were excluded. Cohorts were<br />
created based on site of care where R was administered. Multivariate analyses<br />
examined differences in number of infusions, ER visits and inpatient stays by cohort.<br />
Results: There were 2,594 OC and 286 HO patients with a mean follow-up of 242<br />
days and 209 days, respectively. Compared to <strong>the</strong> HO cohort, <strong>the</strong> OC patients were<br />
significantly younger (71yrs vs. 63 yrs), had a lower mean baseline Charlson<br />
comorbidity index (3.88 vs. 3.40) and a lower percentage were Medicare<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds410 | ix451
Advantage enrollees (83% vs. 25%) [each p < 0.01]. The mean R infusion count was<br />
7.4 (OC) vs. 5.4 (HO) with a monthly mean of 1.19 (OC) vs. 1.00 (HO) [each<br />
p < 0.01]. In adjusted analyses, R infusion counts were also lower for HO compared<br />
to <strong>the</strong> OC cohort (IRR 0.80, CI 0.75-0.86) and HO patients had higher number of<br />
inpatient stays (IRR 1.40, CI 1.07-1.84) though ER visits were not different between<br />
cohorts.<br />
Conclusions: Patients treated in <strong>the</strong> OC setting compared to <strong>the</strong> HO setting had<br />
different treatment patterns and fewer inpatient stays. These results warrant fur<strong>the</strong>r<br />
investigation to assess whe<strong>the</strong>r clinical outcomes differ by site of care.<br />
Disclosure: C. Reyes: Has Roche stock and employment at Genentech/Roche. S.<br />
Dacosta Byfield: Employed at OptumInsight, <strong>the</strong> entity that was paid by<br />
Genentech to conduct <strong>the</strong> study. A. Small: Has Roche stock and employment at<br />
Genentech/Roche.<br />
1385P ABBREVIATED COMPREHENSIVE GERIATRIC ASSESSMENT<br />
(CGA) IN ELDERLY CANCER PATIENTS: PRELIMINARY<br />
RESULTS OF AN OBSERVATIONAL PILOT STUDY<br />
O. Mora 1 , L. Marelli 2 , P. Quadri 3 , M. Tettamanti 4 , C. Pedrazzani 2 , M. Ghielmini 5<br />
1 Oncology, IOSI Istituto Oncologico Svizzera Italiana, Bellinzona, SWITZERLAND,<br />
2 Medical Oncology, IOSI Istituto Oncologico Svizzera ItalianaOspedale Regionale<br />
Bellinzona e Valli, Bellinzona, SWITZERLAND, 3 Internal Medicine, Geriatric<br />
Department, Ospedale Beata Vergine, Mendrisio, SWITZERLAND,<br />
4 Neuroscience, Istituto Mario Negri, Milano, ITALY, 5 Medical Oncology, IOSI<br />
Ospedale San Giovanni, Bellinzona, SWITZERLAND<br />
Background: In Western countries elderly people constitute <strong>the</strong> fastest growing<br />
segment of <strong>the</strong> population and currently in our Institute patients aged ≥70 are about<br />
45% of all cancer patients. CGA is a key component of <strong>the</strong> treatment approach for<br />
this population, but it is time-consuming.<br />
Methods: This is an observational pilot study on consecutive <strong>the</strong>rapy-naive elderly<br />
cancer patients (aged ≥ 70 years). The main aims were to verify <strong>the</strong> feasibility of an<br />
abbreviated CGA (aCGA) in an outpatient setting, <strong>the</strong> acceptability by patients,<br />
physicians, and nurses as well as <strong>the</strong> ability of this tool to discriminate <strong>the</strong> three<br />
prognostic classes of older cancer patients: fit, vulnerable, frail. Patients underwent<br />
aCGA (which consisted in filling in some short questionnaires, instead of <strong>the</strong><br />
standard ones) with a medical oncologist (medical history, clinical examination,<br />
ECOG-performance status, Cumulative Illnesses Rating Scale-CIRS) and with a nurse<br />
(Activities Daily Living-ADL, Instrumental ADL, Mini Nutritional<br />
Assessment-MNA, cognitive Short Blessed Test, Geriatric Depression Scale-GDS,<br />
Quality of Life Health Survey-SF-12, motor status).<br />
Results: From January 2010 to November 2011, 151 patients were enrolled. Median<br />
age was 77 (70-91) years, and 47% were males. Patients, doctors and nurses evaluated<br />
<strong>the</strong> information obtained by aCGA as, respectively: very useful in 47, 66, 42% and<br />
quite useful in 47, 28, 52%. The time required for <strong>the</strong> compilation of <strong>the</strong><br />
questionnaires with nurses was 60 min in 17%. Physicians considered to have had no difficulty (83%) or little<br />
difficulty (10%) in compiling <strong>the</strong> form,. For nurses <strong>the</strong>se figures were 40% and 43%.<br />
aCGA allowed to differentiate patients into three prognostic classes: fit 34%,<br />
vulnerable 36%, and frail 30%. Each of <strong>the</strong>se classes was proposed for treatment<br />
which was curative in 76, 55, 35% of cases, palliative in 20, 35, 27% and supportive<br />
in 4, 10, 38% of cases, respectively.<br />
Conclusions: aCGA is feasible in <strong>the</strong> outpatient setting. It is usually well accepted by<br />
patients, medical staff and nurses. It allows a distinction of prognosis of elderly<br />
cancer patients favouring an appropriate <strong>the</strong>rapeutic choice.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1386P WILL ‘FIT’ OLDER CANCER PATIENTS AS ASSESSED BY<br />
FRAILTY SCREENING TOOLS TOLERATE THE FIRST CYCLE<br />
OF (RADIO) CHEMOTHERAPY WITHOUT SERIOUS ADVERSE<br />
EVENTS?<br />
A. Baitar 1 , F. van Fraeyenhove 1 , A. Vandebroek 1 , E. De Droogh 2 ,<br />
D. Galdermans 2 , J. Mebis 3 , D. Schrijvers 1<br />
1 Medical Oncology, ZNA Middelheim, Antwerp, BELGIUM, 2 Pulmonology, ZNA<br />
Middelheim, Antwerp, BELGIUM, 3 Medical Oncology, Virga Jessa Hospital,<br />
Hasselt, BELGIUM<br />
Background: There is a need for tools to effectively select elderly cancer patients for<br />
<strong>the</strong>rapies with significant potential toxicity such as chemo<strong>the</strong>rapy. The Comprehensive<br />
Geriatric Assessment (CGA) is recommended by several guidelines to guide <strong>the</strong><br />
oncologist in treatment decision making. However, because CGA is time and<br />
man-power consuming a two-step approach with screening has been recommended.<br />
This pilot study was undertaken to evaluate <strong>the</strong> predictive value of 2 frailty screening<br />
tools in relation to <strong>the</strong> tolerability of chemo<strong>the</strong>rapy in ‘fit’ older cancer patients.<br />
Methods: Patients over 65 years with various types and stages of cancer were<br />
screened for CGA before start of treatment with <strong>the</strong> Groningen Frailty Indicator<br />
(GFI) and <strong>the</strong> G8 screening tool. ‘Fit’ patients were defined as having a normal<br />
Annals of Oncology<br />
screening test. A G8 score of ≤14 corresponds with an abnormal screening test. For<br />
<strong>the</strong> GFI we evaluated 2 cut-off values. Serious adverse events (SAE) were recorded<br />
during <strong>the</strong> first cycle of treatment.<br />
Results: From October 2009 to December 2011, 85 patients (44 women) were<br />
included in <strong>the</strong> study. The median age was 76 years old (range: 66-88 years). The<br />
treatment intent was curative in 39 patients (46%) and palliative in 46 patients<br />
(54%). In total, 15 patients (18%) had a SAE of which 3 resulted in death. According<br />
to <strong>the</strong> GFI, 60% were ‘fit’ while <strong>the</strong> G8 identified 30% as ‘fit’ prior to treatment. The<br />
probability to complete <strong>the</strong> 1e cycle of chemo<strong>the</strong>rapy without a SAE for ‘fit’ patients<br />
was according to <strong>the</strong> G8 and <strong>the</strong> GFI (cut-off ≥4) respectively 77% (95%CI: 63-89%)<br />
and 78% (95%CI: 73-86%). The alternative cut-off ≥3 for <strong>the</strong> GFI resulted in<br />
probability of 85% (95%CI: 73-94%) to tolerate treatment.<br />
Conclusion: Patients with a normal screening test for CGA are considered to be able<br />
to tolerate proposed treatments comparable to younger patients. However, no data<br />
exist concerning this assumption. In this study, we attempted to address this in a<br />
heterogenic sample of older cancer patients for 2 screening tools. Fur<strong>the</strong>r research is<br />
needed to compare standard of care with this CGA-based approach with screening.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1387P PREDICTORS OF NONCOMPLETION OF CANCER<br />
TREATMENTS IN ELDERLY PATIENTS: THE ELDERLY<br />
CANCER PATIENTS (ELCAPA) COHORT STUDY<br />
M. Laurent 1 , E. Paillaud 1 , M. Carvalho-Verlinde 2 , P. Caillet 1 , A. Le Thuaut 3 ,<br />
E. Liuu 1 , S. Bastuji-Garin 3 , S. Culine 4 , F. Canouï-Poitrine 3<br />
1 Consultation d’Onco-Gériatrie (UCOG Créteil), AP-HP, Hôpital Henri-Mondor,<br />
Département de Médecine Interne et Gériatrie, Créteil, FRANCE, 2 Service de<br />
Pharmacie, AP-HP, Hôpital Henri-Mondor, Créteil, FRANCE, 3 Pôle Recherche<br />
Clinique et Santé Publique, AP-HP, Hôpital Henri-Mondor, Créteil, FRANCE,<br />
4 Oncology, Hôpital Saint-Louis, Paris, FRANCE<br />
Background: The objective was to assess 1) prevalence and <strong>the</strong> predictors of<br />
non-completion of cancer treatments in elderly and 2) prognosis value of<br />
noncompletion of cancer treatments.<br />
Methods: Between 2007-2010, 421 consecutive patients aged 70 years and older with<br />
solid tumors and indication of surgery, chemo<strong>the</strong>rapy (CT), hormonal <strong>the</strong>rapy (HT)<br />
or radio<strong>the</strong>rapy (RT) were included. Comprehensive Geriatric Assessment was<br />
performed at baseline. Patients were followed up for completion of surgery, first line<br />
CT (observed/expected number of cycles < 1), RT and HT (observed/expected dose <<br />
1) and one year overall survival. Multivariate logistic regression and Cox<br />
-Proportional Hazard Model were used to estimate predictors of noncompletion<br />
treatments and survival.<br />
Results: Mean age was 79.2 years (±5.4) years and 224 patients (53.2%) were<br />
women.190 (45. 1%) had gastro-intestinal, 109 (25.9%) gynaecologic and 97 (23%)<br />
genitor-urinary primary tumors.192 (45.6%) had metastatic disease. 76 (33.8%)<br />
received platinum-based <strong>the</strong>rapy. • Rate of noncompletion was 39.1 % for CT versus<br />
6.5 %, 3.5 % and 2.4 % for HT, surgery and RT respectively. In multivariate analysis,<br />
predictors of noncompletion of CT were: poor performance status (PS ≥ 2) : OR =<br />
2.1, 95 %CI, [1.06-4.17], p = 0.03, (or Activity of Daily Living (ADL): OR 1 point<br />
decrease= 1.5, [1.1-2.0], p= 0.024), decreased renal function: OR 1 ml/min decrease Cockcroft<br />
clearance = 1.02, [1-1.03],p= 0.009 and living alone :OR = 1.9, [1-3.6], p = 0.05. One<br />
year rate of mortality was 26.2 %. Independant prognostic factors for survival were<br />
noncompletion of CT: HR = 3.6, [2.2-6], p < 0.0001, a poor functional status (ADL<br />
HR 1 point decrease =1.5, [1.3-1.9], p < 0.0001, metastatic disease:.HR = 3.3, [1.7-6.3], p<br />
< 0.0001 and malnutrition: HR = 2.6, [1.6-4.4], p < 0.0001.<br />
Conclusion: In <strong>the</strong> elderly with solid tumors, noncompletion of CT was common<br />
whereas HT, RT and surgery were not. Predictors of noncompletion of CT are poor<br />
functional status, decreased renal function and living alone. Noncompletion of CT is<br />
an independent prognostic factor for survival.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1388P COMPLEMENTARY AND ALTERNATIVE MEDICINES (CAM) –<br />
A CURSE TO BREAST CANCERS OF THE INDIAN<br />
SUBCONTINENT<br />
K. Chatterjee1 , S.K. Sarkar2 , S.K. Mondal3 , J. Goswami4 , B. Chatterjee5 1<br />
Oncology, Institute of Post Graduate Medical Education and Research<br />
(IPGMER&SSKM Hospital) Kolkata, Kolkata, INDIA, 2 Oncology, Medical College<br />
Kolkata, Kolkata, INDIA, 3 Oncology, R.G Kar Medical College and Hospital,<br />
Kolkata, INDIA, 4 Radiation Oncology, West Bank Hospital, Howrah, INDIA,<br />
5<br />
Medicine, Mahesh Bhattacharyya Homeopathic P.G Medical College and<br />
Hospital, Howrah, INDIA<br />
Purpose: In India, CAM practitioners get a major share of <strong>the</strong> first visits by patients<br />
with breast lumps, leading to inadvertent delays in <strong>the</strong>ir management. This<br />
multi-institutional prospective study conducted in IPGMER, M.C.H & R.G Kar,<br />
Kolkata, aims to quantify <strong>the</strong> exact percentage prevalence of CAM usage,<br />
ix452 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
demographic factors, magnitude of delay & subsequent prognostic losses incurred by<br />
this population.<br />
Methodology: The study included all breast cancer cases reporting for treatment &<br />
permitting to be interviewed, in three medical colleges of Kolkata, India, between 1 st<br />
Jan’2011 and 31 st Dec’2011. Patients initially treated by CAM were subjected to<br />
detailed Questionnaires, focused on CAM professionals involved in <strong>the</strong> first medical<br />
attention; Initial size of <strong>the</strong> tumor (Based on Lumpometer designed by TMH,<br />
Mumbai); initial presence of nodal disease; history of Biopsy; demographic charters;<br />
<strong>the</strong> perceived benefits of CAM; & <strong>the</strong> time & costs involved. They were <strong>the</strong>n staged<br />
and treated according to <strong>the</strong>ir present status.<br />
Results: Analysis included 736 patients. Prior to reporting at <strong>the</strong> study centers<br />
35.37% (260) patients opted for CAM. Analysis of this group revealed, 73.07 %<br />
came from Rural areas; 67.3% had poor socio-economic status; 46.16% were<br />
uneducated; none were screened or Biopsied. Homeopathy is <strong>the</strong> commonest<br />
form of CAM resorted to 70.76 %; Ayurveda 9.6%; Quack Allopathy 16.15%;<br />
Unani 1.92% & Spiritual Healing 1.53%.The median duration of symptoms at<br />
<strong>the</strong> first visit to <strong>the</strong> CAM professional was10 weeks [2-18]. 65.38% had<br />
non-tender breast lumps. The median initial T- Size was 2.5 cm [1-6.5]; median<br />
time lost 9.3 months [1.5 -28] & median expenditures 980 Rs [150-3500]. The<br />
median T-size at presentation to <strong>the</strong> study centers was 4.2 cm [2.8-12.5]. New<br />
onset nodal disease was seen in 38.0 %; Changes in disease staging seen in 56.15<br />
%. The reasons were overlapping, unaffordability 51.92 %; inaccessibility 34.61%;<br />
38.46% feared disfigurement; homeopathy can liquefy tumors was reasoned by<br />
30.76%.<br />
Conclusion: With more than 1/3 of breast cancer patients still opting for CAM for<br />
obvious reasons, none biopsied, valuable 9.3 months lost & 56% presenting upstaged,<br />
<strong>the</strong> anticipated prognostic losses are unacceptably large.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1389P USE OF INTEGRATIVE THERAPIES IN BREAST CANCER<br />
PATIENTS. HEALTH SERVICE RESEARCH IN A NETWORK OF<br />
INTEGRATIVE ONCOLOGY<br />
F. Schad 1 , J. Axtner 1 , A. Happe 1 , A. Voigt 2 , J. Gutsch 3 , G. Spahn 4 ,<br />
C. Herbstreit 5 , M. Debus 6 , M. Kroez 1 , H. Mat<strong>the</strong>s 7<br />
1 Network Oncology, Research Institute Havelhoehe (FIH), Berlin, GERMANY,<br />
2 Gynaecology, Hospital Herdecke, Herdecke, GERMANY, 3 Outpatient<br />
oncologist, Gevelsberg, GERMANY, 4 Center for Integrative Medicine and Cancer<br />
Therapies, Hospital Oeschelbronn, Niefern-Oeschelbronn, GERMANY,<br />
5 Gynaecology, Hospital Havelhoehe, Berlin, GERMANY, 6 Medical Care Center<br />
Havelhoehe, Outpatient Oncologist, Berlin, GERMANY, 7 Internal Medicine,<br />
Hospital Havelhoehe, Berlin, GERMANY<br />
Background: Diagnosis of breast cancer induces high emotional distress.<br />
Integrative oncology (IO) responds to patients needs by offering a variety of nonpharmaco<strong>the</strong>rapeutic<br />
interventions (NPI) and Viscum album extracts (VA). VA<br />
enhances health-related quality of life and reduces adverse effects caused by<br />
conventional strategies, whereas NPI activate patients’ resources. In <strong>the</strong> present<br />
study we evaluated <strong>the</strong> use of IO <strong>the</strong>rapies in breast cancer patients from a clinical<br />
registry.<br />
Methods: We analyzed 3289 female patients collected by <strong>the</strong> Network Oncology, a<br />
conjoint clinical registry of German hospitals and out-patient practitioners. We used<br />
non-parametric Fisher exact test (F) to compare observed frequencies, Wilcoxon rank<br />
sum (W), Kruskal-Wallis test (KW) for differences between groups. We fitted a<br />
logistic regression model to explain use of VA and NMI.<br />
Results: Mean age was 54.5 ± 11.7 and frequencies of UICC stages were 0: 71%, I:<br />
31%, II: 41%, III: 15% and IV: 7%. 93% of <strong>the</strong> patients got VA and were in median<br />
three years younger than non-VA patients (medVA= 52, W, p= 0.002). Median length<br />
of VA was 4.11 years (1 st Q 0.13, 3 rd Q 7.42) and was nei<strong>the</strong>r influenced by UICC nor<br />
age. Median time until start of VA after diagnosis was 7 month (1 st Q 2.31, 3 rd Q<br />
17.43). Radiation, chemo<strong>the</strong>rapy and surgery were significantly associated with<br />
getting VA (β rad =1.07, p rad< 0.001; β che= 0.49, p che= 0.006; β sur= -1.47, p sur= 0.042).<br />
68% of <strong>the</strong> patients got NPI (eurythmy 60%, massages 52%, embrocations 51%,<br />
wrappings 51%, drawing 41%, modeling 13%, music 8%, psychological 6%, lymph<br />
drainage 6% and hyper<strong>the</strong>rmal <strong>the</strong>rapy 2%) and choose in median 4 different NPI.<br />
Frequencies of NPI quantities were affected by UICC stage (F, p< 0.001). Chemo<br />
<strong>the</strong>rapy, UICC IV, III and radiation were significantly associated with receiving NPI<br />
(βche= -0.83, pche< 0.001; βIV =0.83, pIV= 0.001; βIII =0.62, pIII= 0.003; βrad= -0.28,<br />
prad= 0.003).<br />
Conclusions: In an IO setting VA and NPI are part of standard care and frequently<br />
used by breast cancer patients. Conventional <strong>the</strong>rapies are major predictors if<br />
patients receive VA or NMI. Results suggest that health service research data provide<br />
a solid data basis for warranted prospective studies on outcome related studies in IO.<br />
Disclosure: H. Mat<strong>the</strong>s: PD Dr. med. Harald Mat<strong>the</strong>s is member of <strong>the</strong> board of<br />
directors of <strong>the</strong> Weleda A.G. Arlesheim/ Switzerland. All o<strong>the</strong>r authors have declared<br />
no conflicts of interest.<br />
1390P PATIENT CHARACTERISTICS IN RENAL CELL CARCINOMA<br />
AND DAILY PRACTICE TREATMENT WITH SORAFENIB<br />
(PREDICT) IN CHINA<br />
D-W. Ye 1 , J. Guo 2 , A. Zhou 3 , Y. Huang 4 ,H.Li 5 ,Z.Hu 6 ,C.Fu 7 , J. Liu 8 , M. Irwin 9 ,<br />
J. Ma 10<br />
1 Urologic Oncology Surgery, Fudan University Shanghai Cancer Center,<br />
Shanghai, CHINA, 2 Oncology, Beijing Cancer Hospital, Beijing, CHINA, 3 Urologic<br />
Oncology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences,<br />
Beijing, CHINA, 4 Urologic Surgery, Shang Hai Ren Ji Hospital, Shanghai, CHINA,<br />
5 Urologic Surgery, Union Medical College Hospital, Beijing, CHINA, 6 Urologic<br />
Surgery, Tongji Hospital, Huazhong University of Science and Technology,<br />
Wuhan, CHINA, 7 Urologic Surgery, 7Liaoning Provincial Tumor Hospital,<br />
Shenyang, CHINA, 8 Urologic Surgery, Huaxi Hospital of Sichuan University,<br />
Chengdu, CHINA, 9 Medical, Bayer Healthcare Company Ltd, Beijing, CHINA,<br />
10 Urologic Oncology Surgery, Cancer Institute & Hospital, Chinese Academy of<br />
Medical Sciences, Beijing, CHINA<br />
Background: Sorafenib is indicated for <strong>the</strong> treatment of <strong>the</strong> patients with advanced<br />
renal cell carcinoma (RCC). This post-marketing surveillance study was to evaluate<br />
patient characteristics in RCC patients as well as <strong>the</strong> efficacy and safety of Sorafenib<br />
under daily-life treatment conditions after its regulatory approval.<br />
Methods: This was a prospective, non-interventional, non-controlled multi-center<br />
observational study (NCT00895674). Patients with advanced RCC and <strong>the</strong><br />
decision taken by <strong>the</strong> investigator to prescribe sorafenib were involved in <strong>the</strong><br />
study.<br />
Results: A total of 1033 patients were enrolled. 963 patients were included in <strong>the</strong><br />
safety and 853 patients in <strong>the</strong> efficacy statistical analysis. Baseline characteristics were:<br />
71% male; median age 53.0 years (17∼85 years); 91% ECOG 0-2; 88.3% clear-cell<br />
histology; 24% high MSKCC risk; 30% >1 location of metastasis; 77.6 % prior<br />
nephrectomy; 59.2% prior systemic anticancer treatment. 12.9% of patients had<br />
pre-existing hypertension and 5.6% had diabetes mellitus. The median follow-up<br />
time of this study was 10.0months (mos).A clinical benefit was observed for 72.8 %<br />
of patients (n = 612/841) and radiologically for 71.0 % of patients (n = 597/841) at<br />
<strong>the</strong> last follow-up visit. Median PFS was 10.0mos. The median duration of sorafenib<br />
<strong>the</strong>rapy was 10.0 mos, clinically relevant subgroups was as follows : > = 70 years<br />
(7.6mos), without nephrectomy (7.9mos), not purely clear histologic subtypes<br />
(7.3mos), >1 metastases site (8.6mos). There was no o<strong>the</strong>r demographic or baseline<br />
characteristics revealing any considerable differences. Treatment was well tolerated.<br />
97.7 % received a daily dose of 800 mg sorafenib, only 5.7% with dose reduction at<br />
last visit. Drug-related adverse events (AEs) were 32.61%. The most commonly<br />
reported AEs in this study were HFSR or Palmar-plantar erythrodyses<strong>the</strong>sia (19.4%),<br />
rash (7.0%), diarrhea (6.9%), alopecia (4.7%), hypertension (3.0%) and fatigue<br />
(1.5%). Most of <strong>the</strong> AEs reported were mild to moderate (72.1%) according to<br />
CTCAE.<br />
Conclusions: This study has shown baseline characteristics and safety of advanced<br />
RCC patients treated with sorafenib in Chinese real world setting. The results suggest<br />
that sorafenib is broadly beneficial for advanced RCC patients, regardless of baseline<br />
clinical charateristics and prior cancer treatment.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1391P INTERPRETING OVERALL SURVIVAL (OS) RESULTS WHEN<br />
PROGRESSION FREE SURVIVAL (PFS) BENEFITS EXISTS IN<br />
TODAY’S ONCOLOGY LANDSCAPE - METASTATIC RENAL<br />
CELL CARCINOMA (MRCC) CASE STUDY<br />
S. Negrier 1 , Y. Tang 2 , C. Chen 3 , P. Bycott 2<br />
1 Dept. of Oncology, Centre Léon Bérard, Lyon, FRANCE, 2 Statistics, Pfizer, Inc,<br />
San Diego, CA, UNITED STATES OF AMERICA, 3 Global Outcomes Research,<br />
Pfizer, Inc, New York, NY, UNITED STATES OF AMERICA<br />
Background: New cancer treatments (tx’s) have clinical and health policy challenges<br />
to demonstrate a survival benefit over active tx after showing a PFS benefit.<br />
Subsequent tx and long post progression survival periods can lead to significant<br />
variability posing hurdles in showing OS benefit. The objective of this analysis was to<br />
examine <strong>the</strong> likelihood of OS benefit when a PFS benefit exists. We analyzed Phase<br />
III (P3) AXIS 2nd line trial data of axitinib versus sorafenib in mRCC employing<br />
methods described by Broglio et al 2009.<br />
Methods: We conducted simulations investigating <strong>the</strong> OS and PFS relationship<br />
utilizing <strong>the</strong> AXIS trial. OS was partitioned into 2 parts, expressed as <strong>the</strong> sum of PFS<br />
and survival post progression (SPP). We assumed a median SPP ranging from 6 to<br />
18 months. The actual observed trial pooled SPP was 12.9 months. Median SPP was<br />
assumed equal in both arms. The impact on OS was directly reflective of PFS<br />
translated into a survival benefit. We fur<strong>the</strong>r assumed a median improvement in PFS<br />
to 6.8 months in <strong>the</strong> axitinib arm from 4.7 months for sorafenib which translated<br />
into a HR = 0.69, based on P3 results. By bootstrapping <strong>the</strong> censoring times <strong>the</strong><br />
simulations preserved and mimicked observed accrual, follow-up patterns, and<br />
censoring percentage of <strong>the</strong> P3 trial.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds410 | ix453
Results: Based on 10,000 simulations per median SPP value and a PFS HR = 0.69,<br />
<strong>the</strong> likelihood of randomly observing an OS HR >0.9 ranged from 65% to 74% and<br />
increased with increasing median SPP up to 16 months and <strong>the</strong>n appeared to<br />
plateau.<br />
Conclusion: Between 65% and 74% of <strong>the</strong> time, <strong>the</strong> HR for OS was >0.9 even when<br />
<strong>the</strong> HR was 0.69 for PFS. This gain was assumed to translate directly into a survival<br />
advantage (median SPP per tx arm was assumed identical). This may be due to<br />
variability during SPP follow-up (e.g. subsequent tx) which dilutes <strong>the</strong> OS<br />
comparison making it difficult to show statistical significance (Broglio et al 2009).<br />
The probability increased with increasing SPP up to 16 months. These results have<br />
important health policy implications. Powering a P3 trial and <strong>the</strong> long follow-up<br />
needed to show a statistically significant OS improvement may be costly, and prolong<br />
clinical trial read out in RCC.<br />
Disclosure: S. Negrier: Recieved honoraria from Pfizer and Novartis, and grants/<br />
research support from GlaxoSmithKline and Roche. Y. Tang: Pfizer employee and<br />
stock shareholder. C. Chen: Pfizer employee and stock shareholder. P. Bycott: Pfizer<br />
employee and stock shareholder.<br />
1392P INCREASED INCIDENCE OF RENAL CELL CARCINOMA<br />
(RCC) AMONG MELANOMA PATIENTS<br />
K. Kim, J. Kim, H. Ryu, A. Bedikian, N. Papadopolous, P. Hwu, W. Hwu,<br />
S. Patel<br />
Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, TX,<br />
UNITED STATES OF AMERICA<br />
Purpose: There is scant evidence for an increased risk for developing RCC among<br />
melanoma patients (pts), and evidence for possible risk factors for <strong>the</strong> association<br />
between melanoma and RCC is lacking. We examined <strong>the</strong> risk of developing both<br />
melanoma and RCC, and also <strong>the</strong> possible risk factors.<br />
Methods: We searched our institutional tumor registry for pts with a diagnosis of<br />
melanoma and RCC. We used summary statistics to describe <strong>the</strong> population of pts<br />
and calculate total person-years at risk for RCC. We computed standardized<br />
incidence ratios (SIRs), which is <strong>the</strong> ratio of <strong>the</strong> observed to <strong>the</strong> expected number of<br />
pts with RCC among pts with melanoma using <strong>the</strong> Cohort Analysis for Genetic<br />
Epidemiology program. The expected number of pts with RCC was determined from<br />
SEER data. The 95% confidence intervals (CI) for <strong>the</strong> SIRs were determined by<br />
assuming a Poisson distribution for <strong>the</strong> observed number of RCC. SIRs were also<br />
calculated for subsets of <strong>the</strong> data according to race and gender.<br />
Results: Between 1980 and 2005, we identified 15,482 pts with a diagnosis of<br />
melanoma: 59% were male and 94% were white. Among <strong>the</strong>se pts, 114 (0.7%) pts<br />
had a diagnosis of RCC ei<strong>the</strong>r before or after <strong>the</strong> diagnosis of melanoma. The mean<br />
age of RCC presentation was 59.4 years. The total person-years at risk for RCC were<br />
886,506. We observed a significant excess of RCC (SIR = 1.64, 95% CI = 1.37-1.95)<br />
among our cohort of melanoma pts. This excess of RCC was also significant among<br />
white pts (SIR = 1.64, 95% CI = 1.36-1.92) and among both genders. None of <strong>the</strong> 114<br />
pts with a diagnosis of both melanoma and RCC had a concomitant diagnosis of<br />
immunocompromised disease nor received chronic immunosuppressive drugs. Only<br />
17% of <strong>the</strong> pts received radiation or chemo<strong>the</strong>rapy for melanoma.<br />
Conclusions: There is an increase risk of RCC among melanoma pts. Nei<strong>the</strong>r<br />
preexisting immunocompromised condition nor <strong>the</strong> chronic use of<br />
immunosuppressants were risk factors for developing both malignancies.<br />
Group Observed Expected<br />
SIR (95% CI) for<br />
development of RCC<br />
All (n = 15482) 114 69.53 1.64 (1.37-1.95)<br />
Gender M (n = 9072)<br />
81 33 54.85 14.67 1.48 (1.19-1.82)<br />
F (n = 6410)<br />
2.25 (1.61-3.08)<br />
Ethnicity White (n = 14580) 109 5 66.37 3.15 1.64 (1.36-1.96)<br />
Non-White (n = 902)<br />
1.59 (0.70-3.25)<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1393P INCIDENCE OF HEPATITIS B AND C INFECTIONS IN EARLY<br />
BREAST CANCER PATIENTS AND IMPACT ON SYSTEMIC<br />
TREATMENTS<br />
A. Levaggi 1 , G. Iacono 1 , F. Poggio 1 , C. Bighin 1 , S. Giraudi 1 ,A.D’Alonzo 1 ,<br />
M. Lambertini 1 , A. De Maria 2 , P. Pronzato 1 , L. Del Mastro 3<br />
1 Oncologia Medica A, IRCCS AOU San Martino - IST-Istituto Nazionale per la<br />
Ricerca sul Cancro, Genova, ITALY, 2 Scienze Della Salute Unige, IRCCS AOU<br />
San Martino-IST, Genova, ITALY, 3 SS Sviluppo Terapie Innovative, IRCCS AOU<br />
San Martino - IST-Istituto Nazionale per la Ricerca sul Cancro, Genova, ITALY<br />
Background: few data are available about <strong>the</strong> prevalence of hepatitis B (HB) and C<br />
(HC) infections in early breast cancer patients and its impact on systemic treatments.<br />
Annals of Oncology<br />
Methods: we retrospectively reviewed hepatitis B or C serology in 746 consecutive<br />
early breast cancer patients treated at National Institute for Cancer Research between<br />
January 2009 and March 2011. All patients were screened for hepatitis Bs antigen<br />
(HBsAg), HBc antibodies (HBcAb), HBs antibodies (HBsAb) and HC (HCV)<br />
antibodies. Data collected included patients and tumour characteristics, treatment<br />
received, changes in aminotransferases and impact on systemic treatment (delay or<br />
discontinuation). A comparison between patients with positive serology (cases) and<br />
patients with negative serology or vaccinated for HBV (controls) was performed.<br />
Results: 371 patients were excluded because serology was not available. Among 375<br />
evaluable patients we indentified 312 controls (83.2%) and 63 patients (16.8%) with<br />
positive serology defined as cases: 16 patients (4.2%) with HCV infection, 8 (2.1%)<br />
with occult HBV (HBsAg negative, HBsAg Ab negative, HBcAg Ab positive), 36<br />
(9.6%) with cleared HBV (HBsAg negative, HBsAg Ab positive, HBcAg Ab positive)<br />
and 4 (1%) with chronic HBV (HBsAg positive, HBsAg Ab negative, HBcAg Ab<br />
positive). Because of <strong>the</strong> lack of serum HBV DNA and HCV RNA evaluation, we<br />
adopted only a clinical definition of hepatitis, i.e. at least threefold increase in serum<br />
ALT level. Hepatitis, according to this definition, during systemic treatments<br />
occurred in 9 (20.4%) of 44 evaluable cases and in 14 (5.9%) of <strong>the</strong> 234 evaluable<br />
controls. The increase in transaminases resulted in discontinuation of systemic<br />
treatment in 3 patients (6.8%) among cases and in 2 patients (0.85%) in <strong>the</strong> control<br />
group.<br />
Conclusion: Nearly 16% of newly diagnosed breast cancer patients have positive<br />
serology for viral hepatitis and about 20% of <strong>the</strong>m may develop hepatitis during<br />
systemic treatment. Pretreatment serum detection of viral hepatitis B and C antigen<br />
and antibodies may be useful for adeguate monitoring of liver function during<br />
anti-cancer <strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1394P THE RELATIONSHIP BETWEEN PREECLAMPSIA,<br />
PREGNANCY-INDUCED HYPERTENSION AND MATERNAL<br />
RISK OF BREAST CANCER: A META-ANALYSIS<br />
J.S. Kim 1 , Y.J. Choi 2<br />
1 Hemato-oncology, Korea University Medical Center, Seoul, KOREA, 2 Oncology,<br />
Asan Medical Center, Seoul, KOREA<br />
It has long been recognized that some human breast cancers are “hormone<br />
dependent”. Preeclampsia is a syndrome of pregnancy defined by <strong>the</strong> onset of<br />
hypertension and proteinuria and characterized by dysfunction of <strong>the</strong> maternal<br />
endo<strong>the</strong>lium. Many hormonal changes occur with preeclampsia, and we hypo<strong>the</strong>size<br />
that <strong>the</strong>se changes may influence <strong>the</strong> risk of maternal breast cancer. We also<br />
analyzed relation between PIH and maternal risk of breast cancer. Among 13<br />
relevant publications about preeclampsia and 6 relevant publications about PIH,<br />
some studies might be associated with a lower risk of breast cancer, but o<strong>the</strong>rs did<br />
not. Therefore <strong>the</strong>se results are inconclusive. According to pooled results, reduced<br />
breast cancer risk with preeclampsia was not shown in our meta-analysis (HR = 0.86;<br />
95% C.I = 0.73-1.01, p = 0.06); however, a trend toward reduced maternal risk of<br />
breast cancer was identified. The effect of PIH was similar to that of preeclampsia<br />
(HR = 0.83; 95% C.I = 0.66-1.06, p = 0.13). The results of this meta-analysis suggest<br />
that preeclampsia and PIH do not significantly decrease <strong>the</strong> maternal risk of breast<br />
cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1395P A PRELIMINARY STUDY OF THE EFFECT AND MECHANISM<br />
OF 1,25 (OH) 2D3 ON LUNG ADENOCARCINOMA CELL<br />
PROLIFERATION AND DIFFERENTIATION<br />
R. Li 1 ,Y.Lou 2 , L. Xiong 2 ,A.Gu 2 , B. Han 2 , Q. Dong 3<br />
1 Department of Pulmonary Medicine, 1 Shanghai Chest Hospital affiliated to<br />
Shanghai Jiaotong University, Shanghai, CHINA, 2 Department of Pulmonary<br />
Medicine, Shanghai Chest Hospital affiliated to Shanghai Jiaotong University,<br />
Shanghai, CHINA, 3 Cancer Stem Cells and Tumor Diagnosis, Shanghai Cancer<br />
Institute, Shanghai, CHINA<br />
Background: OCT4 + bronchioloalveolar stem cell (BASC) is a type of cancer stem<br />
cell (CSC)-like cell, and threat to <strong>the</strong> survival of lung cancer patients. Vitamin D has<br />
a certain role in tumor prevention and treatment, but <strong>the</strong> relationship between<br />
vitamin D and lung adenocarcinoma is still unclear.<br />
Objective: To make clear if lung cancer patients occur with vitamin D deficiency in<br />
China. Analyze <strong>the</strong> relationship between vitamin D levels and <strong>the</strong> pathology. To<br />
analyze <strong>the</strong> role of vitamin D on <strong>the</strong> differentiation of CSC-like, AT2-like and<br />
AT1-like lung adenocarcinoma cells.<br />
Methods: Chemiluminescence detection was used to detect serum 25(OH)D<br />
concentrations. The expression of CCSP, SP-C, OCT4, SP-B on CSC-like, AT2-like<br />
and AT1-like lung adenocarcinoma cells were detected by immunofluorescence<br />
detection. The CCK8 assay and <strong>the</strong> immunofluorescence detection were used<br />
separately to detect proliferation activity and <strong>the</strong> expression of OCT4 for <strong>the</strong> OCT4<br />
+BASC.<br />
ix454 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Results: The mean serum 25(OH)D concentration of 197 cases with lung cancer in<br />
China was 10.63 ± 7.04ng/mL; <strong>the</strong> proportion of vitamin D deficiency was 173/197 in<br />
all patients, 103/112 in adenocarcinoma. and 31/39 in squamous cell carcinoma. The<br />
vitamin D deficiency ratio was higher in adenocarcinoma than in squamous cell<br />
carcinoma, p= 0.043. PGJ2\DFOM can induce OCT4 + BASC to be CCSP-\SP-C +<br />
\OCT4- cell, and <strong>the</strong>n 1,25(OH)2D3 can prevent <strong>the</strong> expression re-recovery of<br />
OCT-4 and CCSP. DAPT significantly lowered CCSP expression in OCT4 + BASC,<br />
and <strong>the</strong>n 1,25(OH)2D3 can make it become OCT4-\SP-C-\CCSP-\SP-B+ cell, which<br />
is a mature AT2-like cell. 1,25(OH)2D3 has no effect on OCT4 + BASC or AT1-like<br />
cell differentiation.<br />
Conclusion: Lung cancer patients are generally lacking vitamin D, and lung<br />
adenocarcinoma patients are more likely to be lacking vitamin D. 1,25(OH)2D3 can<br />
promote lung adenocarcinoma progenitor cell differentiation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1396P KBP-2010-CPHG: CHARACTERISTICS OF 6,083 NEW CASES<br />
OF NSCLC ACCORDING TO SEX<br />
D. Debieuvre 1 , C. Locher 2 , I. Bourlaud 3 , M. Zaegel 4 , M. Le Poulain-Doubliez 5 ,<br />
J. Piquet 6 , T. Collon 6 , F. Martin 7 , F. Blanchon 2 , M. Grivaux 2<br />
1 Pneumology, General Hospital, Mulhouse, FRANCE, 2 Pneumology, General<br />
Hospital, Meaux, FRANCE, 3 Pneumology, General Hospital, Niort, FRANCE,<br />
4 Pneumology, General Hospital, Le-Coudray-Chartres, FRANCE, 5 Pneumology,<br />
General Hospital Manchester, Charleville-Mézières, FRANCE, 6 Pneumology,<br />
General Hospital, Montfermeil-Le-Raincy, FRANCE, 7 Pneumology, General<br />
Hospital, Compiègne, FRANCE<br />
Lung cancer is a major public health problem due to its continued increase. In<br />
2010, <strong>the</strong> French College of General Hospital Respiratory Physicians (CPHG)<br />
performed a prospective multicenter epidemiological study (KBP-2010-CPHG) to<br />
describe <strong>the</strong> baseline characteristics and management of all new cases of primary<br />
lung cancer; to evaluate 1, 4 and 5-year patient survival rates; and to compare<br />
results with those from a similar study performed 10 years ago (KBP-2000-CPHG).<br />
Data were collected on a standardized form for all patients ≥18 years with primary<br />
lung cancer, histologically or cytologically diagnosed between January 1 and<br />
December 31, 2010 and managed in a general hospital. 7,610 patients were enrolled<br />
in 119 centers. 6,083 patients (86.3%) had non-small-cell lung cancer (NSCLC);<br />
among <strong>the</strong>m, 24.4% were female (vs. 16% in 2000; p < .0001). There was no<br />
difference between male and female NSCLC patients regarding age (65.7± 10.9 vs.<br />
64.9± 13.0, p = 0.03). Regarding smoking status, between 2000 and 2010, women<br />
remained more frequently non-smoker compared to men (34.2% vs. 4.7%), less<br />
frequently former smoker (21.3% vs. 46.8%) and showed lower consumption (37.2<br />
vs. 43.7 PY) (p < .0001). However, in 2010, <strong>the</strong> percentage of non-smokers nearly<br />
doubled in men (2.5% vs. 4.7%; p < .0001) whereas it remained stable in female (p<br />
< .32). Regarding tumor characteristics, between 2000 and 2010, <strong>the</strong> percentage of<br />
adenocarcinomas significantly increased in both women (53.4% in 2000 vs. 65.9% in<br />
2010; p < .0001) and men (32.4% vs. 49.4%; p < .0001). However, in 2010, tumors<br />
remained more frequently adenocarcinomas in women than in men (65.9%<br />
vs.49.4%; p < .0001). In addition, in 2010, when explored (48.5% in women vs.<br />
31.0% in men; p < .001), an EGFR mutation was more frequently found in women<br />
than men (20.6% vs. 5.2%; p < .0001), stage IV tumor was more frequent in women<br />
than men (62.4% vs. 56.9%; p = 0.0008), and regarding first-line treatment, 64.5% of<br />
women vs. 61.0% of men (p = .01) received chemo<strong>the</strong>rapy and 13.4% of women vs.<br />
5.7% of men (p < .0001) targeted <strong>the</strong>rapy. In 10 years, percentages of women,<br />
non-smokers among men, and adenocarcinomas in both men and women<br />
increased. However, differences between women and men in baseline and tumor<br />
characteristics persist.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1397P CARDIAC SAFETY OF (NEO) ADJUVANT TRASTUZUMAB IN<br />
THE BRAZILIAN COMMUNITY SETTING: A SINGLE CENTER<br />
EXPERIENCE<br />
L.G. Fonseca 1 , T.K. Takahashi 2 , M.P. Mak 2 , R. Barroso-Sousa 1 , L. Testa 2 ,V.<br />
Petry Helena 1 , R. De Paula Costa 1 , P.M. Hoff 1 , M.S. Mano 1<br />
1 Medical Oncology, ICESP, Sao Paulo, BRAZIL, 2 Medical Oncology, Instituto do<br />
Cancer do Estado de Sao Paulo ICESP, Sao Paulo, BRAZIL<br />
Background: Trastuzumab-associated cardiotoxicity (TAC) has been established in<br />
<strong>the</strong> context of clinical trials. However, when newly registered agents are used in a<br />
broader patient population, <strong>the</strong>ir safety profile does not always mirror that of <strong>the</strong><br />
pivotal trials. Trastuzumab (T) only became available in <strong>the</strong> Brazilian public sector in<br />
2008 and herein we report our off-trial experience so far.<br />
Methods: Retrospective, single center cohort of HER-2 positive breast cancer patients<br />
(pts) treated with (neo)adjuvant chemo<strong>the</strong>rapy and T from July 2008 to March <strong>2012</strong>.<br />
95.3% were treated according to local protocol (11.4% TCH; 83.9% AC-TH). Major<br />
cardiac event (MCE) was defined as a left ventricular ejection fraction (LVEF) drop<br />
of 10% and absolute drop to < 50 % by echocardiogram (ECHO) or as symptomatic<br />
heart failure (HF) regardless of <strong>the</strong> LVEF value or any cardiac event considered<br />
clinically meaningful. A multivariable Cox proportional hazards model was used to<br />
control for o<strong>the</strong>r cardiac risk factors.<br />
Results: 237 women were identified: median age 53 y (27-83), 99.6% ECOG-PS 0-1,<br />
median body mass index 27.4 kg/m 2 (17 – 46), 30.4% had hypertension (HTN), 8.8%<br />
had diabetes mellitus (DM), 5.9% had previous cardiopathy. 54.8% had ER-positive<br />
tumors; 40.7% received neoadjuvant T; most were stage II or III (22.3% and 37.1%).<br />
Median number of ECHO assessments was 2.7 (0-6); 136 pts (57.2%) completed T as<br />
planned. 20.2% had MCE (13.9% discontinued T). 3.8% discontinued T due to<br />
symptomatic HF and 5% for non-cardiac reasons. 41.6% of MCE pts recovered<br />
cardiac function. Median initial LVEF was 64.83 ± 1.5 % (no event) vs 64.81 ± 1.5 %<br />
(MCE) p = 0.26; median 3-month LFVE was 64.67 ± 4 % (no event) vs 56.12 ± 3 %<br />
(MCE) p = 0.0036. HTN, DM, obesity, age, radio<strong>the</strong>rapy, use of anthracycline and<br />
previous cardiopathy were not significantly associated with TAC.<br />
Conclusions: Our results suggest that TAC in our routine practice is slightly higher<br />
than reported in literature (6 to 17%), possibly reflecting selection bias in clinical<br />
trials. Symptomatic TAC was as expected for AC-TH (4%). We failed to identify risk<br />
factors for TAC, possibly due to <strong>the</strong> low number of events. Cardiac function must be<br />
closely monitored during T treatment and careful pt selection is crucial.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1398P CLINICO-PATHOLOGICAL CHARACTERISTICS AND<br />
TREATMENT OUTCOME OF YOUNG BREAST CANCER<br />
PATIENTS: AN INSTITUTIONAL STUDY<br />
V. Raina 1 , A. Gogia 2 , S.V.S. Deo 3 , B.K. Mohanti 4 , N.K. Shukla 3<br />
1 Dept. of Medical Oncology, All India Institute of Medical Sciences (AIIMS)<br />
Institute Rotary Cancer Hospital, New Delhi, INDIA, 2 Medical Oncology, All India<br />
Institute of Medical Sciences (AIIMS) Institute Rotary Cancer Hospital, New Delhi,<br />
INDIA, 3 Surgical Oncology, AIIMS, New Delhi, INDIA, 4 Radiation Oncology, All<br />
India Institute of Medical Sciences (AIIMS) Institute Rotary Cancer Hospital, New<br />
Delhi, INDIA<br />
Background: Breast cancer in young women (right side). Ninety percent of patients were married and median age at first child<br />
birth was 23 years. Positive family history was elicited in 10 patients. Five patients<br />
presented with synchronous malignancy. The TNM (7th edition) stage distribution was<br />
stage I - 2.5 %, stage II - 30%, stage III - 46.5%, and stage IV - 22%. The median clinical<br />
tumor size was 5.0 cm. Modified radical mastectomy was <strong>the</strong> commonest surgical<br />
procedure and this was done in 83 % of cases. The histopathological analysis showed<br />
94% had infiltrating ductal carcinoma. Thirty percent of tumors were high grade and<br />
70% had pathological node-positive disease. ER/PR and Her2neu positivity was 33% and<br />
29%, respectively. Triple-negative breast cancer (TNBC) constituted 31%. A combination<br />
of anthracyclines and taxanes were used in <strong>the</strong> majority of patients and trastuzumab was<br />
used only in 3 % of cases. With a median follow up of 28 months (non-metastatic<br />
group), 3-year disease-free survival (DFS) and overall survival (OS) was 50% and 60%.<br />
Higher Nodal stage, tumor size (>5 cm), negative hormonal status (triple negative) and<br />
visceral metastasis at baseline predicted poor outcome.<br />
Conclusion: Young women constituted 7.5 % of breast cancer cases. The proportion<br />
of triple negative (nearly one third) was also higher than <strong>the</strong> Western population.<br />
Higher stage and triple negative status results in poorer outcome.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1399P MALNUTRITION AS A DETERMINANT OF OUTCOME OF<br />
PEDIATRIC CANCER PATIENTS<br />
S. Banerjee 1 , S. Mukhopadhyay 1 , S. Gangopadhyay 1 , A. Mukhopadhyay 2<br />
1 Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute,<br />
Kolkata, INDIA, 2 Medical Oncology, Netaji Subhas Chandra Bose Cancer<br />
Research Institute, Kolkata, INDIA<br />
Childhood cancer is curable. Malnutrition poses a major problem amongst Indian<br />
children with around 40% of <strong>the</strong>m suffering from undernourishment and starvation.<br />
It is one of <strong>the</strong> causes of poor outcome and toxicity of cancer patients. This study<br />
will help to highlight <strong>the</strong> close knitted relationship between <strong>the</strong> nutritional status and<br />
its influence on complete remission, disease free survival (DFS) and<br />
chemo<strong>the</strong>rapeutic toxicity. In <strong>the</strong> present study, 500 cancer affected children were<br />
analyzed, who were being treated during a period from Jan, 2007 to Dec, 2011. The<br />
age range was 1-18 years (mean 12.5 years). There was male preponderance.<br />
Distribution of cases: Acute lymphoblastic leukemia 42%, Acute myeloid leukemia<br />
8%, Non Hodgkin’s and Hodgkin’s leukemia 14%, Rhabdomyosarcoma and o<strong>the</strong>r<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds410 | ix455
cancer tumors 12%, Germ cell tumor 8%, Brain tumor 4% and o<strong>the</strong>r 12%. During<br />
preliminary diagnosis of <strong>the</strong>se patients prior to beginning of <strong>the</strong>rapy, an initial<br />
anthropometry was done in all <strong>the</strong> cases that included measurements of Weight for<br />
age (WFA), Height for age (HFA), Mid arm circumference (MAC) and Biceps Skin<br />
Fold Thickness (BSFT). The values of <strong>the</strong>se variables were compared with <strong>the</strong> ICMR<br />
recommended standards provided by percentile curve of <strong>the</strong> growth chart for that<br />
age and sex. BSFT lies between 3.8cm and 6.5cm but during malnutrition it falls<br />
below 3.8cm. We pursued initial diagnosis based on biochemical parameters, chiefly,<br />
serum total protein and serum albumin levels. The albumin level was considered<br />
normal if <strong>the</strong> value was equal to or more than 3g%. It was seen that 190 (38%)<br />
children were malnourished on diagnosis. The patients with malnutrition had poor<br />
outcome (45%) as compared to well-nourished children (80%). Malnourished<br />
children also showed significantly higher toxicity level (p < .0001). Hence we<br />
concluded that malnutrition was an important determinant factor for outcome of<br />
pediatric cancer patients. Next we would like to focus on assessment of nutritional<br />
status in children starting cancer chemo<strong>the</strong>rapy, radiology and surgery.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1400P IATRIGGER PROJECT: DEVELOPMENT AND VALIDATION OF<br />
A TOOL TO EVALUATE ADVERSE DRUGS EVENTS IN<br />
ONCOLOGY PATIENTS<br />
G. Hebert 1 , F. Netzer 1 , A. Fourcade 2 , M. Ducreux 3 , E. Minvielle 2 , F. Lemare 1<br />
1 Clinical Pharmacy, Institut Gustave Roussy, Villejuif, FRANCE, 2 Quality, Institut<br />
Gustave Roussy, Villejuif, FRANCE, 3 Oncologie Digestive, Institut de Cancérologie<br />
Gustave Roussy, Villejuif, FRANCE<br />
Objective: Adverse events related to drugs occur frequently and many of <strong>the</strong>m are<br />
preventable. Despite cancer treatment are known to involve hazardous drugs, <strong>the</strong>re<br />
are few practical methods to identify adverse drug events (ADEs) and measure harm<br />
to <strong>the</strong> patient. The purpose of this work was to develop a tool for adverse event<br />
detection in oncology patients.<br />
Methods: The Trigger Tool approach has been developed and tested in oncology. First,<br />
27 triggers were identified and flowcharts were constructed, based on international,<br />
national or local recommendations. Second, 11 clinical experts have validated <strong>the</strong><br />
content of each trigger on three criteria: <strong>the</strong> criticality of <strong>the</strong> adverse event, <strong>the</strong><br />
educational value of feedback, and <strong>the</strong> clinical relevance of <strong>the</strong> analysis. For each trigger,<br />
severity has been graded according to <strong>the</strong> NCI CTCAE 4.03. Third, <strong>the</strong> feasibility of <strong>the</strong><br />
analysis based on a random sample of 130 patient records has been assessed through <strong>the</strong><br />
time of analysis for each patient record, and <strong>the</strong> number of trigger and ADE observed.<br />
Results: Experts evaluated <strong>the</strong> criticality of <strong>the</strong> 27 triggers from 5.1 to 10.9/25 and<br />
<strong>the</strong>ir educational value from 4.5 to 7.7/10. Regarding <strong>the</strong> feasibility analysis, 1157<br />
hospital-bed days were reviewed from October 2010 to March 2011.It revealed 387<br />
positive triggers, 80 of which are adverse events and 46 were drug related (ADE).<br />
The study counted 0.6 ADE/patient, including 1 grade 3 or more ADE for 11.8<br />
patients. The most frequently observed ADE were constipation (7 ADE), fall (5<br />
ADE), hypo/hyperglycemia (4 ADE), hypo/hyperkaliemia (3 ADE). The average time<br />
of analysis was established at 26min35s by patient record. Based on <strong>the</strong>se results, 22<br />
triggers have been preserved, composing <strong>the</strong> Iatrigger tool.<br />
Conclusion: ADE detection is an important priority in patient safety research. The<br />
use of a ADE detection method requires some resource commitments. However, a<br />
validated tool like <strong>the</strong> Iatrigger tool can be applied in different hospital settings,<br />
allowing a precise follow-up of this particularly frail population.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1401P ESSOR STUDY: ORAL CHEMOTHERAPIES FOR ONCOLOGY<br />
PRACTICES: A RETROSPECTIVE ANALYSIS IN THE<br />
COMMUNITY SETTING FOR SELECTED DRUGS<br />
F. Grude 1 , J. Douillard 2 , C. El Kouri 3 , P. Donny 4 , M. Urbanski 5 , A. Chaslerie 4 ,<br />
S. Piau 4 , H. Bourgeois 6 , J. Metges 7 , J. Pivette 4<br />
1 ICO Paul Papin, Observatoire dédié au Cancer, Angers, FRANCE, 2 Medical<br />
Oncology, Centre René Gauducheau (ICO) Institut de Cancerologie de l’Ouest,<br />
St Herblain Cedex, FRANCE, 3 Medical Oncology, Ca<strong>the</strong>rine de Sienne Institute,<br />
Nantes, FRANCE, 4 Pharmacy, DRSM Nantes Pays de la Loire, Nantes, FRANCE,<br />
5 Pharmacy, DRSM Rennes Bretagne, Rennes, FRANCE, 6 Medical Oncology,<br />
Centre Jean Bernard, Clinique Victor Hugo, Le Mans, FRANCE, 7 Medical<br />
Oncology, C.H.U. Morvan Institut de Cancerologie et d’Hematologie, Brest<br />
Cedex, FRANCE<br />
Background: Use of oral chemo<strong>the</strong>rapies is still increasing: currently it represents<br />
about 10% of anti-cancer drugs. In 2015, it might be between 25-30%. Oral drugs<br />
take part in <strong>the</strong> increased survival and improvement of patient’s quality of life. The<br />
Observatory of Cancer Bretagne – Pays de la Loire and <strong>the</strong> French Regional Health<br />
Insurance System had made an observationnal study of oral cancer drug use in <strong>the</strong>ses<br />
two area (10% of French Population).<br />
Methods: French Regional Health Insurance System has made an extract in its<br />
database for patients treated with oral cancer drugs (erlotinib, everolimus, gefitinib,<br />
Annals of Oncology<br />
sorafenib, sunitinib) between september 2009 and <strong>the</strong> end of 2010 (projected<br />
three-year follow-up) : prescriber (competence in oncology or not), patient care<br />
reimbursed by <strong>the</strong> health insurance system, gender, age, death, cancer location, type<br />
of drug have been collected.<br />
Results: 1313 patients (846 men and 437 women) were analysed: 630 patients from<br />
Brittany and 683 from Pays de la Loire. According to <strong>the</strong> National health system,<br />
13.5% of patients did not have optimal reimbursement for care. 30% of patients were<br />
under 59 years old, 35% between 60 and 69 and 35% over 70. The more significant<br />
cancer location was lung (53%), kidney (26%), digestive tract (19%) and breast (2%).<br />
Indeed oral cancer drugs have greatly improved <strong>the</strong> management of patients with<br />
non small cell lung cancer (erlotinib, gefitinib) or kidney cancer (sunitinib, sorafenib,<br />
everolimus). More than half of patients (52%) died between 2010 and <strong>the</strong> end of<br />
April 2011. 74% of patients have taken oral drugs for <strong>the</strong> first time in 2010. 82% of<br />
prescriptions have been done according to oral chemo<strong>the</strong>rapy label (10 % for ano<strong>the</strong>r<br />
cancer; 8 % insufficient data). 5% of patient have received more than a first line oral<br />
drug during <strong>the</strong> follow-up (mainly for kidney cancer).<br />
Conclusions: Few data have been published about successive oral chemo<strong>the</strong>rapies and<br />
<strong>the</strong>ir impact on clinical response, overall survival, toxicities and quality of live. That’s<br />
why we wanted to complete <strong>the</strong>se data via two dedicated studies about kidney cancer<br />
(IVOIRE) and lung cancer (EPINIB). Moreover, compliance of patients treated for a<br />
kidney cancer, toxicity of treatment and drugs interaction will be evaluated via a<br />
pharmaco economic approach through face to face interview (TOPTACOS).<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1402P DRUG INTERACTIONS IN CANCER PATIENTS TREATED<br />
WITH ORAL ANTI-CANCER DRUGS<br />
R.W. van Leeuwen 1 , D.H.S. Brundel 1 , C. Neef 2 , R.H.J. Mathijssen 3 , T. van<br />
Gelder 4 , D.M. Burger 5 , F.G.A. Jansman 6<br />
1 Department of Pharmacy, Erasmus University Medical Center, Rotterdam,<br />
NETHERLANDS, 2 Department of Clinical Pharmacy and Toxicology, Maastricht<br />
University Medical Center, Maastricht, NETHERLANDS, 3 Department of Medical<br />
Oncology, Erasmus University Medical Center, Rotterdam, NETHERLANDS,<br />
4 Departments of Internal Medicine and Hospital Pharmacy, Erasmus University<br />
Medical Center, Rotterdam, NETHERLANDS, 5 Department of Pharmacy &<br />
Radboud University Center for Oncology (RUCO), Radboud University Medical<br />
Center, Nijmegen, NETHERLANDS, 6 Department of Clinical Pharmacy, Deventer<br />
Hospital, Deventer, NETHERLANDS<br />
Background: Drug-drug interactions (DDIs) in patients with cancer are common,<br />
and most DDIs can cause considerable adverse reactions. At present, epidemiological<br />
data regarding DDIs in oral anti-cancer <strong>the</strong>rapy is totally absent in <strong>the</strong> literature.<br />
Therefore, we assessed <strong>the</strong> prevalence of DDIs among ambulatory cancer patients on<br />
oral anti-cancer treatment.<br />
Methods: A search was conducted in a computer based medication prescription<br />
system for dispensing oral anti-cancer drugs to out-patients. DDIs were identified<br />
using electronic (Drug Interaction Fact software) and manual screening methods<br />
(peer-reviewed reports). DDIs were classified by <strong>the</strong> level of severity and <strong>the</strong> level of<br />
scientific evidence. Descriptive statistics and binary logistic regression analyses were<br />
performed to analyze <strong>the</strong> data.<br />
Findings: In <strong>the</strong> 898 patients included in <strong>the</strong> study, 1359 DDIs were identified in<br />
426 patients [46%, 95% confidence interval [CI] = 42% to 50%]. In 143 patients<br />
(16%) a major DDI was identified. The drug classes most frequently involved in a<br />
major DDI were coumarins and opioids. The majority of cases concerned central<br />
nervous system interactions (73%). DDIs that can cause gastrointestinal toxicity or<br />
prolongation of QT intervals were also seen frequently. In multivariate analysis,<br />
concomitant use of more drugs [odds ratio [OR] = 1.66, 95% [CI] = 1.54-1.78, P<br />
Annals of Oncology<br />
Aim: To develop a comprehensive database on <strong>the</strong> availability and accessibility of<br />
opioid medication for <strong>the</strong> management of cancer pain in: Africa, Asia, Latin America<br />
and <strong>the</strong> Caribbean and Middle East. The adequacy of formulary availability is<br />
evaluated relative to <strong>the</strong> International Association of Hospice and Palliative Care list<br />
of Essential Medicines for Palliative Care. Overregulation is evaluated according to<br />
descriptors identified by <strong>the</strong> World Health Organization and <strong>the</strong> International<br />
Narcotics Control Board.<br />
Results: Between 12/2010-7/<strong>2012</strong>, 156 reports were submitted from identified<br />
reporters in 76 countries and 19 Indian states (58% countries, 83% population). Very<br />
few countries provide all 7 opioids on <strong>the</strong> essential drug list of <strong>the</strong> IAHPC (codeine,<br />
immediate and slow release oral morphine, oral IR oxycodone and transdermal<br />
fentanyl) and in many countries less than 3/7 drugs are available. Fur<strong>the</strong>rmore, in<br />
most of <strong>the</strong> countries opioids are ei<strong>the</strong>r not or are weakly subsidised by gov. and<br />
availability is often limited. Many countries have highly restrictive regulations that<br />
limit entitlement of cancer patients to receive prescriptions, limit prescriber<br />
privileges, impose restrictive limits on duration of prescription, restrict dispensing,<br />
and increase bureaucratic burden of <strong>the</strong> prescribing and dispensing process.<br />
Conclusions: In many places across Africa, Asia, ME and L + C America<br />
governments are failing cancer patients in delivery of adequate pain relief. There is a<br />
need for increased availability of affordable opioids for <strong>the</strong> management of cancer<br />
pain. A priority action is examination of drug control policies and repeal of excessive<br />
restrictions which impede this most fundamental aspect of cancer care.<br />
1403 FEASIBILITY ANALYSIS OF THE WINHO INDICATORS FOR<br />
OUTPATIENT CARE IN ONCOLOGY<br />
R.E. Buschmann-Maiworm 1 , W. Baumann 1 , A. Zimmermann 1 , S. Schmitz 2 ,U.<br />
R. Kleeberg 3<br />
1 WINHO, Cologne, GERMANY, 2 Hämatologie und Onkologie,<br />
Gemeinschaftspraxis, Cologne, GERMANY, 3 Hämatologie & Onkologie und<br />
Palliativmedizin, Hämatologisch-onkologische Praxis Altona HOPA, Hamburg,<br />
GERMANY<br />
Background: WINHO is an oncologist-led research department working on quality<br />
improvement and assurance and health care services research for out-patient care in<br />
Germany. A quality indicator project started in <strong>the</strong> middle of 2009. The project<br />
consists of 3 main parts: A) development of relevant measures, B) feasibility test, C)<br />
pilot study. QOPI is an important model for <strong>the</strong> scope of application and <strong>the</strong><br />
methodological approach of <strong>the</strong> WINHO project. Taking into account <strong>the</strong> unique<br />
needs of <strong>the</strong> German health care system, a set of 46 relevant, evidence and consensus<br />
based quality measures has been developed. This was done with reference to<br />
internationally available indicator systems (QOPI, PQRSI and o<strong>the</strong>r sources). 13<br />
measures were newly developed by WINHO. This presentation is about <strong>the</strong> feasibility<br />
test (part B) of <strong>the</strong> WINHO quality indicator project.<br />
Methods: The feasibility analysis consists of 4 elements: 1. feasibility ratings of <strong>the</strong><br />
expert panel (n = 15) in <strong>the</strong> RAND/UCLA procedure during part A of <strong>the</strong> project,<br />
2. distribution of a feasibility questionnaire among office-based oncologists,<br />
3. semi-structured depth interviews with 7 office-based oncologists, 4. randomized,<br />
retrospective chart abstraction from 59 charts for all 46 measures.<br />
Results: 2176 feasibility questionnaires went into statistical analysis (response rate 50<br />
%). Results from <strong>the</strong> questionnaire, interviews and trial chart abstraction show that<br />
<strong>the</strong> main problem lies within <strong>the</strong> retrieval of data from charts. Reasons for <strong>the</strong>se<br />
findings may be <strong>the</strong> use of different electronic documentation systems, individual<br />
documentation habits and/or documentation of crucial information in running text.<br />
The estimated time to retrieve all data to calculate an indicator varies widely. A pilot<br />
study about <strong>the</strong> implementation of a routine data collection already started.<br />
(Supported by Deutsche Krebshilfe e. V.).<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1404 INTERNET USE BY CANCER PATIENTS AND THEIR<br />
RELATIVES: AN USEFUL INFORMATION TOOL IR OUR<br />
COUNTRY OR A CONFUSION ELEMENT? : FINAL RESULTS OF<br />
OUR STUDY<br />
C.O. Ruiperez 1 , M.L. Gomez 2 , M. Molina-Garido 3 , L.H. Martinez 4 ,A.<br />
Olaverri Hernandez 1 , M. Muñoz Sanchez 3 , J. Santiago Crespo 3 , F. Lobo 5 ,<br />
A. Carrato 6 , J. Feliu 7<br />
1 Medical Oncology, Virgen de la Luz Hospital, Cuenca, SPAIN, 2 Medical<br />
Oncology Department, Infanta Sofia University Hospital, San Sebastian de los<br />
Reyes, SPAIN, 3 Medical Oncology, Hospital General Virgen de la Luz de Cuenca,<br />
Cuenca, SPAIN, 4 Medical Oncology, Spanish Association against Cancer<br />
(AECC), Cuenca, SPAIN, 5 Servicio de Oncologia, Fundacion Jeminez DiazClin<br />
Nstra Senora de la Concepcion, Madrid, SPAIN, 6 Medical Oncology, Hospital<br />
Ramon y Cajal, Madrid, SPAIN, 7 Medical Oncology, La Paz University Hospital,<br />
Madrid, SPAIN<br />
Introduction and objectives: To analyze Internet use in Cancer patients and <strong>the</strong>ir<br />
relatives, <strong>the</strong> type of information <strong>the</strong>y obtained online, its usefulness and its impact<br />
on <strong>the</strong> patient-physician relationship and in treatment decisions.<br />
Materials and methods: Questionnaires were distributed to cancer patients (304)<br />
and <strong>the</strong>ir companions (231). The population sample came from a tertiary urban<br />
hospital in downtown Madrid, a secundary urban hospital in Cuenca, and two rural<br />
clinics in Ciudad Real. Student t-tests, chi-square tests and multivariate regression<br />
logistic analysis were carried out. The study was approved by <strong>the</strong> local ethics<br />
committee, and participants written informed consent.<br />
Results: Internet use was relatively low (35,2% patients, 55,8% relatives); Cancer specific<br />
information and treatment options were <strong>the</strong> main research topics between patients. In<br />
both subgrups, internet use was stadistical significative correlated with study levels<br />
(24,5% and 38,6% had Universitary studies ). No statistical differences between rural<br />
and urban population. Only 12% patients discussed <strong>the</strong> obtained information with <strong>the</strong>ir<br />
clinicians. The quality of <strong>the</strong> information was unreliable: 20% patients considered <strong>the</strong><br />
information average or bad, and 16% felt more confused after Internet search. For 38%<br />
patients, <strong>the</strong> information had been useful; however, 9,6% patients did not think that<br />
Internet information was important to decide <strong>the</strong> type of treatment.<br />
Conclusions: Internet use to obtain medical information, is a tool which gets more<br />
and more useful in Oncology patients and <strong>the</strong>ir relatives in our country. Quality<br />
information is highly unrealible, althought it helps patients to cope better with<br />
cancer. A low percentaje of patients discusses <strong>the</strong> information with <strong>the</strong> physician.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1405 QUALITY INDICATORS AND NON SMALL CELL LUNG CANCER<br />
INTEGRATED CARE PATHWAY: A SINGLE-CENTER<br />
EXPERIENCE<br />
J. Menis 1 , A. Follador 1 , F. Valent 2 , C. Rossetto 1 , M. Gaiardo 1 , L. Gurrieri 1 ,<br />
E. Lugatti 3 , S. Pizzolitto 4 , V. Tozzi 5 , G. Fasola 1<br />
1 Department of Medical Oncology, University Hospital Santa Maria della<br />
Misericordia, Udine, ITALY, 2 Statistics, Friuli Venezia Giulia, Udine, ITALY, 3 Chest<br />
Medicine, University Hospital Santa Maria della Misericordia, Udine, ITALY,<br />
4 Pathology, University Hospital Santa Maria della Misericordia, Udine, ITALY,<br />
5 ICP Research Responsible, University Bocconi, Milan, ITALY<br />
Background: Non Small Cell Lung Cancer (NSCLC) diagnosis and treatment is a<br />
highly complex process, requiring managerial skills merged with clinical knowledge<br />
and experience. Integrated Care Pathways (ICP) might be a good strategy to overview<br />
and improve patient’s management. The aim of our study was to review our NSCLC<br />
patient’s ICP in order to provide evidence of clinical or organizational<br />
inappropriateness.<br />
Methods: We retrospectively reviewed <strong>the</strong> electronic medical records of 169 NSCLC<br />
patients who had had a first access at <strong>the</strong> Oncology Department of <strong>the</strong> University<br />
Hospital Santa Maria della Misericordia (Udine, Italy) during 2010. The ICP<br />
mapping and few quality indicators had already been settled by a previous study on<br />
<strong>the</strong> 2008 population and were integrated with new uptodate indicators selected from<br />
scientific literature and discussed at <strong>the</strong> weekly MDT.<br />
Results: 146 patients were considered eligible; median age was 67 years old.<br />
Patients were mainly males (65%), had adenocarcinoma histology and advanced<br />
disease at <strong>the</strong> time of diagnosis (52.7%). Distant from benchmark were <strong>the</strong><br />
percentage of diagnostic bronchoscopic procedures (60.7 vs 80-85%), <strong>the</strong> number<br />
of surgical candidates who underwent mediastinoscopy for positive PET for<br />
mediastinal nodes (0 vs 100%), median time from diagnosis to surgery and to<br />
chemo<strong>the</strong>rapy (58.5 vs 21 and 34 vs 21 days; p < 0.0001) and median time from<br />
PET to surgery (53.5 vs 14 days; p < 0.0001). No extemporary citology during<br />
bronchoscopy was performed and only 42.8% of <strong>the</strong> patients received concomitant<br />
chemo-radio<strong>the</strong>rapy for stage III disease. Stage was <strong>the</strong> only indipendent variable<br />
associated with shorter time from first chest physician examination to diagnosis<br />
(p = 0.028) and from diagnosis to <strong>the</strong> first chemo<strong>the</strong>rapy administration (p <<br />
0.0001).<br />
Conclusion: Our analysis has highlighted a good adherence to current national and<br />
intenational guidelines and scientific literature as far as medical oncology treatment<br />
and pathological diagnosis are concerned. There is still room for improvement, most<br />
of all regarding <strong>the</strong> pre-surgical procedures and timing for surgery. The ICP study<br />
has proven to be a feasible ad efficacious methodology to point out <strong>the</strong> patient’s<br />
health management.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1406 KNOWLEDGE ASSESSMENT OF MEDICAL AND<br />
ONCOLOGICAL TERMINOLOGY IN LUNG CANCER PATIENTS<br />
A. Kieszkowska-Grudny 1 , M. Rucinska 2 , E. Meszko 2 , S. Nawrocki 2<br />
1 Fryderic Chopin Memorial Hospital, The European Health Centre Otwock,<br />
Otwock, POLAND, 2 Department of Oncology, University of Warmia and Mazury,<br />
Olsztyn, POLAND<br />
Introduction: Lung cancer is one of <strong>the</strong> most common cancers. Clear information<br />
about diagnosis, prognosis, treatment and its side effects is important in cooperation<br />
between patients and medical staff. The aim of <strong>the</strong> study was to find out what lung<br />
cancer patients know about <strong>the</strong>ir disease and treatment.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds410 | ix457
Material and methods: 50 lung cancer patients (41 - 70 years old) were included to<br />
<strong>the</strong> study. All patients were treated with radio<strong>the</strong>rapy, 39 patients (78%) have been<br />
previously treated by chemo<strong>the</strong>rapy, 13 patients (26%) were after surgery. All<br />
patients have been informed by doctors about <strong>the</strong>ir cancer, treatment and side effects<br />
before radio<strong>the</strong>rapy started and got written information. Subjects filled out<br />
questionnaires that included closed questions with 5 responses, of which one was<br />
correct, 3 incorrect, and <strong>the</strong> last: “I do not know”. The wording used in <strong>the</strong> survey,<br />
such as: neoplasm, cancer, radio<strong>the</strong>rapy, chemo<strong>the</strong>rapy, side effects, itching, peeling<br />
skin, etc., came from a consent form including side effects of treatment. Statistical<br />
analysis was done based on Chi2 test, descriptive statistics and logistic regression.<br />
The significance level was p < 0,05.<br />
Results: No one of lung cancer patients answered all asked questions correctly.<br />
Eleven patients (22%) were unable to properly answer any question. Only 15 pts<br />
(30%) were able to correctly answer at least half of questions. Only 8 people (16%)<br />
knew <strong>the</strong> right definition of cancer and <strong>the</strong>re were no differences in this knowledge<br />
between patients age, sex, education, place of living and treatment obtained. Right<br />
awareness of radio<strong>the</strong>rapy and chemo<strong>the</strong>rapy had 32% and 39% of patients,<br />
respectively. More than 50% of patients did not know what side effects or itching,<br />
skin’s exfoliation, sleep disorders mean. Interestingly, about 42% of patients knew <strong>the</strong><br />
right definition of cardiac arrhythmias. We found out that only level of education is<br />
a predictor of better knowledge for many terms, like e.g.: neoplasm, radio<strong>the</strong>rapy,<br />
chemo<strong>the</strong>rapy, sides effects (p < 0,05).<br />
Conclusions: Knowledge about cancer and treatment-related terms is very poor in<br />
lung cancer patients. Level of understanding varies depending on level of education<br />
and some on place of residence. Fur<strong>the</strong>r studies are needed.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1407 WHAT DO EUROPEAN COMMUNITY ONCOLOGISTS EXPECT<br />
FROM <strong>ESMO</strong>? A SURVEY IN GERMANY, GREECE, HUNGARY,<br />
ITALY, LUXEMBOURG, ROMANIA, AND SPAIN BY THE <strong>ESMO</strong><br />
COMMUNITY ONCOLOGY WORKING GROUP<br />
R. Eckert1 , R. Curca2 ,G.D’Addario3 , M.V. Karamouzis4 , G. Lanzetta5 ,<br />
P. Martin Martorell6 , D. Mauri7 , S. Rauh8 , S. Schmitz9 , K. Tamas10 1 2<br />
Oncology Group Practice, Wendlingen, GERMANY, Oncology, Alba County<br />
Hospital, Alba Iulia, ROMANIA, 3 Onkologie Schaffhausen, Schaffhausen,<br />
SWITZERLAND, 4 Dept. of Biological Chemistry, University of A<strong>the</strong>ns Medical<br />
School, Kolonaki, GREECE, 5 Dept. Oncology, Instituto Neurotraumatologico<br />
Italiano(I.N.I) Grottaferrata, Grottaferrata, ITALY, 6 Oncology, Hospital Clinico<br />
Universitario de Valencia, Valencia, SPAIN, 7 Medical Oncology, General Hospital<br />
of Lamia, Roditsa Lamias, GREECE, 8 Oncologie / Med Interne, Centre<br />
Hospitalier Emile MayrischSite Niedercorn, Differdange, LUXEMBOURG,<br />
9<br />
Haematology and Oncology, Oncology Practice, Cologne, GERMANY,<br />
10<br />
Department of Oncology, Szent Laszlo Teaching Hospital, Budapest,<br />
HUNGARY<br />
Introduction: Community oncologists (COs) mainly work outside academic<br />
institutions and typically treat a wide range of tumours. It is estimated that COs care<br />
for over 50% of all cancer patients. Time-saving and efficient access to relevant and<br />
up to date information and tools could improve <strong>the</strong> quality of patient care and<br />
possibly disease outcomes. We asked COs from 7 European countries for <strong>the</strong>ir needs<br />
and wishes for support by a professional society like <strong>ESMO</strong>.<br />
Methods: In Germany, Greece, Romania, Hungary, Luxembourg, and Spain,<br />
questionnaires were distributed by email by WG members. In Italy and Spain, AIOM<br />
and SEOM member COs were asked to answer an online questionnaire. We asked<br />
about topics like <strong>ESMO</strong> membership, use of Clinical Practice Guidelines (CPG), use<br />
of electronic tools, and <strong>ESMO</strong> conferences.<br />
Results: 389 answers were received from COs in 7 European countries (DE 164, GR<br />
45, HU 21, IT 96, LU 12, RO 41, ES 10; average response rate where evaluable: 27%).<br />
52% of responding COs are <strong>ESMO</strong> members and 82% know <strong>ESMO</strong>’s home page.<br />
The use of <strong>ESMO</strong> CPGs varies greatly among countries (39-95%). 67% of COs have<br />
access to an intranet with electronic tools; yet 83% are interested in web based tools<br />
on <strong>the</strong> <strong>ESMO</strong> homepage, particularly guidelines, score calculators, and <strong>the</strong>rapy<br />
protocols / planning aids. 87% of COs attend <strong>ESMO</strong> conferences at least<br />
occasionally; 62% of <strong>ESMO</strong> members attend regularly vs. 20% of non-members. 49%<br />
of COs are satisfied with <strong>the</strong> conferences’ scientific content, but miss practice<br />
relevance; 72% would like to have sessions particularly for COs.<br />
Conclusions: This is <strong>the</strong> largest survey among COs in Europe to date. In spite of<br />
Europe‘s political and cultural heterogeneity, we find a surprising homogeneity in<br />
most answers across countries. A high proportion of COs are <strong>ESMO</strong> members. There<br />
is a definite interest in <strong>ESMO</strong> also by non-<strong>ESMO</strong>-members. COs wish more practice<br />
relevant sessions at <strong>ESMO</strong> conferences. They are interested in online services<br />
provided by <strong>ESMO</strong>, particularly guidelines and tools. To support practising<br />
oncologists in delivering <strong>the</strong> best available care to <strong>the</strong>ir patients, <strong>ESMO</strong> and <strong>the</strong><br />
Community Oncology WG have already implemented several measures, such as<br />
OncologyPro, a first CO Symposium at <strong>ESMO</strong> <strong>2012</strong>, and additions to <strong>ESMO</strong>’s<br />
web page.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1408 ONCOMOVIES: CANCER IN CINEMA<br />
Annals of Oncology<br />
G. Rosti 1 , A. Costantini 2 , M. Di Maio 3 , E. Bria 4 , D. Lorusso 5 , L. De Fiore 6<br />
1 Oncology, Ospedale Regionale Ca’ Foncello, Treviso, ITALY, 2 Psychology,<br />
Rome, ITALY, 3 Clinical Trials Unit, Istituto Nazionale Tumori di Napoli, Napoli,<br />
ITALY, 4 Oncology, Univesrity, Verona, ITALY, 5 Medical Oncology, Milan, ITALY,<br />
6 Phylosophy University Ll Sapienza, Phylosophy, Rome, ITALY<br />
Aim: To describe how movies portray cancer, and <strong>the</strong> experience of illness, through<br />
an analysis of movies throughout more than 70 years of cinema.<br />
Materials and methods: Cross-sectional descriptive study. In order to retrieve <strong>the</strong><br />
relevant literature, we searched <strong>the</strong> Medline database using different keywords. A<br />
sample of convenience of films was analysed in which cancer had "prompt",<br />
"relevant", or "plot" character. Movies yearbook and databases (allmovie, IMDb,<br />
Movieplayer, Mymovies) were consulted. Each film was viewed by two observers<br />
who recorded patients variables (age, gender, marital status, etc), <strong>the</strong> cancer<br />
process (type, symptoms, <strong>the</strong>rapy, and evolution), and <strong>the</strong> health care<br />
environment, among o<strong>the</strong>rs.<br />
Results: 376 papers have been retrieved, but only a small percentage has been<br />
considered as relevant to <strong>the</strong> study. 75 films produced by 13 countries (years<br />
1939-<strong>2012</strong>) were analyzed. 40 patients were women, 35 men, and 64% belonged<br />
to <strong>the</strong> upper and upper/middle social class. The most common cancers were<br />
lymphoma, CNS tumours, and leukaemia. In 21 films <strong>the</strong> type of cancer was<br />
not mentioned. Symptoms were considered in 72% of <strong>the</strong> movies, while<br />
diagnostic tests were mentioned in 65%. The most frequent treatment<br />
mentioned in <strong>the</strong> movies was chemo<strong>the</strong>rapy followed by antalgic <strong>the</strong>rapy. Death<br />
occurred 46 times (63% of all moveis). Doctors and nurses turned up in 58<br />
films (77%).<br />
Conclusions: <strong>the</strong>re is a trend of cancer narrative in movies, expecially in <strong>the</strong> last<br />
few years. Cancer experiences described in <strong>the</strong> films are quite different from <strong>the</strong><br />
truth: movies prefer younger patients, higher social class; <strong>the</strong> prevalence of<br />
cancer site does not match <strong>the</strong> epidemiological data (e.g. breast cancer only in 5<br />
movies). However, symptoms, diagnostic tests, and treatments tend to be based<br />
on real life, particularly in <strong>the</strong> production of <strong>the</strong> last twenty years. Usually,<br />
cancer patients die at <strong>the</strong> end of <strong>the</strong> movie. Some of <strong>the</strong> films evaluated may be<br />
a first hand resource for training health professionals, while some o<strong>the</strong>rs could<br />
be a valued example of malpractice.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1409 NEOPLASIC DISEASE AND CHRONIC KIDNEY DISEASE:<br />
DOES THE ASSOCIATION WORSEN PROGNOSIS?<br />
D. Romeira 1 , C.T. Carvalho 1 , M. Proença 2 , M. Alface 2 , R. Cardiga 2 , R. Ferreira 2 ,<br />
A. Leitão 2 , C. Fonseca 2 ,F.Ceia 2 , A.M. Martins 1<br />
1 Medical Oncology Unit, Hospital São Francisco Xavier, Lisboa, PORTUGAL,<br />
2 Internal Medicine, HSFX, Lisboa, PORTUGAL<br />
Neoplastic diseases (ND) and chronic kidney disease (CKD) are strongly<br />
related. Side effects of neoplastic treatments can cause CKD and <strong>the</strong> latter can<br />
be a risk factor for ND. Even in early stages of CKD, <strong>the</strong> risk of developing ND<br />
increases, <strong>the</strong> latter being drastically increased in patients (pts) treated with<br />
hemodialysis.<br />
Objectives: Compare, within a population of cancer pts with and without CKD,<br />
demographic characteristics, length of hospital stay, and prognosis.<br />
Methods: Observational prospective study with all consecutively admitted pts in an<br />
Internal Medicine department of a CentralHospital between November 2010 and<br />
October 2011. Collection of data using a previously normalized questionnaire,<br />
completed on admission and date of release, finalized with a posterior telephonic<br />
contact. The following characteristics of pts with ND and CKD (GFR CKD < 60 mL/<br />
min/1,73m2) - GROUP A (GA) and with ND but without CKD - GROUP B (GB)<br />
were compared: demographics, in-hospital evolution, hospital stay and post-release<br />
mortalities<br />
Results: We evaluated 104 pts with ND with an average follow-up of 162 days.<br />
GA= 40 pts (38,5%) 78,9 ± 10,6 years, 52,5% women, GFR =39,6 ±12 mL/min/<br />
1,73m2, stages III = 77,5%, IV = 22,5% GB= 64 pts (61,5%), 72,92 ± 12,6 years;<br />
46,9% women, GFR = 72,9 ± 14,5mL/min/1,73m2. Hospital stay length: GA 9,2 ±<br />
5 vs GB 9.9 ± 9,3 days. Hospital stay mortality: GA: 27,5% VS GB: 3,125%. CKD<br />
correlates with hospital-stay mortality: (χ2(2) = 13,371; p = 0,000 N = 104.);<br />
Significant differences were found between both groups pertaining to average<br />
survival during follow-up: (t(52) = -3,437; p = 0,01). The average length of<br />
hospital-stay and <strong>the</strong> number of readmissions are not related to <strong>the</strong> existence of<br />
CKD: (χ2(2) = 0,399; p = 0,53 N = 90)<br />
Conclusion: More than 1/3 of ND pts had CKD, <strong>the</strong> majority within stage III. ND<br />
pts with CKD were older. CKD contributed to hospital stay mortality and shorter<br />
survival rate on follow-up of pts with ND but did not contribute to an increase of<br />
hospital stay length.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix458 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
1410 CANCER AND LUNG TRANSPLANTATION<br />
D. Pérez Callejo 1 , R. Laporta 2 , E. Almagro Casado 1 , M. Palka 1 ,<br />
A. Ruiz-Valdepeñas 1 , B. Cantos 1 , C. Maximiano 1 , M. Méndez García 1 ,<br />
P. Ussetti 2 , M. Provencio Pulla 3<br />
1 Medical Oncology, Hospital Universitario Puerta de Hierro Majadahonda,<br />
Madrid, SPAIN, 2 Pulmonology, Hospital Universitario Puerta de Hierro<br />
Majadahonda, Madrid, SPAIN, 3 Medical Oncology, Hospital Universitario Puerta<br />
de Hierro Majadahond, Majadahonda, SPAIN<br />
Introducation: Malignacies rank fourth on <strong>the</strong> leading causes of death in recipients<br />
of solid organ transplantation. High-dose immunosuppression, infections with<br />
oncogenic viruses and <strong>the</strong> pre-transplant risk, mainly due to tobacco, make <strong>the</strong>se<br />
patients more susceptible for developing cancer. In <strong>the</strong> present study we reviewed a<br />
collective of 50 patients with lung transplantation (LT) and cancer.<br />
Patients and methods: Retrospective study of 503 lung transplant patients,<br />
performed at <strong>the</strong> Hospital Universitario Puerta de Hierro during 1993 and <strong>2012</strong>. We<br />
included <strong>the</strong> following variables: date of birth, reason and date of transplantation,<br />
date of diagnosis of malignancy, histology and response to treatment, date and cause<br />
of exitus. The contrasts between proportions were performed using Chi-square test<br />
and survival curves using <strong>the</strong> product-limit method of Kaplan-Meier.<br />
Results: The 503 included transplant patients developed a total of 55 post-transplant<br />
malignancies in 50 patients. Four patients presented tumors already previous to <strong>the</strong><br />
transplantation. The main underlying pathologies of <strong>the</strong> patient collective are<br />
idiopathic pulmonary fibrosis (50%), emphysema (30%) and cystic fibrosis (14%)<br />
The histology of <strong>the</strong> 55 post-transplant tumors were 18 skin cancer, 12 lung cancer,<br />
8 gastrointestinal cancer, 6 Non-Hodgkin’s Lymphoma, 2 bladder cancer, 2<br />
myelodysplastic syndrome, 2 sarcomas and 5 o<strong>the</strong>rs. The mean age of diagnosis of<br />
malignancies is at 59 years (18-68). The mean time from transplantation to tumor<br />
diagnosis amounts 4 years (1-15). Of <strong>the</strong> 21 patients (42%) that have died until data<br />
collection, cancer was death cause in 15 (30%)<br />
Conclusion: Relying on our data, <strong>the</strong> majority of malignancies are skin and lung<br />
cancer and lymphoproliferative syndromes, attributing complications that should be<br />
considered in lung transplantation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1411 A REINFORCEMENT LEARNING APPROACH FOR<br />
OPTIMIZATION OF CHEMOTHERAPY AND ITS APPLICATION<br />
IN OPTIMAL CONTROL<br />
A. Fani Pakdel 1 , M. Rezazadeh 2 , M. Naghiby Sustany 2<br />
1 Radiation Oncology, Mashhad University of Medical Sciences Omid Hospital<br />
Cancer Research Center, Mashhad, IRAN, 2 School of Electrical Engineering,<br />
ferdowsi University, Mashhad, IRAN<br />
The diagnosis and treatment of <strong>the</strong> cancer has been <strong>the</strong> subject of discussion in<br />
different scientific fields in <strong>the</strong> recent years. In this paper, an optimal control strategy<br />
for <strong>the</strong> nonlinear systems is presented for application in chemo<strong>the</strong>rapy of <strong>the</strong> cancer.<br />
The tumour growth model can be represented by a system of equations from<br />
population dynamics based on <strong>the</strong> competition between normal cells and tumour<br />
cells. The effect of <strong>the</strong> immune system on cancer is also included in <strong>the</strong> model. An<br />
optimal control method is applied to destroy <strong>the</strong> cancer cell with <strong>the</strong> minimum dose<br />
of chemo<strong>the</strong>rapeutic agent. Reinforcement learning technique is proposed to<br />
construct an optimal control strategy for <strong>the</strong> nonlinear system and it was shown to<br />
be a suitable method to solve this problem. Simulation results show that cancer cells<br />
can be eradicated in a very short time with a small amount of drug using proposed<br />
optimal method of <strong>the</strong> <strong>the</strong>rapy. They also show that <strong>the</strong> method is applicable to<br />
different models. It should be pointed out that <strong>the</strong> presented approach is a<br />
completely general procedure, and <strong>the</strong>refore, it can be applied to many problem of<br />
drug dosage optimization.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1412 ALLOCATION OF PHYSIOLOGIC RESERVE FOLLOWING<br />
CHEMOTHERAPY AS A MARKER OF FRAILTY IN ELDERLY<br />
CANCER PATIENTS<br />
M. Molina-Garido 1 , C. Guillen-Ponce 2 , M. Muñoz Sanchez 1 , C. Ortega Ruiperez 1 ,<br />
A. Olaverri Hernandez 1 , A. Carrato 2 , J. Santiago Crespo 1<br />
1 Medical Oncology, Hospital General Virgen de la Luz de Cuenca, Cuenca,<br />
SPAIN, 2 Medical Oncology, Hospital General Universitario Ramón y Cajal,<br />
Madrid, SPAIN<br />
Introduction: The aim of this study is to identify <strong>the</strong> presence of frailty in elderly<br />
patients with cancer by comparing <strong>the</strong>ir functional reserves before and after<br />
treatment with chemo<strong>the</strong>rapy<br />
Materials and methods: This study is a prospective cohort study of cancer patients<br />
over 70 years of age who were consecutively evaluated between January 2010 and<br />
December 2011 in <strong>the</strong> Cancer Consultation in <strong>the</strong> Elderly program, Medical<br />
Oncology Section, Virgen de la Luz General Hospital in Cuenca. Group A comprised<br />
patients treated with chemo<strong>the</strong>rapy, and group B comprised untreated patients. For<br />
each patient, we collected demographic data, data concerning <strong>the</strong> cancer and data<br />
describing <strong>the</strong> physiologic reserve relating to each individual (muscle mass evaluation<br />
[MME], walking speed, peak-flow, grip strength, creatinine clearance, and Pfeiffer<br />
score). The parameters of each patient’s functional reserve were determined at<br />
baseline (<strong>the</strong> day of <strong>the</strong> patient’s first visit) and 4 months later. Analyses of <strong>the</strong> data<br />
were conducted to identify whe<strong>the</strong>r <strong>the</strong>re were significant differences between <strong>the</strong><br />
groups for each of <strong>the</strong> variables under study pre- and post-chemo<strong>the</strong>rapy (Student’s<br />
t-test and Fisher’s exact test for independent groups).<br />
Results: We analyzed data from 66 patients treated with chemo<strong>the</strong>rapy (group A)<br />
and 68 patients who were not treated with cytostatic drugs (group B). The mean age<br />
of <strong>the</strong> patients was 78.68 +/- 4.90 years. There were 38 cases with metastatic tumors<br />
(28.8%). In our study <strong>the</strong>re were no significant differences in walking speed (p =<br />
0.323), handgrip strength (p = 0.162), expiratory flow (peak-flow) (p = 0.954),<br />
cognitive status (Pfeiffer score) (p = 0.078), or creatinine clearance (p = 0.425).<br />
However, in patients treated with chemo<strong>the</strong>rapy, <strong>the</strong>re was an increase in <strong>the</strong> MME<br />
(0.618 kg/m2, 95% CI: 0.020 to 1.215, p= 0.043).<br />
Discussion: Physiologic reserve in <strong>the</strong> elderly, measured by walking speed, handgrip<br />
strength, creatinine clearance, <strong>the</strong> Pfeiffer questionnaire and peak-flow, does not<br />
change as a result of chemo<strong>the</strong>rapy. Strikingly, <strong>the</strong> only parameter to undergo<br />
significant changes after <strong>the</strong> use of cytostatic medications is skeletal muscle mass.<br />
This work was funded by <strong>the</strong> "Young Investigator Grant SEOM 2008-2010".<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1413TiP QUALITY OF LIFE INCRIMINATING SYMPTOMS IN CANCER<br />
PATIENTS AND THEIR WEIGHT IN THE<br />
DOCTOR-PATIENT-TALK: A SURVEY OF THE “QUALITY OF<br />
LIFE” WORKING GROUP OF THE<br />
“ARBEITSGEMEINSCHAFT INTERNISTISCHE ONKOLOGIE”<br />
(AIO): A PRELIMINARY ANALYSIS<br />
F.K. Tauchert 1 , R. Hofheinz 2 , J. Quidde 3 , N. Marschner 4 , M. Hipp 5 , M. Weber 6 ,<br />
H. Hoeffkes 7 , E. Jaeger 1 , S. Al-Batran 1<br />
1 Medizinische Klinik II für Hämatologie und Onkologie, Institut für klinische<br />
Forschung (IKF) am Krankenhaus Nordwest - UCT, Universitäres Centrum für<br />
Tumorerkrankungen Frankfurt, Frankfurt am Main, GERMANY, 2 , III. Medizinische<br />
Klinik für Hämatologie und Onkologie, Tages<strong>the</strong>rapiezentrum,<br />
2Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, GERMANY,<br />
3 Hubertus Wald Tumorzentrum, 3Universitäres Cancer Center Hamburg,<br />
Hamburg, GERMANY, 4 Praxis für interdisziplinäre Onkologie & Hämatologie,<br />
Freiburg i. Breisgau, GERMANY, 5 Klinik und Poliklinik für Strahlen<strong>the</strong>rapie,<br />
Universitätsklinik Regensburg, Regensburg, GERMANY, 6 Medizinische Klinik III<br />
für Hämatologie, Internistische Onkologie und Pulmologie, Universitätsmedizin<br />
Mainz, Mainz, GERMANY, 7 Tumorklinik, Klinikum Fulda gAG, Fulda, GERMANY<br />
Introduction: Most cancer specific Quality of life (QoL) questioners (including <strong>the</strong><br />
EORTC QLQ-C30) are based on <strong>the</strong> assumption that fatigue, pain, nausea &<br />
vomiting are <strong>the</strong> most important symptoms with impact on QoL of cancer patients.<br />
During <strong>the</strong> last 20 years, progress in supportive care has been made and <strong>the</strong> weight<br />
of symptoms may have changed. Using a standardized questioner, we investigated<br />
which symptoms incriminate cancer patients (pts) most.<br />
Methods: Pts were asked to provide confidential information on <strong>the</strong> following items:<br />
patient characteristics, underlying malignant disease and treatment, performance<br />
status (PS), incrimination of <strong>the</strong> QoL by various symptoms (19 items) and <strong>the</strong>ir<br />
weight in <strong>the</strong> patient-to-doctor talk. Data were collected and analyzed using standard<br />
statistical methods.<br />
Results: 1,300 pts participated so far. The median age was 63 years (18-93). 51.7% of<br />
pts were female and 72.7% had an ECOG PS of 0-2. Most frequent malignancies<br />
were breast cancer (211), colorectal cancer (153), lymphomas (98) and lung cancer<br />
(88). Most pts received chemo- or radio<strong>the</strong>rapy (67%). 16% were in follow-up or<br />
surveillance and 17% had o<strong>the</strong>r forms of <strong>the</strong>rapy or did not state at all. The most<br />
incriminating problems were weakness, tiredness & poor concentration, <strong>the</strong> question<br />
“what is going to happen?” and alopecia. Sexual life, social trouble, depression,<br />
anxiety & sorrows and insomnia were reported as incriminating problems with<br />
inadequate attention in <strong>the</strong> doctor-patient-talk (adequate attention reported in 15.6%<br />
- 46.1% of pts respectively). Pts with metastatic disease reported significant more<br />
incrimination in QoL by weakness, dypsnea, pain, loss of appetite, “state of <strong>the</strong>rapy<br />
and outlook”, “what is going to happen?” and anxiety & sorrows. Pts with colorectal<br />
cancer reported significantly more incrimination by diarrhea but less by weakness,<br />
dyspnea, alopecia, “what is going to happen?” and anxiety & sorrows than o<strong>the</strong>r pts.<br />
Conclusions: Overall pts reported fatigue, alopecia and insomnia as <strong>the</strong> QoL most<br />
incriminating symptoms. Pain and nausea & vomiting were less incriminating,<br />
possibly due to improved supportive care. Sexual life, social trouble, depression,<br />
anxiety & sorrows, and insomnia receive inadequate attention in <strong>the</strong><br />
doctor-patient-talk.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds410 | ix459
1414TiP IMPLEMENTATION OF CANCER REGISTRY IN GEORGIA<br />
N. Jokhadze 1 , M. Maglakelidze 1 , R. Gagua 2<br />
1 Cancer Control, National Cancer Center of Georgia, Tbilisi, GEORGIA, 2 General<br />
Director, National Cancer Center of Georgia, Tbilisi, GEORGIA<br />
Background: Georgian Population–based Cancer Registry was set up in 2000. In<br />
2009 most of medical facilities in Georgia became private. Currently private clinics<br />
are not instructed by law to submit data to central registry and nearly 30% of data<br />
are lost from <strong>the</strong> population registry.<br />
Objectives: The aim of <strong>the</strong> project was to:. 1. Implement Modern Cancer<br />
Registration System in Georgia. 2. Ensure compliance of reporting<br />
standards. 3. Create registry that will meet international data standards.<br />
Methods: In 2011 as a result of active work with Ministry of Health Care (MOH) •<br />
Cancer Registry program was included in NCCP • Government has funded a “State<br />
Program of Modern Cancer Registry Implementation”. By <strong>the</strong> end of <strong>the</strong> project<br />
Cancer Registry will be linked to EMR notification system that itself will be linked to<br />
public and death registry and data on every cancer patient will automatically appear<br />
in <strong>the</strong> cancer registry database<br />
Results: According to <strong>the</strong> schedule I stage of <strong>the</strong> program has been completed<br />
successfully. • New model of cancer registry has been developed • ICD-O third<br />
edition has been translated • Committee of Healthcare at Parliament of Georgia<br />
prepared legislation proposal for consideration. By <strong>the</strong> end of <strong>2012</strong> development of<br />
software, training of registrars and piloting of cancer reporting is planned.<br />
Conclusion: Developed model of Cancer Registry will serve as a basis for clinical,<br />
epidemiologic, and health care services research and for <strong>the</strong> assessment of <strong>the</strong>ir<br />
efficacy in Georgia.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1416PD PROGRESS AND TRENDS FOR CANCER DRUG APPROVAL<br />
– AN ANALYSIS OF FDA ADVISORY COMMITTEE<br />
J.K. Chan 1 , I. Amanam 1 , T.K. Kiet 1 , N. Young-Lin 1 , D. Hoth 1 , D.S. Kapp 2 ,B.<br />
J. Monk 3<br />
1 Ob/Gyn & Reproductive Sciences, UCSF Helen Diller Family Comprehensive<br />
Cancer Center, San Francisco, CA, UNITED STATES OF AMERICA, 2 Radiation<br />
Oncology, Stanford University School of Medicine, Stanford, CA, UNITED<br />
STATES OF AMERICA, 3 Obstetrics and Gynecology, Creighton University School<br />
of Medicine at St. Joseph’s Hospital and Medical Center, a member of Dignity<br />
Health, Phoenix, AZ, UNITED STATES OF AMERICA<br />
Objectives: To evaluate <strong>the</strong> progress and trends for cancer drug approval over <strong>the</strong><br />
last decade.<br />
Methods: From 2001 to 2011, applications from (Oncologic Drug Advisory<br />
committees) ODAC session were reviewed.<br />
Results: Of 46 applications, 34 (74%) involved solid and 12 (26%) hematologic<br />
tumors. These drugs were for leukemia (n = 8, 17%), lymphoma (n = 8, 17%), breast<br />
(n = 5, 11%), prostate (n = 5, 11%), and o<strong>the</strong>rs (n = 20, 44%). 30 (65%) were phase III<br />
and 16 (35%) were phase II trials. 67% (n = 31) were full applications and 33% (n =<br />
15) were for accelerated approval. 22 (48%) drugs were not approved with most<br />
common concerns being: missing or inadequate data (65%), excessive toxicity (55%)<br />
and inappropriate study endpoints (45%). 19 applications used hazard ratios (HR),<br />
(median = 0.67) and 18 used response rates (RR) (median = 0.42%). In a predictive<br />
model combining efficacy and toxicity, drugs with lower HR or higher RR with lower<br />
toxicity were more likely to be approved vs. o<strong>the</strong>r drugs (89% vs. 46%; p = 0.025). We<br />
<strong>the</strong>n divided applications into 3 periods with <strong>the</strong>ir corresponding approval rates:<br />
2001-2004 (n = 11; 55%), 2005-2008 (n = 12; 50%), and 2009-2011 (n = 23; 53%).<br />
Over time, <strong>the</strong>re was a significant increase in <strong>the</strong> proportion of applications using<br />
progression-free survival as an endpoint (0% to 50% to 70%; p = 0.01).<br />
Conclusion: In this analysis of oncology drug applications, our model employing<br />
hazard ratio and toxicity correlates with a high rate of approval. The most common<br />
concerns of <strong>the</strong> rejected applications involved missing or inadequate data, excessive<br />
toxicity, and inadequate study endpoints. Clinical researchers need to consider <strong>the</strong>se<br />
FDA recommendations in <strong>the</strong> future design of clinical trials.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1417PD NICE TECHNOLOGY APPRAISALS AND THE UPTAKE OF<br />
BREAST CANCER DRUGS IN THE UK<br />
D. Bertwistle 1 , P. Anderson 2 , M. Jofre-Bonet 3<br />
1 HEOR, IMS Health, London, UNITED KINGDOM, 2 Swansea Centre for Health<br />
Economics, Swansea University, Swansea, UNITED KINGDOM, 3 Department of<br />
Economics, City University London, London, UNITED KINGDOM<br />
Background: Health technology appraisal (HTA) recommendations from <strong>the</strong> UK<br />
National Institute of Health and Clinical Excellence (NICE) are intended to<br />
Annals of Oncology<br />
standardise health care throughout <strong>the</strong> NHS, and to hasten <strong>the</strong> uptake of new, more<br />
effective medicines that are cost-effective. Although it is compulsory for <strong>the</strong> NHS to<br />
fund drugs recommended by NICE, it is not clear how well NICE guidance is<br />
implemented. A number of studies have investigated whe<strong>the</strong>r NICE guidance<br />
influences UK drug uptake as intended. Most have used sales data, however, this<br />
approach has significant limitations. Sales data do not reveal which indication, line of<br />
<strong>the</strong>rapy, nor patient sub-group a drug has been used to treat. Many drugs are<br />
licensed for multiple indications, and many HTAs only recommend <strong>the</strong> use of drugs<br />
in defined sub-groups, often subsets of <strong>the</strong> licensed indication. To avoid <strong>the</strong><br />
limitations of sales data-based analyses, this study used IMS Health’s Oncology<br />
Analyzer TM as <strong>the</strong> primary data source. Oncology Analyzer TM contains detailed<br />
records for a representative sample of patients, allowing analyses to be focussed on<br />
<strong>the</strong> particular indication and treatment criteria specified in NICE HTAs.<br />
Methods: HTAs for breast cancer drugs appraised by NICE from 2005 to 2008 were<br />
analysed. For each HTA, <strong>the</strong> proportion of <strong>the</strong> eligible patient sub-group that<br />
received <strong>the</strong> recommended (or not recommended) drugs from Q1 2005 to Q1 2009<br />
was determined. Changes in uptake of <strong>the</strong> drugs in <strong>the</strong> relevant patient populations<br />
were assessed for <strong>the</strong> UK, and were also compared to uptake in similar European<br />
countries.<br />
Results: NICE produced 6 HTAs for breast cancer, encompassing 8 drugs, during <strong>the</strong><br />
period assessed. In 5 out of 6 cases, <strong>the</strong> publication of an HTA was followed by <strong>the</strong><br />
recommended change in UK drug uptake. However, when UK uptake of drugs<br />
recommended by NICE was compared to uptake of <strong>the</strong> same drugs in four o<strong>the</strong>r<br />
European countries (France, Germany, Italy and Spain), <strong>the</strong> UK ranked at <strong>the</strong><br />
bottom of <strong>the</strong> group.<br />
Conclusions: The NICE HTAs assessed were mostly followed by <strong>the</strong> intended<br />
changes in drug uptake, suggesting <strong>the</strong>y were implemented, at least by some PCTs.<br />
Despite this, international comparisons of uptake for <strong>the</strong>se drugs revealed that <strong>the</strong><br />
UK performed poorly compared to similar European countries.<br />
Disclosure: D. Bertwistle: This research uses data from <strong>the</strong> IMS Health data asset,<br />
Oncology AnalyzerTM. I am an employee of IMS Health. P. Anderson: This research<br />
uses data from <strong>the</strong> IMS Health data asset, Oncology AnalyzerTM. I am a former<br />
employee of IMS Health. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1419PD COLORECTAL CANCER SCREENING: FACTORS<br />
ASSOCIATED WITH NOT UNDERGOING AN EARLY<br />
COLONOSCOPY AFTER A POSITIVE FECAL OCCULT<br />
BLOOD TEST<br />
E. Ferrat 1 , J. Lebreton 1 , S. Bercier 2 , K. Veerabudun 1 , Z. Brixi 2 , E. Paillaud 3 ,<br />
C. Attali 4 , S. Bastuji-Garin 1<br />
1 Laboratoire d’Investigation Clinique (LIC EA4393), University of Medicine,<br />
Créteil, FRANCE, 2 ADOC94, Association of Organized Cancer Screening,<br />
Joinville-le-Pont, FRANCE, 3 UCOG, Hôpital Henri-Mondor, Créteil, FRANCE,<br />
4 General Practice, Université Paris-Est(UPEC), Créteil, FRANCE<br />
Background: Current screening guidelines recommend a complete colon evaluation<br />
with colonoscopy after a positive fecal occult blood test (FOBT). However, no timing<br />
guidelines are provided. A recent study showed that delay from FOBT to<br />
colonoscopy was associated with an increased risk of neoplasia. Our aim was to<br />
identify individual and contextual predictors of not undergoing an early colonoscopy<br />
after a positive FOBT.<br />
Methods: All average-risk residents of a French county who have had a positive<br />
FOBT from June 2007 to December 2010 (n = 2369) during organized colorectal<br />
cancer (CRC) screening campaigns were included. Individual data were abstracted<br />
from <strong>the</strong> Organized Cancer Screening Association database and aggregated<br />
socioeconomic data (physician density, Townsend deprivation index) from <strong>the</strong><br />
National Institute of Statistics and Economic Studies database. Multilevel and<br />
multinomial logistic regression analyses were performed to assess predictors of<br />
delayed colonoscopy (> median delay, 58 days), no colonoscopy and no response to<br />
cancer screening program after one year. Early colonoscopy was <strong>the</strong> reference<br />
category.<br />
Results: The rate of colonoscopy was 86.9%. 1 037 patients (45.3%) had an early,<br />
and 1 021 (44.6%) a delayed colonoscopy, 106 (4.7%) did not perform colonoscopy<br />
and 123 (5.4%) were nonrespondents. The multilevel analysis displayed a significant<br />
(p < 0.05) inter-area variation for not undergoing an early colonoscopy. In<br />
multivariate analysis, a delayed colonoscopy was associated with a first screening test<br />
(OR 1.61; 95% CI: 1.16-2.25). Not undergoing a colonoscopy and non response were<br />
associated with a FOBT received at home ra<strong>the</strong>r than given by <strong>the</strong> general<br />
practitioner (GP) (OR 1.94; 95%CI: 1.25-3.01 and OR = 2.74; 95%CI: 1.78-4.21,<br />
respectively) and living in <strong>the</strong> most deprived areas (OR 2.29; 95% CI: 1.20-4.37 and<br />
OR = 4.37; 95%CI: 2.23-8.55 respectively). There was no significant association<br />
between physician density, gender, age and follow-up after a positive FOBT.<br />
Conclusion: Actions to improve follow-up after a positive FOBT should focus on<br />
first CRC screening and population living in <strong>the</strong> most deprived areas. This study<br />
emphasizes <strong>the</strong> role of GPs in CRC screening.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix460 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
1420PD SCREENING TOOL FOR UNFITNESS IN GERIATRIC<br />
ONCOLOGY: WHAT DOES IT TELL US IN DAILY PRACTICE?<br />
C. Terret, S. Perrin<br />
Geriatric Oncology Program / Medical Oncology, Centre Léon Bérard, LYON,<br />
FRANCE<br />
Background: We are facing a growing number of cancer patients (pts) aged ≥ 70<br />
years. However, cancer treatment decision-making appears a difficult task in such<br />
heterogeneous population as solid recommendations are still lacking. The G8 scale<br />
was designed to help discriminate older cancer patients needing a geriatrician’s<br />
opinion before cancer treatment decision-making. This 8-item tool can be<br />
completed in
abstracts<br />
palliative care<br />
1422O EFFICACY AND SAFETY OF A TWO DRUG-COMBINATION<br />
REGIMEN FOR CANCER-RELATED CACHEXIA IN THE<br />
CLINICAL PRACTICE<br />
C. Madeddu 1 , A. Macciò 2 , M.C. Cau 1 , M. Dessi’ 1 , F. Panzone 1 , R. Serpe 1 ,<br />
G. Antoni 1 , G. Mantovani 1<br />
1 Department of Medical Oncology, University of Cagliari, Cagliari, ITALY,<br />
2 Department of Obstetrics and Gynecology, Sirai Hospital, Carbonia, ITALY<br />
Background and aims: To test <strong>the</strong> safety and efficacy of a two-drug combination<br />
(including nutraceuticals, i.e. antioxidants) with carnitine + celecoxib for <strong>the</strong><br />
treatment of cancer-related anorexia/cachexia syndrome (CACS) in <strong>the</strong> clinical<br />
practice. Primary endpoints: safety, increase of lean body mass (LBM) and<br />
improvement of quality of life. Secondary endpoints: increase of physical<br />
performance (tested by grip strength and 6-min walk test, 6MWT) and decrease of<br />
inflammation (assessed by serum levels of IL-6 and Glasgow prognostic score, GPS).<br />
Patients and methods: Outpatients with advanced cancer at different sites with<br />
CACS (i.e. loss of body weight >5% of <strong>the</strong> pre-illness or ideal weight in <strong>the</strong> last<br />
3 months) were eligible to receive: L-carnitine 4 g/day + Celecoxib 300 mg/day. All<br />
patients received as basic treatment polyphenols 300 mg/day, lipoic acid 300 mg/day,<br />
carbocysteine 2.7 g/day, Vitamin E, A, C, all orally. Treatment duration was<br />
4 months.<br />
Results: From June 2011 to April <strong>2012</strong>, 50 patients with advanced cancer (all stage<br />
IV) at different sites were enrolled: 40 completed <strong>the</strong> treatment and were evaluable<br />
(mean age 63.8 ± 9.6, range 32-81 years). Results showed a significant increase of<br />
LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) from<br />
baseline as well as physical performance assessed by 6MWT. Quality of life (assessed<br />
by EORTC-QLQ-C30 and EQ-5D) also improved significantly. ECOG PS and GPS<br />
decreased significantly. The treatment was safe, no grade 3–4 toxicities occurred and<br />
no patient had to discontinue <strong>the</strong> treatment due to severe adverse events.<br />
Conclusions: The results of <strong>the</strong> present study confirm <strong>the</strong> efficacy and safety of <strong>the</strong><br />
two-drug combination regimen previously shown in a randomized clinical trial<br />
(Madeddu et al, Clinical Nutrition 31:176-182, <strong>2012</strong>). Therefore, this simple, feasible,<br />
effective, safe, with favorable cost-benefit profile, two-drug approach could be<br />
suggested in <strong>the</strong> clinical practice as a treatment for CACS.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1423O REAL-TIME ELECTRONIC MONITORING OF<br />
PATIENT-REPORTED SYMPTOMS AND SYNDROMES (PRS):<br />
E-MOSAIC, A MULTICENTER PHASE III STUDY (SAKK 95/06)<br />
D. Blum 1 , D. Koeberle 2 , R. von Moos 3 , K. Ribi 4 , S. Aebi 5 , D.C. Betticher 6 ,<br />
S. Hayoz 7 , J. Nadig 8 , S. Mauri 9 , F. Strasser 10<br />
1 Department of Cancer Research and Molecular Medicine, European Palliative<br />
Care Research Center Clinical, Trondheim, NORWAY, 2 Dept. Oncology/<br />
Hematology, Kantonsspital St. Gallen, St. Gallen, SWITZERLAND, 3 Medizinische<br />
Onkologie und H, Cantonal Hospital Graub, Chur, SWITZERLAND, 4 IBCSG,<br />
IBCSG, Berne, SWITZERLAND, 5 Medizinische Onkologie, Luzerner<br />
Kantonsspital, Luzern, SWITZERLAND, 6 Oncology, Hospital Fribourg, Fribourg,<br />
SWITZERLAND, 7 Sakk, SAKK, Berne, SWITZERLAND, 8 Oncology, Oncology<br />
Buelach, Buelach, SWITZERLAND, 9 Oncologia, IOSI Oncology Institute of<br />
Sou<strong>the</strong>rn SwitzerlandOspedale Regionale di Lugano, Sede Italiano, Viganello,<br />
SWITZERLAND, 10 Oncology and Palliative Medecine, Kantonsspital St. Gallen,<br />
St. Gallen, SWITZERLAND<br />
Background: In incurable cancer patients (pts) chemo<strong>the</strong>rapy (CTx) may be used by<br />
oncologists (ONC) to alleviate PRSS. We assessed if E-MOSAIC influences global<br />
quality of life (G-QOL) and patient care.<br />
Methods: In this prospective, cluster (ONC) randomized trial pts with defined PRSS<br />
starting a new line of palliative CTx with expected response rate ≤ 20% completed a<br />
mobile computer-based (E-MOSAIC) assessment (Edmonton Symptom [SYM]<br />
Assessment Scale, ≤3 additional SYM, nutritional intake, body weight, Karnofsky<br />
Score, medications for main PRSS) before 6 consecutive weekly visits. Eligible ONC<br />
Annals of Oncology 23 (Supplement 9): ix462–ix468, <strong>2012</strong><br />
doi:10.1093/annonc/mds411<br />
received (Intervention [IA]) or not (control [CA]) <strong>the</strong> cumulative computer printout<br />
of <strong>the</strong>ir pts results. Primary endpoint (PE) was <strong>the</strong> difference (Δ) between baseline<br />
(BL) and week 6 in G-QOL (EORTC-QLQ-C30, #29&30). Sample size per arm was<br />
84 pts from 20 ONC for 80% power to detect a 10 point Δ, significance level 5%. A<br />
planned interim analysis with 100 pts showed many for <strong>the</strong> PE non-evaluable pts:<br />
sample size was increased to 264 pts. Due to clustering, a mixed effects model<br />
adjusting for BL G-QOL and o<strong>the</strong>r preselected covariates was used. Secondary EP<br />
included SYM Distress (∑ 10 VAS, 0–10), pts-perceived ONC compassion<br />
(∑ 5 VAS, 0–100) and communication, coping, treatment burden and SYM<br />
management by nurse report.<br />
Results: In 8 centers, 84 ONC treated 264 pts (median 66y; overall survival IA 6.3,<br />
CA 5.4 mts) with various tumors. 102 pts (IA: 55; CA: 47) had uninterrupted (> 4/6<br />
visits, same ONC) pat-ONC sequences, required for PE. The between-arm Δ of PE<br />
was 6.8 (p = 0.11) in favor of <strong>the</strong> IA. In a sensitivity analysis with ONC treating ≥2<br />
pts (IA: 50; CA 39 pts) it was 9.0 (p = 0.07). BL G-QOL was <strong>the</strong> most influential<br />
factor (p < 0.01). Intention to treat analysis revealed improvement in SYM Distress<br />
(Δ BL-last study visit: IA -4.9 vs. CA 2.0, p= 0.003), compassion (Δ BL-week 6: IA:<br />
18.9 vs. CA: 4.3), communication, treatment burden and coping in favor of <strong>the</strong> IA.<br />
More pts with high SYM had ONC management.<br />
Conclusion: Our intervention of real-time monitoring of PRSS, delivered to<br />
oncologist, clearly improved SYM distress with a trend to better SYM management,<br />
communication and Qol.Fur<strong>the</strong>r development is warranted.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1424P COMPARISON OF 8GY SINGLE FRACTION RADIOTHERAPY<br />
VERSUS 20GY IN FIVE FRACTIONS OR 30GY IN 10<br />
FRACTIONS FOR THE TREATMENT OF METASTATIC<br />
BONE PAIN<br />
B. El Hawwari, A. Telfah<br />
Department of Hemato- Oncology, King Hussein medical Center, Amman,<br />
JORDAN<br />
Introduction: In 1974 <strong>the</strong> Radiation Therapy Oncology Group (RTOG) initiated a<br />
randomized clinical trial comparing various dose-fractionation schedules in <strong>the</strong><br />
palliation of cancer metastatic to bone. The trial was closed in February of 1980 and<br />
results have been published in 1982, with <strong>the</strong> conclusion that: “low-dose short<br />
schedules are as effective as more aggressive protracted programs. Since that time,<br />
different radio<strong>the</strong>rapy schedules had been employed for palliation of bone metastasis:<br />
40 Gy in 20 fractions, 30 Gy in 10 fractions and single fractions of 8 Gy, 6 Gy or 4<br />
Gy. Several randomized prospective trials and meta-analyses have been reported<br />
showing <strong>the</strong> same results in pain relief when comparing single doses vs protracted<br />
treatments.<br />
Objectives: The aim of this study was to compare <strong>the</strong> most common fractionation<br />
used in oncology to treat bone metastases which are 8Gy single fraction, 20Gy in five<br />
fractions and 30Gy in 10 fractions.<br />
Method: A total dose of 120 patients who is known to have stage VI cancer with<br />
bone metastasis at King Hussein Medical Center between January 2007 and<br />
December 2009, were allocated to receive ei<strong>the</strong>r 8Gy single fraction, 20Gy in five<br />
fractions or 30Gy in 10 fractions for <strong>the</strong> treatment of <strong>the</strong>ir pain. Patient recorded<br />
pain severity and analgesic requirements on questionnaire which was filled by <strong>the</strong><br />
main investigator before treatment, at 2 weeks and at 1,2,3,4,5,6,8,10, and 12 months<br />
after radio<strong>the</strong>rapy. Pain relief was <strong>the</strong> primary endpoint of treatment benefit.<br />
Results: There was no difference in <strong>the</strong> time to first improvement in pain, time to<br />
complete pain relief or in time to first increase in pain at any time up to 12 months<br />
after randomization, nor in <strong>the</strong> class of analgesic used. Retreatment was twice as<br />
common after 8Gy than after multifraction radio<strong>the</strong>rapy, although retreatment for<br />
residual or recurrent pain did not reflect a difference between <strong>the</strong> three groups in <strong>the</strong><br />
probability of pain relief.<br />
Conclusion: A single fraction of 8 Gy when used for <strong>the</strong> treatment of bone<br />
metastasis is as safe and effective as a multifraction regimen for <strong>the</strong> palliation of<br />
metastatic bone pain for at least 12 months. This may make it suitable alternative to<br />
<strong>the</strong> multifraction radio<strong>the</strong>rapy regimens. Keywords: Bone metastases; Radio<strong>the</strong>rapy;<br />
Pain relief; Palliation<br />
Disclosure: All authors have declared no conflicts of interest.<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
Annals of Oncology<br />
1425P PAIN MANAGEMENT IN EIGHT ITALIAN ONCOLOGICAL<br />
CARE CENTRES<br />
S. Barni 1 , K.F. Borgonovo 1 , F. Di Costanzo 2 , F. Cognetti 3 , G. Bernardo 4 ,<br />
C. Boni 5 , B. Agostara 6 , P. Pronzato 7 , G. Colucci 8 , M. Mammucari 9<br />
1 Medical Oncology Division, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio,<br />
ITALY, 2 Medical Oncology Unit, Azienda Ospedaliero Universitaria Careggi,<br />
Firenze, ITALY, 3 Division Medical Oncology A, Istituto Regina Elena, Roma, ITALY,<br />
4 Oncologia Medica 2, Fondazione S. Maugeri IRCCS, Pavia, ITALY, 5 Oncology<br />
Dept., Arcispedale S. Maria NuovaDivisione di Oncologia, Reggio Emilia, ITALY,<br />
6 Oncology Division, A.O. Civico Palermo, Palermo, ITALY, 7 Oncologia Medica A,<br />
IRCCS AOU San Martino - IST-Istituto Nazionale per la Ricerca sul Cancro,<br />
Genova, ITALY, 8 Oncology Division, Istituto Tumori Ospedale Oncologico, Bari,<br />
ITALY, 9 RMF, RMF, Roma, ITALY<br />
Introduction: Management of oncologic patients is different between treating<br />
centers, and in particular management of pain. We decided to perform a<br />
retrospective study to explore different approaches to oncological painful patients<br />
(pts) in different Italian Cancer Units.<br />
Materials and methods: We evaluated in 8 Italian cancer hospitals all consecutive<br />
pts during 5 days in order to investigate level of pain in <strong>the</strong> previous 7 days and in<br />
<strong>the</strong> following two weeks from <strong>the</strong> basal visit. Patients and oncologists filled up a<br />
questionnaire (type of pain, intensity, site of pain, and analgesic <strong>the</strong>rapy).<br />
Results: 265 pts were enrolled, 59% female and 41% male; median age 61.5. 88% of<br />
pts had ECOG PS 0-1; 72.8% of pts reported metastatic disease and 86.4% were<br />
under chemo<strong>the</strong>rapy treatment. Pain measured with VAS (Visual Analogic Scale) at<br />
baseline was 2.9. Pain was somatic in 32.4%, visceral in 12.5% visceral, 13.9%<br />
neuropathic, 41.2% mixed. The current analgesic <strong>the</strong>rapy at baseline had been<br />
prescribed by oncologist in 38.2%, by o<strong>the</strong>r specialist in 42.1%, by family doctor in<br />
18.5% and by o<strong>the</strong>r doctor in 1.1%. The basal analgesic treatment was confirmed in<br />
57.3%, adjusted in 34%, and changed in 8.6%. At baseline we detected NSAIDS in<br />
69.4% pts, weak opioids in 34% of pts; strong opioids in 38.9%, and 27.7% of pts also<br />
had adjuvants (24.5% pregabalin, 57.1% steroids, 18.4% o<strong>the</strong>r drugs). At first weekly<br />
follow-up (216 pts) <strong>the</strong> intensity of pain was 2.6 (VAS). The analgesic <strong>the</strong>rapy was<br />
confirmed in 72.2% and adjusted in 27.8%. New drugs prescribed at first follow-up<br />
were NSAIDS in 43.3%, weak opioids in 21.7%, strong opioids in 86.7%, adjuvants in<br />
55%. At second weekly follow-up (131 pts): 80.9% of <strong>the</strong>rapies were confirmed and<br />
19.1% adjusted. 90.3% <strong>the</strong>rapies of 72 pts coming to third follow-up were confirmed.<br />
In 85.7% of <strong>the</strong> adjusted <strong>the</strong>rapies an adjuvant was prescribed.<br />
Conclusions: Our data suggest two important comments. First, we observed a poor<br />
utilization of adjuvants by physicians in oncologic patients, especially when <strong>the</strong>rapies<br />
are not prescribed by oncologists. Second, our data confirmed <strong>the</strong> need for a close<br />
follow-up to improve analgesic <strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1426P PAIN PALLIATION OF BONE METASTASES USING<br />
MAGNETIC RESONANCE GUIDED FOCUSED ULTRASOUND -<br />
MULTI-CENTER MULTI-TRIAL RESULTS<br />
R. Catane 1 , D. Gianfelice 2 , M. Kawasaki 3 , D. Iozeffi 4 , S. Kanyev 5 , A. Napoli 6 ,<br />
P. Ghanouni 7 ,G.Lo 8 , Y. Inbar 9 , L. Shay Levi 10<br />
1 Division of Oncology, Chaim Sheba Medical Center, Ramat Gan, ISRAEL,<br />
2 Vascular/interventional Radiology, University Health Network, Toronto, CANADA,<br />
3 Orthopaedic Surgery, Kochi Medical School, Kochi, JAPAN, 4 Radiology, Rostov<br />
State Scientific Research Institute of Oncology, Rostov-on-Don, RUSSIAN<br />
FEDERATION, 5 Radiology, N.N. Petrov Institute of Oncology, Saint Petersburg,<br />
RUSSIAN FEDERATION, 6 Radiology, Sapienza University of Rome, Rome, ITALY,<br />
7 Radiology, Stanford University, Stanford, CA, UNITED STATES OF AMERICA,<br />
8 Radiology, Hong Kong Sanatorium & Hospital, Happy Valley, HONG KONG,<br />
9 Radiology, Chaim Sheba Medical Center, Ramat Gan, ISRAEL, 10 Application,<br />
InSightec, Tirat Carmel, ISRAEL<br />
Introduction: Magnetic Resonance guided Focused Ultrasound (MRgFUS) is a<br />
non-invasive, non-ionizing treatment for <strong>the</strong>rmal ablation of tumors. The technology<br />
uses high intensity focused ultrasound ablation combined with continuous MR<br />
imaging to denervate pain. Precise targeting of <strong>the</strong> lesion and real time monitoring<br />
of tissue temperature rise are cornerstones of <strong>the</strong> technique. We present here results<br />
of multiple multi-center studies evaluating <strong>the</strong> safety and effectiveness of MRgFUS<br />
for painful bone metastases.<br />
Methods: 93 patients with painful bone metastases underwent MRgFUS in 14<br />
medical centers worldwide. Treated lesions had to be remote from nervous structures<br />
or joints. Effectiveness of pain palliation was evaluated with a standardized 11-point<br />
pain rating scale (0-no pain/10-worst pain) and by monitoring changes in<br />
pain-relieving medication. A reduction of 2 points or more was considered a<br />
significant response. Safety events were recorded and evaluated by severity. Results of<br />
31 patients treated in initial safety studies were previously reported by Liberman et al<br />
(Ann Surg Oncol. 2009 Jan; 16(1):140-6).<br />
Results: 107 procedures were performed, targeting 96 lesions in 93 patients. 3<br />
patients were treated twice targeting a different lesion; ano<strong>the</strong>r 11 patients underwent<br />
a second treatment due to large lesions. Patients were followed-up for a period of 3<br />
months. Pain response was relatively rapid: within 3 days, on average, <strong>the</strong> clinical<br />
endpoint was met and maintained. Pain scores averaged 6.9 pre-treatment, decreased<br />
to 4.5 within 3 days post-treatment, to 3.3 at one month post-treatment, and fur<strong>the</strong>r<br />
decreased to 2.6 at three month follow-up. There were no serious adverse events<br />
related to <strong>the</strong> treatment. 2 patients had mild skin ery<strong>the</strong>ma following <strong>the</strong> treatment<br />
and 5 patients (5%) had pain progression. Our updated results are similar to early<br />
reports.<br />
Conclusions: The presented results clearly show that MRgFUS can provide a quick,<br />
effective and safe palliative <strong>the</strong>rapy for patients suffering from painful bone<br />
metastases. Current results are consistent with initial reported results. Randomized<br />
trials are being conducted in patients as a first line treatment of painful bone<br />
metastases vs. radiation <strong>the</strong>rapy and in patients who failed radiation <strong>the</strong>rapy vs.<br />
sham.<br />
Disclosure: L. Shay Levi: I work in InSightec as <strong>the</strong> global bone applications<br />
specialist. InSightec is <strong>the</strong> company sponsered <strong>the</strong>se clinical trials.All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
1427P CURCUMA LONGA EXTRACT IS EFFECTIVE IN IMPROVING<br />
INFLAMMATORY STATUS AND REDOX BALANCE IN<br />
PATIENTS WITH CANCER-RELATED CACHEXIA AND<br />
OXIDATIVE STRESS<br />
G. Mantovani 1 , C. Madeddu 1 , F. Panzone 1 , M.C. Cau 1 , G. Antoni 1 ,F.Leo 1 ,<br />
A. Maccio’ 1 , R. Serpe 2<br />
1 Department of Medical Oncology, University of Cagliari, Cagliari, ITALY, 2 Parco<br />
Scientifico e Tecnologico della Sardegna, Nutrisearch SRL, Cagliari, ITALY<br />
Background: Curcumin (diferuloylmethane) is <strong>the</strong> biologically active compound of<br />
Turmeric (Curcuma Longa) and has long been used in traditional Asian medicine to<br />
treat diseases ranging from heartburn to arthritis: it is thought to have antioxidant<br />
and antinflammatory properties.<br />
Aim: To assess <strong>the</strong> antioxidant and antinflammatory properties of a curcumin extract<br />
in advanced cachectic cancer patients.<br />
Methods: From September 2011 to March <strong>2012</strong>, 15 cachectic patients (M 7/F 8; age<br />
range 55–85 y) with cancer at different sites were enrolled, all stage IV. Twenty-one<br />
age/sex matched healthy controls were studied. All enrolled patients had<br />
inflammation and oxidative stress (high blood levels of proinflammatory cytokine<br />
Interleukin-6 (IL-6), high levels of blood C-reactive protein (CRP), high levels of<br />
ROS, low levels of blood antioxidant enzymes GPx and SOD and low levels of total<br />
blood antioxidant status, TAS, compared to controls. Patients were administered 4<br />
tablets (2 g/day, equivalent to 400 mg/day of active curcuminoids extract, Meriva,<br />
Indena, Milan, Italy). Treatment duration was 4 weeks.<br />
Results: A significant reduction of ROS levels ( 510 ± 120 vs 390 ± 186 Fort U)<br />
and a significant improvement of circulating levels of GPx (5630 ± 1189 vs 6590 ±<br />
2390 U/l) as well as a significant improvement of TAS (0.61 ± 0.23 vs 0.69 ± 0.4<br />
mmol Trolox eq.) was observed after treatment. The inflammatory marker CRP<br />
decreased significantly (38.12 ± 28.4 vs 20.24 ± 17.37 mg/dl), no significant decrease<br />
of serum IL-6 (25.58 ± 23.67 vs. 19.9 ± 16.8) was observed. No patient was withdrawn<br />
from <strong>the</strong> study and <strong>the</strong> treatment was safe and well tolerated.<br />
Conclusions: Curcumin extract added to <strong>the</strong> normal diet was able to significantly<br />
improve inflammatory status and counteract key parameters of oxidative stress, such<br />
as ROS, GPx and TAS. Curcumin antinflammatory-antioxidant activity could be<br />
useful in a multi-targeted combined pharmaco-nutritional approach to treat<br />
cancer-cachexia. Dr. Roberto Serpe was supported by grant CRP1_296 from <strong>the</strong><br />
Regione Autonoma della Sardegna by PO Sardegna FSE 2007-2013 (L.R.7/2007)<br />
titled”Promotion of scientific and technological research in Sardinia”, Italy<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1428P APPLICATION OF KM-CART (ADVANCED CELL-FREE AND<br />
CONCENTRATED ASCITES REINFUSION THERAPY)<br />
TREATMENT TO PATIENTS WITH CANCEROUS ASCITES<br />
K. Matsusaki, K. Ohta, A. Yoshizawa, S. Goto<br />
Ascites Treatment Center, Japanese CART Study Group, Tokyo, JAPAN<br />
Purpose: The purpose of our study was to demonstrate <strong>the</strong> utility of KM-CART<br />
<strong>the</strong>rapy in <strong>the</strong> care of patients with refractory ascites. We also report one colon<br />
cancer case treated with a dendritic cell vaccine that was prepared utilizing <strong>the</strong> high<br />
yield number of autologous carcinoma cells collected in KM-CART processing.<br />
Patients with refractory ascites can suffer severe bloating and/or respiratory<br />
discomfort disrupting both <strong>the</strong>ir activities of daily living (ADL) and terminating<br />
<strong>the</strong>ir anticancer <strong>the</strong>rapy. We developed a novel KM-CART system for cancerous<br />
ascites using original CART system approved by <strong>the</strong> Ministry of Health, Labor and<br />
Welfare. KM-CART consists of ex vivo double filtration processing of autologous<br />
ascites fluid to prepare: (1) a protein (albumin and globulins) concentrate fraction<br />
suitable for intravenous fluid <strong>the</strong>rapy back to <strong>the</strong> donor patient intravenously, and<br />
(2) a cell concentrate suitable for research for anticancer drug sensitivity and<br />
immuno<strong>the</strong>rapy.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds411 | ix463
Method and results: A total of 317 cancerous ascites cases with diverse tumor<br />
origins were treated with KM-CART during 2009 to <strong>2012</strong>. The volume of ascites<br />
extracted ranged between 2 to 15 L with an average of 5.9 L. The average KM-CART<br />
processing time was 51 minutes to produce a protein concentrate volume of 80 to<br />
2,000 ml with a total protein concentration range of 8.0 - 21.0 g/dl. The protein<br />
concentrates were administered intravenously with an average infusion volume of<br />
630ml. In all <strong>the</strong> cases, patients had an immediate benefit of KM-CART treatment<br />
including relief of discomfort of abdomen distension, malaise, respiratory distress<br />
and improved resumption of ADL. A total of 3.5L protein concentrates including<br />
611g of albumin and globulin was re-infused into one 37 year old female patient<br />
with colon cancer over 3 periods of KM-CART treatment. Dendritic cell vaccine was<br />
prepared using total of 1.4x108 cancer cells which were collected from hollow fiber<br />
membrane filters.<br />
Conclusion: KM-CART treated patients were observed to reliably respond to<br />
treatment. It is concluded that processing a large quantity of ascites fluid using <strong>the</strong><br />
KM-CART system offers a safe and effective means to enhance refractory ascites<br />
patient care.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1429P ASSESSMENT OF QUALITY OF LIFE OF PATIENTS WITH<br />
CERVICAL CANCER DURING AND AFTER TREATMENT WITH<br />
RADIOTHERAPY IN INSTITUTO DE MEDICINA INTEGRAL<br />
PROFESSOR FERNANDO FIGUEIRA, RECIFE, BRAZIL<br />
A.A. Santos, C. Lima Santos, J.F.P. Moura, A.I. Souza<br />
Medical Oncology, IMIP, Recife, BRAZIL<br />
Introduction: Cervical cancer is <strong>the</strong> 2nd most frequent neoplasm among women in<br />
Brazil. Radio<strong>the</strong>rapy is one of <strong>the</strong> modalities used in <strong>the</strong> treatment of cervical cancer<br />
and may cause adverse events that compromise quality of life. The purpose of this<br />
study was assess quality of life in women with cervical cancer before, during <strong>the</strong> last<br />
week and six months after radio<strong>the</strong>rapy at a hospital in Nor<strong>the</strong>ast, Brazil.<br />
Method: We performed an exploratory, before and after longitudinal study, with 35<br />
women with cervical cancer treated with adjuvant radio<strong>the</strong>rapy, exclusively or<br />
concurrently with chemo<strong>the</strong>rapy in Instituto de Medicina Integral Prof. Fernando<br />
Figueira (IMIP) between August <strong>2012</strong> and May <strong>2012</strong>. The patients underwent three<br />
interviews (pre-treatment, last week and six months after treatment). To assess <strong>the</strong><br />
quality of life it was used FACT-Cx score (Functional Assessment of Cancer<br />
Therapy-Cervix). The mean scores were compared using Student’s t and ANOVA<br />
test, with significance level of 5%.<br />
Results: The mean age was 50 (± 13.9) years. Most were single or widowed (58.8%)<br />
and only 2.9% were employed. About 75% attended just until elementary school. The<br />
FACT-Cx pre-treatment average scores was 110.9 and in <strong>the</strong> last week was 110.8,<br />
with no statistically significant difference (p = 0.966). The results corresponding to<br />
six months after <strong>the</strong>rapy will be presented at <strong>the</strong> Meeting.<br />
Conclusion: The immediate results after radio<strong>the</strong>rapy showed no difference in<br />
quality of life. Analysis after six months may be different. These findings may modify<br />
<strong>the</strong>rapeutic decision.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1430P OPTIMAL CUT-POINTS FOR QLQ-C30 SCALES ASSOCIATED<br />
WITH OVERALL SURVIVAL IN PATIENTS WITH ADVANCED<br />
HEPATOCELLULAR CARCINOMA (AHCC): A COMPARISON<br />
OF TWO METHODS<br />
M. Diouf 1 , F. Bonnetain 2 , J. Barbare 1 , O. Bouché 3 , J. Meynier 1 , L. Dahan 4 ,<br />
X. Paoletti 5 , T. Filleron 6<br />
1 Clinical Research, Amiens University Hospital, Amiens, FRANCE, 2 Biostatistic<br />
and Epidemiological Unit(EA 4184), Centre Georges François Leclerc, Dijon,<br />
FRANCE, 3 Hepatology-Gastroenterology, Hopital Robert Debré, Reims,<br />
FRANCE, 4 Service d’Hépato-Gastroentérologie et Oncologie Digestive, AP-HM,<br />
Marseille, FRANCE, 5 Service de Biostatistique, Institut Curie, Paris, FRANCE,<br />
6 Biostatistics, Institut Claudius Regaud, Toulouse, FRANCE<br />
Introduction: Health-related quality of life (QoL) has been validated as prognostic<br />
factor for patients with aHCC. However, to be used in routine practice, QoL should<br />
be dichotomized. Usually, cut-points were based on arbitrary percentile value. The<br />
main objective of this study was to identify optimal cut-offs for 5 scales: global health<br />
(GH), physical functioning (PF), role functioning (RF), fatigue (FA) and diarrhea<br />
(DIA). Two published methods were used to compare distributions of cut-offs and<br />
<strong>the</strong>ir risk-ratio. We finally evaluated <strong>the</strong> improvement of existing prognostic<br />
classifications (PC) by dichotomized QoL.<br />
Patients and methods: 271 patients with aHCC were included in CHOC trial. QoL<br />
was assessed in <strong>the</strong> 2 weeks prior to randomization with <strong>the</strong> EORTC QLQ-C30.<br />
Identification of optimal cut-points was based on two univariate methods proposed<br />
by Mazumdar and Farragi respectively. Mazumdar method was based on <strong>the</strong><br />
« minimum p-value » approach. Adjustment of type I error were based on Altman<br />
formula. For Farragi method, <strong>the</strong> total sample was divided into two sub-samples:<br />
Annals of Oncology<br />
learning and validation. A cut-point was derived for each sub-sample using<br />
« minimal p-value » and each patient was classified according to <strong>the</strong> cut-point for<br />
<strong>the</strong> sub-sample to which it does not belong. The final cut-point was <strong>the</strong> one that<br />
minimize <strong>the</strong> p-value in <strong>the</strong> total sample. Stability of <strong>the</strong> results was evaluated using<br />
boostrap procedure (n = 500). Improvement of PC was studied with multivariate Cox<br />
model, QoL being dichotomized at its optimal cut-point.<br />
Results: QoL was available in 234 patients (86%). For RF, <strong>the</strong> most frequent<br />
cut-point was 30 with <strong>the</strong> two methods (Mazumdar: 496/500 – Farragi: 500/500).<br />
Univariate HR (95%CI) were 2.99 [1.62 – 5.52] and 2.80 [2.58 – 3.04] respectively<br />
for Mazumdar and Farragi. In Farragi method, <strong>the</strong> 2 sub-samples found <strong>the</strong> same<br />
cut-offs in 486/500B. The recommended cut-points were respectively 45, 50, 30, 30<br />
and 5 for GH, PF, FA, RF and DIA. Compared to CLIP + WHO PS, CLIP + QoL +<br />
clinical factors rose <strong>the</strong> C-index from 0.65 [0.62 – 0.69] to 0.70 [0.66 – 0.74].<br />
Conclusion: The stability of <strong>the</strong> cut-points was good and precision of CI acceptable<br />
for both methods, but better for Farragi. Interestingly, this categorization of QoL<br />
increased <strong>the</strong> performance of all PC and should be considered as competing factor to<br />
WHO performance status.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1431P REVIEW OF PATIENT DEATHS OCCURRING OFF THE END<br />
OF LIFE PATHWAY: A UK ONCOLOGY CENTRES’<br />
EXPERIENCE<br />
C.L. Mitchell, T. Colby, R. Berman<br />
Medical Oncology, The Christie NHS Foundation Trust, Manchester, UNITED<br />
KINGDOM<br />
Background: Within <strong>the</strong> UK national audits have been performed to assess <strong>the</strong> care<br />
of <strong>the</strong> dying within <strong>the</strong> NHS and those receiving systemic cancer <strong>the</strong>rapies. The<br />
National Confidential Enquiry into Patient Outcome and Death (NCEPOD) report<br />
looked at aspects of end of life care in cancer patients in relation to <strong>the</strong><br />
appropriateness of <strong>the</strong> decisions taken and <strong>the</strong> level of seniority at which clinical<br />
decisions were made. We performed an audit to assess patient deaths which did not<br />
occur on <strong>the</strong> end of life pathway (EoLP); specifically <strong>the</strong> input from senior clinicians<br />
in decision making and <strong>the</strong> appropriateness of ongoing interventions.<br />
Methods: All in-patient deaths within our centre for <strong>the</strong> 6 month period of April<br />
2010 until September 2010 were identified. Patients whose death occurred whilst on<br />
<strong>the</strong> EoLP were identified and excluded from <strong>the</strong> analysis. A retrospective case note<br />
review was <strong>the</strong>n performed for <strong>the</strong> remaining patients.<br />
Results: In <strong>the</strong> six month period 82 patient deaths occurred, of <strong>the</strong>se 27% (n = 21)<br />
were not on <strong>the</strong> EoLP at <strong>the</strong> time of death. 90% of <strong>the</strong>se patients received at least one<br />
consultant review during <strong>the</strong>ir admission with 58% of <strong>the</strong> patients having a<br />
consultant review within 48hrs of death. At <strong>the</strong> time of death 84% of <strong>the</strong> patients<br />
were receiving ongoing medical intervention:<br />
Intervention Patients %<br />
Intravenous antibiotics 27<br />
Intravenous fluids 26<br />
Diuretics 15<br />
Steroids 12<br />
Blood Products 8<br />
Table 1: Medical interventions at time of death 95% of <strong>the</strong> patients had a<br />
documented management plan, with a do not resuscitate order present in 73%. 63%<br />
of patients had input from <strong>the</strong> hospital in-patient palliative care team. On review of<br />
<strong>the</strong> clinical notes 68% of <strong>the</strong> patients fulfilled <strong>the</strong> criteria for <strong>the</strong> EoLP.<br />
Conclusions: The audit highlighted that within our current clinical practice a<br />
proportion of patients continue to receive ongoing medical intervention despite<br />
entering <strong>the</strong> terminal phase of illness, with clinical decisions often being made at a<br />
junior level. Focus on education and training of clinical staff with increased<br />
consultant led input into patient care will be aimed at improving end of life care for<br />
our patient population.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1432P THE IMPACT OF PALLIATIVE CARE ON THE<br />
AGGRESSIVENESS OF END-OF-LIFE CANCER CARE IN<br />
PATIENTS WITH ADVANCED PANCREATIC CANCER<br />
R.W. Jang 1 , M.K. Krzyzanowska 1 , C. Zimmermann 2 , S. Alibhai 3<br />
1 Department of Medical Oncology, Princess Margaret Hospital, Toronto,<br />
CANADA, 2 Department of Psychosocial Oncology and Palliative Care, Princess<br />
Margaret Hospital, Toronto, CANADA, 3 Medicine, University Health Network,<br />
Toronto, CANADA<br />
Background: To improve end-of-life care, quality indicators have been developed to<br />
avoid overly aggressive care in patients with advanced cancer. Advanced pancreatic<br />
cancer is a highly lethal disease with few life-prolonging options. Specialized palliative<br />
ix464 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
care (PC) consultation (defined as a physician consultation focusing on PC needs,<br />
lasting at least 40 minutes) could reduce overly aggressive care in this population.<br />
Purpose: To examine <strong>the</strong> impact of PC consultation on (i) subsequent use of<br />
chemo<strong>the</strong>rapy within 14 days of death; (ii) more than one emergency department<br />
(ED) visit; (iii) more than one hospitalization; and (iv) at least one intensive care<br />
unit (ICU) admission, all within 30 days of death.<br />
Methods: A retrospective population-based cohort study using linked administrative<br />
databases was conducted with patients diagnosed with advanced pancreatic cancer<br />
from Jan 1 2005 to Dec 31 2010. Analysis was limited to those who had received<br />
palliative chemo<strong>the</strong>rapy. Multivariable logistic analyses were performed with <strong>the</strong><br />
above quality indicators as <strong>the</strong> outcomes of interest and PC as <strong>the</strong> main covariate,<br />
adjusting for o<strong>the</strong>r variables (age, sex, rurality, and health region).<br />
Results: Of <strong>the</strong> 6076 patients who had advanced pancreatic cancer, 5381 of <strong>the</strong>se<br />
patients had died at last follow-up, and 1644 of those had received palliative<br />
chemo<strong>the</strong>rapy. In this cohort, 986 (60%) received a palliative care consultation, 218<br />
(13%) received chemo<strong>the</strong>rapy near death, 53 (3%) patients went to <strong>the</strong> ICU near<br />
death, 218 (13%) had multiple ED visits near death, and 213 (13%) had multiple<br />
hospitalizations near death. In multivariable analysis, PC consultation was associated<br />
with decreased use of chemo<strong>the</strong>rapy near death (odds ratio (OR) 0.23; 95%<br />
confidence interval (CI) 0.17-0.32), and lower risk of ICU admission near death (OR<br />
0.19; 95% CI 0.10-0.36), multiple ED visits near death (OR 0.41; 95% CI 0.30-0.55),<br />
and multiple hospitalizations near death (OR 0.37; 95% CI 0.27-0.50).<br />
Conclusions: In patients with advanced pancreatic cancer who are receiving<br />
palliative chemo<strong>the</strong>rapy, PC involvement is associated with less frequent overly<br />
aggressive care. Future analysis will explore <strong>the</strong> effect of timing of PC consultation<br />
(early vs late) on outcomes, and expand <strong>the</strong> cohort to all patients with advanced<br />
disease.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1433P FACTORS ASSOCIATD WITH SURROGATE<br />
DECISION-MAKING IN ADVANCED CANCER PATIENTS:<br />
A LONGITUDINAL STUDY<br />
D. Heo, J.K. Lee, A. An, B. Keam, T. Kim, S. Lee, D. Kim<br />
Internal Medicine, Seoul National University Hospital, Seoul, KOREA<br />
Purpose: Although surrogate decision-making in cancer patients is well-known, few<br />
studies investigating <strong>the</strong> prevalence of surrogate decision-making over time have been<br />
reported. The objectives of this study were to investigate <strong>the</strong> level of surrogate<br />
decision-making in advanced cancer patients over time and <strong>the</strong> impact of<br />
demographic and clinical variables on surrogate decision-making.<br />
Methods: The level of surrogate decision-making was measured in 572 consecutive<br />
cancer patients who died between January 1 and December 31, 2009. We reviewed<br />
8,639 informed consent forms of <strong>the</strong>se patients, calculated <strong>the</strong> proportion of<br />
decisions made by a surrogate (PDS) for each patient, and analyzed <strong>the</strong> association<br />
of PDS with demographic and clinical variables.<br />
Results: Surrogates completed 40.3% of all consent forms. The prevalence of<br />
surrogate decision-making was higher in <strong>the</strong> end-of-life period (death 365 days). Surrogates signed consent forms more frequently for<br />
do-not-resuscitate directives, intensive care unit admission, emergency hemodialysis,<br />
surgery and invasive interventions compared with chemo<strong>the</strong>rapy, radio<strong>the</strong>rapy, and<br />
diagnostic tests (OR = 3.88, P < 0.001). Patients of older age (P = 0.036) and those<br />
with a shorter duration of management (P < 0.001) were independently associated<br />
with greater PDS.<br />
Conclusions: Surrogate decision-making was frequently observed among Korean<br />
cancer patients in this study, especially when <strong>the</strong> patient’s death was imminent, and<br />
for decisions related to end-of-life care. Surrogates were also frequently involved in<br />
decisions for elderly or rapidly deteriorating patients. Healthcare professionals should<br />
consider <strong>the</strong> significant role of familial surrogates in <strong>the</strong> end-of-life period;<br />
comprehensive approaches are needed to preserve <strong>the</strong> best interest of <strong>the</strong> patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1434P THE UNDERSTANDING OF TERMINAL CANCER AND ITS<br />
RELATIONSHIP WITH ATTITUDES TOWARD END-OF-LIFE<br />
CARE ISSUES<br />
J.K. Lee 1 , D.S. Heo 1 , A.R. An 2 , Y.H. Yun 3<br />
1 Internal Medicine, Seoul National University Hospital, Seoul, KOREA, 2 Family<br />
Medicine, Seoul National University Hospital, Seoul, KOREA, 3 Department of<br />
Medicine, Seoul National University, Seoul, KOREA<br />
Objective: To investigate differences in <strong>the</strong> understanding of terminal cancer and<br />
determine <strong>the</strong> relationship between this understanding and attitudes toward<br />
end-of-life issues.<br />
Design: A questionnaire survey was performed between 2008 and 2009.Participants:<br />
A total of 1242 cancer patients, 1289 family caregivers, 303 physicians from 17<br />
university hospitals, and 1006 participants from <strong>the</strong> general population responded<br />
(response rates: 90.1%, 95.1%, 81.0%, and 75.9%, respectively).<br />
Main outcome measures: Individual understanding of terminal cancer and its<br />
relationship with preference for disclosure of terminal prognosis and critical<br />
end-of-life interventions.<br />
Results: A “six-month life expectancy” was <strong>the</strong> most common understanding of<br />
terminal cancer (45.6%), followed by “treatment refractoriness” (21.1%),<br />
“metastatic/recurred disease” (19.4%), “survival of a few days/weeks” (11.4%),<br />
and “locally advanced disease” (2.5%). The combined proportion of “treatment<br />
refractoriness” and “six-month life expectancy” differed significantly between<br />
physicians and <strong>the</strong> o<strong>the</strong>r groups combined (76.0% vs 65.9%, P = 0.0003).<br />
Multivariate analyses showed that patients and caregivers who understood<br />
terminal cancer as “survival of a few days/weeks” showed more negative<br />
attitudes toward disclosure of terminal status compared with participants who<br />
chose “treatment refractoriness” (adjusted odds ratio [aOR] 2.39, 95% CI 1.26<br />
to 4.54 for patients; aOR 2.94, 95% CI 1.58 to 5.47 for caregivers). Caregivers<br />
who understood terminal cancer as “metastatic/recurred” or “six-month<br />
survival” tended to disagree with withdrawing futile life-sustaining treatments<br />
(aOR 2.57, 95% CI 1.39 to 4.75 for “metastatic/recurred,” aOR 1.86, 95% CI<br />
1.06 to 3.28 for “six-month survival”) and active pain control (aOR 2.29, 95%<br />
CI 1.13 to 4.64 for “metastatic/recurred”, aOR 1.86, 95% CI 0.97 to 3.54 for<br />
“six-month survival”), compared with caregivers who selected “treatment<br />
refractoriness.”<br />
Conclusion: The understanding of terminal cancer varies among <strong>the</strong> four participant<br />
groups. It was associated with different preferences regarding end-of-life issues.<br />
Standardizing this terminology is needed to better understand end-of-life care.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1435P THE CHARATERISTICS OF PALLIATIVE CARE IN A RURAL<br />
EUROPEAN REGION<br />
T. Sternfeld 1 , M. Flieser-Hartl 2 , U. Vehling-Kaiser 1<br />
1 Onkologische Schwerpunktpraxis, Onkologisches und Palliativmedizinisches<br />
Netzwerk Landshut, Landshut, GERMANY, 2 Krankenhaus Landshut-achdorf,<br />
Onkologisches und Palliativmedizinisches Netzwerk Landshut, Landshut,<br />
GERMANY<br />
The palliative care unit Landshut is one of <strong>the</strong> few centres accredited by <strong>the</strong> <strong>ESMO</strong><br />
serving in a rural area (Lower Bavaria, Germany). It is part of <strong>the</strong> Network for<br />
Oncology and Palliative Care Medicine Landshut (Onkologisches und<br />
Palliativmedizinisches Netzwerk Landshut) which has been accredited 2010 by <strong>the</strong><br />
<strong>ESMO</strong> as Designated Centre of Integrated Oncology and Palliative Care and <strong>the</strong><br />
DGHO in 2011. The Network aims to improve <strong>the</strong> palliative care service with<br />
regard to <strong>the</strong> special needs of <strong>the</strong> rural cancer population. Data regarding palliative<br />
care of tumor patients in rural areas of Europe are lacking. In December 2010, a<br />
continuous data acquisition for patients on <strong>the</strong> palliative care unit located at <strong>the</strong><br />
Hospital Landshut-Achdorf was started. We now present a cross sectional data<br />
analysis. Between December 2010 and March <strong>2012</strong>, 499 patients were admitted for<br />
<strong>the</strong> first time to <strong>the</strong> palliative care unit. The majority of <strong>the</strong>se patients were living<br />
outside <strong>the</strong> town boundaries, mainly in small villages. 84% of <strong>the</strong> patients were<br />
diagnosed with a solid tumour, 6% with a haematological malignancy, and 10% had<br />
a non-malignant disease. Before <strong>the</strong>ir first admission, 50% of <strong>the</strong> patients were<br />
treated with opioids, 44% of <strong>the</strong> patients had a central venous port system, 4% a<br />
gastric tube, and 10% had received parenteral nutrition. The most frequent<br />
symptoms leading to admission were reduced general health status (43%),<br />
uncontrolled pain (20%), dyspnoea (14%), nausea (8%), confusion (3%), and<br />
insufficient social support (3%). 48% of <strong>the</strong> patients died during <strong>the</strong> first admission.<br />
The mean time of hospitalization was 11 ± 7 days. After discharge from hospital,<br />
37% were cared for by <strong>the</strong>mselves or family members, 23% were visited by a<br />
community nurse or o<strong>the</strong>r nursing services, 19% were cared for by <strong>the</strong> outpatient<br />
palliative care program, 14% were admitted to a nursing home, 4% were transferred<br />
to ano<strong>the</strong>r ward, and 3% to <strong>the</strong> hospice which had opened as recently as January<br />
<strong>2012</strong>. Detailed data of <strong>the</strong> hospitalized palliative patients are presented and fur<strong>the</strong>r<br />
discussed regarding <strong>the</strong> special needs of <strong>the</strong> growing rural palliative patient<br />
population.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds411 | ix465
1436P SURVEY ON MODELS OF INTEGRATION OF ONCOLOGY AND<br />
PALLIATIVE CARE (PC) IN ITALIAN ONCOLOGY UNITS <strong>ESMO</strong><br />
DESIGNATED CENTERS<br />
V. Zagonel 1 , C. Mastromauro 2 , M. Ciaparrone 3 , V. Franciosi 4 , L. Verna 5 ,<br />
C. Moro 6 , Z.C. Di Rocco 3 , A.A. Martoni 7 , L. Cavanna 8 , G. Farina 9<br />
1 Italian Association of Medical Oncology, Task Force Continuity of Care, Padova,<br />
ITALY, 2 Italian Association of Medical Oncology, Task Force Continuity of Care,<br />
Venezia, ITALY, 3 Italian Association of Medical Oncology, Task Force Continuity<br />
of Care, Roma, ITALY, 4 Italian Association of Medical Oncology, Task Force<br />
Continuity of Care, Parma, ITALY, 5 Italian Association of Medical Oncology, Task<br />
Force Continuity of Care, L’Aquila, ITALY, 6 Italian Association of Medical<br />
Oncology, Task Force Continuity of Care, Bergamo, ITALY, 7 Italian Association of<br />
Medical Oncology, Task Force Continuity of Care, Bologna, ITALY, 8 Italian<br />
Association of Medical Oncology, Task Force Continuity of Care, Piacenza,<br />
ITALY, 9 Italian Association of Medical Oncology, Task Force Continuity of Care,<br />
Milano – on behalf of Task Force Continuity of Care in Oncology - Italian<br />
Association of Medical Oncology (AIOM), ITALY<br />
Background: The early integration of cancer treatment and palliative care (PC) is<br />
effective but <strong>the</strong> current state of integration in Italian Cancer Centers is unknown.<br />
Aims: To determine <strong>the</strong> models of integration of PC in Italian Oncology Units<br />
<strong>ESMO</strong> Designated Centers of Integrated Oncology and Palliative Care (<strong>ESMO</strong>-DCs).<br />
Methods: A questionnaire was sended by e-mail to <strong>the</strong> executives of <strong>the</strong> 20 Italian<br />
<strong>ESMO</strong>-DCs.<br />
Results: Twenty questionnaires were sent with a response rate of 100%. The<br />
geographical distribution of <strong>the</strong> <strong>ESMO</strong>-DCs is unbalanced: 12 (60%) in North-Italy,<br />
6 (30%) in <strong>the</strong> Center, 2 (10%) in <strong>the</strong> Islands and none in <strong>the</strong> South. The<br />
<strong>ESMO</strong>-DCs organization is oriented to integration of PC through at least one<br />
oncologist oriented to PC in 18 (90%) Centers; guidelines (LG) of symptomatic<br />
treatment in 18 (90%); PC beds in 14 (70%) and PC offices in 14 (70%). The name<br />
“PC office” is used only in 4/14 (29%) centers; in 10 (71%) Centers alternative names<br />
were chosen. <strong>ESMO</strong>-DCs showed a good integration with Home Care (HC): in 9<br />
(45%) Centers HC is managed by Palliative Care Physicians (PCPs); in 6 (30%) by<br />
General Practitioners (GPs); in 3 (15%) by oncologists and in 2 (10%) by PCPs with<br />
GPs. When HC is not directly managed by oncologists, <strong>the</strong> <strong>ESMO</strong>-DCs achieve <strong>the</strong><br />
integration through home visits in 6/17 (35%), meetings and/or GL sharing with<br />
PCPs and GPs in 11/17 (65%) and 6/17 (35%), respectively. The <strong>ESMO</strong>-DCs showed<br />
a good integration with <strong>the</strong> Hospices (Hs): in 14 (79%) Centers Hs are managed by<br />
PCPs; in 2 (11%) by PCPs with GPs, in 1 (5%) by GPs and in 1(5%) by oncologists.<br />
When Hs are not directly managed by oncologists <strong>the</strong> <strong>ESMO</strong>-DCs achieve <strong>the</strong> integration<br />
through hospice visits in 7/17(41%), meetings and GL sharing with PCPs and GPs in<br />
11/17 (65%) and 7/17 (41%), respectively. The integration model of reference for 15/20<br />
(75%) <strong>ESMO</strong>-DCs is Integrated Care Model (see E.Bruera. JCO 2010).<br />
Conclusions: <strong>ESMO</strong>-DCs are not representative of Italian situation and lack in <strong>the</strong><br />
South of Italy. The Integrated Care model of <strong>ESMO</strong>-DCs is Simultaneous<br />
Care-oriented but its achievement is different by Center. The “<strong>ESMO</strong>-DCs”<br />
experience is challenging for Oncology Units to improve early integration of<br />
palliative care, continuity and quality of assistance of cancer patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1437P HEALTH SERVICE RESEARCH IN INTEGRATIVE ONCOLOGY:<br />
VISCUM ALBUM USE AND NON-PHARMACOTHERAPEUTIC<br />
INTERVENTIONS IN LUNG CANCER PATIENTS<br />
F. Schad 1 , J. Axtner 1 , A. Happe 1 , T. Breitkreuz 2 , J. Gutsch 3 , B. Mat<strong>the</strong>s 4 ,<br />
C. Grah 5 , G. Spahn 6 , H. Mat<strong>the</strong>s 7 , M. Kroez 1<br />
1 Network Oncology, Research Institute Havelhoehe (FIH), Berlin, GERMANY,<br />
2 Internal Medicine / Oncology, Paracelsus-Hospital, Bad Liebenzell, GERMANY,<br />
3 Outpatient oncologist, Gevelsberg, GERMANY, 4 Medical Care Center<br />
Havelhoehe, Outpatient oncologist, Berlin, GERMANY, 5 Pneumology, Hospital<br />
Havelhoehe, Berlin, GERMANY, 6 Center For Integrative Medicine and Cancer<br />
Therapies, Hospital Oeschelbronn, Niefern-Oeschelbronn, GERMANY, 7 Internal<br />
Medicine, Hospital Havelhoehe, Berlin, GERMANY<br />
Background: Viscum album extracts (VA) and non-pharmaco<strong>the</strong>rapeutic<br />
interventions (NPI) are frequently used in integrative oncology (IO). NPIs activate<br />
patients’ resources whereas VA enhances health-related quality of life and reduce<br />
adverse effects caused by conventional <strong>the</strong>rapies. In <strong>the</strong> present study we evaluated<br />
<strong>the</strong> use of VA and NPIs in lung cancer patients from a clinical registry with a special<br />
emphasis on IO.<br />
Methods: We analyzed data of 1177 lung cancer patients collected by <strong>the</strong> Network<br />
Oncology, a conjoint clinical registry of German hospitals and out-patient<br />
oncologists. We used non-parametric χ 2 or Fisher exact test (F) to compare observed<br />
frequencies, Wilcoxon rank sum (W), Kruskal-Wallis test (KW) for differences<br />
between groups. We fitted a logistic regression model to explain use of VA.<br />
Results: 73% of <strong>the</strong> patients got VA and 54% NPI [embrocations, wrappings,<br />
eurythmic <strong>the</strong>rapy, massages, music, drawing, modeling, psychological support or<br />
hyper<strong>the</strong>rmal <strong>the</strong>rapy]. No difference in UICC stage between VA patients and o<strong>the</strong>rs<br />
Annals of Oncology<br />
were seen (pχ 2 = 0.213), but VA patients choose more NPI (medo<strong>the</strong>r= 0, medVA= 2,<br />
pW< 0.001). Women got VA more often (pF< 0.001) and chose in median more NPI<br />
(♂ =0,♀ = 2, pW< 0.001). Median length of VA application was 115.1 weeks. Median<br />
time between first diagnosis and start of VA was 3.94 months and was shorter for<br />
more advanced cancer (pKW< 0.001). Surgery was negatively (βsur= -1.93, psur<<br />
0.001), chemo<strong>the</strong>rapy positively associated with getting VA (βche= 0.96, pche= 0.001;<br />
pNPI< 0.001). Median time between first diagnosis and admission did not differ<br />
between UICC stages (χ 2 = 2.61, df= 3, pKW= 0.455), but its variance decreased with<br />
diagnosis severity (χ 2 = 41.60, df= 3, pFK< 0.001). Conventional <strong>the</strong>rapies showed<br />
lower frequencies after than prior admission to NO facilities (che/ sur/ rad; prior:<br />
49%/ 39%/ 39%, post: 38%/ 24%/ 22%; all p< 0.001).<br />
Conclusions: Results show that VA and NPI are part of standard care of lung cancer<br />
patients in IO settings. Female patients are more open-minded to IO <strong>the</strong>rapies and<br />
use <strong>the</strong>m more often. Our results suggest that health service research data provide a<br />
solid basis for generating hypo<strong>the</strong>sis to conduct warranted prospective studies on<br />
effectiveness in IO.<br />
Disclosure: H. Mat<strong>the</strong>s: PD Dr. med. Harald Mat<strong>the</strong>s is member of <strong>the</strong> board of<br />
directors of <strong>the</strong> Weleda Weleda A.G. Arlesheim/ Switzerland.All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
1438P PROGNOSTIC ROLE OF LIPID PROFILE IN PATIENTS WITH<br />
ADVANCED CANCER<br />
F. Panzone 1 , C. Madeddu 1 , A. Macciò 2 , M.C. Cau 1 , G. Antoni 1 , R. Serpe 1 ,<br />
G. Mantovani 3<br />
1 Oncologia Medica 1, Azienda Ospedaliero Universitaria Cagliari, Monserrato,<br />
ITALY, 2 Department of Obstetrics and Gynecology, Sirai Hospital Carbonia,<br />
Carbonia, ITALY, 3 Presidio Di Monserrato, Azienda Ospedaliero Universitaria<br />
Cagliari, Monserrato, ITALY<br />
Aims: Alterations of lipid metabolism and inflammatory parameters are frequently<br />
observed in cancer patients, especially at advanced stage, and are associated with poor<br />
prognosis; <strong>the</strong> pathogenetic mechanisms are not yet fully known and <strong>the</strong> identification<br />
of effective treatment is still far away. This study aimed to evaluate <strong>the</strong> lipid and<br />
inflammatory profile in cancer patients at diagnosis and to assess <strong>the</strong> correlation with<br />
clinical, nutritional, metabolic/functional and quality of life parameters.<br />
Methods: From June 2011 to March <strong>2012</strong>, 116 patients with a new diagnosis of<br />
cancer (breast, lung, gynecological, gastrointestinal tract) were enrolled. Plasma lipids<br />
(i.e. total cholesterol, TC; high-density lipoprotein, HDL; low-density lipoprotein<br />
cholesterol, LDL; and triglyceride,TG), indices of inflammation (i.e. erythrocyte<br />
sedimentation rate, C reactive protein [CRP], ferritin and inflammatory cytokines)<br />
and oxidative stress (reactive oxygen species, ROS; and antioxidant enzymes, SOD<br />
and GPx) were analyzed. The laboratory data obtained were correlated with clinical<br />
variables such as sex, age, ECOG PS, Glasgow prognostic score (GPS), quality of life,<br />
site and stage of disease and survival.<br />
Results: Patients with advanced disease had a lower levels of fatty acids than patients<br />
at early stage. Cholesterol levels (TC, HDL and LDL) were positively correlated with<br />
survival and inversely with <strong>the</strong> GPS and stage. TG showed a direct correlation with<br />
stage only in patients with colon cancer. An inverse correlation between <strong>the</strong> levels of<br />
TC and <strong>the</strong> parameters of inflammation, in particular CRP ad IL-6, was observed. In<br />
<strong>the</strong> regression analysis IL-6 and CRP were predictors of TC and HDL, respectively.<br />
Albumin, a well known parameter of nutritional status, showed a direct correlation<br />
with HDL cholesterol levels, as in <strong>the</strong> general population.<br />
Conclusion: Our results confirm <strong>the</strong> pathogenic role of chronic inflammation in<br />
inducing changes of lipid metabolism that characterize cancer patients. Lipid profile at<br />
diagnosis was correlated with prognostic factors such as stage of disease, GPS and survival.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1439 CHANGES IN SYMPTOM INTENSITIES AMONG CANCER<br />
PATIENTS RECEIVING OUTPATIENT PALLIATIVE CARE<br />
J.H. Kang 1 , D. Hui 2 , Y. Sriram 3 , J.H. Kwon 3 , E. Bruera 3<br />
1 Internal Medicine, Gyeongsang University Hospital, Jinju, KOREA, 2 Palliative<br />
Care and Rehabilitory Medicine, M.D. Anderson Cancer Center, Houston, TX,<br />
UNITED STATES OF AMERICA, 3 Palliative Care and Rehabilitation Medicine,<br />
M.D. Anderson Cancer Center, Houston, TX, UNITED STATES OF AMERICA<br />
Purpose: Symptom changes are usually reported using summary statistics such as<br />
mean and/or median. The main objective of this retrospective study was to<br />
determine <strong>the</strong> magnitude of symptom changes as assessed by <strong>the</strong> Edmonton<br />
Symptom Assessment System (ESAS) after outpatient palliative care (OPC) at <strong>the</strong><br />
first follow-up visit.<br />
Methods: We reviewed 1612 consecutive patients who were referred to <strong>the</strong> outpatient<br />
Supportive Care Center and who completed <strong>the</strong> ESAS at initial and first follow-up<br />
visits between January 2003 and December 2010. All patients received<br />
interdisciplinary care led by palliative care specialists following an institutional<br />
protocol.<br />
ix466 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Results: The distribution of <strong>the</strong> magnitude of symptom changes was stratified by<br />
baseline intensities. Patterns were similar for different ESAS items. At <strong>the</strong> follow-up<br />
visit, 52% to 74% of patients achieved symptom improvement by >= 1 point.<br />
However, 48% to 80% of patients with moderate/severe intensity at baseline<br />
complained of symptoms with ESAS score >= 4 after OPC. Symptoms with absent/<br />
mild intensity worsened ranging from mean of -3.04 to 0.12 at <strong>the</strong> first follow-up<br />
visit, whereas symptoms with moderate/severe intensity improved from -0.2 to 3.86<br />
(p < 0.001).<br />
Conclusion: Considerable patients with moderate or severe intensity at <strong>the</strong> baseline<br />
still had symptoms with ESAS score >= 4. Patients with absent/mild intensities at<br />
baseline complained of symptom exacerbation at <strong>the</strong> first follow-up visit. Various<br />
strategies are needed to optimize symptom control in advanced cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1440 HOW TO IMPROVE THE PAIN MEASUREMENT IN<br />
ONCOLOGICAL DAY HOSPITAL (DH) PATIENTS<br />
M. Cabiddu 1 , K.F. Borgonovo 2 , M. Ghilardi 3 , M. Cremonesi 1 , F. Petrelli 4 ,<br />
F. Maspero 1 , S. Barni 1<br />
1 Medical Oncology Division, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio,<br />
ITALY, 2 Medical Oncology Division, A.O. Treviglio-Caravaggio, Treviglio, ITALY,<br />
3 Medical Oncology Division, A.O. Trevilgio-Caravaggio, Treviglio, ITALY, 4 Uo<br />
Oncologia, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio, ITALY<br />
Introduction: Quite all cancer patients experience pain. The Pain Visual Analogic<br />
Scale (VAS) is a useful tool for pain evaluation in every kind of patient,<br />
independently of his level of schooling and compliance. Patients are often reluctant<br />
to communicate <strong>the</strong> pain <strong>the</strong>y feel to oncologist. In 2011 we conducted a survey in<br />
our Day Hospital about discrepancies between <strong>the</strong> pain score measured by an<br />
oncologist and a nurse using VAS. We explored <strong>the</strong> possible reasons and tried to<br />
overcame this problem.<br />
Materials and methods: From January 2010 to February 2011 we evaluated 1546<br />
DH admissions in 154 patients. Pain was measured by both an oncologist and a<br />
nurse, using VAS. The discrepancies were defined by at least 2 points of difference on<br />
<strong>the</strong> VAS score. On May 2011 we explored <strong>the</strong> possible reasons of discrepancy and we<br />
organized internal meetings with all oncological staff involved in <strong>the</strong> pain evaluation<br />
to examine this problem. From July to December 2011 we performed a new<br />
evaluation of discrepancies between VAS score measured by oncologist and nurse in<br />
194 patients for a total of 979 DH admission.<br />
Results: The characteristics of <strong>the</strong> two samples of patients were similar; <strong>the</strong> staff<br />
involved was <strong>the</strong> some too. In <strong>the</strong> first survey 43,2% of discrepancies were observed:<br />
in 9.4% of admissions <strong>the</strong> VAS score recorded by <strong>the</strong> oncologist was greater than that<br />
registered by <strong>the</strong> nurse; in 33.8% of admissions <strong>the</strong> opposite was noted. Overall <strong>the</strong><br />
concordance between VAS score oncologist/nurse was of 56,8%. In <strong>the</strong> second survey<br />
<strong>the</strong> global discrepancies were only 18,6%, with 9% and 9,6% of discrepancies<br />
between <strong>the</strong> two measurements, with VAS score greater in nurse and oncologist<br />
evaluation, respectively.<br />
Conclusion: Our results appeared to confirm <strong>the</strong> reluctance of patients to reveal<br />
<strong>the</strong>ir pain, especially to <strong>the</strong> oncologist. Sometimes <strong>the</strong> oncologists are more focused<br />
on cancer treatment than on supportive care, and <strong>the</strong> pain measurement is<br />
performed so fast that <strong>the</strong> patient is brought to minimize <strong>the</strong> real entity of pain.<br />
Team training is useful to improve patient’s care and patient’s management in an<br />
oncological staff.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1441 PAIN INTENSITY, PATIENT SATISFACTION AND PHYSICIAN’S<br />
PRESCRIPTION OF OUTPATIENTS WITH CANCER: A KOREA,<br />
REGIONAL CANCER CENTER SURVEY<br />
H. Shim, D.E. Kim, J.E. Hwang, W.K. Bae, I.J. Chung, S. Cho<br />
Department of Internal Medicine, Chonnam National University Medical School,<br />
Gwangju, KOREA<br />
Background: Pain is <strong>the</strong> one of most common and debiliating symptoms of patients<br />
(pts) with cancer. It is known that more than 50-70% of pts with cancer experience<br />
pain. The purpose of this study is to assess <strong>the</strong> prevalence of pain, analgesic use and<br />
