stage IIIA

Corso Integrato di Clinica Medica
ONCOLOGIA MEDICA
AA 2010 - 2011
LUNG CANCER. IV.
THERAPY. I.
NON SMALL CELL LUNG CANCER
Prof. Alberto Riccardi

TREATMENT OF LUNG CARCINOMA
* overall treatment approach to pts with LC
formulated after:
- histologic diagnosis, and
- anatomic and physiologic staging;
* pts encouraged to stop smoking (those
who do fare better than those continuing to
smoke)

SUMMARY
OF TREATMENT APPROACH

NON SMALL CELL LUNG CARCINOMA
Summary of treatment approach. I.
Stages IA, IB, IIA, IIB and some IIIA
* Stages IA, IB, IIA, and IIB → surgical resection;
- Stage IB: discussion of risk / benefits of adjuvant CT
(not routinely given);
- Stage II: adjuvant CT;
- potential curative RT for "nonoperable" pts;
* stage IIIA with "minimal N2 involvement” (discovered at
thoracotomy or mediastinoscopy) → surgical resection
with complete mediastinal lymph node dissection (also
consideration of neoadjuvant CT) ;
- postoperative RT for pts with N2 disease (if no
neoadjuvant CT given)

NON SMALL CELL LUNG CARCINOMA
Summary of treatment approach. II.
Stage IIIA with selected types of stage T3
* tumors with chest wall invasion (T3) = en bloc
resection of tumor with involved chest wall (± post -
operative RT);
- superior sulcus (Pancoast's, T3) tumors = preoperative
RT (30 - 45 Gy) → en bloc resection of involved lung and
chest wall (± postoperative RT or intraoperative
brachytherapy);
* proximal airway involvement (< 2 cm from carina, T3)
without mediastinal nodes = sleeve resection (preserving
distal normal lung) or pneumonectomy

NON SMALL CELL LUNG CARCINOMA
Summary of treatment approach. III.
Stages IIIA "advanced, bulky, clinically evident
N2" (discovered preoperatively)
and IIIB disease includible in tolerable RT port
* potential curative RT + CT (with reasonable good PS
and general medical condition);
- RT alone (if otherwise);
* consider neoadjuvant CT and surgical resection for
IIIA disease with advanced N2 involvement

NON SMALL CELL LUNG CARCINOMA
Summary of treatment approach. IV.
Stage IIIB with carinal invasion (T4) but no N2 involvement
* consider pneumonectomy with tracheal sleeve
resection with direct reanastomosis to contralateral
mainstem bronchus

NON SMALL CELL LUNG CARCINOMA
Summary of treatment approach. IV.
Stage IIIB with carinal invasion (T4) but no N2 involvement
* consider
pneumonectomy
with tracheal sleeve
resection with direct