satisfaction for cancer pain treatment of outpatients.<br />
Methods: Between July and August 2010, we enrolled pts who were taking analgesics<br />
with cancer in outpatients setting. The pts were asked to complete <strong>the</strong><br />
self-administered questionnaire to assess <strong>the</strong>ir pain intensities and o<strong>the</strong>r symptoms<br />
in terms of <strong>the</strong>ir experience during <strong>the</strong> preceding 24 hours.<br />
Results: A total of 111 outpatients completed a questionnaire with characteristics,<br />
intensity of pain and o<strong>the</strong>r related symptoms. The median age of pts was 61 years, and<br />
69.9% were men. Only 8 pts (7%) reported no suffering from pain at <strong>the</strong> time of <strong>the</strong><br />
interview. Approximately, 74 pts (67%) had mild pain, 25 (22%) had moderate pain and<br />
4 (4%) had severe pain. Fifty-five pts (49.5%) were being treated with strong opioids.<br />
Around 45% of pts (n = 50) were experiencing breakthrough pain one to three times a<br />
day and 6.4% (n = 7) were having breakthrough pain more than four times a day, but<br />
only 37 pts (33%) were prescribed short acting analgesics for breakthrough pain. There<br />
was no change of <strong>the</strong> dose of opioids analgesics for 61% of pts who had moderate or<br />
severe pain even if more analgesics were needed. Pts who were satisfied with <strong>the</strong>ir pain<br />
management was only 48%, 87% of <strong>the</strong>m had mild pain. The remaining 52% were<br />
nei<strong>the</strong>r nor dissatisfied, 92% of which had moderate or severe pain. Around 84% (n = 93)<br />
pts thought <strong>the</strong>y were asked about <strong>the</strong>ir pain, and 79% (n = 88) thought <strong>the</strong>ir physicians<br />
believed in reported pain intensities. About 50% (n = 56) pts reported that adverse effects<br />
of opioids should be anticipated and managed more aggressively. The prevalent<br />
symptoms associated with pain were reported; interference of physical activities (68.5%),<br />
loss of appetite (49%) and sleep disturbance (32%).<br />
Conclusions: Many number of outpatients with cancer still experienc pain and pain<br />
related symptoms. Improvement of cancer pain management is needed in outpatients<br />
setting. It is also important to provide adequate information on analgesics and<br />
adeverse effects as well as to assess <strong>the</strong> intensity of pain and change <strong>the</strong> dose of<br />
opioid according to pain intensities.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1442 SURVIVAL PREDICTION IN AMBULATORY STAGE III/ IV NON<br />
SMALL CELL LUNG CANCER PATIENTS USING THE<br />
PALLIATIVE PERFORMANCE SCALE, ECOG AND LUNG<br />
CANCER SYMPTOM SCALE<br />
R. Mohajer 1 , S. Nathan 2 , K. Wells 2 , N. Kern 2 , M. Batus 3 , M. Fidler 3 , P. Bonomi 3 ,<br />
S. O’Mahony 2<br />
1 Hematology and Oncology, Stroger Hospital of Cook County, Chicago, IL,<br />
UNITED STATES OF AMERICA, 2 Palliative Care, Rush University Medical Center,<br />
Chicago, IL, UNITED STATES OF AMERICA, 3 Hematology and Oncology, Rush<br />
University Medical Center, Chicago, IL, UNITED STATES OF AMERICA<br />
Objectives: Patients with advanced NSCLC have a life expectancy of less than one<br />
year, <strong>the</strong>refore, it is important to maximize <strong>the</strong>ir quality of life and to find a tool that<br />
gives <strong>the</strong> patients more accurate means of survival prediction.<br />
Materials: The Palliative Performance Scale has been designed and used for patients<br />
with far advanced disease for predicting survival probabilities. It has five functional<br />
dimensions: ambulation, activity level and evidence of disease, self-care, oral intake,<br />
and level of consciousness. It is scored in 11 levels from PPS 0 % to PPS 100% in 10<br />
percent increments- PPS 0% represents death and PPS 100% represents fully<br />
ambulatory and healthy status.PPS has been shown to be an effective tool in life<br />
expectancy prognostication in palliative and hospice patients. The value of PPS in<br />
ambulatory cancer patients has not been examined to date.The Lung Cancer<br />
Symptom Scale is a tool designed to measure <strong>the</strong> quality of life of lung cancer<br />
patients. It evaluates six major symptoms associated with lung malignancies and<br />
<strong>the</strong>ir affect on overall symptomatic distress and activity.We evaluated 62 adult<br />
patients with stage III or IV NSCLC in <strong>the</strong> thoracic oncology clinic. All of <strong>the</strong>m had<br />
ECOG 1 or greater at <strong>the</strong> time of baseline evaluation. Symptoms and performance<br />
status were evaluated at baseline for 62 patients, of those 54 patients followed- up<br />
after 4 week using LCCS, PPS and ECOG.<br />
Results and conclusions: 54 patients completed baseline and follow-up measures.<br />
The mean age for patients was 63.7 years. 63% were receiving active chemo<strong>the</strong>rapy at<br />
<strong>the</strong> time of evaluation. Seventeen patients died. Mean (range) baseline measures<br />
score were as follows: LCSS 6.18(1-14); PPS 66.6(40-90) and 1.82(1-4) for <strong>the</strong> ECOG.<br />
Censored survival times were calculated from <strong>the</strong> enrollment of <strong>the</strong> first subject for<br />
380 days. The last subject was recruited 357 days after <strong>the</strong> first subject. A<br />
proportional hazardous model was computed for survival status. Hazards ratios for<br />
death were 1.25(p= 0.013) for LCCS, 2.12(p= 0.027) for <strong>the</strong> ECOG and 1.02 for<br />
PPS (p= 0.49). The LCCS performed best as a predictor of prognosis in this<br />
study. Fur<strong>the</strong>r analysis will include an assessment of association between symptom<br />
clusters and biomarkers. The PPS only functioned well as a predictor of survival time<br />
in patients receiving active treatment for advanced cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1443 A RETROSPECTIVE STUDY OF THE FACTORS TENDED TO<br />
TRANSFER TO PALLIATIVE HOME CARE FROM PALLIATIVE<br />
CARE UNIT AT A COMPREHENSIVE CANCER CENTER IN<br />
JAPAN<br />
T. Miura 1 , Y. Matsumoto 1 , A. Okizaki 2 , M. Oishi 3 , S. Motonaga 2 , Y. Higashi 1 ,<br />
A. Sekimoto 4 , K. Abe 5 , M. Fukui 1 , H. Kinoshita 1<br />
1 Palliative Medicine and Psycho-oncology, National Cancer Center Hospital East,<br />
Kashiwa-shi, Chiba, JAPAN, 2 Pharmacy Division, National Cancer Center<br />
Hospital East, Kashiwa-shi, Chiba, JAPAN, 3 Nutrition Management Office,<br />
National Cancer Center Hospital East, Kashiwa-shi, Chiba, JAPAN,<br />
4 Nursing Department, National Cancer Center Hospital East, Kashiwa-shi,<br />
Chiba, JAPAN, 5 Palliative Care Center, Shimane University Hospital, Izumo-shi,<br />
Shimane, JAPAN<br />
Background: There are significant differences in <strong>the</strong> proportion of home death of<br />
cancer patients, 8.3% in Japan and 27.4% in <strong>the</strong> United Kingdom. However 63% of<br />
Japanese population hope home palliative care in <strong>the</strong>ir last 6 months. The palliative<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds411 | ix467
care unit (PCU) at <strong>the</strong> National Cancer Center Hospital East changed <strong>the</strong><br />
administrative policy to amend patients unmet needs and streng<strong>the</strong>n <strong>the</strong> transition to<br />
palliative home care. Previous studies about <strong>the</strong> discharge from hospice indicated <strong>the</strong><br />
factor of old age, female and poor performance status (PS). This study aimed to<br />
identify <strong>the</strong> factors tended to transfer to palliative home care in Japan.<br />
Methods: We reviewed <strong>the</strong> medical records of 333 consecutive cancer patients<br />
admitted to our PCU during period from October 2010 until September 2011.<br />
Patients transferred to o<strong>the</strong>r hospitals were excluded in this study.We identified<br />
variables associated with <strong>the</strong> discharged group and <strong>the</strong> deceased at PCU group, using<br />
<strong>the</strong> univariate and multivariate analyses.<br />
Results: There were 311 patients (Pts) during periods, 68 Pts (21.9%) discharged to<br />
palliative home care and 243 Pts (78.1%) deceased in our PCU. Characteristics of<br />
discharged group (68 Pts) were below: over 65 year-old (32%), female (53.0%), PS 4<br />
(7.4%), a relatively good amount of oral intake in first hospital day (76.1%),<br />
morphine use over 120mg/day at admission (23.5%), living alone (9.7%), married<br />
(74.6%), primary caregiver was partner (67.7%).Univariate and multivariate analysis<br />
identified: admission from <strong>the</strong>ir own home (OR 4.41; 95%CI 2.08-9.75), a good PS<br />
of > 4 (OR 6.21; 95%CI 2.11-23.18), a heart rate < 100 beats per minute (OR 3.72;<br />
95%CI 1.21-14.22), a good amount of oral intake (OR 1.71; 95%CI 1.26-2.43),<br />
dyspnea (OR 3.14; 95%CI 1.24-8.56), fatigue (OR 4.98; 95%CI 1.35-24.54) and<br />
abdominal distention (OR 11.00; 95%CI 1.94-209.60) as predictions of a transition to<br />
home from our PCU.<br />
Conclusion: Our study indicated <strong>the</strong> factors tended to transfer to palliative home<br />
care from PCU in Japan, however this study had some limitations. A prospective<br />
study is required to validate <strong>the</strong>se factors.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1444 INTEGRATED PALLIATIVE AND MEDICAL ONCOLOGY CARE<br />
FOR PATIENTS WITH SMALL CELL LUNG CANCER<br />
L. Selvarajah 1 , A.M. Sharkar 1 , S. Toner 2 , J. Clince 1 , M. Triggs 1 , N. Coleman 1 ,R.<br />
K. Morgan 2 , R. McQuillan 3 , L. Grogan 1 , O.S. Breathnach 1<br />
1 Medical Oncology, Beaumont Hospital Cancer Centre, Dublin, IRELAND,<br />
2 Pulmonary Medicine, Beaumont Hospital Cancer Centre, Dublin, IRELAND,<br />
3 Palliative Medicine, St. Francis Hospice, Dublin, IRELAND<br />
Introduction: Conventionally, palliative care services have been viewed as a terminal<br />
line of management when primary treatment is unsuccessful. Recent studies have<br />
shown that integration of palliative care medicine with medical oncology care<br />
substantially increases quality of life and survival duration in patients with non-small<br />
cell lung cancer 1 . This study was carried out in <strong>the</strong> Beaumont Hospital Cancer<br />
Centre highlighting <strong>the</strong> patterns of palliative care and medical oncology interventions<br />
in <strong>the</strong> management of patients with small cell lung cancer (SCLC).<br />
Methods: Information from patient records, intranetwork hospital databases,<br />
pathological reports, pharmaceutical entries and clinical notes of all patients<br />
diagnosed with SCLC through <strong>the</strong> Rapid Access Lung Cancer Clinic (RALCC)<br />
between 2008 to 2011 was compiled into a database.<br />
Results: Between 2008 to 2011, 58 patients presented to <strong>the</strong> RALCC and were<br />
diagnosed with small cell lung cancer. From this total amount, 50 patients were<br />
actively managed at our multidisciplinary centre. Of <strong>the</strong> 50 patients, 31 had extensive<br />
disease while 19 had limited disease. The median survival duration for actively<br />
treated patients with limited and extensive disease was 13 (range; 4 – 38) and 5.5<br />
(range; 0.5 – 17) months respectively. 46 (92%) patients received chemo<strong>the</strong>rapy with<br />
<strong>the</strong> most common regimen being Etoposide and Carboplatin combination. The o<strong>the</strong>r<br />
4 (8%) patients did not receive chemo<strong>the</strong>rapy due to various reasons mainly;<br />
patient’s preference, rapid deterioration and low performance status. 40 (80%)<br />
patients of <strong>the</strong> total cohort received palliative care services. The remaining 10 (20%)<br />
patients did not receive palliative treatment as <strong>the</strong> disease was well controlled by<br />
chemo<strong>the</strong>rapeutic interventions. All patients who did not receive medical oncology<br />
services benefitted from palliative care treatments.<br />
Conclusion: This study revealed that almost all patients managed with medical<br />
oncology interventions had palliative care involvement, demonstrating significant<br />
integration between <strong>the</strong> disciplines. 1 Temel et al. Early Palliative Care for Patients<br />
with Metastatic Non–Small-Cell Lung Cancer. N Engl J Med. 2010;363:733-42.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1445 LEVEL OF PALLIATIVE CARE EDUCATION AMONG<br />
ONCOLOGY NURSES IN THE STATE OF QATAR<br />
Annals of Oncology<br />
A.A. Hassan 1 , G.F. Abu Zeinah 2 , S.G. Al-Kindi 2<br />
1 Oncology/Haematology Departement, Al Amal HospitalHamad Medical<br />
Corporation, Doha, QATAR, 2 Medical College, Weill Cornell Medical College in<br />
Qatar, Doha, QATAR<br />
Objectives: Formal Palliative Care (PC) education is lacking in <strong>the</strong> Middle Eastern<br />
state of Qatar. This study was done to assess <strong>the</strong> need for PC education among<br />
oncology nurses in Qatar.<br />
Methods: A self-constructed questionnaire was distributed to 115 nurses at <strong>the</strong> Qatar<br />
National Center for Cancer Care and Research in March <strong>2012</strong>.<br />
Results: One hundred fifteen nurses responded to <strong>the</strong> questionnaire. The majority<br />
(87.8%) were female. While 60% had more than ten years of work experience, only<br />
31% had received formal training in PC with only 6.1% having completed<br />
postgraduate training. The majority of responders (75%) attributed this issue to<br />
unavailability of PC courses ra<strong>the</strong>r than lack of time, interest or financial issues.<br />
Currently, only 16.7% did not express interest in <strong>the</strong> field, with 56% showing some<br />
kind of interest. In terms of knowledge, 54% of responders were familiar with <strong>the</strong><br />
WHO ladder for pain relief. Only 43.6% know about Palliative Performance Scale<br />
and half of all nurses know <strong>the</strong> Edmonton Symptom Assesment System. Overall,<br />
56% of <strong>the</strong> nurses indicated a need for training in more than one aspect. These<br />
aspects included training in care of <strong>the</strong> dying patients (14.6 %), communication<br />
strategies (22%), caregiver support (10.6%), psycho-social care (15%), pain<br />
management (10.2%), o<strong>the</strong>r symptom management (13%) and o<strong>the</strong>r ethical/spiritual<br />
issues (14.2%).<br />
Conclusions: There is a clear deficiency in formal PC education among <strong>the</strong> nurses at<br />
<strong>the</strong> NCCCR in Qatar. This is reflected by <strong>the</strong>ir lack of experience and exposure to<br />
PC, and <strong>the</strong>ir mediocre knowledge in <strong>the</strong> field. This could be attributed to <strong>the</strong> fact<br />
that formal PC service was introduced only recently in Qatar (2008). Formal training<br />
courses in PC nursing are required.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1446 VITAMIN D DEFICIENCY IN TERMINAL CANCER PATIENTS<br />
ADMITTED TO HOSPICE CARE CLINIC IN KOREA<br />
H.J. Shim, S. Cho, D.E. Kim, J.E. Hwang, W.K. Bae, I.J. Chung<br />
Department of Internal Medicine, Chonnam National University Medical School,<br />
Gwangju, KOREA<br />
Background: The prevalence of vitamin D deficiency in patients with terminal<br />
cancer is not well documented. The objective of this report was to describe and<br />
understand vitamin D status in terminal cancer patients.<br />
Methods: A total of 67 consecutive terminal cancer patients who were in <strong>the</strong><br />
Hospice and Palliative Care Clinic at Jeonnam Regional Cancer Center during<br />
Aug 2011 to Mar <strong>2012</strong> were analyzed in this study. We investigated serum levels of<br />
25(OH) vitamin D, calcium, albumin and c-reactive protein. We also evaluated<br />
clinical characteristics, common symptoms including delirium, depression, fatigue<br />
and pain.<br />
Results: The median age of patients was 58 years, and 64.2% were men.<br />
Gastrointestinal (47.8%) cancer, hepatobiliary & pancreatic cancer (26.9%)<br />
and lung (13.4%) cancer were predominant. Sixty patients (89.6%) were vitamin D<br />
deficient (30 ng/mL). The level of vitamin D of 37 patients (55.2%) were less<br />
than 10ng/mL. Low serum vitamin D levels were independent of age, gender,<br />
primary disease site, body mass index, history of chemo<strong>the</strong>rapy and disease duration.<br />
No significant association was found between vitamin D and symptoms such as<br />
delirium, depression, fatigue and pain.<br />
Conclusions: Vitamin D deficiencies were very common and severe in hopice<br />
population. There was no significant association between vitamin D levels and<br />
clinical factors. And also, we could not find a relation between vitamin D levels and<br />
symptoms including delirium, depression, fatigue and pain.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix468 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
prevention and screening<br />
1447PD POTENTIAL RISK OF ASBESTOS EXPOSURE AMONG<br />
JAPANESE GENERAL POPULATION: JAPANESE GENERAL<br />
SCREENING STUDY FOR ASBESTOS-RELATED DISEASES<br />
(JGSARD)<br />
N. Seki 1 , K. Eguchi 1 , M. Kusumoto 2 , M. Kaneko 3 , T. Yamaguchi 4 ,<br />
J. Study Group 1<br />
1 Division of Medical Oncology, Department of Internal Medicine, Teikyo University<br />
School of Medicine, Tokyo, JAPAN, 2 Diagnostic Radiology, National Cancer<br />
Center Hospital, Tokyo, JAPAN, 3 Division of Endoscopy, National Cancer Center<br />
Chuo Hospital, Tokyo, JAPAN, 4 Medical Statistics, Tohoku University Hospital,<br />
Miyagi, JAPAN<br />
Background: Patients with pleural meso<strong>the</strong>lioma and lung cancer associated with<br />
asbestos exposure has been recently increasing in Japan. The aim of this study was to<br />
prospectively evaluate <strong>the</strong> actual situation of asbestos exposure and <strong>the</strong> prevalence of<br />
asbestos-related diseases among Japanese general population.<br />
Materials and methods: From 2006 to 2008, 9810 subjects (mean age, 57 years; 54%<br />
male and 50% smokers) underwent low-dose CT (LDCT) in 26 institutions in Japan.<br />
Then, 6286 (64.1%) subjects underwent subsequent screening after 2 years of<br />
interval. Clinical information such as history of asbestos exposure for all life was<br />
reviewed. Images were interpreted independently by 15 experts.<br />
Results: Self-reported history of occupational exposure was present in 2805 (28.5%)<br />
subjects, whereas self-reported history of residential exposure was present in 1193<br />
(12.2%) subjects although asbestos factory actually existed in 2870 (29.3%) subjects.<br />
Pleural plaque, pleural thickening, and pulmonary nodule were identified in 264<br />
(2.7%), 245 (2.5%), and 1003 (10.2%) subjects on LDCT. However, self-reported<br />
history of asbestos exposure was not confirmed in 77 (29.2%) of 264 subjects with<br />
pleural plaque although asbestos factory actually existed in 65 (84.4%) of such 77<br />
subjects. Pleural plaque on LDCT was significantly correlated with male (odds ratio<br />
OR, 2.32), age over 60 years (OR, 1.75), smoking (OR, 1.60), self-reported history of<br />
asbestos exposure (OR, 3.92), residential period in asbestos factory area (OR every 10<br />
years, 1.13), and asbestos-related work period (7 work identified, OR every 10 years,<br />
1.300-3–3.21). Moreover, lung cancer was identified in 29 (0.3%) subjects, resulting<br />
in significant correlation with age over 60 years (OR, 2.67) and pleural plaque (OR,<br />
4.17). After repeated LDCT screening, among 6286 subjects consisting of 165 and<br />
6121 subjects with and without pleural plaque on LDCT at baseline screening,<br />
respectively, 5 (3.0%) of 165 and 7 (0.1%) of 6121 subjects showed marked<br />
progression and new onset of pleural plaque, respectively. Again, lung cancer was<br />
identified in 8 (0.1%) subjects.<br />
Conclusion: Our results indicate <strong>the</strong> potential risk of asbestos exposure among<br />
Japanese general population and <strong>the</strong> importance of public relations and<br />
enlightenment for especially residential asbestos exposure.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1448PD FIGHTING AGAINST CIGARETTE SMOKING AMONG<br />
MEDICAL STUDENTS- A SUCCESS STORY<br />
F. lcli 1 , D. Caliskan 2 , I. Gonullu 3 , H. Akbulut 1 , A. Ozkan 1 , S. Olmez 4 , U. Gonullu 5 ,<br />
K. Sunguroglu 6<br />
1 Medical Oncology, Ankara University School of Medicine, Ankara, TURKEY,<br />
2 Public Health, Ankara University School of Medicine, Ankara, TURKEY, 3 Medical<br />
Education, Ankara University School of Medicine, Ankara, TURKEY, 4 Psychiatry,<br />
Ankara University School of Medicine, Ankara, TURKEY, 5 Pulmonology, Ankara<br />
University School of Medicine, Ankara, TURKEY, 6 Biochemistry, Ankara<br />
University School of Medicine, Ankara, TURKEY<br />
Physicians are important role models for <strong>the</strong> society regarding common health and<br />
disease prevention. Therefore, being aware of <strong>the</strong> health hazards of cigarette smoking,<br />
Annals of Oncology 23 (Supplement 9): ix469–ix473, <strong>2012</strong><br />
doi:10.1093/annonc/mds412<br />
physicians should not smoke. In <strong>the</strong> year 1997 we surveyed 215 medical students<br />
at Ankara University in Ankara, Turkey to assess <strong>the</strong> smoking rates and factors<br />
<strong>the</strong>y account for smoking. We found that 25.1% of <strong>the</strong> students were smoking<br />
(29.5% of males and 22.6% of females). Moreover, smoking rate was 35% for <strong>the</strong><br />
6th year students (last year before graduation). We were sorry to find out that<br />
60% of <strong>the</strong> smokers started smoking following admittance to medical school.<br />
Our sense of responsibility led us to establish a “Cigarette Fighting Group”<br />
composed of voluntary academic staff, nurses, students, psychologists and a social<br />
worker aimed to lower <strong>the</strong> smoking rate and to eliminate it eventually among<br />
our medical students. Because of <strong>the</strong> difficulties of abandoning smoking, our<br />
main strategy was prevention of starting smoking. Several methods used<br />
including regular monthly meetings and <strong>the</strong>y will be elaborated at <strong>the</strong> <strong>ESMO</strong><br />
presentation. Consequently, our surveys in <strong>the</strong> years 2009 (641 students) and<br />
<strong>2012</strong> (1737 students) showed that total smoking rates dropped to 15% and 11%<br />
respectively (p < 0.00001). Moreover, <strong>the</strong> smoking rate for 6th grade students<br />
dropped from 35% in 2007 to 21.8% and 8.8% in <strong>the</strong> years 2009 and <strong>2012</strong><br />
respectively (p = 0.005). In <strong>2012</strong>, <strong>the</strong> smoking rates of 1st year and 6th year<br />
students were 7.8% and 8.8%, respectively. These close rates of smoking at <strong>the</strong><br />
beginning and <strong>the</strong> end of medical school and <strong>the</strong> significant drop in smoking<br />
rates in 5 years confirms that, our group pursued a realistic and successful<br />
strategy against smoking. Details of <strong>the</strong> surveys will be presented at <strong>ESMO</strong><br />
meeting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1449PD BREAST CANCER DETECTION AMONG IRISH BRCA1 &<br />
BRCA2 MUTATION CARRIERS<br />
E. Walsh 1 , M. Farrell 2 , R. Clarke 3 , C. Nolan 3 , M.J. Kennedy 4 , J.A. McCaffrey 5 ,<br />
E. Connolly 6 , M. Kell 7 , T. Boyle 6 , D. Gallagher 8<br />
1 Oncology Dept, Mater Misericordiae University Hospital University College<br />
Dublin, Dublin, IRELAND, 2 Dept Cancer Genetics, Mater Misercordiae University<br />
Hospital & Mater Private, Dublin 7, IRELAND, 3 Dept Cancer Genetics, St James<br />
Hospital, Dublin 8, IRELAND, 4 Dept Medical Oncology, St James’s Hospital,<br />
Dublin, IRELAND, 5 Medical Oncology, Mater Misericordiae University Hospital,<br />
Dublin, IRELAND, 6 Dept Surgery, St James Hospital, Dublin 8, IRELAND, 7 Dept<br />
Surgery, Mater Misercordiae University Hospital, Dublin 7, IRELAND, 8 Dept<br />
Medical Oncology, Mater Misercordiae University Hospital & Mater Private,<br />
Dublin 7, IRELAND<br />
Background: High-risk breast cancer screening for BRCA1/2 mutations carriers with<br />
clinical breast exam, mammography and MRI have sensitivities approaching 100%.<br />
Even with intensive screening, BRCA mutation carriers can present with self-detected<br />
interval cancers. We investigate breast cancer screening practices and presentation<br />
among a cohort of Irish BRCA1/2 mutation carriers.<br />
Methods: Females with breast cancer belonging to kindreds now known to harbour<br />
BRCA1/2 mutations were retrospectively identified. Records were reviewed for BRCA<br />
mutation, demographics, breast cancer diagnosis, stage, histology and screening. We<br />
assessed screening modalities and whe<strong>the</strong>r breast cancers were diagnosed at screening<br />
or as interval cancers.<br />
Results: 53 cases of breast cancer were diagnosed from 1968 to 2010 among 53 Irish<br />
hereditary breast ovarian cancer kindreds. BRCA mutation status was unknown at<br />
time of diagnosis but subsequently confirmed. Detection method was identified in<br />
50% of patients: 84% by clinical breast exam (CBE), 4% by mammography, 4% by<br />
MRI and 8% by a combination of CBE and mammography. Fifteen women (28%)<br />
developed a second breast cancer; 9 (60%) were undergoing screening, 2 were not<br />
and 27% were unknown. Two cancers (22%) were detected by CBE alone; 34% by<br />
mammography; 22% by a combination of mammography and CBE and 22% by MRI.<br />
In 41%, histology changed between first and second diagnosis. Two women<br />
developed a third breast cancer. In one, <strong>the</strong> second was an interval cancer despite<br />
being in a screening programme. Her third was radiologically detected.<br />
Conclusions: In this cohort of Irish BRCA1/2 mutation carriers almost 25% of<br />
second breast cancers were not detected by screening. 4% of cases were phenocopies<br />
and in 41% histology changed between first and second diagnosis.<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com<br />
abstracts
Characteristic No. %<br />
Total 63<br />
1 st Breast Cancer 53 84<br />
Median Age Range 42 24–73<br />
BRCA1 mutation 25 40<br />
BRCA2 mutation 27 42<br />
Stage<br />
I 14 27<br />
II 25 48<br />
III 4 8<br />
Unknown 9 17<br />
Histology<br />
Ductal 30 57<br />
O<strong>the</strong>r 10 19<br />
Unknown 13 24<br />
2 nd Breast Cancer 15 28<br />
Median Age Range 48 36–71<br />
BRCA1 mutation 5 33<br />
BRCA2 mutation 8 53<br />
Stage<br />
Stage I 8 53<br />
Stage II 3 20<br />
Stage III 3 20<br />
Histology<br />
Ductal 12 80<br />
O<strong>the</strong>r 2 13<br />
3 rd Breast Cancer 2 4<br />
Median Age Range 54 53–55<br />
BRCA2 mutation 2 100<br />
Stage<br />
I 1 50<br />
III 1 50<br />
Histology<br />
Ductal 2 100<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1450P EFFECT OF PRIOR METFORMIN INTAKE ON FIRST<br />
DIAGNOSIS OF BREAST CANCER<br />
S. Gupta 1 , D. Avila 2 , E.A. Mino 2 , P. Gosain 2 , K.K. Batra 2 , S. McDunn 3<br />
1 Div of Hematology-Oncology, John H Stroger Jr Hospital of Cook County,<br />
Chicago, IL, UNITED STATES OF AMERICA, 2 Internal Medicine, John H Stroger<br />
Jr Hospital of Cook County, Chicago, IL, UNITED STATES OF AMERICA,<br />
3 Hematology-Oncology, John H Stroger Jr Hospital of Cook County, Chicago,<br />
IL, UNITED STATES OF AMERICA<br />
Introduction: Metformin has been shown in pre clinical studies to have <strong>the</strong> ability to<br />
reduce tumor growth and exert anti cancer effects. It is being tested as a part of<br />
management of breast cancer (BC) in neoadjuvant and adjuvant settings and being<br />
entertained as a modality of chemoprevention in BC. We studied <strong>the</strong> effect of prior<br />
metformin intake on patients with first diagnosis of breast cancer.<br />
Methods: All patients with a diagnosis of BC were identified from <strong>the</strong> Tumor<br />
Registry of our hospital, which serves <strong>the</strong> underserved population of Chicago, USA.<br />
All charts were retrospectively screened for age, tumor grade, node status at<br />
diagnosis, onset of diabetes mellitus (DM) prior to cancer diagnosis and intake of<br />
metformin including duration. Patients with a diagnosis of DM after cancer, intake<br />
of metformin less than 6 months or incomplete medical record were excluded.<br />
Difference in means was calculated using <strong>the</strong> student t-test.<br />
Results: A total of 1569 patients were screened of which 133 patients were identified<br />
to have a diagnosis of DM before breast cancer and met <strong>the</strong> inclusion criteria. Of<br />
<strong>the</strong>se, 95 patients were on metformin for an average 3.57 years (yrs) before BC<br />
diagnosis. Thirty-nine patients on metformin were younger than 60 yrs and 56 were<br />
older than 60 yrs age. Node positive disease was seen in 51.5% of metformin patients<br />
compared to 49% DM patients not on metformin (p = NS). However in patients<br />
younger than 60 yrs, node positive disease was seen in 66% of metformin patients<br />
compared to 86% non-metformin patients. The young patients on metformin had an<br />
average grade of 2.38 compared to non-metformin patients whose average grade was<br />
2.83 (p = 0.02). More patients in young non-metformin group were Her2-neu<br />
positive (43%) compared to 23% in young metformin group. In older patients more<br />
non-metformin patients had triple negative disease (20%) compared to 9% in<br />
metformin group.<br />
Annals of Oncology<br />
Conclusions: Prior metformin use may have a possible positive effect in patients<br />
with initial diagnosis of BC. This effect seems more pronounced in patients younger<br />
than 60 yrs of age where metformin intake was associated with a statistically<br />
significant reduction in tumor grade with a trend towards reduction in node positive<br />
disease and Her2 positivity. Fur<strong>the</strong>r studies are needed to clarify <strong>the</strong> potential<br />
protective role of metformin in this younger group.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1451P FIVE-YEAR RESULTS OF THE BREAST CANCER SCREENING<br />
PROGRAMME IN UGRA<br />
N.A. Zakharova 1 , S.W. Duffy 2 , J. Mackay 3 , E.V. Kotlyarov 4 , A.V. Filimonov 5 ,<br />
K. Barinov 1 , I. Gromut 1 , E.V. Belan 1<br />
1 Oncological, State Oncology Center, Khanty-Mansiysk, RUSSIAN<br />
FEDERATION, 2 Wolfson Institute of Preventive Medicine, Queen Mary University<br />
of London, London, UNITED KINGDOM, 3 Consultant Clinical Genetic<br />
Oncologist, University College London, London, UNITED KINGDOM, 4 Oncology,<br />
State Medical Academy, Khanty-Mansiysk, RUSSIAN FEDERATION, 5 Chief,<br />
State Healthcare Department, Khanty-Mansiysk, RUSSIAN FEDERATION<br />
The main purpose of this study is to estimate <strong>the</strong> five-year result of <strong>the</strong> Breast<br />
Cancer Screening Program (BCSP) performed in <strong>the</strong> Khanty-Mansiysk Autonomous<br />
Okrug - Ugra. This Programme was initiated in 2007. The screening covers women<br />
over 40 years old. The screening interval is 2 years, with two-view mammography<br />
(MLO and CC) and single reading as <strong>the</strong> standard. During 2007–2011 within <strong>the</strong><br />
BCSP, 201668 women were screened (177475 - prevalence screening). The screening<br />
coverage rate is approximately 56.4%. In 2011 we also evaluated <strong>the</strong> efficacy of usage<br />
for <strong>the</strong> mammography equipment in each district. According to <strong>the</strong> standard (RF) –<br />
<strong>the</strong>re are 2840 examinations per day (2381 examinations per day - <strong>the</strong> average<br />
number in Ugra). Thus, <strong>the</strong> coverage rate only for <strong>the</strong> districts with <strong>the</strong> sufficient<br />
number of <strong>the</strong> examinations per day estimated as 68.4%. 10.3% of screened women<br />
were referred for fur<strong>the</strong>r assessment. There were 460 breast cancer cases detected at<br />
<strong>the</strong> first round of screening and 22 cases in subsequent rounds. The cancer detection<br />
rate for prevalence was 2.6 and for subsequent rounds 0.9 per 1000 screened women.<br />
The test sensitivity for <strong>the</strong> first round was estimated as 77%. Also, we have tentatively<br />
evaluated <strong>the</strong> likely future effect on mortality from <strong>the</strong> breast cancer as a result of <strong>the</strong><br />
BCSP in Ugra, on <strong>the</strong> basis of <strong>the</strong> changes in mortality seen at this early stage of <strong>the</strong><br />
programme and of <strong>the</strong> changes in size and node status of <strong>the</strong> cancers diagnosed. In<br />
2009–11, a reduction in breast cancer mortality of <strong>the</strong> order of 15–20% was<br />
observed, compared to previous years. We anticipate a 20% reduction in deaths from<br />
breast cancer by 2015, on <strong>the</strong> basis of this and of reductions in <strong>the</strong> proportion of<br />
tumours of size >20 mm. The changes in <strong>the</strong> tumour size distribution do not appear<br />
to be due to length bias or overdiagnosis, since <strong>the</strong> overall incidence is consistent<br />
with pre-screening trends of increasing incidence. Analysis of node status is<br />
complicated by possible changes in practice with respect to axillary investigation. We<br />
are planning to increase <strong>the</strong> proportion of <strong>the</strong> digital mammography equipment in<br />
order to improve <strong>the</strong> quality of <strong>the</strong> examination and <strong>the</strong>n - to implement <strong>the</strong> CAD<br />
(computer-aided detection) system. Thus, in <strong>the</strong> future in Ugra, it is planned to<br />
continue <strong>the</strong> BCSP, and to continue to improve <strong>the</strong> quality of screening.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1452P CANCER SCREENING IN UNDERSERVED, VULNERABLE<br />
POPULATION. RESULTS FROM THE EDIFICE SURVEY<br />
F. Eisinger 1 , J. Viguier 2 , C. Touboul 3 , Y. Coscas 4 , X. Pivot 5 , J. Blay 6 , C. Lhomel 4 ,<br />
J. Morère 7<br />
1 Oncology, IPC INSERM UMR 599, Marseille, FRANCE, 2 Centre De<br />
Coordination Des Dépistages Des Cancers, CHRU Trousseau, Tours, FRANCE,<br />
3 Oncology, Kantar Health, Montrouge, FRANCE, 4 Oncology, Clinique de la Porte<br />
de Saint Cloud, Boulogne Billancourt, FRANCE, 5 Service Oncologie Medicale, C.<br />
H.U. Jean Minjoz, Besancon, FRANCE, 6 Oncology, Centre Léon Bérard, Lyon,<br />
FRANCE, 7 Oncology, Hôpital Avicenne, Bobigny, FRANCE<br />
Background: Reducing cancer inequalities is one of <strong>the</strong> most critical goals of <strong>the</strong><br />
current National Cancer Plan. The French health system allows fair access to care for<br />
all affected persons. In contrast, exposure to risk factors is far worse for underserved<br />
populations. The issue of cancer screening attendance distribution according to social<br />
factors, deserves to be assessed and regularly monitored.<br />
Methods: Accurate data on cancer screening in <strong>the</strong> population is available; however<br />
it is difficult to assess who belongs to an underserved/vulnerable subgroup. Many<br />
indicators could be used, such as <strong>the</strong> validated questionnaire “EPICES” with eleven<br />
yes/no questions.We analysed a sample of <strong>the</strong> general population (N = 1603) to<br />
ix470 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
assess if screening attendance is correlated with this validated syn<strong>the</strong>tic score or by<br />
any of its components.<br />
Results:<br />
Breast<br />
40–74<br />
Breast<br />
50–74<br />
Official<br />
program CRC 40–74<br />
CRC<br />
50–74<br />
Official<br />
program Prostate<br />
Contact with social workers ns ns ns ns ns<br />
Additional health insurance ns ns ns ns ns<br />
Living alone ns ns p < 0.05 ns p < 0.05<br />
Home ownership p < 0.05 ns p < 0.01 p < 0.05 ns<br />
Financial difficulties p < 0.05 ns p < 0.01 ns ns<br />
Practicing sport p < 0.01 ns ns ns ns<br />
Performance attendance p < 0.01 ns ns ns ns<br />
Taking vacations ns ns p < 0.05 ns p < 0.05<br />
Family ties ns ns ns ns p < 0.05<br />
Housing support ns ns p < 0.01 ns ns<br />
Social support ns ns p < 0.01 ns ns<br />
EPICES Syn<strong>the</strong>tic score ns ns ns ns ns<br />
Conclusions: It appears that social determinants of vulnerability are not key<br />
determinants for screening behaviour. However, <strong>the</strong>re is still an impact on cancer<br />
screening attendance outside <strong>the</strong> official target age group. Under <strong>the</strong>se circumstances,<br />
vulnerable populations use less health screening resources. Social support and home<br />
ownership are <strong>the</strong> most powerful predictors for screening attendance.Our data<br />
support <strong>the</strong> dramatic impact of organised programs which reduce or even remove<br />
inequities in access to cancer screening.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1453P ATTITUDE, KNOWLEDGE AND FEARS CONCERNING<br />
CANCER AMONG LOW-INCOME RURAL WOMEN OF<br />
DIFFERENT RELIGION AND ETHNICITY<br />
S. Bhattacharjee 1 , C.K. Bose 2 , S. Koner 1 , A. Mukhopadhyay 3<br />
1 Community Medicine, Netaji Subhas Chandra Bose Cancer Research Institute,<br />
Kolkata, INDIA, 2 Dept. of Gynocological Oncology, Netaji Subhash Chandra<br />
Bose Cancer Research Institute, Kolkata, INDIA, 3 Medical Oncology, Netaji<br />
Subhas Chandra Bose Cancer Research Institute, Kolkata, INDIA<br />
The low participation level of rural women in cancer screening is a cause of concern<br />
especially in India. The role of predisposing knowledge and attitudes concerning<br />
cancer in many religious and ethnic groups is not studied well to find out cause of<br />
such reluctance in participation. We documented <strong>the</strong> knowledge and fears<br />
concerning such cancer in rural population of women of different ethnicity and<br />
religions in West Bengal province of India and how <strong>the</strong>se factors relate to screening<br />
behaviour and socio-demographic characteristics. A baseline survey was conducted<br />
before <strong>the</strong> start of a community cancer awareness and screening programme. A total<br />
of 2000 rural women of different districts of West Bengal were interviewed in-person<br />
about <strong>the</strong>ir knowledge, attitudes and Pap smear and mammogram screening<br />
practices. Knowledge and attitude about cancer varied with age, education,<br />
socioeconomic status, ethnicity and religion. Women in <strong>the</strong> age range of 40–72 years<br />
(median 56 years) and least knowledgeable of cancer-detection methods and<br />
screening guidelines were considered for our study. Socio-economic markers were<br />
monthly income, literacy, nature of roof, and toilet. About 80% women, who<br />
participated, had no toilet facility. Women, who could not read and write, were more<br />
unaware of cancer signs and symptoms, risk factors and screening guidelines.<br />
However, biggest concern about was poor infrastructural facility for doing cervical<br />
examination and women are shy to have elaborate examination and treatment in<br />
<strong>the</strong>ir private parts in an open camp. Striking finding was full participation and<br />
cooperation in awareness and screening of cervical cancer among scheduled tribal<br />
women. They had near total participation which was far more than scheduled casts<br />
and Muslims. The low screening participation among rural Indian women may be<br />
due to <strong>the</strong>ir shyness to participate in a comparatively open camp and limited<br />
awareness and knowledge about screening examinations. Our study highlights <strong>the</strong><br />
need for wide-scale cancer screening interventions consistent with prevailing rural<br />
belief. Tribal people are most cooperative among all ethnic and religious and<br />
socio-economic groups.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1454P EVALUATION OF COLPOSCOPY AND LOOP<br />
ELECTROSURGICAL EXCISION PROCEDURE (LEEP) IN A<br />
RURAL MOBILE CERVICAL CANCER SCREENING UNIT IN<br />
WEST BENGAL, INDIA<br />
S. Koner 1 , C.K. Bose 2 , A.N. Sen 3 , A. Mukhopadhyay 4<br />
1 Community Medicine, Netaji Subhas Chandra Bose Cancer Research Institute,<br />
Kolkata, INDIA, 2 Dept. of Gynocological Oncology, Netaji Subhash Chandra<br />
Bose Cancer Research Institute, Kolkata, INDIA, 3 Surgical Oncology, Netaji<br />
Subhash Chandra Bose Cancer Research Institute, Kolkata, INDIA, 4 Medical<br />
Oncology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata,<br />
INDIA<br />
Background: In recent years <strong>the</strong>re are many attempts to see accuracy of colposcopy<br />
in poor resource setting where ‘see and treat’ approach is used. Sensitivity and<br />
specificity for colposcopy in India is not determined accurately so far because of<br />
poormethodology of experiments.<br />
Objectives: Hence, in a cervical cancer screening and management project for rural<br />
poor women in West Bengal province of India we tried to calculate specificity and<br />
sensitivity of colposcopy based on management by LEEP.<br />
Methods: VIA combined with colposcopy and LEEP using mobile van is planned in<br />
a biotechnology based programme for women under Department of Biotechnology,<br />
Govt. of India where efficacy of colposcopy was assessed by camp approach in rural<br />
area of a remote district. We used video colposcopy as triage and managed positive<br />
cases by LEEP. We randomly selected 50 cases that wereColposcopy negative & 50<br />
cases with CIN I and did biopsy cervix on all of <strong>the</strong>m. We thus evaluated our early<br />
screeningand management to detect sensitivity & specificity of Colposcopy in this<br />
rural setting.<br />
Results: A total of 2836 women participated in our rural camp for screening during<br />
this period. We could detect 415 VIA positive cases. In this gold standard test we<br />
saw 12 cases of false positive. Only 14 cases of false negative that <strong>the</strong>n underwent<br />
LEEP. Thus colposcopy in our series had 60% sensitivity and 63% positive predictive<br />
value while 87.7% specificity and 86% negative predictive value. Complication Rate<br />
was 3 percent (14 cases).<br />
Conclusion: In our series sensitivity of colposcopy was comparatively low. Main<br />
confounding variable producing false positive result was inflammation of cervix<br />
which seems to be a cause of concern in our country. However, obustness of VIA<br />
needs to be calculated in a bigger study to find out efficacy of such screening.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1455P CERVICAL CANCER SCREENING USING VISUAL<br />
INSPECTION AFTER APPLICATION OF 5% ACETIC ACID<br />
(VIA) IN RURAL WEST BENGAL<br />
A.N. Sen 1 , C.K. Bose 2 , S. Koner 3 , A. Mukhopadhyay 4<br />
1 Surgical Oncology, Netaji Subhash Chandra Bose Cancer Research Institute,<br />
KOLKATA, INDIA, 2 Dept. of Gynocological Oncology, Netaji Subhash Chandra<br />
Bose Cancer Research Institute, Kolkata, INDIA, 3 Community Medicine, Netaji<br />
Subhas Chandra Bose Cancer Research Institute, Kolkata, INDIA, 4 Medical<br />
Oncology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata,<br />
INDIA<br />
Background: Because of problem of manpower in developing countries, cytology<br />
screening for cervical cancer is gradually replaced by a Visual Inspection after<br />
application of 5% acetic acid (VIA) with triage of colposcopy.<br />
Objectives: Hence, government and o<strong>the</strong>r funding bodies in India are now eager to<br />
see its efficacy in <strong>the</strong> field to screen and manage cervical pre cancer (CIN) in a “see<br />
&treat” approach.<br />
Methods: This simple technology combined with colposcopy is planned in a<br />
biotechnology based programme for women under Department of Biotechnology,<br />
Govt. of India where efficacy of VIA was assessed by camp approach in rural area of<br />
a remote district (Burdwan) of West Bengal province in India from August 2010 to<br />
August 2011. We used video colposcopy as triage and managed positive cases by<br />
Loop Electrosurgical Excision Procedure (LEEP). We evaluated our early screening<br />
and management results by finding out detection rates of early lesions of cervix and<br />
in this uncontrolled observational study.<br />
Results: A total of 2836 women participated in our rural camp for screening during<br />
this period. Amongst <strong>the</strong>m 2354women could be subjected to visual inspection by<br />
acetic acid (VIA) using 200 watt bulb and 5% acetic acid by <strong>the</strong> trainedcommunity<br />
nurse. We could not do VIA in 482 subjects because of no consent-22.80%,<br />
non-cooperation-23.40%, unmarried-18.60%, menstruating-12.80%, pregnant-10.50%,<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds412 | ix471
hysterectomised-9.10% and cervix cancer neglected or infollow up-2.50%. We could<br />
detect 415 cases of VIA positive cases showing white lesion in <strong>the</strong>ir cervix.<br />
Colposcopic prediction of cervical Intra-epi<strong>the</strong>lial neoplasia grade I(CIN I) lesion<br />
could be detected in 174 cases. These cases are of no immediate risk and most of<br />
<strong>the</strong>m actually showregression of <strong>the</strong>ir disease. Hence, <strong>the</strong>y are advised to have<br />
follow-up colposcopy after six months. There were 25 cases of condyloma/ polyp.<br />
They were managed by electro- cautery. We could detect and treat 33 cases of CIN II<br />
andIII which are precursor of cervical cancer. They were treated by LEEP.<br />
Conclusion: Our results show that VIA with colposcopy triage is viable option in<br />
rural cervical cancer screening programme in our outreach program.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1456P ENDOSCOPIC ULTRASONOGRAPHY IN HIGH-RISK<br />
POPULATION FOR PANCREATIC CANCER<br />
C. Guillen-Ponce 1 , E. Mocci 2 , A. Amendolara 2 , E. Vazquez-Sequeiros 3 ,<br />
C. Gonzalez Gordaliza 4 , M. Muñoz Beltran 4 , A. Sanjuanbenito 5 , C. Gonzalez<br />
Garcia 6 , A. Custodio 7 , A. Carrato 1<br />
1 Medical Oncology Department, Ramon y Cajal University Hospital, Madrid,<br />
SPAIN, 2 Medical Oncology, Ramon y Cajal University Hospital, Madrid, SPAIN,<br />
3 Digestive Department, Ramon y Cajal University Hospital, Madrid, SPAIN,<br />
4 Radiology Department, Ramon y Cajal University Hospital, Madrid, SPAIN,<br />
5 Surgery Department, Ramon y Cajal University Hospital, Madrid, SPAIN,<br />
6 Pathology Department, Ramon y Cajal University Hospital, Madrid, SPAIN,<br />
7 Medical Oncology, La Paz University Hospital, Madrid, SPAIN<br />
Introduction: Members of families with familial pancreatic cancer (FPC) have high risk<br />
of developing pancreatic cancer (PC). The risk increases with <strong>the</strong> number of PC in<br />
family members. In <strong>the</strong> last decade, several centers around <strong>the</strong> world are using screening<br />
programs for this high risk population, most of <strong>the</strong>m based on endoscopic<br />
ultrasonography (EU) and computed tomography (CT) or magnetic resonance imaging<br />
(MRI). This work assesses <strong>the</strong> findings of screening in individuals at high risk of PC.<br />
Material and methods: It has recommended screening for PC in individuals at high<br />
risk of this cancer by EU and CT. In those cases in which it was suspected some<br />
alteration, we proceeded to MRI and/or puncture of <strong>the</strong> pancreatic suspicious lesions.<br />
Results: Since October 2011, we indicated <strong>the</strong> screening of 50 individuals belonging<br />
to 10 families. 9 families had FPC and one had a hereditary breast and ovarian<br />
cancer syndrome with a case of PC. They have been identified 4 lesions suspicious<br />
for EU, none of <strong>the</strong>se correlated with suspected by CT or MRI. Suspicious lesions<br />
were found in 3 members of <strong>the</strong> same family and ano<strong>the</strong>r from ano<strong>the</strong>r family, all<br />
with FPC. It has been suggested puncture injuries in 2 cases and in both cases, <strong>the</strong><br />
cytology results were negative. In <strong>the</strong> o<strong>the</strong>r two cases it was decided to follow up.<br />
Conclusions: Preliminary results confirm that <strong>the</strong> EU can detect small lesions<br />
undetectable by CT or conventional MRI. The phenotype found by EU has already<br />
been described in patients with strong family history of PC. It should explore <strong>the</strong><br />
utility of o<strong>the</strong>r imaging tests such as MRI with diffusion, for monitoring individuals<br />
at high risk of PC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1457P CONTROL OF CANCER IN WEST BENGAL, INDIA BY<br />
SCREENING AND AWARENESS PROGRAM<br />
J. Basak 1 , A. Chakraborty 2 , S. Dasgupta 1 , D. Bhattacharya(majumder) 1 ,<br />
S. Mukhopadhyay 1 , A. Mukhopadhyay 3<br />
1 Dept of Molecular Biology, Netaji Subhash Chandra Bose Cancer Research<br />
Institute, Kolkata, INDIA, 2 Molecular Biology and Human Genetics, Netaji Subhas<br />
Chandra Bose, Kolkata, INDIA, 3 Dept. Medical Oncology, Netaji Subhas<br />
Chandra BoseCancer Research Institute, Kolkata, INDIA<br />
Background: In India <strong>the</strong>re are about 2.5 million cancer patients and it increases by<br />
1 million new cancer patients every year, which is 1/10 of total cancer burden in <strong>the</strong><br />
world. The aim of our state based non-governmental Cancer Control Program is to<br />
reduce <strong>the</strong> cancer burden by proper awareness and screening. We also intended to<br />
teach about <strong>the</strong> early symptoms of cancer so that it can be detected early to provide<br />
appropriate treatment. Our motto is to serve people residing in remote villages of<br />
West Bengal where <strong>the</strong>re are no modern medical facilities available for detection of<br />
cancer.<br />
Material and methods: During <strong>the</strong> period of January 2004–April <strong>2012</strong>, a cancer<br />
screening & awareness program had been conducted in various districts of West<br />
Bengal, twice in every month by <strong>the</strong> members of NSCBCRI. We mainly dealt with<br />
oral, lung, breast and cervical cancer. We organized <strong>the</strong> awareness camps on a<br />
prefixed day with prior permission of <strong>the</strong> representatives. The cases which were<br />
detected positive were sent to our hospital for proper treatment and advanced cases<br />
were advised for pain and palliative treatment in our institution.<br />
Result: More than 80% of people participated spontaneously in awareness camps.<br />
Female cancer incidence was about 60%. We observed tobacco habits in 80% of<br />
males & 10% of females. The percentage of passive smokers among females is<br />
very high in West Bengal. Among 144256 screened population, we found 11541<br />
(8.0%) cancer patients in different stages of <strong>the</strong> disease. Ratio of male and female<br />
patients was 3:2. A total of 4986 (72%) male and 1200 (26%) female cancers<br />
were tobacco related. Among females <strong>the</strong> incidence of cervical and breast cancer<br />
were 34% and 23%, respectively. Among male oral and lung cancer incidence<br />
were 32% and 35%, respectively. About 67% of <strong>the</strong> cancer had been detected at<br />
an early stage.<br />
Conclusion: Through camps in remote rural areas of West Bengal we came to know<br />
that <strong>the</strong> majority of cancer cases are life style related. This can only be prevented by<br />
proper awareness camps. So, cancer detection and awareness camps are essential and<br />
important in rural areas to reduce <strong>the</strong> huge burden of cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1458P TOBACCO CESSATION IN THE COMMUNITY<br />
Annals of Oncology<br />
P. Hazra 1 , S. Mukhopadhyay 1 , A. Mukhopadhyay 2<br />
1 Community Medicine, Netaji Subhas Chandra Bose Cancer Research Institute,<br />
Kolkata, INDIA, 2 Medical Oncology, Netaji Subhas Chandra Bose Cancer<br />
Research Institute, Kolkata, INDIA<br />
Tobacco smoking is <strong>the</strong> most intensively investigated environmental cause of<br />
cancer. Smokes came out of cigarettes, bidis, hookahs etc. contains nicotine and<br />
o<strong>the</strong>r chemical compounds which are proved as dangerous carcinogens. Cancer<br />
causation by tobacco smoke is not attributable to any one chemical compounds<br />
but to an overall effect of <strong>the</strong> complex mixture of chemicals in smoke. Using<br />
tobacco, active smokers can get affected to lung and cancers in o<strong>the</strong>r organs such<br />
as larynx, oral cavity, pharynx, esophagus, pancreas, kidney and bladder. Non–<br />
smokers who are exposed to environmental tobacco ei<strong>the</strong>r by family members or<br />
workplace are also equally at <strong>the</strong> risk of having lung, laryngeal cancers, o<strong>the</strong>r<br />
respiratory diseases and even breast cancer. This study aims to find out <strong>the</strong><br />
tobacco use in <strong>the</strong> community and to stop usage. This was a population<br />
awareness study during period from September 2007 to <strong>2012</strong> in Mandarihaat<br />
village, Jalpaiguri district of North Bengal by <strong>the</strong> community medicine dept of<br />
NCRI. A population of 5000 people, in <strong>the</strong> age group between 6–45 years, was<br />
randomly interviewed following a structured questionnaire. We attended <strong>the</strong><br />
village and did <strong>the</strong> awareness every three months. In our first visit, we have seen<br />
that 70% of <strong>the</strong> population was tobacco users, ei<strong>the</strong>r by way of smoking (40%) or<br />
chewing (30%). We did a thorough awareness program and explained <strong>the</strong><br />
different hazards of smoking for cancer and heart diseases. In <strong>the</strong> next visit, we<br />
advised <strong>the</strong>m to quit smoking. Again after 3 months, we noticed that about 25%<br />
(875) of <strong>the</strong> tobacco users quit tobacco use. Thereafter, we screened <strong>the</strong><br />
population every 6 months and continued our awareness program. At <strong>the</strong> end of<br />
4 years, only 5% people continued <strong>the</strong> habit of tobacco. We advised <strong>the</strong>m to use<br />
nicotine tablets 4mg three times daily. At <strong>the</strong> end of 5 years, <strong>the</strong> entire smoking<br />
population except 0.05% (p value
Annals of Oncology<br />
a factor 2 to 10) <strong>the</strong> probability of having cancer after a positive test. In contrast,<br />
65% were aware of <strong>the</strong> possibility of a false negative test (nei<strong>the</strong>r gender, educational<br />
level, socio economic level impacted <strong>the</strong> knowledge).<br />
Conclusions: This study demonstrates a lack of detailed knowledge on <strong>the</strong> colorectal<br />
cancer screening process in <strong>the</strong> French national program. This raises <strong>the</strong> issue of <strong>the</strong><br />
fairness of <strong>the</strong> process and may be a reason for <strong>the</strong> current poor uptake. This should<br />
be tackled by improving <strong>the</strong> transmission of information via general practitioners,<br />
institutional letters sent directly to subjects and mass media.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1461 AWARENESS OF CANCER SCREENING DURING THE<br />
TREATMENT OF RENAL FAILURE PATIENTS: PHYSICIAN<br />
QUESTIONNAIRE<br />
O. Uysal Sonmez 1 , U. Uyeturk 2 , I.I. Budakoglu 3 , R. Kazancioglu 4 , I. Turker 5 ,<br />
B. Budakoglu 6 , U. Yalcintas Arslan 6 , O.B. Oksuzoglu 6<br />
1 Department of Medical Oncology, S.B.Sakarya University Hospital, Sakarya,<br />
TURKEY, 2 Departmet of Medical Oncology, Abant Izzet Baysal University<br />
Hospital, BOLU, TURKEY, 3 Medicine Education, Gazi University Faculty of<br />
Medicine, ANKARA, TURKEY, 4 Nephrology Deoartment, Bezmialem Vakıf<br />
University, Istanbul, TURKEY, 5 Department of Medical Oncology, Trabzon<br />
Numune Research and Education Hospital, Trabzon, TURKEY, 6 Department of<br />
Medical Oncology, Ankara Dr.A.Y.Oncology Research and Education Hospital,<br />
ANKARA, TURKEY<br />
Background: Survival of patients with renal insufficiency has increased. With <strong>the</strong><br />
prolonged survival, diagnosis of cancers is not infrequently seen. The aim of cancer<br />
screening is to increase <strong>the</strong> curability.<br />
Method: This study was done by face to face questionnaire in <strong>the</strong> 27th National<br />
Nephrology Congress to determine if <strong>the</strong> physicians dealing with chronic renal<br />
failure, hemodialysis or renal transplanted patients, recommend cancer screening or<br />
not and <strong>the</strong> methods of screening for cervix, prostate, breast and colon cancer.<br />
Results: One hundred and forty four physicians were included in <strong>the</strong> survey. 101<br />
participants were male. The most common age interval was between <strong>the</strong> ages of 40–49<br />
(55.6%). About 28.5% of <strong>the</strong> participants were specialist on nephrology, 27% on internal<br />
medicine, 47.9% of participants were hemodialysis certified general practitioners and<br />
4.9% were o<strong>the</strong>r areas of expertise. About 81.9% of <strong>the</strong> participants were working in <strong>the</strong><br />
city and 59.7% of <strong>the</strong> participants in private dialysis centers. Patients were grouped as<br />
compensated chronic renal failure, hemodialysis or renal transplanted. Of <strong>the</strong> 144 123<br />
physicians recommended breast cancer screening and <strong>the</strong> most recommended subgroup<br />
was HD patients (15.5%). The most preferred methods of screening were combinations of<br />
mammography, self breast examination and physicians’ breast examination. One<br />
hundred and nine physicians recommended cervix cancer screening, and <strong>the</strong> most<br />
preferred method of screening was papsmear. Colon cancer screening was recommended<br />
by 105 physicians and prostate screening by 114 physicians. The most preferred methods<br />
of screening were fecal occult blood test and PSA plus rectal digital test, respectively.<br />
Conclusion: It is not obvious whe<strong>the</strong>r cancer screening in renal failure patients is<br />
different from <strong>the</strong> rest of society. There is a variety of screening methods. An answer<br />
can be found to <strong>the</strong>se questions as a result of studies by a common follow-up<br />
protocol and cooperation of nephrologists and oncologists.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds412 | ix473
abstracts<br />
psycho-oncology<br />
1462PD INTEGRATION OF PSYCHOSOCIAL CARE INTO ROUTINE<br />
CANCER CARE: FINAL RESULTS OF A LARGE<br />
COLLABORATIVE, HOSPITAL-BASED, QUALITY<br />
IMPROVEMENT STUDY (HUCARE PROJECT)<br />
R. Passalacqua 1 , C. Caminiti 2 , M.A. Annunziata 3 , C. Borreani 4 , J. Saleri 5 ,<br />
F. Diodati 6 , L. Isa 7 , S. Filiberti 1 , D. Fagnani 8 and G. Donati 1<br />
1 Oncology Division, Istituti Ospitalieri di Cremona, Cremona, ITALY,<br />
2 Epidemiology, Azienda Ospedaliera Universitaria di Parma, Parma, ITALY,<br />
3 Psychology, CRO Aviano, Pordenone, ITALY, 4 Psychology, INT Milan, Milan,<br />
ITALY, 5 Oncology, Istituti Ospitalieri, Cremona, ITALY, 6 Epidemiology, Azienda<br />
Ospedaliera, Parma, ITALY, 7 Oncology, ASL Melegnano, Milan, ITALY,<br />
8 Oncology, AO Vimercate, Milan, ITALY<br />
Background: Incorporating psychosocial research into practice is challenging. Aim of<br />
this study is to assess <strong>the</strong> feasibility in real life of interventions which have been<br />
tested in RCTs and have demonstrated to improve pts psychosocial conditions.<br />
Methods: This is an implementation study of five EBM interventions, conducted in<br />
28 centers. We adopted <strong>the</strong> model of Pronovost [BMJ 2008], which includes: context<br />
analysis to identify local barriers, introduction of <strong>the</strong> interventions, and evaluation of<br />
how many pts receive <strong>the</strong> recommended interventions. Primary EPs: degree of<br />
implementation detected in a blinded fashion by external trained personnel. EBM<br />
interventions included: 1) communication courses for doctors and nurses [Ann<br />
Oncol 2011]; 2) use of a question prompt list (QPL) [Cancer 2008]; 3) creation of<br />
<strong>the</strong> Point of Information and Support (PIS) in <strong>the</strong> ward [J Clin Oncol 2009]; 4)<br />
identification of a referring nurse (RN) for informing and educating pts [J Clin Nurs<br />
2010]; 5) screening of distress and social needs [J Natl Compr Canc Netw 2010].<br />
Results: 33 centers applied to partecipate, 29 were eligible and 28 are evaluable. Final<br />
blinded analisys was conducted on 305 consecutive patients. 156 oncologists and 401<br />
nurses attended <strong>the</strong> 3 days training course. An Australian QPL was subjected to<br />
cross-cultural adaptation, yielding <strong>the</strong> first validated Italian QPL [BMC Health Serv<br />
Res 2010]. 25 centers (89%) have successfully implemented <strong>the</strong> majority of<br />
interventions; 1 is too early and 3 centers failed for various reasons: internal conflicts<br />
of <strong>the</strong> staff, poor motivation, etc. Main results for each intervention are shown in <strong>the</strong><br />
table:<br />
Conclusions: Using this methodology, a successful implementation of EBM<br />
measures is possible in <strong>the</strong> vast majority of centers and yields significant<br />
improvement in <strong>the</strong> delivery of psychosocial care. Funded by <strong>the</strong> Italian Ministry of<br />
Health and <strong>the</strong> Lombardia Region<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1463P EVALUATION OF SEXUALITY, QUALITY-OF-LIFE AND<br />
DEPRESSION IN ADVANCED CANCER PATIENTS TREATED<br />
IN A DRUG DEVELOPMENT UNIT<br />
M. Rouanne 1 , C. Massard 2 , A. Hollebecque 2 , V. Rousseau 3 , A. Varga 2 ,<br />
A. Gazzah 2 , Y. Neuzillet 1 , T. Lebret 1 and J. Soria 2<br />
1 Urology, Hôpital Foch, Suresnes, FRANCE, 2 SITEP, Institut de Cancérologie,<br />
Villejuif, FRANCE, 3 Biostatistics, Institut Gustave Roussy, Villejuif, FRANCE<br />
Background: The advent of molecular targeted agents (MTA) opened a new era<br />
<strong>the</strong>rapy in oncology. The objective of this study was to investigate quality of life,<br />
depression and sexual function in patients treated in a phase I drug unit evaluating<br />
MTA.<br />
Patients and methods: All patients included in a phase I clinical trial at <strong>the</strong> Gustave<br />
Roussy Institute were proposed a personal interview regarding <strong>the</strong>ir quality of life,<br />
depression, and sexual function. They completed 4 self-questionnaires containing <strong>the</strong><br />
Medical Outcomes Study Short-Form General Health Survey (SF12), <strong>the</strong> Beck<br />
Table: 1462PD<br />
EBM TRAINING COURSES<br />
(No and % of attendee,<br />
oncologists plus nurses)<br />
REFERRING NURSE (RN)<br />
(No and % of<br />
pts with a RN)<br />
Depression Inventory (BDI-II), <strong>the</strong> International Index of Erectile Function (IIEF)<br />
and <strong>the</strong> Female Sexual Function Index (FSFI).<br />
Results: This is, to our knowledge, <strong>the</strong> first evaluation of quality of life, depression<br />
and sexual function in a phase I drug unit. Sixty-three patients were evaluated at<br />
baseline. Patients had a good mental and physical function despite <strong>the</strong>ir disease<br />
progression. The response rate was 75% for sexual questionnaires. For 57% of females<br />
and 68% of males, quality of sexual life was a subject of interest. After one month<br />
treatment, sexual dysfunction increased especially in lubrication and pain in females<br />
and erection in males with a statistical association of anti-angiogenic inhibitors in<br />
males (p = 0.04).<br />
Conclusions: Patients on MTA in phase I clinical trials had a preserved mental and<br />
physical activity whereas <strong>the</strong>ir sexual activity decline in both sexes. The impact of<br />
MTA on sexual function should be routinely assessed.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1464P THE DIFFERENCE IN THE SERUM LEVELS OF BDNF, IL-6,<br />
IL-8, IL-10 AND EGF IN ONCOLOGY PATIENTS DIVIDED<br />
ACCORDING TO THE PRESENCE OF SYMPTOMS OF<br />
DEPRESSION<br />
L. Holubec 1 , O. Fiala 1 , V.M. Matejka 1 , J. Podlipny 2 , J. Dreslerova 1 , J. Vrzalova 3 ,<br />
O. Topolcan 3 , J. Finek 1 and T. Svoboda 1<br />
1 Department of Oncology & Radio<strong>the</strong>rapy, University Hospital Pilsen, Pilsen,<br />
CZECH REPUBLIC, 2 Department of Psychiatry, University Hospital Pilsen, Czech<br />
Republic, Pilsen, CZECH REPUBLIC, 3 Department of Nuclear Medicine,<br />
University Hospital Pilsen, Pilsen, CZECH REPUBLIC<br />
Objective: To assess <strong>the</strong> differences in <strong>the</strong> serum levels of Brain-derived neurotrophic<br />
factor (BDNF), interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 10 (IL-10) and<br />
epidermal growth factor (EGF) in oncology patients with symptoms of depression<br />
and in oncology patients without symptoms of depression.<br />
Methods: We administered <strong>the</strong> following self – report questionnaires to <strong>the</strong><br />
hospitalized oncology patients (n = 32): Zung´s Self-Rating Depression Scale (ZSDS)<br />
and Symptom Check List Psychiatric Rating Scale (SCL 90). We also collected blood<br />
samples from <strong>the</strong>se patients for <strong>the</strong> detection of <strong>the</strong> following factors: BDNF, IL-6,<br />
IL-8, IL-10 and EGF. The procedures had been fully explained to all patients and<br />
written informed consent had been obtained. The patients were divided into two<br />
groups according to <strong>the</strong> scores in ZSDS: a group with <strong>the</strong> presence of symptoms of<br />
depression (n = 20) and a group without <strong>the</strong> symptoms of depression (n = 12). The<br />
differences in <strong>the</strong> levels of BDNF, interleukins and EGF between <strong>the</strong> groups were<br />
statistically assessed by Wilcoxon rank-sum test.<br />
Results: Oncology patients with <strong>the</strong> symptoms of depression showed significantly<br />
lower levels of BDNF (medians 1452.3 vs 3229.0 pg/ml, p = 0.014). There were no<br />
significant differences in <strong>the</strong> levels of IL-6, IL-8, IL-10 and EGF between <strong>the</strong> groups.<br />
Conclusion: This result supports <strong>the</strong> hypo<strong>the</strong>sis of diminished neuroplasticity in<br />
oncology patients with <strong>the</strong> symptoms of depression as measured by <strong>the</strong> serum levels<br />
of BDNF. This study was supported by research project MSM 0021620819.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1465P SLEEP DIFFICULTIES, PAIN AND STRESS IN COLORECTAL<br />
CANCER FEMALE PATIENTS<br />
P. Heras, V. Niarou, E. Andrikopoulos and M. Hera<br />
Internal Medicine, General Hospital of Naflio, A<strong>the</strong>ns, GREECE<br />
Aim: This study examined sleep difficulties, pain and stress among women<br />
undergoing surgery for colorectal cancer(CC).<br />
Methods: Perceived distress was assessed with Perceived Stress Scale (PSS). Sleep<br />
quailty was assessed using <strong>the</strong> Pittsburgh Sleep Quality Index (PSQI). Pain severity<br />
and interference were assessed using <strong>the</strong> Brief Pain Inventory (BPI), while frequency<br />
PIS (No and % of<br />
Units with a PIS)<br />
Annals of Oncology 23 (Supplement 9): ix474–ix477, <strong>2012</strong><br />
doi:10.1093/annonc/mds413<br />
USE OF THE QPL<br />
(No and % of pts who<br />
receive <strong>the</strong> QPL)<br />
PSYCHO-SOCIAL<br />
EVALUATION (No and % of<br />
screened patients)<br />
Pre-Implementation 0/598 (0%) 0% 4/29 (17%) 0% 0%<br />
Post-Implementation 557/598 (93%) 262/305 (86%) 24/29 (83%) 223/305 (73%) 253/305 (83%)<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
Annals of Oncology<br />
of cancer-associated pain was assessed with a single item from <strong>the</strong> Functional<br />
Assessment of Cancer Therapy-Colorectal Cancer (FACT-CC) scale Participants were<br />
assessed immediately prior to surgery and <strong>the</strong>n 4-6 weeks following surgery.<br />
Results: Participants were 68 women who completed at least <strong>the</strong> PSQI at presurgery,<br />
36 to 85 tears old ( M = 61.12, SD = 9.18). Clinically significant sleep disturbance was<br />
evident was evident in 48% of participants prior to surgery, 57% showed clinically<br />
significant sleep disturbance was associated with greater stress (p < 0.01), cancer pain<br />
frequency (p < 0.01) and pain interference (p < 0.01). Frequency of cancer pain<br />
decreased significantly following surgery (p < 0.05); however, <strong>the</strong>re were no changes<br />
in sleep disturbance, pain severity/interference, all stress scores from pre to post<br />
surgery. Following surgery, greater total sleep disturbance remain associated with:<br />
greater stress(p < 0.01) and cancer pain frequency (p < 0.01) but was no longer<br />
associated with pain interference.<br />
Conclusions: Sleep disturbance is prevalent among women both prior to and<br />
following surgical resection for CC. In addition, associations among sleep<br />
disturbance, stress and pain are present shortly following CC diagnosis and persist<br />
throughout <strong>the</strong> perioperative period.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1466P DIFFERENCES IN PERCEIVED AND OBTAINED SOCIAL<br />
SUPPORT IN CERVICAL CANCER PATIENTS AFTER<br />
RADICAL RADIO-CHEMOTHERAPY WITH COMPARISON<br />
WITH HEALTHY POPULATION<br />
A. Kieszkowska-Grudny 1 , M. Rucinska 2 , S. Biedrzycka 2 and S. Nawrocki 2<br />
1 Fryderic Chopin Memorial Hospital, The European Health Centre Otwock,<br />
Otwock, POLAND, 2 Department of Oncology, University of Warmia and Mazury,<br />
Olsztyn, POLAND<br />
Background: Cervical cancer is one of <strong>the</strong> most frequent neoplasms in women.<br />
Diagnosis and treatment engage a lot of patients’ emotion and <strong>the</strong>refore <strong>the</strong> social<br />
support becomes interesting subject of assessment for <strong>the</strong> clinical and psychological<br />
status of cervical cancer survivors. The aim of this study was to compare perceived<br />
and obtained social support in cervical cancer survivors after radical<br />
radio-chemo<strong>the</strong>rapy and healthy women.<br />
Material and methods: 94 women were included to <strong>the</strong> study between November<br />
2009 and May 2010: 47 cervical cancer patients (27-69 years, median 55 years)<br />
minimum 3 months (median 37 months) after radical radio-chemo<strong>the</strong>rapy and 47<br />
healthy women (24-64 years, median 52 years). Subjects filled out a questionnaire<br />
that included Berlin Social Support Scales (BSSS) which measures 10 different types<br />
of support, and additional demographic and medical questionnaires. In <strong>the</strong> statistical<br />
analysis chi2 test, t-Student test and linear regression were used. The significance<br />
level was p < 0.05.<br />
Results: Almost all types of social support were significantly higher assessed by<br />
women after cervical cancer treatment than healthy ones. While <strong>the</strong> need for support<br />
and seeking support was almost at <strong>the</strong> same level in both groups, women with cancer<br />
treatment currently receive more support than healthy women (p < 0.05).<br />
Significantly (p < 0.05) higher perceived emotional support, total currently received<br />
support and currently received instrumental support were found in cancer patients<br />
living in <strong>the</strong> village, city up to 50 thousand, and city between 50 and 200 thousand<br />
inhabitants, respectively. In addition, we uncovered predictors of better support, like:<br />
FIGO stage was predictor to perceived instrumental support and currently received<br />
emotional support, but age was a predictor of most intensive need of seeking for<br />
support (p < 0.05).<br />
Conclusions: Although <strong>the</strong> need for social support was <strong>the</strong> same in both groups,<br />
women after cancer treatment received it more, and evaluate it higher. FIGO stage<br />
and age were <strong>the</strong> most important predictors of perceived instrumental support,<br />
current emotional support and seeking form support.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1467P QUALITY OF LIFE AMONG OLDER PATIENTS (AGE 65+)<br />
WITH CANCER IN A UNIVERSITY HOSPITAL IN INDIA<br />
A. Chandra and J.P. Martin<br />
Medical Oncology Unit, Department of General Medicine, SRI Ramachandra<br />
University, Chennai, INDIA<br />
Background: Cancer in older cancer patients, additional endpoints such as quality of<br />
survival and daily functioning might be considered equally relevant as overall or<br />
disease free survival. However, <strong>the</strong>se factors have been understudied. Therefore, this<br />
study will focus on <strong>the</strong> impact of cancer, ageing, and <strong>the</strong>ir interaction on <strong>the</strong><br />
long-term wellbeing of older cancer patients.<br />
Methods: This is an prospective study. We recruited 45 cancer patients above 65<br />
years with a new diagnosis of breast, prostate, lung or gastrointestinal cancer between<br />
November 2011 and January <strong>2012</strong>. Data collected through personal interviews and<br />
self-administered questionnaire (consisting of socio-demographic information,<br />
general health information, a comprehensive geriatric assessment, quality of life, Mini<br />
Mental Status Examination, Bar<strong>the</strong>l Index, geriatric depressive scale ECOG<br />
Performance status and Mini Nutritional scale), and assessment of medical records.<br />
Results: The four most prevalent symptoms/problems identified were fatigue,<br />
financial difficulties, reduced role function and reduced social function. The geriatric<br />
depressive scale showed 33.3 % normal and 53.3 % had mild depression. The Bar<strong>the</strong>l<br />
index 28.8 % had score range 60-80 and 80-100 in 51.1 % patients. Mini Mental<br />
status majority had score range from 10-30. ECOG Performance status was 0-2 in<br />
70.9 %. Mini Nutritional status revealed risk of malnutrition in 71.1%.<br />
Discussion: This prospective data provides light on psychological adjustment of<br />
patients affected by cancer (diagnosis and treatment) and <strong>the</strong>ir interaction with aging<br />
in a developing country. Results may provide new insights, which might contribute<br />
to <strong>the</strong> improvement of care for older cancer patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1468P THE INFLUENCE OF QUALITY OF LIFE ON PATIENT<br />
SATISFACTION IN AMBULATORY ONCOLOGY<br />
T.V.F. Nguyen 1 , A. Brédart 2 , J. Bosset 3 , A. Monnier 4 and M. Mercier 1<br />
1 Clinical Research Unit in Quality of Life, CHU Jean Minjoz, BESANCON,<br />
FRANCE, 2 Psycho-Oncology Unit, Institut Curie, Paris, FRANCE, 3 Radio<strong>the</strong>rapy,<br />
CHU Jean Minjoz, Besançon, FRANCE, 4 Radio<strong>the</strong>rapy, CH Belfort-Montbéliard,<br />
Montbéliard, FRANCE<br />
In <strong>the</strong> oncology setting, <strong>the</strong>re has been an emphasis in evaluating outcomes of<br />
treatments in terms of quality of life and patient satisfaction. Our study aimed to<br />
investigate determinants of patient satisfaction and to assess <strong>the</strong> relationship between<br />
quality of life and satisfaction with care and <strong>the</strong>ir changes over time in curative<br />
treatment of cancer out-patients. Patients undergoing ambulatory chemo<strong>the</strong>rapy or<br />
radio<strong>the</strong>rapy in 2 centers in France were invited, at <strong>the</strong> beginning of <strong>the</strong> treatment, at<br />
<strong>the</strong> end and 3 months after, to complete <strong>the</strong> OUT-PATSAT35, composed of 35 items<br />
and 13 scales, evaluating perception of doctors, nurses, as well as aspects of care<br />
organization and services. All measures range from 0 to 100, a higher score reflecting<br />
a higher level of satisfaction. Additionally, for each patient, data were collected on<br />
socio-demographic, clinical characteristics and quality of life (EORTC QLQ-C30). Of<br />
691 patients included, 561 answered to <strong>the</strong> 3 assessment timings. In multivariate<br />
analysis, at <strong>the</strong> end of <strong>the</strong> treatment, patients, whose global health was deteriorated,<br />
were less satisfied in most scales, and 3 months after, <strong>the</strong> same patients had lower<br />
satisfaction scores only in doctors’ evaluation. The longitudinal analysis evidenced a<br />
significant relationship between a deterioration of global health and a decrease of<br />
satisfaction in doctors’ domains and, conversely, between an improvement of global<br />
health and an increase of satisfaction in <strong>the</strong> overall satisfaction scale. Fur<strong>the</strong>rmore,<br />
perceived global health at <strong>the</strong> beginning of <strong>the</strong> treatment remained significantly<br />
associated with all satisfaction scores in <strong>the</strong> following timings. Radio<strong>the</strong>rapy (versus<br />
chemo<strong>the</strong>rapy) was linked to less satisfaction with doctors’ and nurses’ provision of<br />
information and waiting-time, and head and neck cancer patients were less satisfied<br />
with <strong>the</strong> hospital environment. Pre-treatment self evaluated global health was <strong>the</strong><br />
major determinant of patient satisfaction in ambulatory oncology. The subsequent<br />
deterioration of global health emphasized <strong>the</strong> decrease of satisfaction, mainly in<br />
doctors’ evaluation. Initiatives targeting <strong>the</strong>se patients with poorer health status,<br />
before starting <strong>the</strong> treatment, should improve <strong>the</strong>ir pattern of care.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1469P INFORMATION DESIRE OF PATIENTS WITH ADVANCED<br />
CANCER<br />
L. Oostendorp 1 , P.B. Ottevanger 2 , W.T.A. van der Graaf 2 and P.F.M. Stalmeier 1<br />
1 Epidemiology, Biostatistics, and Hta, Radboud University Nijmegen Medical<br />
Center, Nijmegen, NETHERLANDS, 2 Medical Oncology, Radboud University<br />
Nijmegen Medical Center, Nijmegen, NETHERLANDS<br />
Background: Studies on information desire of patients with cancer are typically<br />
performed in <strong>the</strong> curative setting or involve hypo<strong>the</strong>tical decisions. In this study, we<br />
investigate <strong>the</strong> information desire of patients with advanced cancer at <strong>the</strong> point of<br />
decision making.<br />
Methods: 77 patients with advanced colorectal or breast cancer were included in this<br />
prospective study and filled in a questionnaire on sociodemographic data, well-being<br />
measures, and psychological measures, believed to be associated with information<br />
desire. Patients were faced with <strong>the</strong> decision whe<strong>the</strong>r or not to pursue second-line<br />
palliative chemo<strong>the</strong>rapy. The oncologist provided <strong>the</strong> usual treatment-related<br />
information and made a substitute judgment of <strong>the</strong> patient’s information desire. A<br />
nurse administered a decision aid with additional information on adverse events,<br />
tumour response, and survival. For each item, <strong>the</strong> nurse asked <strong>the</strong> patient whe<strong>the</strong>r<br />
<strong>the</strong> information was desired and whe<strong>the</strong>r it had been disclosed by <strong>the</strong> oncologist.<br />
Logistic regression analysis was performed to explore factors associated with<br />
information desire.<br />
Results: Median age was 62 years (range 32-80), 38% of patients were male, and 28%<br />
had college education or higher. Oncologists judged that information on adverse<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds413 | ix475
events, tumour response, and survival would be desired by 100%, 97%, and 80% of<br />
patients. The information on <strong>the</strong>se items in <strong>the</strong> decision aid was desired by 95%,<br />
91%, and 74% of patients. The question of whe<strong>the</strong>r <strong>the</strong> doctor had disclosed <strong>the</strong><br />
information was answered positively by 72%, 53%, and 28% of patients. Results of<br />
<strong>the</strong> association between patient’s information desire and demographic, clinical, and<br />
psychological measures will be presented.<br />
Conclusions: Even in this advanced setting, most patients accepted all information<br />
in <strong>the</strong> decision aid. Patients perceived that <strong>the</strong> oncologists had not disclosed all<br />
desired information. While oncologists accurately judged that patients in this study<br />
had a high information desire, <strong>the</strong>ir judgment of information desire on tumour<br />
response and survival for an individual patient was no better than could be expected<br />
by chance. These results demonstrate <strong>the</strong> importance of ascertaining a patient’s<br />
information desire, and communicating more candid, especially on survival.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1470P FAMILY CAREGIVER BURDEN: RESULTS OF A MOROCCAN<br />
PROSPECTIVE STUDY OF CANCER IN THE ELDERLY AND<br />
THEIR CAREGIVERS<br />
S. Lkhoyaali 1 , M. Ait El Haj 2 , S. Raissouni 3 , G. Rais 1 , H. Mrabti 3 and H. Errihani 3<br />
1 Medical Oncology, National Institut of Oncology, Rabat, MOROCCO, 2 National<br />
Institute of Oncology, INO, Rabat, MOROCCO, 3 Medical Oncology, Institut<br />
National d’Oncologie Sidi Mohamed Ben Abdellah, Rabat, MOROCCO<br />
Introduction: The support of older patients affected with cancer by <strong>the</strong>ir natural<br />
caregivers is not a simple task. It could be a painful experience with a major<br />
emotional, physical and economic impact on relatives. Usually family members do<br />
that task and <strong>the</strong>y may not be prepared for <strong>the</strong> challenges. The needs of older<br />
patients are diverse and may include assistance with medication, transportation for<br />
treatment, and emotional support.<br />
Methods: This is a prospective descriptive study, conducted in <strong>the</strong> National Institute<br />
of Oncology in Rabat during a ten month period from December 2010 to September<br />
2011.We included relatives of patients aged 70 or older with histologically proven<br />
cancer and also <strong>the</strong>ir relatives. A questionnaire was given to participants. For all<br />
participants, demographics, disease characteristics, social, economical and<br />
psychological features were recorded. Psychological impact was assessed using<br />
DSM-IV.<br />
Findings: A total of 150 patients’ relative caregivers responded to <strong>the</strong> questionnaire.<br />
Mean age was 44.7 years old. More than two thirds live in urban areas and educated in<br />
62.7%. They were 56.7% sons or daughters, living with <strong>the</strong>ir relatives in 54% of cases.<br />
Most of participants were married and have familial responsibilities. In relatives,<br />
anxiety was found in 79.3%. It was related to fear of losing <strong>the</strong> patient in 57% and led<br />
to <strong>the</strong> use of anxiolytics in 10%. Guilty feelings toward patients regarding neglecting<br />
early symptoms was reported in 38% of <strong>the</strong> relatives. Depression and anxiety were<br />
more frequent among female relatives and in those of urban origin. Obsession with<br />
dying from cancer was present in about 30% and fear of contagion was more common<br />
among those from rural backgrounds and <strong>the</strong> illiterate. Economic resources were<br />
exceeded in 78.7%, and 56% have used credit, sale of properties and work lay-off was<br />
recorded in 54%. Relatives participated in treatment making decisions in 86%.<br />
Conclusion: Even where <strong>the</strong>re was a great impact on older cancer patients’ relatives,<br />
<strong>the</strong> benefits of caregiving was observed in 80% in our study, <strong>the</strong>se included greater<br />
self-esteem, personal growth, meaning and purpose in one’s life, and gratitude for<br />
being able to reciprocate care. Assistance and information from healthcare<br />
professionals remains <strong>the</strong> key to improving <strong>the</strong> ability of caregivers to cope with<br />
caring for older patients with cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1471P ANNOUNCING CANCER IN A DEVELOPING COUNTRY: HOW<br />
IS IT DIFFERENT?<br />
R. Belbaraka 1 , A. Mahfoudi 1 , M. Khouchani 2 and A. Tahri 2<br />
1 Centre Oncologie Hematologie, Cadi Ayad University, Marrakech, MOROCCO,<br />
2 CHU, Mohamed Vi, University Cadi Ayyad, Marrakech, MOROCCO<br />
Background: Announcing a cancer diagnosis, but also a relapse, a progression of <strong>the</strong><br />
disease, or transition towards palliative care constitute particularly difficult<br />
communication issues for <strong>the</strong> patient as well as for <strong>the</strong> clinician, during <strong>the</strong><br />
trajectory of care. The study aimed to describe <strong>the</strong> difficulties in establishing a<br />
“good” announcing consultation, to provide indications or even recommendations on<br />
<strong>the</strong> ways to facilitate communication in order to ensure a optimal quality of care,<br />
responding to patients needs and ensuring <strong>the</strong> continuity of <strong>the</strong> care.<br />
Patients and methods: A semi-directive questionnaire with 21 items in Arabic were<br />
conducted in patients with cancer to evaluate <strong>the</strong>ir perception of <strong>the</strong> announcement<br />
of cancer.<br />
Results: 189 patients aged 18-78 years participated in <strong>the</strong> questionnaire. Participation<br />
was on a voluntary basis and patients were informed <strong>the</strong>y could be accompanied by<br />
an outside person if <strong>the</strong>y wished. The analysis revealed that several factors<br />
determined <strong>the</strong> quality of <strong>the</strong> relation as perceived by <strong>the</strong> patient receiving <strong>the</strong><br />
Annals of Oncology<br />
announcement of cancer: <strong>the</strong> relationship between <strong>the</strong> patient and <strong>the</strong> physician<br />
prior to <strong>the</strong> announcement, <strong>the</strong> practitioner’s consideration of <strong>the</strong> role of o<strong>the</strong>rs<br />
(family, friends) close to <strong>the</strong> patient, <strong>the</strong> practitioner’s respect of <strong>the</strong> patient’s desire<br />
for information, and <strong>the</strong> modalities of <strong>the</strong> announcement. Modalities considered to<br />
be favorable were: <strong>the</strong> physician’s empathy and availability, a progressive<br />
announcement using clear terms, presence of family or friends at <strong>the</strong> time of <strong>the</strong><br />
announcement if desired by <strong>the</strong> patient, absence of half-truths or lies.<br />
Conclusion: Announcing a diagnosis of cancer is a major challenge to <strong>the</strong><br />
physician’s technical competence and human qualities. This is probably one of <strong>the</strong><br />
greatest challenges that we have to face in oncology. This work confirmed that better<br />
knowledge of <strong>the</strong> patient’s experience is useful for examining our practices for<br />
announcing <strong>the</strong> diagnosis of cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1472P WHAT MOROCCAN CANCER ELDERLY PATIENTS WANT<br />
TO KNOW<br />
S. Raissouni 1 , S. Lkoyaali 1 , G. Rais 1 , M. Aitelhaj 2 , H. Mouzount 2 , H. Mrabti 1 and<br />
H. Errihani 1<br />
1 Medical Oncology, National Institute of Oncology, Rabat, MOROCCO, 2 Medical<br />
Oncology, INO, Rabat, MOROCCO<br />
Introduction: Announcing cancer to a patient is not a simple task. Usually doctors<br />
fail to inform patients about this diagnosis and this is still more likely in older<br />
people. The need of information in elderly cancer patients is not well established. In<br />
developed countries <strong>the</strong> majority of old patients demand exhaustive information<br />
about <strong>the</strong>ir disease. However in developing countries where social and cultural issues<br />
are different, perception of cancer in <strong>the</strong> elderly is not well studied. Therefore we<br />
conducted a prospective study on <strong>the</strong> needs of elderly Moroccan cancer patients for<br />
information about <strong>the</strong>ir disease.<br />
Methods: This was a prospective descriptive study, conducted in <strong>the</strong> National<br />
Institute of Oncology of Morocco (December 2010-September 2011). Cancer patients<br />
older than 70 were included. A questionnaire was given to participants.<br />
Demographics, disease characteristics, social and economic features were recorded.<br />
Informed consent was required.<br />
Results: 150 patients responded to <strong>the</strong> questionnaire. Mean age was 73. Men to<br />
woman sex-ratio 0.85. 72.7% of patients were diagnosed in advanced stages. Illiteracy<br />
was found in 76%. 87.3% of patients did not have health insurance. All patients were<br />
Muslim, practicing in 97%. 57% ignored diagnosis. 80% didn’t want to know fur<strong>the</strong>r<br />
information about prognosis and treatment side effects. Family protection from<br />
information was found in 70%.<br />
Conclusion: Elderly Moroccans affected with cancer are less demanding of details<br />
about <strong>the</strong>ir illness. Illiteracy and cultural background may play major roles in this.<br />
Protection by relatives is also an influence. Comparative studies with young patients<br />
are needed.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1473P PATIENT PREFERENCE, ADHERENCE AND OUTCOMES<br />
IN ONCOLOGY: DEVELOPMENT OF A THEORETICAL MODEL<br />
S.L. Shingler 1 , B. Bennett 1 , J. Cramer 2 , C. Twelves 3 , A. Towse 4 and A.J. Lloyd 1<br />
1 Patient Reported Outcomes, <strong>Oxford</strong> Outcomes, An ICON PLC Company,<br />
<strong>Oxford</strong>, UNITED KINGDOM, 2 School of Medicine, Yale University, New Haven,<br />
CT, UNITED STATES OF AMERICA, 3 Leeds Institute of Molecular Medicine & St<br />
James’s Institute of Oncology, St James’s University Hospital, Leeds, UNITED<br />
KINGDOM, 4 Health Economics, Office of Health Economics, London, UNITED<br />
KINGDOM<br />
Introduction: A patient’s preference may guide <strong>the</strong>ir behaviour and influence <strong>the</strong>ir<br />
treatment outcomes. However, <strong>the</strong> importance of understanding patient preferences<br />
within oncology is unclear. The present study was designed to review <strong>the</strong> literature<br />
regarding preferences, adherence and <strong>the</strong>ir link to outcomes specifically in <strong>the</strong><br />
oncology setting and to propose a <strong>the</strong>oretical model.<br />
Methodology: Published data examining patient preference, adherence and<br />
outcomes, specific to oncology, from 1982 to <strong>2012</strong>, was searched for in Embase,<br />
Medline and Cochrane Library databases. Articles were <strong>the</strong>n reviewed independently<br />
by two researchers and rated on <strong>the</strong>ir relevance and quality. Information from <strong>the</strong><br />
retrieved literature and discussion with experts in <strong>the</strong> fields of oncology and patient<br />
preference, informed <strong>the</strong> development of <strong>the</strong> <strong>the</strong>oretical model.<br />
Results: The search yielded 2359 abstracts, of which 93 were reviewed in detail after<br />
de-duplication and abstract review. Evidence from <strong>the</strong> highest quality and most<br />
relevant articles (n = 19) were included in <strong>the</strong> development of <strong>the</strong> <strong>the</strong>oretical model.<br />
Relationships between patient preference, adherence and clinical outcomes/HRQoL<br />
were found to exist. Adverse effects (AEs) were found to have a strong relationship<br />
with adherence. Patient beliefs and values were also identified as having a moderating<br />
effect on adherence.<br />
Discussion: This review identified external and cognitive variables related to patient<br />
preference, adherence behaviour and outcome, which are included in <strong>the</strong> <strong>the</strong>oretical<br />
ix476 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
model. Specifically, external variables have an impact on adherence behaviour.<br />
However, this relationship is moderated by cognitive variables. Central to <strong>the</strong><br />
<strong>the</strong>oretical model is <strong>the</strong> dynamic influence of AEs. AEs are proposed as having an<br />
impact on clinical outcomes and HRQoL, directly and indirectly through adherence<br />
behaviour, as well as impacting on external factors and may influence cognitive<br />
variables. Improving patient preference may improve clinical outcomes/HRQoL in<br />
oncology patients. The proposed <strong>the</strong>oretical model provides <strong>the</strong> opportunity to<br />
identify such hypo<strong>the</strong>ses for fur<strong>the</strong>r research with a view to improving adherence<br />
and clinical outcomes in oncology.<br />
Disclosure: S.L. Shingler: <strong>Oxford</strong> Outcomes were paid a fixed fee for conducting this<br />
research project. B. Bennett: <strong>Oxford</strong> Outcomes were paid a fixed fee to conduct this<br />
research project. J. Cramer: Prof Cramer was paid a fixed honorary payment for her<br />
expert input on this study. C. Twelves: Prof Twelves was paid a fixed honorary fee<br />
for his expert input into this study. A. Towse: Prof towse was paid a fixed honorary<br />
fee forhis expert input into <strong>the</strong> study. A.J. Lloyd: <strong>Oxford</strong> Outcomes were paid a fixed<br />
fee for conducting this research project.<br />
1474 MORBIDITY IN ADVANCED BASAL CELL CARCINOMA (BCC)<br />
AND BCC NEVUS SYNDROME (BCCNS) FROM THE PATIENT<br />
(PT) AND PHYSICIAN PERSPECTIVE: DEVELOPMENT OF A<br />
PATIENT-REPORTED OUTCOME (PRO) QUESTIONNAIRE<br />
S.D. Mathias 1 , M. Chren 2 , Y.M. Yim 3 , H. Colwell 1 ,C.Reyes 3 , D.M. Chen 4 and S.<br />
W. Fosko 5<br />
1 Health Outcomes, Health Outcomes Solutions, Winter Park, FL, UNITED<br />
STATES OF AMERICA, 2 Dermatology, University of California, San Francisco,<br />
San Francisco, CA, UNITED STATES OF AMERICA, 3 Biometrics, Health<br />
Outcomes and Payer Support, Genentech/Roche, South San Francisco, CA,<br />
UNITED STATES OF AMERICA, 4 U.S. Medical Affairs, Genentech, South<br />
San Francisco, CA, UNITED STATES OF AMERICA, 5 Dermatology, St. Louis<br />
University, School of Medicine, St. Louis, MO, UNITED STATES OF AMERICA<br />
Purpose: Although BCC is <strong>the</strong> most common skin cancer, <strong>the</strong> pt experience is not<br />
well understood. In a small subset of BCC pts, extensive invasion to subcutaneous<br />
structures can lead to locally advanced disease or metastases (advanced BCC<br />
(aBCC)). BCCNS is a rare genetic condition associated with life long, multiple BCCs.<br />
BCCNS pts may also develop aBCC. Lesions are common in sun-exposed areas such<br />
as <strong>the</strong> face and upper trunk and may result in disfiguring scars. To inform <strong>the</strong><br />
development of a PRO questionnaire, qualitative concept elicitation interviews were<br />
conducted with aBCC and BCCNS pts and physicians.<br />
Methods: In an IRB approved study, interviews were conducted in pts > 18 yr<br />
diagnosed with aBCC or BCCNS and physicians using an interview guide containing<br />
open-ended questions about impact of symptoms on functioning and well-being.<br />
Transcripts from each 1 hr interview were analyzed.<br />
Results: A total of 30 pts were interviewed, comprised of 14 aBCC (locally advanced,<br />
n = 8 and metastatic, n = 6; 73% male) and 16 BCCNS (50% male) pts. Mean (SD)<br />
age for aBCC pts was 64 (11) and 51 (10) for BCCNS pts. A variety of patient<br />
experiences were reported (eg, bleeding, oozing wounds, vision problems). Physical<br />
appearance, including scarring and disfigurement affected 73% of pts. 80% of pts<br />
made lifestyle changes such as avoidance of outdoor activities, meeting new people,<br />
and intimate relationships. Assistance in tasks was often needed. Emotional effects,<br />
including worry about when and where <strong>the</strong> next lesion would appear, were evident<br />
in BCCNS pts (81%). Physicians (n = 4) noted that aBCC pts worry about cancer in<br />
general and <strong>the</strong> possibility of more tumors, while BCCNS pts face tumor recurrence,<br />
multiple surgeries and disfigurement. Based on <strong>the</strong> interview results and lack of<br />
existing PRO questionnaires capturing <strong>the</strong>se concepts, 2 questionnaires were<br />
developed for aBCC and BCCNS.<br />
Conclusion: aBCC and BCCNS can have significant and unique impacts on<br />
well-being, appearance, daily and emotional functioning, and overall quality of life.<br />
Results from an ongoing validation study will be used to finalize <strong>the</strong>se PRO<br />
questionnaires.<br />
Disclosure: S.D. Mathias: Susan D Mathias is an employee of Health Outcomes<br />
Solutions, which was paid by Genentech Inc to undertake this study. M. Chren:<br />
Consultant for Genentech Y.M. Yim: Roche employment and stock ownership<br />
H. Colwell: Consultant for Genentech and Health Outcomes Solutions C. Reyes:<br />
Roche employment and stock ownership D.M. Chen: Roche employment and stock<br />
ownership S.W. Fosko: Consultant for Genentech<br />
1475 SOMATIC VULNERABILITY IN ONCOLOGICAL PATIENTS<br />
L. Onganía 1 , P. Climentzos 2 , M.P. Bramajo 2 , O. Osores 1 and M. Blanco Villalba 3<br />
1 Psychooncology, Lucha Contra el Cáncer Ushuaia, Ushuaia, ARGENTINA,<br />
2 Psychooncology, Centro Médico Austral Omi, Buenos Aires, ARGENTINA,<br />
3 Oncology, Centro Médico Austral Omi, Buenos Aires, ARGENTINA<br />
Introduction: Making a complete psychosocial diagnosis in oncological patients, at<br />
<strong>the</strong> beginning of medical treatment enriches <strong>the</strong> approach of interdisciplinary teams.<br />
It gives important information that may be used to decide future interventions.<br />
Somatic vulnerability is a psychoanalytic concept that shows some dimensions of <strong>the</strong><br />
personality and environment that may put <strong>the</strong> patient in risk. Some of <strong>the</strong>m are<br />
alexitimia (difficulty to express emotions), operatory thinking, over-adaptation,<br />
depression, anxiety, stress and supportive environment. Doctors are fairly used to<br />
detect some depressive symptoms, but no so familiarized with <strong>the</strong> detection of <strong>the</strong><br />
o<strong>the</strong>r kind of dimensions that are also risky for <strong>the</strong> patient evolution or quality of<br />
life.<br />
Objectives: Observe <strong>the</strong> presence of somatic vulnerability in cancer patients.<br />
Material and methods: Descriptive, transversal and randomized study. Sample: 103<br />
cancer patients that attend to a private cancer center between April and June of<br />
2011. Instruments: Somatic Vulnerability Scale (EVS-25) and specifically designed<br />
questionnaire.<br />
Results: 50 of 103 patients show somatic vulnerability. The 54% of <strong>the</strong> vulnerable<br />
ones, doesn’t evidence any depressive disorder. Only 15% of <strong>the</strong> vulnerable patients<br />
are in psychological treatment. Most of <strong>the</strong>m give high results for <strong>the</strong> o<strong>the</strong>r<br />
dimensions that involve somatic vulnerability (alexitimia, operatory thinking,<br />
over-adaptation, anxiety, stress or unsupportive environment in different<br />
percentages).<br />
Conclusion: This study shows that a high percentage of <strong>the</strong> patients have somatic<br />
vulnerability. The somatic vulnerability seems to be hard to be detected by doctors<br />
because it involves many specific mental dimensions. In fact, only 15% of <strong>the</strong><br />
patients in risk are in psychological treatment. The intervention of a trained<br />
professional seems to be relevant to make an earlier diagnosis of <strong>the</strong> patients in risk,<br />
affecting directly in <strong>the</strong> evolution and quality of life of <strong>the</strong>m and <strong>the</strong>ir families.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1476 SEXUALITY OF BREAST CANCER PATIENTS TREATED WITH<br />
MASTECTOMY<br />
M. Yassine 1 , L. Védrine 2 , C. Chargari 2 , B. Ceccaldi 2 , S. Le Moulec 3 , M. Ichou 4<br />
and H. Errihani 1<br />
1 Department of Oncology, National Institute of Oncology, Rabat, MOROCCO,<br />
2 Oncology and Radiation Oncology, Hôpital d’instruction des armées du<br />
Val-de-Grâce, Paris, FRANCE, 3 Department of Oncology, Val de Grace Hospital,<br />
Paris, FRANCE, 4 Department of Oncology, Hôpital d’instruction des armées<br />
Mohamed V, Rabat, MOROCCO<br />
Background: Approximately 20% of breast cancer diagnoses are made in women<br />
younger than 45 years of age. Anticancer treatments are associated with serious<br />
problems in <strong>the</strong> sexual functioning of breast cancer patients. We assessed <strong>the</strong> sexual<br />
functioning of breast cancer patients treated with mastectomy.<br />
Patients and methods: We performed a prospective study in 110 women who had<br />
been treated with mastectomy for a breast cancer using a self-administered<br />
questionnaire on how <strong>the</strong> mastectomy had changed <strong>the</strong>ir sexual life since <strong>the</strong><br />
primary diagnosis of breast cancer.<br />
Results: All patients expressed not having received sufficient information about how<br />
<strong>the</strong> disease and treatment including surgery might affect <strong>the</strong>ir sexual life. Sixty eight<br />
percent reported being still sexually active, but 62% revealed that <strong>the</strong> cancer<br />
treatment had affected <strong>the</strong>ir sexual desire or possibility to reach orgasm; 25%<br />
observed that <strong>the</strong>ir partner was afraid of sexual intercourse and 18% felt an<br />
emotional separation in <strong>the</strong> couple during <strong>the</strong> course of <strong>the</strong> disease.<br />
Conclusion: Problems related to body image and sexuality were identified in all<br />
women post mastectomy. It is time to better take into account quality of life, and<br />
more particularly <strong>the</strong> sexual function in breast cancer survivors.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds413 | ix477
abstracts<br />
sarcoma<br />
1477O ADHESION TO CLINICAL PRACTICES GUIDELINES (CPG’S)<br />
AND ROLE ON SURVIVAL FOR SOFT TISSUE SARCOMA<br />
PATIENTS. ANALYSIS OF A POPULATION BASED COHORT<br />
FROM RHONE-ALPES REGION<br />
O. Derbel 1 , C. Cropet 2 , P. Meeus 3 , F-N. Gilly 4 ,G.Vaz 5 , P. Thiesse 6 , D. Cellier 7 ,<br />
D. Vince-Ranchere 8 , J-Y. Blay 9 , I. Ray-Coquard 9<br />
1 Department of Medical Oncology, Centre Léon Bérard, Lyon, FRANCE,<br />
2 Biostatistic Department, Centre Léon Bérard, Lyon, FRANCE, 3 Department of<br />
Surgery, Centre Léon Bérard, Lyon, FRANCE, 4 Department of Digestive Surgery,<br />
University Hospital Lyon Sud, Lyon, FRANCE, 5 Department of Surgery, Hopital<br />
Edouard Herriot, Lyon, FRANCE, 6 Department of Imaging, Centre Léon Bérard,<br />
Lyon, FRANCE, 7 Merck Serono, Lyon, FRANCE, 8 Department of Pathology,<br />
Centre Léon Bérard, Lyon, FRANCE, 9 University of Lyon, Department of Medical<br />
Oncology, Centre Léon Bérard, Lyon, FRANCE<br />
Sarcoma treatment has been suggested to be improved by <strong>the</strong> management in a<br />
multidisplinary expert team and adhesion to CPG’s (ann oncol 04). To confirm <strong>the</strong><br />
strong relation between medical practices and survival, an exhaustive analysis of <strong>the</strong><br />
outcome of <strong>the</strong> sarcoma patients population was performed in <strong>the</strong> Rhône–Alpes<br />
region.<br />
Patients and methods: From March 2005 to February 2007, 634 patients > 18<br />
years old, diagnosed with localized sarcoma in Rhone-Alpes were included (Soft<br />
tissue sarcoma (STS): n = 472; GIST: n = 129; bone primary site: n = 33).<br />
Adhesion to national CPG’s was analysed for all patients. Prognostic impact of<br />
conformity to CPG’s on overall survival (OS) and progression free survival (PFS)<br />
was analyzed for STS patients, in in a univariate analysis and a Cox model<br />
regression.<br />
Results: Institutional records of 472 patients with localized STS sarcoma were<br />
reviewed., The sex ratio (male/female) was 1.1 and varied with <strong>the</strong> type of sarcoma.<br />
The median age was 60 years (range from 18 to 92).The most frequent histological<br />
subtypes were liposarcoma (N= 133, 28%), unclassified sarcoma (N= 98, 20.7%), and<br />
leiomyosarcoma (N= 70, 14.8%). Conformity to CPGs for patients with localized<br />
sarcoma was 40, 62, 87, 94 and 82% for global conformity, initial surgery, radiation<br />
<strong>the</strong>rapy, chemo<strong>the</strong>rapy and follow-up, respectively. In multivariate analysis,<br />
conformity of surgery to CPG’s was an independent prognostic factor of PFS in<br />
patients with STS, along with age at diagnosis, grade and histological subtype (HR:<br />
0.5, 95%CI: 0.36-0.67) (p < 0.0001). Conformity of surgery (HR: 2.6), Age (HR: 1.07)<br />
and grade (HR: 0.06) are independents factors for overall survival in multivariate<br />
analysis for patients with liposarcomas.<br />
Conclusion: Conformity to CPG’s improves progression free survival for sarcoma<br />
patients. Conformity of surgical procedure to CPG’s is a major independent factor<br />
predicting PFS for STS patients and OS for patients with liposarcomas.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology 23 (Supplement 9): ix478–ix491, <strong>2012</strong><br />
doi:10.1093/annonc/mds414<br />
1478O CLINICAL BENEFIT WITH REGORAFENIB ACROSS<br />
SUBGROUPS AND POST-PROGRESSION IN PATIENTS WITH<br />
ADVANCED GASTROINTESTINAL STROMAL TUMOR (GIST)<br />
AFTER PROGRESSION ON IMATINIB (IM) AND SUNITINIB<br />
(SU): PHASE 3 GRID TRIAL UPDATE<br />
P.G. Casali 1 , P. Reichardt 2 , Y. Kang 3 , J. Blay 4 , P. Rutkowski 5 , H. Gelderblom 6 ,<br />
P. Hohenberger 7 , M. Leahy 8 , M. von Mehren 9 , H. Joensuu 10 , G. Badalamenti 11 ,<br />
M. Blackstein 12 , A. Le Cesne 13 , P. Schöffski 14 , R. Maki 15 ,J.Xu 16 , T. Nishida 17 ,<br />
I. Kuss 18 , D. Laurent 18 , G.D. Demetri 19<br />
1 Struttura Semplice Trattamento Medico dei Sarcomi dell’Adulto, Istituto<br />
Nazionale Tumori, Milano, ITALY, 2 Hematology, Oncology and Palliative, HELIOS<br />
Klinikum Bad Saarow, Bad Saarow, GERMANY, 3 Dept. of Oncology and<br />
Hematology, Asan Medical Center, Seoul, KOREA, 4 Medical Oncology, Centre<br />
Léon Bérard, Lyon Cedex, FRANCE, 5 Centrum Onkologii-, Instytut im. Marii<br />
Sklodowskiej – Curie, Warszawa, POLAND, 6 Medical Oncology, Leiden<br />
University Medical Center, Leiden, NETHERLANDS, 7 Dept. of Surgery,<br />
UniversitaetsMedizin Mannheim, Mannheim, GERMANY, 8 The Christie Hospital<br />
NHS Foundation Trust, Manchester, UNITED KINGDOM, 9 Fox Chase Cancer<br />
Center, Philadelphia, PA, UNITED STAES OF AMERICA, 10 Dept. of Oncology,<br />
Helsinki University Central Hospital, Helsinki, FINLAND, 11 U.O. di Oncologia<br />
Medica, Azienda Ospedaliero Universitaria Policlinico Paolo Giaccone, Palermo,<br />
ITALY, 12 Mount Sinai Hospital, Toronto, CANADA, 13 Institut Gustave Roussy,<br />
Villejuif, FRANCE, 14 Universitaire Ziekenhuis Gasthuisberg, Leuven, BELGIUM,<br />
15 Departments of Medicine and Pediatrics, Mount Sinai School of Medicine,<br />
New York, NY, UNITED STATES OF AMERICA, 16 307 Hospital of PLA, Beijing,<br />
CHINA, 17 Osaka Police Hospital, Osaka, JAPAN, 18 Global Clinical Development<br />
Oncology 2, Bayer HealthCare Pharmaceuticals, Berlin, GERMANY, 19 Ludwig<br />
Center at Dana-Farber/Harvard Cancer Center and Sarcoma Center,<br />
Dana-Farber Cancer Institute, Boston, MA, UNITED STATES OF AMERICA<br />
Background: Regorafenib (REG) <strong>the</strong>rapy significantly improved progression-free<br />
survival (PFS) in patients (pts) with GIST after failure of both IM and SU (J Clin<br />
Oncol <strong>2012</strong>; 30: suppl; abstr LBA10008). Results of subgroup and post-progression<br />
analyses are presented here.<br />
Methods: Pts were randomized (2:1) to receive best supportive care plus ei<strong>the</strong>r REG<br />
160 mg or placebo (PL) po once daily (3 wks on/1 wk off). The primary endpoint<br />
was PFS. Upon progression in ei<strong>the</strong>r arm, unblinding could occur. Pts on PL were<br />
eligible for crossover to open-label (OL) REG and progressive pts on REG were<br />
allowed to continue REG upon local physician’s choice.<br />
Results: GRID screened 234 pts and randomized 199 (REG: 133, PL: 66), well<br />
balanced for baseline characteristics. The PFS primary endpoint (according to<br />
RECIST) was met both per central review (median PFS 4.8 mo for REG vs. 0.9 mo<br />
for PL), and by investigator assessment (median PFS 7.4 mo for REG vs. 1.7 mo for<br />
PL). Exploratory sensitivity analyses demonstrate similar positive impact on PFS<br />
across pre-specified subgroups by number of prior systemic <strong>the</strong>rapy, geographical<br />
region, age, baseline ECOG score, duration of prior treatment with imatinib, or KIT/<br />
PDGFRA mutation. Median overall survival has not been reached in ei<strong>the</strong>r arm.<br />
Taking <strong>the</strong> double-blind and OL periods toge<strong>the</strong>r, 188 pts received REG.<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
Annals of Oncology<br />
Post-progression PFS per investigator assessment was 5.0 mo for pts in <strong>the</strong> PL arm<br />
who crossed over to REG (n = 56), and 4.5 mo for pts in <strong>the</strong> REG arm who<br />
continued to receive REG after unblinding (n = 41).<br />
Conclusion: REG induced significant PFS benefit in GIST pts following resistance to<br />
both IM and SU across all pre-specified subgroups. Interestingly, 41 pts on REG (out<br />
of 133) whose physicians decided to continue REG after RECIST progression had an<br />
additional PFS benefit which was in <strong>the</strong> same range. This suggests that continuous<br />
kinase inhibition after progression may benefit pts by slowing tumor progression<br />
and/or that RECIST criteria for progression applied by blind central review have<br />
clinical shortcomings.<br />
Disclosure: P.G. Casali: Consultant/advisory: Bayer, MSD, GSK, Infinity, Novartis,<br />
Pfizer, PharmaMar, Sanofi Honoraria: Novartis, Pfizer, PharmaMar Research<br />
funds: Amgen Dompe, Bayer, MSD, GSK, Imclone, Infinity, Lilly, Molmed,<br />
Novartis, Pfizer, PharmaMar, Sanofi. P. Reichardt: Consultant/advisory: Bayer. Y.<br />
Kang: Consultant/advisory: Bayer Research funding: Bayer. J. Blay: Honoraria:<br />
Pharmama, Novartis, Pfizer, Roche, GSK Research funding: Pharmama, Novartis,<br />
Pfizer, Roche, GSK. P. Rutkowski: Consultant/advisory: Novartis, MSD, BMS<br />
Honoraria: Novartis, Pfizer, BMS, MSD, Roche. M. Leahy: Research funding as<br />
PI for GRID study at Christie Hospital, Manchester, UK. M. von Mehren<br />
Consultant/advisory: Novartis, Pfizer, Astex; Honoraria: Novartis, Pfizer. H.<br />
Joensuu Consultant/advisory: Novartis, Boehringer-Ingelheim. A. Le Cesne<br />
Honoraria: Novartis, Pfizer, Pharmamar. P. Schöffski: Research funding: Bayer. R.<br />
Maki: Consultant/advisory: Bayer, Pfizer, Novartis; Honoraria: Bayer, Pfizer,<br />
Novartis; Research funding: Pfizer; Expert testimony: Pfizer. I. Kuss: Employment:<br />
Bayer. D. Laurent: Employment: Bayer Stock ownership: Bayer. G.D. Demetri:<br />
Consultant/advisory: Novartis, Pfizer, GSK, Roche, Deciphra (uncompensated),<br />
Infinity Research funding: Novartis, Pfizer, GSK, Infinity Expert testimony<br />
(uncompensated): Infinity, Pfizer, Novartis, Bayer. All o<strong>the</strong>r authors have declared<br />
no conflicts of interest.<br />
1479PD MULTI-CENTER PHASE II STUDY OF SUNITINIB IN<br />
PATIENTS WITH ADVANCED AGGRESSIVE FIBROMATOSIS<br />
(D<strong>ESMO</strong>ID TUMOR)<br />
J. Jo 1 , K. Kim 1 , Y.S. Hong 1 , J. Lee 1 , J. Lee 2 , Y.S. Park 2 , S.Y. Kim 3 , T.W. Kim 1<br />
1 Department of Oncology, Asian Medical Center, Seoul, KOREA, 2 Medicine,<br />
Samsung Medical Center, Seoul, KOREA, 3 Center for Colorectal Cancer,<br />
National Cancer Center, Goyang, KOREA<br />
Background: There have been reports on <strong>the</strong> efficacy of imatinib, a multi-targeted<br />
tyrosine kinase inhibitor, in <strong>the</strong> treatment of aggressive fibromatosis (AF, also known<br />
as desmoid tumor) by inhibiting PDGFRA and PDGFRB ra<strong>the</strong>r than KIT. Sunitinib<br />
has not only PDGFRs, KIT, and FLT3 inhibiting activity but also VEGFRs blockade<br />
as antiangiogenesis. The aim of this study is to evaluate <strong>the</strong> efficacy and safety of<br />
sunitinib for patients with AF.<br />
Methods: This is a multi-center, phase II study. Nineteen patients with<br />
pathologically proven AF were accrued between Jun 2008 and Mar <strong>2012</strong>. Sunitinib<br />
was administered with 37.5 mg/day for 4 weeks without break, comprising one cycle.<br />
Primary endpoint was response rate.<br />
Results: Ten (53%) patients were female and <strong>the</strong> median age was 30 years (range,<br />
22-67). Most of <strong>the</strong> primary sites were intra-abdominal (12, 63%), and AF associated<br />
with familial adenomatous polyposis was observed in 9 (47%). The median tumor<br />
size was 5.0 cm (range, 2.0-14.2), and 8 patients (42.1) had multifocal tumor lesions.<br />
Of <strong>the</strong> 15 patients who received two or more cycles of treatment, 6 (40%) required<br />
dose reductions. With a median 5 cycles per patients (range, 1-47 cycles), 5 (26%)<br />
achieved a partial response and 8 (42%) had stable disease; <strong>the</strong> overall response rate<br />
was 26% (95% CI, 6.3-45.7). With median follow-up time of 11.8 months (range,<br />
1.4-43.7), <strong>the</strong> 2-year progression-free survival and overall survival were 70% and<br />
100%, respectively. Of 10 patients in whom thyroid function test were checked, 1<br />
(10%) had grade 2 hypothyroidism and 5 (50%) grade 1. Grade 3 or 4 adverse events<br />
of sunitinib with frequency > 5% of patients included neutropenia (33%), diarrhea<br />
(5%), and hand-foot syndrome (5%). Intra-abdominal tumor perforation with cystic<br />
necrosis within first cycle of sunitinib occurred in 3 cases; 2 cases underwent<br />
palliative tumor resection and 1 case recovered with medical treatment. There was no<br />
treatment-related death.<br />
Conclusion: Sunitinib was well-tolerated and showed promising antitumor activity in<br />
patients with AF. Fur<strong>the</strong>r investigations on clinical and translational researches of<br />
sunitinib in <strong>the</strong>se patients are warranted.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1480PD EFFICACY AND SAFETY OF DENOSUMAB IN GIANT CELL<br />
TUMOR OF BONE: UPDATED RESULTS WITH<br />
INDEPENDENT RADIOGRAPHIC ASSESSMENT OF<br />
RESPONSE<br />
J. Blay 1 , S. Chawla 2 , E. Choy 3 , R.J. Grimer 4 , S. Ferrari 5 , P. Reichardt 6 ,<br />
P. Rutkowski 7 , D. Thomas 8 , Y. Qian 9 , I. Jacobs 10<br />
1 University Claude Bernard Lyon I, Centre L, Lyon Cedex 08, FRANCE, 2 Clinical<br />
Research, Sarcoma Oncology Center, Los Angeles, CA, UNITED STATES OF<br />
AMERICA, 3 Dana Farber Cancer Center, Harvard University, Boston, MA,<br />
UNITED STATES OF AMERICA, 4 Orthopaedic Oncology, Royal Orthopaedic<br />
Hospital, Birmingham, UNITED KINGDOM, 5 Chemo<strong>the</strong>rapy, Istituto Ortopedico<br />
Rizzoli, Bologna, ITALY, 6 Hematology, Oncology and Palliative, HELIOS Klinikum<br />
Bad Saarow, Bad Saarow, GERMANY, 7 Centrum Onkologii-, Instytut im. Marii<br />
Sklodowskiej – Curie, Warszawa, POLAND, 8 Oncology, Peter MacCallum Cancer<br />
Centre, East Melbourne, AUSTRALIA, 9 Biostatistics, Amgen Inc., Thousand<br />
Oaks, CA, UNITED STATES OF AMERICA, 10 Clinical Development, Amgen Inc.,<br />
Thousand Oaks, CA, UNITED STATES OF AMERICA<br />
Giant cell tumor of bone (GCTB) is an aggressive osteolytic tumor that causes<br />
substantial morbidity. We present data from a second open label phase 2 study of<br />
denosumab in GCTB. Patients (pts) with surgically unresectable GCTB (Cohort 1),<br />
resectable GCTB with planned surgery (Cohort 2), and pts who transferred from <strong>the</strong><br />
first phase 2 study (Cohort 3) received SC denosumab (120 mg, Q4W), with<br />
additional doses on days 8 and 15 (Cohorts 1–2). Prespecified efficacy and safety<br />
analyses included all pts who received denosumab. Radiographic assessments of<br />
tumor response included pts with ≥1 evaluable time point response (TPR);<br />
assessments included RECIST (lesion size), EORTC (PET Standardized Uptake Value<br />
by Body Weight [SUV bw]), and Density/Size (CT Hounsfield units). Pts (N = 282)<br />
were 58% women, mean age 36 (SD 13) years; 46% had recurrent unresectable<br />
disease. AEs were reported in 236 pts (84%); most frequent were arthralgia 20%;<br />
headache 18%; nausea 17%; fatigue 16%; back pain 15%; and extremity pain 15%.<br />
Osteonecrosis of <strong>the</strong> jaw was reported in 3 pts (1%). One pt died of respiratory failure,<br />
not denosumab-related. Hypocalcemia was reported in 15 pts (5%): 14, grade 1 or 2;<br />
1, grade 3 not deemed clinically significant by <strong>the</strong> investigator. Of 100 pts in Cohort<br />
2, 90% had no surgery or less morbid surgery than planned. Radiologic analyses<br />
included 190 pts. An objective complete or partial tumor response was observed in<br />
72% of pts based on best response, any criteria. Of pts with ≥1 objective tumor<br />
response, response rates were 25% with RECIST, 96% with EORTC, and 76% with<br />
Density/Size criteria. Among pts with ≥1 evaluable TPR, <strong>the</strong> median time to objective<br />
tumor response was 3.1 months (95% CI 2.89, 3.65) based on best response using any<br />
tumor response criteria. Among pts with ≥2 evaluable TPRs ≥12 weeks apart, 96%<br />
had tumor control sustained ≥12 weeks based on <strong>the</strong> best response using any tumor<br />
response criteria. Eleven pts (6%) had disease progression. Conclusion: Denosumab<br />
appeared to be well tolerated in pts with GCTB, reduced requirements for morbid<br />
surgery, and provided a durable objective radiologic response for <strong>the</strong> majority of pts.<br />
Denosumab continues to be studied as a potential treatment for GCTB.<br />
Disclosure: J. Blay: JY Blay has served as an advisory board member for Novartis,<br />
GSK, Roche, MSD, and Pharmamar. He has conducted corporate-funded research for<br />
Novartis, GSK, Roche, MSD, and Pharmamar. S. Chawla: Sant Chawla has been an<br />
advisory board member for and has received corporate-sponsored research funding<br />
from Amgen, Threshold, Cytrax, Glaxxo, and Berg Pharma. E. Choy: E. Choy has<br />
served as an advisory board member for Amgen, Sanofi-Aventis, and Biomed Valley<br />
Discoveries. S. Ferrari: S. Ferrari has received funds from: AMGEN, MOLMED,<br />
PharmaMar, and Pfizer. He received funds for participation to scientific meetings<br />
from Takeda. P. Reichardt: P. Reichardt has received honoraria for lectures from<br />
Amgen Inc. P. Rutkowski: P. Rutkowski has served as an advisory board member for<br />
Norvartis, BMS, and MSD. He has also received honoraria for lectures and travel<br />
grants from Novartis, Pfizer, Roche, BMS, and MSD. D. Thomas: David Thomas<br />
conducts corporate-sponsored research with Pfizer and AMGEN. Y. Qian: Y. Qian is<br />
an employee and stockholder of Amgen Inc. I. Jacobs: I. Jacobs is an employee and<br />
stockholder of Amgen Inc. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds414 | ix479
1481PD A PHASE II STUDY OF DOVITINIB IN PATIENTS WITH<br />
METASTATIC OR UNRESECTABLE GASTROINTESTINAL<br />
STROMAL TUMORS AFTER FAILURE OF TWO OR MORE<br />
TYROSINE KINASE INHIBITORS<br />
Y. Kang 1 , M.H. Ryu 1 , J.J. Lee 2 , I. Park 1 , J.H. Park 3 , B. Ryoo 1<br />
1 Department of Oncology, Asan Medical Center, University of Ulsan College of<br />
Medicine, Seoul, KOREA, 2 Department of Nuclear Medicine, Asan Medical<br />
Center, University of Ulsan College of Medicine, Seoul, KOREA, 3 Department of<br />
Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine,<br />
Seoul, KOREA<br />
Objectives: This prospective, phase 2 study evaluated <strong>the</strong> efficacy and safety of<br />
dovitinib in patients (pts) with advanced gastrointestinal stromal tumors (GISTs)<br />
who failed previous standard tyrosine kinase inhibitors (TKI).<br />
Methods: Thirty pts with pathologically proven metastatic or unresectable GIST who<br />
failed a minimum of both imatinib and sunitinib were accrued between Sep 2011<br />
and Apr <strong>2012</strong>. Dovitinib was administered orally at 500 mg qd for 5 consecutive days<br />
followed by a 2 day rest period.<br />
Results: The median age was 57.5 years (range, 35-76). All had metastatic disease in<br />
<strong>the</strong> peritoneum (n = 22), liver (n = 20), lung (n = 4), or bone (n = 4). Thirteen pts<br />
(43%) also failed nilotinib (n = 8), regorafenib (n = 2) or both nilotinib and<br />
regorafenib (n = 3) after failure of imatinib and sunitinib. By RECIST criteria, <strong>the</strong>re<br />
were no objective responses, 19 (63.3%) had stable disease (SD), 5 (16.7%)<br />
progressive disease (PD), and 6 (20.0%) were not evaluable. By EORTC PET criteria<br />
(at 4 weeks), 3 pts (10.0%) achieved a partial response, 15 (50.0%) had SD, 10 (33.3)<br />
showed PD, and 2 were not evaluable. With a median follow-up of 4.8 months<br />
(range, 0.8-7.5), <strong>the</strong> medi an progression-free survival (PFS) and overall survival were<br />
3.6 months (95% CI, 2.7-4.4) and 6.2 months (95% CI, 4.9-7.5), respectively. PFS<br />
could be predicted by PET response (PD vs no PD) at 4 weeks (p = 0.003). Grade 3<br />
or 4 adverse events of dovitinib with frequency > 5% pts included as<strong>the</strong>nia (16.7%),<br />
leucopenia (6.7%), thrombocytopenia (6.7%), and hypertension (6.7%). Those<br />
toxicities were manageable with dose modification, and <strong>the</strong>re were no<br />
treatment-related deaths.<br />
Conclusions: Dovitinib showed antitumor activity with manageable toxicities in this<br />
heavily pretreated cohort of GIST patients.<br />
Disclosure: Y. Kang: Honoraria, consultant, and research fund from Novartis. All<br />
o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1482PD DASATINIB FIRST-LINE TREATMENT IN<br />
GASTROINTESTINAL STROMAL TUMORS. A MULTICENTER<br />
PHASE II TRIAL OF THE SAKK (SAKK 56/07)<br />
M. Montemurro 1 , J. Domont 2 , P. Rutkowski 3 , A.D. Roth 4 , R. von Moos 5 ,<br />
R. Inauen 6 , D. Dietrich 7 , C. Biaggi 8 , J. Prior 9 , S. Leyvraz 1<br />
1 Centre Pluridisciplinaire d’Oncologie, Centre Hospitalier Universitaire Vaudois -<br />
CHUV, Lausanne, SWITZERLAND, 2 Dept. Medical Oncology, Institut Gustave<br />
Roussy, VILLEJUIF, FRANCE, 3 Department of Soft Tissue/bone Sarcoma and<br />
Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of<br />
Oncology, Warsaw, POLAND, 4 Oncology, University Hospitals of Geneva,<br />
Geneva, SWITZERLAND, 5 Medical Oncology, Kantonal Hospital Graubünden,<br />
Chur, SWITZERLAND, 6 Dept. of Oncology, Kantonsspital St. Gallen, St. Gallen,<br />
SWITZERLAND, 7 Statistics, Swiss Group for Clinical Cancer Research SAKK,<br />
Bern, SWITZERLAND, 8 Trial Coordination, Swiss Group for Clinical Cancer<br />
Research SAKK, Bern, SWITZERLAND, 9 Nuclear Medicine, University Hospital<br />
Lausanne CHUV, Lausanne, SWITZERLAND<br />
Introduction: First line imatinib has improved <strong>the</strong> outcome of patients (pts) with<br />
gastrointestinal stromal tumor (GIST), but primary and secondary resistance remain<br />
a problem. Dasatinib is a second generation tyrosine kinase inhibitor (TKI) of<br />
bcr-abl, src-family kinases and a number of o<strong>the</strong>r oncogenic kinases including kit.<br />
Dasatinib has shown activity against imatinib-resistant cell lines in vitro.<br />
18F-fluorodeoxyglucose positron-emission-tomography (FDG-PET) measures tumor<br />
metabolic activity for early response assessment, which might be of particular use in<br />
<strong>the</strong> clinical trial setting.<br />
Methods: This two-stage phase II trial investigated dasatinib in patients with<br />
histologically proven, FDG-PET positive, TKI-naïve GIST. Dasatinib starting dose<br />
was 2x70mg/day. Response evaluation was done by serial CT and FDG-PET using<br />
EORTC PET response criteria (Young et al. 1999). PET was reviewed centrally.<br />
Elective surgery was allowed after 6 months of trial treatment. Primary endpoint was<br />
response (CR + PR) by FDG-PET after one month of dasatinib.<br />
Results: 47 of planned 52 pts have been enrolled from December 2007 to November<br />
2011, when <strong>the</strong> trial was terminated due to slow accrual. 43 pts were eligible. Median<br />
age was 61 years, 24 pts were male, 19 female. 30 pts had a performance status of 0<br />
and thirteen of 1. Mutational data are available for 28 pts so far. 20 had a KIT exon<br />
11, one a KIT exon 9 mutation, and 7 were wild-type. At a median follow-up of 12.4<br />
Annals of Oncology<br />
months, 15 pts were still on treatment. Pts went off trial for elective surgery (n = 6),<br />
progression (n = 13), toxicity (n = 4), o<strong>the</strong>r reasons (n = 2) and three patients died.<br />
5% of pts experienced G4, and 38% of pts G3 toxicity, which were most often<br />
gastrointestinal or pulmonary. 28 pts had <strong>the</strong>ir dose reduced or interrupted. The<br />
primary endpoint, FDG-PET response rate (CR + PR) at 4 weeks was 72% (14 CR, 17<br />
PR, 7 SD, 3 PD, 2 not evaluable). The response rate in patients with a KIT Exon 11<br />
mutation was 80%, in wild-type patients 57%. Median progression-free survival is<br />
11.1 months and median overall survival not yet reached.<br />
Conclusions: Dasatinib shows promising efficacy in TKI-naïve pts with FDG-PET<br />
positive GIST.<br />
Disclosure: M. Montemurro: Speakers fees and travel grants - Bayer, Pfizer, Novartis.<br />
P. Rutkowski: Consultant - BMS, Novartis, MSD Speakers fees and travel grants -<br />
Novartis, Pfizer, MSD, BMS, Roche. R. von Moos: Consultant/Advisor - AMGEN,<br />
Novartis, Roche, BMS, Pfizer, Merck Speakers fees - Roche, Amgen institutional<br />
Research Funds - AMGEN Expert Testimony - AMGEN. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
1483PD INNO-206 IS AN ACTIVE DRUG FOR RELAPSED ADVANCED<br />
SOFT TISSUE SARCOMA<br />
S. Chawla 1 , V.S. Chua 1 , A. Hendifar 1 , D. Quon 1 , S. Negre 1 , K.N. Ganjoo 2 ,<br />
K. Sankhala 3 , Y. Lavinski 4 , S. Wieland 5 , D. Levitt 5<br />
1 Clinical Research, Sarcoma Oncology Center, Los Angeles, CA, UNITED<br />
STATES OF AMERICA, 2 Medical Oncology, Stanford University Medical School,<br />
Palo Alto, CA, UNITED STATES OF AMERICA, 3 Medical Oncology, University of<br />
Texas Health Science Center, San Antonio, TX, UNITED STATES OF AMERICA,<br />
4 Research, MutualHealth LLC, Newport Beach, CA, UNITED STATES OF<br />
AMERICA, 5 Clinical Development, CytRx Corporation, Los Angeles, CA, UNITED<br />
STATES OF AMERICA<br />
Background: We have studied <strong>the</strong> safety and tumor response of a doxorubicin<br />
conjugate, INNO-206, in patients with metastatic STS who progressed on prior<br />
chemo<strong>the</strong>rapy. INNO-206 is a conjugate of doxorubicin attached to an acid-sensitive<br />
linker that binds covalently to cysteine-34 in circulating albumin.<br />
Methods: INNO-206 was administered IV at 350 mg/m 2 (260 mg/m 2 dox. eq.) every<br />
21 days for up to 8 consecutive cycles. Tumor response was monitored every o<strong>the</strong>r<br />
month and treatment continued until tumor progression or unacceptable toxicity.<br />
Standard safety monitoring was performed and cardiac function was followed<br />
periodically using MUGA or cardiac ultrasound.<br />
Results: As of May 1, <strong>2012</strong>, 19 patients were entered in <strong>the</strong> study. 13/19 patients had<br />
STS of various types. Of <strong>the</strong> initial 19 patients treated at <strong>the</strong> 350 mg/m 2 dose, no<br />
individuals experienced a grade 3 or 4 non-hematological toxicity during Cycle<br />
1. The majority of patients demonstrated transient grade 3 or 4 neutropenias that<br />
resolved prior to <strong>the</strong> next cycle with and without G-CSF treatment. No patient<br />
exhibited relevant cardiotoxicity as determined by MUGA or cardiac ultrasound. Of<br />
19 patients, serious adverse events included febrile neutropenia (3) sepsis (1) and<br />
mucositis (1). Of <strong>the</strong> 13 patients with STS, 5 objective partial responses (3 of whom<br />
received prior doxorubicin) are ongoing as well as 7 patients with stable disease<br />
(median 6.43 months, range 1-10.7+ months). 1/13 patients had progressive disease<br />
at <strong>the</strong> first evaluation. 2/19 patients died with <strong>the</strong> first cycle (1 PD, 1 sepsis).<br />
Conclusion: INNO-206 is an active drug for <strong>the</strong> treatment of patients with advanced<br />
STS who have failed prior chemo<strong>the</strong>rapy. Cumulative doses of 2000 mg/m 2 of<br />
doxorubicin equivalents have been achieved, which is over 3½ x <strong>the</strong> peak cumulative<br />
dose of standard doxorubicin. Adverse events are primarily hematological and no<br />
cardiotoxicity has been observed.<br />
Disclosure: S. Chawla: Corporate sponsored research from CytRx Corporation.<br />
S. Wieland: Salary and stock ownership from CytRx Corporation. D. Levitt:<br />
Salaryand stockownership from CytRx Corporation. All o<strong>the</strong>r authors have declared<br />
no conflicts of interest.<br />
1484PD SELECTIVE INTERNAL RADIATION THERAPY (SIRT) FOR<br />
GIST LIVER METASTASES RESISTANT TO TYROSINE<br />
KINASE INHIBITORS<br />
P. Hohenberger 1 , N. Rathmann 2 , A. Peschel 2 , J. Schuette 3 , S.O. Schoenberg 2 ,<br />
D. Dinter 2 , S. Diehl 2<br />
1 Dept. of Surgery, UniversitaetsMedizin Mannheim, Mannheim, GERMANY,<br />
2 Dept. of Radiology and Nuclear Medicine, UniversitätsMedizin Mannheim,<br />
Mannheim, GERMANY, 3 Department of Oncology and Hematology,<br />
Schwerpunktpraxis Haematoonkologie Duesseldorf, Duesseldorf, GERMANY<br />
Background and aim: The liver is <strong>the</strong> typical location of metastases from<br />
gastrointestinal stromal tumors (GIST). Usually, metastases of GIST are treated by<br />
tyrosine kinase inhibitors (imatinib, sunitinib or o<strong>the</strong>rs). In patients with multiple<br />
metastases resistant to drugs and not amenable to surgical resection interventional<br />
ix480 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
ablation techniques are considered. Selective internal radiation <strong>the</strong>rapy (SIRT),<br />
delivering 90 Y-loaded particles to liver metastases might offer a new treatment option.<br />
Material/methods: We evaluated nine patients with liver metastases of GIST being<br />
progressive under drug (TKI) treatment and referred for SIRT. Five patients had liver<br />
metastases only, in ano<strong>the</strong>r four patients extrahepatic disease was present but<br />
controlled by TKI <strong>the</strong>rapy. One patient had to be excluded from treatment due to a<br />
hepato-pulmonary shunt volume exceeding 20 %. Depending on intrahepatic tumor<br />
distribution, ei<strong>the</strong>r both liver lobes or one lobe were treated using 90 Y spheres.<br />
Follow-up was done via dynamic MRI, contrast-enhanced (CE)-CT and<br />
18 F-FDG-PET-CT using modified RECIST criteria at 3 months intervals. All patients<br />
with targetable mutations in KIT or PD continued with drug to control extrahepatic<br />
tumor spread.<br />
Results: In <strong>the</strong> eight patients, fourteen liver lobes were treated with a mean activity<br />
of 1.07GBq per lobe. No severe side effects occured in 7/8 patients, while one male<br />
developed an ulcer of <strong>the</strong> stomach not responding to high dose antacid <strong>the</strong>rapy.<br />
Radiation induced liver disease (RILD) was not observed. Three patients showed a<br />
complete remission (CR) whereas four o<strong>the</strong>r patients developed a partial remission<br />
(PR) and two patients had to be classified as stable disease (SD). Median follow-up<br />
interval is 16 months (range, 4 - 52 months). The mean progression free interval<br />
regarding hepatic disease was 9,6 months.<br />
Conclusion: SIRT offers a safe and effective treatment option in patients with liver<br />
metastases from GIST being progressive under TKI treatment.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1485PD CLINICAL SIGNIFICANCE OF SURGERY FOR GASTRIC<br />
SUBMUCOSAL TUMORS WITH SIZE ENLARGEMENT<br />
DURING WATCHFUL WAITING PERIOD<br />
Y. Miyazaki 1 , K. Nakajima 2 , Y. Kurokawa 2 , T. Takahashi 2 , S. Takaguchi 2 ,<br />
H. Miyata 2 , M. Yamasaki 2 , T. Nishida 3 , M. Mori 2 , Y. Doki 2<br />
1 Gastroenterological Surgery, Osaka University Graduate School of Medicine,<br />
Suita, JAPAN, 2 Gastroenterological Surgery, Osaka University, Suita, JAPAN,<br />
3 Department of Surgery, Osaka Police Hospital, Osaka, JAPAN<br />
Aims: Recent Japanese clinical practice guidelines for gastrointestinal stromal tumor<br />
(GIST) indicates that surgical resection is optionally considered for small (
1488P ORGANISATION OF SARCOMA PATIENT MANAGEMENT IN<br />
REFERENCE CENTERS IN NETSARC NETWORK: ANALYSIS<br />
OF THE QUALITY OF RESECTION<br />
S. Bonvalot 1 , P. Meeus 2 , E. Stoeckle 3 , B. Bui 4 , A. Le Cesne 5 , N. Penel 6 ,I.<br />
L. Ray-Coquard 7 , J. Coindre 8 , C. Chemin 9 , J. Blay 7 , On Behalf of The Netsarc<br />
National Network (www.netsarc.org)<br />
1 Department of Surgery, Institut Gustave Roussy, Villejuif, FRANCE, 2 Surgery,<br />
Centre Léon Bérard, Lyon, FRANCE, 3 Surgery, Institute Bergonie, Bordeaux<br />
Cedex, FRANCE, 4 Medical Oncology, Institute Bergonie, Bordeaux Cedex,<br />
FRANCE, 5 Dept. Medical Oncology, Institut Gustave Roussy, Villejuif, FRANCE,<br />
6 Medical Oncology, Centre Oscar Lambret, Lille, FRANCE, 7 Medical Oncology,<br />
Centre Léon Bérard, Lyon Cedex, FRANCE, 8 Anatomopathology, Institute<br />
Bergonie, Bordeaux Cedex, FRANCE, 9 Medical Evaluation, Centre Léon Berard,<br />
Lyon, FRANCE<br />
The French National Cancer Institute suggested <strong>the</strong> improvement of sarcoma<br />
management when performed in a multidisplinary expert team. Since 2009, a<br />
network of 26 reference multidisciplinary boards has been created to improve <strong>the</strong><br />
quality of care of sarcoma patients in France. All patient cases presented are<br />
uploaded in <strong>the</strong> NetSarc network collecting patient characteristics, clinical situation<br />
at <strong>the</strong> time of <strong>the</strong> discussion, medical decision, and patient outcome (survival and<br />
relapse).<br />
Patients and methods: From January 2010 to April <strong>2012</strong>, 8934 patients were<br />
included on this database. Patients were presented from centers within (N = 5911,<br />
66%) or outside (N = 2343, 26%) <strong>the</strong> Netsarc Network (parameter unknown in N =<br />
679, 8% patient). Patient and disease characteristics and treatment results are<br />
described.<br />
Results: There were 4662 women (52%) and 4272 men (48%). Median size of <strong>the</strong><br />
sarcoma was 95mm (range2- > 400). Soft tissue, visceral, and bone represented 6381<br />
(71%) 1285 (14%) and 1264 (14%) of patients respectively. In soft tissue tumours,<br />
grade 1, 2, 3 were reported in 44%, 33%, 23% of patients. The most frequent<br />
histological subtypes were leiomyosarcomas (all sites) (n = 769, 9%), GIST (558, 6%),<br />
dedifferentiated liposarcomas (n = 439, 5%). Most frequent primary sites were thigh<br />
(1268, 14%), retroperitoneal (796, 9%), thoracic wall (460, 5%), uterus (405, 4.5%),<br />
legs (325, 4%). 1052 (11%) patients were reported to have metastases. Clinical and<br />
disease status at <strong>the</strong> time of discussion was prior to: biopsy (N = 824, 9%), first<br />
surgery (N = 1751, 20%), adjuvant treatment (N = 2806, 31%). 6161 (67%) patients<br />
had a surgery, n = 1472 (24%) in <strong>the</strong> Netsarc network and outside n = 1843 (30%); in<br />
n = 2846 (46%) this information is not still documented. Patients whose primary<br />
surgery was performed in Netsarc centers had R0, R1, R2, and fragmented primary<br />
surgery in 61%, 31%, 5%, 2% vs 37%, 40%, 16%, 7% in primary care centers<br />
non-Netsarc centers (p < 0.000001).<br />
Conclusions: This first analysis of <strong>the</strong> NetSarc database shows that more patients<br />
had optimal surgery in reference centers than in primary care centers. This tool will<br />
ensure <strong>the</strong> monitoring of dedicated action to improve <strong>the</strong> management of sarcoma<br />
patients in <strong>the</strong> future.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1489P FINAL RESULTS OF A FRENCH SARCOMA GROUP (FSG)<br />
RETROSPECTIVE REVIEW OF 110 PATIENTS WITH PRIMARY<br />
LOCALIZED GASTROINTESTINAL STROMAL TUMORS (GIST)<br />
OF THE DUODENUM<br />
F. Duffaud 1 , T. Huynh 1 , P. Cassier 2 , E. Boucher 3 , O. Bouché 4 , A. Le Cesne 5 ,<br />
B. Landi 6 , J. Mancini 7 , F. Marchal 8 , J. Blay 2<br />
1 Medical Oncology, C.H.U. La Timone Adultes, Marseille Cedex, FRANCE,<br />
2 Medical Oncology, Centre Léon Berard, Lyon, FRANCE, 3 Medical Oncology,<br />
Centre Eugène Marquis, Rennes, FRANCE, 4 Gastroenterology, University<br />
Hospital, Reims, FRANCE, 5 Dept. Medical Oncology, Institut Gustave Roussy,<br />
Villejuif, FRANCE, 6 Gastroenterology, Hopital Européen Georges Pompidou,<br />
Paris, FRANCE, 7 Biostatistics, la Timone University Hospital, Marseille, FRANCE,<br />
8 Surgery, Centre Alexis Vautrin, Nancy, FRANCE<br />
Background: Duodenal GISTs represent 3-5% of all GISTs, with limited<br />
understanding of patient outcomes from small series. We conducted a retrospective<br />
analysis of localized duodenal GISTs over <strong>the</strong> past 18 years.<br />
Methods: Patients (pts) were identified in 2 ways: a group of 101 pts reported via<br />
survey from 20 FSG centers, and a group of 9 pts included in <strong>the</strong> BFR14 trial.<br />
Results: Pts were: 55 females, 55 males, with a median age of 57 years (30-84), and<br />
median ECOG 0 (0-3). Abdominal pain, anemia, and overt GI bleeding were <strong>the</strong><br />
most common symptoms. Tumors (T) originated mainly in D2 (41%), or D3 (27%),<br />
with a median size of 5 cm (1.5-30). All pts except four had resection of <strong>the</strong> primary<br />
T. Surgical procedures were: local resection (LR) [segmental duodenectomy (n = 31),<br />
wedge local resection (n = 31), local excision (n = 6)], and duodenopancreatectomy<br />
(DP, n = 20). Resections were R0 in 84 pts (79%), R1 in 6 pts (6%). T characteristics<br />
included: KIT+ (n = 100), CD34 + (n= 54), mitoses/50 HPF ≤ 5 (n= 70), or > 5 (n =<br />
24), Miettinen low-risk (n = 37), and high-risk (n = 19), necrosis (n = 29), spindle cell<br />
(n = 84). Genotype was evaluated in 36 cases: KIT exon 11 mutant (n = 30), no<br />
mutation (n = 4), and KIT exon 9 mutant (n = 2). 12 pts received neoadjuvant<br />
Annals of Oncology<br />
imatinib (IM) <strong>the</strong>rapy resulting in 6 PR, 3 SD, 1 PD. 17 pts received adjuvant IM<br />
<strong>the</strong>rapy. With a median FU of 32 months (1-250), 95 pts (86%) are alive.<br />
Twenty-eight (26%) pts relapsed: 6 LR, and 26 metastases. The 4-year OS and EFS<br />
rates were 89.5% and 68.2 %. The 6-year OS and EFS rates were 89.5% and 36.5%.<br />
Univariate analysis showed that: age and ECOG PS have an impact on OS (p= 0.008,<br />
p
Annals of Oncology<br />
1491P RESPONSE TO SORAFENIB IN PDGFRA-D842V MUTATED<br />
METASTATIC GASTROINTESTINAL STROMAL TUMOR<br />
(GIST), SUPPORTED BY BIOMOLECULAR FUNCTIONAL<br />
ANALYSES<br />
E. Fumagalli1 , S. Pilotti2 , E. Conca2 , R. Bertulli1 , M. Fiore3 , C. Morosi4 , F. Bozzi2 ,<br />
P.G. Casali1 , E. Tamborini2 1<br />
Adult Mesenchymal Tumour Medical Oncology Unit, Fondazione IRCCS Istituto<br />
Nazionale dei Tumori, Milan, Milan, ITALY, 2 Laboratory of Molecular Pathology,<br />
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ITALY, 3 Department of<br />
Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori Milan, Milan, ITALY,<br />
4<br />
Department of Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori,<br />
Milan, Milan, ITALY<br />
Background: In GIST, KIT/PDGFRA mutations correlate with response to TKI. The<br />
exon 18 PDGFRA-D842V mutation is known to be resistant to imatinib and<br />
sunitinib. Activation of PDGFRA involves two main signal transduction pathways,<br />
RAS/MEK/ERK, which involves BRAF, and PI3K-AKT. We used sorafenib in three<br />
pts with a PDGFRA-D842V mutated metastatic GIST.<br />
Methods: Since January 2010, 3 PDGFRA-D842V mutated GIST pts (age: 57, 71, 72<br />
yrs) have been treated with sorafenib 400 mg twice daily, on an individual use basis.<br />
Two pts were progressing on imatinib in association to mTOR inhibitors (sirolimus<br />
and everolimus), while <strong>the</strong> third had four previous lines of <strong>the</strong>rapy. Molecular/<br />
biochemical analyses were performed on cryopreserved material taken before<br />
sorafenib treatment in two of <strong>the</strong> three patients (one biopsy and one surgical<br />
specimen). A primary cell culture was obtained from one patient.<br />
Results: One pt had a Choi’s response 3 mos after starting <strong>the</strong> treatment; <strong>the</strong> o<strong>the</strong>rs<br />
a RECIST response at 2 mos. The first pt had a tumor progression after 12 mos from<br />
starting <strong>the</strong>rapy and 9 mos from tumor response. The second pt had a partial<br />
response lasting 15 mos. Treatment was relatively well tolerated, with G3 skin toxicity<br />
in one pt, causing a dose reduction. Biochemical analyses on pretreatment tumors<br />
revealed activated S6K and S6, both downstream mTOR, as well as ERK1/2 strong<br />
activation. The primary cell culture was treated with sorafenib 0.5 and 1 µM and<br />
phosphorylation switch-off of both S6K and S6 (Ser 240/244), associated with a<br />
retained ERK1/2 expression/activation, was observed. Fur<strong>the</strong>r analyses are ongoing to<br />
verify which pathways converging on mTOR are inhibited by sorafenib.<br />
Conclusions: In <strong>the</strong> unresponsive PDGFRA-D842V mutated GIST we saw clinical<br />
signs of antitumor activity of sorafenib in 3 pts. This was consistent with biochemical<br />
analyses, which showed an inhibitory effect downstream mTOR. This clinical setting<br />
constitutes a high-priority unmet medical need, since very few clinical data are<br />
known and no functional analyses on sorafenib activity have been reported so far.<br />
Disclosure: P.G. Casali: Advisory role and honoraria for lectures: Novartis Pharma,<br />
Pfizer. Advisory role: Bayer. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1492P MONITORING OF PATIENTS WITH GASTROINTESTINAL<br />
STROMAL TUMOUR: SHOULD THE CHEST BE SCANNED?<br />
A. Findlay 1 , T. Ishfaq 1 , A. Raja 1 , A. Thacoor 1 , P. Hall 2 , M. Marples 3<br />
1 School of Medicine, University of Leeds, Leeds, UNITED KINGDOM, 2 Leeds<br />
Institute of Health Sciences, University of Leeds, Leeds, UNITED KINGDOM, 3 St<br />
James’s Institute of Oncology, St James’s University Hospital, Leeds, UNITED<br />
KINGDOM<br />
Introduction: Thoracic CT scanning is often used for monitoring patients with<br />
sarcoma and upper gastrointestinal carcinoma, but its role in monitoring<br />
gastrointestinal stromal tumour (GIST) is variably defined in guidelines. In line with<br />
study protocols, it has been our practice to include chest CT for monitoring patients<br />
with GIST, and we now report <strong>the</strong> role of <strong>the</strong>se scans.<br />
Method: We reviewed <strong>the</strong> electronic records of all patients diagnosed with GIST at St<br />
James’s Institute of Oncology, Leeds, UK, between 1 January 2001 and 1 January<br />
2011. Primary site, stage at diagnosis, pattern of metastatic disease and frequency of<br />
CT scans were recorded.<br />
Results: We identified 176 patients diagnosed with GIST. All patients had CT scans<br />
of <strong>the</strong> chest, abdomen and pelvis performed at intervals agreed by <strong>the</strong> Yorkshire<br />
Sarcoma Network. Primary site was stomach in 96 patients (55%), small bowel in 27<br />
(15%), rectum in 5 (3%), o<strong>the</strong>r sites in 38 (22%), and unknown in 10 (6%). Median<br />
follow-up was 34.3 months. Of <strong>the</strong> 139 patients who had no metastases at<br />
presentation, five developed local recurrence and 11 developed metastases. 27<br />
patients had metastases at presentation, and <strong>the</strong> status of 10 was unknown. All<br />
patients with metastases had disease below <strong>the</strong> diaphragm, and only two had lung<br />
involvement as well (one at recurrence, one at initial presentation). Thirty-seven<br />
patients with metastatic disease were treated with imatinib. Of <strong>the</strong> 31 patients who<br />
progressed on imatinib, all had progression below <strong>the</strong> diaphragm; <strong>the</strong> patient with<br />
lung and abdominal metastases progressed in both areas. Four of <strong>the</strong>se patients also<br />
developed lung metastases at <strong>the</strong> time of progression elsewhere.<br />
Conclusions: We observed synchronous progression in lungs and abdomen in 5/31<br />
patients progressing on imatinib (16%), but no patients in our cohort relapsed or<br />
progressed in <strong>the</strong> lungs alone. We conclude that progression confined to <strong>the</strong> lungs is<br />
rare in GIST. Patients being monitored for recurrence or progression should have CT<br />
scans of <strong>the</strong> abdomen and pelvis only, with completion CT of <strong>the</strong> thorax being<br />
reserved for baseline and progression of disease.<br />
Disclosure: M. Marples: Dr Marples has accepted sponsorship to research meetings<br />
from Novartis. Novartis support mutation testing for GIST at Dr Marples’<br />
institution. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1493P RESULTS OF HRQOL DATA FROM PALETTE: A<br />
RANDOMIZED DOUBLE BLIND PHASE III TRIAL OF<br />
PAZOPANIB VERSUS PLACEBO IN METASTATIC SOFT<br />
TISSUE SARCOMA (STS) PATIENTS. AN EORTC STBSG<br />
GLOBAL NETWORK STUDY (EORTC 62072)<br />
C. Coens 1 , W.T.A. van der Graaf 2 , J. Blay 3 , S.P. Chawla 4 , D. Kim 5 ,<br />
R. Sanfilippo 6 , S. Manson 7 , M. Ouali 8 , S. Marreaud 9 , A. Bottomley 1<br />
1 Quality of Life Department, EORTC HQ, Brussels, BELGIUM, 2 Medical<br />
Oncology /452, Radboud University Medical Centre NijmegenUniversity Medical<br />
Center St. Radboud, Nijmegen, NETHERLANDS, 3 University Claude Bernard<br />
Lyon I, Centre L, Lyon Cedex, FRANCE, 4 Clinical Research, Sarcoma Oncology<br />
Center, Los Angeles, CA, UNITED STATES OF AMERICA, 5 Internal Medicine,<br />
Seoul National University Hospital, Seoul, KOREA, 6 Cancer Medicine<br />
Department, Istituto Nazionale dei Tumori, Milano, ITALY, 7 R&D,<br />
GlaxoSmithKline, Uxbridge, UNITED KINGDOM, 8 Statistical Department, EORTC<br />
HQ, Brussels, BELGIUM, 9 Medical Department, EORTC HQ, Brussels,<br />
BELGIUM<br />
Background: HRQoL was an important secondary endpoint in this global<br />
double-blind, randomised phase III trial of pazopanib 800 mg QD versus placebo as<br />
second or later line treatment for advanced STS patients (N = 369) where progression<br />
free survival was significantly improved in <strong>the</strong> pazopanib arm (median: 4.6 versus 1.6<br />
months; hazard ratio = 0.31; P < 0.001), but no statistically significant difference was<br />
observed in overall survival. Toxicity of pazopanib consisted mainly of fatigue,<br />
diarrhea, nausea weight loss and hypertension.<br />
Methods: HRQoL was assessed using EORTC QLQ-C30 at baseline, week 4, 8 and<br />
12 in patients who were progression free. The primary HRQoL endpont was <strong>the</strong><br />
QLQ-C30 global health scale, analyzed using linear mixed modeling supplemented<br />
with sensitivity analyses using alternative scales, methods and imputation of missing<br />
data.<br />
Results: Compliance of HRQoL was good in this trial, ranging from 94% at baseline<br />
to 81% at week 12. Placebo patients completed fewer questionnaires, largely due to a<br />
higher progression rate (median number of completed questionnaires- pazopanib: 3<br />
vs placebo: 2). Differences in <strong>the</strong> global health scale between <strong>the</strong> two treatment arms<br />
assessed at weeks 4, 8 and 12 were not significant and did not exceed <strong>the</strong><br />
pre-determined minimally important difference of 10 points (P = 0.291; average<br />
difference = 2.6 points). The EQ-5D data and sensitivity analyses mainly confirmed<br />
this finding. Among <strong>the</strong> o<strong>the</strong>r scales, <strong>the</strong> pazopanib arm reported significantly worse<br />
symptom scores for diarrhea (P < 0.001), loss of appetite (P < 0.001), nausea/vomiting<br />
(P < 0.001) and fatigue (P = 0.012). On <strong>the</strong> pazopanib arm, 74.8% of patients<br />
reported at least one minimally important worsening in any of those four symptom<br />
scales, compared to 51.2% on <strong>the</strong> placebo arm. In general, HRQoL scores tended to<br />
decline over time in both arms, indicative of <strong>the</strong> underlying disease. Exploratory<br />
factor analysis revealed that global health was associated mainly with functioning<br />
scales (Physical, Role and Social) and less with symptom scales except for fatigue.<br />
Conclusion: The toxicity profile of pazopanib is reflected in <strong>the</strong> patients’<br />
self-reported symptoms but did not translate into worse overall global health while<br />
on-treatment, as patients maintained continued good functioning.<br />
Disclosure: J. Blay: research support and honoraria from GSK, Novartis, Roche,<br />
MSD, PharmaMar. S.P. Chawla: consultant GSK. D. Kim: consultant GSK, MEK<br />
Advisory Board. R. Sanfilippo: Honoraria from GSK. S. Manson: employee of GSK,<br />
holds GSK shares. A. Bottomley: Funding for EORTC research projects from Roche,<br />
Genentech, BMS. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1494P IMATINIB MESYLATE IN D<strong>ESMO</strong>PLASTIC SMALL ROUND<br />
CELL TUMOUR<br />
A.F. Bertuzzi 1 , G. Bisogno 2 , M. Carli 2 , A. Ferrari 3 , A. Comandone 4 , M. Gasco 1 ,<br />
R. De Sanctis 1 , C. Gnocchi 5 , A. Santoro 1<br />
1 Medical Oncology and Hematology, Humanitas Cancer Center, IRCCS,<br />
Rozzano, ITALY, 2 Pediatric Medical Oncology and Hematology, Clinica di<br />
Onco-Ematologia Pediatrica, Padova, ITALY, 3 Pediatric Oncology Unit,<br />
Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano, ITALY, 4 Medical<br />
Oncology, Ospedale Gradenigo, Torino, ITALY, 5 Novartis Farma, Novartis,<br />
Origgio, ITALY<br />
Introduction: Desmoplastic small round cell tumor (DSRCT) is a very rare and<br />
aggressive mesenchymal neoplasia with an extremely poor prognosis. The typical<br />
translocation t(11;22) determines <strong>the</strong> overexpression of PDGF-Rα and β, responsible<br />
of clinical stromal fibrosis reaction constantly detected in abdominal lesions. We<br />
investigated <strong>the</strong> role of imatinib, as tyrosine kinase inhibitor of PDGF-R, in DSRCT.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds414 | ix483
Patients and methods: From August 2005 to June 2009 we enrolled patients (pts)<br />
with histologically proven diagnosis of DSRCT, refractory to conventional treatment.<br />
Inclusion criteria comprised immunohistochemical positivity of imatinib targets<br />
(PDGF-Rα and β). Treatment consisted of imatinib 400 mg p.o. daily. Primary<br />
endpoint of <strong>the</strong> study was objective response rate. Secondary endpoint was safety and<br />
tolerability assessment.<br />
Results: Of <strong>the</strong> 13 enrolled patients, 8 pts were evaluable for response (4 screening<br />
failure and 1 never treated). Median age was 20 years (range, 9-32). M/F ratio was 7/<br />
1. ECOG PS was 0 in 6 pts. Median time from diagnosis was 24.5 months (range,<br />
6-148). 75% of pts had metastatic disease. The primary site was abdominal-pelvic for<br />
all pts. PDGFRα and β were expressed with an heterogeneous intensity pattern.<br />
Objective responses at first radiological evaluation at 3 months were: stable disease in<br />
one pt (12.5%) and progressive disease in 7 (87.5%) pts. Treatment-related adverse<br />
events were G1-2 nausea/vomiting, fatigue and periorbital oedema.<br />
Conclusions: In our limited case series, imatinib showed no efficacy in <strong>the</strong> treatment<br />
of DSRCT pts unresponsive to conventional <strong>the</strong>rapy, despite molecular-based<br />
selection of pts. Probably to identify responder pts, it is necessary a more complex<br />
evaluation comprehensive of both levels of expression and activation of PDGFRα and<br />
β. Fur<strong>the</strong>rmore, enrolled pts were affected by advanced refractory disease, probably<br />
less responsive to target <strong>the</strong>rapies. It would be hopeful a global effort to define a new<br />
combined approach based on <strong>the</strong> association of conventional chemo<strong>the</strong>rapy and<br />
biological drugs.<br />
Disclosure: C. Gnocchi: Novartis Patient Advocacy Manager. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
1495P SUNITINIB THERAPY IN ADVANCED ALVEOLAR SOFT PART<br />
SARCOMAS<br />
H.M. Kosela, K. Wiater, T. Switaj, A. Klimczak, S. Falkowski, P. Rutkowski<br />
Soft Tissue/bone Sarcoma and Melanoma, MSC Memorial Cancer Centre and<br />
Institute Maria Sklodowska-Curie, Warsaw, POLAND<br />
Background: Alveolar soft part sarcoma (ASPS) is a rare entity making up < 1% of<br />
soft tissue sarcomas (STS). It is characterized by slow, indolent growth but with a<br />
high frequency of metastatic disease especially to lungs. Chemo<strong>the</strong>rapeutic regimens<br />
used for <strong>the</strong> treatment of o<strong>the</strong>r soft tissue sarcomas lack efficacy in ASPS. The<br />
purpose of our analysis was to assess sunitinib activity in ASPS.<br />
Methods: Since July 2009, 7 patients with metastatic ASPS have been treated with<br />
sunitinib continuous daily dosing 37,5mg (1 pts started treatment at 50mg/d on a 4/2<br />
week schedule). All patients’ initial performance status according to ECOG was 0-1.<br />
Median age at time of diagnosis was 23 yrs (range 18-57), gender distribution M/F was 1/<br />
6. Primary localization of <strong>the</strong> tumor was: lower extremity (3), trunk (2), retroperitoneum<br />
(1), pelvis (1). Primary tumor size ranged from 5 to 12 cm (median 7cm). All patient had<br />
unresectable metastases to <strong>the</strong> lungs. 57% of <strong>the</strong>patientswerepreviouslytreatedwith<br />
standard chemo<strong>the</strong>rapy. Median time from diagnosis to start of sunitinib <strong>the</strong>rapy was 6<br />
months (range: 2-156). Responses were evaluated after 2 months from baseline, <strong>the</strong>n<br />
every 3 months by CT scan and/or MRI, according to RECIST criteria.<br />
Results: At <strong>the</strong> time of present analysis 3 of <strong>the</strong> patient continue <strong>the</strong>rapy. After 2<br />
months of treatment 2 patients had RECIST PR, 5 SD. Median PFS was 15 months<br />
with 86% patients free of progression of <strong>the</strong> disease at 6 months. Median <strong>the</strong>rapy<br />
duration was 18 months (range: 5-31). Median OS was 15 months; 3 patients died due<br />
to disease progression at <strong>the</strong> time of analysis. One of <strong>the</strong> patients had SD after 4<br />
months of treatment, interrupted treatment for 3 months and experienced progression<br />
of <strong>the</strong> disease, after restarting <strong>the</strong>rapy she again gained SD lasting 12 months. Toxicity<br />
was ra<strong>the</strong>r moderate. All <strong>the</strong> patients experienced some side effects, 4 patients (57%)<br />
had toxicity grade 3/4 CTC. The common treatment toxicity was neutropenia,<br />
hypothyroidism, arterial hypertension, hand and foot syndrome. 2 patients required<br />
dose reduction. There was one death related to <strong>the</strong> treatment (sepsis).<br />
Conclusion: Our analysis shows efficacy of sunitinib in patients with advanced ASPS.<br />
Disclosure: P. Rutkowski: honoraria: Pfizer and Novartis. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
1496P SUNITINIB MALATE IN CLEAR CELL SARCOMA<br />
S. Stacchiotti 1 , E. Palassini 1 , T. Negri 2 , C. Morosi 3 , A. Messina 3 , R. Patuzzo 4 ,<br />
A. Gronchi 4 , S. Pilotti 2 , P.G. Casali 1<br />
1 Cancer Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan,<br />
ITALY, 2 Pathology and Molecular Biology, Fondazione IRCCS Istituto Nazionale<br />
dei Tumori, Milan, ITALY, 3 Radiology, Fondazione IRCCS Istituto Nazionale dei<br />
Tumori, Milan, ITALY, 4 Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori,<br />
Milan, ITALY<br />
Background: Clear cell sarcoma (CCS) is a rare soft tissue sarcoma, characterized in<br />
most cases by <strong>the</strong> t(12;22), resulting in <strong>the</strong> EWS-ATFE1 fusion protein. It has a high<br />
Annals of Oncology<br />
metastatic potential. CCS is poorly sensitive to chemo<strong>the</strong>rapy. We already reported<br />
on <strong>the</strong> activity of sunitinib (SM) in one case of CCS.<br />
Methods: Since September 2009, 9 patients with progressive, metastatic CCS (M/<br />
F 3/6; median age 36 yrs; translocated/ non translocated: 6/3; site of primary:<br />
extremities 6, o<strong>the</strong>r 3; pretreated: 9) have been treated with continuous SM 37.5<br />
mg/day, on a named basis. PET response was assessed in 6 cases. Responses<br />
were evaluated after 2 months from baseline, <strong>the</strong>n every 3 months by CT scan<br />
and/or MRI, according to RECIST. Pre-treatment PDGFRB and VEGFR status<br />
analysis by immunohistochemistry, western/blotting and phospho-RTK array is<br />
ongoing in evaluable cases.<br />
Results: At <strong>the</strong> time of <strong>the</strong> present analysis, 6/9 pts are evaluable for response (1<br />
early interruption; 2 just started), and 4 patients are still on treatment. After 3<br />
months of SM, 3 patient had a RECIST partial response (PR) (50%), along with<br />
subjective improvement in symptoms, 1 stable disease (SD), 2 progressive disease<br />
(PD). PET was consistent. One patient had a complicated major response<br />
characterized by an ulcer to <strong>the</strong> site of previous surgery; thus she underwent surgery<br />
with evidence of pathologic partial response, marked by extensive necrosis. The<br />
median PFS is 5 months (range 2-7).<br />
Conclusions: SM is active in a proportion of CCS. Prospective studies are needed.<br />
Disclosure: S. Stacchiotti: Pfizer: reseach grant for studies in which my Institution is<br />
involved; honoraria. E. Palassini: Pfizer: research grant for studies in which my<br />
Institution is involved. P.G. Casali: Pfizer: research funds for studies in which my<br />
Institution is involved; Compensated Advisory; Honoraria. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
1497P SIMULTANEOUS TARGETING OF THE INSULIN-LIKE<br />
GROWTH FACTOR 1 RECEPTOR (IGF-1R) AND ANAPLASTIC<br />
LYMPHOMA KINASE (ALK) IN EMBRYONAL AND ALVEOLAR<br />
RHABDOMYOSARCOMA<br />
J.C. van Gaal 1 , Y.M.H. Versleijen-Jonkers 1 , M.H.S. Roeffen 1 , U.E. Flucke 1 ,<br />
G. van der Heijden 1 , A.J.H. Suurmeijer 2 , E.S.J.M. De Bont 3 , W.T.A. van der<br />
Graaf 4<br />
1 Department of Medical Oncology, Radboud University Nijmegen Medical<br />
Centre, Nijmegen, NETHERLANDS, 2 Pathology, University Medical Center<br />
Groningen, Groningen, NETHERLANDS, 3 Pediatric Oncology, University Medical<br />
Center Groningen, Groningen, NETHERLANDS, 4 Medical Oncology /452,<br />
Radboud University Medical Centre MijmegenUniversity Medical Center<br />
St. Radboud, Nijmegen, NETHERLANDS<br />
Introduction: Rhabdomyosarcoma (RMS) is an aggressive soft tissue tumour that<br />
occurs predominantly in children and adolescents. Its two most common forms<br />
are embryonal (eRMS) and alveolar RMS (aRMS). Although survival has increased<br />
over <strong>the</strong> past decades after <strong>the</strong> introduction of multi-agent chemo<strong>the</strong>rapy, <strong>the</strong><br />
survival for <strong>the</strong> high-risk subpopulation remains poor (not exceeding 50%).<br />
Therefore, <strong>the</strong>re is an urgent need for new systemic treatment options. The aim of<br />
<strong>the</strong> current study is to investigate <strong>the</strong> insulin-like growth factor-1 receptor<br />
(IGF-1R) and anaplastic lymphoma kinase (ALK) pathway as potential targets in<br />
RMS.<br />
Methods: A total of 112 paraffin-embedded RMS tumor specimens (eRMS n = 86;<br />
aRMS n = 26) were collected on a tissue microarray. IGF-1R and ALK expression was<br />
evaluated by immunohistochemistry. A binary scoring system was used in which<br />
staining was scored positive when present in at least 10% of <strong>the</strong> tumour cells. The<br />
effect of <strong>the</strong> ALK small molecule inhibitor NVP-TAE684 (Novartis), <strong>the</strong> IGF-1R<br />
monoclonal antibody R1507 (Roche) and combined treatment was investigated by<br />
cytotoxicity assay MTT in four RMS cell lines (aRMS Rh30 and Rh41; eRMS Rh18<br />
and RD).<br />
Results: Expression of IGF-1R was seen in 72% of aRMS and 62% of eRMS,<br />
respectively. ALK expression was observed in 92% of aRMS and 39% of eRMS.<br />
Co-expression of IGF-1R and ALK was observed in 68% of aRMS and 32% of eRMS.<br />
In vitro, inhibition of <strong>the</strong> IGF-1R by R1507 resulted in diminished cell growth only<br />
in aRMS cell line Rh41 (IC50 11 ng/ml). NVP-TAE-684 resulted in diminished cell<br />
growth in aRMS cell lines Rh41 (IC50 103 nM) and Rh30 (IC50 211 nM), and to a<br />
lesser extent in eRMS cell lines Rh18 (IC50 585 nM) and RD (IC50 734nM).<br />
Simultaneous treatment could be assessed in aRMS cell line Rh41 by using different<br />
concentrations of R1507 and NVP-TAE684, and revealed a synergistic effect<br />
(combination index
Annals of Oncology<br />
1498P A PROGNOSTIC SCORE TO GUIDE APPROPRIATE DELIVERY<br />
OF FIRST LINE PALLIATIVE CHEMOTHERAPY FOR<br />
ADVANCED SOFT TISSUE SARCOMA<br />
N. Gough 1 , C. Smith 1 , J.R. Ross 1 , J. Riley 1 , I. Judson 2<br />
1 Palliative Care, Royal Marsden Hospital, London, UNITED KINGDOM, 2 Sarcoma<br />
Unit, Royal Marsden HospitalCR UK Centre for Cancer Therapeutics, Sutton,<br />
UNITED KINGDOM<br />
Objective: The study investigated predictive variables of overall survival (OS) in<br />
patients treated with first line palliative chemo<strong>the</strong>rapy for locally advanced/<br />
metastatic soft tissue sarcoma (STS) from 1998-2008. Poor performance status (PS)<br />
has been identified as a powerful risk factor for early death in this population.<br />
Establishing additional objective variables may fur<strong>the</strong>r aid decision making when<br />
considering <strong>the</strong> risk/benefit ratio of systemic chemo<strong>the</strong>rapy.<br />
Methods: Pre-treatment demographic, STS-specific and biochemical variables of 501<br />
patients were reviewed retrospectively. Patients with chemo-sensitive subtypes<br />
gastro-intestinal stromal tumour, rhabdomyosarcoma, desmoplatic small round cell<br />
tumour were excluded. Significant prognostic factors in univariate analysis were<br />
fur<strong>the</strong>r evaluated using multivariate analysis (Cox regression).<br />
Results: Median OS was 11.4 months, 90-day mortality 17% and <strong>the</strong> 1, 2 and 5 year<br />
survival was 43, 23 and 2% respectively. The Cox model identified age >60 years<br />
[Hazard ratio: 1.35 (95% confidence interval 1.01-1.80) p = 0.04], >2 sites of<br />
metastases [HR: 1.47 (1.14- 1.90) p =0.003], presence of soft tissue metastases [HR<br />
1.23 (0.99 -1.51) p= 0.054] toge<strong>the</strong>r with lymphocytes
chemo<strong>the</strong>rapy respectively. At a median follow-up of 47 mths, median relapse-free<br />
survival (RFS) for R0/R1 resected pts was 49 mths (2yr RFS 68%). In <strong>the</strong> univariate<br />
analysis, primary tumor site originating in <strong>the</strong> extremities (p = 0.019) and use of<br />
adjuvant radiation (p = 0.008) were significantly associated with improved RFS.<br />
Notably, pts with axial LPS had significantly higher rates of relapse, 58% vs 37%, (p<br />
= 0.043) with a significantly higher proportion being local-only relapses, 77% vs 44%<br />
(p = 0.028) compared with extremity LPS. Median overall survival (OS) of pts with<br />
localized LPS was 113 mths. For pts with metastatic disease, median OS was 21<br />
mths. In univariate analysis, use of palliative chemo<strong>the</strong>rapy (p = 0.046) was<br />
significantly correlated with superior OS. LPS sub-type did not significantly influence<br />
RFS or OS.<br />
Conclusions: Our study demonstrates that primary tumor site and use of adjuvant<br />
RT but not LPS sub-type are important prognostic factors for RFS in pts with<br />
localised LPS. This knowledge may potentially guide local treatment decisions<br />
including <strong>the</strong> use of more aggressive surgery, adjuvant radiation and even<br />
chemo<strong>the</strong>rapy in selected patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1502P VINORELBINE IS AN ACTIVE DRUG IN D<strong>ESMO</strong>ID TUMORS /<br />
AGGRESSIVE FIBROMATOSIS: INSTITUT GUSTAVE ROUSSY<br />
EXPERIENCE<br />
C. Rahal 1 , A. Cioffi 2 , J. Domont 3 , S. Bonvalot 4 , C. Le Pechoux 5 , L. Vilcot 1 ,<br />
P. Terrier 1 ,F.Fayard 1 , A. Rahal 1 , A. Lecesne 1<br />
1 Dept. of Medicine, Institut de Cancérologie Gustave Roussy, Villejuif Cedex,<br />
FRANCE, 2 Dept of Medecine - Sarcoma Division, Institut Gustave Roussy,<br />
Villejuif, FRANCE, 3 Dept. Medical Oncology, Institut Gustave Roussy, Villejuif,<br />
FRANCE, 4 Department of Surgery, Institut Gustave Roussy, Villejuif, FRANCE,<br />
5 Radio<strong>the</strong>rapy, Gustave Roussy, villejuif, FRANCE<br />
Background: Desmoid tumors /aggressive fibromatosis (AF) are locally aggressive<br />
neoplasms with frequent relapses despite optimal loco-regional treatments. In<br />
case of disease progression, non loco-regional <strong>the</strong>rapeutic options include non<br />
steroidal agents, hormonal <strong>the</strong>rapy and systemic chemo<strong>the</strong>rapy including<br />
Anthracyclins or Vinca Alkaloids. Vinorelbine (VNR) has been poorly<br />
investigated in AF.<br />
Methods: This is a retrospective review of patients with recurrent/progressive AF<br />
treated with single agent oral VNR between April 2006 and April <strong>2012</strong> at Institut<br />
Gustave Roussy.<br />
Results: Seventeen patients (pts) received oral VNR (90 mg weekly). There were 3<br />
males and 14 females with a median age of 35 years (14-58 yrs). Eleven pts<br />
(65%) showed PD according to RECIST before inclusion while 6 pts (29%) were<br />
stable but with progressive symptoms. VNR was given as mono<strong>the</strong>rapy in 7 pts,<br />
in combination with hormonal <strong>the</strong>rapy (Tamoxifen plus LHRH agonist) in 9 pts<br />
and with COX 2 non-steroidal anti-inflammatory drugs in 2 pts. The median<br />
tumor size was 11cm (3.7-29cm). AF were extra-abdominal in 12 pts (extremity:<br />
3, superficial trunk: 5, girdle 4) and intra abdominal in 5 pts. Prior <strong>the</strong>rapy<br />
included surgery (53%), radiation <strong>the</strong>rapy (12%), hormonal <strong>the</strong>rapy (53%),<br />
Imatinib (12%) and chemo<strong>the</strong>rapy (6%). The median duration of VNR treatment<br />
was 6 months (2-23m). Tolerance was excellent with no grade III-IV toxicities.<br />
Twelve pts had a tumor shrinkage including 7 RECIST PR (41%), 5 during VNR<br />
and 2 o<strong>the</strong>rs few weeks after drug discontinuation. Nine pts (53%) achieved a<br />
RECIST disease stabilisation and one pt (6%) progressed during chemo<strong>the</strong>rapy.<br />
Symptomatic relief during treatment was observed in 75% of pts. After a median<br />
follow-up of 3 years, <strong>the</strong> 1 and 3-yr PFS rates were 94% (72-99%) and 87%<br />
(62-96%) respectively. VNR was rechallenged in 3 progessing pts and a PR was<br />
seen in 2 cases.<br />
Conclusion: Weekly oral VNR is a well tolerated regimen and highly effective in<br />
achieving significant and durable clinical benefit in AF. Tumor shrinkage can be<br />
observed after drug discontinuation .VNR can be rechallenged in previously<br />
responding pts. This regimen deserves fur<strong>the</strong>r developments.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
1503P METRONOMIC ORAL CYCLOPHOSPHAMIDE IN THE<br />
TREATMENT OF METASTATIC SOFT TISSUE SARCOMA: IS<br />
THERE A ROLE FOR MAINTENANCE THERAPY?<br />
A.C.R. Ferrari, V.P. Camargo, G.M. Bariani, M.S. Goncalves, P.M. Hoff, G. De<br />
Castro, Jr.<br />
Medical Oncology, Instituto do Cancer do Estado de Sao Paulo, Sao Paulo,<br />
BRAZIL<br />
Background: Metronomic chemo<strong>the</strong>rapy has been demonstrated to improve DFS in<br />
advanced STS. Here we aimed to analyze <strong>the</strong> efficacy and safety of metronomic oral<br />
cyclophosphamide (M-CTX) as maintenance or salvage <strong>the</strong>rapy in <strong>the</strong>se patients<br />
(pts).<br />
Methods: It is a retrospective study of all advanced/metastatic STS pts (RMS, GIST,<br />
bone sarcomas excluded) treated in our institution between Feb/2009 and Jan/<strong>2012</strong><br />
with M-CTX 100 mg PO daily 21 out of 28 days, until disease progression (DP).<br />
Tumor response (RECIST 1.1) was assessed every 2 cycles. The primary endpoint of<br />
<strong>the</strong> study was time to treatment failure (TTF). Toxicity was graded according to <strong>the</strong><br />
NCI-CTC v.3.0. criteria.<br />
Results: 27 pts were consecutively included in this analysis. Thirteen pts received<br />
M-CTX as maintenance chemo<strong>the</strong>rapy after presenting best response: median age 60<br />
y, 9 female; 5 LMS, 3 HGUPS, 2 PNET, 3 o<strong>the</strong>rs. Median number of previous<br />
chemo<strong>the</strong>rapy regimens 2; 9 previously treated with doxorubicin and 4 with<br />
ifosfamide; 4 presented PR as best response. Median TTF (mTTF) was 9.2 mo, 4 pts<br />
(2 PNET, 1 LMS, 1 HGUPS) had mTTFs ≥ 6 mo and no deaths were observed in a<br />
median follow-up of 7 mo. 14 pts received M-CTX as salvage chemo<strong>the</strong>rapy after<br />
DP: median age 45.5 y, 8 female; 3 LMS, 3 HGUPS, 3 synovial, 2 ASPS, 3 o<strong>the</strong>rs.<br />
Median number of previous chemo<strong>the</strong>rapy regimens 1.5; 11 previously treated with<br />
doxorubicin and 6 with ifosfamide; 1 PR as best response. mTTF 3.3 mo, 1 ASPS<br />
had mTTFs ≥ 6 mo, and 9 deaths (HR 1.403, 95%CI 0.608-3.236, p = 0.409, in<br />
comparison with maintenance strategy). In general, M-CTX was well tolerated, and<br />
<strong>the</strong> most common toxicity (>10%) included nausea G1 (5 pts), renal failure (3 pts),<br />
anemia G1 (4 pts), anemia G2 (3 pts), lymphopenia G1 (12 pts).<br />
Conclusions: Metronomic oral cyclophosphamide seems to be a valid option as<br />
maintenance chemo<strong>the</strong>rapy after presenting best response in advanced/metastatic<br />
STS, with acceptable toxicity. This compares favorably with historical controls (mPFS<br />
around 4 months). However, after disease progression, it is a futile chemo<strong>the</strong>rapy<br />
regimen.<br />
Disclosure: A.C.R. Ferrari: Travel expenses covered: Roche. G.M. Bariani: Novartis:<br />
lecture fee, travel expenses covered. Roche: travel expenses covered. All o<strong>the</strong>r authors<br />
have declared no conflicts of interest.<br />
1504P ISOLATED LIMB PERFUSION IN LOCALLY-ADVANCED LIMB<br />
SOFT TISSUE SARCOMAS: RETROSPECTIVE STUDY OF A<br />
23-YEAR EXPERIENCE<br />
M. Rastrelli 1 , L.G. Campana 1 , A. Vecchiato 1 , P.L. Pilati 2 , S. Valpione 3 , R. Spina 1 ,<br />
C. Falci 4 , A. Sommariva 1 , A. Zanon 2 , C.R. Rossi 1<br />
1 Sarcoma and Melanoma Unit, Veneto Region Oncology Research Institute<br />
(IOV-IRCCS), Padova, ITALY, 2 Gastroenterological and Surgical Sciences,<br />
University of Padova, Padova, ITALY, 3 Medical Oncology School, University of<br />
Padova, Padova, ITALY, 4 Medical Oncology-ii, Veneto Region Oncology<br />
Research Institute (IOV-IRCCS), Padova, ITALY<br />
Background: Hyper<strong>the</strong>rmic isolated limb perfusion (HILP) is a cytoreductive<br />
treatment to avoid amputation in limb soft tissue sarcomas (LSTS). HILP drug<br />
schedule has been modified to balance treatment activity and toxicity.<br />
Methods: From 1988 to 2011, 117 patients with unresectable primary or recurrent<br />
LSTS underwent HILP. Tumor characteristics, HILP parameters and drugs<br />
(doxorubicin; doxorubicin plus TNFa; TNFa plus L-PAM), postoperative plasma<br />
myoglobin, tumor response, systemic chemo<strong>the</strong>rapy (CT), site of recurrence and<br />
outcome were analyzed.<br />
ix486 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Results: The 3 treatment groups were homogeneous for clinical pathological features.<br />
The tumor response (necrosis in resected specimen) was comparable (P = .473)<br />
(Table) and was correlated with myoglobin (P < .05). Locoregional toxicity was<br />
similar in <strong>the</strong> three groups (P = .233) (Table). Surgical resection was radical in 83.2%<br />
of cases. The 5-year LDFS was 70.2%, with no differences according to HILP<br />
schedule (P = .475). 22.2% of patients required limb amputation, for complications<br />
(n = 1), unresponsiveness (n = 17) or recurrence (n = 8). The amputation rate was<br />
higher in upper LSTS (P = .049). Systemic metastases occurred in 47 patients (40.2%)<br />
after a median of 14.6 months; <strong>the</strong>ir occurrence inversely correlated with post-HILP<br />
necrosis (P = .001). Five-year OS was 48.1%. The avoidance of amputation (P = .044),<br />
CT (P = .003) and lung as site of systemic recurrence (P = .018) were associated with<br />
longer OS. Lung metastases were predictors for longer OS in case of systemic<br />
progression (OR 3.81,95% CI 1.74-8.34,P < .001). Prognosis was not influenced by<br />
CT (P = .087).<br />
Conclusions: Doxorubicin, doxorubicin + TNFa and TNFa + L-PAM schedules are<br />
equally active, with comparable toxicity profiles. Upper LSTS and poor post-HILP<br />
necrosis were related with higher amputation rates. Despite preserving limb function,<br />
40% of HILP patients develop a systemic recurrence, particularly when achieving<br />
lower responses. Lung relapses lung have a relatively better prognosis.<br />
Drug schedule<br />
DOXO<br />
n=47<br />
TNFa + DOXO<br />
n=30<br />
TNFa + L-PAM<br />
n=40<br />
Tumor necrosis,<br />
median %<br />
(range)<br />
Locoregional toxicity<br />
according to Wieberdink<br />
n° of pts (%)<br />
1-2345<br />
54 (7-91) 38 (80.9) 8 (17.0) 1 (2.1) 0<br />
64 (10-100) 24 (80.0) 4 (13.4) 1 (3.3) 1 (3.3)<br />
57 (4-91) 37 (92.5) 1 (2.5) 2 (5.0) 0<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1505P COMPARISON OF TWO CHEMOTHERAPY REGIMENS (AI VS.<br />
EIA) COMBINED WITH REGIONAL HYPERTHERMIA (RHT) IN<br />
HIGH-RISK SOFT-TISSUE SARCOMA (HR-STS)<br />
P.O. Aubele 1 , E. Kampmann 1 , G. Schuebbe 1 , S. Abdel-Rahman 1 , N. Dieterle 1 ,<br />
R. Laubender 2 , R. Issels 3 , L. Lindner 1<br />
1 Dept Internal Medicine III Hematology/Oncology, University Hospital Munich –<br />
Grosshadern, Munich, GERMANY, 2 University of Munich, Institute of Medical<br />
Informatics, Biostatistics, and Epidemiology, Munich, GERMANY, 3 German<br />
Research Center for Environmental Health, Helmholtz Zentrum München,<br />
Neuherberg/Munich, GERMANY<br />
Introduction: A phase III study showed that RHT combined with EIA (E =<br />
etoposide, I = ifosfamide and A= doxorubicin) is effective in HR-STS (Lancet Oncol,<br />
2010). EIA + RHT significantly improved tumor response and prolonged local<br />
progression-free (LPFS) and disease-free survival (DFS). Due to <strong>the</strong> mutagenic<br />
potential of etoposide <strong>the</strong> EIA-regimen was modified <strong>the</strong>reafter. Here we report a<br />
retrospective single center sequential analysis of EIA vs. AI both combined with<br />
RHT.<br />
Methods: Patients (pts) with localized HR-STS received EIA (E:125mg/m2; I:6g/m2;<br />
A:50mg/m2) or AI (A:60mg/m2; I:9g/m2) with RHT (T max. 42°C; 60min.). Inclusion<br />
criteria and procedures were equivalent to <strong>the</strong> protocol of <strong>the</strong> phase III study.<br />
Response was evaluated according to RECIST and survival parameters were analysed<br />
using cox regression models, Kaplan-Meier and chi-square test. Possible confounders<br />
were selected by backward elimination using <strong>the</strong> likelihood ratio test.<br />
Results: 106 Patients (median age 48 years; 19 - 70) were treated with EIA (42pts;<br />
from 2006 – 2008) or AI (64pts; 2009 – <strong>2012</strong>) with a median follow up of 28 months<br />
for EIA and 10 months for AI. Best clinical response rate (CR + PR + SD) for EIA +<br />
RHT was 89% compared with 97% for AI + RHT (p = 0,59). Risk for local disease<br />
progression or death was not significantly different (Hazard ratio (HR) 0.896; 95% CI<br />
0.433 -1.855; p= 0,767). 1-year rates of LPFS and DFS were 73% [95% CI 0.60 - 0.87]<br />
and 73% [95% CI 0.60 - 0.87] for EIA and 77% [95% CI 0.65 - 0.89] and 63% [95%<br />
CI 0.49 - 0.77] for AI. Accordingly, for DFS HR was 0.739 (95% CI 0.382 - 1.428; p<br />
= 0.368) and for OS HR was 1.011 (95% CI 0.306 - 3.339; p = 0.958). There was also<br />
no significant difference in HRs for LPFS, DFS or OS after adjustment for<br />
confounders.<br />
Conclusion: Combining both regimens with RHT, AI is an equally effective regimen<br />
if compared to <strong>the</strong> EIA regimen. The efficacy of both regimens combined with RHT<br />
is comparable to <strong>the</strong> published results of <strong>the</strong> phase III study. P. Aubele,<br />
E. Kampmann, G. Schuebbe contributed equally; this work contains parts of <strong>the</strong><br />
doctoral <strong>the</strong>sis of G. Schuebbe.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1506P SUPERIORITY OF CHOI VS RECIST CRITERIA IN<br />
EVALUATING OUTCOME OF ADVANCED SOFT TISSUE<br />
SARCOMA (STS) PATIENTS TREATED WITH SORAFENIB<br />
R. De Sanctis 1 , A.F. Bertuzzi 1 , P. Magnoni 2 , L. Giordano 3 , M. Gasco 1 ,<br />
R. Lutman 2 , A. Santoro 1<br />
1 Medical Oncology and Hematology, Humanitas Cancer Center, IRCCS,<br />
Rozzano, ITALY, 2 Radiology, Humanitas Cancer Center, IRCCS, Rozzano Milan,<br />
ITALY, 3 Biostatistics Unit, Humanitas Cancer Center, IRCCS, Rozzano Milan,<br />
ITALY<br />
Background: Objective tumor response may be underestimated by RECIST criteria,<br />
since biological agents can cause metabolic response (necrosis) not related to tumor<br />
size. For this reason, CHOI criteria were designed to evaluate both tumor density<br />
and size. We compared CHOI and RECIST criteria in evaluating response to<br />
sorafenib in patients with advanced STS, treated within a phase II trial. The objective<br />
was to compare CHOI and RECIST criteria and to relate response to progression-free<br />
(PFS) and overall survival (OS).<br />
Patients and methods: Sixty one advanced STS patients received sorafenib 400 mg<br />
twice daily for progressive or relapsed disease after anthracycline-based<br />
chemo<strong>the</strong>rapy. Treatment was continued until progression or major toxicity.<br />
Contrast-enhanced CT was performed every 3 months. Thirty patients were<br />
evaluable for response, according to both RECIST and CHOI criteria.<br />
Results: A total of 30 patients were included in <strong>the</strong> analysis. According to RECIST,<br />
we observed 1 (3%) complete response (CR), 1 (3%) partial remission (PR), 18 (60%)<br />
stable diseases (SD) and 10 (34%) progressive diseases (PD) at 3 months. According<br />
to CHOI, we observed 1 (3%) CR, 10 (34%) PR, 5 (16%) SD and 14 (47%) PD. The<br />
agreement between <strong>the</strong> two techniques was low (cohen Kappa: 0.36; CI 95%,<br />
0.17-0.55). Of <strong>the</strong> 18 pts with SD according to RECIST, a total of 13 (72%) pts were<br />
reallocated to responder (8 PR, 44%) and non-responder (5 PD, 28%) groups, while<br />
only in 5 cases SD was confirmed using CHOI criteria. Median PFS and OS for SD<br />
RECIST pts were 8.3 and 22.7 months, respectively. In <strong>the</strong>se 18 pts, we compared<br />
median PFS and OS of responders (CR + PR, n= 8) vs non-responders (SD + PD, n=<br />
10) according to CHOI criteria. PFS was 11.2 vs 7.9 (p= 0.05), and OS 23.3 vs 15<br />
months (p= 0.21).<br />
Conclusions: Our analysis suggests that CHOI criteria may be helpful to define<br />
response to a biological treatment in STS. According to CHOI criteria, SD pts as<br />
defined by RECIST could be better divided in two subgroups (responders and<br />
non-responders) with a different outcome. Therefore, CHOI criteria may have an<br />
early significant predictive value for PFS in STS pts treated with biological<br />
agents.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1507P CORRELATION BETWEEN TUMOUR NECROSIS AND<br />
OVERALL SURVIVAL IN ADULTS WITH OSTEOSARCOMA<br />
TREATED WITH NEOADJUVANT CISPLATIN AND<br />
DOXORUBICIN<br />
G. Rivalland, D. Porter<br />
Cancer and Blood Service, Auckland City Hospital, Auckland, NEW ZEALAND<br />
Purpose: The degree of tumour necrosis following neoadjuvant chemo<strong>the</strong>rapy has<br />
crucial prognostic significance in methotrexate containing regimens. We examined<br />
whe<strong>the</strong>r a similar relationship exists for a non methotrexate containing regimen in a<br />
cohort of adult patients treated at <strong>the</strong> Auckland Regional Cancer Service between Feb<br />
1996 and Feb 2011.<br />
Methods: We retrospectively identified 35 patients with high grade osteosarcoma<br />
using data recorded prospectively in <strong>the</strong> New Zealand Bone Tumour registry<br />
and regional pathology laboratories. All patients received neoadjuvant cisplatin<br />
and doxorubicin, without high dose methotrexate. Reported necrosis rates<br />
following surgery clustered into 3 groups: >90%, 30-65% and
of this group Those with relapsed disease have significant benefit from surgery for<br />
metastases.<br />
Disclosure: D. Porter: Previous consulting fro Pfizer. Current consulting for GSK.<br />
Previous travel grant from Novartis. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
1508P MIFAMURTIDE (L-MTP-PE) FOR METASTATIC AND<br />
RECURRENT OSTEOSARCOMA (OS): SURVIVAL AND SAFETY<br />
PROFILE FROM A PATIENT ACCESS STUDY<br />
P. Anderson 1 , P. Meyers 2 , E. Kleinerman 1 , C. Oliva 3 ,Y.Liu 4<br />
1 Pediatrics, MD Anderson Cancer Center, Houston, TX, UNITED STATES OF<br />
AMERICA, 2 Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY,<br />
UNITED STATES OF AMERICA, 3 Oncology Mdc, Takeda Global Research &<br />
Development (Europe) Ltd, London, UNITED KINGDOM, 4 Biostatistics,<br />
Millennium Pharmaceuticals, Inc., Cambridge, MA, UNITED STATES OF<br />
AMERICA<br />
Introduction and research objectives: Liposomal muramyl tripeptide phosphatidyl<br />
ethanolamine (L-MTP-PE; mifamurtide) is approved for treatment of non-metastatic<br />
osteosarcoma (OS) in Europe, Israel, and Mexico. The primary objective of<br />
MTP-OS-403 was to collect information regarding <strong>the</strong> safety and tolerability of MTP<br />
in patients with high-risk OS. The open label access study called for L-MTP-PE<br />
2mg/m2 twice /week x 24 doses, <strong>the</strong>n weekly (total doses= 48 in 9 months). OS<br />
patients could receive MTP as a single agent or with appropriate chemo<strong>the</strong>rapy.<br />
Results: As of April <strong>2012</strong>, 202 patients were registered at 8 participating centers.<br />
Most had metastases at initial presentation or recurrent OS. Median age was 16 yr.<br />
Time from initial diagnosis to L-MTP-PE treatment was 29 +/- 23 months (median<br />
24 mo). Although >88% had metastases, 27% had been resected to no evidence of<br />
disease (NED) before study entry. The most common Infusion related AE (IRAE)<br />
within 24 hours of infusion were chills (37%), fever (25%), nausea (21%), headache<br />
(19%), and fatigue (15%). The most common AE (grade 3-4) o<strong>the</strong>r than IRAE were<br />
chemo<strong>the</strong>rapy-related and included thrombocytopenia (22%), neutropenia (19%),<br />
leukopenia (18%), febrile neutropenia (16%), lymphopenia (15%), and anaemia<br />
(15%). At MDACC, <strong>the</strong>re was 1 episode of pleural effusion and one episode of<br />
pericardial effusion that were possibly L-MTP-PE related. The median number of<br />
L-MTP-PE doses given was 34 (mean 30.1 +/- 17.5); 32% of <strong>the</strong>se high risk OS<br />
patients received 48 doses. As of April <strong>2012</strong> 45% (90/202) of <strong>the</strong>se high risk OS<br />
patients continue to be followed for survival.<br />
Conclusion: The safety profile of L-MTP-PE in high-risk OS patients is consistent<br />
with <strong>the</strong> known toxicity of <strong>the</strong> product. The infusion related AEs were generally mild<br />
to moderate. Since survival benefit in high-grade OS from MTP may be related to<br />
disease burden (i.e. achieving NED status using local control measures such as<br />
surgery and/or radio<strong>the</strong>rapy), L-MTP-PE may be more effective when used in <strong>the</strong><br />
adjuvant setting. A randomized multi-institutional clinical trial in OS patients<br />
presenting with metastases at diagnosis should be considered.<br />
Disclosure: C. Oliva: Cristina Oliva is a Takeda employee. Y. Liu: I am a Millennium<br />
employee. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1509P CHEMOTHERAPY IS EFFECTIVE IN PRIMITIVE<br />
NEUROECTODERMAL TUMOR (PNET) / EWING SARCOMA<br />
(EWS) OF THE KIDNEY<br />
E. Risi, R. Iacovelli, A. Palazzo, A. Passaro, G. Campennì, F. Morano, K. Truscelli,<br />
P. Trenta, S. Mezi, E. Cortesi<br />
Department of Radiology, Oncology and Human Pathology, Sapienza University<br />
of Rome, Rome, ITALY<br />
Background: PNET/EWS is a rare tumor that occurs most commonly in bone and<br />
soft tissues of children and young. PNET/EWS arise rarely as a primary renal<br />
neoplasm and exhibits highly aggressive biological behavior. Since its first description<br />
in 1975, less than 100 cases of EWS/PNET have been published in medical literature.<br />
We aim to collect and to analyze clinical and pathological features of this tumor.<br />
Patient and methods: All cases reports of PNET/EWS published from 1975 to<br />
February <strong>2012</strong> were collected. When available, clinical and pathological data were<br />
extracted for each case such as previously reported (Iacovelli et al. BJU Int <strong>2012</strong>).<br />
Survivals were estimated with Kaplan-Meier method and compared with log-rank<br />
test with 95% CI.<br />
Results: A total of 117 cases were found, 55% were male and <strong>the</strong> median age was<br />
28.0 y (IQR: 20.0 – 42.0). All patients (pts) had clinical symptoms as first<br />
presentation of disease such as pain (54%), hematuria (29%) and bulky renal mass<br />
(28%); whereas dysuria, fever, weight loss fatigue and abdomen swelling were<br />
reported rarely. 66% of pts had stage IV at diagnosis and <strong>the</strong> main sites of metastases<br />
were lung (60%), liver (37%), abdominal lymph-nodes (20%), bone and local relapse<br />
(
Annals of Oncology<br />
metastatic STS patients in <strong>the</strong> population. These patients were characterized and<br />
followed to determine treatment patterns.<br />
Results: For first line (1L) metastatic patients, 25.4% (n = 35/138) of patients entered<br />
a clinical trial. 68.4% of patients received at least one off-label drug (table 1).<br />
Doxorubicin was <strong>the</strong> most common 1L <strong>the</strong>rapy (63%). In <strong>the</strong> 2L, 25.8% of patients<br />
entered a clinical trial and 51.6% received at least one off-label drug. Doxorubicin<br />
was still <strong>the</strong> most common <strong>the</strong>rapy (29%), but <strong>the</strong>re was no clear standard of care.<br />
Median time to relapse was 250, 123 and 110 days, for 1, 2 and 3L. Median<br />
treatment free interval (TFI) between 1L and 2L was 89 days and reduced to 30 days<br />
between 2L and 3L.<br />
Conclusions: STS is a rare and heterogeneous disease with a high use of unapproved<br />
treatments and short TFIs between two treatment lines. The lack of clear standard of<br />
care, particularly in patients receiving 2L <strong>the</strong>rapy demonstrates important medical<br />
need for new agents in this <strong>the</strong>rapeutic area Table 1: treatment mainly used at 1 st<br />
and 2 nd metastatic treatment lines, ei<strong>the</strong>r given alone or in combination.<br />
1st metastatic line 2nd metastatic line<br />
Therapeutic option N = 145, MD* = 7 N = 83, MD = 4<br />
Systemic Treatment 95 (68.8%) 62 (78.5%)<br />
Drugs administered N = 95 N = 62<br />
Doxorubicin 60 (63.2%) 18 (29.0%)<br />
Ifosfamide 28 (29.5%)<br />
7 (11.3%)<br />
Fully combined with Doxo<br />
42.8% combiend with Doxo<br />
Dacarbazine 18 (18.9%) 2 (3.2%<br />
fully combined with Doxo<br />
Docetaxel‡ 12 (12.6%) 14 (22.6%)<br />
Gemcitabine‡ 12 (12.6%) 14 (22.6%)<br />
of which >80% use was Gemcitabine-Docetaxel regimen<br />
Trabectedine 7 (7.4%)‡ 8 (12.9%)<br />
Ate least 1 off-label drug 65 (68.4%) 35 (56.5%)<br />
*MD: Missing Data‡: off-label use in STS treatment<br />
Disclosure: B. Tehard: GlaxoSmithKline Employee GlaxoSmithKline funded <strong>the</strong> data<br />
analyses leading to resultst mentionned in this abstract. I. Ray-Coquard: Isabelle<br />
Ray-Coquard received fees and Grants from GSK GlaxoSmithKline funded <strong>the</strong> data<br />
analyses leading to resultst mentionned in this abstract. N. Ladarre: GlaxoSmithKline<br />
Employee GlaxoSmithKline funded <strong>the</strong> data analyses leading to resultst mentionned<br />
in this abstract. S. Manson: GlaxoSmithKline Employee GlaxoSmithKline funded <strong>the</strong><br />
data analyses leading to resultst mentionned in this abstract. J. Blay: Jean-Yves Blay<br />
received fees from GSK GlaxoSmithKline funded <strong>the</strong> data analyses leading to resultst<br />
mentionned in this abstract. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1512 CIRCULATING TUMOR CELLS IN SOFT TISSUE SARCOMAS<br />
PATIENTS<br />
B. Vincenzi 1 , E. Rossi 2 , A. Zoccoli 1 , M. Iuliani 1 , F. Pantano 1 , A.M. Frezza 1 ,<br />
M. Silletta 1 , G. Tonini 1 , R. Zamarchi 3 , D. Santini 1<br />
1 Medical Oncology, University Campus Bio-Medico, Rome, ITALY, 2 Department<br />
of Surgery, Oncology and Gastroenterology, University of Padova, Padova,<br />
ITALY, 3 Immunology and Molecular Oncology, IOV-IRCCS, Padova, ITALY<br />
Introduction: Soft tissue sarcomas (STSs) are an heterogeneous group of highly<br />
malignant mesenchymal tumors with only few recognised prognostic and predictive<br />
factors. Circulating tumor cells (CTCs) are considered a prognostic marker classically<br />
associated with poor prognosis in epi<strong>the</strong>lial solid cancer patients. The purpose of this<br />
study was to explore <strong>the</strong> possibility to detect CTCs in blood samples of STSs<br />
metastatic patients.<br />
Methods: Patients with histologically confirmed STSs and known metastases treated<br />
at Campus Bio-Medico Hospital of Rome from June 2011 to February <strong>2012</strong> were<br />
included. Blood was collected from patients who progressed on previous<br />
chemo<strong>the</strong>rapy (1st, 2nd or 3rd line). All patients signed informed consent before<br />
phlebotomy. CTCs were assessed with CellSearchSystem (Veridex, USA). After<br />
immunomagnetic enrichment with an anti-Epcam-antibody, cells were labelled with<br />
anti-Ck8/18/19 and anti-CD45 antibodies to distinguish between epi<strong>the</strong>lial cells and<br />
leukocytes. Wilcoxon rank-sum test was used to test for associations between CTC<br />
assay results and specific histotype, number of previous treatment, number and<br />
localization of metastatic disease sites.<br />
Results: Twenty-three patients with metastatic STSs were evaluated. CTCs were<br />
detectable in 10/23 (43%) patients with CTC counts in <strong>the</strong> range of 0-4 cells/7.5 mL.<br />
The median number of CTCs was significantly lower in patients with only one site of<br />
metastasis compared to those with two or more metastatic sites (0 vs 2; P = 0.003).<br />
There was no statistically significant difference (P = 0.210) in median CTC counts<br />
between patients who received only a first line regimen (0, range 0-4) vs patients who<br />
previously received more anticancer <strong>the</strong>rapies (1, range 0-3). Finally, no statistically<br />
significant correlation was identified between <strong>the</strong> number of CTCs and <strong>the</strong><br />
histological grading evaluated according to <strong>the</strong> FNCLCC grading system (P = 0.468).<br />
Conclusions: To our knowledge this is <strong>the</strong> first detection of circulating Epcam/Ck8/<br />
18/19+ cells in STSs patients, even if <strong>the</strong> identified circulating cells could be epi<strong>the</strong>lial<br />
cells due to direct tumour invasion of <strong>the</strong> blood vessel from <strong>the</strong> surrounding tissue or<br />
tumor cells at <strong>the</strong> moment of mesenchymal-epi<strong>the</strong>lial transition.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1513 PRIMARY SARCOMAS OF THE HEART AND GREAT VESSELS<br />
K. Wiater, H.M. Kosela, M. Zdzienicki, P. Rutkowski<br />
Department of Soft Tissue/Bone Sarcoma and Melanoma, MSC Memorial<br />
Cancer Centre and Institute Maria Sklodowska-Curie, Warsaw, POLAND<br />
Background: Primary sarcomas of <strong>the</strong> heart and great vessels are rare entities,<br />
accounting for less than 25 % of all primary cardiac tumors. They are characterized<br />
by an aggressive course and poor prognosis. The aim of <strong>the</strong> study was to analyze<br />
treatment and outcomes in <strong>the</strong> group of patients referred to sarcoma center.<br />
Methods: We retrospectively analyzed 12 patients (8 male, 4 females) treated at our<br />
institution between 2003 – 2011. Median age at <strong>the</strong> time of diagnosis was 33 years<br />
(range: 27-73). The histological types included angiosarcoma (n = 4), pleomorphic<br />
sarcoma (n = 4), leiomyosarcoma (n = 3), desmoplastic small round cell tumour (n =<br />
1). Primary tumors were located in right atrium (n = 6), left atrium (n = 5) and<br />
pulmonary artery (n = 1). The median tumour size was 50 mm (range 25-112). Four<br />
patients (33%) had a metastatic disease at diagnosis. Nine patients (75%) underwent<br />
curative intended surgery, including one patient who had a heart transplantation.<br />
Five patients (42%) received a perioperative anthracycline-based chemo<strong>the</strong>rapy.<br />
Results: The median overall survival (OS) was 19.5 months (range: 3-42). There was<br />
a significant improvement in overall survival for patients who underwent surgical<br />
resection versus those who did not (median OS 24.5 versus 6 months, respectively).<br />
Even better results were observed in patients receiving perioperative chemo<strong>the</strong>rapy.<br />
The median OS for <strong>the</strong>se patients was 32 months (range 27-42). Despite <strong>the</strong> curative<br />
intention of surgery, 90% of patients have subsequently developed local recurrence.<br />
Conclusion: Complete surgical excision in combination with chemo<strong>the</strong>rapy improves<br />
overall survival in patients with primary sarcomas of heart and great vessels.<br />
It underlines significance of close cooperation of cardiac surgery centers with tertiary<br />
cancer centers in treatment of patients with <strong>the</strong>se rare entities.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1514 BRAIN METASTASES(BM) IN PATIENTS (PTS) WITH SOFT<br />
TISSUE AND BONE SARCOMA (SARCOMA): A<br />
RETROSPECTIVE STUDY OF 107 PTS<br />
A. Cioffi 1 , A. Italiano 2 , R.G. Maki 1 , M.L. Keohan 3<br />
1 Department of Medicine and Pediatrics, Mount Sinai School of Medicine,<br />
New York, NY, UNITED STATES OF AMERICA, 2 Medical Oncology, Institute<br />
Bergoni, Bordeaux Cedex, FRANCE, 3 Department of Medicine - Melanoma and<br />
Sarcoma Service, Memorial Sloan Kettering Cancer Center, New York, NY,<br />
UNITED STATES OF AMERICA<br />
Introduction: Data related to management and outcome of BM of sarcoma are<br />
scarce.<br />
Methods: From 1991 to 2010, from over 4500 sarcoma pts treated at MSKCC, 107<br />
developed BM.<br />
Results: Highest relative frequency came from ASPS (26%,7/27 pts), with an absolute<br />
number highest for LMS(37%). BM metachronous in 96 cases (90%). Median time<br />
between diagnosis of metastatic sarcoma and <strong>the</strong> diagnosis of BM was 9 months<br />
(range 5.5–12.5). Locoregional treatment (surgery ± RT) in 83 pts (78%). Systemic<br />
CT in 18 pts (17%) after diagnosis of BM. One PR (EWS) in 15 evaluable pts. One<br />
hundred-one pts died (94%), 6 still alive. Two living pts with follow-up >24 months<br />
had complete surgery of BM. Deaths related to BM progression were 54 (54%),<br />
related exclusively to systemic PD were 47 (46%). Median OS was 3.6 months (95%<br />
CI: 2.9-4.3). One-year OS rate was 16% (95% CI 9–23). On univariate analysis,<br />
histology, delay between <strong>the</strong> diagnosis of sarcoma and BM relapse, number of<br />
lesions, disease status and PS were significantly associated with OS. Surgery was<br />
significantly related to improved OS while RT was not. On multivariate analysis, time<br />
between diagnosis of sarcoma and BM relapse and disease status were<br />
pre-<strong>the</strong>rapeutic prognostic factors associated with OS.<br />
Conclusions: SARCOMA pts with BM have poor outcome. RT was not associated<br />
with improved survival. Long-term survival is achieved in small proportion of pts<br />
managed by surgery. CT had little activity after BM, consistent with <strong>the</strong> advanced<br />
nature of <strong>the</strong> pts’ sarcomas.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds414 | ix489
1515 PREDICTORS OF SURVIVAL IN ADOLESCENTS AND YOUNG<br />
ADULTS WITH NON METASTATIC EXTREMITY<br />
OSTEOSARCOMA- CANCER INSTITUTE (WIA), A TERTIARY<br />
CANCER CENTER EXPERIENCE FROM SOUTH INDIA<br />
R. Rajendranath 1 , K. Narayanaswamy 2 , S.G. Tenali 1<br />
1 Medical Oncology, Cancer Institute (WIA), Chennai, INDIA, 2 Surgical Oncology,<br />
Cancer Institute (WIA), Chennai, INDIA<br />
Osteosarcoma one of <strong>the</strong> highly curable malignancy is <strong>the</strong> most common primary<br />
malignant neoplasm of bone in adolescents and young adults. The purpose of this<br />
study was to determine <strong>the</strong> predictors of survival in patients with non metastatic<br />
Extremity Osteosarcoma.<br />
Methods: The study was a retrospective analysis of 272 consecutive patients<br />
diagnosed between 1998 and 2008 and 232 of <strong>the</strong>m who had undergone protocol<br />
treatment was included for predictors of survival anal.<br />
Results: Median age of <strong>the</strong> patients was 17 years (6-52) and males constituted<br />
60 % (n = 163). Distal femur was <strong>the</strong> commonest site, 49.4% (n = 134) followed by<br />
proximal tibia 39.5% (n = 107). Classical osteosarcoma was <strong>the</strong> commonest subtype<br />
56% (n = 152) followed by Pleomorphic 21% (n = 57) and chondroblastic variant<br />
16.6%9 (n = 45). Majority of <strong>the</strong> tumours were high grade 96.3% (n = 262).156<br />
(57.6%) patients received Neoadjuvant Chemo<strong>the</strong>rapy and 184 (65%) received ≥ 4<br />
cycles of planned Chemo<strong>the</strong>rapy. 116 (42.4%) of patients underwent limb salvage<br />
surgery (LSS). The proportion of patients undergoing LSS improved from 45.3%<br />
to 53.2% during <strong>the</strong> time periods 1998-2002 and 2003-2008 respectively. Febrile<br />
Neutropenia was noted in 15 % and 3 patients died due to Chemo<strong>the</strong>rapy related<br />
toxicities. Of 156 patients who received neoadjuvant chemo<strong>the</strong>rapy 100 % necrosis<br />
was seen in 20 (12.8%) and >90% necrosis in 31 (19.8%). 5 year Disease free<br />
survival and overall survival among non metastatic osteosarcoma was 52.9% and<br />
55% respectively.Significant factors for predictors of survival included Age 90% necrosis (79.8% v/s 42.2% p = 0.001). Among<br />
Neoadjuvant Chemo<strong>the</strong>rapy patients who received 3-4 cycles of Preoperative<br />
Chemo<strong>the</strong>rapy did significantly better than those whoreceived ≥ 5cycles. (62.4% v/s<br />
46.1% p = 0.036).<br />
Conclusions: Predictivefactors that implicate adverse survival in non metastatic<br />
osteosarcoma in our patients include Age
Annals of Oncology<br />
Methods: This phase 4 study will assess osteosarcoma patients who are candidates<br />
for mifamurtide <strong>the</strong>rapy at European centres. (EudraCT: 2009-017204-89;<br />
NCT01194284). Eligible patients are aged 2–30 years, with a confirmed diagnosis of<br />
high-grade osteosarcoma. Approximately 150 patients are planned to be entered, and<br />
recruited over a 2-year period. Patients will receive <strong>the</strong> standard schedule of 2 mg/m 2<br />
IV mifamurtide, administered twice weekly for 12 weeks <strong>the</strong>n once weekly for 24<br />
weeks (total 36 weeks). The primary objectives are to assess <strong>the</strong> short- (during<br />
treatment) and long-term (≤5 years from last mifamurtide dose or until death) safety<br />
profile of mifamurtide, including evaluation of AEs of special interest (defined as<br />
important identified and potential risks) to take into account <strong>the</strong> risk of recurrence<br />
and comorbidities with chemo<strong>the</strong>rapy. Secondary objectives include assessment of<br />
disease status, disease-free survival and overall survival.<br />
Disclosure: C. Oliva: Employment: Takeda. Y. Liu: Employment: Millennium. All<br />
o<strong>the</strong>r authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds414 | ix491
abstracts<br />
small cell lung cancer and o<strong>the</strong>r<br />
thoracic malignancies<br />
1519PD PHASE II STUDY OF AMRUBICIN IN PATIENTS WITH<br />
REFRACTORY OR RESISTANT RELAPSED SMALL-CELL<br />
LUNG CANCER: JAPAN CLINICAL ONCOLOGY GROUP<br />
STUDY (JCOG0901)<br />
H. Daga 1 , H. Murakami 2 , N. Yamamoto 2 , T. Shibata 3 , M. Endo 4 , H. Watanabe 5 ,<br />
Y. Ichinose 6 , N. Yamamoto 7 ,Y.Ohe 8 , T. Tamura 7<br />
1 Department of Clinical Oncology, Osaka City General Hospital, Osaka, JAPAN,<br />
2 Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, JAPAN, 3 Regulatory<br />
Science Section Multi-institutional Clinical Trial Support Center, National Cancer<br />
Center Hospital, Tokyo, JAPAN, 4 Department of Radiology, Shizuoka Cancer<br />
Center, Shizuoka, JAPAN, 5 Department of Radiology, National Cancer Center<br />
Hospital, Tokyo, JAPAN, 6 Department of Thoracic Oncology, National Kyushu<br />
Cancer Center, Fukuoka, JAPAN, 7 Department of Thoracic Oncology, National<br />
Cancer Center Hospital, Tokyo, JAPAN, 8 Thoracic Oncology, National Cancer<br />
Center Hospital East, Kashiwa, JAPAN<br />
Background: Standard <strong>the</strong>rapy for refractory or resistant relapsed small-cell lung<br />
cancer (SCLC) has not yet been established. We conducted an open-label,<br />
multicenter, non-randomized phase II study to confirm <strong>the</strong> efficacy and safety of<br />
amrubicin, a topoisomerase inhibitor, in <strong>the</strong> treatment of refractory or resistant<br />
SCLC.<br />
Material and methods: Patients with SCLC that is refractory or relapsed within 90<br />
days of completing previous treatment received amrubicin at a dose of 40 mg/m 2 for<br />
3 consecutive days, every 21 days.The study treatment was repeated until disease<br />
progression or intolerable toxicity. The primary end point was overall response rate<br />
(ORR), and secondary end points were progression-free survival (PFS), overall<br />
survival (OS), and safety. Planned sample size was 80 patients to achieve power of at<br />
least 80% with one-sided alpha of 0.05, and expected and threshold value for<br />
primary endpoint as 20% and 10%. All patients were followed-up until one year after<br />
<strong>the</strong> last patient enrollment.<br />
Results: Between November 2009 and February 2011, 82 patients were enrolled from<br />
25 institutions. The median number of treatment cycles was four (range, one to 22<br />
cycles).The ORR was 32.9% (p < 0.0001 by <strong>the</strong> exact binomial test for null hypo<strong>the</strong>sis<br />
that ORR =
Annals of Oncology<br />
1522PD A MULTI-CENTER PHASE II CLINICAL TRIAL OF THE<br />
CHIMERIC ANTI-MESOTHELIN MONOCLONAL ANTIBODY<br />
AMATUXIMAB IN COMBINATION WITH CHEMOTHERAPY<br />
FOR FRONTLINE THERAPY OF MALIGNANT PLEURAL<br />
MESOTHELIOMA: UPDATED CLINICAL OUTCOMES AND<br />
CORRELATIVE STUDIES<br />
M. Reck 1 , R. Hassan 2 , T. Jahan 3 , H.L. Kindler 4 , L. Bazhenova 5 ,P.Fatato 6 ,J.<br />
W. Heyburn 6 , J. Parno 6 , J.D. Maltzman 6 , B. Wallin 6<br />
1 Thoracic Oncology, Krankenhaus Grosshansdorf, Grosshansdorf, GERMANY,<br />
2 Laboratory of Molecular Biology, National Cancer Institute, NIH, Be<strong>the</strong>sda, MD,<br />
UNITED STATES OF AMERICA, 3 Division of Hematology/Oncology, University of<br />
California - San Francisco, San Francisco, CA, UNITED STATES OF AMERICA,<br />
4 University of Chicago, Division of Oncology, Chicago, IL, UNITED STATES OF<br />
AMERICA, 5 Health Sciences, UCSD Moores Cancer Center, La Jolla, UNITED<br />
STATES OF AMERICA, 6 Oncology, Morphotek, Exton, PA, UNITED STATES OF<br />
AMERICA<br />
Background: Amatuximab (MORAb-009) is a chimeric monoclonal antibody to<br />
meso<strong>the</strong>lin, a cell surface glycoprotein highly expressed in malignant meso<strong>the</strong>lioma<br />
(MPM). Based on amatuximab results in a phase I clinical trial and pre-clinical<br />
studies showing synergy in combination with chemo<strong>the</strong>rapy, a single arm phase II<br />
study of amatuximab plus pemetrexed (P) and cisplatin (C) was initiated in MPM<br />
patients (Pts).<br />
Methods: Eligibility criteria: unresectable epi<strong>the</strong>lial or biphasic MPM, no prior<br />
chemo<strong>the</strong>rapy and Karnofsky Performance Status (KPS) >70%. Pts received<br />
amatuximab 5 mg/kg on days 1 and 8 with P 500 mg/m 2 and C 75 mg/m 2 (PC)<br />
given on day 1 of each 21-day cycle for 6 cycles. Pts with objective response or stable<br />
disease received amatuximab mono<strong>the</strong>rapy until disease progression. Primary<br />
endpoint: progression-free survival (PFS) at 6 months (mo). Secondary endpoints:<br />
overall survival (OS), objective response rate (ORR), pulmonary function (PFT), and<br />
safety of amatuximab with PC.<br />
Results: 89 pts with unresectable MPM were enrolled at 26 sites. Pt characteristics:<br />
median age 67 yrs (range 46-80); 78% male; 70% with KPS >90%; 89% epi<strong>the</strong>lial<br />
MPM, 11% biphasic MPM; 88% had stage III/IV disease. Median PC-amatuximab<br />
cycles: 5 (range 1-6). 56 (63%) pts subsequently received single agent amatuximab. In<br />
addition to expected toxicities from PC, hypersensitivity reactions (12.4%; Grade 3/4<br />
= 5%) from amatuximab were noted. By independent radiological review, 30 pts<br />
(39%) had a partial response and 39 (51%) had stable disease. PFS at 6 mo: 52%<br />
(95% CI: 39.5-63.5). Median PFS = 6.1 mo (95% CI: 5.4-6.5). Median OS = 14.8 mo<br />
(95% CI: 12.4 – 19.2). 29 pts are alive and 5 pts are still receiving maintenance<br />
amatuximab. The mean Forced Vital Capacity (FVC) change from baseline was<br />
132ml. The proportion of pts with an FVC improvement of > 400ml was 23%.<br />
Conclusions: Amatuximab in combination with PC was generally well-tolerated in<br />
this study in MPM pts with a disease control rate of 90%. The median OS of 14.8<br />
months compares favorably with historical controls.<br />
Disclosure: M. Reck: Advisory Board (compensated): Hoffmann-La Roche, Lilly,<br />
AstraZeneca, Pfizer, Daiichi-Sankyo, BMS. Honoraria for lectures: Hoffmann-La<br />
Roche, Lilly, AstraZeneca, Daiichi-SankyoT. Jahan: research funding from Genentech,<br />
Lilly and PfizerH.L. Kindler: research funding for morphotekP. Fatato: Employee of<br />
MorphotekJ.W. Heyburn: Employee of MorphotekJ. Parno: Employee of MorphotekJ.<br />
D. Maltzman: Employee of MorphotekB. Wallin: Employee of MorphotekAll o<strong>the</strong>r<br />
authors have declared no conflicts of interest.<br />
1523P THE 8.1 ANCESTRAL HAPLOTYPE IS STRONGLY<br />
ASSOCIATED WITH THE RISK OF SMALL CELL LUNG<br />
CANCER<br />
J. Kocsis 1 ,L.Graf 1 , A. Szilagyi 2 , B. Dome 3 , L. Tamasi 4 , G. Galffy 4 , Z. Orosz 5 ,<br />
Z. Prohaszka 2 , G. Fust 2 , Z. Bartfai 6<br />
1 3rd Dept of Internal Medicine, Oncology, Semmelweis University, Budapest,<br />
HUNGARY, 2 3rd Dept of Internal Medicine, Semmelweis University, Budapest,<br />
HUNGARY, 3 Tumor Biology, National Koranyi Institute of Pulmonology,<br />
Budapest, HUNGARY, 4 Pulmonology, Semmelweis University, Budapest,<br />
HUNGARY, 5 Radiology and Onco<strong>the</strong>rapy, Semmelweis University, Budapest,<br />
HUNGARY, 6 Pulmonology, Erzsebet Hospital, Sopron, HUNGARY<br />
Background: It is well established that <strong>the</strong> risk of lung cancer is related to <strong>the</strong><br />
individual genetic background as it is reflected in <strong>the</strong> increased incidences among<br />
first degree relatives. The discovery of <strong>the</strong>se genetic variations can lead to <strong>the</strong><br />
identification of those individuals who are at high risk of developing lung cancer.<br />
AH8.1 is a haplotype which extends through <strong>the</strong> whole MHC region in <strong>the</strong> short<br />
arm of chromosome 6. It is <strong>the</strong> most frequent and a very conservative haplotype in<br />
<strong>the</strong> Caucasian population. Previously we have reported a strong association between<br />
AH8.1 and colorectal cancer with an odds ratio higher than any risks reported for<br />
SNPs in genome-wide association studies or candidate gene studies. Published data<br />
indicate that AH8.1 is a strong risk factor for ovarian cancer and for non-Hodgkin<br />
lymphoma as well.<br />
Aim/methods: Here we have determined <strong>the</strong> carrier state of AH8.1 in 102<br />
patients with small cell lung cancer (SCLC) (62 + 7.8 years), 94 patients with<br />
non- SCLC (NSCLC) (59+ 8.6 years) and in 248 age-matched control subjects<br />
(66.7 + 6.5 years). Subjects carrying all <strong>the</strong> four marker alleles of AH8.1 (C allele<br />
of AGER 429T > C, G allele of HSP70-2 1267A > G, A allele of TNFalpha -308G<br />
> A, as well as G allele of LTA 252A > G polymorphisms) were considered as<br />
AH8.1 carriers.<br />
Results: 23% (23/102) of SCLC patients, 13.8% (13/94) of NSCLC patients, and 13%<br />
(32/248) of healthy controls carried <strong>the</strong> AH8.1 haplotype. We have found a<br />
significant increased risk for SCLC in those people carrying AH8.1 with an odds<br />
ratio of 1.94 (1.01-3.73; p = 0.046) (for men: 3.09, 1.07-8.82; p = 0.031). However,<br />
<strong>the</strong>re was no significant increase in <strong>the</strong> risk for NSCLC.<br />
Summary: These findings indicate that carriers of <strong>the</strong> AH8.1 haplotype are at<br />
increased risk for SCLC and it can be due to <strong>the</strong> altered immune response that is<br />
characteristic for 8.1 AH.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1524P COMBINATION OF THREE CYTOTOXIC AGENTS IN SMALL<br />
CELL LUNG CANCER<br />
G. Stathopoulos 1 , D. Traphalis 1 , J. Dimitroulis 2 , C. Kosmas 3 , J. Stathopoulos 1 ,<br />
D. Tsavdaridis 4<br />
1 A’ Oncology Clinic Errikos Dunant, Dr. Georgios Stathopoulos, A<strong>the</strong>ns,<br />
GREECE, 2 6th Pneumonic Clinic, Hospital for Thoracic Disease, A<strong>the</strong>ns,<br />
GREECE, 3 Oncology Clinic, Anticancer Hospital Piraeus, Piraeus, GREECE,<br />
4 Oncology Clinic, Anticancer Hospital, Thessaloniki, GREECE<br />
Background: Small-cell lung cancer treatment has been tested by using combinations<br />
of several cytotoxic agents. For quite a number of years, <strong>the</strong> established treatment has<br />
been cisplatin and etoposide as <strong>the</strong> most effective chemo<strong>the</strong>rapy regimen. Paclitaxel<br />
has also been used in combination with cisplatin and etoposide; <strong>the</strong> latter three -<br />
drug treatment has been effective but unacceptable due to toxicity.<br />
Patients and methods: In <strong>the</strong> present trial we tested <strong>the</strong> aforementioned three-drug<br />
combination and avoided <strong>the</strong> toxicity in <strong>the</strong> majority of <strong>the</strong> patients by administering<br />
all 3 drugs on day 1 instead of on <strong>the</strong> established three days of treatment. Fifty patients<br />
were recruited from 5 oncology clinics. All patients had histologically- or cytologicallyconfirmed<br />
small-cell-lung cancer with limited and extensive disease in 40% and 60% of<br />
<strong>the</strong> patients respectively. Treatment was as follows: cisplatin 75mg/m 2 , etoposide<br />
120mg/m 2 with no dosage higher than 200mg/m 2 and paclitaxel 135mg/m 2 . The agents<br />
were administered on day 1 and repeated every three weeks for 6 cycles in total.<br />
Results: The median survival was 14 months (95% CI 10.6-17.4) Forty-five patients<br />
(90%) achieved a response: 20(40%) patients a complete response and 25 (50%) a<br />
partial response. Adverse reactions was grade 3 and 4 neutropenia in 12% and 2% of<br />
<strong>the</strong> patients, respectively. O<strong>the</strong>r side effects involved very low toxicity.<br />
Conclusion: The one-day three-agent (cisplatin, etoposide, paclitaxel) treatment of<br />
small-cell lung cancer is beneficial with respect to response rate and survival, and has<br />
low and well-tolerated toxicity.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1525P THIRD-LINE CHEMOTHERAPY IN SMALL CELL LUNG<br />
CANCER: AN INTERNATIONAL ANALYSIS<br />
D. Simos 1 , G. Sajjady 2 , M. Sergi 3 , M.S. Liew 4 , R. Califano 5 ,C.Ho 2 , N.B. Leighl 3 ,<br />
S. White 4 , Y. Summers 5 , P. Wheatley-Price 1<br />
1 Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, ON, CANADA,<br />
2 Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, CANADA,<br />
3 Medical Oncology, Princess Margaret Hospital, Toronto, ON, CANADA, 4 Austin<br />
Health, Joint Austin-Ludwig Oncology Unit, Victoria, AUSTRALIA, 5 Medical<br />
Oncology, The Christie NHS Foundation Trust & University Hospital South<br />
Manchester NHS Foundation Trust, Manchester, UNITED KINGDOM<br />
Background: Small cell lung cancer (SCLC) is an aggressive disease and<br />
chemo<strong>the</strong>rapy (CT) is <strong>the</strong> mainstay of treatment. Despite good response rates most<br />
patients (pts) will relapse and die of this disease. Standard 1st-line CT in limited<br />
(LD) and extensive stage disease is usually etoposide with platinum (P) or CAV<br />
(cyclophosphamide, doxorubicin, vincristine). At progression, 2nd-line CT may<br />
involve re-challenging with <strong>the</strong> 1st-line regimen. For pts who progress after 2 lines of<br />
CT, <strong>the</strong>re is little evidence to guide treatment decisions, and <strong>the</strong> benefit of 3rd-line<br />
CT is unclear.<br />
Objective: To determine <strong>the</strong> clinical benefit of 3rd-line CT for SCLC.<br />
Study design: An international multi-centre retrospective analysis of pts who<br />
received 3 lines of CT for SCLC from 2001-2011 was performed. Baseline<br />
demographics, known prognostic factors and CT details were recorded. The main<br />
end-points were response rate (RR) and overall survival (OS) after 3rd-line CT.<br />
Results: A total of 124 eligible pts were identified; 59% male, median age 61, 89%<br />
ECOG 0-1, 40% LD. First-line P-based CT was given to 99% of pts, with a RR of<br />
90%. In <strong>the</strong> 2nd-line, 70 pts (56%) were re-challenged with similar CT, with <strong>the</strong><br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds415 | ix493
emaining receiving ei<strong>the</strong>r CAV or topotecan based CT, with an RR of 50%. In <strong>the</strong><br />
3rd-line, 35 pts (28%) were re-challenged with CT similar to a prior regimen. Only<br />
27 pts (22%) received 3 distinct lines of CT. Median progression free survival (PFS)<br />
in <strong>the</strong> 1st, 2nd and 3rd-lines were: 9.0, 4.6 and 2.0 months respectively. The RR in<br />
<strong>the</strong> 3rd-line was 17%, with no complete responses. Median 3rd-line OS was 4.8<br />
months. Factors associated with longer OS were: normal baseline serum LDH (p =<br />
0.02), response to 2nd-line CT (p = 0.04) and PFS >3 months after 2nd-line CT (p =<br />
0.05). Age, sex, initial disease stage, and CT re-challenges did not predict longer<br />
survival. After <strong>the</strong> 3rd-line, 35 pts received fur<strong>the</strong>r CT.<br />
Conclusions: In 5 cancer centres, over 10 years, few SCLC pts received 3 lines of CT.<br />
Most who received 3 lines had been re-challenged with a similar regimen at least<br />
once. OS and RR in <strong>the</strong> 3rd-line are modest. Lack of response to, or progression after<br />
2nd-line CT may predict particular lack of benefit in <strong>the</strong> 3rd-line. Prospective<br />
research in this area is needed.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1526P HYPONATRAEMIA AS A MARKER OF INFERIOR OUTCOMES<br />
IN SMALL CELL LUNG CANCER (SCLC)<br />
N.J. Coleman 1 , J. Clince 2 , W.M. Grogan 2 , O.S. Breathnach 1<br />
1 Medical Oncology, Beaumont Hospital Cancer Centre, Dublin, IRELAND,<br />
2 Medical Oncology, Beaumont Hospital, Dublin, IRELAND<br />
Introduction: Small cell lung cancer (SCLC) represents approximately 15% of all<br />
lung cancer diagnoses and is reducing in incidence. Hyponatremia is a common and<br />
debilitating electrolyte disorder, frequently documented in SCLC. Its occurrence is<br />
typically attributed to paraneoplastic syndrome- induced syndrome of inappropriate<br />
antidiuretic hormone hypersecretion (SIADH). The influence of hyponatremia on<br />
<strong>the</strong> survival of patients with lung cancer remains poorly understood. Aim: The aim<br />
of this retrospective study is to investigate clinical features and <strong>the</strong> prognostic value<br />
of hyponatremia in an unselected Irish patient population with small cell lung cancer<br />
(SCLC) with limited disease (LD) and extensive disease (ED).<br />
Method: The data of patients diagnosed with SCLC in Beaumont hospital over a<br />
3-year period was analysed retrospectively. Patients were identified from analysis of<br />
all lung cancers biopsies via <strong>the</strong> pathology department databank. Data was collected<br />
from clinical notes on identified patients including clinical performance status, serum<br />
sodium values, disease stage, chemo<strong>the</strong>rapy regimens and response, radio<strong>the</strong>rapy,<br />
palliative care input and survival.<br />
Results: 48 patients (22 male, 26 female) with a median age 64 yrs (range 41-87yrs),<br />
29.17%(n = 14) with limited stage were identified. The standard chemo<strong>the</strong>rapy was<br />
carboplatin–etoposide. 7 patients received 2 nd line treatment with irinotecan. 16.6%<br />
patients did not receive chemo<strong>the</strong>rapy (n = 8) due to poor performance status.<br />
Hyponatraemia (plasma sodium [P-Na]
Annals of Oncology<br />
treatment options. There are few data on how delivered treatment has changed<br />
during <strong>the</strong> past decade in routine clinical practice and how this has effected overall<br />
survival.<br />
Methods: We retrospectively analyzed all patients diagnosed with SCLC at our<br />
institution (lung cancer center certified by <strong>the</strong> German Cancer Society (DKG)) since<br />
2002. Analysis included lines of treatment delivered, progression free survival (PFS)<br />
at each <strong>the</strong>rapy line, use of radio<strong>the</strong>rapy, overall survival (OS), and use of PET-CT.<br />
Results: Preliminary analysis included 102 patients, of which 41 % had limited<br />
disease (LD) and 59 % had extensive disease (ED). For all patients, platinum doublet<br />
with etoposide has remained standard first line <strong>the</strong>rapy. For patients with LD, <strong>the</strong><br />
use of simultaneous thoracic radiochemo<strong>the</strong>rapy replaced sequential chemo<strong>the</strong>rapy<br />
followed by thoracic radio<strong>the</strong>rapy. In order to achieve a smaller radiation field,<br />
simultaneous radiochemo<strong>the</strong>rapy was usually preceded by 2 cycles of chemo<strong>the</strong>rapy.<br />
For patients with extensive disease, <strong>the</strong> use of cisplatinum instead of carboplatin<br />
increased in good performance status patients due to improved antiemesis<br />
(apprepitant). As second line <strong>the</strong>rapy, oral topotecan has largely replaced EpiCO<br />
(epirubicin, cyclophosphamide, vincristin). One patient with early recurrence of<br />
brain metastasis after radio<strong>the</strong>rapy and topotecan was treated successfully with oral<br />
temozolomide. Since August 2007, all ED patients responding to first line <strong>the</strong>rapy<br />
received prophylactic cranial radiation. OS tended to increase throughout <strong>the</strong> study<br />
period (LD: from 14 to 17 months, ED: from 6.7 to 10.1 months).<br />
Conclusions: New treatment options were successfully implemented in routine<br />
clinical practice and resulted in improved survival. However, survival remains<br />
unsatisfactory emphasizing <strong>the</strong> need for early detection and development of<br />
additional treatment strategies.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1530P EPIDERMAL GROWTH FACTOR RECEPTOR MUTATION IN<br />
SMALL CELL LUNG CANCER PATIENTS DETECTED BY<br />
MUTANT-ENRICHED LIQUIDCHIP TECHNOLOGY FROM<br />
PLASMA<br />
H. Lu 1 , W. Mao 2 , Q. Cheng 3 , J. Cai 1 , X. Wang 1 , Y. Zhang 4 , C. Lou 1 , J. Qin 1 ,<br />
L. Lei 1 , H. Yang 5<br />
1 Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, CHINA,<br />
2 Department of Thoracic Surgery, Key Laboratory Diagnosis and Treatment<br />
Technology on Thoracic Oncology (Zhejiang Province, China), Zhejiang Cancer<br />
Hospital, Hangzhou, CHINA, 3 Department of Traditional Medicine, Zhejiang<br />
Institute for Food and Drug Control, Hangzhou, CHINA, 4 Oncology, Zhejiang<br />
Cancer Hospital, Hangzhou, CHINA, 5 Department of Research, SurExam<br />
Bio-Tech Co. Ltd., Guangzhou, CHINA<br />
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has been<br />
widely used in non-small cell lung cancer (NSCLC), and <strong>the</strong> incidence of EGFR<br />
mutation in NSCLC is higher in China than in <strong>the</strong> United States and European<br />
countries. Mutations of EGFR exons 19 and 21 in NSCLC is related to response of<br />
tumors to EGFR TKIs, suggesting <strong>the</strong>ir usefulness as biomarkers. Some case studies<br />
reported a gefitinib-responsive small cell lung cancer (SCLC) with EGFR mutation.<br />
However, <strong>the</strong>re are few large studies which reported <strong>the</strong> mutation status of SCLC<br />
patients. It is difficult to obtain tumor tissues to detect EGFR mutations in SCLC<br />
patients especially from surgery. The aim of this study was to determine <strong>the</strong> EGFR<br />
mutation status in SCLC patients in China, and evaluate <strong>the</strong> feasibility of EGFR<br />
mutation detection from plasma by mutant-enriched liquidchip (MEL) technology.<br />
From September 2011 to March <strong>2012</strong>, plasma from 35 cases of SCLC were collected<br />
at <strong>the</strong> Zhejiang Cancer Hospital, Hangzhou, China. There were 7 female, 28 male;<br />
age from 46 to 74 years old and median age of 60 years old. The stage (Veterans<br />
Administration Lung Study Group, VALSG): limited disease (LD) 8 cases, extensive<br />
disease (ED) 27 cases. Smoking history: non-smoker 10 cases, light smoker 0 cases,<br />
moderate smoker 3 cases and heavy smoker 22 cases. MEL technology was used to<br />
detect EGFR exon 19 and exon 21 mutations from plasma of 35 SCLC patients. One<br />
of 35 cases was found with mutation in exon 19 of <strong>the</strong> EGFR gene. The patient with<br />
EGFR exon 19 mutation was a female and non-smoker. EGFR mutation is rare in<br />
SCLC patients, and may more easily occur in females and non-smokers. It is feasible<br />
to detect EGFR mutation for SCLC from plasma by MEL technology.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1531P NUCLEAR FACTOR-KAPPA B AS A MOLECULAR TARGET IN<br />
MALIGNANT PLEURAL MESOTHELIOMA<br />
K.A. Gately 1 , E. Jennions 2 , P. Godwin 3 , M. Barr 3 , S. Heavey 3 , K. Umezawa 4 ,<br />
J. Edwards 5 , S.G. Gray 3 , K.J. O’Byrne 6<br />
1 Clinical Medicine, St James’s Hospital, Dublin, IRELAND, 2 Oncology, University<br />
of Leicester, Leicester, UNITED KINGDOM, 3 Clinical Medicine, Trinity College<br />
Dublin, Dublin, IRELAND, 4 Oncology, Keio University, Yokohama, JAPAN,<br />
5 Department of Cardiothoracic Surgery, Sheffield Thoracic Institute, Sheffield,<br />
UNITED KINGDOM, 6 Hope Directorate, St James’s Hospital, Dublin, IRELAND<br />
Malignant pleural meso<strong>the</strong>lioma (MPM) is an aggressive inflammatory cancer<br />
associated with exposure to asbestos. Currently rates of MPM are rising and<br />
estimates indicate that <strong>the</strong> incidence of MPM will peak within <strong>the</strong> next 10-15 years<br />
for <strong>the</strong> western world. Untreated, MPM has a median survival time of 6 months, and<br />
most patients die within 24 months of diagnosis. Nuclear Factor kappa B (NFkB) is a<br />
pro-inflammatory transcription factor often described as <strong>the</strong> master regulator of<br />
pro-inflammatory responses within <strong>the</strong> cellular setting. We and o<strong>the</strong>rs have shown<br />
that NFκB is linked to cisplatin resistance (abstract 2307). Several lines of evidence<br />
also link NFkB to <strong>the</strong> pathogenesis of MPM.<br />
Using IHC we examined <strong>the</strong> expression of NFkB in a cohort of MPM patients (n =<br />
200) and correlated expression with various clinicopathological variables.<br />
Cytoplasmic or membranous immunostaining was seen in <strong>the</strong> majority of tumour<br />
samples (96.5%), but nuclear localisation of NFkB was seen in only 11% cases. There<br />
was no significant correlation between <strong>the</strong> level of expression of NFkB and standard<br />
clinicopathological prognostic factors. Kaplan-Meier Survival analysis showed that<br />
nuclear NFkB expression correlated with reduced survival with (p = 0.05). NFkB was<br />
expressed in all MPM cell lines tested to a varying extent (n = 20), with no<br />
associations to histology. Although small-molecule inhibitors of NFkB have been<br />
proposed as single-agent <strong>the</strong>rapies for cancers with aberrant NFkB activity, most<br />
classic NFkB inhibitors are poorly selective and result in off-target effects.<br />
Dehydroxymethyl-epoxyquinomicin (DHMEQ) is a novel NFkB inhibitor of low<br />
molecular weight designed from <strong>the</strong> structure of <strong>the</strong> antibiotic epoxyquinomicin<br />
C. When bound DHMEQ irreversibly inhibits NFkB and prevents its translocation to<br />
<strong>the</strong> nucleus. A series of MPM cell lines including a panel of isogenic parent/cisplatin<br />
resistant cell lines were treated with various concentrations of DHMEQ. The effects<br />
of DHMEQ on cellular viability were examined using various methodologies<br />
(including multi-parametric High Content Screening) and <strong>the</strong> results will be<br />
presented at <strong>the</strong> meeting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1532P HIGH EXPRESSION OF MACROPHAGE STIMULATING<br />
PROTEIN (MSP) CORRELATES WITH SURVIVAL BENEFIT IN<br />
MALIGNANT PLEURAL MESOTHELIOMA<br />
D. Easty 1 , A. Baird 1 , K.J. O’Byrne 2 , A. Soltermann 3 , D. Nonaka 4 , D. Fennell 5 ,<br />
L. Mutti 6 , H.I. Pass 7 , I. Opitz 8 , S.G. Gray 9<br />
1 Clinical Medicine, Trinity College Dublin/St. James’s Hospital, Dublin, IRELAND,<br />
2 Hope Directorate, St James’s Hospital, Dublin, IRELAND, 3 Institut für Klinische<br />
Pathologie, Universitätsspital Zürich, Zurich, SWITZERLAND, 4 Pathology, The<br />
Christie NHS Foundation Trust, Manchester, UNITED KINGDOM, 5 Medicine,<br />
University of Leicester, Leicester, UNITED KINGDOM, 6 Dept. of Medicine,<br />
Vercelli Hospital, Vercelli, ITALY, 7 Thoracic Surgery, NYU Langone Medical<br />
Center, New York, UNITED STATES OF AMERICA, 8 Thoracic Surgery, University<br />
Hospital Zurich, Zurich, SWITZERLAND, 9 Clinical Medicine, Trinity College<br />
Dublin, Dublin, IRELAND<br />
Introduction: RON/MST1R is a member of <strong>the</strong> MET tyrosine kinase family and has<br />
a putative role in several cancers. Macrophage stimulating protein (MSP) is <strong>the</strong> only<br />
known ligand for RON/MST1R. The MSP-RON signalling pathway has been<br />
implicated in a variety of cellular functions such as macrophage activity and wound<br />
healing. We have previously identified MST1R/RON as frequently activated in MPM,<br />
and high positivity for RON staining was an independent predictor of favourable<br />
prognosis.<br />
Methods: A panel of meso<strong>the</strong>lioma cell lines were screened for <strong>the</strong> expression of<br />
MSP and RON at <strong>the</strong> mRNA and protein level. The proliferative response of Ju77,<br />
H226 and Met5A (non-malignant transformed human pleural meso<strong>the</strong>lial cells) to<br />
MSP treatment was determined. A phospho-kinase array was utilised to detect <strong>the</strong><br />
downstream signalling pathways activated upon MSP stimulation. The effect of<br />
two MST1R/RON inhibitors (a) a pre-clinical monoclonal antibody (RON8,<br />
Imclone) and (b) a small molecule inhibitor on proliferation and migration was<br />
assessed. In addition, a series of MPM TMAs were stained for MSP and<br />
macrophage markers.<br />
Results: MSP and MST1R expression varied between <strong>the</strong> meso<strong>the</strong>lioma cell line<br />
panel at both <strong>the</strong> mRNA and protein level. Treatment with MSP reduced <strong>the</strong><br />
proliferative capacity of <strong>the</strong> Met5A cell, with a modest effect on <strong>the</strong> Ju77 MPM line.<br />
However, MSP stimulation modified <strong>the</strong> expression of <strong>the</strong> SRC family of kinases. In<br />
terms of targeting MST1R/RON, <strong>the</strong> small molecule inhibitor resulted in a<br />
significant decrease in proliferation and migration. Although treatment with RON8<br />
had no effect on proliferation, it did affect <strong>the</strong> migration capacity of <strong>the</strong> MPM cells.<br />
High expression of MST1R/RON or MSP correlated with better survival by<br />
univariate analysis. In multivariate analysis, MSP was identified as an independent<br />
prognosticator for survival in MPM. We observed no correlation with macrophage<br />
(CD 68) staining and survival.<br />
Conclusion: RON /MST1R comprises of a number of isoforms, <strong>the</strong> most common of<br />
which are flRON (full length) and sf (short form). Our results indicate that although<br />
high levels of RON and MSP correlate with increased survival, in vitro observations<br />
would indicate that this may be isoform dependant. Experiments are ongoing to<br />
fur<strong>the</strong>r elucidate <strong>the</strong> RON-MSP axis in MPM, including in vivo studies.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds415 | ix495
1533P EXPRESSION OF WILM⍰TUMOUR GENE (WT1) IS<br />
ASSOCIATED WITH SURVIVAL IN MALIGNANT PLEURAL<br />
MESOTHELIOMA: RETROSPECTIVE ANALYSIS IN A SINGLE<br />
CENTER SERIES<br />
S. Cedres 1 , D. Torrejon Castro 2 , N. Stjepanovic 2 , P. Martinez 2 , A. Martinez 2 ,<br />
M. Salcedo 2 , M.A. Montero 2 , E. Felip 2<br />
1 Medical Oncology, Vall d`Hebron University Hospital Institut d’Oncologia,<br />
Barcelona, SPAIN, 2 Medical Oncology, Vall d´ Hebron University Hospital,<br />
Barcelona, SPAIN<br />
Background: Calretinin and Wilmśtumour gene (WT1) are meso<strong>the</strong>lial markers<br />
used to confirm <strong>the</strong> diagnosis of malignant pleural meso<strong>the</strong>lioma (MPM). Recently,<br />
calretinin score assessed by immunohistochemistry (IHC) was implicated with poor<br />
prognosis in MPM. We investigated <strong>the</strong> prognostic value of calretinin and WT1<br />
expression in predicting survival in a series of patients (p) diagnosed of MPM in our<br />
institution<br />
Methods: Fifty two patients diagnosed of MPM in Vall d ´ Hebron University Hospital<br />
were retrospectively reviewed. Potential prognostic factors analyzed were age,<br />
performance status (PS), neutrophil to lymphocyte ratio (NLR), clinical stage, histology,<br />
calretinin and WT1 expression. Survival data were calculated by Kaplan-Meier.<br />
Results: Patient’s characteristics: median age 68 years (31-88 years), males 75.5%, PS<br />
1: 67.3%, asbestos exposure 53.1%, clinical stage III: 55.1%, epi<strong>the</strong>lial subtype 71.4%<br />
and NLR > 5 in 44.9% of all patients. Calretinin and WT1 IHC expression were<br />
available in 47 p and 32 p, and were positive in 41 p (83.7%) and 25 p (78.1%)<br />
respectively. All patients were considered initially unresectable and 71.4% received<br />
CT. We found a significant association of calretinin and WT1 expression with<br />
epi<strong>the</strong>lial histology (p= 0.030 and p = 0.010). The median survival (OS) was 15.2<br />
months. We found a significant increase in OS in patients with epi<strong>the</strong>lial subtype<br />
(23.4 vs 5.0 months in epi<strong>the</strong>lial vs no-epi<strong>the</strong>lial, p < 0.001), PS1 (14.7 vs 2.2 m in PS<br />
1 vs PS 2, p = 0.036) and NLR ≤5 (26.5 vs 13.4 m, p = 0.025). In <strong>the</strong> IHC markers<br />
analysis we found a significant increase in OS for p with WT1 positive expression<br />
(16.4 vs 2.3 m, p= 0.013), but not differences for calretinin expression (16.6 m vs 5.0<br />
months, p = 0.37). In <strong>the</strong> multivariate analysis epi<strong>the</strong>lial histology and WT1remained<br />
as significant prognostic factors for survival (HR 22.8; 95%CI,2.7-190, p = 0.004 and<br />
HR 9.5; 95%CI 1.7-52.3, p = 0.010 respectively).<br />
Conclusion: In our series of 52 MPM patients, epi<strong>the</strong>lial histology, PS, NLR and<br />
WT1 expression are significant prognostic factors for survival. The prognostic role of<br />
WT1 is worth of prospective validation in future studies on MPM.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1534P EFFICACY AND TOXICITY OBSERVED IN MALIGNANT<br />
PLEURAL MESOTHELIOMA PATIENTS TREATED IN PHASE I<br />
TRIALS AT A SINGLE INSTITUTION<br />
J. Raphael 1 , A. Hollebecque 2 , G. Le Teuff 3 , C. Massard 2 , R. Bahleda 2 ,<br />
J. Margery 4 , B. Besse 1 , J. Soria 1 , D. Planchard 1<br />
1 Thoracic Group, INSERM U981, Institut Gustave Roussy, Villejuif, FRANCE,<br />
2 Medical Oncology Department, Institut Gustave Roussy, Villejuif, FRANCE,<br />
3 Department of Statistics and Epidemiology, Institut Gustave Roussy, Villejuif,<br />
FRANCE, 4 Pulmonary Department, Percy Hospital, Paris, FRANCE<br />
Background: Malignant Pleural Meso<strong>the</strong>lioma (MPM) is a locally aggressive disease<br />
with a poor prognosis. After failure of first line platinum-based chemo<strong>the</strong>rapy, <strong>the</strong>re<br />
is no widely approved salvage regimen. New strategies for treatment are needed and<br />
phase I trials appear as a rationale alternative. The results of such an approach have<br />
been evaluated.<br />
Materials and methods: MPM patients, were enrolled in 20 different phase I trials<br />
between March 2005 and January <strong>2012</strong>, and <strong>the</strong>ir data analysed retrospectively. The<br />
primary endpoint was response rate and secondary endpoints were toxicity profile,<br />
Overall Survival (OS) and Progression Free Survival (PFS). Median follow-up of<br />
patients was estimated through Schemper’s method. The cut-off date for <strong>the</strong> analysis<br />
was April <strong>2012</strong>. Adverse events were assessed by NCI-CTC v.3.0 and response rate<br />
according to RECIST 1.1 criteria.<br />
Results: Forty-six patients with a confirmed histology of MPM were included in <strong>the</strong><br />
analysis with a median follow up of 20 months. The median age and <strong>the</strong> sex ratio<br />
(M/F) were 61 years old and 2.29 respectively. Radiological disease progression was<br />
observed in 50% of pts, clinical progression in 28%, and dose limiting toxicity in<br />
22%. The best tumour response was as follows: 7% of pts had a RECIST partial<br />
response, 59% had stable disease for a median duration of 2.8 months and 24% had<br />
progressive disease. The median treatment duration in <strong>the</strong> phase I was 1.9 months.<br />
Median OS and PFS were 6 months (95% CI= [4.3-10.7]) and 2.1 months (95% CI=<br />
[1.3-2.8]), respectively. The most common grade 3/4 adverse events (41%) were<br />
haematological (11%), gastro-intestinal (4%), cutaneous (7%), renal (4%) and hepatic<br />
(4%). All adverse events were reversible and no death due to toxicity was reported.<br />
Conclusion: Including MPM pts in phase I trials beyond first line of treatment can<br />
result in clinical benefits with an acceptable toxicity profile. Several molecular<br />
pathways involved in MPM have been identified and fur<strong>the</strong>r novel biologic <strong>the</strong>rapies<br />
might be tested in a phase I setting in a biology-oriented approach ra<strong>the</strong>r than a<br />
Annals of Oncology<br />
stochastical one. We are currently offering a tumour molecular profiling in our pts<br />
(MOSCATO trial) for a better selection of phase I trial.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1535P MULTIMODALITY THERAPY IN MESOTHELIOMA: AN<br />
EPIDEMIOLOGICAL AND EFFECTIVENESS ANALYSIS<br />
M.A. Damiano 1 , A.K. Patané 2 , M. Chacon 1 , R. Chacon 1 , V. Vilchez 1 , A. Rosales 2 ,<br />
A. Falco 1 , C. Poleri 3 , M. Rosenberg 2 , C. Martin 1<br />
1 Clinical Oncology, Instituto Alexander Fleming, Buenos Aires, ARGENTINA,<br />
2 Surgical Oncology, Instituto Alexander Fleming, Buenos Aires, ARGENTINA,<br />
3 Patology, Hospital Ferrer, Buenos Aires, ARGENTINA<br />
Introduction: Malignant pleural meso<strong>the</strong>lioma (MPM) is a rare and aggressive<br />
disease arising from <strong>the</strong> pleural meso<strong>the</strong>lium, with a reported survival (OS) of less<br />
than 12 months. However, patients with early-stage disease and good-performance<br />
status are suitable for multimodality <strong>the</strong>r¬apy (MT) involving surgery, radio<strong>the</strong>rapy<br />
(PORT), and chemo<strong>the</strong>rapy.<br />
Objective: Epidemiological description and analysis of effectiveness in patients with<br />
MPM who performed MT. Methods Retrospective study of patients treated by<br />
multimodality <strong>the</strong>rapy between April 1990 and April 2011 in three institutions from<br />
Argentina.<br />
Results: Of 110 patients, 24 (22%) went to MT. Median (Md) follow-up of 21<br />
months (2-139). Of 21 patients with complete data, 90.5% were epi<strong>the</strong>lioid. 67%<br />
male, Md age 54, 95% PS 0, 43% smokers, mean of 7.6 packs/year, 29% had contact<br />
with asbestos. 60% presented with chest pain or pleural effusion, 3 month (R: 0-38)<br />
Md time to diagnosis. 60% in <strong>the</strong> right pleura. Treatment: 90.5% extrapleural<br />
pneumonectomy, 9.5% pleurectomy/decortications, by single surgical team 92%.<br />
Perioperative mortality 8%, morbidity 63%, 32% bleeding complications (32%). 52%<br />
T3N0M0 postoperative staging. 15 performed neoadjuvant, 3 adjuvant chemo<strong>the</strong>rapy<br />
and 10 PORT. 67% received pemetrexed associated with platinum. 57% relapse after<br />
MT, 80% locoregional, 80% performed chemo<strong>the</strong>rapy. Md disease free survival (DFS)<br />
20.7 months (95% CI 8-46). OS 34.3 months (95% CI 17-43).<br />
Conclusions: Epidemiological and efficiency data obtained are similar to reported<br />
series. The present work shows that MT achieves higher DFS and OS than those<br />
obtained with o<strong>the</strong>r treatments that do not include surgery.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1536P MULTICENTER INSTITUTIONAL EXPERIENCE OF<br />
SURGICALLY RESECTED THYMIC EPITHELIAL TUMORS<br />
(TETS): AN OBSERVATIONAL REPORT ON BEHALF OF F.O.N.<br />
I.C.A.P. (FORZA OPERATIVA NAZIONALE<br />
INTERDISCIPLINARE CONTRO IL CANCRO DEL POLMONE)<br />
G. Genestreti 1 , M.A. Burgio 1 , L. Ampollini 2 , S. Sanna 3 , M. Monti 1 , A. Santo 4 ,<br />
M. Mezzetti 5 , G. Gavelli 6 , A. Verlicchi 7 , R. Buosi 8<br />
1 Medical Oncology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura<br />
dei Tumori (I.R.S.T.), Meldola, Meldola (FC), ITALY, 2 Department of Thoracic<br />
Surgery, University Hospital, Parma, Italy, Parma, ITALY, 3 Department of Thoracic<br />
Surgery, Morgagni-Pierantoni Hospital, Forlì, Italy, Forlì, ITALY, 4 Department of<br />
Medical Oncology, University Hospital, Verona, Italy, Verona, ITALY, 5 Department<br />
of Thoracic Surgery, San Carlo Clinic, Milan, Italy, Milan, ITALY, 6 Department of<br />
Radiology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei<br />
Tumori (IRST), Meldola (FC), ITALY, 7 Dipartimento Di Oncologia/ematologia,<br />
Ospedale Civile di Ravenna - S.ta Maria delle Croci, Ravenna, ITALY,<br />
8 Department of Clinical Oncology, Civil Hospital, Novara, Italy, Novara, ITALY<br />
Purpose: thymic epi<strong>the</strong>lial tumors (TETs) are a rare neoplasms. Due to <strong>the</strong>ir rarity,<br />
large-scale prospective trials are lacking. The present retrospective multicenter<br />
analysis aimed to evaluate clinical outcome and clinical-pathological features of TETs<br />
after complete surgical resection and adjuvant treatments (Adj) such as<br />
chemo<strong>the</strong>rapy (CHT) or radio<strong>the</strong>rapy (RT).<br />
Patients and methods: Patients who underwent a complete surgical resections for<br />
TETs between 2000 and 2007 were reviewed. WHO histological classification criteria<br />
and Masaoka staging system were used. Adj were: anthracycline- and platin-based<br />
CHT, RT on irradiation fields covering <strong>the</strong> primary tumor bed. Overall survival (OS)<br />
was calculated from <strong>the</strong> date of diagnosis until patient death or last follow-up visit.<br />
Disease free-survival (DFS) was defined as <strong>the</strong> interval between surgery and date of<br />
first documentation of recurrence. OS, DFS and 95% Confidence Interval (95% CI)<br />
were estimated by Kaplan-Meier method.<br />
Results: 62 patients were analyzed: 30 patients (48%) male and 32 (52%) female.<br />
Median age was 60 years (range: 33 - 86). At <strong>the</strong> beginning of <strong>the</strong>ir cancer history 20<br />
(32%) patients had myas<strong>the</strong>nia. Clinical staging showed: 31 (50%) stage I disease, 19<br />
(30%) stage II, 5 (8%) stage III, 2 (4%) stage IVa, 5 (8%) stage IVb. Histologies were:<br />
11 (19%) A tumor type, 18 (29%) AB type, 7 (12%) B1 type, 11 (17%) B2 type, 11<br />
(17%) B3 type and 3 (6%) C type. Pathological staging were: 30 (48%) stage I, 22<br />
(35%) stage II, 3 (6%) stage III, 2 (3%) stage IVa, 5 (8%) stage IVb. 3 (5%) patients<br />
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Annals of Oncology<br />
received Adj-CHT and 16 (26%) Adj-RT. Median follow-up was 71 months (range<br />
1-145), DFS and OS are <strong>the</strong> following:<br />
% DFS (95% CI) % OS (95% CI)<br />
Events 48 mo 60 o0 72 mo Events 48 mo 60 mo 72 mo<br />
9 89 (80-97) 89 (80-97) 86 (76-96) 7 97 (92-100) 95 (88-100) 92 (85-100)<br />
mo, months.<br />
Conclusions: TETs are rare and indolent tumors. Surgery offers good results which<br />
can be fur<strong>the</strong>r improved by Adj such as CHT and/or RT. Supported by GIPO.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1537P PROGNOSTIC FACTOR FOR SURVIVAL IN PATIENTS WITH<br />
ADVANCED THYMIC CARCINOMA<br />
Y. Okuma 1 , Y. Hosomi 1 , Y. Nakahara 1 , M. Yomoda 1 , Y. Takagi 2 , M. Iguchi 1 ,<br />
M. Shibuya 1 , T. Okamura 1<br />
1 Department of Thoracic Oncology and Respiratory Medicine, Tokyo<br />
Metropolitan Cancer and Infectious Diseases, Tokyo, JAPAN, 2 Department of<br />
Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and<br />
Infectious Diseases Center Komagome Hospital, Tokyo, JAPAN<br />
Background: Thymic carcinoma is a rare cancer that represents an incidence of 0.15<br />
per 100,000 persons per year. Thus, clinical characteristics and prognostic factors<br />
have not been investigated in detail. In this study, we tried to elucidate <strong>the</strong> disease<br />
profiles, outcomes, and prognostic factors for survival among patients with advanced<br />
thymic carcinoma treated with palliative-intent chemo<strong>the</strong>rapy.<br />
Patients and methods: This study was a retrospective review of medical records of<br />
38 patients treated with palliative-intent chemo<strong>the</strong>rapy for advanced thymic<br />
carcinoma between 1991 and 2011. Clinical demographics, histology, overall survival,<br />
and factors expected to predict survival were analyzed. Differences in survival were<br />
assessed using Kaplan-Meier analysis and uni- and multivariate Cox proportional<br />
hazards regression analyses.<br />
Results: The study included 20 males (52.6%) and 18 females (47.4%). The median<br />
age at diagnosis was 59.5 years. The most common metastatic sites at diagnosis were<br />
lung (44.7%), liver (15.8%), lymph nodes (15.8%), bone (13.2%), and brain (5.7%).<br />
The most common histological subtypes were squamous cell carcinoma (73.7%),<br />
followed by neuroendocrine carcinoma (15.8%), and mucoepidermoid carcinoma<br />
(7.9%). The median survival time was 25.4 months. Overall survival rates at 1- and<br />
2-years were 73.6% and 52.6%, respectively. In univariate and multivariate analyses,<br />
<strong>the</strong> only favorable prognostic factor for overall survival was response to first-line<br />
chemo<strong>the</strong>rapy (p = 0.009).<br />
Conclusion: Response to first-line chemo<strong>the</strong>rapy may be a prognostic factor for<br />
overall survival in patients with advanced thymic carcinoma.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1538P ACUTE EXACERBATION OF PRE-EXISTING INTERSTITIAL<br />
LUNG DISEASE (ILD) IN PATIENTS (PTS) WITH LUNG<br />
CANCER UNDER VARIOUS TREATMENTS<br />
H. Asahina1 , S. Oizumi1 , Y. Fujita2 , K. Takamura3 , T. Kojima4 , T. Harada5 ,<br />
Y. Kawai6 , H. Dosaka-Akita7 , H. Isobe4 , M. Nishimura1 1<br />
First Department of Medicine, Hokkaido University School of Medicine,<br />
Sapporo, JAPAN, 2 Department of Respiratory Medicine, National Hospital<br />
Organization Asahikawa Medical Center, Asahikawa, JAPAN, 3 First Department<br />
of Medicine, Hokkaido P.W.F.A.C Obihiro-Kosei General Hospital, Obihiro,<br />
JAPAN, 4 Department of Medical Oncology and Respiratory Medicine, KKR<br />
Sapporo Medical Center, Sapporo, JAPAN, 5 Center for Respiratory<br />
Disease, Hokkaido Social Insurance Hospital, Sapporo, JAPAN,<br />
6<br />
Department of Respiratory Medicine, Oji General Hospital, Tomakomai, JAPAN,<br />
7<br />
Department of Medical Oncology, Hokkaido University School of Medicine,<br />
Sapporo, JAPAN<br />
Background: Acute deterioration of ILD for unknown causes, sometimes called as<br />
acute exacerbation (AE), can occur at any point in <strong>the</strong> course of ILD. However, little<br />
is known about its incidence and prognostic significance in lung cancer pts with<br />
pre-existing ILD, who receive various treatments; chemo<strong>the</strong>rapy, surgery, palliative<br />
radio<strong>the</strong>rapy, and best supportive care (BSC).<br />
Methods: A total of 242 subjects (6.9% of all) were retrospectively identified to have<br />
pre-existing ILD by computed tomography (CT) from a sum of 3524 pts who had<br />
been hospitalized for lung cancer treatment at 8 institutions during 2004 to 2009. CT<br />
images of all <strong>the</strong> eligible pts were centrally reviewed. Univariate and multivariate<br />
analyses were performed using a Cox proportional hazard model to examine <strong>the</strong><br />
potential role of any prognostic factors for overall survival (OS) from <strong>the</strong> initial lung<br />
cancer diagnosis.<br />
Results: Pts’ characteristics were: male/female = 217/25; median age (range) = 73<br />
(42-98) yrs.; smoking status: ever/never = 223/19; Performance Status: 0/1/2/3/4 = 74/<br />
121/23/19/5; Stage I/II/III/IV = 48/10/98/86; Histology: adeno/squamous/large/NOS/<br />
small = 90/75/6/19/52; CT pattern: usual interstitial pneumonia (UIP)/non-UIP =<br />
118/124; extent of normal lung on baseline CT: 10-50%/60-90% = 154/88;<br />
pre-existing emphysema: yes/no = 178/64. AE occurred in 71 of 242 pts (29%)<br />
overall; 56 of 147 pts (38%) with chemo<strong>the</strong>rapy, 6 of 38 pts (16%) with surgery, 2 of<br />
17 pts (12%) with palliative radio<strong>the</strong>rapy, and 5 of 36 pts (14%) with BSC alone, and<br />
chemo<strong>the</strong>rapy was an independent risk factor for <strong>the</strong> occurrence of AE (P < 0.001).<br />
When separated by histology, in NSCLC, multivariate analysis revealed that age (≥70<br />
yrs., hazard ratio [HR]: 1.84, 95%CI: 1.25-2.71, p = 0.002), PS (≥2, HR: 2.90, 95%CI:<br />
1.80-4.68, p < 0.001), stage (≥3, HR: 4.03, 95%CI: 2.42-6.71, p < 0.001), and AE (HR:<br />
1.84, 95%CI: 1.26-2.69, p = 0.002) were significantly associated with OS, while in<br />
SCLC, AE was <strong>the</strong> only significant prognostic factor (HR: 2.26, 95%CI: 1.08-4.73, p =<br />
0.032).<br />
Conclusions: The occurrence of AE is not rare in <strong>the</strong> lung cancer treatment,<br />
particularly during chemo<strong>the</strong>rapy, and it is a factor for poor prognosis in pts with<br />
pre-existing ILD.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1539P PRIMARY MEDIASTINAL GERM CELL TUMOUR IN<br />
PAKISTANI POPULATION; A SINGLE CENTER EXPERIENCE<br />
K. Das, S. Imtiaz, S. Kumar, I.A. Muazzam, N. Siddiqui, S.A. Kazmi,<br />
N. MuzzafarMedical Oncology, Shaukat Khanum Memorial Cancer Hospital and<br />
Research Center, Lahore, PAKISTAN<br />
Introduction: Primary mediastinal germ cell tumor (PMGCT) constitutes a rare<br />
malignancy and is a diagnostic challenge because of <strong>the</strong> difficult approach and often<br />
small size of <strong>the</strong> biopsy specimen. These tumours have a worse prognosis than <strong>the</strong>ir<br />
gonadal counterparts. This study was performed to review clinical characteristics,<br />
<strong>the</strong>rapeutic strategies and outcome of patients with PMGCT at Shaukat Khanum<br />
Memorial Cancer Hospital and Research Center Lahore Pakistan.<br />
Patient and method: Medical records of patients treated in our hospital during 1996<br />
to <strong>2012</strong> were retrospectively studied.<br />
Results: Of 25 patients, 23 were males with a median age of 23 years (range 16–48).<br />
Forty percent were seminoma and 60% were nonseminoma. More than 80% of<br />
nonseminoma had raised baseline alpha feto protein. The clinical presentation in<br />
order of frequency included; dyspnea (72%), cough (68%), chest pain (56%), pleural/<br />
pericardial effusion (44%), weight loss (32%), fever (28%), superior vena-caval<br />
obstruction (24%), cervical node metastasis (20%) and pulmonary metastasis (12%).<br />
All were treated with initial standard platinum based chemo<strong>the</strong>rapy. Eighty percent<br />
of our patients achieved biochemical complete response and 80% achieved<br />
radiological response (67% Partial response, 13% complete response). Median<br />
survival of patients with seminoma was 37 months with three year survival rate of<br />
60%. Median survival of patients with nonseminoma was 13 months with three year<br />
survival rate of 31%. During study period eleven patients died (seven had disease<br />
progression, 02 had bleomycin lung toxicity and two had neutropenic sepsis).<br />
Conclusion: Nonseminoma constitutes <strong>the</strong> majority of primary mediastinal germ cell<br />
tumors, with prominent male preponderance. Seminomas had a better outcome than<br />
nonseminomas. Cisplatin based chemo<strong>the</strong>rapy continues to be an effective treatment<br />
for <strong>the</strong>se tumours.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1540 COMPARISON OF SECOND LINE TREATMENT OUTCOMES<br />
BETWEEN SENSITIVE AND REFRACTORY SMALL CELL LUNG<br />
CANCER PATIENTS: A RETROSPECTIVE ANALYSIS<br />
T. Korkmaz 1 , S. Seber 2 , E. Sari 2 , M. Canhoroz 3 , B. Oven Ustaalioglu 1 , U. Kefeli 1 ,<br />
O. Balvan 1 , M. Gumus 4 , N. Yasar 1 , S.N. Turhal 5<br />
1 Medical Oncology Department, Dr Lutfi Kirdar Kartal Research and Educational<br />
Hospital, Istanbul, TURKEY, 2 Medical Oncology Department, Marmara University<br />
Hospital, Istanbul, TURKEY, 3 Medical Oncology Department, Uludag University<br />
Hospital, Bursa, TURKEY, 4 Dept. Medical Oncology, Kartal Research and<br />
Training Hospital Division of Medical Oncology, Istanbul, TURKEY, 5 Medical<br />
Oncology, Marmara University Hospital, Istanbul, TURKEY<br />
Introduction: Small cell lung cancer (SCLC) has a high relaps rate despite being very<br />
chemosensitive. The prognosis of <strong>the</strong>se patients is generally poor. The efficasy of<br />
second line treatment is dismal when compared to o<strong>the</strong>r chemosensitive tumors such<br />
as germ cell tumor or lymphoma. Our aim was to evaluate <strong>the</strong> outcome of second<br />
line treatment and to delineate <strong>the</strong> prognostic factors that would effect <strong>the</strong> survival<br />
times and response rates.<br />
Methods: Results we retrospectively assesed 120 SCLC patients who who failed<br />
firstline platinum-etoposide chemo<strong>the</strong>rapy and went on to receive second line<br />
chemo<strong>the</strong>rapy at 3 medical oncology centers.<br />
Results: Median age of <strong>the</strong> study group was 58 (33-78) and %80 percent of our<br />
patients were below 65 years old. %84 patient were male, %82 had an ECOG PS of<br />
0-1. %61 were at extensive stage at <strong>the</strong> time of diagnosis. Patients who progressed<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds415 | ix497
more than 3 months after first line <strong>the</strong>rapy were labelled as platin sensitive (%64).<br />
The patients who received platin based combination based treatment was % 27.<br />
Median PFS and OS starting from <strong>the</strong> initiation of second line treatment were 4 and<br />
7 months respectively. Multivariate analysis identified PS (P= 0.006), extent od<br />
disease at inital stage(0.014) and platin sensitivity (0.001) as <strong>the</strong> independent<br />
prognostic factors for survival. Subgroup analyses of <strong>the</strong> platin sensitive patients<br />
indicated platin re challenge yields higher PFS, OS and RR . There was no difference<br />
was found between irinotecan and topotecan in <strong>the</strong> refractory patient group in terms<br />
of treatment outcomes.<br />
Conclusion: Patients with good PS, who are platin sensitive or initially staged as<br />
limited disease derive <strong>the</strong> most benefit from second line chemo<strong>the</strong>rapy in <strong>the</strong> setting<br />
of relapsed SCLC. Platin combination <strong>the</strong>rapy should be <strong>the</strong> treatment of choice in<br />
<strong>the</strong> platin sensitive patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1541 EXPRESSION OF C-KIT (CD 117) IN EPITHELIAL THYMIC<br />
MALIGNANCIES<br />
M. Wollner 1 , E. Flechter 1 , O. Vaisman 2 , O. Ben Itzhak 2<br />
1 Department of Oncology, Rambam Health Care Center, Haifa, ISRAEL,<br />
2 Department of Pathology, Rambam Health Care Center, Haifa, ISRAEL<br />
Study objectives: The expression of c-kit (CD117) was investigated to evaluate its<br />
usefulness as a marker supporting differential diagnosis and choice of <strong>the</strong>rapy. In<br />
thymic epi<strong>the</strong>lial tumors <strong>the</strong> expression of c-kit may explain a new model of tumor<br />
biology, and support <strong>the</strong> use of determinate target <strong>the</strong>rapy as a new optional<br />
approach.<br />
Methods: We examined <strong>the</strong> immunohistochemical expression of c-kit in 28 cases of<br />
thymic epi<strong>the</strong>lial tumors diagnosed in our department between 2003-2010, that had<br />
been classified on <strong>the</strong> basis of <strong>the</strong> World Health Organization histologic classification<br />
system: 24 thymoma and 4 thymic carcinoma (1 type A, 4 type AB, 1 type B1, 12<br />
type B2, 6 type B3 and 4 type C).<br />
Results: c-kit expression showed immunoreactivity positive in 18% of <strong>the</strong> all cases (5<br />
patients). In this subgroup, 1 type B2, 1 type B3 and 3 type C. In contrast no<br />
immunoreactivity was found in <strong>the</strong> thymoma cases (types A, AB and B1). No<br />
differences were found in <strong>the</strong> c-kit expressing group between <strong>the</strong> genders (12 females,<br />
16 males). All c-kit expressing cases were older than 61 years old.<br />
Conclusion: Expression of c-kit is an immunohistochemical marker for <strong>the</strong> diagnosis<br />
of thymic carcinoma, and represent a new model of tumor biology with potential<br />
development of new targeted <strong>the</strong>rapies as an option for <strong>the</strong> treatment of thymic<br />
carcinoma on <strong>the</strong> basis of <strong>the</strong> kit pathways. Clinical trials are necessary to<br />
demonstrate <strong>the</strong> efficacy of <strong>the</strong>se new <strong>the</strong>oretical strategies.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1542TiP VINORELBINE IN MESOTHELIOMA (VIM): A RANDOMISED<br />
PHASE II TRIAL OF ORAL VINORELBINE AS SECOND-LINE<br />
THERAPY FOR PATIENTS WITH MALIGNANT PLEURAL<br />
MESOTHELIOMA (MPM) EXPRESSING BRCA1 – A STUDY<br />
IN PROGRESS<br />
D.A. Fennell 1 , A. Casbard 2 , L. Nixon 2 , J. Lester 3 , G. Griffiths 2<br />
1 Department of Thoracic Medical Oncology, University of Leicester & Leicester<br />
University Hospitals, Leicester, UNITED KINGDOM, 2 Wales Cancer Clinical Trials<br />
Unit, School of Medicine, Cardiff University, Cardiff, UNITED KINGDOM, 3 Cancer<br />
Centre, Velindre Hospital, Cardiff, UNITED KINGDOM<br />
Background: Meso<strong>the</strong>lioma is increasing worldwide. However <strong>the</strong>re is no approved<br />
<strong>the</strong>rapy in <strong>the</strong> second-line setting. Vinorelbine exhibits promising activity, however<br />
<strong>the</strong>re has been no randomised evaluation or validation of biomarkers to support<br />
patient stratification. We have recently reported that BRCA-1 is an essential regulator<br />
of meso<strong>the</strong>lioma sensitivity to vinorelbine, and its expression is lost in approximately<br />
38% 1 . The Cancer Research UK VIM trial is to be sponsored by <strong>the</strong> University of<br />
Leicester in collaboration with <strong>the</strong> Wales Cancer Clinical Trials Unit.<br />
Aims: To evaluate <strong>the</strong> efficacy of second-line vinorelbine plus active symptom<br />
control (ASC), versus ASC. Secondary endpoints: tolerability, response rate, change<br />
in tumour volume and overall survival. BRCA1 expression IHC will be evaluated as a<br />
stratification factor.<br />
Annals of Oncology<br />
Methods: An open label, randomised trial of weekly vinorelbine 80mg/m 2 plus<br />
ASC versus ASC alone. The control arm of ASC will be defined by local practice.<br />
Both study arms will be continued until documented evidence of radiological<br />
progression or unacceptable toxicity. The sample size has been calculated using<br />
<strong>the</strong> parameters; α = 0.2, β = 0.1 (90% power), hazard ratio 0.65, 1-sided logrank<br />
test and 2:1 randomisation favouring vinorelbine. This requires recruitment of 114<br />
patients. However, as we hypo<strong>the</strong>sis that BRCA-1 expression is required for<br />
vinorelbine activity and have estimated its absence in one third of patients, <strong>the</strong><br />
sample size may be inflated to 171 patients depending on <strong>the</strong> results of an<br />
interim analysis. We aim to open <strong>the</strong> study in Q1 2013 and recruit over 18<br />
months. The results of this study will be used to inform <strong>the</strong> design of a future<br />
phase III study, with stratification of patients to optimise efficacy. BRCA1 is an<br />
essential mediator of vinorelbine-induced apoptosis in meso<strong>the</strong>lioma. Busacca S<br />
et al J Pathol. <strong>2012</strong> Jun; 227(2):200-8<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1543TiP PHASE I/II STUDY TO ASSESS THE SAFETY,<br />
PHARMACOKINETICS (PK) AND EFFICACY OF<br />
LORVOTUZUMAB MERTANSINE (LM, IMGN901) IN<br />
COMBINATION WITH CARBOPLATIN/ETOPOSIDE IN<br />
PATIENTS WITH SOLID TUMORS INCLUDING SMALL-CELL<br />
LUNG CANCER (SCLC)<br />
D.R. Spigel 1 , J. Bendell 1 , A.C. Mita 2 , A. Argiris 2 , C. Kurkjian 3 , C.L. Hann 4 ,<br />
Z. Segota 5 , R. Guild 6 , R. Mastico 6 , M.E. Guiterrez 5<br />
1 Gi Oncology Research/drug Development Unit, Sarah Cannon Research<br />
Institute, Nashville, TN, UNITED STATES OF AMERICA, 2 Oncology, University of<br />
Texas Health Sciences Center, San Antonio, TX, UNITED STATES OF AMERICA,<br />
3 Cancer Center, The Univesity of Oklahoma Cancer Inst., Oklahoma City, OK,<br />
UNITED STATES OF AMERICA, 4 Cancer Center, Johns Hopkins Sidney Kimmel<br />
Comprehensive Cancer Center, Baltimore, MD, UNITED STATES OF AMERICA,<br />
5 Cancer Center, Holy Cross Hospital, Fort Lauderdale, FL, UNITED STATES OF<br />
AMERICA, 6 Pharmacokinetics Lab, ImmunoGen, Inc., Waltham, MA, UNITED<br />
STATES OF AMERICA<br />
Purpose: SCLC expresses CD56 almost universally. LM is a CD56-targeting<br />
antibody-drug conjugate. This study was initiated to evaluate LM for <strong>the</strong> treatment<br />
of SCLC when used in combination with carboplatin (C) and etoposide (E). Its phase<br />
1 portion was designed to establish <strong>the</strong> recommended phase 2 dose (RP2D) of LM<br />
with C and E. PK data with <strong>the</strong> combination also was obtained.<br />
Methods: Patients (pts) with advanced solid tumors were accrued to a standard 3 + 3<br />
dose-escalation study design. Successive cohorts received escalating doses of LM IV<br />
on days 1 and 8 in combination with C IV on day 1 and E IV on days 1-3 every 21<br />
days. LM PK was measured by an ELISA-based method. C and E levels were<br />
measured using optimized LC-MS/MS assays. PK parameters were determined by<br />
noncompartmental analysis.<br />
Results: 33 patients (13M, median age = 57.3) were treated in 5 cohorts (2 using C<br />
AUC6; 3 using C AUC5) at LM doses ranging from 60-112 mg/m 2 . The RP2D was<br />
defined as LM 112 mg/m 2 with C AUC5 and E 100 mg/m 2 . PK samples were<br />
analyzed for Cycle 1, first dose. At <strong>the</strong> RP2D, LM exposure and maximum<br />
concentration were similar to those observed in single-agent trials, with <strong>the</strong> t1/2 of<br />
LM approaching 1 day (24.2 hours). PK findings for C/E were similar to published<br />
reports (Oguri, 1988; D’Incalci, 1982) with <strong>the</strong> observed AUC of C = 5.1 ± 0.7<br />
min*mg/mL and E = 6921 ± 1231 min*µg/mL. The most common treatment-related<br />
adverse events (AEs) were anemia, thrombocytopenia, nausea, peripheral neuropathy,<br />
decreased lymphocytes and neutrophils, and fatigue. The majority of related grade 3/<br />
4 AEs were cytopenias which, while known to occur with C/E regimens, typically<br />
have not been associated with LM mono<strong>the</strong>rapy. Among 13 pts with SCLC accrued<br />
to phase 1, 6 (46%; 4 previously treated) achieved PR after at least one response<br />
assessment.<br />
Conclusion: The combination is well tolerated with no apparent drug-drug<br />
interactions. Preliminary signs of activity have been observed in this predominantly<br />
pre-treated population. The randomized phase 2 portion of <strong>the</strong> study in chemo-naïve<br />
patients with SCLC has opened to accrual. Updated data will be presented.<br />
Disclosure: R. Guild: Employee of ImmunoGen, Inc.R. Mastico: Employee of<br />
ImmunoGen, Inc.All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
ix498 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
supportive care<br />
1544O COMPARISON OF NUTRITIONAL ASSESSMENT WITH A NEW<br />
DEFINITION OF CACHEXIA IN DETERMINING OUTCOMES<br />
OF ADVANCED CANCER PATIENTS<br />
S. Clarke 1 ,C.Tan 2 , J. Read 3 , V. Phan 4 , J.K. Peat 5 and P. Beale 4<br />
1 Medical Oncology Department, Royal North Shore Hospital, Sydney, NSW,<br />
AUSTRALIA, 2 Nutrition and Dietetics Department, Concord Hospital, Sydney,<br />
NSW, AUSTRALIA, 3 Prince of Wales Hospital, Sydney, NSW, AUSTRALIA,<br />
4 Medical Oncology Department and Sydney Cancer Center, Concord Hospital,<br />
Sydney, NSW, AUSTRALIA, 5 Consultant Biostatistician, Concord Hospital,<br />
Sydney, NSW, AUSTRALIA<br />
Background: An international consensus statement providing a definition and<br />
diagnostic criteria for cancer cachexia was recently published. This study aimed to<br />
compare <strong>the</strong> relative prognostic utility of this definition with nutritional status as<br />
defined by <strong>the</strong> Patient-Generated Subjective Global Assessment (PG-SGA) tool.<br />
Methods: A prospective cohort study was conducted in a tertiary hospital where<br />
chemo<strong>the</strong>rapy naive patients with life expectancy ≥3 months were recruited by<br />
medical oncologists and a research dietitian. Kaplan-Meier survival analyses were<br />
used to determine <strong>the</strong> median survival of patients with advanced cancer in <strong>the</strong><br />
cohort study, and a subset of patients who met <strong>the</strong> criteria for cancer cachexia as<br />
defined in <strong>the</strong> international consensus (Fearon 2011). The log rank chi-square test<br />
was used to evaluate <strong>the</strong> strength of predictors of overall survival (OS). A P value of<br />
12, 1:]12-10], 2:]10-9], 3:]9-8], 4: < 8. Scores linear (mean) and<br />
non-linear (polynomial) were calculated using for F: grades from start to end<br />
CT and for anemia: mean grade per cycle. OS was calculated from CT initiation<br />
to death or censured at last contact.<br />
Results: 1279 pts entered <strong>the</strong> program, 662 (equivalent to 4327 CT cycles) had<br />
at least 1 assessment of (fatigue + Hb). Excluded pts (617) due to lacking Hb<br />
results did not differ from <strong>the</strong> 662 (log-Rank = 0.98). Median age = 64.9y,<br />
sex-ratio = 1.1, more frequent localization: lung (23%), breast (21%), prostate<br />
(13%), ovary (10%). 229 and 433 pts had respectively at least 1 or 2 Hb results<br />
at each cycle. There were 5376 episodes of fatigue in total (PSS > 0), 694 pts<br />
experienced at least 1 episode. 516, 232, 101 and 35 pts experienced at least 1<br />
anemia episode on scale 1, 2, 3 and 4 respectively. Median linear F score = 1.08<br />
[0-3], non-linear = 1.57 [0-200.7]. Median linear anemia score = 0.78 [0-1.5],<br />
non-linear = 0.78 [0-1.6]. OS was 24.8m IC95%|21.6-30.4]. Linear scores were<br />
normally distributed and non-linear were discarded since much skewed. As<br />
expected, anemia and fatigue were correlated (ANOVA, p < 0.0001). Linear F<br />
score (LFS) was good predictor of OS (L: HR = 2.5, IC95% [2.0-3.1], p < 0.0001).<br />
Patients with LFS > 2 (N = 72) had an increased death risk of 4.65 (IC95%|<br />
3.15-6.88]) with respect to LFS < 1 (N = 247). Hb mean and linear anemia score<br />
were good predictors for OS, respectively HR = 1.45 IC95% [1.31; 1.6] and HR =<br />
1.86 IC95% [1.57; 2.19]).<br />
Conclusion: A linear score of anemia and fatigue PSS were simple and efficient<br />
predictors of overall survival. They could be monitored to help clinicians in fatigue<br />
and anemia management.<br />
Disclosure: S. Oudard: honoraria: Sanofi, Roche, Bayer. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
1547PD G-CSF AS SECONDARY PROPHYLAXIS OF<br />
CHEMOTHERAPY-INDUCED NEUTROPENIA IN PATIENTS<br />
WITH SOLID TUMORS: RESULTS OF A PROSPECTIVE,<br />
OBSERVATIONAL STUDY<br />
G. Freyer 1 , N. Jovenin 2 , G. Yazbek 2 , C.B. Villanueva 3 , A. Hussain 4 , A. Bethune 5 ,<br />
M. Rotarski 6 , H. Simon 7 , V. Boulanger 8 and M. Hummerlsberger 9<br />
1 Medical Oncology, Centre Hospitalier Lyon Sud, Pierre- Bénite, FRANCE,<br />
2 Medical Oncology, Institut Jean Godinot, Reims, FRANCE, 3 Medical Oncology,<br />
Centre Hospitalier Universitaire, Besançon, FRANCE, 4 Medical Oncology, Centre<br />
Hospitalier Quimper, Quimper, FRANCE, 5 Medical Oncology, Centre René<br />
Huguenin, Saint Cloud, FRANCE, 6 Medical Oncology, Centre Oncologie du Pays<br />
Basque, Bayonne, FRANCE, 7 Oncologie Médicale, Hôpital Augustin Morvan,<br />
Brest, FRANCE, 8 Medical Oncology, Centre Hospitalier de Carcassonne,<br />
Carcassonne, FRANCE, 9 Medical Oncology, Centre de Radiothérapie et<br />
Oncologie Médicale, Béziers, FRANCE<br />
Background: There are little available data on secondary prophylaxis of<br />
chemo-induced neutropenia. We designed this multicentre, prospective and<br />
observational study to identify predictive factors of occurrence of neutropenic events<br />
(NE) subsequent to a previous episode, in patients with solid tumors (primary<br />
objective). Secondary objectives were to determine <strong>the</strong> incidence of NE, describe<br />
prophylactic strategy: cycle delay, dose reduction, G-CSF prescription, and its impact<br />
on <strong>the</strong> recurrence of NE.<br />
Patients and methods: Patients ≥ 18 years were included if <strong>the</strong>y experienced a NE<br />
during any previous cycle (reference cycle A), with no prior G-CSF administration.<br />
Neutropenic events were defined as any neutropenia grade 1-4, febrile or not, that<br />
impacts on <strong>the</strong> subsequent cycles (cycle delay and/or dose reduction and/or use of<br />
G-CSF). Patients were followed for a total of 5 cycles. Risk factors of febrile<br />
neutropenia (FN), and prophylactic strategies (with or without G-CSF) were included<br />
in univariate and multivariate analyses to assess <strong>the</strong>ir predictive value on recurrence<br />
of NE.<br />
Results: 625 patients included, 548 (87.7%) evaluable.378 (69%) female, mean<br />
(SD) age (years) 61.7 (12.3), WHO PS 0-1 88.3%, breast: 40%, colorectal: 15.7%,<br />
lung: 11.9%. Metastatic disease: 53.3%. During cycle A, 88 patients (16.1%)<br />
experienced FN, 42 (7.7%) neutropenic fever and 418 (76.3%) neutropenia (any<br />
grade w/o fever). 44.5% had cycle delay, 22.3% dose reduction and 466 (85%)<br />
received prophylactic G-CSF (pegfilgrastim 59.7%, lenograstim 27.3%, filgrastim<br />
10.3% and biosimilar 2.1%). Incidence of NE in subsequent cycles and<br />
prophylactic strategies are shown in <strong>the</strong> table below. In multivariate analysis,<br />
G-CSF use (HR:0.32 (0.24; 0.43; p < 0.001) was an independent predictor of<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com<br />
abstracts
lower recurrence rate of NE. Pegfilgrastim seemed to offer <strong>the</strong> highest protection<br />
(HR: 0.23 (0.16; 0.32; p < 0.001).<br />
Conclusion: Prophylactic strategy with G-CSF has significant efficacy in reducing <strong>the</strong><br />
incidence of NE, and should be considered as <strong>the</strong> best option in <strong>the</strong> secondary<br />
prophyalxis setting.<br />
Cycle A<br />
(no G-CSF)<br />
N = 548<br />
Cycle B<br />
N = 548<br />
Cycle C<br />
N = 548<br />
CycleD<br />
N = 442<br />
Cycle E<br />
N = 344<br />
Febrile<br />
neutropenia<br />
88 (16.1%) 3 (0.5%) 4 (0.7%) 0 1 (0.3%)<br />
Neutropenic fever 42 (7.7%) 2 (0.4%) 4 (0.7%) 1 (0.2%) 0<br />
Neutropenia w/o<br />
fever<br />
418 (76.3%) 111 (20.3)% 95 (17.3%) 50 (11.3%) 47 (13.7%)<br />
Cycle delay - 244 (44.5%) 44 (8.0%) 23 (5.2%) 18 (5.2%)<br />
Dose reduction - 122 (22.3%) 27 (4.9%) 17 (3.8%) 12 (3.5%)<br />
use of<br />
Prophylactic<br />
G-CSF<br />
- 466 (85.0%) 413 (75.4%) 332 (75.0%) 247 (71.8%)<br />
Disclosure: G. Freyer: Consultant for Amgen. All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
1548PD ABSOLUTE NEUTROPHIL COUNTS IN A STUDY OF<br />
LIPEGFILGRASTIM COMPARED WITH PEGFILGRASTIM IN<br />
PATIENTS WITH BREAST CANCER WHO ARE RECEIVING<br />
CHEMOTHERAPY<br />
O.A. Gladkov 1 , I.M. Bondarenko 2 , R. Elsaesser 3 , A. Buchner 4 and P. Bias 4<br />
1 Chemo<strong>the</strong>rapy, Regional Oncology Center, Chelyabinsk, RUSSIAN<br />
FEDERATION, 2 Oncology, Dnipropetrovsk State Medical Academy,<br />
Dnipropetrovsk, UKRAINE, 3 Biostatistics, Teva Ratiopharm, Ulm, GERMANY,<br />
4 Clinical Research, Teva Ratiopharm, Ulm, GERMANY<br />
Background: Cancer chemo<strong>the</strong>rapy frequently causes neutropenia, leading to an<br />
increased risk of infections and delays in subsequent chemo<strong>the</strong>rapy treatments. In a<br />
randomized, double-blind, phase 3, active-controlled, noninferiority trial, <strong>the</strong> efficacy<br />
and safety of lipegfilgrastim, a glycosylated and pegylated recombinant granulocyte<br />
colony stimulating factor (G-CSF), was compared with pegfilgrastim, a pegylated<br />
recombinant G-CSF. Here we report <strong>the</strong> results of <strong>the</strong> absolute neutrophil counts<br />
(ANC) from this study.<br />
Methods: Patients with high-risk stage II, III, or IV breast cancer and an absolute<br />
neutrophil count ≥1.5x10 9 cells/L were randomly assigned to lipegfilgrastim 6 mg (n<br />
= 101) or pegfilgrastim 6 mg (n = 101). Study medication was injected<br />
subcutaneously on day 2 of <strong>the</strong> chemo<strong>the</strong>rapy cycle (4 cycles maximum). The<br />
primary efficacy endpoint, <strong>the</strong> duration of severe neutropenia, was reported<br />
previously. Secondary endpoints included ANC nadir and time to ANC recovery and<br />
were analyzed using a Poisson regression. The intent-to-treat (ITT) analysis<br />
population included all randomized patients.<br />
Results: ANC nadir and time to ANC recovery for cycle 1 (ITT population) are<br />
summarized in <strong>the</strong> table.<br />
Measurement<br />
Lipegfilgrastim<br />
(n = 101)<br />
Pegfilgrastim<br />
(n = 101)<br />
LS Mean Difference<br />
(95% CI), p value<br />
Depth of ANC nadir<br />
(10 9 /L)<br />
Mean (SD) 1.2 (1.3) 1.0 (1.2) 0.146 (-0.169 to 0.461)<br />
Median (range) 0.6 (0.0 to 5.5) 0.4 (0.0 to 5.2) p = 0.3610<br />
Time to ANC<br />
recovery (days)<br />
Mean (SD) 5.8 (3.3) 7.4 (3.6) −1.570 (-2.547 to −0.592)<br />
Median (range) 7.0 (0.0 to 12.0) 8.0 (0.0 to 21.0) p = 0.0018<br />
Conclusions: Patients who received lipegfilgrastim had significantly faster time to<br />
ANC recovery than those who received pegfilgrastim.<br />
Disclosure: O.A. Gladkov: Investigator in Teva-sponsored studies, I.M. Bondarenko:<br />
Investigator in Teva-sponsored studiesR. Elsaesser: Employee of Teva<br />
Pharmaceuticals and own Teva Pharmaceuticals stock, A. Buchner: Employee of Teva<br />
Pharmaceuticals and own Teva Pharmaceuticals stock, P. Bias: Employee of Teva<br />
Pharmaceuticals and own Teva Pharmaceuticals stock.<br />
Annals of Oncology<br />
1549PD TREATING DIABETIC PATIENTS WITH CHEMOTHERAPY:<br />
SINGLE CENTRE EXPERIENCE OF TOXICITY AND<br />
OUTCOMES<br />
J.F. Seligmann1 , A. Young2 , G. Heath2 , D. Cairns3 , A. Anthoney2 , G. Hall2 ,<br />
M. Seymour2 and D. Swinson2 1<br />
Medical Oncology, St. James Institute of Oncology, Leeds Teaching Hospitals<br />
NHS Trust, Leeds, UNITED KINGDOM, 2 Medical Oncology, The Leeds Teaching<br />
Hospital NHS Trust St. James University Hospital, Leeds, UNITED KINGDOM,<br />
3<br />
Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UNITED<br />
KINGDOM<br />
Background: Diabetes is a common comorbidity in cancer patients, and is associated<br />
with poorer survival in colorectal cancer (CRC). However, <strong>the</strong>re is little data to<br />
describe <strong>the</strong> experience of diabetic patients during chemo<strong>the</strong>rapy. We have compared<br />
a diabetic population of cancer patients with matched controls receiving<br />
chemo<strong>the</strong>rapy in a single centre.<br />
Methods: We performed a retrospective case note analysis using an electronic patient<br />
record database (Patient Pathway Manager) and chemo<strong>the</strong>rapy prescription software<br />
(ChemoCare) between 2001 and 2011. Diabetic patients starting first line<br />
chemo<strong>the</strong>rapy for advanced CRC and advanced gynaecological cancers (GC) were<br />
identified. For each case a non-diabetic control was selected, matched for age (
Annals of Oncology<br />
pruritus recurrence, with a median interval of 7-weeks from first aprepitant<br />
administration. No potentially aprepitant-related toxic effects were registered.<br />
Conclusions: This single-center phase-II study showed a new <strong>the</strong>rapeutic activity of<br />
aprepitant in treating biological <strong>the</strong>rapy-induced pruritus, both after standard<br />
antipruritic-medication failure and as a first-line <strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1551PD ROLE OF TEMPORARY OVARIAN SUPPRESSION OBTAINED<br />
WITH GNRH ANALOG IN REDUCING PREMATURE OVARIAN<br />
FAILURE (POF) INDUCED BY CHEMOTHERAPY IN<br />
PREMENOPAUSAL CANCER PATIENTS: A META-ANALYSIS<br />
OF RANDOMIZED STUDIES<br />
L. Del Mastro 1 , A. Levaggi 2 , F. Poggio 2 , S. Giraudi 2 , C. Bighin 2 ,A.D’Alonzo 2 ,<br />
M. Lambertini 2 , P. Pronzato 2 and P. Bruzzi 3<br />
1 Ss Sviluppo Terapie Innovative, IRCCS AOU San Martino - IST-Istituto Nazionale<br />
per la Ricerca sul Cancro, Genova, ITALY, 2 Oncologia Medica A, IRCCS AOU<br />
San Martino - IST-Istituto Nazionale per la Ricerca sul Cancro, Genova, ITALY,<br />
3 Clinical Epidemiology, IST-San Martino, Genoa, ITALY<br />
Background: premenopausal cancer patients treated with chemo<strong>the</strong>rapy (CT) are at<br />
risk of POF. The role of GnRHa in <strong>the</strong> prevention of CT-induced POF is still<br />
controversial. We performed a pooled analysis of randomized studies that evaluated<br />
<strong>the</strong> role of GnRHa as strategy to prevent POF.<br />
Methods: studies were retrieved by searching <strong>the</strong> PubMed database and <strong>the</strong><br />
proceedings of major conferences. Odds ratios (OR) and 95% CIs for CT induced<br />
POF were extracted from each trial and averaged to obtain pooled estimates using an<br />
inverse-variance model.<br />
Results: we included in <strong>the</strong> meta-analysis 7 randomized trials involving 745<br />
premenopausal women randomly assigned to receive chemo<strong>the</strong>rapy or<br />
chemo<strong>the</strong>rapy + GnRHa: five trials were carried out in breast cancer patients and two<br />
trials in patients with lymphoma. The pooled OR estimate for CT induced POF was<br />
0.46 (95% CI, 0.3-0.72).<br />
Conclusion: temporary ovarian suppression obtained with <strong>the</strong> use of GnRH<br />
analogues reduces <strong>the</strong> incidence of chemo<strong>the</strong>rapy induced POF in premenopausal<br />
cancer patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1552P EVALUATION OF THE QUALITY OF LIFE AND ECONOMIC<br />
BURDEN WITH GRANULOCYTE-COLONY STIMULATING<br />
FACTOR IN CHINESE BREAST CANCER PATIENTS<br />
RECEIVING DOCETAXEL, EPIRUBICIN AND<br />
CYCLOPHOSPHAMIDE<br />
M. He 1 , S. Huang 1 ,L.Yu 1 , G. Shi 1 , J. Deng 1 , X. Zhang 1 , X. Wang 1 , J. Chen 1 ,<br />
X. Nong 2 and P. Shen 1<br />
1 Medical Oncology, First Affiliated Hospital, Zhejiang University School of<br />
Medicine, Hangzhou, CHINA, 2 Department of Medical Oncology, 1st Affiliated<br />
Hospital of ZhejiangUniversity School of Medicine, Hangzhou, CHINA<br />
Background: Docetaxel, Epirubicin, cyclophosphamide (TEC) has been accepted as<br />
<strong>the</strong> standard care in <strong>the</strong> treatment of Chinese patients with breast cancer. However,<br />
little is known about <strong>the</strong> impact of primary prophylactic granulocyte-colony<br />
stimulating factor (G-CSF) on <strong>the</strong> quality of life(QOL) and economic burden in<br />
<strong>the</strong>se patients.<br />
Patients and methods: This was a randomized control study to compare G-CSF as<br />
primary prophylactics or not while breast cancer patients receiving TEC<br />
chemo<strong>the</strong>rapy. Primary prophylactic G-CSF (PPG) was: filgrastim 3mcg/kg/day on<br />
day 3-8 (n = 53 patients); G-CSF for treatment was: filgrastim 5mcg/kg/day on <strong>the</strong><br />
occasion that grade 3-4 neutropenia, febrile neutropenia, and delayed recovery of<br />
absolute neutrophil count on day 21 till <strong>the</strong> neutrophil recovery (n = 54 patients). A<br />
total of 107 patients from single centre in China were included in <strong>the</strong> trial.<br />
Side-effects, costs and <strong>the</strong> scores of <strong>the</strong> EORTC QLQ-C30 questionnaires were<br />
compared in <strong>the</strong> two groups.<br />
Results: The addition of PPG to TEC significantly reduced <strong>the</strong> incidence of<br />
neutropenic fever (15.32% vs 6.94%, P = 0.0482), grade 3–4 neutropenia (52.3% vs<br />
12.2%, P < 0.001) and anaemia, as<strong>the</strong>nia, stomatitis, anorexia, myalgia and dysgeusia.<br />
Patient’s QOL decreased during chemo<strong>the</strong>rapy, more in TEC without PPG than TEC<br />
with PPG, but returned to baseline afterwards. The addition of PPG significantly<br />
reduced <strong>the</strong> percentage of patients with clinically relevant Global Health Status<br />
deterioration at <strong>the</strong> end of treatment (60% versus 47%, P =0.0331). The average cost<br />
of each cycle was quite approaching in <strong>the</strong> two groups (CNY 16432.01 in TEC with<br />
PPG vs CNY 16059.24 in TEC without PPG, P > 0.05), but <strong>the</strong> cost of G-CSF was<br />
increased at <strong>the</strong> end of chemo<strong>the</strong>rapy without PPG.<br />
Conclusions: The addition of PPG significantly reduces <strong>the</strong> incidence of<br />
neutropenic fever as well as that of some TEC-induced haematological and<br />
extrahaematological side-effects. The QOL is elevated during chemo<strong>the</strong>rapy by<br />
using PPG, particularly in <strong>the</strong> end of treatment. Economically speaking, primary<br />
prophylactic G-CSF is cost-effective in Chinese breast cancer patients receiving<br />
TEC chemo<strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1553P COST-EFFECTIVENESS OF PRIMARY PEGFILGRASTIM<br />
PROPHYLAXIS IN BREAST CANCER PATIENTS AT RISK OF<br />
FEBRILE NEUTROPENIA<br />
M.J. Aarts 1 , J.P. Grutters 2 , F.P. Peters 3 , C.M. Mandigers 4 , M.W. Dercksen 5 ,J.<br />
M. Stouthard 6 , J.W. Nortier 7 , H.W. van Laarhoven 8 , L.J. van Warmerdam 9 and<br />
V.C. Tjan-Heijnen 1<br />
1 Department of Medical Oncology, Grow-school for Oncology and<br />
Developmental Biology, Maastricht University Medical Centre+ (MUMC+),<br />
Maastricht, NETHERLANDS, 2 Department of Health Service Research, School<br />
for Public Health and Primary Care (caphri), Maastricht University, Maastricht,<br />
NETHERLANDS, 3 Medical Oncology, Orbis Medical Centre, Sittard,<br />
NETHERLANDS, 4 Medical Oncology, Canisius Wilhelmina Hospital,<br />
Nijmegen, NETHERLANDS, 5 Medical Oncology, Maxima Medical<br />
Centre, Veldhoven, NETHERLANDS, 6 Medical Oncology, Maasstad Medical<br />
Centre, Rotterdam, NETHERLANDS, 7 Medical Oncology, Leiden University<br />
Medical Centre, Leiden, NETHERLANDS, 8 Medical Oncology, Radboud<br />
University Nijmegen Medical Centre and Academic Medical Centre, University of<br />
Amsterdam, Nijmegen, NETHERLANDS, 9 Medical Oncology, Catharina Hospital,<br />
Eindhoven, NETHERLANDS<br />
Purpose: Guidelines advise primary G-CSF prophylaxis during chemo<strong>the</strong>rapy if risk<br />
of febrile neutropenia (FN) is more than 20%, but this comes with considerable costs.<br />
We investigated <strong>the</strong> incremental costs and effects between two treatment strategies of<br />
primary pegfilgrastim prophylaxis.<br />
Methods: Our economic analysis, using a health care perspective, was based on a<br />
randomized study in breast cancer patients with increased risk of FN comparing<br />
primary G-CSF prophylaxis throughout all chemo<strong>the</strong>rapy cycles (G-CSF 1-6 cycles<br />
arm) with prophylaxis during <strong>the</strong> first two cycles only (G-CSF 1-2 cycles arm).<br />
Primary outcome was <strong>the</strong> cost-effectiveness expressed as costs per patient with<br />
episodes of FN prevented.<br />
Results: The incidence of FN increased from 10% (8 out of 84 patients) in <strong>the</strong> G-CSF<br />
1-6 cycles arm to 36% (30 out of 83 patients) in <strong>the</strong> G-CSF 1-2 cycles arm, whereas <strong>the</strong><br />
mean total costs decreased from € 20,658 (95%CI € 20,049 to € 21,247) to € 17,168<br />
(95%CI € 16,239 to € 18,029) per patient, respectively. Chemo<strong>the</strong>rapy and G-CSF<br />
largely determined total costs: 83% in <strong>the</strong> G-CSF 1-6 cycles versus 78% in <strong>the</strong> G-CSF<br />
1-2 cycles arm. As expected, FN-related costs were higher in <strong>the</strong> G-CSF 1-2 cycles<br />
arm. The incremental cost-effectiveness ratio for <strong>the</strong> G-CSF 1-6 cycles compared to<br />
<strong>the</strong> G-CSF 1-2 cycles arm was € 13,112 per patient with episode of FN prevented.<br />
Conclusion: We conclude that G-CSF prophylaxis throughout all chemo<strong>the</strong>rapy<br />
cycles is more effective, but more costly, compared to prophylaxis limited to <strong>the</strong> first<br />
two cycles. Whe<strong>the</strong>r G-CSF prophylaxis throughout all chemo<strong>the</strong>rapy cycles is<br />
considered cost-effective depends on <strong>the</strong> willingness to pay per patient with episode<br />
of FN prevented.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1554P TRENDS IN G-CSF USE IN GERIATRIC ONCOLOGY: 2011<br />
AFSOS SOFOG SURVEY<br />
C. Falandry 1 , I. Krakowski 2 , H. Curé 3 , E. Carola 4 , P. Soubeyran 5 , O. Guérin 6 and<br />
G. Freyer 7<br />
1 Oncologie Médicale, CHU Lyon Sud, Pierre Bénite, FRANCE, 2 Service<br />
d’Oncologie Médicale, Centre Alexis Vautrin, Vandoeuvre-les-Nancy, FRANCE,<br />
3 Oncologie Médicale, Institut Jean Godinot, Reims, FRANCE, 4 Oncologie<br />
Médicale, CH Senlis, Senlis, FRANCE, 5 Department of Medical Oncology, Institut<br />
Bergonié and Université Bordeaux Segalen, Bordeaux, FRANCE, 6 Gériatrie, CHU<br />
Nice, Nice, FRANCE, 7 Oncologie Médicale, CHU Lyon Sud, Lyon, FRANCE<br />
Background: Age is a risk factor for chemo-induced febrile neutropenia (FN).<br />
According international guidelines, it should be considered when discussing G-CSF<br />
use for regimens with FN risk between 10% and 20%. Prophylactic G-CSF remains<br />
controversial for regimens with a lower risk.<br />
Patients and methods: A survey was undertaken in France to describe current<br />
treatment practices in patients aged 70 years and older with gynaecologic cancer.<br />
Individual data from 791 chemo-treated patients were collected (breast 74%, ovary<br />
21%, uterus 5%, adjuvant 30%).<br />
Results: According 101 practitioners, important factors to be considered for GCSF use<br />
are previous FN /neutropenic events (96%), bone radio<strong>the</strong>rapy (92%) or chemo<strong>the</strong>rapy<br />
(86%), comorbidities (91%), performance status (PS) ≥2 (87%), recent septic event<br />
(92%), anemia (54%). In routine practice, GCSF was prescribed in 51% of <strong>the</strong> cases, ie<br />
41% and 9% as primary and secondary prevention respectively and 0.4% in curative<br />
setting. Prophylactic GCSF prescription rates for regimens with FN risk ≥20%, 10-20%<br />
and
egimens (HR = 2.5, p < 0.001). Physicians performing geriatric assessments were more<br />
prone to prescribe GCSF (HR = 1.5, p = 0.015), notably those involved in a<br />
comprehensive geriatric assessment network ((HR = 1.5, p = 0.007). However proven<br />
risk factors for FN were rarely considered: PS ≥2 (HR = 0.7, p = 0.05), comorbidities<br />
(HR = 1.3, p = 0.2), anemia < 12g/dL (HR = 1.0, p = 0.8), malnutrition (albumin < 35g/L,<br />
HR = 0.7, p = 0.03). In metastatic disease, previous FN (HR = 2.6, p < 0.001), or<br />
chemo<strong>the</strong>rapy (HR = 1.9, p < 0.001) were significantly associated with higher rates of<br />
prophylactic GCSF, but not previous irradiation (HR = 1.1, p = 0.5); a limited number of<br />
daily G-CSF injections were given in most cases (mean: 4.9, 64% patients).<br />
Conclusion: Our study suggests a trend to overtreatment in some cases, in<br />
comparison to international guidelines, and insufficient use of validated risk factors<br />
in treatment decision making.<br />
Disclosure: C. Falandry: membership on an advisory board Chugaï, I. Krakowski:<br />
membership on an advisory board Chugaï, H. Curé: membership on an advisory<br />
board Chugaï, E. Carola: membership on an advisory board Chugaï, P. Soubeyran:<br />
membership on an advisory board Chugaï, O. Guérin: membership on an advisory<br />
board Chugaï, G. Freyer: membership on an advisory board Chugaï<br />
1555P BIOSIMILAR FILGRASTIM INITIATION IN PATIENTS<br />
ENROLLED IN THE MONITOR G-CSF OBSERVATIONAL<br />
STUDY RELATIVE TO EORTC GUIDELINES<br />
M.S. Aapro 1 , P. Gascon 2 , H. Ludwig 3 , C. Bokemeyer 4 , M. Boccadoro 5 ,<br />
M. Turner 6 , M. Muenzberg 6 , K. Denhaerynck 7 , I. Abraham 7 and K. Macdonald 7<br />
1 Institut Multidisciplinaire d’Oncologie, Clinique de Genolier, Genolier,<br />
SWITZERLAND, 2 Medical Oncology, Hospital Clinic y Provincial de Barcelona,<br />
Barcelona, SPAIN, 3 1st Department of Medicine, Wilhelminenspital, Wien,<br />
AUSTRIA, 4 Head of The Department for Oncology, Haematology and Bone<br />
Marrow Transplantation, UKE II. Medizinische Klinik und PoliklinikMedizinische<br />
Klinik II., Hamburg-Eppendorf, GERMANY, 5 Section of Hematology, Università<br />
degli Studi di Torino, Torino, ITALY, 6 Sandoz International Gmbh, Sandoz<br />
Biopharmaceuticals, Holzkirchen, GERMANY, 7 Matrix 45, Tucson, AZ, UNITED<br />
STATES OF AMERICA<br />
Introduction: MONITOR G-CSF is a prospective observational study of practice<br />
patterns and outcomes for prophylaxis of chemo<strong>the</strong>rapy-induced febrile neutropenia<br />
(FN) with biosimilar filgrastim (Zarzio®, Sandoz Biopharmaceuticals).<br />
Methods: This analysis describes treatment initiation with biosimilar filgrastim in <strong>the</strong><br />
788 patients enrolled to date (target 1500) in <strong>the</strong> MONITOR G-CSF study relative to<br />
<strong>the</strong> 2010 EORTC G-CSF guidelines. Patients were enrolled at 134 centres (199 open)<br />
across 12 European countries.<br />
Results: In this mainly female (62%) and older (61.6 ± 11.9 years) cohort with<br />
predominately solid tumours (79%), FN risk based on chemo<strong>the</strong>rapy (CT) regimen<br />
was 20% in 39% of patients. All patients with<br />
20%<br />
10-20%<br />
< 10%<br />
Prophylaxis (%) Initiation (%) Duration (%)<br />
Primary Secondary 24-72 h Days 5-8 3 days 5 days<br />
70<br />
70<br />
76<br />
74<br />
56<br />
30<br />
30<br />
24<br />
26<br />
44<br />
Table 2. FN risk 10-20%<br />
Prophylaxis (%)<br />
Patient-related risk factors Primary Secondary<br />
Age >65 years 79 21<br />
Advanced disease (Stage IV) 74 26<br />
History of prior FN 29 71<br />
No antibiotic prophylaxis 73 24<br />
Poor performance (ECOG >2) 83 17<br />
Female 76 24<br />
Hb 20% or 10-20% in combination with o<strong>the</strong>r risk factors did not receive<br />
primary prophylaxis as recommended. The trend to initiate filgrastim in regimens<br />
with
Annals of Oncology<br />
neutropenia in patients with cancer. These consisted of two large multicentre<br />
observational studies plus three small single-centre studies conducted across 12<br />
European countries. All studies were conducted in Europe and reflected real-life<br />
clinical use of biosimilar G-CSF. Patients receiving biosimilar G-CSF for<br />
interventional treatment were excluded from this analysis.<br />
Results: Data from 1302 patients treated with biosimilar G-CSF were available for<br />
analysis. The most frequent types of cancer were breast cancer (n = 541; 42%), lung<br />
cancer (n = 212; 16%) and lymphoma/leukaemia (n = 201; 15%). Thirty-six percent<br />
of patients had a febrile neutropenia risk of >20% while 39.6% had a risk of 10 −<br />
20% based on chemo<strong>the</strong>rapy regimen. A fur<strong>the</strong>r 12.1% of patients received biosimilar<br />
G-CSF despite a febrile neutropenia risk of
1561P PREDICTIVE DIAGNOSTICS FOR RESPONSE TO THERAPY<br />
OF CHEMOTHERAPY ASSOCIATED ANEMIA WITH<br />
DARBEPOETIN ALFA +/- INTRAVENOUS IRON IN CANCER<br />
PATIENTS: PFAD-3 A MULTICENTRE COHORT STUDY IN<br />
OUTPATIENTS<br />
H..T. Steinmetz 1 , K. Kuhr 2 , M. Hellmich 2 , M. Heinz 1 , M. Neise 3 , J. Mittermüller 4 ,<br />
H.W. Tessen 5 , M. Reiser 6 , K. Severin 1 and S. Schmitz 1<br />
1 Hematology and Oncology, Outpatient Clinic, Cologne, GERMANY, 2 University,<br />
Institut für Medizinische Statistik, Informatik und Epidemiologie, Cologne,<br />
GERMANY, 3 Hematology and Oncology, Outpatient Clinic, Krefeld, GERMANY,<br />
4 Hematology and Oncology, Outpatient Clinic, Germering, GERMANY,<br />
5 Hematology and Oncology, Outpatient Clinic, Goslar, GERMANY, 6 Hematology<br />
and Oncology, PIOH - Outpatient Clinic, Cologne, GERMANY<br />
Introduction: Seven randomized studies have demonstrated a benefit of combining<br />
erythropoiesis stimulating agents (ESA) with intravenous iron (iv Fe) in <strong>the</strong><br />
treatment of chemo<strong>the</strong>rapy-associated anemia in cancer patients (pts). Because, so<br />
far <strong>the</strong>re is no proven recommendation for <strong>the</strong> best pre<strong>the</strong>rapeutic diagnostics to<br />
select optimal <strong>the</strong>rapy (ESA, iron or both), we conducted a multicenter cohort study.<br />
Methods: Cancer pts were included and eligible for response if <strong>the</strong>y had a<br />
symptomatic anemia (hemoglobin (Hb) < 11g/dl), received a chemo<strong>the</strong>rapy, gave<br />
written informed consent, and had a pre<strong>the</strong>rapeutic diagnostics of anemia: Ferritin<br />
(F), transferrin saturation (TSAT), endogenous erythropoietin (eEPO) and soluble<br />
transferrin-receptor (sTFR) on day 1 and 14. All pts were treated with Darbepoetin<br />
alfa (DA, 500 µg, q3w) with or without iv Fe-III-hydroxyd-saccharose (200mg in<br />
250ml NaCl 0.9% q3w). The use of iv Fe based on <strong>the</strong> recommendations of <strong>the</strong><br />
NCCN guidelines at <strong>the</strong> discretion of <strong>the</strong> oncologists. Pts with an absolute iron<br />
deficiency (F m < 30ng/ml, f < 15ng/ml) were excluded.<br />
Results: Between 03/07 - 08/10 in 9 outpatient clinics 331 pts received DA on day<br />
0. Mean age was 66.3 years, 58% were women. 202 pts (61%) received at least one<br />
dose iv Fe additionally to DA on day 0. Baseline Hb was 9.53g/dl (SD 0.78) and<br />
increased in average 1.23g/dl (SD 1.34) and 1.53 g/dl (SD 1.49) til weeks 6 and 9,<br />
respectively. Transfusion rate in weeks 3-9 was 15.1%. Associations of relevant<br />
criteria with response are shown in <strong>the</strong> table.<br />
Conclusion: The results confirm <strong>the</strong> increase of Hb within <strong>the</strong> first 3 weeks as strong<br />
predictor for response to DA in week 6. Pts with Hb-increase ≥ 0.6 g/dl have a 6-fold<br />
higher chance of being responders than those without. Ferritin is a stronger predictor<br />
for response to iv Fe than TSAT. Supported by Amgen, Munich, Germany.<br />
Disclosure: H..T. Steinmetz: Member of advisory boards for Amgen, Janssen,<br />
Medice, Novartis, Roche, Vifor. Investigator in studies for Amgen, Janssen, Novartis,<br />
Roche, Vifor., M. Neise: Investigator in studies with Amgen, J. Mittermüller:<br />
Investigator in studies with Amgen, H.W. Tessen: Investigator in studies with<br />
Amgen, M. Reiser: Investigator in studies with Amgen, K. Severin: Ivestigator in<br />
studies with Amgen, Roche, Vifor, S. Schmitz: Investigator in studies with Amgen,<br />
Novartis, Roche, Vifor. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1562P A PROSPECTIVE DATA AUDIT OF THE MANAGEMENT OF<br />
CHEMOTHERAPY-INDUCED ANEMIA WITH DARBEPOETIN<br />
ALFA – THE APRIORI STUDY<br />
P. Boguradzki 1 , K. Boér 2 , A. Cipková 3 , E. Wojciechowska-Lampka 4 ,<br />
M. Schützová 5 , J. Ocvirk 6 and E. Tóth 7<br />
1 Hematology, Warsaw Medical University, Warsaw, POLAND, 2 Oncology<br />
Department, Szent János Kórház és Észak-budai Egyesített Kórházak, Budapest,<br />
HUNGARY, 3 Radio<strong>the</strong>rapy and Oncology, East Slovakian Cancer Institute,<br />
Košice, SLOVAK REPUBLIC, 4 Department of Lymphoma, The Maria<br />
Sklodowska-Curie Memorial Cancer Centre and Institute, Warsaw, POLAND,<br />
5 Hemato-oncologic Department, Faculty Hospital, Plzen-Lochotín, CZECH<br />
REPUBLIC, 6 Medical Oncology, Institute of Oncology Ljubljana, Ljubljana,<br />
SLOVENIA, 7 Amgen Slovakia s.r.o., Piešt´any, SLOVAK REPUBLIC<br />
Background: Darbepoetin alfa (DA, Aranesp®) is an erythropoesis-stimulating agent<br />
(ESA) used to treat chemo<strong>the</strong>rapy (CT) induced anaemia (CIA). In 2008 EORTC<br />
Table: 1561P<br />
guidelines changed to recommend starting ESA treatment at haemoglobin (Hb) 9 -<br />
11 g/dL and stopping ESA if Hb was > 13 g/dL. In February 2008, <strong>the</strong> SmPC for DA<br />
was revised to recommend treatment start at Hb ≤ 10 g/dL and Hb be maintained in<br />
<strong>the</strong> 10 - 12 g/dL range. APRIORI was a prospective, noninterventional, observational,<br />
longitudinal, multicentre study collecting data from patients (pts) in Central and<br />
Eastern Europe with CIA receiving DA and CT. The aims were to evaluate <strong>the</strong><br />
compliance with international guidelines and EU label for use of DA in treating CIA,<br />
to assess effectiveness of DA, and describe DA dosing characteristics.<br />
Methods: This study collected clinical data of cancer pts over 4 consecutive years<br />
(11/2006 – 12/2010), at 120 centers in Poland, Czech Republic, Slovakia, Slovenia,<br />
Hungary, and Russia. Pts were enrolled before <strong>the</strong> label change (BLC) as well as after<br />
<strong>the</strong> label change (ALC). The data were collected at enrolment and at follow-up visits<br />
during CT until <strong>the</strong> first follow-up visit after <strong>the</strong> end of CT.<br />
Results: Out of 6408 pts enrolled (mean (sd) age of 59.9 (±12.57) years, 44.4%<br />
male), 929/1648 (56.4%) pts enrolled BLC had Hb in <strong>the</strong> target 9 - 11 g/dL range,<br />
while 4284/4760 (90.0%) pts enrolled ALC had Hb in <strong>the</strong> target range of ≤ 10 g/dL.<br />
Total 666 (40.4%) pts had Hb < 9 g/dL and 53 (3.2%) pts had Hb > 11 g/dL BLC,<br />
while 476 (10.0%) pts had Hb > 10 g/dL ALC. BLC, 38 (35.8%) pts had any DA<br />
dosing withheld while exceeding <strong>the</strong> 13 g/dL Hb concentration limit, at any time<br />
during <strong>the</strong> study and ALC, 55 (7.8%) pts had <strong>the</strong> doses reduced while exceeding <strong>the</strong><br />
12 g/dL Hb concentration limit, at any time during <strong>the</strong> study. DA effectively<br />
increased Hb concentrations; mean Hb after achieving <strong>the</strong> target anaemia Hb level<br />
BLC 11.94 g/dL vs. 11.29 g/dL ALC. Only 4.9% of pts required RBC transfusion after<br />
5 weeks of DA initiation. Out of 9 ADRs no serious and no fatal ADRs was reported<br />
during <strong>the</strong> study. Mortality was 4.9% (305 pts).<br />
Conclusion: Based on <strong>the</strong>se data, <strong>the</strong> patients are being treated in accordance with<br />
<strong>the</strong> current European SmPC for darbepoetin alfa. This study was sponsored by<br />
Amgen GmbH CEE Headquarters.<br />
Disclosure: P. Boguradzki: Corporate-sponsored research - Amgen APRIORI, K. Boér:<br />
Corporate sponsored study - APRIORI study Amgen, A. Cipková: Corporatesponsored<br />
research - Amgen APRIORI, E. Wojciechowska-Lampka:<br />
Corporate-sponsored research - Amgen -APRIORI, M. Schützová: Corporatesponsored<br />
research - Amgen; member of advisory board - Amgen, J. Ocvirk:<br />
Corporate-sponsored research - Amgen APRIORI, E. Tóth: Amgen contract worker.<br />
1563P THE USE OF BIOSIMILARS IN THE MANAGEMENT OF<br />
CHEMOTHERAPY-INDUCED ANAEMIA (CIA) IN SOLID<br />
TUMOURS, LYMPHOMA AND MYELOMA: THE ORHEO<br />
STUDY<br />
M. Michallet 1 , P. Soubeyran 2 , H. Albrand 3 and E. Luporsi 4<br />
1 Service d’Hématologie, Pavillon Marcel Bérard 1g, Centre Hospitalier Lyon Sud,<br />
Lyon-Pierre Bénite, FRANCE, 2 Department of Medical Oncology, Institut<br />
Bergonié and Université Bordeaux Segalen, Bordeaux, FRANCE, 3 Medical<br />
Director, Laboratoire HOSPIRA France, Meudon La Forêt, FRANCE, 4 Medical<br />
Oncology, Centre Alexis Vautrin, Vandœuvre-lès-Nancy, FRANCE<br />
The approval of epoetin biosimilars in <strong>the</strong> European Union requires extensive<br />
scientific evaluation and stringent regulatory procedures, including post-marketing<br />
studies. The ORHEO (place of biOsimilaRs in <strong>the</strong> <strong>the</strong>rapeutic management of<br />
anaemia secondary to chemo<strong>the</strong>rapy in HaEmatology and Oncology) study was an<br />
observational, longitudinal, multicentre study performed in France to evaluate <strong>the</strong><br />
efficacy and safety of biosimilar epoetins for <strong>the</strong> treatment of CIA in <strong>the</strong> clinical<br />
setting. Patients >18 years with CIA (haemoglobin [Hb] 5 mg/l : FI ≤ 2 *** Odds ratio, confidence intervall,<br />
and number of pts with …<br />
Annals of Oncology<br />
… DA <strong>the</strong>rapy conform with protocol,<br />
treatment response and predictive<br />
factors evaluable<br />
ix504 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
7.4% myeloma. Of those patients with solid tumours, 30.1% of patients had a stage III<br />
and 21.6% had a stage IV tumour. Almost all patients received <strong>the</strong> biosimilar epoetin<br />
zeta (Retacrit®, Hospira UK Ltd., median dose 30,000 IU/week). Mean baseline Hb<br />
level across all patients was 9.6 g/dL, with 35.6% of patients having moderate anaemia<br />
(Hb 8–9.5 g/dL). Following treatment, Hb response was achieved in 81.6% and 86.5%<br />
of patients at 3 and 6 months, respectively. The overall mean change in Hb level was<br />
1.5 ± 1.6 g/dL at 3 months and 1.72 ± 1.61 g/dL at 6 months. Transfusion rates were<br />
9.4% and 5.8%, while <strong>the</strong> rate of thromboembolic events was 2.4% and 1.5%, at 3 and<br />
6 months respectively. In conclusion, Retacrit was effective and well tolerated in <strong>the</strong><br />
management of CIA in patients with solid tumours, lymphoma and myeloma.<br />
Disclosure: M. Michallet: I received honoraria from Hospira for advisory boards and<br />
consulting, P. Soubeyran: I received honoraria from Hospira for advisory boards and<br />
consulting, H. Albrand: Employed by Hospira, E. Luporsi: I received honoraria from<br />
Hospira for advisory boards and consulting.<br />
1564P ANAEMIA-RELATED FATIGUE IN PATIENTS WITH SOLID<br />
TUMOURS: A MULTICENTER, OBSERVATIONAL AND<br />
PROSPECTIVE STUDY (PACS STUDY)<br />
P. Gascon 1 , A. Casas 2 , J. Muñoz 3 , J. De Castro 4 , V. Alberola 5 , M. Cucala 6 and<br />
F. Barón 7<br />
1 Medical Oncology, Hospital Clinic y Provincial de Barcelona, Barcelona, SPAIN,<br />
2 Medical Onology Department, Hospital Virgen del Rocío, Sevilla, SPAIN,<br />
3 Medical Oncology Department, Hospital Dr. Peset, Valencia, SPAIN, 4 Medical<br />
Oncology Department, Hospital La Paz, Madrid, SPAIN, 5 Medical Oncology<br />
Department, Hospital Arnau de Vilanova, Valencia, SPAIN, 6 Medical Advisor,<br />
Vifor Pharma España, Barcelona, SPAIN, 7 Medical Oncology Department,<br />
Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de<br />
Compostela, SPAIN<br />
Background: Quality of life in cancer patients is significantly reduced by anaemia<br />
and associated fatigue. Fatigue is one of <strong>the</strong> most common symptoms of cancer<br />
and cancer <strong>the</strong>rapy. The aim of <strong>the</strong> present study was to evaluate fatigue in<br />
treatment-naive patients with solid tumours and after four months of cancer<br />
<strong>the</strong>rapy using <strong>the</strong> Functional Assessment of Cancer Therapy-Fatigue (FACT-F)<br />
questionnaire.<br />
Methods: Multicenter, prospective and observational study that included newly<br />
diagnosed cancer patients. Patients completed <strong>the</strong> FACT-F questionnaire at<br />
baseline and after four months of cancer <strong>the</strong>rapy. Anaemia status (haemoglobin<br />
Methods: A prospective multicentre observational study conducted in Germany<br />
enrolling 1,066 patients (pts) with non-myeloid malignancies, symptomatic<br />
chemo<strong>the</strong>rapy-induced anaemia and planned treatment with DA. The primary<br />
endpoint was a haemoglobin (Hb) level of 10–12 g/dL at week (wk) 9 or, if earlier, at<br />
<strong>the</strong> end of treatment. Red blood cell (RBC) transfusion needs and quality of life<br />
(QoL) were also assessed.<br />
Results: In total, 984 pts met <strong>the</strong> protocol criteria and were included into <strong>the</strong><br />
analysis. Cancer types included breast (n = 260; 26%), lung (n = 118; 12%), ovarian<br />
(n = 103; 10%), colorectal (n = 95; 10%) and o<strong>the</strong>r (n = 408; 41%). Median Hb<br />
levels rose from 9.6 g/dL at baseline (BL) to 10.8 g/dL at wk9. 519 pts (53%)<br />
reached <strong>the</strong> primary endpoint over 3.7 wks (median; IQR 0.1–7.1) of DA<br />
treatment. Median time to Hb level ≥10 g/dL was 14 days (IQR 0–32 days). RBC<br />
transfusion was required by 32% of pts from wk1 to wk9; 16% of pts required<br />
RBC transfusion in <strong>the</strong> first 3 wks from DA initiation. QoL improved (measured<br />
using FACIT questionnaires and <strong>the</strong> Linear Analog Scale Assessment); however, a<br />
clinically important difference was only found using FACIT-F. Of 30 reported<br />
adverse drug reactions, <strong>the</strong> investigators classified 12 as DA related. Of <strong>the</strong>se, 1<br />
was fatal.<br />
Conclusion: Overall, DA use was in line with <strong>the</strong> current label and guidelines; most<br />
pts started DA at Hb levels of ≤10 g/dL and were treated to <strong>the</strong> Hb target level of<br />
10-12 g/dL. DA seems to be effective in enhancing Hb response and improving QoL.<br />
Study sponsor: Amgen Europe (GmbH). Editorial support: archimed medical<br />
communication ag.<br />
Median (IQR) or n (%). Information available for 984°, 588∞, 726 a , 978¤ or 980^<br />
pts. *Primary endpoint or rise of 2 g/dL from BL.<br />
Baseline<br />
Age, years 66 (57–73)°<br />
Female 617 (63%)°<br />
Hb level, g/dL 9.6 (9–10.1)°<br />
Hb level ≤10 g/dL 716 (73%)°<br />
Performance status 1–2 818 (83%)°<br />
Disease stage III–IV 350 (59%)∞<br />
Prior chemo<strong>the</strong>rapy 387 (53%) a<br />
Anaemia treatment in 4 wks before BL<br />
Wk9<br />
161 (16%)°<br />
Hb level, g/dL 10.8 (9.8–11.8)¤<br />
Met primary endpoint (Hb 10–12 g/dL) 519 (53%)¤<br />
Met modified response* 660 (67%)¤<br />
Hb level >12 g/dL 178 (18%)¤<br />
Required RBC transfusion 312 (32%)¤<br />
Chemo<strong>the</strong>rapy cycles 5 (3–6)^<br />
Disclosure: H.T. Steinmetz: Consultation and advisory boards: Amgen, Roche,<br />
Janssen/Ortho-Biotec, Vifor, Medice, Hexal. Funding for scientific research: Amgen,<br />
Roche, VIifor. Travel costs: Amgen, Roche, Vifor., A. Kuhn: Employee and<br />
shareholder of Amgen., E. Hellebrand: Employee of Amgen. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
1568P THE USE OF BIOSIMILAR EPOETINS IN THE MANAGEMENT<br />
OF CHEMOTHERAPY-INDUCED ANAEMIA (CIA) IN PATIENTS<br />
WITH BREAST CANCER: A SUBANALYSIS OF THE ORHEO<br />
STUDY<br />
M. Michallet 1 , E. Luporsi 2 , P. Soubeyran 3 and H. Albrand 4<br />
1 Service d’Hématologie, Pavillon Marcel Bérard 1G, Centre Hospitalier Lyon Sud,<br />
Lyon-Pierre Bénite, FRANCE, 2 Medical Oncology, Centre Alexis Vautrin,<br />
Vandœuvre-lès-Nancy, FRANCE, 3 Department of Medical Oncology, Institut<br />
Bergonié and Université Bordeaux Segalen, Bordeaux, FRANCE, 4 Medical<br />
Director, Laboratoire HOSPIRA France, Meudon La Forêt, FRANCE<br />
ORHEO (place of biOsimilaRs in <strong>the</strong> <strong>the</strong>rapeutic management of anaemia<br />
secondary to chemo<strong>the</strong>rapy in HaEmatology and Oncology) is an observational,<br />
longitudinal, multicentre study performed in France to evaluate <strong>the</strong> efficacy and<br />
safety of biosimilar epoetins for <strong>the</strong> treatment of CIA in <strong>the</strong> clinical setting. The<br />
study included a total of 2310 patients (mean age 66.5 years) of whom 79.6%<br />
(n = 1838) had solid tumours, 13.0% (n = 171) had lymphoma and 7.4% (n =<br />
301) myeloma. Here we report a subanalysis of <strong>the</strong> study assessing <strong>the</strong> efficacy<br />
and safety of biosimilar epoetins in patients with breast cancer. A total of 266<br />
patients >18 years with CIA (haemoglobin [Hb] 18 years with CIA (haemoglobin [Hb]
Annals of Oncology<br />
bladder bleeding: 1). Platelet transfusions were administered for 8 cycles. No<br />
life-threatening bleeding occurred in any patient. Thrombocytopenia was associated<br />
with more than five previous chemo<strong>the</strong>rapy cycle (p = 0.03), previous radio<strong>the</strong>rapy<br />
(p = 0.0001), disseminated disease (p = 0.006), distant metastatic disease (p = 0.02)<br />
and poor performance status (p = 0.0001). Clinical bleeding was associated with<br />
previous radio<strong>the</strong>rapy (p = 0.003), distant metastatic disease (p = 0.03) and poor<br />
performance status (p = 0.02). Both clinical bleeding were not related with age, bone<br />
marrow metastases or platinum-based regimens. Febrile neutropenia was complicated<br />
with 35% of thrombocytopenia cycles and 43% of clinical bleeding cycles.<br />
Conclusions: By estimating risk factor of clinical bleeding such as progression of<br />
disease and poor bone marrow reserve, safe management of chemo<strong>the</strong>rapy-induced<br />
thrombocytopenia without unnecessary platelet transfusion may be possible in<br />
patients with gynecologic malignancy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1571P PREVENTION OF DELAYED NAUSEA (DN): A POOLED<br />
ANALYSIS OF 562 WOMEN RECEIVING HIGHLY<br />
EMETOGENIC CHEMOTHERAPY (HEC) IN PROSPECTIVE<br />
CLINICAL TRIALS OF PALONOSETRON (PALO)<br />
L. Celio 1 , F. Longo 2 , S. Brugnatelli 3 , G. Mansueto 4 , E. Bonizzoni 5 , F.G.M. De<br />
Braud 1 , F. Ricchini 1 and M.S. Aapro 6<br />
1 Medical Oncology, Fondazione IRCCS “Istituto Nazionale Tumori”, Milan, ITALY,<br />
2 Medical Oncology, Policlinico Umberto Primo, Rome, ITALY, 3 Medical<br />
Oncology, Policlinico San Matteo, Pavia, ITALY, 4 U.O.C. Oncologia Medica,<br />
Ospedale Fabrizio Spaziani, Frosinone, ITALY, 5 Section of Medical Statistics and<br />
Biometry, Faculty of Medicine, University of Milan, Milan, ITALY, 6 Institut<br />
Multidisciplinaire d’Oncologie, Clinique de Genolier, Genolier, SWITZERLAND<br />
Purpose: Chemo<strong>the</strong>rapy-induced nausea occurs more frequently than vomiting, and<br />
women are particularly prone to experience DN instead of delayed vomiting. We<br />
conducted a pooled analysis to evaluate <strong>the</strong> efficacy of three regimens for preventing<br />
DN: 1-day regimen (n = 241): Palo plus dexamethasone 8 mg IV (Day 1); 3-day<br />
regimen (n = 209): Palo plus dexamethasone 8 mg (Day 1) and dexamethasone 8 mg<br />
PO (Days 2 and 3); triple regimen (n = 112): Palo plus dexamethasone 12 mg and<br />
aprepitant (Day 1) and dexamethasone 8 mg PO plus aprepitant (Days 2 and 3).<br />
Methods: The analysis was based upon outcomes in 562 chemo-naïve women (mean<br />
age 52.7 years; PS ECOG 0: 93%; metastatic disease: 11%) with solid tumors (90%<br />
breast cancer) enrolled in two Phase III and two Phase II trials of HEC (AC-based:<br />
91%; cisplatin: 9%). The pre-specified primary end point was <strong>the</strong> proportion of<br />
patients with no nausea during <strong>the</strong> delayed period (Days 2-5) after <strong>the</strong> first cycle of<br />
chemo<strong>the</strong>rapy. The two primary comparisons were 3-day regimen vs. 1-day regimen,<br />
and triple regimen vs. 3-day regimen. Penalized multivariable logistic regressions<br />
were also performed adopting <strong>the</strong> Firth’s correction in order to adjust estimates for<br />
potential over-fitting, skewed data and multi-collinearity. Results were reported as<br />
adjusted odds ratios (OR) with two-sided probability values.<br />
Results: The 3-day to 1-day regimen comparison was not statistically significant<br />
(DN, 46.4% vs. 44.4%, two-sided Fisher’s exact test, P = 0.777). The triple regimen to<br />
3-day regimen comparison was significant (DN, 58.9% vs. 46.4%; P < 0.0001). For no<br />
nausea end point in <strong>the</strong> overall phase (Days 1-5) adjusted ORs (95% CI) were: 3-day<br />
regimen vs. 1-day regimen: OR 1.19 (0.80 - 1.77), P = 0.398; triple regimen vs. 3-day<br />
regimen: OR 2.86 (1.44 - 5.83), P = 0.003.<br />
Conclusions: This analysis suggests that Palo plus 1-day or 3-day dexamethasone<br />
have similar effects on DN. The addition of aprepitant to 3-day regimen improves<br />
<strong>the</strong> prevention of DN in women receiving HEC. Complete results accounting for risk<br />
factors (age and alcohol consumption) will also be presented.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1572P SAFETY AND EFFICACY OF ORAL PALONOSETRON IN<br />
PREVENTING CHEMOTHERAPY-INDUCED NAUSEA AND<br />
VOMITING (CINV) OVER MULTIPLE CYCLES OF<br />
MODERATELY EMETOGENIC CHEMOTHERAPY (MEC)<br />
D. Voisin1 and S. Grunberg2 1<br />
Clinical R&D, Helsinn Healthcare, Pambio Noranco, SWITZERLAND,<br />
2<br />
Hematology/Oncology Unit, Fletcher Allen Health Care, Burlington, UNITED<br />
STATES OF AMERICA<br />
Background: Palonosetron (PALO), a pharmacologically distinct 5-HT3 receptor<br />
antagonist (RA) offers superior CINV prevention compared with o<strong>the</strong>r 5-HT3 RAs<br />
when administered as a single IV dose. Oral PALO doses 0.25, 0.50, 0.75 mg were<br />
clinically comparable to <strong>the</strong> approved 0.25 mg IV dose in a pivotal phase 3<br />
single-cycle trial, with 0.50 mg being <strong>the</strong> FDA/EMA approved dose. A dose of 0.75<br />
mg was selected for <strong>the</strong> present study to best evaluate safety of oral PALO in multiple<br />
cycles of chemo<strong>the</strong>rapy (CT).<br />
Methods: In this multicenter, open-label study, patients received a single 0.75 mg<br />
dose of oral PALO (with [at investigator discretion] or without concomitant<br />
dexamethasone [DEX]) 60 min prior to MEC (up to a maximum of 4 consecutive<br />
cycles). The primary safety and efficacy assessments were adverse event (AE)<br />
reporting and <strong>the</strong> proportion of cycles showing patients complete response (CR: no<br />
emesis, no rescue medication) in <strong>the</strong> acute and delayed intervals.<br />
Results: 217 patients (75% female; 61% white, 36% Hispanic; 66% CT-naive)<br />
received a total of 654 cycles of MEC (median 3 cycles).The median number of<br />
cycles was 3 with ∼ half of patients receiving 4 cycles. Concomitant DEX (8 mg Day<br />
1) was administered in 483 cycles while PALO was given alone in 171 cycles.<br />
Generally, antiemetic efficacy was maintained across <strong>the</strong> CT cycles (Table) with<br />
higher CR rates when DEX was given concomitantly vs PALO alone (acute: 74% vs<br />
61%; delayed: 63% vs 60% respectively, all cycles combined).<br />
CR (%)<br />
Time Period, hrs<br />
Cycle 1<br />
(n = 217)<br />
Cycle 2<br />
(n = 186)<br />
Cycle 3<br />
(n = 143)<br />
Cycle 4<br />
(n = 107)<br />
Acute (0-24h) 75 70 72 60<br />
Delayed (24-120h) Overall (0-120h) 63 57 62 58 63 60 60 55<br />
The majority of AEs were mild, with headache <strong>the</strong> most common related AE in 3.5%<br />
cycles PALO alone and 5.4% cycles PALO + DEX. In both <strong>the</strong> PALO alone and<br />
PALO + DEX groups, AEs decreased slightly from cycle 1 to 3 and remained about<br />
<strong>the</strong> same for cycle 4. There were few severe or serious AEs and <strong>the</strong> profile raised no<br />
safety concerns.<br />
Conclusion: Oral PALO was well tolerated and effective in preventing CINV over<br />
multiple cycles in patients receiving MEC.<br />
Disclosure: D. Voisin: Yes. Daniel Voisin is a Helsinn employee, S. Grunberg: Yes<br />
Steven Grunberg is an Helsinn Helathcare consultant.<br />
1573P THE DOPAMINE D2/D3 RECEPTOR ANTAGONIST APD421 IN<br />
COMBINATION WITH ONDANSETRON EFFECTIVELY<br />
PREVENTS ACUTE CISPLATIN-INDUCED NAUSEA AND<br />
VOMITING (CINV)<br />
J. Herrstedt 1 , Y. Summers 2 , G. Daugaard 3 , T.B. Christensen 4 , K. Holmskov 1 ,<br />
P.D. Taylor 2 ,G.Fox 5 and A. Molassiotis 6<br />
1 Onkologisk Afdeling R, Odense University Hospital, Odense, DENMARK,<br />
2 Pulmonary Oncology Unit, University Hospital South Manchester NHS<br />
Foundation Trust, Manchester, UNITED KINGDOM, 3 Department of Oncology<br />
5073, Rigshospitalet, Copenhagen University Hospital, Copenhagen, DENMARK,<br />
4 Oncology Department RA65 C8, Herlev Hospital, Herlev, DENMARK, 5 Clinical<br />
Development, Acacia Pharma Ltd, Cambridge, UNITED KINGDOM, 6 School of<br />
Nursing, Midwifery and Social Work, Manchester University, Manchester,<br />
UNITED KINGDOM<br />
Conventional dopamine D 2 antagonists are among <strong>the</strong> oldest antiemetics and are<br />
considered to be of only moderate efficacy in CINV. Central dopamine D 3 receptors<br />
have recently been demonstrated to be involved in <strong>the</strong> emetic reflex arc, but so far no<br />
clinical data have been published for any agents acting at <strong>the</strong>se receptors. In preliminary<br />
testing, APD421, a potent D2 and D3-antagonist, showed some single-agent efficacy in<br />
preventing vomiting and especially nausea caused by cisplatin. We <strong>the</strong>refore investigated<br />
its efficacy in combination with ondansetron at preventing acute-phase CINV.<br />
Methods: Chemo<strong>the</strong>rapy-naïve patients receiving cisplatin ≥ 50 mg/m 2 were given<br />
single IV doses of APD421 (20 mg) and ondansetron (8 or 16 mg) 30 minutes prior<br />
to <strong>the</strong> cisplatin. Complete response (CR) was defined as no emetic episodes and no<br />
rescue medication in <strong>the</strong> first 24 h after cisplatin infusion. Prospective nausea scores<br />
were measured on a 100 mm visual analogue scale at times 2, 4, 8 and 24 h. After <strong>the</strong><br />
initial 24 h patients received standard antiemetics.<br />
Results: 17 subjects (15M:2F) have taken part so far, receiving a mean cisplatin dose<br />
of 71 mg/m 2 (range 64-82 mg/m 2 ), of whom 15 have had CR (88%; 95% CI<br />
72-100%). The mean nausea score is 0.7/100 (range 0-8). 57/66 nausea scores<br />
collected have been zero. There have been no clinically-significant APD421-related<br />
adverse events. Recruitment will continue until <strong>the</strong> desired sample size of 23 subjects<br />
is reached (expected to be completed July <strong>2012</strong>). Final results will be presented.<br />
Conclusions: The acute-phase efficacy of APD421 in combination with ondansetron<br />
in CINV compares favourably with historical data on o<strong>the</strong>r 5-HT 3-based<br />
combinations. Randomised trials in acute and delayed phase CINV are merited.<br />
Disclosure: G. Fox: The author is an employee and stock-holder of Acacia Pharma.<br />
All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1574P BIOEQUIVALENCE AND ABSOLUTE BIOAVAILABILITY OF A<br />
SINGLE ORAL DOSE OF TWO FORMULATIONS OF 0.75 MG<br />
PALONOSETRON IN HEALTHY VOLUNTEERS (HV)<br />
D. Voisin 1 , C. Giuliano 2 and S. Baumann 3<br />
1 Clinical R&D, Helsinn Healthcare, Pambio Noranco, SWITZERLAND, 2 Preclinical<br />
R&D, Helsinn Healthcare SA, Lugano, SWITZERLAND, 3 Clinical Research, CRS<br />
Clinical Research Services, Mannheim, GERMANY<br />
Background: Palonosetron HCl (PALO) is a potent 5-HT 3 receptor antagonist<br />
(5HT3-RA) with a stronger receptor binding affinity and unique mechanism of action<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds416 | ix507
Table: 1574P<br />
Pharmacokinetic<br />
parameter palonosetron Ratio<br />
AUC(0-t) [ng h/L] b1 / b3<br />
b2 / b3<br />
AUC(0-inf) [ng h/L] b1 / b3<br />
b2 / b3<br />
Cmax [ng/L] b1 / b3<br />
b2 / b3<br />
compared to older 5HT 3-RAs. The primary objectives were to investigate <strong>the</strong><br />
bioequivalence of two oral PALO 0.75 mg formulation(s) (F (s)) b 1 and b 2 and <strong>the</strong>ir<br />
absolute bioavailability when compared to b 3 PALO 0.75 mg i.v F (see table for: b 1, b 2<br />
and b 3). Secondary objective was to evaluate <strong>the</strong> safety profile of <strong>the</strong> three PALO F (s).<br />
Methods: 36 male and female hv were randomized in this open-label, 3-treatment,<br />
cross-over study. 30 subjects received treatments b1, b2 and b3 in a 3- period<br />
randomized order (14-day interval set between periods). Treatments b 1 and b 2 were<br />
analyzed for bioequivalence by ANOVA CVs and defined bioequivalent if <strong>the</strong> 90%<br />
confidence intervals (CI) for <strong>the</strong> AUC 0-∞, AUC 0-t and C max treatment ratios lie<br />
within 80% to 125% range CI Absolute Ratios. Absolute bioavailability of <strong>the</strong> oral<br />
F (s) was calculated using <strong>the</strong> extent of exposure measure AUC 0-∞ and AUC 0-t.<br />
Results: The oral 0.75 mg F(s) b1 and b2 showed bioequivalence in terms of rate and<br />
extent of absorption: The 90% CI for PALO AUC0-t, AUC0-∞ and Cmax are 97.91%<br />
to 109.47%, 96.47% to 107.76% and 93.40% to 103.59%, respectively. All CI’s are well<br />
within <strong>the</strong> 80-125% equivalence limits. The absolute bioavailability of both oral and<br />
<strong>the</strong> i.v. F (s), calculated using AUC 0-t is essentially not different (97% for b1, and 99%<br />
for b2 F (s)). All study F (s) were safe and well tolerated: constipation and headache<br />
were <strong>the</strong> main adverse events. No clinical influence was observed on safety laboratory<br />
or vital signs variability. No drop out was due to safety issue.<br />
Conclusions: The study has shown bioequivalence of two PALO 0.75 mg oral<br />
formulations. No significant changes were observed in <strong>the</strong> absolute bioavailability<br />
between <strong>the</strong> two oral formulations and <strong>the</strong> i.v. 0.75 mg. All tested formulations<br />
showed a good safety profile.<br />
Disclosure: D. Voisin: The Author is an Helsinn Employee, C. Giuliano: The Author<br />
is an Helsinn Employee, All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1575P ADME STUDY OF [14C]NETUPITANT ADMINISTERED AS AN<br />
ORAL 300 MG SUSPENSION TO HEALTHY MALE SUBJECTS<br />
C. Giuliano 1 , S. Calcagnile 1 , S. Mair 2 , L. Stevens 2 and I. Nisbet 2<br />
1 Clinical Operation, Helsinn Healthcare, Lugano, SWITZERLAND, 2 Radiology,<br />
Quotient Bioresearch, Nottingham, UNITED KINGDOM<br />
Background: Netupitant (NETU) is a highly selective neurokinin 1 receptor<br />
antagonist developed to provide protection from nausea and vomiting induced by<br />
emetogenic chemo<strong>the</strong>rapy. The objectives of <strong>the</strong> study were to investigate <strong>the</strong><br />
pharmacokinetic (PK) profile, <strong>the</strong> mass balance recovery, <strong>the</strong> excretion pathways and<br />
<strong>the</strong> metabolism of [ 14 C]NETU in an open-label study in 6 healthy male subjects<br />
receiving a single-nominal-dose of 300 mg as oral suspension.<br />
Methods: Plasma, urine and feces samples were collected up to 336h after dosing,<br />
plus two additional 24h excreta collections until 696h. Total radioactivity was<br />
measured by liquid scintillation counting (liquid samples) and after combustion in<br />
oxygen (non-liquid samples). PK parameters for NETU and its metabolites were<br />
analyzed by liquid chromatography-tandem mass spectrometry.<br />
Results: [ 14 C]-NETU is rapidly absorbed with peak in plasma concentration ranging<br />
between 2h and 5.5h post dose. Elimination is mainly via <strong>the</strong> feces, with approximately<br />
71% of <strong>the</strong> total radioactivity recovered at 696h. Urinary elimination accounts for less<br />
than 4% of total radioactivity. Cumulative percent of total radioactivity suggests that<br />
approximately half of <strong>the</strong> administered dose was recovered within 120h and, based on<br />
an extrapolation, elimination was completed by 696h. NETU undergoes extensive<br />
metabolism forming phase I and II metabolites. The main metabolites of NETU are M1<br />
(N-demethylated NETU), M2 (NETU N-oxide) and M3 (monohydroxy NETU) which,<br />
on average, account respectively for 29%, 14% and 33% of <strong>the</strong> NETU plasma exposure.<br />
Phase I metabolites observed include those formed through N-demethylation, mono<br />
and di-hydroxylation, N-oxidation, desaturation, N-formylation, oxidation and<br />
reduction to a keto group and oxidation to an acid. Phase II metabolites include those<br />
formed by glucuronidation and conjugation to a hexose group.<br />
Conclusions: These data indicate that <strong>the</strong> hepatic/biliary route, ra<strong>the</strong>r than renal<br />
clearance is <strong>the</strong> major elimination route for drug-related entities. NETU undergoes<br />
extensive metabolism via phase I and II metabolic reactions with M1, M2 and M3 as<br />
<strong>the</strong> main circulating metabolites. NETU was well tolerated.<br />
Disclosure: C. Giuliano: Helsinn employee, S. Calcagnile: Helsinn employee,<br />
All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
Point estimate<br />
Test/Ref. ratio<br />
96.56<br />
99.88<br />
97.26<br />
98.99<br />
72.60<br />
71.71<br />
b1: oral administration of 0.75 mg palonosetron as a softgel capsule (formulation A, clinical trial formulation).<br />
b2: oral administration of 0.75 mg palonosetron as a softgel capsule (formulation B, Proposed commercial formulation).<br />
b3: intravenous administration of 0.75 mg palonosetron (3 x 0.25 mg i.v. Aloxi® - reference for <strong>the</strong> bioavailability analysis).<br />
ANOVA and 90% CIs for l0g-transformed.<br />
Annals of Oncology<br />
90%<br />
Confidence Interval<br />
91.47 - 101-93<br />
94.61 - 105.44<br />
92.33 - 102.45<br />
93.98 - 104.27<br />
67.01 - 78.67<br />
66.18 - 77.70<br />
1576P SAFETY AND PHARMACOKINETIC EVALUATION OF<br />
PALONOSETRON GIVEN ON DAY 1 AND 3 FOR PATIENTS<br />
WHO ARE TO RECEIVE A HIGH OR MODERATE RISK OF<br />
CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING (CINV)<br />
Y. Ikari, Y. Nakasima, E. Sato, M. Masaki, H. Katsuya, A. Shirahashi, T. Tanaka,<br />
K. Ishitsuka, Y. Takamatsu and K. Tamura<br />
Department of Medicine, Division of Medical Oncology, Hematology and<br />
Infectious Diseases, Fukuoka University, Fukuoka, JAPAN<br />
Aim: To assess safety, pharmacokinetics and tolerability of repeated dosing of<br />
palonosetron in patients receiving chemo<strong>the</strong>rapy categorized as having a high or<br />
moderate emetic risk.<br />
Method: Nineteen patients undergoing high or moderate emetic risk for CINV were<br />
given palonosetron 0.75mg intravenously once daily for 30 min on day 1 and<br />
3. Blood samples for <strong>the</strong> first 6 patients were obtained for pharmacokinetics analysis<br />
from day 1 through 5. To evaluate safety profiles, serial complete blood cell counts,<br />
blood chemistry tests and electrocardiograms were also performed.<br />
Result: The pharmacokinetic studies of 6 patients showed mean Cmax values on<br />
day1 and 3 were 2.05 and 2.90ng/mL, respectively, with coefficients of variation (CV)<br />
of 30.9% and 34.2%. Mean AUC0-48hr values were 42.4 and 58.3 ng•hr/mL on day1<br />
and 3, with a CV of 21.2% and 23.2%, respectively. T1/2 of palonosetron was<br />
approximately 40 hours and was constant in day1 and 3. Accumulation of<br />
palonosetron on day3 was 1.42-fold for Cmax and 1.37-fold for AUC0-48hr.<br />
Treatment-related adverse events for 19 patients including above 6 patients were<br />
constipation and loss of appetite which might be secondary to antineoplastic agents,<br />
but were mild and transient. Complete response defined by no emesis and no rescue<br />
antiemetics was 100% for acute and 73% for delayed CINV, respectively.<br />
Conclusions: Repeated dosing of palonosetron on day1 and 3 was safe and well<br />
tolerated in patients who received high to moderate emetic risk chemo<strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1577P EVALUATION OF SUBCUTANEOUS (SC) VERSUS<br />
INTRAVENOUS (IV) PALONOSETRON IN CANCER PATIENTS<br />
TREATED WITH PLATINUM-BASED CHEMOTHERAPY: A<br />
RANDOMIZED PHARMACOKINETIC ASSAY<br />
E. Arevalo, A. Del Barrio, B. Sadaba, M.A. Campanero, J.R. Azanza, A. Gurpide,<br />
J.M. Lopez Picazo, S. Martin Algarra and J.L. Perez Gracia<br />
Clinical Oncology, Clinica Universitaria de Navarra, Pamplona, SPAIN<br />
Background: 5-HT3 antagonists are one of <strong>the</strong> more effective antiemetic preventions<br />
in patients who are receiving platinum-based chemo<strong>the</strong>rapy. Some of <strong>the</strong>se 5-HT3<br />
antagonist are available for oral use, however <strong>the</strong> <strong>the</strong>rapeutic formulations with more<br />
bioavailability and middle course which have been traditionally administrated by <strong>the</strong><br />
intravenous route, have a limited use in <strong>the</strong> hospital environment. Up to now, no<br />
study has examined <strong>the</strong> pharmacokinetics of <strong>the</strong>se drugs when administered<br />
subcutaneously. We have compared pharmacokinetics of palonosetron in <strong>the</strong> two<br />
different routes, SC and IV.<br />
Methods: Patients under platinum-based chemo<strong>the</strong>rapy were randomized to receive<br />
before <strong>the</strong> first cycle of chemo<strong>the</strong>rapy, palonosetron by <strong>the</strong> SC or <strong>the</strong> IV route. In<br />
<strong>the</strong> second cycle, <strong>the</strong> drug was administrated by <strong>the</strong> o<strong>the</strong>r route. The main endpoint<br />
was Area Under <strong>the</strong> Curve between 0-24 hours (AUC 0–24h). Blood samples were<br />
drawn at 10, 15, 30, 45, 60, 90 min and 2, 3, 4, 8, 12, 24 h after palonosetron. Drug<br />
levels were determined by HPLC with fluorescence detection after liquid extraction of<br />
<strong>the</strong> samples, with a quantitation limit of 0.1 ng/ml.<br />
Results: We included 26 patients, from October 2009 to May 2010. We found no<br />
statistically differences in <strong>the</strong> Area Under Curve at 24 hours after <strong>the</strong> drug<br />
administration (AUC 0-24) between both routes. Maximum concentration (Cmax)<br />
reached after its administration was significantly lower via <strong>the</strong> SC route than by IV.<br />
The time to reach <strong>the</strong> Cmax (Tmax) by <strong>the</strong> SC route was superior than <strong>the</strong> IV route.<br />
The elimination of unmetabolized drug in urine (Ae 24h) was similar in both routes,<br />
ix508 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
in <strong>the</strong> first 24 hours, about 20% of <strong>the</strong> administered dose. The prevention of early<br />
and late emesis was equivalent with both alternatives.<br />
Conclusions: Palonosetron SC administration showed similar AUC0-24h to that of<br />
<strong>the</strong> IV route, with <strong>the</strong> same exposure to <strong>the</strong> drug, and good control in <strong>the</strong> prevention<br />
of early and late emesis, which can benefit <strong>the</strong> management of outpatient treatments.<br />
i.v. (mean ± SD)<br />
s.c.<br />
(mean ±SD) p-value<br />
AUC 0-24h (ngxh/ml) 14,10 ± 6,73 12,68 ± 9,70 0,160<br />
Cmax (ng/ml) 11,88 ± 7,38 1,91 ± 1,09 < 0,001<br />
Tmax (h) 0,04 ± 0,04 0,26 ± 0,13 < 0,001<br />
Ae24h (%) 19,48 ± 9,99 22,24 ± 8,50 0,660<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1578P CORRELATION BETWEEN CYCLOPHOSPHAMIDE-INDUCED<br />
HYPONATRAEMIA AND THE USE OF APREPITANT<br />
Y. Tono, T. Mizuno, K. Saito, S. Tamaru, Y. Yamashita, H. Oda, S. Kageyama<br />
and N. Katayama<br />
Medical Oncology, Mie University Hospital, Tsu, JAPAN<br />
Background: For prevention of emesis during anthracyline (A)/cyclophosphamide<br />
(CPA) <strong>the</strong>rapy for breast cancer, use of aprepitant(AP) combined with serotonin<br />
receptor antagonist(5HT3) and dexamethasone(DEX) is recommended. AP, known<br />
to function as a CYP3A4 inhibitor, has been reported to interfere with metabolism of<br />
chemo<strong>the</strong>rapeutic drugs. It has been also reported that AP does not influence <strong>the</strong><br />
AUC’s of 4-OH and DCE. Although, in <strong>the</strong> previous clinical reports for AC, <strong>the</strong><br />
toxicities were not significant in patients who were given AP, compared to those<br />
without AP, we have experienced a cases of severe hyponatremia probably related to<br />
AP. Thus, we investigated an impact of AP on Na metabolism during chemo<strong>the</strong>rapy<br />
using CPA for breast cancer.<br />
Material and methods: We investigated serum levels of Na in primary breast cancer<br />
patients who received CPA-combined <strong>the</strong>rapy with <strong>the</strong> use of AP as anti-emesis, or<br />
not. They all received 600mg/m 2 of CPA combined with ei<strong>the</strong>r of anthracycline or<br />
docetaxel. Their ages were to be less than 65 years, and <strong>the</strong>ir GFR’s were more than<br />
60 ml/min/1.73m 2 . Their prior electrolytes were to be within normal range. In <strong>the</strong><br />
first cycle, we evaluated serum Na levels before <strong>the</strong> CPA start and that at 24 hours<br />
after. We defined serum Na level lower than 135 mEq/L as “hyponatremia” based on<br />
previous study. We enrolled 81 patients, in whom 52 were given AP and 29 were<br />
without AP, between December 2010 and April <strong>2012</strong>.<br />
Results: The background between <strong>the</strong> two groups, with AP and without AP, were<br />
comparable, in whom <strong>the</strong> median ages were 53.0(33-64) and 53.2(38-65), and <strong>the</strong><br />
prior Na levels were139.84 ± 1.89 mEq/L, and 140.25 ± 1.82 mEq/L, in <strong>the</strong> AP-group<br />
and in non-AP-group, respectively. The uses of 5HT3 and DEX were similar between<br />
<strong>the</strong> two groups. The incidence of CPA-induced hyponatremia was significantly<br />
higher in AP-group than in non-AP-group (26.9% v 6.9%; P =0.04). The average Na<br />
level at 24 hours after chemo<strong>the</strong>rapy was 136.32 ± 3.73 mEq/L in AP-group, and<br />
138.60 ± 2.92 mEq/L in non-AP-group. Among 14 patients who developed<br />
hyponateremia in AP-group, <strong>the</strong>y were resolved without any intervention in 13, and<br />
one needed Na replacement. The patient did not develop hyponatremia without AP<br />
in <strong>the</strong> third cycle.<br />
Conclusions: According to our cohort study, AP cause hyponatremia more<br />
frequently in <strong>the</strong> CPA-combined chemo<strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1579P THE EFFICACY OF TRIPLET ANTIEMETIC THERAPY FOR<br />
CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING IN<br />
LUNG CANCER PATIENTS RECEIVING HIGHLY EMETOGENIC<br />
CHEMOTHERAPY: PALONOSETRON (PALO), APREPITANT<br />
(APR), AND DEXAMETHASONE (DEX)<br />
H. Yoshizawa 1 ,K.Sato 2 , M. Makino 3 , O. Kobayashi 4 , H. Tanaka 5 , S. Miura 6 ,<br />
S. Watanabe 1 , J. Tanaka 7 , H. Kagamu 6 and N. Ichiei 6<br />
1 Bioscience Medical Research Center, Niigata University Medical and Dental<br />
Hospital, Niigata, JAPAN, 2 Department of Respiratory Medicine, Nagaoka Red<br />
Cross Hospital, Nagaoka, JAPAN, 3 Department of Internal Medicine, Niigata<br />
Prefectural Shibata Hospital, Shibata, JAPAN, 4 Department of Internal Medicine,<br />
Niigata Prefectural Central Hospital, Jyoetsu, JAPAN, 5 Department of Internal<br />
Medicine, Niigata Cancer Center Hospital, Niigata, JAPAN, 6 Department of<br />
Medicine (II), Niigata University Medical and Dental Hospital, Niigata, JAPAN,<br />
7 Department of Health Promotion Medicine, Niigata University Graduate School<br />
of Medical and Dental Sciences, Niigata, JAPAN<br />
Background: Chemo<strong>the</strong>rapy-induced nausea and vomiting (CINV) is one of <strong>the</strong><br />
most problematic symptoms experienced by patients undergoing cancer treatments.<br />
Triplet <strong>the</strong>rapy with PALO, APR, and DEX, is a guideline-recommended antiemetic<br />
prophylaxis for highly emetogenic chemo<strong>the</strong>rapy (HEC). However, <strong>the</strong> efficacy and<br />
safety of this <strong>the</strong>rapy for lung cancer patients has not yet been well investigated.<br />
Methods: Chemo<strong>the</strong>rapy naïve lung cancer patients scheduled to receive HEC were<br />
enrolled in this study. The eligible patients were pretreated with <strong>the</strong> triplet <strong>the</strong>rapy<br />
(PALO 0.75 mg day 1, APR 125 mg day 1 and 80 mg day 2-3, DEX 9.9 mg day 1 and<br />
8 mg day 2-4) before receiving HEC. The efficacy and safety of <strong>the</strong>se substances were<br />
assessed during an observation period starting from <strong>the</strong> administration of HEC to<br />
120 hours. A questionnaire diary documented patients’ complaints. The primary<br />
endpoint was <strong>the</strong> proportion of <strong>the</strong> patients who did not experience emesis or rescue<br />
antiemetic (Complete Response rate; CR rate) during any part of <strong>the</strong> whole<br />
observation period. The secondary endpoints were (1) <strong>the</strong> CR rate during <strong>the</strong> acute<br />
phase (0-24hrs) and <strong>the</strong> late phase (24-120hrs), (2) <strong>the</strong> proportion of patients who<br />
experienced no emetic episodes and significant nausea with no rescue medication<br />
(Complete Control rate; CC rate), and (3) safety.<br />
Results: A total of 72 patients were enrolled with 65 assessable patients at <strong>the</strong> time of<br />
submission. The median age was 64 years. The CR rate during <strong>the</strong> whole observation<br />
period, <strong>the</strong> acute and late phase was 78.5 %, 95.4% and 80.0%, respectively. The CC<br />
rate in <strong>the</strong> late phase was 62.9%. No severe side effects were observed. In <strong>the</strong> subset<br />
analysis, <strong>the</strong> CC rate in late phase was significantly lower in female subset (71.4% vs.<br />
45.0%). Ano<strong>the</strong>r subset analysis regarding to chemo<strong>the</strong>rapy regimen, <strong>the</strong> proportion<br />
of vomiting event was higher in <strong>the</strong> pemetrexed used regimen.<br />
Conclusion: Triplet <strong>the</strong>rapy using PALO, APR and DEX, was shown to be safe and<br />
effective in preventing CINV in lung cancer patients treated with HEC. Fur<strong>the</strong>r<br />
investigation is needed for to reduce nausea in <strong>the</strong> late phase.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1580P PAIN INTERFERENCE OUTCOMES IN A RANDOMIZED<br />
PHASE 3 CLINICAL TRIAL OF DENOSUMAB VS ZOLEDRONIC<br />
ACID (ZA) IN PATIENTS WITH SOLID TUMORS AND BONE<br />
METASTASES<br />
C. Cleeland1 , L. Fallowfield2 , R. von Moos3 , D. Patrick4 , D.H. Henry5 , V. Hirsh6 ,<br />
K. Zarogoulidis7 , A. Feng8 , Z. Cong9 and A. Braun10 1<br />
Symptom Research Division of Internal Medicine, MD Anderson Cancer Center,<br />
Houston, TX, UNITED STATES OF AMERICA, 2 Sussex Health Outcomes<br />
Research & Education In Cancer (shore-c), University of Sussex, Brighton,<br />
UNITED KINGDOM, 3 Medizinische Onkologie und Hämatologie, Kantonsspital<br />
Graubünden, Chur, SWITZERLAND, 4 Health Services, University of Washington,<br />
Seattle, WA, UNITED STATES OF AMERICA, 5 Joan Karnell Cancer Center,<br />
Pennsylvania Hospital, Philadelphia, PA, UNITED STATES OF AMERICA,<br />
6 7<br />
Oncology, McGill University Health Centre, Montreal, QC, CANADA, G.<br />
Papanikolaou Hospital, Pulmonary Department, Aristotle University of<br />
Thessaloniki, Thessaloniki, GREECE, 8 Global Biostatistical Science, Amgen Inc.,<br />
Thousand Oaks, UNITED STATES OF AMERICA, 9 Global Health Economics,<br />
Amgen Inc., Thousand Oaks, CA, UNITED STATES OF AMERICA,<br />
10<br />
Hematology/Oncology, Amgen Inc., Thousand Oaks, CA, UNITED STATES OF<br />
AMERICA<br />
Background: In patients with advanced cancer, bone metastases cause pain and may<br />
lead to skeletal-related events (SREs). Subcutaneous (SC) denosumab prevented SREs<br />
more effectively than intravenous (IV) ZA in patients with solid tumors and bone<br />
metastases in a phase 3 clinical trial (n = 1597; Henry D, J Clin Oncol. 2010. Abstr<br />
9133). We now describe pain interference outcomes for patients with solid tumors in<br />
this trial (ClinicalTrials.gov NCT00330759; May 25, 2006; sponsor Amgen Inc.).<br />
Methods: Patients received 120 mg of denosumab SC or 4 mg of ZA IV every 4<br />
weeks in a randomized, multinational, double-blind, double-dummy trial.<br />
Patient-reported pain interference (overall, activity, and affect) was assessed by <strong>the</strong><br />
Brief Pain Inventory (0: does not interfere-10: completely interferes) at baseline (BL)<br />
and upon each monthly visit. Analyses included time to clinically meaningful<br />
(≥2-point increase or decrease from BL) worsening or improvement in pain<br />
interference, and percentage of patients reporting clinically meaningful worsening in<br />
pain interference by visit. Analyses were conducted for patients with no/mild pain<br />
(worst pain 0-4) at BL and all patients at risk.<br />
Results: In patients with no/mild pain at BL, denosumab delayed <strong>the</strong> median time to<br />
clinically meaningful worsening in pain interference compared with ZA (overall 3.4<br />
months, P = 0.0213; activity 1.8 months, P = 0.0124; affect 0.9 months, P = 0.0518).<br />
Similarly, fewer of <strong>the</strong>se patients treated with denosumab vs ZA reported clinically<br />
meaningful worsening in pain interference over all visits (average relative difference:<br />
overall 13%; activity 16%; affect 10% fewer). Time to clinically meaningful<br />
improvement in pain interference was similar between treatment groups. Pain<br />
interference outcomes were similar among all patients at risk compared to those with<br />
no/mild pain at BL.<br />
Conclusion: In patients with solid tumors, denosumab delayed time to worsening of<br />
pain interference, and fewer patients reported worsening in pain interference over<br />
time, compared with ZA. Greater effects on pain interference were seen for patients<br />
with no/mild pain at BL, suggesting <strong>the</strong> benefit of early intervention with<br />
denosumab.<br />
Disclosure: C. Cleeland: Advisory board member for Amgen, Genentech, Merck,<br />
and Exelixis, L. Fallowfield: Consultancy honoraria for serving on an advisory board<br />
for Amgen Inc., R. von Moos: Advisory board member for Amgen, Roche, &<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds416 | ix509
Novartis and unrestricted research grants from Amgen and Roche, D. Patrick:<br />
Research funding from Amgen Inc., D.H. Henry: Advisory board member, served on<br />
<strong>the</strong> speakers bureau, and received research funding from Amgen Inc., V. Hirsh:<br />
Advisory board member for Amgen Inc., A. Feng: Employed by and owns stock/<br />
stock options in Amgen Inc., Z. Cong: Employed by and owns stock/stock options in<br />
Amgen Inc., A. Braun: Employed by and owns stock/stock options in Amgen Inc.,<br />
All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1581P A RANDOMIZED PHASE II TRIAL COMPARING STANDARD<br />
PAIN CONTROL WITH OR WITHOUT GABAPENTIN FOR THE<br />
TREATMENT OF PAIN RELATED TO RADIATION-INDUCED<br />
MUCOSITIS IN HEAD AND NECK CANCER<br />
T. Kataoka 1 , N. Kiyota 2 , T. Shimada 2 , M. Toyoda 2 , Y. Fujiwara 2 , K. Nibu 3 ,<br />
T. Komori 4 , R. Sasaki 5 , T. Mukohara 2 and H. Minami 2<br />
1 Division of Oral and Maxillofacial Surgery, Shizuoka Cancer Center, Shizuoka,<br />
JAPAN, 2 Medical Oncology and Hematology, Kobe University Hospital, Kobe,<br />
JAPAN, 3 Otolaryngology and Head and Neck Surgery, Kobe University Hospital,<br />
Kobe, JAPAN, 4 Oral and Maxillofacial Surgery, Kobe University Hospital, Kobe,<br />
JAPAN, 5 Radiation Oncology, Kobe University Hospital, Kobe, JAPAN<br />
Background: Radiation-induced mucositis (RIM) in chemoradiation (CRT) for<br />
head and neck cancer (HNC) causes severe pain and worsens CRT<br />
compliance and outcome. Following retrospective reports that gabapentin<br />
might improve RIM-associated pain during CRT, we conducted a randomized<br />
phase II trial to analyze <strong>the</strong> safety and efficacy of gabapentin for<br />
RIM-associated pain.<br />
Methods: HNC patients (pts) receiving CRT were randomized to receive standard<br />
pain control (SPC) or SPC plus gabapentin (SPC + G). Pts in <strong>the</strong> SPC arm received<br />
acetaminophen and opioids as analgesic, while those in <strong>the</strong> SPC + G arm received<br />
gabapentin in addition to SPC. Gabapentin maintained at dose of 900 mg/day till 4<br />
weeks after CRT. The prescribed RT dose was 66-70 Gy/33-35Fr. Concurrent<br />
chemo<strong>the</strong>rapy consisted of a three-week cycle of cisplatin. Primary endpoint was<br />
maximum VAS score during CRT. Secondary endpoints were total dose of opioids,<br />
change in QOL (EORTC QLQ-C30 and EORTC QLQ-HN 35) from base line to 4<br />
weeks after CRT, and adverse events.<br />
Results: From Apr 2010 to Oct 2011, 22 eligible pts were randomly assigned to<br />
receive SPC (n = 11) or SPC + G (n = 11). All pts were Stage III or IV. Twelve were<br />
treated in a locally advanced setting and 10 in a postoperative setting. No statistically<br />
significant differences were seen in median maximum VAS scores between arms (47<br />
in SPC vs. 74 in SPC + G; p = 0.517). Median total dose of opioids at maximum VAS<br />
and total dose of opioids at 4 weeks after CRT did not statistically differ but<br />
appeared higher in <strong>the</strong> SPC + G arm (215 mg vs. 745.3 mg; p = 0.880, 1260 mg vs.<br />
1537.5 mg; p = 0.9438). QOL analysis showed significantly worse scores in <strong>the</strong> SPC +<br />
G arm for weight gain (p = 0.005). Adverse events related to gabapentin were<br />
manageable. One-year survival rate in both arms was equivalent.<br />
Conclusions: This is <strong>the</strong> first prospective randomized trial to analyze <strong>the</strong> safety and<br />
efficacy of gabapentin for RIM-associated pain. While survival data was equivalent in<br />
both arms, gabapentin may have detrimental effects for RIM and fur<strong>the</strong>r<br />
investigation is warranted.<br />
Disclosure: N. Kiyota: an advisory board member on proper usage of cetuximab for<br />
head and neck cancer in Japan (Merck Serono) All o<strong>the</strong>r authors have declared no<br />
conflicts of interest.<br />
1582P PAIN AND BOWEL FUNCTION EVOLUTION, IN CANCER<br />
PATIENTS TREATED WITH STRONG OPIOIDS AT THE FIRST<br />
TIME THAT THEY REPORT MODERATE-SEVERE PAIN. C2<br />
STUDY<br />
I. López Calderero 1 , L. Zugazabeitia Olabarria 2 , M.Á. Nuñez Viejo 3 , J.M.<br />
García Bueno 4 , E. Blanco Campanario 5 , J. Contreras Martínez 6 ,M.<br />
López Mata 7 , J.L. Marti Ciriquian 8 , D. Isla Casado 9 and M. Provencio Pulla 10<br />
1 Radio-Oncology Service, Hospital Virgen del Rocío, Sevilla, SPAIN, 2 Oncology<br />
Service, Hospital Povisa, S.A, Vigo, SPAIN, 3 Oncology Service, Hospital Santa<br />
María Nai, Ourense, SPAIN, 4 Oncology Service, Hospital General de Albacete,<br />
Albacete, SPAIN, 5 Oncology Service, Hospital Infanta Cristina, Badajoz, SPAIN,<br />
6 Radio-Oncology Service, Complejo Hospitalario Regional Carlos Haya, Málaga,<br />
SPAIN, 7 Radio-Oncology Service, Hospital Clínico Universitario Lozano Blesa,<br />
Zaragoza, SPAIN, 8 Oncology Service, Hospital General Universitario de Alicante,<br />
Alicante, SPAIN, 9 Oncology Service, Hospital Clínico Universitario Lozano Blesa,<br />
Zaragoza, SPAIN, 10 Oncology Service, Hospital Universitario Puerta de Hierro de<br />
Majadahonda, Madrid, SPAIN<br />
Introduction and objectives: Opioids remain <strong>the</strong> cornerstone of analgesic treatment<br />
for cancer patients, but gastrointestinal side effects have a great impact on <strong>the</strong>ir<br />
quality of life. The aim of this analysis was to evaluate <strong>the</strong> use of strong opioids in<br />
Annals of Oncology<br />
<strong>the</strong>se patients, and if oxycodone/naloxone combination provides benefits in terms of<br />
analgesia, without compromising bowel function.<br />
Material and methodology: Interim analysis of an observational multicentre study,<br />
in which patients reporting moderate-severe pain, at 1 st time in <strong>the</strong> oncology<br />
services, were treated following investigator criteria. We present results of <strong>the</strong> patients<br />
treated with strong opioids during 1 month (N= 298).<br />
Results: Baseline characteristics: 65% male, mean ± SD age: 66 ± 13 years (27% ≥ 75<br />
years old), ECOG 1: 54%; receiving chemo<strong>the</strong>rapy 64% and radio<strong>the</strong>rapy 41%. Main<br />
location of <strong>the</strong> primary tumor: lung (28%), colon/rectum (12%), head and neck<br />
(11%). Metastatic cancer: 79%; 67% of patients reported pain secondary to<br />
metastases. Comparison between patients treated with oxycodone/naloxone (n= 217)<br />
with those treated with o<strong>the</strong>r strong opioids (n= 81) showed a good pain control in<br />
both groups (NRS0-10-2.7 and -2.2 points respectively, p = 0,08). It was confirmed a<br />
significant improvement of bowel function (
Annals of Oncology<br />
1584P HOME-BASED ZOLEDRONIC ACID (ZOL) INFUSION<br />
THERAPY IN PATIENTS WITH SOLID TUMOURS:<br />
COMPLIANCE AND PATIENT-NURSE SATISFACTION<br />
T. Lebret 1 , J. Mouysset 2 , A. Lortholary 3 , C. El Kouri 3 , L. Bastit 4 , M. Ktiouet 5 ,<br />
K. Slimane 5 , X. Muracciole 6 and S. Guérif 7<br />
1 Urology, Hôpital Foch, Suresnes, FRANCE, 2 Oncology, Polyclinique Parc<br />
Rambot-Provençale, Aix en Provence, FRANCE, 3 Medical Oncology, Ca<strong>the</strong>rine<br />
de Sienne Institute, Nantes, FRANCE, 4 Radiothérapie, Centre de Radiothérapie,<br />
Evreux, FRANCE, 5 Oncology, Novartis Pharmaceuticals, Rueil-Malmaison,<br />
FRANCE, 6 Service de Radio<strong>the</strong>rapie, CHU La Timone APHM Marseille, Marseille,<br />
FRANCE, 7 Radiothérapie, CHU Poitiers, Poitiers, FRANCE<br />
Objective: To explore patient and nurse satisfaction, compliance with practice<br />
guidelines, technical feasibility, and safety of home infusion of <strong>the</strong> bisphosphonate<br />
ZOL.<br />
Methods: This was a prospective longitudinal 1-year survey of home ZOL <strong>the</strong>rapy in<br />
patients with bone metastases secondary to a solid malignancy. Randomly selected<br />
physicians prescribed home ZOL <strong>the</strong>rapy (4 mg Zometa®, 15-min IV infusion, every<br />
3-4 weeks). Three questionnaires were administered at 3 time points: physician<br />
questionnaire, nurse satisfaction and feasibility questionnaire, and patient satisfaction<br />
questionnaire. The main end-points were patient and nurse satisfaction with home<br />
ZOL <strong>the</strong>rapy.<br />
Results: Of <strong>the</strong> 154 physicians who agreed to participate, 87 (56.5%) enrolled 818<br />
patients for whom 788 case report forms were received of which 763 met inclusion<br />
criteria. Overall, 343 nurses (97.5% community) took part. Patient characteristics<br />
were: median age 68 yrs (30-95); male-female ratio 40/60; primary cancer: breast<br />
55.2%, prostate 28.4%, lung 7.2%, o<strong>the</strong>r 9.4%; ECOG-PS 0 or 1: 78.6%. Overall,<br />
90.9% of nurses were ei<strong>the</strong>r highly satisfied or satisfied with how home ZOL <strong>the</strong>rapy<br />
was run; 96.7% found <strong>the</strong> infusion ei<strong>the</strong>r very easy or easy to perform; 97.5% felt that<br />
home <strong>the</strong>rapy promoted a good relationship with patients, and 73% were ei<strong>the</strong>r<br />
highly satisfied or satisfied with <strong>the</strong>ir hospital contacts. Among patients, 95.3% were<br />
ei<strong>the</strong>r very satisfied or satisfied with home ZOL <strong>the</strong>rapy. Causes for satisfaction were<br />
quality of <strong>the</strong> nurse-patient relationship (57.6%) in addition to expected reasons (e.g.<br />
less time travelling/waiting (68.8%), less disruption to daily routine (36.6%)). ZOL<br />
<strong>the</strong>rapy was well tolerated (discontinuation due to adverse events 6.1%; osteonecrosis<br />
of <strong>the</strong> jaw 0.6%, fractures 0.2%). Practitioner compliance with recommendations was<br />
73% for dental hygiene checks at inclusion and 48-56% <strong>the</strong>reafter, 66% for<br />
pre-infusion patient hydration, and often undocumented for calcium/vitamin D<br />
supplementation.<br />
Conclusions: There was a very high level of both patient and nurse satisfaction with<br />
home ZOL <strong>the</strong>rapy. However, improved compliance with practice guidelines should<br />
be encouraged.<br />
Disclosure: T. Lebret: Consulting fees : Amgen, Novartis Advisory board : Amgen,<br />
Novartis Honorarium study Novartis, J. Mouysset: Honorarium study Novartis, A.<br />
Lortholary: Honorarium study Novartis, C. El Kouri: Honorarium study Novartis, L.<br />
Bastit: Honorarium study NovartisM. Ktiouet: Novartis EmployeeK. Slimane:<br />
Novartis Employee, X. Muracciole: Advisory board Novartis Consulting fees<br />
Novartis, S. Guérif: Consulting fees Novartis.<br />
1585P A PROSPECTIVE MONO-INSTITUTIONAL STUDY ON THE<br />
IMPACT OF A SYSTEMATIC PREVENTION PROGRAM ON<br />
THE INCIDENCE AND OUTCOME OF OSTEONECROSIS OF<br />
THE JAW (ONJ) IN PATIENTS (PTS) TREATED WITH<br />
BISPHOSPHONATES (B) FOR BONE METASTASES<br />
N.M. La Verde, A. Bramati, S. Piva, M.C. Dazzani, S. Girelli, A. Moretti, D. Mihali,<br />
M. Dimaiuta, A. Pinto and G. Farina<br />
Oncology, A.O. Fatebenefratelli e Oftalmico, Milan, ITALY<br />
Background: B are commonly used to treat bone metastases in cancer pts, who have<br />
a higher risk of developing ONJ. The elective involvement of <strong>the</strong> jaw can have an<br />
anatomic rationale, since this region has a thin mucosa and microbiological<br />
contamination. The jaw is exposed to dental microtraumatisms and infections, so<br />
reparation mechanisms are essential. B inhibits bone turnover and since <strong>the</strong><br />
increased demand for bone repair isn’t satisfied, <strong>the</strong> bone is exposed to osteonecrosis.<br />
To reduce this risk we have developed a specific prevention program focused<br />
primarily on reducing its incidence and, wherever it develops, <strong>the</strong> need for<br />
demolitive surgery with permanent sequelae.<br />
Patients and methods: All consecutive pts with bone lesions, that were eligible for<br />
treatment with B (ei<strong>the</strong>r zoledronic or pamidronic acid) were prospectively evaluated.<br />
Before starting B, each patient was referred to an specialized odontoiatric team that<br />
performed: 1. dental examination; 2. orthopantomography; 3. professional dental<br />
hygiene. If <strong>the</strong> oral conditions weren’t satisfactory (i.e., tooth decay, dental plaque,<br />
broken teeth), <strong>the</strong> dentist completed <strong>the</strong> necessary intervention before starting B.<br />
Results: From April 2007 to April <strong>2012</strong> we collected data of 254 pts, 243 of which<br />
were treated with zoledronic acid and 9 with pamidronic acid. The median age was<br />
74 years old (range 37-95), 92 male and 162 female. All pts had bone involvement:<br />
74 pts had breast cancer, 39 lung cancer, 36 prostate cancer, 33 multiple myeloma<br />
and 72 o<strong>the</strong>rs. On average <strong>the</strong> pts received 9.7 cycles (range 1-48). No case of ONJ<br />
was recorded.<br />
Conclusions: Our study demonstrates that ONJ can be effectively prevented with a<br />
serious program that involves a multidisciplinary team. The odontoiatric basal<br />
evaluation is necessary to identify pts with oral pathologies or inadequate oral<br />
hygiene who must undergo preventive dental treatment. When reparative<br />
phaenomena are compromised by B, <strong>the</strong> healthy oral environment prevents<br />
infections and subsequent morbidity. In our opinion, this type of preventive program<br />
should be mandatory for all pts starting B.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1586P QOL AND SURVIVAL SURVEY OF CANCER CACHEXIA IN<br />
ADVANCED NSCLC PATIENTS - JNUQ-LC STUDY, TORG0912<br />
S. Atagi 1 , F. Imamura 2 , A. Yokoyama 3 , K. Minato 4 , T. Harada 5 , N. Katakami 6 ,<br />
T. Yokoyama 7 , Y. Ohashi 8 , K. Watanabe 9 and K. Eguchi 10<br />
1 Department of Thoracic Oncology, Kinki-chuo Chest Medical Center, Osaka,<br />
JAPAN, 2 Department of Thoracic Oncology, Osaka Medical Center for Cancer<br />
and Cardiovascular Diseases, Osaka, JAPAN, 3 Department of Internal Medicine,<br />
Niigata Cancer Center Hospital, Niigata, JAPAN, 4 Department of Respiratory<br />
Medicine, Gunma Prefectural Cancer Center, Ohta, JAPAN, 5 Center for<br />
Respiratory Disease, Hokkaido Social Insurance Hospital, Sapporo, JAPAN,<br />
6 Division of Integrated Oncology, Institute of Biomedical Research and Innovation<br />
Hospital, Kobe, JAPAN, 7 Department of Respiratory Medicine, Kyorin University<br />
Hospital, Tokyo, JAPAN, 8 Department of Biostatistics, School of Public Health,<br />
The University of Tokyo, Tokyo, JAPAN, 9 Department of Respiratory Medicine,<br />
Yokohama Municipal Citizen’s Hospital, Yokohama, JAPAN, 10 Internal Medicine,<br />
Division of Medical Oncology, Teikyo University School of Medicine, Tokyo,<br />
JAPAN<br />
Background: Cancer cachexia, mainly characterized by muscle atrophy and<br />
subsequent cancer induced weight loss (CIWL), is attributed to about a third of<br />
cancer deaths. Despite worsening prognoses with <strong>the</strong> symptoms, clinical factors<br />
involved and <strong>the</strong> effect of CIWL to <strong>the</strong> overall status remain unexplained. We<br />
planned a prospective cohort study, Japan Nutrition and QOL survey in patients<br />
with advanced NSCLC study to investigate changes in CIWL in relation to grip,<br />
QOL, and clinical parameters to understand <strong>the</strong>ir effects on prognosis.<br />
Method: Untreated stage IV NSCLC patients with ECOG PS of 0-2 were registered.<br />
Their body weight (BW), grip, QOL, Karnofsky Performance Scale, biochemical<br />
assay, and survival were recorded every four weeks for one year from <strong>the</strong> start of<br />
cancer treatments. Patients were classified by BW loss ≥ 5% and cachexia diagnosis<br />
by BW loss, fatigue, anorexia, and abnormal assay results. Estimated survival curves<br />
were drawn by Kaplan-Meier method, and Log-rank test was applied. To evaluate <strong>the</strong><br />
effect of cancer cachexia attribution to QOL, we performed principal component<br />
analysis, factor analysis, and analysis on time course data using generalized<br />
estimating equation (GEE).<br />
Results: Out of 466 patients registered, 406 were evaluable and analyzed. Patient<br />
characteristics were: median age: 67 (33-87) years, male/female ratio: 280/126,<br />
median BW: 56.5kg, PS 0: 39.2%, and PS 1: 51.5%. The patients with BW loss of ≥<br />
5% (n = 219) reported more early deaths than those without (n = 166, p < 0.0001).<br />
Patients with cachexia (n = 169) reported more early deaths than those without (n =<br />
216, p < 0.0001). All correlations between principal component scores estimated from<br />
<strong>the</strong> variables considered <strong>the</strong> signs of cancer cachexia (cancer cachexia attributions:<br />
more weight on anorexia, fatigue, BW and grip) and each factor scores of QOL<br />
domains estimated from QOL factor analyses were significant (p < 0.01). From <strong>the</strong><br />
time course data analyses using GEE, cancer cachexia attributions of each visit are<br />
shown as useful variables for all QOL domains (p < 0.01).<br />
Conclusion: Cancer cachexia decreased QOL and possibly affected prognoses.<br />
Cachexia preventions and treatments based on <strong>the</strong> fur<strong>the</strong>r elucidation of its<br />
pathology are needed.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1587P SARCOPENIA AFFECTS TREATMENT TOXICITY IN<br />
METASTATIC COLORECTAL CANCER PATIENTS: RESULTS<br />
OF A PROSPECTIVE MULTICENTER STUDY<br />
M. Barret 1 , C. Dalban 2 , J. Taieb 3 , D. Malka 4 , T. Mansourbakht 5 ,E.Latko 6 and<br />
S. Antoun 7<br />
1 Gastroenterology, Hopital Européen Georges Pompidou, Paris, FRANCE,<br />
2 Department of Biostatistics and Epidemiology (ea4184), Centre Georges<br />
François Leclerc, Dijon, FRANCE, 3 Gastroenterology and Digestive Oncology,<br />
Hopital Européen Georges Pompidou, Paris, FRANCE, 4 Oncology, Institut<br />
Gustave Roussy, Villejuif, FRANCE, 5 Gastroenterology, Hopital de la Pitié<br />
Salpetriere, Paris, FRANCE, 6 Nutricia Advanced Nutrition, Danone, St Ouen,<br />
FRANCE, 7 Emergency Department, Institut Gustave Roussy, Villejuif, FRANCE<br />
Background: Malnutrition reduces tolerance to treatment, quality of life, and survival<br />
in numerous cancers, including metastatic colorectal cancer (mCRC). Previous<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds416 | ix511
studies have shown that chemo<strong>the</strong>rapy toxicity may be linked to low muscle tissue<br />
(sarcopenia). Our study evaluated <strong>the</strong> effect of sarcopenia on chemo<strong>the</strong>rapy toxicity<br />
among mCRC patients.<br />
Methods: In this prospective, cross-sectional, multicenter study, demographic,<br />
oncological, and nutritional data were collected in all consecutive mCRC patients<br />
in three hospitals. Computed tomography (CT) images were analyzed using<br />
Slice-O-Matic software V4.3 (Tomovision) to evaluate cross-sectional areas (cm 2 )<br />
of muscle tissue (MT), visceral adipose tissue (VAT), and subcutaneous adipose<br />
tissue (SAT). The 3 rd lumbar vertebra (L3) was chosen as a reference, since L3<br />
and whole-body measurements are linearly related. Indexed on height, MT, VAT<br />
and SAT (cm 2 /m 2 ), were described, after stratification on sex. Sarcopenia was<br />
defined as MT 90% for all assessments during treatment. CTCAE consistently resulted in<br />
ix512 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
lower sensitivity and correlation compared to PNQ (weighted kappa coefficients of<br />
sensory and motor components were 0.50 and 0.38). Sensory and motor component<br />
grades of PNQ were significantly correlated with <strong>the</strong> FACT/GOG Ntx-subscale (r =<br />
0.63 and 0.45). The test-retest reliability of PNQ sensory and motor components<br />
demonstrated Spearman correlation coefficients of 0.81 and 0.59. PNQ sensory<br />
grades increased similarly with CTCAE. PNQ motor grades were worse compared to<br />
CTCAE.<br />
Conclusions: The PNQ has adequate feasibility and validity to prospectively assess<br />
oxaliplatin neurotoxicity. The PNQ is a convenient, accurate and reliable assessment<br />
tool for oxaliplatin neurotoxicity.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1591P PHASE II STUDY OF TOPICAL MENTHOL FOR<br />
CHEMOTHERAPY-INDUCED PERIPHERAL NEUROTOXICITY<br />
(CIPN)<br />
M. Nakamura, K. Nakamura, T. Onikubo, H. Kamikawa and K. Tauchi<br />
Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto, JAPAN<br />
Background: Chemo<strong>the</strong>rapy-induced Peripheral Neurotoxicity (CIPN) is a major<br />
dose-limiting toxicity of many commonly used chemo<strong>the</strong>rapeutic agents that can<br />
limit successful disease control in cancer care. Although some systemic agents have<br />
been available, a significant proportion of patients are left with long-term pain and<br />
disability which is difficult to treat. Transient Receptor Potential Melastatin-8<br />
(TRPM-8) is distributed in peripheral nerves and has been shown to associate with<br />
cold hypersensitivity, noxious cold, sensory disturbance, and impaired<br />
<strong>the</strong>rmoregulation. Menthol is a compound derived from mint leaves that functions as<br />
an agonist of TRPM-8. Preclinical and clinical works have shown <strong>the</strong> effect of topical<br />
menthol on CIPN. We conducted a phase II study to investigate <strong>the</strong> effects of<br />
menthol on CIPN.<br />
Methods: 27 patients with CIPN caused by treatment with oxaliplatin (n = 22),<br />
paclitaxel (n = 3), capecitabine (n = 1), and irinotecan (n = 1) applied 1% topical<br />
menthol, twice daily to affected skin areas. CIPN symptoms were assessed separately<br />
for <strong>the</strong> hands and feet using <strong>the</strong> Numerical Rating Scale (NRS) and modified<br />
Peripheral Neuropathy Scale (PNS) based on patient questionnaires at baseline, 4 and<br />
8 weeks after treatment. Responders and good responders were defined as 10% and<br />
30% reduction in NRS respectively.<br />
Results: Three patients (11%) could not continue <strong>the</strong> study due to adverse events<br />
(skin swelling, desquamation and aggravation of Hand-Foot Syndrome). Efficacy of<br />
topical menthol was evaluated in 24 patients. Eighteen patients (75%) showed over<br />
10% decrease of NRS, and 12 patients (50%) showed over 30% decrease of NRS.<br />
Median scores of NRS of baseline, 4 and 8weeks were 4.3, 4.1 and3.6 in hands (p =<br />
n.s.; paired t test); 5.4, 4.9 and 4.4 in feet respectively (p = 0.03; paired t test). In<br />
modified PNS that assessed <strong>the</strong> severity of neurological symptoms and functional<br />
disabilities caused by CIPN, a decrease of score was observed in 19 of 24 patients<br />
(79.2%).<br />
Conclusions: Topical menthol was well tolerated and demonstrated significant<br />
<strong>the</strong>rapeutic response for CIPN.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1592P CHEMOTHERAPY INDUCED PERIPHERAL NEUROPATHY:<br />
THE ROLE OF THE MODIFIED TOTAL NEUROPATHY SCORE.<br />
S. Vasquez 1 , M. Guidon 2 , E. McHugh 2 , O. Lennon 2 and O.S. Breathnach 3<br />
1 Physio<strong>the</strong>rapy, Beaumont Hospital Cancer Centre, Dublin, IRELAND,<br />
2 Physio<strong>the</strong>rapy, Royal College of Surgeons in Ireland, 2, IRELAND, 3 Medical<br />
Oncology, Beaumont Hospital Cancer Centre, Dublin, IRELAND<br />
Background: Chemo<strong>the</strong>rapy induced peripheral neuropathy (CIPN) is a common,<br />
potentially reversible side-effect of some chemo<strong>the</strong>rapeutic agents. Common toxicity<br />
scales used in clinical practice are subjective, insensitive to change, and may<br />
underreport this phenomenon. The use of nerve conduction studies is invasive and<br />
impractical in routine practice. The modified total neuropathy score (mTNS)<br />
provides a comprehensive non-invasive measure of CIPN. CIPN is associated with<br />
decreased balance, function and quality of life (QoL). This association has to date<br />
been under-investigated.<br />
Methods: All patients receiving neurotoxic chemo<strong>the</strong>rapy regimes over a seven week<br />
period during July / August 2011 were identified using <strong>the</strong> hospital pharmacy<br />
database and once screened for inclusion/exclusion criteria, were invited to complete<br />
<strong>the</strong> mTNS, Berg Balance Scale (BBS), Timed Up and Go (TUG), and <strong>the</strong> FACT-G<br />
QoL questionnaire. mTNS scores were profiled and correlated with BBS, TUG and<br />
FACT-G using Spearmans correlation coefficient. All assessments were carried out<br />
under <strong>the</strong> supervision of a Senior Physio<strong>the</strong>rapist.<br />
Results: A total of 29 patients undergoing a variety of neurotoxic chemo<strong>the</strong>rapy<br />
regimes (taxanes n = 9, vinca-alkaloids n = 3, platinums n = 13, combination<br />
platinum/taxane regimes n = 4) were assessed. The patients mTNS scores ranged<br />
between 1 and 12 (median score = 5), indicating that all patients had some signs of<br />
neuropathy on mTNS, and 93% (n = 27) had scores indicative of CIPN. No<br />
significant correlations were found between mTNS and BERG (r = -.289; p = 0.05),<br />
TUG (r = .136; p = 0.05), or FACT-G (r = 0.050; p = 0.05).<br />
Conclusion: This study found a high prevalence of CIPN in patients treated with<br />
neurotoxic chemo<strong>the</strong>rapy regimes as assessed by <strong>the</strong> mTNS. The mTNS provided a<br />
clinically applicable, sensitive screening tool for CIPN which could prove useful in<br />
clinical practice. mTNS did not correlate with BERG, TUG or FACT-G in this study,<br />
which may be due to relatively mild levels of CIPN and consequent subtle<br />
impairments which were not adequately captured by gross functional assessments.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1593P INFLUENCE OF BASELINE OXIDATIVE STRESS LEVEL ON<br />
CHANGES IN LEFT VENTRICLE ECHOCARDIOGRAPHIC<br />
PARAMETERS IN PATIENTS WITH BREAST CANCER<br />
RECEIVING ANTHRACYCLINE CHEMOTHERAPY<br />
L. Petruzelka 1 , M. Kocik 2 , M. Zimovjanova 1 , J. Kodytkova 3 ,L.Vavrova 3 ,<br />
O. Mestek 4 , K. Gorican 2 and A. Zak 5<br />
1 Oncology, First Faculty of Medicine Charles University, Prague, CZECH<br />
REPUBLIC, 2 4thdepartment of Internal Medicine, First Medical Faculty Charles<br />
University, Prague, CZECH REPUBLIC, 3 Institute for Clinical Biochemistry and<br />
Laboratory Diagnostics, First Medical Faculty Charles University, Prague, CZECH<br />
REPUBLIC, 4 Department of Analytical Chemistry, Institute of Chemical<br />
Technology, Prague, CZECH REPUBLIC, 5 4st Department of Internal Medicine,<br />
First Medical Faculty Charles University, Prague, CZECH REPUBLIC<br />
Introduction: Breast cancer (BC), like o<strong>the</strong>r malignancies, is associated with<br />
chronic increase of oxidative stress (OS). Anthracyclines (ANTS), potent<br />
inductors of OS, represent first-line <strong>the</strong>rapy of advanced BC. OS induction by<br />
ANTS is believed to be <strong>the</strong> key factor in ANTS- related left ventricle dysfunction<br />
and <strong>the</strong> subsequent development of heart failure, which are major complications<br />
of ANTS <strong>the</strong>rapy. The aim of <strong>the</strong> present study is to establish <strong>the</strong> role of<br />
malignancy-related OS present before ANTS <strong>the</strong>rapy in <strong>the</strong> development of<br />
changes in echocardiografic (ECHO) parameters after chemo<strong>the</strong>rapy in patients<br />
with breast cancer.<br />
Patients and methods: The study population consists of 99 adult female suffering<br />
from breast cancer (mean age 52 ± 12 years) receiving ANTS chemo<strong>the</strong>rapy. Catalase<br />
(CAT) activity as a surrogate marker of OS level and ECHO examination were<br />
established at <strong>the</strong> baseline in all patients. Follow-up ECHO examinations were<br />
performed at <strong>the</strong> end of <strong>the</strong>rapy and again one year after <strong>the</strong> start of <strong>the</strong>rapy. The<br />
correlations between baseline CAT activities and changes in ECHO parameters were<br />
evaluated.<br />
Results: Statistically significant correlation between baseline CAT activity and<br />
unfavorable change in end-diastolic left ventricle diameter ( r = 0.24; p = 0.02) was<br />
observed soon after <strong>the</strong> ANTS <strong>the</strong>rapy. Statistically significant correlation between<br />
baseline CAT activities and unfavorable change in end-diastolic left ventricle<br />
diameter (r = 0.30;p = 0.003) was found at one year following <strong>the</strong> start of ANTS<br />
<strong>the</strong>rapy.<br />
Conclusion: The results of our study suggest a possible correlation between baseline<br />
OS level and <strong>the</strong> future development of morphological cardiac changes after ANTS<br />
chemo<strong>the</strong>rapy in patients with breast cancer. Whe<strong>the</strong>r pre-treatment levels of OS can<br />
predict ANTS induced left ventricle dysfunction and/or <strong>the</strong> development of heart<br />
failure will be shown by a fur<strong>the</strong>r follow-up of <strong>the</strong> study population. The study was<br />
supported by <strong>the</strong> grant awarded by Ministry of Health, Czech republic, IGA MZ ĆR<br />
NS 9774-4<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1594P PREVENTION STRATEGIES FOR CHEMOTHERAPY INDUCED<br />
HAND-FOOT SYNDROME: A META-ANALYSIS OF<br />
PROSPECTIVE RANDOMISED TRIALS<br />
L. Traldi Macedo 1 and A. Sasse 2<br />
1 Medical Oncology, State University of Campinas (UNICAMP), Campinas,<br />
BRAZIL, 2 Cevon Centre for Evidences in Oncology, UNICAMP - Universidade<br />
Estadual de Campinas, Campinas, BRAZIL<br />
Introduction: Hand-foot syndrome (HSF) is a distinctive adverse event relatively<br />
frequent to some chemo<strong>the</strong>rapeutic agents as capecitabine, pegylated liposomal<br />
doxorubicin, docetaxel or sorafenib, and often recognized as a dose-limiting<br />
reaction. The prevention of HSF would be <strong>the</strong>refore crucial to avoid treatment<br />
interruptions, and many studies have been developed in <strong>the</strong> attempt to reach this<br />
purpose. The aim of this meta-analysis is to analyze <strong>the</strong> clinical efficacy of current<br />
prevention strategies.<br />
Methods: A wide search through PubMed/MEDLINE was performed using <strong>the</strong> terms<br />
related to hand-foot syndrome, erythrodyses<strong>the</strong>sia and random in all fields. ASCO<br />
and <strong>ESMO</strong> Meeting <strong>Abstract</strong>s from 2000 to 2011 were also scanned. Randomized<br />
trials comparing intervention versus observation or placebo were selected and had<br />
<strong>the</strong>ir data collected. The end-points evaluated were <strong>the</strong> dichotomic data for mild<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds416 | ix513
(Grade 1) and moderate to severe (Grades 2 to 3) HSF. Meta-analysis was calculated<br />
through RevMan v5.1 software.<br />
Results: Amongst 195 potential articles, only six matched <strong>the</strong> inclusion criteria,<br />
with details described on <strong>the</strong> table below. In regards to mild HSF, <strong>the</strong> use of<br />
celecoxib presented statistical benefit (OR 0.35, 95% CI 0.22 to 0.58, p < 0.0001),<br />
while pyridoxine (OR 0.58, 95% CI 0.56 to 4.01) and topical urea/lactic acid<br />
(OR 1.6, 95% CI 0.5 to 5.16) failed to prove efficacy. The same pattern was<br />
observed for moderate to severe HSF, where celecoxib significantly reduced <strong>the</strong><br />
number of events (OR 0.38, 95% CI 0.2 to 0.7, p = 0.002), unlike pyridoxine<br />
(OR 0.99, 95% CI 0.65 to 1.52) or topical urea/lactic acid (OR 1.55, 95% CI<br />
0.69 to 3.45).<br />
Author Year N Intervention Blinding<br />
Köhne 2008 44 Celecoxib 800 mg Yes<br />
Zhang <strong>2012</strong> 139 Celecoxib 400 mg No<br />
Zhang 2011 110 Celecoxib 400 mg No<br />
von Gruenigen 2010 34 Pyridoxine 200 mg Yes<br />
Kang 2010 389 Pyridoxine 200 mg Yes<br />
Wolf 2010 137 Urea/lactic acid-based topic agent Yes<br />
Conclusions: From all available possibilities for prevention of HSF, celecoxib appears<br />
to be <strong>the</strong> most promising agent, with statistically significant results. Larger,<br />
multicentric studies would be ideal to reinforce this hypo<strong>the</strong>sis.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1595P TOPICAL APPLICATION OF TJ-14 (HANGESHASHINTO) IN<br />
THE TREATMENT OF CHEMOTHERAPY-INDUCED ORAL<br />
MUCOSITIS: A RADOMIZED, PLACEBO-CONTROLLED,<br />
DOUBLE-BLIND, PHASE II TRIAL<br />
N. Nagata 1 , C. Matsuda 2 , Y. Munemoto 3 , M. Oshiro 4 , M. Kataoka 5 , Y. Shindo 6 ,<br />
S. Morita 7 , T. Kono 8 , J. Sakamoto 9 and H. Mishima 10<br />
1 Surgery, Kitakyushu General Hospital, Kitakyushu, JAPAN, 2 Surgery, Osaka<br />
General Medical Center, Osaka, JAPAN, 3 Surgery, Fukui Saiseikai Hospital,<br />
Fukui, JAPAN, 4 Surgery, Toho University Sakura Medical Center, Sakura,<br />
JAPAN, 5 Surgery, Nagoya National Hospital, Nagoya, JAPAN, 6 Digestive<br />
Surgery, Nakadori General Hospital, Akita, JAPAN, 7 Biostatistics and<br />
Epidemiology, Yokohama City University Medical Center, Yokohama, JAPAN,<br />
8 Advanced Surgery Center, Higashi-Tokusyukai Hospital, Sapporo, JAPAN,<br />
9 Young Leaders Program, Nagoya University, Nagoya, JAPAN, 10 Clinical<br />
Oncology, Aichi Medical University, Nagakute, JAPAN<br />
Background and aims: Although chemo<strong>the</strong>rapy-induced oral mucositis (COM) is a<br />
common side effect of many anticancer <strong>the</strong>rapies, <strong>the</strong> optimal treatment for this<br />
condition is not well established. Recent studies showed that one of <strong>the</strong> traditional<br />
Japanese herbal medicines (Kampo) called TJ-14 (hangeshashinto) may be useful for<br />
COM via downregulating pro-inflammatory prostaglandins in <strong>the</strong> cyclooxygenase<br />
pathway (ASCO-GI2011, AGA<strong>2012</strong>). The efficacy of TJ-14 for <strong>the</strong> prevention and/or<br />
treatment of COM was exploratively tested in a randomized, double-blind,<br />
placebo-controlled trial in colorectal cancer patients.<br />
Methods: Ninety-three patients who developed COM during FOLFOX, FOLFIRI or<br />
XELOX treatment for advanced colorectal cancer were centrally randomized to<br />
receive ei<strong>the</strong>r a topical application of TJ-14 or placebo. Patients were advised to<br />
dissolve 2.5 g of TJ-14 or placebo in 50 mL of tap water and rinse <strong>the</strong>ir oral cavity<br />
three times daily for 10 seconds with <strong>the</strong> solution before expectorating it. Patients<br />
followed this oral care throughout <strong>the</strong> treatment before <strong>the</strong> next course of<br />
chemo<strong>the</strong>rapy began. The COM grade was evaluated using <strong>the</strong> Common<br />
Terminology Criteria for Adverse Events (CTCAE) version 4 and a self-administered<br />
questionnaire before and after <strong>the</strong> 2-week treatment with <strong>the</strong> TJ-14 or placebo<br />
solution. The study endpoints included <strong>the</strong> incidence of worst grade COM, <strong>the</strong><br />
incidence of grade 2 or higher COM, <strong>the</strong> duration of grade 2 or higher COM, and<br />
<strong>the</strong> healing time of COM.<br />
Results: Ninety patients (43 in <strong>the</strong> TJ-14 group, 47 in <strong>the</strong> placebo group) were<br />
included in <strong>the</strong> statistical analysis. The incidence of grade 3 COM was 9.5% vs. 17%,<br />
while no significant difference in <strong>the</strong> incidence of grade 2 or higher COM was found<br />
between <strong>the</strong> two groups. The median duration of grade 2 or higher COM was 5.5<br />
days vs. 10.5 days (p = 0.018). No significant difference was observed between <strong>the</strong><br />
two groups with regard to <strong>the</strong> incidence of grade 2 or higher adverse events.<br />
Conclusions: Topical TJ-14 rinse appears to have a significant ability to treat grade 2<br />
or higher COM and reduce <strong>the</strong> risk of developing grade 3 COM. Our results are<br />
encouraging and warrant fur<strong>the</strong>r phase III trials.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
1596P MAINTENANCE OF QUALITY OF LIFE IN PATIENTS WITH<br />
MALIGNANT ASCITES DURING TREATMENT WITH THE<br />
TRIFUNCTIONAL ANTIBODY CATUMAXOMAB: RESULTS<br />
FROM THE PHASE III B CASIMAS TRIAL<br />
F. Lordick 1 , J. Sehouli 2 , I.B. Vergote 3 , P. Rosenberg 4 , A. Schneeweiss 5 ,<br />
A. Block 6 , C. Salat 7 , G. Scambia 8 , D. Berton-Rigaud 9 and P. Wimberger 10<br />
1 Medizinische Klinik III, Staedtisches Klinikum Braunschweig, Braunschweig,<br />
GERMANY, 2 Department of Gynecology, Charite Medical University, Berlin,<br />
GERMANY, 3 Obstetrics & Gynaecology, BGOG and University Hospital Leuven,<br />
Leuven, BELGIUM, 4 Onkologiska Kliniken Universitetssjukhuset, University<br />
Hospital Linköping, Linköping, SWEDEN, 5 Heidelberg, National Center for Tumor<br />
Diseases, Heidelberg, GERMANY, 6 Internal Medicine, UKE Universit, Hamburg,<br />
GERMANY, 7 Munich, Hematology Oncology Clinic, Munich, GERMANY,<br />
8 Department of Gynecologic Oncology, Catholic University, Rome, ITALY,<br />
9 Oncology, Centre René Gaducheau, Nantes, FRANCE, 10 University of<br />
Duisburg-essen, AGO and Department of Gynecology and Obstetrics, Essen,<br />
GERMANY<br />
Background: Malignant Ascites (MA) is associated with a poor prognosis and a<br />
major deterioration in quality of life (QoL). To demonstrate <strong>the</strong> value of a new<br />
treatment <strong>the</strong> assessment of QoL is of particular importance. Results from <strong>the</strong> pivotal<br />
study demonstrated catumaxomab’s potential to stabilize QoL and prolong <strong>the</strong> time<br />
to first deterioration of QoL in <strong>the</strong>se patients. Observations from <strong>the</strong> two-arm,<br />
open-label, multicentre CASIMAS trial now give evidence that QoL remains<br />
unaffected during catumaxomab treatment<br />
Methods: In our trial, 219 patients were randomized to receive catumaxomab plus<br />
premedication of 25 mg prednisolone (CP, 111 pts) or catumaxomab alone (C, 108<br />
pts). QoL was measured using <strong>the</strong> EQ-5D visual analogue scale (EQ-VAS). The<br />
EQ-VAS reports <strong>the</strong> respondent’s self-rated health on a vertical scale where <strong>the</strong><br />
endpoints are labelled “Best imaginable health state” (100) and “Worst imaginable<br />
health state” (0). This information is used as a quantitative measure of health<br />
outcome. Patients were asked to complete <strong>the</strong> EQ-VAS during <strong>the</strong> treatment period<br />
(d 0, 3 and 10) and follow-up (d8, 28). Descriptive analyses were performed<br />
according to EQ-5D User Guide (Version 4.0). In addition, ascites-related symptoms<br />
were measured with a disease specific patient questionnaire (Functional Assessment<br />
of Chronic Illness Therapy, FACIT).<br />
Results: Longitudinal analysis of <strong>the</strong> EQ-VAS for <strong>the</strong> pooled population (CP and C)<br />
showed no relevant changes in mean score during <strong>the</strong> treatment period with<br />
catumaxomab (d0: 51.5; d3: 50.9; d10: 51.0) and compared to screening (52.7).<br />
During <strong>the</strong> follow-up period (d8: 53.9, d28: 57.1), an increase in mean values was<br />
observed. Descriptive comparison of both treatment groups revealed no major<br />
differences in QoL and ascites-related symptoms during <strong>the</strong> treatment and follow-up<br />
period, indicating that prednisolone has no impact on patient’s self-rated health.<br />
Conclusions: Quality of Life as measured by EQ-VAS remains unchanged during<br />
treatment with catumaxomab and improves after <strong>the</strong> treatment period. The<br />
improvement is plausible due to <strong>the</strong> prolonged-puncture-free survival and is<br />
consistent with previous observations of QoL changes during and after<br />
intraperitoneal treatment with catumaxomab.<br />
Disclosure: F. Lordick: consultant for Fresenius Biotech GmbH, J. Sehouli:<br />
consultant for Fresenius Biotech GmbH and financial support for clinical studies, I.B.<br />
Vergote: consultant for Fresenius Biotech GmbH, P. Rosenberg: financial support for<br />
clinical studies from Fresenius Biotech GmbH, A. Schneeweiss: financial support for<br />
clinical studies from Fresenius Biotech GmbH, A. Block: financial support for clinical<br />
studies from Fresenius Biotech GmbH, C. Salat: financial support for clinical studies<br />
from Fresenius Biotech GmbH, G. Scambia: financial support for clinical studies<br />
from Fresenius Biotech GmbH, D. Berton-Rigaud: financial support for clinical<br />
studies from Fresenius Biotech GmbH, P. Wimberger: consultant for Fresenius<br />
Biotech GmbH<br />
1597P PROPHYLACTIC TOPICAL ADAPALENE AND ORAL<br />
MINOCYCLINE FOR PANITUMUMAB-INDUCED SKIN<br />
TOXICITY<br />
T. Yanai 1 , H. Hashimoto 1 , N. Yamazaki 2 , H. Yasui 3 , G. Sakai 4 , S. Akatsuka 5 ,<br />
K. Ogawa 6 , S. Hirai 7 , H. Yamamoto 1 and T. Hamaguchi 8<br />
1 Division of Pharmacy, National Cancer Center Hospital, Tokyo, JAPAN, 2 Division<br />
of Dermatological Oncology, National Cancer Center Hospital, Tokyo, JAPAN,<br />
3 Medical Oncology, Kyoto Medical Center, Kyoto, JAPAN, 4 Division of<br />
Gastrointestinal Medicine, Saiseikai Utsunomiya Hospital, Utsunomiya, JAPAN,<br />
5 Division of Medical Oncology, Yokohama Rosai Hospital, Yokohama, JAPAN,<br />
6 Gastroenterology, University of Toyama, Toyama, JAPAN, 7 Division of<br />
Gastrointestinal Medicine, Toyama Prefectural Central Hospital, Toyama, JAPAN,<br />
8 Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, JAPAN<br />
Background: Panitumumab (Pmab) has been associated with a high incidence of<br />
skin toxicity. The STEPP study evaluated whe<strong>the</strong>r prophylactic treatment with a<br />
topical steroid and oral doxycycline during <strong>the</strong> first 6 weeks of Pmab-containing<br />
ix514 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
<strong>the</strong>rapy reduced incidence of grade 2 or higher skin toxicities compared to reactive<br />
treatment. Prophylactic treatment resulted in skin toxicity incidence of 29%<br />
compared with 62% in <strong>the</strong> reactive treatment arm.<br />
Purpose: The aim of this study was to evaluate <strong>the</strong> efficacy of combination<br />
prophylactic <strong>the</strong>rapy with topical adapalene and oral minocycline in patients<br />
receiving Pmab.<br />
Methods: Patients with KRAS wild-type unresectable/recurrent colorectal cancer<br />
enrolled in a prospective phase II clinical trial of third-line Pmab plus irinotecan<br />
(CPT-11) or Pmab mono<strong>the</strong>rapy were included. Prophylactic <strong>the</strong>rapy with<br />
topical adapalene, a third-generation topical retinoid used in <strong>the</strong> treatment of<br />
mild-to-moderate acne, and oral minocycline were started from one day prior to<br />
<strong>the</strong> first Pmab dose and continued for 6 weeks. Adapalene was administered<br />
once daily in <strong>the</strong> evening, along with oral minocycline 100 mg twice per day.<br />
Skin toxicity was evaluated according to NCI CTCAE, version 4. The primary<br />
endpoint was incidence of grade 2 or higher skin toxicities during <strong>the</strong> 6-week<br />
skin treatment period.<br />
Results: Between January 2011 and December 2011, 48 patients were included in this<br />
study (27 men, 21 women; median age, 62.0 years; 43 CPT-11 + Pmab, 5 Pmab<br />
alone). During <strong>the</strong> 6 weeks of prophylactic <strong>the</strong>rapy, incidence of skin toxicities (rash,<br />
dry skin, and paronychia) was 83.3%. The incidence of skin toxicities of grade 2 or<br />
higher was 29.2%, similar to STEPP trial results (29%). The median adherence to<br />
topical adapalene was 90% (range, 0-100%), while minocycline was 100% (range,<br />
17-100%). In <strong>the</strong> good adapalene adherence group (≥median), <strong>the</strong> incidence of skin<br />
toxicity of grade 2 or higher was 20.8% compared to 37.5% in <strong>the</strong> poor adherence<br />
group (
declined to relatively lower level of QOL and <strong>the</strong>n steadily back to moderate QOL“.<br />
The third type of QOL covered 39.6% of patients and represented “steadily moderate<br />
level of QOL“. The factors significantly related to <strong>the</strong> first type of QOL trajectory<br />
were physical function, pain, poor appetite, uncertainty, and self efficacy; pain,<br />
uncertainty and self-efficacy were related to <strong>the</strong> second type of QOL trajectory; and<br />
depression and uncertainty were related to <strong>the</strong> third type of QOL trajectory.<br />
Conclusion: Based on <strong>the</strong> QOL trajectories and identified factors, <strong>the</strong> timely and<br />
tailoring interventions should be developed, applied to and tested for <strong>the</strong>ir clinical<br />
effectiveness in enhancing advanced lung cancer patients’ QOL during <strong>the</strong> most<br />
distressful first 6 months of having lung cancer. Acknowledge This study is<br />
supported by National Health Research Institute (NHRI) in Taiwan.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1601P PATIENT DIGNITY INVENTORY (PDI) QUESTIONNAIRE: THE<br />
VALIDATION STUDY IN ITALIAN PATIENTS WITH SOLID AND<br />
HAEMATOLOGICAL CANCERS ON ACTIVE ONCOLOGICAL<br />
TREATMENTS<br />
C.I. Ripamonti 1 , L. Buonaccorso 2 , A. Maruelli 3 , E. Bandieri 4 , M.A. Pessi 5 ,<br />
S. Boldini 6 , C. Primi 7 and G. Miccinesi 8<br />
1 Supportive Care in Cancer, Fondazione IRCCS, Istituto Nazionale Tumori,<br />
Milano, ITALY, 2 Psychology, AMO Association of Oncological Patients from nine<br />
towns and villages in <strong>the</strong> Nor<strong>the</strong>n Area of Modena, Mirandola, ITALY,<br />
3 Psychology Unit, LILT and Centre for Oncological Rehabilitation CERION of<br />
Florence, Firenze, ITALY, 4 Oncological Unit, Azienda USL Modena CeVEAS<br />
Modena, Mirandola Modena, ITALY, 5 Supportive Care In Cancer, Fondazione<br />
IRCCS, Istituto Nazionale dei Tumori Milano, Milano, ITALY, 6 Supportive Care in<br />
Cancer, Fondazione IRCCS, Istituto Nazionale dei Tumori Milano, Milano, ITALY,<br />
7 Psycology, University of Florence, Florence, ITALY, 8 Epidemiology, Cancer<br />
Prevention and Research Institute ISPO Florence, Florence, ITALY<br />
Background: In Oncology, little is known about <strong>the</strong> dignity – related distress and <strong>the</strong><br />
issues that influence <strong>the</strong> sense of dignity for patients. W validated <strong>the</strong> Patient Dignity<br />
Inventory (PDI) questionnaire in Italian patients on oncological active treatments.<br />
Methods: After <strong>the</strong> translation procedures, <strong>the</strong> PDI was administered to 266 patients<br />
along with o<strong>the</strong>r questionnaires to assess <strong>the</strong> psychometric properties of <strong>the</strong> Italian<br />
version of PDI. Factor structure was tested by both explorative and confirmatory<br />
factor analyses. Concurrent validity was tested through convergent and divergent<br />
validity with validated questionnaires inquiring about physical and psychological<br />
symptoms, and religiosity. The test/retest reliability was assessed through <strong>the</strong><br />
concordance coefficient of Linn (two weeks interval, 80 patients).<br />
Results: The explorative analysis suggested one factor only loading highly on all <strong>the</strong><br />
25 items (>.45) and explaining <strong>the</strong> 48% of variance; confirmative analysis and<br />
Cronbach alpha (0.96) confirmed <strong>the</strong> adequacy of <strong>the</strong> one-factor model. In <strong>the</strong> 2<br />
weeks test-retest study a concordance coefficient of 0.73 (95% C.I.:0.64; 0.83) was<br />
found. High correlations of problems with dignity were found with both physical and<br />
psychological symptoms (0.52 and 0.64 rho coefficient, respectively), and moderate<br />
inverse correlation with spiritual well being (-.40). The dignity construct, as<br />
measured by PDI; showed to be orthogonal to that of religiosity (-.02).<br />
Conclusions: The Italian version of PDI is a valid and reliable tool to evaluate <strong>the</strong><br />
dignity related-distress in out-patients with ei<strong>the</strong>r solid and haematological cancers,<br />
on active oncological treatments, in non advanced stage of <strong>the</strong> disease.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1602P HOPE HERTH INDEX (HHI): A VALIDATION STUDY IN ITALIAN<br />
PATIENTS WITH SOLID AND HAEMATOLOGICAL<br />
MALIGNANCIES ON ACTIVE ONCOLOGICAL THERAPIES<br />
C.I. Ripamonti 1 , L. Buonaccorso 2 , A. Maruelli 3 , E. Bandieri 4 , S. Boldini 1 ,<br />
M.A. Pessi 1 , F. Chiesi 5 and G. Miccinesi 6<br />
1 Supportive Care in Cancer, Fondazione IRCCS, Istituto Nazionale Tumori,<br />
Milano, ITALY, 2 Psychology, AMO Association of Oncological Patients from nine<br />
towns and villages in <strong>the</strong> Nor<strong>the</strong>n Area of Modena, Mirandola, ITALY,<br />
3 Psychology Unit, LILT and Centre for Oncological Rehabilitation CERION of<br />
Florence, Firenze, ITALY, 4 Oncological Unit, Azienda USL Modena CeVEAS<br />
Modena, Mirandola Modena, ITALY, 5 Psychology, University of Florence,<br />
Florence, ITALY, 6 Epidemiology, Cancer Prevention and Research Institute ISPO<br />
Florence, Florence, ITALY<br />
Aims and background: Although Hope is a term widely used, <strong>the</strong> experience of<br />
hope in patients with chronic diseases or even life threatening is often disregarded<br />
due to <strong>the</strong> scarcity of assessment tools carefully crafted and validated. The aim of <strong>the</strong><br />
study was to validate <strong>the</strong> Hope Herth Index (HHI) questionnaire in <strong>the</strong> Italian<br />
population of patients with solid or haematological cancers during oncological active<br />
treatment.<br />
Methods: After <strong>the</strong> translation procedures, <strong>the</strong> psychometric properties of <strong>the</strong> Italian<br />
version of <strong>the</strong> Hope Herth Index (HHI) were evaluated in 266 patients with<br />
non-advanced cancer cared for in four different settings. Summative scores ranged<br />
Annals of Oncology<br />
from 12-48, with a higher score denoting greater hope. Confirmative factorial<br />
analysis to assess dimensionality was performed. The test/retest reliability was<br />
assessed by means of <strong>the</strong> Linn concordance coefficient (two weeks interval, 80<br />
patients). Concurrent validity was assessed through <strong>the</strong> following questionnaires:<br />
Hospital Anxiety and Depression Scale (HADS), Functional Assessment of Chronic<br />
Illness Therapy-Spiritual Well-Being (FACIT-Sp), Edmonton Symptom Assessment<br />
Scale (ESAS) and System Belief Inventory (SBI-15R).<br />
Results: A total of 266 patients were enrolled. Confirmative Factor analysis did not<br />
confirm <strong>the</strong> original three factors solution, whereas a one factor solution did perform<br />
well. Cronbach alpha was 0.84. Test-retest reliability was 0.64 (95% C.I.: 0.51; 0.76).<br />
Large convergence was found with spiritual well being as measured by <strong>the</strong> FACIT-Sp<br />
(0.69) and with anxiety-depression as measured by <strong>the</strong> HADS (inverse correlation:<br />
-0.51). Physical symptoms and religiousness were only slightly correlated, as<br />
expected.<br />
Conclusions: The Italian version of Herth Hope Index (HHI) is a valid and reliable<br />
assessment tool, useful to initiate conversation with someone who is troubled but<br />
finds it difficult to talk, in cancer patients on active oncological treatment during <strong>the</strong><br />
non advanced stage of <strong>the</strong> disease, with ei<strong>the</strong>r solid and haematological cancers.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1603P SERUM PLASMA LEPTIN LEVELS AND LIFE EXPECTANCY<br />
IN CANCER PATIENTS WITH TERMINAL ILLNESS<br />
C. Spoto, M. Iuliani, A. Zoccoli, F. Pantano, F.M. Guida, S. Intagliata, V. Limetti,<br />
B. Vincenzi, G. Tonini and D. Santini<br />
Medical Oncology, University Campus Bio-Medico, Rome, ITALY<br />
Introduction: Excess body fat (assessed by Body Mass Index, BMI) is an established<br />
risk factor in various cancers and high BMI is directly associated with elevated levels<br />
of leptin. Leptin, in addition to its neuroendocrine function involved in <strong>the</strong><br />
regulation of appetite, can act as a mitogen and an angiogenic factor and it seems<br />
also associated with cancer cachexia and chronic inflammation. However, data on <strong>the</strong><br />
association between leptin levels and cancer progression are contradictory and not<br />
definitive. The objective of <strong>the</strong> present prospective study was to investigate <strong>the</strong><br />
relationship between leptin and life expectancy in advanced cancer patients,<br />
regardless of <strong>the</strong> primitive tumor.<br />
Methods: We assessed Palliative Prognostic (PaP)-Score in cancer patients from <strong>the</strong><br />
Medical Oncology Unit at CampusBio-MedicoHospital in Rome. PaP-score ranked<br />
patients into three groups with a different 30-day survival probability (A = 82%; B =<br />
52.7%; C = 9.6% respectively). We enrolled 20 patients for each PaP-Score subgroup.<br />
For each patient, leptin serum levels were measured by ELISA (Enzyme-Linked<br />
ImmunoSorbent Assay) using commercially available kit (R&D System). Statistical<br />
analysis was performed using Mann-Whitney U-test.<br />
Results: The mean leptin serum concentration in PaP-Score C subgroup was<br />
significantly higher compared to PaP-Score A patients subgroup (P = 0.046) with an<br />
increase in mean leptin levels of 115%. No statistically significant difference was<br />
observed in mean leptin serum levels beetwen PaP-Score B vs PaP-Score A patients<br />
(increase of 7%).<br />
Conclusions: This study showed for <strong>the</strong> first time a correlation between leptin serum<br />
levels and life expectancy in end-stage cancer patients according to PaP-Score.<br />
Fur<strong>the</strong>r studies in larger populations are warranted to clarify <strong>the</strong> weight of <strong>the</strong>se<br />
preliminary results.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1604P CASE-CONTROL PHASE II CLINICAL TRIAL TO ASSESS<br />
EFFICACY AND SAFETY, OF THE SAME ANTINEOPLASTIC<br />
TREATMENT(S) IN ELDERLY “FIT” COMPARED TO ADULT<br />
PATIENTS WITH CANCER AT DIFFERENT SITES<br />
G. Mantovani, E. Massa, A. Dessi’, M. Dessi’, L. Orgiano and F.M. Tanca<br />
Department of Medical Oncology, University of Cagliari, Cagliari, ITALY<br />
Background: We designed a case-control phase II open, prospective non-randomized<br />
trial in elderly “fit” (≥65 yo) cancer patients (pts) compared to well-matched adult<br />
(45-65 yo) cancer pts to assess whe<strong>the</strong>r <strong>the</strong> same standard antineoplastic treatment<br />
could achieve comparable results as for efficacy and safety. Planned sample size: 125<br />
pts per arm. Endpoints: safety, QoL, PFS, ORR, dose intensity.<br />
Patients and methods: Only elderly “fit” pts at MGA were included. Inclusion<br />
criteria for elderly: histological diagnosis of cancer with ei<strong>the</strong>r advanced disease with<br />
measurable lesions or radically resected (adjuvant setting); life expectancy >3 mo.;<br />
adequate baseline functional parameters; written informed consent. Inclusion criteria<br />
for adults: <strong>the</strong> same as for elderly plus ECOG-PS 0-1.<br />
Results: At September 2011, 254 pts were enrolled, 127 elderly and 127 adults, all<br />
evaluable for toxicity. Elderly pts clinical characteristics: M/F ratio 69/58; mean age<br />
70.8 ± 4.5 y. Adult pts: M/F ratio, 58/69; mean age 53 ± 5.4 y. Tumor sites: colo-rectal<br />
(23.5%), head and neck (16.4%), breast (14.1%), lung (11.7%), ovarian (9.3%);<br />
prostate (6.2%), NHL (4.7%), gastric (4.7%), liver (4.7%), uterus (3.9%), pancreas<br />
(0.8%); 92.1% of pts were stage IV, 5.9% stage III and 2.0% stage II. In <strong>the</strong> elderly no<br />
ix516 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
grade 4 toxicity were observed, hematological and non hematological grade 3<br />
toxicities were observed in 12.21% and 13.8% of pts, respectively. In <strong>the</strong> adults, grade<br />
4 hematological and non hematological toxicity were observed in 3.8% and 1.9% of<br />
pts, respectively; grade 3 hematological toxicity in 23.2% and non hematological<br />
toxicities in 21.3% of pts. The difference was statistically significant (p = 0.042) in<br />
favor of <strong>the</strong> elderly. At September 2011, 234 pts were assessable for response: <strong>the</strong><br />
ORR was 50.7% for elderly and 51.1% for adults. No differences were observed for<br />
quality of life and dose intensity between <strong>the</strong> two groups. PFS was 10.6 mo. (3-12 +<br />
mo) for elderly and 9.05 mo. (3-12 + ) for adults.<br />
Conclusion: The promising results of this single Institution study warrant to be<br />
confirmed by a larger clinical trial.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1605P OPINIONS OF NURSES ON THE APPLICATION AND<br />
IMPLICATIONS OF DNR/DNI ORDERS<br />
I.C. Glitza 1 , H.J. Conter 1 , R. Turner 2 , S.K. Reddy 3 and E. Bruera 4<br />
1 Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX,<br />
UNITED STATES OF AMERICA, 2 Palliative Care, Albert Einstein Medical Center,<br />
Philadelphia, PA, UNITED STATES OF AMERICA, 3 Department of Palliative Care<br />
and Rehabilitation Medicine, MD Anderson Cancer Center, Houston, TX,<br />
UNITED STATES OF AMERICA, 4 Palliative Care and Rehabilitation Medicine, M.<br />
D. Anderson Cancer Center, Houston, TX, UNITED STATES OF AMERICA<br />
Background: Although do not resuscitate (DNR)/ do not intubate (DNI) orders have<br />
a technically limited mandate, <strong>the</strong> implication of such orders may be broad.<br />
Moreover, <strong>the</strong> patient factors that may influence healthcare providers’ decisions may<br />
be debated. This study aimed to evaluate nurses’ opinions on DNR/DNI orders.<br />
Methods: The study was conducted as an anonymous, single institution survey.<br />
Fulltime nurses (RNs) were identified by payroll and received a questionnaire.<br />
Nurses’ demographics and background, <strong>the</strong>ir rating of factors leading to DNR/DNI<br />
and rating of appropriateness of treatments were obtained.<br />
Results: Of <strong>the</strong> 350 distributed surveys, 83% were returned. Work locations included<br />
general floors (47%), intermediate care (21%) and ICU (32%). Sixty-seven percent<br />
were ≤ 40 years old, 88% were female, and 73% had ≤ 10 years of work experience.<br />
204 RNs felt that DNR/DNI orders influence treatment choices of physicians, 81%<br />
felt <strong>the</strong>y should be more included in <strong>the</strong> discussion process. Female RNs were more<br />
likely to change <strong>the</strong> amount of time spent at bedside (OR 0.32, 95%CI 0.12-0.92) and<br />
<strong>the</strong>y felt that physician’s treatment choices were influenced by DNR orders (OR 0.36,<br />
95% CI 0.17-0.74) compared to males. From an RN view, most important factors<br />
leading to a DNR/DNI order were patients’ wishes (99%), untreated/untreatable<br />
cancer (94%) and quality of life before admission (89%). For less experienced RNs,<br />
<strong>the</strong>re was a general trend to support <strong>the</strong> administration of blood products,<br />
antibiotics, feeding tube placement, invasive procedures, vasopressors, and ICU<br />
transfer. Their support for hemodialysis was <strong>the</strong> only variable that was statistically<br />
significant (OR 1.74, 95% CI 1.03- 2.97). Pooled analysis demonstrated that less<br />
experienced were more likely to support a more agressive treatment approach (OR<br />
1.41, 95%CI 1.17-1.71, i^2= 0%).<br />
Conclusion: Nurses regard patients’ wishes, quality of life, serious diseases as <strong>the</strong><br />
most important factors leading to a DNR/DNI order. Less experienced nurses favor a<br />
more aggressive treatment approach. Nursing staff feel that <strong>the</strong>y should be a vital part<br />
of <strong>the</strong> DNR/DNI discussion. Fur<strong>the</strong>r continuous education of <strong>the</strong> whole health care<br />
team on <strong>the</strong> meaning and implication of DNR/DNI orders is mandated.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1606P PARENTAL CANCER: REVIEWING THE CONCERNS OF<br />
BREAST CANCER PATIENTS WITH CHILDREN<br />
E. Miura and T. Ishida<br />
Child Support, St.Luke’s International Hospital, Tokyo, JAPAN<br />
Background: In recent years, it is estimated that 24% of cancer patients have a child<br />
under 18 years of age. Affected parents may experience heightened distress related to<br />
<strong>the</strong> worries about <strong>the</strong>ir illness as well as <strong>the</strong>ir inability to perform parenting<br />
activities. Many parents also struggle with what and how to tell <strong>the</strong>ir children about<br />
<strong>the</strong>ir own or <strong>the</strong>ir loved one’s illness and future. Since 2008, St. Luke’s International<br />
Hospital (Tokyo, Japan) started a service called “Child Support”, for <strong>the</strong>se patients to<br />
discuss <strong>the</strong>ir concerns, providing <strong>the</strong>m with appropriate suggestions and useful<br />
resources.<br />
Objective: The objective of this research is to review and organize <strong>the</strong> concerns<br />
breast cancer patients with children have, and to review <strong>the</strong> types of support<br />
provided by <strong>the</strong> professionals.<br />
Method: Medical charts of breast cancer patients with under aged children, who<br />
were offered to a child support service between <strong>the</strong> period of April 2010 and<br />
November 2011, were reviewed (n = 172).<br />
Result: 75% of <strong>the</strong> child support sessions started from <strong>the</strong> direct offering by <strong>the</strong><br />
Child Life Specialist (CLS). Nurses were slightly more active in referring <strong>the</strong> patients<br />
to <strong>the</strong> service. 70% of <strong>the</strong> patients’ concerns were topics that directly related to <strong>the</strong>ir<br />
children. The two most common concerns were “confrontation to <strong>the</strong> children about<br />
parent’s illness” (30%), and “how <strong>the</strong> illness will impact <strong>the</strong> child” (40%). While less<br />
than 10% showed absolutely no concern, o<strong>the</strong>rs showed concerns in topics related to<br />
one’s own illness (
1609P PHYSICAL ACTIVITY (PA) AND PHYSICAL FITNESS (PF) IN<br />
LYMPHOMA PATIENTS BEFORE DURING AND AFTER<br />
CHEMOTHERAPY (PAFILP): A PROSPECTIVE<br />
OBSERVATIONAL PILOT-STUDY<br />
P. Wolter 1 , N. Vermaete 2 , D. Dierickx 3 , A. Janssens 3 , P. Schöffski 1 , G. Verhoef 3<br />
and R. Gosselink 2<br />
1 Department of General Medical Oncology, University Hospitals Leuven, Leuven,<br />
BELGIUM, 2 Department of Rehabilitation Sciences, KU Leuven, Leuven,<br />
BELGIUM, 3 Department of Hematology, University Hospitals, Leuven, BELGIUM<br />
Background: We performed a prospective longitudinal single-center pilot study to<br />
investigate physical activity (PA) and physical fitness (PF) in Hodgkin Lymphoma<br />
(HL) and Non-Hodgkin-Lymphoma (NHL) patients before, during and after<br />
first-line systemic chemo<strong>the</strong>rapy. Fur<strong>the</strong>r aims were to correlate different patient-,<br />
disease-, and treatment-related factors with <strong>the</strong> possible decline or increase of PA<br />
and PF and to identify patients at risk of developing a significant decline in PA and<br />
PF who might be candidates for an individualized exercise training program.<br />
Methods: PA was assessed with an activity monitor (Dynaport MiniMod McRoberts,<br />
The Hague, The Ne<strong>the</strong>rlands), PF by incremental cycle ergometry and by a 6 minute<br />
walking test (6MWD). Isometric quadriceps strength was measured using a Cybex II<br />
dynamometer (Lumex, Bay Shore, United States). Pulmonary function tests,<br />
electrocardiogram, echocardiography, blood pressure measurements were routinely<br />
performed.<br />
Results: The pilot study involved a total of 22 lymphoma patients (♂: 19, ♀: 3,<br />
median age 57 years, NHL: 14, HL: 8) from 10/2010 to 01/<strong>2012</strong>. At baseline PA,<br />
6MWD, maximal inspiratory pressure, quadriceps strenght, diffusion capacity at<br />
pulmonary function tests were significantly lower than predicted. In contrast, forced<br />
expiratory volume in one second (FEV1), forced vital capacity (FVC), maximal<br />
oxygen consumption (VO2max), maximal expiratory force and hand grip force were<br />
not significantly different. We observed a broad variation in <strong>the</strong> different test results<br />
between patients at baseline. After 2-3 cycles of chemo<strong>the</strong>rapy we did not identify a<br />
significant decrease in PA, whereas VO2max decreased significantly after 2-3 cycles<br />
but recovered after completion of chemo<strong>the</strong>rapy (6-8 cycles). Importantly, a huge<br />
interpatient variability could be observed at all different time points.<br />
Conclusions: Preliminary results of <strong>the</strong> PAFILP pilot study suggest that levels of PA<br />
and PF probably evolve very differently between lymphoma patients. The study is<br />
ongoing to identify possible risk factors predictive for decline in PA and PF. Such a<br />
screening tool would allow us to identify early in <strong>the</strong> course of treatment patients at<br />
risk of developing a significant decline in PA and PF who might benefit from an<br />
individualized exercise training program.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1610P SURVEY OF OUTPATIENT CANCER CHEMOTHERAPY:<br />
OCCURRENCE OF SIDE EFFECTS AND REASONS FOR<br />
DISCONTINUATION OR DELAY<br />
H. Kushihara 1 , K. Kawada 2 , T. Kushihara 3 , N. Hamajima 4 , M. Amano 4 , K. Ooji 4 ,<br />
K. Honda 2 , F. Nomura 2 , Y. Ikeda 1 and K. Mori 1<br />
1 Pharmacy, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, JAPAN,<br />
2 Medical Oncology, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya,<br />
JAPAN, 3 Pharmacy, Japanese Red Cross Nagoya First Hospital, Nagoya,<br />
JAPAN, 4 Nursing, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya,<br />
JAPAN<br />
Background: In cancer chemo<strong>the</strong>rapy, patients have various side effects. In general, if<br />
patients’ quality of life is negatively affected (e.g., toxicity of grade 3 or higher), <strong>the</strong><br />
treatment will be discontinued. On <strong>the</strong> o<strong>the</strong>r hand, if symptoms are mild or<br />
moderate (e.g., toxicity of grade 2 or lower), <strong>the</strong> treatment will be continued with<br />
supportive <strong>the</strong>rapy. Patients with mild or moderate side effects must tolerate such<br />
adverse effects for a prolonged period. Therefore, to continue chemo<strong>the</strong>rapy safety, it<br />
is very important to understand <strong>the</strong> extent of symptoms and to provide suitable<br />
supportive care as required. We conducted a survey of outpatient cancer<br />
chemo<strong>the</strong>rapy.<br />
Methods: We retrospectively investigated <strong>the</strong> characteristics of side effects and <strong>the</strong><br />
reasons for discontinuation or delay of chemo<strong>the</strong>rapy between July 2009 and March<br />
2011 at Nagoya Daiichi Red Cross Hospital in Japan.<br />
Result: Data on 924 patients (8221 cases) were analyzed. The following data are<br />
presented in <strong>the</strong> order of grade 2 and grade 3 or higher. Nonhematologic toxicities<br />
were constipation (32.0, 0.7%), fatigue (21.3, 2.7%), anorexia (17.0, 0.6%), neuropathy<br />
(15.3, 1.4%), nausea (14.4, 0.6%), pain (13.7, 1.0%), vomiting (7.5, 0.6%), diarrhea<br />
(6.3, 0.2%), dysgeusia (6.0, − %), oral mucositis (4.1, 0.1%), and nail changes (3.6,<br />
0.1%). Hematologic toxicities were neutropenia (16.3, 19.1%), thrombocytopenia (4.1,<br />
2.1%), and anemia (26.1, 7.0%). Nonhematologic toxicities Grade 2 or lower had a<br />
high average incidence of 44.6%. Chemo<strong>the</strong>rapy was discontinued in 1341 patients<br />
(16.3%). The reasons for discontinuation or delay were laboratory abnormalities<br />
(35.4%), chief complaints of patients (34.0%), and o<strong>the</strong>rs (30.1%).<br />
Conclusion: In patients with grade 3 or higher toxicity, appropriate care was<br />
provided, including dose reduction or discontinuation of treatment. In patients with<br />
grade 2 or lower toxicity, treatment tended to be continued. Our results showed that<br />
a large proportion of patients tolerate mild or moderate side effects that do not lead<br />
to discontinuation or delay of treatment. It is necessary to evaluate <strong>the</strong> extent of<br />
symptoms and to provide supportive care from an early stage.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1611P IMPROVING PATIENT ADHERENCE BY USING THE<br />
FLOWCHART TYPE LEAFLET<br />
Annals of Oncology<br />
S. Suzuki 1 , M. Yoshida 1 , Y. Yajima 2 , T. Kobayashi 2 , S. Kobayashi 1 , T. Enokida 2 ,<br />
H. Ishiki 2 , K. Endo 3 , K. Izumi 1 and M. Tahara 4<br />
1 Pharmacy, National Cancer Center Hospital East, Kashiwa, JAPAN, 2 Head and<br />
Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa,<br />
JAPAN, 3 Drug Safety Management, Meiji Pharmaceutical University, Tokyo,<br />
JAPAN, 4 Endoscopy & Gi Oncology, National Cancer Center Hospital East,<br />
Kashiwa, JAPAN<br />
Background: Most information sheets cover <strong>the</strong> schedule of chemo<strong>the</strong>rapy sessions<br />
and <strong>the</strong> adverse reactions of <strong>the</strong> respective drugs. However, <strong>the</strong> leaflets do not<br />
provide enough information instructing <strong>the</strong>m how to take <strong>the</strong>ir supportive<br />
medications while at home for patients that have adverse drug reactions. We have<br />
developed a flowchart type leaflet to help improve <strong>the</strong> patients’ adherence. The<br />
flowchart consisted of yes/no questions to guide how to take supportive medicine for<br />
adverse drug reactions or when patients should call to a hospital.<br />
Objective: This study was designed to evaluate <strong>the</strong> benefits associated with <strong>the</strong><br />
flowchart type leaflet (FC). [Subjects and methods] Subjects include head and neck<br />
cancer inpatients who received induction chemo<strong>the</strong>rapy, TPF (docetaxel, cisplatin,<br />
and 5FU) or TPS (docetaxel, cisplatin, and S-1), from September 2009 to April <strong>2012</strong>.<br />
Group A used FC while Group B did not use FC in <strong>the</strong>ir chemo<strong>the</strong>rapy. A<br />
retrospective study was performed using patient records. The endpoints of this study<br />
were: (1) To determine <strong>the</strong> emergency hospital admissions/visits, (2) To determine<br />
<strong>the</strong> nonadherence, (3) To determine <strong>the</strong> telephone calls from patients.<br />
Results: There were 49 patients and a total of 139 chemo<strong>the</strong>rapy sessions in group A<br />
while <strong>the</strong>re were 60 patients and a total of 163 chemo<strong>the</strong>rapy sessions in group B with<br />
no significant differences in age, performance status, and <strong>the</strong>ir chemo<strong>the</strong>rapy regimen.<br />
The results are: (1) Incidence of emergency hospital admission was significantly lower<br />
in group A compared to group B. (Group A v.s. Group B: 1% v.s. 10%, p < 0.01) (2)<br />
The nonadherence rate in supportive medication for adverse drug reactions due to<br />
chemo<strong>the</strong>rapy was significantly lower in group A than group B (Group A v.s. Group<br />
B: 5% v.s. 23%, p < 0.01). (3) Telephone call rates were statistically significant in group<br />
A (16%, total 30 calls) compared to group B (7%, total 11 calls) in each chemo<strong>the</strong>rapy<br />
regimen. Of <strong>the</strong> 30 telephone calls in group A, 24 calls (80%) were in a situation<br />
where patients needed to call a hospital and 5 calls (45%) in group B.<br />
Conclusions: The FC could contribute to reducing emergency hospital admissions to<br />
prevent nonadherence and encourage patients’ judgments in chemo<strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1612P BREAKTHROUGH PAIN (BTP) IN OPIOID-TOLERANT<br />
CANCER PATIENTS: A PAN-EUROPEAN OPEN-LABEL<br />
MULTICENTRE STUDY WITH FENTANYL BUCCAL TABLET<br />
(FBT)<br />
S. Mercadante 1 , A. Davies 2 , J. Jarosz 3 , U.R. Kleeberg 4 ,T.O’Brien 5 , P. Poulain 6<br />
and H. Schneid 7<br />
1 Anes<strong>the</strong>sia and Intensive Care Unit & Pain Relief and Palliative Care Unit, La<br />
Maddacena Cancer Center, Palermo, ITALY, 2 Palliative Medicine, Royal Surrey<br />
County Hospital NHS Foundation Trust, Guildford, UNITED KINGDOM, 3 Palliative<br />
Medicine Unit, SCMCC and Institute of Oncology, Warsaw, POLAND,<br />
4 Hematology and Medical Oncology, H, Hamburg, GERMANY, 5 Palliative<br />
Medicine, Marymount Hospice, Cork, IRELAND, 6 Palliative Unit, Polyclinique de<br />
l’Ormeau, Tarbes, FRANCE, 7 Medical Affairs EU, Teva Pharmaceutical,<br />
Maisons-Alfort, FRANCE<br />
BTP, a transitory exacerbation of pain that occurs on a background of o<strong>the</strong>rwise<br />
controlled persistent pain, is a common problem in cancer patients. FBT is indicated<br />
for <strong>the</strong> treatment of BTP in adults with cancer already receiving maintenance opioid<br />
<strong>the</strong>rapy for chronic cancer pain and should be titrated to an effective dose that<br />
provides adequate analgesia and minimises undesirable events. In this study, patients<br />
entered a screening period and were randomized during an open-label titration<br />
period to a starting FBT dose of 100 µg (group A) or 200 µg (group B) to identify<br />
<strong>the</strong> FBT effective dose and <strong>the</strong>n treated in an open-label period (for 8 BTP episodes).<br />
Patients’ inclusion followed <strong>the</strong> FBT label. 442 patients were screened from 135<br />
European sites (7 countries) and 330 were enrolled into <strong>the</strong> titration period [group A<br />
(156); group B (174)]. Cancer history of <strong>the</strong> patients: breast (20.3%), lung (14.2%),<br />
colon/rectum (12.1%), o<strong>the</strong>r (24.5%). The most frequent extent of <strong>the</strong> disease was<br />
bone metastasis and local disease, for 45.8% and 40.6% of patients, respectively. 312<br />
(94.5%) received at least one dose of study drug during <strong>the</strong> titration period [group A<br />
(145; 92.9%); group B (167; 96.0%). The effective dose rate (primary outcome) was<br />
75.2% in <strong>the</strong> group A compared to 81.4% in <strong>the</strong> group B with non-inferiority<br />
ix518 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
established. Medication performance was assessed during <strong>the</strong> treatment period using<br />
a 5-point scale (0 = poor to 4 = excellent). Responses at 30 min. and at 60 min. post<br />
dose were “good” to “excellent” for 70.3% (1248/1176 BTP) and 82.4% (1374/1668<br />
BTP) respectively. Patients’ quality of life and functional status [modified Brief Pain<br />
Inventory-short version 7 item subscale (BPI-7S)] improved after treatment with FBT<br />
[BPI-7S global score [mean (SD)] decreased from 39.7 (15.85) before to 31.6 (16.8)<br />
after treatment. The ease of use of FBT was rated “very easy/convenient” and “easy/<br />
convenient” for 82.5% (174/211) of patients. Safety data do not indicate concerns<br />
with use of FBT and were as expected for cancer patients with opioid treatments.<br />
These results demonstrate that FBT was safe and efficacious in a real-world clinical<br />
practice setting with a large number of cancer patients experiencing BTP.<br />
Disclosure: S. Mercadante: Investigator, A. Davies: Investigator, J. Jarosz:<br />
Investigator, U.R. Kleeberg: Investigator, T. O’Brien: Investigator, P. Poulain:<br />
InvestigatorH. Schneid: Teva Pharmaceutical employee.<br />
1613P ACUTE ONCOLOGY SERVICE AND REDUCTION OF<br />
INPATIENT LENGTH OF STAY FOR CANCER PATIENTS. A<br />
REPORT FOR 846 PATIENTS ADMITTED WITH<br />
ONCOLOGICAL EMERGENCIES<br />
A. Mostyn-Jones, L. Burton, M. Keni and M. Karina<br />
Beacon Cancer Centre, Musgrove Park Hospital, Taunton Somerset, UNITED<br />
KINGDOM<br />
Background: The Acute Oncology Service (AOS) has been recommended in <strong>the</strong> UK<br />
since 2008, when <strong>the</strong> National Chemo<strong>the</strong>rapy Advisory Group (NCAG), and <strong>the</strong><br />
National Confidential Enquiry into Patient Outcome and Death (NCEPOD) reported<br />
<strong>the</strong> results of safety and quality in systemic <strong>the</strong>rapy for cancer patients. The National<br />
Patient Safety agency (NPSA) recommended that cancer related emergencies be dealt<br />
in a systematic approach. This abstract refers to <strong>the</strong> data from patients with known<br />
or undiagnosed cancer, admitted in Musgrove Park Hospital (MPH) and referred to<br />
<strong>the</strong> AOS.<br />
Materials and method: We collected <strong>the</strong> data of patients admitted to MPH because<br />
of cancer or treatment-induced complications or undiagnosed cancer. Patients were<br />
referred via <strong>the</strong> inpatient referral system and were registered daily in a purpose built<br />
database. We recorded patients’ demographics, diagnosis, metastatic sites, treatment<br />
type, reason of admission and length of in-hospital stay (LOS).<br />
Results: From June 2010 to April <strong>2012</strong>, 846 patients were admitted with oncological<br />
complications. 48% had multiple metastatic sites, 18% had primary diagnosis of<br />
breast cancer, 19% urological, 16% lung, 24% upper and lower GI cancers and 5% of<br />
unknown primary. Only 1% of patients were referred from A&E department, 28%<br />
from medical assessment unit and 71% from <strong>the</strong> medical wards. 29% of patients were<br />
admitted during <strong>the</strong>ir chemo<strong>the</strong>rapy period, 8% during <strong>the</strong>ir radio<strong>the</strong>rapy treatment,<br />
whereas for 38%, <strong>the</strong> type of treatment was not reported. The reasons of admission<br />
were: Dyspnoea 14%, Neutropenic sepsis 8%, CNS related 9%, metastatic spinal cord<br />
compression 6%, pain 12%, miscellaneous/unclear 51%. Admission was attributed to<br />
cancer and/or treatment in 73% of patients and it was unclear/unknown in 23%. The<br />
number of referrals has increased from 50 for <strong>the</strong> first 2 months to 97, <strong>the</strong> last 2<br />
months. The LOS ranged from 0-102 days and <strong>the</strong> median remained stable at 10<br />
days.<br />
Conclusion: The majority of cancer patients with complications are admitted in<br />
medical wards. This real time audit will be used to re-define <strong>the</strong> appropriate AOS<br />
model. Fur<strong>the</strong>r education, communication, recourses and training are mandatory to<br />
reduce <strong>the</strong> patients’ LOS and develop a cost-efficient service.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1614P OCULAR ADVERSE EFFECTS (OAES) OF MOLECULARLY<br />
TARGETED AGENTS (MTAS) APPROVED IN ONCOLOGY: A<br />
SYSTEMATIC REVIEW<br />
O. Huillard 1 , S. Bakalian 2 , C. Levy 2 , L. Desjardins 2 , L. Lumbroso 2 ,S.Pop 2 ,<br />
M. Sablin 1 , V. Diéras 1 and C. Le Tourneau 1<br />
1 Department of Medical Oncology, Clinical Trial Unit, Institut Curie, Paris,<br />
FRANCE, 2 Department of Ophthalmology, Institut Curie, Paris, FRANCE<br />
Background: MTAs display different toxicity profiles than conventional cytotoxic<br />
agents, with primarily non-hematological toxicity. This study aimed to describe <strong>the</strong><br />
OAEs reported with <strong>the</strong> use of MTAs approved in oncology.<br />
Methods: EMEA and FDA product information files (PIFs) were reviewed including<br />
all MTAs approved in oncology as of January 1st, <strong>2012</strong>. Incidence, severity and types<br />
of OAEs were recorded. OAEs reported in <strong>the</strong>se files were compared to <strong>the</strong> ones<br />
described in <strong>the</strong> publications of <strong>the</strong> trials that led to drug approval.<br />
Results: OAEs were reported in <strong>the</strong> PIFs for 14 out of <strong>the</strong> 16 reviewed MTAs (88%).<br />
44 different types of OAEs were reported in <strong>the</strong> PIFs, 30% and 52% being items<br />
appearing in <strong>the</strong> National Cancer Institute Common Terminology Criteria for<br />
Adverse Events (NCI CTCAE) version 3 and 4, respectively. Common OAEs<br />
occurring with a frequency ranging from 1 to 10% were reported for 75% of MTAs.<br />
The most common reported OAEs were increased lacrimation, dry eye, blurred<br />
vision, ocular hyperemia, eyelash changes, eye pain, eye irritation, eye pruritus, eyelid<br />
irritation, conjunctivitis, eyelid edema, blepharitis, keratitis, periorbital edema,<br />
amblyopia, conjunctival hemorrhage, eye hemorrhage, eye infection, eye edema and<br />
eyelid infection. Serious OAEs (Grade ≥3 or with a warning in <strong>the</strong> PIFs) were<br />
reported for 62.5% of <strong>the</strong> MTAs, and included conjunctivitis, periorbital edema,<br />
keratitis, eyelid edema, blepharitis, papilledema, uveitis, cataract, irititis, episcleritis,<br />
scleritis, corneal perforation, and retinal vein occlusion. All <strong>the</strong>se serious OAEs were<br />
uncommon with a frequency ranging from 0.1% to 1%. Intriguingly, OAEs were<br />
reported in <strong>the</strong> publications of <strong>the</strong> corresponding pivotal trials for only 5 out of <strong>the</strong><br />
14 MTAs for which OAEs were reported in <strong>the</strong> PIFs.<br />
Conclusions: MTAs display frequent and varied OAEs that sometimes clearly lack<br />
precision in <strong>the</strong>ir descriptions. These OAEs can be severe and are not well captured<br />
by <strong>the</strong> NCI CTCAE. Finally, <strong>the</strong>se OAEs are not well reported in <strong>the</strong> publications of<br />
<strong>the</strong> pivotal clinical trials. Efficient collaboration between clinical trial conductors and<br />
ophthalmologists should help defining and handling <strong>the</strong> OAEs occurring in patients<br />
treated with MTAs.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1615P THE IMPACT OF ANEMIA IN ADVANCED SOLID TUMORS<br />
TREATED WITH SORAFENIB (SO) AND SUNITINIB (SU): A<br />
POOLED ANALYSIS OF 6 TRIALS<br />
S. Barni 1 , K.F. Borgonovo 1 , M. Ghilardi 2 , M. Cabiddu 1 , F. Maspero 1 ,<br />
M. Cremonesi 1 and F. Petrelli 1<br />
1 Medical Oncology Division, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio,<br />
ITALY, 2 Medical Oncology Division, A.O. Trevilgio-Caravaggio, Treviglio, ITALY<br />
Introduction: Anemia is a frequent and serious complication experienced by many<br />
cancer patients, especially those receiving chemo<strong>the</strong>rapy. Targeted <strong>the</strong>rapies are<br />
associated with a significant risk of anemia too but this data is often underreported in<br />
clinical trials. We described in a published meta-analysis of 24.310 patients affected by<br />
solid tumours, that <strong>the</strong> addition of targeted <strong>the</strong>rapies to standard treatment increased by<br />
7% <strong>the</strong> risk of all grades anemia (p = 0.09). Now we perform a pooled analysis to<br />
evaluate <strong>the</strong> risk of anemia in patients treated with So and Su as single agent <strong>the</strong>rapy<br />
Materials and methods: We searched PubMed for published, randomized,<br />
controlled, Phase II and III trials (RCTs), and we have performed a pooled-analysis<br />
to calculate <strong>the</strong> incidence of anemia associated with So and Su. Relative risk (RR)<br />
with 95% confidence interval has been calculated to quantify <strong>the</strong> burden of anemia<br />
in <strong>the</strong>se patients.<br />
Results: Six studies have been selected, for a total of 2802 patients analysed. Four<br />
trials included Su and 2 So. Comparison arms were: Axitinib in 1 trial, Bevacizumab/<br />
INF or Bevacizumab/Temsirolimus in 1 trial, placebo in 3 trials and no <strong>the</strong>rapy in 1<br />
trial The overall incidence of anemia was 44% in experimental vs 34% in control<br />
arms (incidence difference 9.8%; p =
patients were admitted to <strong>the</strong> oncology day care unit for 8 hours in order to facilitate<br />
repeated blood testing. Blood samples were obtained before <strong>the</strong> injection of LMWH<br />
and 1, 2, 3, 4, 6 and 8 hours after LMWH subcutaneous administration, and tested<br />
for anti Xa activity as a surrogate marker of bioavailable LMWH levels. The trial was<br />
approved by <strong>the</strong> ethics committee of Shaare Zedek Medical Center. ClinicalTrials.gov<br />
Identifier: NCT00716898. Study funding: Israel Cancer Association.<br />
Results: Eleven patients were enrolled; one was excluded from analysis due to<br />
complete remission at time of VTE diagnosis. Peak anti Xa activity was achieved<br />
after 2, 3, 4, 6, and 8 hours in 2, 3, 2, 2, and 1 patient respectively. 60% of <strong>the</strong><br />
patients (n = 6) did not reach <strong>the</strong> <strong>the</strong>rapeutic anti Xa activity target (0.6 -1.0 IU/ml)<br />
at 4 hours after subcutaneous administration of LMWH. Average anti Xa activity at 4<br />
hours was 0.62 ± 0.29 IU/ml as opposed to 1.1 IU/ml in historical controls of<br />
non-oncology patients.<br />
Conclusions: Our results show that a substantial number of cancer patients suffering<br />
from VTE and treated with standard dose enoxoparin do not reach <strong>the</strong>rapeutic target<br />
anti Xa activity. If confirmed in a larger study, our results suggests that cancer<br />
patients suffering from VTE should be tested for anti Xa activity and LMWH dose<br />
should be titrated accordingly in order to achieve effective anticoagulation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1617 EDMONTON SYMPTOM ASSESSMENT SCALE (ESAS) FOR<br />
ROUTINE SYMPTOM ASSESSMENT OF NON-ADVANCED<br />
PATIENTS WITH SOLID OR HAEMATOLOGICAL<br />
MALIGNANCIES ON ONCOLOGICAL THERAPIES<br />
C.I. Ripamonti1 , S. Boldini2 , L. Buonaccorso3 , E. Bandieri4 , A. Maruelli5 ,M.<br />
A. Pessi6 and G. Miccinesi7 1<br />
Supportive Care in Cancer Unit, Fondazione IRCCS - Istituto Nazionale dei<br />
Tumori, Milano, ITALY, 2 Supportive Care in Cancer, Fondazione IRCCS, Istituto<br />
Nazionale dei Tumori Milano, Milano, ITALY, 3 Psychology, AMO Association of<br />
Oncological Patients from nine towns and villages in <strong>the</strong> Nor<strong>the</strong>n Area of<br />
Modena, Mirandola, ITALY, 4 Oncological Unit, Azienda USL Modena CeVEAS<br />
Modena, Mirandola Modena, ITALY, 5 Psychology Unit, LILT and Centre for<br />
Oncological Rehabilitation CERION of Florence, Firenze, ITALY, 6 Supportive Care<br />
in Cancer, Fondazione IRCCS, Istituto Nazionale Tumori, Milano, ITALY,<br />
7<br />
Epidemiology, Cancer Prevention and Research Institute ISPO Florence,<br />
Florence, ITALY<br />
The Edmonton Symptom Assessment Scale (ESAS) was developed for use in daily<br />
symptom assessment of palliative care patients. We used <strong>the</strong> ESAS validated version in<br />
Italian Language to assess <strong>the</strong> presence and intensity of symptoms (not at all = 0; mild<br />
1-4, not controlled ≥5) in 108 patients with solid and 86 with haematologic malignancies<br />
and no metastases, on active oncological treatments (156 patients) or during follow-up.<br />
In haematologic group, dyspnoea was ≥ 5 in 12% of <strong>the</strong> patients in respect to 3% of solid<br />
tumour group (chi2 test, p = 0.002). Not controlled fatigue, drowsiness and dyspnoea<br />
were significantly more frequent in patients on cure (p = 0.041; p = 0.026; p = 0.010<br />
respectively). The intensity of all <strong>the</strong> symptoms was higher in patients with a KPS of<br />
70-90 in respect to those with KPS > 90, and in patients above <strong>the</strong> clinical HADS cutoff<br />
(10/11) in respect to those below. The intensity of psychological suffering was higher for<br />
patients who requested psychological support. The correlation (rho of Pearson) between<br />
<strong>the</strong> anxiety and depression items of ESAS with HADs was >.5, whereas <strong>the</strong> feeling of<br />
well- being in ESAS inversely strongly correlated with all <strong>the</strong> o<strong>the</strong>r ESAS symptoms (rho<br />
> .4); anorexia with nausea and drowsiness; drowsiness with fatigue; and anxiety with<br />
depression. As <strong>the</strong> ESAS assesses <strong>the</strong> most frequent symptoms referred to by <strong>the</strong> patients<br />
during oncological treatments, its administration to <strong>the</strong> patients in <strong>the</strong> routine practice<br />
before each visit with <strong>the</strong> oncologist can give him/her <strong>the</strong> information on <strong>the</strong> presence<br />
and intensity of physical and emotional symptoms.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1618 IN VITRO DRUG-DRUG INTERACTION STUDIES WITH THE<br />
ANTIEMETIC DRUG NETUPITANT AND ITS MAJOR<br />
METABOLITES M1 AND M2, INVOLVING SEVERAL HUMAN<br />
CYTOCHROME P450 ISOENZYMES<br />
C. Giuliano 1 ,E.Lovati 1 , C. Funk 2 , M. Potthast 2 and C. Pietra 1<br />
1 Preclinical R&D, Helsinn Healthcare SA, Lugano, SWITZERLAND, 2 Non-clinical<br />
Drug Safety, Hoffmann La-Roche Ltd., Basel, SWITZERLAND<br />
Introduction: Nausea and emesis are significant adverse events of chemo<strong>the</strong>rapy.<br />
Substance P plays a major role in <strong>the</strong> emetic process especially in <strong>the</strong> delayed emesis<br />
occurring 24h after treatment and beyond. Antagonism of substance P effect at <strong>the</strong><br />
neurokinin 1 (NK1) receptor level is a validated target in showing a broad antiemetic<br />
activity in animal models of emesis and also in humans. Within <strong>the</strong> new NK1<br />
antagonists in clinical trials, Netupitant (Netu) has been characterized as an<br />
antiemetic in vitro and in vivo in various pharmacological experiments against<br />
emesis induced by chemo<strong>the</strong>rapeutics. In vitro studies have shown that <strong>the</strong> CYP3A4<br />
isoenzyme is <strong>the</strong> major enzyme involved in <strong>the</strong> oxidative metabolism of Netu.<br />
Methods: The in vitro inhibition potential of Netu and its major metabolites M1 and<br />
M2 has been studied for <strong>the</strong> human cytochrome P450 isoenzymes CYP1A2, 2C9,<br />
2C19, 2D6 and 3A4 utilizing human liver microsomes and isoform selective<br />
substrates.<br />
Results: Netu inhibited <strong>the</strong> CYP3A4-dependent metabolism of <strong>the</strong> two isoform<br />
selective probe-substrates midazolam and testosterone with estimated IC 50 (±S.E.)<br />
values of 5.9 ± 1 and 1.7 ± 0.2 µM, respectively. For <strong>the</strong> hydroxylation of diclofenac,<br />
catalyzed by CYP2C9, IC50 (±S.E.) of 18.0 ± 6 and 22.6 ± 3 µM were calculated in two<br />
different experiments, utilizing both <strong>the</strong> free base, and <strong>the</strong> Netu hydrochloride as<br />
inhibitors. Netu showed no significant inhibition potential for CYP1A2, 2C19 and<br />
2D6 (IC 50s >100 µM).<br />
Conclusions: Significant metabolic drug-drug interactions in human are not<br />
anticipated for compounds metabolized mainly by CYP1A2, 2C19 and 2D6 and are<br />
very unlikely for CYP2C9 metabolized drugs based on <strong>the</strong> expected human plasma<br />
concentration of Netu in <strong>the</strong> low μmolar range. However, metabolic drug-drug<br />
interactions are possible for co-medicated drugs metabolized mainly by CYP3A4,<br />
based on <strong>the</strong> high in vitro affinity of Netu for this isoenzyme, as tested with<br />
testosterone and midazolam (app Ki ∼ 1.1 to 2.2 µM) and for <strong>the</strong> inhibition potential<br />
of <strong>the</strong> metabolites M1 and M2 similar to <strong>the</strong> parent compound. The in vivo CYP3A4<br />
interaction has been studied in appropriate designed clinical interaction studies.<br />
Disclosure: C. Giuliano: Helsinn healthcare employee, E. Lovati: Helsinn Healthcare<br />
employee, C. Funk: Roche employee, M. Potthast: Roche employee, C. Pietra: Helsinn<br />
employee.<br />
1619 CILASTATIN ATTENUATES CISPLATIN-INDUCED<br />
NEPHROTOXICITY WITHOUT COMPROMISING<br />
ANTITUMORAL ACTIVITY<br />
Annals of Oncology<br />
B. Humanes1 , M. Blanco Codesido2 , A. Lázaro1 , S. Camaño1 and A. Tejedor1 1<br />
Nephrology, Hospital General Universitario Gregorio Marañón, Madrid, SPAIN,<br />
2<br />
Servicio de Oncología Médica, Hospital General Univ. Gregorio Marañon,<br />
Madrid, SPAIN<br />
Introduction: Cisplatin (CDDP) is a very effective and common treatment in solid<br />
malignancies used mostly in breast, ovarian, bladder, esophageal, gastric, head and<br />
neck cancer and germ cell tumors. One of <strong>the</strong> most important side effects of CDDP<br />
is <strong>the</strong> nephrotoxicity, especially with CDDP doses higher than 60 mg/m2, affecting as<br />
much as 30% of <strong>the</strong> patients. Nephrotoxicity is a limitating side effect on treatment<br />
with CDDP, preventing patients with limit kidney function of receiving <strong>the</strong> drug and<br />
stopping treatment once kidney function has worsened. Cilastatin (Cls) is a specific<br />
inhibitor of renal dedydrodipeptidase I (DHP-I) which prevents hydrolysis of<br />
imipenem and its accumulation in <strong>the</strong> proximal tubule. In this work we hypo<strong>the</strong>sized<br />
that Cls acts as a nephroprotector against CDDP-induced damage without<br />
compromising antitumor activity.<br />
Methods: Primary cultures of proximal tubular cells (PTCs) and cell lines of different<br />
malignancies (colon, breast, ovarian, bladder) were cultured with different<br />
concentrations of CDDP (1, 10 and 30 µM) in <strong>the</strong> presence or absence of Cls. Cell<br />
viability was assessed with MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5diphenyltetrazolium<br />
bromide) assay. Raft staining was measured with toxine B<br />
choleric and FasL by confocal microscopy.<br />
Results: Cls interfered with CDDP-induced FasL signalling at raft level on PTCs<br />
brush border. Concomitant treatment with Cls reduced CDDP-induced changes.<br />
Several tumoral cell lines were tested with CDDP and Cls toge<strong>the</strong>r. Cls did not<br />
increase or decreased tumor growth alone or in combination with CDDP. CDDP<br />
sensitivity was not affected by Cls.<br />
Conclusion: By binding a DHP-I, Cls blocks CDDP-induced PTCs apoptosis but it<br />
does not affect <strong>the</strong> CDDP antitumoral activity. Our findings suggest that <strong>the</strong> affinity<br />
of Cls for renal DHP-I makes this effect specific for proximal tubular cells and may<br />
be related to a reduction in intracellular drug accumulation. Cls administration might<br />
represent a novel strategy in <strong>the</strong> prevention of CDDP-induced acute renal injury. Cls<br />
treatment could potentially increase <strong>the</strong> number of patients undergoing CDDP<br />
treatment or maintaining treatment. Fur<strong>the</strong>r clinical trials for renal function<br />
preservation in cancer patients are on development.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1620 WEIGHT LOSS DESPITE ORAL GLUTAMINE<br />
SUPPLEMENTATION PREDICTS POOR PROGNOSIS IN<br />
LOCALLY ADVANCED NON-SMALL CELL LUNG CANCER<br />
PATIENTS TREATED WITH CONCURRENT<br />
CHEMORADIOTHERAPY<br />
C. Parlak 1 , S. Topuk 1 , O. Ozyilkan 2 and E. Topkan 1<br />
1 Department of Radiation Oncology, Baskent University Adana Medical Faculty,<br />
Adana, TURKEY, 2 Medical Oncology, Baskent University Faculty of<br />
MedicineAdana Uygulama Ve Arastirma Mer., Adana, TURKEY<br />
Background: In this retrospective study, we investigated potential impact of weight<br />
change according to oral glutamine supplementation (GLT) on survival in patients<br />
with stage IIIB non-small cell lung cancer (NSCLC) treated with concurrent<br />
chemoradio<strong>the</strong>rapy.<br />
ix520 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
Table: 1620 Survival results according to glutamine supplementation (GLT) and wieght loss (WL)<br />
GLT- and KK+ GLT- and KK- GLT+ and KK+ GLT+ and KK- P-value<br />
Median OS Months) (95%CI) 15.7 (11.8-19.6) 21,7 (12.1-31.3) 13.5 (9.8-17.2) Not reached yet
Dicarbamin 100 mg/day on day 5 before chemo<strong>the</strong>rapy administration. Treatment<br />
with Dicarbamin continued for all treatment period. 34 patients of control group<br />
(202 cycles of chemo<strong>the</strong>rapy) were not giver any prophylaxis of neutropenia.<br />
Neutropenia was evaluated with Common Toxicity Criteria, Version 3.0.<br />
Results: Median age was 48 (29 – 55). Grade 4 neutropenia was reported in 6<br />
(14.2%) patients treated with Dicarbamin and in 11 (32.3%) patients treated without<br />
Dicarbamin. The beneficial effect of Dicarbamin was also demonstrated by a quick<br />
recovery of granulocytes levels than in controls. In 15 (35.7%) patients treated with<br />
Dicarbamin granulocytes levels were normal all period of chemo<strong>the</strong>rapy. The dose<br />
intensity of chemo<strong>the</strong>rapy was more in group with Dicarbamin prophylaxis. The<br />
toxicity of Dicarbamin was not observed.<br />
Conclusions: Dicarbamin is an active agent for prophylaxis of neutropenia without<br />
specific toxicity.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1624 NEXT AND VENICE: DESIGN OF TWO MULTICENTRE, PHASE<br />
IV, PROSPECTIVE, LONGITUDINAL STUDIES EVALUATING<br />
THE SAFETY PROFILE OF A BIOSIMILAR FILGRASTIM IN<br />
PATIENTS TREATED WITH CYTOTOXIC CHEMOTHERAPY<br />
S. Fruehauf 1 , C. Berthou 2 , S. Lepretre 3 , L. Cals 4 , F. Maloisel 5 and D. Kamioner 6<br />
1 Haemato/Onkologie, Paracelsus Klinik Center for Tumor Diagnostics and<br />
Therapy, Osnabrück, GERMANY, 2 Département d’Clinique Hématologie, Hôpital<br />
Morvan, Brest, FRANCE, 3 Département D’Hématologie, 3Centre Henri<br />
Becquerel, Rouen, FRANCE, 4 Department of Medical Oncology, CHRU de<br />
Besançon, Besançon, FRANCE, 5 Department of Hematology and Oncology,<br />
Clinique Saint Anne, Strasbourg, FRANCE, 6 Oncologue Médical et<br />
Hématologue, Hôpital Privé de l’Ouest Parisien, Trappes, FRANCE<br />
Introduction: Nivestim is a European Union (EU)-licensed biosimilar filgrastim<br />
used in <strong>the</strong> treatment of chemo<strong>the</strong>rapy-induced neutropenia and febrile neutropenia.<br />
Nivestim has similar pharmacokinetic and pharmacodynamic properties to its<br />
reference compound Neupogen®, and has demonstrated equivalent safety and efficacy<br />
in clinical trials. However, <strong>the</strong> safety of biosimilars in general is closely scrutinised.<br />
We present designs for two observational phase IV studies that will examine <strong>the</strong><br />
safety profile of prophylactic and curative Nivestim in patients treated with<br />
cytotoxic chemo<strong>the</strong>rapy in real-world clinical-practice.<br />
Method: NEXT (Tolérance de Nivestim chez les patients traités par une<br />
chimiothérapie anticancéreuse cytotoXique en praTique courante) and VENICE<br />
(VErträglichkeit von NIvestim unter zytotoxischer Chemo<strong>the</strong>rapie in der<br />
Behandlung malinger Erkrankungen) are multicentre, prospective, longitudinal,<br />
observational studies that aim to monitor 2000 adult and 700 adult and paediatric<br />
patients respectively 12 months. The primary objective of <strong>the</strong> studies is to assess <strong>the</strong><br />
safety of Nivestim in patients undergoing cytotoxic chemo<strong>the</strong>rapy for malignancy<br />
through <strong>the</strong> evaluation of adverse events in all organ system classes, as required by<br />
EU pharmacovigilance guidelines. Secondary objectives include obtaining data on<br />
efficacy outcomes, lab values, patterns of use of Nivestim, dose intensity,<br />
indications for treatment, patient characteristics, physician knowledge of filgrastim<br />
prescribing, and <strong>the</strong> reasons for choosing Nivestim. VENICE will also include data<br />
on levels of CD34+ cells to assess predictive value as a marker of response. Data will<br />
be ga<strong>the</strong>red over 3 patient visits: 1) inclusion visit, 2) first follow-up after first course<br />
of Nivestim, and 3) second follow-up after completion of chemo<strong>the</strong>rapy.<br />
Results: Accrual figures as of 1 May <strong>2012</strong> are 630 (NEXT) and 136 (VENICE).<br />
Completion dates are June 2013 and June 2014 respectively.<br />
Conclusion: Data from NEXT and VENICE will provide additional information on<br />
<strong>the</strong> long-term safety and efficacy of Nivestim in patients receiving cytotoxic<br />
chemo<strong>the</strong>rapy in clinical practice.<br />
Disclosure: S. Fruehauf: Receiving support from Hospira for <strong>the</strong> conduct of <strong>the</strong><br />
VENICE study, C. Berthou: Receives support from Hospira for <strong>the</strong> conduct of <strong>the</strong><br />
NEXT study, S. Lepretre: Receives support from Hospira for <strong>the</strong> conduct of <strong>the</strong><br />
NEXT study, L. Cals: Received support from Hospira for <strong>the</strong> conduct of <strong>the</strong> NEXT<br />
study, F. Maloisel: Receive support from Hospira for <strong>the</strong> conduct of <strong>the</strong> NEXT study,<br />
D. Kamioner: Receives support from Hospira for <strong>the</strong> conduct of <strong>the</strong> NEXT study.<br />
1625 NEUTROPENIA IN LUNG CANCER PATIENTS TREATED WITH<br />
CHEMOTHERAPY IN A ROUTINE CLINICAL PRACTICE – AN<br />
INSTITUTIONAL EXPERIENCE<br />
N.T. Hitij 1 , K. Mohorcic 1 , A. Sadikov 2 and T. Cufer 1<br />
1 Department of Medical Oncology, University Clinic Golnik, Golnik, SLOVENIA,<br />
2 Department of Artificial Intelligence, Faculty of Computer and Information<br />
Science Ljubljana, Ljubljana, SLOVENIA<br />
Background: Febrile neutropenia (FN) is a serious complication of chemo<strong>the</strong>rapy<br />
(ChT). Lung cancer patients are fragile with much comorbidity mostly receiving<br />
intermediate FN (iFN) risk ChT schemas and primary prophylaxis with granulocyte<br />
colony-stimulating factors (ppG-CSF) should be used in a majority of pts according<br />
to recommendations. A routine use of ppG-CSF in clinical practice seems to be<br />
variable. Therefore, we conducted a retrospective analysis of lung cancer pts treated<br />
with ChT in a routine clinical practice at University Clinic Golnik (2009-2011),<br />
estimating <strong>the</strong> rate and severity of neutropenia, <strong>the</strong> rate of FN and treatment<br />
strategies.<br />
Patients and methods: A typical collective of 190 pts with advanced lung cancer<br />
(SCLC 29% and NSCLC 71%) treated with ChT alone were included. Most pts<br />
received platinum based ChT (cisplatin 64.7%, carboplatin 20.0%), only 15.3%<br />
received o<strong>the</strong>r ChT schemas. For most of <strong>the</strong> pts it was first line ChT (86.8%).<br />
Majority of <strong>the</strong> pts received 6 cycles of ChT (46.3%), 53.7% of pts received 2-6<br />
cycles. Only one patient received ppG-CSF.<br />
Results: Neutropenia at any time during ChT was recorded in 100/190 (52.6%) of<br />
pts, in 60/190 (31.6%) of pts it was grade 3 or 4. FN was recorded in 16/190 (8.4%)<br />
of pts. Mostly, neutropenia developed after <strong>the</strong> first three cycles of ChT (76.0%). One<br />
patient died due to FN. There was no correlation between occurrence of neutropenia<br />
and cisplatin- vs. carboplatin- based ChT, nor <strong>the</strong> line of ChT. Secondary<br />
prophylactic G-CSF was used in 14/190 (7.4%) of pts, 8 of <strong>the</strong>m received G-CSF after<br />
<strong>the</strong> episode of FN, and 6 of <strong>the</strong>m due to higher grade neutropenia without FN. All<br />
pts with FN received standard antibiotic treatment, while secondary prophylaxis with<br />
G-CSF has not been initiated in 8 pts due to <strong>the</strong> dose reduction in following cycles<br />
and death in one case. No patient suffered from recurrent FN episode.<br />
Conclusion: Despite a negligible use of ppG-CSF in our collective of pts a very low<br />
rate of FN (8.4%) was observed. Due to retrospective nature of <strong>the</strong> analysis we<br />
certainly might have missed some cases of FN, less likely <strong>the</strong>re were some major<br />
complications due to missed FN. Based on this retrospective analysis we cannot<br />
neglect <strong>the</strong> use of ppG-CSF in lung cancer patients receiving iFN risk ChT, though,<br />
<strong>the</strong> actual proportion of patients needing ppG-CSF is questionable.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1626 CHLORHEXIDINE FOR THE PREVENTION OF BLOODSTREAM<br />
INFECTION (BSI) ASSOCIATED WITH PERMANENTLY<br />
IMPLANTABLE VENOUS PORTS (PORT-A) IN SOLID CANCER<br />
PATIENTS: A PROSPECTIVE COHORT STUDY<br />
H. Kao 1 , I. Chen 1 , S. Chang 2 , M. Hong 2 , S. Chien 3 ,F.Hu 4 , C. Hsu 5 and K. Yeh 6<br />
1 Department of Oncology, National Taiwan University Hospital, Yun-Lin Branch,<br />
Yunlin, TAIWAN, 2 Department of Nursing, National Taiwan University Hospital,<br />
Taipei, TAIWAN, 3 Center for Infection Control, National Taiwan University<br />
Hospital, Taipei, TAIWAN, 4 Graduate Institute of Clinical Medicine, National<br />
Taiwan University College of Medicine, Taipei, TAIWAN, 5 Department of<br />
Oncology, National Taiwan University Hospital, Taipei, TAIWAN, 6 Oncology Dept.,<br />
National Taiwan University Hospital, Taipei, TAIWAN<br />
Background: Chlorhexidine can prevent surgical wound infection and BSI related to<br />
central venous ca<strong>the</strong>ters, but its effects on preventing BSI associated with Port-A use<br />
in cancer patients remain obscure.<br />
Methods: Solid cancer patients who were implanted with a Port-A since Dec 2010 at<br />
our department for systemic anti-cancer <strong>the</strong>rapies were prospectively followed for <strong>the</strong><br />
occurrence of Port-A-associated BSI (PABSI), defined as BSI without o<strong>the</strong>r<br />
identifiable infection foci. All patients used chlorhexidine for Port-A topical care.<br />
The time to first PABSI in this cohort was compared with a previous cohort for<br />
whom iodine was used as topical anti-septic. Risk factors of PABSI were analyzed by<br />
Cox proportional hazards model.<br />
Results: The baseline characteristics of <strong>the</strong> two cohorts were similar (table). The<br />
PABSI incidence was 0.740 and 1.051 per 1000 ca<strong>the</strong>ter-day for <strong>the</strong> chlorhexidine<br />
and <strong>the</strong> iodine cohorts, respectively. The use of chlorhexidine can significantly delay<br />
<strong>the</strong> time to first Gram-positive-cocci (GPC) PABSI (hazard ratio (HR) 0.41, 95% CI<br />
0.20-0.84, p = 0.015). O<strong>the</strong>r Independent predictors of increased GPC PABSI<br />
occurrence included previous chemo<strong>the</strong>rapy (HR = 13.65, 95% CI = 4.12-45.26), total<br />
parental nutrition (HR =5.17, 95% CI = 2.51-10.63), chronic steroid use (HR = 7.02,<br />
95% CI = 2.60-18.90), and postoperative antibiotics (HR = 2.06, 95% CI = 1.02-4.14).<br />
Chlorhexidine had no significant effects on preventing Gram-negative bacilli or<br />
fungal PABSI.<br />
Conclusion: The use of chlorhexidine as topical anti-septic may help prevent<br />
GPC-related PABSI in cancer patients.(supported by grants NTUH 100-S1805)<br />
Iodine chlorhexidine p value<br />
Enrollment Oct 2009-Aug 2010 Dec 2010-Nov 2011<br />
N 396 487<br />
M/F 202/194 242/245 0.697<br />
median age 57.7 59.1 0.121<br />
Cancer type 0.892<br />
GI 169 209<br />
Lung 115 129<br />
Breast 46 71<br />
H&N cancer + NPC 20 26<br />
O<strong>the</strong>rs 46 52<br />
N of stage IV 324 (0.82) 376 (0.77) 0.136<br />
Total ca<strong>the</strong>ter-day 81752 99977<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Annals of Oncology<br />
ix522 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
1627 RETROSPECTIVE ANALYSIS OF CANCER AND<br />
CHEMOTHERAPY INDUCED ANAEMIA TREATED WITH<br />
FERRIC CARBOXYMALTOSE ONLY, AN INTRAVENOUS IRON<br />
THERAPY<br />
B. Tschechne 1 , S. Broszeit-Luft 2 , O. Harlin 3 , W.O. Jordan 2 and H. Zakaria 4<br />
1 Haematologisch-Onkologische Praxis Neustadt, Neustadt a. Rbge., GERMANY,<br />
2 Haematologisch-Onkologische Praxis Lehrte, Lehrte, GERMANY, 3 Vifor Pharma<br />
Deutschland GmbH, München, GERMANY, 4 NewConceptOncology GmbH,<br />
Lehrte, GERMANY<br />
Chemo<strong>the</strong>rapy induced anaemia is often treated with ESAs and/or blood<br />
transfusions. Oral or intravenous iron substitution represent alternatives for both<br />
cancer and chemo<strong>the</strong>rapy induced anaemia. Current discussions focus on<br />
intravenous treatment to increase Hb levels in cancer patients, as oral treatments are<br />
often associated with limited response rates and gastrointestinal side effects. This<br />
retrospective, single centre analysis investigates <strong>the</strong> effectiveness of an iv iron<br />
compound, ferric carboxymaltose (Ferinject® [FCM]) as <strong>the</strong> only anaemia treatment<br />
in an unselected, routinely treated anaemic cancer patient population between 2009<br />
and <strong>2012</strong>. Patients fulfilling <strong>the</strong> following criteria were included in <strong>the</strong> analysis:<br />
malignant cancer diagnosis, anaemia, FCM treatment ≧ 4 weeks, complete available<br />
documentation ≧ 12 weeks, no ESA or o<strong>the</strong>r iron medication and no blood<br />
transfusion during <strong>the</strong> observation period. At baseline, sex, age, tumour history,<br />
anti-tumour treatment and history of anaemia treatment during <strong>the</strong> four weeks prior<br />
<strong>the</strong> retrospective analysis were recorded. Modalities of FCM treatment and serum<br />
levels of available relevant laboratory parameters (e.g. Hb, transferrin saturation<br />
[TSAT], ferritin, haematocrit) were recorded at baseline and throughout <strong>the</strong><br />
observation period. Treatment response, tolerability and adverse reactions for a total<br />
of 59 cancer patients were investigated. The median age was 61 (20-91) years, of<br />
<strong>the</strong>se 14 were male and 45 female. During <strong>the</strong> FCM <strong>the</strong>rapy, 52 patients were not<br />
treated actively for cancer and 7 patients were on anticancer treatment. Median Hb<br />
increase was 2.0 g/dl compared to baseline (range: 0 to 6.2 g/dl). Patients received on<br />
average 336 mg iron (range: 100-1700mg). No adverse events related to FCM were<br />
recorded. The results of our retrospective analysis demonstrate <strong>the</strong> safety and<br />
effectiveness of FCM <strong>the</strong>rapy in correction of anaemia in cancer patients prior,<br />
during or after completed chemo<strong>the</strong>rapy. More long-term data on FCM exposure in<br />
cancer patients with iron deficiency are needed in order to characterize which<br />
patients benefit most from this <strong>the</strong>rapy and to determine optimal dosing and<br />
frequency of FCM use.<br />
Disclosure: B. Tschechne: I am a member of <strong>the</strong> Advisory Board of Vifor Pharma<br />
DeutschlandO. Harlin: employee of Vifor Pharma GermanyH. Zakaria: The data<br />
analysis shown was sponsored by Vifor Pharma DeutschlandAll o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
1628 ANEMIA POINT PREVALENCE IN PATIENTS RECEIVING<br />
CHEMOTHERAPY IN 56 CENTERS IN ITALY AND AUSTRIA<br />
L. Merlini 1 , G. Carteni 2 , S. Iacobelli 3 , C. Stelitano 4 , M. Airoldi 5 , P. Balke 6 , F. Keil 7 ,<br />
F. Haslbauer 8 , L. Belton 9 and B. Pujol 10<br />
1 Medical Oncology, Ospedale Civile S. Bortolo, Vicenza, ITALY,<br />
2 Onco-Hematology, Azienda Ospedaliera Cardarelli, Napoli, ITALY, 3 Medical<br />
Oncology, Ospedale Clinicizzato SS.Annunziata, Chieti, ITALY, 4 Hematology,<br />
Azienda Ospedaliera Bianchi Melacrino Morelli, Reggio Calabria, ITALY, 5 Medical<br />
Oncology, Azienda Ospedaliero Universitaria Le Molinette, Torino, ITALY, 6 1st<br />
Medical Department, General Hospital St. Pölten and Karl Landsteiner Institute of<br />
Oncology, St. Pölten, AUSTRIA, 7 Hematology-Oncology, Landeskrankenhaus<br />
Leoben, Leoben, AUSTRIA, 8 Internal Medicine, Landeskrankenhaus<br />
Vöcklabruck, Vöcklabruck, AUSTRIA, 9 Biostatistics, Amgen Ltd, Uxbridge,<br />
UNITED KINGDOM, 10 Haematology/Oncology, Amgen Europe, Zug,<br />
SWITZERLAND<br />
Purpose: To evaluate <strong>the</strong> point prevalence of anemia in patients with non-myeloid<br />
tumors being treated with chemo<strong>the</strong>rapy (±radio<strong>the</strong>rapy) in a clinical practice setting.<br />
Methods: This was a cross-sectional, observational survey. Centers had to prespecify<br />
a single day, during a 4-month enrollment window, to report specific data collected<br />
as part of normal clinical practice for patients attending in relation to chemo<strong>the</strong>rapy<br />
treatment. Data for all centers/consenting patients were included in <strong>the</strong> analyses. The<br />
primary endpoint was <strong>the</strong> point prevalence of anemia as determined using a<br />
prespecified algorithm, which defined a patient as anemic based on 1) hemoglobin<br />
(Hb) ≤10 g/dL on/within 3 days prior to visit, 2) ongoing anemia treatment at visit,<br />
or 3) physician diagnosis of anemia toge<strong>the</strong>r with ≥1 anemia symptom at visit.<br />
Reasons for visit, patient demography, tumor type, systemic chemo<strong>the</strong>rapy, Hb levels,<br />
and consequences of anemia, were secondary endpoints. Patients provided informed<br />
consent where required by local regulations.<br />
Results: Between 18/11/2010-18/3/2011, data for 1412 patients were collected (Italy n<br />
= 1130 [80%]; Austria n = 282 [20%]). Of <strong>the</strong>se, 49% were men, median age was 65<br />
years and most (80%) had solid tumors (colorectal: 18%; breast: 18%; lung: 14%;<br />
prostate: 3%; o<strong>the</strong>r solid tumors: 28%). Overall, 57% of patients had received ≤3<br />
chemo<strong>the</strong>rapy cycles. The point prevalence of anemia was 32% (95% CI: 29.4%, 34.2%);<br />
14% of patients were deemed anemic based on Hb levels ≤10 g/dL, 9% based on<br />
evidence of anemia treatment and 8% based on physician assessment of anemia<br />
toge<strong>the</strong>r with ≥1 anemia symptom. Overall, 82% of patients had Hb data; <strong>the</strong> mean<br />
(SD) Hb level was 11.7 (1.7) g/dL. 32% of patients had anemia symptoms, <strong>the</strong> most<br />
common were fatigue (28%), depression (9%) and dyspnea (8%). Few patients (4%) had<br />
had <strong>the</strong>ir current chemo<strong>the</strong>rapy cycle delayed due to anemia. On visit day or ≤28 days<br />
prior, 6% of patients had evidence of whole blood or red blood cell transfusion, 13%<br />
had evidence of erythropoiesis-stimulating agent use and 6% had evidence of iron use.<br />
Conclusions: In this survey one-third of patients with non-myeloid tumors<br />
undergoing chemo<strong>the</strong>rapy were found to be anemic on <strong>the</strong> prespecified study day.<br />
Disclosure: L. Belton: Contract worker for Amgen Ltd, B. Pujol: Employed by<br />
Amgen EuropeAll o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1629 HIGH PREVALENCE AND INCIDENCE OF ANAEMIA IN<br />
CANCER PATIENTS IN SPAIN<br />
P. Gascón 1 , A. Casas 2 , J. Muñoz 3 , J. De Castro 4 , V. Alberola 5 , M. Cucala 6 and<br />
F. Barón 7<br />
1 Medical Oncology Department, Hospital Clínic i Provincial de Barcelona,<br />
Barcelona, SPAIN, 2 Medical Onology Department, Hospital Virgen del Rocío,<br />
Sevilla, SPAIN, 3 Medical Oncology Department, Hospital Dr. Peset, Valencia,<br />
SPAIN, 4 Medical Oncology Department, Hospital La Paz, Madrid, SPAIN,<br />
5 Medical Oncology Department, Hospital Arnau de Vilanova, Valencia, SPAIN,<br />
6 Medical Advisor, Vifor Pharma España, Barcelona, SPAIN, 7 Medical Oncology<br />
Department, Complejo hospitalario Universitario de Santiago de Compostela,<br />
Santiago de Compostela, SPAIN<br />
Background: Anaemia is a frequent complication in cancer patients. This<br />
haematological abnormality may be related to cancer itself and/or induced by<br />
chemo<strong>the</strong>rapy. The objective of <strong>the</strong> present study was to describe <strong>the</strong> prevalence of<br />
anaemia in treatment-naïve patients with solid tumours, <strong>the</strong> incidence of anaemia<br />
after four months of cancer treatment and anaemia management.<br />
Methods: Multicenter, prospective and observational study that included newly<br />
diagnosed cancer patients. Data on anaemia parameters and its management were<br />
collected at baseline and after four months of cancer treatment. The primary<br />
outcome was <strong>the</strong> proportion of patients with anaemia defined as a haemoglobin (Hb)<br />
concentration
Results: Anemia was detected in 83.6% (122/146) of pts. 23.8% (29/122) of pts were<br />
anemic already before ChT and 55.7% (68/122) of all anemic pts experienced anemia<br />
after <strong>the</strong> first cycle of ChT. Statistically significant correlation was found between<br />
chemo<strong>the</strong>rapy induced anemia and Hb value before starting ChT (p= 0.002). ESA<br />
treatment was administred in 60/122(49.2%) of all anemic pts and targeted value of<br />
Hb level >110g/L was achieved in 65.5% of those pts. The red blood cell transfusion<br />
was given to only 19/122 (15%) of anemic patients, half of which were also treated<br />
with ESA. PFS of patients with anemia before ChT was significantly shorter<br />
compared to non-anemic pts (p = 0.001). ESA treatment did not affect PFS despite<br />
<strong>the</strong> fact that <strong>the</strong> proportion of trombembolic events was higher in patients receiving<br />
ESA or not (8.3% vs 3.8%, respectively).<br />
Conclusions: Our results confirmed that anemia is a frequent complication in lung<br />
cancer patients treated with ChT. Treatment with ESA was safe but marginally<br />
effective in our group of patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1631 PHYISICAL AND EMOTIONAL SYMPTOMS IN PATIENTS WITH<br />
SOLID AND HAEMATOLOGIC MALIGNANCIES WITHOUT<br />
METASTASES, ON CURE OR FOLLOW-UP: ARE THEY<br />
OVERLAPPING?<br />
C.I. Ripamonti 1 , M.A. Pessi 2 , A. Maruelli 3 , S. Boldini 4 , G. Miccinesi 5 , E. Bandieri 6<br />
and L. Buonaccorso 7<br />
1 Supportive Care In Cancer Unit, Fondazione IRCCS - Istituto Nazionale dei<br />
Tumori, Milano, ITALY, 2 Supportive Care in Cancer, Fondazione IRCCS, Istituto<br />
Nazionale Tumori, Milano, ITALY, 3 Psychology Unit, LILT and Centre for<br />
Oncological Rehabilitation CERION of Florence, Firenze, ITALY, 4 Supportive Care<br />
in Cancer, Fondazione IRCCS, Istituto Nazionale dei Tumori Milano, Milano,<br />
ITALY, 5 Epidemiology, Cancer Prevention and Research Institute ISPO Florence,<br />
Florence, ITALY, 6 Oncological Unit, Azienda USL Modena CeVEAS Modena,<br />
Mirandola Modena, ITALY, 7 Psychology, AMO Association of Oncological<br />
Patients from nine towns and villages in <strong>the</strong> Nor<strong>the</strong>n Area of Modena, Mirandola,<br />
ITALY<br />
In a prospective study carried out on 88 patients with solid cancer on cure and 20 on<br />
follow up (Group A) and 86 patients with haematologic malignancies (68 on cure)<br />
(Group B), we assessed <strong>the</strong> presence and intensity of physical and emotional<br />
symptoms through <strong>the</strong> Edmonton Symptom Assessment Scale (ESAS). In both<br />
groups, whereas no correlation was observed between age or religiousness and ESAS<br />
symptoms, a score above <strong>the</strong> clinical cut off for HADS (10/11) was associated with<br />
higher intensity of almost all symptoms. Drowsiness was less reported by patients<br />
with HADS 90 for group A only. Whereas, for group B <strong>the</strong> associations with<br />
low KPS were for uncontrolled anorexia, not-well being and dyspnoea (p = 0.002; p<br />
= 0.029; p = 0.018 respectively). In both groups patients with higher proportion of<br />
uncontrolled depression or drowsiness were significantly associated to receiving<br />
psychological support. Pain, anxiety and not-well being were correlated with<br />
psychological support for group A only. We believe that <strong>the</strong> routinary assessment of<br />
physical and emotional symptom in patients with both malignancies is mandatory to<br />
recognize all <strong>the</strong> symptoms with a particular attention to <strong>the</strong> emotional ones.<br />
Phyisical and emotional symptoms in patients with solid and haematologic<br />
malignancies without metastases, on cure or follow-up: are <strong>the</strong>y overlapping<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1632 HEMODIALYSIS IN CERVICAL CANCER PATIENTS: CLINICAL<br />
ASPECTS AND OUTCOME IN 95 PATIENTS FROM THE<br />
BRAZILIAN NATIONAL CANCER INSTITUTE (INCA)<br />
D.G. Candido Reis 1 , L.M.C. Soares 1 , D. Herchenhorn 1 , I.S. Martins 2 and<br />
E. Rocha 3<br />
1 Medical Oncology, Brazilian National Cancer Institute, Rio de Janeiro, BRAZIL,<br />
2 Serviço de Infectologia, Universidade Federal Fluminense, Niterói, BRAZIL,<br />
3 Departamento de Nefrologia, Hospital Universitário Clementino Fraga Filho-<br />
UFRJ, Rio de Janeiro, BOUVET ISLAND<br />
Cervical Cancer is a serious issue in development and underdeveloped countries. It is<br />
<strong>the</strong> second most prevalent (18000 new cases expected for <strong>2012</strong>) and <strong>the</strong> fourth<br />
deadliest cancer among women in Brazil. Most patients (pts) (68,3%) are diagnosed<br />
with advanced disease- increasing <strong>the</strong>ir risk of renal failure due to local progression<br />
and cisplatin-based chemo<strong>the</strong>rapy. Benefits of hemodialysis in <strong>the</strong>se patients are<br />
unknown, and it should be better clarified due to its cost and morbidity.<br />
Material and methods: Data were retrospectively assessed from all 95 consecutive<br />
patients diagnosed with cervical cancer submitted to renal substitute <strong>the</strong>rapy in <strong>the</strong><br />
years of 2007/2008, with a follow-up until March 2010. Statistical analysis was<br />
performed using software SPSS v11.0. Median Age of Diagnosis and at 1st<br />
Hemodialysis (1HD) were, respectively, 50.72y (25.39-95.13) and 52.06y<br />
(25.41-95.70). 70 pts (73,7%) had stage III or IV at <strong>the</strong> moment of diagnosis and 81<br />
pts (85,3%) had disease progression at <strong>the</strong> moment of <strong>the</strong> 1HD. Main reason for HD<br />
was post-renal kidney failure in 84pts (88%). 34 pts (36%) received any kind of<br />
chemo<strong>the</strong>rapy at <strong>the</strong> moment of 1HD and 5 pts (5%) developed nephrotoxicity due<br />
to chemo<strong>the</strong>rapy. 87pts (91,6%) were dead at <strong>the</strong> moment of analysis, and 67pts<br />
(77%) died in <strong>the</strong> first 3 months after <strong>the</strong> 1HD. The Median Survival for <strong>the</strong> entire<br />
cohort was 41 days (CI95% 25-57 days). The main causes of death were cancer<br />
(83%) and sepsis (5%). In a Multiple Logistic Analysis using Cox Model, a significant<br />
difference was found in <strong>the</strong> Median Survival in <strong>the</strong> following categories: Age at First<br />
HD (55 years: 25 days (CI95: 9-41), HR = 0.259,<br />
p = 0.020); Tumor Status at <strong>the</strong> moment of HD (stable diase/partial response/no<br />
evidence of disease: 52 days (CI95: 30-74); Disease Progression/active disease: 39 days<br />
(CI95: 20-58), HR = 0.052, p = 0.003); Renal Drainage (not performed: 20 days (CI95:<br />
7-33); performed: 67 days (CI95: 39-95), HR = 2.287, p = 0.003).<br />
Conclusions: Overtreatment is common in oncology, from anti-cancer <strong>the</strong>rapy to<br />
supportive care, and this can be hazardous to <strong>the</strong> patients. Most patients who were<br />
submitted to HD in this cohort had active advanced disease, and renal failure seemed<br />
to be a surrogate of poor prognosis/outcome. Patients who most benefited from HD<br />
was those younger than 55y and those with controlled disease.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1633 BISPHOSPHONATES IN BONE METASTATIC PATIENTS:<br />
EXPERIENCE OF MEDICAL ONCOLOGY, UNIVERSITY OF<br />
L’AQUILA OVER 17 YEARS<br />
E. Ricevuto 1 , A. Irelli 1 , K. Cannita 1 , G. Bruera 1 , P. Lanfiuti Baldi 1 , V. Cocciolone 1 ,<br />
E. Palluzzi 1 , L. Rinaldi 1 , A. Teti 2 and C. Ficorella 1<br />
1 Medical Oncology Division, S. Salvatore Hospital, University of L’Aquila,<br />
L’Aquila, ITALY, 2 Department of Experimental Medicine, University of L’Aquila,<br />
L’Aquila, ITALY<br />
Three hundred and twenty-nine bone metastatic patients (BMP) followed at Medical<br />
Oncology Division, San Salvatore Hospital L’Aquila from 1995 were evaluated.<br />
Primary tumors were: breast 113, 55%; prostate 29, 14%; lung 26, 13%. Treatment<br />
with bisphosphonates was administered in 204 patients, 62% (male/female, 80/124):<br />
zoledronic acid and/or intravenous pamidronate 178, 87%; ibandronate 16, 8%; and<br />
ibandronate followed by intravenous bisphosphonate 10, 5%. Median duration of<br />
treatment was 7 months (range 1-47months), 19,5 months (range 1-57months) and<br />
27 months (range 9-44months), respectively. Features of bone metastases: multiple<br />
bone sites 193 (95%), one bone site 11 (5%); osteolytic 124 (61%), osteosclerotic<br />
lesions 35 (17%), mixed 28 (14%), undetermined 17 (8%). Involved sites: spinal<br />
column, 172 (84%); pelvis/hip, 146 (72%); long bones, 102 (50%); o<strong>the</strong>r skeletal sites,<br />
156 (76%). Overall skeletal–related events (SREs) during follow up were 140 (69%):<br />
pathologic fracture, 45 (22%); spinal cord compression, 6 (3%); bone RT, 120 (59%);<br />
bone surgery, 14 (7%). The first occurring SRE was: pathologic fracture in 28 patients<br />
(20%); spinal cord compression, 3 (2%); bone RT, 108 (77%); bone surgery, 1 (1%).<br />
Number of SREs in individual patient was: 1 in 54%; 2 in 25%; 3 in 17%; 4 in 7%; 6<br />
in 1%. SREs before onset of treatment with bisphosphonate were 99 (71%), after<br />
treatment were 41 (29%). A baseline mouth assessment with dental visit and/or<br />
orthopantomography of <strong>the</strong> jaws was performed in 58% of patients, 2% also with<br />
TAC or RMN. Median survival after diagnosis of bone metastases was 32 months.<br />
Median time to first SRE after diagnosis of bone metastases was 15 days. Median<br />
survival after first SRE was 29 months. Events related to bisphosphonate were: acute<br />
phase reactions (first 3 days), 6 (2,5%); pyrexia, 5 (2%); bone pain, 2 (0,8%);<br />
arthralgia, 1 (0,4%); hypercalcemia, 4 (1,7%); hypocalcemia, 7 (2,9%); toothache, 3<br />
(1,25%); osteonecrosis of <strong>the</strong> jaw (ONJ), 6 (2,5%); uveitis, 1 (0,4%). ONJ before and<br />
after introduction of baseline mouth assessment, 4/65 patients (6.1%) and 2/139<br />
patients (1,4%), respectively. Our experience confirms <strong>the</strong> relevance of SREs and<br />
efficacy of bisphosphonate treatment in BMP.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1634 MEETING THE CHALLENGE OF ORAL ANTI-CANCER<br />
THERAPY EDUCATION – AN IRISH PERSPECTIVE<br />
D.M. Graham, E. Duignan, A. Campbell and K. O’Byrne<br />
Medical Oncology, St James’s Hospital, Dublin, IRELAND<br />
Annals of Oncology<br />
Background: Prescription of oral anti-cancer <strong>the</strong>rapy (OAT) is increasing. Safety and<br />
adherence issues surrounding OAT are causing a shift in <strong>the</strong> traditional roles and<br />
responsibilities of oncologists, nurses and pharmacists. The aim of this study was to<br />
evaluate education provided to patients receiving OAT and to develop a standardised<br />
tool to improve <strong>the</strong> education process and its documentation.<br />
Method: Over a 1-month period patients attending St James’s Hospital oncology<br />
department for OAT were identified. Charts were reviewed for each of <strong>the</strong>se patients.<br />
Analysis: Criteria were established to assess standards of documentation. 1. All charts<br />
should have documentary evidence of patient education for OAT. 2. Documentary<br />
ix524 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
evidence should include: side effects, schedule of treatment, support services, storage,<br />
handling, disposal and interactions.<br />
Results: During <strong>the</strong> review period, 35 patients receiving OAT were identified. Of<br />
<strong>the</strong>se, 12 patients had documentation of education by a doctor (34%), 15 (43%) by a<br />
nurse. Documentary evidence of education about side effects was noted in 22 cases<br />
(63%), schedule of treatment in 16 cases (46%), support services in 16 (46%), safe<br />
storage in 3 cases (9%), safe disposal, safe handling and interactions in 2 cases each<br />
(6%). Recommendations: A standardised tool has been developed to enable<br />
healthcare staff to accurately document issues discussed during patient education for<br />
OAT. This is in <strong>the</strong> form of a checklist to ensure that all elements including safety,<br />
timing of medication, interactions, monitoring and support are documented<br />
accurately. All patients prescribed OAT will be referred to a nurse-led OAT clinic to<br />
facilitate education. Healthcare staff in <strong>the</strong> oncology department will be educated<br />
about <strong>the</strong> tool and clinic and, following a pilot period, a repeat audit will be<br />
performed to assess <strong>the</strong> effectiveness of <strong>the</strong> tool. These results will also be presented.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1635 INTENSIVE CARE AS A KEY PLAYER IN THE CHANGING<br />
PARADIGM OF MODERN CANCER CARE: A SINGLE<br />
INSTITUTION EXPERIENCE<br />
L.C. Connell 1 , F. Othman 2 , B. Marsh 2 , D.N. Carney 1 , J.A. McCaffrey 1 ,P.<br />
O Gorman 3 and C.M. Kelly 4<br />
1 Medical Oncology, Mater Misericordiae University Hospital, Dublin, IRELAND,<br />
2 Department of Intensive Care, Mater Misericordiae University Hospital, Dublin,<br />
IRELAND, 3 Haematology, Mater Misericordiae University Hospital, Dublin,<br />
IRELAND, 4 Medical Oncolgy, Mater Misericordiae University Hospital, Dublin,<br />
IRELAND<br />
Background: Many metastatic cancers are now treated similar to o<strong>the</strong>r chronic<br />
diseases. Expanding treatment options, increasing age; co-morbid illness; and<br />
improving cancer-specific survival means that decisions regarding <strong>the</strong> timeliness &<br />
appropriateness of transfer to <strong>the</strong> Intensive Care Unit (ICU) are complex. We sought<br />
to examine <strong>the</strong> clinical, demographic & outcome characteristics of oncology/<br />
haematology patients (pts) transferred to ICU at a large academic teaching hospital.<br />
Methods: Data was extracted from a prospectively maintained database for all pts<br />
with documented malignancy admitted to ICU between September 2009 &<br />
December 2011. Clinicopathological variables examined included; cancer type;<br />
tumour stage; time from diagnosis; age; co-morbidities; and treatment history. The<br />
Sequential Organ Failure Assessment (SOFA), an ICU-specific scoring system, was<br />
reviewed for each patient (pt). We report 30 day & 6-month mortality.<br />
Results: A total of 52 of an eligible 83 pts have been analysed in detail to date. The<br />
common cancer types were well represented; breast (11.5%),colorectal(11.5%), lung<br />
(11.5%) & acute leukaemia(19.2%). Mean age at time of ICU admission was 60 years<br />
(range 29-82). The maximum number of prior lines of chemo<strong>the</strong>rapy (CT) was 5<br />
(range 0-5). Approximately 50% of pts had metastatic disease at time of ICU<br />
admission. The most frequent reasons for admission were sepsis (n = 16, 31%) &<br />
respiratory distress (n = 15, 29 %). Use of mechanical ventilation, vasopressors &<br />
renal dialysis was 51.9%, 61.5% & 21.1% respectively. Four pts (7.7 %) received CT in<br />
<strong>the</strong> ICU setting. ICU-specific mortality was 28.8% (n = 15). Thirty-day and 6-month<br />
mortality rates were 38.5% & 61.5% respectively. Data on <strong>the</strong> remaining 31 pts is<br />
currently being analysed and will be available for presentation at <strong>the</strong> meeting.<br />
Conclusions: A significant proportion of pts admitted to ICU had advanced disease<br />
& had received multiple lines of CT previously. The ICU-specific mortality rate was<br />
lower than expected at 28.8% and may reflect stringent selection criteria. Pts<br />
transferred tended to have had long periods of disease remission/stabilisation or had<br />
a new diagnosis of malignancy with unknown CT sensitivity status. Analysis of pt<br />
selection at ward level is on-going and will identify o<strong>the</strong>r factors influencing ICU<br />
transfer decisions.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1636 A PROSPECTIVE STUDY OF SUBACUTE THYROID<br />
DYSFUNCTION FOLLOWING SUPRACLAVICULAR<br />
IRRADIATION IN THE MANAGEMENT OF CARCINOMA OF THE<br />
BREAST<br />
S. Akyurek 1 , I. Babalioglu 1 , S. Yuksel 2 and S. Cakir Gokce 1<br />
1 Radiation Oncology, Ankara University School of Medicine, Ankara, TURKEY,<br />
2 Biostatistic, Ankara University School of Medicine, Ankara, TURKEY<br />
Purpose: To evaluate <strong>the</strong> relationship between irradiation and early thyroid<br />
dysfunction, focusing on radiation dose-volume factors.<br />
Patients and methods: Between December 2010 and January <strong>2012</strong> a total of 21<br />
patients with breast cancer received supraclavicular irradiation were evaluated<br />
Thyroid function tests, including serum thyroid stimulating hormone (TSH), free<br />
thyroxine (fT4), free triiodothyronine (fT3), were analyzed prior to irradiation and<br />
every three months <strong>the</strong> first year and <strong>the</strong>n 18th month after radio<strong>the</strong>rapy. Based on<br />
each patient’s dose volume histogram (DVH), total volume of <strong>the</strong> thyroid, mean<br />
radiation dose <strong>the</strong> thyroid and percentages of thyroid volume which received<br />
radiation doses 10-60Gy (V10-V60) were considered for statistical analysis.<br />
Results: Mean TSH levels before irradiation, at 3, 6, 9 and 12 months were 1.4 µIU/<br />
ml, 1.5 µIU/ml, 1.7 µIU/ml, 3.6 µIU/ml and 4.6 µIU/ml, respectively. Serum TSH<br />
levels did not change significantly at 3 and 6 months after irradiation (p = 0.1).<br />
However, a significant elevation was noted at 9 months (p = 0.005). Mean thyroid<br />
dose was 32 Gy (19-48 Gy) and mean thyroid volume was 35 cc (24-64 cc). Median<br />
values of V10-20-30-40-50-60 were 68%, 58%, 55%, 53%, 48% and 0%, respectively.<br />
With a median follow-up was 9 months (range, 3-18 months), only one patient (5%)<br />
developed clinical hypothyroidism requiring thyroid replacement treatment.<br />
Conclusion: According to early results of our study, irradiation of <strong>the</strong> thyroid<br />
develops early thyroid dysfunction. This damage is initially manifested within 9<br />
months after radio<strong>the</strong>rapy. However we could not analyze <strong>the</strong> radiation dose-volume<br />
factors of <strong>the</strong> peak level of serum TSH because of inefficient follow up time.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1637 COMBINATION OF SERUM PROCALCITONIN AND<br />
C-REACTIVE PROTEIN LEVEL AS A DIAGNOSTIC MARKER OF<br />
DISCRIMINATING INFECTION FROM NEOPLASTIC FEVER IN<br />
FEBRILE LUNG CANCER PATIENTS<br />
K. Miyamoto 1 , R. Seki 2 , D. Taniyama 1 , H. Kamata 1 and F. Sakamaki 1<br />
1 Pulmonary Medicine, Saiseikai Central Hospital, Minato-ku, Tokyo, JAPAN,<br />
2 Pathology, Saiseikai Central Hospital, Tokyo, JAPAN<br />
Background: Neoplastic fever in lung cancer is assessed on clinical course only, and<br />
is difficult to discriminate from infection.<br />
Objective: To evaluate <strong>the</strong> diagnostic role of procalcitonin (PCT) and C-reactive<br />
protein (CRP) in discriminating neoplastic fever and infection.<br />
Methods: We reviewed <strong>the</strong> medical records of 112 consecutive febrile episodes of 52<br />
patients (39 males, mean age 67.1y/o), who were diagnosed as lung cancer from<br />
November 2009 to April <strong>2012</strong> at our Saiseikai Central Hospital in Tokyo, Japan.<br />
Based on clinical, laboratory, and bacteriological results, patients were classified as<br />
having neoplastic fever (NF, n = 53), suspected or definite bacterial infection (BI, n = 59).<br />
Values of white blood cell count (WBC), PCT, and CRP were measured on day 1 of<br />
onset of fever. Microbiological specimen and radiological imaging study were also<br />
performed to diagnose infectious diseases or o<strong>the</strong>r febrile conditions.<br />
Results: The most common infection was pneumonia (38.4 %). Mean WBC (12000<br />
vs. 14800) were not statistically significant. Mean values of PCT were significantly<br />
higher in patients with BI compared with NF (0.14 vs. 3.95 ng/ml, p < 0.05). Mean<br />
values of CRP were also significantly higher in patients with BI compared with NF<br />
(8.6 vs. 15.2 mg/dl, p < 0.05). Combination of CRP level at <strong>the</strong> threshold value of<br />
10.2 mg/dl and PCT level at <strong>the</strong> threshold value of 0.32 ng/ml were <strong>the</strong> most<br />
sensitive from ROC curve for discriminating infection to neoplastic fever.<br />
Conclusions: Combination of PCT and CRP on <strong>the</strong> day of onset of fever is useful in<br />
discriminating neoplastic fever from infection in febrile lung cancer patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1639 INCIDENCE OF THROMBOEMBOLIC EVENTS IN PATIENTS<br />
TREATED WITH CISPLATIN-BASED CHEMOTHERAPY<br />
A.C. Fernandes 1 , S.R. Meireles 2 , I. Augusto 2 , L. Aguas 2 and M. Damasceno 2<br />
1 Oncologia Médica, Hospital de São João, Porto, PORTUGAL, 2 Medical<br />
Oncology Department, Hospital São João, Porto, PORTUGAL<br />
Introduction: Cancer patients on chemo<strong>the</strong>rapy have higher risk in developing<br />
thromboembolic events (TEE), with great impact on morbidity and mortality. The<br />
aim of this study is to determine <strong>the</strong> incidence of venous and arterial TEE in patients<br />
treated with cisplatin-based chemo<strong>the</strong>rapy. We also analysed <strong>the</strong> prognostic value of<br />
patientś baseline and treatment characteristics in predicting TEE occurrence.<br />
Methods: We performed a retrospective analysis of all patients with cancer treated<br />
with cisplatin-based chemo<strong>the</strong>rapy between January 1, 2011, and April 10, <strong>2012</strong>,<br />
with at least 4 weeks of follow-up after <strong>the</strong>ir last cisplatin dose. A TEE was<br />
considered cisplatin-associated if it occurred between <strong>the</strong> time of <strong>the</strong> first dose of<br />
cisplatin and 4 weeks after <strong>the</strong> last dose.<br />
Results: Among 141 patients, 27 (19.1%) experienced a TEE. The TEE observed<br />
were: deep vein thrombosis (DVT) in 9.9% (14), pulmonary embolism (PE) in 5.7%<br />
(8), DVT plus PE in 0.7% (4) and arterial thrombosis in 2.8%. The majority of<br />
patients (51.9%) had a TEE after 63 days, and after <strong>the</strong> 3 rd dose of cisplatin, with a<br />
cumulative dose of 160 mg/m 2 . By univariate analysis, active smoking (p = 0.016),<br />
hypertension (p = 0.007), site of cancer (p = 0.025), Khorana site of cancer (p =<br />
0.001), Khorana score (p = 0.049) and risk group (p = 0.04) were all identified as risk<br />
factors. However, by multivariate analysis, only hypertension (p = 0.18; HR 3.59; 95%<br />
CI, 1.25 to 10.34) and Khorana site of cancer (p = 0.03) retained statistic significance.<br />
Conclusion: As we expected, gastric and pancreatic cancers had <strong>the</strong> highest<br />
incidence of TEE. We verified a very high incidence of TEE in patients treated with<br />
cisplatin-based regimens, also described in o<strong>the</strong>r published studies. It is <strong>the</strong>refore<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds416 | ix525
important to carry out randomized studies to conclude <strong>the</strong> need for prophylaxis of<br />
TEE in <strong>the</strong>se patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1640 ARE THERE FACTORS THAT PREDICT ACUTE CARE<br />
ADMISSION IN CANCER PATIENTS AGE ≥65 YEARS<br />
RECEIVING CHEMOTHERAPY? A RETROSPECTIVE ANALYSIS<br />
M.S. Lung, Y. Yeung, C. Maddison, A. Hutchinson and S. White<br />
Medical Oncology, Nor<strong>the</strong>rn Health, Epping, VIC, AUSTRALIA<br />
Background: There is growing evidence that older patients derive <strong>the</strong> same benefits<br />
from chemo<strong>the</strong>rapy as younger patients, but often at <strong>the</strong> cost of increased toxicity. A<br />
retrospective analysis was done of cancer patients ≥65 years who received<br />
chemo<strong>the</strong>rapy, with <strong>the</strong> aim of identifying patient or treatment factors associated<br />
with subsequent hospital admission.<br />
Methods: Medical records and an electronic prescribing system (EPS) were used to<br />
identify all cancer patients ≥65 years who received chemo<strong>the</strong>rapy at Nor<strong>the</strong>rn<br />
Health. For each patient, age, treatment dose at onset, ECOG, presence of metastases,<br />
cardiac comorbidities, chronic kidney disease stage, liver function tests and reason<br />
for admission were documented. Univariate and multivariate logistic regression<br />
analysis was used to assess <strong>the</strong> association between a factor and subsequent<br />
hospitalisation. An Odds Ratio greater than or less than 1, and a P value
Annals of Oncology<br />
progression-free survival very useful from <strong>the</strong> viewpoint of side effects, even in phase<br />
III clinical trials.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1705 PROSPECTIVE EVALUATION OF THE EFFECT OF A MANUAL<br />
FOR DIABETIC PATIENTS WHO RECEIVE CANCER<br />
CHEMOTHERAPY<br />
H. Kato1 , T. Mineta2 , K. Chikamori2 , N. Hamajima2 , S. Koyama3 , H. Kushihara3 ,<br />
B. Hiroyuki4 , M. Yamauchi5 , K. Kawada1 and F. Nomura1 1<br />
Medical Oncology, Japanese Red Cross Nagoya First Hospital, Nagoya,<br />
JAPAN, 2 Nursing, Japanese Red Cross Nagoya First Hospital, Nagoya, JAPAN,<br />
3<br />
Pharmacy, Japanese Red Cross Nagoya First Hospital, Nagoya, JAPAN,<br />
4<br />
Nutrition, Japanese Red Cross Nagoya First Hospital, Nagoya, JAPAN,<br />
5<br />
Endocrinology and Diabetes, Japanese Red Cross Nagoya First Hospital,<br />
Nagoya, JAPAN<br />
Background: How to safely administer cancer chemo<strong>the</strong>rapy to patients with<br />
diabetes mellitus is an important issue. Our institution is a general core hospital in<br />
Japan. In 2010, we surveyed <strong>the</strong> current status of diabetic patients given cancer<br />
chemo<strong>the</strong>rapy. Adequate medical examinations were not performed. In 2011, we<br />
designed a manual for diabetic patients who receive cancer chemo<strong>the</strong>rapy. We now<br />
report an improvement in medical examinations of diabetic patients who receive<br />
cancer chemo<strong>the</strong>rapy since introducing our manual.<br />
Methods: We decided that adequate medical examinations should include <strong>the</strong><br />
following: adequate measurement of blood sugar levels; evaluation of <strong>the</strong> patient by a<br />
diabetologist; making standards for decreasing <strong>the</strong> dose of steroids given before<br />
cancer chemo<strong>the</strong>rapy; and making standards for nutritional guidance. We compared<br />
<strong>the</strong> present status (as of March <strong>2012</strong>) with that before <strong>the</strong> introducing our manual<br />
for diabetic patients receiving cancer chemo<strong>the</strong>rapy.<br />
Results: The proportion of diabetic patients increased from 12% to 19%. The<br />
rate of measuring blood sugar levels at <strong>the</strong> start of new regimens of<br />
chemo<strong>the</strong>rapy increased from 69% to 72%. The rate of adequate continuous<br />
monitoring of blood sugar levels increased from 48% to 81%. The rate of<br />
evaluation by a diabetologist increased from 36% to 50%. The rate of decreased<br />
premedication with steroids increased from 55% to 66%. The rate of providing<br />
nutritional guidance was unchanged (23% to 24%).<br />
Conclusions: The rates of adequate continuous monitoring of blood sugar levels,<br />
decreasing premedication with steroids, and evaluation by a diabetologist improved.<br />
The increase in <strong>the</strong> proportion of diabetic patients was attributed to adequate blood<br />
sugar examinations. However, <strong>the</strong> low rate of providing of nutritional guidance<br />
remains an unsolved problem.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds416 | ix527
abstracts<br />
translational research<br />
1644PD ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY<br />
(ADCC) EVOLUTION UNDER TREATMENT BY CETUXIMAB<br />
AND LINKS WITH TREATMENT OUTCOME IN LOCALLY<br />
ADVANCED HEAD AND NECK (LAHNSCC) AND IN<br />
METASTATIC COLORECTAL CANCER (MCRC) PATIENTS<br />
C. Lo Nigro 1 , M. Monteverde 1 , G. Strola 2 ,M.Maffi 1 , E. Miraglio 1 , L. Lattanzio 1 ,<br />
D. Vivenza 1 , F. Messa 1 , G. Milano 3 , M. Merlano 1<br />
1 Oncology, S. Croce General Hospital, Cuneo, ITALY, 2 Laboratory, S. Croce<br />
General Hospital, Cuneo, ITALY, 3 Oncopharmacology Unit, Lacassagne, Nice,<br />
FRANCE<br />
Background: ADCC may play a role in antitumor activity of IgG1 mAb by inducing<br />
immune cell-mediated tumor lysis. We evaluated ADCC ability before and under<br />
cetuximab treatment and impact on survival in locally advanced Head and Neck<br />
(LAHNSCC) or metastatic colorectal cancer (mCRC).<br />
Methods: 82 patients (60 men, 22 women; median age 64, range 39-87), 39<br />
LAHNSCC and 43 mCRC, treated with chemo<strong>the</strong>rapy (irinotecan or folfiri) plus<br />
cetuximab, were prospectively enrolled. ADCC ex-vivo was measured before<br />
treatment and every 2 months (1 to 7 measurements/patient, 44 patients with<br />
≥2 measurements). 400 000 purified Natural Killer cells (CD3- CD56+) from<br />
patients were incubated with 10 000 target cells (CAL166 cell line expressing<br />
EGFR) and 10 µg/ml cetuximab. Cytotoxicity was measured by LDH-release<br />
assay. ADCC was expressed as % of lysed target cells. Polymorphisms of Fcg<br />
receptors FcgR2a (131Arg > His) and FcgR3a (158Phe > Val) were analyzed by<br />
Allelic Discrimination assay.<br />
Results: The feasibility rate of ADCC measurements was 85-90%. Basal ADCC<br />
ranged between 30% and 100% (mean 62%, median 66%) and was not<br />
influenced by gender. A trend for an increased basal ADCC was observed in<br />
younger patients: median was 66% in <strong>the</strong> 22 patients < 65 vs 56% in <strong>the</strong> 22<br />
patients ≥ 65 years (p = 0.084), with a marked difference by tumour site (H&N<br />
p = 0.056; colon p= 0.16). FcgR2a and FcgR3a gene polymorphisms were not<br />
linked to basal ADCC. The evolution of individual ADCC ability before<br />
treatment and 2 months later revealed a significant drop in ADCC (intra-patient<br />
comparison, N = 44, p = 0.003, absolute median drop of 20%). 82 patients were<br />
assessable for survival (43 deaths; median follow up = 10.3 month). Cutaneous<br />
rash, but not basal ADCC, was related to survival (p = 0.043). There were no<br />
correlation between ADCC evolution (decrease/increase during <strong>the</strong> two months)<br />
vs EGFR status nor vs cutaneous rash.<br />
Conclusions: A new generation of mAb is currently being developed with <strong>the</strong> aim to<br />
amplify ADCC. Present data illustrate <strong>the</strong> feasibility of ADCC measurement in<br />
mAb-treated patients and reveal an initial drop in ADCC under treatment that may<br />
reflect <strong>the</strong> variable chemo<strong>the</strong>rapy-induced impact on host immunity.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1645PD MICRORNA-9 AND -224 IN TRASTUZUMAB RESISTANT<br />
HER2 POSITIVE BREAST CANCER CELLS<br />
K. Howe, A. Eustace, S. Souahli, B.C. Browne, S. Aherne, N. Barron, N. Walsh,<br />
J.P. Crown, N. O’Donovan<br />
National Institute for Cellular Biotechnology, Molecular Therapeutics for Cancer<br />
Ireland, Dublin City University, Dublin, IRELAND<br />
HER2 positive breast cancer accounts for approximately 25 % of all breast<br />
cancer cases. Trastuzumab, a humanised monoclonal antibody, is an approved<br />
established treatment for HER2 positive breast cancer; however, patients that<br />
initially respond frequently develop resistance. The aim of this study is to<br />
investigate microRNAs in cell line models of acquired and innate trastuzumab<br />
resistance. MicroRNA was extracted from <strong>the</strong> HER2 positive cells; SKBR3,<br />
BT474, and <strong>the</strong> acquired trastuzumab resistant variants SKBR3-T and BT474-T,<br />
and from a panel of innate trastuzumab sensitive (BT474, EFM-192A, SKBR3<br />
and MDA-MB-361) or resistant cell lines (UACC-732, JIMT-1, HCC-202,<br />
HCC-1954, HCC1569 and MDA-MB-453), in triplicate. MicroRNA profiling was<br />
performed on SKBR3 and SKBR3-T using Taqman Low Density Arrays (TLDA).<br />
Annals of Oncology 23 (Supplement 9): ix528–ix540, <strong>2012</strong><br />
doi:10.1093/annonc/mds417<br />
Differentially regulated miRNAs were selected using > 2-fold change and a<br />
P-value of < 0.05. Individual quantitative RT-PCR (qRT-PCR) was performed to<br />
confirm alterations in miRNAs. Functional studies were carried out using<br />
Ambion® Pre-miR miRNA Precursors and Anti-miR miRNA Inhibitors for<br />
miR-224 in SKBR3 cells. TLDA analysis identified nine differentially regulated<br />
microRNAs in <strong>the</strong> SKBR3-T cells. Individual qRT-PCR assays confirmed that 5<br />
miRNAs were up-regulated and 4 were down-regulated. MiR-9 was 2.2-fold<br />
up-regulated (p = 0.04), while miR-224 was 1.6-fold down-regulated (p = 0.01) in<br />
SKBR3-T compared to <strong>the</strong> SKBR3 cells. Fur<strong>the</strong>r validation of <strong>the</strong>se targets in <strong>the</strong><br />
BT474 model showed that miR-224 expression is lost in <strong>the</strong> resistant cells<br />
compared to <strong>the</strong> parental BT474 cells. MiR-9 is not significantly altered in <strong>the</strong><br />
BT474-T cells. In <strong>the</strong> innate resistant models, miR-224 expression is reduced or<br />
lost in 4/6 resistant cell lines. Expression of miR-9 does not significantly differ<br />
between <strong>the</strong> innately sensitive and resistant cell lines. Transfection of SKBR3<br />
cells with pre-miR-224 significantly decreases cell proliferation by 23.5% (p =<br />
0.04).<br />
Conclusions: This is <strong>the</strong> first report of <strong>the</strong> involvement of miR-9 and miR-224 in<br />
trastuzumab resistance in HER2 positive breast cancer. Preliminary functional studies<br />
suggest that miR-224 may play a role in regulating cell growth in HER2 positive<br />
breast cancer cells.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1646PD CUSTOMIZED FIRST LINE CHEMOTHERAPY ACCORDING<br />
TO ERCC1 AND RRM1 SNPS IN ADVANCED<br />
NON-SMALL-CELL LUNG CANCER (NSCLC) PATIENTS: A<br />
PHASE II STUDY<br />
F. Mazzoni 1 , G. Meoni 1 , F.L. Cecere 1 , C. Giuliani 2 , A. Camerini 3 , G. Allegrini 4 ,<br />
F. Martella 5 , L. Boni 6 , F. Torricelli 2 , F. Di Costanzo 1<br />
1 Medical Oncology Unit, Azienda Ospedaliero Universitaria Careggi, Firenze,<br />
ITALY, 2 Genetic Diagnosis Laboratory, AOU Careggi, Firenze, ITALY, 3 Medical<br />
Oncology Unit, Versilia Hospital, Viareggio, ITALY, 4 Medical Oncology Unit,<br />
Pontedera Hospital, Pontedera, ITALY, 5 Oncology Unit, Ospedale di S. Maria<br />
Annunziata, Bagno a Ripoli, ITALY, 6 Centro Coordinamento Sperimentazioni<br />
Cliniche, ITT-AOU Careggi, Firenze, ITALY<br />
Introduction: Excision repair cross complementation group 1 (ERCC1) and<br />
ribonucleotide reductase 1 (RRM1) expression levels are predictive of chemo<strong>the</strong>rapy<br />
(CT) efficacy in some malignancies. Customized CT has several advantages: patients<br />
(pts) are more likely to be treated with agents that <strong>the</strong>y will respond to, pts can be<br />
spared <strong>the</strong> toxicity of agents that <strong>the</strong>y are resistant to.<br />
Methods: We planned a phase II multicentric trial in two steps based on Simon<br />
design. Pts affected by advanced NSCLC are treated with first line CT according<br />
to Single Nucleotide Polymorphisms (SNPs) of ERCC1 (T118C and C8092A)<br />
and RRM1 (-37C > A and -524T > C), which are supposed to be correlated with<br />
specific expression levels. CT is delivered as follow: treatment A (low ERCC1<br />
and RRM1) Cisplatin plus Gemcitabine; treatment B (low ERCC1, high RRM1)<br />
Cisplatin plus Docetaxel; treatment C (high ERCC1, low RRM1) Gemcitabine<br />
plus Docetaxel; treatment D (high ERCC1 and RRM1) Docetaxel plus<br />
Vinorelbine.<br />
Results: Here we report <strong>the</strong> first step analysis for futility: 42 pts were enrolled from<br />
January 2010 to November 2011; 40 pts received at least 1 cycle of CT; median age<br />
was 66 years (range 47-72); 30(75%) pts were males; 21(52%) pts showed ECOG PS<br />
0, 19(48%) PS 1; 36(90%) pts had stage IV and 4(10%) IIIB; 23(58%) pts had<br />
adenocarcinoma, 14(35%) squamous, 3(7%) o<strong>the</strong>r types; 25(62%) pts received<br />
treatment A, 3(8%) treatment B, 11(27%) treatment C, 1(3%) treatment D. As<br />
primary end-point we assessed <strong>the</strong> overall best response and found a 55% response<br />
rate (RR) [38.7 – 70.4, 95% CI] in <strong>the</strong> intention to treat population. Subgroups<br />
analysis showed 46.2% RR in non squamous pts and 71.4% RR in squamous pts.<br />
Secondary end-points were progression free survival (PFS), overall survival (OS) and<br />
safety. The median follow-up time is 7.1 months, 12 pts did not show progression<br />
disease and 23 pts are still alive, <strong>the</strong>n data for PFS and OS are not mature. CT was<br />
well tolerated: only 17(42%) pts showed grade 3-4 toxicity and <strong>the</strong>re were no<br />
treatment related deaths.<br />
Conclusions: We observed an increase of RR in advanced NSCLC pts treated with<br />
CT according to ERCC1 and RRM1 SNPs status, <strong>the</strong> treatment strategy overcomes<br />
<strong>the</strong> first step of <strong>the</strong> study.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
© European Society for Medical Oncology <strong>2012</strong>. Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com
Annals of Oncology<br />
1647PD MOLECULAR PROFILING AS AN OUTCOME PREDICTOR IN<br />
THE GALAXY TRIALTM (NCT01348126): A RANDOMIZED<br />
IIB/III STUDY OF GANETESPIB (STA-9090) IN<br />
COMBINATION WITH DOCETAXEL VERSUS DOCETAXEL<br />
ALONE IN SUBJECTS WITH STAGE IIIB/IV NSCLC<br />
R. Rosell 1 , S.S. Ramalingam 2 , D. Fennell 3 , C. Manegold 4 , I. El Hariry 5 ,<br />
V. Vukovic 6 , F. Teofilovici 5 , V. Reichert 7 , G. Goss 8<br />
1 Medical Oncology Service, Catalan Institute of Oncology ICO Badalona Hospital<br />
Germans Trias i Pujol, Medical Oncology, Badalona, SPAIN, 2 Division of Medical<br />
Oncology, Emory University Winship Cancer Institute, Atlanta, GA, UNITED<br />
STATES OF AMERICA, 3 Medicine, University of Leicester, Leicester, UNITED<br />
KINGDOM, 4 Interdisziplinare Thorakale Onkologie, Klinikum Mannheim GmbH,<br />
Mannheim, GERMANY, 5 Oncology, Synta Pharmaceuticals, Lexington, MA,<br />
UNITED STATES OF AMERICA, 6 Clinical Development, Synta Pharmaceuticals<br />
Corp., Lexington, VA, UNITED STATES OF AMERICA, 7 Oncology, Synta<br />
Pharmaceuticals, Lexington, MA, UNITED STATES OF AMERICA, 8 Medical<br />
Oncology, The Ottawa Hospital Cancer Centre, Ottawa, ON, CANADA<br />
Background: Inhibition of Hsp90, a key molecular chaperone required for activation<br />
of many oncoproteins, can lead to cancer cell death. Ganetespib is an Hsp90<br />
inhibitor that has shown single agent activity in molecularly defined disease,<br />
including ELM4-ALK rearrangement, KRAS mutations, HER2 amplification and<br />
BRAF mutations. The AS/RAF/MEK/ERK pathway is a potential <strong>the</strong>rapeutic target<br />
in non-small cell lung cancer (NSCLC).<br />
Methods: This randomized trial compares ganetespib (G) + docetaxel (D) to D in 2 nd<br />
line advanced NSCLC patients. Archival tissue collection was mandatory and<br />
included formalin-fixed paraffin-embedded (FFPE) 10 unstained slides at 5 or 10 um<br />
and 1 matching hematoxylin-eosin (HE)-stained slide. The aim of this study is to<br />
investigate <strong>the</strong> predictive value of most commonly occurring known mutations in<br />
NSCLC in association with <strong>the</strong> efficacy of G + D, including KRAS, EGFR, BRCA,<br />
MET, BRAF and o<strong>the</strong>rs. Genetic mutational analysis was analyzed using Affymetrix<br />
OncoScan FFPE Express platform, which provides information on copy number<br />
variation, allele ration and somatic mutations, Additionally, KRAS mutations were<br />
also analyzed separately using real-time PCR based sequencing. Results are correlated<br />
with baseline demographics and efficacy outcome data.<br />
Results: Approximately 160 of <strong>the</strong> 300 planned patients were enrolled by early May.<br />
Median age was 60 yrs (range 39-86), M/F: 105/53; adeno/o<strong>the</strong>r: 91/67; never/<br />
former/current smokers: 30/77/51. KRAS mutation was detected in 21 of first 140<br />
patients (15%). Full genetic profiling is ongoing, and will be correlated with <strong>the</strong><br />
efficacy outcomes from a planned interim analysis in early September, including<br />
disease control rate, PFS, and OS.<br />
Disclosure: I. El Hariry: stock ownership. V. Vukovic: Stock options. F. Teofilovici:<br />
stock options. V. Reichert: stock options. All o<strong>the</strong>r authors have declared no conflicts<br />
of interest.<br />
1648P NEOADJUVANT ADDITION OF BEVACIZUMAB TO<br />
CHEMORADIATION IN RECTAL CANCER: IMPACT ON<br />
ANGIOGENIC BIOMARKERS<br />
B. Laquente 1 , J. Capdevila 2 , M. Martínez-Villacampa 3 , C. López 4 , M.J. Safont 5 ,<br />
A. Gómez 6 , J.L. Manzano 7 , C. Grávalos 8 , R. Salazar 3 , E. Aranda Aguilar 6<br />
1 Medical Oncology, ICO. Hospital Duran i Reynals, Barcelona, SPAIN, 2 Medical<br />
Oncology, Hospital Vall d’Hebrón, Barcelona, SPAIN, 3 Medical Oncology, ICO<br />
Hospital Duran i Reynals, Barcelona, SPAIN, 4 Medical Oncology, Hospital<br />
Marqués de Valdecilla, Santander, SPAIN, 5 Medical Oncology, Hospital General<br />
de Valencia, Valencia, SPAIN, 6 Medical Oncology, Hospital Reina Sofía,<br />
Córdoba, SPAIN, 7 Medical Oncology, ICO Hospital Germans Trias i Pujol,<br />
Barcelona, SPAIN, 8 Medical Oncology, Hospital Doce de Octubre, Madrid,<br />
SPAIN<br />
Purpose: We report <strong>the</strong> clinical results of adding bevacizumab (BEV) to preoperative<br />
chemoradiation (CRT), in patients (pts) with locally advanced rectal cancer (LARC).<br />
This pre-planned sub-study was aimed to evaluate <strong>the</strong> evolution of several<br />
biomarkers and <strong>the</strong>ir correlation with downstaging.<br />
Methods: Patients with LARC were randomized to radio<strong>the</strong>rapy 45Gy/25f/5 weeks +<br />
capecitabine (CAP: 825mg/m/bid) + BEV every 2 weeks (5 mg/kg for 3 doses) (arm<br />
A) or <strong>the</strong> same schedule without BEV (arm B): surgery was scheduled 6-8 weeks<br />
after completing CRT. Plasma levels of vascular endo<strong>the</strong>lial growth factor (VEGF),<br />
VEGF receptor 2 (VEGFR-2) and angiopoietin-2 (Ang-2) were measured at baseline<br />
(d1), day 15 (d15) and day 57 (d57). Tissue samples (baseline and at surgery) were<br />
assessed for microvessel density (MVD). Comparisons between concentrations at<br />
different time points were assessed by using appropriate statistical paired tests.<br />
Logistic regression model was adopted to estimate and test <strong>the</strong> biomarkers for <strong>the</strong>ir<br />
association with downstaging.<br />
Results: Samples for biomarker analyses were obtained for 50 out of 90 randomized<br />
pts (arm A/B: 22/28): paired plasma samples were available for 18/23 pts at d1 and<br />
d15, and for 14/17 pts at d57; paired tumor samples were obtained from 12/18 pts.<br />
Eleven pts in each arm were downstaged (lower pT compared with <strong>the</strong> pretreatment<br />
cT). No differences were observed in baseline levels of any biomarker between both<br />
arms. Ang-2 levels were significantly higher in arm B than in arm A at d15 and d57<br />
(p = 0.0056 and p = 0.0133, respectively). Ang-2 levels significantly decreased at d15<br />
only in arm A (p < 0.05 ). Plasma Ang-2 levels decreased in arm A and increased in<br />
arm B (p < 0.05 at all time points). There were no significant changes in o<strong>the</strong>r<br />
biomarker levels. Overall, decrease in Ang-2 levels from baseline to d57, was<br />
significantly associated with tumor downstaging (OR: 0.95, p < 0.0001).<br />
Conclusions: Additional larger tailored studies are needed to corroborate <strong>the</strong> observed<br />
association between decreasing Ang-2 levels, tumoral downstaging and <strong>the</strong> role of<br />
Bevacizumab in this effect.<br />
Disclosure: E. Aranda Aguilar: Consultant or Advisory Role: Roche and Merck<br />
Serono. All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1649P MUTATIONS IN NRAS CODON 61 AND KRAS CODON 146<br />
ARE POOR PROGNOSTIC FACTORS IN PATIENTS WHO<br />
RECEIVED ANTI-EGFR MONOCLONAL ANTIBODY FOR<br />
METASTATIC COLORECTAL CANCER<br />
N. Takahashi 1 , Y. Yamada 1 , H. Taniguchi 2 , Y. Honma 3 , S. Iwasa 3 , K. Kato 4 ,<br />
T. Hamaguchi 5 , Y. Shimada 3<br />
1 Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo,<br />
Japan., Tokyo, JAPAN, 2 Division of Pathology, National Cancer Center Hospital,<br />
Tokyo, JAPAN, 3 Gastrointestinal Oncolgoy, National Cancer Center Hospital,<br />
Tokyo, JAPAN, 4 Gastrointestinal Oncology, National Cancer Center Hospital,<br />
Tokyo, JAPAN, 5 Gastrointestinal Oncology Division, National Cancer Center<br />
Hospital, Tokyo, JAPAN<br />
Background: Previous studies showed that gene mutations (NRAS, BRAF, PIK3CA)<br />
are associated with a poor prognosis or resistance of anti-EGFR antibody in<br />
metastatic colorectal cancer (mCRC) patients with wild type (WT) of KRAS codon<br />
12/13 (KRAS-WT). However <strong>the</strong> significance of <strong>the</strong>se biomarkers has not been<br />
clarified. In addition, EGFR immunohistochemistry (IHC) and EGFR gene<br />
amplification by DISH to evaluate <strong>the</strong> efficacy of anti-EGFR antibody treatment has<br />
not been reported for mCRC.<br />
Method: We evaluated tumor response and survival in patients who received anti-EGFR<br />
antibody by mutation analysis of KRAS, NRAS, BRAF, and PIK3CA in KRAS-WT<br />
patients with mCRC. Tumor DNA samples were obtained from patients treated in our<br />
hospital with anti-EGFR antibody between August 2008 and August 2011.<br />
Result: A total of 117 patients were eligible for this analysis, including 100<br />
KRAS-WT patients. Seventy-one patients (60.7%) were all WT for KRAS, NRAS,<br />
BRAF, and PIK3CA, and 46 patients (39.3%) had at least 1 mutation or had<br />
insufficient DNA samples to analyze. Mutations of KRAS codon 61 (2 patients),<br />
KRAS codon 146 (5), BRAF V600E (2), PIK3CA exon9 (8), NRAS codon 12/13 (2),<br />
and NRAS codon 61 (5) were detected. No patients had a mutation of PIK3CA exon<br />
20. Patients with at least 1 mutation had no response. Mutations of KRAS codon<br />
146, NRAS 61, and BRAF V600E were associated with a shorter progression free<br />
survival (PFS) compared with all WT patients (p = 0.049, p = 0.004, p = 0.036,<br />
respectively). Twelve patients (12% of KRAS-WT patients) with a mutation of KRAS<br />
codon 146, BRAF V600E, NRAS codon 61 had poor prognosis compared with <strong>the</strong><br />
o<strong>the</strong>r KRAS-WT patients (PFS, 6.4 vs 2.0 months, p < 0.001; overall survival (OS),<br />
13.7 vs 7.9 months, p = 0.012). In all WT patients, EGFR IHC 3+ and gene<br />
amplification by DISH were associated with a better response rate than negative and<br />
weak IHC and no gene amplification (p = 0.046). Conclusion: Mutations of KRAS<br />
codon 146, NRAS codon 61, and BRAF V600E were a strong prognostic factor of<br />
anti-EGFR antibody in patients with mCRC. Combination of IHC and DISH of<br />
EGFR could identify patients with a tumor response to anti-EGFR antibody in<br />
patients that are all wild type for KRAS, NRAS, BRAF, and PIK3CA.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1650P ANALYSIS OF CD40 EXPRESSION ON CIRCULATING<br />
COLORECTAL CANCER CELLS<br />
M. Torchio 1 , G. Comolli 2 , M. Danova 1 , G. Mazzini 3<br />
1 Medical Oncology and Internal Medicine, Azienda Ospedaliera della Provincia di<br />
Pavia, Ospedale Civile di Vigevano, Vigevano, ITALY, 2 Microbiology and<br />
Molecular Biology, IRCCS San Matteo Pavia, Pavia, ITALY, 3 IGM-CNR di Pavia,<br />
Istituto di Genetica Molecolare IGM-CNR, Pavia, ITALY<br />
Background: In colorectal cancer circulating tumor cells (CTCs) can be clinically<br />
relevant as: prognostic factor and predictive biomarker for treatment efficacy. The<br />
detecting and <strong>the</strong> carachterization of CTCs remains technically challenging. The cell<br />
surface costimulatory molecule CD40, widely expressed by lymphoid cells and by<br />
various tumour types, has been indicated as prognostic/predictive biomarker and as a<br />
potential target for <strong>the</strong>rapy. In <strong>the</strong> present study we wanted to demonstrate <strong>the</strong> value<br />
of a multiparameter flow cytometry (FCM) approach for <strong>the</strong> detection and <strong>the</strong><br />
characterization of circulating colorectal cancer cells in vivo.<br />
Methods: SW48 and HCT116 human colorectal cancer cells (highly positive for<br />
CD40) were serially diluted in normal whole blood to evaluate <strong>the</strong> sensitivity of <strong>the</strong><br />
method in both <strong>the</strong> cancer cell identification and characterization for CD40<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds417 | ix529
expression. Then, we analyzed PB samples from 10 patients with advanced colorectal<br />
cancer to identify CTCs; PB from normal subjects was utilized as negative control.<br />
Analyses were performed using a Navios FCM (Beckman Coulter ®) equipped with a<br />
dedicated software for multidimensional analyses.<br />
Results: The method was found to have a sensitivity limit of 10(-5). The specificity was<br />
100%. In 8 patients we were able to differentiate in vivo CTCs from normal mononuclear<br />
cells based on increased light scatter parameters, cell marker expression (EpCAM+<br />
CD45-) and nuclear stain with 4’6-diamidino-2-phenylindole. In half of <strong>the</strong> patients <strong>the</strong><br />
simultaneous analysis of <strong>the</strong> CD40 expression revealed significant high levels.<br />
Conclusions: Multiparameter FCM can detect CTCs in colorectal cancer patients<br />
and allows simultaneous immunophenotype analysis. CTC identification and<br />
characterization represent emerging applications of FCM in solid tumor biology.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1651P SPHINGOSINE KINASE 1 (SPHK1) OVEREXPRESSION<br />
CONTRIBUTES TO CETUXIMAB RESISTANCE IN HUMAN<br />
COLORECTAL CANCER MODELS<br />
L. Formisano 1 , L. Nappi 1 , R. Rosa 1 , V. Damiano 1 , R. Marciano 1 ,C.D’Amato 1 ,<br />
C. Carlomagno 1 , G. Troncone 2 , S. De Placido 1 , R. Bianco 1<br />
1 Medical Oncology, University Federico II, Napoli, ITALY, 2 Surgical Pathology,<br />
Università Federico II, Napoli, ITALY<br />
Purpose: Although <strong>the</strong> anti-Epidermal Growth Factor (EGFR) monoclonal antibody<br />
(mAb) cetuximab is an effective strategy in colorectal cancer <strong>the</strong>rapy, its clinical use<br />
is limited by intrinsic or acquired resistance. Alterations in <strong>the</strong> ‘sphingolipid rheostat’<br />
- <strong>the</strong> balance between <strong>the</strong> proapoptotic molecule ceramide and <strong>the</strong> mitogenic factor<br />
sphingosine-1-phosphate (S1P) - due to sphingosine kinase 1 (SphK1) overactivation<br />
have been involved in resistance to anticancer targeted agents. Moreover, cross-talks<br />
between SphK1 and EGFR-dependent signalling pathways have been described.<br />
Experimental design: In this study, we investigated SphK1 contribution to<br />
cetuximab resistance in colorectal cancer in preclinical in vitro/in vivo models and in<br />
tumor specimens from patients.<br />
Results: Immunohistochemical analysis on colorectal cancer tissues revealed a<br />
correlation between SphK1 expression and K-Ras mutations. Moreover, SphK1 was<br />
found overexpressed and overactivated in colorectal cancer cells with intrinsic or<br />
acquired resistance to cetuximab. SphK1 contribution to resistance was supported by<br />
<strong>the</strong> demonstration that SphK1 inhibition by N,N-dimethyl-sphingosine (DMS) or<br />
silencing via siRNA in resistant cells restores sensitivity to cetuximab, whereas<br />
exogenous SphK1 overexpression in sensitive cells confers resistance to <strong>the</strong>se agents.<br />
Finally, treatment of resistant cells with fingolimod (FTY720), a S1P receptor (S1PR)<br />
inhibitor, resulted in re-sensitization to cetuximab both in vitro and in vivo, with<br />
significant inhibition of tumor growth, interference with signal transduction,<br />
induction of cancer cells apoptosis and prolongation of mice survival.<br />
Conclusion: Our data could contribute to clarify SphK1 role in cetuximab resistance<br />
and may suggest SphK1 inhibition as a part of novel targeting strategies potentially<br />
effective also in resistant colorectal cancer patients.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1652P CYCLOOXYGENASE-2 INHIBITION ENHANCES THE<br />
ANTI-TUMORAL ACTIVITY OF THE MULTI-TARGET KINASE<br />
INHIBITOR AEE788 IN COLORECTAL CANCER CELLS<br />
A.M. Valverde Estepa 1 , A. Cañas 1 , V. Hernández Nieto 2 , C. Lopez Pedrera 2 ,<br />
J. De La Haba Rodriguez 2 , A. Rodríguez Ariza 2 , E. Aranda Aguilar 2<br />
1 Oncology Department, IMIBIC, Hospital Reina Sofia, Córdoba, SPAIN,<br />
2 Oncology Deparment, IMIBIC-Hospital Reina Sofía, Córdoba, SPAIN<br />
Introduction: KRAS and BRAF mutations are common in colorectal cancer and<br />
confer resistance to anti-EGFR <strong>the</strong>rapy. AEE788 is a multiple kinase inhibitor, with a<br />
potent inhibitory activity against both EGFR and VEGFR. The aim of this study was<br />
to determine <strong>the</strong> efficacy of AEE788 as anti-tumor treatment in colorectal cancer<br />
cells with different RAS/BRAF mutational status.<br />
Material and method: The human colorectal cancer cell lines SW48 (KRAS/BRAF<br />
non-mutated), Caco-2 (BRAF V600E) and HCT-116 (KRAS G13D) were treated<br />
with AEE788, in <strong>the</strong> presence or <strong>the</strong> absence of EGF or VEGF. Cell proliferation was<br />
measured using a colorimetric XTT assay, cellular apoptosis was measured using<br />
flow-cytometry and VEGF production was analyzed by ELISA. The expression and/<br />
or phosphorylation levels of EGFR, VEGFR, Akt, Erk1/2, and COX-2 were<br />
determined by western-blot using <strong>the</strong> corresponding specific antibodies.<br />
Results: Although AEE788 effectively inhibited EGFR phosphorylation in all three<br />
cell lines, <strong>the</strong> more effective inhibition of EGF-dependent growth was observed in<br />
Caco-2 cells. In <strong>the</strong>se cells AEE788 inhibited <strong>the</strong> activation of intracellular kinases<br />
Akt and ERK1 / 2, efficiently induced apoptosis and caused cell cycle arrest at G1/<br />
M transition. Fur<strong>the</strong>rmore, AEE788 reduced in Caco-2 cells both VEGF<br />
production and VEGF-dependent growth, effects that were associated with <strong>the</strong><br />
inhibition of ERK1/2 phosphorylation and <strong>the</strong> increased expression of COX-2<br />
Annals of Oncology<br />
observed in <strong>the</strong>se cells. Accordingly, <strong>the</strong> addition of specific inhibitors of COX-2<br />
(celecoxib and NS-398) significantly enhanced <strong>the</strong> antitumor effect of AEE788 in<br />
Caco-2 cells.<br />
Conclusion: Our results support <strong>the</strong> notion that that AEE788 can be effective in <strong>the</strong><br />
treatment of colorectal cancer. Besides, its antitumoral efficacy may be potentiated by<br />
combination with COX-2 inhibitors.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1653P DICER AND DROSHA EXPRESSION AND RESPONSE TO<br />
BEVACIZUMAB-BASED THERAPY IN ADVANCED<br />
COLORECTAL CANCER PATIENTS<br />
A. Zoccoli 1 , M. Iuliani 1 , F. Pantano 1 , G. Schiavon 2 , R. Ratta 1 , P. Correale 3 ,<br />
A. Onetti Muda 4 , D. Santini 1 , G. Tonini 1 , B. Vincenzi 1<br />
1 Medical Oncology, University Campus Bio-Medico, Rome, ITALY, 2 Internal<br />
Oncology, Erasmus MC Daniel den Hoed Cancer Center, Rotterdam,<br />
NETHERLANDS, 3 Medical Oncology Unit, Oncology Department, Azienda<br />
Ospedaliera Universitaria Senese, Siena, ITALY, 4 Pathology Department,<br />
university campus bio-medico, rome, ITALY<br />
Introduction: The miRNA-regulating enzyme Dicer and Drosha exhibit aberrant<br />
expression in several cancer types. Dicer and Drosha play a crucial role during <strong>the</strong><br />
angiogenetic process in vitro and, for Dicer, in vivo. We aimed to investigate <strong>the</strong><br />
potential role of Dicer and Drosha in predicting response to Bevacizumab-based<br />
<strong>the</strong>rapy in advanced CRC patients.<br />
Methods: We measured Dicer and Drosha messenger RNA (mRNA) levels in<br />
formalin-fixed paraffin-embedded specimens of advanced CRC treated with (n = 76)<br />
or without (n = 28) Bevacizumab-containing regimens and patients with<br />
diverticulosis (normal mucosa) (n = 20), using a quantitative reverse-transcriptasepolymerase-chain<br />
reaction assay, and compared <strong>the</strong> results with clinical outcome.<br />
Results: We found that lower Dicer levels predicted a longer Progression-Free<br />
Survival (PFS) (P = .0001) and Overall Survival (OS) (P = .031) in<br />
Bevacizumab-treated patients. Conversely, Drosha levels were not associated<br />
with prognosis. Low Dicer levels were associated with better response to<br />
Bevacizumab-based treatments versus high Dicer levels (2.6% complete<br />
responses and 43.4% partial responses versus 1.3% and 28.9%, respectively;<br />
P = .045). Multivariate analysis identified three independent predictors of<br />
improved OS: high performance status [Relative Risk (RR) 1.56; P = .009], lower<br />
organs involvement (RR 0.72; P = .025) and low Dicer expression (RR 0.62;<br />
P = .009). Importantly, Dicer and Drosha expression did not correlate with<br />
outcome in not Bevacizumab-treated patients. Moreover we analysed Dicer and<br />
Drosha mRNA levels; our results showed a significantly higher Drosha<br />
expression in primary tumors than in normal mucosa (P =
Annals of Oncology<br />
stabilisation, but no objective responses were observed. The median PFS and OS were<br />
2.8 (range 2.1-4.0) and 5.4 (range 4.3-7.0) months (mo), respectively. Pre-treatment<br />
blood samples and archival tumor tissue were available for analysis in all patients.<br />
Thirty-three mutations were detectable in <strong>the</strong> peripheral blood, whereas 7 patients<br />
had primary tumor mutations and wildtype status according to <strong>the</strong> blood sample.<br />
The median level of pKRAS alleles was 900 alleles/ml. When divided into quartiles of<br />
pKRAS, significantly shorter PFS and OS were revealed with increasing levels of<br />
alleles. The median PFS was 2.1 mo (95%CI 1.9-2.1) in patients with high levels (><br />
median) compared to 4.2 mo (95%CI 2.5-5.1) in those with lower levels (< median)<br />
(HR = 3.0, p = 0.0002), and <strong>the</strong> OS 4.1 (95%CI 3.0-5.2) and 8.0 (95%CI 5.1-9.6) mo,<br />
respectively (HR = 3.0, p = 0.0005).<br />
Conclusion: A high pre-treatment level of pKRAS alleles had a detrimental effect<br />
on both PFS and OS, whereas low levels were correlated to a better chance of<br />
disease stabilisation. This confirms our data from two previous study cohorts and<br />
pKRAS could <strong>the</strong>refore serve as a new prognostic marker in KRAS mutant<br />
mCRC.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1655P HIGH MRNA EXPRESSION OF LMO4, A BRCA1<br />
DOWNREGULATOR, CORRELATES WITH BETTER<br />
PROGNOSIS IN ERLOTINIB-TREATED NON-SMALL-CELL<br />
LUNG CANCER (NSCLC) PATIENTS (P) WITH EGFR<br />
MUTATIONS<br />
N. Karachaliou 1 , C. Costa 2 , A. Gimenez-Capitan 2 , S. Viteri 1 , A. Gasco 1 ,<br />
C. Camps 3 , E. Carcereny 4 , B. Massuti Sureda 5 , J. Souglakos 6 , R. Rosell 4<br />
1 Oncology, Instituto Oncologico Dr Rosell, USP Dexeus University Institute,<br />
Barcelona, SPAIN, 2 Laboratoy of Biology Department, Pangaea Biotech, USP<br />
Dexeus University Institute, Barcelona, SPAIN, 3 Oncology, Hospital General de<br />
Valencia, Valencia, SPAIN, 4 Medical Oncology Service, Catalan Institute of<br />
Oncology, Hospital Germans Trias i Pujol, Badalona, SPAIN, 5 Medical Oncology<br />
Dpt, Hospital General Universitario de Alicante, Alicante, SPAIN, 6 Oncology,<br />
University Hospital of Heraklion, Crete, GREECE<br />
Background: High BRCA1 mRNA levels affected progression-free survival (PFS) to<br />
erlotinib in EGFR-mutant NSCLC p (Rosell et al. CCR 2011). LMO4 is a negative<br />
regulator of BRCA1 function, and CtIP can bind to BRCA1 and LMO4. We have<br />
assessed <strong>the</strong> expression of CtIP, LMO4 and BRCA1 and examined <strong>the</strong> impact of CtIP<br />
and LMO4 levels on outcome.<br />
Methods: mRNA expression of BRCA1, LMO4 and CtIP was examined by RT-PCR<br />
in <strong>the</strong> original pretreatment tumor biopsies of 72 erlotinb-treated NSCLC p with<br />
sensitive EGFR mutations.<br />
Results: p characteristics: median age, 68; 61.8% female; 98.2% Caucasian; 63.6%<br />
never-smokers; 81.8% ECOG PS < 2; 95 adenocarcinoma; 94.5% stage IV. BRCA1<br />
expression correlated with that of CtIP (ρ = 0.31; P = 0.01) and LMO4 (ρ = 0.32; P<br />
= 0.02). PFS for p with high LMO4 levels was not reached while it was 13<br />
months (m) for p with low levels (P = 0.006). Overall survival (OS) was not<br />
reached for p with high levels of LMO4 and was 31 m for p with low levels (P =<br />
0.17). PFS was not reached for p with low BRCA1 and high LMO4 levels and was<br />
19 m for p with low levels of both genes (P = 0.04). PFS was 8 m for p with high<br />
BRCA1 and low LMO4 levels and 18 m for p with high levels of both genes (P =<br />
0.03). In <strong>the</strong> multivariate analysis, BRCA1 and LMO4 expression emerged as<br />
markers of PFS (Table).<br />
Conclusions: Low BRCA1 and high LMO4 levels were associated with longer<br />
PFS in erlotinib-treated advanced NSCLC p with EGFR mutations. We<br />
recommend baseline assessment of BRCA1 and LMO4 mRNA expression to<br />
predict outcome and provide alternative individualized treatment to patients<br />
when indicated.<br />
HR 95%CI P<br />
BRCA1<br />
≤4.92 1 ref.<br />
4.92-10.7 5.32 1.45-19.52 0.03<br />
>10.7<br />
CtIP<br />
5.13 1.25-20.99 0.02<br />
≤1.21 1 ref.<br />
1.21-2.1 0.69 0.24-2.02 0.50<br />
>2.1<br />
LMO4<br />
1.10 0.42-2.89 0.84<br />
≤1.29 6.02 1.51-23.94 0.01<br />
1.29-1.86 2.81 0.85-9.21 0.09<br />
>1.86 1 ref.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1656P BREAST CANCER (BC) AND THE STUDY OF INTRATUMORAL<br />
HETEROGENEITY THROUGH PI3K PATHWAY-BIOMARKERS<br />
L. De Mattos-Arruda 1 , J. Cortes 1 , C.M. Aura 2 , J. Gregori 3 , G. Caratú 4 , C. Saura 1 ,<br />
M. Oliveira 1 , J. Tabernero 1 , J. Seoane 5 , A. Vivancos 4<br />
1 Medical Oncology Department, Vall d’Hebron Institute of Oncology, Vall<br />
d’Hebron University Hospital, Barcelona, SPAIN, 2 Molecular Pathology, Vall<br />
d’Hebron University Hospital, Barcelona, SPAIN, 3 Statistics Department, Faculty<br />
of Biology, Barcelona University, Barcelona, SPAIN, 4 Genomics Laboratory, Vall<br />
d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona,<br />
SPAIN, 5 Gene Expression and Cancer Laboratory, Vall d’Hebron Institute of<br />
Oncology, Vall d’Hebron University Hospital, Barcelona, SPAIN<br />
Introduction: Alterations of <strong>the</strong> PI3K pathway are BC drivers. Intratumoral<br />
heterogeneity seems to be key to deal with <strong>the</strong>rapeutic resistance. In this study, we<br />
analyzed <strong>the</strong> presence, intratumor distribution and prognostic implications of<br />
PI3K-pathway biomarkers (PTEN expression and PIK3CA point mutations).<br />
Methods: 99 BC formalin-fixed, paraffin-embedded (FFPE) tumor-tissues and 20<br />
matched plasma samples were assessed. PTEN expression was determined by<br />
immunohistochemistry (IHC); <strong>the</strong> H-score was calculated by multiplying <strong>the</strong> percentage<br />
fraction of positively stained tumor area (TA) by staining intensity (0, 1 + , 2 + , or 3+).<br />
Sorting <strong>the</strong> H-scores, with h 1 as <strong>the</strong> highest and h 3 as <strong>the</strong> lowest, and normalizing <strong>the</strong>m<br />
to add to 100, i.e. h` 1 =h 1/(h 1 +h 2 +h 3)*100, and taking <strong>the</strong> maximum value: Hm =<br />
max i (h’ i)=h’ 1. The sample was classified as homogeneous (Ho) when ei<strong>the</strong>r Hm ≥ 90<br />
or Hm = 0, o<strong>the</strong>rwise as heterogeneous (He). PTEN low: H-score< 50. PIK3CA and its<br />
% mutant alleles (mA) from FFPE or cell-free DNA (cfDNA) in plasma were<br />
determined by OncoCarta Panel v1.0 (Sequenom). TA and stromal area (SA) were<br />
scored by H&E; real tumor area: RTA = TA-SA. Metastatic BC patients (pts) were<br />
classified: ER + /HER2- (LUM); HER2+ (HER2); triple negative (TN).<br />
Results: 42% (41/97) of FFPE had PTEN Ho, 29.9% (29/97) PTEN low and 36% (33/<br />
96) PIK3CA mutations. For PTEN, <strong>the</strong>re was a trend for less homogeneity among LUM<br />
vs. non-LUM tumors (41 vs. 59%, p = 0.067). PIK3CA was more homogeneously<br />
distributed within LUM than non-LUM as <strong>the</strong>re was a significant linear correlation<br />
between mA and RTA (r = 0.77, p = 0.00008). Prognosis was better for LUM pts (N =<br />
98, p = 0.0002), but did not differ between Ho vs. He (N = 95, p = 0.123) or PIK3CA<br />
mutant vs. non mutant pts (N = 89, p = 0.23). CfDNA among PIK3CA mutant pts had<br />
a concordance of 58% (7/12, 1 st sample for advanced BC pts) and 12.5% (1/8, 2 nd<br />
matched sample in 1 st follow-up), reflecting changes with treatment as compared with<br />
<strong>the</strong> primary/metastatic FFPE. Updated analysis will be presented.<br />
Conclusions: The intratumoral heterogeneity of PTEN and PIK3CA mutations were<br />
detected. In <strong>the</strong> case of LUM tumors, while PIK3CA mutations seemed to be more<br />
homogeneously distributed, reassuring its driver role, PTEN tended to be more<br />
heterogeneous. Profiling cfDNA could be essential to mirror <strong>the</strong> tumor from which<br />
<strong>the</strong>y derive.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1657P BIOMARKER (BM) RESULTS FROM THE PHASE III AVEREL<br />
TRIAL OF 1ST-LINE BEVACIZUMAB (BV), TRASTUZUMAB (H)<br />
+ DOCETAXEL (T) FOR HER2-POSITIVE LOCALLY<br />
RECURRENT/METASTATIC BREAST CANCER (LR/MBC)<br />
L. Gianni 1 , A. Chan 2 , M. Mansutti 3 , X. Pivot 4 , R. Greil 5 , L. Provencher 6 ,S.Prot 7 ,<br />
N. Moore 8 , S.J. Scherer 9 , C. Pallaud 10<br />
1 Medical Oncology, IRCCS San Raffaele, Milano, ITALY, 2 Breast Clinical Trials<br />
Unit, Mount Hospital, Perth, AUSTRALIA, 3 Oncology, University Hospital<br />
S. Maria Misericordia, Udine, ITALY, 4 Service Oncologie Medicale, C.H.U. Jean<br />
Minjoz, Besancon Cedex, FRANCE, 5 IIIrd Medical Department, Paracelsus<br />
University Hospital Salzburg, Salzburg, AUSTRIA, 6 Centre Des Maladies Du Sein<br />
Deschenes-fabia, CHA-Hôpital du Saint-Sacrement, Quebec, CANADA, 7 PDC, F<br />
Hoffmann-La Roche Ltd, Basel, SWITZERLAND, 8 Biostatistics, F Hoffmann-La<br />
Roche Ltd, Basel, SWITZERLAND, 9 Pharma Development, Genentech, Inc.,<br />
South San Francisco, CA, UNITED STATES OF AMERICA, 10 Pharma<br />
Development Oncology Business, F Hoffmann-La Roche Ltd, Basel,<br />
SWITZERLAND<br />
Background: AVEREL efficacy and safety results have been reported. We present<br />
exploratory analyses from <strong>the</strong> optional BM substudy.<br />
Methods: Patients (pts) with HER2-positive LR/mBC received 1st-line T (100 mg/m 2<br />
q3w) + H (8 → 6 mg/kg q3w) ± BV (15 mg/kg q3w). The primary endpoint was<br />
investigator-assessed PFS. Baseline (BL) blood and tissue samples were collected from<br />
consenting pts. BL plasma levels of candidate BMs were measured using a novel<br />
ELISA. Median BL values for each BM were used to define high (> median; H) vs<br />
low (≤ median; L) BM cohorts and to correlate BMs with PFS using Cox regression<br />
corrected for prognostic factors.<br />
Results: Plasma samples were available from 162/424 pts (38%). ICAM-1 correlated<br />
statistically significantly with PFS at α = 0.05.<br />
Conclusions: High BL ICAM-1 correlated significantly with greater PFS benefit from<br />
BV at α = 0.05, consistent with data in lung cancer. VEGF-A, VEGFR-2 and -3 and<br />
E-selectin showed potential predictive value. VEGF-A and VEGFR-2 results are in<br />
line with data in HER2-negative mBC and pancreatic cancer.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds417 | ix531
Table: 1657P<br />
TH BV + TH<br />
HR (95% CI) Interaction p value a<br />
Subgroup Events/pts, n Median, mo Events/pts, n Median, mo<br />
All 64/82 11.2 66/80 16.5 0.78 (0.56–1.11)<br />
E-selectin L H 31/44 32/37 16.4 8.2 30/36 35/43 16.5 16.6 1.01 (0.61–1.68) 0.57 (0.35–0.92) 0.241<br />
IL-8 L H 35/45 28/36 13.6 8.4 28/35 37/44 16.4 17.8 0.84 (0.51–1.40) 0.74 (0.45–1.22) 0.506<br />
ICAM-1 L H 30/45 33/36 16.4 10.3 29/35 36/44 16.5 16.2 1.13 (0.68–1.89) 0.49 (0.30–0.80) 0.017<br />
bFGF L H 32/41 31/40 13.3 11.1 33/39 32/40 16.4 19.1 0.80 (0.49–1.30) 0.80 (0.49–1.32) 0.837<br />
PDGF-C L H 29/40 35/42 17.1 8.5 32/41 34/39 16.5 16.6 0.87 (0.52–1.44) 0.72 (0.45–1.16) 0.342<br />
VEGF-A L 33/45 13.6 30/36 16.5 0.83 (0.50–1.36) 0.795<br />
H 31/37 8.5 35/43 16.6 0.70 (0.43–1.14)<br />
VEGF-C L H 35/42 29/40 13.5 9.6 32/39 34/41 14.8 19.1 0.70 (0.43–1.15) 0.92 (0.56–1.51) 0.649<br />
VEGFR-1 L H 30/40 33/41 11.1 13.3 33/40 32/39 16.2 16.6 0.76 (0.46–1.25) 0.84 (0.52–1.37) 0.982<br />
VEGFR-2 L H 35/44 28/37 11.2 11.0 30/36 35/43 13.7 19.2 0.95 (0.58–1.55) 0.67 (0.40–1.10) 0.174<br />
VEGFR-3 L H 35/48 28/33 12.2 11.0 25/32 40/47 15.3 16.6 0.88 (0.52–1.47) 0.65 (0.40–1.06) 0.051<br />
a Model includes prognostic factors.<br />
Disclosure: L. Gianni: LG acts as a Consultant and has sat on Advisory Boards for Roche,<br />
Genentech, GSK, Novartis, Pfizer, Boehringer Ingelheim, Astra Zeneca, and Celgene. A.<br />
Chan: AC has acted as a Consultant, sat on Advisory Boards, and received honoraria and<br />
research funding from Roche. X. Pivot: XP has acted as a Consultant and sat on Advisory<br />
Boards for Roche, Eisai and GlaxoSmithKline, and has received honoraria from Sanofi. R.<br />
Greil: RG has acted as a Consultant for, sat on Advisory Boards for, and received<br />
honoraria and research funding from Roche. L. Provencher: LP has received a travel grant<br />
and honoraria from Roche.S. Prot: SP is an employee of F Hoffmann-La Roche Ltd. N.<br />
Moore: NM is an employee and holds stock in F Hoffmann-La Roche Ltd. S.J. Scherer: SS<br />
is an employee of Genentech. C. Pallaud: CP is an employee of F Hoffmann-La Roche Ltd.<br />
.All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1658P DIFFUSE REFLECTANCE SPECTROSCOPY; TOWARDS<br />
CLINICAL APPLICATION IN BREAST CANCER<br />
T.J.M. Ruers 1 , D. Evers 1 , R. Nachabé 2 , M.J. Vranken Peeters 1 , J. van der Hage 1 ,<br />
H. Oldenburg 1 , E. Rutgers 1 , G. Lucassen 2 , B. Hendriks 2 , J. Wesseling 3<br />
1 Surgery, The Ne<strong>the</strong>rlands Cancer Institute Antoni van Leeuwenhoek Hospital,<br />
Amsterdam, NETHERLANDS, 2 Minimally Invasive Healthcare, Philips Research,<br />
Eindhoven, NETHERLANDS, 3 Pathology, The Ne<strong>the</strong>rlands Cancer Institute<br />
Antoni van Leeuwenhoek Hospital, Amsterdam, NETHERLANDS<br />
Background: Diffuse reflectance spectroscopy (DRS) is a promising new technique<br />
for breast cancer diagnosis. During DRS tissue is illuminated by a selected light<br />
spectrum. By specific absorption and scattering characteristics of <strong>the</strong> tissue an<br />
‘optical fingerprint’ is obtained which represents specific morphological information.<br />
In this way DRS is able to differentiate normal tissue from tumor tissue. Here we<br />
compared <strong>the</strong> diagnostic accuracy of DRS in a cohort of patients and each patient<br />
individually to <strong>the</strong> pathology analysis of normal and malignant breast tissue.<br />
Methods: Breast tissue from 47 female patients was analysed ex-vivo by DRS. A total<br />
of 1073 optical spectra were collected from fat, glandular tissue and fibroadenoma<br />
lesions as well as from (pre)-malignant tissue samples. These spectra were analyzed<br />
for each patient individually as well as for all patients collectively. Results were<br />
compared to <strong>the</strong> pathology analysis of biopsies from each measurement location.<br />
Results: Collective patient data analysis for discrimination between normal and<br />
malignant breast tissue resulted in a sensitivity of 90%, a specificity of 88% and an<br />
overall accuracy of 89%. For individual analysis all measurements per patient were<br />
categorized as ei<strong>the</strong>r benign or malignant. The discriminative accuracy of this individual<br />
analysis was nearly 100%. When an arbitrary threshold was used of a 90% agreement<br />
between all DRS measurements and <strong>the</strong> pathology analysis for each individual patient to<br />
ascertain a diagnosis, only in one patient <strong>the</strong> diagnosis was classified as uncertain.<br />
Conclusions: Our results demonstrate that diffuse reflectance spectroscopy can be<br />
considered as an important new optical sensing technique that could improve <strong>the</strong><br />
diagnostic workflow in breast cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1659P EFFECTS OF SRC INHIBITION ON SURVIVAL, MIGRATION<br />
AND INVASION OF HUMAN BREAST CANCER CELLS<br />
RESISTANT TO LAPATINIB<br />
L. Nappi, L. Formisano, R. Rosa, V. Damiano, T. Gelardi, C. D’Amato,<br />
V. D’Amato, R. Marciano, A.P. De Maio, R. Bianco<br />
Medical Oncology, University Federico II, Napoli, ITALY<br />
Background: HER2, a member of <strong>the</strong> HER family, is a transmembrane tyrosine<br />
kinase receptor overexpressed in almost 30% of breast cancer patients. Lapatinib is a<br />
small molecule HER2 inhibitor approved in metastatic breast cancer patients after<br />
Annals of Oncology<br />
trastuzumab failure. Unfortunately, <strong>the</strong> resistance against lapatinib is observed even<br />
in responding patients. Src is an intracellular kinase involved in tumor growth,<br />
angiogenesis and migration and it is related to trastuzumab resistance in human<br />
breast cancer cell lines.<br />
Materials and methods: We used different HER2 expressing human breast cancer<br />
cell lines, such as MDA-MB-361, MDA-MB-231 and BT474 (sensitive to lapatinib)<br />
JIMT-1 and KPL-4 (low sensitivity against lapatinib), and MDA-MB-361-LR<br />
(acquired resistance to lapatinib). We performed survival, migration and invasion<br />
assays and WB analysis in all cell lines treated with lapatinib, saracatinib (a Src<br />
inhibitor) or <strong>the</strong> combination. We also used nude mice xenografted with JIMT-1<br />
cells and in vivo artificial metastatic assay.<br />
Results: We observed that <strong>the</strong> combination treatment of lapatinib plus saracatinib is<br />
able to inhibit survival, migration and invasion in vitro and to regulate several<br />
proteins such as Src, Akt, MAPK, paxillin and FAK in all cancer cell lines tested. In<br />
nude mice xenografted with JIMT-1 cells, <strong>the</strong> combined treatment reduced tumor<br />
growth, prolonged survival and strongly decreased <strong>the</strong> incidence of lung metastases.<br />
Interestingly, we observed that Src preferentially binds to HER2 in lapatinib sensitive<br />
cells and with EGFR in resistant ones. EGFR inhibition, through <strong>the</strong> use of<br />
cetuximab or siRNA silencing, strongly enhanced <strong>the</strong> effect of lapatinib on <strong>the</strong><br />
growth of resistant cancer cells. The combined treatment of lapatinib and cetuximab,<br />
moreover, significantly reduced <strong>the</strong> activation of several intracellular transducers.<br />
Conclusions: We demonstrated that Src plays an important role in <strong>the</strong> development<br />
of resistance to lapatinib in breast cancer cell lines, in particular affecting invasion<br />
and migration, and that EGFR may mediate its activation. These results may suggest<br />
<strong>the</strong> clinical development of lapatinib and cetuximab combination in patients resistant<br />
to lapatinib.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1660P EPIGENETIC SILENCING OF ARGININO-SUCCINATE<br />
SYNTHASE (ASS1) DEFINES ARGININE DEPLETION<br />
THERAPY AS A NOVEL TREATMENT STRATEGY FOR<br />
BREAST CANCER<br />
F. Cavicchioli 1 , A. Shia 1 ,K.O’Leary 1 , V. Haley 1 , C. Palmieri 2 ,N.Syed 3 ,<br />
T. Crook 4 , A.M. Thompson 5 , C. Lo Nigro 6 , P. Schmid 7<br />
1 Oncology, Brighton and Sussex Medical School, Brighton, UNITED KINGDOM,<br />
2 Hammersmith Campus, Charing Cross HospitalImperial College Healthcare<br />
NHS Trust, London, UNITED KINGDOM, 3 Faculty of Medicine, Imperial College<br />
of London, London, UNITED KINGDOM, 4 Dundee Cancer Centre, University of<br />
Dundee, Dundee, UNITED KINGDOM, 5 Surgery and Molecular Oncology,<br />
University of Dundee, Dundee, UNITED KINGDOM, 6 Oncology, S. Croce General<br />
Hospital, Cuneo, ITALY, 7 Clinical Investigation and Research Unit, Brighton and<br />
Sussex Medical School, Brighton, UNITED KINGDOM<br />
Background: Loss of argininosuccinate syn<strong>the</strong>tase (ASS1) or lyase (ASL) expression,<br />
critical for <strong>the</strong> biosyn<strong>the</strong>sis of arginine in normal tissues, due to<br />
methylation-dependent silencing sensitises ovarian or glioblastoma cells to arginine<br />
depletion <strong>the</strong>rapy (ADT). Cells not expressing sufficient levels of ASS1 or ASL<br />
become auxotrophic for arginine and require exogenous supply. Arginine deiminase<br />
(ADI), a novel arginine-degrading enzyme, can eliminate arginine from <strong>the</strong><br />
circulation and has shown activity in cancers with low ASS1 and/or ASL activity.<br />
This study was performed to establish whe<strong>the</strong>r ASS1 or ASL are subject to<br />
methylation-dependent silencing in breast cancer to validate ADT as a novel<br />
<strong>the</strong>rapeutic strategy for breast cancer.<br />
Methods: Methylation of ASS1 and/or ASL was analysed by pyrosequencing and<br />
methylation-specific PCR (MSP) using primer sets validated by bisulphite<br />
sequencing. We used a panel of 19 breast cancer cell lines and two independent<br />
series of stage I-III primary breast cancers with linked mature clinical outcome that<br />
ix532 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
were randomly selected from <strong>the</strong> Tayside (n = 224) and Cuneo (n = 150) Tissue<br />
Banks. Tissue samples were subject to histopathological review to ensure adequate<br />
representation of cancer cells.<br />
Results: Although ASS1 or ASL methylation could not be verified in breast cancer cell<br />
lines, ASS1 methylation was evident in a significant proportion of primary or metastatic<br />
breast cancer samples. In two independent series, aberrant methylation of ASS1 was<br />
detected in 4.5% and 16% of primary breast cancers. The incidence was even higher in<br />
metastatic breast cancer, with 47% of resected brain metastases (n = 19) showing<br />
methylation of ASS1 and 26% showing additional methylation of ASL, a combination<br />
that has shown to be highly sensitive to ADT. ASS1 methylation status as called by MSP<br />
agreed with that determined by pyrosequencing in all cases assessed by both methods.<br />
No significant association with a specific tumour type or outcome was found.<br />
Conclusions: A significant proportion of primary and metastatic breast cancers show<br />
methylation-dependent transcriptional silencing of ASS1 or ASL and might be<br />
candidates for arginine depletion <strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1661P THE PREDICTIVE ROLE OF THE 53BP1 PATHWAY IN<br />
ADVANCED NON-SMALL-CELL LUNG CANCER (NSCLC)<br />
PATIENTS (P) TREATED WITH FIRST-LINE<br />
PLATINUM-BASED CHEMOTHERAPY<br />
L. Bonanno 1 , C. Costa 2 , M. Majem 3 , A. Gimenez-Capitan 2 , I. Rodriguez 4 ,J.<br />
J. Sánchez 5 , B. Massuti Sureda 6 , A. Favaretto 1 , M. Rugge 7 , R. Rosell 8<br />
1 U.o.Oncologia Medica, Istituto Oncologico Veneto IOV-IRCCS, Padova, ITALY,<br />
2 Laboratoy of Biology Department, Pangaea Biotech, USP Dexeus University<br />
Institute, Barcelona, SPAIN, 3 Oncology, Hospital de Sant Pau, Barcelona,<br />
SPAIN, 4 Statistics, USP Dexeus University Institute, Barcelona, SPAIN,<br />
5 Statistics, Autonomous University of Madrid, Madrid, SPAIN, 6 Medical<br />
Oncology Dpt, Hospital General Universitario de Alicante, Alicante, SPAIN,<br />
7 Pathology and Cytopathology Unit, University of Padova, Padova, ITALY,<br />
8 Medical Oncology Service, Catalan Institute of Oncology, Hospital Germans<br />
Trias i Pujol, Badalona, SPAIN<br />
Background: Preclinical and clinical data have shown that low BRCA1 expression<br />
increases sensitivity to platinum. However, <strong>the</strong> complexity of DNA repair pathways<br />
suggests that <strong>the</strong> BRCA1 function could be modulated by several proteins. MDC1,<br />
<strong>the</strong> protein initiating <strong>the</strong> response to DNA double strand breaks, activates two<br />
parallel pathways: 53BP1 and BRCA1. We hypo<strong>the</strong>sized that <strong>the</strong> mRNA expression<br />
of components involved in <strong>the</strong> 53BP1 pathway could influence <strong>the</strong> predictive value of<br />
BRCA1.<br />
Methods: mRNA expression levels of BRCA1, MDC1, UBC13, RNF8, 53BP1, PIAS4,<br />
MMSET and UBC9 were assessed by real-time PCR analysis in 115<br />
paraffin-embedded tumor samples collected from advanced NSCLC p treated with<br />
first-line platinum-based chemo<strong>the</strong>rapy without taxanes.<br />
Results: Expression levels of BRCA1 were correlated with MDC1 (ρ = 0.47, P <<br />
0.0001), UBC13 (ρ = 0.41, P = 0.001), RNF8 (ρ = 0.41, P = 0.001), 53BP1 (ρ = 0.37,<br />
P = 0.003), PIAS4 (ρ = 0.51, P < 0.0001), MMSET (ρ = 0.57, P < 0.0001) and UBC9<br />
(ρ = 0.31,P = 0.01). Median overall survival (OS) was 11 months (m), and<br />
progression-free survival (PFS) was 7 m. Among p with low levels of BRCA1, median<br />
OS was 19.3 m and PFS was 10 m for p with low levels of 53BP1, compared to 8.2 m<br />
and 5.9 m, respectively, for p with high levels of 53BP1 (OS: P = 0.01; PFS: P <<br />
0.0001). Among p with high levels of BRCA1, no significant differences in OS were<br />
observed according to 53BP1 expression levels.<br />
Conclusions: Advanced NSCLC p with low levels of both BRCA1 and 53BP1 showed<br />
significantly improved outcome to first-line platinum-based chemo<strong>the</strong>rapy. The<br />
assessment of BRCA1 and 53BP1 can be useful for customizing chemo<strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1662P MCPH1 (BRIT1) AND OUTCOME TO ERLOTINIB IN<br />
NON-SMALL-CELL LUNG CANCER (NSCLC) PATIENTS (P)<br />
HARBORING EGFR MUTATIONS<br />
R. Garcia-Campelo 1 , J.J. Sánchez 2 , C. Costa 3 , C. Queralt 4 , I. De Aguirre 4 ,<br />
M.A. Molina, 3 , M. Majem 5 ,S.Cros 4 , L. Capdevila 4 , R. Rosell 4<br />
1 Oncology, Complejo Hospitalario Universitario A Coruña, A Coruña, SPAIN,<br />
2 Statistics, Autonomous University of Madrid, Madrid, SPAIN, 3 Laboratoy of<br />
Biology Department, Pangaea Biotech, USP Dexeus University Institute,<br />
Barcelona, SPAIN, 4 Medical Oncology Service, Catalan Institute of Oncology,<br />
Hospital Germans Trias i Pujol, Badalona, SPAIN, 5 Oncology, Hospital de Sant<br />
Pau, Barcelona, SPAIN<br />
Background: Progression-free survival (PFS) in EGFR-mutant NSCLC p treated with<br />
erlotinib can range from a few months (m) to more than two years, but genetic<br />
influences on <strong>the</strong> duration of response remain unclear. The cytotoxic effect of<br />
erlotinib has been related to several proteins that regulate DNA damage response (eg,<br />
BRCA1, BRCA2). MCPH1 contains 3 BRCT domains which are conserved in<br />
important molecules involved in DNA damage signaling, including BRCA1, MDC1<br />
and 53BP1. MCPH1 binds to BRCA2 and regulates <strong>the</strong> localization of BRCA2 and<br />
Rad51 at sites of DNA damage. MCPH1 also regulates <strong>the</strong> ATP-dependent SWI-SNF<br />
chromatin remodeling complex during DNA repair.<br />
Methods: We used <strong>the</strong> NanoString nCounter gene expression system, which captures<br />
and counts individual mRNA transcripts, to analyze <strong>the</strong> expression of 44 selected genes,<br />
many of which are involved in DNA damage response, in 55 erlotinib-treated NSCLC<br />
p. We identified MCPH1 and correlated expression levels with clinical outcomes.<br />
Results: p characteristics: 16 males, 39 females (70.9%); 39 never-smokers (70.9%),<br />
12 former smokers, 4 current smokers; 34 with EGFR deletion in exon 19 (61.8%),<br />
21 with L858R mutation (38.2%). PFS was not reached for patients with high<br />
MCPH1, while it was 19 m for those with intermediate levels and 9 m for those with<br />
low levels (P = 0.01). Median survival was 31 m for p with high levels, not reached<br />
for p with intermediate levels and 17 m for p with low levels (P = 0.004).<br />
Conclusions: The enhanced effect of erlotinib in <strong>the</strong> presence of elevated MCPH1<br />
could be due to <strong>the</strong> fact that MCPH1 can interfere with <strong>the</strong> function of MDC1 and<br />
53BP1. The role of MCPH1 merits validation as a predictive marker of erlotinib<br />
response.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1663P THE ROLE OF HEDGEHOG (HH) SIGNALING IN THE<br />
PREDICTION OF CLINICAL OUTCOME FOR ADVANCED<br />
NON-SMALL CELL LUNG CANCER (NSCLC)<br />
R. Berardi 1 , A. Santinelli 2 , M. Caramanti 1 , A. Savini 1 , A. Onofri 1 , T. Biscotti 2 ,<br />
A. Brunelli 3 , P. Mazzanti 1 , I. Bearzi 4 , S. Cascinu 1<br />
1 Clinica di Oncologia Medica, AOU Ospedali Riuniti Ancona Università<br />
Politecnica delle Marche, Ancona, ITALY, 2 Anatomia Patologica, AOU Ospedali<br />
Riuniti Ancona Università Politecnica delle Marche, Ancona, ITALY, 3 Thoracic<br />
Surgery, AOU Ospedali Riuniti Ancona, Ancona, ITALY, 4 Anatomia Patologica,<br />
AOU Ospedali Riuniti Ancona Università Politecnica delle Marche,, Ancona,<br />
ITALY<br />
Background: NSCLC lacks validated biomarkers to predict clinical outcome. The Hh<br />
pathway is critical for cell growth and differentiation. The aim of our study is to<br />
evaluate <strong>the</strong> role of <strong>the</strong> Hh signaling pathway in determining prognosis of NSCLC<br />
patients.<br />
Methods: In this single-center prospective study, <strong>the</strong> expression of Hh-related<br />
molecules including Ptch1 and Gli1 (nuclear and cytoplasmic) was determined by<br />
immunohistochemistry in 35 histologic samples (biopsies and surgical specimens) of<br />
advanced NSCLC patients. All <strong>the</strong> neoplastic area included in <strong>the</strong> slides was<br />
considered and both cytoplasmic and nuclear stainings were evaluated, according to<br />
<strong>the</strong> positive neoplastic cells. The intensity of <strong>the</strong> staining was considered and scored<br />
as 0 (absent), 1+ (low), 2+ (medium) and 3+ (high).<br />
Results: We analyzed 18 adenocarcinomas and 17 squamous cell carcinomas.<br />
Positivity of Gli1-cytoplasmic expression and Gli1-nuclear expression were expressed<br />
in adenocarcinoma at a significantly higher level and more frequently than compared<br />
to squamous cell carcinoma (p < 0.05), while Ptch1 did not differ significantly in <strong>the</strong><br />
two histotypes. Overall survival was higher in Gli1 and Ptch1 negative tumor samples<br />
compared to <strong>the</strong> positive group (p = 0.02). The 18 patients with adenocarcinoma<br />
received erlotinib as second line <strong>the</strong>rapy and those presenting a lower Gli1 and Ptch1<br />
expression experienced a significantly better progression free survival.<br />
Conclusion: At our best knowledge this is <strong>the</strong> first study investigating <strong>the</strong> role of HH<br />
in NSCLC patients. The results suggest that <strong>the</strong> Hh pathway might play a major<br />
prognostic role in NSCLC with significant differences between <strong>the</strong> histotype.<br />
Fur<strong>the</strong>rmore it might predict <strong>the</strong> efficacy of erlotinib as second-line treatment in<br />
patients with advanced lung adenocarcinoma.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1664P PROTEOMIC AND CIRCULATING FREE DNA ANALYSIS<br />
OUTCOME PREDICTORS IN THE GALAXY TRIALTM<br />
(NCT01348126): A RANDOMIZED PHASE IIB/III STUDY OF<br />
GANETESPIB (STA-9090) IN COMBINATION WITH<br />
DOCETAXEL VERSUS DOCETAXEL ALONE IN SUBJECTS<br />
WITH STAGE IIIB/IV NSCLC<br />
D. Fennell 1 , E. Petricoin 2 , J. Shaw 3 , I. El Hariry 4 , V. Vukovic 5 , F. Teofilovici 5 ,<br />
V. Reichert 4 , R. Rosell 6<br />
1 Medicine, University of Leicester, Leicester, UNITED KINGDOM, 2 Applied<br />
Proteomics and Molecular Medicine, George Mason University, Manassas, VA,<br />
UNITED STATES OF AMERICA, 3 Cancer Studies & Molecular Medicine,<br />
University of Leicester, Leicester, UNITED KINGDOM, 4 Oncology, Synta<br />
Pharmaceuticals, Lexington, MA, UNITED STATES OF AMERICA, 5 Clinical<br />
Development, Synta Pharmaceuticals Corp., Lexington, VA, UNITED STATES OF<br />
AMERICA, 6 Medical Oncology Service, Catalan Institute of Oncology ICO<br />
Badalona Hospital Germans Trias i Pujol, Medical Oncology, Badalona, SPAIN<br />
Background: Inhibition of Hsp90, a key molecular chaperone required for activation<br />
of many oncoproteins, can lead to cancer cell death. Ganetespib (G) is an Hsp90<br />
inhibitor that has shown single agent activity in molecularly defined disease,<br />
including ELM4-ALK rearrangement, KRAS mutations, HER2 amplification and<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds417 | ix533
BRAF mutations. Circulating free DNA (cfDNA) is present at low levels in plasma of<br />
healthy individuals, whereas its increased concentration was observed in patients<br />
with malignant tumors including non-small cell lung cancer (NSCLC). Cancer gene<br />
somatic mutations can be detected in cfDNA.<br />
Methods: This is a randomized trial, comparing G+ docetaxel (D), to D in 2 nd line<br />
advanced NSCLC patients. This study aimed at investigating <strong>the</strong> potential usefulness<br />
of plasma DNA concentration in NSCLC patients for efficacy of <strong>the</strong>rapy. We<br />
performed a prospective exploratory analysis to identify serum biomarkers as<br />
predictors of improved outcomes with G. Plasma samples were collected from 160<br />
pts at baseline prior to initiation of treatment, and at end of cycles 1 and 2. cfDNA<br />
was evaluated using <strong>the</strong> Ion Torrent platform to survey mutations in 46 cancer<br />
genes. Serum levels were correlated with progression free survival (PFS) and overall<br />
survival (OS) in both treatment arms. Upfront enrichment using both nanoparticle<br />
capture and phosphoprotein capture technologies were coupled to high resolution<br />
Orbitrap-LTQ MS/MS analysis followed by spectral counting for each samples.<br />
Results: By early May approximately half of <strong>the</strong> 300 planned patients were enrolled.<br />
Baseline characteristics were balanced. Full proteomic profiling and cfDNA analysis<br />
is ongoing, and will be correlated with <strong>the</strong> efficacy outcomes from a planned interim<br />
analysis in early September, including disease control rate, PFS, and OS.<br />
Disclosure: I. El Hariry: stock ownership. V. Vukovic: stock ownership. F. Teofilovici:<br />
stock option. V. Reichert: stock options. All o<strong>the</strong>r authors have declared no conflicts<br />
of interest.<br />
1665P INTER-OBSERVER AGREEMENT OF THE RESPONSE TO<br />
THERAPY ASSESSMENT IN ADVANCED LUNG CANCER<br />
WITHIN A NORMATIVE MEASUREMENT ENVIRONMENT<br />
H. Beaumont 1 , E. Oubel 1 , A. Iannessi 2 , D. Wormanns 3<br />
1 Science, MEDIAN Technologies, Valbonne, FRANCE, 2 Radiology, Centre<br />
Antoine Lacassagne, Nice, FRANCE, 3 Department of Radiology, ELK Berlin<br />
Chest Hospital, Berlin, GERMANY<br />
Purpose: Image-based biomarkers play an increasing role in <strong>the</strong> assessment of<br />
response to <strong>the</strong>rapy. The value of a biomarker comes, in part, from its ability to<br />
guarantee reproducibility in a varying context. This study aims at evaluating <strong>the</strong><br />
impact of workflow normalization and automation on <strong>the</strong> reproducibility of<br />
volume-based response assessment. This impact is measured in terms of inter-reader<br />
agreement (IRA).<br />
Method: A retrospective study was performed on 10 patients with Non-Small Cell Lung<br />
Cancer (NSCLC) lesions followed over 7 time points (TP) on average with Computed<br />
Tomography. Five imaging scientists measured sequentially <strong>the</strong> volume of each lesion at<br />
each TP and <strong>the</strong> time required to perform segmentations. We relied on a software<br />
providing semi-automatic segmentation capabilities and follow-up (FU) display. After 6<br />
months, a second reading session used no automation for segmentation. The response<br />
to treatment was assessed according to +/-30% thresholds as recommended by <strong>the</strong><br />
Quantitative Imaging Biomarker Alliance (QIBA). The IRA was measured by using<br />
Kappa coefficient. From <strong>the</strong> initial reading, where <strong>the</strong> same reader reviewed<br />
consecutively all TPs from <strong>the</strong> same patient, additional IRA assessments where<br />
performed by random mixing of measurements from different readers. Different types<br />
of mixing patterns simulated several deviations from normalization, this corresponding<br />
to FUs involving more than one radiologist or method.<br />
Results: The IRA of a normalized and automated workflow yielded a significantly<br />
higher kappa = 0.69 [0.59; 0.79] compared to mixed manual segmentations where<br />
kappa was 0.24 [0.06; 0.42]. Analyzed separately, both single-reviewer assessment and<br />
semi-automated segmentation led to higher reproducibility. The recourse to<br />
semi-automated segmentation reduces <strong>the</strong> average segmentation time by a factor of 4.<br />
Conclusions: Normalization and automation of <strong>the</strong> measurements improved<br />
significantly <strong>the</strong> IRA. Both normalization and automation contribute to improved<br />
reproducibility. Even small deviations from a normalized review may impair <strong>the</strong><br />
global reliability of FUs. Single-reviewer reading and automation must be considered<br />
for a highly reproducible assessment of response to <strong>the</strong>rapy.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1666P UTILITY OF A NOVEL QUANTITATIVE EGFR MUTATED<br />
PROTEIN ANALYSIS USING AQUA SYSTEM FOR EGFR-TKI<br />
TREATMENT IN NON-SMALL CELL LUNG CANCER<br />
PATIENTS<br />
K. Goto 1 , G. Ishii 2 , K. Fujimoto-Ouchi 3 , M. Shirane 4 , H. Ohmatsu 1 , S. Niho 1 ,<br />
K. Yoh 1 , S. Umemura 1 , K. Nagai 5 ,Y.Ohe 1<br />
1 Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa,<br />
JAPAN, 2 Department of Pathology, National Cancer Center Hospital East,<br />
Kashiwa, JAPAN, 3 Discovery Pharmacology Department 2, Chugai<br />
Pharmaceutical Co., Ltd., Kanagawa, JAPAN, 4 Medical Affairs Devision, Chugai<br />
Pharmaceuticals Co. Ltd, Tokyo, JAPAN, 5 Department of Thoracic Oncology,<br />
National Cancer Center Hospital East, Kashiwa, JAPAN<br />
Background: Lung cancer carrying EGFR mutation (muEGFR) expresses good<br />
response to EGFR tyrosine kinase inhibitors (TKIs). However, not all patients (pts)<br />
Annals of Oncology<br />
with mutation showed similar clinical benefits from EGFR-TKIs. Heterogeneity of<br />
tumor cells is considered to be one plausible reason. MuEGFR was usually genotyped<br />
in qualitative manner in present clinical practice. In addition, new technology of<br />
AQUA system enables us to measure protein levels objectively with considering<br />
expression heterogeneity in tissues. Here we investigated <strong>the</strong> correlation between<br />
AQUA score obtained from each specimen and <strong>the</strong> response and <strong>the</strong> response<br />
duration by EGFR-TKIs.<br />
Methods: Slice sections from genotyped 105 pts with muEGFR and 33 pts with<br />
wild-type EGFR were stained by E746-A750 deletion (6B6)- and L858R<br />
(43B2)-specific antibodies. Homo- or heterogeneous staining and muEGFR protein<br />
levels of <strong>the</strong>se specimens were evaluated with AQUA system.<br />
Results: Concordance rate between genotypes and AQUA-based phenotypes<br />
(deletion and L858R), with cut-off values based on ROC curve, were 60% and<br />
82%. Low sensitivity of 6B6 was due to lucking of reactivity for o<strong>the</strong>r<br />
deletion variants. Alternatively, specificities of both antibodies were 96% and<br />
92%, indicating highly selectivity to muEGFR protein. The AQUA score of 28<br />
pts treated with EGFR-TKIs were varied (5.4 – 798.5) but <strong>the</strong> falls plot<br />
analysis indicated that pts with high AQUA score showed better objective<br />
response. Specimens of partial response (PR) had significantly higher AQUA<br />
score than those of progression disease (67.4 vs 9.6, p = 0.025). However,<br />
<strong>the</strong>re were no differences of AQUA score between specimens of PR and stable<br />
disease. When divided pts into two groups based on median AQUA score,<br />
<strong>the</strong> pts with high AQUA score showed a tendency of longer treatment<br />
duration (24 mo vs 15 mo, p = 0.210). Especially, <strong>the</strong> high AQUA score with<br />
low intratumoral deviation pts showed longer treatment duration in compared<br />
to o<strong>the</strong>rs. These results indicate that AQUA-based analysis can classify pts<br />
carrying genotyped muEGFR into susceptible and less susceptible ones to<br />
EGFR-TKIs.<br />
Conclusions: We observed that pts with high AQUA score were more sensitive<br />
to EGFR-TKIs. It is important for predicting sensitivity to EGFR-TKIs to<br />
examine not only genotyping but also muEGFR protein levels by using AQUA<br />
system.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1667P INFLUENCE OF DRUG EXPOSURE AND GENETIC VARIATION<br />
ON PACLITAXEL–INDUCED NEUROTOXICITY<br />
A.M. De Graan 1 , L. Elens 2 , A. Sparreboom 3 , L.E. Friberg 4 , B. van der Holt 5 ,<br />
P.J. De Raaf 1 , E.A.C. Wiemer 1 , J. Verweij 1 , R.H. van Schaik 2 , R.H.J. Mathijssen 1<br />
1 Medical Oncology, Erasmus MC, Rotterdam, NETHERLANDS, 2 Clinical<br />
Chemistry, Erasmus MC, Rotterdam, NETHERLANDS, 3 Pharmaceutical<br />
Sciences, St. Jude Children’s Research Hospital, Memphis, TN, UNITED<br />
STATES OF AMERICA, 4 Pharmaceutical Biosciences, Uppsala University,<br />
Uppsala, SWEDEN, 5 Trials and Statistics, Erasmus MC, Rotterdam,<br />
NETHERLANDS<br />
Objectives: Paclitaxel is used for <strong>the</strong> treatment of several solid tumors and displays a<br />
high inter-individual variation in exposure and toxicity. Neurotoxicity is a frequent<br />
and sometimes serious adverse event frequently of paclitaxel treatment. This study<br />
aims to find predictive pharmacokinetic (PK) and pharmacogenetic determinants for<br />
<strong>the</strong> development of neurotoxicity.<br />
Methods: In 261 patients treated with paclitaxel, incidence of neurotoxicity during<br />
all courses (according to CTC 4.0 criteria) and PK parameters were determined. PK<br />
samples were measured by HPLC or LC-MS/MS, and individual PK parameters were<br />
estimated from previously developed population PK models by non-linear mixed<br />
effects modeling in <strong>the</strong> software NONMEM. Univariate and multivariate stepwise<br />
regression analysis were used to study <strong>the</strong> influence of co-variables on <strong>the</strong><br />
development of neurotoxicity. Variables tested were age, dose, tumor type, ethnicity,<br />
co-medication, smoking status, and genetic variants in <strong>the</strong> PK-pathway of paclitaxel<br />
(CYP3A4*22, CYP3A5*3, CYP2C8*3, CYP2C8 rs1058932, and ABCB1 3435 C > T,<br />
determined by TaqMan genotyping assays on <strong>the</strong> ABI PRISM 7500 Fast real-time<br />
PCR System).<br />
Results: Exposure to paclitaxel (logAUC) was predictive for <strong>the</strong> development<br />
(P
Annals of Oncology<br />
1668P SYSTEMS BIOLOGY IN TRANSLATIONAL ONCOLOGY:<br />
COMPUTATIONAL AND EXPERIMENTAL STUDY OF EGFR<br />
AND IGF1R PATHWAYS IN NSCLC CELL LINES<br />
F. Bianconi 1 , K. Perruccio 2 , V. Ludovini 3 , E. Baldelli 3 , G. Bellezza 4 , A. Flacco 2 ,<br />
P. Valigi 5 , L. Crinò 3<br />
1 Department of Surgical and Medical Specialties, and Public Health, University of<br />
Perugia, Perugia, ITALY, 2 Medical Oncology Division, S. Maria della Misericordia<br />
Hospital, Perugia, ITALY, 3 Medical Oncology, S. Maria della Misericordia<br />
Hospital, Perugia, ITALY, 4 University of Perugia, Institute of Pathological Anatomy<br />
and Histology, University of Perugia, Perugia, Italy, Perugia, ITALY, 5 Department<br />
of Electronic and Information Engineering, University of Perugia, Perugia, ITALY<br />
Background: The epidermal growth factor receptor (EGFR) and type 1<br />
insulin-like growth factor receptor (IGF1R) pathways are complex networks<br />
involving interactions between membrane-bound receptors, ligands, binding<br />
proteins, downstream effectors and mutual interactions. In this study we<br />
have designed a computational model of EGFR and IGF1R pathways in<br />
NSCLC and we validated <strong>the</strong>ir dynamic responses in several tumor cell<br />
lines.<br />
Materials and methods: EGFR and IGF1R pathways and <strong>the</strong> downstream MAPK<br />
and PIK3 networks have been modeled by means a ma<strong>the</strong>matical model based on<br />
ODE. A549, H1299, H1675 and H1650 tumor cell lines were stimulated by EGF,<br />
IGF-I, EGF/IGF-I and without ligands. For <strong>the</strong>se induction conditions we quantified<br />
at 0, 2, 5, 10, 20, 30, 40, 50, 60 minutes by western blotting <strong>the</strong> following proteins:<br />
phospho-AKT, AKT, phospho-EGFR, EGFR, phospho-p44/42 MAPK(ERK 1/2), p44/<br />
42 MAPK(ERK1/2), phospho-IGF1R and IGF1R. Model simulations and experiment<br />
data have been combined toge<strong>the</strong>r.<br />
Results: The time series performed in all cell lines under <strong>the</strong> four induction<br />
conditions allowed us to characterize <strong>the</strong> signal transduction through EGFR and<br />
IGF1R pathways. Our model has reproduced proteins behavior of A549, H1299,<br />
H1675 and H1650 cell lines and also <strong>the</strong> robustness of <strong>the</strong> network has been<br />
confirmed.<br />
Conclusions: We propose a Systems Biology approach, combined with Translational<br />
Oncology tolls, to understand <strong>the</strong> interaction between EGFR and IGF1R pathways in<br />
NSCLC cell lines and validate model predictions. Future work will investigate <strong>the</strong><br />
effect of drugs action on cell lines.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1669P ONCO-I2B2 PROJECT: A BIOINFORMATICS TOOL<br />
INTEGRATING –OMICS AND CLINICAL DATA TO SUPPORT<br />
TRANSLATIONAL RESEARCH<br />
A. Zambelli 1 , D. Segagni 2 , V. Tibollo 2 , A. Dagliati 2 , A. Malovini 2 , V. Fotia 1 ,<br />
S. Manera 1 , R. Bellazzi 3<br />
1 Oncology, Fondazione Salvatore Maugeri, Pavia, ITALY, 2 Information<br />
Technology, Fondazione Salvatore Maugeri, Pavia, ITALY, 3 Industrial and<br />
Information Engineering, University of Pavia, Pavia, ITALY<br />
The ONCO-i2b2 project, supported by <strong>the</strong> University of Pavia and <strong>the</strong> Fondazione<br />
Salvatore Maugeri (FSM), aims at supporting translational research in oncology and<br />
exploits <strong>the</strong> software solutions implemented by <strong>the</strong> Informatics for Integrating<br />
Biology and <strong>the</strong> Bedside (i2b2) research centre, an initiative funded by <strong>the</strong> NIH<br />
Roadmap National Centres for Biomedical Computing. The ONCO-i2b2 software is<br />
designed to integrate <strong>the</strong> i2b2 infrastructure with <strong>the</strong> FSM hospital information<br />
system and <strong>the</strong> Bruno Boerci Biobank, in order to provide well-characterized cancer<br />
specimens along with an accurate patients clinical data-base. The i2b2 infrastructure<br />
provides a web-based access to all <strong>the</strong> electronic medical records of cancer patients,<br />
and allow researchers analyzing <strong>the</strong> vast amount of biological and clinical<br />
information, relying on a user-friendly interface. Data coming from multiple sources<br />
are integrated and jointly queried.<br />
In 2011 at AIOM Meeting we reported <strong>the</strong> preliminary experience of <strong>the</strong><br />
ONCO-i2b2 project, now we’re able to present <strong>the</strong> up and running platform and <strong>the</strong><br />
Table: 1670P<br />
extended data set. Currently, more than 4400 specimens are stored and more than<br />
600 of breast cancer patients give <strong>the</strong> consent for <strong>the</strong> use of specimens in <strong>the</strong> context<br />
of clinical research, in addition, more than 5000 histological reports are stored in<br />
order to integrate clinical data.<br />
Within <strong>the</strong> ONCO-i2b2 project is possible to query and merge data regarding:<br />
• Anonymous patient personal data;<br />
• Diagnosis and <strong>the</strong>rapy ICD9-CM subset from <strong>the</strong> hospital information system;<br />
• Histological data (tumour SNOMED and TNM codes) and receptor profile testing<br />
(Her2, Ki67) from anatomic pathology database;<br />
• Specimen molecular characteristics (DNA, RNA, blood, plasma and cancer tissues)<br />
from <strong>the</strong> Bruno Boerci biobank management system.<br />
The research infrastructure will be completed by <strong>the</strong> development of new set of<br />
components designed to enhance <strong>the</strong> ability of an i2b2 hive to utilize data generated<br />
by NGS technology, providing a mechanism to apply custom genomic annotations.<br />
The translational tool created at FSM is a concrete example regarding how <strong>the</strong><br />
integration of different information from heterogeneous sources could bring scientific<br />
research closer to understand <strong>the</strong> nature of disease itself and to create novel<br />
diagnostics through handy interfaces.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1670P EVALUATION OF ALTERNATE TUMOR METRICS AND<br />
CUT-POINTS FOR RESPONSE CATEGORIZATION USING THE<br />
RECIST 1.1 DATA WAREHOUSE<br />
S.J. Mandrekar 1 ,M.An 2 , J. Meyers 1 , A. Gro<strong>the</strong>y 3 , J. Bogaerts 4 , D.J. Sargent 1<br />
1 Health Sciences Research, Mayo Clinic, Rochester, MN, UNITED STATES OF<br />
AMERICA, 2 Ma<strong>the</strong>matics, Vassar College, Poughkeepsie, UNITED STATES OF<br />
AMERICA, 3 Medical Oncology, Mayo Clinic, Rochester, MN, UNITED STATES<br />
OF AMERICA, 4 Statistics Dept, EORTC, Brussels, BELGIUM<br />
Purpose: We previously showed that <strong>the</strong> trichotomized response metric (TriTR:<br />
Complete or Partial Response (CR or PR) vs. Stable (SD) vs. Progression (PD)) had<br />
better predictive ability than <strong>the</strong> Response Evaluation Criteria in Solid Tumors<br />
(RECIST) best response (BR) metrics (CR/PR vs. o<strong>the</strong>rs) (An et al., 2011). We<br />
sought to test and validate TriTR, disease control rate (DCR: CR/PR/SD vs. PD) and<br />
BR metrics utilizing alternate cut-points for PR and PD using <strong>the</strong> RECIST data<br />
warehouse.<br />
Methods: Data from 13 trials (5994 patients with breast, lung or colorectal<br />
cancer) were randomly split (60:40) into training and test sets stratified by<br />
tumor type, survival and progression status. 21 pairs of cut points for (PR,<br />
PD) were considered: PR (20-50% decrease, by 5% increments) and PD<br />
(10-20% increase, by 5% increments), where <strong>the</strong> pair (30%, 20%),<br />
corresponds to <strong>the</strong> RECIST categorization. Cox proportional hazards models<br />
with a flexible landmark analysis at 12- and 24-weeks post-baseline, adjusted<br />
for baseline tumor burden, were used to assess <strong>the</strong> impact of <strong>the</strong> metrics<br />
(using alternate cutoffs) on overall survival (OS). Model discrimination was<br />
assessed using <strong>the</strong> concordance (c-) index [c = 0.5: no association; c = 1.0:<br />
perfect association].<br />
Results: Standard RECIST cutoffs demonstrated similar predictive ability as <strong>the</strong><br />
alternate (PR, PD) cutoffs for all metrics at both time points. Regardless of<br />
tumor type, <strong>the</strong> last TriTR and DCR metrics (assessed at <strong>the</strong> landmark time<br />
point) had higher (or similar) c-indices to BR, and best TriTR and DCR metrics<br />
(assessed any time before <strong>the</strong> landmark time point). The 24-week metrics were<br />
no better than those at 12-weeks. None of <strong>the</strong> metrics did particularly well for<br />
breast cancer.<br />
Conclusions: Alternative cut-points to RECIST standards provided no<br />
meaningful improvement in OS prediction. TriTr and DCR metrics assessed after<br />
12-weeks have good predictive performance. These results are currently being<br />
validated.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
C-Index at 12 and 24 weeks (Training Set)<br />
Breast Colon Lung<br />
Metric (based on RECIST cutoffs) 12 wks (N = 1048) 24 wks (N = 1060) 12 wks (N = 710) 24 wks (N = 727) 12 wks (N = 1816) 24 wks (N = 1819)<br />
BR 0.57 0.58 0.61 0.64 0.62 0.62<br />
Last TriTR 0.58 0.59 0.63 0.66 0.64 0.63<br />
Best TriTR 0.58 0.58 0.62 0.64 0.63 0.62<br />
Last DCR 0.58 0.58 0.62 0.65 0.61 0.61<br />
Best DCR 0.57 0.56 0.59 0.59 0.62 0.59<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds417 | ix535
1671P PHASE I CLINICAL TRIAL OF CANCER VACCINE COMBINED<br />
WITH CHEMOTHERAPY TARGETING BOTH TUMOR<br />
ANTIGEN AND IMMUNE TOLERANCE AGAINST ADVANCED<br />
SOLID TUMORS<br />
M. Murahashi 1 , Y. Hijikata 1 , Y. Tanaka 2 , H. Inoue 2 , T. Marumoto 2 , Y. Nakanishi 3 ,<br />
K. Yoshida 4 , T. Tsunoda 4 , Y. Nakamura 5 , K. Tani 2<br />
1 Department of Advanced Cell and Molecular Therapy, Kyushu University<br />
Hospital, Fukuoka, JAPAN, 2 Medical Institute of Bioregulation, Kyushu University,<br />
Fukuoka, JAPAN, 3 Research Institute for Diseases of <strong>the</strong> Chest, Kyushu<br />
University Hospital, Fukuoka, JAPAN, 4 Cancer Immunology, OncoTherapy<br />
Science, Inc., Tokyo, JAPAN, 5 Institute of Medical Science, University of Tokyo,<br />
Tokyo, JAPAN<br />
Background: Antitumor immuno<strong>the</strong>rapy to target tumor antigens and evade<br />
immune tolerance is considered reasonable and promising. However, no combined<br />
immuno<strong>the</strong>rapy has been established. We designed a phase I trial of cancer vaccine<br />
combined with chemo<strong>the</strong>rapy to investigate safety as <strong>the</strong> primary endpoint, and<br />
immune responses and clinical benefits as secondary endpoints.<br />
Methods: Patients positive for HLA-A2402 who showed locally advanced,<br />
metastatic, and/or recurrent gastrointestinal, lung or cervical cancer were<br />
evaluated in a phase I clinical trial of cancer vaccine and chemo<strong>the</strong>rapy.<br />
Cyclophosphamide (CPM) was administered 4 days before vaccination to<br />
eliminate regulatory T cells (Treg). 18 patients were treated in cohorts of six<br />
patients, each with escalating CPM dose (150, 300 and 600 mg/m2). Five<br />
HLA-A2402-restricted tumor-associated antigen (TAA) epitope peptides from<br />
KOC1, TTK, URLC10, DEPDC1, and MPHOSPH1 were injected once a week<br />
for 4 weeks. Patients without gastrointestinal bleeding, pleural effusion or ascites<br />
also received low dose IL-2 every after vaccination.<br />
Results: The treatment was tolerated well without any associated adverse events<br />
above grade 3. The study included primary disease with 9 cases of colorectal<br />
cancer, 3 cholangiocellular carcinoma, 3 lung cancer, and one each of esophageal,<br />
gastric and cervical cancer. Nine of 13 patients (69%) assessed by Elispot assay<br />
showed cytotoxic T lymphocytes (CTL) specific for TAA to more than one of five<br />
antigens after vaccination. Log-rank test among <strong>the</strong>se demonstrated that CTL<br />
responses induced by vaccine contributed significantly to overall survival (MST:<br />
9.2 vs 3.9 months, P = 0.003). In addition, a significantly broader antigenic<br />
repertoire was found in longer survivors (p = 0.033). Treg number dropped from<br />
baseline with dose just after CPM administration. This seems to reflect direct<br />
inhibition of CPM on Treg. Interestingly, reduced Treg correlated significantly<br />
with longer overall survival (P = 0.024), suggesting CPM augmented,<br />
vaccine-induced CTL responses through Treg reduction.<br />
Conclusion: This phase I clinical study demonstrated promising survival associated<br />
with Treg inhibition, as well as CTL responses that warrants fur<strong>the</strong>r clinical studies.<br />
Disclosure: K. Yoshida: I am a research staff of <strong>the</strong> company, OncoTherapy<br />
Science Inc. providing <strong>the</strong> peptide vaccines used in this study. T. Tsunoda: I am<br />
<strong>the</strong> President and CEO of <strong>the</strong> company, OncoTherapy Science, Inc. providing<br />
<strong>the</strong> peptide vaccines used in this study. Y. Nakamura: I am one of <strong>the</strong> major<br />
stock holders of <strong>the</strong> company, OncoTherapy Science, Inc. K. Tani: Our<br />
department obtained <strong>the</strong> partial research funding in 2007 from <strong>the</strong> comapany,<br />
OncoTherapy Science, Inc. All o<strong>the</strong>r authors have declared no conflicts of<br />
interest.<br />
1672P NOVEL STRATEGY FOR DESIGNING AND OPTIMIZING OF<br />
DENDRITIC – CELL – BASED ANTICANCER VACCINE<br />
N. Khranovska 1 , G.P. Potebnia 2 , O.V. Skachkova 1 , O.A. Tanasienko 2 ,<br />
N.M. Svergun 1 , V.V. Sitko 1 , O.G. Fedorchuk 3 , V.V. Niculina 1<br />
1 Experimental Oncology, National Cancer Institute of <strong>the</strong> MPH Ukraine, Kiev,<br />
UKRAINE, 2 Department of Bio<strong>the</strong>rapy Means Construction, R.E.Kavetsky<br />
Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine,<br />
Kiev, UKRAINE, 3 Department of Medical Correction of Oncogenesis, R.E.<br />
Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS<br />
of Ukraine, Kiev, UKRAINE<br />
Background: Despite widely explore of DC based immuno<strong>the</strong>rapy in cancer,<br />
optimal conditions for <strong>the</strong> generation of phenotypically and functionally<br />
mature DCs remain to be established. Maturation of DC can be achieved by<br />
several stimuli: pathogen-associated triggers or endogenous danger signals. In<br />
this study, we diversely explore <strong>the</strong> new approach for creating effective<br />
DC-vaccine employing <strong>the</strong> exogenous cytotoxic lectins (CLs) from Bacillus<br />
subtilis.<br />
Methods: To study <strong>the</strong> effect of CLs on degree of DCs maturity and ability to<br />
produce IL-12 DCs of 10 healthy donors were used. DCs were generated from<br />
peripheral blood monocytes ex vivo in <strong>the</strong> presence of GM-CSF and IL-4<br />
during 8 days. CLs from Bacillus subtilis (18,5 and 79 kDa) were added to<br />
immature DCs on day 6. Maturation state and functional activity of DCs were<br />
evaluated by <strong>the</strong> expression of cell surface markers CD83, CD86, HLA-DR<br />
and IL-10, 12 p35, p40 mRNA levels. For clinical trial DCs loaded with lysate<br />
of tumor cells (LTC) and treated with CLs were used. DC-vaccine has been<br />
Annals of Oncology<br />
tested in adjuvant regimen in 73 stage III-IV ovarian cancer (OC) patients.<br />
Patients of control group received <strong>the</strong> same treatment, except <strong>the</strong><br />
DC-immuno<strong>the</strong>rapy.<br />
Results: IL-12 p40, p35 and IL-10 mRNA levels were strongly up-regulated by CLs.<br />
Exposure DCs to CLs caused 2-10 - fold increase in mRNA cytokine level expression<br />
in comparison with control DC incubated in <strong>the</strong> presence of grows factors only. The<br />
effect of CLs was dose dependent and was not due to a block of DCs maturation as<br />
determined by analysis of DC surface markers. CLs contributed to a simultaneously<br />
significant increasing in CD86/HLA-DR expression (up to 89,44 ±5.26 vs 55,94 ±<br />
12,0 %) and slightly augmented CD83 expression. The most prominent changes in<br />
<strong>the</strong> expression of maturation-associated molecules was observed in DCs treated with<br />
CLs in <strong>the</strong> concentrations 0,04-0,1 mg/ml and thus appear to be <strong>the</strong> most suitable<br />
CLs concentrations for use in <strong>the</strong> DC-immuno<strong>the</strong>rapy clinical trial. Kaplan-Meier<br />
analysis revealed prolonged 4 - year overall survival of OC patients treated with<br />
elaborated DC – vaccine compared with <strong>the</strong> control group (50 vs 39 %; F Cox test:<br />
P = 0,034).<br />
Conclusion: Manipulation of DCs with CLs from B.subtilis may prove to be a<br />
particularly effective way to stimulate antitumor immunity in cancer patients which<br />
leads to a clinical benefit.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1673P INTEGRATED GENOMIC APPROACHES TO THERAPEUTIC<br />
TARGET IDENTIFICATION FOR HEPATOCELLULAR<br />
CARCINOMA<br />
T. Yamada, R. Satow, M. Masuda, K. Honda<br />
Division of Chemo<strong>the</strong>rapy and Clinical Research, National Cancer Center<br />
Research Institute, Tokyo, JAPAN<br />
Purpose: Recently, a multi-kinase inhibitor, sorafenib, has been approved as a<br />
systemic chemo<strong>the</strong>rapeutic drug for advanced hepatocellular carcinoma (HCC), but<br />
fur<strong>the</strong>r improvement seems to be necessary. To identify an “Achilles heel” of HCC<br />
cells, we performed an unbiased survey of <strong>the</strong> whole genome.<br />
Methods: To develop new <strong>the</strong>rapeutic agents that act specifically on HCC but<br />
interfere only minimally with residual liver function, we adopted a combined<br />
functional approach. We first searched for genes that were up-regulated in<br />
HCC in comparison with <strong>the</strong> background non-tumorous liver tissue. This was<br />
followed by siRNA-based screening of genes required for HCC cell<br />
proliferation.<br />
Results: We searched for genes that were upregulated in 20 cases of HCC in<br />
comparison with corresponding non-tumorous liver and a panel representing<br />
normal organs using high-density microarrays capable of detecting all exons in<br />
<strong>the</strong> human genome. Eleven transcripts whose expression was significantly<br />
increased in HCC were subjected to small-interfering RNA (siRNA)-based<br />
secondary screening of genes required for HCC cell proliferation as well as<br />
quantitative RT-PCR analysis [Validation Sets 1 (n = 20) and 2 (n = 44)] and<br />
immunohistochemistry (n = 19). We finally extracted 4 genes, AKR1B10,<br />
HCAP-G, RRM2, and TPX2, as candidate <strong>the</strong>rapeutic targets for HCC.<br />
siRNA-mediated knockdown of <strong>the</strong>se candidate genes inhibited <strong>the</strong> proliferation<br />
of HCC cells and <strong>the</strong> growth of HCC xenografts transplanted into<br />
immunodeficient mice.<br />
Conclusions: The 4 genes we identified were highly expressed in HCC, and HCC<br />
cells are highly dependent on <strong>the</strong>se genes for proliferation. Technologies such as<br />
microarray, high-speed sequencing, and mass spectrometry have advanced rapidly in<br />
recent years, allowing genome-wide-scale examination of alterations in chromosomal<br />
gains and losses, <strong>the</strong> structure, epigenetic modification, and expression of genes, <strong>the</strong><br />
expression and post-translational modification of proteins, and cell signaling<br />
pathways. I would like to discuss <strong>the</strong> possible combination of <strong>the</strong>se technologies for<br />
<strong>the</strong>rapeutic target identification.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1674P IDENTIFICATION OF PHOSPHORYLATED RIBOSOMAL<br />
PROTEIN S6 AS A POTENTIAL PREDICTOR OF<br />
HEPATOCELLULAR CARCINOMA RESPONSE TO SORAFENIB<br />
BY PATHWAY-BASED PHOSPHOPROTEIN PROFILING<br />
M. Masuda, K. Honda, T. Yamada<br />
Division of Chemo<strong>the</strong>rapy and Clinical Research, National Cancer Center<br />
Research Institute, Tokyo, JAPAN<br />
Backgroud: Sorafenib is a multi-kinase inhibitor that has been proved to be effective<br />
for <strong>the</strong> treatment of advanced hepatocellular carcinoma (HCC). However, only a<br />
small proportion of patients receiving sorafenib obtain <strong>the</strong> anticipated <strong>the</strong>rapeutic<br />
benefits. It would <strong>the</strong>refore be desirable to clarify <strong>the</strong> precise molecular mechanisms<br />
that confer resistance to sorafenib and identify a predictive biomarker for<br />
unresponsiveness to sorafenib.<br />
Methods: We constructed reverse-phase protein microarrays (RPPAs) onto which<br />
whole lysates of 95 cell lines derived from various tumors, including 23 HCCs, were<br />
ix536 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
plotted and examined for phosphorylation expression of 183 proteins serving as<br />
nodes in 120 signaling pathways registered in <strong>the</strong> NCI-Nature curated pathway<br />
(NCI-Nature_Curated.bp2.owl 2011.12.19). The sensitivity (IC50 value) of <strong>the</strong> 23<br />
HCC cell lines to sofafenib was quantified using <strong>the</strong> CellTiter-Glo Luminescent Cell<br />
Viability Assay kit.<br />
Results: Use of fluorescence dye significantly expanded <strong>the</strong> sensitivity and dynamic<br />
range of <strong>the</strong> RPPAs. We found that <strong>the</strong> relative level of phosphorylation of ribosomal<br />
protein S6 (p-rpS6) at <strong>the</strong> Ser235/236 residues showed <strong>the</strong> highest correlation with<br />
sensitivity to sorafenib among <strong>the</strong> 183 signaling nodes (P = 0.0044, Spearman<br />
correlation analysis), followed by phosphorylation of <strong>the</strong> same protein at <strong>the</strong> Ser240/<br />
244 residues (P = 0.0070). Immunoblot analysis confirmed that <strong>the</strong> sorafenib-resistant<br />
cell lines had <strong>the</strong> highest level of rpS6 phosphorylation. We found that in some HCC<br />
cell lines <strong>the</strong> mitogen-activated protein kinase (MAPK) pathway was activated<br />
downstream of RAF kinase and showed sensitivity to MEK (CI-1040) and RSK<br />
(SL0101) inhibitors.<br />
Conclusions: To achieve personalization of molecular <strong>the</strong>rapies, precise mapping of<br />
activated signaling pathways in individual patients is essential. RPPA requires only a<br />
small amount of protein and is ideal for application to clinical settings. We are<br />
collecting tumor biopsy samples from HCC patients to verify <strong>the</strong> present findings,<br />
and plan to present <strong>the</strong> data at <strong>the</strong> meeting.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1675P PRECLINICAL AND PRELIMINARY CLINICAL ACTIVITY OF<br />
NVP-BKM120, AN ORAL PAN-CLASS I PI3K INHIBITOR, IN<br />
THE BRAIN<br />
M. Maira 1 , C. Schnell 1 , P. Lollini 2 , C. Chouaid 3 , P. Schmid 4 , P. Nanni 5 , D. Lam 6 ,<br />
E. Di Tomaso 7 , C. Massacesi 8 , J. Rodon 9<br />
1 Oncology, Novatis Institute for Biomedical Research, Basel, SWITZERLAND,<br />
2 Department of Hematology and Oncological Sciences, University of Bologna,<br />
Bologna, ITALY, 3 Pulmonology, Hopital Saint-Antoine, Paris, FRANCE, 4 Clinical<br />
Investigation and Research Unit, Brighton and Sussex Medical School, Brighton,<br />
UNITED KINGDOM, 5 Department of Experimental Pathology, University of<br />
Bologna, Bologna, ITALY, 6 Oncology, Novartis, Florham Park, NJ, UNITED<br />
STATES OF AMERICA, 7 Institutes for Biomedical Research, Novartis,<br />
Cambridge, MA, UNITED STATES OF AMERICA, 8 Oncology, Novartis, Paris,<br />
FRANCE, 9 Medical Oncology, Vall d’Hebron University Hospital, Barcelona,<br />
SPAIN<br />
Background: New <strong>the</strong>rapies that penetrate <strong>the</strong> blood–brain barrier (BBB) are needed<br />
to combat brain metastases (BM). Activity of BKM120, an oral pan-class I PI3K<br />
inhibitor, in <strong>the</strong> brain was assessed in vivo, with additional evidence collected from<br />
Ph I/II clinical trials.<br />
Methods: The ability of BKM120 to penetrate <strong>the</strong> BBB and inhibit PI3K signaling<br />
was determined by: (1) comparison of IHC staining of insulin-induced S473P-AKT<br />
levels in <strong>the</strong> brains of untreated/BKM120-treated (5 mg/kg, po, once) rats; and (2)<br />
regular monitoring of drug concentrations and S473P-AKT levels over 24 hrs upon<br />
BKM120 (50 mg/kg, po, once) or pan-PI3K inhibitor GDC0941 (150 mg/kg, po,<br />
once) treatment in plasma, tumor and brain tissue of Rat1-myr-p110 tumor-bearing<br />
(subcutaneous) mice. Activity of BKM120 against BM was also assessed in 1<br />
preclinical model of HER2+ breast cancer (BC) BM and in 2 clinical trials of pts<br />
with advanced solid tumors (CBKM120X2101) and metastatic NSCLC<br />
(CBKM120D2201).<br />
Results: BKM120 strongly reduced insulin-induced S473P-AKT in <strong>the</strong> brain vs.<br />
untreated controls, with <strong>the</strong> most notable effects observed in <strong>the</strong> cerebellum.<br />
Uptake of BKM120 in Rat1-myr-p110 tumor-bearing mice over 24 hrs was<br />
similar across plasma, tumor and brain tissues, with <strong>the</strong> highest concentration of<br />
BKM120 at 1 hr post-administration. At this time point, BKM120 completely<br />
reduced S473P-AKT in both tumor and brain samples. In contrast, uptake of<br />
GDC0941 was undetectable in <strong>the</strong> brain and had no effect on S473P-AKT levels<br />
in this tissue. Uptake of GDC0941 and inhibition of S473P-AKT was similar to<br />
BKM120 in plasma and tumor. In addition, BKM120 strongly inhibited growth<br />
of BM by human HER2+ BC cells MDA-MB-453 in immunodeficient Rag2 −/- /<br />
Il2rg −/- mice. In 2 clinical trials, 4 pts with BM have been treated with<br />
single-agent BKM120 to date: 1 pt with metastatic BC had a 29% reduction in a<br />
brain lesion, while disappearance of a non-target brain lesion was seen in 1 pt<br />
with squamous NSCLC.<br />
Conclusions: Preclinical data suggest that BKM120 penetrates <strong>the</strong> BBB and inhibits<br />
PI3K signaling in <strong>the</strong> brain. This unique property of BKM120 is not a class effect.<br />
Preliminary clinical evidence supports <strong>the</strong>se findings. Clinical trials of BKM120 in<br />
pts with BM are planned.<br />
Disclosure: M. Maira: Stock ownership and employee of Novartis. C. Schnell:<br />
Stockholder and employee of Novartis. C. Chouaid: Member of <strong>the</strong> advisory boards<br />
for Lilly, Amgen, Roche and has undertaken research sponsored by Lilly, Amgen,<br />
Roche, Novartis and AstraZeneca. D. Lam: Employee of Novartis. E. Di Tomaso:<br />
Employee of Novartis. C. Massacesi: Employee of Novartis. All o<strong>the</strong>r authors have<br />
declared no conflicts of interest.<br />
1676P GEMCITABINE, PI3KINASE-AKT PATHWAY INHIBITION AND<br />
RADIATION IN HUMAN GLIOMA CELL LINES<br />
M.S. Elnaggar 1 , P. Sminia 2 , S. Shehata 3 , C. Fedrigo 4 , G. Peters 1<br />
1 Medical Oncology Department, VUMC, Amsterdam, NETHERLANDS,<br />
2 Radiation Oncology, VUMC, Amsterdam, NETHERLANDS, 3 Clinical Oncology<br />
Department, Assiut University Hospital, Assiut, EGYPT, 4 Medicina e Ciências da<br />
Saúde, 2Pontifícia Universidade Católica do Rio Grande do Sul, Rio Grande do<br />
Sul, BRAZIL<br />
Introduction: Glioblastoma multiforme (GBM) is <strong>the</strong> most common primary brain<br />
tumor. Standard treatment is surgery and Radio<strong>the</strong>rapy (RT) with temozolomide.<br />
The median survival is ranging from 12-14 months. However, patients with an<br />
unmethylated MGMT gene promoter do not show a survival advantage for<br />
temozolomide, and might be eligible for alternative treatment. Gemcitabine is an<br />
excellent radiosensitizer and is investigated as an alternative for temozolomide in<br />
GBM patients. Activation of <strong>the</strong> PI3Kinase-Akt pathway may preclude effective RT;<br />
<strong>the</strong>refore we investigated <strong>the</strong> radiosensitizing effect of gemcitabine in combination<br />
with <strong>the</strong> Akt inhibitor MK-2206.<br />
Materials and methods: Three malignant glioma cell lines (U87, U251, and D384)<br />
were tested on cell proliferation (SRB assay) cell survival (clonogenic assay) and<br />
spheroid growth following treatment by <strong>the</strong> allosteric Akt-inhibitor MK-2206 (1 uM,<br />
10 uM), gemcitabine and γ-irradiation (4 Gy single dose or 5 fractions of 2 Gy).<br />
Expression of Akt and pAkt was assessed by Western blot.<br />
Results: The U87 cell line was most sensitive and D384 was <strong>the</strong> most resistant one.<br />
MK-2206 decreased <strong>the</strong> IC50 of gemcitabine in all cell lines from 86, 237, 903 nM<br />
for gemcitabine alone to 57, 93, 860 nM, respectively. MK-2206 down regulated pAkt<br />
expression in a concentration and time dependent manner; at 0.1 µM pAkt was<br />
partly inhibited at 30 min and completely at 1, 2, 4 and 24 h, but started to recover<br />
at 48 h. At 1 µM pAkt inhibition was immediate and lasted longer. Since 25 nM<br />
gemcitabine and 4 GY RT alone stimulated pAKT expression, cells were preincubated<br />
with MK-2206 (1 µM for 1h). MK-2206 was additive to Gemcitabine and RT in<br />
reducing clonogenic cell survival, but MK-2206 was synergistic with gemcitabine<br />
alone and with RT in inhibition of spheroid growth The effect was more pronounced<br />
with RT.<br />
Conclusion: Addition of MK-2206 to gemcitabine significantly enhanced inhibition<br />
of cell proliferation and spheroid growth and inhibited <strong>the</strong> gemcitabine and RT<br />
mediated pAkt stimulation. The use of gemcitabine in combination with<br />
PI3kinase-Akt pathway inhibitors is a promising tool in GBM <strong>the</strong>rapy and might be<br />
an alternative for patients resistant to temozolomide.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1677P COMBINING EXTERNAL BEAM RADIOTHERAPY WITH<br />
MEASLES-VIRUS ONCOLYTIC THERAPY AND SAR-020106,<br />
A NOVEL RADIOSENSITIZER, IN HEAD AND NECK CANCER<br />
MODELS<br />
Y. Touchefeu 1 , A. Khan 2 , V. Roulstone 2 , K.J. Harrington 2<br />
1 Institut des Maladies de ’Appareil Digestif, University Hospital, Nantes,<br />
FRANCE, 2 Targeted Therapy Laboratory, Institute of Cancer Reserach, London,<br />
UNITED KINGDOM<br />
We have previously demonstrated <strong>the</strong> antitumour activity of a treatment combining a<br />
replication-defective adenovirus encoding <strong>the</strong> sodium iodide symporter (NIS),<br />
external beam radio<strong>the</strong>rapy (EBRT) and DNA repair inhibitors. Engineered Measles<br />
viruses (MeV) expressing NIS are replication-competent, oncolytic viruses, currently<br />
being tested in phase 1 trials. The aim of this study was to evaluate <strong>the</strong> <strong>the</strong>rapeutic<br />
efficacy of a combination of MeV-NIS, EBRT, and a novel checkpoint-1 inhibitor,<br />
SAR-020106. This approach was investigated in HN-3, HN-5 and PJ-41 head and<br />
neck cancer models. In vitro toxicity was assessed by MTS and clonogenic assays.<br />
CD46 (cell receptor for MeV) expression on head and neck cell lines was evaluated by<br />
flow cytometry. NIS viral transgene expression was assessed by 125I uptake assays.<br />
Apoptosis was evaluated by Caspase Glo® and western blot assays. In vivo <strong>the</strong>rapy<br />
experiments were performed in CD1 nude mice with subcutaneous tumour<br />
xenografts. In this study, we have demonstrated that EBRT and MeV-NIS had in vitro<br />
synergistic antitumour effects in head and neck cancer cell lines. EBRT did increase<br />
nei<strong>the</strong>r CD46 expression nor viral replication, but significantly increased viral gene<br />
expression in infected cells. In vitro, SAR-020106 had synergistic antitumour effect<br />
with EBRT. This effect was related to increased apoptosis. In vitro, <strong>the</strong> combination of<br />
MeV-NIS and SAR-020106 was associated with a significantly increased antitumour<br />
effect, as compared with control, MeV-NIS alone or SAR-020106 alone (P < 0.05). In<br />
<strong>the</strong> HN5 in vivo model, we observed significant differences in overall survival. In <strong>the</strong><br />
control and EBRT groups, we observed a median survival of 32.5 and 35 days,<br />
respectively. In <strong>the</strong> MeV-NIS, MeV-NIS with EBRT and <strong>the</strong> MeV-NIS combined with<br />
EBRT and SAR-020106 groups we observed significantly improved overall survival<br />
(Log-rank (Mantel-Cox) Χ2 = 12.8; df = 5; p = 0.025) with fewer than 50% of animals<br />
in each group achieving humane end point. Our study strongly supports fur<strong>the</strong>r<br />
translational and clinical research on MeV in combination with radiation <strong>the</strong>rapy and<br />
radiosensitising agents in head and neck cancers.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds417 | ix537
1678P PREDICTIVE VALUE OF TWO PHENOTYPING PROBES FOR<br />
THE PHARMACOKINETICS OF SUNITINIB IN CANCER<br />
PATIENTS<br />
J.S.L. Kloth 1 , H.J. Klumpen 2 , C.F. Samer 3 , K. Eechoute 1 , N.A.G. Lankheet 4 ,<br />
B.L. Kam 5 , M. Wong 6 , J.H.M. Schellens 7 , R.H.J. Mathijssen 8 , H. Gurney 9<br />
1 Medical Oncology, Erasmus Medical Center, Rotterdam, NETHERLANDS,<br />
2 Medical Oncology, Academic Medical Center (AMC), Amsterdam,<br />
NETHERLANDS, 3 Swiss Center for Applied Human Toxicities (SCAHT), Geneva<br />
University, Geneve, SWITZERLAND, 4 Department of Pharmacy and<br />
Pharmacology, Slotervaart Hospital/The Ne<strong>the</strong>rlands Cancer Institute,<br />
Amsterdam, NETHERLANDS, 5 Department of Nuclear Medicine, Erasmus<br />
Medical Center, Rotterdam, NETHERLANDS, 6 Department of Nuclear Medicine,<br />
Westmead institute for Cancer Research, Sydney, NSW, AUSTRALIA,<br />
7 Department of Clinical Pharmacology, The Ne<strong>the</strong>rlands Cancer Institute,<br />
Amsterdam, NETHERLANDS, 8 Department of Medical Oncology, Erasmus<br />
University Medical Center, Rotterdam, NETHERLANDS, 9 Medical Oncology,<br />
Westmead Hospital, Sydney, NSW, AUSTRALIA<br />
Background: Cancer patients treated with sunitinib show a wide inter-patient<br />
variability in drug exposure. This may at least partly explain <strong>the</strong> variation in toxicity<br />
and efficacy related to sunitinib treatment. The primary aim of this study was to<br />
investigate whe<strong>the</strong>r <strong>the</strong> clearance of 2 phenotyping probes are related to <strong>the</strong><br />
pharmacokinetics (PK) of sunitinib.<br />
Patients and methods: A prospective multi-center study was performed in cancer<br />
patients treated with single agent sunitinib. PK of sunitinib and its active metabolite<br />
N-desethyl-sunitinib were measured at start of sunitinib intake and within 4 weeks of<br />
continuous daily dosing. A correlation analysis was performed between <strong>the</strong>se PK data<br />
and midazolam clearance (as a CYP3A phenotyping probe) and hepatic 99m Tc-MIBI<br />
scans (as a probe for ABCB1 [P-glycoprotein] activity).<br />
Results: A total of 52 GIST and renal cell cancer patients were included in this study,<br />
of whom 46 were evaluable for analysis of sunitinib PK. Mean trough level of<br />
sunitinib, adjusted for dose, at day 1 of a new course was 14.7 ng/mL (range 7.2-28.9<br />
ng/mL), and 56.2 ng/mL (range 19.1-151.1 ng/mL) in <strong>the</strong> 4 th week of a treatment<br />
cycle. A significant correlation between N-desethyl-sunitinib trough levels and<br />
plasma clearance of midazolam (r = 0.58, P = 0.006) within 24 hours after <strong>the</strong> first<br />
intake of sunitinib was found. In addition, a trend was seen for <strong>the</strong> correlation<br />
between midazolam clearance and sunitinib trough levels at steady state (r = 0.26, P<br />
= 0.09). No correlation between sunitinib trough levels and hepatic 99m Tc-MIBI<br />
clearance was seen in an interim analysis after 27 patients.<br />
Conclusions: These observations show a correlation between <strong>the</strong> midazolam<br />
clearance test that serves as a probe for CYP3A and <strong>the</strong> exposure to sunitinib.<br />
Meanwhile, a lack of correlation was seen between sunitinib PK and <strong>the</strong> studied<br />
ABCB1 probe. These data could ultimately lead to a fur<strong>the</strong>r personalization of<br />
sunitinib dosing. Additional investigations are in progress, including population PK<br />
modeling of sunitinib, and incorporation of pharmacogenetic parameters to fur<strong>the</strong>r<br />
unravel <strong>the</strong> mechanisms behind <strong>the</strong>se findings.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1679P HEAT SHOCK PROTEIN 90 INHIBITION DOWNREGULATES<br />
C-KIT EXPRESSION IN GIST CELLS THROUGH DIMINISHING<br />
TRANSCRIPTION AND ENHANCING PROTEIN DEGRADATION<br />
VIA BOTH AUTOPHAGY AND PROTEASOME PATHWAYS<br />
Y. Hsueh 1 ,C.Yen 2 , N. Shih 1 , N. Chiang 1 ,C.Li 3 , L. Chen 1<br />
1 National Institute of Cancer Research, National Health Research Institutes,<br />
Tainan, TAIWAN, 2 Hematology/Oncology, Taipei Veteran General Hospital, Taipei,<br />
TAIWAN, 3 Department of Pathology, Chi-Mei Foundation Medical Center, Tainan,<br />
TAIWAN<br />
Background: Gastrointestinal stromal tumor (GIST) is a mutant oncoprotein c-Kit<br />
droved cancer. Patients suffered drug resistance after prolonged standard treatment of<br />
tyrosine kinase inhibitor (TKI), imatinib mesylate (IM). Inhibition of heat-shock<br />
protein 90 (Hsp90), a chaperone responsible for protein maturation and stability,<br />
causing its client proteins degradation, as c-Kit, is a developing <strong>the</strong>rapy for cancer.<br />
However, <strong>the</strong> mechanisms of Hsp90 inhibition-induced c-Kit downregulation in<br />
post-translational and transcriptional levels have rarely been investigated.<br />
Methods and results: Our data showed that NVP-AUY922 (AUY922), a new<br />
class of Hsp90 inhibitor, inhibited <strong>the</strong> growth of GIST882 and GIST48 cells with<br />
mutant c-Kit protein expression that was accompanied with reduction of both<br />
total and phosphor-c-Kit protein and induction of apoptosis. Pharmacological<br />
inhibition on ei<strong>the</strong>r autophagy or proteasome degradation pathway could<br />
partially reverse endogenous c-Kit turnover and AUY922-induced c-Kit<br />
reduction. These findings were fur<strong>the</strong>r confirmed by <strong>the</strong> co-localization of c-Kit<br />
with ei<strong>the</strong>r LC-3B or acridine orange-labeled autophagosome in confocal<br />
microscopy, and delay of c-Kit degradation by silencing autophagosome essential<br />
Beclin-1 protein. In addition, AUY922 could also reduce c-Kit mRNA without<br />
affecting its degradation. Our preliminary data showed that activities and nuclear<br />
levels of several transcription factors in GIST cells were diminished after<br />
AUY922 treatment. DNA affinity precipitation assay and chromatin<br />
immunoprecipitation (ChIP) will be performed to validate <strong>the</strong> binding of <strong>the</strong><br />
candidate transcript factors on <strong>the</strong> c-Kit promoter.<br />
Annals of Oncology<br />
Conclusions: This is <strong>the</strong> first report showing <strong>the</strong> involvement of autophagy in<br />
endogenous as well as Hsp90 inhibitor-induced c-Kit degradation. Moreover,<br />
AUY922 treatment resulted in downregulation of c-Kit through protein degradation<br />
and transcriptional mRNA regulation in GIST cells. These findings address <strong>the</strong><br />
mechanisms of AUY922 on c-Kit protein downregulation and highlight <strong>the</strong> potential<br />
use of AUY922 in TKI-refractory, c-Kit-expressing GIST.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1680P MOLECULAR PROFILING OF HIGH-RISK LOCALIZED<br />
PROSTATE CANCER (HRLPC) TREATED WITH DOCETAXEL<br />
(D) AND COMPLETE ANDROGEN BLOCKADE (CAB) PRIOR<br />
TO RADICAL PROSTATECTOMY<br />
M. Marín-Aguilera 1 , A. Font 2 , E. Gallardo 3 , A. Alcaraz 4 , V. Pereira 5 , M.J. Ribal 4 ,<br />
J. Areal 6 , N. Hannaoui 7 , P. Gascon 8 , B. Mellado 5<br />
1 Translational Oncology Laboratory, Fundacio Clínic per a la Recerca Biomèdica,<br />
Barcelona, SPAIN, 2 Medical Oncology, Institut Català d’Oncologia-Badalona,<br />
Badalona, SPAIN, 3 Oncologia Medica, Hospital de Sabadell Corporacis Parc<br />
Tauli, Sabadell, SPAIN, 4 Urology, Hospital Clínic, Barcelona, SPAIN, 5 Medica<br />
Oncology, Hospital Clínic, Barcelona, SPAIN, 6 Urology, Hospital Germans Trias i<br />
Pujol, Badalona, SPAIN, 7 Urology, Hospital Parc Tauli, Sabadell, SPAIN,<br />
8 Medical Oncology, Hospital Clinic y Provincial de Barcelona, Barcelona, SPAIN<br />
Background: HRLPC has an increased risk of positive margins and recurrence after<br />
local treatment. Neoadjuvant docetaxel has not shown to increase <strong>the</strong> percentage of<br />
pathological complete responses (pRCs) respect to hormone-<strong>the</strong>rapy alone. In a<br />
previous phase II trial of neoadjuvant D plus CAB in patients with HRLPC we<br />
reported a 6% pRCs. (Mellado B, Br J Cancer 2009). We proposed that <strong>the</strong> molecular<br />
analysis of residual tumor cells after D + CAB may help to identify molecular<br />
mechanisms of treatment resistance.<br />
Methods: 93 genes potentially involved in D resistance were selected from a previous<br />
molecular study of our group (Marin-Aguilera M, Mol Cancer Ther <strong>2012</strong>). Gene<br />
transcriptional levels were analyzed by using Taqman low density arrays in 28<br />
formalin-fixed paraffin-embedded (FFPE) tumors from HRLPC patients treated with<br />
D + CAG prior radical prostatectomy, and in 36 HRLPC patients who underwent<br />
radical prostatectomy without neoadjuvant <strong>the</strong>rapy. GUSB housekeeping gene was<br />
<strong>the</strong> reference for normalization. Gene expression determination was performed with<br />
RQ Manager Software for manual data analysis.<br />
Results: Differential gene expression of 67.7% (63 of 93 analyzed genes) was found<br />
in neoadjuvant treated tumors versus samples without neoadjuvant treatment (P <<br />
0.05). Among <strong>the</strong>m, <strong>the</strong>re were found differences in <strong>the</strong> expression of genes related<br />
with androgen receptor signalling, NFkB transcription factor and<br />
epi<strong>the</strong>lial-mesenquimal transition processes. Data on gene expression and its<br />
correlation with clinical outcome will be presented at <strong>the</strong> meeting.<br />
Conclusions: Residual tumor cells in prostatectomy specimens after neoadjuvant<br />
hormone- and chemo<strong>the</strong>rapy treatment already exhibits a gene expression profile<br />
that may be involved in hormone/chemo resistant phenotype.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1681P THE ROLE OF MACROPHAGES POLARIZATION IN<br />
PREDICTING PROGNOSIS IN RADICALLY RESECTED<br />
GASTRIC CANCER<br />
F. Pantano 1 , P. Berti 1 , F.M. Guida 1 , S. Intagliata 1 , F. Graziano 2 , G. Perrone 3 ,<br />
A. Onetti Muda 3 , B. Vincenzi 1 , G. Tonini 1 , D. Santini 1<br />
1 Medical Oncology, University Campus Bio-Medico, Rome, ITALY, 2 Medical<br />
Oncology, Ospedale di Urbino, Urbino, ITALY, 3 Department of Pathology,<br />
University Campus Bio-Medico, Rome, ITALY<br />
Introduction: Macrophages are one of <strong>the</strong> major populations of tumor-infiltrating<br />
immune cells. Tumor associated Macrophages (TAM) present two different phenotypes<br />
or polarizations: classical (M1) characterized by immunostimulation activity and tumor<br />
suppression; alternative (M2) characterized by angiogenesis, tumor promotion, and<br />
immune suppression. Despite <strong>the</strong>se opposite properties, most of <strong>the</strong> previous studies<br />
focused merely on evaluating absolute TAM count. In this work, for <strong>the</strong> first time in<br />
literature, we evaluated <strong>the</strong> correlation between <strong>the</strong> two forms of TAM with survival<br />
time in patients affected by gastric cancer after radical surgery.<br />
Methods: 52 chemo- and radio-naïve gastric cancer patients undergone to resection for<br />
curative intent were included in this retrospective study. Two slides were prepared for<br />
each patients and double-stained for CD68/NOS2 (M1) or CD68/CD163 (M2) and five<br />
representative high-power fields (×400 magnification) per slide were evaluated for TAM<br />
count. The median value of <strong>the</strong> two macrophage populations density (M1 = 7.0; M2 =<br />
6.4) and <strong>the</strong> median value of M1/M2 ratio (1.16) was used as cut-off.<br />
Results: 27 patients with M1 density above <strong>the</strong> median had a significantly higher<br />
survival compared to those below <strong>the</strong> median (median OS of 25.6 months,<br />
CI95%:22.33-44.85 vs 17.1 months, CI95%:13.66-27.98; P = 0.041). 26 patients with<br />
M1/M2 ratio above <strong>the</strong> median showed median OS of 27.2 months<br />
(CI95%:25.45-47.51) compared to 15.5 months (CI95%:11.36-25.50) of <strong>the</strong> patients<br />
below <strong>the</strong> median (P = 0.001). No statistically significant difference in terms of M1/<br />
M2 ratio was observed between intestinal vs diffuse histological type. No association<br />
ix538 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
between M2 macrophage density and patients outcome (P= 0.724) was found. In<br />
multivariate analysis M1/M2 was a positive independent predictor of survival (P=<br />
0.001; HR 0.420, CI95%: 0.22-0.78) whereas grading, histotype and TNM stage were<br />
not statistically significant.<br />
Conclusion: The M1 macrophage density and in particular M1/M2 ratio, as<br />
confirmed in multivariate analysis, is an independent factor that can predict patients<br />
survival time in gastric cancer after radical surgery. The role of macrophage<br />
phenotype in influencing <strong>the</strong> gastric cancer prognosis warrant fur<strong>the</strong>r investigation.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1682P ANTHRACYCLINE-INDUCED CARDIOTOXICITY IN MICE IS<br />
PREVENTED BY LATE INA INHIBITION WITH RANOLAZINE,<br />
WITH IMPROVEMENT IN HEART FUNCTION, FIBROSIS AND<br />
APOPTOSIS<br />
N. Maurea 1 , C. Coppola 1 , C. Quintavalle 2 ,D.Rea 3 , A. Barbieri 3 , G. Piscopo 4 ,<br />
R.V. Iaffaioli 4 , G. Condorelli 2 , C. Arra 3 , C.G. Tocchetti 1<br />
1 Cardiology, National Cancer Institute, Pascale Foundation, Naples, ITALY,<br />
2 Biology and Cellular and Molecular Pathology, Federico II University, Naples,<br />
ITALY, 3 Animal Experimental Research, National Cancer Institute, Pascale<br />
Foundation, Naples, ITALY, 4 Colorectal Oncology, National Cancer Institute,<br />
Pascale Foundation, Naples, ITALY<br />
Background: Doxorubicin (DOX) produces a well-known cardiomyopathy through<br />
multiple mechanisms, which include, among many, Ca2+ overload due to reduced<br />
SERCA2a activity and inappropriate opening of <strong>the</strong> RyR2, and impaired myocardial<br />
energetics. DOX generates Reactive Oxygen and Nitrogen Species (ROS and RNS),<br />
posing <strong>the</strong> heart at increased demand for oxygen, setting <strong>the</strong> stage for metabolic<br />
ischemia that also activates late INa, target of ranolazine (RAN). Here, we aim at<br />
assessing whe<strong>the</strong>r RAN, diminishing intracellular Ca2+ through inhibition of late<br />
I Na, and enhancing myocardial glucose utilization (and/or reverting impairment of<br />
glucose utilization caused by chemo<strong>the</strong>rapy) prevents DOX cardiotoxicity.<br />
Methods: We measured left ventricular (LV) function with fractional shortening (FS)<br />
by echocardiography in C57BL6 mice, 2-4 mo old, pretreated with RAN (370mg/kg/<br />
day, a dose comparable to <strong>the</strong> one used in humans) per os for 3 days. RAN was <strong>the</strong>n<br />
administered for additional 7 days, alone and toge<strong>the</strong>r with DOX (2.17mg/kg/day ip),<br />
according to our well established protocol. Hearts were <strong>the</strong>n excised, mRNA<br />
expression was analyzed by qRT- PCR, interstitial fibrosis with picrosirius red<br />
staining. By Western blotting, we measured <strong>the</strong> activation of <strong>the</strong> apoptotic pathway.<br />
Results: After 7 days with DOX, FS decreased to 50 ± 2%, p = .002 vs 60 ± 1%<br />
(sham). RAN alone did not change FS (59 ± 2%). Interestingly, in mice treated with<br />
RAN + DOX, <strong>the</strong> reduction in FS was milder: 57 ± 1%, p = 0.01 vs DOX alone.<br />
DOX-cardiotoxicity was accompanied by significant elevations in ANP (1000 folds),<br />
BNP (500 folds), CTGF (26 folds) and MMP2 (81 folds) mRNAs, while co-treatment<br />
with RAN significantly lowered <strong>the</strong>se same genes compared to DOX. The alterations<br />
in extracellular matrix remodeling were confirmed by an increase of interstitial<br />
collagen with DOX (3.66%), p = .004 vs 2.19% (sham), which was normal in hearts<br />
co-treated with RAN (2.02%, p = .0002 vs DOX). Finally, <strong>the</strong> levels of PARP and<br />
pro-Caspase 3 were significantly decreased in DOX (indicating activation of<br />
apoptosis) but not in RAN + DOX.<br />
Conclusions: In mice, RAN prevents DOX cardiotoxic effects. We plan to test RAN<br />
as a cardioprotective agent with o<strong>the</strong>r antineoplastic cardiotoxic drugs in mice, and<br />
to better characterize <strong>the</strong> cardioprotective mechanisms of RAN in <strong>the</strong>se settings.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1683P CATUMAXOMAB VERSUS CATUMAXOMAB PLUS<br />
PREDNISOLONE IN PATIENTS WITH MALIGNANT ASCITES<br />
DUE TO EPITHELIAL CANCER: RESULTS FROM THE<br />
CASIMAS STUDY<br />
J. Sehouli 1 , P. Wimberger 2 , I.B. Vergote 3 , P. Rosenberg 4 , A. Schneeweiss 5 ,<br />
C. Bokemeyer 6 , C. Salat 7 , G. Scambia 8 , D. Berton-Rigaud 9 , F. Lordick 10<br />
1 Department of Gynecology, Charite Medical University, Berlin, GERMANY,<br />
2 University of Duisburg-essen, AGO and Department of Gynecology and<br />
Obstetrics, Essen, GERMANY, 3 Obstetrics & Gynaecology, University Hospital<br />
Gasthuisberg, Leuven, BELGIUM, 4 Onkologiska Kliniken Universitetssjukhuset,<br />
University Hospital Linköping, Linköping, SWEDEN, 5 Heidelberg, National Center<br />
for Tumor Diseases, Heidelberg, GERMANY, 6 Head of The Department for<br />
Oncology, Haematology and Bone Marrow Transplantation, UKE II. Medizinische<br />
Klinik und PoliklinikMedizinische Klinik II., Hamburg-Eppendorf, GERMANY,<br />
7 Munich, Hematology Oncology Clinic, Munich, GERMANY, 8 Department of<br />
Gynecologic Oncology, Catholic University, Rome, ITALY, 9 Oncology, Centre<br />
René Gaducheau, Nantes, FRANCE, 10 Medizinische Klinik III, Staedtisches<br />
Klinikum Braunschweig, Braunschweig, GERMANY<br />
Purpose: This phase III b study compared catumaxomab with prednisolone (CP) to<br />
catumaxomab without prednisolone (C) as 3-hour intraperitoneal (i.p.) infusion in<br />
patients with malignant ascites from epi<strong>the</strong>lial cancers.<br />
Patients and methods: We randomised 219 patients to receive catumaxomab plus<br />
25 mg prednisolone as premedication (111 pts) or catumaxomab alone (108 pts).<br />
Primary endpoint of <strong>the</strong> study was <strong>the</strong> composite safety score (CSS) summarizing <strong>the</strong><br />
worst CTCAE grades for <strong>the</strong> main TEAEs (pyrexia, nausea, vomiting, and abdominal<br />
pain). A potential impact of prednisolone on efficacy was assessed by <strong>the</strong> co-primary<br />
endpoint puncture-free survival (PuFS). Fur<strong>the</strong>r parameters included overall survival<br />
(OS) and time to next <strong>the</strong>rapeutic puncture (TTPu).<br />
Results: The primary objective, to demonstrate superiority for safety of <strong>the</strong> CP arm<br />
was not met as <strong>the</strong> mean CSS was comparable for <strong>the</strong> two groups (CP: 4.1; C: 3.8<br />
for; p= 0.383). The median PuFS was slightly lower in CP (30 days) compared to C<br />
(37 days). However <strong>the</strong> hazard ratio (HR) for PuFS (HR: 1.130, p = 0.402) as well as<br />
<strong>the</strong> 75% quartiles (CP: 155 days, C: 92 days) were in favour of CP compared to<br />
C. The median TTPu was similar in both groups (CP: 78 days; C: 102 days, p=<br />
0.599). The majority of patients (123 pts) had no <strong>the</strong>rapeutic paracentesis prior to<br />
death (CP: 54.8%; C; 61.7%, p = 0.297). Median OS was longer for CP (CP: 124 days;<br />
C: 86 days, p= 0.186), but lacking statistical significance.<br />
Conclusions: The administration of 25mg prednisolone as premedication prior to<br />
catumaxomab infusion did not change <strong>the</strong> safety profile and did not negatively impact<br />
<strong>the</strong> efficacy of catumaxomab. The efficacy results of <strong>the</strong> CASIMAS study are in<br />
concordance with <strong>the</strong> data of <strong>the</strong> pivotal study and thus confirm <strong>the</strong> robustness of <strong>the</strong><br />
treatment effect of catumaxomab in malignant ascites. The composite safety score after<br />
3-hour infusion time was comparable to that seen in <strong>the</strong> pivotal study using 6 hours.<br />
Disclosure: J. Sehouli: consultant for Fresenius Biotech GmbH. P. Wimberger:<br />
consultant for Fresenius Biotech GmbH. I.B. Vergote: consultant for Fresenius<br />
Biotech GmbH. P. Rosenberg: financial support for clinical studies from Fresenius<br />
Biotech GmbH. A. Schneeweiss: financial support for clinical studies from Fresenius<br />
Biotech GmbH. C. Bokemeyer: consultant for Fresenius Biotech GmbH. C. Salat:<br />
financial support for clinical studies from Fresenius Biotech GmbH. G. Scambia:<br />
financial support for clinical studies from Fresenius Biotech GmbH.<br />
D. Berton-Rigaud: financial support for clinical studies from Fresenius Biotech<br />
GmbH. F. Lordick: consultant for Fresenius Biotech GmbH<br />
1684P CHARACTERISATION OF A NOVEL ROLE OF MST2 IN<br />
CANCER CELL MIGRATION IN THE CONTEXT OF HEAD AND<br />
NECK CANCER<br />
C. Escriu, F. Watt<br />
Medical Oncology, Li Ka Shing Centre, Cancer Research UK, Cambridge<br />
Research Institute Addenbrooke’s Hospital, Cambridge, UNITED KINGDOM<br />
MST2 has so far been considered a tumour suppressor, however, its expression<br />
correlates with poor prognosis in several cancer types. We aimed to understand <strong>the</strong><br />
unknown mechanism by which <strong>the</strong>se tumours appear more aggressive in <strong>the</strong> context of<br />
head and neck cancers, where MST2 is highly expressed. We tested <strong>the</strong> role of MST2 in<br />
cell migration in automated boyden chambers and scratch wound assays in several early<br />
passage oral squamous cell cancer cell lines. Interestingly, cancer cell migration was<br />
significantly reduced in knock down cells using short hairpin and short interfering RNA<br />
knock down systems. Fur<strong>the</strong>rmore, overexpression of wild type MST2 promoted cell<br />
migration, whereas overexpression of kinase dead MST2 had a dominant negative effect.<br />
In 3D confocal microscopy quantification of inverted matrigel invasion assays MST2<br />
knock down also showed reduced invasion. Trying to characterise this effect fur<strong>the</strong>r we<br />
quantified cell attachment using confocal microscopy and image analysis in different<br />
laminin substrate concentrations. MST2 knock down cells showed a reduced cell<br />
number attachement and impaired cell spreading ability. Fur<strong>the</strong>r image analysis of<br />
migrating cells revealed, in keeping with <strong>the</strong> attachment defect, that MST2 knock down<br />
cells had larger focal adhesions with lower proportional surface of paxillin<br />
phosphorylation than control cells. MST2 knock down cells also required a longer time<br />
for actin cytoskeleton recovery after cytochalasin D treatment, suggesting a role in actin<br />
polymerisation that could explain <strong>the</strong> cell-spreading defect. Fur<strong>the</strong>rmore, using<br />
automated boyden chamber assays, Akt inhibition reduced cell migration over time in a<br />
directly proportional manner to cell MST2 expression levels. We are currently testing<br />
<strong>the</strong> effect of MST2 modulation in time to metastasis and survival using a tongue<br />
injection xenograft model. We describe here a novel role for MST2 in cell migration,<br />
explained by focal adhesion architecture and activity change, and by modulating actin<br />
polymerisation. Akt inhibirors can reverse this migration effect, which may lead to<br />
MST2 potentially becoming a predictor marker of response to biological <strong>the</strong>rapies in<br />
head and neck cancers.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1685P PROSTATE CANCER STEM CELLS DISPLAY LOWERED<br />
ACTIVITY OF THE MTOR PATHWAY AND RESISTANCE<br />
AGAINST MTOR INHIBITION CAUSED BY ELEVATED<br />
HYPOXIC SIGNALING<br />
M. Marhold 1 , E. Tomasich 1 , A. Haschemi 2 , G. Hofbauer 3 , A. Spittler 3 ,<br />
M. Krainer 1 , P. Horak 1<br />
1 Department of Internal Medicine I, Medical University of Vienna, Vienna,<br />
AUSTRIA, 2 Department of Laboratory Medicine, Medical University of Vienna,<br />
Vienna, AUSTRIA, 3 ASCTR Core Facility Flow Cytometry, Medical University of<br />
Vienna, Vienna, AUSTRIA<br />
Tumor-initiating subpopulations of cancer cells, also known as cancer stem cells<br />
(CSCs), were recently identified and characterized in Prostate cancer (PCa). We<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds417 | ix539
<strong>the</strong>orized that <strong>the</strong> PI3K/AKT pathway and mTOR, one of its main effectors, play a role<br />
in CSC maintenance. Moreover, hypoxia was known to be involved in CSC<br />
maintenance and to have a regulating effect on mTOR signaling.<br />
In our study, we <strong>the</strong>refore evaluated <strong>the</strong> effects of mTOR inhibitors on proliferation,<br />
assessed <strong>the</strong> activity of <strong>the</strong> mTOR pathway and measured <strong>the</strong> mitochondrial activity<br />
as well as levels of radical oxygen species (ROS) of human as well as murine CSCs<br />
in vitro. Fur<strong>the</strong>r, we examined basal levels of mediators of hypoxic signaling such<br />
as HIF1α and its effectors.We isolated CSC like cells from <strong>the</strong> human PCa cell line<br />
DU145 and <strong>the</strong> murine PCa cell line TRAMPC1 using FACS according to <strong>the</strong>ir<br />
expression of <strong>the</strong> stem cell markers CD44, CD49f and Sca-1. We used sphere<br />
formation assays to confirm stem and progenitor cell properties. Next, we treated<br />
<strong>the</strong> CSC and non-CSC cell populations with mTOR inhibitors under normoxic and<br />
hypoxic conditions in order to determine <strong>the</strong>ir cell viability at time points up to<br />
72h. Mitochondrial activity was measured using extracellular flux (XF) analysis and<br />
levels of ROS were obtained using ROS-specific fluorescent dyes and flow cytometry.<br />
Our results suggest that CSC like PCa cells are more resistant to mTOR inhibitors<br />
when compared to <strong>the</strong>ir non-CSC counterparts. Most interestingly, while <strong>the</strong><br />
non-CSC population displays higher sensitivity to mTOR inhibitors under hypoxic<br />
conditions, <strong>the</strong> viability of CSCs remains unaffected. Immunoblotting uncovers<br />
generally lower mTOR activity in CSCs compared to non-CSCs. Hypoxia leads to a<br />
decrease in mTOR activity in both subpopulations, though this effect is stronger in<br />
CSC like subpopulations through higher HIF1α-mediated negative feedback in both<br />
cell lines studied. At <strong>the</strong> same time we do not observe alterations in signaling<br />
through AR or PI3K downstream effectors besides mTOR, such as AKT. We<br />
propose that prostate CSCs might be resistant against mTOR inhibition and that<br />
inhibitors targeting multiple kinases along <strong>the</strong> PI3K/AKT/mTOR axis would be<br />
more effective. Our findings could be helpful to assess <strong>the</strong> impact of mTOR<br />
targeted <strong>the</strong>rapy in prostate cancer in light of ongoing clinical trials.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1686P SRC INHIBITION AS A METHOD TO OVERCOME<br />
TEMOZOLOMIDE RESISTANCE IN MELANOMA<br />
E.J. Jordan 1 , A. Eustace 2 , D.M. Collins 2 , N. O Donovan 2 , J.P. Crown 3<br />
1 Medical Oncology, Mater University Hospital, Dublin, IRELAND, 2 Dublin City<br />
University, N.I.C.B, Dublin, IRELAND, 3 Medical Oncology, St Vincents University<br />
Hospital, Dublin, IRELAND<br />
Background: Malignant melanoma is resistant to chemo<strong>the</strong>rapeutic agents. Src<br />
signalling plays a role in many malignancies including melanoma. Src is important in<br />
cell adhesion regulation, invasiveness and activating o<strong>the</strong>r downstream cellular<br />
pathways. Src activity is elevated in melanoma and has potential to provide a<br />
treatment target for melanoma. Temozolomide is an oral alkylating prodrug.<br />
Dasatinib is a dual Src/Abl kinase inhibitor with antiproliferative activity. AZD0530<br />
is a selective oral Src kinase inhibitor.<br />
Methods: We examined <strong>the</strong> anti-proliferative effects of dasatinib and AZD0530 alone<br />
and in combination with temozolomide (TMZ) in melanoma cell lines - MALME,<br />
HT144 parent and temozolomide resistant cell lines MALME-TMZ and<br />
HT144-TMZ. MALME-TMZ and HT144-TMZ were produced by <strong>the</strong> pulse method.<br />
IC50 and combination proliferation assays were performed using an acid<br />
phosphatase-based colourimetric assay.<br />
Results: IC50 (50% inhibitory concentrations ± SD) values for TMZ were 338 ±25<br />
µM in HTI44 and 490 ±19 µM in HT144-TMZ. IC50 values for TMZ were 306 ±29<br />
µM in MALME and 515 ±45 µM in MALME-TMZ. Dasatinib was more effective as<br />
a single agent in HT144-TMZ (71 ± 8% growth inhibition at 1 µM) and<br />
Annals of Oncology<br />
MALME-TMZ (60 ± 6% growth inhibition at 1 µM) as compared to MALME (14 ±<br />
10% inhibition at 1 µM) and HTI44 (0 ± 3% inhibition at 1 µM). The combination of<br />
dasatinib/TMZ was more effective than TMZ alone in HT144 and HT144-TMZ.<br />
AZD0530 increased proliferation in HT144 (25 ± 8% at 1 µM) and HT144-TMZ<br />
(35 ± 9% at 1 µM) as a single agent. AZD0530 caused growth inhibition as a single<br />
agent in MALME-TMZ (18 ± 6% inhibition at 1 µM) and MALME (4 ± 2% at 1 µM).<br />
The combination of AZD0530 and TMZ had no effect in HT144 or HT144-TMZ<br />
while AZD0530 combined with TMZ was more effective than TMZ alone in<br />
MALME and MALME-TMZ.<br />
Conclusion: Dasatinib improved response to TMZ in both <strong>the</strong> chemo<strong>the</strong>rapy naive<br />
and resistant cell line models tested (HT144, HT144-TMZ, MALME,<br />
MALME-TMZ). AZD0530 improved response to TMZ in one of <strong>the</strong> models only–<br />
MALME and MALME-TMZ. These in vitro results support fur<strong>the</strong>r preclinical<br />
evaluation of Src Kinase inhibitors in combination with TMZ, and o<strong>the</strong>r<br />
DNA-targeting agents, particularly in TMZ-refractory melanoma.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1687 VEGF AND VEGF RECEPTORS IN THYMIC EPITHELIAL<br />
TUMORS (TET): PATHOLOGICAL FEATURES AND CLINICAL<br />
IMPLICATIONS<br />
L. Nappi 1 , V. Damiano 1 , M. Marino 2 , T. Gelardi 1 , L. Formisano 1 , P. Federico 1 ,<br />
E. Matano 1 , L. Puglia 1 , S. De Placido 1 , G. Palmieri 1<br />
1 Medical Oncology, University Federico II, Naples, ITALY, 2 Department of<br />
Pathology, National Cancer Institute “Regina Elena”, Rome, ITALY<br />
Background: Thymic Epi<strong>the</strong>lial Tumors (TET) are very rare cancers. They derives<br />
from Thymic gland and are associated with different clinical syndromes, such as<br />
miastenic and Good syndrome and o<strong>the</strong>r immunological and paraneoplastic<br />
disorders. The principal treatment of <strong>the</strong>se patients is chemo<strong>the</strong>rapy with<br />
schedule containing cisplatin characterized by high response rates (60%).<br />
Unfortunately some patients do not respond at all and most patients do not<br />
achieve long-lasting remission. For <strong>the</strong>se patients have not o<strong>the</strong>r <strong>the</strong>rapeutic<br />
chances at <strong>the</strong> moment. There are few data of <strong>the</strong> efficacy of anti-angiogenetic<br />
drugs in TET but new knowledges are emerging on <strong>the</strong> potential use of this class<br />
of drugs in patients with TET on <strong>the</strong> basis of laboratory and preclinical<br />
translational findings.<br />
Materials and methods: we investigated <strong>the</strong> expression of Vascular Endo<strong>the</strong>lial<br />
Growth Factor (VEGF) and its receptors (VEGFR1, 2 and 3) in 200 TET arranged in<br />
Tissue Micro Array (TMA). We observed both histotype distribution and modulation<br />
of angiogenetic factors (both VEGFRs and VEGFs) in TET.<br />
Results: we observed that, when compared with <strong>the</strong> low-grade counterpart, high<br />
grade TET (B2, B3 and Carcinomas) contained significantly higher numbers of<br />
VEGFA, VEGFC, VEGFD, VEGFR1 and VEGFR2 expressing tumor cells. In<br />
addition, in high grade TET, strong positive correlations between staining for<br />
VEGFA and those for all o<strong>the</strong>r markers were found. In <strong>the</strong> same tumors, VEGFC<br />
staining was not associated with VEGFR1, VEGFR3 and PDGFRB staining and no<br />
correlation was obtained between VEGFD and VEGFR1 or VEGFR3 staining. The<br />
co-expression in epi<strong>the</strong>lial cells of growth factors and <strong>the</strong>ir receptors suggests <strong>the</strong><br />
presence of autocrine mechanisms in TET.<br />
Conclusions: according to our data VEGFs and VEGFRs in TET are potential targets<br />
of anti-angiogenesis drugs. Fur<strong>the</strong>r studies are needed to investigate <strong>the</strong> potential role<br />
of anti-angiogenetic agents.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
ix540 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
tumor biology and pathology<br />
1688PD THE COMBINED EXPRESSION OF CXCR7 AND ITS LIGAND<br />
CXCL12 IS A MARKER FOR UNFAVORABLE PROGNOSIS IN<br />
GASTRIC CANCER<br />
H.J. Lee 1 , K.S. Lee 1 , H. Ryu 2 , I.C. Song 2 , S.M. Huang 3 , H.J. Yun 2 , J. Kim 3 ,<br />
D.Y. Jo 2 and S. Kim 2<br />
1 Intenal Medicine, Chungnam National University, Daejeon, KOREA, 2 Internal<br />
Medicine, Chungnam National University Hospital, Daejeon, KOREA, 3 Pathology,<br />
Chungnam National University Hospital, Daejeon, KOREA<br />
Background: Chemokines and <strong>the</strong>ir receptors have been shown to play a critical role<br />
in cancer growth and metastasis. In particular, recent data have suggested that <strong>the</strong><br />
chemokine CXCL12 and its receptor CXCR7 (also known as RDC1), which has been<br />
recently identified as a chemokine receptor, have key functions in promoting tumor<br />
development and progression. However, <strong>the</strong>re is little information regarding <strong>the</strong>ir<br />
expression and clinical relevance in gastric cancer. Here we investigated for <strong>the</strong> first<br />
time <strong>the</strong> effects of combined CXCR7 and CXCL12 expression on <strong>the</strong> prognosis of<br />
patients with gastric cancer.<br />
Methods: We studied CXCL12 and CXCR7 protein expression in 221 specimens of<br />
primary gastric cancer using immunohistochemistry, and investigated <strong>the</strong><br />
relationaship between CXCL12/CXCR7 expression and clinicopathological features<br />
and clinical outcomes.<br />
Results: Patients were categorized into four groups according to CXCR7 and<br />
CXCL12 expression: low CXCR7/low CXCL12, high CXCR7/low CXCL12, low<br />
CXCR7/high CXCL12, and high CXCR7/high CXCL12. No significant differences<br />
existed in age, gender, histology, tumor location, lymphovascular invasion among <strong>the</strong><br />
four groups. However, high CXCR7/high CXCL12 expression in tumor cells was<br />
significantly associated with invasion depth of <strong>the</strong> tumor (T status; P < 0.001), lymph<br />
node involvement (N status; P = 0.002), higher tumor stage (P = 0.002), and<br />
proportion of tumor size >5 cm (P = 0.006) compared to tumors with low CXCR7/<br />
low CXCL12 expression or high CXCR7/low CXCL12–low CXCR7/high CXCL12<br />
expression. Fur<strong>the</strong>rmore, patients with high CXCR7/high CXCL12 expression had<br />
<strong>the</strong> worst prognosis (5-year survival rate 30.6%; median, 2.3 years; range, 0.1 - 5.7<br />
years) compared to those of o<strong>the</strong>r patient groups (5-year survival rate, 52.4%;<br />
median, not reached; log-rank test, P = 0.008) .<br />
Conclusions: CXCR7 and CXCL12 are useful prognostic factors in gastric cancer,<br />
and <strong>the</strong> combination of high CXCR7 protein expression with high CXCL12<br />
expression suggests a dismal prognosis.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1689P CACHEXIA IN PANCREATIC CANCERS. COMPARISON OF<br />
ADENOCARCINOMA AND NEUROENDOCRINE TUMORS<br />
M.K. Mallath, A. Yelsengekar, S.A. Mehta and P.S. Patil<br />
Digestive Diseases, Tata Memorial Hospital Centre, Mumbai, INDIA<br />
Background: Patients with pancreatic adenocarcinoma (pCA) have high propensity<br />
for weight loss and cachexia. Patients with pancreatic neuroendocrine tumors<br />
(pNET) maintain <strong>the</strong>ir muscle mass for long period of time. Aims: We undertook a<br />
study to quantify <strong>the</strong> magnitude of cachexia in patients with pNET and compare it<br />
with pCA.<br />
Methods: An audit of <strong>the</strong> nutrition clinic database from 2000 to 2011 was reviewed<br />
and identified patients with pNET or pCA who had full nutritional work up<br />
including subjective global assessment scores (SGA) and body mass index (BMI).<br />
Cachexia was defined as a SGC score = C or BMI
Material and methods: 101 patients who underwent surgical resection due to lung<br />
cancer were participated in this study. None of <strong>the</strong>m received any kind of treatment<br />
prior to surgery. 86 were men and 15 women with a mean age of 62 years old. The<br />
tumors were classified histologically as adenocarcinoma in 48, squamous cell<br />
carcinoma in 33, large cell carcinoma in 11 and small cell carcinoma in 9 cases.<br />
Using tissue microarray technology, 101 paraffin-embedded tissue samples were<br />
cored, re-embedded to <strong>the</strong> final recipient block and used for EphA4 protein<br />
immunohistochemical expression. All analyses were performed by SPSS for Windows<br />
Software (SPSS Inc, Chicago, IL, USA) and a p value less than 0.05 was considered<br />
<strong>the</strong> limit of statistical significance.<br />
Results: EphA4 positivity was noted in 36 out of 101 (36%) cases. EphA4 staining<br />
intensity was classified as mild in 11 (31%), moderate in 23 (64%) and intense in 2<br />
(5%) out of 36 positive cases. Increased EphA4 positivity and moderate/intense<br />
EphA4 staining intensity were noted in adenocarcinoma and squamous cell lung<br />
carcinoma cases compared to large cell and neuroendocrine carcinoma ones (p =<br />
0.0049 and p = 0.0170, respectively). EphA4 positivity and staining intensity were<br />
associated with <strong>the</strong> presence of lymph node metastases (p = 0.0349 and p = 0.0404,<br />
respectively). EphA4 staining intensity was also correlated with tumor<br />
histopathological stage (p = 0.0145). No association of EphA4 positivity nor staining<br />
intensity were noted with tumor histopathological grade, size and organ metastasis.<br />
Conclusions: The current study supports evidence for possible EphA4 participation<br />
in lung cancer biological behaviour, implying also its potent role as a <strong>the</strong>rapeutic<br />
target. However, fur<strong>the</strong>r molecular and clinical studies are required in order to define<br />
<strong>the</strong> significance of Ephs and <strong>the</strong>ir ligands (ephs) in lung cancer prognosis and<br />
management.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1692P CORRELATION OF WTEGFR ACTIVATION ASSESSED BY<br />
MAB806 BINDING AND EGFR KINASE MUTATIONS IN STAGE<br />
IIIA N2 NSCLC<br />
M.S. Liew 1 , C. Murone 2 , M. Walkiewicz 2 , P. Mitchell 1 , H. Gan 1 , S. Barnett 3 ,<br />
P. Russell 4 , G. Wright 5 , A. Scott 2 and T. John 1<br />
1 Joint Austin-ludwig Oncology Unit, Austin Health, Heidelberg, VIC, AUSTRALIA,<br />
2 Ludwig Institute for Cancer Research (licr), Austin Health, Heidelberg, VIC,<br />
AUSTRALIA, 3 Department of Thoracic Surgery, Austin Health, Heidelberg, VIC,<br />
AUSTRALIA, 4 Department of Pathology, St Vincent’s Health, Fitzroy, SA,<br />
AUSTRALIA, 5 Department Thoracic Surgery, St Vincent’s Health, Fitzroy, VIC,<br />
AUSTRALIA<br />
The epidermal growth factor receptor (EGFR) pathway is a regulator of cellular<br />
proliferation and tumour progression. EGFR overexpression occurs with gene<br />
amplification and activating EGFR kinase mutations (EGFRmt). Monoclonal<br />
antibody 806 (mAb806) is an anti-EGFR antibody which targets tumours with EGFR<br />
mutation variant III and overexpression but not cells with low EGFR expression<br />
(wild type EGFR, wtEGFR) and normal tissues. To characterise mAb806 binding, we<br />
correlated mAb806 expression with EGFRmt, EGFR immunohistochemical (IHC)<br />
expression and overall survival (OS). Formalin fixed paraffin embedded tissues were<br />
stained using <strong>the</strong> mAb806 (Ludwig Institute for Cancer Research) and EGFR (Dako,<br />
PharmDx kit). A H-score was obtained based on staining intensity and percentage of<br />
cells stained. mAb806 H-scores 0-50 were classified as negative (mAb806-) and ≥50<br />
as positive expression (mAb806+). EGFR H-scores were calculated to stratify patients<br />
into low (Dako score
Annals of Oncology<br />
expression, but not in Gli3-undetectable HCT116 or DLD-1 cells. Silencing of<br />
endogenous Gli3 down-regulated colony formation and proliferation in HT29 and<br />
SW480 cells. However, truncated Gli3 (Gli3-R; repressor isoform) transduction had<br />
no effect on <strong>the</strong>se phenotypes although Gli1 expression was inhibited. After<br />
implantation of Gli3- or mock-transfected DLD-1 cells into immunedeficient SCID<br />
mice, tumor formation was observed in only Gli3-transfectant DLD-1 group but not<br />
in mock control. In surgically resected colorectal cancer specimen, Gli3 expression<br />
was heterogeneously detected and Shh expression was highly observed.<br />
Conclusions: Gli3-FL and Shh signals induce tumorigenicity in Gli1 independent<br />
manner, and Gli3-FL may be molecular targets for refractory colorectal cancer.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1695P FIBROBLAST INDUCED EPITHELIAL TO MESENCHYMAL<br />
TRANSITION (EMT) IN A NOVEL NON-SMALL CELL LUNG<br />
CANCER (NSCLC) MODEL<br />
A. Amann 1 , M. Zwierzina 2 , M. Bitsche 2 , G. Gamerith 3 , J. Huber 1 , S. Koeck 1 ,<br />
J. Kelm 4 , W. Hilbe 3 and H. Zwierzina 1<br />
1 Internal Medicine 1, Medical University Innsbruck, Innsbruck, AUSTRIA,<br />
2 Anatomy, Histology and Embryology, Medical University Innsbruck, Innsbruck,<br />
AUSTRIA, 3 Internal Medicine 5, Medical University Innsbruck, Innsbruck,<br />
AUSTRIA, 4 Insphero AG, Zürich, SWITZERLAND<br />
Introduction: Different molecular processes lead to metastatic spread and <strong>the</strong><br />
occurrence of tumour cell resistance to <strong>the</strong>rapeutic interventions. Among <strong>the</strong>m, <strong>the</strong><br />
epi<strong>the</strong>lial to mesenchymal transition (EMT) process plays a key role. During EMT,<br />
epi<strong>the</strong>lial tumour cells lose <strong>the</strong> expression of specific proteins and adopt <strong>the</strong><br />
phenotype of mesenchymal cells. These structural conversions are substantially<br />
dependent on <strong>the</strong> tumour microenvironment. EMT of tumour cells can induce drug<br />
resistance and metastasis. Thus, EMT inhibition may offer a new strategy for<br />
overcoming tumour progression.<br />
Methods: To evaluate EMT in a non-small cell lung cancer (NSCLC) model a 2D<br />
and a 3D- cell culture system was applied using both <strong>the</strong> human lung cancer cell line<br />
(A549) and <strong>the</strong> human lung fibroblast cell line (SV-80). For generating 3D cell<br />
spheroids, a novel system was established consisting of 96-well hanging drop<br />
microtiter plates (InSphero AG, Zürich, Switzerland). 2D co-culture assays were<br />
performed in transwell filter inserts (Costar). EMT was induced with transforming<br />
growth factor-β (TGF-β) or co-cultivation with fibroblasts in 2D/3D. The switch<br />
from epi<strong>the</strong>lial to mesenchymal cells was monitored by Western Blot (WB) analyses<br />
of e-cadherin, vimentin and n-cadherin. Fur<strong>the</strong>rmore, immunohistochemical<br />
analyses of e-cadherin, vimentin, α-smooth muscle actin, fibronectin, KI-67 and<br />
CA-IX were done on paraffin embedded spheroids.<br />
Results: EMT could be induced in <strong>the</strong> 2D not only by incubating tumour cells with<br />
TGF-β but also by co-culturing <strong>the</strong>m with fibroblasts in transwell filter inserts. In<br />
A549 cells a change in morphology as well as in protein expression defined by WB<br />
analysis (down regulation: E-cadherin; up regulation; Vimentin, n-cadherin) could be<br />
detected. When cultivated in <strong>the</strong> 3D system, A549 cells showed an up regulation of<br />
<strong>the</strong> mesenchymal protein vimentin without TGF-ß stimulation. Fur<strong>the</strong>rmore, a<br />
significant up regulation of vimentin, KI-67, CA-IX, and a slight down regulation of<br />
e-cadherin could be measured compared to monocultures.<br />
Conclusion: 3D culture represents a model to study EMT in tumour cell lines<br />
without addition of growth factors and thus reflects in vivo conditions closer than<br />
2D culture.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1696P CANCER STEM CELL MARKERS IN CLINICAL PANCREATIC<br />
CANCER: IMPACT OF CD44 + /CD24 + /EPCAM+<br />
EXPRESSION ON HISTOLOGY AND PROGNOSIS<br />
Y. Ohara, T. Oda, Y. Akashi, R. Miyamoto, K. Yamada, S. Hashimoto and<br />
N. Ohkohchi<br />
Surgery, University of Tsukuba, Tsukuba, JAPAN<br />
Purpose: Emerging evidence suggests that <strong>the</strong> capability of a tumor to grow and<br />
propagate is dependent on a small subset of cells within it, termed cancer stem cells<br />
(CSCs). In pancreatic cancer, CD44 + /CD24 + /EpCAM+ cells have been reported to<br />
be CSCs; however, <strong>the</strong> histological and clinical importance of <strong>the</strong>se cells has not yet<br />
been investigated. Here we clarified <strong>the</strong> characteristics of CD44 + /CD24 + /EpCAM+<br />
cells in clinical specimens of pancreatic cancer using immunohistochemical assay.<br />
Materials and methods: We used surgical specimens of pancreatic ductal<br />
adenocarcinoma from 30 patients. In view of tumor heterogeneity, we randomly<br />
selected 10 high-power fields per case, and triple-positive CD44 + /CD24 + /EpCAM+<br />
expression was identified using our scoring system. The distribution, histological<br />
characteristics, and prognostic importance of CD44 + /CD24 + /EpCAM+ cells were<br />
<strong>the</strong>n analyzed.<br />
Results: Among a total of 300 assessed fields, 41 (14%) were evaluated as<br />
triple-positive. The distribution of CD44 + /CD24 + /EpCAM+ cells varied widely<br />
among <strong>the</strong> 30 cases examined, and CD44 + /CD24 + /EpCAM+ expression was<br />
correlated with poor glandular differentiation and high proliferation (high Ki-67<br />
labeling). Analysis of <strong>the</strong> three markers individually showed that CD44 and CD24<br />
were also correlated with poor differentiation and high proliferation, while EpCAM<br />
was not. Survival analysis showed that CD44 + /CD24 + /EpCAM+ expression was<br />
not correlated with patient outcome; however, CD44 and CD24 each appeared to be<br />
correlated with poor prognosis.<br />
Conclusion: In pancreatic cancer, CD44 + /CD24 + /EpCAM+ cells overlapped with<br />
poorly differentiated cells and possess high proliferative potential. In particular,<br />
double-positive CD44 + /CD24+ cells seem to have relevance when considering<br />
clinical aspects.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1697P SEMULOPARIN EFFICIENTLY INHIBITS THROMBIN<br />
GENERATION TRIGGERED BY PANCREAS<br />
ADENOCARCINOMA CELLS BXPC3. DISTINCT ROLES OF<br />
ANTI-XA AND ANTI-IIA ACTIVITY<br />
G. Gerotziafas 1 , M.P. Roman 1 , E. Mdemba 1 , M. Hatmi 1 , J. Fareed 2 ,J.<br />
F. Bernaudin 1 and I. Elalamy 1<br />
1 ER2UPMC, Faculty of Medicin, Université Pierre et Marie Curie (Paris VI), Paris,<br />
FRANCE, 2 Pathology, Loyola University Medical Center, Maywood, IL, UNITED<br />
STATES OF AMERICA<br />
Background: Venous thromboembolism (VTE) is a common complication in<br />
patients with cancer receiving chemo<strong>the</strong>rapy. Currently no anticoagulant is approved<br />
for VTE prophylaxis in this setting. Semuloparin is an ultra-LMWH generated<br />
through a highly selective depolymerization of heparin which protects <strong>the</strong><br />
antithrombin (AT) binding site in order to improve <strong>the</strong> benefit/risk ratio compared<br />
to existing anitcoagulants.<br />
Aims: We studied in vitro <strong>the</strong> mechanism of action of semuloparin on <strong>the</strong> inhibition<br />
of thrombin generation (TG) of human platelet poor plasma (PPP) triggered by<br />
human pancreatic cancer cells BXPC3. We compared <strong>the</strong> antithrombotic efficiency of<br />
semuloparin to that of enoxaparin and <strong>the</strong> specific AT-dependent factor Xa inhibitor<br />
fondaparinux.<br />
Materials and methods: BXPC3 cells were suspended in PPP spiked with clinically<br />
relevant concentrations of semuloparin, enoxaparin and fondaparinux. The<br />
endogenous thrombin potential (ETP) and <strong>the</strong> mean rate index (MRI) of <strong>the</strong><br />
propagation phase of TG were monitored with <strong>the</strong> CAT assay (Stago France) as<br />
described previously (Gerotziafas et al Thromb Res 2011). Anti-Xa and anti-IIa<br />
specific activities were assessed assays obtained from Diagnostica Stago.<br />
Results: Both semuloparin and enoxaparin, at <strong>the</strong> concentration of 0.4 anti-Xa IU/<br />
ml, completely abrogated TG. Total inhibition of TG occured in <strong>the</strong> presence of<br />
0.002 anti-IIa IU/ml of semuloparin and 0.05 anti-IIa IU/ml of enoxaparin.<br />
Fondaparinux, even at concentrations higher than 2 µg/ml, reduced <strong>the</strong> MRI but did<br />
not significantly affect <strong>the</strong> ETP and did not completely inhibited TG,. The IC50 for<br />
<strong>the</strong> ETP of <strong>the</strong> anti-IIa activity of enoxaparin was 37-fold higher as compared to that<br />
of semuloparin.<br />
Conclusion: In a cancer cell model of hypercoagulability, semuloparin reduced<br />
efficiently thrombin generation. The unique anticoagulant profile of semuloparin<br />
based on its high AT-affinity differentiates it from enoxaparin and fondaparinux. The<br />
residual anti-IIa activity of semuloparin amplifies its antithrombotic efficacy. This<br />
profile is expected to translate into an improved benefit/risk ratio.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1698P DO THE WELL-KNOWN RISK FACTORS OF BREAST CANCER<br />
HAVE THE SAME IMPACT ON DEVELOPMENT OF<br />
MOLECULAR SUBTYPES?<br />
F. Paksoy Türköz 1 , M. Solak 1 , O. Keskin 2 ,Z.Arık 1 , F.S. Sarıcı 1 ,I_.H. Petekkaya 1 ,<br />
T. Babacan 2 and K.M. Altundag 2<br />
1 Medical Oncology, Abdurrahman Yurtaslan Ankara Oncology Research and<br />
Education Hospital, Ankara, TURKEY, 2 Medical Oncology, Hacettepe University<br />
Oncology Institute, Ankara, TURKEY<br />
Background: Altough clinical differences between breast cancer (BC) subtypes have<br />
been well-described, etiologic heterogeneity have not been fully studied. The aim of<br />
this study was to assess <strong>the</strong> associations between risk factors and molecular subtypes<br />
of BC.<br />
Methods: 1884 invasive BC cases were retrospectively analyzed. The odds ratios (OR)<br />
and 95% confidence intervals (CI) were estimated using multiple logistic regression<br />
analysis.<br />
Results: 1249 patients had luminal A, 234 had luminal B, 169 had HER-2<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds418 | ix543
overexpressing and 232 had triple negative BC. The age of ≥40 years was found to be<br />
a risk factor for luminal A (OR 1.41 95% CI 1.15-1.74; p = 0.001) and HER-2<br />
overexpressing subtype (OR:1.51, 95% CI:1.01-2.25; p = 0.04). Women who were<br />
nulliparous (OR 1.48, 95% CI 1,03-2,13; p = 0.03) or who had <strong>the</strong>ir first full-term<br />
pregnancy ≥30 years (OR 1.25 95% CI 0.83-1.88; p = 0.04) were at increased risk of<br />
luminal BC, whereas women with >2 children had a decreased risk (OR 0.68, 95% CI<br />
0.47-0.97; p = 0.03). Breast-feeding was a protective factor for luminal BC (OR 0.74,<br />
95% CI 0.53-1.04; p = 0.04). We found increased risks for postmenopausal women<br />
with HER-2 overexpressing (OR 2.20, 95% CI 0.93-5.17; p = 0.04) and luminal A<br />
(OR 1.87, 95% CI 0.93-3.90, p = 0.02) BC, who used hormone replacement <strong>the</strong>rapy<br />
for ≥5 years. Overweight and obesity increased <strong>the</strong> risk of triple negative BC (OR<br />
1.89 95% CI 1.06-3.37; p = 0.04 and OR 1.90 95% CI 1.00-3.61; p = 0.03), on <strong>the</strong><br />
contrary, decreased <strong>the</strong> risk of luminal BC (OR 0.63 95% CI 0.43-0.95; p = 0.02 and<br />
OR 0.50 95% CI 0.32-0.76; p = 0.002, respectively) in premenopausal women. There<br />
were no significant differences between risk of BC subtypes and early menarche, late<br />
menopause, family history, postmenopausal obesity, oral contraseptive use, smoking,<br />
in vitro fertilization and blood groups.<br />
Conclusions: Reproductive and hormonal characteristics were associated with luminal<br />
BC. Obesity and overweight increased <strong>the</strong> risk of triple negative subtype, particularly<br />
in premenopausal women. Older age and use of hormone replacement <strong>the</strong>rapy were<br />
related to <strong>the</strong> risk of HER-2 overexpressing BC. Our data suggest a significant<br />
heterogeneity in association of traditional BC risk factors and tumor subtypes.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1699P IDENTIFYING TRANS-ACTING COPY-NUMBER<br />
ALTERATIONS IN LUNG ADENOCARCINOMAS<br />
S. Camilleri-Broet<br />
Department of Pathology, HEGP, Paris, FRANCE<br />
Background: One of <strong>the</strong> main challenges in genomic oncology is to identify somatic<br />
copy-number alterations (CNAs) that include critical genes driving ei<strong>the</strong>r <strong>the</strong><br />
initiation or <strong>the</strong> progression of cancer disease. Most integrated genomic/<br />
transcriptomic analyses have primarily focused on identifying cis-acting CNAs,<br />
whose copy gains or losses are significantly associated with gene expression changes<br />
for <strong>the</strong> genes <strong>the</strong>y regulate. In this work, we do not restrict our analysis to cis-acting<br />
CNAs but focus on CNAs whose changes are associated with large number of<br />
significant transcriptomic changes distributed over <strong>the</strong> entire genome. We<br />
hypo<strong>the</strong>size that CNAs influencing a large number of transcripts ei<strong>the</strong>r by direct or<br />
indirect effect are likely to harbor candidate targetable genes.<br />
Material and methods: A homogeneous series of 129 early stage lung<br />
adenocarcinomas, profiled using both high-resolution array-based genotyping<br />
(SNP-array) and gene expression, was analyzed. After classical preprocessing, we<br />
selected recurrent CNAs that were exclusively amplified or deleted using a previously<br />
published latent class model analysis (BMC Med Genomics. 2009 Jul 14;2:43). For<br />
each genomic area, we computed genome-wide statistics measuring <strong>the</strong> relationship<br />
between transcriptomic changes over <strong>the</strong> different levels of copy number changes<br />
(copy loss/modal/copy gain). Then, we reported <strong>the</strong> number of significant<br />
associations taking into account multiple testing. We finally focused on “trans-acting<br />
CNAs” defined as those having extreme values.<br />
Results: Main trans-acting CNAs were found on 1q, 4q, 5q, 9p, 14q, harboring<br />
several known oncogenes/tumor suppressor genes. In contrast, o<strong>the</strong>r classical<br />
recurrent CNAs (such as 5p amplification) were not selected, suggesting <strong>the</strong>y were<br />
not associated with significant phenotype changes, as defined by transcriptomic<br />
analysis. The relationship between each “trans-acting CNAs” and clinico-pathological<br />
variables, as well as outcome is discussed.<br />
Conclusion: Using an integrative high-throughput microarray analysis in a series of lung<br />
adenocarcinomas, we identify “trans-acting CNAs”. We show <strong>the</strong> interest of focusing on<br />
<strong>the</strong>se CNAs which are likely to harbor potentially targetable candidate genes.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1700 WNT-2, BUT NOT WNT-1 EXPRESSION INCREASES DURING<br />
TUMORGENESIS IN BREAST, PROSTATE, LUNG CANCER<br />
AND MELANOMA<br />
A. Stanczak 1 , A. Brozyna 2 , H. Wisniewska 2 , W. Jozwicki 2 , L. Bodnar 3 ,<br />
M. Lamparska-Przybysz 1 and M. Wieczorek 4<br />
1 Research and Development, Celon Pharma, Lomianki, POLAND, 2 Department<br />
of Tumor Pathology and Pathomorphology of The Franciszek Lukaszczyk<br />
Oncology Center, The Ludwik Rydygier Collegium Medicum, Nicolaus<br />
Copernicus University, Bydgoszcz, POLAND, 3 Department of Oncology, Military<br />
Institute of Medicine, Warsaw, POLAND, 4 Celon Pharma, Lomianki, POLAND<br />
WNT/β-catenin pathway regulates cell cycle and proliferation. It is triggered by WNT<br />
ligands, and drives β-catenin regulated expression of cyclin D1, c-Myc, MMP7.<br />
Moreover β-catenin, along with E-cadherin, forms adherent junctions mediating cell<br />
adhesion. WNT-1 is a known oncogene and its expression occurs in several<br />
malignancies such as breast, prostate and lung cancers, while WNT-2 is less known<br />
member of WNT ligands family. The aim of our study was to investigate <strong>the</strong><br />
expression of WNT-1, WNT-2, β-catenin, E-cadherin and cyclin D1 in melanoma,<br />
breast, lung, prostate cancer in comparison to adjacent normal tissue and to fur<strong>the</strong>r<br />
understand WNT ligands significance as a potential biomarker. Formalin-fixed,<br />
paraffin-embedded samples were obtained from tumors and adjacent-normal tissues<br />
from 26 breast cancer patients, 22 non small cell lung cancers patients, 23 prostate<br />
cancers patients, 24 melanomas patients in I-III stage of <strong>the</strong> disease. Expression of<br />
WNT-1, WNT-2, β-catenin, E-cadherin and cyclin D1 was assessed by<br />
immunohistochemistry and analyzed by two independent histopathologists. Changes<br />
of studied proteins expression profiles between normal and malignant tissues were<br />
measured with Wilcoxon test, while comparison of expression of analyzed proteins<br />
between tumors was performed with Kruskall-Wallis and post hoc test. A value of p<br />
< 0,05 was considered significant. The study received approval by <strong>the</strong> Local Bioethics<br />
Committee. In our study, WNT-1 cytoplasmic expression was increased in breast<br />
cancer (p = 0,003) and melanoma (p = 0,0001), while in lung cancer it was decreased<br />
(p = 0,002). WNT-2 cytoplasmic expression was increased in breast (p < 0,0001),<br />
prostate cancer (p = 0,0002), melanoma (p = 0,0007), while in lung cancer WNT-2<br />
increased expression showed a trend towards significance (p = 0,06). Moreover<br />
WNT-2 ligand was found in cell nuclei in all tumors and its expression level was<br />
increased in breast cancer (p = 0,007) and decreased in melanoma (p = 0,042). Our<br />
study revealed that WNT-2, but not WNT-1 expression was increased in all analyzed<br />
tumors. Moreover WNT-2 ligand was detected in cell nuclei, what could implicated<br />
its yet undiscovered role in gene expression regulation.<br />
Disclosure: M. Wieczorek: Maciej Wieczorek is Chief Executive Officer of Celon<br />
Pharma Ltd.All o<strong>the</strong>r authors have declared no conflicts of interest.<br />
1701 PROTEOMIC ANALYSIS OF HUMAN LUNG CANCER<br />
CELL LINES<br />
Annals of Oncology<br />
M. Nomura 1 , J. Mobley 2 , D. Chen 3 , T. Ohira 1 , N. Gotoh 4 , A.F. Gazdar 5 and<br />
N. Ikeda 1<br />
1 1st Department of Surgery, Tokyo Medical University Hospital, Tokyo, JAPAN,<br />
2 Division of Urology, University of Alabama at Birmingham, Birmingham, AL,<br />
UNITED STATES OF AMERICA, 3 Division of Preventive Medicine, University of<br />
Alabama at Birmingham, Birmingham, AL, UNITED STATES OF AMERICA,<br />
4 Division of Systems Biomedical Technology, The University of Tokyo, The<br />
Institute of Medical Science, Tokyo, JAPAN, 5 Hamon Center for Therapeutic<br />
Cancer Research, UT Southwestern Medical Center, Dallas, TX, UNITED<br />
STATES OF AMERICA<br />
The causes and morphological appearances of human lung cancers are variable. We<br />
analyzed thirty seven lung cancer cell lines including thirty adenocarcnima (ADC),<br />
three small cell carcinoma (SCLC), one large cell carcinoma (LCC) and one<br />
adenosquamous carcinoma (AdSq) with LC/MS and identified less than 500 proteins of<br />
each cell line. We compared proteomic profiles between EGFR mutations and K-Ras<br />
mutations, smokers and non/less-smokers, and non-small cell carcinoma (NSCLC) and<br />
small cell carcinoma (SCLC). Eleven proteins, CALR, KYNU, SLC3A2, ALDH2, PGD,<br />
LAP3, DLC1, KIAA0664, ILKAP, ABCA13 and PTGR1 are related to <strong>the</strong> relationship<br />
between cell lines with EGFR mutations and K-Ras mutations and some of <strong>the</strong>m are<br />
associated to <strong>the</strong> signal network of cell cycle. Twelve proteins, PPP2R1B, RAP1A, RPS3,<br />
RNF113, TGM2, KIF22, UBA6, IFT122, IFI16, AKR1C1/AKR1C2, RPS5 and AKR1C3<br />
are related to <strong>the</strong> relationship between cell lines in from non/less-smokers and those<br />
from smokers and all proteins are associated to <strong>the</strong> signal network of cell morphology.<br />
Fifteen proteins, ANXA2, P4HB, ACTN4, MSN, ANXA5, IDH2, DPYSL2, DPYSL3,<br />
DPYSL5, CKB, IPO8, MAP1B, ETFA, TRIM28 and USP5, are related to <strong>the</strong><br />
relationship between cell lines of NSCLC and SCLC, and some of <strong>the</strong>m are associated<br />
to many signal pathways including cancer. Principle Component Analaysis could<br />
separate NSCLC from SCLC distinctly. We also detected common proteins among each<br />
group as candidate markers of cancer stem cells. AKR1C1/AKR1C2 was detected as<br />
common proteins between EGFR mutations vs K-ras mutations and smokers vs non/<br />
less smokers and has been reported as one of cancer stem cell markers. These results<br />
suggested that this methodology was very useful to detect not only specific proteins of<br />
each group but also protein-related signal pathways.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1702 HISTOLOGY OF SYNCHRONOUS AND METACHRONOUS<br />
CONTRA-LATERAL BREAST CARCINOMA<br />
Z. Tomasevic 1 , Z. Tomasevic 2 , D. Kolarevic 1 and Z. Milovanovic 3<br />
1 Daily Chmo<strong>the</strong>rapy Hospital, Institute for Oncology and Radiology, Belgrade,<br />
SERBIA, 2 Medical Oncology, Institute for Oncology and Radiology, Belgrade,<br />
SERBIA, 3 Pathology, Institute for Oncology and Radiology, Belgrade, SERBIA<br />
Background: Contra-lateral breast cancer (CBC) is considered to be <strong>the</strong> most<br />
frequent new malignancy after primary breast cancer (PBC). However, <strong>the</strong>re are few<br />
reports about concordance of <strong>the</strong> histology and o<strong>the</strong>r major molecular characteristics<br />
between PBC and CBC. Also, to <strong>the</strong> best of our knowledge, <strong>the</strong>re is no report about<br />
CBC histology according to <strong>the</strong> time of development from PBC.<br />
Aim: To evaluate and compare PBC/CBC histology type according to time of CBC<br />
development. Age at CBC and o<strong>the</strong>r major molecular characteristics (tumor grade,<br />
estrogen/progesterone receptors, HER2) have also been analyzed. Patients and<br />
ix544 | <strong>Abstract</strong>s Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology<br />
method A cohort of 113 CBC patients, without distant metastases, has been<br />
prospectively registered during 28 months. Patients are divided in 2 groups according<br />
to <strong>the</strong> time of CBC diagnose: 1. Synchronous, if <strong>the</strong> CBC (S-CBC) was diagnosed<br />
ei<strong>the</strong>r simultaneously or within 6 months after PBC; 2. Metachronous (M-CBC) if<br />
CBC was diagnosed > 6 months after PBC. (Table 1)<br />
Pts N = 113<br />
Synchronous<br />
CBC N = 49<br />
Metachronous<br />
CBC N = 64 P<br />
Median age at CBC diagnose (yrs) 57 (33-74) 50 (25-75) 0.007<br />
Median time to CBC (months) 0 (0-≤ 6) 60,5 (0-408) /<br />
PBC-CBC Histology identical (%) 76% 52% 0.006<br />
Lobular/Ductal (%) 41%/59% 41%/59% /<br />
Results: Patient with S-CBC are median 7 years older than patients with M- CBC<br />
(p-0.007). S-CBC is more likely to be of <strong>the</strong> same histological type (76%) than<br />
M-CBC (56%) (P- 0.006) In <strong>the</strong> whole analyzed group, and each subgroup<br />
separately, lobular carcinoma is registered in higher percentage (41%) than expected.<br />
For all o<strong>the</strong>r characteristics (tumor grade, estrogen/progesterone receptors and HER2<br />
status) <strong>the</strong>re was no statistical difference.<br />
Conclusion: According to <strong>the</strong>se results, it seems that patients destined to develop<br />
S-CBC or M-CBC, as a first recurrence site, have a greater susceptibility to lobular<br />
carcinoma, because this histology type was confirmed in significantly higher<br />
percentage than expected. Whe<strong>the</strong>r this reflects different genetic susceptibility for<br />
S-CBC and M-CBC, and what could be implications on fur<strong>the</strong>r prognosis, is yet to<br />
be analyzed.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
1704P PROSPECTIVE FEASIBLE STUDY TO EVALUATE<br />
NEOADJUVANT-SYNCHRONUS S-1 + RT FOR LOCALLY<br />
ADVANCED RECTAL CANCER: A MULTICENTER PHASE-II<br />
TRIAL (UMIN ID03396)<br />
M. Inomata<br />
Department of Gastroenterological Surgery, Oita University Faculty of Medicine,<br />
Oita, JAPAN<br />
Background: Fluorouracil-based chemoradio<strong>the</strong>rapy (CRT) is regarded as a standard<br />
perioperative treatment in locally advanced rectal cancer. We investigated <strong>the</strong> efficacy<br />
and safety of substituting fluorouracil with <strong>the</strong> oral prodrug TS-1.<br />
Methods: A multi-institutional (17 specialized centers), interventional phase II trial,<br />
was conducted from April 2009 to August 2011.This study is registered with<br />
UMIN-CTR, number C003396. For inclusion, patients must fulfill <strong>the</strong> following<br />
requirements before neoadjuvant CRT: (i) histologically proven rectal carcinoma; (ii)<br />
tumor located in <strong>the</strong> rectum (upper,lower); (iii) cancer classified as T3-4, N0–3 and<br />
M0; Two cycles of neoadjuvant CRT with TS-1 (100 mg/m2 on days 1-5, 8-12,<br />
22-26, and 29-33) is administered, and irradiation (total 45Gy/25fr, 1.8Gy/day, on<br />
days 1-5, 8-12, 15-19, 22-26, and 29-33) is performed. Total mesorectal excision with<br />
D3 lymphadenectomy is performed during <strong>the</strong> 4th and 8th week after <strong>the</strong> end of <strong>the</strong><br />
neoadjuvant CRT. The primary end-point is rate of complete treatment of<br />
neoadjuvant CRT. Secondary endpoints are response rate of neoadjuvant CRT,<br />
short-term clinical outcomes, rate of curative resection, and pathological response<br />
(grade2/3).<br />
Results: This trial included 37 patients. A complete treatment of neoadjuvant CRT<br />
was found in 83.3% of patients (95%CI;71.2 ∼ 95.5%), and an adverse event (grade 3/<br />
4) occurred in 4 patients (11.1%). A rate of an overall downstaging (PR/CR;RECIST<br />
1.0) was 83.3% (95%CI; 71.2 ∼ 95.5%), and a pathologic response rate was 50.0%<br />
(95%CI; 33.7 ∼ 66.3%).<br />
Conclusion: Our prospective phase-II study demonstrated that a<br />
neoadjuvant-synchronus TS-1 + RT for locally advanced rectal cancer was feasible in<br />
terms of pathological response and adverse events.<br />
Disclosure: All authors have declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds418 | ix545
author<br />
index<br />
author index<br />
A<br />
Aamdal S. ix32 (27IN)<br />
Aapro M.S. ix502 (1555P), ix507 (1571P)<br />
Aarntzen E. ix363 (1114PD)<br />
Aarts M.J. ix501 (1553P)<br />
Aasebø U. ix392 (1200P)<br />
Abbadessa G. ix225 (669PD), ix244 (738P),<br />
ix245 (739P)<br />
Abd Elwahab A.A. ix111 (304)<br />
Abdalaziz K.K. ix98 (256P)<br />
Abdel Azim H. ix288 (874)<br />
Abdel Halim I. ix341 (1039P), ix398 (1221)<br />
Abdel Karim K. ix150 (432)<br />
Abdel Latif H.A. ix93 (239)<br />
Abdel Latif R. ix341 (1039P)<br />
Abdel Metaal G. ix288 (874)<br />
Abdel-Rahman S. ix487 (1505P)<br />
Abdelhafez M.N. ix111 (304)<br />
Abdelrhman O. ix253 (770)<br />
Abdelwahab M. ix253 (770)<br />
Abdelwahab S. ix253 (770)<br />
Abdiganieva S.R. ix71 (162P)<br />
Abdul Rahman R. ix248 (750)<br />
Abdulkhalek H. ix337 (1028P)<br />
Abdullah H. ix337 (1028P)<br />
Abdurakhmanov D.A. ix71 (162P)<br />
Abe K. ix467 (1443)<br />
Abella L.E. ix291 (886)<br />
Abotouk N. ix114 (314)<br />
Abouelnaga S. ix448 (1374P)<br />
Abraham I. ix502 (1555P)<br />
Abraira V. ix205 (604P)<br />
Abreu M.H. ix132 (371P), ix222 (661)<br />
Abrial C. ix102 (270P)<br />
Abu Zeinah G.F. ix468 (1445)<br />
Abul Khair K. ix341 (1039P)<br />
Achilles K. ix255 (778TiP)<br />
Acikgoz O. ix110 (300)<br />
Ackerl M. ix145 (415PD), ix147 (421P)<br />
Acosta F. ix314 (952)<br />
Adachi S. ix227 (677P)<br />
Adam K. ix485 (1499P)<br />
Adam R. ix243 (733P)<br />
Adam Z. ix348 (1064O)<br />
Adamo B. ix104 (276P)<br />
Adamo V. ix104 (276P)<br />
Adamopoulos C. ix92 (236)<br />
Adams L. ix153 (442O)<br />
Adamson A. ix149 (431)<br />
Adaway G. ix199 (582P)<br />
Adenis A. ix206 (607P)<br />
Adetchessi T. ix150 (434)<br />
Adewole I. ix65 (135IN)<br />
Adhoute X. ix181 (529PD)<br />
Adjei A.A. ix155 (447PD), ix158 (456P)<br />
Adu-Aryee N.A. ix257 (782TiP)<br />
Advani R. ix348 (1063O)<br />
Aebi S. ix462 (1423O)<br />
Afc G. ix241 (727P)<br />
Afchain P. ix234 (703P)<br />
Afonso F.J. ix436 (1333), ix273 (826P)<br />
Afonso N. ix132 (371P)<br />
Afzal P. ix298 (904P)<br />
Agarwal N. ix153 (442O)<br />
Agarwal S. ix391 (1198P), ix154 (443PD)<br />
Agarwala S.S. ix371 (1137P), ix258 (783O)<br />
Agati R. ix147 (424P)<br />
Agbaje O. ix133 (372P)<br />
Agbor-Tarh D. ix95 (247O)<br />
Agelaki S. ix436 (1335)<br />
Agelidou M. ix436 (1335)<br />
Aghajanian C. ix319 (967O)<br />
Aglietta M. ix369 (1131P), ix205 (605P),<br />
ix270 (818P)<br />
Agostara B. ix463 (1425P)<br />
Agrawal R.K. ix97 (253PD)<br />
Agrawal S. ix502 (1557P)<br />
Aguas L. ix525 (1639)<br />
Aguila C. ix126 (349P)<br />
Aguilar A. ix136 (386)<br />
Aguirre I. ix418 (1273P)<br />
Agus D.B. ix302 (918P)<br />
Aherne S. ix528 (1645PD)<br />
Ahluwalia A. ix337 (1028P)<br />
Ahmad A. ix69 (154P)<br />
Ahmadizar F. ix122 (335P)<br />
Ahmed S. ix182 (531P)<br />
Ahmed S.A. ix145 (413PD)<br />
Ahmedov O.M. ix325 (985P)<br />
Ahn H. ix276 (834P), ix287 (872)<br />
Ahn J-H. ix108 (291P)<br />
Ahn J. ix276 (834P), ix287 (872)<br />
Ahn J.B. ix185 (543P)<br />
Ahn J.S. ix424 (1292P), ix97 (254PD)<br />
Ahn M. ix402 (1230PD)<br />
Ahn M.A. ix424 (1292P), ix430 (1311P)<br />
Ahn S-H. ix108 (291P)<br />
Ahn S. ix492 (1520PD)<br />
Ahn Y. ix276 (834P)<br />
Ährlund-Richter L. ix299 (906P)<br />
Aiello R.A. ix104 (275P)<br />
Aieta M. ix370 (1135P), ix280 (846P)<br />
Aikawa K. ix69 (153P)<br />
Airoldi M. ix343 (1047P), ix346 (1058),<br />
ix523 (1628)<br />
Aissa F. ix350 (1070PD)<br />
Aissat N. ix334 (1017O)<br />
Ait El Haj M. ix476 (1470P)<br />
Aitelhaj M. ix476 (1472P)<br />
Aitini E. ix280 (846P)<br />
Aizawa M. ix234 (702P)<br />
Ajani J.A. ix224 (668PD), ix232 (695P)<br />
Akahane M. ix441 (1351)<br />
Akamaru S. ix230 (688P)<br />
Akamatsu H. ix430 (1310P)<br />
Akasbi Y. ix137 (389)<br />
Akashi Y. ix543 (1696P)<br />
Akatsuka S. ix514 (1597P), ix203 (598P)<br />
Akbulut H. ix469 (1448PD)<br />
Akel S.Y. ix134 (376)<br />
Akgün Cetinkaya Z. ix394 (1207P)<br />
Akimoto T. ix396 (1215)<br />
Akimov M. ix152 (438O)<br />
Akita H. ix434 (1326), ix512 (1590P)<br />
Akiyoshi K. ix203 (598P)<br />
Akman L. ix173 (508)<br />
Akman T. ix173 (508), ix234 (701P)<br />
Akram M. ix98 (257P)<br />
Aksu G. ix110 (300)<br />
Aktas B. ix118 (323PD), ix186 (547P), ix217 (645)<br />
Akyurek S. ix525 (1636)<br />
Al Buali A. ix337 (1028P)<br />
Al Jamali M. ix72 (164)<br />
Alì M. ix104 (275P)<br />
Al-Batran S. ix459 (1413TiP), ix231 (691P)<br />
Al-Hajeili M. ix342 (1043P)<br />
Al-Kindi S.G. ix468 (1445)<br />
Al-Sakaff N. ix103 (273P)<br />
Álvarez Suárez S. ix198 (579P)<br />
Álvarez-Ossorio J.L. ix266 (805P)<br />
Alabiso O. ix123 (340P)<br />
Alagizy H.A. ix352 (1078P)<br />
Alba-Conejo E. ix101 (268P), ix128 (356P),<br />
ix140 (400)<br />
Albaghdadi J. ix327 (996P)<br />
Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
Annals of Oncology 23 (Supplement 9): ix546–ix585, <strong>2012</strong><br />
doi:10.1093/annonc/mds466<br />
Albanell J. ix97 (252PD)<br />
Albano A. ix370 (1135P)<br />
Alberola V. ix505 (1564P), ix523 (1629)<br />
Albert S. ix340 (1036P)<br />
Alberts D. ix324 (982P)<br />
Albiges L. ix277 (837P), ix278 (841P),<br />
ix304 (924P), ix313 (951)<br />
Albrand H. ix504 (1563P), ix506 (1568P),<br />
ix506 (1569P)<br />
Alcaraz A. ix538 (1680P), ix266 (805P)<br />
Alcindor T. ix200 (586P)<br />
Aledavood S.A. ix248 (749)<br />
Alekseev B. ix258 (783O), ix267 (809P)<br />
Alemany I. ix276 (835P)<br />
Alessandra P. ix164 (476P)<br />
Alexander H.R.Jr. ix371 (1141P), ix246 (743P)<br />
Alexandre J. ix170 (498P), ix327 (993P)<br />
Alexandre M.T.A. ix176 (514P)<br />
Alfaar A.S. ix448 (1374P), ix449 (1376P)<br />
Alface M. ix458 (1409)<br />
Alfaraj A.A. ix337 (1028P)<br />
Alfonsi S. ix86 (214P)<br />
Alfonso S. ix406 (1238PD)<br />
Algaba F. ix275 (832P)<br />
Ali G.T. ix134 (376)<br />
Alibay A.T. ix503 (1559P), ix517 (1607P)<br />
Aliberti C. ix371 (1140P)<br />
Aliberti G. ix344 (1050P)<br />
Alibhai S. ix464 (1432P)<br />
Alkis N. ix332 (1015)<br />
Allani B. ix254 (774)<br />
Allard A. ix410 (1250P)<br />
Allard M. ix243 (733P)<br />
Allegra C. ix198 (581P), ix214 (633)<br />
Allegrini G. ix528 (1646PD), ix94 (243),<br />
ix127 (354P), ix176 (515P)<br />
Allen A. ix236 (709P)<br />
Alloul K. ix205 (602P)<br />
Almagro Casado E. ix459 (1410), ix494 (1527P),<br />
ix112 (307)<br />
Almagro-Casado E. ix492 (1521PD)<br />
Almeida A. ix357 (1096)<br />
Almeida D. ix147 (423P)<br />
Almeida M. ix357 (1095), ix357 (1097)<br />
Almici C. ix338 (1029P)<br />
Almotlak H. ix128 (357P)<br />
Aloj L. ix193 (567P)<br />
Alonso-Jara J. ix380 (1165P)<br />
Alonso-Orduna V. ix195 (571P)<br />
Alonso I. ix135 (380)<br />
Alonso L. ix374 (1150)<br />
Alonso M. ix436 (1333)<br />
Alonso V. ix380 (1165P)<br />
Aloui A. ix254 (774)<br />
Alousi A. ix342 (1043P)<br />
Alsan Cetin I. ix394 (1207P)<br />
Alsner J. ix96 (249PD)<br />
Altaei T.S. ix163 (473P)<br />
Altomonte M. ix364 (1117PD), ix367 (1128P),<br />
ix373 (1148)<br />
Altug S. ix400 (1225O)<br />
Altun A. ix220 (654)<br />
Altundağ K.M. ix543 (1698P)<br />
Altundag M.K. ix104 (278P)<br />
Alumkal J. ix303 (920P), ix317 (964TiP)<br />
Alvarado-Zermeño A. ix329 (1003P)<br />
Alvarez Fernandez C. ix218 (647)<br />
Alvarez E. ix440 (1349)<br />
Alvarez I. ix82 (200P)<br />
Alvarez L. ix330 (1005P)<br />
Alvarez R.H. ix160 (461P)<br />
Alves F. ix331 (1010)<br />
Amadori A. ix91 (230P)
Annals of Oncology author index<br />
Amadori D. ix119 (327PD), ix285 (863P)<br />
Amanam I. ix460 (1416PD)<br />
Amann A. ix543 (1695P)<br />
Amano M. ix518 (1610P), ix526 (1643)<br />
Amano T. ix512 (1590P), ix220 (653)<br />
Amato R.J. ix300 (911P)<br />
Ambavane A. ix283 (856P)<br />
Amendolara A. ix472 (1456P)<br />
Ameye L. ix408 (1243P), ix199 (584P)<br />
Amiel C. ix337 (1025P)<br />
Amin A. ix368 (1129P)<br />
Amin H.M. ix154 (444PD)<br />
Amir E. ix91 (231P), ix158 (455P)<br />
Amitay Y. ix164 (477P)<br />
Amler L.C. ix89 (226P)<br />
Amling C. ix310 (939P)<br />
Amorim J. ix357 (1097)<br />
Ampollini L. ix496 (1536P)<br />
An A. ix465 (1433P)<br />
An A.R. ix465 (1434P)<br />
An H.J. ix108 (291P)<br />
An H.J. ix250 (757)<br />
An M. ix535 (1670P)<br />
Anak Ö. ix258 (783O)<br />
Anand A. ix89 (223P)<br />
Anand A.S. ix356 (1092P), ix134 (377)<br />
Anand B. ix317 (963TiP)<br />
Ananda S. ix321 (975PD)<br />
Anderes K. ix300 (911P)<br />
Anderhuber W. ix340 (1038P)<br />
Andersen R. ix530 (1654P), ix73 (168O)<br />
Anderson P. ix460 (1417PD), ix488 (1508P)<br />
Anderson S. ix327 (996P)<br />
Andersson M. ix142 (408TiP)<br />
Ando M. ix427 (1301P)<br />
Ando Y. ix220 (655)<br />
András C. ix223 (665TiP)<br />
André F. ix29 (18IN), ix122 (336P)<br />
André T. ix180 (525PD), ix190 (559P),<br />
ix195 (571P), ix206 (607P), ix218 (648)<br />
Andrade E.M.P.D. ix331 (1009)<br />
Andre F. ix84 (206P), ix116 (319O), ix125 (346P)<br />
Andreo Garcia F. ix431 (1315)<br />
Andreopoulos D. ix337 (1026P)<br />
Andreozzi M. ix77 (181P)<br />
Andresen C. ix269 (814P)<br />
Andrews E. ix207 (610P)<br />
Andric Z.G. ix428 (1304P), ix436 (1332)<br />
Andrikopoulos E. ix474 (1465P)<br />
Ang J.E. ix161 (464P), ix162 (469P)<br />
Ang M.K. ix412 (1257P)<br />
Ang S.F. ix245 (741P)<br />
Angevin E. ix170 (498P)<br />
Anghel R. ix116 (317O)<br />
Angouridakis N. ix338 (1030P), ix338 (1031P)<br />
Anguera G. ix292 (888)<br />
Anicic M. ix359 (1104)<br />
Anido U. ix273 (826P), ix312 (945)<br />
Annunziata M.A. ix474 (1462PD)<br />
Anota A. ix109 (296P)<br />
Ansari F.A. ix149 (430P)<br />
Ansell P.J. ix83 (203P), ix173 (505)<br />
Anserini P. ix521 (1621)<br />
Antón A. ix82 (200P), ix118 (323PD)<br />
Anter A.H. ix129 (360P)<br />
Anthoney A. ix500 (1549PD), ix129 (358P)<br />
Anthony S. ix170 (496P)<br />
Antoine E. ix128 (355P)<br />
Anton Aparicio L.M. ix306 (931P), ix314 (953)<br />
Anton-Aparicio L. ix380 (1165P), ix440 (1349),<br />
ix273 (826P)<br />
Antonarakis E.S. ix303 (920P), ix317 (964TiP)<br />
Antonello J. ix91 (230P)<br />
Antoni G. ix462 (1422O), ix463 (1427P),<br />
ix466 (1438P), ix164 (476P)<br />
Antonia S.J. ix405 (1237PD)<br />
Antonietti M. ix252 (767)<br />
Antoun S. ix511 (1587P), ix168 (491P)<br />
Anvari K. ix248 (749)<br />
Aoki Y. ix226 (672P)<br />
Aomatsu N. ix84 (205P)<br />
Aoyagi K. ix248 (751)<br />
Aoyama I. ix226 (673P)<br />
Aparicio A.M. ix261 (790O)<br />
Aparicio J. ix181 (527PD)<br />
Aparicio T. ix181 (529PD), ix234 (703P),<br />
ix237 (710P)<br />
Appaji L. ix358 (1102)<br />
Aquino L.C.M. ix215 (637)<br />
Arıcan A. ix312 (947)<br />
Arık Z. ix543 (1698P)<br />
Arab A. ix344 (1051)<br />
Arafat W. ix265 (801P), ix265 (803P)<br />
Aragane N. ix438 (1340)<br />
Arai J. ix71 (161P)<br />
Arai R. ix450 (1380P)<br />
Arai Y. ix243 (732P)<br />
Aramaki T. ix243 (732P)<br />
Aramendia J.M. ix149 (429P)<br />
Arance A. ix366 (1124P), ix135 (380)<br />
Aranda Aguilar E. ix529 (1648P), ix530 (1652P),<br />
ix131 (365P), ix186 (546P)<br />
Araujo A.M.F. ix78 (184P)<br />
Arbayo C. ix309 (938P)<br />
Arbea L. ix239 (718P)<br />
Arcana C. ix140 (399)<br />
Archer V. ix405 (1236PD), ix406 (1239P)<br />
Ardeleanu C. ix67 (146P)<br />
Ardigo M.L. ix406 (1238PD)<br />
Ardizzone A. ix95 (248O)<br />
Ardizzoni A. ix442 (1355), ix174 (509TiP),<br />
ix175 (513PD), ix216 (642)<br />
Areal J. ix538 (1680P), ix265 (802P)<br />
Arena V. ix433 (1322)<br />
Ares L. ix166 (484P)<br />
Areses C. ix436 (1333)<br />
Aretini P. ix176 (515P)<br />
Arevalo E. ix508 (1577P), ix239 (718P),<br />
ix291 (886), ix305 (927P)<br />
Argal csov S. ix81 (196P)<br />
Argiris A. ix424 (1291P), ix498 (1543TiP)<br />
Ariad S. ix373 (1147)<br />
Arias Santos I. ix92 (234)<br />
Aricò D. ix137 (388)<br />
Arifi S. ix137 (389)<br />
Armengol-Alonso A. ix135 (380)<br />
Armstrong A. ix303 (919P)<br />
Armstrong A.J. ix297 (899PD)<br />
Armstrong A.J. ix297 (901PD), ix311 (943P)<br />
Armstrong G. ix378 (1161P)<br />
Arnold D. ix35 (40IN), ix178 (518O),<br />
ix190 (559P), ix193 (565P), ix228 (680P)<br />
Arnould L. ix125 (346P)<br />
Arpaci F. ix286 (866P)<br />
Arpin D. ix391 (1199P)<br />
Arpino G. ix142 (407TiP)<br />
Arqueros C. ix292 (888)<br />
Arra C. ix539 (1682P)<br />
Arranz Arija J.A. ix264 (799P)<br />
Arruti M. ix212 (627)<br />
Artal-Cortes A. ix414 (1264P)<br />
Artale S. ix205 (605P)<br />
Artru P. ix85 (210P), ix237 (710P)<br />
Arts J. ix222 (663TiP)<br />
Arya D. ix356 (1092P), ix134 (377)<br />
Arzoz M. ix265 (802P)<br />
Asahara T. ix200 (585P)<br />
Asahina H. ix497 (1538P), ix159 (459P),<br />
ix164 (475P)<br />
Asai K. ix412 (1258P)<br />
Asaka M. ix202 (592P)<br />
Asami K. ix439 (1344)<br />
Asamura H. ix383 (1174P), ix387 (1186P)<br />
Ascierto P.A. ix361 (1110O), ix364 (1118PD),<br />
ix366 (1124P), ix367 (1128P), ix369 (1131P),<br />
ix369 (1133P), ix373 (1148), ix375 (1152)<br />
Ashabe Yamin R. ix107 (287P)<br />
Asselain B. ix218 (648)<br />
Asser T. ix146 (418PD), ix149 (431)<br />
Assi H. ix316 (960)<br />
Assikis V. ix303 (919P)<br />
Astone A. ix84 (207P)<br />
Ata A. ix312 (947)<br />
Ataergin A.S. ix286 (866P)<br />
Atagi S. ix393 (1204P), ix511 (1586P), ix91 (232)<br />
Ataman O. ix207 (609P)<br />
Atanackovic D. ix228 (680P)<br />
Ataseven B. ix114 (315TiP), ix117 (321PD)<br />
Ataseven H. ix220 (654)<br />
Atasoy B.M. ix394 (1207P), ix186 (547P)<br />
Atchison C. ix449 (1377P)<br />
Atif E. ix216 (639)<br />
Atil B. ix72 (165)<br />
Atilli S. ix174 (510TiP)<br />
Atkins M.B. ix258 (784O)<br />
Atsushi N. ix234 (702P)<br />
Attali C. ix460 (1419PD)<br />
Attard G. ix298 (903P), ix301 (913P), ix304 (924P)<br />
Atz J. ix163 (472P)<br />
Atzori F. ix276 (836P)<br />
Aubele P.O. ix487 (1505P)<br />
Aucoin N. ix202 (594P), ix316 (960)<br />
Augusto I. ix525 (1639)<br />
Augusto J.S. ix357 (1096)<br />
Aung K. ix87 (219P)<br />
Aung T. ix199 (583P)<br />
Aura C.M. ix531 (1656P), ix84 (204P),<br />
ix98 (255PD)<br />
Aust D. ix211 (622)<br />
Avallone A. ix193 (567P)<br />
Avci N. ix129 (359P)<br />
Avila D. ix470 (1450P)<br />
Avsar E. ix152 (438O)<br />
Awad I. ix353 (1081P), ix114 (314)<br />
Awada A. ix33 (32IN), ix125 (347P), ix157 (454P),<br />
ix23 (6IN)<br />
Awan U.E.K. ix358 (1100)<br />
Axtner J. ix453 (1389P), ix466 (1437P)<br />
Ayadi M. ix254 (774)<br />
Ayala F. ix364 (1118PD)<br />
Ayers S. ix319 (969PD), ix324 (983P)<br />
Azad A.K. ix78 (186P)<br />
Azanza J.R. ix508 (1577P)<br />
Azevedo S. ix255 (776TiP)<br />
Azim H.A. ix355 (1088P), ix114 (315TiP)<br />
Azim H.A.Jr ix58 (103IN), ix95 (247O),<br />
ix98 (255PD)<br />
Azkona E. ix212 (627)<br />
Aznar I. ix106 (284P)<br />
Azzarà M. ix138 (391)<br />
Azzarello D. ix505 (1565P), ix137 (388)<br />
Azzarello G. ix335 (1020PD)<br />
B<br />
Baas P. ix385 (1179O), ix392 (1203P)<br />
Baba H. ix188 (552P), ix217 (646)<br />
Baba T. ix436 (1334)<br />
Babacan N.A. ix220 (654)<br />
Babacan T. ix543 (1698P)<br />
Babaee N. ix346 (1059)<br />
Babaev A. ix229 (684P)<br />
Babakulov S. ix290 (882)<br />
Babalioglu I. ix525 (1636)<br />
Bachellier P. ix241 (727P)<br />
Bachelot T. ix62 (121IN), ix142 (409TiP)<br />
Bachet J. ix180 (525PD), ix238 (716P)<br />
Bachleitner-Hofmann T. ix179 (522PD)<br />
Bachour M. ix72 (164)<br />
Backen A. ix207 (609P)<br />
Bacon L. ix126 (349P)<br />
Badalamenti G. ix478 (1478O)<br />
Badar F. ix327 (994P)<br />
Badescu C. ix356 (1094)<br />
Badescu M. ix356 (1094)<br />
Volume 23 | Supplement 9 | June <strong>2012</strong> doi:10.1093/annonc/mds466 | ix547
author index<br />
Badran A. ix288 (874)<br />
Badulescu O.V. ix356 (1094)<br />
Bae W.K. ix467 (1441), ix468 (1446)<br />
Baertschi D. ix302 (917P)<br />
Bafaloukos D. ix373 (1146), ix85 (211P),<br />
ix94 (242)<br />
Bagalà C. ix84 (207P)<br />
Bagal B. ix350 (1069PD), ix351 (1074P)<br />
Bagayatkar P. ix350 (1069PD)<br />
Bago-Horvath Z. ix145 (414PD)<br />
Bagriacik Ü.E. ix277 (838P)<br />
Bahary N. ix224 (666O)<br />
Bahl A. ix449 (1377P), ix242 (729P), ix306 (931P)<br />
Bahleda R. ix496 (1534P), ix116 (319O),<br />
ix155 (446PD)<br />
Bai L. ix349 (1066PD)<br />
Bai M. ix213 (630)<br />
Bai Y. ix231 (690P)<br />
Baiget M. ix408 (1244P), ix183 (536P),<br />
ix185 (544P), ix216 (641)<br />
Bailey S. ix152 (438O)<br />
Bailly C. ix286 (864P)<br />
Bair A. ix268 (811P)<br />
Baird A. ix68 (150P), ix495 (1532P)<br />
Baitar A. ix452 (1386P)<br />
Bajetta E. ix373 (1148), ix288 (873)<br />
Bakalian S. ix519 (1614P)<br />
Baker-Neblett K.L. ix275 (833P)<br />
Bakhouche H. ix81 (196P)<br />
Bakhshi R. ix349 (1067PD)<br />
Bakhshi S. ix349 (1067PD), ix358 (1103)<br />
Bal O. ix105 (279P)<br />
Balakumaran A. ix360 (1108TiP)<br />
Baldelli E. ix535 (1668P)<br />
Baldini C. ix101 (266P)<br />
Baldini E. ix123 (340P)<br />
Baldo X. ix388 (1189P)<br />
Balke P. ix523 (1628)<br />
Ballas M. ix422 (1287P)<br />
Ballesteros A. ix374 (1150)<br />
Ballesteros P. ix254 (773)<br />
Balogh A. ix368 (1129P)<br />
Balvan O. ix497 (1540)<br />
Bambury R. ix248 (750)<br />
Bamias A. ix278 (841P)<br />
Ban H. ix492 (1520PD)<br />
Banal A. ix340 (1036P)<br />
Banani A. ix137 (389)<br />
Bandai Y. ix211 (625)<br />
Bandieri E. ix516 (1601P), ix516 (1602P),<br />
ix520 (1617), ix524 (1631)<br />
Bando H. ix164 (474P), ix196 (574P)<br />
Banerjee S. ix455 (1399P), ix320 (972PD)<br />
Banerji U. ix162 (469P)<br />
Bang Y. ix376 (1155O)<br />
Bannink M. ix109 (295P)<br />
Bapsy P.P. ix174 (510TiP)<br />
Barón F. ix395 (1212), ix505 (1564P), ix523 (1629)<br />
Bara I. ix411 (1254P), ix417 (1271P)<br />
Baracos V. ix168 (491P)<br />
Baranda J.C. ix223 (664TiP)<br />
Baranowski W. ix323 (979P)<br />
Barbare J. ix464 (1430P)<br />
Barbareschi M. ix99 (259P)<br />
Barber B. ix192 (564P)<br />
Barbero S. ix247 (747P)<br />
Barbi S. ix226 (675P)<br />
Barbieri A. ix539 (1682P)<br />
Barboriak D.P. ix146 (417PD)<br />
Baretti M. ix238 (714P)<br />
Bargallo-Rocha J.E. ix107 (289P), ix126 (349P)<br />
Bariani G.M. ix450 (1380P), ix486 (1503P)<br />
Barinov K. ix470 (1451P)<br />
Barista I. ix286 (866P)<br />
Barker H. ix502 (1557P)<br />
Barlesi F. ix403 (1232PD), ix426 (1299P),<br />
ix152 (438O)<br />
Barletta G. ix79 (187P)<br />
Barlier A. ix146 (419PD)<br />
Barnadas A. ix408 (1244P), ix183 (536P),<br />
ix185 (544P), ix216 (641)<br />
Barnett S. ix542 (1692P)<br />
Barney B. ix329 (1002P)<br />
Barni S. ix435 (1328), ix463 (1425P), ix467 (1440),<br />
ix515 (1599P), ix519 (1615P), ix131 (368P),<br />
ix192 (563P), ix229 (685P)<br />
Barone C. ix433 (1322), ix84 (207P)<br />
Barr M. ix68 (148P), ix68 (149P), ix495 (1531P),<br />
ix69 (154P)<br />
Barret M. ix511 (1587P)<br />
Barriga S. ix395 (1211)<br />
Barrios C. ix403 (1233PD), ix115 (316TiP),<br />
ix258 (783O)<br />
Barriuso J. ix165 (480P)<br />
Barron N. ix528 (1645PD)<br />
Barroso-Sousa R. ix331 (1009), ix455 (1397P),<br />
ix308 (935P)<br />
Barroso S. ix357 (1096)<br />
Barsoum E. ix288 (874)<br />
Bartfai Z. ix493 (1523P)<br />
Bartlett C.H. ix415 (1267P), ix416 (1268P)<br />
Bartlett N.L. ix348 (1063O)<br />
Bartoli C. ix343 (1047P)<br />
Bartolini S. ix145 (416PD)<br />
Bartolotti M. ix147 (424P)<br />
Bartosiewicz M. ix236 (709P)<br />
Bartsch R. ix145 (414PD)<br />
Baryshnikov K. ix371 (1138P)<br />
Basak J. ix355 (1090P), ix356 (1093P),<br />
ix359 (1105), ix359 (1106), ix448 (1375P),<br />
ix472 (1457P), ix135 (381)<br />
Basaran M. ix306 (931P)<br />
Basch E. ix295 (895O), ix295 (896O)<br />
Bascoul-Mollevi C. ix109 (296P)<br />
Basdra E.K. ix92 (236)<br />
Baselga J. ix27 (16IN), ix84 (204P), ix95 (247O),<br />
ix118 (324PD), ix121 (334P), ix124 (344P),<br />
ix126 (350P), ix126 (351P), ix154 (443PD),<br />
ix158 (457P)<br />
Basile P. ix252 (767)<br />
Bassett R. ix366 (1126P)<br />
Basso M. ix84 (207P)<br />
Basso S.M.M. ix287 (868)<br />
Basso U. ix91 (230P)<br />
Basté N. ix388 (1189P)<br />
Bastiaannet E. ix100 (263P)<br />
Bastie A. ix85 (210P)<br />
Bastit L. ix511 (1584P)<br />
Bastuji-Garin S. ix452 (1387P), ix460 (1419PD)<br />
Bastus R. ix136 (386)<br />
Basu S. ix301 (912P)<br />
Batagelj E.J. ix448 (1373P)<br />
Batinic D. ix359 (1104)<br />
Batist G. ix200 (586P)<br />
Batista N. ix314 (953)<br />
Batra K.K. ix470 (1450P)<br />
Battley J.E. ix248 (750)<br />
Batty A. ix370 (1134P), ix372 (1143P)<br />
Batus M. ix467 (1442)<br />
Baudelet C. ix319 (966O)<br />
Baudin E. ix378 (1160P), ix85 (209P)<br />
Baudrin L. ix419 (1276P)<br />
Bauduceau O. ix150 (433), ix285 (862P)<br />
Bauer S. ix481 (1486PD)<br />
Baumann S. ix507 (1574P)<br />
Baumann W. ix457 (1403)<br />
Baumert B. ix425 (1296P)<br />
Baurain J. ix321 (975PD)<br />
Bavington M. ix98 (255PD)<br />
Bay J. ix260 (789O)<br />
Baykara M. ix227 (678P)<br />
Bazan F. ix332 (1014), ix128 (357P)<br />
Bazhenova L. ix493 (1522PD), ix152 (439O)<br />
Bazin H. ix84 (206P)<br />
Beale P. ix499 (1544O)<br />
Beare S. ix206 (608P)<br />
Annals of Oncology<br />
Bearzi I. ix533 (1663P), ix86 (214P), ix86 (215P),<br />
ix239 (720P), ix243 (734P), ix250 (756)<br />
Beau-Faller M. ix388 (1190P), ix403 (1232PD)<br />
Beauchemin C. ix350 (1070PD), ix119 (328PD)<br />
Beaumont H. ix534 (1665P)<br />
Beaumont J. ix261 (792PD)<br />
Bebb D.G. ix440 (1350)<br />
Beccari S. ix166 (483P)<br />
Beck J.T. ix121 (334P)<br />
Beckman R. ix222 (662TiP)<br />
Bedard P. ix155 (448PD), ix156 (450PD),<br />
ix158 (455P)<br />
Bedenne L. ix181 (529PD), ix242 (730P)<br />
Bedikian A. ix363 (1115PD), ix366 (1126P),<br />
ix454 (1392P)<br />
Bedini N. ix315 (959)<br />
Bedognetti D. ix215 (636)<br />
Beebe-Dimmer J. ix244 (735P)<br />
Beech J. ix199 (582P)<br />
Beecham K. ix257 (782TiP)<br />
Beeram M. ix165 (481P), ix169 (492P)<br />
Beghelli S. ix226 (675P)<br />
Behlendorf T. ix357 (1098)<br />
Bekaii-Saab T. ix191 (560P)<br />
Belan E.V. ix470 (1451P)<br />
Belani C.P. ix421 (1281P)<br />
Belathur K.V. ix358 (1102)<br />
Belbaraka R. ix476 (1471P)<br />
Belderbos J. ix392 (1203P), ix396 (1213),<br />
ix396 (1216)<br />
Bell R. ix115 (316TiP)<br />
Bella M.A. ix175 (513PD)<br />
Bellardita L. ix315 (959)<br />
Bellazzi R. ix535 (1669P)<br />
Bellezza G. ix387 (1185P), ix535 (1668P)<br />
Belli C. ix240 (724P)<br />
Belli R. ix439 (1346)<br />
Belli S. ix379 (1164P)<br />
Bellido-Ribes C. ix136 (386)<br />
Bellmunt J. ix39 (53IN), ix260 (787O),<br />
ix265 (804P), ix266 (805P), ix266 (806P),<br />
ix267 (809P), ix278 (840P), ix312 (945)<br />
Bello P. ix106 (284P)<br />
Belloc J. ix340 (1036P)<br />
Belton L. ix523 (1628)<br />
Ben Ahmed S ix332 (1013)<br />
Ben Fatma L. ix332 (1013)<br />
Ben Itzhak O. ix498 (1541)<br />
Ben-Horin I. ix72 (163P)<br />
Benaim E. ix160 (461P), ix303 (921P)<br />
Benard M. ix339 (1033P)<br />
Benbrahim Z. ix137 (389)<br />
Bendahmane B. ix193 (565P)<br />
Bendell J. ix498 (1543TiP), ix158 (457P),<br />
ix159 (458P), ix191 (560P)<br />
Benedetti A. ix243 (734P)<br />
Benedetto L. ix375 (1152)<br />
Benedict A. ix279 (843P)<br />
Benekli M. ix227 (678P), ix277 (838P)<br />
Benelli G. ix122 (336P)<br />
Bengrine-Lefevre L. ix378 (1160P), ix85 (209P)<br />
Benhamouda N. ix75 (174O)<br />
Benitez J. ix281 (850P)<br />
Benjaafar N. ix328 (999P)<br />
Benkovičová J. ix503 (1560P)<br />
Benlloch S. ix86 (213P)<br />
Bennati C. ix387 (1185P), ix423 (1288P),<br />
ix427 (1302P)<br />
Bennett B. ix476 (1473P), ix298 (902P)<br />
Bennett K. ix368 (1129P)<br />
Bennett L. ix121 (334P), ix191 (560P)<br />
Bennett M.W. ix248 (750)<br />
Bennouna J. ix409 (1247P), ix410 (1250P),<br />
ix160 (461P), ix165 (478P), ix169 (494P),<br />
ix190 (559P), ix193 (565P), ix218 (648)<br />
Bensouda Y. ix432 (1318)<br />
Bento S. ix176 (514P)<br />
Benusiglio P.R. ix175 (511PD)<br />
ix548 | author index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology author index<br />
Benzidane B. ix249 (753)<br />
Bepler G. ix67 (144PD), ix49 (77IN)<br />
Berard H. ix406 (1240P)<br />
Berardi R. ix387 (1184P), ix533 (1663P),<br />
ix148 (425P)<br />
Bercier S. ix460 (1419PD)<br />
Bercovich D. ix109 (294P)<br />
Berdel W.E. ix284 (858P)<br />
Berenato F. ix140 (399)<br />
Berg E. ix390 (1195P)<br />
Bergamini C. ix335 (1019O), ix341 (1040P)<br />
Bergamo F. ix209 (618), ix240 (724P)<br />
Bergan E.Q. ix271 (819P)<br />
Berghian A. ix339 (1033P)<br />
Berghmans T. ix408 (1243P)<br />
Berghoff A.S. ix145 (414PD), ix148 (426P)<br />
Berghold A. ix340 (1038P)<br />
Bergmann L. ix274 (828P), ix278 (841P),<br />
ix288 (875)<br />
Berkenblit A. ix263 (796PD), ix293 (892TiP)<br />
Berman D.M. ix260 (788O)<br />
Berman R. ix363 (1113PD), ix464 (1431P)<br />
Bernardez Ferran B. ix92 (234)<br />
Bernardo A. ix123 (339P), ix138 (391)<br />
Bernardo G. ix463 (1425P), ix123 (339P),<br />
ix138 (391)<br />
Bernards R. ix32 (30IN)<br />
Bernaudin J.F. ix543 (1697P)<br />
Bernengo M.G. ix367 (1128P), ix369 (1131P)<br />
Berney D. ix172 (501)<br />
Bernhard S. ix332 (1014), ix128 (357P)<br />
Berrino L. ix67 (143PD)<br />
Berrocal A. ix374 (1150), ix374 (1151)<br />
Berry S. ix316 (960)<br />
Berry W. ix303 (920P)<br />
Bersani S. ix226 (675P)<br />
Bertarelli G. ix212 (628)<br />
Bertelli G. ix113 (311)<br />
Berthou C. ix522 (1624)<br />
Berti P. ix500 (1550PD), ix538 (1681P)<br />
Bertocci E. ix364 (1117PD)<br />
Berton-Rigaud D. ix514 (1596P), ix539 (1683P)<br />
Bertorelle R. ix144 (411O)<br />
Bertulli R. ix483 (1491P)<br />
Bertuzzi A.F. ix483 (1494P), ix487 (1506P)<br />
Bertwistle D. ix460 (1417PD), ix122 (337P)<br />
Bes¸irog˘lu M. ix186 (547P)<br />
Beslija S. ix116 (317O)<br />
Besova N. ix250 (760)<br />
Besse B. ix403 (1232PD), ix406 (1240P),<br />
ix415 (1267P), ix416 (1268P), ix421 (1284P),<br />
ix426 (1299P), ix496 (1534P), ix94 (244),<br />
ix152 (438O)<br />
Bestani C. ix379 (1164P)<br />
Besterman J. ix163 (471P), ix169 (492P),<br />
ix169 (493P)<br />
Bethune A. ix499 (1547PD)<br />
Betsuyaku T. ix422 (1285P)<br />
Betta P.G. ix247 (747P)<br />
Betticher D. ix396 (1214)<br />
Betticher D.C. ix462 (1423O)<br />
Beuzeboc P. ix125 (346P), ix259 (786O),<br />
ix294 (893O)<br />
Beveridge R. ix425 (1297P)<br />
Bhalla K. ix223 (664TiP)<br />
Bhat K. ix343 (1049P)<br />
Bhatt M. ix339 (1034P)<br />
Bhattacharjee S. ix471 (1453P)<br />
Bhattacharya(Majumdar) D. ix355 (1090P)<br />
Bhattacharya(majumder) D. ix472 (1457P)<br />
Bhattacharyya D. ix359 (1106), ix135 (381)<br />
Bhattacharyya G.S. ix301 (912P)<br />
Biagetti S. ix86 (214P)<br />
Biaggi C. ix480 (1482PD)<br />
Biagioli M. ix364 (1117PD)<br />
Biagioni F. ix183 (535P)<br />
Bianchini D. ix298 (903P), ix301 (913P),<br />
ix304 (924P)<br />
Bianchini G. ix74 (172O)<br />
Bianco R. ix530 (1651P), ix532 (1659P),<br />
ix287 (869)<br />
Bianconi F. ix387 (1185P), ix535 (1668P)<br />
Bianconi M. ix86 (214P), ix86 (215P), ix219 (652),<br />
ix239 (720P), ix243 (734P), ix250 (756),<br />
ix274 (829P)<br />
Bianconi M.I. ix330 (1005P)<br />
Bias P. ix500 (1548PD)<br />
Biasco E. ix290 (881)<br />
Biasoni D. ix285 (861P)<br />
Bidoli P. ix418 (1275P)<br />
Biedrzycka S. ix475 (1466P)<br />
Bier A. ix409 (1249P)<br />
Biggs H. ix74 (171O)<br />
Bighin C. ix454 (1393P), ix501 (1551PD),<br />
ix521 (1621), ix123 (340P)<br />
Biglia N. ix123 (340P)<br />
Bikov K. ix205 (603P), ix214 (634)<br />
Bilic E. ix359 (1104)<br />
Billiot F. ix94 (244)<br />
Binder C. ix284 (858P)<br />
Bines J. ix128 (356P)<br />
Binkhorst L. ix109 (295P)<br />
Bins S.B. ix111 (301)<br />
Biondani P. ix212 (628)<br />
Bíró K. ix281 (849P), ix286 (867P)<br />
Biron P. ix481 (1487P), ix260 (789O)<br />
Birrer M.J. ix81 (198P)<br />
Birtle A.J. ix284 (859P), ix292 (887)<br />
Bisagni G. ix101 (267P)<br />
Biscotti T. ix533 (1663P)<br />
Bisogno G. ix483 (1494P)<br />
Biswas B. ix264 (800P)<br />
Biswas J. ix301 (912P)<br />
Bitsche M. ix543 (1695P)<br />
Bittoni A. ix86 (215P), ix148 (425P), ix219 (652),<br />
ix239 (720P), ix250 (756), ix274 (829P)<br />
Biville-Hedouin F. ix409 (1247P)<br />
Bjarnason G.A. ix259 (785O), ix271 (820P)<br />
Blackhall F. ix73 (167O)<br />
Blackhall F.H. ix403 (1231PD), ix80 (193P),<br />
ix86 (213P)<br />
Blackstein M. ix478 (1478O)<br />
Blake-Cerda M. ix329 (1003P)<br />
Blanc J.F. ix238 (716P)<br />
Blanchet B. ix91 (229P)<br />
Blanchon F. ix455 (1396P)<br />
Blanckmeister C. ix415 (1266P)<br />
Blanco Campanario E. ix510 (1582P)<br />
Blanco Codesido M. ix520 (1619), ix198 (579P)<br />
Blanco Villalba M. ix448 (1373P), ix477 (1475)<br />
Blanco-Prieto S. ix92 (234)<br />
Blanco G. ix505 (1565P), ix104 (276P)<br />
Blandino G. ix183 (535P)<br />
Blank C. ix366 (1124P)<br />
Blank S.V. ix319 (967O)<br />
Blasi L. ix104 (276P)<br />
Blay J-Y. ix478 (1477O), ix54 (92IN)<br />
Blay J-Y ix21 (1IN)<br />
Blay J. ix470 (1452P), ix472 (1460), ix478 (1478O),<br />
ix479 (1480PD), ix481 (1487P), ix482 (1488P),<br />
ix482 (1489P), ix483 (1493P), ix488 (1511P),<br />
ix236 (708P)<br />
Blayau M. ix175 (511PD)<br />
Blidaru A. ix67 (146P)<br />
Block A. ix514 (1596P)<br />
Blohmer J.U. ix117 (321PD)<br />
Blons H. ix77 (180P)<br />
Blough D. ix203 (596P)<br />
Blum D. ix462 (1423O)<br />
Blumenstein B.A. ix313 (949)<br />
Boér K. ix504 (1562P)<br />
Bobos M. ix337 (1026P), ix430 (1312),<br />
ix213 (630)<br />
Boccadoro M. ix502 (1555P)<br />
Boccardo F. ix276 (836P), ix301 (914P)<br />
Boccardo S. ix301 (914P)<br />
Bocci G. ix127 (354P)<br />
Bodei L. ix47 (75IN)<br />
Bodnar L. ix544 (1700), ix268 (812P),<br />
ix320 (971PD), ix323 (979P)<br />
Bodoky G. ix224 (668PD), ix232 (695P),<br />
ix255 (777TiP)<br />
Bodrogi I. ix286 (867P), ix307 (933P)<br />
Body J. ix447 (1372P)<br />
Boeckenhoff A. ix270 (817P), ix279 (844P)<br />
Boehm A. ix336 (1023PD)<br />
Boelle E. ix198 (581P)<br />
Boerman O. ix192 (562P)<br />
Boeru S.E. ix398 (1222)<br />
Bogaerts J. ix60 (111IN), ix535 (1670P)<br />
Boggi U. ix241 (726P)<br />
Boguradzki P. ix504 (1562P)<br />
Boher J.M. ix241 (727P)<br />
Boichuk I. ix69 (151P)<br />
Boige V. ix194 (568P), ix198 (580P)<br />
Bokemeyer C. ix502 (1555P), ix539 (1683P),<br />
ix228 (680P), ix284 (858P)<br />
Boku N. ix200 (587P), ix231 (689P), ix233 (697P)<br />
Bol K. ix363 (1114PD)<br />
Boland W. ix440 (1350)<br />
Boldini S. ix516 (1601P), ix516 (1602P),<br />
ix520 (1617), ix524 (1631)<br />
Boleti E. ix272 (822P)<br />
Bollag D. ix322 (978P)<br />
Bolzoni-Villaret A. ix338 (1029P)<br />
Bona E. ix94 (243), ix127 (354P), ix176 (515P)<br />
Bonanni B. ix83 (201P)<br />
Bonanno L. ix533 (1661P)<br />
Bonardi C. ix355 (1089P)<br />
Bonastre J. ix397 (1217)<br />
Bondarenko I. ix367 (1127P)<br />
Bondarenko I.M. ix500 (1548PD)<br />
Bonfils C. ix163 (471P)<br />
Boni C. ix463 (1425P), ix280 (846P)<br />
Boni L. ix528 (1646PD)<br />
Boni V. ix166 (484P)<br />
Bonizzoni E. ix507 (1571P), ix515 (1599P)<br />
Bonnetain F. ix464 (1430P), ix109 (296P),<br />
ix120 (331P), ix237 (710P)<br />
Bonneterre J. ix101 (266P), ix106 (285P),<br />
ix113 (309)<br />
Bonnin N. ix286 (864P)<br />
Bono P. ix261 (792PD)<br />
Bonomi M. ix117 (322PD), ix273 (825P)<br />
Bonomi P. ix408 (1245P), ix467 (1442)<br />
Bonvalot S. ix482 (1488P), ix486 (1502P)<br />
Booth C.M. ix260 (788O)<br />
Bootsma G. ix396 (1213), ix425 (1296P)<br />
Borad M. ix156 (449PD), ix222 (662TiP),<br />
ix224 (666O)<br />
Boral A.L. ix153 (440O)<br />
Borbath I. ix376 (1155O), ix225 (669PD)<br />
Bordi P. ix442 (1355)<br />
Bordignon C. ix410 (1251P), ix167 (487P),<br />
ix167 (488P), ix172 (502)<br />
Bordonaro R. ix104 (276P)<br />
Borg C. ix332 (1014), ix193 (565P), ix204 (600P),<br />
ix206 (607P), ix249 (753)<br />
Borg J. ix184 (539P)<br />
Borgato L. ix326 (991P)<br />
Borget I. ix397 (1219)<br />
Borgonovo K.F. ix435 (1328), ix463 (1425P),<br />
ix467 (1440), ix519 (1615P), ix131 (368P),<br />
ix192 (563P)<br />
Borreani C. ix474 (1462PD)<br />
Borrego M. ix208 (614P)<br />
Borresen-Dale A. ix96 (249PD)<br />
Børresen-Dale A. ix25 (9IN)<br />
Borsellino N. ix104 (276P)<br />
Bortesi B. ix175 (513PD)<br />
Bosch-Barrera J. ix388 (1189P)<br />
Bosch A. ix111 (301)<br />
Bosdet I. ix412 (1255P)<br />
Bose C.K. ix359 (1105), ix448 (1375P),<br />
ix471 (1453P), ix471 (1454P), ix471 (1455P),<br />
ix135 (381)<br />
Boshoff C. ix421 (1282P)<br />
Volume 23 | Supplement 9 | June <strong>2012</strong> doi:10.1093/annonc/mds466 | ix549
author index<br />
Bösmüller H. ix209 (616)<br />
Bosomworth M. ix171 (500P)<br />
Bosset J. ix475 (1468P), ix206 (607P)<br />
Bossi L.S. ix133 (374P)<br />
Bossi P. ix335 (1019O), ix341 (1040P),<br />
ix342 (1045P), ix344 (1050P)<br />
Boterberg T. ix341 (1042P)<br />
Botta M. ix247 (747P)<br />
Botteri E. ix83 (201P)<br />
Botti C. ix142 (406TiP)<br />
Bottini A. ix101 (267P)<br />
Bottomley A. ix483 (1493P)<br />
Bouattour M. ix379 (1163P), ix167 (485P)<br />
Bouché O. ix464 (1430P), ix482 (1489P),<br />
ix180 (525PD), ix236 (708P)<br />
Bouchahda M. ix194 (568P)<br />
Bouche O. ix190 (559P)<br />
Boucher E. ix482 (1489P), ix196 (572P),<br />
ix198 (580P)<br />
Boucher K.M. ix260 (787O)<br />
Boucher T. ix205 (602P)<br />
Bouda D. ix421 (1284P)<br />
Boudagga M. ix332 (1013)<br />
Boudghène F. ix206 (607P)<br />
Boudou-Rouquette P. ix91 (229P)<br />
Bouhlel A. ix103 (272P)<br />
Boukir A. ix432 (1318)<br />
Boukovinas I. ix139 (395), ix236 (707P)<br />
Boulanger V. ix499 (1547PD)<br />
Bourgeois H. ix456 (1401P)<br />
Bourlaud I. ix455 (1396P)<br />
Bourré L. ix312 (946)<br />
Boussen H. ix332 (1013)<br />
Bouzid K. ix344 (1051), ix221 (658)<br />
Bowden S.J. ix97 (253PD)<br />
Bowen Jones S.C. ix381 (1168P)<br />
Bowman A. ix119 (325PD)<br />
Bowman L. ix421 (1281P)<br />
Boye M. ix421 (1281P)<br />
Boyko I.N. ix311 (944P)<br />
Boyle H. ix286 (864P)<br />
Boyle T. ix469 (1449PD)<br />
Bozón V. ix158 (456P)<br />
Bozionelou V. ix139 (395)<br />
Bozzetti C. ix216 (642)<br />
Bozzi F. ix483 (1491P)<br />
Brédart A. ix475 (1468P)<br />
Brümmendorf T.H. ix342 (1044P)<br />
Bracarda S. ix264 (798PD), ix267 (809P),<br />
ix271 (820P), ix273 (825P), ix278 (840P),<br />
ix278 (842P), ix307 (932P), ix315 (958)<br />
Brada M. ix31 (26IN)<br />
Bradbury I. ix95 (247O)<br />
Brade A. ix148 (428P)<br />
Bradley R. ix436 (1332), ix125 (347P)<br />
Brady G. ix87 (219P)<br />
Bragagni M. ix285 (863P)<br />
Brahmadhi A. ix88 (221P)<br />
Brahmer J.R. ix405 (1237PD), ix157 (453P)<br />
Braiteh F. ix170 (496P)<br />
Bramajo M.P. ix448 (1373P), ix477 (1475)<br />
Bramati A. ix511 (1585P)<br />
Bramley S. ix90 (227P)<br />
Bramley T. ix122 (338P)<br />
Brammer M. ix122 (338P)<br />
Brana Garcia I. ix156 (450PD), ix158 (455P)<br />
Brandes A. ix145 (416PD), ix147 (424P)<br />
Braun A. ix509 (1580P), ix115 (316TiP)<br />
Braun E.R. ix381 (1170P)<br />
Braun M. ix199 (582P)<br />
Braun S. ix190 (558P), ix192 (564P)<br />
ix194 (570P)<br />
Bravo Marques J. ix141 (404)<br />
Breathnach O.S. ix468 (1444), ix494 (1526P),<br />
ix513 (1592P)<br />
Brechenmacher T. ix272 (823P)<br />
Brega N. ix424 (1291P)<br />
Breitenbuecher F. ix437 (1339)<br />
Breitkreuz T. ix466 (1437P)<br />
Bremnes R. ix392 (1200P)<br />
Brenner A.J. ix150 (435TiP)<br />
Brhane Y. ix78 (186P)<br />
Bria E. ix442 (1355), ix458 (1408), ix117 (322PD),<br />
ix226 (675P), ix237 (713P), ix240 (721P),<br />
ix273 (825P)<br />
Brichard V. ix361 (1110O), ix386 (1182P)<br />
Bridgewater J.A. ix178 (520O)<br />
Bridgewater J.A. ix242 (731P)<br />
Brighenti M. ix232 (693P)<br />
Brindel I. ix260 (789O)<br />
Brito M. ix141 (404)<br />
Brixi Z. ix460 (1419PD)<br />
Broadbridge V.T. ix208 (612P)<br />
Brocia C. ix363 (1113PD)<br />
Brodowicz T. ix116 (317O)<br />
Brogi E. ix98 (257P)<br />
Bronowicki J. ix225 (670PD)<br />
Brookes C. ix97 (253PD)<br />
Brose M. ix154 (445PD)<br />
Brossard J. ix350 (1071P)<br />
Broszeit-Luft S. ix523 (1627)<br />
Brouchet L. ix388 (1190P)<br />
Brown C. ix414 (1263P), ix151 (437TiP)<br />
Brown J.E. ix309 (937P)<br />
Brown M. ix366 (1124P)<br />
Browne B.C. ix528 (1645PD)<br />
Brozos E. ix92 (234)<br />
Brozyna A. ix544 (1700)<br />
Bruce J. ix317 (963TiP)<br />
Bruera E. ix466 (1439), ix517 (1605P)<br />
Bruera G. ix524 (1633), ix213 (629)<br />
Bruey J. ix101 (267P)<br />
Brugger W. ix417 (1271P)<br />
Brugiati C. ix431 (1313)<br />
Brugnatelli S. ix507 (1571P)<br />
Bruix J. ix63 (125IN)<br />
Brundel D.H.S. ix456 (1402P)<br />
Brunelli A. ix387 (1184P), ix533 (1663P)<br />
Brunello A. ix131 (367P)<br />
Brunner A. ix100 (261P)<br />
Brunt A.M. ix97 (253PD)<br />
Brusa F. ix291 (884)<br />
Bruzgin V. ix382 (1172)<br />
Bruzzi P. ix501 (1551PD), ix119 (327PD)<br />
Bruzzone A. ix80 (192P)<br />
Brzeska B. ix354 (1084P)<br />
B S A.K. ix358 (1102)<br />
Bu Y-Z. ix126 (348P)<br />
Bubendorf L. ix385 (1179O), ix73 (167O),<br />
ix80 (193P)<br />
Büchler M. ix228 (680P)<br />
Buchner A. ix500 (1548PD)<br />
Buckley A. ix505 (1566P)<br />
Budakoglu B. ix473 (1461), ix105 (279P)<br />
Budakoglu I.I. ix473 (1461)<br />
Buder R. ix255 (778TiP)<br />
Budillon A. ix193 (567P)<br />
Budisin E. ix428 (1304P)<br />
Buecher B. ix175 (511PD)<br />
Buettner R. ix481 (1486PD)<br />
Buges Sanchez C. ix431 (1315)<br />
Buges C. ix265 (802P)<br />
Buglione M. ix338 (1029P)<br />
Bui B. ix482 (1488P), ix236 (708P)<br />
ix260 (789O)<br />
Bullinger L. ix349 (1068PD)<br />
Bulotta A. ix410 (1251P), ix167 (487P),<br />
ix172 (502)<br />
Buonaccorso L. ix516 (1601P), ix516 (1602P),<br />
ix520 (1617), ix524 (1631)<br />
Buonerba C. ix316 (962TiP)<br />
Buosi R. ix496 (1536P)<br />
Buque A. ix212 (627)<br />
Burattini L. ix148 (425P), ix274 (829P)<br />
Burcoveanu D. ix260 (789O)<br />
Burdaeva O. ix406 (1239P)<br />
Annals of Oncology<br />
Burger D.M. ix456 (1402P)<br />
Burger R.A. ix81 (198P)<br />
Burggraaf K. ix103 (274P)<br />
Burgio M.A. ix496 (1536P)<br />
Burian M. ix340 (1038P)<br />
Burke E. ix107 (289P)<br />
Burkholder T. ix336 (1022PD)<br />
Burlaka D. ix69 (151P)<br />
Burrill W. ix93 (240)<br />
Burris H. ix121 (334P)<br />
Burtness B. ix42 (59IN)<br />
Burton L. ix519 (1613P)<br />
Burudpakdee C. ix122 (337P)<br />
Buschke S. ix162 (468P)<br />
Buschmann-Maiworm R.E. ix457 (1403)<br />
Bushmakin A. ix269 (815P)<br />
Bussink J. ix192 (562P)<br />
Busson P. ix337 (1025P)<br />
Buti S. ix442 (1355)<br />
Büttner R. ix394 (1208)<br />
Butts C. ix395 (1210)<br />
Buxó M. ix388 (1189P)<br />
Buyse M. ix91 (229P)<br />
Büyükafs¸ar K. ix312 (947)<br />
Buyukberber S. ix227 (678P), ix277 (838P)<br />
Buzyn A. ix66 (140IN)<br />
Buzzoni R. ix288 (873)<br />
Bycott P. ix409 (1246P), ix453 (1391P)<br />
C<br />
Caballero M. ix343 (1046P)<br />
Cabanne A. ix379 (1164P)<br />
Cabiddu M. ix435 (1328), ix467 (1440),<br />
ix519 (1615P), ix131 (368P), ix192 (563P)<br />
Cabrera P. ix308 (934P)<br />
Cabuk D. ix110 (300)<br />
Caccialanza R. ix355 (1089P)<br />
Cadeddu C. ix164 (476P)<br />
Cadiot G. ix378 (1160P)<br />
Cadoo K. ix176 (516P)<br />
Caeiro C. ix147 (423P)<br />
Cagnazzo C. ix205 (605P)<br />
Cagossi K. ix101 (267P)<br />
Cai J. ix495 (1530P), ix217 (643)<br />
Cai K. ix77 (182P)<br />
Cai L. ix421 (1283P)<br />
Cai S. ix216 (640), ix217 (643)<br />
Cai W. ix81 (195P)<br />
Caillet P. ix452 (1387P)<br />
Caires I.Q.S. ix331 (1009)<br />
Cairns D. ix500 (1549PD)<br />
Cakar M. ix286 (866P)<br />
Cakir Gokce S. ix525 (1636)<br />
Calabek B. ix145 (415PD)<br />
Calabrò L. ix364 (1117PD), ix369 (1131P)<br />
Calazan C. ix331 (1010)<br />
Calcagnile S. ix508 (1575P)<br />
Caldara A. ix99 (259P)<br />
Caldas C. ix74 (171O)<br />
Calderero V. ix275 (832P)<br />
Calderon M. ix281 (850P)<br />
Caldes T. ix183 (537P)<br />
Calegari A. ix84 (207P)<br />
Calhoun R. ix49 (77IN)<br />
Califano R. ix386 (1183P), ix493 (1525P),<br />
ix90 (227P)<br />
Caligo M.A. ix176 (515P)<br />
Caliskan D. ix469 (1448PD)<br />
Call J.A. ix329 (1002P)<br />
Callari M. ix74 (172O)<br />
Cals L. ix522 (1624), ix128 (357P)<br />
Calvo E. ix166 (484P), ix272 (823P)<br />
Camaño S. ix520 (1619)<br />
Cámara J.C. ix113 (310)<br />
Camargo V.P. ix486 (1503P)<br />
Camboni M.G. ix116 (319O)<br />
Camerini A. ix528 (1646PD), ix127 (354P)<br />
Cameron D. ix125 (347P)<br />
ix550 | author index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology author index<br />
Camidge D.R. ix389 (1191PD), ix401 (1227O),<br />
ix408 (1245P), ix422 (1287P), ix423 (1290P),<br />
ix152 (439O), ix153 (440O)<br />
Camilleri-Broet S. ix544 (1699P)<br />
Caminal J.M. ix370 (1136P)<br />
Caminiti C. ix474 (1462PD)<br />
Camisa R. ix442 (1355), ix175 (513PD)<br />
Campana L.G. ix371 (1140P), ix486 (1504P),<br />
ix131 (367P)<br />
Campanero M.A. ix508 (1577P)<br />
Campayo M. ix135 (380), ix282 (853P)<br />
Campbell A. ix524 (1634)<br />
Campbell P. ix57 (99IN)<br />
Campennì G. ix488 (1509P)<br />
Campone M. ix62 (121IN), ix118 (324PD)<br />
Campos-Gomez S. ix184 (541P)<br />
Campos A. ix187 (549P)<br />
Campos B. ix374 (1151), ix436 (1333),<br />
ix440 (1349)<br />
Camps C. ix531 (1655P)<br />
Cañadas C. ix187 (549P)<br />
Cañamares I. ix281 (850P)<br />
Cañas A. ix530 (1652P)<br />
Candamio Folgar S. ix328 (1000P)<br />
Candido Reis D.G. ix524 (1632)<br />
Canela M. ix385 (1179O)<br />
Canhoroz M. ix497 (1540)<br />
Cannita K. ix524 (1633), ix213 (629)<br />
Cano Osuna M.T. ix131 (365P), ix186 (546P)<br />
Canon J. ix197 (578P)<br />
Canonici A.M. ix108 (292P)<br />
Canouï-Poitrine F. ix452 (1387P)<br />
Cantley L.C. ix21 (2IN)<br />
Cantos B. ix459 (1410), ix494 (1527P), ix112 (307)<br />
Canturk Z. ix110 (300)<br />
Cao Q. ix108 (290P)<br />
Caparello C. ix238 (714P), ix251 (761), ix251 (762)<br />
Caparros X. ix135 (380)<br />
Capasso A. ix67 (143PD)<br />
Capdevila Riera L. ix431 (1315)<br />
Capdevila J. ix377 (1156O), ix377 (1157O),<br />
ix380 (1165P), ix529 (1648P), ix157 (452P)<br />
Capdevila L. ix533 (1662P), ix266 (806P)<br />
Capelletto E. ix444 (1360)<br />
Caplin M. ix378 (1161P)<br />
Caponi S. ix238 (714P), ix241 (726P), ix251 (761),<br />
ix251 (762)<br />
Cappelleri J.C. ix269 (815P)<br />
Cappelli C. ix241 (726P)<br />
Cappetta A. ix283 (854P)<br />
Cappuzzo F. ix417 (1271P), ix423 (1288P),<br />
ix77 (181P), ix183 (535P)<br />
Caracò C. ix375 (1152)<br />
Caramanti M. ix387 (1184P), ix533 (1663P)<br />
Caramella C. ix198 (580P)<br />
Carames C. ix187 (549P)<br />
Carapezza M. ix123 (340P)<br />
Caratú G. ix531 (1656P)<br />
Carbognin L. ix117 (322PD)<br />
Carcas A. ix165 (480P)<br />
Carcereny E. ix418 (1273P), ix531 (1655P),<br />
ix152 (438O)<br />
Cardiga R. ix458 (1409)<br />
Cardoso-Filho C. ix133 (374P)<br />
Carducci M. ix268 (811P), ix303 (919P),<br />
ix309 (937P)<br />
Carles J. ix266 (806P), ix302 (916P)<br />
Carli M. ix483 (1494P)<br />
Carlomagno C. ix530 (1651P)<br />
Carlson D.M. ix83 (203P), ix173 (505), ix173 (507)<br />
Carlton R. ix122 (338P)<br />
Carneiro A.F. ix201 (591P)<br />
Carneiro F. ix210 (620), ix221 (657)<br />
Carnell D. ix347 (1061TiP)<br />
Carney D.N. ix525 (1635)<br />
Carnio S. ix343 (1047P), ix346 (1058)<br />
Carola E. ix501 (1554P)<br />
Caron O. ix175 (511PD)<br />
Caro<strong>the</strong>rs T. ix244 (738P)<br />
Carpino A. ix142 (406TiP)<br />
Carranza Rua O.E. ix149 (429P), ix239 (718P)<br />
Carranza A.C. ix183 (534P)<br />
Carranza O.E. ix291 (886), ix305 (927P)<br />
Carrasco E. ix118 (323PD)<br />
Carrasco J. ix197 (578P), ix211 (622)<br />
Carrato A. ix377 (1157O), ix457 (1404),<br />
ix459 (1412), ix472 (1456P), ix205 (604P),<br />
ix232 (695P), ix255 (776TiP)<br />
Carrera C. ix343 (1046P)<br />
Carrera S. ix212 (627)<br />
Carroll P. ix310 (939P)<br />
Carteni G. ix523 (1628)<br />
Carthon B. ix302 (918P)<br />
Caruso M. ix104 (275P), ix104 (276P)<br />
Carvajal R. ix361 (1109O), ix363 (1115PD)<br />
Carvalho-Verlinde M. ix452 (1387P)<br />
Carvalho B. ix339 (1032P)<br />
Carvalho C. ix194 (568P)<br />
Carvalho C.T. ix458 (1409)<br />
Casadei V. ix127 (354P)<br />
Casado A. ix321 (975PD)<br />
Casado V. ix80 (194P)<br />
Casal Rubio J. ix395 (1212)<br />
Casal J. ix436 (1333)<br />
Casali P.G. ix478 (1478O), ix483 (1491P),<br />
ix484 (1496P), ix485 (1500P)<br />
Casalta-Lopes J. ix208 (614P)<br />
Casanova C. ix335 (1020PD)<br />
Casanovas O. ix377 (1157O)<br />
Casas A. ix505 (1564P), ix523 (1629)<br />
Casbard A. ix498 (1542TiP)<br />
Casciano R. ix272 (823P)<br />
Cascinu S. ix387 (1184P), ix431 (1313),<br />
ix533 (1663P), ix86 (214P), ix86 (215P),<br />
ix148 (425P), ix37 (43IN), ix205 (605P),<br />
ix219 (652), ix239 (720P), ix243 (734P),<br />
ix250 (756), ix274 (829P)<br />
Casinello J. ix125 (345P)<br />
Cassano A. ix433 (1322), ix84 (207P)<br />
Cassier P. ix482 (1489P)<br />
Cassoni P. ix140 (402)<br />
Castañeda C. ix96 (250PD)<br />
Castaing D. ix243 (733P)<br />
Castanon Alvarez E. ix365 (1123P), ix149 (429P),<br />
ix239 (718P), ix291 (886), ix305 (927P)<br />
Castella Fernandez E. ix431 (1315)<br />
Castellano D. ix377 (1157O)<br />
Castellano D.E. ix266 (806P), ix314 (953)<br />
Castellano D.E. ix276 (835P), ix281 (850P)<br />
Castillo A. ix291 (886), ix305 (927P)<br />
Castonguay V. ix155 (448PD)<br />
Castro J.E. ix395 (1212)<br />
Castro L. ix147 (423P)<br />
Catalán G. ix125 (345P)<br />
Catane R. ix463 (1426P), ix34 (37IN)<br />
Catanzaro M. ix285 (861P)<br />
Catarino R. ix78 (184P)<br />
Cathomas R. ix283 (857P), ix302 (917P)<br />
Caty A. ix260 (789O)<br />
Catzeddu T. ix113 (311)<br />
Cau M.C. ix462 (1422O), ix463 (1427P),<br />
ix466 (1438P)<br />
Causeret S. ix109 (296P), ix120 (331P)<br />
Cauvin C. ix150 (434)<br />
Cavaliere C. ix316 (962TiP)<br />
Cavalli F. ix65 (137IN)<br />
Cavanagh M. ix176 (517P)<br />
Cavanna L. ix466 (1436P), ix216 (642)<br />
Cavicchioli F. ix532 (1660P), ix73 (169O)<br />
Cazap E.L. ix65 (132IN)<br />
Cazes A. ix77 (180P)<br />
Cazzaniga M.E. ix127 (354P)<br />
Ceccaldi B. ix477 (1476), ix150 (433), ix285 (862P)<br />
Cecere F.L. ix528 (1646PD)<br />
Cedres S. ix496 (1533P)<br />
Ceia F. ix458 (1409)<br />
Cejas P. ix181 (527PD)<br />
Celik I. ix334 (1018O), ix417 (1272P)<br />
Celio L. ix507 (1571P)<br />
Celiz P. ix265 (802P), ix266 (807P)<br />
Cella D. ix261 (792PD), ix269 (815P)<br />
Cellerino R. ix431 (1313)<br />
Cellier D. ix478 (1477O), ix481 (1487P)<br />
Cerbone L. ix270 (818P), ix278 (840P)<br />
Cereda E. ix355 (1089P)<br />
Cereda R. ix116 (319O)<br />
Cereda S. ix240 (724P)<br />
Ceric T. ix436 (1332)<br />
Cervantes Ruiperez A. ix381 (1170P), ix159 (458P)<br />
Cesic D. ix293 (892TiP)<br />
Cetintas S. ix291 (885)<br />
Cetto G.L. ix166 (483P)<br />
Chabaud S. ix391 (1199P), ix397 (1219)<br />
Chabolle F. ix340 (1036P)<br />
Chabowski M. ix395 (1211)<br />
Chachaty E. ix503 (1559P)<br />
Chacon Lopez-Muniz J.I. ix125 (345P)<br />
Chacon M. ix496 (1535P)<br />
Chacon R. ix496 (1535P)<br />
Chadjaa M. ix410 (1250P)<br />
Chae Y.S. ix208 (613P)<br />
Chahine G. ix288 (874)<br />
Chai F. ix244 (738P), ix245 (739P)<br />
Chaib I. ix266 (807P)<br />
Chaiet N. ix254 (774)<br />
Chaigneau L. ix128 (357P), ix236 (708P)<br />
Chairion Sileni V. ix369 (1133P)<br />
Chakrabandhu S. ix339 (1035P)<br />
Chakrabarty B. ix381 (1168P)<br />
Chakraborty A. ix359 (1106), ix472 (1457P),<br />
ix135 (381)<br />
Chakravartty A. ix83 (203P)<br />
Challacombe B. ix275 (831P)<br />
Chami S. ix344 (1051)<br />
Chamming’S F. ix99 (258P)<br />
Chan A. ix531 (1657P)<br />
Chan B. ix179 (522PD)<br />
Chan C.H.T. ix70 (157P)<br />
Chan J. ix515 (1600P)<br />
Chan J.K. ix460 (1416PD)<br />
Chan K. ix200 (586P)<br />
Chan K.S. ix412 (1257P)<br />
Chan P. ix244 (736P)<br />
Chan S. ix116 (318O), ix173 (505), ix310 (939P)<br />
Chand V. ix174 (509TiP)<br />
Chandra A. ix475 (1467P), ix275 (831P)<br />
Chandran R.K. ix173 (505)<br />
Chang A.L.S. ix362 (1111PD)<br />
Chang H. ix69 (152P)<br />
Chang S. ix336 (1022PD), ix522 (1626)<br />
Chang T. ix107 (286P)<br />
Chang W. ix375 (1153), ix430 (1311P),<br />
ix450 (1381P)<br />
Chang Y. ix345 (1052), ix253 (769)<br />
Chang Y.H. ix69 (152P)<br />
Chao C. ix107 (289P)<br />
Chao R. ix376 (1155O)<br />
Chaput-Gras N. ix169 (495P)<br />
Chargari C. ix477 (1476), ix150 (433),<br />
ix285 (862P)<br />
Charpentier J. ix312 (946)<br />
Chasalow S.D. ix75 (175PD)<br />
Chaslerie A. ix456 (1401P)<br />
Chatterjee B. ix452 (1388P)<br />
Chatterjee K. ix452 (1388P)<br />
Chatziioannou M. ix136 (385)<br />
Chau I. ix199 (582P), ix213 (632), ix224 (667PD)<br />
Chau N.M. ix412 (1257P)<br />
Chaubet Houdu M. ix421 (1284P)<br />
Chauffert B. ix242 (730P)<br />
Chaves A.C.R. ix308 (935P)<br />
Chawla S. ix479 (1480PD), ix480 (1483PD)<br />
Chawla S.P. ix483 (1493P), ix166 (482P)<br />
Chemin C. ix482 (1488P)<br />
Volume 23 | Supplement 9 | June <strong>2012</strong> doi:10.1093/annonc/mds466 | ix551
author index<br />
Chen A. ix319 (966O)<br />
Chen B. ix432 (1319)<br />
Chen C. ix453 (1391P), ix130 (361P), ix279 (843P)<br />
Chen D. ix376 (1154O), ix544 (1701),<br />
ix278 (842P)<br />
Chen D.M. ix362 (1111PD), ix477 (1474)<br />
Chen E.X. ix155 (448PD), ix156 (450PD)<br />
Chen G. ix443 (1359), ix444 (1362TiP),<br />
ix180 (524PD), ix189 (556P)<br />
Chen G.Y. ix438 (1341)<br />
Chen H. ix345 (1052), ix437 (1336),<br />
ix155 (448PD)<br />
Chen I. ix522 (1626)<br />
Chen J. ix415 (1266P), ix501 (1552P),<br />
ix227 (676P), ix246 (744P), ix247 (746P)<br />
Chen L. ix351 (1075P), ix482 (1490P),<br />
ix538 (1679P), ix77 (182P), ix247 (746P),<br />
ix281 (847P), ix292 (889TiP)<br />
Chen P. ix355 (1087P)<br />
Chen S. ix103 (272P), ix103 (273P)<br />
Chen W. ix108 (290P)<br />
Chen X. ix81 (195P), ix117 (320PD)<br />
Chen Y. ix345 (1052), ix93 (238), ix245 (739P),<br />
ix268 (811P)<br />
Chen Z. ix78 (186P)<br />
Cheng A. ix351 (1075P), ix246 (744P), ix253 (769)<br />
Cheng D. ix78 (186P)<br />
Cheng L. ix107 (286P)<br />
Cheng Q. ix495 (1530P)<br />
Cheng Y. ix415 (1266P), ix444 (1362TiP),<br />
ix253 (769)<br />
Chenoufi S. ix446 (1367TiP)<br />
Cher L. ix151 (437TiP)<br />
Cherny N. ix456 (1707)<br />
Cherny N.I. ix64 (128IN)<br />
Chester J. ix292 (887)<br />
Cheung M. ix377 (1158P), ix380 (1167P)<br />
Cheung W. ix188 (551P), ix204 (601P),<br />
ix231 (691P)<br />
Cheung W.Y. ix215 (635)<br />
Chevreau C. ix263 (797PD)<br />
Chi K. ix295 (896O), ix297 (899PD),<br />
ix297 (900PD), ix304 (922P), ix305 (925P)<br />
Chi P. ix217 (643)<br />
Chia S. ix83 (202P)<br />
Chiang N. ix538 (1679P)<br />
Chiannilkulchai N. ix327 (993P)<br />
Chiappino I. ix291 (884)<br />
Chiara G.B. ix287 (868)<br />
Chiarenza M. ix104 (275P)<br />
Chiari R. ix387 (1185P), ix423 (1288P),<br />
ix427 (1302P)<br />
Chiarion Sileni V. ix367 (1128P), ix368 (1130P),<br />
ix371 (1140P), ix373 (1148)<br />
Chiba T. ix226 (673P)<br />
Chiba Y. ix393 (1204P)<br />
Chibaudel B. ix334 (1017O), ix340 (1036P),<br />
ix180 (525PD)<br />
Chien S. ix522 (1626)<br />
Chiesi F. ix516 (1602P)<br />
Chikamori K. ix413 (1260P), ix527 (1705)<br />
Chin F. ix485 (1499P), ix485 (1501P)<br />
Chin K. ix363 (1116PD), ix367 (1127P)<br />
Chin S. ix74 (171O)<br />
Chinot O. ix146 (419PD)<br />
Chiritescu G. ix222 (663TiP)<br />
Chirivella Gonzalez I. ix266 (805P)<br />
Chitapanarux I. ix339 (1035P)<br />
Chiu C. ix349 (1066PD)<br />
Chiu J. ix244 (736P)<br />
Chiu Y. ix173 (507)<br />
Chkadua G.Z. ix371 (1138P)<br />
Chkhikvadze N. ix130 (364P)<br />
Chmielowska E. ix409 (1246P), ix322 (978P)<br />
Chmielowski B. ix158 (456P)<br />
Cho B. ix424 (1292P)<br />
Cho G.J. ix172 (503)<br />
Cho H.J. ix72 (166)<br />
Cho J.Y. ix240 (722P)<br />
Cho S. ix467 (1441), ix468 (1446)<br />
Chodak G. ix310 (940P)<br />
Choi C.W. ix352 (1077P)<br />
Choi D.R. ix193 (566P)<br />
Choi E.J. ix512 (1589P)<br />
Choi H. ix253 (771)<br />
Choi H.J. ix276 (834P)<br />
Choi M. ix72 (166), ix244 (735P)<br />
Choi M.K. ix375 (1153), ix430 (1311P)<br />
Choi Y.J. ix454 (1394P), ix172 (503)<br />
Choi Y.N. ix512 (1589P)<br />
Chollet P. ix102 (270P)<br />
Cholujova D. ix286 (865P)<br />
Chone C.T. ix339 (1032P)<br />
Chong D. ix182 (533P), ix199 (583P)<br />
Choo S. ix182 (533P), ix245 (741P), ix247 (746P)<br />
Chou C. ix69 (152P)<br />
Chou Y. ix355 (1087P)<br />
Chouahnia K. ix414 (1265P)<br />
Chouaid C. ix397 (1219), ix446 (1367TiP),<br />
ix537 (1675P)<br />
Chouaki N. ix395 (1211), ix418 (1275P)<br />
Choueiri T.K. ix258 (784O), ix260 (787O),<br />
ix265 (804P), ix278 (840P)<br />
Choussy O. ix339 (1033P)<br />
Chow-Maneval E. ix303 (920P), ix317 (964TiP)<br />
Chow S. ix324 (983P)<br />
Chowdhury S. ix271 (821P), ix272 (822P),<br />
ix275 (831P)<br />
Choy E. ix479 (1480PD)<br />
Chren M. ix477 (1474)<br />
Christensen T.B. ix507 (1573P)<br />
Christofilakis C. ix435 (1329)<br />
Christophylakis C. ix436 (1335), ix139 (395)<br />
Chrysafi S. ix337 (1026P)<br />
Chu L. ix171 (499P)<br />
Chua C. ix199 (583P)<br />
Chua V.S. ix480 (1483PD), ix166 (482P)<br />
Chubenko V.A. ix139 (397)<br />
Chumsri S. ix108 (290P)<br />
Chung C. ix425 (1295P), ix428 (1305P),<br />
ix144 (410O)<br />
Chung I.J. ix467 (1441), ix468 (1446), ix193 (566P)<br />
Chung J.S. ix172 (503)<br />
Churn M. ix97 (253PD)<br />
Chwieduk A. ix353 (1082P)<br />
Cianci C. ix290 (881)<br />
Ciaparrone M. ix466 (1436P)<br />
Ciardiello F. ix430 (1309P), ix451 (1382P),<br />
ix67 (143PD), ix75 (173O)<br />
Cichowicz M. ix268 (812P), ix323 (979P)<br />
Cierniak S. ix268 (812P)<br />
Cilingir F. ix221 (660)<br />
Cinefra M. ix95 (248O)<br />
Cinieri S. ix95 (248O)<br />
Cintra M.L. ix365 (1122P)<br />
Cioè A. ix80 (192P)<br />
Ciocoiu M. ix356 (1094)<br />
Cioffi A. ix486 (1502P), ix489 (1514)<br />
Cipková A. ix504 (1562P)<br />
Cirera L. ix136 (386)<br />
Cirri L. ix124 (342P)<br />
Ciruelos E. ix96 (250PD), ix96 (251PD),<br />
ix134 (378), ix142 (409TiP), ix325 (986P)<br />
Cislo P. ix283 (856P)<br />
Ciuffreda L. ix140 (402), ix291 (884)<br />
Ciuffrida L. ix75 (173O)<br />
Ciuleanu E. ix337 (1026P)<br />
Civelli E. ix344 (1050P)<br />
Clack G. ix87 (219P), ix90 (227P)<br />
Clackson T. ix152 (439O)<br />
Claes K. ix34 (33IN)<br />
Clamp A. ix319 (969PD), ix324 (983P),<br />
ix326 (992P)<br />
Clara A. ix141 (404), ix175 (512PD)<br />
Claringbold P. ix379 (1162P)<br />
Clark-Langone K.M. ix179 (523PD)<br />
Annals of Oncology<br />
Clark J. ix389 (1191PD)<br />
Clark W.R. ix302 (918P)<br />
Clarke R. ix469 (1449PD)<br />
Clarke S. ix499 (1544O)<br />
Clatot F. ix339 (1033P)<br />
Clayton M. ix425 (1297P)<br />
Cleeland C. ix509 (1580P), ix295 (895O)<br />
Clemente C. ix78 (183P)<br />
Clementi S. ix104 (275P)<br />
Climent M. ix266 (805P), ix276 (835P),<br />
ix293 (891TiP), ix307 (932P)<br />
Climentzos P. ix477 (1475)<br />
Clince J. ix468 (1444), ix494 (1526P)<br />
Clottens N. ix287 (870)<br />
Cobo M. ix441 (1352)<br />
Coccia-Portugal M.A. ix103 (272P)<br />
Cocciolone V. ix524 (1633)<br />
Coebergh J.W. ix53 (89IN)<br />
Coeffic D. ix125 (346P)<br />
Coelho A. ix78 (184P)<br />
Coens C. ix483 (1493P)<br />
Coffey J.C. ix114 (312)<br />
Cognetti F. ix367 (1128P), ix463 (1425P),<br />
ix237 (713P), ix240 (721P), ix273 (825P),<br />
ix280 (846P)<br />
Cogoni A.A. ix35 (41IN)<br />
Cohen A.T. ix447 (1369P)<br />
Cohen D.P. ix259 (785O)<br />
Cohen E.E.W. ix154 (445PD)<br />
Cohn Cedermark G. ix299 (906P)<br />
Cohn A.L. ix224 (666O)<br />
Coindre J. ix482 (1488P)<br />
Cojocarasu O. ix196 (572P)<br />
Colacchi A.M. ix439 (1346)<br />
Colas C. ix175 (511PD)<br />
Colbeck M. ix208 (612P)<br />
Colby T. ix464 (1431P)<br />
Colecchia M. ix285 (861P)<br />
Coleman N. ix468 (1444)<br />
Coleman N.J. ix494 (1526P)<br />
Coleman R.E. ix115 (316TiP), ix296 (898PD),<br />
ix308 (936P)<br />
Collard O. ix488 (1511P)<br />
Collins D.M. ix540 (1686P)<br />
Collinson F. ix171 (500P)<br />
Collon T. ix455 (1396P)<br />
Colombino M. ix364 (1118PD)<br />
Colombo N. ix322 (978P), ix324 (982P)<br />
Colomer D. ix44 (66IN)<br />
Colucci G. ix370 (1135P), ix463 (1425P),<br />
ix229 (685P)<br />
Colussi O. ix75 (174O)<br />
Colwell H. ix477 (1474)<br />
Comandone A. ix483 (1494P)<br />
Comber H. ix315 (957)<br />
Comino A. ix73 (169O)<br />
Commenges B. ix446 (1367TiP), ix218 (648)<br />
Comolli G. ix529 (1650P)<br />
Comte A. ix282 (852P)<br />
Conca E. ix483 (1491P)<br />
Condò S. ix439 (1346)<br />
Conde M.C. ix183 (534P)<br />
Condorelli G. ix539 (1682P)<br />
Condori D. ix292 (888)<br />
Condrea I. ix67 (146P)<br />
Conen K. ix372 (1144)<br />
Cong N. ix161 (466P)<br />
Cong Z. ix509 (1580P)<br />
Conkling P. ix170 (496P)<br />
Connell L.C. ix525 (1635)<br />
Connolly E. ix469 (1449PD)<br />
Conroy T. ix109 (296P), ix120 (331P)<br />
Consoli F. ix338 (1029P)<br />
Conte P.F. ix101 (267P), ix119 (327PD),<br />
ix278 (842P), ix290 (879)<br />
Conter D. ix451 (1383P)<br />
Conter H.J. ix451 (1383P), ix517 (1605P)<br />
Contreras Martínez J. ix510 (1582P)<br />
ix552 | author index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology author index<br />
Conway A. ix326 (992P)<br />
Coombs J. ix235 (704P), ix272 (823P)<br />
Cooper D. ix119 (328PD)<br />
Coppola C. ix539 (1682P)<br />
Coriat R. ix167 (485P), ix238 (716P)<br />
Corman J. ix310 (939P), ix311 (943P)<br />
Corn P.G. ix296 (897O)<br />
Cornic M. ix339 (1033P)<br />
Corona G. ix144 (411O)<br />
Coronado M. ix165 (480P)<br />
Corral J. ix418 (1275P)<br />
Correale P. ix530 (1653P)<br />
Corrie P. ix374 (1149), ix378 (1161P),<br />
ix242 (731P)<br />
Cortes-Funes H. ix96 (250PD), ix134 (378),<br />
ix281 (850P), ix325 (986P)<br />
Cortes J. ix370 (1136P), ix531 (1656P),<br />
ix83 (202P), ix29 (21IN), ix120 (330P),<br />
ix124 (344P), ix140 (400)<br />
Cortes P.A. ix128 (356P)<br />
Cortesi E. ix440 (1348), ix488 (1509P)<br />
Corti L. ix131 (367P)<br />
Cortot A. ix403 (1232PD), ix408 (1243P)<br />
Coscas Y. ix470 (1452P), ix472 (1460)<br />
Coskun U. ix227 (678P), ix277 (838P)<br />
Cossu Rocca M. ix335 (1020PD)<br />
Cossu A. ix364 (1118PD)<br />
Costa-Gurgel M.S. ix133 (374P)<br />
Costa A.S.A. ix147 (423P)<br />
Costa C. ix531 (1655P), ix533 (1661P),<br />
ix533 (1662P), ix229 (686P)<br />
Costa E.F.D. ix364 (1119P), ix365 (1121P)<br />
Costa F.F. ix339 (1032P)<br />
Costa L. ix289 (878)<br />
Costantini A. ix458 (1408)<br />
Costantini C. ix231 (691P)<br />
Costantini S. ix75 (173O)<br />
Cotreau M. ix263 (796PD)<br />
Counsell N. ix324 (982P)<br />
Cousin P. ix481 (1487P)<br />
Cousin S. ix168 (491P)<br />
Cousin T. ix165 (481P), ix167 (486P)<br />
Couto E. ix357 (1097)<br />
Coventry B.J. ix371 (1137P)<br />
Cowens J.W. ix75 (176PD)<br />
Cox M. ix304 (922P)<br />
Crabb S. ix272 (822P)<br />
Crafa P. ix216 (642)<br />
Cragg M.S. ix70 (157P)<br />
Craig J. ix377 (1158P), ix380 (1167P)<br />
Cramarossa A. ix370 (1135P)<br />
Cramer J. ix476 (1473P)<br />
Crea F. ix85 (208P)<br />
Credi M. ix391 (1198P), ix154 (443PD)<br />
Cremonesi M. ix435 (1328), ix467 (1440),<br />
ix519 (1615P), ix131 (368P), ix192 (563P),<br />
ix47 (75IN)<br />
Crespo C. ix118 (323PD)<br />
Cresti N. ix129 (358P)<br />
Crevenna R. ix145 (415PD)<br />
Crinò L. ix387 (1185P), ix402 (1230PD),<br />
ix423 (1288P), ix427 (1302P), ix535 (1668P),<br />
ix183 (535P)<br />
Crino L. ix403 (1231PD), ix403 (1233PD),<br />
ix419 (1278P), ix271 (820P)<br />
Criscitiello C. ix95 (247O)<br />
Critchfield J.J. ix244 (735P)<br />
Croce M.V. ix210 (619)<br />
Croitoru A. ix255 (777TiP)<br />
Crook T. ix532 (1660P), ix73 (169O)<br />
Cropet C. ix62 (121IN), ix478 (1477O),<br />
ix481 (1487P)<br />
Cros S. ix533 (1662P)<br />
Cross A. ix308 (936P)<br />
Crowe S. ix302 (917P)<br />
Crown J.P. ix528 (1645PD), ix540 (1686P),<br />
ix108 (292P)<br />
Cruz Jurado J. ix490 (1517TiP)<br />
Cruz Mora M.A. ix351 (1073P)<br />
Csoszi T. ix503 (1560P)<br />
Cstoth I. ix408 (1243P)<br />
Cuadra Urteaga J.L. ix265 (802P), ix266 (807P)<br />
Cubedo R. ix490 (1517TiP)<br />
Cubillo A. ix166 (484P)<br />
Cubukcu E. ix129 (359P)<br />
Cucala M. ix505 (1564P), ix523 (1629)<br />
Cueff A. ix238 (716P)<br />
Cueva J.F. ix328 (1000P)<br />
Cufer T. ix65 (136IN), ix522 (1625), ix523 (1630)<br />
Cuffe S. ix78 (186P)<br />
Cuisnier J. ix120 (331P)<br />
Culic S. ix359 (1104)<br />
Culine S. ix452 (1387P), ix259 (786O)<br />
Cumplido D. ix374 (1151)<br />
Cunningham D. ix378 (1161P), ix224 (667PD),<br />
ix242 (731P)<br />
Curé H. ix501 (1554P)<br />
Curca R. ix458 (1407)<br />
Curiel M.T. ix328 (1000P)<br />
Curigliano G. ix29 (22IN)<br />
Currà F. ix423 (1288P)<br />
Currà M.F. ix427 (1302P)<br />
Curran D. ix191 (561P)<br />
Curran V. ix207 (610P)<br />
Curran W.J. ix148 (428P)<br />
Curti E. ix204 (600P)<br />
Custodio Cabello S. ix176 (517P)<br />
Custodio A. ix472 (1456P), ix181 (527PD)<br />
Cusumano P. ix96 (251PD)<br />
Cuttone F. ix140 (399)<br />
Cuzick J. ix75 (176PD), ix53 (86IN)<br />
Cvancarova M. ix188 (553P)<br />
Cykowski L. ix363 (1116PD)<br />
Cynober L. ix91 (229P)<br />
Czaykowski P. ix316 (960)<br />
Czerw T. ix353 (1082P)<br />
Czibere A. ix321 (974PD)<br />
D<br />
Dąbek A. ix323 (979P)<br />
Dabakuyo T.S. ix109 (296P), ix120 (331P)<br />
Dabrowska Z. ix320 (971PD)<br />
Dacosta Byfield S. ix451 (1384P)<br />
D’Addario G. ix458 (1407)<br />
Dafni O. ix385 (1179O), ix73 (167O)<br />
D’Aiuto E. ix75 (173O)<br />
Daga H. ix432 (1320), ix433 (1321),<br />
ix492 (1519PD)<br />
Dagliati A. ix535 (1669P)<br />
Dahan L. ix464 (1430P)<br />
Dai D. ix153 (440O)<br />
Dai W.S. ix447 (1369P)<br />
Daidone M.G. ix88 (222P)<br />
Daiko H. ix89 (224P)<br />
Daisne J. ix334 (1016O)<br />
Daisuke A. ix422 (1285P)<br />
Dal Bello M.G. ix79 (187P)<br />
Dal Mas A. ix213 (629)<br />
Dalagiorgou G. ix92 (236)<br />
Dalal D. ix419 (1278P), ix420 (1279P),<br />
ix191 (560P)<br />
Dalal N. ix267 (808P)<br />
Dalban C. ix511 (1587P)<br />
Dalenc F. ix62 (121IN)<br />
Dall’Occa P. ix147 (424P)<br />
Dalla Palma M. ix326 (991P)<br />
D’Alonzo A. ix454 (1393P), ix501 (1551PD),<br />
ix521 (1621)<br />
Dalton J.T. ix304 (923P)<br />
Damasceno M. ix525 (1639), ix147 (423P)<br />
Damato A. ix288 (873)<br />
D’Amato C. ix530 (1651P), ix532 (1659P)<br />
D’Amato V. ix532 (1659P)<br />
D’Ambrosio C. ix335 (1020PD)<br />
Damian S. ix102 (269P)<br />
Damiano M.A. ix496 (1535P)<br />
Damiano V. ix530 (1651P), ix532 (1659P),<br />
ix540 (1687), ix287 (869)<br />
D’Amico R. ix101 (267P)<br />
Dane F. ix394 (1207P), ix186 (547P), ix217 (645)<br />
Daneshmand S. ix261 (790O)<br />
Danesi R. ix85 (208P)<br />
Daniele B. ix225 (669PD), ix255 (777TiP)<br />
Danielli R. ix364 (1117PD)<br />
D’Aniello C. ix316 (962TiP)<br />
Daniels I. ix215 (638)<br />
Danila D. ix89 (223P)<br />
Dank M. ix102 (271P), ix116 (317O)<br />
Danova M. ix529 (1650P)<br />
Dansin E. ix406 (1240P), ix409 (1247P),<br />
ix419 (1278P), ix426 (1299P)<br />
Danson S. ix374 (1149)<br />
Daprada G. ix99 (260P)<br />
Da Prat V. ix238 (714P)<br />
Darai E. ix322 (977P)<br />
D’Arcangelo M. ix423 (1288P), ix77 (181P)<br />
Darwish A. ix265 (801P), ix265 (803P)<br />
Darwish A.D. ix111 (304)<br />
Das A. ix171 (499P)<br />
Das K. ix358 (1100), ix497 (1539P), ix285 (860P)<br />
Das M. ix396 (1216)<br />
Das P. ix448 (1375P)<br />
Dasgupta S. ix355 (1090P), ix356 (1093P),<br />
ix359 (1105), ix359 (1106), ix472 (1457P),<br />
ix133 (375P)<br />
Dass R.N. ix314 (954)<br />
Datwyler S. ix83 (203P)<br />
Dauba J. ix419 (1276P)<br />
Daud A. ix153 (442O)<br />
Daugaard G. ix507 (1573P)<br />
D’Auria G. ix105 (280P)<br />
Davidenko I. ix230 (687P), ix322 (978P)<br />
Davidson C. ix107 (288P)<br />
Davies A. ix348 (1063O), ix69 (154P),<br />
ix518 (1612P), ix78 (185P)<br />
Davies F. ix44 (67IN)<br />
Davis D.W. ix300 (911P)<br />
Davis G. ix173 (505)<br />
Davis M.P. ix259 (785O)<br />
Davison C. ix190 (558P)<br />
Dawood T. ix114 (314)<br />
Dawson N. ix311 (943P)<br />
Dawson S. ix74 (171O)<br />
Day F. ix383 (1173P)<br />
Dazzani M.C. ix511 (1585P), ix102 (269P)<br />
De Aguirre I. ix533 (1662P)<br />
De Angelis V. ix427 (1302P), ix315 (958)<br />
De Azambuja E. ix95 (247O), ix98 (255PD)<br />
De Baere T. ix198 (580P)<br />
De Benedetto A. ix440 (1348)<br />
De Benedictis E. ix102 (269P)<br />
De Besi P. ix409 (1246P)<br />
De Blas B. ix334 (1018O)<br />
de Bono J.S. ix119 (325PD), ix161 (464P),<br />
ix162 (469P), ix38 (48IN), ix294 (894O),<br />
ix295 (896O), ix296 (897O), ix297 (899PD),<br />
ix298 (903P), ix301 (913P), ix304 (924P),<br />
ix307 (933P)<br />
De Bont E.S.J.M. ix484 (1497P)<br />
De Both A. ix287 (870)<br />
De Braud F. ix187 (550P)<br />
De Braud F.G.M. ix507 (1571P), ix88 (222P),<br />
ix102 (269P), ix116 (319O), ix212 (628),<br />
ix288 (873), ix305 (926P)<br />
De Braud F.G.M. ix272 (824P)<br />
De Bree R. ix450 (1379P)<br />
De Bruin D.M. ix330 (1006P)<br />
De Camargo Cancela M. ix315 (957)<br />
De Castro G.Jr. ix486 (1503P), ix308 (935P)<br />
De Castro J. ix414 (1264P), ix441 (1352),<br />
ix505 (1564P), ix523 (1629)<br />
De Censi A. ix83 (201P)<br />
De Cock E. ix103 (274P)<br />
De Coene E. ix287 (870)<br />
Volume 23 | Supplement 9 | June <strong>2012</strong> doi:10.1093/annonc/mds466 | ix553
author index<br />
De Droogh E. ix452 (1386P)<br />
De Fiore L. ix458 (1408)<br />
De Fromont M. ix263 (797PD)<br />
De Galitiis F. ix367 (1128P), ix368 (1130P),<br />
ix369 (1131P), ix369 (1132P), ix369 (1133P)<br />
De Geus-Oei L. ix160 (462P), ix192 (562P)<br />
De Giorgi U. ix285 (863P)<br />
De Giorgi V. ix364 (1118PD)<br />
De Graan A.M. ix534 (1667P)<br />
De Gregorio N. ix322 (976P)<br />
De Gregorio V. ix85 (208P)<br />
De Gruijl T. ix301 (915P)<br />
De Haan T. ix179 (521O)<br />
De Haas S. ix81 (198P)<br />
De Herder W.W. ix377 (1156O)<br />
de Jong J. ix73 (167O)<br />
De Jong J. ix80 (193P)<br />
De Jong R.S. ix124 (342P)<br />
De Jonge M. ix319 (966O)<br />
De Jonge M.J.A. ix158 (457P)<br />
De Kam M. ix103 (274P)<br />
De Koning H. ix53 (87IN)<br />
De La Cruz L. ix351 (1073P)<br />
De La Cueva H. ix106 (284P)<br />
De La Haba Rodriguez J. ix530 (1652P)<br />
De La Haba Rodriguez J. ix140 (400), ix186 (546P)<br />
De La Haba J. ix131 (365P)<br />
De La Haba J.R. ix118 (323PD), ix142 (407TiP)<br />
De La Motte Rouge T. ix125 (346P), ix313 (951)<br />
De La Piedra C. ix266 (805P), ix312 (945)<br />
De Laroche G. ix481 (1487P)<br />
De Las Penas R. ix490 (1517TiP)<br />
De Lio N. ix241 (726P)<br />
De Maglio G. ix78 (183P)<br />
De Maio A.P. ix532 (1659P)<br />
De Manzoni G. ix226 (675P)<br />
De Maria A. ix454 (1393P)<br />
De Marinis F. ix404 (1235PD), ix439 (1346)<br />
De Mattos-Arruda L. ix531 (1656P), ix159 (458P)<br />
De Meerleer G. ix330 (1007), ix325 (987P)<br />
De Minicis S. ix243 (734P)<br />
De Mont-Serrat H. ix165 (478P), ix169 (494P)<br />
De Never G. ix325 (987P)<br />
De Pas T. ix386 (1182P), ix402 (1230PD),<br />
ix410 (1251P)<br />
De Pas T. ix153 (440O)<br />
De Pasquale M. ix95 (248O)<br />
De Paula Costa R. ix455 (1397P)<br />
De Pauw A. ix175 (511PD)<br />
De Placido S. ix530 (1651P), ix540 (1687),<br />
ix280 (846P), ix316 (962TiP)<br />
De Raaf P.J. ix534 (1667P)<br />
de Revel T. ix260 (789O)<br />
De Roock W. ix213 (630)<br />
De Rooij S. ix100 (263P)<br />
De Roos W. ix111 (301)<br />
De Rosa F. ix369 (1132P)<br />
De Ruysscher D. ix392 (1201P), ix396 (1213),<br />
ix396 (1216), ix397 (1217), ix425 (1296P),<br />
ix212 (626), ix49 (80IN)<br />
De Sanctis R. ix483 (1494P), ix487 (1506P)<br />
De Santis S. ix439 (1346)<br />
de Schultz W. ix306 (931P)<br />
De Souza P. ix100 (262P), ix294 (894O)<br />
De Torres I. ix302 (916P)<br />
de Velasco G. ix377 (1157O)<br />
De Velasco G.A. ix96 (250PD)<br />
De Vincenzo F. ix167 (488P)<br />
De Visser I. ix103 (274P)<br />
De Vita F. ix229 (685P)<br />
De Vivo R. ix285 (863P)<br />
De Vriendt V. ix75 (173O)<br />
De Vries A. ix340 (1038P)<br />
De Vries E.G.E. ix40 (57IN)<br />
De Vries J. ix363 (1114PD)<br />
Dean E. ix326 (992P)<br />
Dearnaley D. ix301 (913P)<br />
Deb R. ix83 (202P)<br />
Debieuvre D. ix419 (1276P), ix455 (1396P)<br />
Debois M. ix386 (1182P)<br />
Debruyne P.R. ix341 (1042P)<br />
Debucquoy A. ix222 (663TiP)<br />
Debus M. ix453 (1389P)<br />
Decensi A. ix119 (327PD)<br />
Decillis A. ix174 (1708PD)<br />
Dediu M. ix418 (1275P)<br />
Dees E.C. ix153 (442O)<br />
Defilles C. ix146 (419PD)<br />
Degardin M. ix160 (461P)<br />
Degiovanni D. ix247 (747P)<br />
Degli Esposti R. ix145 (416PD)<br />
Deguiral P. ix196 (572P)<br />
Degun R. ix122 (336P)<br />
Dei Tos A.P. ix485 (1500P)<br />
Del Barrio A. ix508 (1577P)<br />
Del Buono S. ix315 (958)<br />
Del Mastro L. ix454 (1393P), ix501 (1551PD),<br />
ix521 (1621), ix142 (408TiP)<br />
Del Prete M. ix219 (652), ix239 (720P),<br />
ix250 (756), ix274 (829P)<br />
Del Rio E. ix408 (1244P)<br />
Del Signore E. ix439 (1346)<br />
Del Valle E. ix233 (699P)<br />
Del Vecchio M. ix366 (1124P), ix367 (1128P),<br />
ix368 (1130P), ix369 (1131P)<br />
Delabaye I. ix510 (1583P)<br />
Delaloge S. ix110 (297P), ix175 (511PD)<br />
Delaney G. ix100 (262P)<br />
Delaunoit T. ix194 (569P)<br />
Delaurentiis M. ix114 (315TiP)<br />
Delcorso L. ix80 (192P)<br />
Deleporte A. ix194 (569P), ix199 (584P)<br />
Delforge M. ix510 (1583P)<br />
Delgado J.R. ix351 (1073P), ix254 (773)<br />
Della Corte C.M. ix430 (1309P)<br />
Della Puppa A. ix144 (411O)<br />
Delmonte A. ix116 (319O)<br />
Delord J. ix165 (478P), ix169 (494P)<br />
Delord J.P. ix334 (1017O), ix342 (1044P)<br />
Delpero J. ix184 (539P), ix241 (727P)<br />
Delrio P. ix193 (567P)<br />
Delrue L. ix330 (1007), ix325 (987P)<br />
Delva R. ix260 (789O), ix294 (893O)<br />
Demarchi M. ix332 (1014)<br />
Demetri G. ix482 (1490P)<br />
Demetri G.D. ix478 (1478O)<br />
Demichellis S. ix210 (619)<br />
Demidkina A. ix70 (156P)<br />
Demidov L.V. ix371 (1138P)<br />
Demir G. ix217 (645)<br />
Demirag G. ix221 (660)<br />
Demirci U. ix227 (678P), ix277 (838P)<br />
Demura Y. ix420 (1280P)<br />
Denda T. ix449 (1378P), ix217 (646)<br />
Deng H. ix437 (1337)<br />
Deng J. ix501 (1552P)<br />
Deng Q. ix389 (1193P)<br />
Denhaerynck K. ix502 (1555P)<br />
Denis L.J. ix401 (1227O)<br />
Denkert C. ix117 (321PD)<br />
Dennis M. ix349 (1068PD)<br />
Deo S.V.S. ix455 (1398P), ix110 (298P)<br />
Deonarain M. ix160 (463P)<br />
Deplanque G. ix259 (786O), ix294 (893O)<br />
Deptala A. ix230 (687P)<br />
Derbel O. ix478 (1477O)<br />
Dercksen M.W. ix501 (1553P)<br />
Derosa L. ix290 (881)<br />
Des Guetz G. ix414 (1265P)<br />
Desai B. ix148 (428P)<br />
Desai J. ix383 (1173P), ix220 (656)<br />
Desar I.M.E. ix160 (462P)<br />
Desauw C. ix241 (725P)<br />
Descallar J. ix100 (262P)<br />
Deshmukh S.P. ix101 (265P)<br />
Desjardins A. ix146 (417PD)<br />
Desjardins L. ix519 (1614P)<br />
Dessi’ A. ix516 (1604P)<br />
Annals of Oncology<br />
Dessi’ M. ix462 (1422O), ix516 (1604P),<br />
ix164 (476P)<br />
Destro A. ix77 (181P)<br />
Deutsch E. ix155 (446PD)<br />
Deutschbauer S. ix209 (616)<br />
Devanarayan V. ix173 (505)<br />
Devesa M. ix205 (604P)<br />
Devi B.C. ix136 (383)<br />
Devries T. ix310 (941P)<br />
Dhadda A.S. ix106 (283P)<br />
D’Hoore A. ix222 (663TiP)<br />
Di Bartolomeo M. ix212 (628)<br />
Di Battista M. ix145 (416PD), ix147 (424P)<br />
Di Benedetto A. ix142 (406TiP)<br />
Di Cosimo S. ix95 (247O), ix98 (255PD)<br />
Di Costanzo F. ix463 (1425P), ix528 (1646PD)<br />
Di Fiore F. ix339 (1033P), ix234 (703P),<br />
ix252 (767)<br />
Di Gennaro E. ix193 (567P)<br />
Di Giacomo A.M. ix364 (1117PD), ix369 (1132P),<br />
ix373 (1148)<br />
Di Giacomo D. ix213 (629)<br />
Di Guardo L. ix369 (1132P), ix369 (1133P)<br />
Di Hariry I. ix436 (1332)<br />
Di Lauro L. ix142 (406TiP)<br />
Di Leo A. ix27 (13IN)<br />
Di Lorenzo G. ix270 (818P), ix280 (846P),<br />
ix290 (879), ix306 (931P), ix316 (962TiP)<br />
Di Lucca G. ix240 (724P)<br />
Di Maio M. ix458 (1408), ix78 (183P)<br />
Di Monta G. ix375 (1152)<br />
Di Noia V.P. ix433 (1322)<br />
Di Palma M. ix517 (1607P)<br />
Di Palma T. ix229 (685P)<br />
Di Pasquale M.C. ix99 (259P)<br />
Di Rocco R. ix330 (1004P)<br />
Di Rocco Z.C. ix466 (1436P)<br />
Di Salvatore M. ix84 (207P)<br />
Di Tomaso E. ix537 (1675P), ix158 (457P)<br />
Diéras V. ix62 (121IN), ix519 (1614P),<br />
ix120 (329P), ix128 (355P)<br />
Diamand F. ix214 (633)<br />
Diaz-Padilla I. ix156 (450PD)<br />
Diaz-Rubio E. ix438 (1342), ix183 (537P)<br />
Diaz A. ix325 (986P)<br />
Diaz C. ix251 (763)<br />
Diaz G. ix494 (1527P)<br />
Diaz J. ix261 (792PD)<br />
Dicato M.A. ix186 (548P), ix209 (615), ix56 (98IN)<br />
Dickman E. ix223 (664TiP)<br />
Diebold M.D. ix180 (525PD)<br />
Dieckmann K. ix147 (421P)<br />
Diederich C.J. ix130 (363P)<br />
Diehl S. ix480 (1484PD)<br />
Dienstmann R. ix116 (319O)<br />
Dierickx D. ix518 (1609P)<br />
Dietel M. ix390 (1195P), ix394 (1208), ix86 (213P)<br />
Dieterle N. ix487 (1505P)<br />
Dietrich D. ix480 (1482PD)<br />
Dietz A. ix336 (1022PD)<br />
Díez J.J. ix377 (1157O)<br />
Digumarti R. ix400 (1225O)<br />
Dilsizian V. ix108 (290P)<br />
Dimaiuta M. ix511 (1585P)<br />
Dimitroulis J. ix493 (1524P)<br />
Dimopoulos M. ix95 (246O)<br />
Dimoudis S.T. ix239 (717P)<br />
D’Incecco A. ix77 (181P)<br />
Ding K.F. ix202 (595P)<br />
Ding X.Y. ix140 (401)<br />
Dingemans A-M. ix385 (1179O)<br />
Dingemans A.C. ix392 (1201P), ix396 (1213),<br />
ix396 (1216), ix425 (1296P), ix212 (626)<br />
Dini G. ix80 (192P)<br />
Dinter D. ix480 (1484PD)<br />
Diodati F. ix474 (1462PD)<br />
Dionysopoulos D. ix338 (1031P)<br />
Diouf M. ix464 (1430P)<br />
Dipalma M. ix503 (1559P)<br />
ix554 | author index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology author index<br />
Dirix L. ix362 (1112PD), ix157 (454P)<br />
Dittrich C. ix100 (261P), ix32 (28IN)<br />
Dive C. ix87 (219P), ix90 (227P), ix199 (582P),<br />
ix207 (609P)<br />
Dixit S. ix298 (904P)<br />
Diz M. ix331 (1009)<br />
Djedi H. ix221 (658)<br />
Djuraev M. ix229 (684P), ix254 (772)<br />
Dobbs N. ix119 (325PD)<br />
Dobi E. ix128 (357P), ix204 (600P)<br />
Dobon F. ix106 (284P)<br />
Dockry É. ix68 (150P)<br />
Doebele R. ix408 (1245P)<br />
Doebele R.C. ix422 (1287P)<br />
Doger de Speville B.G. ix494 (1527P)<br />
Doherty M. ix300 (909P)<br />
Doi T. ix164 (474P)<br />
Doihara H. ix74 (172O)<br />
Doki Y. ix481 (1485PD), ix227 (677P)<br />
Dolcimascolo S. ix215 (636)<br />
Domanska-Czyz K. ix354 (1084P)<br />
Dombret H. ix349 (1068PD)<br />
Dome B. ix493 (1523P)<br />
Domenech M. ix265 (802P), ix275 (832P)<br />
Domerg C. ix74 (170O)<br />
Domine M. ix414 (1264P), ix441 (1352),<br />
ix80 (194P)<br />
Domingues N. ix357 (1095)<br />
Dominguez-Tinajero S. ix378 (1160P)<br />
Dominichini E. ix379 (1164P)<br />
Domont J. ix480 (1482PD), ix486 (1502P)<br />
Donadio M. ix123 (340P), ix140 (402)<br />
Donat D.A. ix137 (390)<br />
Donati G. ix474 (1462PD)<br />
Donegani S. ix315 (959)<br />
Donehower R.C. ix230 (687P)<br />
Dong Q. ix454 (1395P)<br />
Dong W. ix416 (1269P)<br />
Donnadieu A. ix101 (266P)<br />
Donnini A. ix93 (240)<br />
Donny P. ix456 (1401P)<br />
Donovan J. ix292 (887)<br />
Donskov F. ix259 (785O), ix271 (819P)<br />
Dooms C. ix73 (167O)<br />
Dorer D.J. ix152 (439O)<br />
Dorff T.B. ix261 (790O), ix314 (952)<br />
ix316 (961)<br />
Doroumian S. ix170 (497P)<br />
Dosaka-Akita H. ix443 (1358),<br />
ix497 (1538P)<br />
Douillard J-Y. ix194 (570P)<br />
Douillard J. ix389 (1192PD), ix417 (1272P),<br />
ix456 (1401P), ix190 (558P), ix192 (564P),<br />
ix196 (572P)<br />
Doval D.C. ix128 (356P)<br />
Dowler Nygaard A. ix73 (168O)<br />
Dowsett M. ix75 (176PD), ix119 (325PD)<br />
Doyen C. ix510 (1583P)<br />
Dražd ˇ áková M. ix81 (196P)<br />
Drake C.G. ix258 (784O)<br />
Dreslerova J. ix474 (1464P)<br />
Dreyer C. ix334 (1017O), ix379 (1163P),<br />
ix167 (485P)<br />
Dreyling M.H. ix354 (1084P), ix359 (1107TiP),<br />
ix44 (65IN)<br />
Droege C. ix396 (1214)<br />
Dromain C. ix378 (1159P)<br />
Drouin M. ix169 (493P)<br />
Droz J. ix286 (864P), ix308 (934P)<br />
D’Souza A. ix122 (338P)<br />
Du Bois A. ix322 (976P), ix323 (980P)<br />
Du Y. ix110 (299), ix130 (361P)<br />
Dua D. ix503 (1558P)<br />
Dubey S. ix230 (687P)<br />
Dubot C. ix260 (789O)<br />
Dubray-Longeras P. ix102 (270P)<br />
Ducimetiere F. ix488 (1511P)<br />
Duck L. ix510 (1583P)<br />
Ducreux M. ix456 (1400P), ix85 (209P),<br />
ix85 (210P), ix194 (568P), ix198 (580P),<br />
ix218 (648)<br />
Ducreux M.P. ix378 (1159P), ix378 (1160P)<br />
Duffaud F. ix482 (1489P)<br />
Duffy S.W. ix470 (1451P)<br />
Dufour H. ix146 (419PD)<br />
Duhamel A. ix241 (725P)<br />
Duignan E. ix524 (1634)<br />
Duin S. ix88 (221P)<br />
Duman B.B. ix326 (990P)<br />
Dumas L.E. ix139 (398)<br />
Dummer R. ix366 (1125P)<br />
Dumon K. ix222 (663TiP)<br />
Dunant A. ix389 (1192PD)<br />
Dünne A. ix142 (409TiP)<br />
Dupont-Gossard A.C. ix237 (710P)<br />
Duprez F. ix341 (1042P)<br />
Dupuis O. ix196 (572P)<br />
Duque C.G. ix215 (637)<br />
Durán I. ix377 (1157O)<br />
Duran I. ix449 (1377P), ix277 (839P)<br />
Durand J. ix91 (229P)<br />
Durando X. ix102 (270P)<br />
Durante M. ix153 (442O)<br />
Duranti S. ix427 (1302P)<br />
Durie B.G. ix360 (1108TiP)<br />
Durnali A. ix332 (1015)<br />
Durusoy R. ix274 (830P)<br />
Duus E. ix512 (1588P), ix161 (465P)<br />
Duvillard P. ix322 (977P)<br />
Dy G.K. ix155 (447PD)<br />
Dy G.K. ix158 (456P)<br />
Dykstra K. ix263 (796PD)<br />
Dyson G. ix244 (735P)<br />
Dyszkiewicz W. ix395 (1211)<br />
Dzik C. ix308 (935P)<br />
E<br />
Eaddy M. ix428 (1303P)<br />
Earl J. ix377 (1157O)<br />
Easaw J. ix202 (594P)<br />
Easty D. ix495 (1532P)<br />
Eatock M.M. ix249 (754)<br />
Eaton K. ix424 (1291P)<br />
Eberhardt W. ix407 (1241P), ix437 (1339)<br />
Ebert M. ix37 (44IN)<br />
Eccher C. ix99 (259P)<br />
Echeveste J.I. ix365 (1123P), ix432 (1316)<br />
Eckert L. ix447 (1369P)<br />
Eckert R. ix440 (1347), ix458 (1407),<br />
ix494 (1529P)<br />
Eckhardt S.G. ix155 (447PD), ix156 (449PD)<br />
Edeline J. ix105 (281P)<br />
Edenfield W. ix170 (496P)<br />
Edmonds K. ix273 (827P)<br />
Edwards J. ix495 (1531P)<br />
Eechoute K. ix538 (1678P)<br />
Efstathiou E. ix308 (934P)<br />
Egamberdiev D. ix229 (684P), ix254 (772)<br />
Egawa S. ix211 (624)<br />
Eggert J. ix505 (1567P)<br />
Eggmann N. ix366 (1125P)<br />
Eguchi K. ix442 (1354), ix469 (1447PD),<br />
ix511 (1586P)<br />
Eidtmann H. ix95 (247O)<br />
Eiermann W. ix97 (252PD)<br />
Eigl B.J. ix304 (922P)<br />
Eisen T.Q.G. ix407 (1241P), ix262 (795PD)<br />
Eisenberger M. ix317 (963TiP)<br />
Eisenhauer E.A. ix40 (54IN), ix304 (922P)<br />
Eisinger F. ix470 (1452P), ix472 (1460)<br />
Eisterer W. ix249 (755)<br />
Ekici F. ix137 (387)<br />
Ekinci O. ix227 (678P), ix277 (838P)<br />
El Hajbi F. ix241 (725P)<br />
El Hariry I. ix529 (1647PD), ix533 (1664P)<br />
El Hawwari B. ix462 (1424P)<br />
El Hussiny G. ix265 (801P)<br />
El Kouri C. ix456 (1401P), ix511 (1584P)<br />
El Mansy H. ix199 (584P)<br />
El Mesbahi O. ix137 (389)<br />
El Ouagari K. ix235 (704P)<br />
El Shehaby A. ix150 (432)<br />
El-Ashry M. ix398 (1221)<br />
El-Hadaad H. ix353 (1081P), ix93 (239)<br />
El-Sadda W. ix341 (1039P), ix398 (1221)<br />
Elaidi R.T. ix499 (1545O), ix280 (845P),<br />
ix282 (852P)<br />
Elalamy I. ix543 (1697P)<br />
Elbassiouny M. ix253 (770)<br />
Eldebaway E. ix145 (413PD)<br />
Elef<strong>the</strong>raki A. ix95 (246O)<br />
Elens L. ix534 (1667P)<br />
Elez E. ix154 (443PD)<br />
Elfakir S. ix137 (389)<br />
Elghissassi I. ix432 (1318)<br />
Elhussiny G. ix265 (803P)<br />
Elias D. ix35 (38IN)<br />
Elisei R. ix154 (445PD)<br />
Elkabets M. ix126 (350P)<br />
Elkhateeb N. ix145 (413PD)<br />
Elkhouly E.A. ix98 (256P)<br />
Ellard S. ix297 (900PD), ix305 (925P)<br />
Ellis-Pegler R.B. ix162 (470P)<br />
Ellis M.J. ix57 (102IN), ix27 (15IN)<br />
Ellis P.M. ix395 (1210)<br />
Ellis S. ix374 (1149), ix283 (857P)<br />
Ellithy M. ix253 (770)<br />
Elmajjaoui S. ix328 (999P)<br />
Elmashad N.M. ix150 (432)<br />
Elnaggar M.S. ix537 (1676P)<br />
Elsaesser R. ix500 (1548PD)<br />
Elyan F. ix109 (294P)<br />
Elzawahrey H.M. ix111 (304)<br />
Emelianova G. ix382 (1172)<br />
Emi M. ix226 (672P)<br />
Emiliani A. ix105 (282P), ix111 (303)<br />
Emmanouilides C. ix289 (876)<br />
Emori Y. ix384 (1177P)<br />
Emoto S. ix233 (698P)<br />
Enatsu S. ix393 (1206P), ix397 (1218)<br />
Endo K. ix518 (1611P)<br />
Endo M. ix430 (1310P), ix492 (1519PD)<br />
Eng C. ix150 (435TiP), ix224 (666O)<br />
Engelman J. ix389 (1191PD)<br />
English P.A. ix262 (794PD)<br />
Eniu A. ix116 (317O)<br />
Enjalbert A. ix146 (419PD)<br />
Enokida T. ix518 (1611P)<br />
Enomoto T. ix436 (1334)<br />
Enserink J. ix111 (301)<br />
Enting D. ix161 (464P)<br />
Eom H. ix353 (1080P)<br />
Epenetos A.A. ix160 (463P)<br />
Erbas O. ix173 (508)<br />
Erdel M. ix209 (616)<br />
Erdem D. ix221 (660)<br />
Erdem G. ix286 (866P)<br />
Ermani M. ix145 (416PD), ix147 (424P),<br />
ix287 (868)<br />
Errihani H. ix432 (1318), ix476 (1470P),<br />
ix476 (1472P), ix477 (1476)<br />
Esaki M. ix225 (671P)<br />
Esaki T. ix512 (1590P)<br />
Esbah O. ix105 (279P)<br />
Escrig V. ix374 (1150)<br />
Escriu C. ix539 (1684P)<br />
Escudero P. ix377 (1157O)<br />
Escudier B. ix261 (792PD), ix262 (793PD),<br />
ix263 (797PD), ix264 (798PD), ix270 (817P),<br />
ix277 (837P), ix278 (842P), ix279 (844P),<br />
ix293 (892TiP)<br />
Eser E.P. ix227 (678P)<br />
Eskens F. ix158 (457P)<br />
Esmaeili J. ix184 (538P)<br />
Espírito-Santo A. ix357 (1095)<br />
Espinos Jimenez J. ix149 (429P)<br />
Volume 23 | Supplement 9 | June <strong>2012</strong> doi:10.1093/annonc/mds466 | ix555
author index<br />
Esposito G. ix209 (618)<br />
Ess S.M. ix132 (370P)<br />
Essa E. ix352 (1078P)<br />
Esteban E. ix266 (805P), ix273 (826P),<br />
ix275 (832P), ix276 (835P), ix277 (839P),<br />
ix312 (945), ix314 (953)<br />
Esterni B. ix150 (434), ix294 (893O)<br />
Esteves B. ix262 (795PD), ix263 (796PD)<br />
Esteves S. ix141 (404)<br />
Etchberger J. ix122 (336P)<br />
Eto T. ix348 (1062O)<br />
Etxaniz O. ix266 (806P)<br />
Eustace A. ix528 (1645PD), ix540 (1686P)<br />
Evans D.G.R. ix34 (35IN), ix319 (969PD)<br />
Evans T.L. ix403 (1231PD)<br />
Evans T.R.J. ix129 (358P)<br />
Evers D. ix532 (1658P)<br />
Ewald-Riegler N. ix322 (976P)<br />
Eymard J. ix278 (841P), ix314 (955)<br />
Ezoe Y. ix226 (673P)<br />
Ezz Alarab M. ix352 (1079P)<br />
Ezz Elarab L. ix352 (1079P)<br />
Ezzat S. ix448 (1374P)<br />
F<br />
Fabbri F. ix285 (863P)<br />
Fabbri M.A. ix105 (280P)<br />
Fabbro M. ix327 (993P)<br />
Faber D.J. ix330 (1006P)<br />
Fabre E. ix499 (1545O), ix77 (180P)<br />
Fabrini M.G. ix251 (761), ix251 (762)<br />
Facchinetti A. ix91 (230P)<br />
Fadoukhair Z. ix110 (297P)<br />
Faehling M. ix440 (1347), ix494 (1529P)<br />
Faez L. ix218 (647)<br />
Faggioni G. ix124 (343P)<br />
Fagnani D. ix474 (1462PD)<br />
Faivre S. ix334 (1017O), ix376 (1155O),<br />
ix379 (1163P), ix167 (485P)<br />
Falagán S. ix113 (310)<br />
Falandry C. ix501 (1554P)<br />
Falchook G.S. ix153 (442O)<br />
Falchook G.S. ix154 (444PD), ix168 (489P)<br />
Falci C. ix486 (1504P), ix131 (367P)<br />
Falco A. ix496 (1535P)<br />
Falcon S. ix103 (273P), ix224 (668PD)<br />
Falcone A. ix85 (208P), ix94 (243), ix127 (354P),<br />
ix176 (515P), ix206 (606P), ix238 (714P),<br />
ix241 (726P), ix251 (761), ix251 (762),<br />
ix290 (881)<br />
Falk M. ix395 (1210)<br />
Falk S. ix421 (1282P)<br />
Falkowski S. ix484 (1495P)<br />
Fallai C. ix341 (1040P), ix342 (1045P)<br />
Fallowfield L. ix509 (1580P)<br />
Faloppi L. ix86 (214P), ix86 (215P), ix219 (652),<br />
ix239 (720P), ix243 (734P), ix250 (756),<br />
ix274 (829P)<br />
Fan J. ix146 (417PD)<br />
Fan N. ix231 (690P)<br />
Fan S.T. ix244 (736P)<br />
Fan Y. ix140 (401)<br />
Fanale M. ix348 (1063O), ix353 (1083P)<br />
Fang H. ix248 (748)<br />
Fang I. ix345 (1052)<br />
Fang L. ix120 (329P)<br />
Fang W. ix256 (779TiP)<br />
Fani Pakdel A. ix459 (1411)<br />
Fanti S. ix60 (114IN), ix130 (362P), ix148 (425P)<br />
Farace F. ix406 (1240P), ix94 (244)<br />
Farace F.F. ix85 (209P)<br />
Faratian D. ix96 (249PD)<br />
Fareed J. ix543 (1697P)<br />
Farfan C. ix281 (850P)<br />
Fargues G. ix280 (845P)<br />
Farid M. ix485 (1501P)<br />
Farina G. ix466 (1436P), ix511 (1585P)<br />
Farina P. ix144 (411O)<br />
Farnesi A. ix290 (881)<br />
Faron M. ix198 (580P)<br />
Farrell M. ix469 (1449PD)<br />
Farrus B. ix135 (380)<br />
Farsi F. ix481 (1487P)<br />
Fasola G. ix457 (1405)<br />
Fatato P. ix493 (1522PD)<br />
Fatigoni S. ix485 (1500P)<br />
Faustino C. ix201 (591P), ix210 (620), ix221 (657),<br />
ix222 (661)<br />
Fauvet R. ix322 (977P)<br />
Favaretto A. ix533 (1661P)<br />
Faviana P. ix85 (208P)<br />
Favilla B. ix113 (311)<br />
Fayard F. ix486 (1502P)<br />
Fayette J. ix334 (1017O)<br />
Fedele P. ix95 (248O)<br />
Federico P. ix540 (1687), ix316 (962TiP)<br />
Fedorchuk O.G. ix536 (1672P)<br />
Fedorenko D.A. ix141 (403)<br />
Fedrigo C. ix537 (1676P)<br />
Fehr M. ix283 (857P)<br />
Fei F. ix130 (361P)<br />
Fekih M. ix340 (1037P)<br />
Felici A. ix280 (846P)<br />
Felip E. ix414 (1264P), ix496 (1533P), ix73 (167O),<br />
ix152 (438O), ix153 (440O), ix174 (509TiP)<br />
Feliu J. ix457 (1404), ix165 (480P), ix181 (527PD)<br />
Fellous M. ix125 (346P)<br />
Femenic R. ix359 (1104)<br />
Feng A. ix509 (1580P)<br />
Feng S. ix362 (1111PD)<br />
Fennell D. ix495 (1532P), ix529 (1647PD),<br />
ix533 (1664P)<br />
Fennell D.A. ix68 (149P), ix498 (1542TiP)<br />
Fenner M. ix299 (908P)<br />
Ferec M. ix196 (572P)<br />
Ferland E. ix200 (586P)<br />
Fernández Martos C. ix181 (527PD)<br />
Fernández-Parra E. ix275 (832P)<br />
Fernández J. ix136 (386)<br />
Fernández M. ix101 (268P), ix101 (268P)<br />
Fernández P.L. ix135 (380)<br />
Fernandes A.C. ix525 (1639)<br />
Fernandes I. ix289 (878)<br />
Fernandez Aceñero M. ix80 (194P)<br />
Fernandez-Cruz L. ix67 (145P)<br />
Fernandez O. ix436 (1333), ix273 (826P)<br />
Fernando I.N. ix97 (253PD)<br />
Ferrand F.R. ix337 (1025P), ix340 (1037P),<br />
ix341 (1041P), ix345 (1053)<br />
Ferrandez D. ix183 (537P)<br />
Ferrara R. ix229 (685P)<br />
Ferraresi V. ix369 (1132P)<br />
Ferrari A. ix483 (1494P), ix311 (943P)<br />
Ferrari A.C.R. ix486 (1503P)<br />
Ferrari A.C.R.C. ix450 (1380P)<br />
Ferrari D. ix335 (1020PD), ix245 (739P)<br />
Ferrari J.-. ix521 (1622)<br />
Ferrari L. ix240 (724P)<br />
Ferrari S. ix479 (1480PD)<br />
Ferrari V.D. ix338 (1029P)<br />
Ferrarini I. ix94 (243), ix176 (515P)<br />
Ferrario C. ix285 (863P)<br />
Ferraris E. ix99 (260P)<br />
Ferraro L. ix342 (1045P)<br />
Ferrat E. ix460 (1419PD)<br />
Ferree S. ix75 (176PD)<br />
Ferreira M. ix345 (1056)<br />
Ferreira P. ix201 (591P), ix210 (620), ix221 (657),<br />
ix222 (661)<br />
Ferreira R. ix458 (1409)<br />
Ferrero J. ix125 (346P), ix142 (407TiP)<br />
Ferrero J.M. ix294 (893O)<br />
Ferro A. ix99 (259P), ix127 (354P)<br />
Ferron G. ix327 (993P)<br />
Ferrucci P.F. ix369 (1131P)<br />
Ferry D. ix198 (581P)<br />
Annals of Oncology<br />
Ferry D.R. ix178 (519O), ix181 (530PD)<br />
Fetterly G. ix155 (447PD)<br />
Fiala O. ix474 (1464P)<br />
Ficorella C. ix524 (1633), ix213 (629)<br />
Fidler M. ix467 (1442)<br />
Fiduccia P. ix144 (411O), ix326 (991P)<br />
Fiegl M. ix494 (1528P), ix76 (178P)<br />
Field K. ix151 (437TiP)<br />
Figarella-Branger D. ix146 (419PD)<br />
Figdor C. ix363 (1114PD)<br />
Figg W. ix246 (743P)<br />
Figlin R.A. ix262 (794PD)<br />
Figueras J. ix219 (651)<br />
Figueredo M.A. ix165 (480P)<br />
Filatova L.V. ix139 (397)<br />
Filiberti S. ix474 (1462PD)<br />
Filimonov A.V. ix470 (1451P)<br />
Filipits M. ix389 (1192PD), ix86 (213P)<br />
Filleron T. ix464 (1430P)<br />
Fillitz M. ix348 (1064O)<br />
Findlay A. ix483 (1492P)<br />
Finek J. ix447 (1372P), ix474 (1464P)<br />
Fink M. ix449 (1377P)<br />
Finkelstein D.M. ix115 (316TiP)<br />
Fiore M. ix483 (1491P)<br />
Firat U. ix137 (387)<br />
Firvida J.L. ix436 (1333)<br />
Firvida X.L. ix395 (1212)<br />
Fischbach W. ix252 (766)<br />
Fischer von Weikersthal L. ix180 (526PD),<br />
ix204 (599P)<br />
Fischer G. ix278 (841P)<br />
Fischer J.R. ix390 (1194P)<br />
Fischer N. ix372 (1144)<br />
Fish S. ix420 (1279P)<br />
Fishman M.N. ix268 (811P)<br />
Fiteni F. ix249 (753)<br />
Fitzpatrick J.M. ix315 (957)<br />
Fizazi K. ix260 (789O), ix277 (837P), ix285 (862P),<br />
ix294 (893O), ix295 (895O), ix295 (896O),<br />
ix297 (899PD), ix304 (924P), ix309 (937P),<br />
ix313 (951)<br />
Flacco A. ix535 (1668P)<br />
Flaherty K.T. ix46 (70IN)<br />
Flamen P. ix194 (569P), ix199 (584P)<br />
Flament C. ix169 (495P)<br />
Flamm-Horak A. ix521 (1622)<br />
Flechl B. ix145 (415PD), ix147 (421P)<br />
Flechon A. ix260 (789O), ix286 (864P)<br />
Flechter E. ix498 (1541)<br />
Fleisher M. ix89 (223P)<br />
Fleury J. ix128 (355P)<br />
Flick E.D. ix420 (1279P)<br />
Flieser-Hartl M. ix465 (1435P)<br />
Floquet A. ix327 (993P)<br />
Flor M.J. ix235 (705P)<br />
Flores Arredondo J.H. ix184 (541P)<br />
Flores-Balcázar C. ix329 (1003P)<br />
Floriani I.C. ix335 (1020PD)<br />
Floyd J.R. ix150 (435TiP)<br />
Flucke U.E. ix484 (1497P)<br />
Fly K. ix482 (1490P), ix271 (820P)<br />
Focan C. ix194 (568P)<br />
Focaraccio L. ix444 (1360)<br />
Fode K. ix271 (819P)<br />
Fojo T. ix198 (579P)<br />
Follador A. ix457 (1405)<br />
Folprecht G. ix178 (520O), ix191 (561P),<br />
ix211 (622)<br />
Fong L. ix310 (939P)<br />
Fonsatti E. ix364 (1117PD)<br />
Fonseca C. ix458 (1409)<br />
Fonseca L.G. ix455 (1397P), ix308 (935P)<br />
Font A. ix538 (1680P), ix265 (802P), ix266 (806P),<br />
ix266 (807P)<br />
Fontana A. ix94 (243), ix127 (354P), ix176 (515P),<br />
ix290 (881)<br />
Fontanini G. ix85 (208P), ix183 (535P)<br />
ix556 | author index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology author index<br />
Fonteyne V. ix325 (987P), ix330 (1007)<br />
Foo Siang Sheng L. ix485 (1499P), ix485 (1501P)<br />
Fora G. ix343 (1047P), ix346 (1058)<br />
Formenti S.C. ix130 (363P)<br />
Formisano L. ix530 (1651P), ix532 (1659P),<br />
ix540 (1687), ix287 (869)<br />
Fornaro L. ix85 (208P)<br />
Forsberg G. ix303 (919P)<br />
Forshew T. ix74 (171O)<br />
Forssman U. ix342 (1044P)<br />
Forster M. ix347 (1061TiP)<br />
Fosko S.W. ix477 (1474)<br />
Fossa S. ix307 (932P)<br />
Foster L. ix381 (1168P)<br />
Foster M. ix166 (484P)<br />
Fotia V. ix535 (1669P)<br />
Fotopoulou C. ix322 (976P)<br />
Fougeray R. ix260 (787O), ix265 (804P)<br />
Fountzilas E. ix338 (1030P), ix338 (1031P)<br />
Fountzilas G. ix337 (1026P), ix338 (1030P),<br />
ix338 (1031P), ix430 (1312), ix95 (246O),<br />
ix213 (630), ix239 (717P)<br />
Fouque J. ix280 (845P), ix282 (852P)<br />
Fourcade A. ix456 (1400P)<br />
Fouret P. ix388 (1190P)<br />
Fournel M. ix163 (471P), ix169 (492P)<br />
Fournel P. ix391 (1199P), ix416 (1270P)<br />
Fournier C. ix113 (309)<br />
Fournier M. ix178 (519O)<br />
Fourrier-Réglat A. ix219 (649)<br />
Fox G. ix507 (1573P)<br />
Fragoso M. ix210 (620), ix221 (657)<br />
Fragoso R. ix201 (591P), ix222 (661)<br />
Fragoso S. ix175 (512PD), ix176 (514P)<br />
Franceschi E. ix145 (416PD), ix147 (424P)<br />
Franciosi V. ix466 (1436P)<br />
Francis S. ix367 (1127P)<br />
Francois E. ix219 (649), ix238 (716P)<br />
Franke F.A. ix403 (1233PD)<br />
Franzese E. ix105 (282P), ix111 (303)<br />
Frasci G. ix102 (271P)<br />
Frassoldati A. ix101 (267P)<br />
Frati L. ix105 (282P), ix111 (303)<br />
Fratte S. ix204 (600P)<br />
Freas E. ix157 (452P)<br />
Frebourg T. ix213 (629)<br />
Fregoni V. ix99 (260P)<br />
Freire J. ix141 (404)<br />
Fresno J.A. ix96 (250PD)<br />
Freudensprung U. ix128 (356P)<br />
Freyer G. ix499 (1547PD), ix501 (1554P),<br />
ix299 (907P)<br />
Frezza A.M. ix489 (1512), ix500 (1550PD)<br />
Frias J. ix165 (480P)<br />
Friberg L.E. ix534 (1667P)<br />
Fridrik M.A. ix352 (1076P)<br />
Fridrik M.A. ix249 (755)<br />
Friend J. ix512 (1588P)<br />
Frittelli P. ix105 (280P)<br />
Frizziero M. ix226 (675P)<br />
Frohlich M.W. ix310 (941P)<br />
Frosch A. ix417 (1271P)<br />
Fruehauf S. ix522 (1624)<br />
Frye J. ix174 (1708PD)<br />
Frye S. ix170 (496P)<br />
Fu C. ix453 (1390P)<br />
Fu S. ix154 (444PD)<br />
Fu Y. ix401 (1227O)<br />
Fuchs B.C. ix542 (1693P), ix246 (742P)<br />
Fuchs C. ix255 (776TiP)<br />
Fuchs H. ix162 (468P)<br />
Fuchs M. ix211 (622)<br />
Fucikova T. ix81 (197P)<br />
Fuentes S. ix150 (434)<br />
Fujii H. ix449 (1378P)<br />
Fujii S. ix344 (1706P), ix196 (574P)<br />
Fujii T. ix433 (1323), ix542 (1693P), ix220 (655),<br />
ix246 (742P)<br />
Fujimoto-Ouchi K. ix390 (1197P), ix534 (1666P)<br />
Fujimura Y. ix383 (1175P)<br />
Fujisaka Y. ix393 (1204P), ix424 (1293P),<br />
ix167 (486P)<br />
Fujita J. ix227 (677P)<br />
Fujita S. ix422 (1286P), ix423 (1289P)<br />
Fujita T. ix139 (396)<br />
Fujita Y. ix434 (1326), ix443 (1358), ix497 (1538P)<br />
Fujiuchi S. ix434 (1326)<br />
Fujiwara K. ix163 (472P)<br />
Fujiwara T. ix250 (758)<br />
Fujiwara Y. ix510 (1581P), ix90 (228P),<br />
ix250 (758)<br />
Fukma E. ix87 (216P)<br />
Fukuda T. ix200 (588P), ix320 (973PD)<br />
Fukui M. ix467 (1443)<br />
Fukuoka M. ix426 (1298P), ix91 (232)<br />
Fukushima N. ix228 (682P)<br />
Fukutomi A. ix241 (728P)<br />
Fulvi A. ix439 (1346)<br />
Fumagalli D. ix57 (100IN)<br />
Fumagalli E. ix483 (1491P)<br />
Funahashi Y. ix517 (1608P)<br />
Funakoshi A. ix241 (728P)<br />
Funk C. ix520 (1618)<br />
Füreder T. ix253 (768)<br />
Furini L. ix326 (991P)<br />
Furlanetto J. ix117 (322PD)<br />
Furugaki K. ix390 (1197P)<br />
Furukawa H. ix196 (573P)<br />
Furukawa T. ix385 (1180PD)<br />
Furumoto H. ix326 (989P)<br />
Furuse J. ix63 (124IN)<br />
Furuta K. ix89 (224P)<br />
Fusco J.P. ix149 (429P), ix239 (718P), ix291 (886),<br />
ix305 (927P)<br />
Fuse N. ix164 (474P), ix231 (689P)<br />
Fushida S. ix228 (682P)<br />
Fust G. ix493 (1523P)<br />
Fuster J. ix377 (1157O)<br />
Futamura Y. ix439 (1343)<br />
G<br />
Gaba Garcia L. ix300 (910P)<br />
Gabizon A.A. ix519 (1616P), ix164 (477P)<br />
Gachet J. ix499 (1545O)<br />
Gachot B. ix503 (1559P)<br />
Gadgeel S. ix174 (509TiP)<br />
Gagliardini D. ix431 (1313)<br />
Gagua R. ix460 (1414TiP)<br />
Gaiardo M. ix457 (1405)<br />
Galdermans D. ix452 (1386P)<br />
Gale D. ix74 (171O)<br />
Galetta D. ix423 (1288P)<br />
Galffy G. ix493 (1523P)<br />
Galicia I. ix165 (480P)<br />
Galizia E. ix431 (1313)<br />
Gallagher D. ix469 (1449PD)<br />
Gallagher M. ix192 (564P)<br />
Gallardo E. ix538 (1680P)<br />
Galle P. ix255 (778TiP)<br />
Gallego Plazas J. ix181 (527PD)<br />
Galli L. ix290 (881)<br />
Galligioni E. ix99 (259P)<br />
Gallizzi G. ix99 (260P)<br />
Galsky M.D. ix297 (901PD)<br />
Galun D. ix237 (712P)<br />
Galuppo S. ix131 (367P)<br />
Galve Calvo E. ix125 (345P)<br />
Galvis V. ix267 (808P)<br />
Gambardella V. ix430 (1309P)<br />
Gamerith G. ix543 (1695P)<br />
Gamez A. ix96 (250PD)<br />
Gamez C. ix370 (1136P)<br />
Gamucci T. ix229 (685P)<br />
Gan H. ix542 (1692P)<br />
Gandara D. ix445 (1365TiP), ix49 (77IN)<br />
Gandhi J.G. ix302 (918P)<br />
Gandhi L. ix405 (1237PD), ix152 (438O)<br />
Gangolli E. ix158 (456P)<br />
Gangopadhyay S. ix455 (1399P), ix133 (375P)<br />
Ganjoo K.N. ix480 (1483PD)<br />
Ganser A. ix299 (908P)<br />
Gansert J. ix255 (776TiP)<br />
Ganten T. ix255 (778TiP)<br />
Garanzini E. ix272 (824P)<br />
Garbe C. ix367 (1127P)<br />
García Alfonso P. ix380 (1165P), ix198 (579P)<br />
García Bueno J.M. ix510 (1582P)<br />
García Palomo A. ix125 (345P)<br />
García Sanz R. ix360 (1108TiP)<br />
García-Campelo R. ix414 (1264P)<br />
García-Carbonero R. ix377 (1157O)<br />
García-Herrera A. ix135 (380)<br />
Garcia Arroyo F.R. ix351 (1073P)<br />
Garcia Castaño A. ix374 (1150)<br />
Garcia Del Muro X. ix490 (1517TiP), ix235 (705P)<br />
Garcia Foncillas J. ix187 (549P)<br />
Garcia Martinez A. ix106 (284P)<br />
Garcia-Bueno J.M. ix441 (1352)<br />
Garcia-Campelo R. ix440 (1349), ix533 (1662P)<br />
Garcia-Carbonero R. ix183 (534P)<br />
Garcia-Donas J. ix113 (310), ix276 (835P),<br />
ix293 (891TiP)<br />
Garcia-Foncillas J. ix80 (194P), ix82 (200P),<br />
ix183 (537P)<br />
Garcia-Gomez R. ix441 (1352)<br />
Garcia-Vargas J.E. ix308 (936P)<br />
Garcia A. ix136 (386)<br />
Garcia C. ix199 (584P)<br />
Garcia E. ix416 (1270P)<br />
Garcia J.M. ix512 (1588P)<br />
Garcia P.E. ix183 (534P)<br />
Gardiman M.P. ix144 (411O)<br />
Gardini G. ix216 (642)<br />
Gardner E. ix246 (743P)<br />
Garey J. ix425 (1297P)<br />
Gargalionis A.N. ix92 (236)<br />
Gargot D. ix181 (529PD)<br />
Garmo H. ix133 (372P)<br />
Garnero P. ix84 (206P)<br />
Garon E.B. ix152 (438O)<br />
Garralda E. ix233 (699P)<br />
Garrido Lopez P. ix414 (1264P), ix419 (1278P)<br />
Garrone O. ix113 (311), ix123 (340P)<br />
Garzaro M. ix343 (1047P), ix346 (1058)<br />
Gascón P. ix523 (1629), ix300 (910P)<br />
Gasco A. ix531 (1655P)<br />
Gasco M. ix483 (1494P), ix487 (1506P)<br />
Gascon P. ix343 (1046P), ix502 (1555P),<br />
ix502 (1557P), ix505 (1564P), ix538 (1680P)<br />
Gasmi M. ix181 (529PD), ix242 (730P)<br />
Gasparini G. ix515 (1599P)<br />
Gąsowska- Bodnar A. ix323 (979P)<br />
Gately K.A. ix68 (148P), ix495 (1531P),<br />
ix69 (154P), ix78 (185P)<br />
Gatineau M. ix334 (1017O)<br />
Gau J. ix355 (1087P)<br />
Gauler T.C. ix336 (1022PD), ix336 (1023PD),<br />
ix437 (1339), ix284 (858P)<br />
Gauler T.C. ix288 (875)<br />
Gaulet M. ix260 (789O)<br />
Gauthier M. ix237 (710P)<br />
Gautschi O. ix403 (1232PD), ix49 (78IN)<br />
Gavelli G. ix496 (1536P)<br />
Gawel S. ix173 (505)<br />
Gazdar A.F. ix544 (1701)<br />
Gazzah A. ix474 (1463P)<br />
Geater S.L. ix391 (1198P), ix393 (1205P)<br />
Gebbia V. ix140 (399)<br />
Gebski V. ix414 (1263P), ix178 (519O)<br />
Géczi L. ix281 (849P), ix286 (867P)<br />
Gedamke M. ix299 (905P), ix306 (930P)<br />
Gedouin D. ix105 (281P)<br />
Gee A.S. ix215 (638)<br />
Geertsen P.F. ix271 (819P)<br />
Volume 23 | Supplement 9 | June <strong>2012</strong> doi:10.1093/annonc/mds466 | ix557
author index<br />
Geiges G. ix306 (930P)<br />
Geitona M. ix236 (707P)<br />
Gelardi T. ix532 (1659P), ix540 (1687)<br />
Geldart T. ix283 (857P)<br />
Gelderblom H. ix478 (1478O), ix184 (540P)<br />
Gelibter A. ix237 (713P), ix240 (721P)<br />
Gemma A. ix383 (1174P), ix404 (1234PD),<br />
ix412 (1256P), ix427 (1301P), ix200 (587P)<br />
Generali D.G. ix96 (251PD)<br />
Genestreti G. ix496 (1536P)<br />
Gennari A. ix119 (327PD)<br />
Gennma A. ix387 (1186P)<br />
Genova C. ix79 (187P)<br />
Gentilcore G. ix375 (1152)<br />
Gentile A.L. ix285 (863P)<br />
George A. ix320 (972PD)<br />
George D.J. ix292 (889TiP), ix310 (941P)<br />
Georgoulias V. ix381 (1170P), ix429 (1308P),<br />
ix431 (1314), ix435 (1329), ix436 (1335),<br />
ix139 (395), ix174 (509TiP), ix213 (631)<br />
Geraedts W. ix425 (1296P)<br />
Gerber B. ix117 (321PD)<br />
Gereke U. ix409 (1249P)<br />
Gerevini F. ix232 (693P)<br />
Gerken G. ix255 (778TiP)<br />
Gerletti P. ix292 (889TiP)<br />
Gerotziafas G. ix543 (1697P)<br />
Gerritsen W. ix307 (932P)<br />
Gerritsen W.R. ix363 (1114PD), ix301 (915P)<br />
Gerritsen W.R. ix306 (931P)<br />
Gershanovich M.L. ix139 (397)<br />
Gervais R. ix397 (1219), ix409 (1247P),<br />
ix446 (1367TiP)<br />
Gervasi M.T. ix326 (991P)<br />
Gettinger S. ix401 (1227O), ix403 (1231PD),<br />
ix405 (1237PD), ix415 (1267P), ix152 (439O),<br />
ix157 (453P)<br />
Getzenberg R.H. ix304 (923P)<br />
Ghanem I. ix96 (250PD), ix96 (251PD),<br />
ix134 (378), ix325 (986P)<br />
Ghanouni P. ix463 (1426P)<br />
Gharami F.H. ix355 (1090P)<br />
Gharami F.H. ix359 (1105)<br />
Gharbi O. ix332 (1013)<br />
Ghate S.W. ix343 (1049P)<br />
Ghazal H. ix449 (1377P)<br />
Ghi M.G. ix335 (1020PD)<br />
Ghielmini M. ix452 (1385P), ix45 (68IN)<br />
Ghilardi M. ix435 (1328), ix467 (1440),<br />
ix519 (1615P), ix131 (368P), ix192 (563P)<br />
Ghiotto C. ix124 (343P), ix131 (367P)<br />
Giaccone G. ix423 (1290P)<br />
Giaginis C. ix541 (1691P)<br />
Giagkas G. ix429 (1308P)<br />
Giaj Levra M. ix444 (1360)<br />
Giampieri R. ix431 (1313), ix86 (214P),<br />
ix86 (215P), ix219 (652), ix239 (720P),<br />
ix250 (756), ix274 (829P)<br />
Gianatti A. ix365 (1120P)<br />
Gianfelice D. ix463 (1426P)<br />
Giannarelli D. ix364 (1117PD), ix427 (1302P),<br />
ix117 (322PD), ix273 (825P)<br />
Giannatempo P. ix88 (222P), ix285 (861P)<br />
Gianni A.M. ix88 (222P), ix285 (861P)<br />
Gianni L. ix531 (1657P), ix74 (172O), ix89 (226P)<br />
Giantonio B.J. ix189 (555P)<br />
Giassas S. ix139 (395)<br />
Gibbs P. ix383 (1173P), ix220 (656)<br />
Giebel S. ix353 (1082P)<br />
Giessen C. ix180 (526PD), ix204 (599P)<br />
Giganti M.O. ix270 (818P)<br />
Gigot J. ix197 (578P)<br />
Gil-Aldea I. ix305 (927P)<br />
Gil-Bazo I. ix149 (429P), ix291 (886)<br />
ix305 (927P)<br />
Gil R.D.A. ix215 (637)<br />
Gilabert M. ix241 (727P)<br />
Gillessen S. ix302 (917P)<br />
Gillet M. ix361 (1110O)<br />
Gillmore R. ix242 (731P)<br />
Gilly F-N. ix478 (1477O)<br />
Gimbergues P. ix102 (270P)<br />
Gimenez-Capitan A. ix531 (1655P), ix533 (1661P),<br />
ix229 (686P)<br />
Gingerich J.R. ix297 (900PD)<br />
Gingrich J.R. ix303 (919P)<br />
Ginocchi L. ix238 (714P), ix241 (726P),<br />
ix251 (761), ix251 (762)<br />
Giordano C. ix343 (1047P), ix346 (1058)<br />
Giordano L. ix487 (1506P)<br />
Giovannetti E. ix240 (724P)<br />
Giovannini M. ix410 (1251P)<br />
Giralt J. ix334 (1016O)<br />
Giranda V.L. ix148 (428P)<br />
Girard M. ix315 (956)<br />
Girardi F. ix145 (416PD), ix147 (424P)<br />
Giraudi S. ix454 (1393P), ix501 (1551PD),<br />
ix521 (1621)<br />
Girelli S. ix511 (1585P)<br />
Gissmann L. ix22 (4IN)<br />
Giuffrida D. ix505 (1565P), ix137 (388)<br />
Giuliani C. ix528 (1646PD)<br />
Giuliano C. ix507 (1574P), ix508 (1575P),<br />
ix520 (1618)<br />
Gizzi M. ix197 (578P)<br />
Gläser U. ix357 (1098)<br />
Gladkov O.A. ix500 (1548PD)<br />
Glas A. ix179 (522PD)<br />
Glassock R.J. ix171 (499P)<br />
Glaudemans A.W.J.M. ix40 (57IN)<br />
Gleave M.E. ix297 (900PD)<br />
Glennie M.J. ix70 (157P)<br />
Gligorov J. ix97 (252PD), ix114 (315TiP),<br />
ix128 (356P), ix260 (789O)<br />
Glimelius B. ix188 (553P)<br />
Glitza I.C. ix517 (1605P)<br />
Glowala-Kosinska M. ix353 (1082P)<br />
Gnant M. ix126 (351P)<br />
Gnocchi C. ix483 (1494P)<br />
Goéré D. ix169 (495P), ix198 (580P)<br />
Gocze P. ix322 (978P)<br />
Goda F. ix93 (237)<br />
Goddemeier T. ix342 (1044P)<br />
Godinho Bexiga J. ix201 (591P), ix210 (620),<br />
ix221 (657)<br />
Godwin A. ix223 (664TiP)<br />
Godwin P. ix68 (148P), ix495 (1531P)<br />
Goessl C. ix309 (937P)<br />
Goethals L. ix341 (1042P)<br />
Goff B. ix319 (967O)<br />
Gogas H. ix95 (246O)<br />
Gogia A. ix358 (1101), ix455 (1398P),<br />
ix110 (298P)<br />
Gogov S. ix278 (842P)<br />
Göhler T. ix255 (778TiP)<br />
Goh B.C. ix70 (155P), ix83 (203P)<br />
Gokgoz S. ix129 (359P)<br />
Gökmen E. ix274 (830P)<br />
Gold A. ix269 (814P)<br />
Goldberg Y. ix109 (294P)<br />
Goldberg Z. ix401 (1228O), ix423 (1290P)<br />
Goldinger S. ix366 (1125P)<br />
Goldkorn A. ix316 (961)<br />
Goldman J. ix157 (452P), ix168 (489P)<br />
Goldman J.W. ix156 (449PD)<br />
Göldner R. ix162 (468P)<br />
Goldwasser F. ix91 (229P), ix167 (485P),<br />
ix259 (786O)<br />
Goldwasser M. ix153 (440O)<br />
Gollins S. ix199 (582P), ix206 (608P)<br />
Gomella L.G. ix310 (941P)<br />
Gomes M. ix78 (184P)<br />
Gómez Caamaño A. ix312 (945)<br />
Gomez Codina J. ix351 (1073P)<br />
Gomez Dorronsoro M. ix219 (651)<br />
Gómez García J. ix324 (984P)<br />
Annals of Oncology<br />
Gomez-Martin C. ix233 (699P)<br />
Gómez A. ix529 (1648P), ix186 (546P)<br />
Gómez N. ix365 (1123P)<br />
Gómez R.E. ix406 (1238PD)<br />
Gomez M.L. ix457 (1404)<br />
Gonçalves A. ix150 (434), ix184 (539P)<br />
Goncalves M.S. ix486 (1503P)<br />
Gong G. ix108 (291P)<br />
Gong Y. ix247 (745P)<br />
Gonullu I. ix469 (1448PD)<br />
Gonullu U. ix469 (1448PD)<br />
González Beca R. ix264 (799P)<br />
González-Farré X. ix135 (380)<br />
González-Lois C. ix112 (307)<br />
González-Piñeiro A. ix92 (234)<br />
González-Rivas C. ix254 (773)<br />
González-Vicente A. ix254 (773)<br />
González B. ix266 (805P)<br />
Gonzalez Cao M. ix374 (1151)<br />
Gonzalez Costas S. ix92 (234)<br />
Gonzalez Del Alba A. ix276 (835P)<br />
Gonzalez Garcia C. ix472 (1456P)<br />
Gonzalez Gordaliza C. ix472 (1456P)<br />
Gonzalez Martin A. ix140 (400), ix324 (982P)<br />
Gonzalez Patiño E. ix328 (1000P)<br />
Gonzalez-Angulo A.M. ix57 (101IN), ix96 (249PD)<br />
Gonzalez-Astorga B. ix254 (773)<br />
Gonzalez-De-Castro D. ix224 (667PD)<br />
Gonzalez-Larriba J.L. ix438 (1342)<br />
Gonzalez A. ix216 (641)<br />
Gonzalez A.A. ix183 (534P)<br />
Gonzalez J.A. ix239 (718P)<br />
Gonzalez S. ix136 (386)<br />
Good J. ix304 (922P)<br />
Goonetilleke D. ix326 (992P)<br />
Gopalakrishna P. ix393 (1205P)<br />
Gorana A. ix378 (1159P)<br />
Gorbounova V.A. ix382 (1172), ix410 (1250P),<br />
ix435 (1330)<br />
Gorbunova V.A. ix405 (1236PD), ix224 (668PD),<br />
ix250 (760)<br />
Gorbunova V.A. ix255 (777TiP)<br />
Gordon D. ix503 (1558P)<br />
Gordon M. ix363 (1115PD)<br />
Gore M.E. ix262 (793PD), ix267 (809P),<br />
ix271 (820P), ix273 (827P), ix320 (972PD)<br />
Gori B. ix439 (1346)<br />
Gorican K. ix513 (1593P)<br />
Gornadha Y. ix499 (1545O)<br />
Gornet J. ix234 (703P)<br />
Gosain P. ix470 (1450P)<br />
Goss G. ix395 (1210), ix529 (1647PD),<br />
ix174 (509TiP)<br />
Goss P.E. ix115 (316TiP)<br />
Gosselink R. ix518 (1609P)<br />
Goswami J. ix452 (1388P)<br />
Goto K. ix413 (1260P), ix515 (1598P),<br />
ix534 (1666P)<br />
Goto S. ix463 (1428P)<br />
Goto Y. ix429 (1306P)<br />
Gotoh N. ix544 (1701)<br />
Gouerant S. ix339 (1033P)<br />
Gough N. ix485 (1498P)<br />
Gourzones C. ix337 (1025P)<br />
Gousia A. ix213 (630)<br />
Gouy S. ix322 (977P)<br />
Govindan R. ix424 (1291P), ix445 (1365TiP)<br />
Grávalos C. ix529 (1648P), ix125 (345P)<br />
Grünwald V. ix336 (1023PD), ix264 (798PD),<br />
ix268 (811P), ix268 (813P), ix278 (842P),<br />
ix288 (875), ix299 (908P)<br />
Graf L. ix493 (1523P)<br />
Graff J. ix303 (921P)<br />
Grah C. ix466 (1437P)<br />
Graham D.M. ix524 (1634)<br />
Graillon T. ix146 (419PD)<br />
Gralla R. ix414 (1263P)<br />
Grana C.M. ix47 (75IN)<br />
ix558 | author index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology author index<br />
Granata R. ix335 (1019O), ix341 (1040P),<br />
ix342 (1045P), ix344 (1050P)<br />
Grande E. ix377 (1157O), ix380 (1165P),<br />
ix206 (606P)<br />
Grandjouan S. ix175 (511PD)<br />
Graser A. ix60 (113IN), ix188 (554P)<br />
Grasic Kuhar C. ix112 (308)<br />
Grau J.J. ix343 (1046P)<br />
Gravis-Mescam G. ix150 (434), ix259 (786O),<br />
ix260 (789O)<br />
Gravis G. ix263 (797PD), ix294 (893O),<br />
ix307 (933P)<br />
Gray L. ix235 (706P)<br />
Gray S.G. ix68 (149P), ix68 (150P), ix495 (1531P),<br />
ix495 (1532P)<br />
Grazi G. ix237 (713P)<br />
Graziano F. ix538 (1681P)<br />
Graziano P. ix78 (183P)<br />
Graziano S. ix389 (1192PD)<br />
Greco C. ix241 (726P)<br />
Green M. ix428 (1303P)<br />
Greenberg J. ix222 (662TiP)<br />
Greggi S. ix323 (980P)<br />
Gregorc V. ix410 (1251P), ix167 (487P),<br />
ix172 (502)<br />
Gregori J. ix531 (1656P)<br />
Gregory W. ix171 (500P)<br />
Greijer A.E. ix88 (221P)<br />
Greil R. ix340 (1038P), ix348 (1064O),<br />
ix352 (1076P), ix531 (1657P), ix116 (317O),<br />
ix193 (565P), ix195 (571P), ix249 (755)<br />
Greillier L. ix391 (1199P), ix397 (1219)<br />
Greiner R. ix148 (427P)<br />
Greshock J. ix153 (442O)<br />
Gridelli C. ix404 (1235PD), ix418 (1275P)<br />
Griebsch I. ix191 (561P)<br />
Griesinger F. ix419 (1278P)<br />
Griffin M. ix153 (442O)<br />
Griffin T. ix294 (894O), ix295 (895O)<br />
Griffiths G. ix498 (1542TiP)<br />
Grigorescu A. ix398 (1222)<br />
Griguolo G. ix209 (618)<br />
Gril B. ix61 (120IN)<br />
Grimaldi A.M. ix375 (1152)<br />
Grimer R.J. ix479 (1480PD)<br />
Grincuka E. ix124 (344P)<br />
Grinsted L. ix403 (1233PD)<br />
Grisanti S. ix338 (1029P)<br />
Grivaux M. ix455 (1396P)<br />
Groen H.J.M. ix401 (1227O), ix152 (438O)<br />
Grogan L. ix468 (1444)<br />
Grogan T. ix383 (1173P)<br />
Grogan W.M. ix494 (1526P)<br />
Gromut I. ix470 (1451P)<br />
Gronchi A. ix484 (1496P)<br />
Gronesova P. ix286 (865P)<br />
Gronowitz S.J. ix88 (220P)<br />
Groshen S. ix261 (790O), ix316 (961)<br />
Grosman G. ix210 (619)<br />
Gross Goupil M. ix313 (951)<br />
Grossi F. ix410 (1250P), ix410 (1251P),<br />
ix79 (187P)<br />
Grosso F. ix247 (747P)<br />
Gro<strong>the</strong>y A. ix329 (1002P), ix535 (1670P),<br />
ix191 (560P), ix222 (662TiP)<br />
Grover K. ix106 (283P)<br />
Grude F. ix456 (1401P), ix196 (572P)<br />
Gruenberger B. ix249 (755)<br />
Grumett S. ix181 (530PD)<br />
Grunberg S. ix64 (129IN), ix507 (1572P)<br />
Gruschkus S. ix428 (1303P)<br />
Grutters J.P. ix397 (1217), ix501 (1553P),<br />
ix212 (626)<br />
Guérif S. ix511 (1584P)<br />
Guérin O. ix501 (1554P)<br />
Gu A. ix454 (1395P)<br />
Gu W. ix217 (643)<br />
Gu X. ix389 (1193P), ix130 (361P)<br />
Gu Y. ix174 (509TiP)<br />
Guan Q. ix437 (1337)<br />
Guan Z. ix189 (555P), ix217 (643)<br />
Guardino E. ix89 (226P), ix120 (329P)<br />
Guarducci C. ix27 (13IN)<br />
Guarin M.J. ix106 (284P)<br />
Guarneri V. ix101 (267P)<br />
Gucalp A. ix98 (257P)<br />
Guderian G. ix278 (841P)<br />
Guerra P.P. ix406 (1238PD)<br />
Guerrieri Gonzaga A. ix83 (201P)<br />
Guettier C. ix243 (733P)<br />
Gui L. ix394 (1209)<br />
Guida F.M. ix500 (1550PD), ix516 (1603P),<br />
ix538 (1681P), ix206 (606P)<br />
Guida M. ix369 (1132P), ix369 (1133P),<br />
ix370 (1135P)<br />
Guidon M. ix513 (1592P)<br />
Guigay J. ix337 (1025P), ix340 (1037P),<br />
ix341 (1041P), ix345 (1053)<br />
Guild R. ix498 (1543TiP)<br />
Guillemin F. ix109 (296P), ix120 (331P)<br />
Guillen-Ponce C. ix459 (1412), ix472 (1456P)<br />
Guillot A. ix289 (876), ix313 (951)<br />
Guimbaud R. ix194 (568P)<br />
Guirado Rueño M. ix140 (400)<br />
Guiterrez M.E. ix498 (1543TiP)<br />
Guiu M. ix85 (210P)<br />
Gujral S. ix351 (1074P)<br />
Guler O.C. ix425 (1294P), ix526 (1641),<br />
ix237 (711P), ix238 (715P)<br />
Gullo G. ix108 (292P)<br />
Guma J. ix351 (1073P)<br />
Gumurdulu D. ix326 (990P)<br />
Gumus M. ix497 (1540)<br />
Gunsilius E. ix76 (178P)<br />
Gün<strong>the</strong>r O. ix298 (902P)<br />
Gun<strong>the</strong>r O. ix447 (1372P)<br />
Guntinas-Lichius O. ix336 (1023PD)<br />
Güntsch F. ix357 (1098)<br />
Guo J. ix453 (1390P), ix279 (844P), ix282 (851P)<br />
Guo W. ix436 (1332), ix216 (640)<br />
Guo X. ix346 (1057)<br />
Gupta A. ix361 (1109O), ix405 (1237PD),<br />
ix157 (453P), ix258 (784O)<br />
Gupta G. ix98 (257P)<br />
Gupta P. ix356 (1091P), ix328 (997P)<br />
Gupta R. ix349 (1067PD), ix358 (1101),<br />
ix242 (729P)<br />
Gupta R.K. ix114 (312)<br />
Gupta S. ix470 (1450P), ix224 (667PD),<br />
ix320 (972PD)<br />
Gurney H. ix538 (1678P)<br />
Gurpide A. ix365 (1123P), ix432 (1316),<br />
ix508 (1577P)<br />
Gurrieri L. ix457 (1405)<br />
Gut P.A. ix148 (427P)<br />
Gutiérrez Damian E.I. ix212 (627)<br />
Gutierrez M. ix424 (1291P)<br />
Gutsch J. ix453 (1389P), ix466 (1437P)<br />
Gutzmer R. ix361 (1110O)<br />
Gyergyay F. ix281 (849P)<br />
H<br />
Habibian M. ix294 (893O)<br />
Hackshaw A. ix421 (1282P)<br />
Haddock M.G. ix329 (1002P)<br />
Haga N. ix69 (153P)<br />
Hager H. ix73 (167O)<br />
Häggman M. ix303 (919P)<br />
Hagiwara E. ix436 (1334)<br />
Hagiwara K. ix412 (1256P), ix413 (1259P)<br />
Hahn H. ix236 (709P)<br />
Hahn N.M. ix303 (921P)<br />
Haibo M. ix256 (779TiP)<br />
Haid V. ix490 (1516)<br />
Haider K. ix182 (531P)<br />
Haigentz M. ix422 (1287P)<br />
Hainaut P. ix389 (1192PD), ix74 (170O)<br />
Hainsworth J.D. ix362 (1111PD), ix362 (1112PD)<br />
Halabi A. ix162 (468P)<br />
Halawani H. ix337 (1028P)<br />
Haley V. ix532 (1660P), ix73 (169O)<br />
Hall E. ix292 (887)<br />
Hall G. ix329 (1001P), ix500 (1549PD),<br />
ix171 (500P)<br />
Hall P. ix483 (1492P)<br />
Hall S. ix311 (943P)<br />
Haller D. ix187 (550P)<br />
Haluska F. ix152 (439O)<br />
Hamada C. ix449 (1378P)<br />
Hamaguchi T. ix514 (1597P), ix529 (1649P),<br />
ix200 (587P), ix202 (593P), ix203 (598P),<br />
ix251 (764)<br />
Hamai Y. ix226 (672P)<br />
Hamajima N. ix518 (1610P), ix526 (1643),<br />
ix527 (1705)<br />
Hamaker M. ix100 (263P)<br />
Hamamoto Y. ix241 (728P)<br />
Hamberg P. ix314 (954)<br />
Hamburger T. ix109 (294P)<br />
Hamdan D. ix340 (1037P)<br />
Hamed A. ix323 (981P)<br />
Hamed R.H. ix129 (360P)<br />
Hamid O. ix336 (1022PD), ix362 (1111PD),<br />
ix368 (1129P), ix124 (342P), ix261 (790O)<br />
Hamidou Z. ix120 (331P)<br />
Hammel P. ix379 (1163P)<br />
Hammerschmid N. ix100 (261P)<br />
Hammon R. ix136 (385)<br />
Hamoir M. ix336 (1021PD)<br />
Hamzaj A. ix315 (958)<br />
Han B. ix400 (1225O), ix413 (1261P),<br />
ix454 (1395P), ix193 (566P)<br />
Han H.S. ix116 (318O)<br />
Han J. ix403 (1231PD)<br />
Han K. ix253 (771)<br />
Han M. ix391 (1198P), ix154 (443PD)<br />
Han M.H. ix353 (1080P)<br />
Han X. ix390 (1196P), ix394 (1209), ix435 (1331),<br />
ix111 (302)<br />
Hanada S. ix348 (1062O), ix433 (1323)<br />
Hanahan D. ix23 (5IN)<br />
Hanazaki K. ix250 (758)<br />
Hancock M. ix304 (923P)<br />
Handforth C. ix171 (500P)<br />
Hanin F. ix336 (1021PD)<br />
Hann C.L. ix498 (1543TiP)<br />
Hanna G.G. ix107 (288P)<br />
Hanna N. ix205 (603P), ix214 (634)<br />
Hannan A. ix327 (994P)<br />
Hannaoui N. ix538 (1680P)<br />
Hansen S. ix307 (933P)<br />
Hao D. ix440 (1350)<br />
Hao X. ix435 (1331)<br />
Hao Y. ix295 (895O)<br />
Haouas S. ix99 (258P)<br />
Happe A. ix453 (1389P), ix466 (1437P)<br />
Harada M. ix413 (1259P), ix420 (1280P),<br />
ix434 (1326), ix153 (441O)<br />
Harada T. ix427 (1301P), ix434 (1326),<br />
ix443 (1358), ix497 (1538P)<br />
ix511 (1586P)<br />
Harano K. ix320 (973PD)<br />
Harding T. ix301 (915P)<br />
Hardingham J. ix182 (532P), ix208 (612P)<br />
Hariharan S. ix262 (793PD)<br />
Harita S. ix434 (1327)<br />
Harlin O. ix523 (1627)<br />
Harmankaya K. ix363 (1116PD)<br />
Harmenberg U. ix281 (848P), ix299 (906P)<br />
Harries M. ix133 (372P)<br />
Harrington K.J. ix537 (1677P), ix42 (61IN)<br />
Harrison D. ix93 (240)<br />
Harrison M. ix242 (731P)<br />
Hart C. ix150 (435TiP)<br />
Harter P. ix323 (980P)<br />
Hartford A. ix317 (963TiP)<br />
Hartmann J.T. ix284 (858P)<br />
Volume 23 | Supplement 9 | June <strong>2012</strong> doi:10.1093/annonc/mds466 | ix559
author index<br />
Hartono S. ix70 (155P)<br />
Hartwigsen D. ix409 (1249P)<br />
Harunal Rashid M.F. ix485 (1499P)<br />
Haryana S.M. ix88 (221P)<br />
Harza M. ix262 (795PD)<br />
Harzstark A.L. ix296 (897O)<br />
Hasan J. ix199 (582P), ix319 (969PD),<br />
ix324 (983P), ix326 (992P)<br />
Haschemi A. ix539 (1685P)<br />
Hase T. ix445 (1366TiP)<br />
Hasegawa H. ix230 (688P)<br />
Hasegawa K. ix163 (472P), ix211 (625)<br />
Hasegawa Y. ix434 (1325), ix439 (1343),<br />
ix445 (1366TiP), ix144 (412O)<br />
Hashem T.A. ix98 (256P)<br />
Hashiguchi Y. ix506 (1570P)<br />
Hashimoto H. ix514 (1597P)<br />
Hashimoto K. ix248 (751)<br />
Hashimoto S. ix407 (1242P), ix543 (1696P)<br />
Haslbauer F. ix523 (1628)<br />
Hassan A.A. ix468 (1445)<br />
Hassan E.A. ix337 (1028P)<br />
Hassan R. ix493 (1522PD)<br />
Hassanain O. ix448 (1374P)<br />
Hassouni K. ix328 (999P)<br />
Hata A. ix423 (1289P), ix437 (1338)<br />
Hatake K. ix87 (218P)<br />
Hatanaka K. ix202 (592P)<br />
Hatmi M. ix543 (1697P)<br />
Hato S. ix250 (758)<br />
Hatoum G. ix334 (1016O)<br />
Hatsuse K. ix211 (625)<br />
Hattori M. ix139 (396)<br />
Hattori Y. ix422 (1286P)<br />
Hauke R. ix317 (964TiP)<br />
Hauptmann S. ix322 (976P)<br />
Hauschild A. ix362 (1112PD), ix366 (1124P)<br />
Hauschild M. ix124 (344P)<br />
Hauser S. ix268 (813P)<br />
Hausheer F.H. ix512 (1590P)<br />
Haustermans K. ix222 (663TiP)<br />
Havel L. ix409 (1246P), ix409 (1247P),<br />
ix436 (1332)<br />
Hawes D. ix316 (961)<br />
Hawkins R. ix267 (808P)<br />
Hayashi H. ix424 (1293P), ix167 (486P)<br />
Hayashi N. ix82 (199P), ix100 (264P),<br />
ix133 (373P), ix220 (655)<br />
Hayashi R. ix344 (1706P)<br />
Hayashi T. ix71 (161P)<br />
Haynes H. ix311 (942P)<br />
Hayoz S. ix462 (1423O)<br />
Hazama S. ix93 (237), ix159 (460P), ix200 (588P),<br />
ix240 (723P)<br />
Hazra P. ix472 (1458P)<br />
He A. ix398 (1220), ix119 (326PD)<br />
He J. ix389 (1193P)<br />
He M. ix501 (1552P)<br />
He P. ix389 (1193P)<br />
Heath E.I. ix302 (918P)<br />
Heath G. ix500 (1549PD)<br />
Heavey S. ix68 (148P), ix495 (1531P), ix69 (154P),<br />
ix78 (185P)<br />
Hebbar M. ix194 (568P)<br />
Hebert G. ix456 (1400P)<br />
Hechmati G. ix447 (1372P), ix449 (1377P)<br />
Heerschap A. ix192 (562P)<br />
Hege K. ix301 (915P)<br />
Hegg R. ix83 (202P), ix103 (273P)<br />
Heidegger I.M. ix76 (178P)<br />
Heideman D.A.M. ix179 (521O)<br />
Heidenreich A. ix306 (931P), ix307 (932P),<br />
ix308 (934P)<br />
Heigener D. ix407 (1241P)<br />
Heijmen L. ix192 (562P)<br />
Heil J. ix117 (321PD)<br />
Heilbrun L. ix342 (1043P)<br />
Heinemann V. ix180 (526PD), ix188 (554P),<br />
ix204 (599P)<br />
Heinz M. ix504 (1561P)<br />
Heinzmann D. ix102 (271P), ix103 (273P),<br />
ix162 (470P)<br />
Hejna M. ix249 (755)<br />
Hela R. ix254 (774)<br />
Helbekkmo N. ix392 (1200P)<br />
Held C.P. ix409 (1249P)<br />
Helissey C. ix150 (433), ix285 (862P)<br />
Hellebrand E. ix505 (1567P)<br />
Heller G. ix89 (223P)<br />
Hellerstedt B. ix170 (496P)<br />
Hellmich M. ix504 (1561P)<br />
Helvaci K. ix105 (279P)<br />
Hembry N. ix136 (385)<br />
Hendifar A. ix480 (1483PD), ix166 (482P)<br />
Hendlisz A. ix63 (127IN), ix194 (569P),<br />
ix199 (584P)<br />
Hendriks B. ix532 (1658P)<br />
Henin E. ix299 (907P)<br />
Hennemann B. ix336 (1023PD)<br />
Hennessy B. ix96 (249PD)<br />
Henrique R. ix132 (371P)<br />
Henry D.H. ix509 (1580P)<br />
Henschel V. ix81 (198P)<br />
Hense J. ix437 (1339)<br />
Hentic O. ix379 (1163P)<br />
Heo D. ix465 (1433P)<br />
Heo D.S. ix465 (1434P), ix283 (855P)<br />
Hera M. ix474 (1465P)<br />
Heras P. ix474 (1465P)<br />
Herbst F. ix114 (315TiP)<br />
Herbstreit C. ix453 (1389P)<br />
Herchenhorn D. ix524 (1632), ix215 (637),<br />
ix289 (877)<br />
Hermann G.G. ix271 (819P)<br />
Hermine O. ix354 (1084P)<br />
Hernández Nieto V. ix530 (1652P)<br />
Hernández E. ix395 (1212)<br />
Hernandez-Guerrero T. ix187 (549P)<br />
Hernandez I. ix219 (651)<br />
Hernandez S. ix438 (1342)<br />
Hernando B. ix82 (200P)<br />
Hernando S. ix113 (310), ix293 (891TiP)<br />
Herráez-Baranda L.A. ix162 (470P)<br />
Herrera L. ix126 (349P)<br />
Herrera M.D.P. ix183 (534P)<br />
Herrstedt J. ix507 (1573P)<br />
Herzberg C. ix359 (1107TiP)<br />
Hess D. ix157 (454P)<br />
Hess G. ix359 (1107TiP)<br />
Heudel P. ix481 (1487P)<br />
Heyburn J.W. ix493 (1522PD)<br />
Heyd B. ix204 (600P), ix249 (753)<br />
Heymach J.V. ix261 (791PD)<br />
ix275 (833P)<br />
Hibshoosh H. ix84 (204P)<br />
Hida T. ix393 (1204P), ix413 (1260P),<br />
ix433 (1324), ix153 (441O)<br />
Hidalgo M. ix374 (1151), ix156 (449PD)<br />
Higano C. ix303 (920P), ix303 (921P),<br />
ix311 (942P)<br />
Higashi T. ix384 (1177P)<br />
Higashi Y. ix467 (1443)<br />
Hihara J. ix226 (672P)<br />
Hijikata Y. ix536 (1671P)<br />
Hijri F.Z. ix137 (389)<br />
Hilal A.M. ix111 (304)<br />
Hilbe W. ix494 (1528P), ix543 (1695P),<br />
ix76 (178P)<br />
Hilfiker P.R. ix366 (1125P)<br />
Hill M. ix187 (550P)<br />
Hinoda Y. ix93 (237)<br />
Hipp M. ix459 (1413TiP)<br />
Annals of Oncology<br />
Hirabayashi M. ix442 (1356)<br />
Hirabayashi N. ix228 (681P)<br />
Hirai F. ix387 (1187P)<br />
Hirai S. ix514 (1597P), ix203 (598P)<br />
Hirai T. ix250 (758)<br />
Hirakawa K. ix84 (205P)<br />
Hirami Y. ix541 (1690P)<br />
Hirano H. ix220 (653)<br />
Hirashima T. ix424 (1293P), ix432 (1320),<br />
ix433 (1321), ix439 (1344)<br />
Hirata K. ix412 (1258P), ix79 (189P), ix79 (190P),<br />
ix92 (235)<br />
Hirmand M. ix295 (896O), ix297 (899PD)<br />
Hironaka S. ix233 (697P)<br />
Hiroyuki B. ix527 (1705)<br />
Hirsch F.R. ix445 (1365TiP)<br />
Hirsh V. ix402 (1229PD), ix410 (1252P),<br />
ix414 (1263P), ix509 (1580P)<br />
Hirte H.W. ix155 (448PD), ix156 (450PD)<br />
Hitier S. ix306 (931P), ix307 (932P)<br />
Hitij N.T. ix522 (1625), ix523 (1630)<br />
Hitre E. ix191 (561P)<br />
Hjelm-Eriksson M. ix299 (906P)<br />
Ho-Pun-Cheung A. ix84 (206P)<br />
Ho A. ix98 (257P)<br />
Ho C. ix412 (1255P), ix493 (1525P)<br />
Ho J.C.M. ix383 (1176P)<br />
Hochlef M. ix332 (1013)<br />
Hocke J. ix245 (740P), ix246 (744P)<br />
Hodge L. ix263 (796PD)<br />
Hodi F.S. ix361 (1109O), ix368 (1129P),<br />
ix157 (453P)<br />
Hoefeler H. ix449 (1377P)<br />
Hoeffkes H. ix459 (1413TiP)<br />
Hoefliger M. ix132 (370P)<br />
Hoersch S. ix187 (550P)<br />
Hofbauer G. ix539 (1685P)<br />
Hofbauer G.F. ix372 (1144)<br />
Hofert K. ix110 (297P)<br />
Hoff P.M. ix331 (1009), ix450 (1380P),<br />
ix455 (1397P), ix486 (1503P), ix181 (528PD),<br />
ix308 (935P)<br />
Hoffman D. ix422 (1287P)<br />
Hoffmann A.C. ix68 (149P)<br />
Hofheinz R. ix459 (1413TiP)<br />
Hofman P. ix388 (1190P)<br />
Hohenberger P. ix478 (1478O), ix480 (1484PD),<br />
ix481 (1486PD)<br />
Hohenegger M. ix72 (165)<br />
Hoiczyk M. ix437 (1339)<br />
Hokka D. ix92 (233)<br />
Holbrechts S. ix194 (569P)<br />
Holcroft C. ix200 (586P)<br />
Holford C. ix101 (267P)<br />
Hollebecque A. ix474 (1463P), ix496 (1534P),<br />
ix94 (244), ix116 (319O), ix155 (446PD),<br />
ix159 (458P), ix168 (491P)<br />
Holmberg L. ix133 (372P)<br />
Holmskov K. ix507 (1573P)<br />
Holowiecki J. ix353 (1082P)<br />
Holt S. ix97 (252PD)<br />
Holubec L. ix474 (1464P)<br />
Homesley H. ix81 (198P)<br />
Honda-Okubo Y. ix503 (1558P)<br />
Honda K. ix383 (1174P), ix387 (1186P),<br />
ix518 (1610P), ix526 (1643), ix536 (1673P),<br />
ix536 (1674P), ix89 (224P), ix156 (451P),<br />
ix159 (459P), ix164 (475P)<br />
Hong D.S. ix154 (444PD)<br />
Hong J.H. ix276 (834P)<br />
Hong J.H. ix287 (872)<br />
Hong J.Y. ix375 (1153), ix430 (1311P)<br />
Hong M. ix522 (1626)<br />
Hong S.H. ix250 (757)<br />
Hong Y. ix355 (1087P)<br />
Hong Y.S. ix479 (1479PD), ix250 (757)<br />
ix560 | author index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology author index<br />
Honma N. ix104 (277P)<br />
Honma Y. ix529 (1649P), ix202 (593P),<br />
ix251 (764)<br />
Hooftman L. ix103 (274P)<br />
Hooper B. ix208 (612P)<br />
Hopper C. ix347 (1061TiP)<br />
Hor P. ix356 (1091P)<br />
Horai T. ix418 (1274P), ix441 (1353)<br />
Horak P. ix539 (1685P)<br />
Horchani A. ix308 (934P)<br />
Hori K. ix517 (1608P)<br />
Horiike A. ix413 (1260P), ix418 (1274P),<br />
ix441 (1353)<br />
Horimatsu T. ix226 (673P)<br />
Horio A. ix139 (396)<br />
Horio Y. ix433 (1324)<br />
Horn E. ix260 (789O)<br />
Horn L. ix401 (1227O), ix405 (1237PD)<br />
Horsch D. ix377 (1156O)<br />
Hortobagyi G.N. ix118 (324PD), ix121 (334P),<br />
ix126 (351P)<br />
Hosokawa A. ix203 (598P)<br />
Hosomi Y. ix441 (1351), ix497 (1537P)<br />
Hospers G.A.P. ix40 (57IN)<br />
Hossain A.M. ix336 (1022PD)<br />
Hoth D. ix460 (1416PD)<br />
Hotta K. ix397 (1218), ix434 (1327)<br />
Hotte S.J. ix155 (448PD), ix156 (450PD),<br />
ix297 (900PD)<br />
Hou J. ix362 (1112PD)<br />
Hou M. ix443 (1359), ix247 (745P)<br />
Houben R. ix212 (626)<br />
Houbiers G. ix194 (569P)<br />
Houede N. ix314 (955)<br />
Houlgatte A. ix285 (862P)<br />
Hoverman J.R. ix425 (1297P)<br />
Hovey E. ix151 (437TiP)<br />
Howe K. ix528 (1645PD)<br />
Howlett M. ix123 (341P)<br />
Hoyos S. ix325 (986P)<br />
Hsiao L. ix355 (1087P)<br />
Hsiao S. ix425 (1295P), ix428 (1305P)<br />
Hsieh R. ix345 (1052)<br />
Hsu C. ix522 (1626), ix246 (744P), ix246 (744P),<br />
ix253 (769)<br />
Hsu P. ix351 (1075P)<br />
Hsueh Y. ix538 (1679P)<br />
Hu F. ix522 (1626)<br />
Hu J. ix261 (790O)<br />
Hu X. ix394 (1209), ix435 (1331)<br />
Hu Z. ix453 (1390P)<br />
Huang C. ix444 (1362TiP)<br />
Huang D.C. ix246 (744P)<br />
Huang S. ix501 (1552P), ix32 (30IN)<br />
Huang S.M. ix541 (1688PD)<br />
Huang X. ix376 (1155O), ix262 (794PD)<br />
Huang Y. ix346 (1057), ix453 (1390P), ix219 (650),<br />
ix282 (851P)<br />
Hubay S. ix316 (960)<br />
Hubbard J.M. ix157 (452P)<br />
Huber J. ix543 (1695P)<br />
Hubert A. ix255 (777TiP)<br />
Hubner R. ix381 (1168P)<br />
Hucke C. ix350 (1072P)<br />
Hudes G.R. ix262 (794PD)<br />
Hudis C.A. ix98 (257P)<br />
Huebner G. ix409 (1249P)<br />
Hughes A. ix87 (219P), ix90 (227P)<br />
Hui D. ix466 (1439)<br />
Huillard O. ix519 (1614P)<br />
Huitzil Melendez D. ix184 (541P)<br />
Humanes B. ix520 (1619)<br />
Hummel M. ix390 (1195P), ix394 (1208)<br />
Hummerlsberger M. ix499 (1547PD)<br />
Humphrey R.W. ix163 (471P), ix169 (492P)<br />
Hunt W. ix169 (493P)<br />
Huovinen R. ix384 (1178TiP)<br />
Hurtado A. ix113 (310)<br />
Hurvitz S. ix89 (226P), ix120 (329P)<br />
Hurwitz H.I. ix163 (471P), ix189 (555P),<br />
ix191 (560P)<br />
Husain A. ix319 (967O)<br />
Huss S. ix481 (1486PD)<br />
Hussain A. ix499 (1547PD), ix107 (288P)<br />
Hussain M. ix317 (965TiP)<br />
Hutajulu S.H. ix88 (221P)<br />
Hutchinson A. ix526 (1640)<br />
Hutson T.E. ix262 (794PD), ix263 (796PD),<br />
ix269 (814P), ix278 (840P)<br />
Huynh T. ix482 (1489P)<br />
Hwang J.E. ix467 (1441), ix468 (1446)<br />
Hwu P. ix366 (1126P), ix454 (1392P)<br />
Hwu W. ix366 (1126P), ix454 (1392P)<br />
Hyodo I. ix233 (697P)<br />
I<br />
Iacobelli S. ix523 (1628)<br />
Iacono C. ix104 (276P)<br />
Iacono G. ix454 (1393P), ix521 (1621)<br />
Iacovelli R. ix440 (1348), ix488 (1509P),<br />
ix270 (818P), ix272 (824P), ix276 (836P)<br />
Iaffaioli R.V. ix539 (1682P)<br />
Iaffaioli V.R. ix193 (567P)<br />
Iafrate A. ix389 (1191PD)<br />
Iannace A. ix105 (282P), ix111 (303)<br />
Iannessi A. ix534 (1665P)<br />
Ianotti N. ix393 (1205P)<br />
Ibba T. ix341 (1040P)<br />
Ibeas P. ix492 (1521PD), ix494 (1527P)<br />
Ibragimov J.M. ix71 (162P)<br />
Ibrahim N.H. ix134 (376)<br />
Ibuki Y. ix385 (1180PD)<br />
Ichiei N. ix509 (1579P)<br />
Ichikawa K. ix71 (159P)<br />
Ichinose Y. ix387 (1187P), ix438 (1340),<br />
ix492 (1519PD)<br />
Ichou M. ix477 (1476)<br />
Icli F. ix469 (1448PD)<br />
Idoate M.A. ix365 (1123P)<br />
Igaki H. ix89 (224P)<br />
Igarashi S. ix388 (1188P)<br />
Ignatiadis M. ix98 (255PD)<br />
Iguchi M. ix441 (1351), ix497 (1537P)<br />
Iida M. ix240 (723P)<br />
Iizasa T. ix144 (412O)<br />
Ikari Y. ix508 (1576P)<br />
Ikeda K. ix244 (737P)<br />
Ikeda M. ix241 (728P), ix244 (737P)<br />
Ikeda N. ix544 (1701)<br />
Ikeda Y. ix518 (1610P), ix526 (1643)<br />
Ikejiri K. ix217 (646)<br />
Ikemura S. ix422 (1285P)<br />
Ileana E. ix304 (924P)<br />
Ilhan-Mutlu A. ix148 (426P)<br />
Ilie S.M. ix341 (1041P), ix345 (1053)<br />
Illidge T. ix348 (1063O)<br />
Imai M. ix91 (232)<br />
Imamura F. ix411 (1253P), ix422 (1286P),<br />
ix437 (1338), ix511 (1586P)<br />
Imanaka K. ix243 (732P)<br />
Imbeaud S. ix180 (525PD)<br />
Imberti G. ix365 (1120P)<br />
Imbevaro S. ix439 (1345), ix447 (1370P),<br />
ix283 (854P)<br />
Imperatori M. ix500 (1550PD)<br />
Imtiaz S. ix497 (1539P)<br />
Inaba Y. ix243 (732P)<br />
Inagaki H. ix230 (688P)<br />
Inal A. ix137 (387)<br />
_Inanc M. ix332 (1015)<br />
Inauen R. ix480 (1482PD)<br />
Inbar M. ix116 (317O)<br />
Inbar Y. ix463 (1426P)<br />
Incarbone M. ix77 (181P)<br />
Indraccolo S. ix209 (618)<br />
Indrasari S.R. ix88 (221P)<br />
Indrawati L.P.L. ix88 (221P)<br />
Ingemi M.C. ix140 (399)<br />
Ingle J. ix28 (17IN)<br />
Ingles Garces A.H. ix331 (1010)<br />
Inno A. ix433 (1322)<br />
Inomata M. ix208 (1704P), ix545 (1704P)<br />
Inoue A. ix404 (1234PD), ix412 (1256P),<br />
ix413 (1259P), ix414 (1263P), ix427 (1301P),<br />
ix153 (441O)<br />
Inoue H. ix536 (1671P)<br />
Inoue Y. ix196 (574P), ix201 (590P), ix202 (592P),<br />
ix232 (692P), ix240 (723P), ix93 (237)<br />
Inrhaoun H. ix432 (1318)<br />
Insa Molla A. ix418 (1273P)<br />
Intagliata S. ix516 (1603P), ix538 (1681P)<br />
Ioannou E. ix136 (385)<br />
Ioka T. ix254 (775)<br />
Ionescu D. ix412 (1255P)<br />
Ionova T.I. ix141 (403)<br />
Iozeffi D. ix463 (1426P)<br />
Ip M.S. ix383 (1176P)<br />
Iqbal S. ix349 (1067PD), ix354 (1085P)<br />
Iqbal S.U. ix203 (597P), ix213 (632)<br />
Iqbal U. ix214 (633)<br />
Irelli A. ix524 (1633)<br />
Irwin M. ix453 (1390P)<br />
Isa L. ix474 (1462PD)<br />
Isaacson J. ix236 (709P)<br />
Isakoff S. ix159 (458P), ix321 (974PD)<br />
Isambert N. ix165 (478P), ix169 (494P),<br />
ix170 (498P)<br />
Isayama H. ix241 (728P)<br />
Ishfaq T. ix483 (1492P)<br />
Ishibashi K. ix69 (153P)<br />
Ishibashi M. ix433 (1323)<br />
Ishida T. ix517 (1606P)<br />
Ishida Y. ix100 (264P)<br />
Ishigami H. ix233 (698P)<br />
Ishigure K. ix220 (655)<br />
Ishiguro M. ix197 (576P), ix200 (588P)<br />
Ishii G. ix387 (1186P), ix534 (1666P)<br />
Ishii Y. ix413 (1259P), ix420 (1280P)<br />
Ishikawa T. ix84 (205P), ix197 (576P)<br />
Ishikawa Y. ix418 (1274P)<br />
Ishiki H. ix518 (1611P), ix344 (1706P)<br />
Ishimoto O. ix420 (1280P)<br />
Ishitani K. ix326 (989P)<br />
Ishitsuka K. ix348 (1062O), ix508 (1576P)<br />
Ishiyama A. ix220 (655)<br />
Isikdogan A. ix137 (387)<br />
Isla Casado D. ix414 (1264P), ix418 (1273P),<br />
ix510 (1582P)<br />
Ismael G. ix102 (271P), ix103 (273P)<br />
Ismaili N. ix328 (999P)<br />
Isobe H. ix404 (1234PD), ix413 (1259P),<br />
ix434 (1326), ix443 (1358), ix497 (1538P)<br />
Isobe T. ix248 (751)<br />
Issels R. ix487 (1505P)<br />
Itakura M. ix144 (412O)<br />
Italiano A. ix489 (1514)<br />
Ito M. ix210 (621)<br />
Ito S. ix385 (1181PD)<br />
Ito T. ix376 (1154O)<br />
Ito Y. ix396 (1215), ix126 (351P)<br />
Itoh K. ix131 (366P)<br />
Itri L. ix165 (481P)<br />
Iuchi T. ix144 (412O)<br />
Iuliani M. ix489 (1512), ix516 (1603P),<br />
ix530 (1653P)<br />
Ivanyi P. ix336 (1023PD)<br />
Iveson T. ix230 (687P), ix242 (731P)<br />
Ivy S.P. ix155 (448PD), ix156 (450PD)<br />
Iwai T. ix390 (1197P)<br />
Iwamoto S. ix93 (237), ix196 (573P)<br />
Iwamoto T. ix74 (172O), ix112 (305)<br />
Iwamoto Y. ix385 (1181PD)<br />
Iwanicki-Caron I. ix252 (767)<br />
Iwasa S. ix529 (1649P), ix202 (593P), ix251 (764)<br />
Volume 23 | Supplement 9 | June <strong>2012</strong> doi:10.1093/annonc/mds466 | ix561
author index<br />
Iwasaki H. ix542 (1694P)<br />
Iwasaku M. ix422 (1286P), ix437 (1338)<br />
Iwase H. ix225 (671P)<br />
Iwata H. ix115 (316TiP), ix139 (396)<br />
Iyer S. ix403 (1231PD), ix416 (1268P)<br />
Izarzugaza Y. ix80 (194P)<br />
Izquierdo A. ix388 (1189P)<br />
Izumi K. ix518 (1611P)<br />
J<br />
Jaal J. ix146 (418PD), ix149 (431)<br />
Jackisch C. ix97 (254PD), ix102 (271P),<br />
ix103 (272P)<br />
Jackson A. ix207 (609P)<br />
Jacob A. ix220 (656)<br />
Jacob J. ix150 (433)<br />
Jacob U. ix136 (385)<br />
Jacobasch L. ix289 (876)<br />
Jacobs I. ix479 (1480PD)<br />
Jacobs J. ix342 (1043P), ix363 (1114PD)<br />
Jaeger E. ix459 (1413TiP)<br />
Jaén-Morago A. ix101 (268P)<br />
Jafarian A. ix107 (287P), ix184 (538P)<br />
Jäger D. ix270 (817P), ix279 (844P)<br />
Jahan T. ix422 (1287P), ix493 (1522PD)<br />
Jahanzeb M. ix420 (1279P)<br />
Jain A. ix412 (1257P)<br />
Jain K. ix503 (1558P)<br />
Jain M. ix174 (510TiP)<br />
Jain N. ix244 (735P)<br />
Jakic-Razumovic J. ix86 (212P)<br />
Jakobsen A. ix530 (1654P), ix73 (168O)<br />
Jakobsen J.N. ix443 (1357), ix80 (191P)<br />
Jakobsson M. ix281 (848P)<br />
Jakovljevic G. ix359 (1104)<br />
Jamal N. ix339 (1034P)<br />
Jambor I. ix384 (1178TiP)<br />
James C.R. ix107 (288P)<br />
Jamnig H. ix494 (1528P)<br />
Janciauskiene R. ix267 (809P)<br />
Jang R.W. ix464 (1432P)<br />
Janjigian Y.Y. ix401 (1227O)<br />
Jankilevich G. ix330 (1005P)<br />
Janne P.A. ix401 (1228O), ix403 (1233PD),<br />
ix423 (1290P), ix74 (170O), ix51 (84IN)<br />
Janot F. ix340 (1037P), ix341 (1041P),<br />
ix345 (1053)<br />
Jansen M. ix244 (738P)<br />
Jansman F.G.A. ix456 (1402P)<br />
Janssens A. ix518 (1609P)<br />
Jantus-Lewintre E. ix385 (1179O)<br />
Jara C. ix113 (310)<br />
Jardin F. ix339 (1033P)<br />
Jarosz J. ix518 (1612P)<br />
Jasas K. ix395 (1210)<br />
Jassem J. ix319 (966O)<br />
Jasso-Mosqueda J. ix203 (597P)<br />
Jayaram A. ix248 (750)<br />
Jayson G. ix326 (992P)<br />
Jayson G.C. ix207 (609P), ix324 (983P)<br />
Jayson G.C. ix319 (969PD)<br />
Jazeih A.R. ix288 (874)<br />
Jeannin G. ix403 (1233PD)<br />
Jebali M. ix280 (845P), ix282 (852P)<br />
Jego V. ix154 (444PD)<br />
Jelaca-Maxwell K. ix317 (963TiP)<br />
Jenkins J. ix108 (290P)<br />
Jennions E. ix495 (1531P)<br />
Jensen N.V. ix271 (819P)<br />
Jensen S.A. ix443 (1357)<br />
Jeon E. ix250 (757)<br />
Jerez, Y. ix176 (517P)<br />
Jerjes W. ix347 (1061TiP)<br />
Jerusalem G. ix96 (251PD), ix116 (318O),<br />
ix122 (336P)<br />
Jerzak M. ix323 (979P)<br />
Jeske W. ix481 (1486PD)<br />
Ji L. ix316 (961)<br />
Jia L.Q. ix438 (1341)<br />
Jiang H. ix144 (410O), ix256 (779TiP)<br />
Jiang J. ix389 (1193P)<br />
Jiang Y. ix226 (674P), ix230 (687P)<br />
Jiang Z. ix128 (356P)<br />
Jiang Z.F. ix58 (104IN)<br />
Jiao S. ix231 (690P)<br />
Jiménez J. ix131 (365P), ix186 (546P)<br />
Jimenez Fonseca P. ix380 (1165P), ix218 (647),<br />
ix233 (699P)<br />
Jimenez M. ix62 (121IN), ix263 (797PD)<br />
Jimeno A. ix43 (62IN)<br />
Jin B. ix437 (1337)<br />
Jin J. ix282 (851P)<br />
Jin L. ix233 (696P)<br />
Jin W. ix256 (780TiP)<br />
Jinga D.C. ix67 (146P)<br />
Jinga V. ix262 (795PD)<br />
Jiratrachu R. ix339 (1035P)<br />
Jirillo A. ix439 (1345), ix447 (1370P), ix283 (854P)<br />
Jitlal M. ix206 (608P)<br />
Jo D.Y. ix541 (1688PD)<br />
Jo J. ix479 (1479PD)<br />
Jochum W. ix394 (1208)<br />
Joensuu H. ix478 (1478O)<br />
Jofre-Bonet M. ix460 (1417PD)<br />
John T. ix542 (1692P)<br />
John W. ix404 (1235PD), ix421 (1281P)<br />
Johne A. ix154 (444PD)<br />
Johnson M. ix292 (887)<br />
Johnson P. ix44 (64IN)<br />
Johnston C. ix129 (358P)<br />
Johnston D.S. ix246 (743P)<br />
Johnston J.B. ix350 (1070PD)<br />
Johnston M. ix102 (271P), ix103 (272P)<br />
Johnston M.A. ix304 (923P)<br />
Johnston S.R.D. ix27 (14IN), ix119 (325PD)<br />
Jokhadze N. ix460 (1414TiP)<br />
Jolly D. ix109 (296P), ix120 (331P)<br />
Joly Lobbedez F. ix294 (893O), ix329 (1001P)<br />
Joly K. ix85 (209P)<br />
Jones A. ix119 (325PD)<br />
Jones E. ix292 (887)<br />
Jones L. ix108 (290P)<br />
Jones R.J. ix272 (822P), ix292 (887)<br />
Joore M.A. ix397 (1217)<br />
Jordan E.J. ix540 (1686P)<br />
Jordan K. ix357 (1098)<br />
Jordan W.O. ix523 (1627)<br />
Josephs D.H. ix139 (398)<br />
Joshua A.M. ix297 (900PD)<br />
Jouinot A. ix280 (845P)<br />
Joulain F. ix214 (633)<br />
Jouve J. ix181 (529PD), ix242 (730P)<br />
Jovanovic D. ix428 (1304P)<br />
Jove J. ix219 (649)<br />
Jovenin N. ix499 (1547PD)<br />
Jozwicki W. ix544 (1700)<br />
Ju L. ix76 (179P)<br />
Ju Z. ix96 (249PD)<br />
Juan O. ix441 (1352)<br />
Judde J-G. ix312 (946)<br />
Judson I. ix485 (1498P), ix54 (90IN)<br />
Juhasz E. ix405 (1236PD), ix406 (1239P)<br />
Julier P. ix181 (530PD)<br />
Julieron M. ix340 (1037P)<br />
Jung A. ix180 (526PD)<br />
Jung H.A. ix430 (1311P)<br />
Jung J. ix168 (489P)<br />
Jung K.H. ix108 (291P), ix114 (315TiP)<br />
Junqueira M. ix309 (938P)<br />
Juretic M. ix163 (471P), ix169 (493P)<br />
Jusko W.J. ix155 (447PD)<br />
Jyothi B.M. ix345 (1055)<br />
K<br />
Kabakov A. ix70 (156P)<br />
Kabbinavar F.F. ix189 (555P)<br />
Annals of Oncology<br />
Kabilan S. ix133 (372P)<br />
Kaburaki K. ix418 (1274P)<br />
Kacar-Kukric V. ix428 (1304P)<br />
Kadowaki S. ix196 (574P)<br />
Kaduri L. ix109 (294P)<br />
Kagamu H. ix509 (1579P), ix71 (159P)<br />
Kageyama H. ix144 (412O)<br />
Kageyama S. ix509 (1578P)<br />
Kahan Z. ix116 (317O)<br />
Kahl C. ix288 (875)<br />
Kaiser K. ix261 (792PD)<br />
Kaji R. ix423 (1289P)<br />
Kajiura S. ix196 (574P)<br />
Kajiura Y. ix82 (199P), ix100 (264P)<br />
Kakeji Y. ix188 (552P)<br />
Kalanovic D. ix359 (1107TiP), ix274 (828P)<br />
Kalbacher E. ix332 (1014)<br />
Kalbakis K. ix435 (1329)<br />
Kalogeras K.T. ix338 (1031P)<br />
Kalykaki A. ix139 (395)<br />
Kam B.L. ix538 (1678P)<br />
Kamal M. ix448 (1374P), ix449 (1376P)<br />
Kamata H. ix525 (1637)<br />
Kamijo A. ix185 (542P), ix197 (575P),<br />
ix207 (611P)<br />
Kamikawa H. ix513 (1591P)<br />
Kaminsky M.C. ix342 (1044P)<br />
Kamioner D. ix522 (1624)<br />
Kamiran J. ix327 (996P)<br />
Kammler R. ix80 (193P)<br />
Kamp T. ix440 (1347)<br />
Kampmann E. ix487 (1505P)<br />
Kamura T. ix326 (989P), ix327 (995P)<br />
Kanıtez M. ix186 (547P), ix217 (645)<br />
Kanai F. ix243 (732P)<br />
Kanaka G.B. ix301 (912P)<br />
Kanat O. ix129 (359P)<br />
Kane A. ix322 (977P)<br />
Kaneko M. ix469 (1447PD)<br />
Kaneko S. ix243 (732P)<br />
Kaneko Y. ix170 (498P)<br />
Kang B. ix332 (1012)<br />
Kang B.W. ix208 (613P)<br />
Kang H. ix492 (1520PD)<br />
Kang J.H. ix466 (1439)<br />
Kang S.Y. ix135 (382)<br />
Kang W.K. ix186 (545P), ix209 (617)<br />
Kang Y. ix478 (1478O), ix480 (1481PD),<br />
ix482 (1490P), ix227 (679P), ix234 (700P)<br />
Kannan K. ix331 (1011)<br />
Kantoff P. ix310 (940P)<br />
Kantoff P.W. ix38 (46IN)<br />
Kanyev S. ix463 (1426P)<br />
Kao H. ix522 (1626)<br />
Kaplan M.A. ix137 (387)<br />
Kapoor R. ix242 (729P)<br />
Kapp D.S. ix460 (1416PD)<br />
Kapp K. ix340 (1038P)<br />
Kaprin A. ix267 (809P)<br />
Karaüç G. ix394 (1207P)<br />
Karachaliou N. ix531 (1655P), ix229 (686P)<br />
Karadurmus N. ix286 (866P)<br />
Karam N. ix416 (1270P)<br />
Karameris A. ix541 (1691P)<br />
Karamouzis M.V. ix458 (1407)<br />
Karaoz E. ix110 (300)<br />
Karapetis C.S. ix503 (1558P), ix178 (519O)<br />
Karasmanis I. ix338 (1030P)<br />
ix338 (1031P)<br />
Karavasilis V. ix430 (1312), ix239 (717P)<br />
Karayannopoulou G. ix337 (1026P)<br />
Kargar-Samani K. ix341 (1042P)<br />
Karimi Shahri M. ix184 (538P)<br />
Karina M. ix519 (1613P)<br />
Karsan A. ix412 (1255P)<br />
Karsh L. ix309 (937P)<br />
Kase M. ix146 (418PD), ix149 (431)<br />
Kase S. ix146 (418PD), ix149 (431)<br />
ix562 | author index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology author index<br />
Kasem I. ix72 (164)<br />
Kashiwagi N. ix197 (576P)<br />
Kashiwagi S. ix84 (205P)<br />
Kasparu H. ix348 (1064O)<br />
Kassem N.M. ix355 (1088P)<br />
Kastrissios H. ix244 (738P)<br />
Katakami N. ix413 (1260P), ix422 (1286P),<br />
ix423 (1289P), ix437 (1338), ix511 (1586P),<br />
ix91 (232)<br />
Katalinic D. ix86 (212P)<br />
Katano M. ix542 (1694P), ix79 (188P)<br />
Kataoka M. ix514 (1595P)<br />
Kataoka T. ix510 (1581P)<br />
Katayama N. ix509 (1578P)<br />
Katayose Y. ix211 (624)<br />
Kato B. ix225 (671P)<br />
Kato G. ix321 (974PD)<br />
Kato H. ix527 (1705)<br />
Kato K. ix529 (1649P), ix89 (224P), ix202 (593P),<br />
ix251 (764)<br />
Kato M. ix79 (188P)<br />
Kato T. ix436 (1334), ix196 (573P), ix202 (592P),<br />
ix217 (646)<br />
Katsumata K. ix188 (552P)<br />
Katsumata N. ix320 (973PD)<br />
Katsuya H. ix348 (1062O), ix508 (1576P)<br />
Katz A. ix112 (306)<br />
Kaufman B. ix116 (317O)<br />
Kavan P. ix200 (586P)<br />
Kawabata R. ix227 (677P)<br />
Kawachi Y. ix228 (682P)<br />
Kawada K. ix518 (1610P), ix526 (1643),<br />
ix527 (1705)<br />
Kawada S. ix197 (575P)<br />
Kawaguchi T. ix439 (1344)<br />
Kawahara M. ix439 (1344)<br />
Kawai H. ix231 (689P)<br />
Kawai Y. ix497 (1538P)<br />
Kawajiri H. ix84 (205P)<br />
Kawakami H. ix167 (486P)<br />
Kawakami S. ix438 (1340)<br />
Kawano J. ix133 (373P)<br />
Kawasaki K. ix144 (412O)<br />
Kawasaki M. ix463 (1426P)<br />
Kawazoe S. ix244 (737P)<br />
Kaya S. ix110 (300)<br />
Kaya T. ix220 (654)<br />
Kayal S. ix354 (1085P)<br />
Kaye S.B. ix162 (469P), ix40 (55IN), ix319 (966O),<br />
ix320 (972PD)<br />
Kayser J. ix186 (548P)<br />
Kazakin J. ix245 (739P)<br />
Kazancioglu R. ix473 (1461)<br />
Kazmi S.A. ix497 (1539P)<br />
Ke C. ix115 (316TiP)<br />
Keam B. ix465 (1433P)<br />
Kebdani T. ix328 (999P)<br />
Keefe D. ix64 (130IN)<br />
Kefeli U. ix497 (1540)<br />
Keil F. ix340 (1038P), ix523 (1628), ix249 (755)<br />
Keilholz U. ix336 (1023PD)<br />
Kell M. ix469 (1449PD)<br />
Keller U. ix342 (1044P)<br />
Kelly C.M. ix525 (1635), ix74 (172O)<br />
Kelly P.J. ix207 (610P)<br />
Kelly Z. ix68 (147P), ix325 (988P)<br />
Kelm J. ix543 (1695P)<br />
Kemal Y. ix221 (660)<br />
Keni M. ix519 (1613P)<br />
Kenmotsu H. ix430 (1310P)<br />
Kennecke H. ix188 (551P), ix204 (601P),<br />
ix215 (635)<br />
Kennedy D.A. ix348 (1063O), ix353 (1083P)<br />
Kennedy M.J. ix469 (1449PD), ix108 (292P),<br />
ix176 (516P)<br />
Kentepozidis N. ix435 (1329), ix436 (1335),<br />
ix139 (395)<br />
Keohan M.L. ix489 (1514)<br />
Kerboua E. ix344 (1051)<br />
Kerbrat P. ix105 (281P)<br />
Kern J. ix76 (178P)<br />
Kern N. ix467 (1442)<br />
Kernstine K. ix49 (77IN)<br />
Kerr D.J. ix181 (530PD), ix184 (540P)<br />
Kerr K. ix80 (193P), ix86 (213P)<br />
Kerr K.M. ix417 (1272P), ix73 (167O)<br />
Kertmen N. ix104 (278P)<br />
Keskin O. ix543 (1698P), ix104 (278P)<br />
Ketchens C. ix261 (790O)<br />
Keyser R. ix283 (856P)<br />
Khabra K. ix273 (827P)<br />
Khairi H. ix332 (1013)<br />
Khaled H.M. ix288 (874)<br />
Khalil J. ix260 (789O)<br />
Khalifa R.H. ix355 (1088P)<br />
Khan A. ix537 (1677P)<br />
Khanin R. ix89 (223P)<br />
Khater L. ix339 (1032P)<br />
Khattak M.A. ix273 (827P)<br />
Khattry N. ix350 (1069PD), ix351 (1074P)<br />
Khays S. ix197 (577P)<br />
Kheoh T. ix294 (894O), ix295 (895O)<br />
Khoja L.T. ix87 (219P), ix90 (227P)<br />
Khouchani M. ix476 (1471P)<br />
Khranovska N. ix536 (1672P)<br />
Khudayorov S. ix229 (684P), ix254 (772)<br />
Kichenadasse G. ix503 (1558P)<br />
Kida Y. ix225 (671P)<br />
Kiemle-Kallee J. ix390 (1194P)<br />
Kiermaier A. ix83 (202P)<br />
Kiesewetter B. ix352 (1076P)<br />
Kiessling R. ix541 (1690P)<br />
Kieszkowska-Grudny A. ix457 (1406),<br />
ix475 (1466P)<br />
Kiet T.K. ix460 (1416PD)<br />
Kigawa J. ix326 (989P)<br />
Kii T. ix232 (692P)<br />
Kijima T. ix411 (1253P)<br />
Kilickap S. ix220 (654)<br />
Kilmartin L. ix68 (150P)<br />
Kim B.S. ix352 (1077P), ix227 (679P)<br />
Kim C. ix287 (872), ix308 (934P)<br />
Kim C.H. ix414 (1262P), ix72 (166)<br />
Kim C.H.S. ix204 (600P), ix249 (753)<br />
Kim D-W. ix152 (438O)<br />
Kim D. ix401 (1228O), ix402 (1230PD),<br />
ix416 (1268P), ix465 (1433P), ix483 (1493P),<br />
ix153 (440O), ix283 (855P)<br />
Kim D.E. ix467 (1441), ix468 (1446)<br />
Kim D.S. ix352 (1077P)<br />
Kim D.W. ix415 (1267P)<br />
Kim G. ix222 (662TiP)<br />
Kim H-K. ix400 (1225O)<br />
Kim H. ix352 (1077P), ix353 (1080P), ix89 (225P)<br />
Kim H.J. ix172 (503), ix227 (679P)<br />
Kim H.S. ix193 (566P)<br />
Kim I. ix352 (1077P)<br />
Kim J. ix454 (1392P), ix541 (1688PD),<br />
ix283 (855P)<br />
Kim J.E. ix108 (291P)<br />
Kim J.G. ix208 (613P)<br />
Kim J.H. ix193 (566P), ix250 (757)<br />
Kim J.S. ix454 (1394P)<br />
Kim K-P. ix108 (291P)<br />
Kim K. ix366 (1126P), ix454 (1392P),<br />
ix479 (1479PD), ix492 (1520PD)<br />
Kim K.S. ix135 (382)<br />
Kim M. ix424 (1292P)<br />
Kim M.H. ix127 (353P)<br />
Kim N.K. ix185 (543P)<br />
Kim S-B. ix108 (291P)<br />
Kim S. ix349 (1065O), ix375 (1153),<br />
ix424 (1292P), ix450 (1381P), ix450 (1381P),<br />
ix541 (1688PD), ix249 (752), ix262 (793PD),<br />
ix268 (811P)<br />
Kim S.H. ix185 (543P)<br />
Kim S-W. ix400 (1225O), ix152 (438O),<br />
ix186 (545P)<br />
Kim S.Y. ix479 (1479PD)<br />
Kim T. ix465 (1433P)<br />
Kim T.I. ix185 (543P)<br />
Kim T.M. ix271 (820P), ix283 (855P)<br />
Kim T.W. ix479 (1479PD)<br />
Kim W. ix492 (1520PD)<br />
Kim Y. ix492 (1520PD), ix283 (855P)<br />
Kim Y.A. ix512 (1589P)<br />
Kim Y.H. ix442 (1356)<br />
Kim Y.S. ix375 (1153), ix430 (1311P)<br />
Kimura T. ix412 (1258P), ix434 (1325),<br />
ix79 (189P), ix79 (190P), ix92 (235)<br />
Kimura Y. ix227 (677P)<br />
Kindler H.L. ix493 (1522PD)<br />
Kindler M. ix505 (1567P)<br />
Kindyanova L.V. ix141 (403)<br />
King B. ix87 (217P)<br />
Kinoshita F. ix197 (576P)<br />
Kinoshita H. ix467 (1443)<br />
Kinoshita I. ix443 (1358)<br />
Kinugasa Y. ix200 (588P)<br />
Kira Y. ix79 (189P), ix92 (235)<br />
Kirches E. ix147 (420PD)<br />
Kirchhoff T. ix363 (1113PD)<br />
Kirchner T. ix180 (526PD)<br />
Kireeva L. ix134 (379)<br />
Kishi K. ix429 (1306P), ix433 (1323), ix442 (1354)<br />
Kishimoto J. ix438 (1340)<br />
Kitagawa C. ix517 (1608P)<br />
Kitagawa R. ix327 (995P)<br />
Kitayama J. ix233 (698P)<br />
Kiura K. ix397 (1218), ix434 (1327), ix153 (441O)<br />
Kiyohara Y. ix426 (1298P)<br />
Kiyota N. ix510 (1581P)<br />
Kizaki J. ix248 (751)<br />
Kjaer A. ix47 (74IN)<br />
Kjaer S.K. ix22 (3IN)<br />
Klaase J. ix96 (251PD)<br />
Klech J. ix253 (768)<br />
Kleeberg U.R. ix457 (1403), ix518 (1612P)<br />
Kleha J.F. ix153 (442O)<br />
Klein Gunnewiek J. ix111 (301)<br />
Kleinberg L. ix148 (428P)<br />
Kleinerman E. ix488 (1508P)<br />
Klement T. ix100 (261P)<br />
Klersy C. ix355 (1089P)<br />
Klevesath M.B. ix154 (444PD)<br />
Klimczak A. ix484 (1495P)<br />
Klimenko V.V. ix139 (397)<br />
Klingelschmitt G. ix417 (1271P)<br />
Kloecker G. ix76 (177PD), ix87 (217P)<br />
Kloth J.S.L. ix538 (1678P)<br />
Klughammer B. ix400 (1226O), ix411 (1254P),<br />
ix417 (1271P)<br />
Klumpen H.J. ix538 (1678P)<br />
Knackmuss S. ix350 (1072P)<br />
Knecht H. ix350 (1071P)<br />
Kneeshaw P. ix106 (283P)<br />
Knoblauch P. ix349 (1068PD)<br />
Knopf K. ix203 (597P)<br />
Knudsen S. ix349 (1068PD)<br />
Koçar M. ix186 (547P)<br />
Ko Y.H. ix490 (1516), ix250 (757)<br />
Kobayashi A. ix210 (621)<br />
Kobayashi D. ix200 (585P)<br />
Kobayashi K. ix404 (1234PD), ix412 (1256P),<br />
ix413 (1259P), ix420 (1280P)<br />
Kobayashi M. ix228 (681P)<br />
Kobayashi O. ix509 (1579P)<br />
Kobayashi S. ix518 (1611P)<br />
Kobayashi T. ix518 (1611P), ix344 (1706P)<br />
Kocak I. ix307 (933P)<br />
Kocik M. ix513 (1593P)<br />
Kockelbergh R. ix292 (887)<br />
Kocsis J. ix493 (1523P)<br />
Koczwara B. ix503 (1558P)<br />
Volume 23 | Supplement 9 | June <strong>2012</strong> doi:10.1093/annonc/mds466 | ix563
author index<br />
Kodaira M. ix90 (228P), ix164 (474P)<br />
Kodaira S. ix188 (552P)<br />
Kodera Y. ix542 (1693P), ix220 (655), ix246 (742P)<br />
Kodytkova J. ix513 (1593P)<br />
Koeberle D. ix462 (1423O)<br />
Koeck S. ix543 (1695P)<br />
Koenen R. ix162 (468P)<br />
Koepl L. ix203 (596P)<br />
Kogure Y. ix517 (1608P)<br />
Koh T.S. ix70 (155P)<br />
Koh Y. ix383 (1175P)<br />
Köhler J. ix437 (1339)<br />
Köhne C. ix191 (561P)<br />
Koizumi F. ix383 (1175P), ix90 (228P)<br />
Koizumi W. ix231 (689P)<br />
Kojima E. ix434 (1325), ix445 (1366TiP)<br />
Kojima M. ix210 (621)<br />
Kojima T. ix497 (1538P), ix89 (224P)<br />
Kojima Y. ix69 (153P)<br />
Kokudo N. ix211 (625)<br />
Kolaitis G. ix103 (273P)<br />
Kolarevic D. ix544 (1702)<br />
Kollia G. ix361 (1109O), ix405 (1237PD),<br />
ix258 (784O)<br />
Kollmannsberger C.K. ix163 (471P)<br />
Kollmeier J. ix409 (1247P)<br />
Komatsu Y. ix512 (1590P), ix201 (590P),<br />
ix202 (592P)<br />
Kommoss F. ix322 (976P)<br />
Komori T. ix510 (1581P)<br />
Komuta K. ix411 (1253P)<br />
Kondo C. ix433 (1324), ix232 (692P)<br />
Kondo H. ix71 (161P)<br />
Kondo K. ix188 (552P)<br />
Kondo M. ix445 (1366TiP)<br />
Kondo N. ix139 (396)<br />
Kondratova T. ix134 (379)<br />
Koner S. ix355 (1090P), ix359 (1105),<br />
ix471 (1453P), ix471 (1454P), ix471 (1455P)<br />
Kong A. ix116 (318O)<br />
Kong S. ix353 (1080P)<br />
Kong W. ix260 (788O)<br />
Kongruttanachok N. ix350 (1071P)<br />
Kongsted P. ix444 (1361)<br />
Konja J. ix359 (1104)<br />
König D. ix132 (370P)<br />
Königsberg R. ix100 (261P)<br />
Kono T. ix514 (1595P)<br />
Konopasek B. ix81 (197P)<br />
Kontopodis E. ix435 (1329), ix436 (1335),<br />
ix139 (395)<br />
Koo D.H. ix234 (700P)<br />
Koo J.S. ix127 (353P)<br />
Koo S.L. ix412 (1257P), ix485 (1501P),<br />
ix182 (533P)<br />
Kooiman G. ix275 (831P)<br />
Koopman M. ix179 (521O)<br />
Kopetz S. ix220 (656)<br />
Kopf B. ix285 (863P)<br />
Kopic A. ix136 (385)<br />
Kopp M.V. ix398 (1223), ix521 (1623),<br />
ix97 (254PD)<br />
Korach J. ix322 (978P)<br />
Korbenfeld E. ix270 (817P), ix279 (844P)<br />
Korkmaz T. ix497 (1540), ix217 (645)<br />
Korkolopoulou P. ix92 (236)<br />
Korn C. ix261 (790O), ix314 (952)<br />
Kornek G.V. ix340 (1038P), ix253 (768)<br />
Koroleva I.A. ix398 (1223), ix521 (1623)<br />
Korotkova O.V. ix371 (1138P)<br />
Korse T. ix392 (1203P)<br />
Korytowsky B. ix269 (815P)<br />
Kosaka S. ix442 (1356)<br />
Koscielny S. ix168 (491P)<br />
Kosela H.M. ix484 (1495P), ix489 (1513)<br />
Koshio J. ix71 (159P)<br />
Kosmas C. ix493 (1524P)<br />
Kosmider S. ix220 (656)<br />
Kosmidis P. ix430 (1312), ix85 (211P)<br />
Kostakis I. ix541 (1691P)<br />
Kostopoulos I. ix338 (1030P)<br />
Kosty M.P. ix420 (1279P)<br />
Kota I. ix422 (1285P)<br />
Kotecki N. ix113 (309)<br />
Kotek A. ix526 (1642)<br />
Kotelnikov A. ix197 (577P)<br />
Kothbauer K.F. ix148 (427P)<br />
Kotlyarov E.V. ix470 (1451P)<br />
Kotoula V. ix338 (1030P), ix338 (1031P),<br />
ix430 (1312)<br />
Kotsakis A. ix431 (1314), ix435 (1329),<br />
ix436 (1335)<br />
Kouakam C. ix113 (309)<br />
Koufuji K. ix248 (751)<br />
Koulouridi A. ix429 (1308P)<br />
Kousparou C. ix160 (463P)<br />
Koutoulaki A. ix431 (1314)<br />
Koutras A. ix95 (246O)<br />
Kovac V. ix446 (1368TiP)<br />
Kovalenko N. ix103 (273P)<br />
Kovel S. ix313 (950)<br />
Kowalski D. ix410 (1250P)<br />
Kowalski J. ix281 (848P)<br />
Koyama A. ix210 (621)<br />
Koyama S. ix527 (1705)<br />
Kozłowski W. ix268 (812P), ix323 (979P)<br />
Kozlov S.V. ix398 (1223)<br />
Kozuki T. ix434 (1327)<br />
Krüger C. ix228 (680P)<br />
Kraemer S. ix378 (1160P)<br />
Krainer M. ix539 (1685P)<br />
Krakowski I. ix501 (1554P), ix294 (893O)<br />
Kramar A. ix101 (266P)<br />
Kranewitter W. ix209 (616)<br />
Kratzke R. ix74 (170O)<br />
Krebs M. ix199 (582P)<br />
Kreipe H. ix394 (1208)<br />
Krekeler G. ix359 (1107TiP), ix274 (828P)<br />
Kriegshäuser G. ix373 (1145)<br />
Krieken V.H. ix184 (540P)<br />
Krikelis D. ix337 (1026P)<br />
Kris M. ix401 (1228O)<br />
Kristeleit R. ix161 (464P)<br />
Krivorotko P.V. ix139 (397)<br />
Kroening H. ix178 (518O)<br />
Kroez M. ix453 (1389P), ix466 (1437P)<br />
Kruse V. ix287 (870)<br />
Kruzel T. ix353 (1082P)<br />
Krzakowski M.J. ix409 (1247P)<br />
Krzyzanowska M.K. ix464 (1432P)<br />
Ktiouet M. ix511 (1584P), ix278 (841P),<br />
ix289 (876)<br />
Kuan S. ix156 (449PD)<br />
Kube U. ix278 (841P), ix288 (875)<br />
ix288 (875)<br />
Kubicka S. ix193 (565P), ix195 (571P)<br />
Kubisa B. ix386 (1182P)<br />
Kuboki Y. ix87 (218P)<br />
Kubota K. ix396 (1215), ix397 (1218),<br />
ix404 (1234PD)<br />
Kucuk O. ix342 (1043P)<br />
Kucukoner M. ix332 (1015), ix137 (387)<br />
Kudaba I. ix124 (344P)<br />
Kudo K. ix418 (1274P), ix441 (1353)<br />
Kudo M. ix381 (1171P), ix202 (592P),<br />
ix225 (670PD), ix243 (732P), ix244 (737P)<br />
Kudoh S. ix393 (1204P), ix404 (1234PD),<br />
ix412 (1258P), ix79 (189P), ix79 (190P),<br />
ix92 (235)<br />
Kudoh T. ix167 (486P)<br />
Kudryavtsev V. ix70 (156P)<br />
Kueppers F. ix309 (937P)<br />
Kühn T. ix117 (321PD)<br />
Kuhn A. ix505 (1567P)<br />
Kuhr K. ix504 (1561P)<br />
Kührer I. ix253 (768)<br />
Annals of Oncology<br />
Kuisma A.K. ix384 (1178TiP)<br />
Kumada H. ix244 (737P)<br />
Kumagai S. ix69 (153P)<br />
Kumaki N. ix112 (305)<br />
Kumanogoh A. ix411 (1253P)<br />
Kumar A. ix188 (551P)<br />
Kumar C. ix174 (510TiP)<br />
Kumar D. ix339 (1034P)<br />
Kumar L. ix349 (1067PD), ix358 (1101),<br />
ix264 (800P)<br />
Kumar R. ix354 (1085P), ix358 (1101),<br />
ix503 (1558P)<br />
Kumar S. ix339 (1034P), ix358 (1100),<br />
ix374 (1149), ix497 (1539P), ix285 (860P)<br />
Kümmel S. ix117 (321PD)<br />
Kunimasa K. ix434 (1327)<br />
Kunitoh H. ix429 (1306P)<br />
Kunz G. ix97 (254PD)<br />
Kuo S. ix351 (1075P)<br />
Kuo Y. ix107 (286P)<br />
Kuom S. ix494 (1529P)<br />
Kurata T. ix167 (486P)<br />
Kurbatova K.A. ix141 (403)<br />
Kuriyama N. ix391 (1198P), ix154 (443PD)<br />
Kurkjian C. ix498 (1543TiP)<br />
Kuroi K. ix104 (277P)<br />
Kurokawa Y. ix481 (1485PD), ix227 (677P)<br />
Küronya Z. ix281 (849P), ix286 (867P)<br />
Kurt E. ix291 (885)<br />
Kurt H. ix312 (947)<br />
Kurt M. ix291 (885)<br />
Kurtz J.E. ix378 (1160P)<br />
Kurzrock R. ix153 (442O), ix154 (444PD),<br />
ix168 (489P)<br />
Kushihara H. ix518 (1610P), ix526 (1643),<br />
ix527 (1705)<br />
Kushihara T. ix518 (1610P), ix526 (1643)<br />
Kuss I. ix478 (1478O)<br />
Kusumoto M. ix469 (1447PD)<br />
Kusunoki Y. ix197 (576P)<br />
Kut E. ix221 (660)<br />
Kutarska E. ix329 (1001P)<br />
Kutyreva J.G. ix398 (1223)<br />
Kuwabara S. ix228 (682P)<br />
Kvist A. ix90 (227P)<br />
Kwon H. ix249 (752)<br />
Kwon J.H. ix466 (1439)<br />
Kwon S.Y. ix414 (1262P)<br />
L<br />
La Verde N.M. ix511 (1585P)<br />
Laack E. ix404 (1235PD)<br />
Labbe-Devilliers C. ix62 (121IN)<br />
Labianca R. ix365 (1120P), ix515 (1599P)<br />
Labiano T. ix365 (1123P), ix432 (1316)<br />
Lacas B. ix389 (1192PD)<br />
Lacau Saint Guily J. ix340 (1036P)<br />
Lacave R. ix340 (1036P)<br />
Lachaine J. ix350 (1070PD), ix119 (328PD)<br />
Lackey J. ix317 (963TiP)<br />
Ladarre N. ix488 (1511P)<br />
Ladrera G.E.I. ix400 (1226O)<br />
Lafayette R. ix171 (499P)<br />
Lafitte J. ix408 (1243P)<br />
Laforest A. ix234 (703P)<br />
Lagerwaard F.J. ix62 (123IN)<br />
Lagha N. ix344 (1051)<br />
Lagoudaki E. ix381 (1170P), ix429 (1308P)<br />
Laguerre B. ix294 (893O)<br />
Lai Y. ix515 (1600P)<br />
Lainez N. ix277 (839P)<br />
Lake J. ix451 (1382P)<br />
Lakis S. ix430 (1312)<br />
Lakkis Z. ix204 (600P), ix249 (753)<br />
Lakomy R. ix198 (581P), ix223 (665TiP)<br />
Lakshmaiah K.C. ix358 (1102)<br />
Laktionov P.P. ix109 (293P)<br />
Lalla D. ix120 (329P), ix122 (338P)<br />
ix564 | author index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology author index<br />
Lam D. ix537 (1675P)<br />
Lam D.C. ix383 (1176P)<br />
Lamar M. ix245 (739P)<br />
Lambertini M. ix454 (1393P), ix501 (1551PD),<br />
ix521 (1621)<br />
Lambertz H. ix204 (599P)<br />
Lambiase A. ix410 (1251P), ix167 (487P),<br />
ix167 (488P), ix172 (502)<br />
Lambin P. ix392 (1201P), ix396 (1213),<br />
ix396 (1216), ix425 (1296P), ix212 (626)<br />
Lammering G. ix212 (626)<br />
Lamparska-Przybysz M. ix544 (1700)<br />
Lampron M.E. ix278 (840P)<br />
Lamy A. ix213 (629)<br />
Lamy R. ix391 (1199P)<br />
Lancashire M. ix87 (219P)<br />
Landi B. ix482 (1489P)<br />
Landi L. ix423 (1288P), ix77 (181P), ix183 (535P)<br />
Landsman-Blumberg P. ix267 (810P)<br />
ix269 (816P)<br />
Landucci E. ix176 (515P)<br />
Lanfiuti Baldi P. ix524 (1633)<br />
Láng I. ix191 (561P)<br />
Lang I. ix116 (317O), ix224 (668PD)<br />
Lang P. ix337 (1025P)<br />
Lange O. ix505 (1567P)<br />
Lankes H. ix81 (198P)<br />
Lankheet N.A.G. ix538 (1678P)<br />
Lannert H. ix317 (965TiP)<br />
Lannoy V. ix197 (578P)<br />
Lanoy E. ix421 (1284P), ix110 (297P)<br />
Lanza G. ix179 (522PD)<br />
Lanzalone S. ix402 (1230PD)<br />
Lanzetta G. ix458 (1407)<br />
Lao-Sirieix S. ix378 (1161P)<br />
Laperriere N. ix144 (410O)<br />
Lapierre M. ix350 (1070PD), ix119 (328PD)<br />
Lapinska-Szumczyk S. ix320 (970PD)<br />
Lapolla A.M. ix95 (248O)<br />
Laporta R. ix459 (1410)<br />
Laquente B. ix529 (1648P)<br />
Lara F. ix107 (289P), ix126 (349P)<br />
Lara P.C. ix266 (805P)<br />
Laramas M. ix488 (1511P)<br />
Larkin J. ix366 (1124P), ix374 (1149),<br />
ix269 (814P), ix271 (821P), ix273 (827P),<br />
ix279 (843P)<br />
Larocca L.M. ix433 (1322)<br />
Larson S. ix294 (894O)<br />
Lasan Trcic R. ix359 (1104)<br />
Laskar S. ix351 (1074P)<br />
Laskin J. ix412 (1255P), ix419 (1278P)<br />
Lastoria S. ix193 (567P)<br />
Lata S. ix261 (792PD)<br />
Lathia C. ix407 (1241P)<br />
Latipova D.H. ix139 (397)<br />
Latko E. ix511 (1587P)<br />
Latorzeff I. ix294 (893O)<br />
Lattanzio L. ix528 (1644PD)<br />
Laubender R. ix487 (1505P), ix180 (526PD),<br />
ix188 (554P), ix204 (599P)<br />
Laurent-Puig P. ix77 (180P), ix85 (210P),<br />
ix180 (525PD), ix234 (703P)<br />
Laurent D. ix478 (1478O)<br />
Laurent M. ix452 (1387P)<br />
Lavinski Y. ix480 (1483PD), ix166 (482P)<br />
Lavole A. ix397 (1219)<br />
Lavoué V. ix105 (281P)<br />
Law C. ix377 (1158P), ix380 (1167P), ix490 (1516)<br />
Lawrence D. ix368 (1129P), ix202 (594P)<br />
Lawrence D.P. ix361 (1109O)<br />
Lazarev A. ix197 (577P)<br />
Lazarev I. ix373 (1147)<br />
Lazarev S. ix197 (577P)<br />
Lázaro A. ix520 (1619)<br />
Lazaro M. ix395 (1212), ix273 (826P)<br />
Lazzarelli S. ix232 (693P)<br />
Lazzeroni M. ix83 (201P)<br />
Le Cesne A. ix478 (1478O), ix482 (1488P),<br />
ix482 (1489P), ix236 (708P)<br />
Le Frère Belda M. ix99 (258P)<br />
Le Maignan C. ix128 (355P)<br />
Le Moulec S. ix406 (1240P), ix426 (1299P),<br />
ix477 (1476), ix150 (433), ix277 (837P),<br />
ix313 (951)<br />
Le Moulec S. ix285 (862P)<br />
Le Pechoux C. ix397 (1217), ix421 (1284P),<br />
ix486 (1502P)<br />
Le Pimpec-Bar<strong>the</strong>s F. ix77 (180P)<br />
Le Poulain-Doubliez M. ix455 (1396P)<br />
Le Rhun E. ix62 (121IN)<br />
Le Teuff G. ix496 (1534P), ix74 (170O), ix94 (244)<br />
Le Thuaut A. ix452 (1387P)<br />
Le Tourneau C. ix334 (1017O), ix519 (1614P)<br />
León L. ix275 (832P), ix277 (839P)<br />
Le I.P. ix244 (735P)<br />
Leahy, T. ix148 (428P)<br />
Leahy M. ix478 (1478O)<br />
Lebbe C. ix363 (1116PD)<br />
Lebmeier M. ix370 (1134P)<br />
Leboreiro Enriquez B. ix92 (234)<br />
Lebret T. ix474 (1463P), ix511 (1584P)<br />
Lebreton J. ix460 (1419PD)<br />
Lebrun F. ix121 (334P)<br />
Lecesne A. ix486 (1502P)<br />
Lechuga M. ix297 (901PD)<br />
Lecleire S. ix252 (767)<br />
Lecomte T. ix85 (209P), ix237 (710P)<br />
Lécuru F. ix99 (258P), ix323 (980P)<br />
Ledermann J.A. ix324 (982P)<br />
Lee C. ix182 (532P)<br />
Lee C.K. ix414 (1263P)<br />
Lee D. ix370 (1134P), ix372 (1143P)<br />
Lee D.H. ix400 (1225O), ix424 (1292P),<br />
ix287 (872)<br />
Lee D.K. ix240 (722P)<br />
Lee H-J. ix108 (291P)<br />
Lee H. ix353 (1080P)<br />
Lee H.J. ix541 (1688PD)<br />
Lee J. ix345 (1052), ix375 (1153), ix450 (1381P),<br />
ix479 (1479PD), ix479 (1479PD), ix250 (757),<br />
ix276 (834P), ix287 (872)<br />
Lee J.D. ix72 (166)<br />
Lee J.J. ix480 (1481PD)<br />
Lee J.K. ix465 (1433P), ix465 (1434P)<br />
Lee J.S. ix400 (1225O), ix400 (1226O)<br />
Lee K.H. ix193 (566P)<br />
Lee K.S. ix541 (1688PD)<br />
Lee K.Y. ix185 (543P)<br />
Lee L. ix199 (583P)<br />
Lee M. ix179 (523PD)<br />
Lee M.A. ix186 (545P), ix209 (617)<br />
Lee P. ix160 (461P)<br />
Lee S. ix332 (1012), ix352 (1077P), ix421 (1282P),<br />
ix465 (1433P), ix127 (353P), ix253 (771),<br />
ix271 (820P), ix283 (855P)<br />
Lee S.J. ix375 (1153), ix430 (1311P),<br />
ix450 (1381P), ix208 (613P), ix240 (722P)<br />
Lee S.R. ix352 (1077P)<br />
Lee V. ix393 (1205P)<br />
Lee Y. ix515 (1600P)<br />
Lee Y.J. ix208 (613P)<br />
Lefebvre-Kuntz D. ix488 (1510P)<br />
Lefesvre P. ix197 (578P)<br />
Lefeuvre-Plesse C. ix105 (281P)<br />
Lefeuvre D. ix110 (297P)<br />
Lefevre M. ix340 (1036P)<br />
Legrier M. ix312 (946)<br />
Lehle M. ix162 (470P)<br />
Lehr H. ix61 (117IN)<br />
Lei L. ix495 (1530P)<br />
Leibetseder A. ix147 (421P)<br />
Leighl N.B. ix493 (1525P)<br />
Leis A. ix182 (531P)<br />
Leitão A. ix458 (1409)<br />
Leitgeb C. ix348 (1064O)<br />
Lemare F. ix456 (1400P)<br />
Lemke M. ix490 (1516)<br />
Lencioni M. ix238 (714P), ix251 (761), ix251 (762)<br />
Lencioni R. ix225 (670PD)<br />
Lennon O. ix513 (1592P)<br />
Lenze D. ix390 (1195P)<br />
Leo F. ix463 (1427P)<br />
Leo S. ix229 (685P)<br />
Leon A. ix187 (549P), ix233 (699P)<br />
Leon L. ix419 (1277P), ix419 (1278P),<br />
ix420 (1279P)<br />
Leonard E.J. ix303 (921P)<br />
Leonard G. ix248 (750)<br />
Leonard J. ix68 (150P)<br />
Leonardi M.C. ix83 (201P)<br />
Leone F. ix205 (605P)<br />
Leong S. ix157 (452P)<br />
Leonhartsberger N. ix270 (817P), ix279 (844P)<br />
Lepère C. ix378 (1159P)<br />
Lepage B. ix388 (1190P)<br />
Lepage C. ix178 (520O)<br />
Lepretre S. ix522 (1624)<br />
Lerer I. ix109 (294P)<br />
Leridant A.M. ix340 (1037P)<br />
Leschke M. ix494 (1529P)<br />
Leseur J. ix105 (281P)<br />
Lester J. ix498 (1542TiP)<br />
Lesterhuis W.J. ix363 (1114PD)<br />
Leu Y. ix345 (1052)<br />
Leung R. ix244 (736P)<br />
Levaggi A. ix454 (1393P), ix501 (1551PD),<br />
ix521 (1621)<br />
Levchenko E. ix361 (1110O), ix386 (1182P)<br />
Levesque E. ix316 (960)<br />
Levi F. ix194 (568P)<br />
Levidou G. ix92 (236)<br />
Levitt D. ix480 (1483PD)<br />
Levva S. ix338 (1030P), ix430 (1312)<br />
Levy-Lahad E. ix34 (34IN)<br />
Levy A. ix277 (837P)<br />
Levy C. ix519 (1614P), ix128 (355P)<br />
Lewanski C. ix421 (1282P)<br />
Lewis I.J. ix490 (1518TiP)<br />
Lewis K. ix362 (1112PD), ix363 (1115PD)<br />
Lewis R. ix292 (887)<br />
Leyden J.C. ix380 (1166P)<br />
Leyvraz S. ix480 (1482PD)<br />
Lhomel C. ix470 (1452P), ix472 (1460)<br />
Lhomme C. ix322 (977P)<br />
Lhommel R. ix336 (1021PD)<br />
Lhoumeau A. ix184 (539P)<br />
Lièvre A. ix85 (210P)<br />
Li C. ix538 (1679P), ix162 (470P), ix247 (746P),<br />
ix299 (906P)<br />
Li D. ix390 (1196P), ix256 (780TiP)<br />
Li G. ix260 (788O)<br />
Li H. ix453 (1390P), ix245 (741P)<br />
Li J. ix394 (1209), ix435 (1331), ix97 (254PD),<br />
ix111 (302), ix202 (595P), ix216 (640),<br />
ix217 (646), ix294 (894O)<br />
Li N. ix77 (182P)<br />
Li N.F. ix171 (499P)<br />
Li P. ix180 (524PD)<br />
Li Q. ix343 (1048P), ix140 (401)<br />
Li R. ix413 (1261P), ix454 (1395P)<br />
Li S. ix295 (895O)<br />
Li W. ix216 (640), ix217 (643), ix218 (647)<br />
Li X. ix67 (144PD), ix81 (195P), ix93 (238),<br />
ix117 (320PD), ix173 (507), ix227 (676P)<br />
Li Y. ix179 (522PD)<br />
Li Z. ix337 (1027P), ix416 (1269P), ix416 (1269P),<br />
ix443 (1359), ix219 (650)<br />
Liao G. ix77 (182P)<br />
Liao W. ix515 (1600P)<br />
Liao Y. ix515 (1600P)<br />
Libener R. ix247 (747P)<br />
Libertini M. ix485 (1500P)<br />
Lichinitser M. ix224 (668PD)<br />
Volume 23 | Supplement 9 | June <strong>2012</strong> doi:10.1093/annonc/mds466 | ix565
author index<br />
Lichtensztejn D. ix350 (1071P)<br />
Lichtensztejn Z. ix350 (1071P)<br />
Licitra L. ix334 (1018O), ix335 (1019O),<br />
ix336 (1022PD), ix341 (1040P), ix342 (1045P),<br />
ix344 (1050P)<br />
Licour M. ix416 (1270P)<br />
Liebaert F. ix180 (525PD)<br />
Liede A. ix298 (902P)<br />
Liefers G. ix100 (263P)<br />
Liew M.S. ix493 (1525P), ix542 (1692P)<br />
Lifrange E. ix96 (251PD)<br />
Ligier K. ix241 (725P)<br />
Liguigli W. ix232 (693P)<br />
Lilja H. ix89 (223P)<br />
Lim F.L. ix290 (880)<br />
Lim H. ix188 (551P), ix204 (601P), ix215 (635)<br />
Lim J.Y. ix240 (722P)<br />
Lim S. ix253 (771)<br />
Lim S.H. ix70 (157P), ix100 (262P)<br />
Lim W-T. ix393 (1205P)<br />
Lim W.T. ix412 (1257P)<br />
Lima Santos C. ix464 (1429P)<br />
Lima C.S.P. ix364 (1119P), ix365 (1121P),<br />
ix365 (1122P), ix133 (374P)<br />
Lima R.C.A.D. ix331 (1009)<br />
Limetti V. ix516 (1603P)<br />
Lin C. ix349 (1066PD), ix351 (1075P)<br />
Lin D. ix311 (942P)<br />
Lin F. ix398 (1220), ix119 (326PD)<br />
Lin H. ix342 (1043P)<br />
Lin J. ix302 (918P)<br />
Lin J.C. ix25 (11IN)<br />
Lin K. ix236 (709P)<br />
Lin L. ix69 (152P)<br />
Lin P. ix349 (1066PD)<br />
Lin S. ix425 (1295P)<br />
Lin W. ix157 (452P)<br />
Lin X. ix259 (785O)<br />
Lin Y. ix219 (650), ix247 (746P), ix253 (769),<br />
ix261 (791PD), ix275 (833P)<br />
Linardou H. ix373 (1146), ix85 (211P), ix94 (242)<br />
Lindner L. ix487 (1505P)<br />
Linhares P. ix147 (423P)<br />
Linkesch W. ix348 (1064O), ix352 (1076P)<br />
Lipman P. ix158 (456P)<br />
Lipton L. ix255 (776TiP)<br />
Liskova S. ix293 ( )<br />
Liskovsky G. ix316 (961)<br />
Lissia A. ix364 (1118PD)<br />
Little M. ix350 (1072P)<br />
Liu B. ix229 (686P)<br />
Liu C. ix345 (1052), ix355 (1087P)<br />
Liu G. ix78 (186P), ix153 (440O), ix302 (918P),<br />
ix303 (920P)<br />
Liu H.E. ix428 (1305P)<br />
Liu J. ix355 (1087P), ix453 (1390P), ix226 (674P),<br />
ix321 (974PD)<br />
Liu L. ix141 (405TiP)<br />
Liu M. ix343 (1048P)<br />
Liu S.V. ix306 (928P)<br />
Liu T. ix231 (690P)<br />
Liu W. ix346 (1057), ix443 (1359), ix77 (182P),<br />
ix300 (911P)<br />
Liu X. ix402 (1230PD)<br />
Liu Y. ix390 (1196P), ix435 (1331), ix437 (1337),<br />
ix488 (1508P), ix490 (1518TiP), ix515 (1600P),<br />
ix93 (238), ix138 (394), ix202 (595P),<br />
ix231 (690P), ix247 (745P), ix261 (791PD),<br />
ix275 (833P)<br />
Liuu E. ix452 (1387P)<br />
Livingstone A. ix151 (437TiP)<br />
Ljungberg B. ix281 (848P)<br />
Lkhoyaali S. ix476 (1470P)<br />
Lkoyaali S. ix476 (1472P)<br />
Llacer C. ix101 (268P)<br />
Llanos M. ix351 (1073P)<br />
Llombart A. ix82 (200P), ix114 (315TiP)<br />
Llorca C. ix125 (345P)<br />
Llorente R.M. ix125 (345P)<br />
Lloyd A.J. ix476 (1473P), ix296 (898PD)<br />
Lluch-Hernandez A. ix96 (249PD)<br />
Lo Nigro C. ix528 (1644PD), ix532 (1660P),<br />
ix73 (169O)<br />
Lo Re G. ix280 (846P), ix287 (868)<br />
Lo A. ix345 (1052)<br />
Lo G. ix463 (1426P)<br />
Lobo F. ix457 (1404), ix80 (194P)<br />
Locati L. ix335 (1019O), ix341 (1040P),<br />
ix342 (1045P), ix344 (1050P)<br />
Locher C. ix416 (1270P), ix446 (1367TiP),<br />
ix455 (1396P)<br />
Loembé A.B. ix245 (740P)<br />
Loewy J. ix263 (796PD)<br />
Logo<strong>the</strong>tis C.J. ix295 (895O)<br />
Loh E. ix230 (687P)<br />
Lohneis P. ix390 (1195P)<br />
Loi S. ix59 (108IN)<br />
Loibl S. ix117 (321PD), ix118 (323PD)<br />
Lolkema M.P. ix153 (442O)<br />
Lollini P. ix537 (1675P)<br />
Lomas-Garrido M. ix101 (268P)<br />
Lombard-Bohas C. ix85 (209P)<br />
Lombardi G. ix144 (411O)<br />
Lombardo L. ix145 (416PD)<br />
Lonardi S. ix209 (618)<br />
Longo F. ix377 (1157O), ix507 (1571P)<br />
Loos A.H. ix395 (1210)<br />
Lopatin M. ix179 (523PD)<br />
Lopes C. ix132 (371P)<br />
Lopez Ben S. ix219 (651)<br />
López Juarez E. ix264 (799P)<br />
Lopez Lopez M.C. ix264 (799P)<br />
López Martí M.P. ix264 (799P)<br />
López Mata M. ix510 (1582P)<br />
Lopez Martin J.A. ix374 (1151)<br />
Lopez Pedrera C. ix530 (1652P)<br />
Lopez Picazo J.M. ix508 (1577P)<br />
Lopez Pousa A. ix408 (1244P), ix235 (705P)<br />
López Calderero I. ix510 (1582P), ix166 (484P),<br />
ix183 (534P)<br />
Lopez-Crapez E. ix84 (206P)<br />
López-González A. ix492 (1521PD)<br />
Lopez-Picazo J.M. ix336 (1022PD)<br />
Lopez-Pousa A. ix490 (1517TiP)<br />
Lopez-Rios F. ix233 (699P)<br />
Lopez-Vega J.M. ix82 (200P), ix142 (408TiP)<br />
Lopez-Vivanco G. ix212 (627)<br />
López-Tarruella S. ix176 (517P)<br />
López-Trabada D. ix176 (517P)<br />
López C. ix529 (1648P)<br />
Lopez A. ix277 (839P)<br />
Lopez G. ix379 (1164P)<br />
Lopez R. ix328 (1000P)<br />
Lopez R.I. ix102 (271P)<br />
Lora D. ix134 (378)<br />
Lorch A. ix284 (858P)<br />
Lordick F. ix514 (1596P), ix539 (1683P)<br />
Lorente D. ix106 (284P)<br />
Lorenzetti I.T. ix99 (260P)<br />
Lorenzi E. ix167 (488P)<br />
Loretelli C. ix431 (1313), ix86 (214P), ix86 (215P),<br />
ix239 (720P), ix243 (734P), ix274 (829P)<br />
Lorigan P. ix87 (219P), ix90 (227P)<br />
Loriot Y. ix277 (837P), ix304 (924P), ix313 (951)<br />
Lortholary A. ix511 (1584P), ix125 (346P)<br />
Lorusso D. ix330 (1004P), ix458 (1408)<br />
LoRusso P.M. ix362 (1111PD), ix158 (456P),<br />
ix170 (497P), ix173 (507)<br />
Lorusso V. ix276 (836P)<br />
Lorvidhaya V. ix339 (1035P)<br />
Losanno T. ix105 (282P), ix111 (303)<br />
Losonczy G. ix429 (1307P)<br />
Lotz J.-P. ix260 (789O)<br />
Lotz J. ix502 (1556P)<br />
Lou C. ix69 (152P), ix495 (1530P)<br />
Lou H. ix256 (780TiP)<br />
Annals of Oncology<br />
Lou Y. ix413 (1261P), ix454 (1395P)<br />
Lourenço G.J. ix364 (1119P), ix365 (1121P),<br />
ix365 (1122P), ix133 (374P)<br />
Lourenco G.J. ix339 (1032P)<br />
Louveau A. ix258 (783O)<br />
Lovati E. ix520 (1618)<br />
Love S. ix181 (530PD)<br />
Löser H. ix481 (1486PD)<br />
Lowy I. ix301 (915P)<br />
Lozano J.J. ix300 (910P)<br />
Lozano M.D. ix365 (1123P), ix432 (1316)<br />
Luís A. ix175 (512PD), ix176 (514P)<br />
Lu H. ix495 (1530P)<br />
Lu J. ix110 (299)<br />
Lu K.H. ix438 (1341)<br />
Lu S. ix385 (1179O), ix438 (1341), ix174 (509TiP)<br />
Lu Y. ix172 (501), ix247 (745P)<br />
Lu Z. ix189 (556P)<br />
Lub-De Hooge M.N. ix40 (57IN)<br />
Lubel J. ix56 (96IN)<br />
Lucassen G. ix532 (1658P)<br />
Lucchesi M. ix238 (714P), ix251 (761), ix251 (762)<br />
Lucchesi S. ix94 (243)<br />
Lucchini E. ix117 (322PD), ix240 (721P)<br />
Lucey D.J. ix207 (610P)<br />
Lucisano G. ix365 (1120P)<br />
Ludovini V. ix387 (1185P), ix427 (1302P),<br />
ix535 (1668P), ix183 (535P)<br />
Ludwig H. ix348 (1064O), ix502 (1555P)<br />
Lueck H. ix322 (976P)<br />
Lueftner D. ix449 (1377P)<br />
Luelmo S. ix256 (781TiP)<br />
Lueza B. ix397 (1217)<br />
Lugatti E. ix457 (1405)<br />
Lui L. ix302 (917P)<br />
Lum B.L. ix162 (470P)<br />
Lumachi F. ix287 (868)<br />
Lumbroso L. ix519 (1614P)<br />
Lundstam S. ix281 (848P)<br />
Lung M.S. ix526 (1640)<br />
Lungershausen J. ix402 (1229PD)<br />
Luo Y. ix437 (1337), ix93 (238)<br />
Luporsi E. ix504 (1563P), ix506 (1568P),<br />
ix506 (1569P)<br />
Luppi G. ix231 (691P)<br />
Lutiger B. ix267 (809P)<br />
Lutke Holzik M. ix96 (251PD)<br />
Lutman R. ix487 (1506P)<br />
Lwin Z. ix144 (410O)<br />
Lycke M. ix341 (1042P)<br />
Lyman G.H. ix447 (1369P)<br />
Lymperatou D.V. ix136 (384)<br />
Lynch T.J. ix420 (1279P)<br />
M<br />
Ma F. ix140 (401)<br />
Ma J. ix453 (1390P), ix270 (817P)<br />
Ma L. ix390 (1196P), ix111 (302)<br />
Ma M. ix363 (1113PD)<br />
Ma W.W. ix155 (447PD)<br />
Ma X. ix389 (1192PD)<br />
Maass N. ix124 (342P)<br />
Macías A. ix406 (1238PD)<br />
Maccaroni E. ix219 (652)<br />
Macciò A. ix462 (1422O), ix466 (1438P)<br />
Maccio’ A. ix463 (1427P)<br />
Macdonald K. ix502 (1555P)<br />
Macedo D. ix289 (878)<br />
Macedo T. ix357 (1097)<br />
Machado D. ix141 (404)<br />
Machado M. ix201 (591P), ix210 (620),<br />
ix221 (657), ix222 (661)<br />
Machado P. ix175 (512PD), ix176 (514P)<br />
Machalova A.S. ix521 (1623)<br />
Machida N. ix201 (590P)<br />
Machiels J. ix157 (454P), ix307 (933P)<br />
Machiels J.P. ix336 (1021PD), ix342 (1044P),<br />
ix42 (58IN), ix259 (786O)<br />
ix566 | author index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology author index<br />
Maci E. ix433 (1322)<br />
Mack P. ix49 (77IN)<br />
Mackay J. ix470 (1451P)<br />
Mackillop W.J. ix260 (788O)<br />
Macpherson I. ix119 (325PD)<br />
Madan R. ix223 (664TiP)<br />
Maddison C. ix526 (1640)<br />
Madeddu C. ix462 (1422O), ix463 (1427P),<br />
ix466 (1438P), ix164 (476P)<br />
Madero R. ix181 (527PD)<br />
Madhumathi D.S. ix358 (1102)<br />
Madhuri K. ix68 (147P)<br />
Madoz J. ix80 (194P), ix183 (537P)<br />
Madroszyk A. ix391 (1199P), ix406 (1240P),<br />
ix150 (434)<br />
Maeda A. ix541 (1690P)<br />
Maeda Y. ix381 (1171P), ix164 (474P),<br />
ix240 (723P)<br />
Maemondo M. ix412 (1256P), ix413 (1259P),<br />
ix413 (1260P), ix420 (1280P), ix427 (1301P),<br />
ix443 (1358), ix153 (441O)<br />
Maeng C.H. ix375 (1153)<br />
Maeng C.H. ix430 (1311P)<br />
Maetens M. ix98 (255PD)<br />
Maffi M. ix528 (1644PD)<br />
Mafodda A. ix505 (1565P), ix137 (388)<br />
Maglakelidze M. ix460 (1414TiP)<br />
Magnani T. ix315 (959)<br />
Magnoni P. ix487 (1506P)<br />
Magnusson A. ix236 (709P)<br />
Magremanne M. ix336 (1021PD)<br />
Magri V. ix440 (1348)<br />
Magrini S.M. ix338 (1029P)<br />
Mahalingam D. ix168 (489P)<br />
Mahfoudi A. ix476 (1471P)<br />
Mahmood A. ix449 (1377P), ix174 (510TiP)<br />
Mahner S. ix322 (976P)<br />
Maho S. ix442 (1354)<br />
Mahon G. ix186 (548P), ix209 (615)<br />
Mai S. ix350 (1071P)<br />
Maier G. ix298 (903P)<br />
Maier S. ix75 (175PD)<br />
Maillard E. ix181 (529PD)<br />
Maillet D. ix299 (907P)<br />
Mailliez A. ix106 (285P), ix113 (309)<br />
Maimon O. ix109 (294P)<br />
Maines F. ix273 (825P)<br />
Maingon P. ix206 (607P)<br />
Mainwaring P.N. ix295 (895O)<br />
Maio M. ix363 (1116PD), ix364 (1117PD),<br />
ix367 (1127P), ix368 (1130P), ix369 (1133P),<br />
ix373 (1148)<br />
Mair S. ix508 (1575P)<br />
Maira M. ix537 (1675P)<br />
Maisano R. ix505 (1565P), ix137 (388)<br />
Maitland-Vd Zee A. ix122 (335P)<br />
Majem Tarruella M. ix408 (1244P),<br />
ix414 (1264P)<br />
Majem M. ix533 (1661P), ix533 (1662P)<br />
Majumder R. ix328 (997P)<br />
Mak M.P. ix455 (1397P)<br />
Makar A.P. ix330 (1007), ix325 (987P)<br />
Maki R. ix478 (1478O)<br />
Maki R.G. ix489 (1514), ix54 (93IN)<br />
Makino M. ix509 (1579P)<br />
Maksymiuk A. ix395 (1210)<br />
Makuuchi M. ix211 (625)<br />
Makuuchi Y. ix89 (224P)<br />
Malassé S. ix409 (1247P)<br />
Malatesta S. ix385 (1179O)<br />
Maldonado-Martinez H. ix107 (289P)<br />
Maldonado X. ix302 (916P)<br />
Malejczyk J. ix320 (971PD)<br />
Malet J. ix265 (802P)<br />
Malfer<strong>the</strong>iner P. ix255 (778TiP)<br />
Malheiro Sarmento T. ix222 (661)<br />
Malhotra H. ix301 (912P)<br />
Malik Z.I. ix306 (931P)<br />
Malka D. ix511 (1587P), ix175 (511PD),<br />
ix198 (580P), ix237 (710P), ix238 (716P)<br />
Mallath M.K. ix350 (1069PD), ix541 (1689P)<br />
Malli T. ix209 (616)<br />
Maloisel F. ix522 (1624)<br />
Malorni L. ix27 (13IN)<br />
Malovini A. ix535 (1669P)<br />
Maltzman J.D. ix493 (1522PD)<br />
Malvehy J. ix343 (1046P)<br />
Mammucari M. ix463 (1425P)<br />
Mamontov K. ix197 (577P)<br />
Manceau G. ix180 (525PD)<br />
Mancini J. ix482 (1489P)<br />
Mancini M. ix330 (1004P)<br />
Mandala M. ix365 (1120P), ix369 (1131P),<br />
ix369 (1133P)<br />
Mandigers C.M. ix501 (1553P)<br />
Mandolesi A. ix86 (214P), ix86 (215P),<br />
ix239 (720P), ix243 (734P), ix250 (756)<br />
Mandrekar S.J. ix535 (1670P)<br />
Mane A.D. ix101 (265P)<br />
Manegold C. ix529 (1647PD)<br />
Manera S. ix535 (1669P)<br />
Mangat R. ix162 (470P)<br />
Mangia A. ix331 (1010)<br />
Maniadakis N. ix447 (1372P)<br />
Maniar T. ix115 (316TiP)<br />
Manihkas A. ix103 (272P)<br />
Manikhas A. ix114 (315TiP)<br />
Maniwa Y. ix92 (233)<br />
Manji A. ix158 (455P)<br />
Mann Hong T. ix485 (1499P), ix485 (1501P)<br />
Manna G. ix105 (282P), ix111 (303)<br />
Manneh R.A. ix134 (378), ix325 (986P)<br />
Mannel R. ix81 (198P)<br />
Mano M.S. ix455 (1397P), ix112 (306),<br />
ix125 (347P)<br />
Manoharan P. ix207 (609P)<br />
Mansi J.L. ix139 (398)<br />
Mansi L. ix332 (1014), ix128 (357P)<br />
Mansmann U. ix180 (526PD)<br />
Manso L. ix96 (251PD), ix125 (345P), ix134 (378),<br />
ix325 (986P)<br />
Manso R. ix183 (537P)<br />
Manson S. ix483 (1493P), ix488 (1511P)<br />
Mansoor W. ix381 (1168P)<br />
Mansour M. ix138 (392)<br />
Mansourbakht T. ix511 (1587P)<br />
Mansouri K. ix124 (342P)<br />
Mansueto G. ix507 (1571P)<br />
Mansutti M. ix531 (1657P)<br />
Mantion G. ix206 (607P)<br />
Mantovani G. ix462 (1422O), ix463 (1427P),<br />
ix466 (1438P), ix516 (1604P), ix164 (476P)<br />
Manzano A. ix438 (1342)<br />
Manzano J.L. ix380 (1165P), ix529 (1648P)<br />
Manzo A. ix430 (1309P)<br />
Mao C. ix256 (779TiP)<br />
Mao W. ix495 (1530P), ix226 (674P)<br />
Marín-Aguilera M. ix538 (1680P), ix300 (910P)<br />
Marais R. ix46 (69IN)<br />
Marasà S. ix215 (636)<br />
Marcenaro S. ix80 (192P)<br />
Marchal F. ix482 (1489P)<br />
Marchesi L. ix365 (1120P)<br />
Marcheteau E. ix75 (174O)<br />
Marchetti A. ix423 (1288P), ix73 (167O),<br />
ix78 (183P)<br />
Marchetti S. ix32 (29IN)<br />
Marciano R. ix530 (1651P), ix532 (1659P)<br />
Marconcini R. ix368 (1130P), ix369 (1132P),<br />
ix290 (881)<br />
Mardiak J. ix270 (817P), ix279 (844P),<br />
ix286 (865P), ix293 (890TiP)<br />
Mare M. ix505 (1565P), ix137 (388)<br />
Marechal R. ix194 (569P)<br />
Marelli L. ix452 (1385P)<br />
Mareschal S. ix339 (1033P)<br />
Margaret Sheehan M. ix248 (750)<br />
Margery J. ix496 (1534P), ix94 (244)<br />
Marhold M. ix539 (1685P)<br />
Mariani G. ix124 (342P)<br />
Mariani L. ix88 (222P), ix212 (628)<br />
Mariani P. ix102 (269P)<br />
Mariano C. ix412 (1255P)<br />
Marino A. ix95 (248O)<br />
Marino D. ix205 (605P)<br />
Marino M. ix540 (1687)<br />
Marinsek N. ix122 (336P)<br />
Mariz J. ix357 (1095)<br />
Markou K. ix338 (1030P), ix338 (1031P)<br />
Markovich A. ix382 (1172)<br />
Marlow S. ix126 (350P)<br />
Marmé F. ix163 (472P), ix172 (504)<br />
Marmissolle F. ix379 (1164P)<br />
Marmol E. ix388 (1189P)<br />
Marone U. ix375 (1152)<br />
Marosi C. ix145 (415PD), ix147 (421P),<br />
ix148 (426P)<br />
Maroto J.P. ix264 (798PD)<br />
Maroto P. ix266 (806P), ix275 (832P),<br />
ix277 (839P), ix292 (888)<br />
Maroun C. ix163 (471P), ix169 (492P),<br />
ix169 (493P)<br />
Maroun J.A. ix187 (550P), ix205 (602P)<br />
Marples M. ix483 (1492P)<br />
Márquez-Rodas I. ix176 (517P)<br />
Marques A. ix78 (184P)<br />
Marques A.D. ix357 (1097)<br />
Marques D.S. ix201 (591P), ix210 (620),<br />
ix221 (657)<br />
Marques H. ix357 (1097)<br />
Marques M.T. ix345 (1056)<br />
Marques R.J. ix112 (306)<br />
Marques T. ix141 (404)<br />
Marquez R. ix140 (400)<br />
Marreaud S. ix483 (1493P)<br />
Marrero J. ix225 (670PD)<br />
Marrocolo F. ix315 (958)<br />
Marrodan I. ix212 (627)<br />
Marroni P. ix80 (192P)<br />
Marschner N. ix459 (1413TiP)<br />
Marschon R. ix209 (616)<br />
Marsh B. ix525 (1635)<br />
Marshall E. ix374 (1149), ix421 (1282P)<br />
Marshall M. ix215 (638)<br />
Martín-Richard M. ix183 (536P), ix185 (544P),<br />
ix216 (641)<br />
Martín P. ix149 (429P), ix305 (927P)<br />
Martínez-Monge R. ix291 (886)<br />
Martínez-Villacampa M. ix529 (1648P)<br />
Martarello L. ix70 (155P)<br />
Martel-Lafay I. ix391 (1199P)<br />
Martella F. ix528 (1646PD)<br />
Mar<strong>the</strong>y L. ix238 (716P)<br />
Marti Ciriquian J.L. ix510 (1582P)<br />
Marti Marti F.E. ix207 (609P)<br />
Martignoni G. ix287 (869)<br />
Martin Algarra S. ix365 (1123P), ix374 (1150),<br />
ix432 (1316), ix508 (1577P)<br />
ix239 (718P)<br />
Martin Broto J. ix490 (1517TiP)<br />
Martin Lorente C. ix266 (806P)<br />
Martin Martorell P. ix458 (1407)<br />
Martin-Valades J.I. ix187 (549P)<br />
Martin A.L. ix203 (597P)<br />
Martin C. ix496 (1535P)<br />
Martin F. ix455 (1396P)<br />
Martin J.P. ix475 (1467P)<br />
Martin M. ix115 (316TiP), ix118 (323PD)<br />
Martinelli E. ix430 (1309P), ix67 (143PD),<br />
ix75 (173O)<br />
Martinez Del Prado P. ix82 (200P)<br />
Martinez Lago N. ix328 (1000P)<br />
Martinez-Galan J. ix254 (773)<br />
Martinez-Trufero J. ix490 (1517TiP)<br />
Volume 23 | Supplement 9 | June <strong>2012</strong> doi:10.1093/annonc/mds466 | ix567
author index<br />
Martinez A. ix496 (1533P)<br />
Martinez L.H. ix457 (1404)<br />
Martinez P. ix496 (1533P)<br />
Martini G. ix430 (1309P)<br />
Martini J. ix262 (794PD)<br />
Martini M. ix433 (1322)<br />
Martinius H. ix163 (472P)<br />
Martins A.M. ix458 (1409)<br />
Martins D.F. ix127 (352P)<br />
Martins I.S. ix524 (1632)<br />
Martins R. ix401 (1228O)<br />
Martoni A.A. ix466 (1436P), ix130 (362P),<br />
ix205 (605P)<br />
Martorell M. ix73 (167O), ix80 (193P)<br />
Marucci G. ix147 (424P)<br />
Maruelli A. ix516 (1601P), ix516 (1602P),<br />
ix520 (1617), ix524 (1631)<br />
Marumoto T. ix536 (1671P)<br />
Marzin K. ix155 (446PD)<br />
Masaki M. ix508 (1576P)<br />
Mascaux C. ix408 (1243P)<br />
Maschio M. ix202 (594P)<br />
Masi G. ix85 (208P)<br />
Masini C. ix270 (818P), ix290 (879)<br />
Mason M. ix307 (932P)<br />
Mason W. ix144 (410O)<br />
Maspero F. ix435 (1328), ix467 (1440),<br />
ix519 (1615P), ix131 (368P), ix192 (563P)<br />
Massa E. ix516 (1604P)<br />
Massacesi C. ix537 (1675P)<br />
Massard C. ix474 (1463P), ix496 (1534P),<br />
ix94 (244), ix155 (446PD), ix277 (837P),<br />
ix285 (862P), ix304 (924P), ix313 (951)<br />
Massari A. ix105 (280P)<br />
Massari F. ix117 (322PD), ix240 (721P),<br />
ix273 (825P), ix276 (836P), ix287 (869)<br />
Massey D. ix410 (1252P), ix424 (1292P)<br />
Massi D. ix364 (1118PD)<br />
Massopust K. ix261 (790O)<br />
Massuti Sureda B. ix531 (1655P), ix533 (1661P)<br />
Mastico R. ix498 (1543TiP)<br />
Mastromauro C. ix466 (1436P)<br />
Masuda M. ix383 (1174P), ix536 (1673P),<br />
ix536 (1674P)<br />
Masuda N. ix104 (277P), ix124 (344P)<br />
Masuda S. ix112 (305)<br />
Matache C. ix67 (146P)<br />
Matano E. ix540 (1687)<br />
Matas Ochoa A. ix198 (579P)<br />
Matczak E. ix269 (815P)<br />
Mateescu C. ix379 (1163P)<br />
Matejka V.M. ix474 (1464P)<br />
Mateo J. ix159 (458P), ix162 (469P)<br />
Ma<strong>the</strong>ny S. ix294 (894O)<br />
Mathias S.D. ix477 (1474)<br />
Mathieu M. ix84 (206P), ix110 (297P)<br />
Mathijssen R.H.J. ix456 (1402P), ix534 (1667P),<br />
ix538 (1678P), ix109 (295P)<br />
Mathis G. ix84 (206P)<br />
Mathurin P. ix255 (777TiP)<br />
Matos E. ix112 (308), ix132 (371P)<br />
Matoušková O. ix81 (196P)<br />
Matsko D.E. ix139 (397)<br />
Matsubara N. ix131 (366P)<br />
Matsubara Y. ix197 (576P)<br />
Matsuda C. ix514 (1595P)<br />
Matsuguma H. ix388 (1188P)<br />
Matsui S. ix91 (232)<br />
Matsuki A. ix234 (702P)<br />
Matsumoto H. ix250 (758)<br />
Matsumoto S. ix515 (1598P)<br />
Matsumoto Y. ix467 (1443)<br />
Matsumura Y. ix247 (746P)<br />
Matsuo K. ix232 (694P)<br />
Matsuoka J. ix74 (172O)<br />
Matsuoka M. ix196 (573P)<br />
Matsusaka S. ix87 (218P)<br />
Matsusaki K. ix463 (1428P)<br />
Matsuura K. ix412 (1258P), ix79 (189P),<br />
ix79 (190P), ix92 (235)<br />
Matsuura N. ix227 (677P)<br />
Matta-Castro T. ix215 (637)<br />
Mat<strong>the</strong>s B. ix466 (1437P)<br />
Mat<strong>the</strong>s H. ix453 (1389P), ix466 (1437P)<br />
Matulonis U. ix321 (974PD)<br />
Matveev V. ix267 (809P)<br />
Matzkowitz A.J. ix130 (363P)<br />
Maughan B. ix260 (787O)<br />
Maughan T.S. ix179 (521O)<br />
Mauguen A. ix397 (1217)<br />
Maur M. ix373 (1148)<br />
Maurea N. ix539 (1682P)<br />
Maurel J. ix67 (145P), ix490 (1517TiP),<br />
ix181 (527PD)<br />
Mauri D. ix458 (1407)<br />
Mauri S. ix462 (1423O)<br />
Maurina T. ix204 (600P)<br />
Maute L. ix288 (875)<br />
Mavroudis D. ix381 (1170P), ix431 (1314),<br />
ix435 (1329), ix139 (395)<br />
Mawrin C. ix147 (420PD)<br />
Maximiano C. ix459 (1410), ix492 (1521PD),<br />
ix494 (1527P), ix112 (307)<br />
May C. ix264 (798PD)<br />
Mayer A. ix175 (512PD)<br />
Mayer F. ix178 (518O)<br />
Mayordomo J. ix374 (1151)<br />
Mazdai G. ix346 (1059)<br />
Mazières J. ix417 (1271P)<br />
Mazieres J. ix388 (1190P), ix403 (1232PD),<br />
ix406 (1240P), ix426 (1299P)<br />
Mazouni C. ix110 (297P)<br />
Mazur G. ix503 (1560P)<br />
Mazzanti C. ix94 (243)<br />
Mazzanti P. ix387 (1184P), ix533 (1663P)<br />
Mazzara C. ix229 (685P)<br />
Mazzini G. ix529 (1650P)<br />
Mazzoni F. ix528 (1646PD)<br />
Mc Keegan E.M. ix83 (203P), ix173 (505)<br />
McCaffrey J.A. ix469 (1449PD), ix525 (1635)<br />
McCall B. ix171 (499P), ix195 (571P)<br />
McCann L. ix261 (792PD)<br />
McCarthy M.T. ix71 (160P)<br />
McCook J. ix166 (482P)<br />
McCourt M. ix207 (610P)<br />
McCroskery P. ix222 (662TiP)<br />
McDermott D.F. ix361 (1109O), ix368 (1129P),<br />
ix157 (453P), ix258 (784O)<br />
McDermott R. ix248 (750), ix300 (909P)<br />
McDonagh C. ix170 (496P)<br />
McDonnell F. ix300 (909P)<br />
McDunn S. ix470 (1450P)<br />
McGrane J. ix215 (638)<br />
McHenry M.B. ix363 (1116PD)<br />
McHugh E. ix513 (1592P)<br />
McIntosh A. ix70 (157P)<br />
McKee K. ix391 (1198P)<br />
McKee M.D. ix83 (203P), ix173 (505)<br />
McKendrick J. ix198 (581P)<br />
McKenna E. ix362 (1111PD)<br />
McLennan B. ix165 (479P)<br />
McManus P. ix106 (283P)<br />
McNally V. ix83 (202P), ix124 (344P)<br />
McNamara M. ix144 (410O)<br />
McNicholas N. ix176 (516P)<br />
McPartlin A.J. ix284 (859P)<br />
McQuillan R. ix468 (1444)<br />
Mdemba E. ix543 (1697P)<br />
Mead G. ix283 (857P)<br />
Mebis J. ix452 (1386P)<br />
Medeiros R. ix78 (184P)<br />
Medhat F. ix337 (1028P)<br />
Median D. ix67 (146P)<br />
Medina J. ix374 (1151)<br />
Annals of Oncology<br />
Medina M. ix186 (546P)<br />
Medioni J. ix499 (1545O), ix99 (258P),<br />
ix280 (845P), ix282 (852P), ix319 (966O)<br />
Meeus P. ix478 (1477O), ix482 (1488P)<br />
Mego M. ix286 (865P), ix293 (890TiP)<br />
Mehmud F. ix261 (792PD)<br />
Mehra R. ix153 (440O)<br />
Mehta J. ix213 (632), ix323 (981P)<br />
Mehta K. ix118 (323PD)<br />
Mehta M.P. ix148 (428P)<br />
Mehta S.A. ix541 (1689P)<br />
Meier W. ix323 (980P)<br />
Meireles S.R. ix525 (1639), ix147 (423P)<br />
Meister M. ix390 (1194P)<br />
Mekki F. ix344 (1051)<br />
Mel J.R. ix440 (1349)<br />
Meldgaard P. ix385 (1179O)<br />
Melhouf A. ix137 (389)<br />
Melichar B. ix329 (1001P), ix97 (254PD),<br />
ix116 (317O), ix160 (461P), ix258 (783O),<br />
ix267 (809P)<br />
Melisi D. ix117 (322PD)<br />
Mellado B. ix538 (1680P), ix266 (805P),<br />
ix282 (853P), ix300 (910P)<br />
Mellas N. ix137 (389)<br />
Mellemgaard A. ix444 (1361)<br />
Mellor S. ix492 (1521PD)<br />
Melnikova V. ix300 (911P)<br />
Melnychuk D. ix200 (586P)<br />
Melo A. ix331 (1010)<br />
Melosky B. ix412 (1255P)<br />
Melotti F. ix212 (628)<br />
Mencoboni M. ix80 (192P)<br />
Méndez García M. ix459 (1410), ix492 (1521PD),<br />
ix112 (307)<br />
Méndez-Vidal M.J. ix275 (832P)<br />
Mendez G. ix379 (1164P)<br />
Mendez P. ix266 (807P)<br />
Mendiola C. ix134 (378), ix322 (978P),<br />
ix325 (986P)<br />
Mendoza I. ix406 (1238PD)<br />
Meng R. ix159 (458P)<br />
Menichetti F. ix56 (97IN)<br />
Menis J. ix444 (1360), ix457 (1405)<br />
Menon H. ix350 (1069PD), ix351 (1074P)<br />
Menu Y. ix60 (112IN)<br />
Menzel A. ix209 (615)<br />
Meoni G. ix528 (1646PD)<br />
Merad M. ix503 (1559P), ix517 (1607P)<br />
Meran J. ix521 (1622)<br />
Mercadante S. ix518 (1612P)<br />
Mercier-Blas A. ix128 (355P)<br />
Mercier M. ix475 (1468P), ix109 (296P),<br />
ix120 (331P)<br />
Mercuro G. ix164 (476P)<br />
Merelli B. ix365 (1120P)<br />
Mergenthaler H. ix284 (858P)<br />
Merkelbach-Bruse S. ix481 (1486PD)<br />
Merlano M. ix528 (1644PD), ix113 (311),<br />
ix123 (340P)<br />
Merlin J. ix85 (210P)<br />
Merlini G. ix355 (1089P)<br />
Merlini L. ix523 (1628)<br />
Merlo F. ix79 (187P)<br />
Mesbah H. ix105 (281P)<br />
Mescallado N. ix319 (969PD)<br />
Mescoli C. ix209 (618)<br />
Mesker W. ix184 (540P)<br />
Mesnard N. ix128 (355P)<br />
Messa F. ix528 (1644PD)<br />
Messaritakis I. ix213 (631)<br />
Messersmith W.A. ix155 (447PD)<br />
Messina A. ix484 (1496P)<br />
Messina C. ix270 (818P)<br />
Messina M. ix215 (636)<br />
Messinger D. ix116 (317O)<br />
Mestek O. ix513 (1593P)<br />
ix568 | author index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology author index<br />
Meszko E. ix457 (1406)<br />
Metges J. ix456 (1401P), ix196 (572P)<br />
Metro G. ix423 (1288P), ix427 (1302P)<br />
Metwally H.M. ix98 (256P)<br />
Metzer C. ix377 (1156O)<br />
Metzger B. ix186 (548P), ix209 (615)<br />
Metzner B. ix284 (858P)<br />
Meyboom R. ix122 (335P)<br />
Meyer A. ix409 (1249P)<br />
Meyer T. ix378 (1161P), ix245 (740P)<br />
Meyers J. ix535 (1670P)<br />
Meyers M. ix295 (895O)<br />
Meyers P. ix488 (1508P)<br />
Meynier J. ix464 (1430P)<br />
Mezi S. ix488 (1509P)<br />
Mezlini A. ix254 (774)<br />
Mezzetti M. ix496 (1536P)<br />
M-H T. ix258 (783O)<br />
Miccinesi G. ix516 (1601P), ix516 (1602P),<br />
ix520 (1617), ix524 (1631)<br />
Michael A. ix68 (147P), ix325 (988P)<br />
Michaelson M.D. ix259 (785O), ix269 (814P),<br />
ix297 (901PD)<br />
Michalarea V. ix139 (398)<br />
Michallet M. ix504 (1563P), ix506 (1568P),<br />
ix506 (1569P)<br />
Michel P. ix242 (730P), ix252 (767)<br />
Michelazzi L.A. ix80 (192P)<br />
Michiara M. ix175 (513PD)<br />
Michie C.O. ix162 (469P)<br />
Michielin O. ix366 (1125P)<br />
Michoux N. ix336 (1021PD)<br />
Mickisch G. ix267 (809P)<br />
Miclea J.M. ix260 (789O)<br />
Middel P. ix417 (1271P)<br />
Middeldorp J.M. ix88 (221P)<br />
Middleton G. ix224 (667PD)<br />
Midena E. ix371 (1140P)<br />
Midgley R.S. ix181 (530PD)<br />
Mielgo X. ix113 (310)<br />
Migden M.R. ix362 (1112PD)<br />
Migliorati C.A. ix56 (95IN)<br />
Migliorino M.R. ix439 (1346)<br />
Mihali D. ix511 (1585P)<br />
Mihaylov G. ix503 (1560P)<br />
Mikhaylova I.N. ix371 (1138P)<br />
Mikulski S. ix70 (155P)<br />
Milano G. ix528 (1644PD)<br />
Milch C. ix168 (489P)<br />
Milella M. ix237 (713P), ix240 (721P),<br />
ix273 (825P), ix280 (846P), ix290 (879)<br />
Miles D. ix59 (110IN), ix120 (329P),<br />
ix142 (409TiP)<br />
Miles D.R. ix154 (445PD)<br />
Milewski L. ix320 (971PD)<br />
Milia J. ix388 (1190P), ix403 (1232PD)<br />
Milićević M. ix237 (712P)<br />
Milione M. ix212 (628)<br />
Millar B. ix144 (410O)<br />
Miller K. ix295 (896O), ix317 (965TiP)<br />
Miller R. ix244 (738P)<br />
Miller V. ix401 (1227O)<br />
Milleron B. ix419 (1276P)<br />
Mills G.B. ix96 (249PD)<br />
Millward C. ix179 (523PD)<br />
Milner R. ix90 (227P)<br />
Milovanovic Z. ix544 (1702)<br />
Mimae T. ix385 (1180PD)<br />
Min D. ix119 (326PD)<br />
Min Y.H. ix240 (722P)<br />
Minajeva A. ix146 (418PD), ix149 (431)<br />
Minami H. ix510 (1581P)<br />
Minami M. ix161 (465P)<br />
Minato K. ix511 (1586P)<br />
Minear F.G. ix215 (638)<br />
Minegishi Y. ix412 (1256P)<br />
Mineta T. ix527 (1705)<br />
Mini E. ix178 (520O)<br />
Minichsdorfer C. ix72 (165)<br />
Mink J. ix146 (417PD)<br />
Mino E.A. ix470 (1450P)<br />
Minor D.R. ix371 (1137P)<br />
Minotti V. ix427 (1302P)<br />
Minvielle E. ix456 (1400P)<br />
Miolo G. ix287 (868)<br />
Mir O. ix91 (229P), ix167 (485P)<br />
Mir R. ix139 (398)<br />
Mirabelli D. ix247 (747P)<br />
Mirabile A. ix335 (1019O)<br />
Miraglio E. ix528 (1644PD), ix113 (311)<br />
Miron M.L.L. ix183 (534P)<br />
Mishima H. ix514 (1595P), ix93 (237)<br />
Mishima M. ix442 (1356)<br />
Miskovska’ V. ix286 (865P), ix293 (890TiP)<br />
Misra V. ix207 (609P)<br />
Misumi K. ix385 (1180PD)<br />
Mita A.C. ix422 (1287P), ix498 (1543TiP)<br />
Mitchell C.L. ix464 (1431P)<br />
Mitchell L. ix366 (1124P), ix366 (1125P),<br />
ix142 (407TiP), ix142 (408TiP), ix142 (409TiP),<br />
ix189 (555P)<br />
Mitchell P. ix542 (1692P)<br />
Mitry E. ix378 (1159P), ix378 (1160P),<br />
ix85 (209P), ix181 (529PD), ix219 (649),<br />
ix234 (703P)<br />
Mitsudomi T. ix433 (1324), ix51 (81IN)<br />
Mitsukawa Y. ix412 (1258P)<br />
Mitsuoka S. ix412 (1258P), ix79 (190P), ix92 (235)<br />
Mittermüller J. ix504 (1561P)<br />
Mittica G. ix140 (402)<br />
Miura E. ix517 (1606P)<br />
Miura K. ix211 (624)<br />
Miura N. ix387 (1186P)<br />
Miura S. ix509 (1579P), ix71 (159P)<br />
Miura T. ix467 (1443)<br />
Miyagawa S. ix211 (625)<br />
Miyagi M. ix248 (751)<br />
Miyagishima T. ix202 (592P)<br />
Miyake Y. ix93 (237), ix196 (573P)<br />
Miyamoto A. ix433 (1323)<br />
Miyamoto K. ix525 (1637)<br />
Miyamoto R. ix543 (1696P)<br />
Miyamoto S. ix226 (673P)<br />
Miyanaga A. ix383 (1174P)<br />
Miyashita I. ix170 (498P)<br />
Miyashita Y. ix228 (681P)<br />
Miyata H. ix481 (1485PD)<br />
Miyata Y. ix385 (1180PD)<br />
Miyazaki Y. ix481 (1485PD)<br />
Mizuno T. ix509 (1578P)<br />
Mizunuma N. ix87 (218P)<br />
Mizusawa J. ix231 (689P)<br />
Mobley J. ix544 (1701)<br />
Mocci E. ix472 (1456P)<br />
Mocciaro F. ix215 (636)<br />
Modest D.P. ix180 (526PD)<br />
Moecks J. ix411 (1254P)<br />
Moghaddamnia A. ix346 (1059)<br />
Mohajer R. ix467 (1442)<br />
Mohamed A. ix146 (419PD)<br />
Mohamed Z. ix381 (1169P)<br />
Mohammadian Roshan N. ix184 (538P)<br />
Mohanti B. ix149 (430P)<br />
Mohanti B.K. ix455 (1398P), ix110 (298P),<br />
ix264 (800P)<br />
Mohar-Betancourt A. ix107 (289P), ix251 (763)<br />
Mohd Noor A. ix165 (479P)<br />
Mohd Sharial M.S.N. ix300 (909P)<br />
Mohorcic K. ix522 (1625), ix523 (1630)<br />
Moiseyenko V. ix198 (581P), ix224 (668PD)<br />
Mok T.S.K. ix391 (1198P), ix393 (1205P),<br />
ix400 (1226O), ix401 (1228O), ix402 (1229PD),<br />
ix405 (1236PD), ix406 (1239P), ix410 (1252P),<br />
ix411 (1254P), ix51 (83IN)<br />
Molassiotis A. ix507 (1573P)<br />
Molero X. ix67 (145P)<br />
Molife L.R. ix159 (458P)<br />
Molife L.R. ix162 (469P)<br />
Molina, M.A. ix533 (1662P)<br />
Molina-Garido M. ix457 (1404), ix459 (1412)<br />
Molina-Pinelo S. ix183 (534P)<br />
Molina A. ix294 (894O), ix295 (895O)<br />
Molina A.M. ix269 (814P)<br />
Molina M.A. ix418 (1273P)<br />
Molinas E. ix448 (1373P)<br />
Molinier O. ix404 (1235PD)<br />
Moliterni A. ix102 (269P)<br />
Moller H. ix165 (479P)<br />
Molnár L. ix429 (1307P)<br />
Molnar E. ix223 (665TiP)<br />
Moncayo G.E. ix71 (160P)<br />
Mondal S.K. ix452 (1388P)<br />
Mondejar Solis R. ix264 (799P)<br />
Moneer M.M. ix111 (304)<br />
Monges G. ix184 (539P)<br />
Monk B.J. ix460 (1416PD)<br />
Monnereau A. ix219 (649)<br />
Monnier A. ix475 (1468P)<br />
Montañana M. ix365 (1123P), ix432 (1316)<br />
Montella T. ix289 (877)<br />
Montemurro G. ix212 (628)<br />
Montemurro M. ix480 (1482PD)<br />
Montero J.C.M. ix205 (604P)<br />
Montero M.A. ix496 (1533P)<br />
Monteverde M. ix528 (1644PD), ix113 (311)<br />
Monti M. ix496 (1536P)<br />
Montin E. ix344 (1050P)<br />
Montironi R. ix274 (829P)<br />
Moodley S.D. ix103 (272P)<br />
Moon J. ix49 (77IN)<br />
Moore M. ix255 (776TiP)<br />
Moore N. ix531 (1657P), ix219 (649)<br />
Morère J. ix414 (1265P), ix470 (1452P),<br />
ix472 (1460)<br />
Mora O. ix452 (1385P)<br />
Mora P. ix331 (1010)<br />
Moraes A.M. ix364 (1119P), ix365 (1121P),<br />
ix365 (1122P)<br />
Morales Juarez L. ix184 (541P)<br />
Morales-Barrera R. ix266 (806P), ix302 (916P)<br />
Morales C. ix186 (546P)<br />
Morales S. ix118 (323PD)<br />
Moran Bueno T. ix431 (1315)<br />
Moran S. ix302 (918P)<br />
Morano F. ix488 (1509P)<br />
Mordenti G. ix317 (965TiP)<br />
Moreau M. ix194 (569P)<br />
Moreira A. ix345 (1056), ix141 (404)<br />
Moreira I. ix357 (1095)<br />
Morelli D. ix335 (1019O)<br />
Morelli F. ix335 (1020PD)<br />
Moreno A. ix131 (365P)<br />
Moreno J. ix181 (527PD)<br />
Moreno V. ix165 (480P)<br />
Morente M. ix276 (835P)<br />
Moretti A. ix511 (1585P)<br />
Morgan G. ix44 (67IN)<br />
Morgan M.A. ix299 (908P)<br />
Morgan R. ix68 (147P), ix325 (988P)<br />
Morgan R.K. ix468 (1444)<br />
Morgillo F. ix430 (1309P), ix67 (143PD),<br />
ix75 (173O)<br />
Mori K. ix518 (1610P), ix526 (1643)<br />
ix112 (305)<br />
Mori M. ix411 (1253P), ix481 (1485PD),<br />
ix227 (677P)<br />
Mori S. ix375 (1152)<br />
Mori Y. ix427 (1301P)<br />
Morice P. ix322 (977P)<br />
Morikawa N. ix420 (1280P), ix427 (1301P)<br />
Morimoto C. ix170 (498P)<br />
Morin F. ix419 (1276P)<br />
Morinaga R. ix438 (1340)<br />
Morise M. ix439 (1343), ix445 (1366TiP)<br />
Volume 23 | Supplement 9 | June <strong>2012</strong> doi:10.1093/annonc/mds466 | ix569
author index<br />
Morishita N. ix432 (1320), ix433 (1321)<br />
Morita S. ix411 (1253P), ix412 (1256P),<br />
ix422 (1286P), ix437 (1338), ix442 (1354),<br />
ix514 (1595P), ix226 (673P), ix228 (681P),<br />
ix230 (688P), ix233 (697P)<br />
Moriuchi Y. ix348 (1062O)<br />
Moriya Y. ix390 (1197P)<br />
Morley S. ix347 (1061TiP)<br />
Mornex F. ix206 (607P)<br />
Moro-Sibilot D. ix403 (1231PD), ix403 (1232PD),<br />
ix426 (1299P), ix446 (1367TiP)<br />
Moro C. ix466 (1436P)<br />
Morodomi Y. ix387 (1187P)<br />
Morokawa N. ix433 (1323)<br />
Morosi C. ix483 (1491P), ix484 (1496P),<br />
ix88 (222P)<br />
Moroso S. ix99 (259P)<br />
Morote J. ix302 (916P), ix312 (945)<br />
Morreau H. ix61 (116IN)<br />
Morris D. ix440 (1350)<br />
Morris K. ix199 (582P)<br />
Morris M. ix294 (894O), ix317 (963TiP)<br />
Morris S.R. ix153 (442O)<br />
Morse N. ix126 (350P)<br />
Morsli N. ix155 (446PD)<br />
Mortara V. ix80 (192P)<br />
Mosca F. ix241 (726P)<br />
Moscetti L. ix105 (280P)<br />
Moscheni O. ix330 (1005P)<br />
Mosconi S. ix365 (1120P)<br />
Mosillo C. ix440 (1348)<br />
Moslemi D. ix346 (1059)<br />
Mossman T. ix447 (1372P)<br />
Mostyn-Jones A. ix519 (1613P)<br />
Mota-García A. ix329 (1003P)<br />
Motizuki S. ix433 (1323)<br />
Motoi N. ix418 (1274P)<br />
Motoki T. ix74 (172O)<br />
Motonaga S. ix467 (1443)<br />
Mottolese M. ix78 (183P), ix142 (406TiP)<br />
Motzer R.J. ix259 (785O), ix269 (814P)<br />
Motzer R.J. ix262 (793PD), ix262 (794PD),<br />
ix262 (795PD), ix263 (796PD), ix278 (842P),<br />
ix292 (889TiP)<br />
Mougiakakos D. ix541 (1690P)<br />
Moukoko R. ix340 (1036P)<br />
Moulard O. ix213 (632), ix323 (981P)<br />
Moulton B. ix108 (292P)<br />
Mountzios G. ix338 (1030P)<br />
Moura J.F.P. ix464 (1429P)<br />
Mourad C. ix138 (392)<br />
Mouret-Reynier M. ix102 (270P)<br />
Mourey L. ix294 (893O)<br />
Moussaid Y. ix150 (433)<br />
Mouysset J. ix511 (1584P)<br />
Mouzount H. ix476 (1472P)<br />
Moya Ortega B. ix264 (799P)<br />
Moya A.C. ix183 (534P)<br />
Moya B. ix176 (517P)<br />
Moyo V. ix170 (496P), ix321 (974PD)<br />
Mozzillo N. ix375 (1152)<br />
Mpananis K. ix213 (631)<br />
Mrabti H. ix432 (1318), ix476 (1470P),<br />
ix476 (1472P)<br />
Muazzam I.A. ix358 (1100), ix497 (1539P),<br />
ix285 (860P)<br />
Muddapur M.V. ix343 (1049P), ix345 (1055)<br />
Muehlbauer S. ix97 (254PD)<br />
Mueller N. ix252 (766)<br />
Mueller U. ix274 (828P)<br />
Muenzberg M. ix502 (1555P), ix502 (1557P)<br />
Muggia F. ix130 (363P)<br />
Mukai H. ix131 (366P)<br />
Mukherji D. ix296 (897O), ix298 (903P),<br />
ix301 (913P)<br />
Mukhopadhyay A. ix355 (1090P), ix356 (1091P),<br />
ix356 (1093P), ix359 (1105), ix359 (1106),<br />
ix448 (1375P), ix455 (1399P), ix471 (1453P),<br />
ix471 (1454P), ix471 (1455P), ix472 (1457P),<br />
ix472 (1458P), ix133 (375P), ix135 (381),<br />
ix328 (997P)<br />
Mukhopadhyay S. ix355 (1090P), ix356 (1091P),<br />
ix356 (1093P), ix359 (1105), ix359 (1106),<br />
ix448 (1375P), ix455 (1399P), ix472 (1457P),<br />
ix472 (1458P), ix133 (375P), ix135 (381)<br />
Mukohara T. ix510 (1581P)<br />
Mulcahey S. ix436 (1332)<br />
Mulders P. ix295 (896O)<br />
Mulick Cassidy A. ix298 (903P), ix301 (913P)<br />
Müllauer L. ix352 (1076P)<br />
Müller S.P. ix154 (445PD)<br />
Müller U. ix132 (370P)<br />
Muller E. ix322 (977P)<br />
Mullins C.D. ix205 (603P), ix214 (634)<br />
Mullot H. ix285 (862P)<br />
Mummy D. ix203 (596P)<br />
Mun Y. ix191 (560P)<br />
Munemoto Y. ix514 (1595P)<br />
Munot K. ix358 (1103)<br />
Muñoz Beltran M. ix472 (1456P)<br />
Muñoz Martín A.J. ix198 (579P)<br />
Muñoz Sanchez M. ix457 (1404), ix459 (1412)<br />
Muñoz A. ix212 (627)<br />
Muñoz E. ix370 (1136P)<br />
Muñoz J. ix505 (1564P), ix523 (1629)<br />
Muñoz M. ix135 (380)<br />
Munroe C. ix182 (532P)<br />
Munster P. ix153 (442O)<br />
Muracciole X. ix511 (1584P)<br />
Murahashi M. ix536 (1671P)<br />
Murakami H. ix424 (1293P), ix430 (1310P),<br />
ix492 (1519PD)<br />
Murakami Y. ix517 (1608P)<br />
Muranyi A. ix383 (1173P)<br />
Murata E.P. ix216 (641)<br />
Murdock M.I. ix311 (943P)<br />
Muro K. ix139 (396), ix200 (587P), ix232 (692P),<br />
ix232 (694P)<br />
Murone C. ix542 (1692P)<br />
Murphy A. ix207 (610P)<br />
Murray N. ix412 (1255P)<br />
Murray R.N. ix395 (1210)<br />
Murray S. ix373 (1146), ix85 (211P), ix86 (213P),<br />
ix94 (242)<br />
Murtaza M. ix74 (171O)<br />
Murtezani Z. ix428 (1304P)<br />
Musante F. ix247 (747P)<br />
Musha N. ix228 (682P)<br />
Muskett D. ix284 (859P)<br />
Musolino A. ix175 (513PD)<br />
Mustacchi G. ix128 (356P)<br />
Musya H. ix211 (624)<br />
Mut P. ix374 (1150)<br />
Muto M. ix226 (673P)<br />
Mutti L. ix495 (1532P)<br />
Muylle K. ix33 (31IN)<br />
Muzaffar N. ix358 (1100), ix285 (860P)<br />
Muzzafar N. ix497 (1539P)<br />
Myerson R.J. ix130 (363P)<br />
Myhre S. ix96 (249PD)<br />
Myint A.S. ix206 (608P)<br />
Myleiko V.A. ix109 (293P)<br />
N<br />
Na’Amad M. ix519 (1616P)<br />
Na I.I. ix414 (1262P)<br />
Na K. ix492 (1520PD)<br />
Nabhan C. ix310 (941P), ix311 (943P)<br />
Nabholtz J. ix102 (270P)<br />
Nabiço R. ix357 (1097)<br />
Nacci A. ix95 (248O)<br />
Nachabé R. ix532 (1658P)<br />
Nadal E. ix418 (1273P)<br />
Nadig J. ix462 (1423O)<br />
Nagai H. ix442 (1356)<br />
Nagai K. ix387 (1186P), ix534 (1666P)<br />
Annals of Oncology<br />
Nagai Y. ix203 (598P)<br />
Nagaraj N. ix283 (857P)<br />
Nagase H. ix185 (542P)<br />
Nagase M. ix241 (728P)<br />
Nagata K. ix423 (1289P)<br />
Nagata M. ix79 (189P), ix79 (190P), ix92 (235)<br />
Nagata N. ix514 (1595P), ix228 (681P)<br />
Nagata S. ix438 (1340)<br />
Nagata Y. ix197 (576P)<br />
Nagayasu T. ix71 (161P)<br />
Naghiby Sustany M. ix459 (1411)<br />
Nagtegaal I.D. ix179 (521O)<br />
Nagy B. ix235 (706P)<br />
Nagyivanyi K. ix281 (849P)<br />
Naini V. ix294 (894O)<br />
Nair R. ix350 (1069PD), ix351 (1074P)<br />
Naito T. ix430 (1310P)<br />
Naito Y. ix429 (1306P), ix131 (366P)<br />
Najda J. ix353 (1082P)<br />
Nakagawa A. ix423 (1289P)<br />
Nakagawa K. ix385 (1181PD), ix393 (1204P),<br />
ix393 (1206P), ix397 (1218), ix424 (1293P),<br />
ix153 (441O), ix167 (486P), ix211 (624)<br />
Nakagawa Y. ix407 (1242P)<br />
Nakahara R. ix388 (1188P)<br />
Nakahara Y. ix441 (1351), ix497 (1537P)<br />
Nakai M. ix412 (1258P)<br />
Nakai T. ix79 (189P), ix79 (190P), ix92 (235)<br />
Nakajima K. ix481 (1485PD), ix225 (670PD)<br />
Nakamichi S. ix156 (451P), ix161 (467P),<br />
ix174 (1708PD)<br />
Nakamori S. ix241 (728P)<br />
Nakamura F. ix384 (1177P)<br />
Nakamura K. ix513 (1591P), ix79 (188P),<br />
ix231 (689P)<br />
Nakamura M. ix513 (1591P), ix196 (573P),<br />
ix200 (588P), ix202 (592P), ix232 (692P)<br />
Nakamura S. ix82 (199P)<br />
Nakamura Y. ix536 (1671P), ix159 (460P)<br />
Nakanishi Y. ix385 (1181PD), ix407 (1242P),<br />
ix438 (1340), ix536 (1671P)<br />
Nakano K. ix542 (1694P)<br />
Nakashima M. ix71 (161P)<br />
Nakasima Y. ix508 (1576P)<br />
Nakata M. ix541 (1690P)<br />
Nakayama G. ix542 (1693P), ix220 (655),<br />
ix246 (742P)<br />
Nakayama N. ix449 (1378P)<br />
Nakazawa Y. ix411 (1253P)<br />
Nalbantov G. ix396 (1216)<br />
Naldi N. ix175 (513PD)<br />
Namba Y. ix411 (1253P)<br />
Namikawa K. ix372 (1142P)<br />
Namikawa T. ix250 (758)<br />
Nandi A. ix356 (1091P)<br />
Nanni C. ix148 (425P)<br />
Nanni O. ix119 (327PD)<br />
Nanni P. ix537 (1675P)<br />
Naoki K. ix422 (1285P)<br />
Naomoto Y. ix250 (758)<br />
Naoshy S. ix213 (632)<br />
Napoli A. ix463 (1426P)<br />
Napolitano S. ix67 (143PD)<br />
Nappi A. ix67 (143PD)<br />
Nappi L. ix530 (1651P), ix532 (1659P),<br />
ix540 (1687), ix287 (869)<br />
Narain N. ix166 (482P)<br />
Naranjo Hans D. ix431 (1315)<br />
Narasimhan N.I. ix152 (439O)<br />
Narasimhan V. ix166 (482P)<br />
Narayanaswamy K. ix490 (1515)<br />
Nardelli G.B. ix326 (991P)<br />
Nardi M. ix505 (1565P), ix137 (388)<br />
Nardin M. ix209 (618)<br />
Narine N. ix93 (240)<br />
Narita I. ix71 (159P)<br />
Nascimento E.C. ix112 (306)<br />
Nashimoto A. ix228 (682P)<br />
ix570 | author index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology author index<br />
Nasim M. ix129 (358P)<br />
Naskhletashvili D.R. ix435 (1330)<br />
Nasser N.J. ix519 (1616P)<br />
Nathan P. ix374 (1149), ix264 (798PD)<br />
Nathan S. ix467 (1442)<br />
Nava Garcia P. ix198 (579P)<br />
Navarro A. ix377 (1157O)<br />
Navez B. ix197 (578P)<br />
Navruzov S. ix331 (1008), ix254 (772), ix290 (882)<br />
Navruzova V. ix331 (1008), ix328 (998P)<br />
Nawrocki S. ix457 (1406), ix475 (1466P)<br />
Necchi A. ix88 (222P), ix285 (861P)<br />
Neef C. ix456 (1402P)<br />
Neeman M. ix59 (109IN)<br />
Negoro S. ix422 (1286P)<br />
Negre S. ix480 (1483PD)<br />
Negri F.M. ix232 (693P)<br />
Negri F.V. ix216 (642)<br />
Negri T. ix484 (1496P), ix485 (1500P)<br />
Negrier S. ix453 (1391P), ix262 (793PD),<br />
ix264 (798PD), ix279 (843P)<br />
Neibart S. ix312 (948)<br />
Neise M. ix504 (1561P)<br />
Nelli F. ix105 (280P)<br />
Nematov O. ix229 (684P), ix254 (772)<br />
Nemeth H. ix281 (849P), ix286 (867P)<br />
Nemoto N. ix407 (1242P)<br />
Nered S. ix252 (765)<br />
Neri T.M. ix175 (513PD)<br />
Nerich V. ix332 (1014), ix128 (357P), ix249 (753)<br />
Nesrine M. ix254 (774)<br />
Netto E. ix345 (1056)<br />
Netzer F. ix456 (1400P)<br />
Neubauer A. ix349 (1068PD)<br />
Neuzillet Y. ix474 (1463P)<br />
Neves J. ix289 (878)<br />
Neveux N. ix91 (229P)<br />
Nevinny M. ix494 (1528P)<br />
Neyns B. ix363 (1116PD)<br />
Nezu M. ix131 (366P)<br />
Nezu R. ix200 (588P)<br />
Ng C.H.M. ix119 (325PD)<br />
Ng Q.S. ix412 (1257P), ix70 (155P)<br />
Ng V. ix89 (226P)<br />
Ngai Y. ix421 (1282P)<br />
Nguyen H. ix319 (967O)<br />
Nguyen L.T. ix154 (445PD)<br />
Nguyen T. ix204 (600P), ix249 (753), ix289 (876)<br />
Nguyen T.V.F. ix475 (1468P)<br />
Niarou V. ix474 (1465P)<br />
Niazi T. ix200 (586P)<br />
Nibu K. ix510 (1581P)<br />
Nicacio L. ix312 (948)<br />
Niccoli P. ix376 (1155O)<br />
Nicodemo M. ix290 (879)<br />
Nicolai N. ix88 (222P), ix285 (861P),<br />
ix315 (959)<br />
Nicolai P. ix338 (1029P)<br />
Nicolas P. ix414 (1265P)<br />
Nicolau C. ix282 (853P)<br />
Nicoletti S.V.L. ix369 (1133P)<br />
Nicoletto M.O. ix326 (991P)<br />
Nicolle D. ix312 (946)<br />
Nicolson M. ix385 (1179O)<br />
Niculina V.V. ix536 (1672P)<br />
Niedersuess-Beke D. ix521 (1622)<br />
Niegisch G. ix260 (787O), ix265 (804P)<br />
Niethammer A. ix409 (1246P)<br />
Nigita G. ix111 (303)<br />
Nihei K. ix396 (1215)<br />
Niho S. ix396 (1215), ix515 (1598P),<br />
ix534 (1666P)<br />
Niikura N. ix112 (305)<br />
Niinepuu K. ix146 (418PD), ix149 (431)<br />
Nikaidoh J. ix442 (1356)<br />
Nikitina T.P. ix141 (403)<br />
Nikoglou T. ix370 (1134P), ix372 (1143P)<br />
Nikolaou A. ix338 (1030P), ix338 (1031P)<br />
Nilsson S. ix296 (898PD), ix299 (906P),<br />
ix308 (936P)<br />
Ninomiya M. ix250 (758)<br />
Nisbet I. ix508 (1575P)<br />
Nisenbaum B. ix116 (317O)<br />
Nishida T. ix478 (1478O), ix481 (1485PD)<br />
Nishikawa G. ix220 (653)<br />
Nishikawa K. ix227 (677P), ix230 (688P)<br />
Nishimoto H. ix384 (1177P)<br />
Nishimura G. ix188 (552P)<br />
Nishimura M. ix434 (1326), ix443 (1358),<br />
ix497 (1538P)<br />
Nishimura Y. ix393 (1204P)<br />
Nishina T. ix512 (1590P), ix196 (574P),<br />
ix233 (697P)<br />
Nishino K. ix437 (1338)<br />
Nishio M. ix404 (1234PD), ix413 (1260P),<br />
ix418 (1274P), ix441 (1353), ix153 (441O)<br />
Nishio S. ix326 (989P)<br />
Nishio W. ix92 (233)<br />
Nishiyama A. ix434 (1327), ix437 (1338)<br />
Nishizawa Y. ix210 (621)<br />
Nisman B. ix88 (220P)<br />
Nistér M. ix299 (906P)<br />
Nitsche D. ix178 (518O)<br />
Nixon L. ix498 (1542TiP)<br />
Nobes J. ix374 (1149)<br />
Nobre-Góis I. ix208 (614P)<br />
Nogami N. ix393 (1206P), ix434 (1327)<br />
Noguchi S. ix118 (324PD), ix126 (351P)<br />
Nogueira G.A.S. ix364 (1119P), ix365 (1121P)<br />
Noh S. ix332 (1012)<br />
Noize P. ix219 (649)<br />
Nokihara H. ix396 (1215), ix156 (451P),<br />
ix159 (459P), ix161 (467P), ix164 (475P),<br />
ix174 (1708PD)<br />
Nolan C. ix469 (1449PD)<br />
Nomoto K. ix200 (585P)<br />
Nomura F. ix518 (1610P), ix526 (1643),<br />
ix527 (1705)<br />
Nomura M. ix544 (1701)<br />
Nomura S. ix210 (621)<br />
Nonaka D. ix495 (1532P), ix80 (193P)<br />
Nong X. ix501 (1552P)<br />
Noonan K. ix305 (925P)<br />
Noonan S. ix176 (516P)<br />
Nordle Ö. ix303 (919P)<br />
Normanno N. ix78 (183P), ix86 (213P)<br />
Noro R. ix387 (1186P)<br />
North S. ix304 (922P)<br />
Northrup R. ix161 (465P)<br />
Nortier J.W. ix501 (1553P)<br />
Nosov D. ix263 (796PD)<br />
Nosrati F. ix248 (749)<br />
Nourani C.L. ix306 (929P)<br />
Novarino A. ix240 (724P)<br />
Novello S. ix442 (1355), ix444 (1360)<br />
Novy M. ix373 (1145)<br />
Nowak A.K. ix151 (437TiP)<br />
Nozaki K. ix71 (159P)<br />
Nukiwa T. ix412 (1256P), ix427 (1301P)<br />
Numico G. ix229 (685P)<br />
Nunez Hernandez I. ix302 (916P)<br />
Nuñez Viejo M.A. ix510 (1582P)<br />
Nuyts S. ix334 (1016O)<br />
Nuzzo C. ix368 (1130P)<br />
Nuzzo P.V. ix301 (914P)<br />
Nycum L.R. ix319 (967O)<br />
O<br />
Oaknin Benzaquen A. ix321 (975PD)<br />
Oba M. ix211 (625)<br />
Obadia V. ix136 (386)<br />
Obasaju C. ix421 (1281P)<br />
Oberaigner W. ix494 (1528P)<br />
Oberg K. ix377 (1156O)<br />
Oberkanins C. ix373 (1145)<br />
Oberndorfer S. ix145 (415PD)<br />
Obertin S. ix186 (548P)<br />
Obertova J. ix286 (865P), ix293 (890TiP)<br />
O’Brien J.P. ix146 (417PD), ix244 (737P)<br />
O’Brien T. ix518 (1612P), ix275 (831P)<br />
O’Bryan-Tear C.G. ix308 (936P)<br />
O’Byrne K. ix385 (1179O), ix524 (1634),<br />
ix73 (167O)<br />
O’Byrne K.J. ix402 (1229PD), ix410 (1252P),<br />
ix417 (1272P), ix68 (148P), ix68 (149P),<br />
ix68 (150P), ix495 (1531P), ix495 (1532P),<br />
ix69 (154P), ix78 (185P)<br />
O’Callaghan C. ix71 (160P)<br />
Ocana A. ix91 (231P)<br />
Occelli M. ix113 (311)<br />
Ochiai A. ix210 (621)<br />
Ochiai K. ix326 (989P), ix327 (995P)<br />
Ochoa de Olza M. ix370 (1136P)<br />
O’Connell J. ix401 (1228O)<br />
O’Connell M.J. ix179 (523PD)<br />
O’Connor B.M. ix130 (363P)<br />
Oconnor J.M. ix379 (1164P)<br />
Ocvirk J. ix504 (1562P)<br />
O Donovan N. ix540 (1686P)<br />
O’Donovan N. ix528 (1645PD), ix108 (292P)<br />
Oda H. ix509 (1578P)<br />
Oda T. ix436 (1334), ix543 (1696P)<br />
Odate S. ix79 (188P)<br />
O’Dwyer P. ix319 (966O)<br />
O’Dwyer P.J. ix169 (492P)<br />
Oeberg K. ix47 (1703IN)<br />
Oellers M. ix396 (1216)<br />
Ofosu-Appiah W. ix152 (438O)<br />
O Gorman P. ix525 (1635)<br />
Ogasawara M. ix239 (719P)<br />
Ogasawara T. ix434 (1325)<br />
Ogawa K. ix433 (1323), ix514 (1597P)<br />
Ogawa T. ix515 (1598P)<br />
Ogiwara A. ix91 (232)<br />
Ogura T. ix436 (1334)<br />
Oguro T. ix69 (153P)<br />
Oh H. ix193 (566P)<br />
Oh I. ix492 (1520PD)<br />
Oh S.T. ix186 (545P), ix209 (617), ix227 (679P)<br />
Oh W.K. ix302 (918P)<br />
O’Hanlon-Brown C. ix161 (464P)<br />
Ohara Y. ix543 (1696P)<br />
Ohashi Y. ix429 (1306P), ix511 (1586P),<br />
ix512 (1590P), ix220 (653), ix254 (775)<br />
Ohata K. ix220 (653)<br />
Ohba T. ix387 (1187P)<br />
Ohe Y. ix396 (1215), ix492 (1519PD),<br />
ix515 (1598P), ix534 (1666P)<br />
Ohgino K. ix422 (1285P)<br />
Ohigashi S. ix200 (585P)<br />
Ohira T. ix544 (1701)<br />
Ohkawa S. ix241 (728P)<br />
Ohkohchi N. ix543 (1696P)<br />
Öhlschlegel C. ix132 (370P)<br />
Ohmatsu H. ix515 (1598P), ix534 (1666P)<br />
Ohno S. ix104 (277P)<br />
Ohno Y. ix439 (1343)<br />
Ohta K. ix463 (1428P)<br />
Ohtsu A. ix449 (1378P), ix164 (474P),<br />
ix200 (587P), ix201 (590P), ix232 (694P)<br />
Ohyanagi F. ix418 (1274P), ix441 (1353)<br />
Oikawa M. ix71 (161P), ix211 (624)<br />
Oishi M. ix467 (1443)<br />
Oizumi S. ix412 (1256P), ix434 (1326),<br />
ix443 (1358), ix497 (1538P)<br />
Oka M. ix93 (237), ix159 (460P), ix240 (723P)<br />
Oka S. ix517 (1608P)<br />
Okada H. ix432 (1320), ix433 (1321)<br />
Okada K. ix185 (542P), ix197 (575P)<br />
ix207 (611P)<br />
Okada M. ix385 (1180PD), ix226 (672P)<br />
Okamoto A. ix327 (995P)<br />
Okamoto H. ix404 (1234PD)<br />
Okamoto I. ix385 (1181PD), ix233 (697P)<br />
Volume 23 | Supplement 9 | June <strong>2012</strong> doi:10.1093/annonc/mds466 | ix571
author index<br />
Okamoto N. ix432 (1320), ix433 (1321)<br />
Okamoto R. ix381 (1171P)<br />
Okamoto W. ix167 (486P)<br />
Okamura T. ix441 (1351), ix497 (1537P),<br />
ix112 (305)<br />
Okayama N. ix93 (237)<br />
Oki M. ix517 (1608P)<br />
Okishio K. ix439 (1344)<br />
Okita K. ix244 (737P)<br />
Okita R. ix541 (1690P)<br />
Okizaki A. ix467 (1443)<br />
Oksuzoglu B. ix332 (1015)<br />
Oksuzoglu O.B. ix473 (1461), ix105 (279P)<br />
Okudera K. ix420 (1280P)<br />
Okuma T. ix439 (1344)<br />
Okuma Y. ix441 (1351), ix497 (1537P)<br />
Okumura N. ix542 (1693P), ix246 (742P)<br />
Okuno K. ix159 (460P)<br />
Okusaka T. ix241 (728P), ix244 (737P),<br />
ix254 (775), ix255 (776TiP)<br />
Okutur K. ix217 (645)<br />
Olaverri Hernandez A. ix457 (1404), ix459 (1412)<br />
Oldenburg H. ix532 (1658P)<br />
O’Leary J.J. ix68 (149P)<br />
O’Leary K. ix532 (1660P), ix73 (169O)<br />
Olier C. ix113 (310)<br />
Oliner K. ix334 (1016O)<br />
Oliner K.S. ix230 (687P)<br />
Oliva C. ix488 (1508P), ix490 (1518TiP)<br />
Olivares R. ix213 (632), ix323 (981P)<br />
Oliveira Â. ix357 (1095)<br />
Oliveira C. ix364 (1119P), ix365 (1121P),<br />
ix365 (1122P)<br />
Oliveira C.B.M. ix133 (374P)<br />
Oliveira I. ix357 (1095)<br />
Oliveira J. ix345 (1056)<br />
Oliveira M. ix531 (1656P), ix141 (404)<br />
Oliveira M.A. ix215 (637)<br />
Oliveira V. ix49 (77IN)<br />
Olivo Y.S. ix174 (509TiP)<br />
Öllers M. ix392 (1201P)<br />
Olmez F. ix129 (359P)<br />
Olmez S. ix469 (1448PD)<br />
Olmos D. ix162 (469P), ix298 (903P)<br />
Olsson A. ix303 (919P)<br />
Olszanski A.J. ix170 (497P)<br />
Omachi N. ix439 (1344)<br />
O’Mahony S. ix467 (1442)<br />
Omar A. ix288 (874)<br />
Omidi Ashrafi A. ix107 (287P), ix184 (538P)<br />
Omlin A.G. ix298 (903P), ix301 (913P)<br />
Omuro Y. ix381 (1171P)<br />
Onal C. ix526 (1641), ix526 (1642)<br />
Ondrus D. ix286 (865P)<br />
Onetti Muda ix530 (1653P), ix538 (1681P)<br />
Ong M. ix162 (469P)<br />
Onganía L. ix477 (1475)<br />
Onikubo T. ix513 (1591P)<br />
Onishi H. ix542 (1694P), ix79 (188P)<br />
Onland-Moret C. ix122 (335P)<br />
Ono A. ix430 (1310P)<br />
Onoda N. ix84 (205P)<br />
Onodera H. ix200 (585P)<br />
Onofri A. ix533 (1663P), ix290 (879)<br />
Onukwugha E. ix205 (603P), ix214 (634)<br />
Onuma H. ix201 (590P)<br />
Ooji K. ix518 (1610P), ix526 (1643)<br />
Oon L. ix412 (1257P)<br />
Oostendorp L. ix475 (1469P)<br />
Opatt McDowell D. ix363 (1116PD)<br />
Opinião A. ix175 (512PD), ix176 (514P)<br />
Opitz I. ix495 (1532P)<br />
Orel N. ix382 (1172)<br />
O’Reilly S. ix207 (610P), ix300 (909P)<br />
O’Riordain M. ix207 (610P)<br />
Orgiano L. ix516 (1604P), ix164 (476P)<br />
Orlandi A. ix84 (207P)<br />
Orlandi E. ix341 (1040P), ix342 (1045P)<br />
Orlandi F. ix290 (881)<br />
Orlando L. ix95 (248O)<br />
Orlando M. ix400 (1225O)<br />
Orlov S. ix405 (1236PD), ix406 (1239P)<br />
Orlowski T. ix395 (1211)<br />
Oro A. ix362 (1111PD), ix362 (1112PD)<br />
Orosz Z. ix493 (1523P)<br />
Ortega Ruiperez C. ix459 (1412)<br />
Ortega E. ix374 (1150)<br />
Ortega J.A. ix254 (773)<br />
Ortega L. ix377 (1157O)<br />
Ortega V. ix300 (910P)<br />
Ortiz Durán R.M. ix219 (651)<br />
Ortiz-Morales M.J. ix131 (365P), ix186 (546P)<br />
Ortiz Á. ix112 (307)<br />
Oruzio D. ix204 (599P)<br />
Orvieto E. ix124 (343P)<br />
Osório L. ix147 (423P)<br />
Osaka Y. ix89 (224P)<br />
Osaki Y. ix244 (737P)<br />
Osamu Taguchi O. ix439 (1343)<br />
Osanto S. ix256 (781TiP)<br />
Osborne M. ix215 (638)<br />
Osborne S. ix114 (315TiP)<br />
O’Shea T. ix108 (292P)<br />
Oshima T. ix220 (653)<br />
Oshiro M. ix514 (1595P)<br />
Osiadacz W. ix354 (1084P)<br />
Oskay-Özcelik G. ix172 (504)<br />
Osman I. ix363 (1113PD)<br />
Osores O. ix477 (1475)<br />
Ost P. ix325 (987P), ix330 (1007)<br />
Ostellino O. ix343 (1047P), ix346 (1058)<br />
Oster J. ix419 (1276P)<br />
Österlund P. ix190 (559P), ix195 (571P)<br />
Ostoros G. ix429 (1307P)<br />
Ostwal V.S. ix350 (1069PD)<br />
Ota S. ix239 (719P)<br />
Otero S. ix330 (1005P)<br />
Othman F. ix525 (1635)<br />
Otsuji T. ix196 (573P), ix233 (697P)<br />
Otsuka K. ix422 (1286P), ix423 (1289P),<br />
ix423 (1289P)<br />
Otsuka S. ix440 (1350)<br />
Ott G. ix440 (1347)<br />
Otterson G. ix424 (1291P)<br />
Ottevanger P.B. ix475 (1469P), ix160 (462P)<br />
Otto F. ix132 (370P)<br />
O’Toole D. ix378 (1159P)<br />
Otvos L.J. ix166 (483P)<br />
Ou D. ix253 (769)<br />
Ou S. ix401 (1228O)<br />
Ou S.I. ix389 (1191PD), ix415 (1267P),<br />
ix424 (1291P)<br />
Ouali M. ix483 (1493P)<br />
Oubel E. ix534 (1665P)<br />
Oudard S. ix499 (1545O), ix99 (258P),<br />
ix259 (786O), ix263 (797PD), ix271 (820P),<br />
ix278 (842P), ix280 (845P), ix282 (852P),<br />
ix294 (893O), ix307 (933P), ix312 (946)<br />
Ould Kaci M. ix155 (446PD)<br />
Ouyang M. ix438 (1341)<br />
Oven Ustaalioglu B. ix497 (1540)<br />
Overgaard J. ix96 (249PD)<br />
Overman M.J. ix220 (656)<br />
Oyama R. ix201 (590P)<br />
Oyen W.J.G. ix60 (115IN), ix192 (562P)<br />
Oyen W.J.G. ix160 (462P)<br />
Oza A.M. ix155 (448PD), ix156 (450PD),<br />
ix158 (455P), ix322 (978P)<br />
Ozaki Y. ix226 (673P)<br />
Ozatli T. ix105 (279P)<br />
Ozaydin S. ix286 (866P)<br />
Özçimen A. ix312 (947)<br />
Ozdemir N. ix332 (1015)<br />
Oze I. ix232 (692P)<br />
Ozen H. ix307 (932P), ix308 (934P)<br />
Ozer-Stillman I. ix283 (856P)<br />
Annals of Oncology<br />
Ozet A. ix227 (678P), ix277 (838P)<br />
Özgüroğlu M. ix307 (933P)<br />
Ozkan A. ix469 (1448PD)<br />
Ozkan L. ix291 (885)<br />
Ozkan M. ix332 (1015)<br />
Ozkan S. ix277 (838P)<br />
Ozsahin E.M. ix334 (1016O)<br />
Oztop I. ix234 (701P)<br />
Ozturk H. ix291 (885)<br />
Ozturk M. ix286 (866P)<br />
Ozturk M.A. ix186 (547P)<br />
Ozyilkan O. ix392 (1202P), ix425 (1294P),<br />
ix520 (1620), ix526 (1641), ix526 (1642),<br />
ix237 (711P), ix238 (715P)<br />
P<br />
Paccagnella A. ix335 (1020PD)<br />
Paccapelo A. ix148 (425P)<br />
Pachón V. ix377 (1157O)<br />
Pachow D. ix147 (420PD)<br />
Paesmans M. ix408 (1243P)<br />
Páez de La Cadena M. ix92 (234)<br />
Páez D. ix408 (1244P), ix183 (536P), ix185 (544P),<br />
ix216 (641)<br />
Paganelli G. ix47 (75IN)<br />
Pagani A. ix99 (260P)<br />
Pahwa P. ix182 (531P)<br />
Pai J. ix355 (1087P)<br />
Paik S. ix179 (523PD)<br />
Paillaud E. ix452 (1387P), ix460 (1419PD)<br />
Pailler M. ix414 (1265P)<br />
Pairet G. ix197 (578P)<br />
Paksoy Türköz F. ix543 (1698P)<br />
Paksoy F. ix104 (278P)<br />
Pal S. ix309 (938P)<br />
Palacios Ozores P. ix328 (1000P)<br />
Palacka P. ix293 (890TiP)<br />
Palassini E. ix484 (1496P), ix485 (1500P)<br />
Palazzo A. ix440 (1348), ix488 (1509P)<br />
Palka M. ix459 (1410), ix492 (1521PD),<br />
ix494 (1527P), ix112 (307)<br />
Pall G. ix494 (1528P)<br />
Palladini G. ix355 (1089P)<br />
Pallarés C. ix408 (1244P)<br />
Pallaud C. ix405 (1236PD), ix406 (1239P),<br />
ix531 (1657P), ix81 (198P)<br />
Palleschi D. ix145 (416PD)<br />
Pallier K. ix77 (180P)<br />
Pallisgaard N. ix530 (1654P), ix73 (168O)<br />
Palluzzi E. ix524 (1633)<br />
Palmer D. ix242 (731P), ix245 (740P)<br />
Palmer M. ix402 (1229PD)<br />
Palmieri C. ix532 (1660P)<br />
Palmieri G. ix364 (1118PD), ix540 (1687)<br />
Palomar L. ix106 (284P)<br />
Palou J. ix292 (888)<br />
Palozzo A.C. ix439 (1345), ix283 (854P)<br />
Palozzo A.C. ix447 (1370P)<br />
Palumbo A. ix360 (1108TiP)<br />
Palumbo R. ix123 (339P), ix138 (391)<br />
Pan E. ix146 (417PD)<br />
Pan H. ix256 (780TiP)<br />
Pan J. ix281 (847P)<br />
Pan K. ix227 (676P)<br />
Pan Q. ix256 (780TiP)<br />
Pan S. ix485 (1499P), ix485 (1501P), ix282 (851P)<br />
Pan Z. ix189 (556P)<br />
Panchapakesan B. ix87 (217P)<br />
Pandha H. ix68 (147P), ix292 (889TiP)<br />
Pandiella A. ix91 (231P)<br />
Pandite L.N. ix261 (791PD), ix275 (833P)<br />
Pandolfi P.P. ix59 (107IN)<br />
Pang H. ix389 (1193P)<br />
Panneerselvam A. ix376 (1154O), ix118 (324PD),<br />
ix126 (351P), ix278 (842P)<br />
Panni S. ix442 (1355)<br />
Paño B. ix282 (853P)<br />
Pant M.C. ix339 (1034P)<br />
ix572 | author index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology author index<br />
Pantano F. ix489 (1512), ix516 (1603P),<br />
ix530 (1653P), ix538 (1681P), ix206 (606P)<br />
Pantuck A. ix292 (889TiP)<br />
Panzone F. ix462 (1422O), ix463 (1427P),<br />
ix466 (1438P)<br />
Pao W. ix401 (1227O)<br />
Paoletti X. ix464 (1430P)<br />
Paolicchi E. ix85 (208P)<br />
Paolini B. ix285 (861P)<br />
Paolini J. ix297 (901PD)<br />
Papa S. ix165 (479P)<br />
Papadaki C. ix381 (1170P), ix429 (1308P),<br />
ix213 (631)<br />
Papadatos G. ix100 (262P)<br />
Papadopolous N. ix454 (1392P)<br />
Papadopoulos K. ix165 (481P), ix169 (492P)<br />
Papadopoulos N. ix366 (1126P)<br />
Papadopoulou K. ix430 (1312)<br />
Papakostas P. ix213 (630)<br />
Papandreou C. ix95 (246O), ix255 (777TiP),<br />
ix289 (876), ix307 (932P)<br />
Papasotiriou I. ix136 (385)<br />
Papavassiliou A.G. ix92 (236)<br />
Papiani G. ix285 (863P)<br />
Paré L. ix408 (1244P), ix185 (544P)<br />
Parati M. ix102 (269P)<br />
Pardo F. ix239 (718P)<br />
Pardo N. ix265 (802P), ix266 (807P)<br />
Paredes J. ix127 (352P)<br />
Parekh B.B. ix356 (1092P), ix134 (377)<br />
Parente P. ix306 (931P)<br />
Parikh A. ix156 (449PD)<br />
Parikh B. ix356 (1092P), ix134 (377)<br />
Parikh P.M. ix301 (912P)<br />
Park C. ix492 (1520PD)<br />
Park I. ix480 (1481PD), ix227 (679P),<br />
ix234 (700P), ix276 (834P), ix287 (872)<br />
Park J. ix433 (1324), ix227 (679P)<br />
Park J.H. ix480 (1481PD)<br />
Park J.S. ix240 (722P)<br />
Park K. ix391 (1198P), ix424 (1292P),<br />
ix430 (1311P), ix276 (834P), ix287 (872)<br />
Park K.H. ix102 (271P), ix185 (543P)<br />
Park K.U. ix193 (566P)<br />
Park K.W. ix249 (752)<br />
Park K.W. ix250 (757)<br />
Park L.C. ix450 (1381P)<br />
Park S. ix375 (1153), ix430 (1311P), ix276 (834P)<br />
Park S.J. ix287 (872)<br />
Park W.S. ix353 (1080P)<br />
Park Y. ix352 (1077P)<br />
Park Y.S. ix450 (1381P), ix479 (1479PD),<br />
ix227 (679P)<br />
Parker C. ix38 (49IN), ix296 (898PD),<br />
ix301 (913P), ix308 (936P)<br />
Parker I. ix108 (292P)<br />
Parkes E.E. ix107 (288P)<br />
Parlak C. ix392 (1202P), ix425 (1294P),<br />
ix520 (1620), ix526 (1641), ix526 (1642),<br />
ix237 (711P), ix238 (715P)<br />
Parmar D. ix339 (1034P)<br />
Parmar M.K. ix324 (982P)<br />
Parno J. ix493 (1522PD)<br />
Parreira J. ix175 (512PD), ix176 (514P)<br />
Parrozzani R. ix371 (1140P)<br />
Parthan A. ix235 (704P)<br />
Pascual T. ix134 (378), ix325 (986P)<br />
Pasov V. ix311 (944P)<br />
Pass H.I. ix495 (1532P)<br />
Passalacqua R. ix474 (1462PD), ix232 (693P)<br />
Passardi A. ix240 (724P)<br />
Passaro A. ix488 (1509P)<br />
Passos Lima C.S. ix339 (1032P)<br />
Pastorek M. ix286 (865P)<br />
Pastorelli D. ix439 (1345), ix447 (1370P)<br />
Patané A.K. ix496 (1535P)<br />
Patard J. ix292 (889TiP)<br />
Patel A. ix292 (889TiP)<br />
Patel A.A. ix356 (1092P), ix134 (377)<br />
Patel K.M. ix356 (1092P), ix134 (377)<br />
Patel R. ix321 (974PD)<br />
Patel S. ix366 (1126P), ix454 (1392P)<br />
Patel T. ix124 (344P)<br />
Pathania S. ix358 (1103)<br />
Paties C. ix216 (642)<br />
Patil B.R. ix343 (1049P)<br />
Patil P.S. ix541 (1689P)<br />
Patil S. ix98 (257P)<br />
Patnaik A. ix165 (481P), ix169 (492P)<br />
Patnick J. ix53 (88IN)<br />
Paton V.E. ix445 (1364TiP), ix445 (1365TiP)<br />
Patrick D. ix509 (1580P)<br />
Patsouris E. ix541 (1691P)<br />
Patton S. ix86 (213P)<br />
Patuzzo R. ix484 (1496P)<br />
Patyna S. ix376 (1155O)<br />
Paule B. ix243 (733P)<br />
Pauly M. ix209 (615)<br />
Pautier P. ix329 (1001P), ix322 (977P),<br />
ix322 (978P), ix327 (993P)<br />
Pauwels P. ix481 (1487P)<br />
Pavel M. ix376 (1154O), ix377 (1156O)<br />
Pavesi L. ix99 (260P)<br />
Pavlakis K. ix338 (1031P)<br />
Pavlakis N. ix419 (1278P)<br />
Pavlick A. ix363 (1113PD), ix363 (1115PD)<br />
Pavlidis N. ix381 (1170P), ix95 (246O)<br />
Pawaskar D.K. ix155 (447PD)<br />
Pawaskar P. ix350 (1069PD)<br />
Pawitan Y. ix299 (906P)<br />
Pawlyn C. ix44 (67IN)<br />
Paye F. ix241 (727P)<br />
Paz-Ares L. ix404 (1235PD), ix407 (1241P),<br />
ix411 (1254P), ix418 (1275P), ix157 (454P),<br />
ix235 (705P)<br />
Paze E. ix291 (884)<br />
Peña J.A. ix292 (888)<br />
Pearlberg J. ix321 (974PD)<br />
Peat J.K. ix499 (1544O)<br />
Peck R. ix385 (1179O)<br />
Pécuchet N. ix499 (1545O), ix77 (180P),<br />
ix99 (258P)<br />
Pecorari G. ix343 (1047P), ix346 (1058)<br />
Pecori B. ix193 (567P)<br />
Pectasides D. ix95 (246O)<br />
Pedani F. ix346 (1058)<br />
Pedrazzani C. ix452 (1385P)<br />
Pedrazzi G. ix216 (642)<br />
Peeters M. ix190 (558P), ix194 (569P),<br />
ix194 (570P)<br />
Pelizon C. ix142 (407TiP), ix142 (408TiP)<br />
Pellegrino D. ix440 (1348)<br />
Pellegrino R. ix339 (1032P)<br />
Pelletier G. ix243 (733P)<br />
Pelling K. ix161 (464P)<br />
Pelov D. ix258 (783O)<br />
Pelt V.G. ix184 (540P)<br />
Pemberton K. ix161 (464P)<br />
Pena C. ix395 (1212)<br />
Penault-Llorca F. ix102 (270P), ix105 (281P),<br />
ix180 (525PD)<br />
Penel N. ix482 (1488P), ix488 (1510P)<br />
Peng Y. ix260 (788O)<br />
Peng Z. ix299 (906P)<br />
Pennert K. ix273 (827P)<br />
Pen<strong>the</strong>roudakis G. ix381 (1170P), ix239 (717P)<br />
Penzel R. ix390 (1194P)<br />
Pereira A.A.L. ix112 (306), ix181 (528PD)<br />
Pereira B.S.V. ix215 (637)<br />
Pereira D. ix132 (371P)<br />
Pereira J. ix447 (1372P)<br />
Pereira J.R. ix403 (1233PD)<br />
Pereira V. ix538 (1680P)<br />
Peretz-Yablonski T. ix88 (220P), ix109 (294P),<br />
ix142 (409TiP)<br />
Pérez R. ix406 (1238PD)<br />
Perez Alvarez S.I. ix184 (541P)<br />
Pérez-Callejo D. ix492 (1521PD)<br />
Pérez Callejo D. ix459 (1410), ix494 (1527P),<br />
ix112 (307)<br />
Perez Cano M. ix431 (1315)<br />
Pérez Gracia J.L. ix275 (832P), ix432 (1316)<br />
Perez Gracia J.L. ix508 (1577P)<br />
Pérez González N. ix183 (537P)<br />
Perez-Carrion R. ix125 (345P)<br />
Perez-Galan P. ix44 (66IN)<br />
Perez-Moreno P. ix419 (1278P)<br />
Pérez Ramírez S. ix176 (517P)<br />
Perez-Sánchez V. ix107 (289P)<br />
Pérez-Valderrama B. ix275 (832P), ix314 (953)<br />
Perez E.A. ix89 (226P), ix142 (408TiP)<br />
Perez J. ix370 (1136P)<br />
Perez Q. ix218 (647), ix314 (953)<br />
Pericay C. ix235 (705P)<br />
Pericleous L. ix370 (1134P), ix372 (1143P)<br />
Permyakova V.I. ix109 (293P)<br />
Pernot S. ix75 (174O)<br />
Perol D. ix397 (1219)<br />
Perol M. ix397 (1219), ix426 (1299P)<br />
Perracchio L. ix142 (406TiP)<br />
Perricone G. ix215 (636)<br />
Perrin C. ix105 (281P)<br />
Perrin P. ix299 (907P)<br />
Perrin S. ix461 (1420PD)<br />
Perrone F. ix342 (1045P), ix212 (628)<br />
Perrone G. ix538 (1681P)<br />
Perrone T. ix515 (1599P)<br />
Perruccio K. ix535 (1668P)<br />
Pertuželka L. ix81 (196P)<br />
Pescarmona E. ix142 (406TiP)<br />
Pesce I. ix364 (1117PD)<br />
Pesce V. ix379 (1164P)<br />
Peschel A. ix480 (1484PD)<br />
Pessi M.A. ix516 (1601P), ix520 (1617),<br />
ix524 (1631)<br />
Pessi M.A. ix516 (1602P)<br />
Petekkaya _I.H. ix543 (1698P)<br />
Peters F.P. ix501 (1553P)<br />
Peters G. ix537 (1676P)<br />
Peters K. ix146 (417PD)<br />
Peters S. ix385 (1179O), ix61 (119IN),<br />
ix403 (1232PD), ix73 (167O)<br />
Petersen I. ix394 (1208)<br />
Petersen I.A. ix329 (1002P)<br />
Peterson P. ix428 (1303P)<br />
Petit T. ix142 (408TiP)<br />
Petrakis D. ix381 (1170P)<br />
Petrelli F. ix435 (1328), ix467 (1440),<br />
ix515 (1599P), ix519 (1615P), ix131 (368P),<br />
ix192 (563P)<br />
Petremolo A. ix316 (962TiP)<br />
Petricoin E. ix533 (1664P)<br />
Petrillo A. ix193 (567P)<br />
Petrillo P. ix370 (1135P)<br />
Petruzelka L. ix513 (1593P), ix81 (197P),<br />
ix116 (317O)<br />
Petry Helena V. ix455 (1397P)<br />
Petrylak D.P. ix302 (918P), ix311 (943P)<br />
Petzer A.L. ix209 (616)<br />
Pezaro C. ix298 (903P), ix301 (913P), ix304 (924P)<br />
Pfeiffer P. ix188 (553P)<br />
Pfeiler G. ix100 (261P)<br />
Pfister S.M. ix31 (25IN)<br />
Pfisterer J. ix324 (982P)<br />
Pfreundschuh M. ix349 (1068PD)<br />
Phan V. ix499 (1544O)<br />
Phelip J. ix181 (529PD), ix218 (648)<br />
Phelip J.M. ix242 (730P)<br />
Philip P.A. ix244 (735P)<br />
Phillips H.S. ix505 (1566P)<br />
Phuan C. ix199 (583P)<br />
Piacentini F. ix101 (267P)<br />
Piard F. ix206 (607P)<br />
Piatek C. ix314 (952)<br />
Volume 23 | Supplement 9 | June <strong>2012</strong> doi:10.1093/annonc/mds466 | ix573
author index<br />
Piau S. ix456 (1401P)<br />
Piazzalunga D. ix365 (1120P)<br />
Piccart M. ix58 (103IN), ix95 (247O),<br />
ix118 (324PD), ix126 (351P)<br />
Pichler J. ix147 (421P)<br />
Pichon E. ix419 (1276P)<br />
Pickering L. ix273 (827P)<br />
Picozzi V. ix236 (709P)<br />
Picquenot J.M. ix339 (1033P)<br />
Pienkowski T. ix103 (273P), ix116 (317O)<br />
Pierantoni C. ix387 (1184P)<br />
Pierdomenico F. ix357 (1096)<br />
Pietra C. ix520 (1618), ix161 (465P)<br />
Pietrantonio F. ix410 (1251P), ix212 (628)<br />
Pignon J. ix397 (1217), ix74 (170O), ix198 (580P)<br />
Pigozzo J. ix369 (1131P), ix371 (1140P)<br />
Piha-Paul S.A. ix154 (444PD)<br />
Pikó B. ix223 (665TiP)<br />
Pilati P.L. ix371 (1140P), ix486 (1504P)<br />
Pili F. ix287 (868)<br />
Pili R. ix303 (919P)<br />
Pilla L. ix369 (1133P)<br />
Pilotti S. ix342 (1045P), ix483 (1491P),<br />
ix484 (1496P), ix485 (1500P)<br />
Pilotto S. ix442 (1355), ix117 (322PD)<br />
Pinato D.J. ix381 (1169P)<br />
Pini A. ix448 (1373P)<br />
Pinitpatcharalerd A. ix339 (1035P)<br />
Pino M.S. ix237 (713P), ix240 (721P)<br />
Pinski J. ix261 (790O), ix306 (928P), ix314 (952),<br />
ix316 (961)<br />
Pinto A. ix511 (1585P), ix277 (839P)<br />
Pinto C. ix78 (183P)<br />
Piperi C. ix92 (236)<br />
Piquet J. ix455 (1396P)<br />
Pircher A. ix494 (1528P), ix76 (178P)<br />
Pirker R. ix417 (1272P)<br />
Pisconti S. ix370 (1135P)<br />
Piscopo G. ix539 (1682P)<br />
Pistelli M. ix250 (756)<br />
Pistilli B. ix116 (318O)<br />
Pitot H. ix222 (662TiP)<br />
Pittman K. ix208 (612P)<br />
Pitz C. ix425 (1296P)<br />
Piulats J.M. ix370 (1136P)<br />
Piulats J.R. ix294 (894O)<br />
Piutti M. ix206 (607P)<br />
Piva F. ix86 (215P)<br />
Piva S. ix511 (1585P)<br />
Pivette J. ix456 (1401P)<br />
Pivot X. ix332 (1014), ix470 (1452P), ix472 (1460),<br />
ix531 (1657P), ix103 (272P), ix114 (315TiP),<br />
ix128 (357P), ix249 (753)<br />
Pizzolitto S. ix457 (1405)<br />
Pizzuti L. ix142 (406TiP)<br />
Planchard D. ix496 (1534P), ix94 (244)<br />
Plante M. ix324 (982P)<br />
Plasswilm L. ix132 (370P)<br />
Plata Fernandez M.Y. ix101 (268P)<br />
Plaza J.C. ix233 (699P)<br />
Plazaola A. ix82 (200P)<br />
Pless M. ix396 (1214)<br />
Plestina S. ix86 (212P)<br />
Plummer R. ix374 (1149), ix129 (358P)<br />
Poddar S. ix356 (1091P), ix328 (997P)<br />
Podlipny J. ix474 (1464P)<br />
Podoll T. ix170 (498P)<br />
Poehlein C. ix267 (810P), ix269 (816P)<br />
Poggi R. ix145 (416PD), ix147 (424P)<br />
Poggio F. ix454 (1393P), ix501 (1551PD)<br />
Poitevin-Chacón A. ix329 (1003P)<br />
Polat O. ix227 (678P)<br />
Poleri C. ix496 (1535P)<br />
Poletti P. ix485 (1500P)<br />
Poli R. ix232 (693P)<br />
Pollak M. ix302 (917P)<br />
Polli A. ix402 (1230PD)<br />
Polyakova N.A. ix141 (403)<br />
Pompei L. ix105 (280P)<br />
Pompili C. ix387 (1184P)<br />
Pond G.R. ix265 (804P), ix297 (901PD)<br />
Pons Valladares F. ix233 (699P), ix278 (840P)<br />
Pontikakis S. ix429 (1308P)<br />
Poole C. ix142 (407TiP)<br />
Poon R. ix244 (736P)<br />
Pop S. ix519 (1614P)<br />
Popat S. ix409 (1246P)<br />
Popova M.E. ix398 (1223)<br />
Popovski T. ix99 (258P)<br />
Porneuf M. ix196 (572P)<br />
Porras I. ix131 (365P)<br />
Porta C. ix225 (669PD), ix261 (792PD),<br />
ix264 (798PD), ix271 (820P), ix273 (825P),<br />
ix278 (840P)<br />
Porta R. ix388 (1189P)<br />
Portela C. ix357 (1097)<br />
Porter D. ix487 (1507P)<br />
Portielje J.E.A. ix100 (263P)<br />
Portnoy S. ix130 (364P)<br />
Porzio R. ix216 (642)<br />
Postigo A. ix67 (145P)<br />
Potebnia G.P. ix536 (1672P)<br />
Potepan P. ix344 (1050P)<br />
Pottel H. ix341 (1042P)<br />
Pottel L. ix341 (1042P)<br />
Potter V. ix181 (530PD)<br />
Potthast M. ix520 (1618)<br />
Pouessel D. ix294 (893O)<br />
Poulain P. ix518 (1612P)<br />
Poupon M. ix312 (946)<br />
Pour L. ix348 (1064O)<br />
Pourali L. ix107 (287P)<br />
Pourel N. ix391 (1199P)<br />
Pourrli Neelakantan R. ix331 (1011)<br />
Poveda A.M. ix490 (1517TiP), ix324 (984P)<br />
Powderly J.D. ix258 (784O)<br />
Powell S. ix98 (257P)<br />
Power D.G. ix207 (610P), ix248 (750),<br />
ix300 (909P)<br />
Powers J. ix304 (922P)<br />
Powles T. ix172 (501), ix290 (880)<br />
Powles T.B. ix272 (822P), ix278 (840P),<br />
ix292 (887)<br />
Pozzi E. ix123 (339P), ix138 (391)<br />
Pozzo C. ix433 (1322), ix84 (207P)<br />
Prévost S. ix350 (1071P)<br />
Pradhan R. ix173 (507)<br />
Prager G. ix221 (659)<br />
Prasad Sahoo T. ix404 (1235PD)<br />
Prasad R.R. ix291 (883)<br />
Prasongsook N. ix339 (1035P)<br />
Prati V. ix290 (879)<br />
Prausova J. ix198 (581P)<br />
Precivale M. ix450 (1380P)<br />
Prestifilippo A. ix505 (1565P), ix137 (388)<br />
Prete A. ix440 (1348)<br />
Preusser M. ix145 (414PD), ix145 (415PD),<br />
ix147 (421P), ix148 (426P)<br />
Price N. ix73 (167O)<br />
Price T. ix178 (519O), ix182 (532P), ix187 (550P),<br />
ix194 (570P), ix208 (612P)<br />
Prickett T.D. ix25 (11IN)<br />
Primi C. ix516 (1601P)<br />
Principe E. ix113 (311)<br />
Prior J. ix480 (1482PD)<br />
Priou F. ix259 (786O), ix294 (893O)<br />
Pritchard K. ix118 (324PD), ix126 (351P)<br />
Procopio G. ix270 (818P), ix272 (824P),<br />
ix276 (836P), ix288 (873), ix305 (926P),<br />
ix315 (959)<br />
Proença M. ix458 (1409)<br />
Prohaszka Z. ix493 (1523P)<br />
Pronzato P. ix454 (1393P), ix463 (1425P),<br />
ix501 (1551PD), ix521 (1621), ix79 (187P),<br />
ix123 (340P)<br />
Proskorovsky I. ix279 (843P)<br />
Prot S. ix531 (1657P)<br />
Provencher L. ix531 (1657P)<br />
Provencio Pulla M. ix351 (1073P), ix414 (1264P),<br />
ix459 (1410), ix492 (1521PD), ix494 (1527P),<br />
ix510 (1582P), ix112 (307)<br />
Provent S. ix260 (789O)<br />
Prudkin L. ix154 (443PD)<br />
Pruegsanusak K. ix339 (1035P)<br />
Psyrri A. ix334 (1018O), ix42 (60IN), ix43 (63IN)<br />
Puccia F. ix215 (636)<br />
Puente J. ix438 (1342)<br />
Puertolas T. ix374 (1150)<br />
Puglia L. ix540 (1687), ix316 (962TiP)<br />
Puglisi F. ix142 (409TiP)<br />
Puhlmann M. ix321 (975PD)<br />
Pujade-Lauraine E. ix324 (984P), ix327 (993P)<br />
Pujol B. ix523 (1628)<br />
Pujol E. ix441 (1352)<br />
Pujol J. ix386 (1182P), ix418 (1275P)<br />
Pulatov D.A. ix71 (162P)<br />
Pulido G. ix131 (365P), ix140 (400), ix186 (546P)<br />
Puma E. ix102 (269P)<br />
Puma F. ix387 (1185P)<br />
Puneri G. ix83 (201P)<br />
Punt C.J.A. ix363 (1114PD), ix179 (521O),<br />
ix192 (562P)<br />
Puntoni M. ix119 (327PD)<br />
Puntus T. ix521 (1622)<br />
Purcell C. ix249 (754)<br />
Purohith S. ix358 (1102)<br />
Purushotham A. ix133 (372P)<br />
Pusceddu S. ix288 (873)<br />
Pusztai L. ix74 (172O), ix29 (19IN)<br />
Puyol J.R. ix448 (1373P)<br />
Puzanov I. ix170 (497P), ix259 (785O)<br />
Q<br />
Qi W. ix398 (1220), ix119 (326PD)<br />
Qi Y. ix74 (172O)<br />
Qian J. ix148 (428P), ix256 (779TiP)<br />
Qian W. ix378 (1161P)<br />
Qian Y. ix360 (1108TiP), ix479 (1480PD)<br />
Qiang L. ix416 (1269P)<br />
Qiang X. ix229 (686P)<br />
Qin J. ix495 (1530P)<br />
Qin S. ix416 (1269P), ix282 (851P)<br />
Qiu J. ix281 (847P)<br />
Qu X. ix437 (1337), ix93 (238), ix138 (394)<br />
Quadri P. ix452 (1385P)<br />
Quantin X. ix406 (1240P)<br />
Quaratino S. ix211 (622)<br />
Quarleri L. ix355 (1089P)<br />
Queirolo P. ix366 (1124P), ix367 (1128P),<br />
ix368 (1130P), ix369 (1131P), ix369 (1132P),<br />
ix369 (1133P), ix373 (1148)<br />
Queiroz L. ix357 (1095), ix357 (1097)<br />
Quek R. ix485 (1499P), ix485 (1501P)<br />
Queralt Herrero C. ix431 (1315)<br />
Queralt B. ix219 (651)<br />
Queralt C. ix418 (1273P), ix533 (1662P)<br />
Quercia S. ix130 (362P)<br />
Quero C. ix351 (1073P)<br />
Quidde J. ix459 (1413TiP)<br />
Quietzsch D. ix204 (599P)<br />
Quinn D.I. ix261 (790O), ix311 (942P),<br />
ix314 (952), ix316 (961)<br />
Quintavalle C. ix539 (1682P)<br />
Quintero G. ix440 (1349)<br />
Quintyne K.I. ix114 (312)<br />
Quirke P. ix179 (521O)<br />
Quoix E. ix419 (1276P)<br />
Quon D. ix480 (1483PD), ix166 (482P)<br />
Qvortrup C. ix188 (553P)<br />
R<br />
Rabault B. ix157 (454P)<br />
Radema S.A. ix122 (335P)<br />
Raderer M. ix352 (1076P)<br />
Annals of Oncology<br />
ix574 | author index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology author index<br />
Raemdonck D.V. ix212 (626)<br />
Raggi D. ix285 (861P)<br />
Raghavan D. ix261 (790O), ix314 (952)<br />
Rahal A. ix486 (1502P)<br />
Rahal C. ix486 (1502P)<br />
Rahal M. ix337 (1028P)<br />
Rahhali R. ix110 (297P)<br />
Raies H. ix254 (774)<br />
Raikou M. ix236 (707P)<br />
Raimondo L. ix343 (1047P), ix346 (1058)<br />
Raimundo A. ix201 (591P), ix210 (620),<br />
ix221 (657)<br />
Raina P. ix312 (948)<br />
Raina V. ix349 (1067PD), ix354 (1085P),<br />
ix358 (1101), ix455 (1398P), ix110 (298P)<br />
Rais G. ix476 (1470P), ix476 (1472P)<br />
Raissouni S. ix476 (1470P), ix476 (1472P)<br />
Raja A. ix483 (1492P)<br />
Raja F.A. ix324 (982P)<br />
Rajappa S. ix174 (510TiP)<br />
Raje N. ix360 (1108TiP)<br />
Rajec J. ix293 (890TiP)<br />
Rajendranath R. ix490 (1515)<br />
Rajer M. ix446 (1368TiP)<br />
Rajic L. ix359 (1104)<br />
Rajkovic E. ix350 (1072P)<br />
Raju R. ix170 (496P)<br />
Rako I. ix86 (212P)<br />
Ramée J.F. ix196 (572P)<br />
Ramón Y Cajal T. ix408 (1244P)<br />
Ram Z. ix72 (163P)<br />
Ramaekers B.L.T. ix397 (1217)<br />
Ramalingam S.S. ix529 (1647PD)<br />
Ramirez Fallas R.A. ix184 (541P)<br />
Ramlau R. ix395 (1211)<br />
Rammer M. ix209 (616)<br />
Ramon Y Cajal S. ix84 (204P)<br />
Ramondino S. ix330 (1004P)<br />
Ramos Vazquez M. ix273 (826P)<br />
Ramos D. ix181 (527PD)<br />
Ramos T. ix432 (1316), ix183 (537P)<br />
Ramsey S. ix203 (596P)<br />
Rana D.N. ix93 (240)<br />
Ranade A.A. ix301 (912P)<br />
Rancic M. ix428 (1304P)<br />
Rangarajan, V. ix351 (1074P)<br />
Rangarajan B. ix174 (510TiP)<br />
Ransom D. ix178 (519O)<br />
Raoul J.L. ix376 (1155O), ix184 (539P),<br />
ix241 (727P)<br />
Rapetti S.G. ix442 (1355), ix444 (1360)<br />
Raphael J. ix496 (1534P), ix94 (244)<br />
Raponi M. ix236 (709P)<br />
Rasco D. ix165 (481P)<br />
Raspagliesi F. ix330 (1004P)<br />
Rastrelli M. ix486 (1504P)<br />
Ratain M.J. ix319 (966O)<br />
Rathkopf D. ix296 (897O), ix303 (920P),<br />
ix317 (964TiP)<br />
Rathkopf D.E. ix295 (895O)<br />
Rathmann N. ix480 (1484PD)<br />
Ratnayake J. ix83 (202P)<br />
Ratta R. ix530 (1653P)<br />
Ratti M. ix330 (1004P), ix232 (693P)<br />
Rauch E. ix348 (1064O)<br />
Rauh S. ix458 (1407)<br />
Rauscher B. ix373 (1145)<br />
Ravaioli A. ix232 (695P)<br />
Ravaud A. ix258 (783O), ix259 (786O),<br />
ix263 (797PD), ix292 (889TiP)<br />
Ravic M. ix350 (1072P)<br />
Ray-Coquard I. ix478 (1477O), ix488 (1511P),<br />
ix327 (993P)<br />
Ray-Coquard I.L. ix481 (1487P), ix482 (1488P)<br />
Ray U.K. ix356 (1093P)<br />
Raymond E. ix334 (1017O), ix376 (1155O),<br />
ix379 (1163P), ix167 (485P)<br />
Razak A.R.A. ix156 (450PD), ix158 (455P),<br />
ix158 (457P)<br />
Razis E. ix213 (630)<br />
Rea D. ix539 (1682P), ix97 (253PD),<br />
ix119 (325PD)<br />
Read J. ix499 (1544O)<br />
Reardon D.A. ix146 (417PD)<br />
Reck M. ix404 (1235PD), ix405 (1236PD),<br />
ix406 (1239P), ix408 (1245P), ix409 (1249P),<br />
ix410 (1250P), ix493 (1522PD), ix75 (175PD),<br />
ix52 (85IN)<br />
Reckova M. ix293 (890TiP)<br />
Reda W. ix150 (432)<br />
Reddy S. ix224 (666O)<br />
Reddy S.K. ix517 (1605P)<br />
Redekop W.K. ix450 (1379P)<br />
Redmond K. ix66 (142IN)<br />
Redondo A. ix490 (1517TiP)<br />
Reed G. ix223 (664TiP)<br />
Reed N. ix329 (1001P), ix378 (1161P)<br />
Rego J.F.M. ix181 (528PD)<br />
Reguart N. ix418 (1273P)<br />
Reichardt P. ix478 (1478O), ix479 (1480PD),<br />
ix481 (1486PD), ix482 (1490P)<br />
Reichert V. ix529 (1647PD), ix533 (1664P)<br />
Reid G. ix169 (493P)<br />
Reif M. ix237 (712P)<br />
Reig Torras O. ix282 (853P)<br />
Reig O. ix343 (1046P)<br />
Reijers J. ix103 (274P)<br />
Reijneveld J. ix145 (415PD)<br />
Reina J.J. ix380 (1165P)<br />
Reinisch S. ix340 (1038P)<br />
Reinmuth N. ix390 (1194P)<br />
Reis-Filho J. ix224 (667PD)<br />
Reis L.O. ix306 (929P)<br />
Reiser M. ix504 (1561P)<br />
Reisman A. ix403 (1231PD), ix416 (1268P)<br />
Reisman D. ix78 (186P)<br />
Ren L. ix190 (557P), ix201 (589P), ix217 (644)<br />
Ren S. ix81 (195P)<br />
Ren X. ix282 (851P)<br />
Rendleman J. ix363 (1113PD)<br />
Renehan A.G. ix207 (609P)<br />
Reni M. ix240 (724P)<br />
Renouf D. ix188 (551P), ix204 (601P), ix215 (635)<br />
Repana D. ix430 (1312)<br />
Rescigno P. ix439 (1345), ix447 (1370P),<br />
ix283 (854P), ix316 (962TiP)<br />
Resiga L. ix337 (1026P)<br />
Resteghini C. ix335 (1019O), ix341 (1040P)<br />
Reusch U. ix350 (1072P)<br />
Reuss A. ix390 (1194P), ix322 (976P),<br />
ix323 (980P)<br />
Reuter C.W.M. ix299 (908P)<br />
Rey A. ix410 (1250P)<br />
Reychler H. ix336 (1021PD)<br />
Reyderman L. ix129 (358P)<br />
Reyes-Rivera I. ix190 (559P), ix193 (565P),<br />
ix195 (571P)<br />
Reyes C. ix451 (1384P), ix477 (1474)<br />
Reymen B. ix396 (1213), ix425 (1296P)<br />
Reyners A.K.L. ix40 (57IN)<br />
Reyno L. ix317 (963TiP)<br />
Reynolds C. ix393 (1205P)<br />
Reynoso N. ix251 (763)<br />
Rezai M. ix117 (321PD)<br />
Rezazadeh M. ix459 (1411)<br />
Rha S.Y. ix185 (543P)<br />
Riahi K. ix321 (974PD)<br />
Ribal M.J. ix538 (1680P), ix312 (945)<br />
Ribas A. ix158 (456P)<br />
Ribeiro J. ix289 (878)<br />
Ribeiro K.B. ix112 (306)<br />
Ribelles N. ix101 (268P)<br />
Ribi K. ix462 (1423O)<br />
Riccardi A. ix123 (339P), ix138 (391)<br />
Ricchini F. ix507 (1571P)<br />
Ricci F. ix301 (914P)<br />
Ricci J. ix121 (334P), ix122 (336P)<br />
Ricci S. ix238 (714P), ix251 (761), ix251 (762)<br />
Ricciardi G.R.R. ix104 (276P)<br />
Ricciardi S. ix439 (1346)<br />
Ricevuto E. ix524 (1633), ix213 (629)<br />
Richard D. ix68 (149P)<br />
Richard F. ix241 (725P)<br />
Richards D. ix170 (496P)<br />
Richards J. ix368 (1129P)<br />
Richman S.D. ix179 (521O)<br />
Rick O. ix284 (858P)<br />
Ricker J.L. ix83 (203P), ix173 (505), ix173 (507)<br />
Rickmann M. ix67 (145P)<br />
Ridolfi L. ix367 (1128P)<br />
Ridolfi R. ix370 (1135P), ix373 (1148)<br />
Ridwelski K. ix228 (680P)<br />
Riechelmann R.P. ix450 (1380P), ix181 (528PD)<br />
Riely G.J. ix415 (1267P)<br />
Riera-Knorrenschild J. ix178 (518O)<br />
Riess H. ix255 (776TiP)<br />
Riet F. ix277 (837P)<br />
Rigaux P. ix488 (1510P)<br />
Rijavec E. ix79 (187P)<br />
Riley J. ix485 (1498P)<br />
Rimassa L. ix225 (669PD)<br />
Rimawi M.F. ix142 (407TiP)<br />
Rinaldi G. ix368 (1130P)<br />
Rinaldi L. ix524 (1633)<br />
Rinck-Junior J.A. ix364 (1119P), ix365 (1121P),<br />
ix365 (1122P)<br />
Rinck J.A.Jr ix308 (934P)<br />
Rinderknecht J.D. ix366 (1125P)<br />
Rindi G. ix47 (73IN)<br />
Rini B.I. ix259 (785O), ix262 (793PD)<br />
Rini B.I. ix268 (811P)<br />
Rios M. ix236 (708P)<br />
Ripamonti C.I. ix516 (1601P), ix516 (1602P),<br />
ix520 (1617), ix524 (1631)<br />
Riquelme A. ix205 (604P)<br />
Riquet M. ix77 (180P)<br />
Risi E. ix488 (1509P)<br />
Rittmeyer A. ix386 (1182P)<br />
Rittweger K. ix445 (1364TiP), ix187 (550P)<br />
Riva G. ix343 (1047P), ix346 (1058)<br />
Rivalland G. ix487 (1507P)<br />
Rivera Salceda A.D. ix126 (349P)<br />
Rivera D. ix126 (349P)<br />
Rivera F. ix233 (699P)<br />
Rivera P. ix198 (580P)<br />
Rivera V.M. ix152 (439O)<br />
Rivoire M. ix286 (864P)<br />
Rivoltini L. ix361 (1110O)<br />
Rixe O. ix170 (497P)<br />
Rizvi S. ix231 (691P)<br />
Rizzo G. ix99 (260P)<br />
Rizzo M. ix276 (836P)<br />
Rizzolo C.A. ix215 (636)<br />
Robert C. ix367 (1127P)<br />
Robert F. ix424 (1291P)<br />
Robinot G. ix426 (1299P)<br />
Roca E. ix379 (1164P)<br />
Rocca Cossu P. ix287 (868)<br />
Rocchetto M. ix326 (991P)<br />
Rocha E. ix524 (1632)<br />
Roche P. ix146 (419PD)<br />
Rochlitz C. ix372 (1144)<br />
Roda D. ix159 (458P)<br />
Roder H. ix407 (1241P)<br />
Rodionova M. ix130 (364P)<br />
Rodon J. ix537 (1675P), ix84 (204P), ix157 (454P),<br />
ix158 (457P)<br />
Rodrigues Pereira J. ix400 (1225O)<br />
Rodrigues A. ix331 (1010)<br />
Rodrigues H. ix132 (371P)<br />
Rodríguez Ariza A. ix530 (1652P)<br />
Volume 23 | Supplement 9 | June <strong>2012</strong> doi:10.1093/annonc/mds466 | ix575
author index<br />
Rodríguez Rodríguez M. ix92 (234)<br />
Rodríguez Rubí D. ix218 (647)<br />
Rodríguez-Moreno J.F. ix276 (835P)<br />
Rodríguez R.M. ix131 (365P)<br />
Rodriguez Alonso M. ix198 (579P)<br />
Rodriguez Garrote M. ix206 (606P)<br />
Rodriguez Gayo L. ix198 (579P)<br />
Rodriguez Pantigoso W. ix224 (668PD)<br />
Rodriguez-Antona C. ix276 (835P)<br />
Rodriguez-Lescure A. ix140 (400)<br />
Rodriguez-Vida A. ix370 (1136P)<br />
Rodriguez C. ix281 (850P)<br />
Rodriguez I. ix533 (1661P)<br />
Rodriguez J. ix149 (429P), ix239 (718P)<br />
Roeffen M.H.S. ix484 (1497P)<br />
Rofe C. ix172 (501)<br />
Roganovic J. ix359 (1104)<br />
Roghanian A. ix70 (157P)<br />
Rogowski W. ix223 (665TiP)<br />
Roh J.K. ix185 (543P)<br />
Roh S.Y. ix250 (757)<br />
Rojas P. ix363 (1115PD)<br />
Rojo F. ix80 (194P), ix187 (549P)<br />
Roldão M. ix345 (1056)<br />
Rolfe L. ix236 (709P)<br />
Rolland F. ix294 (893O)<br />
Roman M.P. ix543 (1697P)<br />
Romeder F. ix249 (755)<br />
Romeira D. ix458 (1409)<br />
Romejko-Jarosinska J. ix354 (1084P)<br />
Romero Laorden N. ix113 (310)<br />
Romero-Ventosa E.Y. ix92 (234)<br />
Romero I. ix324 (984P)<br />
Romieu G. ix62 (121IN)<br />
Rommel D. ix336 (1021PD)<br />
Roncalli M. ix77 (181P)<br />
Roncella M. ix176 (515P)<br />
Rong A. ix194 (570P)<br />
Roos M. ix157 (452P)<br />
Rosa R. ix530 (1651P), ix532 (1659P), ix287 (869)<br />
Rosales-Pérez S. ix329 (1003P)<br />
Rosales A. ix496 (1535P)<br />
Rosas Camargo V. ix184 (541P)<br />
Rosati M.S. ix502 (1557P)<br />
Rosbrook B. ix262 (793PD)<br />
Rose C. ix409 (1249P), ix241 (725P)<br />
Rosell R. ix385 (1179O), ix418 (1273P),<br />
ix431 (1315), ix529 (1647PD), ix531 (1655P),<br />
ix533 (1661P), ix533 (1662P), ix533 (1664P),<br />
ix73 (167O), ix74 (170O), ix229 (686P),<br />
ix266 (807P)<br />
Rosen L.S. ix482 (1490P), ix156 (449PD),<br />
ix157 (452P), ix168 (489P)<br />
Rosen P. ix160 (461P)<br />
Rosenberg J.E. ix39 (50IN)<br />
Rosenberg M. ix496 (1535P)<br />
Rosenberg P. ix514 (1596P), ix539 (1683P),<br />
ix172 (504)<br />
Rosenberg R. ix179 (522PD)<br />
Rosenberg S.A. ix25 (11IN)<br />
Rosenblatt J.D. ix353 (1083P)<br />
Rosenfeld N. ix74 (171O)<br />
Rosenthal M.A. ix151 (437TiP)<br />
Roshan V. ix149 (430P)<br />
Ross G. ix83 (202P)<br />
Ross J.R. ix485 (1498P)<br />
Ross M. ix371 (1137P)<br />
Rossetto C. ix457 (1405)<br />
Rossi C.R. ix486 (1504P), ix131 (367P)<br />
Rossi E. ix489 (1512), ix77 (181P), ix91 (230P)<br />
Rossi J. ix349 (1068PD)<br />
Rossi M.S. ix215 (637)<br />
Rossi S. ix370 (1136P)<br />
Rossoni G. ix410 (1251P), ix167 (487P),<br />
ix172 (502)<br />
Rosti G. ix458 (1408), ix285 (863P)<br />
Rotarski M. ix499 (1547PD)<br />
Roth A.D. ix480 (1482PD), ix37 (45IN)<br />
Ro<strong>the</strong> A. ix350 (1072P)<br />
Ro<strong>the</strong> F. ix98 (255PD)<br />
Ro<strong>the</strong>rmundt C.A. ix302 (917P)<br />
Rotmensz N. ix83 (201P)<br />
Rottenberg G. ix275 (831P)<br />
Rottey S. ix341 (1042P), ix287 (870)<br />
Roué G. ix44 (66IN)<br />
Rouanne M. ix474 (1463P)<br />
Rouas G. ix98 (255PD)<br />
Rougier P. ix191 (561P), ix194 (568P)<br />
Rouleau E. ix175 (511PD)<br />
Roulstone V. ix537 (1677P)<br />
Rouquette I. ix388 (1190P)<br />
Rousseau V. ix389 (1192PD), ix474 (1463P)<br />
Rouyer M. ix219 (649)<br />
Roveta A. ix247 (747P)<br />
Rowen D. ix372 (1143P)<br />
Rowsell C. ix490 (1516)<br />
Roy P.S. ix351 (1074P)<br />
Roy R. ix284 (859P)<br />
Roy U.K. ix355 (1090P), ix359 (1105),<br />
ix359 (1106), ix133 (375P)<br />
Rozumna-Martynyuk N. ix300 (909P)<br />
Ruíz Vozmediano J. ix254 (773)<br />
Ru Q. ix116 (318O)<br />
Rubagotti A. ix301 (914P)<br />
Rubin J. ix222 (662TiP)<br />
Rubini F. ix440 (1348)<br />
Rubino C. ix364 (1118PD)<br />
Rubio B. ix441 (1352)<br />
Rubio G. ix80 (194P)<br />
Rubio I. ix212 (627)<br />
Rubio I.T. ix95 (247O)<br />
Rubio M. ix388 (1189P)<br />
Rucinska M. ix457 (1406), ix475 (1466P)<br />
Rudà R. ix140 (402)<br />
Rudd R. ix421 (1282P)<br />
Rudin C.M. ix319 (966O)<br />
Rudman S. ix275 (831P)<br />
Rueda A. ix351 (1073P)<br />
Ruers T.J.M. ix330 (1006P), ix532 (1658P),<br />
ix35 (39IN), ix211 (622)<br />
Ruff P. ix198 (581P)<br />
Ruffion A. ix299 (907P)<br />
Rugge M. ix533 (1661P), ix209 (618)<br />
Ruggeri E.M. ix105 (280P)<br />
Ruginescu I. ix341 (1041P), ix345 (1053)<br />
Rugo H. ix118 (324PD), ix121 (334P)<br />
Rugo H.S. ix130 (363P)<br />
Ruijter E. ix111 (301)<br />
Ruiperez C.O. ix457 (1404)<br />
Ruiz-Valdepeñas A. ix459 (1410), ix492 (1521PD),<br />
ix494 (1527P), ix112 (307)<br />
Ruíz Voxmediano J. ix254 (773)<br />
Ruiz E.B. ix251 (763)<br />
Ruiz G.C. ix251 (763)<br />
Ruiz L. ix218 (647), ix277 (839P)<br />
Rumpold H. ix209 (616)<br />
Ruperez Blanco A.B. ix176 (517P)<br />
Ruquet S. ix116 (318O)<br />
Rüssel J. ix357 (1098)<br />
Russell P. ix542 (1692P)<br />
Russo L. ix99 (259P)<br />
Ruszniewski P. ix378 (1160P), ix379 (1163P)<br />
Rutgers E. ix532 (1658P)<br />
Rutkowski P. ix478 (1478O), ix479 (1480PD),<br />
ix480 (1482PD), ix482 (1490P), ix484 (1495P),<br />
ix489 (1513)<br />
Ryabchikov D. ix130 (364P)<br />
Ryan C.J. ix294 (894O), ix295 (895O),<br />
ix303 (920P)<br />
Ryan C.J. ix317 (964TiP)<br />
Ryan D.P. ix156 (449PD), ix224 (666O)<br />
Rykov I.V. ix141 (403)<br />
Ryoo B. ix480 (1481PD), ix227 (679P),<br />
ix234 (700P)<br />
Annals of Oncology<br />
Ryu H. ix454 (1392P), ix541 (1688PD)<br />
Ryu M.H. ix480 (1481PD), ix227 (679P),<br />
ix234 (700P)<br />
Ryuge M. ix517 (1608P)<br />
Ryuge N. ix225 (671P)<br />
S<br />
Sá A. ix208 (614P)<br />
Sa-Cunha A. ix219 (649), ix238 (716P),<br />
ix243 (733P)<br />
Saad F. ix295 (896O), ix297 (899PD), ix315 (956),<br />
ix316 (960)<br />
Saada E. ix337 (1025P), ix340 (1037P),<br />
ix341 (1041P), ix345 (1053)<br />
Sabbatini R. ix290 (879)<br />
Saber M.M. ix134 (376)<br />
Sabin Domínguez P. ix264 (799P)<br />
Sablin M. ix519 (1614P)<br />
Sabourin J.C. ix416 (1270P), ix85 (210P),<br />
ix213 (629), ix252 (767)<br />
Sabry M. ix448 (1374P), ix449 (1376P)<br />
Saburi Y. ix348 (1062O)<br />
Sacco C. ix276 (836P)<br />
Sacconi A. ix183 (535P)<br />
Sachiko O. ix82 (199P)<br />
Sacks N. ix301 (915P)<br />
Sadaba B. ix508 (1577P)<br />
Sadahiro S. ix185 (542P), ix188 (552P),<br />
ix197 (575P), ix207 (611P)<br />
Sadikov A. ix522 (1625), ix523 (1630)<br />
Sadus-Wojciechowska M. ix353 (1082P)<br />
Saeb-Parsy K. ix93 (240)<br />
Safanda M. ix503 (1560P)<br />
Saffery C. ix224 (667PD)<br />
Safont M.J. ix529 (1648P)<br />
Sagaert X. ix222 (663TiP)<br />
Saghatchian M. ix128 (355P)<br />
Sagi M. ix109 (294P)<br />
Sahebjam S. ix155 (448PD)<br />
Sahin B. ix326 (990P)<br />
Sahmoud T. ix118 (324PD), ix121 (334P),<br />
ix126 (351P), ix231 (691P)<br />
Sahoo R.K. ix264 (800P)<br />
Sahoo T.P. ix400 (1225O)<br />
Said S. ix332 (1013)<br />
Saida Y. ix71 (159P)<br />
Saijo Y. ix420 (1280P)<br />
Sainato A. ix241 (726P)<br />
Sairi A. ix485 (1499P), ix485 (1501P)<br />
Saisho S. ix541 (1690P)<br />
Saito H. ix434 (1325), ix445 (1366TiP)<br />
Saito K. ix509 (1578P)<br />
Saito M. ix327 (995P)<br />
Saito N. ix210 (621)<br />
Saito Y. ix112 (305)<br />
Saiura A. ix211 (625)<br />
Saji S. ix104 (277P), ix188 (552P),<br />
ix200 (588P)<br />
Sajjady G. ix493 (1525P)<br />
Saka H. ix445 (1366TiP), ix517 (1608P)<br />
Sakai D. ix196 (573P)<br />
Sakai G. ix514 (1597P), ix203 (598P)<br />
Sakai H. ix404 (1234PD)<br />
Sakaida T. ix144 (412O)<br />
Sakamaki F. ix525 (1637)<br />
Sakamoto J. ix514 (1595P), ix93 (237),<br />
ix200 (588P), ix228 (681P), ix230 (688P)<br />
Sakamoto M. ix87 (216P)<br />
Sakata Y. ix202 (592P)<br />
Sakr H. ix129 (360P), ix216 (639)<br />
Sakurai N. ix211 (624)<br />
Salah A.F. ix109 (294P)<br />
Salamoon M.I. ix72 (164)<br />
Salat C. ix514 (1596P), ix539 (1683P)<br />
Salati M. ix387 (1184P)<br />
Salaun B. ix361 (1110O), ix386 (1182P)<br />
Salazar Blanco J. ix183 (536P), ix185 (544P)<br />
ix576 | author index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology author index<br />
Salazar R. ix377 (1156O), ix377 (1157O),<br />
ix529 (1648P), ix178 (520O), ix179 (522PD)<br />
Salcedo M. ix496 (1533P)<br />
Saleh M. ix317 (964TiP)<br />
Salem M. ix342 (1043P), ix244 (735P)<br />
Salem N. ix150 (434)<br />
Saleri J. ix474 (1462PD)<br />
Salesi N. ix502 (1557P)<br />
Saletan S. ix122 (336P)<br />
Salgado M.A.V. ix205 (604P)<br />
Salgado M.L. ix147 (423P)<br />
Salgia R. ix403 (1231PD), ix416 (1268P),<br />
ix152 (439O)<br />
Salman T. ix234 (701P)<br />
Saloustros E. ix139 (395)<br />
Salud A. ix233 (699P)<br />
Salvador Garrido N. ix328 (1000P)<br />
Salvador C. ix106 (284P)<br />
Salvadori B. ix94 (243)<br />
Salvagni S. ix225 (669PD)<br />
Salvalaggio A. ix144 (411O)<br />
Salvi S. ix301 (914P)<br />
Salvini J. ix183 (535P)<br />
Salvioni R. ix88 (222P), ix285 (861P), ix315 (959)<br />
Salzberg M. ix396 (1214)<br />
Samantas E. ix337 (1026P), ix430 (1312),<br />
ix239 (717P)<br />
Samer C.F. ix538 (1678P)<br />
Sami A. ix503 (1559P), ix517 (1607P)<br />
Samoylenko I.V. ix371 (1138P)<br />
Samper E. ix67 (145P)<br />
Samper P. ix312 (945)<br />
Samuels Y. ix25 (11IN)<br />
Sánchez-Ollé G. ix302 (916P)<br />
Sánchez-Rovira P. ix101 (268P)<br />
Sanchez-Muñoz A. ix101 (268P)<br />
Sanchez-Muñoz A. ix140 (400)<br />
Sanchez-Tilo E. ix67 (145P)<br />
Sánchez J.J. ix533 (1661P), ix533 (1662P),<br />
ix229 (686P), ix265 (802P), ix266 (807P)<br />
Sánchez M.L. ix218 (647)<br />
Sánchez P. ix131 (365P), ix186 (546P)<br />
Sanchez A. ix314 (953)<br />
Sanchez B. ix266 (807P)<br />
Sanchez F.B. ix331 (1009)<br />
Sanchez R. ix82 (200P)<br />
Sancho Gutiérrez A. ix212 (627)<br />
Sandell M. ix384 (1178TiP)<br />
Sandhu S. ix298 (903P), ix304 (924P)<br />
Sandin R. ix269 (815P), ix279 (843P),<br />
ix281 (848P)<br />
Sandoval F. ix75 (174O)<br />
Sands R. ix312 (948)<br />
Sandström P. ix281 (848P)<br />
Sane S.P. ix101 (265P)<br />
Sanfilippo R. ix483 (1493P)<br />
Sanjuanbenito A. ix472 (1456P)<br />
Sankhala K. ix480 (1483PD)<br />
Sanmamed M.F. ix365 (1123P)<br />
Sanna S. ix496 (1536P)<br />
Sano M.V. ix104 (275P)<br />
Sanon M. ix235 (704P)<br />
Santaballa A. ix106 (284P)<br />
Santarpia L. ix74 (172O)<br />
Santegoets S. ix301 (915P)<br />
Santeufemia D. ix287 (868)<br />
Santi S. ix251 (761), ix251 (762)<br />
Santiago Crespo J. ix457 (1404), ix459 (1412)<br />
Santiesteban E. ix406 (1238PD)<br />
Santinelli A. ix387 (1184P), ix533 (1663P)<br />
Santini D. ix489 (1512), ix500 (1550PD),<br />
ix516 (1603P), ix530 (1653P), ix538 (1681P),<br />
ix130 (362P), ix206 (606P)<br />
Santini F.C. ix112 (306)<br />
Santisteban M. ix149 (429P)<br />
Santo A. ix496 (1536P)<br />
Santomé L. ix273 (826P)<br />
Santoni-Rugiu E. ix80 (191P)<br />
Santoni M. ix148 (425P), ix270 (818P),<br />
ix290 (879)<br />
Santoro A. ix407 (1241P), ix483 (1494P),<br />
ix487 (1506P), ix153 (440O), ix167 (488P),<br />
ix172 (504), ix225 (669PD)<br />
Santos A.A. ix464 (1429P)<br />
Santos S. ix175 (512PD), ix176 (514P)<br />
Sanz J. ix438 (1342)<br />
Sapino A. ix140 (402)<br />
Sarıcı F.S. ix543 (1698P)<br />
Saracino B. ix237 (713P)<br />
Sarangarajan R. ix166 (482P)<br />
Sarantopoulos J. ix168 (489P), ix303 (921P)<br />
Saretok M. ix149 (431)<br />
Sargent D.J. ix535 (1670P)<br />
Sargento I. ix345 (1056)<br />
Sari E. ix497 (1540)<br />
Saridaki Z. ix213 (631)<br />
Sarkar S.K. ix452 (1388P)<br />
Sarker D. ix165 (479P)<br />
Sarker S. ix272 (822P)<br />
Sárosi V. ix429 (1307P)<br />
Sarr C. ix158 (457P)<br />
Sarsık B. ix274 (830P)<br />
Sartor A.O. ix296 (898PD), ix307 (933P)<br />
Sartor O. ix38 (47IN), ix308 (936P)<br />
Sartor O.A. ix296 (897O)<br />
Sartorius U. ix188 (554P), ix191 (561P)<br />
Saruwatari K. ix438 (1340)<br />
Sarwar N. ix272 (822P)<br />
Sasajima Y. ix372 (1142P)<br />
Sasaki A. ix87 (216P)<br />
Sasaki E. ix381 (1171P)<br />
Sasaki H. ix327 (995P)<br />
Sasaki K. ix188 (552P)<br />
Sasaki R. ix510 (1581P)<br />
Sasaki T. ix381 (1171P)<br />
Sasaki Y. ix202 (593P)<br />
Sasatomi T. ix248 (751)<br />
Sasse A. ix513 (1594P), ix181 (528PD),<br />
ix306 (929P)<br />
Sastre J. ix377 (1157O), ix190 (559P), ix195 (571P)<br />
Sato E. ix508 (1576P)<br />
Sato K. ix509 (1579P)<br />
Sato S. ix220 (653)<br />
Sato T. ix196 (573P)<br />
Satoh T. ix167 (486P)<br />
Satouchi M. ix393 (1204P), ix424 (1293P)<br />
Satow R. ix536 (1673P)<br />
Satre J. ix183 (537P)<br />
Saunders M.P. ix199 (582P), ix206 (608P),<br />
ix207 (609P)<br />
Saura C. ix531 (1656P), ix116 (318O)<br />
Saura S. ix441 (1352)<br />
Savage R. ix244 (738P), ix245 (739P)<br />
Savarino G. ix79 (187P)<br />
Saveanu A. ix146 (419PD)<br />
Savic S. ix385 (1179O), ix73 (167O)<br />
Savini A. ix387 (1184P), ix533 (1663P)<br />
Savulsky C. ix129 (358P)<br />
Sawa T. ix439 (1343)<br />
Sawada T. ix383 (1175P), ix87 (216P)<br />
Sawaki A. ix231 (689P)<br />
Sawaki M. ix139 (396)<br />
Sawan B. ix350 (1071P)<br />
Sawicki S. ix320 (970PD)<br />
Sawkins K. ix151 (437TiP)<br />
Sawrycki P. ix409 (1246P)<br />
Sawyer E. ix139 (398)<br />
Sax C. ix145 (415PD), ix147 (421P)<br />
Sayaloune P. ix100 (262P)<br />
Sayer H.G. ix284 (858P)<br />
Scagliotti G. ix415 (1267P)<br />
Scagliotti G.V. ix444 (1360)<br />
Scalese M. ix127 (354P)<br />
Scaltriti M. ix126 (350P)<br />
Scambia G. ix514 (1596P), ix539 (1683P),<br />
ix323 (980P)<br />
Scaramellini G. ix341 (1040P), ix342 (1045P)<br />
Scarpa A. ix25 (12IN), ix226 (675P), ix287 (869)<br />
Scarpellini P. ix335 (1019O)<br />
Scartozzi M. ix431 (1313), ix86 (214P),<br />
ix86 (215P), ix219 (652), ix239 (720P),<br />
ix243 (734P), ix250 (756), ix274 (829P)<br />
Schöffski P. ix478 (1478O), ix518 (1609P),<br />
ix154 (445PD)<br />
Schützová M. ix504 (1562P)<br />
Schachar R. ix416 (1268P)<br />
Schad F. ix453 (1389P), ix466 (1437P)<br />
Schaeper C. ix409 (1249P)<br />
Schalhorn A. ix204 (599P)<br />
Scheithauer W. ix178 (518O), ix253 (768)<br />
Schellens J. ix153 (442O)<br />
Schellens J.H.M. ix538 (1678P), ix32 (29IN)<br />
Schellhammer P. ix310 (940P)<br />
Schelman W. ix224 (666O)<br />
Schepotin I. ix134 (379)<br />
Scher H.I. ix89 (223P), ix294 (894O),<br />
ix295 (896O), ix297 (899PD), ix317 (964TiP)<br />
Scherer S.J. ix390 (1194P), ix405 (1236PD),<br />
ix406 (1239P), ix531 (1657P), ix81 (198P)<br />
Scherpereel A. ix408 (1243P)<br />
Schiavon G. ix500 (1550PD), ix530 (1653P)<br />
Schiavone P. ix95 (248O)<br />
Schildhaus H. ix481 (1486PD)<br />
Schilf A. ix340 (1037P), ix341 (1041P),<br />
ix345 (1053)<br />
Schiller J.H. ix409 (1246P)<br />
Schinzari G. ix433 (1322)<br />
Schirmacher P. ix394 (1208)<br />
Schlenk R.F. ix349 (1068PD)<br />
Schlichting C. ix195 (571P)<br />
Schlichting M. ix188 (554P)<br />
Schlijper R. ix212 (626)<br />
Schlumberger M.J. ix154 (445PD)<br />
Schmalfeldt B. ix322 (976P)<br />
Schmid K.W. ix437 (1339)<br />
Schmid P. ix532 (1660P), ix537 (1675P),<br />
ix73 (169O), ix123 (341P)<br />
Schmid T. ix494 (1528P)<br />
Schmidinger M. ix278 (841P)<br />
Schmidt-Wolf I.G. ix268 (813P)<br />
Schmidt M. ix178 (518O), ix268 (813P)<br />
Schmitt F. ix127 (352P)<br />
Schmitz J. ix289 (876)<br />
Schmitz S. ix336 (1021PD), ix457 (1403),<br />
ix458 (1407), ix504 (1561P), ix42 (58IN)<br />
Schmoll H. ix357 (1098), ix187 (550P)<br />
Schmoll H.J. ix336 (1023PD), ix178 (518O)<br />
Schnabel P. ix390 (1194P)<br />
Schneeweiss A. ix514 (1596P), ix539 (1683P),<br />
ix83 (202P), ix142 (409TiP)<br />
Schneid H. ix518 (1612P)<br />
Schneider M. ix332 (1014)<br />
Schneider V. ix337 (1025P)<br />
Schnell C. ix537 (1675P)<br />
Schnell D. ix161 (464P), ix162 (468P)<br />
Schoenberg S.O. ix480 (1484PD)<br />
Schott E. ix255 (778TiP)<br />
Schreibelt G. ix363 (1114PD)<br />
Schrijvers D. ix452 (1386P)<br />
Schroff M. ix268 (813P)<br />
Schuckman A. ix261 (790O)<br />
Schuebbe G. ix487 (1505P)<br />
Schuette J. ix480 (1484PD), ix482 (1490P)<br />
Schuhmacher C. ix228 (680P)<br />
Schuler M. ix402 (1229PD), ix410 (1252P),<br />
ix437 (1339), ix157 (454P)<br />
Schultz N. ix89 (223P)<br />
Schulze M. ix306 (930P)<br />
Schumann A. ix237 (712P)<br />
Schusterbauer C. ix160 (461P)<br />
Schwabe C. ix162 (470P)<br />
Schwartz B. ix244 (738P), ix245 (739P)<br />
Schwartz G.K. ix319 (966O)<br />
Schwartz J. ix363 (1115PD)<br />
Volume 23 | Supplement 9 | June <strong>2012</strong> doi:10.1093/annonc/mds466 | ix577
author index<br />
Scoggins C.R. ix371 (1137P)<br />
Scott A. ix542 (1692P)<br />
Scotte F. ix499 (1545O)<br />
Scudder C. ix181 (530PD)<br />
Sculier J. ix408 (1243P)<br />
Seah T. ix182 (533P)<br />
Seal B. ix205 (603P), ix214 (634)<br />
Sebag-Montefiori D. ix206 (608P)<br />
Sebagh M. ix243 (733P)<br />
Sebastia M.C. ix282 (853P)<br />
Sebastian F. ix388 (1189P)<br />
Seber E.S. ix217 (645)<br />
Seber S. ix497 (1540)<br />
Sebio Garcia A. ix183 (536P), ix185 (544P),<br />
ix216 (641)<br />
Secen N. ix428 (1304P)<br />
Seddon B. ix482 (1490P)<br />
Segagni D. ix535 (1669P)<br />
Segal-Eiras A. ix210 (619)<br />
Segelov E. ix181 (530PD)<br />
Segnan N. ix53 (88IN)<br />
Segota Z. ix498 (1543TiP)<br />
Sehouli J. ix514 (1596P), ix539 (1683P),<br />
ix172 (504), ix323 (980P)<br />
Seilanian Toosi M. ix107 (287P), ix184 (538P)<br />
Seilanian Tousi M. ix248 (749)<br />
Seiler R. ix148 (427P)<br />
Seitz J. ix378 (1159P), ix242 (730P)<br />
Sejda A. ix73 (167O)<br />
Seki A. ix426 (1298P)<br />
Seki N. ix442 (1354), ix469 (1447PD)<br />
Seki R. ix525 (1637)<br />
Seki Y. ix159 (459P)<br />
Sekiguchi R. ix393 (1206P), ix397 (1218)<br />
Sekimoto A. ix467 (1443)<br />
Sekine I. ix396 (1215)<br />
Sekulic A. ix362 (1112PD)<br />
Selby B. ix297 (899PD)<br />
Selek U. ix237 (711P)<br />
Seligmann J.F. ix500 (1549PD)<br />
Sella A. ix313 (950)<br />
Sella T. ix313 (950)<br />
Selle F. ix260 (789O), ix322 (978P), ix327 (993P)<br />
Selvarajah L. ix468 (1444)<br />
Selzer E. ix340 (1038P)<br />
Semiglazov V. ix103 (272P)<br />
Semiglazov V.F. ix139 (397)<br />
Semiglazov V.V. ix139 (397)<br />
Semiglazova T.Y. ix139 (397)<br />
Seminara P. ix105 (282P)<br />
Sempoux C. ix197 (578P)<br />
Şen S. ix274 (830P)<br />
Sen A.N. ix471 (1454P), ix471 (1455P),<br />
ix328 (997P)<br />
Senellart H. ix406 (1240P), ix426 (1299P),<br />
ix169 (494P), ix218 (648)<br />
Senetta R. ix140 (402)<br />
Sengar M. ix350 (1069PD), ix351 (1074P)<br />
Sengelov L. ix307 (932P)<br />
Senn-Schönenberger I.K. ix132 (370P)<br />
Senn H. ix132 (370P)<br />
Sensi E. ix183 (535P)<br />
Seoane J. ix531 (1656P)<br />
Seol Y.M. ix172 (503)<br />
Sepúlveda J. ix96 (250PD)<br />
Sepulveda Sanchez J. ix281 (850P)<br />
Sequist L.V. ix402 (1229PD), ix405 (1237PD),<br />
ix410 (1252P), ix152 (438O), ix51 (82IN)<br />
Serejo F. ix255 (777TiP)<br />
Sereno M. ix374 (1151), ix441 (1352)<br />
Sergi D. ix142 (406TiP)<br />
Sergi M. ix493 (1525P)<br />
Serke M. ix409 (1247P)<br />
Seronde A. ix85 (210P)<br />
Serpe R. ix462 (1422O), ix463 (1427P),<br />
ix466 (1438P), ix164 (476P)<br />
Serra V. ix84 (204P)<br />
Serrano D. ix83 (201P)<br />
Serrano G. ix187 (549P)<br />
Sersch M. ix191 (560P)<br />
Sersch M.A. ix190 (559P)<br />
Sertic J. ix86 (212P)<br />
Seruga B. ix91 (231P)<br />
Servent V. ix101 (266P)<br />
Sessa C. ix40 (56IN)<br />
Sestak I. ix75 (176PD)<br />
Seth A. ix264 (800P)<br />
Sethugavalar B. ix106 (283P)<br />
Seto T. ix387 (1187P), ix153 (441O)<br />
Severin K. ix504 (1561P)<br />
Sevilla I. ix377 (1157O), ix380 (1165P)<br />
Sevin E. ix263 (797PD)<br />
Seymour L. ix389 (1192PD)<br />
Seymour M. ix500 (1549PD)<br />
Sezer O. ix360 (1108TiP)<br />
Sfakianaki M. ix429 (1308P), ix213 (631)<br />
Sfiniadakis I. ix541 (1691P)<br />
Sforza V. ix67 (143PD)<br />
Sgargi P. ix175 (513PD)<br />
Sgouros J. ix239 (717P)<br />
Sgroi D. ix126 (350P)<br />
Shablak A. ix267 (808P)<br />
Shafaeddin-Schreve B. ix372 (1144)<br />
Shah M. ix376 (1154O), ix428 (1303P),<br />
ix154 (445PD)<br />
Shah P.M. ix356 (1092P), ix134 (377)<br />
Shah S.A. ix356 (1092P), ix134 (377)<br />
Shah V. ix70 (157P)<br />
Shahabi V. ix75 (175PD)<br />
Shahid R.K. ix182 (531P)<br />
Shahid T. ix301 (912P)<br />
Shahidi M. ix402 (1229PD), ix410 (1252P)<br />
Shak S. ix179 (523PD)<br />
Shaker M. ix253 (770)<br />
Shalenkov V. ix252 (765)<br />
Shamash J. ix272 (822P), ix290 (880)<br />
Shamseddine A. ix288 (874)<br />
Shang S. ix363 (1113PD)<br />
Shankar G. ix157 (452P)<br />
Shankar S. ix355 (1090P)<br />
Shankaran V. ix203 (596P)<br />
Shanks J. ix267 (808P)<br />
Shanmugam K. ix383 (1173P)<br />
Shao W. ix161 (466P)<br />
Shao Y. ix363 (1113PD)<br />
Shao Z. ix130 (361P)<br />
Shapiro G. ix163 (471P)<br />
Shapiro R. ix363 (1113PD)<br />
Shaplygin L.V. ix398 (1223), ix521 (1623)<br />
Sharan B. ix174 (510TiP)<br />
Sharawat S.K. ix349 (1067PD)<br />
Sharif S. ix179 (523PD)<br />
Sharifi H. ix396 (1216)<br />
Sharkar A.M. ix468 (1444)<br />
Sharma A. ix349 (1067PD), ix354 (1085P),<br />
ix358 (1101)<br />
Sharma M. ix304 (922P)<br />
Sharma R. ix381 (1169P)<br />
Sharma S. ix153 (440O)<br />
Sharma S.C. ix242 (729P)<br />
Sharp L. ix315 (957)<br />
Sharpe K. ix172 (501)<br />
Shaw Dulin R.J. ix107 (289P), ix126 (349P)<br />
Shaw A. ix402 (1230PD), ix416 (1268P)<br />
Shaw A.T. ix389 (1191PD), ix403 (1233PD),<br />
ix415 (1267P), ix423 (1290P), ix152 (439O),<br />
ix153 (440O)<br />
Shaw H. ix374 (1149)<br />
Shaw J. ix533 (1664P)<br />
Shay Levi L. ix463 (1426P)<br />
Shehata S. ix537 (1676P)<br />
Sheikh N. ix311 (942P), ix311 (943P)<br />
Shen K. ix117 (320PD)<br />
Shen L. ix217 (646), ix231 (690P), ix231 (691P),<br />
ix307 (933P)<br />
Shen P. ix501 (1552P)<br />
Annals of Oncology<br />
Shen W. ix421 (1281P)<br />
Shen Y. ix246 (744P)<br />
Shen Z. ix398 (1220), ix427 (1300P),<br />
ix119 (326PD), ix126 (348P)<br />
Shenjere P. ix90 (227P)<br />
Shepherd F.A. ix417 (1272P), ix74 (170O),<br />
ix78 (186P)<br />
Sherer S. ix82 (200P)<br />
Sherman S. ix154 (445PD)<br />
Sherrill B. ix191 (560P), ix192 (564P)<br />
Sheth S. ix425 (1297P)<br />
Shi G. ix501 (1552P)<br />
Shi J. ix138 (394)<br />
Shi N. ix267 (810P), ix269 (816P)<br />
Shi P. ix124 (342P)<br />
Shi S. ix138 (394)<br />
Shi Y. ix390 (1196P), ix394 (1209), ix424 (1292P),<br />
ix435 (1331), ix77 (182P), ix111 (302)<br />
Shia A. ix532 (1660P), ix73 (169O)<br />
Shiah H. ix246 (744P)<br />
Shibata T. ix492 (1519PD), ix159 (459P),<br />
ix233 (697P), ix327 (995P)<br />
Shibuya M. ix441 (1351), ix497 (1537P)<br />
Shieh F. ix432 (1316)<br />
Shields A.F. ix244 (735P)<br />
Shigeki Satoh S. ix439 (1343)<br />
Shih N. ix538 (1679P)<br />
Shim H. ix467 (1441)<br />
Shim H.J. ix468 (1446)<br />
Shimada A.K. ix112 (306)<br />
Shimada K. ix217 (646)<br />
Shimada M. ix442 (1356), ix225 (671P),<br />
ix326 (989P)<br />
Shimada T. ix510 (1581P)<br />
Shimada Y. ix512 (1590P), ix529 (1649P),<br />
ix202 (593P), ix203 (598P), ix251 (764)<br />
Shimamoto T. ix164 (474P)<br />
Shimamura H. ix211 (624)<br />
Shimizu C. ix90 (228P)<br />
Shimizu J. ix433 (1324)<br />
Shimizu K. ix360 (1108TiP), ix541 (1690P)<br />
Shimizu R. ix159 (460P)<br />
Shimizu T. ix407 (1242P)<br />
Shimoi T. ix381 (1171P)<br />
Shimoyama T. ix381 (1171P)<br />
Shimozuma K. ix512 (1590P)<br />
Shin D. ix414 (1262P)<br />
Shin S.J. ix185 (543P)<br />
Shindo Y. ix514 (1595P), ix240 (723P)<br />
Shindoh J. ix439 (1343), ix445 (1366TiP)<br />
Shingler S.L. ix476 (1473P)<br />
Shingyoji M. ix144 (412O)<br />
Shinohara T. ix436 (1334)<br />
Shinozaki E. ix87 (218P), ix196 (574P)<br />
Shinozaki K. ix512 (1590P)<br />
Shirahashi A. ix508 (1576P)<br />
Shirane M. ix534 (1666P), ix112 (305)<br />
Shiroiwa T. ix200 (588P), ix320 (973PD)<br />
Shirouzu K. ix248 (751)<br />
Shitara K. ix232 (692P), ix232 (694P)<br />
Shmeeda H. ix164 (477P)<br />
Shoji H. ix251 (764)<br />
Shore N.D. ix303 (920P), ix309 (937P),<br />
ix317 (964TiP)<br />
Shreeve S.M. ix423 (1290P)<br />
Shridhar E. ix351 (1074P)<br />
Shucai Z. ix416 (1269P)<br />
Shukla N.K. ix455 (1398P), ix110 (298P)<br />
Shukla P. ix149 (430P)<br />
Shukla S.N. ix356 (1092P), ix134 (377)<br />
Shukuya T. ix430 (1310P)<br />
Shun L. ix443 (1359)<br />
Shustov A.R. ix348 (1063O), ix353 (1083P)<br />
Siannis F. ix373 (1146), ix85 (211P), ix94 (242)<br />
Sica L. ix102 (269P)<br />
Sicard E. ix169 (493P)<br />
Siddiqui N. ix358 (1100), ix497 (1539P),<br />
ix327 (994P)<br />
ix578 | author index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology author index<br />
Siddqui N. ix285 (860P)<br />
Sidhu R. ix190 (558P), ix192 (564P), ix194 (570P)<br />
Sidoni A. ix387 (1185P)<br />
Sieber O. ix383 (1173P)<br />
Sieber P. ix309 (937P)<br />
Sieczkowski E. ix72 (165)<br />
Siemens D.R. ix260 (788O)<br />
Siena S. ix190 (558P), ix194 (570P), ix205 (605P)<br />
Sigal D.S. ix224 (666O)<br />
Silletta M. ix489 (1512)<br />
Silva J.R.D. ix331 (1009)<br />
Silvestris N. ix206 (606P), ix229 (685P)<br />
Simões C. ix175 (512PD), ix176 (514P)<br />
Simeon C. ix347 (1061TiP)<br />
Simeone E. ix368 (1130P), ix369 (1132P),<br />
ix375 (1152)<br />
Simes R.J. ix151 (437TiP), ix178 (519O),<br />
ix182 (532P)<br />
Simko J. ix310 (939P)<br />
Simmonds P.D. ix283 (857P)<br />
Simon H. ix499 (1547PD), ix128 (355P)<br />
Simon I. ix179 (522PD)<br />
Simoncini E. ix338 (1029P)<br />
Simonelli M. ix167 (488P)<br />
Simons W.R. ix120 (330P), ix121 (332P)<br />
Simos D. ix493 (1525P)<br />
Sims R.B. ix310 (939P), ix310 (940P)<br />
Sinagra D. ix215 (636)<br />
Sinagra E. ix215 (636)<br />
Singh A.O. ix242 (729P)<br />
Singh J.K. ix301 (912P)<br />
Singh M. ix301 (912P)<br />
Singh P. ix291 (883)<br />
Singh R.B. ix358 (1103)<br />
Singh S. ix339 (1034P), ix377 (1158P),<br />
ix380 (1167P), ix383 (1173P)<br />
Sini C. ix79 (187P)<br />
Sini M. ix364 (1118PD)<br />
Siow T. ix139 (398)<br />
Sirbu D. ix116 (317O)<br />
Sisani M. ix315 (958)<br />
Sitko V.V. ix536 (1672P)<br />
Sittampalam K. ix485 (1499P), ix485 (1501P)<br />
Siu L. ix155 (448PD), ix156 (450PD), ix158 (455P)<br />
Siu L.L. ix319 (966O)<br />
Sivakumar A.T. ix343 (1049P), ix345 (1055)<br />
Sizoo E. ix145 (415PD)<br />
Skachkova O.V. ix536 (1672P)<br />
Skailes G. ix421 (1282P)<br />
Skalidaki E. ix431 (1314)<br />
Skarlos D. ix95 (246O)<br />
Skladowski K. ix334 (1016O)<br />
Skoblar Vidmar M. ix229 (683P)<br />
Skock-Lober R. ix409 (1249P)<br />
Skoog L. ix299 (906P)<br />
Slanarˇ O. ix81 (196P)<br />
Slater S. ix319 (966O)<br />
Sleeboom H. ix447 (1372P)<br />
Slichenmyer W. ix391 (1198P)<br />
Slimane K. ix334 (1017O), ix511 (1584P),<br />
ix264 (798PD), ix289 (876)<br />
Sloane R. ix87 (219P)<br />
Small A. ix451 (1384P)<br />
Small E. ix294 (894O)<br />
Small E.J. ix310 (939P), ix311 (942P)<br />
Smethurst D.P. ix354 (1086P)<br />
Sminia P. ix537 (1676P)<br />
Smit E. ix385 (1179O), ix152 (438O)<br />
Smit E.F. ix401 (1227O)<br />
Smit J.M. ix211 (622)<br />
Smith C. ix485 (1498P)<br />
Smith C.G. ix179 (521O)<br />
Smith C.J. ix395 (1210)<br />
Smith D. ix378 (1159P), ix393 (1205P),<br />
ix194 (568P), ix219 (649), ix242 (730P)<br />
Smith D.A. ix153 (442O)<br />
Smith D.C. ix157 (453P), ix296 (897O)<br />
Smith D.C. ix258 (784O)<br />
Smith H. ix231 (691P)<br />
Smith I. ix403 (1233PD)<br />
Smith M. ix108 (290P)<br />
Smith M.R. ix295 (895O), ix296 (897O),<br />
ix297 (901PD), ix303 (920P)<br />
Smi<strong>the</strong>rs B.M. ix371 (1137P)<br />
Smorczewska M. ix354 (1084P)<br />
Smorenburg C. ix100 (263P)<br />
Smoter M. ix268 (812P)<br />
Smyth E.N. ix421 (1281P)<br />
So S. ix227 (676P)<br />
Soares L.M.C. ix524 (1632)<br />
Soares P. ix208 (614P)<br />
Soberino García J. ix254 (773)<br />
Sobrero A. ix35 (41IN), ix205 (605P)<br />
Soejima K. ix422 (1285P)<br />
Soerensen A.V. ix271 (819P)<br />
Soetekouw P.M.M.B. ix319 (966O)<br />
Sohaib A. ix273 (827P)<br />
Sohn J. ix120 (329P)<br />
Solís Hernández M.D.P. ix218 (647)<br />
Solak M. ix543 (1698P), ix104 (278P)<br />
Soldatenkova V. ix395 (1211)<br />
Solitro F. ix444 (1360)<br />
Söling U. ix505 (1567P)<br />
Solomon B. ix416 (1268P), ix423 (1290P)<br />
Solomon J.A. ix362 (1111PD)<br />
Solsona E. ix312 (945)<br />
Soltermann A. ix495 (1532P), ix73 (167O)<br />
Somers A. ix287 (870)<br />
Sommariva A. ix486 (1504P)<br />
Son B.H. ix108 (291P)<br />
Sonderen M.J. ix160 (462P)<br />
Song C. ix217 (643), ix276 (834P), ix287 (872)<br />
Song I.C. ix541 (1688PD)<br />
Song J. ix161 (466P)<br />
Song P. ix166 (482P)<br />
Song X. ix438 (1341)<br />
Song X.Q. ix400 (1225O)<br />
Song Y.M. ix202 (595P)<br />
Sonke G.S. ix124 (342P)<br />
Sonke J. ix396 (1213)<br />
Sonmez O.U. ix332 (1015), ix105 (279P)<br />
Sonpavde G. ix260 (787O), ix265 (804P),<br />
ix297 (901PD)<br />
Sorbye H. ix188 (553P)<br />
Sorensen J.B. ix443 (1357), ix80 (191P)<br />
Soria I. ix165 (480P)<br />
Soria J. ix426 (1299P), ix474 (1463P),<br />
ix496 (1534P), ix74 (170O), ix94 (244),<br />
ix116 (319O), ix155 (446PD), ix168 (491P),<br />
ix174 (509TiP), ix24 (7IN)<br />
Soriano J. ix219 (651)<br />
Sosman J. ix361 (1109O)<br />
Sosman J.A. ix158 (456P)<br />
Sotiriou C. ix57 (100IN), ix98 (255PD)<br />
Soto-Matos A. ix166 (484P)<br />
Sottotetti F. ix123 (339P), ix138 (391)<br />
Souahli S. ix528 (1645PD)<br />
Soubeyran P. ix501 (1554P), ix504 (1563P),<br />
ix506 (1568P), ix506 (1569P)<br />
Souglakos I. ix429 (1308P)<br />
Souglakos J. ix381 (1170P), ix531 (1655P),<br />
ix213 (631)<br />
Soulières D. ix395 (1210), ix411 (1254P)<br />
Soulie M. ix294 (893O)<br />
Souquet P. ix416 (1270P)<br />
Sousa B. ix127 (352P)<br />
Sousa N. ix201 (591P), ix210 (620), ix221 (657),<br />
ix222 (661)<br />
Soussan P. ix340 (1036P)<br />
Souverein P. ix122 (335P)<br />
Souza A.I. ix464 (1429P)<br />
Sovak M. ix81 (198P)<br />
Sowmya P. ix345 (1055)<br />
Spadaro P. ix140 (399)<br />
Spahn G. ix453 (1389P), ix466 (1437P)<br />
Spanik S. ix286 (865P)<br />
Sparreboom A. ix534 (1667P)<br />
Specht J. ix153 (442O)<br />
Speel E-J.M. ix73 (167O)<br />
Speel E.J. ix80 (193P)<br />
Speelers B. ix330 (1007)<br />
Speers C. ix188 (551P)<br />
Spencer-Shaw A. ix267 (808P)<br />
Spencer M. ix314 (954)<br />
Spengler W. ix440 (1347)<br />
Sperduti I. ix105 (280P), ix226 (675P),<br />
ix237 (713P), ix240 (721P)<br />
Spicer J. ix422 (1287P), ix119 (325PD),<br />
ix161 (464P), ix165 (479P)<br />
Spiegl Kreinecker S. ix147 (421P)<br />
Spigel D. ix405 (1237PD), ix408 (1245P)<br />
Spigel D.R. ix420 (1279P), ix498 (1543TiP)<br />
Spigno F. ix80 (192P)<br />
Spina R. ix486 (1504P)<br />
Spindler K. ix530 (1654P), ix73 (168O)<br />
Spira A. ix393 (1205P)<br />
Spittler A. ix539 (1685P)<br />
Spliid H. ix271 (819P)<br />
Spoto C. ix500 (1550PD), ix516 (1603P)<br />
Squiban P. ix165 (478P), ix169 (494P)<br />
Squire J. ix304 (922P)<br />
Sreenivas V. ix349 (1067PD)<br />
Sridhar S.S. ix260 (787O), ix265 (804P),<br />
ix315 (956), ix316 (960)<br />
Sridharan N. ix331 (1011)<br />
Srimuninnimit V. ix400 (1226O), ix97 (254PD)<br />
Srinivasan P. ix275 (831P)<br />
Sriram Y. ix466 (1439)<br />
Srisu<strong>the</strong>p A. ix339 (1035P)<br />
Srivastava M. ix174 (510TiP)<br />
Stål P. ix255 (777TiP)<br />
Störkel S. ix417 (1272P)<br />
Stacchiotti S. ix484 (1496P), ix485 (1500P)<br />
Stadler W.M. ix265 (804P), ix303 (919P)<br />
Staehler M. ix292 (889TiP)<br />
Stagni S. ix305 (926P)<br />
Stahel R.A. ix58 (105IN), ix385 (1179O),<br />
ix66 (138IN), ix73 (167O), ix80 (193P),<br />
ix86 (213P)<br />
Staines H. ix155 (446PD)<br />
Stalmeier P.F.M. ix475 (1469P)<br />
Stam A. ix301 (915P)<br />
Stamatis G. ix49 (79IN)<br />
Stanczak A. ix544 (1700)<br />
Stanković N. ix237 (712P)<br />
Starikov A.V. ix109 (293P)<br />
Staroslawska E. ix103 (273P)<br />
Stasi I. ix94 (243), ix176 (515P)<br />
Stathopoulos G. ix493 (1524P)<br />
Stathopoulos J. ix493 (1524P)<br />
Stauber R. ix255 (778TiP)<br />
Stauch K. ix270 (817P), ix279 (844P)<br />
Staudacher K. ix296 (898PD), ix308 (936P)<br />
Stebbing J. ix132 (369P)<br />
Stec R. ix268 (812P)<br />
Steeghs N. ix157 (454P)<br />
Steelman L. ix293 (892TiP)<br />
Steenbergen R.D. ix88 (221P)<br />
Stefanescu M. ix67 (146P)<br />
Steffens C. ix190 (559P)<br />
Steger G. ix116 (317O)<br />
Steger G.G. ix145 (414PD)<br />
Stein A. ix35 (40IN)<br />
Steiner M.S. ix304 (923P)<br />
Steiner T. ix274 (828P)<br />
Steinmetz H.T. ix504 (1561P), ix505 (1567P)<br />
Stelitano C. ix523 (1628)<br />
Stemke-Hale K. ix84 (204P)<br />
Stemmer S.M. ix116 (317O)<br />
Stephenson J. ix224 (666O)<br />
Stephenson P. ix389 (1191PD)<br />
Stephenson R.A. ix310 (939P)<br />
Stergiopoulos S. ix376 (1154O), ix272 (823P)<br />
Sterlacci W. ix494 (1528P)<br />
Volume 23 | Supplement 9 | June <strong>2012</strong> doi:10.1093/annonc/mds466 | ix579
author index<br />
Stern L. ix272 (823P)<br />
Sternberg C.N. ix260 (787O), ix262 (795PD),<br />
ix265 (804P), ix270 (818P), ix278 (840P),<br />
ix295 (896O), ix297 (899PD)<br />
Sternberg D.W. ix116 (318O), ix158 (457P)<br />
Sternfeld T. ix465 (1435P)<br />
Steven J.H. ix97 (253PD)<br />
Stevens L. ix508 (1575P)<br />
Stewart D. ix78 (185P)<br />
Stewart F. ix311 (942P), ix311 (943P)<br />
Stewart G. ix93 (240)<br />
Stewart S. ix156 (449PD), ix157 (452P)<br />
Stilidi I. ix252 (765)<br />
Stinchi S. ix154 (444PD)<br />
Stintzing S. ix180 (526PD), ix188 (554P),<br />
ix204 (599P)<br />
Stjepanovic N. ix496 (1533P)<br />
St.-Laurent Thibault C. ix316 (960)<br />
Stoeckle E. ix482 (1488P)<br />
Stoehlmacher-Williams J. ix336 (1022PD)<br />
Stoltidis D. ix436 (1335)<br />
Stoltz M. ix223 (664TiP)<br />
Stopfer P. ix162 (468P)<br />
Storino C. ix330 (1005P)<br />
Stork-Sloots L. ix96 (251PD)<br />
Stouthard J.M. ix501 (1553P)<br />
Sträter J. ix440 (1347)<br />
Strøm H.H. ix392 (1200P)<br />
Stradella A. ix216 (641)<br />
Stragliotto S. ix369 (1132P), ix371 (1140P)<br />
Strasser F. ix64 (131IN), ix462 (1423O)<br />
Stratton M. ix25 (10IN)<br />
Straubinger R.M. ix155 (447PD)<br />
Strausz J. ix429 (1307P)<br />
Stravodimou A. ix138 (393)<br />
Strebel R. ix302 (917P)<br />
Streich G. ix448 (1373P)<br />
Strippoli A. ix84 (207P)<br />
Strola G. ix528 (1644PD)<br />
Stroyakovskiy D. ix97 (254PD)<br />
Studeny M. ix245 (740P)<br />
Sturgeon J. ix200 (586P)<br />
Stylianou S. ix160 (463P)<br />
Su N. ix345 (1052)<br />
Su W. ix246 (744P), ix247 (746P)<br />
Su Y. ix267 (810P), ix269 (816P)<br />
Suarez C. ix266 (806P), ix277 (839P), ix302 (916P)<br />
Subiza J.L. ix165 (480P)<br />
Subramanian S. ix174 (510TiP)<br />
Subtil F. ix178 (520O), ix242 (730P)<br />
Suder A. ix275 (831P)<br />
Sudo K. ix200 (585P)<br />
Suenaga M. ix542 (1693P), ix87 (218P),<br />
ix246 (742P)<br />
Sugawara S. ix412 (1256P), ix413 (1259P),<br />
ix427 (1301P), ix443 (1358)<br />
Sugihara K. ix197 (576P), ix200 (587P)<br />
Sugimoto H. ix542 (1693P)<br />
Sugino T. ix69 (153P)<br />
Sugino Y. ix434 (1325)<br />
Sugio K. ix387 (1187P)<br />
Sugito M. ix210 (621)<br />
Sugiyama T. ix326 (989P)<br />
Sukari A. ix342 (1043P)<br />
Sukhaboon J. ix339 (1035P)<br />
Sukumaran S. ix503 (1558P)<br />
Sullivan I.G. ix408 (1244P), ix292 (888)<br />
Sullivan R. ix66 (141INIS)<br />
Sultan A. ix347 (1061TiP)<br />
Sumi M. ix396 (1215)<br />
Summers Y. ix493 (1525P), ix507 (1573P)<br />
Sun F.F. ix202 (595P)<br />
Sun H. ix283 (857P)<br />
Sun J. ix413 (1261P), ix424 (1292P),<br />
ix150 (435TiP)<br />
Sun L. ix247 (745P)<br />
Sun M. ix216 (640)<br />
Sun S. ix412 (1255P)<br />
Sun T. ix438 (1341)<br />
Sun X.J. ix226 (674P)<br />
Sun Y. ix394 (1209), ix119 (326PD)<br />
Sundarraj S. ix70 (158P)<br />
Sundstrøm S. ix392 (1200P)<br />
Sunguroglu K. ix469 (1448PD)<br />
Sunnetci N. ix394 (1207P)<br />
Supernat A.M. ix320 (970PD)<br />
Surmacz E. ix166 (483P)<br />
Susnerwala S. ix206 (608P)<br />
Suurmeijer A.J.H. ix484 (1497P)<br />
Suzuki H. ix388 (1188P), ix432 (1320),<br />
ix433 (1321)<br />
Suzuki K. ix233 (697P), ix320 (973PD)<br />
Suzuki N. ix240 (723P)<br />
Suzuki R. ix434 (1325), ix445 (1366TiP)<br />
Suzuki S. ix518 (1611P), ix156 (451P),<br />
ix164 (475P)<br />
Suzuki T. ix185 (542P), ix197 (575P),<br />
ix207 (611P), ix244 (737P)<br />
Suzuki Y. ix112 (305)<br />
Suzumiya J. ix348 (1062O)<br />
Suzumura T. ix79 (189P), ix79 (190P), ix92 (235)<br />
Svedman C. ix97 (252PD)<br />
Svegliati Baroni G. ix243 (734P)<br />
Svergun N.M. ix536 (1672P)<br />
Svetlovska D. ix293 (890TiP)<br />
Svoboda T. ix474 (1464P)<br />
Svrcek M. ix234 (703P)<br />
Swain S. ix124 (344P)<br />
Sweeney C. ix296 (897O)<br />
Swellam M. ix352 (1079P)<br />
Swennenhuis J.F. ix91 (230P)<br />
Swieboda-Sadlej A. ix409 (1246P)<br />
Swinson D. ix500 (1549PD)<br />
Switaj T. ix484 (1495P)<br />
Sycova-Mila Z. ix293 (890TiP)<br />
Syed N. ix532 (1660P)<br />
Synowiec A. ix320 (971PD)<br />
Szczylik C. ix255 (776TiP), ix264 (798PD),<br />
ix268 (812P), ix271 (820P), ix320 (971PD),<br />
ix323 (979P)<br />
Szilagyi A. ix493 (1523P)<br />
Szima B. ix405 (1236PD), ix406 (1239P)<br />
Sznol M. ix361 (1109O), ix157 (453P),<br />
ix258 (784O)<br />
Szyldergemajn S. ix166 (484P)<br />
Szymczyk M. ix354 (1084P)<br />
T<br />
Tabernero J. ix451 (1382P), ix531 (1656P),<br />
ix84 (204P), ix116 (319O), ix154 (443PD),<br />
ix159 (458P), ix179 (522PD), ix187 (550P),<br />
ix189 (555P), ix190 (558P), ix198 (581P),<br />
ix214 (633)<br />
Tablot D. ix378 (1161P)<br />
Taboada B. ix328 (1000P), ix395 (1212)<br />
Tabouret E. ix150 (434)<br />
Tachikawa R. ix423 (1289P)<br />
Tachikawa T. ix87 (216P)<br />
Tada H. ix385 (1181PD)<br />
Taddei G.L. ix78 (183P)<br />
Taffurelli M. ix130 (362P)<br />
Taghizadeh Kermani A. ix107 (287P), ix184 (538P)<br />
Tagliaferri B. ix123 (339P), ix138 (391)<br />
Tagliapietra A. ix300 (910P)<br />
Taguchi K. ix387 (1187P)<br />
Tahara K. ix159 (460P)<br />
Tahara M. ix518 (1611P), ix344 (1706P)<br />
Tahri A. ix476 (1471P)<br />
Tai D.W.M. ix199 (583P)<br />
Taibi E. ix104 (275P)<br />
Taieb J. ix511 (1587P), ix75 (174O), ix178 (520O),<br />
ix234 (703P), ix237 (710P), ix238 (716P)<br />
Taira K. ix432 (1320), ix433 (1321)<br />
Taira N. ix74 (172O)<br />
Taira T. ix430 (1310P)<br />
Takada M. ix104 (277P)<br />
Annals of Oncology<br />
Takagi M. ix230 (688P)<br />
Takagi Y. ix441 (1351), ix497 (1537P)<br />
Takaguchi S. ix481 (1485PD)<br />
Takahari D. ix232 (692P)<br />
Takahashi K. ix434 (1325)<br />
Takahashi N. ix407 (1242P), ix442 (1354),<br />
ix69 (153P), ix529 (1649P)<br />
Takahashi O. ix200 (585P)<br />
Takahashi T. ix424 (1293P), ix430 (1310P),<br />
ix481 (1485PD), ix200 (585P)<br />
Takahashi T.K. ix455 (1397P)<br />
Takakura S. ix327 (995P)<br />
Takamatsu Y. ix508 (1576P)<br />
Takamura K. ix420 (1280P), ix434 (1326),<br />
ix443 (1358), ix497 (1538P)<br />
Takao T. ix442 (1354)<br />
Takasa A. ix436 (1334)<br />
Takashima A. ix231 (689P)<br />
Takashima T. ix84 (205P)<br />
Takaya H. ix433 (1323)<br />
Takayama K. ix438 (1340)<br />
Takayama T. ix449 (1378P), ix211 (625)<br />
Takeda K. ix424 (1293P), ix432 (1320),<br />
ix433 (1321)<br />
Takeda S. ix542 (1693P), ix246 (742P)<br />
Takeda Y. ix161 (465P)<br />
Takenaka T. ix387 (1187P)<br />
Takeshima N. ix326 (989P)<br />
Takeshita J. ix437 (1338)<br />
Takeuchi K. ix418 (1274P)<br />
Takeuchi M. ix404 (1234PD)<br />
Takeuchi N. ix439 (1344)<br />
Takhar H. ix503 (1558P)<br />
Takigawa N. ix434 (1327)<br />
Takiguchi S. ix227 (677P)<br />
Taku K. ix220 (653)<br />
Talati S.S. ix356 (1092P)<br />
Talati S.S. ix134 (377)<br />
Tamagnini I. ix216 (642)<br />
Tamaru S. ix509 (1578P)<br />
Tamas K. ix458 (1407)<br />
Tamasi L. ix493 (1523P)<br />
Tamborini E. ix483 (1491P)<br />
Tamiya M. ix432 (1320), ix433 (1321)<br />
Tamkovich S.N. ix109 (293P)<br />
Tampellini M. ix205 (605P)<br />
Tamura K. ix348 (1062O), ix508 (1576P),<br />
ix90 (228P), ix164 (474P)<br />
Tamura S. ix230 (688P)<br />
Tamura T. ix174 (1708PD), ix383 (1175P),<br />
ix393 (1206P), ix396 (1215), ix397 (1218),<br />
ix413 (1260P), ix492 (1519PD), ix153 (441O),<br />
ix156 (451P), ix159 (459P), ix161 (467P),<br />
ix164 (475P)<br />
Tamura Y. ix156 (451P), ix159 (459P),<br />
ix161 (467P), ix164 (475P)<br />
Tan A.R. ix153 (442O)<br />
Tan C. ix499 (1544O), ix199 (583P)<br />
Tan D.S.W. ix412 (1257P), ix153 (440O)<br />
Tan E.H. ix391 (1198P), ix409 (1247P),<br />
ix412 (1257P)<br />
Tan I.B. ix182 (533P), ix199 (583P), ix245 (741P)<br />
Tan M.H. ix245 (741P)<br />
Tan W. ix424 (1291P)<br />
Tanabe H. ix327 (995P)<br />
Tanabe K.K. ix542 (1693P), ix246 (742P)<br />
Tanabe Y. ix159 (459P), ix164 (474P)<br />
Tanaka A. ix185 (542P), ix197 (575P),<br />
ix207 (611P)<br />
Tanaka H. ix509 (1579P), ix159 (460P)<br />
Tanaka J. ix509 (1579P)<br />
Tanaka K. ix167 (486P)<br />
Tanaka M. ix79 (188P)<br />
Tanaka R. ix372 (1142P)<br />
Tanaka T. ix508 (1576P), ix71 (159P),<br />
ix243 (732P)<br />
Tanaka Y. ix536 (1671P), ix225 (671P)<br />
Tanase T. ix449 (1378P)<br />
ix580 | author index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology author index<br />
Tanasienko O.A. ix536 (1672P)<br />
Tanca F.M. ix516 (1604P)<br />
Tancredi R. ix99 (260P)<br />
Tane S. ix92 (233)<br />
Tang L. ix119 (326PD)<br />
Tang R. ix314 (952)<br />
Tang V. ix244 (736P)<br />
Tang Y. ix415 (1267P), ix423 (1290P),<br />
ix453 (1391P)<br />
Tangsakar E. ix248 (748)<br />
Tani K. ix536 (1671P)<br />
Taniguchi H. ix445 (1366TiP), ix529 (1649P)<br />
Tanii M. ix168 (490P)<br />
Tanimoto M. ix434 (1327)<br />
Taniyama D. ix525 (1637)<br />
Tannir N. ix83 (203P)<br />
Tannock I.F. ix158 (455P), ix260 (788O)<br />
Tanovic A. ix324 (984P)<br />
Tao J. ix126 (350P)<br />
Tapia Rico G. ix264 (799P)<br />
Taplin M. ix297 (899PD)<br />
Taran T. ix118 (324PD), ix121 (334P),<br />
ix126 (351P)<br />
Tarazi J. ix262 (793PD)<br />
Targarona E. ix216 (641)<br />
Taron M. ix418 (1273P), ix266 (807P)<br />
Tartour E. ix75 (174O)<br />
Tas P. ix105 (281P)<br />
Tatangelo F. ix193 (567P)<br />
Tateyama M. ix202 (592P)<br />
Taube J.M. ix157 (453P)<br />
Tauchert F.K. ix459 (1413TiP)<br />
Tauchi K. ix513 (1591P)<br />
Tauchi S. ix92 (233)<br />
Tausch C. ix83 (202P)<br />
Tawashi M. ix169 (492P)<br />
Taylo S. ix342 (1043P)<br />
Taylor A. ix133 (372P)<br />
Taylor C. ix76 (177PD)<br />
Taylor D. ix76 (177PD)<br />
Taylor I. ix401 (1228O)<br />
Taylor P.D. ix507 (1573P)<br />
Taylor R.P. ix304 (923P)<br />
Taylor S. ix244 (735P)<br />
Tazawa-Ogata N. ix161 (465P)<br />
Teague T. ix451 (1382P)<br />
Teama S. ix216 (639)<br />
Tebbutt N. ix182 (532P), ix231 (691P)<br />
Tebbutt N.C. ix178 (519O), ix189 (555P)<br />
Teer J.K. ix25 (11IN)<br />
Teghom C. ix282 (852P)<br />
Teh B.T. ix39 (51IN)<br />
Tehard B. ix488 (1511P)<br />
Tehfe M. ix408 (1245P)<br />
Teixeira T. ix208 (614P)<br />
Tejedor A. ix520 (1619)<br />
Tejpar S. ix451 (1382P), ix75 (173O), ix213 (630)<br />
Teker F. ix221 (660)<br />
Telfah A. ix462 (1424P)<br />
Telli F. ix186 (547P)<br />
Temam S. ix340 (1037P)<br />
Temby I. ix260 (789O)<br />
Temiz S. ix110 (300)<br />
Tempero M.A. ix37 (42IN)<br />
Templeton A. ix302 (917P)<br />
Temraz S. ix398 (1221)<br />
Tenali S.G. ix490 (1515)<br />
Teng Y. ix437 (1337), ix93 (238), ix138 (394)<br />
Teo M. ix485 (1499P), ix485 (1501P)<br />
Teo M.Y. ix248 (750), ix300 (909P)<br />
Teofilovici F. ix436 (1332), ix529 (1647PD),<br />
ix533 (1664P), ix125 (347P)<br />
Tepavac A. ix428 (1304P)<br />
Ter Voert E.E.G.W. ix192 (562P)<br />
Teragni C.M. ix123 (339P), ix138 (391)<br />
Terai H. ix422 (1285P)<br />
Terekhov O. ix311 (944P)<br />
Terme M. ix75 (174O)<br />
Terpos E. ix360 (1108TiP), ix447 (1372P)<br />
Terracciano L. ix77 (181P)<br />
Terret C. ix461 (1420PD)<br />
Terrier P. ix486 (1502P)<br />
Terstappen L.W. ix91 (230P)<br />
Tesch H. ix502 (1557P)<br />
Tessari A. ix102 (269P)<br />
Tessen H.W. ix504 (1561P)<br />
Testa I. ix272 (824P), ix288 (873), ix305 (926P)<br />
Testa L. ix455 (1397P)<br />
Testori A. ix361 (1110O), ix367 (1127P),<br />
ix367 (1128P), ix368 (1130P), ix373 (1148)<br />
Testori O. ix247 (747P)<br />
Teti A. ix524 (1633)<br />
Tettamanti M. ix452 (1385P)<br />
Teulé A. ix377 (1157O)<br />
Théodore C. ix294 (893O)<br />
Thürlimann B. ix132 (370P)<br />
Thacoor A. ix483 (1492P)<br />
Thaler J. ix178 (520O), ix249 (755)<br />
Tham C.K. ix182 (533P)<br />
Thatcher N. ix419 (1278P)<br />
Theegarten D. ix437 (1339)<br />
Theocharis S. ix541 (1691P)<br />
Theodore C. ix263 (797PD), ix289 (876)<br />
Thiesse P. ix478 (1477O)<br />
Thillai K. ix275 (831P)<br />
Thippeswamy R. ix350 (1069PD)<br />
Thirot-Bidault A. ix237 (710P)<br />
Thistlethwaite F. ix267 (808P)<br />
Thng C.H. ix70 (155P)<br />
Thomale J. ix68 (149P)<br />
Thomas D. ix479 (1480PD)<br />
Thomas L. ix367 (1127P)<br />
Thomas M. ix390 (1194P), ix407 (1241P),<br />
ix418 (1275P)<br />
Thomas S. ix408 (1245P)<br />
Thompson A.M. ix532 (1660P)<br />
Thompson J. ix363 (1115PD), ix278 (842P)<br />
Thompson J.F. ix371 (1137P)<br />
Thongprasert S. ix393 (1205P), ix400 (1226O)<br />
Thottakam B.M. ix93 (240)<br />
Thunnissen E. ix73 (167O), ix80 (193P),<br />
ix86 (213P)<br />
Tian H. ix415 (1266P)<br />
Tibollo V. ix535 (1669P)<br />
Tie J. ix220 (656)<br />
Tierno Garcia M. ix431 (1315)<br />
Tiftik N. ix312 (947)<br />
Timo<strong>the</strong>adou E. ix95 (246O)<br />
Tiseo M. ix442 (1355)<br />
Tito J. ix298 (904P)<br />
Tjørnelund J. ix349 (1068PD)<br />
Tjan-Heijnen V.C. ix501 (1553P)<br />
Tjulandin S. ix230 (687P)<br />
Tkaczuk K.H.R. ix108 (290P)<br />
Tobeña Puyal M. ix183 (536P), ix185 (544P),<br />
ix216 (641)<br />
Tocchetti C.G. ix539 (1682P)<br />
Tochino Y. ix412 (1258P)<br />
Tod M. ix299 (907P)<br />
Toda M. ix515 (1598P)<br />
Todisco G. ix167 (487P), ix172 (502)<br />
Tofanetti F.R. ix387 (1185P)<br />
Toffoli G. ix144 (411O)<br />
Toh H.C. ix83 (203P), ix245 (741P)<br />
Toh Y. ix217 (646)<br />
Toi M. ix104 (277P)<br />
Tokluoğlu S. ix332 (1015)<br />
Tokuda Y. ix112 (305)<br />
Tokui T. ix244 (738P)<br />
Tokunaga S. ix432 (1320), ix433 (1321),<br />
ix230 (688P)<br />
Tolcher A.W. ix165 (481P), ix169 (492P)<br />
Tolia M. ix541 (1691P)<br />
Tollenaar R. ix184 (540P)<br />
Tolnay E. ix429 (1307P)<br />
Toloudi M. ix136 (385)<br />
Tolunay S. ix129 (359P)<br />
Tomar P. ix242 (729P)<br />
Tomasello G. ix232 (693P)<br />
Tomasevic Z. ix544 (1702), ix544 (1702)<br />
Tomasich E. ix539 (1685P)<br />
Tomczak P. ix262 (793PD), ix262 (795PD)<br />
Tomezzoli A. ix226 (675P)<br />
Tomii K. ix423 (1289P)<br />
Tomita N. ix200 (588P)<br />
Tondini C. ix365 (1120P)<br />
Toner S. ix468 (1444)<br />
Tonini G. ix489 (1512), ix500 (1550PD),<br />
ix516 (1603P), ix530 (1653P), ix538 (1681P),<br />
ix206 (606P)<br />
Tono Y. ix509 (1578P)<br />
Topal U. ix129 (359P)<br />
Topalian S.L. ix361 (1109O), ix157 (453P)<br />
Topkan E. ix392 (1202P), ix520 (1620),<br />
ix526 (1641), ix526 (1642), ix237 (711P),<br />
ix238 (715P)<br />
Topolcan O. ix474 (1464P)<br />
Topp M. ix350 (1072P)<br />
Toppo L. ix232 (693P)<br />
Topuk S. ix392 (1202P), ix520 (1620),<br />
ix526 (1642)<br />
Torchio M. ix529 (1650P)<br />
Toriihara A. ix441 (1351)<br />
Torrejon Castro D. ix496 (1533P), ix140 (400),<br />
ix302 (916P)<br />
Torres S. ix345 (1056)<br />
Torricelli F. ix528 (1646PD)<br />
Tortora G. ix117 (322PD), ix39 (52IN),<br />
ix226 (675P), ix240 (721P), ix273 (825P),<br />
ix287 (869)<br />
Tosi M. ix213 (629)<br />
Touboul C. ix470 (1452P), ix472 (1460)<br />
Touchefeu Y. ix537 (1677P)<br />
Toure E. ix252 (767)<br />
Tovanabutra C. ix339 (1035P)<br />
Tóth E. ix503 (1560P), ix504 (1562P)<br />
Townsend A. ix182 (532P), ix208 (612P)<br />
Towse A. ix476 (1473P)<br />
Toyazaki T. ix442 (1356)<br />
Toyoda M. ix510 (1581P)<br />
Toyokawa G. ix387 (1187P)<br />
Tozzi V. ix457 (1405)<br />
Tröger W. ix237 (712P)<br />
Trager J.B. ix311 (942P)<br />
Traina T.A. ix98 (257P)<br />
Traldi Macedo L. ix513 (1594P)<br />
Tran B. ix220 (656)<br />
Tran H.T. ix261 (791PD), ix275 (833P)<br />
Traphalis D. ix493 (1524P)<br />
Trask P. ix323 (981P)<br />
Traversa M. ix370 (1135P)<br />
Tredan O. ix125 (346P)<br />
Trejo-Duran G. ix329 (1003P)<br />
Trejo E. ix251 (763)<br />
Trenta P. ix440 (1348), ix488 (1509P)<br />
Triggs M. ix468 (1444)<br />
Trigo J.M. ix334 (1016O)<br />
Trill J.D. ix205 (604P)<br />
Trillet-Lenoir V. ix170 (498P)<br />
Trindade I. ix357 (1097)<br />
Triolo R. ix99 (259P)<br />
Troch M. ix352 (1076P)<br />
Troiani T. ix430 (1309P), ix67 (143PD),<br />
ix75 (173O)<br />
Trojniak M.P. ix439 (1345), ix447 (1370P),<br />
ix283 (854P)<br />
Troncone G. ix530 (1651P), ix78 (183P)<br />
Trouilloud I. ix237 (710P), ix238 (716P)<br />
Truini M. ix79 (187P), ix301 (914P)<br />
Truman M.I. ix400 (1226O)<br />
Truscelli K. ix488 (1509P)<br />
Trusilova E. ix250 (760)<br />
Tryfonopoulos D. ix108 (292P)<br />
Tryon P. ix309 (938P)<br />
Volume 23 | Supplement 9 | June <strong>2012</strong> doi:10.1093/annonc/mds466 | ix581
author index<br />
Trypaki M. ix429 (1308P), ix213 (631)<br />
Tsai H. ix351 (1075P)<br />
Tsakalaki E. ix429 (1308P), ix213 (631)<br />
Tsao-Wei D. ix261 (790O), ix316 (961)<br />
Tsao M. ix389 (1192PD), ix74 (170O), ix78 (186P)<br />
Tsavaris N. ix92 (236)<br />
Tsavdaridis D. ix493 (1524P)<br />
Tschaika M. ix178 (518O), ix268 (813P)<br />
Tschechne B. ix523 (1627)<br />
Tschoepe I. ix165 (478P), ix169 (494P)<br />
Tsolaki E. ix213 (630)<br />
Tsolakis K. ix541 (1691P)<br />
Tsoukalas N.G. ix541 (1691P)<br />
Tsuboi R. ix517 (1608P)<br />
Tsuburaya A. ix228 (681P)<br />
Tsuchida A. ix89 (224P)<br />
Tsuchihara K. ix196 (574P)<br />
Tsuchiya T. ix188 (552P)<br />
Tsuda H. ix372 (1142P), ix383 (1174P),<br />
ix387 (1186P)<br />
Tsuda T. ix232 (692P)<br />
Tsui D. ix74 (171O)<br />
Tsuji A. ix233 (697P)<br />
Tsuji Y. ix232 (692P)<br />
Tsujinaka T. ix230 (688P)<br />
Tsujino I. ix407 (1242P), ix442 (1354)<br />
Tsujino K. ix393 (1204P)<br />
Tsujitani S. ix168 (490P)<br />
Tsunoda A. ix211 (623)<br />
Tsunoda T. ix536 (1671P), ix159 (460P)<br />
Tsunoda Y. ix87 (216P), ix211 (623)<br />
Tsuta K. ix383 (1174P), ix387 (1186P)<br />
Tsutani Y. ix385 (1180PD)<br />
Tsutsumida A. ix372 (1142P)<br />
Tsuzuki T. ix225 (671P)<br />
Tu L. ix247 (745P)<br />
Tuccari G. ix104 (276P)<br />
Tummers P. ix330 (1007), ix325 (987P)<br />
Tumolo S. ix287 (868)<br />
Tun T.T. ix319 (969PD)<br />
Tunali D. ix274 (830P)<br />
Tunariu N. ix296 (897O), ix301 (913P),<br />
ix320 (972PD)<br />
Turcotte É. ix350 (1071P)<br />
Turhal N.S. ix394 (1207P)<br />
Turhal S.N. ix497 (1540), ix186 (547P),<br />
ix217 (645)<br />
Turker I. ix473 (1461), ix105 (279P)<br />
Turker T. ix286 (866P)<br />
Turkington R.C. ix249 (754)<br />
Turner B. ix93 (240)<br />
Turner J.H. ix379 (1162P)<br />
Turner M. ix502 (1555P), ix502 (1557P)<br />
Turner N. ix29 (20IN)<br />
Turner N.H. ix27 (13IN)<br />
Turner P. ix123 (341P)<br />
Turner R. ix517 (1605P)<br />
Turnes J. ix255 (777TiP)<br />
Turpin A. ix106 (285P)<br />
Turrini O. ix241 (727P)<br />
Turtoi I. ix398 (1222)<br />
Turtschi C. ix366 (1125P)<br />
Tutrone R. ix317 (964TiP)<br />
Tuydjanova K.K. ix71 (162P)<br />
Tuyev H. ix229 (684P), ix254 (772)<br />
Twardowski P. ix309 (938P)<br />
Twelves C. ix409 (1246P), ix476 (1473P),<br />
ix171 (500P)<br />
Twelves C.J. ix129 (358P), ix132 (369P)<br />
Tye L. ix389 (1191PD)<br />
Tzardi M. ix213 (631)<br />
Tzeng C. ix355 (1087P)<br />
Tzeng Y. ix351 (1075P)<br />
Tzovaras A. ix541 (1691P)<br />
U<br />
Uchida J. ix185 (542P)<br />
Uchiyama A. ix79 (188P)<br />
Ueda K. ix226 (673P)<br />
Ueda M. ix91 (232)<br />
Uehara K. ix220 (655)<br />
Uehara Y. ix383 (1175P)<br />
Ueno H. ix200 (587P)<br />
Ueno T. ix104 (277P), ix240 (723P)<br />
Uetake H. ix197 (576P)<br />
Ulker M. ix326 (990P)<br />
Ulyanov A. ix311 (944P)<br />
Umarova N. ix325 (985P)<br />
Umekawa K. ix79 (189P), ix79 (190P),<br />
ix92 (235)<br />
Umemura S. ix515 (1598P), ix534 (1666P)<br />
Umezawa K. ix495 (1531P)<br />
Unal O.U. ix234 (701P)<br />
Unek I.T. ix234 (701P)<br />
Uner A. ix227 (678P)<br />
Unno M. ix211 (624)<br />
Untergasser G. ix76 (178P)<br />
Upadhyay S. ix421 (1282P)<br />
Urakci Z. ix137 (387)<br />
Urata N. ix225 (671P)<br />
Urban T. ix403 (1232PD)<br />
Urban Z. ix320 (970PD)<br />
Urbanski M. ix456 (1401P)<br />
Uronis H. ix224 (666O)<br />
Urosa Velasco D. ix264 (799P)<br />
Urruticoechea A. ix116 (318O)<br />
Uruga H. ix433 (1323)<br />
Urzua L. ix126 (349P)<br />
Usakova V. ix286 (865P)<br />
Usari T. ix424 (1291P)<br />
Ussetti P. ix459 (1410)<br />
Usui K. ix427 (1301P)<br />
Utikal J. ix361 (1110O)<br />
Utsunomiya A. ix348 (1062O)<br />
Uttenreu<strong>the</strong>r-Fischer M. ix161 (464P),<br />
ix162 (468P)<br />
Uyeturk U. ix473 (1461), ix105 (279P)<br />
Uygun K. ix110 (300)<br />
Uyl-De Groot C.A. ix450 (1379P)<br />
Uysal Sonmez O. ix473 (1461)<br />
Uyterlinde W. ix392 (1203P)<br />
Uzan C. ix322 (977P)<br />
Uzzan B. ix414 (1265P)<br />
V<br />
Vaccaro V. ix237 (713P), ix240 (721P)<br />
Vacher-Lavenu M. ix327 (993P)<br />
Vaira F. ix123 (340P)<br />
Vaisman O. ix498 (1541)<br />
Val P.C. ix215 (637)<br />
Valdagni R. ix305 (926P), ix315 (959)<br />
Valdez Bocanegra D. ix184 (541P)<br />
Valdivia J. ix374 (1150)<br />
Valduga F. ix276 (836P)<br />
Valent F. ix457 (1405)<br />
Validire P. ix388 (1190P)<br />
Valigi P. ix535 (1668P)<br />
Vallati G. ix237 (713P)<br />
Valle J. ix378 (1161P), ix381 (1168P)<br />
Valle J.W. ix376 (1155O), ix377 (1156O),<br />
ix242 (731P)<br />
Valleix F. ix170 (498P)<br />
Vallejos-Sologuren C. ix65 (133IN)<br />
Vallieres E. ix386 (1182P)<br />
Valota O. ix262 (794PD)<br />
Valpione S. ix371 (1140P), ix486 (1504P),<br />
ix124 (343P), ix131 (367P)<br />
Valverde Estepa A.M. ix530 (1652),<br />
ix425 (1296P)<br />
Valverde Morales C. ix302 (916P)<br />
van Baardwijk A. ix396 (1213), ix425 (1296P)<br />
van Belle S. ix325 (987P), ix330 (1007),<br />
ix287 (870)<br />
van Beurden M. ix330 (1006P)<br />
van Bortel L. ix287 (870)<br />
van Boven H.H. ix330 (1006P)<br />
Annals of Oncology<br />
Van Cutsem E. ix178 (520O), ix187 (550P),<br />
ix191 (561P), ix198 (581P), ix212 (626),<br />
ix214 (633), ix222 (663TiP)<br />
Van Cutsem E.J.D. ix193 (565P), ix195 (571P)<br />
van Dam G.M. ix40 (57IN)<br />
van den Bent M.J. ix31 (23IN)<br />
Van den Broecke R. ix330 (1007), ix325 (987P)<br />
van den Eertwegh A. ix301 (915P)<br />
van den Eynde M. ix194 (569P), ix197 (578P),<br />
ix211 (622)<br />
van den Heuvel M. ix392 (1203P)<br />
van den Noortgate N. ix341 (1042P)<br />
van den Wyngaert T. ix510 (1583P)<br />
van der Akker J. ix179 (522PD)<br />
van der Graaf W.T.A. ix475 (1469P),<br />
ix483 (1493P), ix484 (1497P), ix160 (462P),<br />
ix54 (91IN)<br />
van der Hage J. ix532 (1658P)<br />
van der Heijden G. ix484 (1497P)<br />
van der Holt B. ix534 (1667P)<br />
van der Horst T. ix97 (254PD), ix103 (272P)<br />
van der Noll R. ix153 (442O)<br />
van der Zee A.G.J. ix40 (57IN)<br />
van Dongen G.A.M.S. ix450 (1379P)<br />
van Elmpt W. ix392 (1201P), ix396 (1213),<br />
ix396 (1216)<br />
van Fraeyenhove F. ix452 (1386P)<br />
van Gaal J.C. ix484 (1497P)<br />
van Gelder T. ix456 (1402P), ix109 (295P)<br />
van Gool R. ix296 (898PD)<br />
van Halteren H.K. ix111 (301)<br />
van Herk-Sukel M.P.P. ix109 (295P)<br />
van Herpen C.M.L. ix160 (462P)<br />
van Laarhoven H.W. ix501 (1553P)<br />
van Laarhoven H.W.M. ix192 (562P)<br />
van Lae<strong>the</strong>m J. ix178 (520O), ix225 (669PD),<br />
ix255 (776TiP)<br />
van Leeuwen R.W. ix456 (1402P)<br />
van Leeuwen T.G. ix330 (1006P)<br />
van Os S. ix103 (274P)<br />
van Praagh-Doreau I. ix102 (270P)<br />
van Rossum M. ix363 (1114PD)<br />
van Schaik R.H. ix534 (1667P)<br />
van Vlierberghe H. ix225 (669PD)<br />
van Warmerdam L.J. ix501 (1553P)<br />
Vandebroek A. ix452 (1386P)<br />
Vandecasteele K. ix330 (1007), ix325 (987P)<br />
Vandendries R. ix396 (1216)<br />
Vanderpuye V.D.N.K. ix257 (782TiP)<br />
Vanderwalde A. ix334 (1016O)<br />
Vanella P. ix73 (169O), ix113 (311)<br />
Vanhoutte N. ix361 (1110O), ix386 (1182P)<br />
Vannucci J. ix387 (1185P)<br />
Vano Y. ix499 (1545O)<br />
Vansteenkiste J. ix385 (1179O)<br />
Vansteenkiste J.F. ix403 (1233PD), ix407 (1241P),<br />
ix451 (1382P), ix153 (440O)<br />
Vaquero E.C. ix67 (145P)<br />
Vardakis N. ix435 (1329), ix436 (1335)<br />
Vardja M. ix146 (418PD), ix149 (431)<br />
Varea R. ix395 (1211)<br />
Varela S. ix436 (1333), ix440 (1349)<br />
Varella-Garcia M. ix389 (1191PD)<br />
Varga A. ix474 (1463P), ix155 (446PD),<br />
ix168 (491P)<br />
Varricchio C. ix83 (201P)<br />
Varthalitis I. ix239 (717P)<br />
Varughese T. ix346 (1060)<br />
Vasile E. ix206 (606P), ix238 (714P), ix241 (726P),<br />
ix251 (761), ix251 (762)<br />
Vasiliou V. ix337 (1026P)<br />
Vasquez S. ix513 (1592P)<br />
Vaughan A.T. ix70 (157P)<br />
Vavala T. ix444 (1360)<br />
Vavrova L. ix513 (1593P)<br />
Vaz F. ix175 (512PD), ix176 (514P)<br />
Vaz G. ix478 (1477O)<br />
Vazquez-Estevez S. ix440 (1349), ix273 (826P)<br />
ix582 | author index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology author index<br />
Vazquez-Sequeiros E. ix472 (1456P)<br />
Vázquez A.M. ix406 (1238PD)<br />
Vázquez F. ix312 (945)<br />
Vazquez S. ix395 (1212), ix436 (1333)<br />
Vecchiato A. ix486 (1504P)<br />
Vecchione L. ix75 (173O)<br />
Védrine L. ix477 (1476), ix150 (433), ix285 (862P)<br />
Veerabudun K. ix460 (1419PD)<br />
Vehling-Kaiser U. ix465 (1435P), ix505 (1567P),<br />
ix180 (526PD), ix204 (599P)<br />
Velástegui A. ix113 (310)<br />
Velasco A. ix166 (484P)<br />
Velasco G. ix281 (850P), ix314 (953)<br />
ix325 (986P)<br />
Velinovic M. ix428 (1304P)<br />
Velten M. ix109 (296P), ix120 (331P)<br />
Veltri A. ix444 (1360)<br />
Venat-Bouvet L. ix181 (529PD)<br />
Venderbosch S. ix179 (521O)<br />
Venditti O. ix500 (1550PD)<br />
Vendrely V. ix242 (730P)<br />
Venkatakrishnan K. ix168 (489P)<br />
Vennin P. ix106 (285P)<br />
Venook A. ix225 (670PD)<br />
Vera Badillo F. ix91 (231P)<br />
Vera R. ix219 (651)<br />
Verardi R. ix338 (1029P)<br />
Vergauwe P. ix222 (663TiP)<br />
Vergnenegre A. ix397 (1219)<br />
Vergote I.B. ix514 (1596P), ix539 (1683P),<br />
ix172 (504), ix321 (975PD), ix324 (982P)<br />
Verheul H.M. ix240 (724P)<br />
Verhoef G. ix518 (1609P)<br />
Verillaud B. ix337 (1025P)<br />
Verlicchi A. ix496 (1536P)<br />
Verma S. ix408 (1245P)<br />
Vermaete N. ix518 (1609P)<br />
Vermorken J.B. ix334 (1018O), ix336 (1022PD)<br />
Verna L. ix466 (1436P)<br />
Veronese L. ix366 (1124P), ix366 (1125P)<br />
Verpoort K. ix502 (1557P)<br />
Verri E. ix335 (1020PD)<br />
Versleijen-Jonkers Y.M.H. ix484 (1497P)<br />
Versluis J. ix301 (915P)<br />
Verso M. ix515 (1599P)<br />
Verstraete M. ix222 (663TiP)<br />
Verweij J. ix534 (1667P), ix55 (94IN)<br />
Verzoni E. ix272 (824P), ix288 (873),<br />
ix305 (926P), ix315 (959)<br />
Vetsika E.K. ix431 (1314)<br />
Viada C. ix406 (1238PD)<br />
Vibert E. ix243 (733P)<br />
Vici P. ix142 (406TiP)<br />
Victor A. ix211 (622)<br />
Victoria I. ix343 (1046P), ix282 (853P)<br />
Vidal M. ix91 (229P)<br />
Vieillefond A. ix259 (786O)<br />
Viéitez J.M. ix218 (647)<br />
Vieitez de Prado J.M. ix193 (565P)<br />
Vieito Villar M. ix328 (1000P), ix395 (1212)<br />
Viens P. ix150 (434)<br />
Viganò M.G. ix167 (487P), ix172 (502)<br />
Viguier J. ix470 (1452P), ix472 (1460), ix85 (210P)<br />
Vilalta A. ix343 (1046P)<br />
Vilar E. ix34 (36IN), ix220 (656)<br />
Vilardell L. ix388 (1189P)<br />
Vilchez V. ix496 (1535P)<br />
Vilcot L. ix486 (1502P)<br />
Villa E. ix280 (846P)<br />
Villa S. ix305 (926P), ix315 (959)<br />
Villacampa F. ix281 (850P)<br />
Villanueva C.B. ix499 (1547PD), ix128 (355P),<br />
ix128 (357P)<br />
Villanueva M.J. ix436 (1333)<br />
Villarreal-Garza C. ix107 (289P), ix126 (349P)<br />
Villavicencio H. ix292 (888)<br />
Villegas T. ix254 (773)<br />
Vinayek N. ix76 (177PD)<br />
Vince-Ranchere D. ix478 (1477O)<br />
Vincent A.D. ix330 (1006P), ix392 (1203P)<br />
Vincenzi B. ix485 (1500P), ix489 (1512),<br />
ix500 (1550PD), ix516 (1603P), ix530 (1653P),<br />
ix538 (1681P), ix206 (606P)<br />
Vinolas Segarra N. ix414 (1264P)<br />
Viqueira A. ix277 (839P)<br />
Visa L. ix67 (145P)<br />
Visich J. ix124 (344P)<br />
Vismara C. ix335 (1019O)<br />
Visseren-Grul C.M. ix395 (1211), ix404 (1235PD),<br />
ix418 (1275P)<br />
Vitagliano D. ix430 (1309P), ix67 (143PD)<br />
Viterbo L. ix357 (1095)<br />
Viteri S. ix531 (1655P)<br />
Viudez A. ix219 (651)<br />
Vivaldi C. ix85 (208P)<br />
Vivancos A. ix531 (1656P), ix84 (204P)<br />
Vivenza D. ix528 (1644PD)<br />
Vizor S. ix165 (479P)<br />
Vlassak S. ix451 (1382P)<br />
Vlassov V.V. ix109 (293P)<br />
Vocka M. ix81 (197P)<br />
Voest E. ix153 (442O)<br />
Vogelzang N. ix296 (898PD), ix308 (936P),<br />
ix316 (961)<br />
Voigt A. ix453 (1389P)<br />
Voisin D. ix507 (1572P), ix507 (1574P)<br />
Volovitz I. ix72 (163P)<br />
von Heydebreck A. ix417 (1272P)<br />
von Karsa L. ix53 (88IN)<br />
von Laffert M. ix390 (1195P), ix394 (1208)<br />
von Mehren M. ix478 (1478O)<br />
von Minckwitz G. ix117 (321PD), ix118 (323PD)<br />
von Moos R. ix396 (1214), ix447 (1372P),<br />
ix462 (1423O), ix480 (1482PD), ix509 (1580P),<br />
ix157 (454P), ix190 (559P), ix193 (565P),<br />
ix283 (857P)<br />
von Pawel J. ix410 (1250P)<br />
von Roemeling R. ix225 (669PD), ix245 (739P)<br />
Voortman G. ix103 (274P)<br />
Vorotnikov I. ix130 (364P)<br />
Voutsadakis I.A. ix138 (393)<br />
Vrankar M. ix446 (1368TiP)<br />
Vranken Peeters M.J. ix532 (1658P)<br />
Vredenburgh J.J. ix146 (417PD)<br />
Vrignaud P. ix312 (946)<br />
Vrzalova J. ix474 (1464P)<br />
Vuillemin A. ix332 (1014), ix289 (876)<br />
Vukobradovic Djoric N. ix428 (1304P)<br />
Vukovic V. ix436 (1332), ix529 (1647PD),<br />
ix533 (1664P), ix125 (347P)<br />
Vuong T. ix200 (586P)<br />
Vynnychenko I. ix224 (668PD)<br />
W<br />
Waaka D.S. ix162 (470P)<br />
Wachter E. ix371 (1137P)<br />
Waddell T.S. ix224 (667PD)<br />
Wadsley J. ix224 (667PD)<br />
Wagner L. ix148 (426P)<br />
Wahab M.M.A.M. ix352 (1079P)<br />
Wahba H. ix353 (1081P)<br />
Wahlgren T. ix281 (848P)<br />
Wakelee H. ix445 (1364TiP)<br />
Wakui H. ix156 (451P), ix161 (467P),<br />
ix174 (1708PD)<br />
Walewski J.A. ix354 (1084P)<br />
Walkiewicz M. ix542 (1692P)<br />
Wallerek S. ix443 (1357)<br />
Wallin B. ix493 (1522PD)<br />
Wallis M. ix74 (171O)<br />
Walsh E. ix469 (1449PD)<br />
Walsh N. ix528 (1645PD), ix108 (292P)<br />
Walter E. ix121 (333P)<br />
Walter T.A. ix378 (1160P)<br />
Wan D. ix189 (556P)<br />
Wan M. ix89 (223P)<br />
Wanders J. ix129 (358P)<br />
Wanders R. ix396 (1213), ix425 (1296P)<br />
Wang-Lopez Q. ix102 (270P)<br />
Wang D. ix148 (428P), ix227 (676P)<br />
Wang F. ix111 (302), ix148 (428P), ix219 (650)<br />
Wang H. ix351 (1075P), ix435 (1331)<br />
Wang J. ix400 (1225O), ix443 (1359), ix93 (238),<br />
ix140 (401), ix163 (471P), ix169 (493P),<br />
ix192 (564P), ix231 (690P), ix247 (745P),<br />
ix248 (748), ix282 (851P)<br />
Wang J.W. ix202 (595P)<br />
Wang L. ix70 (155P), ix158 (457P), ix281 (847P)<br />
Wang M. ix77 (182P)<br />
Wang P. ix421 (1281P)<br />
Wang Q. ix282 (851P), ix306 (928P)<br />
Wang S. ix394 (1209), ix297 (901PD)<br />
Wang W. ix227 (676P)<br />
Wang X. ix394 (1209), ix400 (1225O),<br />
ix495 (1530P), ix501 (1552P)<br />
Wang Y. ix435 (1331), ix84 (204P)<br />
Wang Y.Z. ix438 (1341)<br />
Wang Z. ix435 (1331), ix219 (650)<br />
Ward S.E. ix235 (706P)<br />
Wardelmann E. ix481 (1486PD)<br />
Waring P. ix383 (1173P)<br />
Wasan H. ix242 (731P)<br />
Wasinger C. ix72 (165)<br />
Wass M. ix357 (1098)<br />
Watanabe H. ix492 (1519PD)<br />
Watanabe K. ix511 (1586P)<br />
Watanabe M. ix383 (1175P), ix220 (653),<br />
ix320 (973PD)<br />
Watanabe S. ix413 (1259P), ix509 (1579P),<br />
ix71 (159P), ix320 (973PD)<br />
Watanabe T. ix233 (698P)<br />
Waterkamp D. ix189 (555P)<br />
Waters J. ix242 (731P)<br />
Watt F. ix539 (1684P)<br />
Waxman I. ix267 (810P), ix269 (816P)<br />
Wcisło G. ix323 (979P)<br />
Weaver A. ix181 (530PD)<br />
Weber H. ix102 (271P)<br />
Weber J.S. ix363 (1116PD), ix368 (1129P),<br />
ix46 (71IN)<br />
Weber M. ix459 (1413TiP)<br />
Webersinke G. ix209 (616)<br />
Weder W. ix385 (1179O)<br />
Weekes C. ix155 (447PD)<br />
Wei J. ix229 (686P)<br />
Wei R. ix449 (1377P), ix309 (937P)<br />
Wei X. ix25 (11IN)<br />
Wei Y. ix190 (557P), ix201 (589P), ix217 (644)<br />
Weickhardt A. ix182 (532P)<br />
Weijl N. ix256 (781TiP)<br />
Weikert S. ix268 (813P), ix288 (875)<br />
Weinberg V. ix310 (939P)<br />
Weinstein M. ix202 (594P)<br />
Weiss G.J. ix362 (1111PD), ix152 (439O)<br />
Weith E. ix268 (813P)<br />
Weller M. ix31 (24IN)<br />
Wells K. ix467 (1442)<br />
Welslau M. ix120 (329P)<br />
Wen P.Y. ix146 (417PD)<br />
Wen Y.H. ix98 (257P)<br />
Werner P. ix171 (499P)<br />
Werner T.L. ix153 (442O)<br />
Wesley J.D. ix311 (942P)<br />
Wesseling J. ix532 (1658P)<br />
Wessels R. ix330 (1006P)<br />
West H. ix422 (1287P)<br />
West N. ix206 (608P)<br />
Westeel V. ix419 (1276P)<br />
Weynand B. ix336 (1021PD)<br />
Wheater M. ix283 (857P)<br />
Wheatley Price P. ix314 (954)<br />
Wheatley-Price P. ix493 (1525P)<br />
Wheeler H. ix151 (437TiP)<br />
White S. ix493 (1525P), ix526 (1640)<br />
Volume 23 | Supplement 9 | June <strong>2012</strong> doi:10.1093/annonc/mds466 | ix583
author index<br />
Whitmore J.B. ix310 (940P), ix310 (941P)<br />
Wiater K. ix484 (1495P), ix489 (1513)<br />
Widhalm G. ix148 (426P)<br />
Wieczorek M. ix544 (1700)<br />
Wiedenmann B. ix377 (1156O)<br />
Wieland S. ix480 (1483PD)<br />
Wiemer E.A.C. ix534 (1667P), ix109 (295P)<br />
Wigginton J.M. ix361 (1109O), ix405 (1237PD),<br />
ix157 (453P), ix258 (784O)<br />
Wilbaux M. ix299 (907P)<br />
Wildberger J.E. ix212 (626)<br />
Wildiers H. ix510 (1583P)<br />
Wilkerson J. ix198 (579P)<br />
Wilkins D. ix166 (484P)<br />
Wilkinson N. ix320 (972PD)<br />
Willems L. ix408 (1243P)<br />
Willenbacher E. ix352 (1076P)<br />
Willenbacher W. ix352 (1076P), ix360 (1108TiP)<br />
Williams C. ix49 (77IN)<br />
Williams D. ix383 (1173P)<br />
Williams E. ix206 (608P)<br />
Williams J.A. ix262 (794PD)<br />
Williamson S. ix223 (664TiP)<br />
Wilner K. ix389 (1191PD), ix403 (1231PD),<br />
ix415 (1267P), ix416 (1268P)<br />
Wilson A. ix93 (240)<br />
Wilson K. ix178 (519O), ix182 (532P)<br />
Wilson P. ix290 (880)<br />
Wilson R.H. ix249 (754)<br />
Wiltshire R. ix259 (785O)<br />
Wimberger P. ix514 (1596P), ix539 (1683P)<br />
Wind S. ix162 (468P)<br />
Winfree K.B. ix421 (1281P), ix428 (1303P)<br />
Winkfield B. ix204 (600P)<br />
Winn B. ix370 (1134P), ix372 (1143P)<br />
Winquist E. ix304 (922P), ix315 (956), ix316 (960)<br />
Winterhalder R.C. ix302 (917P)<br />
Win<strong>the</strong>rhalder R. ix372 (1144)<br />
Wischnewsky M. ix73 (169O)<br />
Wisman L. ix103 (274P)<br />
Wisniewska H. ix544 (1700)<br />
Witkowski M. ix284 (859P)<br />
Wittig B. ix178 (518O), ix268 (813P)<br />
Wöhrer A. ix147 (421P), ix148 (426P)<br />
Wojciechowska-Lampka E. ix504 (1562P)<br />
Wojtowicz-Praga S. ix419 (1277P)<br />
Wolchok J. ix363 (1115PD), ix367 (1127P)<br />
Wolchok J.D. ix363 (1116PD), ix368 (1129P),<br />
ix75 (175PD)<br />
Wolf M. ix390 (1194P)<br />
Wolff J.M. ix299 (905P)<br />
Wolff R.A. ix451 (1383P)<br />
Wöll E. ix228 (680P), ix249 (755)<br />
Wollner M. ix498 (1541)<br />
Wolmark N. ix179 (523PD)<br />
Wolter P. ix518 (1609P)<br />
Won H.S. ix250 (757)<br />
Wong H. ix244 (736P)<br />
Wong J. ix309 (938P)<br />
Wong M. ix538 (1678P)<br />
Wong M.K. ix383 (1176P)<br />
Wong S. ix220 (656), ix298 (902P), ix321 (975PD)<br />
Wong Y. ix260 (787O), ix265 (804P)<br />
Wood B.A. ix297 (901PD)<br />
Wood K. ix269 (814P)<br />
Wood L. ix262 (794PD)<br />
Woods R. ix188 (551P)<br />
Worm K. ix437 (1339)<br />
Wormanns D. ix534 (1665P)<br />
Wo<strong>the</strong>rspoon A. ix224 (667PD)<br />
Woulfe B. ix114 (312)<br />
Wouters C. ix510 (1583P)<br />
Wouters K. ix510 (1583P)<br />
Wozniak A. ix420 (1279P)<br />
Wright A. ix319 (969PD)<br />
Wright G. ix542 (1692P)<br />
Wright L. ix223 (664TiP)<br />
Wrin J. ix182 (532P)<br />
Wrona A. ix385 (1179O)<br />
Wu B. ix321 (975PD)<br />
Wu D. ix415 (1266P)<br />
Wu G. ix77 (182P)<br />
Wu H. ix217 (644)<br />
Wu J. ix130 (361P)<br />
Wu M. ix351 (1075P)<br />
Wu X. ix189 (556P)<br />
Wu Y-L ix444 (1362TiP)<br />
Wu Y. ix58 (106IN), ix400 (1226O),<br />
ix415 (1266P), ix437 (1336), ix443 (1359)<br />
Wu Y.L. ix438 (1341)<br />
Wu Z. ix437 (1336)<br />
Wydra D. ix320 (970PD)<br />
Wynne C. ix162 (470P)<br />
X<br />
Xanthaki D. ix278 (841P)<br />
Xanthakis I. ix213 (630)<br />
Xavier P. ix236 (708P)<br />
Xi M. ix343 (1048P)<br />
Xia J. ix227 (676P)<br />
Xiao X. ix281 (847P)<br />
Xiaoqing L. ix416 (1269P)<br />
Xie M. ix337 (1027P)<br />
Xie Z. ix415 (1266P)<br />
Xiong L. ix413 (1261P), ix454 (1395P)<br />
Xiong S. ix306 (928P)<br />
Xu B. ix114 (313), ix140 (401)<br />
Xu D. ix202 (595P)<br />
Xu F. ix346 (1057), ix219 (650)<br />
Xu J. ix478 (1478O), ix190 (557P), ix201 (589P),<br />
ix217 (643), ix217 (644), ix217 (646),<br />
ix231 (690P), ix231 (691P)<br />
Xu L. ix138 (394)<br />
Xu N. ix256 (779TiP)<br />
Xu R. ix217 (646), ix231 (690P)<br />
Xu W. ix78 (186P)<br />
Xu Y. ix203 (597P), ix217 (643), ix226 (674P),<br />
ix247 (745P)<br />
Xue C. ix219 (650)<br />
Xyrafas A. ix435 (1329), ix436 (1335)<br />
Y<br />
Yabusaki H. ix234 (702P)<br />
Yachi Y. ix201 (590P)<br />
Yacoubene K. ix517 (1607P)<br />
Yagata H. ix82 (199P), ix100 (264P), ix133 (373P)<br />
Yajima Y. ix518 (1611P), ix344 (1706P)<br />
Yakobson A. ix373 (1147)<br />
Yakout T. ix355 (1088P)<br />
Yalcin S. ix482 (1490P), ix258 (783O)<br />
Yalcintas Arslan U. ix473 (1461), ix105 (279P)<br />
Yamada K. ix438 (1340), ix543 (1696P)<br />
Yamada S. ix542 (1693P), ix246 (742P)<br />
Yamada T. ix383 (1174P), ix387 (1186P),<br />
ix536 (1673P), ix536 (1674P), ix89 (224P),<br />
ix170 (498P)<br />
Yamada Y. ix529 (1649P), ix156 (451P),<br />
ix159 (459P), ix161 (467P), ix164 (475P),<br />
ix174 (1708PD), ix202 (593P), ix231 (689P),<br />
ix251 (764)<br />
Yamaguchi H. ix233 (698P)<br />
Yamaguchi K. ix241 (728P)<br />
Yamaguchi M. ix387 (1187P)<br />
Yamaguchi O. ix436 (1334), ix69 (153P)<br />
Yamaguchi T. ix469 (1447PD)<br />
Yamakado K. ix243 (732P)<br />
Yamamoto G. ix87 (216P)<br />
Yamamoto H. ix514 (1597P), ix90 (228P)<br />
Yamamoto J. ix211 (625)<br />
Yamamoto M. ix434 (1325)<br />
Yamamoto N. ix393 (1204P), ix402 (1229PD),<br />
ix410 (1252P), ix413 (1260P), ix424 (1293P),<br />
ix430 (1310P), ix492 (1519PD), ix492 (1519PD),<br />
ix156 (451P), ix159 (459P), ix161 (467P),<br />
ix164 (475P), ix174 (1708PD)<br />
Yamamoto S. ix411 (1253P)<br />
Annals of Oncology<br />
Yamamoto T. ix243 (732P)<br />
Yamamoto Y. ix442 (1356), ix104 (277P)<br />
Yaman M. ix277 (838P)<br />
Yamanaka T. ix348 (1062O), ix385 (1181PD)<br />
Yamasaki M. ix481 (1485PD)<br />
Yamashita H. ix104 (277P)<br />
Yamashita Y. ix509 (1578P)<br />
Yamatsuji T. ix250 (758)<br />
Yamauchi H. ix82 (199P), ix100 (264P),<br />
ix133 (373P)<br />
Yamauchi J. ix211 (624)<br />
Yamauchi M. ix527 (1705)<br />
Yamazaki K. ix196 (574P), ix201 (590P),<br />
ix220 (653)<br />
Yamazaki N. ix372 (1142P), ix426 (1298P),<br />
ix514 (1597P), ix156 (451P), ix164 (475P),<br />
ix200 (587P)<br />
Yan H. ix415 (1266P), ix437 (1336)<br />
Yan S. ix416 (1269P)<br />
Yan Y. ix512 (1588P)<br />
Yanagida T. ix69 (153P)<br />
Yanagitani N. ix418 (1274P), ix441 (1353)<br />
Yanai T. ix514 (1597P)<br />
Yang C.J. ix414 (1263P)<br />
Yang H. ix389 (1193P), ix495 (1530P), ix111 (302)<br />
Yang J. ix415 (1266P), ix437 (1336)<br />
Yang J.C. ix402 (1229PD), ix410 (1252P)<br />
Yang M. ix89 (225P)<br />
Yang P. ix402 (1230PD), ix515 (1600P)<br />
Yang S. ix492 (1520PD), ix77 (182P)<br />
Yang S.H. ix414 (1262P)<br />
Yang X. ix321 (975PD)<br />
Yano H. ix71 (161P)<br />
Yao J.C. ix376 (1154O), ix47 (76IN)<br />
Yao Y. ix398 (1220), ix119 (326PD)<br />
Yasar N. ix497 (1540)<br />
Yashiro M. ix84 (205P)<br />
Yassine M. ix477 (1476)<br />
Yasuda H. ix422 (1285P)<br />
Yasuda K. ix541 (1690P)<br />
Yasui H. ix514 (1597P), ix203 (598P),<br />
ix231 (689P)<br />
Yatabe Y. ix433 (1324)<br />
Yau T. ix244 (736P)<br />
Yazbek G. ix499 (1547PD)<br />
Ychou M. ix85 (209P)<br />
Ye D-W. ix453 (1390P)<br />
Ye D. ix282 (851P)<br />
Ye G. ix117 (320PD), ix281 (847P)<br />
Ye L. ix190 (557P), ix281 (847P)<br />
Ye S. ix225 (670PD)<br />
Ye W. ix309 (938P)<br />
Yeh K. ix351 (1075P), ix522 (1626), ix253 (769)<br />
Yeh S. ix349 (1066PD)<br />
Yelle L. ix119 (328PD)<br />
Yelsengekar A. ix541 (1689P)<br />
Yen C. ix538 (1679P), ix246 (744P)<br />
Yermachenkova A.M. ix141 (403)<br />
Yerragudi S.R. ix150 (435TiP)<br />
Yetimoglu E. ix110 (300)<br />
Yeung Y. ix526 (1640)<br />
Yildirim A. ix308 (934P)<br />
Yilmaz A.U. ix173 (508), ix234 (701P)<br />
Yilmaz B. ix221 (660)<br />
Yim Y.M. ix477 (1474), ix203 (596P)<br />
Yin J. ix170 (497P)<br />
Yin W. ix154 (443PD), ix263 (796PD)<br />
Yip D. ix178 (519O)<br />
Yirmibesoglu E. ix110 (300)<br />
Yoda S. ix422 (1285P)<br />
Yoh K. ix429 (1306P), ix515 (1598P),<br />
ix534 (1666P)<br />
Yokoi S. ix144 (412O)<br />
Yokota M. ix210 (621)<br />
Yokota S. ix411 (1253P), ix422 (1286P),<br />
ix437 (1338)<br />
Yokouchi H. ix434 (1326)<br />
Yokoyama A. ix511 (1586P)<br />
ix584 | author index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology author index<br />
Yokoyama T. ix434 (1325), ix442 (1354),<br />
ix511 (1586P)<br />
Yokoyama Y. ix326 (989P)<br />
Yomoda M. ix497 (1537P)<br />
Yonemitsu Y. ix168 (490P)<br />
Yonemori K. ix90 (228P), ix164 (474P)<br />
Yoo C. ix234 (700P)<br />
Yoo G. ix342 (1043P)<br />
Yoo S. ix362 (1112PD)<br />
Yook J.H. ix227 (679P)<br />
Yoon D.S. ix240 (722P)<br />
Yoshida A. ix82 (199P), ix100 (264P),<br />
ix133 (373P)<br />
Yoshida K. ix433 (1324), ix536 (1671P),<br />
ix159 (460P)<br />
Yoshida M. ix436 (1334), ix518 (1611P),<br />
ix196 (573P)<br />
Yoshida T. ix515 (1598P)<br />
Yoshifumi H. ix442 (1354)<br />
Yoshikawa H. ix327 (995P)<br />
Yoshimatsu K. ix159 (460P)<br />
Yoshimura K. ix203 (598P), ix240 (723P)<br />
Yoshimura M. ix385 (1181PD), ix92 (233)<br />
Yoshimura N. ix412 (1258P), ix79 (189P),<br />
ix79 (190P)<br />
Yoshino I. ix385 (1181PD)<br />
Yoshino S. ix228 (681P), ix240 (723P)<br />
Yoshino T. ix63 (126IN), ix449 (1378P),<br />
ix196 (574P), ix200 (587P), ix201 (590P)<br />
Yoshioka H. ix385 (1181PD), ix422 (1286P),<br />
ix434 (1327), ix437 (1338), ix91 (232),<br />
ix153 (441O)<br />
Yoshiura K. ix71 (161P)<br />
Yoshiya T. ix385 (1180PD)<br />
Yoshizawa A. ix463 (1428P)<br />
Yoshizawa C. ix107 (289P)<br />
Yoshizawa H. ix397 (1218), ix413 (1259P),<br />
ix509 (1579P), ix71 (159P)<br />
Yossef T. ix129 (360P)<br />
Yo<strong>the</strong>rs G. ix179 (523PD)<br />
You B. ix125 (346P), ix299 (907P)<br />
You S.Y. ix209 (617)<br />
Youcef L. ix72 (164)<br />
Younes A. ix350 (1072P)<br />
Young-Lin N. ix460 (1416PD)<br />
Young A. ix500 (1549PD)<br />
Young A.M. ix162 (469P)<br />
Yousif M.G. ix327 (996P)<br />
Yousif N.G. ix327 (996P)<br />
Yu C. ix400 (1226O), ix405 (1236PD),<br />
ix406 (1239P), ix515 (1600P)<br />
Yu E. ix203 (596P)<br />
Yu E.Y. ix297 (900PD)<br />
Yu J. ix156 (449PD), ix270 (817P), ix279 (844P)<br />
Yu L. ix501 (1552P), ix229 (686P)<br />
Yu P. ix437 (1337)<br />
Yu Q. ix216 (640)<br />
Yu W. ix445 (1364TiP), ix445 (1365TiP)<br />
Yu Y. ix355 (1087P)<br />
Yuan J.Y. ix281 (847P)<br />
Yuan P. ix140 (401)<br />
Yuanfeng X. ix161 (465P)<br />
Yuankai S. ix416 (1269P)<br />
Yücel I. ix221 (660)<br />
Yue H. ix362 (1112PD)<br />
Yukawa T. ix541 (1690P)<br />
Yuki S. ix196 (574P), ix201 (590P), ix202 (592P),<br />
ix232 (692P)<br />
Yuksel O. ix526 (1641)<br />
Yuksel S. ix525 (1636)<br />
Yuldasheva N.S. ix325 (985P)<br />
Yumuk P.F. ix394 (1207P), ix186 (547P),<br />
ix217 (645)<br />
Yun H.J. ix541 (1688PD)<br />
Yun Y.H. ix465 (1434P), ix512 (1589P)<br />
Yunger S. ix202 (594P)<br />
Yunokawa M. ix90 (228P)<br />
Yurasov S. ix408 (1245P), ix422 (1287P)<br />
Yvonnet V. ix312 (946)<br />
Z<br />
Zaanan A. ix234 (703P)<br />
Zabotina T.N. ix371 (1138P)<br />
Zaczek A.J. ix320 (970PD)<br />
Zade B.P. ix101 (265P)<br />
Zaegel M. ix455 (1396P)<br />
Zafar S.Y. ix191 (560P)<br />
Zaffaroni N. ix88 (222P)<br />
Zaghloul M.S. ix145 (413PD)<br />
Zagloul H. ix337 (1028P)<br />
Zagonel V. ix466 (1436P), ix91 (230P),<br />
ix144 (411O), ix209 (618), ix326 (991P)<br />
Zahir H. ix244 (738P), ix245 (739P)<br />
Zaim R. ix450 (1379P)<br />
Zairi F. ix332 (1013)<br />
Zaivelieva J. ix134 (379)<br />
Zak A. ix513 (1593P)<br />
Zakaria H. ix523 (1627)<br />
Zakharova N.A. ix470 (1451P)<br />
Zakotnik B. ix112 (308)<br />
Zalcman G. ix397 (1219), ix419 (1276P)<br />
Zalipsky S. ix164 (477P)<br />
Zamagni C. ix130 (362P)<br />
Zaman K. ix138 (393)<br />
Zamarchi R. ix489 (1512), ix91 (230P)<br />
Zambelli A. ix535 (1669P)<br />
Zambrana F. ix374 (1151)<br />
Zanelli P. ix175 (513PD)<br />
Zanetta S. ix165 (478P), ix263 (797PD),<br />
ix294 (893O)<br />
Zang D.Y. ix193 (566P)<br />
Zang R. ix323 (980P)<br />
Zangerl G. ix494 (1528P)<br />
Zanon A. ix486 (1504P)<br />
Zapf A. ix336 (1023PD)<br />
Zappa M. ix379 (1163P)<br />
Zarogoulidis K. ix509 (1580P)<br />
Zavadova E. ix81 (197P)<br />
Zavaglia K. ix94 (243)<br />
Zavagno G. ix131 (367P)<br />
Zayed D. ix114 (314), ix216 (639)<br />
Zazo S. ix80 (194P), ix183 (537P), ix187 (549P)<br />
Zazpe C. ix219 (651)<br />
Zazulina V. ix410 (1252P)<br />
Zdzienicki M. ix489 (1513)<br />
Zebisch A. ix352 (1076P)<br />
Zehnder M. ix89 (223P)<br />
Zeimet A. ix323 (980P)<br />
Zelek L. ix414 (1265P)<br />
Zemanova M. ix270 (817P), ix279 (844P)<br />
Zengin N. ix332 (1015)<br />
Zerbi V. ix192 (562P)<br />
Zhang A. ix334 (1016O)<br />
Zhang B. ix160 (461P), ix303 (921P)<br />
Zhang B.X. ix141 (405TiP)<br />
Zhang C. ix117 (320PD)<br />
Zhang H. ix401 (1228O)<br />
Zhang J. ix93 (238), ix141 (405TiP), ix152 (439O),<br />
ix192 (564P), ix248 (748)<br />
Zhang K. ix281 (847P)<br />
Zhang L. ix343 (1048P), ix346 (1057),<br />
ix400 (1226O), ix421 (1283P), ix444 (1362TiP),<br />
ix447 (1369P), ix138 (394)<br />
Zhang N.N. ix390 (1196P)<br />
Zhang P. ix140 (401)<br />
Zhang R. ix189 (556P)<br />
Zhang S. ix77 (182P), ix141 (405TiP)<br />
Zhang S.Z. ix202 (595P)<br />
Zhang W. ix432 (1319), ix216 (640), ix217 (643)<br />
Zhang X. ix415 (1266P), ix435 (1331),<br />
ix437 (1336), ix501 (1552P), ix256 (779TiP),<br />
ix281 (847P)<br />
Zhang Y. ix413 (1261P), ix443 (1359),<br />
ix67 (144PD), ix495 (1530P), ix300 (911P)<br />
Zhang Z. ix216 (640)<br />
Zhao C. ix346 (1057)<br />
Zhao H. ix438 (1341), ix219 (650)<br />
Zhao J. ix216 (640), ix227 (676P)<br />
Zhao L. ix346 (1057), ix394 (1209), ix93 (238),<br />
ix219 (650)<br />
Zhao M. ix389 (1193P), ix437 (1337)<br />
Zhao P. ix256 (779TiP)<br />
Zhao Z. ix192 (564P), ix248 (748)<br />
Zheng L. ix389 (1193P)<br />
Zheng S. ix93 (238)<br />
Zheng Y. ix256 (779TiP), ix256 (779TiP)<br />
Zheng Y.D. ix226 (674P)<br />
Zhi X. ix170 (497P)<br />
Zhong Y. ix201 (589P), ix217 (644)<br />
Zhong Z. ix321 (975PD)<br />
Zhou A. ix453 (1390P)<br />
Zhou C. ix407 (1241P), ix416 (1269P),<br />
ix443 (1359), ix444 (1362TiP), ix76 (179P),<br />
ix81 (195P), ix87 (219P)<br />
Zhou F. ix282 (851P)<br />
Zhou J. ix202 (595P)<br />
Zhou J.J. ix202 (595P)<br />
Zhou J.X. ix389 (1193P)<br />
Zhou L. ix247 (745P)<br />
Zhou Q. ix444 (1362TiP)<br />
Zhou X. ix158 (456P), ix168 (489P), ix247 (745P),<br />
ix303 (921P)<br />
Zhou Y. ix443 (1359)<br />
Zhu D. ix201 (589P), ix216 (640), ix217 (644)<br />
Zhu J. ix421 (1283P)<br />
Zhu M. ix230 (687P)<br />
Zhukovsky E. ix350 (1072P)<br />
Zielinski C. ix116 (317O), ix145 (414PD),<br />
ix221 (659), ix253 (768)<br />
Zilembo N. ix410 (1251P)<br />
Zima T. ix81 (196P)<br />
Zimmermann A. ix404 (1235PD), ix418 (1275P),<br />
ix457 (1403)<br />
Zimmermann C. ix464 (1432P)<br />
Zimovjanova M. ix513 (1593P)<br />
Zinner R. ix49 (77IN)<br />
Zinoli L. ix301 (914P)<br />
Zippelius A. ix372 (1144)<br />
Zitvogel L. ix169 (495P)<br />
Zizi-Sermpetzoglou A. ix92 (236)<br />
Zoccoli A. ix489 (1512), ix516 (1603P),<br />
ix530 (1653P)<br />
Zojer N. ix348 (1064O)<br />
Zong J.H. ix447 (1369P)<br />
Zörner A. ix336 (1023PD)<br />
Zotov O. ix134 (379)<br />
Zou J. ix308 (936P)<br />
Zou Z. ix229 (686P)<br />
Zoubir T. ix314 (955)<br />
Zubiri L. ix149 (429P), ix239 (718P), ix305 (927P)<br />
Zucali P.A. ix167 (488P), ix276 (836P)<br />
Zucchini G. ix130 (362P)<br />
Zudaire J.J. ix291 (886)<br />
Zudaire M.E. ix291 (886), ix305 (927P)<br />
Zugazabeitia Olabarria L. ix510 (1582P)<br />
Zugazagoitia J. ix438 (1342)<br />
Zulato E. ix209 (618)<br />
Zulueta J. ix432 (1316)<br />
Zuniga R.M. ix150 (435TiP)<br />
Zuo Y. ix427 (1300P)<br />
Zurita Saavedra A.J. ix275 (833P)<br />
Zurita-Saavedra A. ix261 (791PD)<br />
Zustovich F. ix144 (411O)<br />
Zvirbule Z. ix116 (317O)<br />
Zwenger A. ix210 (619)<br />
Zwierzina H. ix543 (1695P)<br />
Zwierzina M. ix543 (1695P), ix446 (1368TiP)<br />
Volume 23 | Supplement 9 | June <strong>2012</strong> doi:10.1093/annonc/mds466 | ix585
subject<br />
index<br />
subject index<br />
A<br />
AAV-HGFK1, ix126 (348P)<br />
abiraterone acetate, comorbidity, ix305 (926P)<br />
abiraterone acetate, ix294 (894O), ix315 (958)<br />
abiraterone, ix119 (325PD)<br />
abiraterone, ix38 (48IN), ix304 (924P), ix305<br />
(925P), ix313 (951)<br />
ablation, ix371 (1137P), ix35 (40IN)<br />
AC-T, ix135 (382)<br />
ACC, ix209 (618)<br />
accelerated radio<strong>the</strong>rapy, ix397 (1217)<br />
access to clinical trials, ix165 (479P)<br />
acetic acid, ix471 (1455P)<br />
acquired resistance, ix401 (1227O), ix51 (82IN)<br />
acral melanoma, ix374 (1149), ix90 (227P)<br />
actinin-4, ix383 (1174P)<br />
activating EGFR kinase mutation, ix542 (1692P)<br />
active cellular <strong>the</strong>rapy, ix268 (813P), ix310 (939P),<br />
ix310 (941P), ix311 (942P)<br />
ACTN4, ix387 (1186P)<br />
acute exacerbation, ix497 (1538P)<br />
acute lymphoblastic leukemia (ALL), ix359 (1104),<br />
ix359 (1106)<br />
acute myelogenous leukemia (AML), ix349<br />
(1067PD), ix349 (1068PD)<br />
acute myeloid leukemia, ix349 (1066PD), ix356<br />
(1092P)<br />
acute oncology, ix519 (1613P)<br />
AD, ix135 (382)<br />
adapalene, ix514 (1597P)<br />
adaptive radio<strong>the</strong>rapy, ix35 (40IN)<br />
ADC, ix498 (1543TiP)<br />
ADCC, ix90 (228P), ix93 (237)<br />
adenocarcinoma, ix388 (1189P), ix429 (1307P),<br />
ix430 (1310P), ix435 (1331), ix439 (1343), ix446<br />
(1367TiP), ix455 (1396P), ix544 (1699P), ix77<br />
(182P), ix152 (438O), ix249 (753)<br />
adherence, ix460 (1419PD), ix476 (1473P), ix518<br />
(1611P)<br />
adipokines, ix79 (190P)<br />
adiponectin, ix79 (190P)<br />
adjuvant chemo-radio<strong>the</strong>rapy, ix345 (1056), ix97<br />
(253PD)<br />
adjuvant chemo<strong>the</strong>rapy timing, ix210 (620)<br />
adjuvant chemo<strong>the</strong>rapy, ix330 (1004P), ix385<br />
(1181PD), ix386 (1183P), ix389 (1192PD), ix95<br />
(246O), ix112 (306), ix121 (333P), ix178<br />
(520O), ix188 (551P), ix197 (576P), ix200<br />
(586P), ix200 (588P), ix210 (621), ix211 (625),<br />
ix212 (627), ix228 (681P)<br />
adjuvant docetaxel, ix108 (291P)<br />
adjuvant endocrine <strong>the</strong>rapy, ix105 (282P)<br />
adjuvant mFOLFOX6, ix201 (591P), ix221 (657)<br />
adjuvant radiochemo<strong>the</strong>rapy, ix229 (683P)<br />
adjuvant radio<strong>the</strong>rapy, ix386 (1183P)<br />
adjuvant <strong>the</strong>rapy, ix113 (311), ix235 (706P), ix281<br />
(847P), ix286 (867P), ix292 (889TiP)<br />
adjuvant treatment, ix96 (251PD), ix100 (261P),<br />
ix112 (308), ix181 (530PD)<br />
adjuvant, ix107 (288P), ix264 (799P)<br />
adme, ix508 (1575P)<br />
Adoptive Immuno<strong>the</strong>rapy, ix240 (723P)<br />
adrenoceptors, ix110 (299)<br />
adrenocortical carcinoma, ix293 (891TiP)<br />
Adult T-cell Leukemia/Lymphoma, ix348 (1062O)<br />
advanced basal cell carcinoma, ix362 (1111PD),<br />
ix362 (1112PD), ix477 (1474)<br />
advanced biliary cancers, ix288 (873)<br />
advanced breast cancer, ix123 (341P), ix138 (394),<br />
ix140 (400)<br />
advanced cancer patients, ix475 (1469P)<br />
advanced cancer, ix499 (1544O)<br />
advanced cervical cancer, ix327 (995P)<br />
advanced colorectal cancer, ix63 (127IN), ix511<br />
(1587P), ix35 (41IN), ix181 (528PD), ix181<br />
(529PD), ix183 (537P), ix185 (544P)<br />
advanced colorectal neoplasms, ix216 (640)<br />
advanced gastric cancer, ix228 (682P), ix93 (238),<br />
ix230 (688P), ix231 (691P), ix234 (701P), ix250<br />
(758)<br />
advanced gastroesophageal cancer, ix224 (667PD)<br />
advanced kidney cancer, ix258 (783O), ix264<br />
(798PD), ix278 (841P), ix278 (842P), ix280<br />
(845P)<br />
advanced lung cancer, ix515 (1600P), ix522<br />
(1625), ix523 (1630)<br />
advanced neuroendocrine tumours, ix378 (1161P),<br />
ix85 (209P)<br />
advanced non-small cell lung cancer, ix391<br />
(1199P), ix398 (1221), ix422 (1285P), ix434<br />
(1325), ix442 (1354), ix173 (505), ix422 (1286P)<br />
advanced NSCLC, ix398 (1223), ix411 (1253P),<br />
ix440 (1349), ix153 (440O)<br />
advanced prostate cancer, ix295 (895O)<br />
advanced soft tissue sarcoma, ix480 (1483PD)<br />
advanced solid tumors, ix157 (454P)<br />
advanced stage breast cancer, ix121 (332P)<br />
advanced uro<strong>the</strong>lial carcinoma, ix259 (786O)<br />
advanced/metastatic NSCLC, ix408 (1244P), ix423<br />
(1288P), ix436 (1335), ix444 (1361), ix78<br />
(186P), ix80 (194P)<br />
adverse event, ix519 (1614P), ix230 (688P)<br />
adverse events, ix203 (596P), ix259 (785O), ix280<br />
(845P)<br />
afatinib, ix401 (1227O), ix402 (1229PD), ix410<br />
(1252P), ix423 (1288P), ix424 (1292P), ix437<br />
(1339), ix155 (446PD), ix161 (464P), ix162<br />
(468P), ix165 (478P), ix169 (494P), ix174<br />
(509TiP)<br />
aflibercept, ix198 (581P), ix214 (633)<br />
Africa, ix65 (135IN)<br />
AGC, ix224 (668PD), ix232 (695P)<br />
aggressive disease, ix307 (933P)<br />
aggressive fibromatosis (desmoid tumor), ix479<br />
(1479PD)<br />
8.1 AH haplotype, ix493 (1523P)<br />
AI / EIA, ix487 (1505P)<br />
airway stenosis, ix517 (1608P)<br />
airway stent, ix517 (1608P)<br />
AITL, ix352 (1077P)<br />
AJCC, ix245 (741P)<br />
AKT inhibitor, ix159 (458P)<br />
Akt, ix338 (1031P)<br />
AKT, ix164 (474P)<br />
albumin-bound paclitaxel, ix141 (405TiP), ix256<br />
(780TiP)<br />
ALC, ix75 (175PD)<br />
alisertib, ix168 (489P)<br />
ALK rearrangement, ix390 (1195P)<br />
alk-positive diffuse large b-cell lymphoma, ix357<br />
(1098)<br />
ALK-positive NSCLC, ix402 (1230PD)<br />
ALK-positive, ix416 (1268P), ix80 (193P)<br />
ALK1, ix43 (62IN)<br />
ALK, ix387 (1187P), ix389 (1193P), ix73 (167O),<br />
ix153 (440O), ix153 (441O), ix51 (81IN)<br />
Alkaline phosphatase, ix306 (930P)<br />
all-case surveillance, ix200 (587P)<br />
allopurinol, ix358 (1103)<br />
alpha v-integrin, ix317 (965TiP)<br />
alpha-emitter pharmaceutical, ix296 (898PD),<br />
ix308 (936P)<br />
amatuximab, ix493 (1522PD)<br />
ambulatory oncology, ix475 (1468P)<br />
Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
Annals of Oncology 23 (Supplement 9): ix586–600, <strong>2012</strong><br />
doi:10.1093/annonc/mds467<br />
amino acid metabolism, ix532 (1660P)<br />
Amphinex, ix347 (1061TiP)<br />
amphiregulin, ix180 (526PD), ix183 (536P)<br />
AMPK, ix209 (618)<br />
amrubicin, ix443 (1358), ix492 (1519PD), ix92<br />
(235)<br />
amrubicinol, ix92 (235)<br />
anaemia, ix504 (1562P), ix505 (1564P), ix505<br />
(1566P), ix523 (1629)<br />
anamorelin, ix512 (1588P), ix161 (465P)<br />
anand, ix339 (1034P)<br />
anaplastic glioma, ix31 (23IN)<br />
anaplastic large cell lymphoma, ix348 (1063O),<br />
ix353 (1083P)<br />
Anaplastic Lymphoma Kinase (ALK) Gene<br />
Rearrangement, ix394 (1208)<br />
anaplastic lymphoma kinase (ALK), ix415<br />
(1266P), ix418 (1274P), ix484 (1497P), ix152<br />
(439O), ix390 (1196P), ix433 (1324)<br />
anastrozole, ix123 (341P)<br />
androgen deprivation <strong>the</strong>rapy, ix309 (938P), ix314<br />
(952)<br />
androgen receptor, ix344 (1706P), ix98 (257P),<br />
ix38 (48IN), ix295 (896O), ix297 (899PD)<br />
androgen, ix104 (277P)<br />
anemia point prevalence, ix523 (1628)<br />
anemia, ix499 (1545O), ix519 (1615P), ix523<br />
(1630)<br />
angiogenesis inhibitor, ix150 (435TiP), ix154<br />
(445PD), ix47 (76IN)<br />
angiogenesis inhibitors, ix40 (54IN)<br />
angiogenesis, ix59 (110IN), ix70 (155P), ix76<br />
(178P), ix88 (222P), ix39 (52IN), ix243 (734P),<br />
ix287 (869), ix54 (91IN), ix321 (975PD)<br />
angiogenic factor, ix286 (865P)<br />
angiopoietin (ANG), ix78 (184P)<br />
angiopoietins (ANGs), ix321 (975PD)<br />
announcing, ix476 (1471P)<br />
ANOVA models, ix164 (474P)<br />
anthracycline rechallenge, ix128 (357P)<br />
anthracycline-based chemo<strong>the</strong>rapy, ix352 (1077P)<br />
anthracycline, ix117 (320PD)<br />
anti HER-2 <strong>the</strong>rapy, ix164 (476P)<br />
anti VEGF <strong>the</strong>rapies, ix278 (840P)<br />
anti-androgen <strong>the</strong>rapy, ix344 (1706P), ix303<br />
(920P)<br />
anti-angiogenesis, ix220 (654)<br />
anti-angiogenic TKI, ix272 (822P), ix296 (897O)<br />
anti-CD26 monoclonal antibody, ix170 (498P)<br />
anti-EGFR <strong>the</strong>rapy, ix86 (214P), ix42 (58IN),<br />
ix224 (667PD)<br />
anti-EGFR, ix336 (1021PD)<br />
anti-emetic, ix508 (1575P), ix520 (1618)<br />
anti-emetics, ix507 (1573P), ix508 (1576P)<br />
anti-estrogen treatment, ix126 (350P)<br />
anti-idiotype monoclonal antibodies, ix406<br />
(1238PD)<br />
anti-microbial resistance, ix503 (1559P)<br />
anti-tumor activity, ix163 (472P), ix169 (495P)<br />
anti-tumor immunity, ix541 (1690P)<br />
anti-VEGF, ix269 (814P)<br />
antiangiogenic <strong>the</strong>rapy, ix186 (546P)<br />
antibiotics, ix351 (1075P)<br />
antibody-dependent cell-mediated cytotoxicity<br />
(ADCC), ix350 (1072P), ix528 (1644PD)<br />
antibody-drug conjugate, ix348 (1063O)<br />
antidepressant, ix109 (295P)<br />
antiemetic control, ix64 (129IN)<br />
antiemetic prevention, ix508 (1577P)<br />
antigen-specific cancer immuno<strong>the</strong>rapy, ix536<br />
(1671P)<br />
antineoplastic chemo<strong>the</strong>rapy, ix516 (1604P)
Annals of Oncology subject index<br />
antiprogressive treatment, ix303 (919P)<br />
antitumor activity, ix361 (1109O), ix405<br />
(1237PD), ix157 (453P), ix160 (461P), ix258<br />
(784O)<br />
anthracycline induced left ventricle dysfunction<br />
prediction, ix513 (1593P)<br />
AP26113, ix152 (439O)<br />
aplastic anemia, ix357 (1095)<br />
apoptosis, ix365 (1122P), ix72 (165), ix197<br />
(575P), ix253 (769)<br />
appendix carcinoma, ix222 (661)<br />
aprepitant, ix500 (1550PD), ix509 (1578P)<br />
ARN-509, ix303 (920P)<br />
aromatase inhibitor, ix27 (14IN), ix28 (17IN),<br />
ix104 (277P), ix105 (280P), ix105 (282P), ix124<br />
(342P)<br />
ARQ 197, ix225 (669PD)<br />
array CGH, ix71 (161P)<br />
arthralgia, ix113 (310)<br />
asbestos exposure, ix469 (1447PD)<br />
ASG-5ME, ix317 (963TiP)<br />
ASPS, ix484 (1495P)<br />
assessment, ix517 (1607P)<br />
association, ix260 (787O)<br />
asymptomatic brain metastases, ix137 (387)<br />
asymptomatic distant metastasis, ix106 (285P)<br />
aurora A kinase inhibitor, ix160 (461P)<br />
Aurora A kinase, ix168 (489P)<br />
Aurora-A, ix134 (376)<br />
autologous stem cell transplantation, ix353<br />
(1082P), ix353 (1083P), ix354 (1084P), ix260<br />
(789O)<br />
autologous transplantation, ix354 (1086P)<br />
automated quantitative protein expression analysis<br />
(AQUA), ix534 (1666P)<br />
autophagy, ix538 (1679P)<br />
avb3 integrin, ix86 (214P)<br />
awareness and willingness to participate, ix450<br />
(1381P)<br />
Awareness, ix472 (1458P)<br />
axitinib, ix409 (1246P), ix453 (1391P), ix268<br />
(811P), ix279 (843P), ix283 (856P)<br />
ayurveda, ix452 (1388P)<br />
5-azacytidine, ix357 (1096)<br />
B<br />
53BP1, ix533 (1661P), ix229 (686P)<br />
B-cell receptor, ix44 (65IN)<br />
bacteremia, ix503 (1559P)<br />
BAP 1, ix427 (1300P)<br />
barriers, ix65 (136IN)<br />
basal cell carcinoma, ix477 (1474)<br />
basal cell nevus syndrome, ix477 (1474)<br />
base of tongue squamous cell carcinoma, ix339<br />
(1032P)<br />
Bax, ix212 (628)<br />
BCC, ix362 (1111PD), ix362 (1112PD)<br />
BDNF, ix474 (1464P), ix79 (188P)<br />
BELIEF, ix58 (105IN)<br />
belinostat, ix349 (1068PD)<br />
Belotean, ix492 (1520PD)<br />
bendamustine, ix348 (1064O)<br />
benefit, ix332 (1014)<br />
best response, ix282 (852P)<br />
bevacizumab beyond progression, ix140 (400),<br />
ix192 (562P), ix220 (655)<br />
bevacizumab, ix118 (323PD), ix220 (653), ix378<br />
(1159P), ix378 (1160P), ix390 (1194P), ix405<br />
(1236PD), ix406 (1239P), ix406 (1240P), ix419<br />
(1277P), ix419 (1278P), ix420 (1279P), ix426<br />
(1299P), ix428 (1303P), ix441 (1351), ix441<br />
(1352), ix441 (1353), ix445 (1364TiP), ix70<br />
(155P), ix529 (1648P), ix530 (1653P), ix531<br />
(1657P), ix75 (174O), ix81 (198P), ix85 (209P),<br />
ix108 (292P), ix116 (317O), ix122 (335P), ix125<br />
(345P), ix127 (354P), ix128 (356P), ix139 (395),<br />
ix146 (417PD), ix151 (437TiP), ix161 (464P),<br />
ix171 (499P), ix181 (530PD), ix182 (532P),<br />
ix189 (555P), ix190 (559P), ix191 (560P), ix193<br />
(565P), ix193 (567P), ix195 (571P), ix196<br />
(573P), ix202 (592P), ix202 (594P), ix203<br />
(596P), ix206 (607P), ix209 (618), ix211 (624),<br />
ix218 (648), ix219 (651), ix219 (652), ix221<br />
(659), ix249 (755), ix267 (809P), ix289 (876),<br />
ix319 (967O), ix320 (973PD), ix322 (978P),<br />
ix325 (986P)<br />
beyond PD, ix439 (1343), ix439 (1344)<br />
BEZ235, ix157 (454P)<br />
BI-RADS classification, ix107 (286P)<br />
BIBF 1120, ix245 (740P), ix246 (744P)<br />
bilateral breast cancer, ix175 (513PD)<br />
biliary tract cancer, ix241 (725P), ix242 (730P),<br />
ix242 (731P), ix245 (739P)<br />
biliary tract cancers, ix254 (773)<br />
bioavailability, ix507 (1574P)<br />
biobank, ix385 (1179O), ix535 (1669P)<br />
Biobanking, ix61 (117IN)<br />
biochemo<strong>the</strong>rapy, ix373 (1147)<br />
bioequivalence, ix507 (1574P)<br />
biological characteristics, ix215 (638)<br />
biological marker, ix85 (211P)<br />
biological markers, ix474 (1464P)<br />
biological response, ix354 (1086P), ix303 (919P)<br />
biological <strong>the</strong>rapy, ix500 (1550PD)<br />
biology of colorectal cancer, ix92 (236)<br />
biomarker discovery, ix262 (794PD)<br />
biomarker, ix451 (1382P), ix529 (1647PD), ix531<br />
(1656P), ix531 (1657P), ix73 (169O), ix77<br />
(180P), ix78 (186P), ix81 (198P), ix83 (202P),<br />
ix84 (206P), ix88 (220P), ix89 (226P), ix93<br />
(238), ix93 (240), ix158 (457P), ix173 (505),<br />
ix187 (550P), ix212 (628), ix263 (796PD), ix275<br />
(832P), ix278 (842P), ix285 (861P), ix300<br />
(910P)<br />
biomarkers for antihormone responsiveness, ix96<br />
(249PD)<br />
biomarkers, ix59 (110IN), ix383 (1173P), ix390<br />
(1194P), ix400 (1226O), ix405 (1236PD), ix406<br />
(1239P), ix406 (1240P), ix430 (1312), ix529<br />
(1648P), ix47 (1703IN), ix76 (177PD), ix78<br />
(183P), ix80 (194P), ix84 (207P), ix86 (213P),<br />
ix87 (219P), ix32 (28IN), ix124 (343P), ix259<br />
(785O), ix49 (78IN), ix301 (915P)<br />
biomolecular analysis, ix483 (1491P)<br />
biosimilar, ix351 (1074P), ix103 (274P)<br />
biosimilars, ix504 (1563P), ix506 (1568P), ix506<br />
(1569P)<br />
bio<strong>the</strong>rapeutics, ix488 (1508P)<br />
bispecific monoclonal antibody, ix350 (1072P)<br />
bispecific, ix170 (496P)<br />
bisphosphates, ix443 (1359)<br />
bisphosphonate, ix511 (1584P), ix511 (1585P)<br />
bisphosphonates, ix524 (1633)<br />
biweekly carboplatin and paclitaxel, ix422 (1285P)<br />
BKM120, ix116 (318O), ix157 (454P), ix223<br />
(664TiP)<br />
bladder cancer, ix39 (50IN), ix39 (53IN), ix260<br />
(788O), ix264 (799P), ix265 (802P), ix266<br />
(805P), ix266 (806P), ix266 (807P), ix290 (882),<br />
ix291 (884), ix291 (885)<br />
bladder preservation, ix265 (801P), ix291 (883)<br />
bladder, ix93 (239), ix265 (803P)<br />
bleomycin, ix347 (1061TiP), ix285 (862P)<br />
blood flow in tumor, ix134 (379)<br />
blood pressure monitoring, ix268 (811P)<br />
blood vessels, ix149 (431)<br />
blood–brain barrier, ix537 (1675P)<br />
blood-brain barrier permeability, ix61 (120IN)<br />
BOADICEA, ix34 (35IN)<br />
body composition, ix168 (491P)<br />
Body Mass Index (BMI), ix206 (606P)<br />
body mass index, ix515 (1599P), ix119 (327PD),<br />
ix135 (380)<br />
bone disease, ix126 (351P)<br />
bone growth, ix526 (1642)<br />
bone health, ix449 (1377P)<br />
bone marker, ix126 (351P)<br />
bone marrow transplantation, ix357 (1095)<br />
bone marrow, ix69 (152P)<br />
bone metastases, ix447 (1372P), ix509 (1580P),<br />
ix510 (1583P), ix511 (1585P), ix133 (372P),<br />
ix140 (401), ix309 (937P)<br />
Bone Metastasis, c-MET, ix296 (897O)<br />
bone metastasis, ix344 (1050P), ix432 (1320),<br />
ix433 (1321), ix443 (1359), ix126 (348P), ix229<br />
(685P)<br />
bone metastatic patients, ix524 (1633)<br />
bone mineral density, ix105 (282P)<br />
bone resorption biomarker, ix432 (1320)<br />
bone turnover markers, ix266 (805P), ix312 (945)<br />
bone-targeted treatment, ix38 (49IN)<br />
borderline ovarian cancer, ix322 (976P)<br />
borderline subgroup (12-20% split signals), ix390<br />
(1195P)<br />
bortezomib, ix348 (1064O), ix249 (754)<br />
bowel obstruction, ix326 (992P)<br />
brachy<strong>the</strong>rapy, ix329 (1003P)<br />
BRAF inhibitor, ix366 (1125P)<br />
BRAF mutation, ix365 (1123P), ix373 (1145),<br />
ix383 (1173P), ix94 (242), ix220 (656)<br />
BRAF status, ix383 (1173P)<br />
BRAF-mutations, ix373 (1147)<br />
BRAF, ix387 (1187P), ix529 (1649P), ix196<br />
(574P), ix216 (641), ix46 (69IN), ix46 (70IN)<br />
brain metastases, ix366 (1125P), ix369 (1132P),<br />
ix394 (1207P), ix61 (120IN), ix62 (123IN),<br />
ix421 (1283P), ix421 (1284P), ix428 (1305P),<br />
ix435 (1330), ix446 (1368TiP), ix489 (1514),<br />
ix537 (1675P), ix31 (26IN), ix144 (412O), ix145<br />
(414PD), ix148 (427P), ix148 (428P), ix150<br />
(433), ix253 (771)<br />
brain metastasis, ix62 (121IN), ix414 (1262P)<br />
brain, ix221 (660)<br />
BRCA 1/2 mutations, ix109 (294P)<br />
BRCA mutation, ix176 (515P), ix319 (969PD)<br />
BRCA1/2, ix469 (1449PD), ix34 (35IN), ix175<br />
(512PD), ix175 (513PD)<br />
BRCA1, ix498 (1542TiP), ix531 (1655P), ix533<br />
(1661P), ix34 (34IN), ix229 (686P), ix266<br />
(807P)<br />
BRCA2 mutation, ix176 (514P)<br />
BRCA2, ix34 (34IN)<br />
breakthrough cancer pain (BTcP), ix518 (1612P)<br />
breast cancer screening, ix469 (1449PD)<br />
Breast Cancer Stem Cells (BCSCs), ix133 (375P)<br />
breast cancer stem cells, ix110 (300)<br />
breast cancer subtypes, ix100 (261P), ix110<br />
(297P), ix131 (366P)<br />
breast cancer, HER2, EGFR, ix127 (353P)<br />
breast cancer, ix57 (100IN), ix57 (101IN), ix57<br />
(102IN), ix58 (103IN), ix58 (104IN), ix59<br />
(108IN), ix384 (1178TiP), ix61 (120IN), ix62<br />
(121IN), ix452 (1388P), ix453 (1389P), ix454<br />
(1393P), ix454 (1394P), ix455 (1397P), ix455<br />
(1398P), ix27 (13IN), ix460 (1417PD), ix470<br />
(1450P), ix470 (1451P), ix67 (146P), ix477<br />
(1476), ix501 (1552P), ix501 (1553P), ix506<br />
(1568P), ix70 (156P), ix513 (1593P), ix27<br />
(15IN), ix521 (1621), ix525 (1636), ix72 (164),<br />
ix531 (1656P), ix532 (1658P), ix532 (1660P),<br />
ix543 (1698P), ix74 (172O), ix29 (18IN), ix82<br />
(200P), ix83 (202P), ix84 (204P), ix84 (206P),<br />
ix87 (216P), ix87 (217P), ix94 (243), ix95<br />
(246O), ix96 (249PD), ix96 (250PD), ix97<br />
(253PD), ix97 (254PD), ix100 (261P), ix100<br />
(264P), ix101 (265P), ix101 (266P), ix101<br />
(268P), ix102 (269P), ix102 (270P), ix103<br />
(273P), ix104 (276P), ix104 (277P), ix104<br />
(278P), ix105 (279P), ix105 (281P), ix106<br />
(283P), ix106 (284P), ix107 (286P), ix107<br />
(288P), ix108 (290P), ix109 (293P), ix110<br />
(297P), ix110 (299), ix110 (300), ix111 (302),<br />
ix112 (305), ix112 (306), ix112 (308), ix113<br />
(309), ix113 (311), ix114 (313), ix114 (314),<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds467 | ix587
subject index<br />
ix115 (316TiP), ix116 (318O), ix116 (319O),<br />
ix117 (320PD), ix117 (321PD), ix117 (322PD),<br />
ix118 (323PD), ix118 (324PD), ix119 (325PD),<br />
ix120 (331P), ix121 (333P), ix121 (334P), ix124<br />
(343P), ix125 (347P), ix126 (348P), ix126<br />
(349P), ix34 (34IN), ix126 (350P), ix126 (351P),<br />
ix127 (352P), ix129 (359P), ix34 (35IN), ix130<br />
(362P), ix130 (363P), ix131 (365P), ix131<br />
(367P), ix133 (372P), ix133 (373P), ix133<br />
(374P), ix134 (376), ix137 (387), ix137 (388),<br />
ix139 (396), ix139 (397), ix139 (398), ix140<br />
(402), ix141 (405TiP), ix142 (406TiP), ix162<br />
(470P), ix166 (483P), ix175 (511PD), ix175<br />
(512PD), ix176 (515P), ix321 (974PD), ix57<br />
(99IN), ix25 (9IN)<br />
breast carcinoma, ix107 (287P)<br />
breast self examination, ix136 (383), ix136 (383)<br />
brentuximab vedotin, ix348 (1063O), ix353<br />
(1083P)<br />
brivanib, ix319 (966O)<br />
Brm, ix78 (186P)<br />
bronchoscopic intervention, ix517 (1608P)<br />
brown fat, ix108 (290P)<br />
BTK inhibitors, immunotoxins, ix45 (68IN)<br />
C<br />
c-kit, heat shock protein 90 inhibitor, ix538<br />
(1679P)<br />
c-kit, ix365 (1123P), ix498 (1541)<br />
c-Met inhibitor, ix67 (143PD), ix154 (444PD),<br />
ix174 (1708PD)<br />
c-MET, ix424 (1293P), ix76 (179P), ix84 (205P)<br />
c-Myc, statin, ix302 (916P)<br />
c-Myc, ix275 (832P)<br />
C-reactive protein, prognosis, ix381 (1169P)<br />
C-reactive protein, ix525 (1637)<br />
Ca 125, ix324 (983P)<br />
cabazitaxel, ix170 (497P), ix306 (931P), ix307<br />
(932P), ix307 (933P), ix312 (946), ix312 (948),<br />
ix313 (951), ix314 (953), ix314 (955), ix315<br />
(956), ix315 (958), ix316 (960), ix316 (962TiP)<br />
cachexia, ix499 (1544O), ix512 (1588P), ix161<br />
(465P)<br />
CagA, ix351 (1075P)<br />
calendula officinalis,, ix346 (1059)<br />
CAM, ix452 (1388P)<br />
cancer and chemo<strong>the</strong>rapy, ix515 (1599P)<br />
cancer associated anemia, ix504 (1561P)<br />
cancer awareness, ix380 (1166P), ix448 (1375P),<br />
ix472 (1457P)<br />
cancer burden, ix65 (137IN)<br />
cancer cachexia, ix64 (131IN), ix511 (1586P)<br />
cancer clinical trial, ix450 (1381P), ix483 (1493P)<br />
cancer genomics, ix544 (1699P)<br />
cancer immuno<strong>the</strong>rapy, ix406 (1238PD), ix536<br />
(1672P), ix268 (813P), ix301 (915P), ix313 (949)<br />
cancer informatics, ix449 (1376P)<br />
cancer nanotechnology, ix87 (217P)<br />
cancer of unknown primary origin (CUP), ix381<br />
(1169P), ix381 (1170P), ix381 (1171P)<br />
cancer patient, ix457 (1404)<br />
cancer policy, ix66 (141INIS)<br />
cancer registry implementation, ix460 (1414TiP)<br />
cancer registry, ix449 (1376P), ix175 (513PD),<br />
ix241 (725P)<br />
cancer risk, ix53 (89IN)<br />
cancer screening, ix460 (1419PD), ix470 (1452P),<br />
ix471 (1453P), ix473 (1461)<br />
cancer stem cells <strong>the</strong>rapeutics, ix160 (463P)<br />
cancer stem cells, ix71 (159P), ix72 (164), ix539<br />
(1685P), ix543 (1696P), ix86 (215P), ix136<br />
(385), ix160 (463P)<br />
cancer, ix65 (135IN), ix447 (1369P), ix456<br />
(1401P), ix458 (1408), ix459 (1412), ix476<br />
(1471P), ix478 (1477O), ix519 (1616P), ix71<br />
(161P), ix242 (729P), ix56 (98IN)<br />
capecitabine, ix128 (356P), ix129 (358P), ix138<br />
(394), ix139 (398), ix140 (399), ix187 (550P),<br />
ix193 (566P), ix200 (588P), ix234 (700P), ix240<br />
(722P), ix250 (757), ix256 (781TiP), ix257<br />
(782TiP), ix229 (683P)<br />
CAPOX, ix218 (647)<br />
carboplatin and pemetrexed, ix434 (1326)<br />
carboplatin plus paclitaxel, ix398 (1221)<br />
carboplatin, ix340 (1037P), ix397 (1218), ix409<br />
(1246P), ix151 (437TiP), ix283 (857P), ix286<br />
(867P)<br />
carcinoembryonic antigen (CEA), ix199 (583P),<br />
ix221 (659)<br />
carcinoids, ix47 (73IN)<br />
carcinoma cervix, ix328 (997P)<br />
cardiac safety, ix128 (357P), ix178 (519O)<br />
cardiac toxicity, ix113 (309)<br />
cardio-toxicity, cardio-protection, anthracyclines,<br />
echocardiography, ix539 (1682P)<br />
cardiotoxicity, ix455 (1397P)<br />
care satisfaction, ix475 (1468P)<br />
caregiver, ix343 (1047P)<br />
cargiverś burden, ix145 (415PD)<br />
castrate-resistant prostate cancer (CRPC), PSA,<br />
ix304 (923P)<br />
castrate-resistant prostate cancer (CRPC), ix296<br />
(897O), ix298 (902P), ix298 (903P), ix300<br />
(909P), ix301 (913P), ix301 (915P), ix305<br />
(927P), ix308 (934P), ix315 (958), ix316 (960),<br />
ix317 (964TiP)<br />
castrate-resistant prostate cancer, ix38 (47IN),<br />
ix296 (898PD), ix308 (936P)<br />
castration resistant prostate cancer, ix300 (911P),<br />
ix302 (917P), ix303 (921P), ix305 (926P), ix314<br />
(954), ix317 (963TiP)<br />
castration-resistant prostate cancer, ix304 (924P),<br />
ix305 (925P)<br />
catumaxomab, ix514 (1596P), ix539 (1683P),<br />
ix163 (472P), ix172 (504), ix228 (680P)<br />
caucasian patients, ix337 (1026P), ix439 (1346)<br />
CD10, ix107 (287P)<br />
CD117, ix349 (1067PD)<br />
CD133-positive blood vessels, ix146 (418PD)<br />
CD133, ix205 (604P)<br />
CD135, ix349 (1067PD)<br />
CD20, ix70 (157P)<br />
CD24, ix87 (216P)<br />
CD30+ lymphomas, ix348 (1063O)<br />
CD30 + , ix285 (861P)<br />
CD32, ix70 (157P)<br />
CD34+ stem cell mobilization and collection,<br />
ix353 (1082P), ix353 (1083P)<br />
CD40, ix529 (1650P)<br />
CD44 + /CD24-/Lin-cells, ix110 (300)<br />
CD44, ix87 (216P)<br />
2 CdA, ix352 (1076P)<br />
cediranib, ix155 (448PD), ix207 (609P)<br />
cell growth, ix88 (220P)<br />
cell-free DNA, ix73 (168O)<br />
CellSearch, ix338 (1029P), ix90 (227P)<br />
CellSearchSystem, ix489 (1512)<br />
central nerve system metastasis, ix251 (764)<br />
cervical cancer screening, ix471 (1454P), ix471<br />
(1455P)<br />
cervical cancer, ix328 (1000P), ix330 (1007), ix330<br />
(1007), ix331 (1008), ix331 (1009), ix331 (1010),<br />
ix475 (1466P), ix524 (1632), ix22 (3IN), ix327<br />
(996P), ix328 (998P), ix328 (999P)<br />
cetuximab resistance, ix67 (143PD), ix530<br />
(1651P), ix42 (59IN), ix334 (1018O)<br />
cetuximab, ix340 (1036P), ix342 (1044P), ix345<br />
(1052), ix372 (1144), ix396 (1213), ix396 (1216),<br />
ix417 (1272P), ix528 (1644PD), ix87 (218P),<br />
ix93 (237), ix178 (520O), ix180 (526PD), ix183<br />
(535P), ix190 (557P), ix191 (561P), ix192<br />
(563P), ix194 (568P), ix196 (572P), ix198<br />
(580P), ix199 (582P), ix206 (606P), ix206<br />
(608P), ix213 (630), ix217 (643), ix233 (696P)<br />
cfDNA, ix533 (1664P)<br />
CH5424802, ix153 (441O)<br />
Annals of Oncology<br />
challenges, ix65 (135IN)<br />
Charson comorbidity index, ix349 (1065O)<br />
checklist, ix524 (1634)<br />
checkpoint protein biomarker antibody, ix46<br />
(71IN)<br />
chemo-radio<strong>the</strong>rapy, ix342 (1045P), ix206 (608P),<br />
ix208 (612P), ix225 (671P), ix328 (999P)<br />
chemo-resistance, ix159 (458P)<br />
chemoembolisation, ix35 (40IN), ix254 (772)<br />
chemokine ligand 2, ix277 (838P)<br />
chemomodulation, ix370 (1135P)<br />
chemoprevention, ix34 (36IN)<br />
chemoradiation, ix330 (1007), ix215 (638)<br />
chemoradio<strong>the</strong>rapy, ix520 (1620), ix207 (609P),<br />
ix215 (637), ix226 (673P), ix237 (711P)<br />
chemoresistance, ix370 (1135P)<br />
chemosensitivity, ix429 (1308P)<br />
chemo<strong>the</strong>rapeutic drugs, ix38 (47IN)<br />
chemo<strong>the</strong>rapy combination, ix371 (1138P), ix138<br />
(391), ix166 (484P)<br />
chemo<strong>the</strong>rapy holiday, ix181 (528PD)<br />
chemo<strong>the</strong>rapy induced peripheral neuropathy,<br />
ix521 (1622)<br />
chemo<strong>the</strong>rapy regimens, ix214 (634), ix320<br />
(972PD)<br />
chemo<strong>the</strong>rapy toxicity, ix452 (1386P), ix511<br />
(1587P)<br />
chemo<strong>the</strong>rapy-induced anaemia, ix504 (1563P),<br />
ix506 (1568P), ix506 (1569P), ix523 (1627)<br />
chemo<strong>the</strong>rapy-induced anemia, ix505 (1565P),<br />
ix505 (1567P)<br />
chemo<strong>the</strong>rapy-induced mucositis, ix163 (473P)<br />
chemo<strong>the</strong>rapy-induced nausea and vomiting,<br />
ix509 (1579P)<br />
chemo<strong>the</strong>rapy-induced neutropenia, ix499<br />
(1547PD), ix500 (1548PD)<br />
chemo<strong>the</strong>rapy-induced oral mucositis, ix514<br />
(1595P)<br />
chemo<strong>the</strong>rapy-induced peripheral neurotoxicity,<br />
ix512 (1590P), ix513 (1591P)<br />
chemo<strong>the</strong>rapy-naive, ix294 (894O)<br />
chemo<strong>the</strong>rapy, ix331 (1010), ix332 (1013), ix340<br />
(1036P), ix342 (1044P), ix352 (1076P), ix378<br />
(1159P), ix378 (1160P), ix378 (1161P), ix381<br />
(1171P), ix391 (1199P), ix62 (121IN), ix398<br />
(1222), ix398 (1223), ix408 (1243P), ix408<br />
(1244P), ix411 (1254P), ix427 (1301P), ix429<br />
(1306P), ix429 (1308P), ix435 (1331), ix440<br />
(1348), ix443 (1357), ix447 (1369P), ix457<br />
(1406), ix459 (1411), ix459 (1412), ix484<br />
(1496P), ix485 (1500P), ix493 (1525P), ix496<br />
(1536P), ix497 (1537P), ix500 (1549PD), ix503<br />
(1558P), ix504 (1562P), ix513 (1592P), ix515<br />
(1598P), ix27 (15IN), ix518 (1609P), ix518<br />
(1611P), ix521 (1623), ix523 (1628), ix526<br />
(1640), ix72 (164), ix75 (175PD), ix85 (209P),<br />
ix29 (21IN), ix31 (24IN), ix107 (288P), ix113<br />
(309), ix117 (321PD), ix122 (336P), ix133<br />
(373P), ix37 (45IN), ix164 (477P), ix171 (500P),<br />
ix172 (504), ix194 (569P), ix208 (614P), ix212<br />
(628), ix218 (647), ix218 (648), ix222 (661),<br />
ix231 (690P), ix242 (730P), ix242 (731P), ix244<br />
(736P), ix250 (756), ix250 (757), ix256<br />
(780TiP), ix260 (788O), ix264 (799P), ix265<br />
(803P), ix307 (932P), ix56 (96IN), ix325 (985P),<br />
ix327 (995P)<br />
chest CT screening, ix469 (1447PD)<br />
chest wall irradiation, ix114 (314)<br />
chest wall, ix130 (363P), ix131 (367P)<br />
Child-Pugh status, ix244 (736P)<br />
children, ix359 (1104), ix517 (1606P)<br />
chimeric anti-meso<strong>the</strong>lin monoclonal antibody,<br />
ix493 (1522PD)<br />
China, ix501 (1552P), ix114 (313)<br />
Chinese, ix282 (851P)<br />
chk1, ix42 (61IN)<br />
chlorhexidine, ix522 (1626)<br />
choi response criteria, ix379 (1163P)<br />
ix588 | subject index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology subject index<br />
Choi response criteria, ix487 (1506P)<br />
Choriocarcinoma, ix330 (1005P)<br />
chromosomal aberration (CA), ix91 (230P)<br />
chromosome 7 polysomy, ix287 (868)<br />
chromothripsis, ix31 (25IN)<br />
chronic lymphocytic leukemia (CLL), ix350<br />
(1070PD), ix451 (1384P)<br />
chronic myeloid leukemia, ix355 (1090P), ix359<br />
(1105)<br />
cigarette smoking, ix469 (1448PD)<br />
cilastatin, ix520 (1619)<br />
CINV, ix507 (1573P), ix508 (1576P)<br />
circulating DNA, ix74 (171O), ix109 (293P)<br />
circulating endo<strong>the</strong>lial cells, ix85 (209P), ix193<br />
(567P)<br />
circulating free DNA, ix87 (219P)<br />
circulating melanoma cells, ix533 (1664P), ix87<br />
(219P)<br />
circulating tumor cells, ix383 (1175P), ix431<br />
(1313), ix489 (1512), ix529 (1650P), ix74<br />
(171O), ix87 (217P), ix87 (218P), ix89 (223P),<br />
ix91 (230P), ix98 (255PD), ix111 (304), ix199<br />
(582P), ix300 (910P), ix300 (911P), ix304<br />
(922P)<br />
circulating tumour cells, ix338 (1029P), ix90<br />
(227P), ix94 (244)<br />
cirrhosis, ix243 (733P)<br />
cisplatin doxorubicin, ix487 (1507P)<br />
cisplatin plus S-1, ix385 (1181PD)<br />
cisplatin-based chemo<strong>the</strong>rapy, ix266 (807P)<br />
cisplatin, ix336 (1022PD), ix346 (1058), ix396<br />
(1215), ix68 (148P), ix68 (149P), ix507 (1573P),<br />
ix70 (158P), ix515 (1598P), ix520 (1619), ix525<br />
(1639), ix129 (359P), ix138 (394), ix139 (397),<br />
ix225 (671P), ix234 (700P), ix234 (701P), ix247<br />
(745P), ix247 (746P)<br />
citrulline, ix91 (229P)<br />
clear renal cell carcinoma, ix287 (868)<br />
clinical benefit, ix536 (1672P), ix128 (357P)<br />
clinical cancer research, ix65 (136IN)<br />
clinical feature, ix140 (400)<br />
clinical management, ix61 (116IN), ix284 (859P)<br />
clinical oncology, ix538 (1678P)<br />
clinical practice, ix447 (1370P)<br />
clinical practices guidelines, ix481 (1487P), ix505<br />
(1567P)<br />
clinical predictors, ix490 (1515)<br />
clinical profile, ix441 (1352)<br />
clinical research, ix65 (133IN), ix448 (1374P)<br />
clinical significance, ix248 (748)<br />
clinical staging, surgical staging, ix384 (1177P)<br />
clinical study, ix518 (1612P)<br />
clinical trial design, ix460 (1416PD), ix35 (41IN)<br />
clinical trial, ix404 (1235PD), ix63 (124IN), ix507<br />
(1573P), ix158 (457P), ix295 (895O)<br />
clinical trials, ix58 (106IN), ix535 (1670P), ix37<br />
(43IN), ix43 (63IN)<br />
clinicopathological feature, ix99 (258P)<br />
clinicopathological parameters, ix94 (242)<br />
CNS metastases, ix406 (1240P), ix426 (1299P),<br />
ix132 (370P)<br />
co-clinical, ix59 (107IN)<br />
Cockroft-Gault, ix283 (857P)<br />
cognitive function, ix144 (412O)<br />
cohort study, ix218 (648)<br />
collaborative clinical T = trials, ix64 (131IN)<br />
colon cancer, ix86 (214P), ix178 (520O), ix179<br />
(522PD), ix179 (523PD), ix183 (534P), ix183<br />
(535P), ix187 (550P), ix188 (551P), ix188<br />
(552P), ix197 (576P), ix200 (588P), ix201<br />
(591P), ix205 (603P), ix205 (604P), ix205<br />
(605P), ix209 (616), ix210 (620), ix219 (652),<br />
ix221 (657), ix223 (664TiP)<br />
colon, ix86 (215P)<br />
ColoPrint, ix179 (522PD)<br />
colorectal cancer cells, ix220 (654)<br />
colorectal cancer screening, ix472 (1460)<br />
colorectal cancer, ix383 (1173P), ix460 (1419PD),<br />
ix67 (143PD), ix474 (1465P), ix512 (1590P),<br />
ix529 (1649P), ix529 (1650P), ix530 (1654P),<br />
ix542 (1694P), ix75 (174O), ix85 (208P), ix35<br />
(40IN), ix157 (452P), ix159 (460P), ix166<br />
(483P), ix180 (526PD), ix181 (530PD), ix182<br />
(531P), ix182 (533P), ix183 (536P), ix184<br />
(539P), ix184 (540P), ix185 (542P), ix185<br />
(543P), ix186 (546P), ix186 (547P), ix186<br />
(548P), ix189 (555P), ix191 (560P), ix193<br />
(566P), ix194 (568P), ix196 (572P), ix198<br />
(579P), ix198 (580P), ix199 (582P), ix199<br />
(583P), ix200 (585P), ix200 (587P), ix201<br />
(590P), ix202 (592P), ix202 (593P), ix202<br />
(594P), ix203 (598P), ix205 (605P), ix208<br />
(613P), ix209 (615), ix209 (617), ix210 (619),<br />
ix211 (623), ix212 (626), ix212 (628), ix213<br />
(630), ix215 (636), ix216 (641), ix217 (643),<br />
ix218 (647), ix219 (649), ix219 (651), ix220<br />
(653), ix220 (655), ix221 (659), ix223 (665TiP)<br />
colorectal carcinogenesis, ix86 (212P)<br />
colorectal liver metastases, ix190 (557P), ix197<br />
(577P), ix211 (624), ix211 (625), ix217 (644)<br />
colorectal surgery, ix202 (595P)<br />
colorectal, ix209 (618), ix220 (656)<br />
Colposcopy, ix471 (1454P)<br />
combination <strong>the</strong>rapy, ix75 (173O), ix258 (783O)<br />
combined modality <strong>the</strong>rapy, ix334 (1016O), ix396<br />
(1213), ix425 (1296P), ix49 (80IN)<br />
community cancer awareness, ix471 (1453P)<br />
community oncology, ix458 (1407)<br />
community-based clinical trial, ix442 (1354)<br />
comorbidities, ix279 (844P)<br />
comorbidity, ix349 (1065O)<br />
compassionate use programme, ix306 (931P)<br />
complete pathological remission (PCR), ix95<br />
(247O), ix130 (361P)<br />
complete pathological response, ix101 (268P)<br />
compliance, ix481 (1487P), ix511 (1584P), ix200<br />
(586P), ix287 (870)<br />
complications, ix252 (765)<br />
comprehensive geriatric assessment, ix341<br />
(1042P), ix452 (1385P), ix452 (1386P), ix452<br />
(1387P)<br />
computed tomography, ix60 (112IN), ix534<br />
(1665P), ix301 (913P)<br />
concomitant chemoradiation, ix328 (1000P),<br />
ix392 (1200P)<br />
concomitant chemoradio<strong>the</strong>rapy, ix335 (1020PD),<br />
ix341 (1039P)<br />
concordance index (c-index), ix241 (727P)<br />
concurrent chemoradio<strong>the</strong>rapy, ix392 (1202P),<br />
ix393 (1204P), ix395 (1212)<br />
concurrent radiochemo<strong>the</strong>rapy, ix339 (1035P),<br />
ix238 (715P), ix242 (730P)<br />
conditional probability of survival, ix144 (410O)<br />
conservative treatment, ix322 (977P)<br />
consolidation treatment, ix351 (1073P)<br />
constipation, ix510 (1582P)<br />
continuous administration of EGFR-TKI, ix423<br />
(1289P)<br />
contra-lateral breast cancer, ix544 (1702)<br />
copy number gain/loss, ix39 (50IN)<br />
correlation, ix350 (1070PD), ix119 (328PD)<br />
cosmesis, ix97 (253PD)<br />
cost analysis, ix448 (1373P)<br />
cost effectiveness, ix428 (1303P), ix501 (1553P),<br />
ix202 (594P), ix235 (704P), ix235 (706P), ix236<br />
(707P), ix320 (973PD)<br />
cost utility, ix121 (333P)<br />
cost-effectiveness, ix447 (1370P), ix450 (1379P),<br />
ix283 (854P), ix283 (856P)<br />
cost, ix448 (1373P), ix269 (816P)<br />
costs, ix122 (336P), ix205 (602P)<br />
COX-2, ix530 (1652P), ix184 (538P)<br />
crizotinib, ix357 (1098), ix389 (1191PD), ix402<br />
(1230PD), ix403 (1231PD), ix415 (1267P), ix416<br />
(1268P), ix424 (1291P), ix153 (441O)<br />
crossover, ix376 (1155O)<br />
CRPC, ix303 (920P), ix313 (951), ix314 (953)<br />
CT density, ix396 (1216)<br />
CT imaging, ix483 (1492P)<br />
CT induction, ix344 (1051)<br />
CT perfusion, ix60 (113IN)<br />
CT-guided lung biopsy, ix425 (1295P)<br />
curative resection, ix197 (578P)<br />
cutaneous melanoma, ix364 (1119P), ix365<br />
(1122P), ix87 (219P)<br />
CXCL12, ix541 (1688PD)<br />
CXCR7, ix541 (1688PD)<br />
Cyclin D1, ix338 (1031P)<br />
cyclin-dependent kinase inhibitor, ix253 (769)<br />
cyclophosphamide, ix509 (1578P), ix273 (827P),<br />
ix308 (935P), ix325 (986P)<br />
CYFRA 21-1, ix430 (1310P)<br />
CYP1A1, ix133 (374P)<br />
CYP2C19, ix424 (1293P)<br />
CYP2D6 inhibitors, ix81 (196P)<br />
CYP2D6 polymorphism, ix79 (189P)<br />
CYP2D6, ix109 (295P)<br />
cytarabine, ix353 (1082P)<br />
cytochrome P450 isoenzyme, ix520 (1618)<br />
Cytokine, ix286 (865P)<br />
Cytokines, ix21 (1IN)<br />
cytology samples, ix365 (1123P), ix431 (1315),<br />
ix432 (1316)<br />
cytoreductive surgery, ix323 (980P), ix254 (774)<br />
cytototoxic effect, ix220 (654)<br />
cytotoxic chemo<strong>the</strong>rapy, ix308 (936P)<br />
cytotoxic drugs, ix29 (21IN)<br />
cytotoxic T-lymphocyte antigen-4, ix75 (175PD)<br />
D<br />
dacarbazine (DTIC), ix363 (1115PD)<br />
dacomitinib, ix401 (1228O)<br />
darbepoetin alfa, ix504 (1561P), ix504 (1562P),<br />
ix505 (1567P), ix284 (858P)<br />
dasatinib, ix480 (1482PD)<br />
DCE-MRI (dynamic contrast-enhanced magnetic<br />
resonance imaging), ix59 (109IN), ix70 (155P)<br />
DCIS, ix83 (201P)<br />
DCS, ix228 (682P)<br />
DDS, ix247 (746P)<br />
debulking, ix321 (975PD)<br />
decision-making, ix475 (1469P)<br />
dedifferentiated liposarcoma, ix54 (93IN)<br />
definitive chemoradio<strong>the</strong>rapy, ix425 (1294P)<br />
degarelix, ix299 (905P), ix306 (930P)<br />
dendritic cell <strong>the</strong>rapy in recurrent solid tumors,<br />
ix174 (510TiP), ix239 (719P)<br />
dendritic cell vaccine, ix363 (1114PD), ix371<br />
(1138P), ix168 (490P), ix174 (510TiP)<br />
dendritic cell, ix172 (503)<br />
dendritic cells, ix536 (1672P), ix240 (723P)<br />
denosumab, ix360 (1108TiP), ix479 (1480PD),<br />
ix509 (1580P), ix115 (316TiP), ix309 (937P)<br />
dental examination, ix511 (1585P)<br />
depression, ix474 (1464P)<br />
DESKTOP Study, ix323 (980P)<br />
desmoplastic small round cell tumor, ix483<br />
(1494P)<br />
dethylstilbestrol, ix306 (929P)<br />
developing countries, ix448 (1374P), ix65 (137IN)<br />
developing country, cost, ix356 (1092P)<br />
developmental <strong>the</strong>rapeutics, ix154 (443PD)<br />
diabetes, ix500 (1549PD), ix126 (349P), ix215<br />
(636)<br />
diagnosis, ix380 (1166P), ix383 (1174P), ix476<br />
(1471P), ix532 (1658P)<br />
diagnostic, ix60 (114IN)<br />
diagnostics, ix109 (293P)<br />
diarrhea, ix120 (329P)<br />
Dicer, ix530 (1653P)<br />
differentiation, ix454 (1395P)<br />
diffuse large B cell lymphoma, ix352 (1078P),<br />
ix353 (1080P)<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds467 | ix589
subject index<br />
diffuse large B-cell lymphoma, ix351 (1074P)<br />
diffuse reflectance spectroscopy, ix532 (1658P)<br />
diffuse type, ix175 (511PD)<br />
diffuse, ix250 (756)<br />
dignity related-distress, ix516 (1601P)<br />
diltiazem, ix173 (508)<br />
discordance, ix373 (1146), ix82 (199P)<br />
disease progression, ix231 (689P), ix301 (912P)<br />
disease-free survival (DFS), ix99 (260P), ix208<br />
(612P), ix328 (997P)<br />
DNA repair, ix408 (1244P)<br />
do not resuscitate order, ix517 (1605P)<br />
docetaxel failure, ix314 (953)<br />
docetaxel plus cisplatin, ix404 (1234PD)<br />
docetaxel, body mass index, ix300 (909P)<br />
docetaxel, ix437 (1338), ix438 (1341), ix441<br />
(1353), ix114 (313), ix119 (326PD), ix129<br />
(359P), ix129 (360P), ix139 (395), ix169 (494P),<br />
ix226 (673P), ix231 (690P), ix234 (701P), ix250<br />
(760), ix251 (761), ix294 (893O), ix298 (904P),<br />
ix303 (921P), ix308 (934P), ix312 (946), ix314<br />
(952)<br />
dose escalation, ix154 (444PD), ix164 (475P),<br />
ix245 (740P), ix246 (744P), ix49 (80IN)<br />
dose-dense chemo<strong>the</strong>rapy, ix320 (973PD)<br />
dose-intensity, ix201 (591P)<br />
doublet, ix398 (1220)<br />
dovitinib, ix480 (1481PD), ix293 (891TiP)<br />
doxorubicin and hyper<strong>the</strong>rmia, ix130 (363P)<br />
doxorubicin, ix490 (1517TiP)<br />
driver mutation, ix61 (119IN)<br />
drug development, ix58 (103IN), ix33 (31IN),<br />
ix158 (455P)<br />
drug interaction, ix520 (1618)<br />
drug resistance, ix423 (1290P), ix172 (501)<br />
drug sensitivity, ix133 (375P)<br />
drug <strong>the</strong>rapy, ix216 (640)<br />
drug uptake, ix460 (1417PD)<br />
drug–drug interaction, ix456 (1402P)<br />
dual energy CT, ix60 (113IN)<br />
dual-colored in situ hybridization (DISH), ix372<br />
(1142P)<br />
Ductal Intraepi<strong>the</strong>lial neoplasia, ix83 (201P)<br />
duodenal Gist, ix482 (1489P)<br />
dysadherin, ix277 (838P)<br />
dysphonia, ix122 (335P)<br />
E<br />
E-3810, ix116 (319O)<br />
E-cadherin, ix277 (838P)<br />
E7080, ix244 (737P)<br />
early access programme, ix306 (931P)<br />
early breast cancer, ix95 (247O), ix96 (251PD),<br />
ix97 (252PD), ix98 (256P), ix100 (262P), ix100<br />
(263P), ix102 (271P), ix106 (285P), ix111 (301),<br />
ix111 (304), ix113 (310), ix114 (315TiP)<br />
early detection, ix88 (221P)<br />
early drug development - personalized medicine,<br />
ix33 (32IN)<br />
early evaluation, ix392 (1201P)<br />
early nsclc, ix386 (1183P), ix387 (1185P), ix49<br />
(78IN)<br />
early phase trials, ix150 (435TiP), ix165 (479P)<br />
early response assessment, ix63 (127IN)<br />
early response evaluation, ix130 (362P)<br />
early response, ix199 (584P)<br />
early stage breast cancer, ix107 (289P), ix108<br />
(292P), ix111 (303)<br />
early stage disease, ix329 (1002P), ix99 (258P)<br />
early tumor shrinkage (ETS), ix190 (558P), ix204<br />
(599P)<br />
economic evaluation, ix397 (1217)<br />
Edmonton Symptom Assessment Scale, ix520<br />
(1617), ix524 (1631)<br />
efatutazone, ix201 (590P)<br />
effectiveness, ix428 (1303P)<br />
efficacy, ix402 (1230PD), ix419 (1277P), ix460<br />
(1416PD), ix516 (1604P), ix117 (320PD), ix316<br />
(962TiP)<br />
egf mutations, ix414 (1264P)<br />
EGFR expression, ix338 (1029P), ix417 (1272P),<br />
ix433 (1322), ix87 (218P)<br />
EGFR IHC, ix417 (1271P)<br />
EGFR inhibitor, ix372 (1144), ix391 (1199P),<br />
ix414 (1265P), ix421 (1283P), ix430 (1309P),<br />
ix79 (190P), ix85 (210P), ix180 (525PD)<br />
EGFR mutant lung adenocarcinoma, ix412<br />
(1257P)<br />
EGFR mutant NSCLC, ix401 (1227O), ix401<br />
(1228O)<br />
EGFR mutation aqcuired resistance erlotinib,<br />
ix418 (1273P)<br />
EGFR mutation, ix412 (1258P), ix413 (1260P),<br />
ix414 (1262P), ix416 (1269P), ix416 (1270P),<br />
ix417 (1272P), ix418 (1274P), ix420 (1280P),<br />
ix430 (1310P), ix431 (1315), ix432 (1318), ix433<br />
(1322), ix434 (1325), ix437 (1339), ix438 (1340),<br />
ix439 (1343), ix439 (1344), ix440 (1347), ix531<br />
(1655P), ix533 (1662P), ix534 (1666P), ix77<br />
(182P), ix78 (183P), ix152 (438O)<br />
EGFR mutations, ix411 (1254P), ix412 (1256P),<br />
ix413 (1259P), ix86 (213P), ix144 (412O)<br />
EGFR TKI, ix411 (1254P)<br />
EGFR TKIs, ix433 (1323), ix435 (1330)<br />
EGFR tyrosine kinase inhibitor, ix412 (1256P),<br />
ix437 (1338), ix76 (179P)<br />
EGFR-HER3, ix43 (62IN)<br />
EGFR-TKI, ix416 (1269P), ix437 (1336), ix440<br />
(1347), ix79 (189P)<br />
EGFR, ix338 (1031P), ix387 (1187P), ix390<br />
(1197P), ix414 (1263P), ix423 (1290P), ix425<br />
(1295P), ix427 (1302P), ix432 (1316), ix495<br />
(1530P), ix530 (1652P), ix542 (1692P), ix74<br />
(170O), ix78 (183P), ix86 (213P), ix98 (257P),<br />
ix152 (439O), ix42 (59IN), ix42 (60IN), ix239<br />
(720P), ix51 (81IN)<br />
Elastic Laminal Invasion (ELI), ix210 (621)<br />
elderly cancer patients, ix374 (1151), ix433 (1323),<br />
ix452 (1385P), ix476 (1472P), ix516 (1604P),<br />
ix100 (261P), ix100 (263P), ix205 (603P), ix307<br />
(932P), ix326 (991P)<br />
elderly Medicare patients, ix214 (634)<br />
elderly patients, ix345 (1053), ix422 (1285P),<br />
ix436 (1333), ix442 (1354), ix181 (529PD),<br />
ix203 (596P), ix427 (1301P), ix443 (1357)<br />
elderly, ix331 (1009), ix392 (1202P), ix398 (1220),<br />
ix419 (1276P), ix422 (1286P), ix434 (1325),<br />
ix442 (1356), ix443 (1358), ix452 (1387P), ix459<br />
(1412), ix476 (1470P), ix101 (266P), ix221<br />
(657), ix229 (684P), ix232 (693P), ix279 (844P),<br />
ix308 (934P)<br />
Electrochemo<strong>the</strong>rapy, ix343 (1046P), ix131 (367P)<br />
electroporation, ix343 (1046P), ix131 (367P)<br />
ELISA (enzyme-linked immunosorbent assay),<br />
ix111 (302)<br />
EMD 1214063, ix154 (444PD)<br />
EMD 525797, ix317 (965TiP)<br />
emergency visit, ix517 (1607P)<br />
EML4-ALK fusion gene, ix415 (1266P)<br />
EML4-ALK, ix81 (195P)<br />
EMPHASIS, ix58 (105IN)<br />
end-of-life care, ix145 (415PD)<br />
endobronchial ultrasound guided transbronchial<br />
needle aspiration, ix383 (1176P)<br />
endocrine <strong>the</strong>rapy response, ix57 (102IN)<br />
endocrine <strong>the</strong>rapy, ix75 (176PD), ix105 (281P)<br />
endometrial cancer, ix329 (1001P), ix329 (1002P),<br />
ix329 (1003P), ix40 (56IN), ix320 (970PD)<br />
endoscopic ultrasonography, ix472 (1456P), ix252<br />
(767)<br />
endostar, ix437 (1337)<br />
endpoints, ix535 (1670P)<br />
enhancer of zeste homolog 2, ix349 (1066PD)<br />
Annals of Oncology<br />
enzalutamide, ix38 (48IN), ix295 (896O), ix297<br />
(899PD)<br />
EphA4, ix541 (1691P)<br />
ephrin receptor A4, ix541 (1691P)<br />
epidemiology, ix403 (1232PD), ix428 (1304P),<br />
ix213 (632), ix298 (902P), ix323 (981P)<br />
epidermal growth factor (EGF), ix246 (742P),<br />
ix287 (868)<br />
epidermal growth factor receptor (EGFR), ix412<br />
(1255P), ix514 (1597P), ix203 (598P)<br />
epidermal growth factor receptor mutation-positive<br />
non-small cell lung cancer, ix433 (1323)<br />
epidermal growth factor receptor, ix70 (158P)<br />
epigenetics, ix68 (150P)<br />
epiregulin, ix180 (526PD), ix183 (536P)<br />
epirubicin, ix129 (359P)<br />
epi<strong>the</strong>lial cancer, ix539 (1683P)<br />
epi<strong>the</strong>lial ovarian cancer (EOC), ix320 (971PD)<br />
epi<strong>the</strong>lial ovarian carcinoma, ix320 (972PD)<br />
epi<strong>the</strong>lial to mesenchymal transition, ix67 (145P),<br />
ix542 (1693P), ix543 (1695P)<br />
epi<strong>the</strong>lial-mesenchymal transition, ix432 (1319)<br />
epoetin zeta, ix505 (1566P)<br />
epoetin, ix504 (1563P), ix506 (1568P), ix506<br />
(1569P)<br />
Epstein-Barr virus (EBV), ix88 (221P)<br />
ER status, ix69 (151P)<br />
ercc 1 and rrm1, ix528 (1646PD)<br />
ERCC1, ix84 (207P)<br />
eribulin mesilate, ix393 (1205P), ix129 (358P)<br />
eribulin, ix120 (330P)<br />
ERIVANCE, ix362 (1112PD)<br />
erlotinib, ix390 (1194P), ix390 (1197P), ix393<br />
(1205P), ix397 (1219), ix398 (1222), ix400<br />
(1225O), ix400 (1226O), ix413 (1260P), ix414<br />
(1263P), ix417 (1271P), ix419 (1276P), ix420<br />
(1280P), ix421 (1282P), ix424 (1291P), ix424<br />
(1293P), ix426 (1298P), ix429 (1307P), ix433<br />
(1322), ix435 (1328), ix436 (1333), ix437 (1338),<br />
ix438 (1340), ix438 (1342), ix439 (1345), ix439<br />
(1346), ix445 (1366TiP), ix446 (1367TiP), ix533<br />
(1662P), ix533 (1663P), ix91 (232), ix174<br />
(509TiP), ix240 (722P)<br />
erythropoiesis-stimulating agents, ix523 (1628)<br />
esophageal cancer, ix89 (224P), ix225 (671P),<br />
ix226 (672P), ix226 (674P)<br />
esophageal carcinoma, ix248 (749)<br />
esophageal squamous cell carcinoma, ix248 (748)<br />
esophagectomy, ix226 (672P), ix226 (674P)<br />
essential thrombocy<strong>the</strong>mia, ix355 (1087P), ix356<br />
(1094)<br />
estrogen receptor, ix87 (216P), ix388 (1190P),<br />
ix27 (15IN), ix119 (325PD), ix126 (350P), ix183<br />
(534P)<br />
estrogen, ix104 (277P)<br />
ethical aspects, ix64 (128IN)<br />
ethnic minority, ix100 (262P)<br />
ETOP, ix58 (105IN)<br />
etoposide intravenous and oral, ix494 (1527P)<br />
Europe, ix447 (1372P), ix97 (252PD), ix132<br />
(369P)<br />
European Society for Medical Oncology, ix458<br />
(1407)<br />
Euroqol EQ-5D, ix315 (956)<br />
evaluation, ix481 (1487P)<br />
everolimus, ix376 (1154O), ix377 (1156O), ix379<br />
(1162P), ix118 (324PD), ix121 (334P), ix126<br />
(351P), ix127 (352P), ix155 (447PD), ix231<br />
(691P), ix256 (781TiP), ix271 (821P), ix279<br />
(843P), ix283 (855P), ix288 (873), ix288 (875),<br />
ix289 (876), ix290 (879), ix293 (890TiP)<br />
evidence-based guidelines, ix53 (88IN)<br />
Ewing sarcoma, ix488 (1509P), ix54 (90IN)<br />
expanded access program, ix367 (1128P), ix368<br />
(1130P), ix369 (1131P), ix369 (1132P), ix369<br />
(1133P), ix374 (1149), ix374 (1151), ix271<br />
(821P)<br />
expanded access study, ix362 (1111PD)<br />
ix590 | subject index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology subject index<br />
expanded access, ix271 (820P)<br />
expert center, ix327 (993P)<br />
exposure, ix91 (229P), ix231 (691P)<br />
external quality control, ix80 (193P)<br />
external-beam irradiation, ix309 (938P)<br />
extracellular matrix (ECM), ix301 (914P)<br />
extramammary Paget’s disease, ix372 (1142P)<br />
Extranodal Non-Hodgkin Lymphomas, ix357<br />
(1097)<br />
EXTREME, ix334 (1018O)<br />
EZH2, ix85 (208P)<br />
F<br />
52 kDa, ix93 (239)<br />
factor analysis, ix109 (296P)<br />
failure, ix437 (1336)<br />
familial cancer, ix34 (36IN)<br />
family caregivers, ix476 (1470P)<br />
family physicians, ix517 (1607P)<br />
fast-track surgery, ix202 (595P)<br />
Fasting Blood Glucose (FBG), ix206 (606P)<br />
FcGR polymorphisms, ix93 (237), ix163 (472P)<br />
18F-FDG PET/CT, ix370 (1136P), ix60 (114IN),<br />
ix392 (1201P), ix130 (362P), ix193 (567P),<br />
ix199 (584P)<br />
18FDG-PET, ix63 (127IN), ix160 (462P)<br />
feasibility study, ix228 (681P), ix250 (758)<br />
febrile neutropenia, ix499 (1547PD), ix501<br />
(1553P), ix502 (1556P), ix503 (1560P), ix522<br />
(1625)<br />
fecal pH, ix200 (585P)<br />
female patients, ix388 (1190P)<br />
female, ix414 (1264P)<br />
fentanyl bucal tablet (FBT), ix518 (1612P)<br />
fertility preservation, ix521 (1621)<br />
fertility sparing surgery(FSS), ix331 (1011)<br />
FFPE tissue, ix71 (161P), ix148 (426P)<br />
FGF (fibroblast growth factor), ix116 (319O),<br />
ix269 (814P), ix272 (822P)<br />
FGFR-1, ix77 (181P)<br />
FGFR1, ix116 (319O)<br />
fibroblast growth factor receptor (FGFR), ix27<br />
(16IN)<br />
fibrosis, ix396 (1216)<br />
fibrous solitary tumor, ix485 (1500P)<br />
filgrastim, ix502 (1555P), ix502 (1557P)<br />
film, ix458 (1408)<br />
Firmagon, ix299 (905P)<br />
first line <strong>the</strong>rapy, ix401 (1228O)<br />
first line treatment, ix435 (1329), ix436 (1333),<br />
ix118 (323PD)<br />
first line, ix402 (1229PD), ix410 (1252P), ix138<br />
(392)<br />
first-line chemo<strong>the</strong>rapy, ix434 (1326), ix528<br />
(1646PD), ix116 (317O), ix224 (667PD)<br />
first-line <strong>the</strong>rapy, ix413 (1260P), ix434 (1325)<br />
first-line, ix400 (1226O), ix405 (1236PD), ix406<br />
(1239P), ix445 (1365TiP)<br />
FISH analysis, ix364 (1118PD)<br />
FISH, ix355 (1088P)<br />
FLEX, ix417 (1272P)<br />
flow cytometry, ix359 (1106), ix72 (163P), ix529<br />
(1650P), ix356 (1093P)<br />
flu vaccine in cancer patients, ix56 (97IN)<br />
fluorescent in situ hybridization (FISH), ix372<br />
(1142P)<br />
fluorescent in situ hybridization, ix390 (1196P)<br />
fluorine-18 fluorodeoxyglucose, ix72 (166)<br />
fluoropyrimidine, ix178 (519O)<br />
5-fluorouracil, ix234 (701P)<br />
FOLFIRI, ix181 (529PD), ix191 (561P), ix201<br />
(590P), ix203 (597P), ix222 (662TiP), ix251<br />
(762)<br />
FOLFIRINOX, ix238 (716P), ix240 (721P)<br />
FOLFOX4, ix178 (520O)<br />
FOLFOX, ix203 (597P)<br />
FOLFOXIRI, ix238 (714P), ix241 (726P)<br />
follicular lymphoma, ix351 (1073P)<br />
follow-up, ix324 (983P)<br />
food effects, ix168 (489P), ix169 (493P)<br />
frail patients, ix196 (573P)<br />
frailty, ix459 (1412)<br />
France, ix416 (1270P), ix488 (1511P)<br />
French Regional Health Insurance System, ix456<br />
(1401P)<br />
front-line treatment, ix436 (1335)<br />
front-line, ix322 (978P)<br />
fulvestrant, ix123 (339P), ix123 (340P), ix123<br />
(341P), ix136 (384)<br />
5-FU, ix346 (1057)<br />
function sparing surgeries, ix331 (1008)<br />
functional imaging, ix60 (113IN), ix392 (1201P),<br />
ix192 (562P)<br />
functional status, pain, ix295 (895O)<br />
functional tumor volume, ix199 (584P)<br />
fusion gene, ix81 (195P)<br />
G<br />
G-CSF primary prophylaxis, ix501 (1553P), ix502<br />
(1556P), ix522 (1625)<br />
G-CSF, ix499 (1547PD), ix500 (1548PD), ix501<br />
(1552P), ix501 (1554P), ix502 (1555P), ix502<br />
(1557P), ix503 (1560P), ix522 (1624)<br />
G719X, ix413 (1259P)<br />
G8, ix345 (1053)<br />
gamma knife, ix150 (432)<br />
ganetespib, ix436 (1332), ix529 (1647PD), ix533<br />
(1664P)<br />
ganitumab, ix255 (776TiP)<br />
gastric cancer, ix538 (1681P), ix89 (225P), ix175<br />
(511PD), ix176 (514P), ix226 (675P), ix227<br />
(676P), ix227 (677P), ix227 (678P), ix228<br />
(680P), ix228 (681P), ix229 (683P), ix229<br />
(684P), ix229 (685P), ix229 (686P), ix230<br />
(687P), ix231 (689P), ix231 (690P), ix232<br />
(692P), ix232 (693P), ix232 (694P), ix233<br />
(696P), ix233 (697P), ix233 (698P), ix233<br />
(699P), ix234 (700P), ix234 (702P), ix249 (752),<br />
ix249 (754), ix249 (755), ix250 (756), ix250<br />
(757), ix250 (760), ix251 (761), ix251 (762),<br />
ix251 (763), ix251 (764), ix256 (779TiP), ix256<br />
(780TiP), ix257 (782TiP)<br />
gastric GIST, ix481 (1486PD)<br />
gastric lymphoma, ix252 (765)<br />
gastric submucosal tumor, ix481 (1485PD)<br />
gastroesophageal cancer, ix169 (492P), ix248<br />
(750), ix249 (754)<br />
gastroesophageal junction cancer, ix227 (678P)<br />
gastrointestinal cancer, ix221 (660)<br />
gastrointestinal lymphoma, ix252 (766)<br />
gastrointestinal stromal tumor (GIST), ix478<br />
(1478O), ix480 (1482PD), ix480 (1484PD),<br />
ix483 (1492P), ix490 (1516), ix538 (1679P),<br />
ix235 (705P), ix236 (707P), ix236 (708P)<br />
gastrointestinal stromal tumor, ix480 (1481PD)<br />
gastrointestinal toxicity, ix64 (130IN)<br />
GBM, ix146 (417PD)<br />
GDC-0980, ix157 (452P)<br />
gefitinib; drug resistance, lung cancer, ix32 (30IN)<br />
gefitinib, ix411 (1253P), ix412 (1255P), ix412<br />
(1258P), ix413 (1259P), ix414 (1263P), ix423<br />
(1289P), ix432 (1319), ix435 (1328), ix435<br />
(1331), ix439 (1343), ix439 (1344), ix79 (189P)<br />
Gem-refractory, ix241 (728P)<br />
gemcitabine, ix67 (144PD), ix537 (1676P), ix139<br />
(395), ix139 (397), ix165 (478P), ix170 (497P),<br />
ix236 (709P), ix239 (717P), ix240 (722P), ix259<br />
(786O), ix291 (885), ix320 (972PD)<br />
GEMOX plus erlotinib, ix253 (768)<br />
gene amplification, ix387 (1186P)<br />
gene dosage, ix320 (970PD)<br />
gene expression profile, ix349 (1068PD)<br />
gene expression signatures, ix299 (906P)<br />
gene expresssion profiling, ix57 (100IN)<br />
gene signature, ix112 (305)<br />
general population, ix188 (553P)<br />
genetic counseling, ix34 (37IN)<br />
genetic polymorphism, ix365 (1122P), ix134 (376)<br />
genetic polymorphisms, ix364 (1119P), ix127<br />
(354P), ix133 (374P)<br />
genetic screening, epi<strong>the</strong>lial-mesenchymal<br />
transition, ix32 (30IN)<br />
genetic susceptibility, ix544 (1702), ix34 (37IN)<br />
70-gene prognostic profile, ix96 (251PD)<br />
genitourinary cancer, ix266 (805P), ix291 (886),<br />
ix312 (945)<br />
genome profile, ix51 (83IN)<br />
genomic profile, ix107 (289P), ix179 (522PD),<br />
ix179 (523PD), ix54 (92IN)<br />
genomics, ix57 (101IN)<br />
geriatric oncology, ix461 (1420PD), ix475<br />
(1467P), ix501 (1554P), ix526 (1640)<br />
geriatric screening tool, ix461 (1420PD)<br />
germ cell tumor, ix285 (860P), ix285 (861P),<br />
ix286 (866P)<br />
germ cell tumors, ix260 (789O), ix261 (790O),<br />
ix285 (862P), ix285 (863P), ix286 (864P), ix293<br />
(890TiP)<br />
Germany, ix121 (333P)<br />
GEST QOL, ix254 (775)<br />
Gestational Trophoblastic Neoplasia GTN, ix330<br />
(1005P)<br />
GETNE, ix377 (1157O)<br />
GFR, ix49 (78IN)<br />
ghrelin agonist, ix161 (465P)<br />
giant cell tumor of bone, ix479 (1480PD)<br />
GIDEON, ix255 (777TiP)<br />
GIST, ix481 (1485PD), ix481 (1486PD), ix482<br />
(1490P), ix483 (1491P), ix235 (704P), ix235<br />
(705P), ix235 (706P)<br />
Gli3, ix542 (1694P)<br />
glioblastoma multiforme, ix72 (163P), ix144<br />
(410O), ix145 (415PD), ix147 (423P)<br />
glioblastoma, ix31 (24IN), ix145 (416PD), ix146<br />
(418PD), ix147 (424P), ix148 (426P), ix149<br />
(431), ix150 (435TiP), ix151 (437TiP)<br />
glioma cell lines, ix537 (1676P)<br />
glioma, ix144 (411O), ix148 (425P)<br />
global cancer research, ix65 (132IN)<br />
global estimates, ix323 (981P)<br />
global research, ix65 (132IN)<br />
glucose transporters, ix385 (1180PD)<br />
glucose, ix71 (160P)<br />
glutamine supplementation, ix520 (1620)<br />
γ-glutamyl hydrolase (GGH), ix185 (542P)<br />
glycolysis, ix72 (166)<br />
GnRH agonist, ix501 (1551PD)<br />
good use, ix456 (1401P)<br />
GRANITE, ix231 (691P)<br />
great vessels sarcoma, ix489 (1513)<br />
Greece, ix236 (707P)<br />
GSTM1, ix352 (1078P)<br />
GSTT1, ix352 (1078P)<br />
guidelines, ix458 (1407), ix478 (1477O)<br />
gynecologic cancer, ix501 (1554P), ix321 (974PD)<br />
gynecologic malignancy, ix506 (1570P)<br />
H<br />
haemodialysis, ix290 (879)<br />
hallmarks of cancer, ix23 (5IN)<br />
hand-foot syndrome (HFS), ix513 (1594P)<br />
hazard ratio, ix313 (949)<br />
HBV reactivation, ix56 (96IN)<br />
HCC, ix253 (771), ix255 (777TiP)<br />
HCT-CI, ix354 (1085P)<br />
HCV, ix352 (1079P)<br />
HDAC, ix43 (62IN)<br />
head and neck cancer, ix335 (1020PD), ix341<br />
(1042P), ix343 (1047P), ix345 (1056), ix347<br />
(1061TiP), ix510 (1581P), ix528 (1644PD),<br />
ix537 (1677P), ix42 (59IN)<br />
head and neck squamous cell carcinoma<br />
(HNSCC), ix334 (1016O), ix338 (1029P), ix339<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds467 | ix591
subject index<br />
(1033P), ix340 (1036P), ix340 (1038P), ix345<br />
(1052), ix539 (1684P)<br />
head and neck squamous cell carcinoma, ix340<br />
(1037P), ix450 (1379P)<br />
health care costs, ix299 (905P)<br />
health economics, ix397 (1219), ix451 (1383P),<br />
ix66 (141INIS), ix122 (337P)<br />
health resource utilisation, ix447 (1372P), ix449<br />
(1377P)<br />
health services research, ix260 (788O)<br />
health state utilities, ix121 (332P)<br />
health-related quality of life (HRQoL), ix372<br />
(1143P), ix299 (905P)<br />
health-related quality of life, ix109 (296P), ix200<br />
(588P)<br />
heat shock protein 27, ix297 (900PD)<br />
HEC, ix507 (1571P)<br />
Hedgehog signal, ix533 (1663P), ix542 (1694P)<br />
Hedgehog signalling pathway, ix156 (449PD)<br />
Hedgehog, ix430 (1309P), ix43 (62IN)<br />
heme oxygenase, ix320 (971PD)<br />
hemodialysis, ix473 (1461), ix524 (1632)<br />
hENT1, ix236 (709P)<br />
hepatic arterial infusion chemo<strong>the</strong>rapy, ix194<br />
(568P), ix198 (580P)<br />
hepatic impairment, ix162 (468P)<br />
hepatic metastases, ix371 (1141P), ix212 (627),<br />
ix246 (743P)<br />
hepatic resection, ix254 (772)<br />
hepatic toxicity, ix454 (1393P)<br />
hepatitis B virus, ix454 (1393P), ix56 (96IN)<br />
hepatitis C virus, ix352 (1079P), ix454 (1393P),<br />
ix56 (96IN)<br />
hepatocellular carcinoma (HCC), ix70 (155P),<br />
ix536 (1673P), ix542 (1693P), ix161 (466P),<br />
ix225 (669PD), ix243 (733P), ix243 (734P),<br />
ix244 (735P), ix244 (736P), ix244 (737P), ix245<br />
(740P), ix245 (741P), ix246 (742P), ix246<br />
(744P), ix253 (770), ix255 (778TiP)<br />
hepatocellular carcinoma, ix63 (124IN), ix225<br />
(670PD), ix243 (732P), ix244 (738P), ix245<br />
(739P), ix254 (772), ix256 (781TiP)<br />
hepatocyte growth factor (HGF), ix154 (443PD),<br />
ix230 (687P)<br />
HER (ErbB) receptors, ix86 (214P), ix248 (750),<br />
ix320 (970PD)<br />
HER receptors, ix541 (1690P)<br />
HER2 dimerization, ix84 (206P)<br />
HER2 extracellular domain, ix111 (302)<br />
HER2 negative breast cancer, ix108 (292P)<br />
HER2 overexpressing breast cancer, ix528<br />
(1645PD)<br />
HER2 overexpression, ix372 (1142P), ix89 (226P),<br />
ix102 (270P), ix137 (387), ix227 (678P), ix259<br />
(786O)<br />
HER2 positive breast cancer, ix82 (199P), ix102<br />
(271P), ix124 (344P), ix125 (346P), ix132<br />
(370P), ix142 (407TiP), ix142 (408TiP), ix142<br />
(409TiP)<br />
HER2 treatment, ix98 (255PD)<br />
HER2-positive, ix62 (121IN), ix117 (322PD),<br />
ix120 (329P)<br />
HER2/HER3, ix170 (496P)<br />
HER2, ix401 (1228O), ix403 (1232PD), ix74<br />
(172O), ix83 (202P), ix97 (254PD), ix103<br />
(273P), ix104 (276P), ix125 (345P), ix141 (404),<br />
ix162 (470P), ix226 (675P), ix227 (677P), ix233<br />
(699P), ix234 (703P)<br />
HER3 inhibitor, ix161 (467P)<br />
HER3, ix91 (231P)<br />
hereditary cancer, ix34 (33IN), ix34 (36IN), ix176<br />
(517P)<br />
heregulin, ix170 (496P)<br />
herpes simplex virus, ix71 (162P)<br />
heterogeneity, ix25 (12IN), ix534 (1666P)<br />
2HG, ix144 (411O)<br />
HIF-1α, ix248 (751)<br />
high-dose chemo<strong>the</strong>rapy, ix260 (789O), ix284<br />
(858P), ix285 (863P), ix286 (866P)<br />
high-grade neuroendocrine tumour, ix383 (1174P)<br />
high-risk gestational trophoblastic neoplasia, ix330<br />
(1005P)<br />
high-risk, ix281 (847P)<br />
high-throughput genotype, ix430 (1311P)<br />
HIPEC, ix35 (38IN)<br />
histologic grade, ix112 (306)<br />
histological grade, ix135 (381)<br />
histological type, ix393 (1204P)<br />
histology, ix388 (1189P)<br />
histone deacetylase (HDAC) inhibitor, ix349<br />
(1068PD), ix304 (922P)<br />
histopathological diagnosis, ix241 (725P)<br />
histopathology, neuroendocrine tumours, ix381<br />
(1168P)<br />
HNC, ix346 (1057)<br />
Hodgkin lymphoma, ix350 (1072P)<br />
Hodgkin, ix492 (1521PD)<br />
homeopathy, ix452 (1388P)<br />
homologous recombination deficiency, PARP<br />
inhibitor, BRCA associated ovarian cancer, ix40<br />
(55IN)<br />
Hope Herth Index (HHI) Italian version, ix516<br />
(1602P)<br />
horizontal lateral thyroidectomy, ix346 (1060)<br />
hormonal <strong>the</strong>rapy, ix329 (1001P), ix113 (310),<br />
ix113 (311), ix123 (340P), ix299 (906P)<br />
hormone receptor (HR), ix142 (407TiP)<br />
hormone receptor-positive, ix96 (249PD)<br />
hormone-resistant, ix312 (946)<br />
hormone-senstive metastatic prostate cancer,<br />
ix294 (893O)<br />
hospitalization, ix526 (1640)<br />
HOX (homeobox) genes, ix325 (988P)<br />
HOX genes, ix68 (147P)<br />
HPV vaccination, cervical screening, ix53 (86IN)<br />
HPV, ix342 (1045P)<br />
HRAS, ix42 (60IN)<br />
HRQOL, ix402 (1229PD), ix483 (1493P)<br />
Hsp90, ix70 (156P), ix42 (61IN)<br />
HTA, ix460 (1417PD)<br />
human genome DNA sequence, ix57 (102IN),<br />
ix25 (10IN)<br />
human papillomavirus (HPV), ix334 (1018O),<br />
ix22 (3IN)<br />
hyperbaric oxygenation, ix398 (1223)<br />
hyperfibrinogenemia, ix93 (238)<br />
hyperfractionated radio<strong>the</strong>rapy, ix397 (1217)<br />
hyperglycemia, ix126 (349P)<br />
hypertension, ix263 (796PD)<br />
hyper<strong>the</strong>rmia, ix487 (1505P)<br />
hyper<strong>the</strong>rmic intraperitoneal chemo<strong>the</strong>rapy<br />
(HIPEC), ix222 (661)<br />
hypofractionation, ix145 (413PD)<br />
hyponatremia, ix494 (1526P), ix509 (1578P)<br />
hypoxia, ix339 (1033P), ix539 (1685P), ix78<br />
(185P), ix150 (435TiP), ix224 (666O), ix248<br />
(751)<br />
I<br />
iatrogeny, ix456 (1400P)<br />
ICAM-1, ix531 (1657P)<br />
ICD, catumaxomab, ix169 (495P)<br />
icotinib, ix416 (1269P)<br />
idh, ix31 (23IN), ix144 (411O)<br />
idiopathic pulmonary fibrosis, ix436 (1334)<br />
IHC and FISH, ix394 (1208)<br />
IHC score, ix75 (176PD)<br />
IHC subtypes, ix99 (259P)<br />
IHC, ix73 (167O)<br />
IIIA N2 NSCLC, ix413 (1261P)<br />
IL-1, leptin, ix163 (473P)<br />
IL-23, ix68 (150P)<br />
IL-6, ix355 (1088P), ix72 (165)<br />
imaging staging, ix106 (285P), ix241 (727P)<br />
imaging test, ix449 (1378P)<br />
Annals of Oncology<br />
imaging, ix59 (109IN), ix384 (1178TiP)<br />
IMAT, ix325 (987P)<br />
imatinib mesylate, ix358 (1102), ix490 (1516),<br />
ix236 (708P)<br />
imatinib, ix355 (1090P), ix359 (1105), ix482<br />
(1489P), ix483 (1494P), ix235 (704P), ix235<br />
(705P)<br />
IMC-1121B, ix363 (1115PD), ix408 (1245P),<br />
ix422 (1287P)<br />
immune response, ix503 (1558P), ix211 (622)<br />
immune studies, ix165 (480P)<br />
immune system, ix29 (22IN)<br />
immune tolerance, ix536 (1671P)<br />
immunodeficiency, ix81 (197P)<br />
immunogenic cell death, ix169 (495P)<br />
immunohistochemical predictors, ix130 (364P)<br />
immunohistochemical prognostic factors, ix111<br />
(303)<br />
immunohistochemistry, ix337 (1026P), ix390<br />
(1196P), ix80 (193P), ix107 (287P), ix135 (381)<br />
immunologic, ix371 (1137P)<br />
immunomodulator, ix178 (518O)<br />
immunomodulatory treatment, ix303 (919P)<br />
immunophenotyping, ix359 (1106)<br />
immunosuppressive <strong>the</strong>rapy, ix357 (1095)<br />
immuno<strong>the</strong>rapy, ix361 (1109O), ix361 (1110O),<br />
ix363 (1116PD), ix367 (1127P), ix367 (1128P),<br />
ix368 (1129P), ix369 (1131P), ix369 (1132P),<br />
ix373 (1148), ix386 (1182P), ix395 (1210), ix405<br />
(1237PD), ix72 (163P), ix21 (1IN), ix157<br />
(453P), ix38 (46IN), ix172 (503), ix258 (784O),<br />
ix267 (808P), ix310 (939P), ix310 (941P), ix311<br />
(942P)<br />
immunotoxins, ix44 (64IN)<br />
in vitro, ix484 (1497P)<br />
Inadequate Medical Intervention (IMI), ix330<br />
(1005P)<br />
incidence, ix454 (1392P), ix94 (242)<br />
independent research, ix65 (132IN)<br />
India, ix101 (265P)<br />
indicators, ix457 (1403)<br />
indirect comparison, ix279 (843P)<br />
individual patient data, ix324 (982P)<br />
induction chemo<strong>the</strong>rapy, ix335 (1020PD), ix340<br />
(1037P), ix341 (1039P), ix341 (1040P)<br />
induction <strong>the</strong>rapy, ix340 (1036P), ix356 (1092P)<br />
infection, ix335 (1019O)<br />
inflammation, ix239 (720P)<br />
influenza, ix503 (1558P)<br />
information process, ix474 (1462PD)<br />
information technology, ix535 (1669P)<br />
information, ix66 (142IN)<br />
inmunohistochemistry, ix186 (546P)<br />
INNO-206, ix480 (1483PD)<br />
insulin-like growth factor (IGF), ix54 (90IN)<br />
insulin-like growth factor 1 receptor, ix432 (1319),<br />
ix32 (30IN)<br />
insulin-like growth factor receptor (IGFR), ix338<br />
(1030P), ix484 (1497P), ix27 (16IN), ix255<br />
(776TiP), ix54 (90IN)<br />
integrated care pathways, ix457 (1405)<br />
integration of oncology and palliative care, ix64<br />
(131IN)<br />
integrin, ix76 (179P)<br />
intensity-modulated radio<strong>the</strong>rapy, ix247 (745P)<br />
interferon alpha-2a, ix267 (809P)<br />
interleukin 6, ix69 (153P)<br />
interleukin 8, ix88 (222P)<br />
interleukin-2, ix267 (808P)<br />
Intermittent androgen deprivation <strong>the</strong>rapy, ix306<br />
(930P)<br />
intermittent chemo<strong>the</strong>rapy, ix181 (528PD)<br />
international research, ix65 (136IN)<br />
international survey, ix386 (1183P)<br />
Internet 3.0, ix449 (1376P)<br />
internet use, ix457 (1404)<br />
interstitial lung disease, ix436 (1334), ix497<br />
(1538P), ix91 (232)<br />
ix592 | subject index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology subject index<br />
interstitial pneumonitis, ix283 (855P)<br />
interstitial pulmonary disorder, ix226 (673P)<br />
interval debulking surgery, ix332 (1013)<br />
intestine, ix69 (152P)<br />
intralesional, ix371 (1137P)<br />
intraperitoneal chemo<strong>the</strong>rapy, ix233 (698P), ix234<br />
(702P), ix254 (774)<br />
intratechal trastuzumab, ix141 (404)<br />
intratumor heterogeneity, ix69 (151P), ix51<br />
(83IN)<br />
intratumoral heterogeneity, ix373 (1146), ix531<br />
(1656P)<br />
intravenous iron, ix504 (1561P), ix523 (1627)<br />
intravisical chemo<strong>the</strong>rapy, ix290 (882)<br />
intrinsic subtypes, ix131 (366P)<br />
invasion, ix345 (1055)<br />
invasive lobular carcinoma, ix175 (511PD)<br />
invasiveness, ix136 (384)<br />
investigational, ix158 (456P)<br />
iodine, ix522 (1626)<br />
IPCW, ix194 (570P)<br />
ipilimumab, ix363 (1116PD), ix364 (1117PD),<br />
ix366 (1126P), ix366 (1126P), ix367 (1127P),<br />
ix367 (1128P), ix368 (1129P), ix368 (1130P),<br />
ix369 (1131P), ix369 (1132P), ix369 (1133P),<br />
ix370 (1134P), ix372 (1143P), ix373 (1148),<br />
ix374 (1149), ix374 (1150), ix374 (1151), ix375<br />
(1152), ix75 (175PD), ix38 (46IN)<br />
irinotecan, ix204 (599P), ix205 (602P), ix230<br />
(688P), ix237 (710P), ix249 (755)<br />
IRIS, ix202 (592P)<br />
iron supplementation, ix523 (1627)<br />
ISET, ix338 (1029P), ix90 (227P)<br />
isolation perfusion, ix486 (1504P)<br />
item response <strong>the</strong>ory, ix109 (296P)<br />
J<br />
Japanese population, ix167 (486P), ix220 (653)<br />
jaw osteonecrosis, ix511 (1585P), ix56 (95IN)<br />
juvenile glioblastoma, ix147 (421P)<br />
K<br />
K-RAS mutation, ix530 (1652P), ix234 (703P)<br />
K-ras status, ix80 (194P)<br />
K-RAS, ix429 (1307P), ix216 (641)<br />
ketoconazole, ix305 (927P)<br />
Ki-67 antigen, ix377 (1158P), ix184 (538P)<br />
Ki-67, ix80 (191P), ix83 (201P), ix101 (268P),<br />
ix131 (366P)<br />
Ki67, ix92 (233), ix112 (305)<br />
kidney cancer, ix266 (805P), ix272 (822P), ix276<br />
(835P), ix281 (849P)<br />
kidney failure, ix444 (1361), ix458 (1409)<br />
kidney, ix267 (810P), ix269 (816P), ix290 (879)<br />
kinase inhibitor, ix433 (1324), ix124 (342P)<br />
kinases, ix21 (1IN)<br />
KIT exon 9 mutation, ix481 (1486PD)<br />
knowledge about cancer, ix457 (1406)<br />
Kochers’ thyroidectomy, ix346 (1060)<br />
KRAS and BRAF, ix85 (208P), ix182 (532P),<br />
ix183 (537P), ix186 (548P), ix187 (549P)<br />
KRAS genotyping, ix85 (210P)<br />
KRAS mutations, ix431 (1315)<br />
KRAS wild-type metastatic colorectal cancer,<br />
ix191 (561P), ix202 (594P)<br />
KRAS, ix387 (1187P), ix403 (1233PD), ix427<br />
(1302P), ix432 (1316), ix530 (1654P), ix74<br />
(170O), ix84 (207P), ix85 (211P), ix182 (533P),<br />
ix185 (543P), ix196 (574P)<br />
L<br />
L-BLP25, ix395 (1210), ix211 (622)<br />
L861Q, ix413 (1259P)<br />
lactobacterin, ix290 (882)<br />
laparoscopic surgery, ix292 (888)<br />
lapatinib resistance, ix532 (1659P)<br />
lapatinib, ix58 (104IN), ix101 (267P), ix139 (396)<br />
large cell neuroendocrine carcinoma (LCNEC),<br />
ix79 (188P)<br />
laryngeal carcinoma, ix338 (1031P)<br />
late relapse, ix75 (176PD)<br />
late stage, ix136 (383)<br />
Latin America, ix65 (133IN)<br />
LDK378, ix153 (440O)<br />
leaflet, ix518 (1611P)<br />
lean body mass, ix512 (1588P)<br />
lenalidomide, ix44 (67IN)<br />
length of hospital stay, ix354 (1085P)<br />
lenvatinib, ix244 (737P)<br />
leptin receptor antagonist, ix166 (483P)<br />
leptin, ix516 (1603P), ix166 (483P)<br />
leptomeningeal carcinomatosis, ix140 (402), ix149<br />
(429P)<br />
leptomeningeal metastasis, ix141 (404)<br />
leucovorin, ix217 (646)<br />
lidocain patch, ix521 (1622)<br />
life extending, ix132 (369P)<br />
limb-sparing surgery, ix486 (1504P)<br />
linifanib, ix83 (203P), ix173 (505), ix173 (507)<br />
liposarcoma, ix54 (93IN)<br />
liposomal cytarabine, ix149 (429P)<br />
liposomal doxorubicin, ix160 (462P)<br />
liposome, ix164 (477P)<br />
liver cancer, ix63 (125IN), ix245 (741P)<br />
liver limited disease, ix217 (643)<br />
liver metastases, ix358 (1100), ix370 (1136P),<br />
ix198 (580P), ix219 (651)<br />
liver toxicity, ix290 (880)<br />
LKB1, ix77 (180P)<br />
LMO4, ix531 (1655P)<br />
lobular carcinoma, ix544 (1702)<br />
local advanced triple negative breast cancer<br />
(LATNBC), ix130 (361P)<br />
local radiation-induced damages, ix311 (944P)<br />
locally advanced breast cancer, ix120 (330P),<br />
ix134 (377), ix135 (380), ix137 (389)<br />
locally advanced cervical cancer, ix330 (1007)<br />
locally advanced disease, ix241 (726P)<br />
locally advanced head and neck cancer, ix335<br />
(1020PD), ix341 (1039P)<br />
locally advanced non-small cell lung cancer, ix520<br />
(1620)<br />
locally advanced stage III NSCLC, ix392 (1200P),<br />
ix392 (1203P), ix330 (1007), ix330 (1007)<br />
locally advanced, ix331 (1008), ix395 (1211),<br />
ix238 (716P)<br />
locally-advanced pancreas cancer, ix238 (715P)<br />
locally-advanced pancreatic carcinoma, ix237<br />
(711P)<br />
longitudinal study, ix515 (1600P)<br />
long QTc, ix173 (508)<br />
long-term follow-up, ix522 (1624), ix148 (425P),<br />
ix273 (826P)<br />
long-term responders, ix125 (346P)<br />
long-term response, ix446 (1367TiP)<br />
long-term survival, ix412 (1256P), ix307 (933P)<br />
long-term use, ix510 (1583P)<br />
loss of mismatch repair protein expression, ix176<br />
(516P)<br />
low doses, ix139 (397)<br />
low malignant potential tumor, ix331 (1011)<br />
low molecular weight heparin, ix519 (1616P)<br />
low-dose radio<strong>the</strong>rapy in lymphoma, ix353<br />
(1081P)<br />
low-grade lymphoma, ix353 (1081P)<br />
LRIG, ix185 (544P)<br />
luminal A and B, ix102 (270P)<br />
luminal A, ix27 (13IN)<br />
luminal B, ix27 (13IN)<br />
lung adenocarcinoma, ix391 (1198P), ix412<br />
(1255P), ix414 (1262P), ix432 (1318), ix444<br />
(1362TiP), ix454 (1395P), ix92 (233)<br />
lung cancer stem cells, ix454 (1395P)<br />
lung cancer, ix383 (1175P), ix383 (1176P), ix385<br />
(1180PD), ix388 (1188P), ix388 (1190P), ix396<br />
(1214), ix414 (1264P), ix414 (1265P), ix423<br />
(1290P), ix425 (1297P), ix430 (1310P), ix432<br />
(1320), ix433 (1321), ix446 (1368TiP), ix457<br />
(1406), ix497 (1538P), ix506 (1569P), ix525<br />
(1637), ix541 (1691P), ix544 (1699P), ix73<br />
(169O), ix544 (1701), ix76 (177PD), ix78<br />
(183P), ix79 (188P), ix79 (190P), ix92 (235),<br />
ix49 (78IN), ix24 (7IN)<br />
lung metastases, ix212 (626)<br />
lung toxicity, ix396 (1213), ix396 (1216)<br />
lung, ix492 (1521PD)<br />
Lungscape, ix58 (105IN)<br />
lutenizing hormone releasing harmone, ix306<br />
(928P), ix321 (928P)<br />
lymph node, ix207 (611P), ix254 (773)<br />
lymph nodes, ix387 (1184P), ix135 (381)<br />
lymphadenectomy, ix112 (307)<br />
lymphoid malignancies, ix353 (1082P)<br />
lymphoma, ix352 (1079P), ix358 (1100), ix492<br />
(1521PD), ix518 (1609P), ix44 (64IN)<br />
lymphoplasmacytic reaction, ix99 (260P)<br />
lymphovascular invasion (LVI), ix186 (547P)<br />
Lynch syndrome, ix176 (516P)<br />
M<br />
macrocytosis, ix442 (1355)<br />
magnetic resonance imaging (MRI), ix207 (610P)<br />
maintenance chemo<strong>the</strong>rapy, ix397 (1219), ix409<br />
(1247P), ix486 (1503P), ix128 (356P)<br />
maintenance pem beva, ix434 (1327)<br />
maintenance <strong>the</strong>rapy, ix393 (1206P), ix397 (1218),<br />
ix404 (1235PD), ix417 (1271P), ix418 (1275P),<br />
ix305 (927P)<br />
maintenance, ix421 (1281P)<br />
male breast cancer, ix110 (298P), ix132 (371P)<br />
malignancies, ix492 (1521PD), ix158 (456P)<br />
malignant ascites, ix514 (1596P), ix539 (1683P),<br />
ix172 (504)<br />
malignant lymphoma, ix44 (65IN)<br />
malignant melanoma, ix365 (1120P), ix373 (1147)<br />
malignant meso<strong>the</strong>lioma, ix469 (1447PD)<br />
malignant pleural meso<strong>the</strong>lioma (MPM), ix78<br />
(185P), ix496 (1533P), ix496 (1534P), ix94 (244)<br />
malignant transformation, ix286 (864P)<br />
malnutrition, ix350 (1069PD), ix355 (1089P),<br />
ix356 (1091P), ix455 (1399P), ix499 (1544O),<br />
ix511 (1587P)<br />
MALT lymphoma, ix351 (1075P), ix352 (1076P)<br />
mammaglobin, ix111 (304)<br />
mammographic breast density, ix34 (35IN)<br />
mammography screening, ix470 (1451P)<br />
management decision, ix485 (1498P), ix237<br />
(711P)<br />
management of soft tissue sarcoma, ix478<br />
(1477O)<br />
management, ix482 (1488P), ix236 (708P)<br />
mantle cell lymphoma, ix354 (1084P), ix359<br />
(1107TiP), ix44 (66IN)<br />
manual for diabetic patients, ix527 (1705)<br />
MAP kinase, ix338 (1030P)<br />
MAPK, ix156 (451P), ix164 (475P)<br />
MASS criteria, ix244 (735P)<br />
mass screening, ix53 (88IN)<br />
mastectomy, ix477 (1476), ix137 (389)<br />
maximum tolerated dose, ix170 (497P)<br />
MCC, ix365 (1121P)<br />
MCPH1, ix533 (1662P)<br />
mCRC, ix93 (237), ix178 (518O), ix188 (554P),<br />
ix198 (581P), ix213 (632), ix214 (633), ix217<br />
(646), ix222 (662TiP)<br />
mCRPC, ix311 (943P), ix312 (948), ix316<br />
(962TiP), ix317 (965TiP)<br />
MDM2, ix54 (93IN)<br />
MDV3100, ix295 (896O), ix297 (899PD), ix304<br />
(924P), ix305 (925P)<br />
measurement of glomerular filtration rate, ix171<br />
(500P), ix283 (857P)<br />
media, ix66 (142IN)<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds467 | ix593
subject index<br />
medical information, ix457 (1404)<br />
medical oncology, ix451 (1383P)<br />
medical practice, ix478 (1477O)<br />
medical treatment, ix488 (1509P)<br />
medullary thyroid carcinoma, ix154 (445PD)<br />
medulloblastoma, ix31 (25IN)<br />
MEK inhibitor, ix403 (1233PD), ix69 (154P), ix75<br />
(173O), ix156 (451P), ix158 (456P)<br />
MEK1, ix389 (1193P)<br />
melanoma, ix361 (1109O), ix361 (1110O), ix363<br />
(1113PD), ix363 (1114PD), ix363 (1116PD),<br />
ix364 (1117PD), ix365 (1121P), ix365 (1123P),<br />
ix366 (1125P), ix366 (1126P), ix367 (1127P),<br />
ix367 (1128P), ix368 (1129P), ix369 (1131P),<br />
ix369 (1132P), ix370 (1134P), ix371 (1137P),<br />
ix371 (1138P), ix371 (1141P), ix373 (1148),<br />
ix374 (1149), ix374 (1151), ix375 (1152), ix454<br />
(1392P), ix72 (165), ix72 (166), ix540 (1686P),<br />
ix94 (242), ix46 (69IN), ix46 (70IN)<br />
melphalan, ix371 (1141P), ix246 (743P)<br />
meningioma, ix147 (420PD), ix150 (432)<br />
meningiomas, ix146 (419PD)<br />
menthol, ix513 (1591P)<br />
mesoporous silica nanoparticle, ix70 (158P)<br />
meso<strong>the</strong>lioma, ix495 (1531P), ix495 (1532P),<br />
ix496 (1535P), ix498 (1542TiP), ix80 (192P)<br />
MET, ix423 (1290P), ix42 (60IN), ix225 (669PD),<br />
ix230 (687P)<br />
meta-analyses, ix414 (1265P)<br />
meta-analysis, ix414 (1263P), ix454 (1394P), ix501<br />
(1551PD), ix513 (1594P), ix119 (326PD), ix181<br />
(528PD), ix324 (982P)<br />
metabolic imaging, ix63 (127IN)<br />
metabolic response, ix194 (569P)<br />
metabolic syndrome, ix111 (301)<br />
metabolism, ix21 (2IN)<br />
metastasectomy, ix186 (545P), ix275 (831P)<br />
metastases, ix488 (1508P), ix184 (539P), ix221<br />
(660), ix270 (817P), ix298 (904P), ix497 (1537P)<br />
metastasis, ix209 (616)<br />
metastatic breast cancer, ix531 (1657P), ix74<br />
(171O), ix89 (226P), ix116 (317O), ix119<br />
(326PD), ix119 (327PD), ix119 (328PD), ix122<br />
(335P), ix122 (336P), ix122 (337P), ix122<br />
(338P), ix123 (339P), ix123 (340P), ix124<br />
(342P), ix127 (354P), ix128 (356P), ix128<br />
(357P), ix131 (368P), ix132 (369P), ix132<br />
(370P), ix137 (389), ix138 (391), ix138 (392),<br />
ix138 (393), ix139 (395), ix140 (399), ix141<br />
(403), ix142 (407TiP), ix142 (408TiP), ix142<br />
(409TiP), ix145 (414PD)<br />
metastatic ca prostate, ix301 (912P)<br />
metastatic castration resistant prostate cancer,<br />
ix297 (900PD), ix297 (901PD), ix307 (932P)<br />
metastatic castration-resistant prostate cancer,<br />
ix294 (894O), ix300 (910P), ix302 (918P), ix306<br />
(929P), ix306 (931P), ix307 (933P), ix308<br />
(935P), ix315 (956)<br />
metastatic colorectal cancer, ix63 (126IN), ix449<br />
(1378P), ix514 (1595P), ix528 (1644PD), ix530<br />
(1653P), ix180 (525PD), ix187 (549P), ix188<br />
(553P), ix190 (558P), ix190 (559P), ix192<br />
(564P), ix193 (565P), ix194 (569P), ix194<br />
(570P), ix195 (571P), ix197 (578P), ix203<br />
(596P), ix203 (597P), ix204 (599P), ix205<br />
(602P), ix206 (606P), ix213 (631), ix217 (645),<br />
ix218 (648)<br />
metastatic colorectal carcinoma, ix85 (210P)<br />
metastatic head and neck squamous cell<br />
carcinoma, ix342 (1043P)<br />
metastatic melanoma, ix363 (1115PD), ix366<br />
(1124P), ix370 (1134P), ix370 (1135P), ix372<br />
(1143P), ix375 (1153)<br />
metastatic NSCLC, ix429 (1308P), ix440 (1350)<br />
metastatic pancreatic cancer, ix239 (717P)<br />
metastatic renal cell carcinoma (mRCC), ix261<br />
(791PD), ix269 (815P), ix271 (821P), ix275<br />
(831P), ix275 (833P), ix282 (851P), ix282<br />
(852P), ix288 (873)<br />
metastatic renal cell carcinoma, ix259 (785O),<br />
ix271 (819P), ix271 (820P), ix272 (824P), ix287<br />
(870), ix289 (878)<br />
metastatic renal-cell carcinoma, ix290 (881)<br />
metastatic sarcoma, ix484 (1495P)<br />
metastatic soft tissue sarcoma, ix488 (1511P)<br />
metastatic spinal cord compression, ix150 (434),<br />
ix301 (913P)<br />
metastatic, ix384 (1178TiP), ix425 (1297P), ix435<br />
(1329), ix438 (1341), ix139 (397), ix240 (724P),<br />
ix294 (893O), ix308 (934P)<br />
metformin, ix470 (1450P), ix126 (349P), ix302<br />
(917P)<br />
11C methionine PET, ix148 (425P)<br />
methodological pitfall, ix390 (1195P)<br />
methodology, ix158 (455P)<br />
methylation marker, ix88 (221P)<br />
methylation-specific PCR, ix109 (293P)<br />
methylation, ix73 (169O), ix532 (1660P), ix89<br />
(225P), ix185 (543P)<br />
metoprolol, ix173 (508)<br />
metronomic chemo<strong>the</strong>rapy, ix486 (1503P)<br />
Mexican, ix251 (763)<br />
mFOLFOX-6, ix217 (643)<br />
mFOLFOX6, ix210 (620)<br />
MGMT, ix31 (23IN), ix186 (548P), ix274 (830P)<br />
MICA, ix71 (160P)<br />
microarray gene-expression profiling, ix300 (910P)<br />
microarray technology, ix71 (161P)<br />
microarray, ix57 (100IN)<br />
microbial stimuli, ix536 (1672P)<br />
microbiota, ix200 (585P)<br />
microenvironment, ix29 (22IN)<br />
micrometastasis, ix106 (284P), ix112 (307)<br />
microRNA (miRNA), ix408 (1243P), ix528<br />
(1645PD), ix96 (250PD), ix148 (426P), ix180<br />
(525PD), ix183 (535P), ix209 (616)<br />
microRNA, ix68 (149P)<br />
microsatellite instability (MSI), ix220 (656)<br />
mifamurtide, ix488 (1508P), ix490 (1518TiP)<br />
migration, ix539 (1684P)<br />
minichromosome maintenance (MCM) protein,<br />
ix93 (240)<br />
miR-BART, ix337 (1025P)<br />
mistletoe extract, ix237 (712P)<br />
mitomycin C,, ix164 (477P)<br />
mixed mullerian tumor, ix330 (1004P)<br />
MK 2206, ix537 (1676P)<br />
MLH1, ix239 (720P)<br />
MLN8237, ix160 (461P), ix168 (489P), ix303<br />
(921P)<br />
MM-111, ix170 (496P)<br />
MMMT, ix332 (1012)<br />
MMP9, ix186 (545P)<br />
MMPs, ix67 (146P)<br />
MMSET, ix229 (686P)<br />
mode, ix437 (1336)<br />
modelling, ix459 (1411)<br />
modified FOLFIRI, ix233 (696P)<br />
modified RECIST, ix243 (732P)<br />
modified RPMI, ix196 (573P)<br />
molecular biology, ix37 (43IN)<br />
molecular biomarker, ix31 (24IN), ix51 (84IN),<br />
ix52 (85IN)<br />
molecular biomarkers, ix89 (223P), ix33 (31IN)<br />
molecular characterization, ix61 (119IN)<br />
molecular cytogenetics, ix91 (230P)<br />
molecular diagnosis, ix60 (114IN), ix61 (116IN),<br />
ix430 (1311P)<br />
molecular epidemiology, ix412 (1257P)<br />
molecular imaging, ix60 (115IN), ix47 (1703IN),<br />
ix40 (57IN), ix47 (74IN)<br />
molecular marker, ix66 (140IN), ix134 (377)<br />
molecular modeling, ix535 (1668P)<br />
molecular subtype, ix543 (1698P)<br />
molecular subtypes, ix111 (303)<br />
Annals of Oncology<br />
molecular targeted agents, ix474 (1463P), ix519<br />
(1614P), ix84 (205P)<br />
molecular targeted <strong>the</strong>rapy, ix290 (881)<br />
molecular telomere, ix350 (1071P)<br />
molecular <strong>the</strong>rapeutics, ix450 (1379P)<br />
molecular-based risk assessment, ix179 (522PD)<br />
monoclonal antibody 806, ix542 (1692P)<br />
monoclonal antibody, ix32 (29IN), ix192 (564P),<br />
ix44 (64IN), ix222 (662TiP)<br />
morbidity, ix226 (672P)<br />
Moroccan, ix432 (1318), ix476 (1470P)<br />
mortality, ix355 (1089P)<br />
mouse model, ix51 (84IN)<br />
movies, ix458 (1408)<br />
MSP, ix495 (1532P)<br />
MST2, ix539 (1684P)<br />
MTD, ix155 (446PD), ix165 (478P), ix169 (494P)<br />
mTOR inhibitor, ix336 (1023PD), ix27 (16IN),<br />
ix147 (420PD), ix47 (76IN), ix258 (783O), ix264<br />
(798PD), ix268 (812P), ix270 (818P), ix272<br />
(822P), ix277 (837P), ix278 (841P), ix278<br />
(842P)<br />
mTor inhibitors, ix334 (1017O), ix146 (419PD),<br />
ix44 (65IN), ix280 (845P), ix282 (852P)<br />
mTOR signaling pathway, ix92 (236)<br />
mTOR, prostate cancer, ix539 (1685P)<br />
mTOR, ix338 (1031P), ix377 (1156O), ix290 (881)<br />
MUC1, ix395 (1210), ix240 (723P)<br />
mucin, ix184 (541P)<br />
mucinous carcinoma, ix184 (541P)<br />
mucins, ix210 (619)<br />
mucosa adjacent, ix210 (619)<br />
mucosal melanoma, ix368 (1130P)<br />
mucositis, ix510 (1581P)<br />
multicenter phase II study, ix436 (1335), ix208<br />
(1704P), ix545 (1704P)<br />
multi-cycle, ix507 (1572P)<br />
multi-targeting, ix75 (173O)<br />
multidisciplinary approach, ix239 (718P), ix315<br />
(959)<br />
multifocal multicentric, ix117 (321PD)<br />
multimodal personalized <strong>the</strong>rapy, ix423 (1289P)<br />
multimodality <strong>the</strong>rapy, ix496 (1535P)<br />
multimodality treatment, ix222 (663TiP)<br />
multiple chemo<strong>the</strong>rapy lines, ix214 (634)<br />
multiple melanoma, ix364 (1118PD)<br />
multiple myeloma, ix349 (1065O), ix355 (1088P),<br />
ix360 (1108TiP), ix510 (1583P)<br />
multitargeted drug, ix32 (29IN)<br />
muscle invasive carcinoma of urinary bladder,<br />
ix264 (800P)<br />
muscle-invasive, ix265 (802P)<br />
mutant-enriched liquidchip technology, ix495<br />
(1530P)<br />
mutation analysis, ix364 (1118PD), ix213 (631)<br />
mutation, ix59 (108IN), ix390 (1197P), ix92 (234)<br />
mutational analysis, ix490 (1516)<br />
mutations, ix86 (212P)<br />
myelodysplastic syndrome, ix357 (1096)<br />
myeloid-derived suppressor cells, ix431 (1314)<br />
myeloma, ix348 (1064O), ix354 (1086P)<br />
myelomonocytic cells, ix69 (152P)<br />
myofibroblasts, ix345 (1055)<br />
N<br />
N-telopeptide of type 1 collagen (NTX), ix433<br />
(1321)<br />
N-telopeptides of type I collogen, ix432 (1320)<br />
NANOG, ix205 (604P)<br />
nasopharyngeal cancer, ix337 (1026P), ix337<br />
(1027P), ix339 (1035P)<br />
nasopharyngeal carcinoma, ix337 (1025P), ix337<br />
(1028P), ix343 (1048P), ix88 (221P)<br />
nation wide survey, ix348 (1062O), ix501 (1554P),<br />
ix315 (957)<br />
national cohort, ix271 (819P)<br />
nausea, ix507 (1571P)<br />
NC-6004, ix247 (746P)<br />
ix594 | subject index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology subject index<br />
NCAG report 2008, ix519 (1613P)<br />
near miss events, ix456 (1400P)<br />
need of information, ix476 (1472P)<br />
negative predictive value, ix373 (1146)<br />
neo adjuvant chemo<strong>the</strong>rapy, ix328 (1000P), ix487<br />
(1507P), ix80 (191P), ix82 (199P), ix228 (682P)<br />
neo-adjuvant <strong>the</strong>rapy, ix134 (378), ix141 (405TiP)<br />
neoadjuvant chemoradiation, ix237 (713P), ix248<br />
(749)<br />
neoadjuvant chemoradio<strong>the</strong>rapy, ix334 (1017O),<br />
ix131 (366P), ix226 (672P)<br />
neoadjuvant chemo<strong>the</strong>rapy, ix332 (1013), ix339<br />
(1035P), ix95 (247O), ix101 (268P), ix102<br />
(269P), ix117 (320PD), ix124 (343P), ix130<br />
(361P), ix131 (365P), ix134 (377), ix135 (380),<br />
ix135 (382), ix142 (406TiP), ix211 (624), ix264<br />
(800P), ix265 (802P), ix328 (997P)<br />
neoadjuvant endocrine <strong>the</strong>rapy, ix27 (15IN)<br />
neoadjuvant <strong>the</strong>rapy, ix395 (1211), ix98 (255PD),<br />
ix101 (267P), ix184 (538P), ix200 (586P), ix206<br />
(607P)<br />
neoadjuvant, ix58 (103IN), ix413 (1261P), ix97<br />
(254PD), ix102 (270P), ix117 (321PD), ix117<br />
(322PD), ix37 (45IN), ix129 (359P)<br />
neoplastic disease, ix458 (1409)<br />
neoplastic fever, ix525 (1637)<br />
nephrectomy, ix289 (878)<br />
nephrotoxicity, ix515 (1598P), ix520 (1619)<br />
NETNs, ix47 (73IN)<br />
NETs, ix377 (1157O), ix47 (73IN)<br />
netupitant, ix508 (1575P)<br />
network, ix482 (1488P)<br />
neural cell adhesion molecule, ix72 (166)<br />
neuroectodermal tumor, ix488 (1509P), ix47<br />
(76IN)<br />
neuroendocrine tumor, ix377 (1158P), ix379<br />
(1164P), ix380 (1167P), ix288 (873)<br />
neuroendocrine tumors, ix377 (1156O), ix378<br />
(1160P), ix379 (1162P), ix380 (1165P), ix47<br />
(1703IN), ix47 (74IN), ix47 (75IN), ix380<br />
(1166P), ix382 (1172)<br />
neurokinin 1, ix508 (1575P), ix520 (1618)<br />
neuron-specific enolase, ix291 (886)<br />
neurotoxicity, ix534 (1667P)<br />
neutropenia, ix521 (1623), ix522 (1624), ix232<br />
(692P), ix244 (738P)<br />
neutrophil to lymphocyte ratio, ix313 (950)<br />
neutrophils, ix500 (1548PD)<br />
never-smoker, ix414 (1264P)<br />
new drugs, ix63 (126IN)<br />
new <strong>the</strong>rapies, ix355 (1088P)<br />
next generation sequencing, ix61 (116IN), ix25<br />
(12IN), ix34 (33IN)<br />
NF II, ix150 (432)<br />
NFkB, ix68 (148P)<br />
NGR-hTNF, ix410 (1251P), ix167 (487P), ix167<br />
(488P), ix172 (502)<br />
NICE, ix460 (1417PD)<br />
nintedanib, ix155 (446PD), ix245 (740P), ix246<br />
(744P)<br />
nitroglycerin, ix409 (1249P)<br />
NK cells, ix350 (1072P)<br />
NKG2D, ix71 (160P)<br />
NMP-52, ix93 (239)<br />
nodal metastasis, ix345 (1055)<br />
node negative, ix104 (278P)<br />
node-positive breast cancer, ix129 (360P)<br />
non metastatic, ix490 (1515), ix303 (920P)<br />
non small cell lung cancer, ix386 (1182P), ix396<br />
(1213), ix396 (1214), ix396 (1215), ix403<br />
(1232PD), ix403 (1233PD), ix408 (1243P), ix408<br />
(1245P), ix412 (1256P), ix421 (1284P), ix425<br />
(1294P), ix430 (1312), ix431 (1314), ix436<br />
(1334), ix438 (1340), ix439 (1346), ix440 (1348),<br />
ix442 (1356), ix443 (1358), ix444 (1360), ix445<br />
(1366TiP), ix66 (138IN), ix457 (1405), ix67<br />
(144PD), ix528 (1646PD), ix533 (1663P), ix534<br />
(1665P), ix535 (1668P), ix542 (1692P), ix543<br />
(1695P), ix76 (178P), ix77 (180P), ix80 (193P),<br />
ix91 (232), ix49 (77IN), ix427 (1300P)<br />
non smokers, ix388 (1190P)<br />
non-Hodgkin lymphoma, ix353 (1080P), ix252<br />
(765)<br />
Non-Hodgkin’s lymphoma (NHL), ix451 (1384P)<br />
non-Hodgkins lymphoma, ix71 (162P)<br />
non-inferiority, ix224 (668PD)<br />
non-interventional, ix225 (670PD), ix255<br />
(778TiP), ix288 (875)<br />
non-myeloid tumors, ix523 (1628)<br />
non-seminomatous germ-cell tumor, ix292 (888)<br />
non-small cell lung cancer (NSCLC), ix387<br />
(1184P), ix390 (1194P), ix392 (1201P), ix397<br />
(1219), ix400 (1226O), ix404 (1234PD), ix405<br />
(1236PD), ix406 (1239P), ix406 (1240P), ix409<br />
(1247P), ix411 (1254P), ix415 (1266P), ix417<br />
(1271P), ix418 (1274P), ix420 (1280P), ix425<br />
(1296P), ix426 (1299P), ix429 (1306P), ix430<br />
(1311P), ix433 (1324), ix437 (1337), ix441<br />
(1351), ix446 (1367TiP), ix76 (179P), ix49<br />
(80IN)<br />
non-small cell lung cancer, ix174 (1708PD), ix391<br />
(1198P), ix393 (1205P), ix394 (1207P), ix395<br />
(1212), ix405 (1237PD), ix421 (1283P), ix427<br />
(1302P), ix428 (1305P), ix435 (1330), ix435<br />
(1331), ix439 (1344), ix441 (1352), ix443 (1359),<br />
ix150 (433)<br />
non-small-cell lung cancer (NSCLC), ix397<br />
(1217), ix455 (1396P)<br />
non-small-cell lung cancer, ix398 (1220)<br />
non-squamous non-small cell lung cancer, ix434<br />
(1326), ix438 (1342), ix441 (1352)<br />
non-squamous, ix442 (1356)<br />
noncompletion treatment, ix452 (1387P)<br />
nonhematologic tumor, ix156 (449PD)<br />
nonhematological, ix158 (456P)<br />
noninterventional trial, ix274 (828P)<br />
nonsq NSCLC, ix441 (1353)<br />
not advanced cancer patients, ix516 (1601P),<br />
ix520 (1617)<br />
not advanced cancer, ix516 (1602P)<br />
Notch1, ix327 (996P)<br />
NPC, ix344 (1051)<br />
NPRA, ix248 (748)<br />
NRAS, ix529 (1649P), ix196 (574P)<br />
NRP-1 (neuropilin 1), ix186 (546P)<br />
NSCLC, EGFR, EGFR ligands, ix394 (1209)<br />
NSCLC, ix58 (106IN), ix385 (1179O), ix388<br />
(1189P), ix389 (1191PD), ix389 (1192PD), ix389<br />
(1193P), ix390 (1196P), ix393 (1206P), ix394<br />
(1208), ix395 (1210), ix395 (1211), ix397 (1218),<br />
ix398 (1222), ix400 (1225O), ix401 (1227O),<br />
ix402 (1229PD), ix403 (1231PD), ix404<br />
(1235PD), ix406 (1238PD), ix408 (1245P), ix409<br />
(1246P), ix409 (1249P), ix410 (1250P), ix410<br />
(1252P), ix412 (1258P), ix415 (1267P), ix416<br />
(1268P), ix416 (1269P), ix416 (1270P), ix418<br />
(1273P), ix418 (1274P), ix419 (1276P), ix419<br />
(1277P), ix419 (1278P), ix420 (1279P), ix421<br />
(1282P), ix422 (1287P), ix423 (1289P), ix423<br />
(1290P), ix424 (1291P), ix424 (1292P), ix424<br />
(1293P), ix427 (1301P), ix428 (1304P), ix429<br />
(1307P), ix430 (1309P), ix431 (1315), ix432<br />
(1316), ix433 (1322), ix435 (1329), ix436 (1332),<br />
ix436 (1333), ix437 (1336), ix437 (1339), ix438<br />
(1341), ix439 (1343), ix440 (1347), ix442 (1355),<br />
ix443 (1357), ix445 (1364TiP), ix445 (1365TiP),<br />
ix68 (148P), ix68 (149P), ix68 (150P), ix69<br />
(154P), ix70 (158P), ix529 (1647PD), ix531<br />
(1655P), ix533 (1661P), ix533 (1662P), ix533<br />
(1664P), ix534 (1666P), ix73 (167O), ix73<br />
(168O), ix74 (170O), ix77 (181P), ix77 (182P),<br />
ix78 (184P), ix79 (187P), ix80 (191P), ix81<br />
(195P), ix85 (211P), ix152 (438O), ix152<br />
(439O), ix166 (484P), ix169 (492P), ix49<br />
(79IN), ix51 (84IN), ix52 (85IN)<br />
nuclear factor-κB, ix249 (752)<br />
nucleotide excision repair, ix345 (1052)<br />
nurses, ix517 (1605P)<br />
nutrition, ix541 (1689P)<br />
O<br />
observational study, ix416 (1270P), ix449 (1377P),<br />
ix452 (1385P), ix502 (1556P), ix191 (560P),<br />
ix314 (954)<br />
octreotide, ix382 (1172)<br />
ocular melanoma, ix369 (1133P)<br />
oestrus cycles, ix69 (151P)<br />
old age, ix494 (1527P)<br />
older cancer patients, ix461 (1420PD)<br />
older patients, ix341 (1041P)<br />
oligometastases, ix425 (1296P)<br />
oligometastatic disease, ix309 (938P)<br />
oligonucleotide microarray chip, ix536 (1673P)<br />
OMAS (Oral Mucositis Assessment Scale), ix346<br />
(1059)<br />
ombrabulin, ix410 (1250P)<br />
onartuzumab, ix445 (1364TiP), ix445 (1365TiP)<br />
oncogene addiction, ix61 (119IN), ix51 (81IN)<br />
oncogene, ix46 (70IN)<br />
oncologic imaging, ix60 (113IN)<br />
oncological emergencies, ix519 (1613P)<br />
oncologist, ix64 (128IN)<br />
oncology care, ix474 (1464P)<br />
oncology, ix456 (1402P), ix457 (1403), ix476<br />
(1473P)<br />
oncolytic virus, ix537 (1677P)<br />
Oncotype DX, ix97 (252PD), ix107 (289P), ix112<br />
(306)<br />
ong-term responders to first-line Bevacizumab in<br />
metastatic breast cancer, ix128 (355P)<br />
ONO-4538, ix159 (459P)<br />
operable laryngeal cancer, ix338 (1030P)<br />
opioids, ix510 (1582P)<br />
opportunities, ix65 (136IN)<br />
optical coherence tomography, ix330 (1006P)<br />
oral administration, ix507 (1572P), ix524 (1634)<br />
oral chemo<strong>the</strong>rapy, ix456 (1401P), ix524 (1634),<br />
ix138 (392)<br />
oral form, ix507 (1574P)<br />
oral liposomal iron, ix505 (1565P)<br />
oral microflora, ix343 (1049P)<br />
oral squamous cell carcinoma, ix345 (1055)<br />
oral squamus cell carcinoma, ix343 (1049P)<br />
oral taxane, ix167 (486P)<br />
oral vinorelbine, ix409 (1247P), ix409 (1249P),<br />
ix138 (392), ix140 (399)<br />
organisation of care, ix315 (959)<br />
oropharyngeal cancer, ix341 (1040P), ix342<br />
(1045P)<br />
OSNA, ix106 (284P)<br />
osteonecrosis of <strong>the</strong> jaw, ix524 (1633)<br />
osteosarcoma, ix487 (1507P), ix488 (1508P), ix490<br />
(1515), ix490 (1518TiP), ix54 (93IN)<br />
outcome results, ix65 (137IN)<br />
outcome, ix385 (1179O), ix168 (491P)<br />
outcomes, ix440 (1350), ix500 (1549PD), ix260<br />
(788O), ix328 (999P)<br />
outpatient, ix518 (1610P)<br />
ovarian cancer, ix332 (1013), ix68 (147P), ix81<br />
(198P), ix34 (34IN), ix175 (512PD), ix40<br />
(54IN), ix40 (56IN), ix40 (57IN), ix319 (966O),<br />
ix319 (967O), ix320 (973PD), ix322 (978P),<br />
ix323 (979P), ix323 (981P), ix324 (983P), ix325<br />
(985P), ix325 (986P), ix325 (987P), ix325<br />
(987P), ix325 (988P), ix326 (990P), ix326<br />
(991P), ix326 (992P), ix327 (993P)<br />
ovarian epi<strong>the</strong>lial cancer, ix332 (1014)<br />
ovarian failure, ix501 (1551PD)<br />
ovarian germ cell tumors, ix327 (994P)<br />
ovarian mucinous adenocarcinoma, ix326 (989P)<br />
ovary, ix322 (977P)<br />
overall survival (OS), ix350 (1070PD), ix415<br />
(1266P), ix437 (1339), ix441 (1351), ix453<br />
(1391P), ix485 (1498P), ix499 (1544O), ix119<br />
(328PD), ix148 (425P), ix204 (599P), ix208<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds467 | ix595
subject index<br />
(612P), ix214 (633), ix232 (694P), ix237 (712P),<br />
ix260 (787O), ix272 (824P), ix273 (825P)<br />
overall survival, ix376 (1155O), ix496 (1534P),<br />
ix87 (219P), ix271 (819P), ix296 (898PD)<br />
overtreatment, ix105 (281P)<br />
oxaliplatin, ix84 (207P), ix179 (523PD), ix193<br />
(566P), ix201 (591P), ix205 (602P), ix220 (653),<br />
ix237 (713P), ix241 (728P), ix249 (755), ix261<br />
(790O)<br />
oxycodone/naloxone, ix510 (1582P)<br />
P<br />
1p/19q co-deletion, ix31 (23IN)<br />
p-medicine, ix66 (141INIS)<br />
p16INK4a, ix185 (543P)<br />
p40, ix77 (181P)<br />
p53, ix389 (1192PD), ix74 (170O), ix98 (257P),<br />
ix108 (291P), ix323 (979P)<br />
p95-HER2, ix94 (243), ix101 (267P)<br />
paclitaxel plus gemcitabine, ix342 (1043P)<br />
paclitaxel/carboplatin, ix375 (1153)<br />
paclitaxel, ix409 (1246P), ix534 (1667P), ix116<br />
(317O), ix119 (326PD), ix157 (454P), ix161<br />
(464P), ix228 (681P), ix232 (692P), ix233<br />
(698P), ix247 (745P), ix261 (790O), ix265<br />
(801P), ix321 (974PD)<br />
pain control, ix510 (1581P)<br />
pain, ix488 (1510P), ix509 (1580P), ix510 (1582P)<br />
pAkt, ix78 (185P)<br />
palliative care, ix64 (128IN)<br />
palliative chemo<strong>the</strong>rapy, ix343 (1046P), ix440<br />
(1350)<br />
palonosetron subcutaneous, ix508 (1577P)<br />
palonosetron, ix507 (1571P), ix507 (1572P), ix507<br />
(1574P), ix508 (1576P)<br />
pancreatic adenocarcinoma, ix543 (1697P), ix37<br />
(42IN), ix224 (666O), ix252 (767), ix253 (768)<br />
pancreatic cancer, ix25 (12IN), ix472 (1456P),<br />
ix543 (1696P), ix37 (43IN), ix155 (447PD),<br />
ix237 (710P), ix237 (712P), ix237 (713P), ix238<br />
(714P), ix238 (716P), ix239 (718P), ix239<br />
(720P), ix240 (721P), ix240 (722P), ix240<br />
(723P), ix240 (724P), ix241 (725P), ix241<br />
(726P), ix241 (727P), ix241 (728P), ix252 (767),<br />
ix255 (776TiP)<br />
pancreatic ductal adenocarcinoma, ix236 (709P)<br />
pancreatic fibroblast, ix67 (145P)<br />
pancreatic neuroendocrine tumor, ix376 (1155O)<br />
pancreatic neuroendocrine tumors, ix376 (1154O),<br />
ix378 (1159P)<br />
panitumumab, ix334 (1016O), ix514 (1597P),<br />
ix190 (558P), ix192 (563P), ix194 (570P), ix196<br />
(572P), ix200 (587P), ix203 (598P), ix205<br />
(605P), ix223 (665TiP)<br />
PaP Score, ix516 (1603P)<br />
papillary renal cell cancer, ix263 (797PD)<br />
papillary renal cell carcinoma, ix277 (837P)<br />
papillomavirus general, ix71 (162P)<br />
paradoxical pathway activation, ix46 (69IN)<br />
parental cancer, ix517 (1606P)<br />
PARP, ix42 (61IN), ix43 (63IN)<br />
pat. selection on molecular bases, ix32 (27IN)<br />
pathological complete response, ix135 (380), ix215<br />
(637), ix222 (663TiP)<br />
pathological response, ix219 (651)<br />
pathological tumor response, ix197 (578P)<br />
patient benefit, ix66 (142IN)<br />
patient characteristics, ix453 (1390P)<br />
patient consent, ix61 (117IN)<br />
patient enrichment, ix32 (28IN)<br />
patient management, ix525 (1635)<br />
patient physician communication, ix474 (1462PD)<br />
patient preferences, ix476 (1473P)<br />
patient reported outcomes, ix403 (1231PD), ix477<br />
(1474), ix512 (1590P)<br />
patient safety, ix418 (1275P), ix522 (1624)<br />
patient satisfaction, ix475 (1468P)<br />
patient stratification, ix85 (211P)<br />
patient survey, ix451 (1382P), ix132 (369P)<br />
patient-reported outcomes, ix120 (329P)<br />
patient, ix293 (892TiP)<br />
pattern of failure, ix393 (1204P)<br />
patterns of progression, ix441 (1352), ix238<br />
(715P)<br />
PAZONET, ix377 (1157O)<br />
pazopanib, ix377 (1157O), ix483 (1493P), ix88<br />
(222P), ix173 (508), ix261 (791PD), ix261<br />
(792PD), ix275 (833P), ix278 (840P), ix290<br />
(880)<br />
PD-1, ix361 (1109O), ix405 (1237PD), ix157<br />
(453P), ix159 (459P), ix258 (784O)<br />
PD-L1, ix159 (459P)<br />
PDGFRA mutation, ix483 (1491P)<br />
PDM08, ix165 (480P)<br />
pediatric cancer, ix455 (1399P)<br />
pediatric, ix358 (1102), ix145 (413PD)<br />
pegfilgrastim, ix500 (1548PD), ix503 (1560P)<br />
pemetrexed, cetuximab, ix336 (1022PD)<br />
pemetrexed, ix393 (1206P), ix395 (1211), ix396<br />
(1214), ix396 (1215), ix397 (1218), ix400<br />
(1225O), ix404 (1235PD), ix407 (1242P), ix409<br />
(1247P), ix412 (1258P), ix415 (1267P), ix418<br />
(1275P), ix421 (1281P), ix422 (1286P), ix428<br />
(1303P), ix437 (1338), ix438 (1342), ix442<br />
(1354), ix442 (1355), ix442 (1356), ix444 (1361)<br />
peptide, ix159 (460P)<br />
percutaneous hepatic perfusion, ix371 (1141P),<br />
ix246 (743P)<br />
performance status, ix541 (1689P)<br />
perfusion CT, ix282 (853P)<br />
periampullary, ix242 (729P)<br />
perineural invasion, ix186 (547P)<br />
perioperative chemo<strong>the</strong>rapy, ix249 (753), ix292<br />
(887)<br />
periostin, ix301 (914P)<br />
peripheral neuropathy, ix513 (1592P)<br />
peritoneal carcinoma, ix326 (992P)<br />
peritoneal carcinomatosis, ix35 (38IN), ix202<br />
(593P)<br />
peritoneal meso<strong>the</strong>lioma, ix247 (747P)<br />
peritoneal metastasis, ix233 (698P), ix234 (702P)<br />
peritumoral vascular invasion, ix99 (260P)<br />
personalized medicine, ix65 (137IN), ix451<br />
(1382P), ix66 (140IN), ix66 (142IN), ix81<br />
(196P), ix88 (220P)<br />
personalized treatment, ix54 (92IN)<br />
perspectives, ix23 (6IN)<br />
pertuzumab, ix124 (344P)<br />
pesonalized <strong>the</strong>rapy, ix66 (138IN)<br />
PET/CT, ix60 (114IN), ix385 (1180PD), ix37<br />
(45IN)<br />
PET/TC, ix137 (388)<br />
PET, ix33 (31IN), ix47 (74IN)<br />
Ph positive CML, ix358 (1102)<br />
pharmaco-épidémiology, ix219 (649)<br />
pharmacodynamic, ix346 (1057), ix167 (485P),<br />
ix219 (650), ix263 (796PD)<br />
pharmacodynamics, ix158 (457P)<br />
pharmacoepidemiology, ix456 (1402P)<br />
pharmacogenetic analysis, ix381 (1170P)<br />
pharmacogenetics, ix534 (1667P)<br />
pharmacogenomics, ix81 (196P), ix281 (850P)<br />
pharmacokinetics, ix346 (1057), ix498 (1543TiP),<br />
ix534 (1667P), ix538 (1678P), ix103 (274P),<br />
ix124 (344P), ix129 (358P), ix155 (447PD),<br />
ix162 (468P), ix169 (493P), ix219 (650), ix244<br />
(738P), ix245 (739P), ix246 (743P)<br />
phase 1 drugs, ix166 (482P)<br />
phase 1 study, ix163 (471P), ix164 (474P)<br />
phase 1 trials, ix158 (455P), ix167 (486P)<br />
phase 1, ix103 (274P), ix148 (428P), ix153<br />
(440O), ix156 (449PD), ix156 (450PD), ix159<br />
(458P), ix159 (459P), ix160 (462P), ix165<br />
(480P), ix165 (481P), ix173 (507)<br />
phase 2, ix378 (1159P), ix378 (1160P), ix63<br />
(126IN), ix435 (1329), ix438 (1340), ix152<br />
Annals of Oncology<br />
(438O), ix159 (460P), ix211 (624), ix263<br />
(797PD)<br />
phase 3 clinical trial, ix188 (552P), ix309 (937P),<br />
ix319 (967O)<br />
phase 3, ix418 (1275P), ix421 (1282P)<br />
phase I clinical trial, ix536 (1671P), ix153 (442O),<br />
ix154 (444PD)<br />
phase I clinical trials, ix162 (469P)<br />
phase I study, ix155 (448PD), ix156 (451P), ix164<br />
(475P)<br />
phase I trial, ix474 (1463P)<br />
phase I trials, ix32 (27IN)<br />
phase I/II study, ix336 (1021PD)<br />
phase I, ix424 (1291P), ix496 (1534P), ix155<br />
(446PD), ix161 (464P), ix161 (467P), ix167<br />
(485P), ix168 (491P), ix170 (497P), ix207<br />
(609P), ix239 (717P)<br />
phase II clinical trial, ix425 (1296P), ix228 (682P),<br />
ix275 (833P), ix304 (922P)<br />
phase II, sunitinib, ix479 (1479PD)<br />
phase II, ix441 (1353), ix512 (1588P)<br />
phase III clinical trial, ix404 (1234PD), ix231<br />
(689P), ix233 (697P)<br />
phase IV studies, ix282 (851P)<br />
phenotype, ix538 (1678P)<br />
phosphatase and tensin homolog (PTEN), ix84<br />
(204P), ix182 (532P)<br />
phospho-Met, ix154 (443PD)<br />
physical activity, ix518 (1609P)<br />
physical and emotional symptoms in not advanced<br />
cancer patients, ix524 (1631)<br />
physical examination, ix324 (983P)<br />
physical fitness, ix518 (1609P)<br />
physician survey, ix380 (1166P)<br />
physio<strong>the</strong>rapy, ix513 (1592P)<br />
PI3K alternations, ix40 (56IN)<br />
PI3K inhibitor, ix69 (154P), ix126 (350P), ix158<br />
(457P)<br />
PI3K inhibitors, ix27 (16IN), ix78 (185P), ix45<br />
(68IN)<br />
PI3K mTOR inhibitor, ix59 (108IN), ix69 (154P),<br />
ix153 (442O)<br />
PI3K pathway inhibitor, ix153 (442O), ix159<br />
(458P)<br />
PI3K pathway, ix531 (1656P), ix94 (243), ix223<br />
(664TiP)<br />
PI3K/Akt pathway, ix268 (812P)<br />
PI3K/mTOR, ix157 (452P)<br />
PI3K, ix537 (1675P), ix21 (2IN), ix42 (60IN),<br />
ix213 (630)<br />
PI3KCA mutation, ix153 (442O)<br />
PIH, ix454 (1394P)<br />
PIK3CA mutation, ix84 (204P)<br />
PIK3CA, ix59 (108IN), ix389 (1193P), ix196<br />
(574P)<br />
PKM2 expression, ix429 (1308P)<br />
placental growth factor, ix83 (203P)<br />
plasma biomarkers, ix73 (168O)<br />
plasma VEGF-A, ix81 (198P)<br />
plasma, ix495 (1530P), ix530 (1654P)<br />
platin sensitivity, ix497 (1540)<br />
platinum and trastuzumab, ix259 (786O)<br />
platinum resistance, ix320 (972PD)<br />
platinum-based chemo<strong>the</strong>rapy, ix329 (1002P),<br />
ix427 (1302P)<br />
platinum-based regimens, ix130 (361P), ix323<br />
(981P)<br />
platinum-resistant, ix336 (1023PD)<br />
platinum-sensitive, ix324 (982P)<br />
platinum, ix533 (1661P), ix320 (972PD)<br />
pleural meso<strong>the</strong>lioma, ix493 (1522PD)<br />
pleural plaque, ix469 (1447PD)<br />
POLARSTAR, ix426 (1298P)<br />
policy, ix451 (1383P)<br />
polycystins, ix92 (236)<br />
polycy<strong>the</strong>mia vera3hemorrhage, ix355 (1087P)<br />
polymer micelle, ix247 (746P)<br />
polymorphism of genes, ix240 (724P)<br />
ix596 | subject index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology subject index<br />
polymorphism, ix183 (536P), ix208 (613P), ix216<br />
(640)<br />
polymorphisms, ix352 (1078P), ix185 (544P),<br />
ix281 (850P)<br />
pontine glioma, ix145 (413PD)<br />
pooled analysis, ix273 (825P)<br />
poor PS, ix421 (1282P), ix433 (1323)<br />
poorly differentiated carcinoma, ix89 (225P)<br />
population-based programme, ix53 (88IN)<br />
population-based study, ix53 (89IN)<br />
port central venous ca<strong>the</strong>ters, ix522 (1626)<br />
positive predictive value, ix373 (1146)<br />
positron emission tomography (PET), ix480<br />
(1482PD)<br />
post-induction <strong>the</strong>rapy, ix419 (1278P)<br />
post-marketing surveillance, ix505 (1566P)<br />
post-marketing, ix504 (1563P)<br />
post-PD, ix482 (1490P)<br />
postoperative radiation, ix226 (674P)<br />
postoperative radio<strong>the</strong>rapy, ix216 (639)<br />
power doppler, ix134 (379)<br />
ppar, ix201 (590P)<br />
PRAME antigen, ix361 (1110O), ix386 (1182P)<br />
pre-menopausal cancer patients, ix501 (1551PD)<br />
pre-operative chemoradio<strong>the</strong>rapy, ix197 (575P),<br />
ix207 (610P)<br />
pre-operative staging, ix384 (1177P)<br />
preclinical model, ix337 (1027P)<br />
preclinical models, ix61 (120IN)<br />
preclinical, ix537 (1675P)<br />
prediction of response, ix504 (1561P), ix282<br />
(852P)<br />
predictive biomarker, ix84 (204P), ix107 (289P)<br />
predictive biomarkers, ix180 (525PD), ix197<br />
(575P), ix275 (833P)<br />
predictive factors, ix407 (1241P), ix429 (1306P),<br />
ix218 (647)<br />
predictive impact, ix182 (532P)<br />
predictive marker, ix74 (172O), ix265 (803P)<br />
predictive markers, ix364 (1117PD)<br />
predictive role, ix216 (640)<br />
predictive significance, ix381 (1170P)<br />
predictive/ prognostic value, ix431 (1314)<br />
predictors factors, ix276 (835P)<br />
prednisone, ix302 (918P)<br />
preeclampsia, ix454 (1394P)<br />
preference, ix293 (892TiP)<br />
pregnancy, ix355 (1090P), ix133 (373P)<br />
preoperative chemo<strong>the</strong>rapy, ix130 (362P)<br />
preoperative concomitant chemoradio<strong>the</strong>rapy,<br />
ix89 (224P)<br />
preoperative radiochemo<strong>the</strong>rapy, ix208 (1704P),<br />
ix545 (1704P)<br />
preoperative radio<strong>the</strong>rapy, ix216 (639)<br />
preoperative treatment, ix197 (578P)<br />
pretreated patients, ix325 (986P)<br />
prevalence, ix298 (902P), ix213 (632)<br />
prevention, ix473 (1461), ix477 (1475), ix513<br />
(1594P), ix173 (508)<br />
prgnosis, ix119 (327PD)<br />
primary cardiac sarcoma, ix489 (1513)<br />
primary endocrine <strong>the</strong>rapy, ix100 (263P)<br />
primary lesion, ix276 (834P)<br />
primary mediastinal germ cell tumour, ix497<br />
(1539P)<br />
primary tumor, ix131 (368P), ix182 (531P)<br />
procalcitonin, ix525 (1637)<br />
progesteron reseptor, ix105 (279P)<br />
progesterone receptor, ix104 (278P)<br />
prognosis factors, ix94 (244)<br />
prognosis, SIADH, small cell lung cancer (SCLC),<br />
retrospective study, ix494 (1528P)<br />
prognosis, ix348 (1062O), ix353 (1080P), ix365<br />
(1120P), ix427 (1300P), ix516 (1603P), ix538<br />
(1681P), ix541 (1688PD), ix83 (201P), ix100<br />
(264P), ix110 (299), ix184 (539P), ix184 (540P),<br />
ix201 (589P), ix208 (613P), ix217 (644), ix287<br />
(868), ix53 (89IN)<br />
prognostic biomarker, ix338 (1030P), ix350<br />
(1071P), ix76 (178P), ix79 (187P), ix92 (233),<br />
ix199 (582P), ix226 (675P), ix261 (791PD),<br />
ix300 (911P)<br />
prognostic factor, ix332 (1015), ix350 (1069PD),<br />
ix387 (1186P), ix430 (1310P), ix496 (1533P),<br />
ix73 (168O), ix145 (414PD), ix186 (547P), ix253<br />
(771), ix265 (804P)<br />
prognostic factors, ix332 (1012), ix357 (1097),<br />
ix380 (1167P), ix387 (1184P), ix387 (1185P),<br />
ix392 (1203P), ix441 (1351), ix485 (1498P),<br />
ix497 (1537P), ix497 (1538P), ix497 (1540), ix79<br />
(187P), ix99 (258P), ix107 (288P), ix132 (371P),<br />
ix197 (577P), ix216 (641), ix262 (793PD), ix276<br />
(836P), ix298 (903P), ix328 (999P)<br />
prognostic marker, ix530 (1654P), ix74 (172O),<br />
ix182 (533P)<br />
prognostic model, ix299 (907P)<br />
prognostic score, ix162 (469P), ix298 (903P)<br />
prognostic significance, ix381 (1170P)<br />
prognostic, ix338 (1031P), ix339 (1033P)<br />
progression free survival, ix339 (1035P), ix392<br />
(1203P), ix217 (645)<br />
progression, survival, ix297 (901PD)<br />
progression-free survival (PFS), ix331 (1011),<br />
ix350 (1070PD), ix381 (1171P), ix453 (1391P),<br />
ix526 (1643), ix119 (328PD), ix232 (694P),<br />
ix260 (787O), ix273 (825P)<br />
progression-free survival, ix449 (1378P), ix231<br />
(690P)<br />
proliferation, ix112 (305)<br />
promoter methylation, ix186 (548P)<br />
prophylactic cranial irradiation, ix394 (1207P)<br />
prophylaxis, ix521 (1623)<br />
prospective cohort, ix488 (1511P)<br />
prostate cancer ibandronate y-27632 rho-kinase<br />
inhibitor, ix312 (947)<br />
prostate cancer screening, ix53 (87IN)<br />
prostate cancer working group (PCWG)-2, ix297<br />
(901PD)<br />
prostate cancer, ix384 (1178TiP), ix538 (1680P),<br />
ix89 (223P), ix38 (49IN), ix291 (884), ix294<br />
(893O), ix295 (896O), ix297 (899PD), ix298<br />
(902P), ix298 (904P), ix299 (906P), ix301<br />
(914P), ix302 (916P), ix304 (922P), ix306<br />
(928P), ix309 (937P), ix309 (938P), ix310<br />
(939P), ix310 (941P), ix311 (942P), ix311<br />
(944P), ix312 (945), ix313 (950), ix314 (952),<br />
ix314 (953), ix314 (955), ix315 (957), ix315<br />
(959), ix316 (961)<br />
prostate tumor xenograft, ix312 (946)<br />
prostate volume, ix306 (930P)<br />
prostate-specific antigen (PSA), ix299 (907P)<br />
prostate, ix39 (53IN)<br />
prostvac, ix38 (46IN)<br />
proteasome inhibitor, ix44 (66IN)<br />
protein S, ix356 (1094)<br />
protein tyrosine phosphatase non-receptor type 12<br />
(PTPN 12), ix127 (353P)<br />
protein-expression profiling, ix337 (1026P)<br />
proteinuria, ix171 (499P)<br />
proteomic biomaker, ix89 (224P), ix91 (232)<br />
proteomics, ix407 (1241P)<br />
prophylactic cranial irradiation, ix98 (256P)<br />
PRRT, ix47 (75IN)<br />
pruritus, ix500 (1550PD)<br />
PSA response, ix313 (951)<br />
PSA, mCRPC, ix310 (940P)<br />
pseudomyxoma peritonei, ix254 (774)<br />
PSF3, ix92 (233)<br />
psycho-oncology, ix474 (1462PD), ix475 (1467P),<br />
ix476 (1470P)<br />
psycho-social outcomes, ix474 (1462PD), ix475<br />
(1466P)<br />
psychological distress, ix343 (1047P), ix517<br />
(1606P)<br />
psychometric properties of Patient Dignity<br />
Inventory Italian version, ix516 (1601P)<br />
psychometric properties, ix516 (1602P)<br />
psychooncology, ix477 (1475)<br />
PTCH1, ix365 (1121P)<br />
PTEN, ix213 (630)<br />
PTK7, ix184 (539P)<br />
pulmonary adenocarcinoma, ix391 (1198P)<br />
pulmonary embolism, ix444 (1360)<br />
pulmonary neoplasm, ix383 (1174P)<br />
Q<br />
13q deletion, ix355 (1088P)<br />
QOL, ix511 (1586P), ix232 (695P)<br />
QTc, ix173 (507)<br />
quality assurance, ix86 (213P)<br />
quality of care indicators, ix457 (1405)<br />
quality of care, ix457 (1403), ix458 (1407), ix53<br />
(89IN)<br />
quality of documentation, ix448 (1374P)<br />
quality of life (QOL) assessment, ix512 (1590P),<br />
ix141 (403), ix211 (623), ix314 (954)<br />
quality of life (QoL), ix346 (1060), ix436 (1332),<br />
ix512 (1589P), ix514 (1596P), ix515 (1600P),<br />
ix120 (330P), ix120 (331P), ix145 (415PD),<br />
ix237 (712P), ix261 (792PD), ix269 (815P)<br />
quality of life, ix343 (1047P), ix459 (1413TiP),<br />
ix474 (1463P), ix475 (1468P), ix121 (334P),<br />
ix191 (561P), ix296 (898PD), ix315 (956), ix328<br />
(998P)<br />
quality-adjusted survival, ix192 (564P)<br />
R<br />
radiation <strong>the</strong>rapy, ix148 (428P), ix200 (586P)<br />
radiation-induced malignancy, ix343 (1048P)<br />
radiation, ix69 (152P), ix537 (1676P), ix257<br />
(782TiP)<br />
radical mastectomy, ix131 (365P)<br />
radical prostatectomy, ix299 (907P)<br />
radical treatment, ix212 (626)<br />
radiochemo<strong>the</strong>rapy, ix37 (45IN)<br />
radiographic progression-free survival, ix294<br />
(894O)<br />
radiopeptide <strong>the</strong>rapy, ix379 (1162P)<br />
radiosensitiser, ix42 (61IN)<br />
radiosensitization, ix537 (1677P)<br />
radio<strong>the</strong>rapy induced epiphyseal injury, ix526<br />
(1642)<br />
radio<strong>the</strong>rapy-induced epiphyseal injury, ix526<br />
(1641)<br />
radio<strong>the</strong>rapy-induced oral mucositis, ix346 (1059)<br />
radio<strong>the</strong>rapy, ix329 (1003P), ix334 (1016O), ix343<br />
(1048P), ix343 (1049P), ix391 (1199P), ix457<br />
(1406), ix475 (1466P), ix496 (1536P), ix70<br />
(156P), ix525 (1636), ix537 (1677P), ix31<br />
(26IN), ix131 (365P), ix148 (427P), ix150 (433),<br />
ix172 (503), ix206 (607P), ix207 (611P), ix208<br />
(614P), ix242 (729P), ix265 (801P), ix265<br />
(803P), ix291 (885)<br />
Raf/MEK inhibitor, ix164 (475P)<br />
raltitrexed, ix178 (519O)<br />
ramucirumab, ix363 (1115PD), ix408 (1245P),<br />
ix422 (1287P)<br />
randomised phase II trial, ix378 (1161P)<br />
randomized clinical trial, ix410 (1250P), ix450<br />
(1380P)<br />
randomized discontinuation trial, ix319 (966O)<br />
randomized phase II trial, ix224 (666O), ix242<br />
(730P), ix297 (900PD)<br />
randomized phase III trial, ix211 (625)<br />
randomized trial, ix145 (413PD)<br />
Rapalogues, ix334 (1017O)<br />
rare cancer, ix66 (140IN)<br />
rare tumor, ix488 (1509P), ix110 (297P), ix327<br />
(993P)<br />
RAS, ix46 (69IN)<br />
rash, ix426 (1298P), ix435 (1328), ix79 (189P),<br />
ix192 (563P)<br />
rat food intake, ix161 (465P)<br />
rat model, ix526 (1641), ix526 (1642)<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds467 | ix597
subject index<br />
RCC, ix274 (830P)<br />
re-staging PET-CT, ix237 (711P)<br />
re-surgery, ix145 (416PD)<br />
receptor tyrosine kinase inhibitor, ix319 (966O)<br />
rechallenge, ix281 (849P)<br />
RECIST, ix60 (112IN), ix487 (1506P), ix188<br />
(554P), ix276 (834P)<br />
rectal cancer, ix529 (1648P), ix208 (1704P), ix545<br />
(1704P), ix197 (575P), ix206 (607P), ix206<br />
(608P), ix207 (609P), ix207 (610P), ix207<br />
(611P), ix208 (612P), ix208 (614P), ix211 (622),<br />
ix215 (637), ix215 (638), ix222 (663TiP)<br />
rectal cancers, ix184 (538P), ix193 (567P)<br />
recurrence factor, ix132 (371P)<br />
recurrence risk, ix179 (523PD)<br />
recurrence, ix148 (426P), ix322 (977P)<br />
recurrent cervical cancer, ix327 (995P)<br />
recurrent ovarian cancer, ix323 (980P), ix324<br />
(982P)<br />
recurrent/metastatic salivary gland malignancies,<br />
ix346 (1058)<br />
recurrent, ix332 (1014), ix147 (424P)<br />
reflex screening, ix176 (516P)<br />
refractory Hodgkin’s lymphoma, ix350 (1071P)<br />
refractory, ix492 (1519PD), ix286 (866P)<br />
regorafenib, ix478 (1478O)<br />
regulatory T-cells, ix75 (174O)<br />
rehabilitation, ix513 (1592P)<br />
reinforcement learning, ix459 (1411)<br />
relapse, disease-free survival (DFS), ix356 (1091P)<br />
relapse, ix227 (679P)<br />
relapsed non-Hodgkin’s lymphoma, ix353 (1081P)<br />
reliability, ix534 (1665P)<br />
renal cancer, ix39 (51IN), ix39 (52IN), ix267<br />
(808P)<br />
renal cell cancer, ix274 (828P), ix281 (848P),<br />
ix281 (850P), ix287 (869), ix288 (875), ix290<br />
(880)<br />
renal cell carcinoma (RCC), ix268 (811P), ix273<br />
(827P), ix278 (840P), ix282 (853P), ix283<br />
(856P)<br />
renal cell carcinoma, ix453 (1390P), ix453<br />
(1391P), ix454 (1392P), ix69 (153P), ix172<br />
(501), ix39 (53IN), ix258 (784O), ix261<br />
(792PD), ix262 (793PD), ix262 (794PD), ix262<br />
(795PD), ix267 (809P), ix268 (812P), ix268<br />
(813P), ix270 (817P), ix270 (818P), ix272<br />
(823P), ix273 (825P), ix273 (826P), ix274<br />
(829P), ix275 (832P), ix276 (834P), ix276<br />
(836P), ix277 (838P), ix277 (839P), ix279<br />
(844P), ix280 (846P), ix281 (847P), ix283<br />
(855P), ix287 (872), ix288 (874), ix289 (876),<br />
ix289 (877), ix289 (878), ix292 (889TiP)<br />
renal function, ix171 (500P)<br />
renal, ix267 (810P), ix269 (816P)<br />
reproductive age, ix328 (998P)<br />
research informatics, ix449 (1376P)<br />
research, ix65 (135IN)<br />
resectable gastroesophageal carcinoma, ix249<br />
(753)<br />
resectable locally-advanced, ix265 (802P)<br />
resectable muscle-invasive, ix266 (807P)<br />
resectable rectal cancer, ix216 (639)<br />
resistance to treatment, ix287 (869)<br />
resistance, ix390 (1197P), ix68 (148P), ix68<br />
(149P), ix116 (318O), ix39 (52IN)<br />
resource utilization, ix122 (336P)<br />
response-shift, ix120 (331P)<br />
response criteria, ix289 (877)<br />
Response Evaluation Criteria in Solid Tumors<br />
(RECIST), ix60 (111IN), ix535 (1670P), ix198<br />
(579P)<br />
response evaluation, ix483 (1492P)<br />
response prediction, ix29 (19IN), ix37 (44IN)<br />
response rate, ix389 (1191PD), ix415 (1267P),<br />
ix496 (1534P)<br />
response shift, ix109 (296P)<br />
response to <strong>the</strong>rapy, ix534 (1665P)<br />
response to tyrosine kinase inhibitors, ix412<br />
(1257P)<br />
response, ix358 (1100)<br />
retinoblastoma, ix149 (430P)<br />
retroperitoneal lymph nodes, ix292 (888)<br />
retrospective analysis, ix526 (1640)<br />
retrospective study, ix370 (1136P), ix487 (1505P),<br />
ix525 (1635), ix114 (313)<br />
reverse-phase protein microarrays, ix536 (1674P)<br />
review, ix49 (78IN)<br />
RFA, ix35 (39IN)<br />
rhabdomyosarcoma, ix484 (1497P)<br />
rilotumumab, ix230 (687P)<br />
risk factors, ix543 (1698P), ix134 (376), ix227<br />
(679P), ix284 (859P)<br />
risk, ix339 (1032P), ix364 (1119P), ix365 (1121P),<br />
ix365 (1122P), ix133 (374P)<br />
rituximab, ix351 (1074P), ix352 (1076P), ix352<br />
(1079P), ix451 (1384P), ix70 (157P)<br />
RNA sequencing, ix57 (100IN)<br />
RNA, ix76 (177PD)<br />
RO4929097, ix155 (448PD), ix156 (450PD)<br />
RON, ix495 (1532P)<br />
ROS1, ix389 (1191PD), ix81 (195P)<br />
round robin panel testing, ix394 (1208)<br />
Rrca1 mutant breast cancer mouse models, ix108<br />
(290P)<br />
RRM 1, ix67 (144PD)<br />
S<br />
S-1 plus cisplatin, ix404 (1234PD)<br />
S-1 plus oxaliplatin, ix256 (779TiP), ix326 (989P)<br />
s-1 plus paclitaxel, ix256 (779TiP)<br />
S-1, ix385 (1181PD), ix436 (1334), ix193 (566P),<br />
ix197 (576P), ix224 (668PD), ix225 (671P),<br />
ix232 (695P), ix241 (728P), ix250 (758)<br />
S1, ix217 (646)<br />
safety and tolerability, ix403 (1231PD), ix163<br />
(471P), ix240 (721P)<br />
safety, cardio-toxicity, ix164 (476P)<br />
safety, ix366 (1124P), ix402 (1230PD), ix419<br />
(1277P), ix508 (1576P), ix516 (1604P), ix114<br />
(315TiP), ix171 (499P), ix173 (507), ix224<br />
(668PD), ix262 (795PD), ix308 (936P)<br />
salivary duct carcinoma, ix344 (1706P)<br />
salvage chemo<strong>the</strong>rapy N, ix375 (1153)<br />
salvage chemo<strong>the</strong>rapy, ix63 (126IN), ix285 (860P)<br />
sample size calculation, ix450 (1380P)<br />
sarcoma, ix481 (1487P), ix482 (1488P), ix485<br />
(1500P), ix485 (1501P), ix486 (1502P), ix486<br />
(1504P), ix487 (1505P), ix489 (1514), ix490<br />
(1517TiP), ix21 (1IN), ix166 (482P), ix54<br />
(91IN), ix54 (92IN), ix55 (94IN)<br />
satisfaction, ix511 (1584P)<br />
SCCHN, ix334 (1018O)<br />
schwannoma, ix150 (432)<br />
SCLC, ix492 (1519PD), ix494 (1529P), ix498<br />
(1543TiP)<br />
screening process, ix53 (88IN)<br />
screening tools, ix452 (1386P)<br />
screening, ix456 (1402P), ix472 (1456P), ix252<br />
(767)<br />
second line <strong>the</strong>rapy, ix438 (1342), ix497 (1540),<br />
ix203 (597P), ix213 (632), ix242 (731P), ix265<br />
(804P), ix277 (837P), ix314 (955)<br />
second line, ix251 (761)<br />
second-line chemo<strong>the</strong>rapy, ix381 (1171P), ix429<br />
(1306P), ix230 (688P), ix233 (697P)<br />
second-line <strong>the</strong>rapy, ix419 (1276P), ix232 (692P),<br />
ix280 (846P)<br />
second-line treatment, ix400 (1225O)<br />
second-line, ix438 (1341)<br />
secondary prophyalaxis, ix499 (1547PD)<br />
secondary resection, ix190 (557P)<br />
SEER-Medicare, ix205 (603P)<br />
selective targeted drug, ix32 (29IN)<br />
aelumetinib, ix403 (1233PD)<br />
seminoma Stage 1, ix283 (857P)<br />
Annals of Oncology<br />
seminoma, ix284 (859P), ix286 (867P)<br />
semuloparin, ix543 (1697P)<br />
sensitive EGFR mutations, ix391 (1198P)<br />
sensitivity analyses trabectedin progression-free<br />
survival, ix324 (984P)<br />
sentinel lymph node, ix112 (307)<br />
sentinel node, ix106 (284P)<br />
sequencing, ix38 (47IN)<br />
sequential adjuvant chemo<strong>the</strong>rapy, ix129 (360P)<br />
sequential treatment, ix97 (253PD), ix272 (824P),<br />
ix278 (840P), ix290 (881), ix314 (952), ix315<br />
(958)<br />
sequential, ix289 (876)<br />
Serbian patients, ix428 (1304P)<br />
serial evaluation, ix341 (1042P)<br />
SERM, ix28 (17IN)<br />
serous borderline tumor, ix322 (977P)<br />
serous ovarian carcinoma, ix319 (969PD)<br />
serum albumin levels, ix356 (1091P)<br />
serum chromogranin-A, ix301 (912P)<br />
serum HER2, ix136 (386)<br />
serum tumor markers, ix80 (192P)<br />
serum, ix78 (184P)<br />
sex hormone binding globulin, ix304 (923P)<br />
sex, ix455 (1396P)<br />
sexual dysfunctions, ix474 (1463P)<br />
sexuality, ix477 (1476)<br />
shared, ix475 (1469P)<br />
SHH, ix31 (25IN)<br />
short chain fatty acid, ix200 (585P)<br />
short-time infusion, ix203 (598P)<br />
side-effects, ix518 (1610P), ix526 (1643)<br />
signaling pathways, ix541 (1690P), ix40 (56IN)<br />
signet ring cell, ix89 (225P), ix184 (541P), ix249<br />
(753)<br />
simultaneous resection, ix201 (589P)<br />
simvastatin, ix72 (165)<br />
single agent, ix398 (1220)<br />
single institutional review, ix133 (373P)<br />
single nucleotide polymorphism (SNP), ix434<br />
(1326), ix528 (1646PD), ix85 (208P), ix92 (235),<br />
ix209 (615), ix246 (742P)<br />
sipuleucel-t, ix38 (46IN), ix310 (939P), ix310<br />
(940P), ix310 (941P), ix311 (942P), ix311<br />
(943P), ix313 (949)<br />
siRNA (short-interfering RNA), ix536 (1673P)<br />
skeletal–related events, ix447 (1372P), ix524<br />
(1633)<br />
skeletal-related event (SRE), ix360 (1108TiP),<br />
ix449 (1377P)<br />
skin toxicity, ix426 (1298P), ix435 (1328), ix514<br />
(1597P), ix192 (563P)<br />
skin-test infiltrating lymphocytes, ix363 (1114PD)<br />
sleep difficulties, ix474 (1465P)<br />
SMAD7, ix209 (615)<br />
small bowel adenocarcinoma, ix234 (703P)<br />
small breast cancer, ix111 (303)<br />
small cell cancer, ix291 (886)<br />
small cell lung cancer (SCLC), ix492 (1520PD),<br />
ix493 (1525P), ix494 (1526P), ix494 (1527P),<br />
ix497 (1540)<br />
small cell lung cancer, ix493 (1523P), ix495<br />
(1530P)<br />
small molecule, ix32 (29IN)<br />
small tumors, ix104 (276P)<br />
smoking status, ix412 (1257P), ix420 (1280P),<br />
ix455 (1396P), ix469 (1448PD)<br />
SN-38, ix167 (485P)<br />
SNPs, ix339 (1032P), ix243 (734P)<br />
socio-econonomic status, ix165 (479P)<br />
SOCS (suppressor of cytokine signaling), ix69<br />
(153P)<br />
sodium folinic acid (S-FA), ix185 (542P)<br />
soft tissue sarcoma, ix483 (1493P), ix484 (1496P),<br />
ix486 (1503P), ix487 (1506P), ix54 (91IN)<br />
soft tissue sarcomas, ix485 (1498P), ix489 (1512)<br />
solid and haematological malignancies, ix520<br />
(1617), ix524 (1631)<br />
ix598 | subject index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals of Oncology subject index<br />
solid tumor, ix503 (1559P)<br />
solid tumors, ix59 (108IN), ix452 (1387P), ix83<br />
(203P), ix154 (443PD), ix160 (461P), ix165<br />
(478P), ix166 (482P), ix169 (494P), ix170<br />
(498P), ix303 (921P)<br />
solitary brain metastasis, ix425 (1294P)<br />
somatic mutation#melanoma, DNA sequencing,<br />
ix25 (11IN)<br />
somatic mutation, ix430 (1311P)<br />
somatostatin analogs, ix380 (1165P), ix146<br />
(419PD)<br />
somatostatin receptor expression, ix379 (1164P)<br />
somatostatin receptor, ix47 (74IN)<br />
sorafenib, ix407 (1241P), ix63 (124IN), ix440<br />
(1349), ix444 (1362TiP), ix453 (1390P), ix483<br />
(1491P), ix487 (1506P), ix519 (1615P), ix536<br />
(1674P), ix91 (229P), ix155 (447PD), ix161<br />
(466P), ix194 (569P), ix220 (654), ix225<br />
(670PD), ix243 (734P), ix244 (736P), ix253<br />
(769), ix255 (777TiP), ix255 (778TiP), ix270<br />
(817P), ix279 (844P), ix283 (856P), ix287 (872),<br />
ix288 (874)<br />
Spanish Melanoma Group (GEM), ix374 (1150)<br />
speckle tracking echocardiography, ix164 (476P)<br />
squamous carcinoma head and neck, ix336<br />
(1023PD)<br />
squamous cell cancer of <strong>the</strong> skin, ix372 (1144)<br />
squamous cell carcinoma of head and neck<br />
(SSCHN), ix336 (1022PD)<br />
squamous cell carcinoma, ix174 (509TiP), ix328<br />
(997P)<br />
Src, ix540 (1686P), ix172 (501)<br />
stage 1 gastric cancer, ix227 (679P)<br />
stage I adenocarcinoma of <strong>the</strong> lung, ix387 (1186P)<br />
stage II colon cancer, ix188 (551P), ix210 (621)<br />
stage III, ix49 (79IN)<br />
stage IIIB non-small cell lung cancer, ix392<br />
(1202P)<br />
stage IV colon cancer, ix214 (634)<br />
stage IV, ix409 (1249P)<br />
staging, ix106 (283P)<br />
statistical analysis, ix449 (1378P)<br />
stem cells, ix354 (1086P), ix110 (300), ix146<br />
(418PD), ix205 (604P), ix299 (906P)<br />
stereotactic radiosurgery, ix62 (123IN)<br />
stereotactic radio<strong>the</strong>rapy, ix62 (123IN)<br />
steroid sulphatase inhibitor, ix329 (1001P)<br />
steroidogenesis, ix306 (928P)<br />
STK11, ix77 (180P)<br />
stomach cancer, ix512 (1589P), ix541 (1688PD)<br />
stomach, ix351 (1075P)<br />
stromal cell, ix107 (287P), ix184 (540P)<br />
structural equation modeling, ix511 (1586P)<br />
subcutaneous trastuzumab, ix97 (254PD), ix103<br />
(272P), ix114 (315TiP)<br />
subcutaneous, ix103 (273P), ix162 (470P)<br />
subtypes, ix250 (756)<br />
subtyping NSCLC, ix425 (1295P)<br />
suicide ideation, ix512 (1589P)<br />
sunitinib, patient-reported outcomes, ix269 (815P)<br />
sunitinib, ix376 (1155O), ix482 (1490P), ix484<br />
(1495P), ix484 (1496P), ix519 (1615P), ix538<br />
(1678P), ix91 (229P), ix235 (705P), ix240<br />
(724P), ix259 (785O), ix276 (835P), ix283<br />
(854P), ix262 (794PD), ix263 (797PD), ix271<br />
(820P), ix273 (826P), ix273 (827P), ix274<br />
(829P), ix275 (832P), ix281 (847P), ix281<br />
(849P), ix281 (850P), ix282 (851P), ix287 (870),<br />
ix287 (872), ix292 (889TiP), ix293 (892TiP),<br />
ix290 (881)<br />
supportive care, ix64 (128IN)<br />
supportive <strong>the</strong>rapy, ix425 (1297P), ix518 (1611P),<br />
ix284 (858P)<br />
surgery, ix329 (1003P), ix496 (1536P), ix131<br />
(368P), ix35 (38IN), ix217 (644), ix229 (684P),<br />
ix49 (79IN)<br />
surgical immunology, ix202 (595P)<br />
surgical nutriology, ix202 (595P)<br />
surgical resection, ix388 (1189P), ix182 (531P)<br />
surgical treatment, ix342 (1045P)<br />
surrogate decision-making, ix475 (1469P)<br />
surveillance, ix292 (887)<br />
survey, ix450 (1381P), ix110 (297P), ix229 (685P)<br />
survival analysis, ix370 (1134P), ix380 (1167P),<br />
ix439 (1345), ix494 (1529P), ix145 (414PD),<br />
ix175 (512PD), ix201 (589P), ix327 (996P)<br />
survival outcome, ix392 (1202P), ix393 (1204P)<br />
survival prediction factors, ix149 (429P)<br />
survival, ix350 (1069PD), ix387 (1185P), ix421<br />
(1281P), ix455 (1398P), ix487 (1507P), ix511<br />
(1586P), ix101 (266P), ix131 (368P), ix149<br />
(431), ix188 (553P), ix189 (555P), ix226 (674P),<br />
ix233 (699P), ix248 (749), ix298 (903P), ix319<br />
(967O), ix327 (994P)<br />
Survivin, ix323 (979P)<br />
symptom assessment, ix141 (403)<br />
symptom management, ix64 (129IN)<br />
symptom, ix517 (1607P)<br />
symptoms, ix421 (1281P), ix459 (1413TiP)<br />
synchronous hepatic metastases, ix201 (589P)<br />
systematic review, ix450 (1379P), ix123 (341P)<br />
systemic chemo<strong>the</strong>rapy, ix202 (593P), ix213 (631)<br />
systemic immunoglobulin light-chain amyloidosis,<br />
ix355 (1089P)<br />
systemic inflammation, ix381 (1169P)<br />
systems biology, ix535 (1668P)<br />
T<br />
3D cell culture, ix543 (1695P)<br />
3D interactive digital anatomy, ix346 (1060)<br />
3D radio<strong>the</strong>rapy, ix114 (314)<br />
3D-Q-FISH, ix350 (1071P)<br />
3rd line, ix493 (1525P)<br />
T-DM1, ix89 (226P), ix120 (329P)<br />
T790M mutation, ix418 (1273P)<br />
TACE, ix371 (1140P)<br />
TAK-441, ix156 (449PD)<br />
TAK-700, docetaxel, ix302 (918P)<br />
TAK1/p38 MAPK, ix126 (348P)<br />
tamoxifen, ix109 (295P), ix136 (384)<br />
target lesion, ix276 (834P)<br />
target <strong>the</strong>rapies, ix345 (1053), ix66 (140IN)<br />
target <strong>the</strong>rapy, ix40 (56IN)<br />
targeted agent, ix276 (836P)<br />
targeted agents, ix31 (26IN)<br />
targeted <strong>the</strong>rapies, ix334 (1017O), ix379 (1163P),<br />
ix380 (1165P), ix519 (1614P), ix34 (36IN), ix39<br />
(50IN), ix39 (53IN), ix23 (5IN), ix43 (63IN),<br />
ix46 (70IN), ix270 (818P), ix272 (824P), ix52<br />
(85IN), ix55 (94IN), ix321 (975PD)<br />
targeted <strong>the</strong>rapy, ix51 (81IN), ix32 (28IN), ix44<br />
(66IN), ix23 (6IN), ix271 (819P), ix289 (877)<br />
targeted treatment, ix54 (92IN)<br />
targeted, ix267 (810P), ix269 (816P)<br />
taxane, ix407 (1242P)<br />
taxanes, ix325 (985P)<br />
taxotere chemo<strong>the</strong>rapy, ix298 (904P)<br />
TCF dose-dense, ix232 (693P)<br />
teamwork, ix477 (1475)<br />
TEC, ix501 (1552P)<br />
temozolomide, ix147 (424P), ix366 (1126P), ix446<br />
(1368TiP), ix494 (1529P), ix540 (1686P), ix144<br />
(410O)<br />
temsirolimus, ix336 (1023PD), ix359 (1107TiP),<br />
ix156 (450PD), ix160 (462P), ix239 (717P),<br />
ix274 (828P), ix277 (839P), ix280 (846P), ix290<br />
(879)<br />
teratoma, ix286 (864P)<br />
tesetaxel, ix165 (481P), ix167 (486P)<br />
testicular cancer, ix261 (790O)<br />
testicular germ cell cancer, ix286 (865P)<br />
testicular nonseminomatous germ cell tumor<br />
(NSGCT), ix284 (858P)<br />
testis cancer, ix286 (866P)<br />
testosterone prostate cancer chemo<strong>the</strong>rapy, ix299<br />
(908P)<br />
testosterone, ix304 (923P)<br />
tetraploidy, ix31 (25IN)<br />
TGase-2, ix274 (830P)<br />
TGF-ß (transforming growth factor beta), ix209<br />
(615)<br />
TGF, ix81 (197P)<br />
TH-302, ix224 (666O)<br />
<strong>the</strong>oretical model, ix476 (1473P)<br />
<strong>the</strong>ragnostics, ix32 (27IN)<br />
<strong>the</strong>rapeutic target, ix532 (1660P)<br />
<strong>the</strong>rapeutic targets, ix536 (1673P)<br />
<strong>the</strong>rapeutic vaccine, ix406 (1238PD)<br />
<strong>the</strong>rapy-related, ix357 (1096)<br />
third- or fourth-line chemo<strong>the</strong>rapy, ix443 (1358)<br />
third- or fourth-line treatment, ix440 (1349)<br />
third-line <strong>the</strong>rapy, ix276 (836P)<br />
third-line treatment, ix424 (1292P)<br />
third-line, ix251 (762)<br />
thoracic oncology, ix515 (1598P)<br />
thoracic radio<strong>the</strong>rapy, ix396 (1215)<br />
thoracic tumours, ix497 (1539P)<br />
three cytotoxic agents SCLC, ix493 (1524P)<br />
three year imatinib, ix235 (706P)<br />
thrombin generation, ix543 (1697P)<br />
thrombocytopenia, ix506 (1570P)<br />
thromboembolic disease, ix519 (1616P)<br />
thromboembolism, ix519 (1616P)<br />
thromboses, ix356 (1094)<br />
thrombosis, ix515 (1599P)<br />
thymic carcinoma, ix497 (1537P), ix498 (1541)<br />
thymic epi<strong>the</strong>lial tumor, ix498 (1541)<br />
thymic epi<strong>the</strong>lial tumors, ix540 (1687)<br />
thymic tumors, ix496 (1536P)<br />
thymidine kinase 1, ix88 (220P), ix217 (645)<br />
thymidylate synthase (TS), ix407 (1242P)<br />
thymoma, ix498 (1541)<br />
thyroid cancer, ix344 (1050P)<br />
thyroid dysfunction, ix525 (1636)<br />
thyroid tumor, ix517 (1608P)<br />
time from prior chemo<strong>the</strong>rapy, ix265 (804P)<br />
time of disease control, ix332 (1014)<br />
time to progression, ix80 (194P)<br />
time to QoL deterioration, ix120 (331P)<br />
time-dependent analysis, ix420 (1279P)<br />
time-trend, ix365 (1120P)<br />
TIMPs, ix67 (146P)<br />
tissue microarray, ix276 (835P)<br />
tissue repository, ix61 (117IN)<br />
tivantinib, ix424 (1293P), ix225 (669PD), ix244<br />
(738P), ix245 (739P)<br />
tivozanib, ix262 (795PD), ix263 (796PD)<br />
TJ-14, ix514 (1595P)<br />
TKI, ix440 (1348), ix290 (881)<br />
TKIs, ix51 (82IN), ix290 (881)<br />
TNBC metastaticum first line tretment, ix137<br />
(390)<br />
TNF-a (tumor necrosis factor alpha), ix486<br />
(1504P)<br />
TNM classification, ix388 (1188P), ix414 (1262P)<br />
TNM, ix385 (1179O)<br />
tobacco habit, ix343 (1049P)<br />
tobacco smoking, ix472 (1458P)<br />
tocilizumab, ix69 (153P)<br />
tolerability, ix238 (714P), ix267 (810P), ix280<br />
(845P)<br />
toll-like receptor agonist, ix342 (1044P)<br />
topoisomerase I, ix167 (485P)<br />
topotecan, ix492 (1520PD), ix494 (1529P)<br />
total body irradiation, ix354 (1084P)<br />
total lesion glycolysis, ix199 (584P)<br />
toxicities, ix64 (131IN)<br />
toxicity score, ix354 (1085P)<br />
toxicity, ix342 (1044P), ix346 (1057), ix460<br />
(1416PD), ix500 (1549PD), ix519 (1614P), ix168<br />
(491P), ix181 (530PD), ix219 (650), ix229<br />
(683P), ix273 (826P)<br />
TP53, ix234 (703P)<br />
TPF, ix341 (1041P), ix344 (1051)<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds467 | ix599
subject index<br />
TR-FRET, ix84 (206P)<br />
trabectedin, ix490 (1517TiP)<br />
training, ix65 (133IN)<br />
transarterial chemoembolization, ix161 (466P),<br />
ix243 (732P)<br />
transforming alteration, ix61 (119IN)<br />
translational research, ix336 (1021PD), ix451<br />
(1383P), ix535 (1668P), ix535 (1669P), ix42<br />
(58IN), ix224 (667PD), ix300 (911P)<br />
transplantation-related malignancy, ix459 (1410)<br />
trastuzumab her2 small tumors, ix104 (275P)<br />
trastuzumab resistance, ix528 (1645PD)<br />
trastuzumab retreatment, ix139 (396)<br />
trastuzumab, ix58 (104IN), ix455 (1397P), ix94<br />
(243), ix101 (267P), ix103 (273P), ix103 (274P),<br />
ix104 (276P), ix112 (308), ix113 (309), ix116<br />
(318O), ix124 (343P), ix124 (344P), ix125<br />
(346P), ix138 (391), ix142 (406TiP), ix162<br />
(470P), ix233 (699P)<br />
treatment across multiple lines, ix190 (559P),<br />
ix193 (565P), ix195 (571P)<br />
treatment algorithm, ix52 (85IN)<br />
treatment beyond progression, ix440 (1347), ix190<br />
(559P), ix193 (565P), ix195 (571P)<br />
treatment duration, ix188 (552P)<br />
treatment failure, ix345 (1056)<br />
treatment monitoring, ix483 (1492P)<br />
treatment patterns, ix451 (1384P)<br />
treatment selection, ix407 (1242P)<br />
treatment-use, ix482 (1490P)<br />
treatment, ix359 (1104), ix458 (1408), ix488<br />
(1511P), ix315 (957)<br />
tregs, ix431 (1314)<br />
trial design, ix31 (26IN), ix55 (94IN)<br />
trial in progress, ix57 (101IN), ix174 (1708PD),<br />
ix347 (1061TiP), ix359 (1107TiP), ix360<br />
(1108TiP), ix444 (1362TiP), ix445 (1364TiP),<br />
ix445 (1365TiP), ix445 (1366TiP), ix446<br />
(1367TiP), ix446 (1368TiP), ix459 (1413TiP),<br />
ix460 (1414TiP), ix490 (1517TiP), ix490<br />
(1518TiP), ix493 (1522PD), ix498 (1542TiP),<br />
ix498 (1543TiP), ix119 (325PD), ix141<br />
(405TiP), ix142 (406TiP), ix142 (407TiP), ix142<br />
(409TiP), ix150 (435TiP), ix151 (437TiP), ix153<br />
(441O), ix156 (451P), ix157 (452P), ix170<br />
(498P), ix172 (501), ix174 (509TiP), ix174<br />
(510TiP), ix222 (662TiP), ix222 (663TiP), ix223<br />
(664TiP), ix223 (665TiP), ix225 (670PD), ix255<br />
(776TiP), ix255 (777TiP), ix255 (778TiP), ix256<br />
(779TiP), ix256 (780TiP), ix256 (781TiP), ix257<br />
(782TiP), ix292 (889TiP), ix293 (890TiP), ix293<br />
(891TiP), ix293 (892TiP), ix316 (962TiP), ix317<br />
(963TiP), ix317 (965TiP), ix321 (974PD)<br />
trials in progress, ix114 (315TiP), ix115 (316TiP),<br />
ix142 (408TiP), ix211 (622), ix317 (964TiP),<br />
ix322 (978P)<br />
trigger tools, ix456 (1400P)<br />
triple negative breast cancer, ix84 (205P), ix29<br />
(20IN), ix29 (21IN), ix29 (22IN), ix98 (257P),<br />
ix99 (260P), ix132 (370P), ix135 (381), ix140<br />
(401), ix175 (513PD)<br />
triple negative, ix102 (270P)<br />
triple-negative breast cancer (TNBC), ix99 (258P),<br />
ix134 (378)<br />
TrkB, ix79 (188P)<br />
TS-1, ix250 (757)<br />
TSU-68, ix243 (732P)<br />
TTF1, ix77 (181P)<br />
tumor antigen, ix386 (1182P)<br />
Tumor Associated Macrophages (TAM), ix538<br />
(1681P)<br />
tumor cell division, ix111 (301)<br />
tumor endo<strong>the</strong>lial cells, ix76 (178P)<br />
tumor growth rate, ix198 (579P)<br />
tumor marker, ix93 (239)<br />
tumor markers, ix123 (339P)<br />
tumor metabolism, ix339 (1033P)<br />
tumor response, ix535 (1670P)<br />
tumor tolerance, ix303 (919P)<br />
tumor treating fields (TTFields), ix396 (1214)<br />
tumor volume, ix188 (554P)<br />
tumour response, ix60 (112IN)<br />
tumour, ix458 (1408), ix190 (558P)<br />
tyrosine kinase inhibitor (TKI), ix413 (1261P),<br />
ix478 (1478O), ix83 (203P), ix154 (445PD),<br />
ix163 (471P), ix169 (492P), ix169 (493P), ix244<br />
(737P), ix270 (818P)<br />
tyrosine kinase inhibitors (TKIs), ix480 (1482PD),<br />
ix144 (412O), ix261 (792PD)<br />
tyrosine kinase receptor, ix154 (445PD)<br />
U<br />
U3-1287, ix161 (467P)<br />
ubidecaranone, ix166 (482P)<br />
UFT, ix188 (552P)<br />
uncommon EGFR mutations, ix410 (1252P)<br />
undifferentiated pleomorphic sarcoma, ix485<br />
(1499P)<br />
unresectable colorectal liver metastases, ix35<br />
(39IN)<br />
unresectable liver metastases, ix194 (568P), ix205<br />
(605P)<br />
upper esophageal carcinoma, ix247 (745P)<br />
upper tract uro<strong>the</strong>lial cancer, ix292 (887)<br />
uracil-tegafur (UFT), ix185 (542P), ix197 (576P)<br />
ureteric cancer, ix292 (887)<br />
urinary bladder, ix291 (883)<br />
urine, ix144 (411O)<br />
uro<strong>the</strong>lial bladder carcinoma, ix93 (240)<br />
uro<strong>the</strong>lial cancer, ix88 (222P), ix266 (806P)<br />
uro<strong>the</strong>lial carcinoma, ix39 (50IN), ix260 (787O),<br />
ix265 (804P)<br />
uterine leiomyosarcoma, ix332 (1015)<br />
utility, ix372 (1143P)<br />
uveal melanoma, ix370 (1136P), ix371 (1140P),<br />
ix374 (1149), ix90 (227P)<br />
V<br />
vaccine, ix503 (1558P), ix159 (460P)<br />
vaginal brachy<strong>the</strong>rapy, ix329 (1002P)<br />
valproic acid, ix147 (423P)<br />
vascular disrupting agent, ix410 (1250P)<br />
vascular endo<strong>the</strong>lial growth factor (VEGF), ix353<br />
(1080P)<br />
vascular endo<strong>the</strong>lial growth factor receptor<br />
(VEGFR), ix376 (1154O), ix186 (545P), ix271<br />
(821P)<br />
vascular endo<strong>the</strong>lial growth factor, ix249 (752)<br />
vascular invasion, ix387 (1184P)<br />
vascular permeability factor (VPF), ix59 (109IN)<br />
VEGF inhibitor, ix146 (417PD), ix277 (837P)<br />
VEGF receptor inhibitor, ix173 (505)<br />
VEGF-targeted <strong>the</strong>rapy, ix258 (783O), ix264<br />
(798PD), ix278 (841P), ix278 (842P)<br />
VEGF-trap, ix198 (581P), ix214 (633)<br />
VEGF, ix540 (1687), ix75 (174O), ix78 (184P),<br />
ix81 (197P), ix108 (292P), ix248 (751), ix274<br />
(829P), ix54 (91IN)<br />
VEGFR-2, ix422 (1287P)<br />
VEGFR, ix540 (1687)<br />
veliparib, ix148 (428P)<br />
VELOUR Study, ix198 (581P)<br />
vemurafenib, ix366 (1124P), ix366 (1125P)<br />
venous thromboembolic disease, ix543 (1697P)<br />
venous thromboembolism, ix447 (1369P), ix56<br />
(98IN)<br />
VeriStrat, ix407 (1241P)<br />
vinorelbine, ix346 (1058), ix498 (1542TiP), ix138<br />
(393), ix138 (394)<br />
virus infection, ix71 (162P)<br />
vismodegib, ix362 (1111PD), ix362 (1112PD)<br />
visual effects, ix416 (1268P)<br />
vitamin D3, ix526 (1642)<br />
vitamin D, ix454 (1395P)<br />
vorinostat, ix234 (700P)<br />
vulnerability, ix477 (1475)<br />
W<br />
Warburg, ix71 (160P)<br />
WB DWI, ix344 (1050P)<br />
web-based network, ix327 (993P)<br />
weekly paclitaxel, ix398 (1221)<br />
weight gain, breast cancer, ix95 (248O)<br />
weight loss, ix520 (1620), ix541 (1689P)<br />
Wer<strong>the</strong>im surgery, ix330 (1007)<br />
Wer<strong>the</strong>im surgery post chemoradiation, ix330<br />
(1007)<br />
wild type EGFR, ix424 (1292P), ix439 (1346),<br />
ix445 (1366TiP)<br />
willingness to pay, ix122 (338P)<br />
window study, ix336 (1021PD), ix42 (58IN)<br />
Wnt signaling pathway, ix544 (1700), ix209 (617)<br />
Wnt, ix43 (62IN)<br />
WT1, ix496 (1533P)<br />
X<br />
XELOX, ix187 (550P)<br />
Annals of Oncology<br />
Y<br />
Y90-ibritumomab tiuxetan, ix351 (1073P)<br />
young adults, ix490 (1515)<br />
Young CLL, ix358 (1101)<br />
young women, ix455 (1398P), ix100 (264P)<br />
young, ix101 (265P)<br />
yttrium-90 microsphere radioembolization (SIRT),<br />
ix480 (1484PD), ix244 (735P)<br />
zeb, ix67 (145P)<br />
zoledronic acid, ix509 (1580P), ix510 (1583P),<br />
ix511 (1584P), ix526 (1641)<br />
ix447 (1369P)<br />
ix600 | subject index Volume 23 | Supplement 9 | September <strong>2012</strong>
drug index<br />
17AAG: 156P<br />
2CdA: 1076P<br />
3-Aminobenzamide: 988P<br />
5-Azacytidine: 1096P<br />
5-Fluorouracil: 39IN, 42IN, 155P, 208P, 209P,<br />
224P, 228P, 245O, 246O, 253PD, 267P, 269P,<br />
333P, 360P, 377, 373P, 390, 452P, 458P, 460P,<br />
515P, 518O, 519O, 520O, 523PD, 524PD,<br />
527PD, 529PD, 542P, 543P, 547P, 550P, 557P,<br />
558P, 560P, 561P, 564P, 567P, 568P, 570P, 573P,<br />
577P, 580P, 581P, 586P, 587P, 590P, 591P, 592P,<br />
597P, 599P, 600P, 601P, 602P, 603P, 607P, 610P,<br />
618, 620, 624, 627, 633, 634, 635, 637, 639, 640,<br />
643, 650, 653, 655, 656, 657, 659, 661, 662TiP,<br />
665TiP, 668PD, 672P, 683P, 686P, 689P, 690P,<br />
693P, 695P, 696P, 701P, 710P, 711P, 714P, 715P,<br />
716P, 721P, 726P, 730P, 731P, 745P, 749, 753,<br />
760, 762, 782TiP, 989P, 1018O, 1020PD, 1028P,<br />
1034P, 1035P, 1036P, 1037P, 1038P, 1039P,<br />
1040P, 1041P, 1044P, 1045P, 1051, 1054, 1057,<br />
1159P, 1595P, 1161P, 1644PD<br />
AAV-HGFK1: 348P<br />
Abiraterone acetate: 47IN, 53IN, 325P, 894O,<br />
895O, 897O, 918P, 920P, 924P, 925P, 926P, 946,<br />
951, 958, 964TiP, 920P, 924P, 946, 950<br />
ABT-510: 505<br />
ABT-751: 505<br />
AEE788: 1652P<br />
Afatinib: 7IN, 78IN, 446PD, 464P, 468P, 478P,<br />
494P, 509TiP, 1227O, 1229PD, 1232PD, 1252P,<br />
1288P, 1292P, 1288P, 1339<br />
Aflibercept: 53IN, 581P, 597P, 633<br />
Alemtuzumab: 1095<br />
Allo-aca: 483P<br />
Allopurinol: 1103<br />
Alpharadin: 53IN<br />
Altretamine: 986P<br />
Amatuximab: 1522PD<br />
AMEP: 1139P<br />
AMG 102: 687P<br />
AMG 386: 975PD<br />
AMG 479: 776TiP<br />
Amrubicin: 235, 1358, 1519PD<br />
Anastrozole: 280P, 310, 341P, 407TiP<br />
AP26113: 7IN, 439O<br />
APC8015F: 941P<br />
APD421: 1573P<br />
Aprepitant: 721P, 1550PD, 1571P, 1578P, 1579P<br />
ARN-509: 920P, 964TiP<br />
ARQ 197: 7IN, 669PD, 1293P, 669PD, 1293P<br />
AS703026: 7IN<br />
ASG-5ME: 963TiP<br />
ASP 3026: 7IN<br />
AT-101: 901PD<br />
AUY922: 438O, 1679P<br />
Axitinib: 43IN, 53IN, 793PD, 811P, 824P, 843P,<br />
856P, 1246P, 1391P, 1391P, 1615P<br />
AZD0530: 1686P<br />
AZD4547: 7IN<br />
BCNU: 1147<br />
Belinostat: 1068PD<br />
Belotecan: 1520PD<br />
Bendamustine: 65IN, 1064O<br />
Bevacizumab: 18IN, 21IN, 24IN, 39IN, 43IN,<br />
53IN, 54IN, 57IN, 76IN, 78IN, 95IN, 105IN,<br />
115IN, 126IN, 154P, 155P, 174O, 194P, 198P,<br />
200P, 208P, 209P, 241, 292P, 317O, 323PD,<br />
335P, 337P, 345P, 354P, 355P, 356P, 395, 400,<br />
417PD, 435TiP, 437TiP, 452P, 464P, 499P,<br />
518O, 530PD, 532P, 555P, 559P, 560P, 562P,<br />
565P, 567P, 571P, 573P, 577P, 592P, 593P, 594P,<br />
596P, 597P, 600P, 602P, 603P, 607P, 618, 624,<br />
629, 633, 634, 635, 642, 648, 651, 652, 653, 654,<br />
655, 659, 663TiP, 755, 783O, 793PD, 809P,<br />
810P, 816P, 818P, 824P, 837P, 840P, 846P, 876,<br />
877, 966O, 967O, 973PD, 978P, 986P, 1159P,<br />
1160P, 1165P, 1194P, 1224O, 1236PD, 1239P,<br />
1240P, 1242P, 1246P, 1264P, 1277P, 1278P,<br />
1279P, 1287P, 1297P, 1299P, 1302P, 1303P,<br />
1327, 1329, 1335, 1351, 1352, 1353, 1364TiP,<br />
1365TiP, 1370P, 1373P, 1615P, 1648P, 1653P,<br />
1657P<br />
Bicalutamide: 48IN, 929P<br />
Biosimilar epoetin zeta: 1563P<br />
Biosimilar filgrastim: 1555P, 1624<br />
Biosimilar G-CSF: 1557P<br />
BJG398: 7IN<br />
BKM 120: 7IN, 318O, 454P, 457P, 664TiP, 1675P<br />
Bleomycin: 862P, 888, 1046P, 1061TiP, 1071P,<br />
1152, 1539P, 1061TiP<br />
Blinotumumab: 68IN<br />
BMS-36558: 453P<br />
BMS-936558: 459P, 784O, 1109O, 1237PD<br />
Bortezomib: 66IN, 68IN, 754, 1064O,<br />
1088P,1064O, 1088, 1622<br />
BPM 31510: 482P<br />
Brentixumab: 68IN, 1063O, 1083P<br />
Brivanib: 966O<br />
Budesonide: 1116PD<br />
Buserelin: 928P<br />
BYL 719: 7IN, 350P<br />
Cabazitaxel: 47IN, 53IN, 497P, 897O, 931P, 932P,<br />
933P, 946, 948, 951, 953, 955, 956, 958, 960,<br />
962TiP<br />
Cabozantinib: 7IN, 445PD, 840P, 897O<br />
CAL 101: 68IN<br />
Capecitabine: 21IN, 121IN, 154P, 209P, 245O,<br />
317O, 330P, 355P, 356P, 358P, 391, 394, 397,<br />
398, 399, 401, 452P, 496P, 518O, 519O, 524PD,<br />
526PD, 527PD, 530PD, 532P, 538P, 550P, 560P,<br />
562P, 566P, 569P, 586P, 588P, 592P, 600P, 601P,<br />
605P, 608P, 609P, 622, 635, 640, 647, 653,<br />
663TiP, 667PD, 683P, 687P, 700P, 718P, 722P,<br />
731P, 736P, 754, 757, 759, 770, 781TiP, 782TiP,<br />
1160P, 1161P, 1169P, 1355, 1591P, 1594P,<br />
1595P, 1648P, 1703IN<br />
Carboplatin: 55IN, 80IN, 154P, 168O, 175PD,<br />
191P, 194P, 202P, 430P, 433, 437TiP, 505, 754,<br />
789O, 799P, 857P, 859P, 863P, 866P, 867P, 887,<br />
908P, 952, 967O, 972PD, 973PD, 975PD, 978P,<br />
985P, 986P, 991P, 995P, 997P, 1004P, 1009,<br />
1010, 1017O, 1035P, 1037P, 1040P, 1153,<br />
1062O, 1183P, 1200P, 1204P, 1206P, 1218, 1221,<br />
1224O, 1226O, 1236PD, 1239P, 1240P, 1242P,<br />
1245P, 1246P, 1250P, 1255P, 1256P, 1259P,<br />
1276P, 1285P, 1287P, 1297P, 1299P, 1301P,<br />
1303P, 1326, 1334, 1352, 1357, 1361, 1363TiP,<br />
1365TiP, 1444, 1526P, 1527P, 1529P, 1543TiP,<br />
1625<br />
Catumaxomab: 459P, 504, 680P, 1596P, 1683P<br />
Cediranib: 54IN, 448PD, 501, 609P, 840P, 877,<br />
840P<br />
Celecoxib: 1422O, 1594P<br />
Cetuximab: 28IN, 29IN, 43IN, 53IN, 58IN, 62IN,<br />
78IN, 80IN, 126IN, 143PD, 210P, 214P, 218P,<br />
237, 520O, 525PD, 526PD, 535P, 536P, 543P,<br />
557P, 561P, 563P, 568P, 572P, 574P, 580P, 582P,<br />
594P, 598P, 599P, 603P, 606P, 608P, 630, 631,<br />
634, 643, 649, 652, 654, 659, 696P, 755, 804P,<br />
1018O, 1020PD, 1021PD, 1022PD, 1023PD,<br />
1027P, 1036P, 1038P, 1044P, 1052, 1053, 1054,<br />
1144, 1199P, 1213, 1216, 1227O, 1271P, 1272P,<br />
1370P, 1379P, 1550PD, 1581P, 1644PD, 1651P,<br />
1659P<br />
Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
Annals Of Oncology 23 (Supplement 9): ix601–ix603, <strong>2012</strong><br />
doi:10.1093/annonc/mds479<br />
CH5424802: 7IN, 441O<br />
CI-1040: 1674P<br />
Cilastatin: 1619P<br />
Cilengitide: 24IN<br />
Cisplatin: 77IN, 80IN, 148P, 149P, 158P, 194P,<br />
224P, 359P, 375P, 390, 394, 397, 433, 496P,<br />
668PD, 671P, 672P, 682P, 686P, 687P, 688P,<br />
689P, 690P, 693P, 695P, 700P, 701P, 730P, 731P,<br />
745P, 746P, 749, 753, 757, 759, 760, 761,<br />
782TiP, 786O, 789O, 799P, 801P, 802P, 803P,<br />
807P, 858P, 860P, 862P, 864P, 883, 887, 888,<br />
890TiP, 972PD, 988P, 990P, 995P, 999P, 1000P,<br />
1004P, 1007, 1009, 1010, 1012, 1016O, 1018O,<br />
1020PD, 1022PD, 1023PD, 1028P, 1034P,<br />
1035P, 1036P, 1037P, 1038P, 1039P, 1040P,<br />
1041P, 1044P, 1045P, 1051, 1054, 1057, 1058,<br />
1138P, 1144, 1147, 1161P, 1169P, 1181PD,<br />
1183P, 1191P, 1194P, 1199P, 1201P, 1202P,<br />
1203P, 1204P, 1211, 1212, 1213, 1215, 1219,<br />
1223, 1224O, 1226O, 1229PD, 1234PD,<br />
1235PD, 1241P, 1242P, 1243P, 1245P, 1247P,<br />
1249P, 1250P, 1251P, 1252P, 1272P, 1274P,<br />
1275P, 1294P, 1303P, 1308P, 1327, 1329, 1335,<br />
1337, 1352, 1365TiP, 1507P, 1520PD, 1522PD,<br />
1524P, 1529P, 1531P, 1539P, 1571P, 1573P,<br />
1581P, 1598P, 1611P, 1619, 1620, 1625, 1632,<br />
1639, 1645PD, 1687<br />
Cladribine: 1076P<br />
Combrastatin A4: 1250P<br />
Crizotinib: 7IN, 78IN, 81IN, 119IN, 138IN, 438O,<br />
439O, 440O, 441O, 508, 1098, 1191PD, 1195P,<br />
1208P, 1230PD, 1231PD, 1267P, 1268P, 1267P,<br />
1268P, 1290P, 1291P, 1312, 1324, 1383P<br />
Custirsen: 53IN<br />
Cyclopamine: 1095, 1309P<br />
Cyclophosphamide: 228P, 245O, 246O, 253PD,<br />
267P, 268P, 269P, 291P, 292P, 313, 320PD,<br />
333P, 360P, 373P, 377, 382, 390, 405TiP,<br />
406TiP, 515P, 622, 799P, 827P, 935P, 936P,<br />
986P, 1062O, 1063O, 1073P, 1074P, 1079P,<br />
1080P, 1082P, 1083P, 1098, 1210, 1503P, 1503P,<br />
1525P, 1529P, 1552P, 1578P, 1623, 1671P<br />
Cytarabine: 429P, 1082P, 1084P, 1092P, 1102,<br />
1105<br />
Dacarbazine: 175PD, 426P, 1115PD, 1127P,<br />
1138P, 1147, 1511P<br />
Dacomitinib: 7IN, 1228O, 1290P<br />
Darbepoetin alfa: 858P, 1561P, 1562P, 1567P<br />
Dasatinib: 53IN, 508, 1481PD, 1686P<br />
Daunorubicin: 1092P<br />
Degarelix: 905P, 930P<br />
Dendritic cell vaccines: 490P, 502, 510TiP, 719P,<br />
723P, 1114PD, 1138P, 1363TiP, 1672P<br />
Denosumab: 49IN, 95IN, 316TiP, 937P, 1108TiP,<br />
1400PD, 1480PD, 1580P<br />
DHMEQ: 148P, 1531P<br />
Dicarbamin: 1623<br />
Docetaxel: 47IN, 48IN, 53IN, 105IN, 106IN, 194P,<br />
200P, 224P, 226P, 245O, 246O, 271P, 291P,<br />
292P, 309, 313, 320PD, 326PD, 333P, 344P,<br />
345P, 355P, 356P, 359P, 360P, 375P, 382, 390,<br />
391, 395, 406TiP, 407TiP, 408TiP, 409TiP, 458P,<br />
478P, 492P, 493P, 494P, 497P, 505, 515P, 519P,<br />
672P, 673P, 682P, 686P, 690P, 693P, 701P, 702P,<br />
753, 755, 759, 760, 761, 762, 804P, 893O, 896O,<br />
897O, 898PD, 899PD, 901PD, 903P, 904P, 908P,<br />
909P, 910P, 918P, 921P, 924P, 925P, 926P, 927P,<br />
931P, 932P, 933P, 934P, 935P, 936P, 943P, 946,<br />
948, 950, 951, 952, 953, 955, 956, 958, 960,<br />
962TiP, 1012, 1020PD, 1028P, 1035P, 1036P,<br />
1037P, 1038P, 1039P, 1040P, 1041P, 1045P,<br />
1051, 1199P, 1202P, 1212, 1233PD, 1234PD,<br />
drug index
drug index<br />
drug index<br />
1248P, 1250P, 1286P, 1297P, 1301P, 1327, 1329,<br />
1332, 1335, 1338, 1341, 1342, 1345, 1353, 1356,<br />
1511P, 1552P, 1578P, 1594P, 1611P, 1623,<br />
1645PD, 1647PD, 1657P, 1664P, 1680P<br />
Dovitinib (TKI258): 7IN, 822P, 875, 891TiP,<br />
1483PD<br />
Doxorubicin: 68IN, 200P, 268P, 269P, 291P, 313,<br />
320PD, 333P, 357P, 363P, 373P, 377, 382, 462P,<br />
487P, 495P, 502, 772, 799P, 882, 984P, 986P,<br />
1062O, 1063O, 1071P, 1073P, 1074P, 1077P,<br />
1079P, 1080P, 1084P, 1098, 1482PD, 1500P,<br />
1503P, 1504P, 1505P, 1507P, 1511P, 1517TiP,<br />
1525P, 1594P, 1623, 1682P<br />
DTS-108: 485P<br />
E-3810: 319O<br />
Efatutazone: 590P<br />
EMD 1214063: 444PD<br />
EMD 525797 (DI17E6): 965TiP<br />
Enzastaurin: 342P<br />
EOS 3810: 7IN<br />
Epirubicin: 44IN, 228P, 245O, 246O, 267P, 268P,<br />
320PD, 333P, 359P, 360P, 377, 405TiP, 406TiP,<br />
667PD, 687P, 754, 762, 782TiP, 789O, 1077P,<br />
1169P, 1500P, 1529P, 1552P, 1529P<br />
Epoetin alfa: 858P, 1561P, 1562P, 1565P, 1567P,<br />
1630<br />
Epoetin zeta: 1566P, 1568P, 1569P<br />
Eribulin mesylate: 21IN, 330P, 337P, 358P, 1205P<br />
Erlotinib: 7IN, 28IN, 29IN, 78IN, 105IN, 106IN,<br />
138IN, 189P, 211P, 234, 412O, 492P, 506,<br />
509TiP, 722P, 768, 1194P, 1197P, 1205P, 1219,<br />
1222, 125O, 1226O, 1227O, 1240P, 1254P,<br />
1257P, 1260P, 1261P, 1263P, 1265P, 1271P,<br />
1273P, 1276P, 1277P, 1280P, 1282P, 1283P,<br />
1290P, 1291P, 1293P, 1298P, 1299P, 1304P,<br />
1307P, 1309P, 1311P, 1322, 1323, 1328, 1330,<br />
1333, 1338, 1339, 1340, 1342, 1343, 1345, 1346,<br />
1347, 1348, 1362TiP, 1365TiP, 1366TiP,<br />
1367TiP, 1370P, 1401P, 1550PD, 1655P, 1662P,<br />
1663P<br />
Estramustine: 952<br />
Etoposide: 80IN, 789O, 858P, 860P, 862P, 863P,<br />
866P, 888, 1062O, 1083P, 1199P, 1213, 1223,<br />
1304P, 1505P, 1520PD, 1524P, 1525P, 1526P,<br />
1527P, 1529P, 1543TiP<br />
Everolimus: 53IN, 76IN, 83IN, 173O, 324PD,<br />
334P, 351P, 352P, 419PD, 447PD, 690P, 781TiP,<br />
783O, 798PD, 810P, 812P, 814P, 816P, 818P,<br />
821P, 822P, 823P, 824P, 837P, 840P, 841P, 842P,<br />
843P, 845P, 852P, 855P, 869, 873, 875, 876, 879,<br />
881, 890TiP, 1017O, 1154O, 1156O, 1162P,<br />
1163P, 1165P, 1401P, 1703IN<br />
Exemestane: 277P, 280P, 310, 311, 334P, 351P<br />
Fentanyl: 1612P<br />
Ficlatuzumab: 443PD, 1198P<br />
Figitumumab: 58IN, 90IN<br />
Filgrastim: 863P, 1547P, 1552P, 1555P<br />
Fingolimod: 1651P<br />
Fluoropyrimidine: 126IN, 218P, 237, 452P, 620,<br />
653<br />
Flutamide: 929P<br />
Folinic acid: 567P, 597P, 662TiP, 643, 710P, 714P,<br />
726P<br />
Foretinib: 1027P<br />
Fotemustine: 426P, 1135P, 1140P<br />
Fulvestrant: 323PD, 337P, 339P, 340P, 341P, 342P,<br />
350P, 384<br />
Gabapentin: 1581P<br />
Ganetespib (STA-9090): 347P, 1248P, 1332,<br />
1664P, 1647PD<br />
Ganitumab: 776TiP<br />
G-CSF: 693P, 714P, 716P, 721P, 790O, 931P, 951,<br />
953, 1037P, 1039P, 1051, 1082P, 1356, 1357,<br />
1547PD, 1548PD, 1552P, 1553P, 1554P, 1555P,<br />
1556P, 1557P, 1560P, 1625<br />
GDC-0068: 458P<br />
GDC-0941: 7IN, 154P, 1675P<br />
GDC-0973: 154P<br />
GDC-0980: 7IN, 154P, 452P<br />
Gefitinib: 7IN, 53IN, 78IN, 106IN, 138IN, 179P,<br />
189P, 211P, 412O, 1198P, 1227O, 1253P, 1254P,<br />
1255P, 1256P, 1257P, 1258P, 1259P, 1263P,<br />
1265P, 1269P, 1270P, 1283P, 1289P, 1290P,<br />
1309P, 1319, 1323, 1325, 1328, 1330, 1331,<br />
1339, 1343, 1344, 1348, 1362TiP, 1401P,<br />
1550PD<br />
Gemcitabine: 42IN, 77IN, 144PD, 150P, 268P,<br />
337P, 395,397, 447PD, 478P, 484P, 497P, 666O,<br />
709P, 710P, 711P, 713P, 715P, 717P, 718P, 719P,<br />
722P, 723P, 728P, 730P, 731P, 746P, 768, 773,<br />
775, 776TiP, 786O, 790O, 799P, 800P, 802P,<br />
804P, 807P, 883, 885, 887, 967O, 972PD, 985P,<br />
986P, 1043P, 1183P, 1194P, 1219, 1224O,<br />
1226O, 1236PD, 1239P, 1241P, 1251P, 1276P,<br />
1286P, 1297P, 1301P, 1304P, 1329, 1356, 1511P,<br />
1645PD, 1654P, 1676P<br />
GM-CSF: 436TiP, 510TiP, 1147<br />
GS-1101: 65IN<br />
GSK1120212: 7IN<br />
GSK1363089: 1027P<br />
GSK2126458 (GSK458): 442O<br />
GTX-758: 923P<br />
Ibandronate: 947, 1633<br />
Icotonib: 1269P,<br />
Idarubicin: 1068PD<br />
IFN alpha: 53IN, 153P, 783O, 793PD, 809P, 810P,<br />
815P, 816P, 825P, 839P, 876, 877, 1147<br />
IFN beta: 747P<br />
Ifosfamide: 789O, 858P, 860P, 863P, 866P, 1004P,<br />
1083P, 1498P, 1500P, 1503P, 1505P, 1511P<br />
IL-2: 808P, 1147<br />
IMA50: 436TiP<br />
Imatinib: 6IN, 29IN, 92IN, 94IN, 704P, 705P,<br />
706P, 707P, 708P, 1090P, 1478O, 1483PD,<br />
1484PD, 1489P, 1490P, 1492P, 1494P, 1102,<br />
1105, 1123P, 1516, 1550PD, 1679P<br />
IMO-2055: 1044P<br />
Iniparib: 18IN<br />
INO-206: 1482PD<br />
Inotuzumab ozogamicin: 68IN<br />
Interferon: 76IN<br />
IPI-504: 66IN<br />
Ipilimumab: 53IN, 71IN, 175PD, 1116PD,<br />
1117PD, 1124P, 1126P, 1127P, 1128P, 1129P,<br />
1130P, 1131P, 1132P, 1133P, 1134P, 1143P,<br />
1148, 1149, 1150, 1151, 1152<br />
Irinotecan: 42IN, 126IN, 208P, 214IN, 218P,<br />
518O, 525PD, 526PD, 529PD, 536P, 543P, 559P,<br />
561P, 565P, 568P, 570P, 571P, 573P, 578P, 579P,<br />
581P, 582P, 587P, 590P, 592P, 593P, 597P, 598P,<br />
599P, 600P, 602P, 603P, 606P, 608P, 618, 627,<br />
628, 630, 633, 634, 635, 640, 646, 649, 650, 656,<br />
659, 662TiP, 664TiP, 665TiP, 688P, 689P, 696P,<br />
697P, 710P, 714P, 716P, 721P, 726P, 755, 762,<br />
1204P, 1526P, 1591P, 1595P, 1644PD<br />
Irosustat (BN83495): 1001P<br />
K252a: 188P<br />
Ketoconazole: 927P, 953<br />
KNTR-102: 21IN<br />
Lapatinib: 53IN, 103IN, 104IN, 115IN, 121IN,<br />
247O, 255PD, 267P, 318O, 322PD, 337P,<br />
407TiP, 409TiP, 496P, 1232PD, 1550PD, 1659P<br />
L-BLP25: 622, 1210<br />
Annals Of Oncology<br />
LDK-378: 7IN, 440O<br />
Lenalidomide: 68IN, 1064O<br />
Lenograstim: 1547PD<br />
Lenvatinib (E7080) : 417PD, 737P, 814P<br />
Letrozole: 280P, 310, 323PD, 407TiP<br />
Leucovorin: 39IN, 42IN, 208P, 452P, 458P, 460P,<br />
518O, 519O, 520O, 523PD, 524PD, 527PD,<br />
529PD, 542P, 543P, 550P, 552P, 557P, 558P,<br />
560P, 561P, 564P, 570P, 573P, 576P, 577P, 580P,<br />
581P, 586P, 587P, 590P, 591P, 592P, 597P, 600P,<br />
601P, 602P, 603P, 607P, 618, 620, 623, 624, 625,<br />
627, 628, 633, 634, 635, 640, 643, 646, 650, 653,<br />
655, 657, 659, 661, 662TiP, 683P, 686P, 696P,<br />
701P, 710P, 716P, 721P, 731P, 760, 762,<br />
Linifanib (ABT-869) : 203P, 505, 507<br />
Lipegfilgrastim: 1548PD<br />
Lorvotuzumab mertansine: 1543TiP<br />
LU-DOTATATE: 75IN, 1703IN<br />
Lurbinectedin (PM01183): 484P, 968O<br />
Lutelium-177 octreotate: 1162P<br />
LY24002: 185P<br />
Masitinib: 174O<br />
MDV3100: 47IN, 48IN, 53IN, 896O, 899PD, 924P,<br />
925P<br />
Megestrol acetate: 1001P<br />
MEK162: 7IN<br />
Melphalan: 743P, 1085P, 1141P<br />
Metformin: 1450P<br />
Methotrexate: 130IN, 246O, 253PD, 269P, 333P,<br />
390, 404, 515P, 799P, 802P, 807P, 1507P<br />
MetMAb: 7IN, 1364TiP, 1365TiP<br />
MG132: 144 PD<br />
MGCD265: 471P, 492P, 493P<br />
MGN1601: 813P<br />
MGN1703: 518O<br />
Mifamurtide: 1508P, 1518TiP<br />
Mitomycin C: 477P, 532P, 756P, 1204P<br />
Mitoxantrone: 497P, 931P, 932P, 933P, 936P, 952<br />
MK-2206: 474P, 1676P<br />
MLN8237 (alisertib): 461P, 489P, 921P<br />
MM-111: 496P<br />
MM-121: 974PD<br />
Nab-paclitaxel: 409TiP, 780TiP, 804P<br />
Naloxone: 1582P<br />
NC-6004: 746P<br />
Netupitant: 1575P, 1618<br />
NGR-hTNF: 487P, 488P, 502, 1251P<br />
Nilotinib: 740P, 744P, 1483PD<br />
Nintedanib: 54IN, 446PD<br />
NKTR-102: 21IN<br />
NVP-AUY22: 61IN<br />
NVP-TAE684: 1497P<br />
Octreotide: 419PD, 1172<br />
OGX-427: 900PD<br />
OK432: 719P<br />
Olaparib (AZD2281): 18IN, 55IN<br />
Omrabulin: 1250P<br />
Ondansetron: 1573P<br />
ONO-7643: 465P<br />
Oxaliplatin: 39IN, 42IN, 208P, 126IN, 207P, 218P,<br />
452P, 458P, 460P, 495P, 518O, 519O, 520O,<br />
523PD, 524PD, 526PD, 527PD, 544P, 547P,<br />
556P, 557P, 558P, 559P, 560P, 562P, 564P, 565P,<br />
566P, 567P, 568P, 570P, 571P, 573P, 577P, 578P,<br />
579P, 580P, 582P, 586P, 587P, 591P, 592P, 593P,<br />
597P, 598P, 599P, 600P, 601P, 602P, 603P, 605P,<br />
607P, 620, 624, 627, 628, 630, 633, 635, 640,<br />
643, 646, 647, 649, 650, 653, 655, 656, 657, 659,<br />
661, 663TiP, 665TiP, 667PD, 686P, 713P, 714P,<br />
716P, 718P, 721P, 726P, 728P, 730P, 731P, 736P,<br />
755, 768, 779TiP, 780TiP, 782TiP, 790O, 989P,<br />
1590P, 1591P, 1595P, 1638<br />
ix602 | drug index Volume 23 | Supplement 9 | September <strong>2012</strong>
Annals Of Oncology drug index<br />
Oxycodone: 1582P<br />
Paclitaxel: 55IN, 80IN, 103IN, 115IN, 154P,<br />
175PD, 191P, 228P, 245O, 246O, 247O, 255PD,<br />
267P, 268P, 269P, 313, 317O, 326PD, 335P,<br />
337P, 345P, 355P, 373P, 382, 405TiP, 454P,<br />
464P, 496P, 505, 681P, 692P, 697P, 698P, 745P,<br />
762, 779TiP, 780TiP, 789O, 790O, 801P, 803P,<br />
804P, 863P, 883, 971PD, 973PD, 974PD, 975PD,<br />
978P, 985P, 986P, 991P, 995P, 997P, 1000P,<br />
1004P, 1010, 1012, 1013, 1017O, 1034P, 1043P,<br />
1153, 1183P, 1204P, 1221, 1224O, 1236PD,<br />
1239P, 1240P, 1242P, 1246P, 1250P, 1255P,<br />
1256P, 1259P, 1276P, 1285P, 1287P, 1297P,<br />
1299P, 1301P, 1303P, 1304P, 1363TiP, 1364TiP,<br />
1524P, 1591P, 1667P<br />
Palonosetron: 721P, 1571P, 1572P, 1574P, 1576P,<br />
1577P, 1579P<br />
Pamidronic acid: 1585P, 1633<br />
Panitumumab: 29IN, 126IN, 525PD, 535P, 536P,<br />
558P, 563P, 564P, 570P, 572P, 587P, 594P, 598P,<br />
603P, 605P, 631, 634, 652, 665TiP, 667PD,<br />
1016O, 1370P, 1597P<br />
Panobinostat: 68IN<br />
Pasireotide: 419PD<br />
Pazopanib: 29IN, 52IN, 53IN, 54IN, 91IN, 92IN,<br />
222P, 508, 791PD, 792PD, 810P, 816P, 833P,<br />
837P, 840P, 875, 880, 1157O, 1165P, 1493P<br />
PDM08: 480P<br />
Pegfilgrastim: 1004P, 1547PD, 1548PD, 1553P,<br />
1560P<br />
Pegylated liposomal doxorubicin: 984P, 986P,<br />
1594P<br />
Pemetrexed: 106IN, 433, 505, 747P, 1022PD,<br />
1206P, 1214, 1215, 1218, 1224O, 1225O,<br />
1235PD, 1242P, 1245P, 1247P, 1251P, 1252P,<br />
1258P, 1267P, 1274P, 1275P, 1281P, 1286P,<br />
1297P, 1302P, 1303P, 1304P, 1326, 1327, 1338,<br />
1342, 1345, 1347, 1354, 1355, 1356, 1361,<br />
1362TiP, 1364TiP, 1370P, 1522PD, 1535P,<br />
1654P<br />
Pertuzumab: 202P, 322PD, 344P, 407TiP, 408TiP,<br />
409TiP<br />
PF-05212384: 7IN<br />
PLX4032: 70IN<br />
Pralatrexate: 68IN<br />
Prostvac-VF Tricom: 46IN<br />
PRRgama: 1703IN<br />
PV-10: 1137P<br />
R1507: 1497P<br />
Racotumomab: 1238PD<br />
Radium-223 chloride: 49IN, 898PD, 936P<br />
Raltitrexed: 519O, 567P, 747P<br />
Ramucirumab: 1115PD, 1245P, 1287P,<br />
Ranimustine: 1062O<br />
Ranolazine: 1682P<br />
Rasburicase: 1103<br />
recPRAME: 1110O, 1182P<br />
Regorafenib: 92IN, 173O, 1478O, 1483PD<br />
Ridaforolimus (MK-8669): 92IN<br />
Rilotumumab: 687P<br />
Rituximab: 29IN, 64IN, 65IN, 68IN, 96IN, 97IN,<br />
157P, 1073P, 1076P, 1079P, 1080P, 1373P,<br />
1384P<br />
RO4929097: 448PD, 450PD<br />
RO4987655: 7IN, 451P<br />
RO5126766: 475P<br />
Romidepsin: 68IN<br />
Rosiglitazone: 590P<br />
S-1: 566P, 575P, 576P, 592P, 611P, 646, 668PD,<br />
671PD, 681P, 682P, 688P, 689P, 693P, 698P,<br />
702P, 719P, 728P, 757, 758, 775, 779TiP, 989P,<br />
1181PD, 1234PD, 1334, 1704P<br />
Sandostatin-LAR: 1172<br />
SAR-020106: 61IN, 1677P<br />
Saracatinib (AZD0530): 501, 1659P<br />
SB203580: 348P<br />
SB939: 922P<br />
Selumetinib: 7IN, 609P, 1233PD<br />
Silumarin: 473P<br />
Sipuleucel-T: 46IN, 53IN, 939P, 940P, 941P, 942P,<br />
943P, 949, 950<br />
SLO101: 1674P<br />
SN38: 485P, 664TiP<br />
Somatostatin: 75IN, 419PD, 873, 1167P, 1172<br />
Sorafenib: 7IN, 29IN, 43IN, 53IN, 124IN, 173O,<br />
229P, 447PD, 466P, 569P, 654, 670PD, 734P,<br />
736P, 737P, 744P, 770, 777TiP, 778TiP, 781TiP,<br />
793PD, 795PD, 810P, 812P, 816P, 817P, 818P,<br />
823P, 824P, 837P, 840P, 843P, 844P, 846P, 848P,<br />
856P, 869, 871, 872, 874, 875, 877, 879, 881,<br />
1165P, 1241P, 1349, 1362TiP, 1370P, 1390P,<br />
1391P, 1401P, 1491P, 1506P, 1594P, 1615P,<br />
1674P<br />
Streptozocin: 209P, 1159P, 1161P<br />
Sunitinib: 29IN, 52IN, 53IN, 58IN, 76IN, 92IN,<br />
95IN, 174O, 229P, 508, 705P, 724P, 785O,<br />
792PD, 793PD, 794PD, 797PD, 81OP, 812P,<br />
815P, 816P, 818P, 820P, 821P, 823P, 824P, 826P,<br />
827P, 829P, 830P, 832P, 834P, 835P, 837P, 840P,<br />
843P, 846P, 847P, 848P,849P, 850P, 851P, 853P,<br />
854P, 856P, 869, 870, 872, 875, 877, 879, 881,<br />
889TiP, 892TIP, 901PD, 1155O, 1163P, 1165P,<br />
1370P, 1401P, 1478O, 1483PD, 1484PD, 1490P,<br />
1491P, 1495P, 1496P, 1550PD, 1615P, 1678P,<br />
1703IN<br />
TAK-441: 449PD<br />
TAK-700: 918P<br />
TAK-733: 456P,<br />
Talactoferrin: 1363TiP,<br />
Tamoxifen: 14IN, 17IN, 196P, 249PD, 279P, 280P,<br />
295P, 311, 339P, 360P, 384, 1147, 1502P<br />
TAS-102: 126IN<br />
Tasquinimod: 919P<br />
T-DM1: 318O<br />
Temozolomide: 410O, 416PD, 424P, 426P, 436TiP,<br />
437TiP, 1126P, 1135P, 1368TiP, 1529P, 1676P,<br />
1686P, 1703IN<br />
Temsirolimus: 65IN, 68IN, 420PD, 450PD, 462P,<br />
717P, 793PD, 810P, 816P, 818P, 824P, 828P,<br />
839P, 845P, 846P, 852P, 875, 879, 1023PD,<br />
1107TiP<br />
Tesetaxel: 481P, 486P<br />
TH-302: 435TiP, 666O<br />
Thalidomide: 1088P<br />
Thiotepa: 789O<br />
Tigatuzumab (CS-1008): 662TiP<br />
Tipifarnib: 43IN<br />
Tivatinib: 738P, 739P, 1293P<br />
Tivozanib: 53IN, 795PD, 796PD, 892TiP<br />
TNFalpha: 1504P<br />
Tocilizumab: 153P<br />
Topotecan: 968O, 986P, 1529P<br />
Trabectedin: 984P, 986P, 1511P, 1517TiP<br />
Trastuzumab: 6IN, 7IN, 29IN, 44IN, 53IN, 57IN,<br />
103IN, 104IN, 115IN, 154P, 202P, 226P, 228P,<br />
243, 246O, 247O, 245PD, 255PD, 266P, 267P,<br />
268P, 270P, 271P, 272P, 273P, 274P, 275P, 276P,<br />
308, 309, 315TiP, 318O, 322PD, 325PD, 337P,<br />
343P, 344P, 346P, 373P, 380, 389, 391, 393, 396,<br />
404, 406TiP, 407TiP, 408TiP, 40TiP, 454P, 470P,<br />
476P, 496P, 677P, 699P, 761, 762, 786O,<br />
1232PD, 1373P, 1397P, 1398P, 1646PD, 1657P<br />
TSU-68: 732P<br />
U3-1287: 467P<br />
Uracil-tegafur (UFT): 542P, 552P, 575P, 576P,<br />
582P, 611P, 623, 625, 628, 681P<br />
Vandetanib: 7IN, 508, 804P<br />
Vedotin: 68IN, 1083P<br />
Veliparib: 428P<br />
Vemurafenib: 6IN, 28IN, 29IN, 227P, 242, 1124P,<br />
1125P, 1146<br />
Vinblastine: 799P, 802P, 807P, 860P, 1138P<br />
Vincristine: 1062O, 1063O, 1071P, 1073P, 1074P,<br />
1079P, 1080P, 1098, 1525P, 1529P<br />
Vindesine: 1062O, 1204P, 1234PD<br />
Vinflunine: 21IN, 787O, 804P<br />
Vinorelbine: 80IN, 106IN, 168O, 391, 392, 393,<br />
394, 399, 408TiP, 1058, 1183P, 1199P, 1201P,<br />
1202P, 1243P, 1247P, 1249P, 1272P, 1276P,<br />
1286P, 1297P, 1301P, 1304P, 1329, 1337, 1356,<br />
1357, 1502P, 1542TiP, 1645PD<br />
Vismodegib: 1111PD, 1112PD<br />
Volasertib: 804P<br />
Vorinostat: 68IN, 700P, 1273P,<br />
XL-147: 7IN<br />
XL-765: 7IN<br />
XL880: 1027P<br />
Y-27632: 947<br />
Y90 Iritumomab: 1073P,<br />
Y-DOTATOC: 75IN, 1703IN<br />
YS110: 498P<br />
YTTRIUM-90: 735P<br />
Zalypsis: 806P<br />
Zoledronic acid: 49IN, 937P, 945, 1108TiP, 1321,<br />
1580P, 1583P, 1584P, 1585P, 1633, 1641<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds479 | ix603<br />
drug index
translational<br />
research<br />
index<br />
translational research index<br />
3’-UTR: 1032P<br />
4EB-P1:<br />
5HT3: 129IN<br />
9F1: 562P<br />
A488G: 374P<br />
ABCA13: 1701<br />
ABCB1: 724P, 1667P, 1678P<br />
ABCG2: 215P, 64O, 724P<br />
ABL1: 1311P<br />
ACC: 618<br />
ACTN4: 1174P, 1186P, 1701<br />
Adiponectin: 190P<br />
AEG-1: 807P<br />
AFP: T33P, 790O, 866P, 994P, 1539P, 1693P<br />
AFR: 1211<br />
AKR1C: 928P, 1701<br />
AKT: 2IN, 7IN,52IN, 65IN, 76IN, 90IN, 102IN,<br />
107IN, 108IN, 119IN, 154P, 156P, 173O, 179P,<br />
180P, 185P, 214P, 318O, 343P, 347P, 350P,<br />
41PD, 442O, 450PD, 458P, 474P, 483P, 781TiP,<br />
807P, 812P, 80TiP, 917P, 1031P, 1196P, 1491P,<br />
1652P, 1659P, 1668P, 1675P, 1676P, 1685P,<br />
1690P<br />
ALCAM: 215P, 720P<br />
ALDH1: 149P, 216P, 375P<br />
ALDH2: 1701<br />
ALK: 6IN, 7IN, 62IN, 78IN, 81IN, 82IN, 83IN,<br />
108IN, 119IN, 138IN, 167O, 193P, 195P, 438O,<br />
439O, 440O, 441O, 1063O, 1176P, 1187P,<br />
1191PD, 1193P, 1195P, 1208, 1230PD, 1231PD,<br />
1248P, 1266P, 1267P, 1268P, 1274P, 1284P,<br />
1290P, 1312, 1324, 1497P, 1647PD, 1664P<br />
ALPHA-2A: 299<br />
ALPHA-6: 214P<br />
Amphiregulin: 526PD, 536P<br />
AMPK: 618<br />
Ang-1: 975PD<br />
Ang-2: 184P, 600P, 794PD, 975PD, 1648P<br />
Annexin A4:<br />
ANP: 1682P<br />
ANXA: 1701<br />
APC: 7IN, 92IN, 675P<br />
APOA1: 232<br />
Apoptosis: 66IN, 81IN, 109IN, 148P, 149P, 156P,<br />
158P, 165, 173O, 177PD, 179P, 236, 482P, 539P,<br />
575P, 769, 806P, 988P, 1122P, 1677P, 1682P<br />
AR: 20IN, 48IN, 257P, 325PD, 899PD, 900PD,<br />
922P, 924P, 925P, 1680P, 1689P<br />
ASL: 1660P<br />
ASS1: 1660P<br />
ATM: 7IN, 156P, 186P<br />
ATP: 159P, 166, 444PD, 458P, 495P<br />
ATRX: 12IN<br />
AURKA: 93IN<br />
Aurora-A kinase: 376, 461P, 489P, 921P<br />
AXL: 1027P<br />
B-actin: 1170P<br />
Bad: 156P, 405TiP<br />
BALP: 805P, 945, 1122P<br />
BAP1: 1300P<br />
Bax: 628, 1122P<br />
Bcl-2: 65IN, 156P, 249PD, 482P, 1075P<br />
Bcl-xl: 769, 1075P<br />
BCR-ABL: 1093P, 1481PD, 1102, 1105<br />
BDNF: 188P, 1464P<br />
Beclin-1: 1679P<br />
BETA: 179P, 214P, 299<br />
Beta-catenin: 675P, 703P, 1700<br />
beta-CTX: 805P, 945<br />
bFGF: 152P, 842P, 1236PD, 1657P<br />
BHCG: 790O, 865P, 994P<br />
BHR: 66IN<br />
BIM: 154P, 185P<br />
BIP/GRP78: 66IN<br />
Bmi1: 144PD<br />
BMP4: 720P<br />
BNIP3: 1033P<br />
BNP: 1682P<br />
BRAF: 6IN, 7IN, 19IN, 28IN, 29IN, 50IN, 70IN,<br />
78IN, 83IN, 102IN, 108IN, 119IN, 180P, 208P,<br />
212P, 227P, 237, 456P, 475P, 521O, 525PD,<br />
526PD, 532P, 535P, 536P, 537P, 548P, 557P,<br />
574P, 580P, 593P, 608P, 629, 631, 641, 656,<br />
696P, 1017O, 1118PD, 1123P, 1124P, 1125P,<br />
1135P, 1145, 1146, 1147, 1173, 1187P, 1349,<br />
1491P, 1647PD, 1649P, 1652P, 1664P<br />
BRCA: 55IN, 220P<br />
BRCA1: 7IN, 17IN, 20IN,33IN, 35IN, 36IN, 187P,<br />
294P, 511PD, 512PD, 513PD, 514P, 515P, 686P,<br />
720P, 807P, 969PD, 972PD, 1170P, 1300P,<br />
1449P, 1542TiP, 1655P, 1661P, 1662P<br />
BRCA2: 33IN, 35IN, 36IN, 294P, 371P, 511PD,<br />
512PD, 513PD, 514P, 515P, 720P, 969PD,<br />
972PD, 1449P, 1662P<br />
BRM: 186P<br />
BTK: 65IN, 68IN<br />
BXPC3: 1697P<br />
C26: 477P<br />
C3: 232<br />
C4: 232<br />
CA 72-4: 679P<br />
CA: 786O, 1167P<br />
CA125: 147P, 972PD, 978P, 983P, 987P, 1012,<br />
1013, 1203P<br />
CA15-3: 302, 339P, 376, 388<br />
CA19-9: 645, 666O, 679P, 713P, 721P<br />
CA9: 1033P<br />
CACO-2: 229P<br />
CADM1: 221P<br />
CAF: 833P<br />
CA-IX: 185P, 435TiP, 562P, 794PD, 835P, 1695P<br />
CALR: 1701<br />
Calreticulin: 495P<br />
Calretinin: 1533P<br />
Cancer stem cells: 375P, 385, 418PD, 463P<br />
Caspase-3: 443PD<br />
CBFB: 102IN<br />
CCL2: 838P<br />
CCNA2: 215P<br />
CCNB1: 24PD<br />
CCND: 180P, 1031P<br />
CCNE: 180P<br />
CD10: 287P, 1106<br />
CD105: 169O<br />
CD117: 1067PD, 1106<br />
CD11b: 480P, 1314<br />
CD127: 1138P, 1314<br />
CD13: 1314<br />
CD133: 149P, 159P, 418PD, 431, 604P<br />
CD135: 1067PD<br />
CD138: 66IN<br />
CD14: 1314<br />
CD144: 227P<br />
CD15: 480P, 676P, 1314<br />
CD154: 813P<br />
CD163: 1681P<br />
CD16b: 480P<br />
CD19: 1106<br />
CD2: 1106<br />
CD20: 64IN, 157P, 216P, 1079P<br />
CD22: 1106<br />
CD24: 720P<br />
CD25: 1138P, 1314<br />
CD26: 498P<br />
Published by <strong>Oxford</strong> University Press on behalf of <strong>the</strong> European Society for Medical Oncology.<br />
Annals Of Oncology 23 (Supplement 9): ix604–ix608, <strong>2012</strong><br />
doi:10.1093/annonc/mds480<br />
CD3: 495P, 939P, 1106, 1314, 1644PD<br />
CD30: 861P, 1063O, 1083P<br />
CD31: 443PD, 501<br />
CD33: 480P, 1106, 1314<br />
CD34: 751, 1083P, 1085P, 1489P, 1106, 1624<br />
CD39: 1314<br />
CD4: 436TiP, 480P, 495P, 622, 915P, 939P, 1106,<br />
1110O, 1117PD, 1138P, 1314,<br />
CD40: 1645P<br />
CD44: 720P, 1685P<br />
CD44+/CD24-: 149P, 164, 215P, 300, 375P, 1696P<br />
CD45: 227P, 480P, 1067PD, 1175P, 1512, 1650P<br />
CD45RO: 622, 1314<br />
CD46: 1677P<br />
CD49f: 1685P<br />
CD5: 1106<br />
CD54: 942P<br />
CD56: 480P, 1543TiP, 1644PD<br />
CD68: 1681P<br />
CD7: 1106<br />
CD74: 195P<br />
CD8: 436TiP, 495P, 503, 915P, 939P, 1110O,<br />
1114PD, 1117PD, 1314<br />
CD80: 510TiP, 813P<br />
CD83: 510TiP, 1672P<br />
CD86: 510TiP, 1673P<br />
CDH1: 225P, 511PD<br />
CDH13: 221P, 548P<br />
CDK4: 70IN, 92IN, 93IN<br />
CDKN2A: 7IN, 12IN, 180P, 720P, 1118PD<br />
CDS: 1032P<br />
CDX2: 675P<br />
CEA: 339P, 388, 505, 518O, 579P, 583P, 622, 627,<br />
637, 644, 645, 647, 653, 659, 679P, 911P, 1203P,<br />
1313<br />
CEBPA: 93IN<br />
CFDNA: 219P<br />
CHFR: 221P<br />
CHK1: 20IN, 61IN, 1677P<br />
CHR: 615<br />
Chromogranin A: 911P, 912P<br />
Circulating endo<strong>the</strong>lial cells: 209P, 567P, 1240P<br />
Circulating endo<strong>the</strong>lial progenitors: 1240P<br />
Circulating tumor cells (CTCs): 171O, 217P,<br />
218P, 223P, 227P, 230P, 255PD, 304, 582P, 767,<br />
897O, 900PD, 910P, 911P, 922P, 961, 963TiP,<br />
965TiP, 1029P, 1175P, 1240P, 1313, 1512, 1650P<br />
CIT: 229P<br />
CKB: 1701<br />
Class III beta tubulin: 187P, 291P<br />
Clec14: 178P<br />
CMCS: 21P, 227P<br />
c-MET: 7IN, 51IN, 70IN, 78IN, 83IN, 102IN,<br />
119IN, 143PD, 179P, 205P, 443PD, 444PD,<br />
445PD, 471P, 492P, 493P, 669PD, 687P, 720P,<br />
738P, 739P, 897O, 1027P, 1191PD, 1198P,<br />
1290P, 1291P, 1219P, 1293P, 1309P, 1322,<br />
1365TiP, 1532P<br />
COL1A1: 215P<br />
COX-2: 538P, 720P, 1026P, 1502P, 1652P<br />
Cparp: 154P<br />
C-RAF: 1349<br />
CSF1R: 102IN<br />
CTC: 223P<br />
CTDNEP1: 25IN<br />
CTGF: 1682P<br />
CTLA4: 22IN, 46IN, 53IN, 71IN, 175PD, 915P,<br />
1149<br />
CTNNB1: 7IN, 12IN, 25IN<br />
CXCL1: 228P<br />
CXCL10: 865P<br />
CXCL12: 1688PD
Annals Of Oncology translational research index<br />
CXCL14: 925P<br />
CXCL3: 228P<br />
CXCL9: 865P<br />
CXCR4: 1033P<br />
CXCR7: 1688PD<br />
Cyclin D1: 165, 483P, 1026P, 1027P, 1031P,<br />
1118PD, 1700<br />
Cyclin dependent kinases: 543P, 769<br />
Cyclin E1: 769<br />
Cycline H: 527PD<br />
CYFRA 21-1: 1310P<br />
CYFRA: 505, 1203P<br />
Cyp P450 2D6: 1034P<br />
CYP1: 17IN<br />
CYP11A1: 928P<br />
CYP17: 325PD, 925P, 927P, 946<br />
CYP17A1: 48IN<br />
CYP1A1: 374P, 724P<br />
CYP1A2: 850P<br />
CYP2C19: 1293P<br />
CYP2C9: 850P, 1667P<br />
CYP2D6: 17IN, 129IN, 189P, 196P, 295P<br />
CYP3A: 1678P<br />
CYP3A4: 291P, 1293P, 1578P, 1667P<br />
CYP3A5: 724P, 1667P<br />
Cytochrome P450: 506, 873, 1618P<br />
D2: 129IN<br />
DAPK1: 221P<br />
DAXX: 12IN<br />
DDR: 61IN, 81IN, 102IN, 119IN<br />
DDX3X: 25IN, 159P<br />
DEPDC1: 1671P<br />
DHEA: 277P<br />
DHFR: 1211<br />
DHH: 720P<br />
DLC1: 221P, 1701<br />
DLD30: 245O<br />
DLL4: 642<br />
DNA: 2IN, 10IN, 11IN, 20IN, 42IN, 5OIN, 61IN,<br />
86IN, 96IN, 116IN, 149P, 150P, 156P, 161P,<br />
168O, 171O, 185P, 22OP, 221P, 225P, 240,<br />
245O, 293P, 376, 397, 428P, 435TiP, 484P, 516P,<br />
518O, 527PD, 537P, 543P, 544P, 548P, 549P,<br />
613P, 656, 666O, 686P, 703P, 699P, 806P, 812P,<br />
813P, 85OP, 920P, 964TiP, 968O, 971PD, 988P,<br />
1025P, 1028P, 1032P, 1052, 1118PD, 1119PD,<br />
1121P, 1122P, 1123P, 1135P, 1139P, 1145, 1147,<br />
1192PD, 1242P, 1244P, 1266P, 1273P, 1315,<br />
1316, 1339, 1393P, 1649P, 1651P, 1662P, 1664P,<br />
1677P, 1679P, 1686P<br />
DPD: 550P, 1211<br />
DPYSL: 1701<br />
DR5: 662TiP<br />
D-SER: 483P<br />
DTX2: 215P<br />
DWS: 1032P<br />
Dysadherin: 838P<br />
E1: 277P<br />
E2: 277P<br />
E6: 62IN<br />
E7: 62IN<br />
EBER: 1026P<br />
EC: 861P<br />
E-cadherin: 145P, 483P, 511PD, 548P, 675P, 838P,<br />
1026P, 1693P, 1695P, 1700<br />
ECSCR: 178P<br />
EGF: 536P, 544P, 742P, 1464P, 1652P, 1668P<br />
EGFR: 6IN, 7IN, 19IN, 24IN, 28IN, 29IN, 58IN,<br />
60IN, 62IN, 63IN, 78IN, 81IN, 82IN, 83IN,<br />
85IN, 90IN, 105IN, 106IN, 119IN, 138IN,<br />
143PD, 158P, 170O, 179P, 180P, 182P, 183P,<br />
190P, 194P, 211P, 213P, 218P, 232, 234, 237,<br />
257P, 343P, 347P, 353P, 412O, 438O, 439O,<br />
467P, 509TiP, 525PD, 526PD, 533P, 535P, 536P,<br />
537P, 544P, 549P, 558P, 563P, 570P, 578P, 597P,<br />
605P, 606P, 630, 631, 641, 664TIP, 665TIP,<br />
667PD, 720P, 868, 970PD, 1016O, 1017O,<br />
1021PD, 1026P, 1027P, 1029P, 1031P, 1036P,<br />
1145, 1176P, 1187P, 1190P, 1193P, 1197P,<br />
1198P, 1209, 1211, 1218, 1226O, 1227O, 1228O,<br />
1229PD, 1232PD, 1251P, 1252P, 1254P, 1255P,<br />
1257P, 1258P, 1259P, 1260P, 1261P,<br />
1262P,1263P, 1264P, 1265P, 1266P, 1269P,<br />
1270P, 1271P, 1272P, 1273P, 1274P, 1277P,<br />
1280P, 1282P, 1283P, 1284P, 1286P, 1288P,<br />
1289P, 1291P, 1292P, 1293P, 1295P, 1300P,<br />
1302P, 1309P, 1310P, 1311P, 1313, 1315, 1316,<br />
1318, 1323, 1325, 1328, 1330, 1331, 1333,1336,<br />
1338, 1339, 1340, 1342, 1343, 1344, 1345, 1346,<br />
1347, 1348, 1362TiP, 1366TiP, 1367TiP, 1396P,<br />
1530P, 1644PD, 1649P, 1651P, 1652P, 1655P,<br />
1659P, 1662P, 1666P, 1668P, 1690P, 1692P, 1701<br />
ELAM-1: 732P<br />
EML4: 81IN, 108IN, 119IN, 195P, 1187P, 1193P,<br />
1195P, 1208, 1324<br />
EOMES: 71IN<br />
EP4: 1033P<br />
EPAS-1: 354P<br />
EpCAM: 217P, 472P, 495P, 911P, 1175P, 1313,<br />
1512, 1650P, 1696P<br />
EPHA4: 1691P<br />
Epiregulin: 526PD, 536P, 1027P<br />
ER: 14IN, 15IN, 19IN, 21IN, 151P, 172O, 176PD,<br />
197P, 199P, 201P, 205P, 206P, 216P, 245O,<br />
247O, 248O, 249PD, 252PD, 257P, 258P, 259P,<br />
264P, 265P, 266P, 278P, 279P, 283P, 284P, 288P,<br />
289P, 291P, 294P, 298P, 299, 301, 302, 305, 308,<br />
309, 323PD, 325PD, 336P, 340P, 343P, 345P,<br />
347P, 350P, 353P, 362P, 368P, 370P, 372P, 373P,<br />
376, 377, 378, 381, 384, 386, 397, 399, 406TIP,<br />
414PD, 513PD, 923P, 11090P, 1397P, 1398P,<br />
1656P, 1702<br />
ERCC1: 7IN, 77IN, 187P, 207P, 524P, 527PD,<br />
613P, 628, 803P, 990P, 1026P, 1052, 1170P,<br />
1193P, 1211, 1226O, 1244P, 1645PD<br />
Erk: 108IN, 119IN, 153P, 456P, 475P, 483P, 1075P,<br />
1349, 1491P, 1647PD, 1652P, 1668P<br />
ERP29: 1032P, 1119P<br />
E-selectin: 791PD, 833P, 1236PD, 1657P<br />
ESR1: 17IN<br />
ESR2: 17IN<br />
ETPA: 1701<br />
EWS/FLI1: 92IN<br />
EXE: 324PD<br />
EZH2: 208P, 1066PD<br />
F3: 906P<br />
FAK: 179P, 384, 1027P, 1659P<br />
FASCIN-1: 1026P<br />
FC: 64IN<br />
FCGR: 237<br />
FCyR: 472P, 495P<br />
FGF: 20IN, 52IN, 319O, 822P, 966O<br />
FGFR: 7IN, 50IN, 81IN, 119IN, 181P, 319O,<br />
417PD, 446PD, 737P, 744P, 814P, 81TIP<br />
FHIT: 675P<br />
FLAGS: 668PD<br />
FLR-B/FOX: 629<br />
FLT: 115IN, 1066PD,1067PD, 1194P, 1479PD<br />
FOXA1: 23P<br />
FOXL2: 993P<br />
FOXO3a: 185P<br />
FOXP3: 939P, 1314<br />
FPGH: 1211<br />
FPGS: 1211<br />
FRAP1: 812P<br />
FYC: 102IN<br />
GARFT: 1211<br />
Gata3:71IN, 102IN<br />
G-CSF: 246O, 1085P<br />
GDNF: 225P<br />
GGH: 542P<br />
GHRL2: 223P, 465P<br />
GLI1: 1309P, 1663P, 1693P<br />
GLUT1: 166, 562P, 1033P, 1180PD<br />
GLUT2: 166<br />
GM-CSF: 723P, 813P, 943P, 1672P<br />
GNAS: 12IN, 227P<br />
GRIN2A: 11IN<br />
GRM3: 11IN<br />
GSK-3: 156P, 1026P<br />
GSTM1: 1078P<br />
GSTT1: 1078P<br />
H2AX: 435TIP<br />
H3: 442O<br />
H-cadherin: 548P<br />
HDI: 150P<br />
Hedgehog: 62IN, 63IN, 449PD, 463P, 720P,<br />
1111PD, 1112PD, 1309P, 1663P, 1694P<br />
HENT1: 709P<br />
HER2: 7 IN, 15IN, 19IN, 21IN, 28IN, 44IN, 50IN,<br />
57IN, 78IN, 81IN, 83IN, 102IN, 103IN, 104IN,<br />
108IN, 119IN, 121IN, 172O, 180P,197P, 199P,<br />
201P, 202P, 205P, 206P, 216P, 217P, 228P, 231P,<br />
241, 243, 245O, 246O, 248O, 252PD, 254PD,<br />
255PD, 257P, 258P, 259P, 264P, 265P, 266P,<br />
267P, 268P, 269P, 270P, 271P, 272P, 274P, 275P,<br />
276P, 278P, 279P, 283P, 284P, 286P, 288P, 289P,<br />
291P, 292P, 294P, 298P, 299, 300, 301, 303, 304,<br />
308, 309, 315TIP, 316TIP, 317O, 318O, 319O,<br />
320PD, 321PD, 322PD, 323PD, 324PD, 325PD,<br />
336P, 342P, 343P, 344P, 345P, 346P, 347P, 352P,<br />
353P, 356P, 357P, 362P, 364P, 365P, 366P, 368P,<br />
370P, 373P, 377, 378, 379, 380, 381, 386, 387,<br />
389, 391, 392, 395, 396, 397, 399, 402, 404,<br />
406TIP, 407TIP, 408TIP, 409TIP, 414PD,<br />
446PD, 454P, 458P, 464P, 467P, 470P, 476P,<br />
494P, 496P, 509TiP, 513PD, 515P, 675P, 677P,<br />
678P, 699P, 703P, 720P, 750, 762, 768O, 970PD,<br />
974PD, 1142P, 1185P, 1228O, 1232PD, 1252P,<br />
1288P, 1290P, 1311P, 1313, 1322, 1397P, 1398P,<br />
1450P, 1646PD, 1647PD, 1656P, 1657P, 1659P,<br />
1664P, 1675P, 1698P, 1702<br />
HER3: 7IN, 202P, 214P, 226P, 231P, 343P, 467P,<br />
496P, 720P, 970PD, 974PD, 1185P, 1690P<br />
HER4: 7IN, 11IN, 50TiP, 970PD, 1185P, 1228O,<br />
1252P<br />
HGF: 70IN, 143PD, 205P, 222P, 443PD, 444PD,<br />
669PD, 687P, 720P, 791PD, 833P, 1291P,<br />
1365TIP<br />
HIF: 109IN, 156P, 354P, 532P, 751, 794PD, 830P,<br />
832P, 835P, 869, 1033P, 1170P, 1180PD, 1685P<br />
HIPEC: 774<br />
HK II: 166, 1033P<br />
HLA-A24: 460P<br />
HLA-A2402: 1671P<br />
HLA-DR: 197P<br />
HMGB1: 495P<br />
HMOX-1: 971PD<br />
HOX: 147P, 223P<br />
HRAS: 1311P<br />
HSP27: 900PD<br />
HSP90: 7IN, 57IN, 61IN, 66IN, 156P, 215P, 347P,<br />
438O, 922P, 1332, 1679P<br />
HXR3: 988P<br />
ICAM: 431, 1236PD, 1657P<br />
ICOS: 71IN<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds480 | ix605<br />
translational<br />
research<br />
index
translational<br />
research<br />
index<br />
translational research index<br />
IDH: 23IN, 421P, 1701<br />
IFI16: 1701<br />
IFN alpha: 224P<br />
IFN gama: 163P, 622, 865P<br />
IFN: 503<br />
IGF: 90IN, 202P, 776TIP<br />
IGFBP3: 92IN, 411O, 906P, 1030P<br />
IGFR: 13IN, 90IN, 217P, 301, 606P, 776TIP, 830P,<br />
917P, 1030P, 1319, 1322, 1497P, 1668P, 1703IN<br />
IGluR: 11IN<br />
IHH: 720P<br />
IKBA: 148P<br />
IKBKAP: 1032P, 1119P<br />
IL-10: 190P, 1464P, 1672P<br />
IL-12: 17IN, 163P, 222P, 1672P<br />
IL-13: 480P<br />
IL-17: 17IN, 71IN, 150P, 480P<br />
IL-1B: 473P, 480P<br />
IL-2: 224P, 723P<br />
IL-22: 480P<br />
IL-23: 150P<br />
IL-2RA: 865P<br />
IL-4: 480P, 510TiP, 1314, 1672P<br />
IL-5: 480P<br />
IL-6: 153P, 165, 222P, 228P, 354P, 476P, 720P,<br />
791PD, 833P, 1088P, 1464P, 1693P<br />
IL-7: 813P<br />
IL-8: 52IN, 190P, 222P, 354P, 732P, 791PD, 1194P,<br />
1464P, 1657P<br />
ILKAP: 1701<br />
IL-RB2: 17IN<br />
INI1: 92IN<br />
Integrin b1: 179P<br />
IPO8: 1701<br />
IRF4: 66IN,<br />
JAK: 102IN, 483P<br />
KDM6A: 25IN<br />
KDR: 7IN, 266P<br />
Ki-67: 13IN, 15IN, 19IN, 71IN, 73IN, 102IN,<br />
191P, 200P, 201P, 233, 268P, 270P, 276P, 281P,<br />
284P, 303, 305, 306, 343P, 364P, 366P, 406TiP,<br />
442O, 443PD, 457P, 538P, 562P, 575P, 1026P,<br />
1158P, 1160P, 1164P, 1167P, 1695P<br />
KIF22: 1701<br />
KIF5B: 119IN<br />
KIT: 19IN, 92IN, 94IN, 102IN, 174O, 222P, 227P,<br />
244, 385, 417PD, 705P, 706P, 707P, 708P, 737P,<br />
814P, 880, 1067PD, 1118PD, 1123P, 1157O,<br />
1478O, 1479PD, 1486PD, 1489P, 1491P, 1516,<br />
1541, 1679P<br />
KIAA0664: 1701<br />
KLC1: 119IN<br />
KLF7: 225P<br />
KLK: 223P<br />
KOC1: 460P, 1671P<br />
KRAS: 6IN, 7IN, 12IN, 28IN, 78IN, 83IN, 119IN,<br />
143PD, 170O, 180P, 207P, 208P, 21OP, 211P,<br />
214P, 218P, 237, 438O, 442O, 475P, 520O,<br />
525PD, 526PD, 532P, 533P, 535P, 536P, 537P,<br />
543P, 548P, 549P, 555P, 557P, 558P, 561P, 564P,<br />
565P, 568P, 570P, 574P, 580P, 582P, 587P, 593P,<br />
594P, 597P, 598P, 605P, 606P, 608P, 629, 630,<br />
631, 641,643, 647, 649, 651, 653, 665TiP,<br />
667PD, 696P, 703P, 720P, 1017O, 1187P, 1190P,<br />
1193P, 1226O, 1233PD, 1248P, 1266P, 1282P,<br />
1302P, 1307P, 1311P, 1315, 1316, 1322, 1339,<br />
1349, 1362TiP, 1366TiP, 1647PD, 1649P, 1652P,<br />
1654P, 1664P, 1701<br />
KYNU: 1701<br />
LAP3: 1701<br />
LDHA: 1033P<br />
Lea: 619<br />
LEF1: 1032P<br />
Leptin: 190P, 473P, 483P, 1603P<br />
Lex: 619<br />
Ley: 619<br />
LGR5: 720P<br />
LINE1: 225P<br />
LKB1: 180B<br />
LMO4: 1655P<br />
LMP1: 221P, 1027P<br />
LRIG: 544P<br />
LRRK2: 51IN<br />
LTK: 102IN<br />
MA2K1: 1030P<br />
MAGE: 1182P<br />
Mamaglobin: 304<br />
MAP: 102IN, 154P<br />
MAP1B: 1701<br />
MAP2K4: 102IN<br />
MAP3K1: 102IN<br />
MAPK: 119IN, 143PD, 154P, 173O, 348P, 451P,<br />
475P, 483P, 483P, 869, 1026P, 1030P, 1075P,<br />
1039P, 1185P, 1659P, 1668P, 1674P, 1693P<br />
MAPT: 1026P<br />
Matrix metalloproteinases (MMPs): 384, 617<br />
MCC: 1032P<br />
MCL-1: 1027P<br />
MCM2: 240<br />
MCMs: 240<br />
MCPH1: 1662P<br />
MCT1: 1033P<br />
MDC1: 686P, 1661P, 1662P<br />
MDM2: 7IN, 92IN, 93IN, 156P, 1122P<br />
MDR1: 196P<br />
MEK: 11IN, 90IN, 108IN, 119IN, 143PD, 154P,<br />
173O, 451P, 456P, 475P, 609P, 147P, 1124P,<br />
1193P, 1197P, 1349, 1647PD, 1674P<br />
Merlin protein: 419PD<br />
MGMT: 23IN, 24IN, 416PD, 421P, 424P, 435TiP,<br />
548P, 830P, 1676P<br />
MICA: 160P, 1690P<br />
MINT: 225P, 543P<br />
MIP1: 224P, 865P<br />
miRNA: 60IN, 143PD, 145P, 148P, 149P, 150P,<br />
159P, 160P, 169O, 178P, 188P, 202P, 205P, 215P,<br />
223P, 226P, 250PD, 305, 385, 426P, 525P, 535P,<br />
542P, 615, 686P, 723P, 807P, 1025P, 1027P,<br />
1030P, 1031P, 1139P, 1170P, 1242P, 1243P,<br />
1309P, 1312, 1532P, 1646PD, 1653P, 1655P,<br />
1661P, 1672P, 1679P, 1682P, 1693P<br />
Mismatch repair deficiency (dMMR): 516P, 521O,<br />
524P, 703P<br />
MLH1: 516P, 543P, 703P, 720P, 1311P<br />
MLL2: 25IN, 102IN<br />
MMP-1: 287P<br />
MMP-2: 146P, 384, 794PD, 1682P<br />
MMP-3: 224P<br />
MMP-7: 1700<br />
MMP-8: 910P<br />
MMP-9: 146P, 384, 545P, 617<br />
MMSET: 686P, 1661P<br />
MPHOSPH1: 1671P<br />
MSH2: 7IN, 516P, 703P, 720P<br />
MSH3: 720P<br />
MSH6: 516P, 703P<br />
MSI-H: 656, 675P<br />
MSN: 1701<br />
MSP: 1532P<br />
MST1R: 1532P<br />
MST2: 1684P<br />
MT: 1203P<br />
MTHFR: 640, 1244P, 1326<br />
Annals Of Oncology<br />
mTOR: 2IN,13IN, 52IN, 57IN, 65IN, 76IN, 83IN,<br />
90IN, 92IN, 107IN, 108IN, 130IN, 154P, 173O,<br />
185P, 236, 318O, 324PD, 350P, 352P, 405TiP,<br />
419PD, 420PD, 442O, 450PD, 452P, 454P, 462P,<br />
532P, 717P, 781TiP, 783O, 798PD, 812P, 814P,<br />
818P, 819P, 822P, 823P, 828P, 837P, 839P, 840P,<br />
841P, 845P, 846P, 849P, 852P, 869, 873, 879,<br />
881, 890TiP, 917P, 1017O, 1026P, 1031P,<br />
1154O, 1156O, 1157O, 1491P, 1107TiP, 1162P,<br />
1165P, 1685P, 1703IN<br />
MUC1: 619, 622, 723P<br />
MUC2: 619, 719P<br />
MUC5AC: 619<br />
MUC6: 720P<br />
MVD: 1236PD<br />
MYC: 102IN, 202P, 490P, 832P, 916P, 1185P, 1210,<br />
1700<br />
MYH9: 102IN<br />
MYST1: 215P<br />
NANOG: 149P, 604P<br />
N-cadherin: 1695P<br />
NeuGc-GM3: 1238PD<br />
Neurokinin receptor: 1550PD, 1575P<br />
NF1: 92IN<br />
NF2: 419PD<br />
NF-kB: 17IN, 66IN, 148P, 150P, 348P, 752, 807P,<br />
1531P, 1680P<br />
NGF-B: 865P<br />
NK-1: 129IN<br />
NKG2D: 160P<br />
NMP-52: 239<br />
NOS2: 1681P<br />
NOTCH1: 62IN, 216P, 448PD, 463P, 642, 720P,<br />
996P<br />
NOXA: 66IN<br />
NPRA: 748<br />
NQO1: 235<br />
NRAS: 7IN, 119IN, 227P, 574P, 1649P<br />
NRP1: 1236PD<br />
NRP1: 546P<br />
NRP2: 915P<br />
NSE: 886, 911P, 1203P<br />
NTX: 132O, 1321<br />
OCT-4: 149P, 720P<br />
OPN: 791PD, 833P<br />
Osteopontin: 833P<br />
p14: 543P, 1118PD<br />
p16: 86IN, 221P, 543P, 1018O, 1045P, 1118PD,<br />
1211<br />
p19: 150P<br />
P1NP: 805P, 945<br />
p21: 575P<br />
P38: 348P, 1075P<br />
P40: 150P, 181P<br />
P4EBP1: 457P<br />
P4HB: 1701<br />
p53: 7IN, 12IN, 20IN, 25IN, 50IN, 61IN, 62IN,<br />
92IN, 93IN, 102IN, 156P, 170O, 180P, 187P,<br />
291P, 575P, 615, 628, 675P, 686P, 703P, 979P,<br />
1026P, 1031P, 1068PD, 1122P, 1192PD, 1311P,<br />
1661P, 1662P<br />
P63: 1026P<br />
p70S6K: 236, 420PD<br />
P85: 419PD<br />
P95: 243, 267P, 347P<br />
PAI: 615<br />
pAkt: 60IN, 154P, 343P, 405TiP, 406TiP, 442O,<br />
443PD, 457P, 474P, 1026P, 1031P, 1668P, 1676P<br />
PAL1: 249PD<br />
PAM50: 176PD<br />
PAP: 943P<br />
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PARP: 7IN, 20IN, 21IN, 35IN, 36IN, 55IN, 61IN,<br />
66IN, 428, 972PD, 988P<br />
Paxillin: 1659P<br />
PBRM1: 51IN<br />
PC1/2: 236<br />
P-cadherin: 1026P<br />
PD-1: 22IN, 53IN, 71IN, 453P, 459P, 784O, 915P,<br />
1109O, 1237PD<br />
PDGF: 92IN, 102IN, 152P, 203P, 505, 507, 663TiP,<br />
732P, 814P, 835P, 865P, 1657P<br />
PDGFR: 92IN, 174O, 417PD, 446PD, 720P, 737P,<br />
744P, 880, 1027P, 1157O, 1349, 1478O, 1479PD,<br />
1486PD, 1494P, 1496P, 1516, 1687P<br />
PDK1: 185P<br />
PD-L1: 453P<br />
PDX1: 215P<br />
p-EGFR: 1668P<br />
p-ER: 534P<br />
p-ERK: 443PD, 451P, 475P<br />
PGD: 1701<br />
PGF: 720P<br />
PGK1: 1170P<br />
P-glycoprotein: 364P, 481P, 486P, 873, 1678P<br />
PI3K: 2IN, 7IN, 13IN, 20IN, 2IN, 62IN, 65IN,<br />
70IN, 76IN,78IN, 83IN, 107IN, 108IN, 119IN,<br />
148P, 154P, 173O, 185P, 204P, 214P, 237, 318O,<br />
343P, 347P, 350P, 405TiP, 419PD, 442O,<br />
450PD, 452P, 454P, 457P, 458P, 483P, 532P,<br />
664TiP, 781TiP, 807P, 812P, 890TiP, 917P,<br />
1017O, 1030P, 1491P, 1656P, 1668P, 1675P,<br />
1676P, 1685P, 1693P<br />
PIAS4: 686P, 1661P<br />
PIGF: 203P, 1154O<br />
PIK: 548P<br />
PIK3CA: 20IN, 50IN, 102IN, 108IN, 119IN, 180P,<br />
202P, 204P, 243, 406TiP, 442O, 452P, 457P,<br />
574P, 630, 667PD, 675P, 696P, 812P, 1017O,<br />
1030P, 1193P, 1649P, 1656P<br />
PIP3: 2IN<br />
PKM2: 1308P<br />
PLGF: 1236PD<br />
p-MAPK: 406TiP<br />
p-MEK: 475P<br />
p-MET: 443PD<br />
PMS1/2: 516P<br />
PNPO: 915P<br />
POSTN: 914P<br />
PPARγ: 590P<br />
PPP2R1B: 1701<br />
PR: 21IN, 197P, 199P, 201P, 205P, 248O, 249PD,<br />
257P, 258P, 259P, 264P, 265P, 266P, 278P, 279P,<br />
284P, 291P, 298P, 302, 323PD, 343P, 353P,<br />
357P, 370P, 376, 377, 378, 381, 386, 397,<br />
406TiP, 414PD, 513PD, 1398P, 1702<br />
PROM1: 720P<br />
PS6: 154P, 443PD, 457P<br />
PSA: 46IN, 87IN, 893O, 900PD, 901PD, 902P,<br />
905P, 906P, 907P, 908P, 911P, 912P, 914P, 917P,<br />
918P, 919P, 920P, 922P, 923P, 925P, 929P, 930P,<br />
934P, 935P, 938P, 940P, 950, 951, 952, 953, 961,<br />
962TiP, 963TiP, 964TiP<br />
PSF: 233<br />
PSMA: 915P<br />
pSTAT3: 501<br />
PTCH1: 25IN, 720P, 1032P, 1119P, 1121P, 1309P,<br />
1663P<br />
PTCH2: 720P<br />
PTEN: 7IN, 12IN, 20IN, 55IN, 107IN, 108IN,<br />
119IN, 173O, 202P, 204P, 343P, 406TiP, 457P,<br />
458P, 532P, 548P, 630, 890TiP, 917P, 922P,<br />
1026P, 1031P, 1656P<br />
PTGR1: 1701<br />
PTK7: 539P<br />
PTPN12: 20IN, 353P<br />
p-VHL: 835P<br />
Rad51: 1662P<br />
Raf: 92IN, 143PD, 173O, 475P, 874, 1349, 1647PD<br />
RANKL: 49IN, 316TiP, 348P, 1108TiP<br />
RAP1A: 1701<br />
RAP80: 807P<br />
RARB2: 293P, 1211<br />
Ras: 143PD, 173O, 242, 1146, 1349, 1491P,<br />
1647PD<br />
RASSF: 221P, 1211<br />
RB1: 7IN, 50IN<br />
RDH5: 928P<br />
RESISTIN: 190P,<br />
RET: 7IN, 81IN, 119IN, 417PD, 445PD, 737P,<br />
814P<br />
RFC: 1211<br />
RHO: 947<br />
RIZ1: 221P<br />
RNA: 2IN, 100IN, 145P, 147P, 159P, 177PD, 216P,<br />
223P, 245O, 426P, 769, 803P, 1025P, 1031P,<br />
1032P, 1393P, 1673P, 1684P<br />
RNF113: 1701<br />
RNF43: 12IN, 144PD, 460P<br />
Robo4: 178P<br />
RON: 471P, 492P, 1532P<br />
RORA: 225P<br />
ROS: 7IN, 78IN, 81IN, 82IN, 119IN, 195P,<br />
1119PD<br />
RPS3: 1701<br />
RPS5: 1701<br />
Rrca1: 290P<br />
RRM1: 77IN, 144PD, 187P, 1645PD<br />
RRM2: 187P<br />
RSK: 1674P<br />
RUNX1: 102IN<br />
RyR2: 1682P<br />
S100: 227P, 919P<br />
S1PR: 1651P<br />
S6: 1491P, 1674P<br />
S6K: 1491P<br />
Sca-1: 1685P<br />
SCC: 1203P,<br />
SCGF-B: 865P,<br />
SDF-1: 865P, 1033P<br />
SDH: 92IN<br />
SELENBP1: 910P<br />
SERCA2a: 1682P<br />
SF3B1: 102IN<br />
SHH: 720P<br />
SHP-1: 1075P<br />
shRNA: 30IN, 539P<br />
siRNA: 144PD, 145P, 169O, 185P, 188P, 205P,<br />
1659P, 1673P<br />
SKDR: 1194P<br />
SLC34A2: 195P<br />
SLC3A2: 1701<br />
SLC44A4: 963TiP<br />
SLCAM: 1194P<br />
SLCO1B1: 17IN<br />
SLD5: 233<br />
Slug: 145P<br />
SMAD: 12IN, 605, 720P<br />
SMARCA4: 25IN<br />
SMO: 720P, 1309P<br />
SMRP: 192P<br />
Snail: 145P<br />
SOCS: 153P, 1030P<br />
Somatostatin receptor: 1164P, 1703IN<br />
SOX-2: 149P, 216P<br />
SPARC: 720P<br />
SPHK1: 1651P<br />
sRAGE: 919P<br />
SRC: 44IN, 53IN, 501, 1481PD, 1659P, 1686P<br />
STAT: 150P, 153P, 483P<br />
STK11: 7IN, 180P, 22OP<br />
STNF-RS: 488P<br />
Survivin: 156P, 979P<br />
SWI-SNF: 51IN, 186P<br />
SYK: 65IN<br />
T2E: 922P<br />
T6235C: 374P<br />
TAK1: 348P<br />
Tau: 291P<br />
TCL1A: 17IN<br />
TGASE-2: 830P<br />
TGF beta: 169O, 197P, 865P, 919P, 1209, 1695P<br />
TGFBR1: 615<br />
TGF-α: 143PD, 1027P, 1209<br />
TGM2: 1701<br />
TIE-2: 471P, 492P, 975PD, 1027P, 1194P<br />
TIMP-1/2: 146P, 791PD, 833P<br />
TK1: 645<br />
TLG: 567P<br />
TLR: 719P, 813P<br />
Tn: 619<br />
TNFa: 163P, 190P, 476P, 480P<br />
TNFSF: 228P<br />
TOMM34: 460P<br />
Topoisomerase IIα: 202P, 245O, 291P, 406TiP,<br />
485P, 1170P<br />
TP: 542P, 550P<br />
TPS: 302<br />
TR4: 463P<br />
T-regulatory cells (TREG): 174O<br />
TRIK128: 1701<br />
TrkB: 188P<br />
TROLOX: 473P<br />
TS: 187P, 550P, 1211, 1242P, 1243P<br />
TSC1: 5OIN<br />
TSC2: 12IN<br />
TSP-1: 354P, 919P<br />
TSPYL5: 17IN<br />
TTF1: 181P<br />
TTK: 1671P<br />
Twist: 1693P<br />
TX: 313<br />
TXR: 1170P<br />
TYMS: 1170P<br />
UBA6: 1701<br />
UBC9: 686P, 1661P<br />
URLC10: 1671P<br />
USP5: 1701<br />
VCAM-1: 732P<br />
VEGF: 52IN, 54IN, 57IN, 91IN, 109IN, 152P,155P,<br />
156P, 174O, 184P, 194P, 197P, 203P, 222P,<br />
292P, 323PD, 354P, 377, 417PD, 435TiP,<br />
448PD, 493P, 501, 505, 507, 529PD, 532P, 578P,<br />
581P, 594P, 600P, 633, 642, 659, 663TiP, 696P,<br />
734P, 737P, 751, 752, 791PD, 796PD, 814P,<br />
822P, 829P, 831P, 835P, 837P, 840P, 841P, 842P,<br />
843P, 855P, 869, 876, 829TiP, 966O, 1080P,<br />
1154O, 1159P, 1160P, 1194P, 1245P, 1687<br />
VEGF-A: 155P, 198P, 241, 546P, 720P, 724P, 734P,<br />
794PD, 829P, 830P, 919P, 1026P, 1154O, 1194P,<br />
1236PD, 1239P, 1657P, 1687<br />
VEGF-B: 720P<br />
VEGF-C: 734P, 829P, 919P, 1026P, 1657P, 1687P<br />
VEGF-D: 1687P<br />
VEGFR: 91IN, 174O, 198P, 200P, 222P, 319O,<br />
347P, 354P, 417PD, 445PD, 446PD, 448PD,<br />
460P, 471P, 492P, 545P, 609P, 617, 659, 720P,<br />
724P, 734P, 737P, 740P, 744P, 794PD, 796PD,<br />
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811P, 814P, 821P, 823P, 829P, 830P, 835P, 837P,<br />
841P, 842P, 875, 880, 897O, 1026P, 1027P,<br />
1115PD, 1154O, 1157O, 1194P, 1236PD, 1239P,<br />
1245P, 1287P, 1349, 1479PD, 1496P, 1648P,<br />
1652P, 1657P, 1687P<br />
VGLL3: 906P<br />
VHL: 52IN, 501, 794PD, 830P, 832P, 835P, 869<br />
ViViD: 163P<br />
WEE1: 20IN<br />
WIF1: 221P<br />
Wnt: 463P, 545P, 617, 720P, 1700<br />
WT1: 490P, 1533P<br />
XIAP: 156P<br />
XPD: 1244P<br />
XRCC: 527PD, 1052<br />
YEATS4: 93IN<br />
YPK-1: 723P<br />
ZEB-1/2: 145P, 1693P<br />
ZNF415: 1032P, 1119P<br />
αv integrins: 965TiP<br />
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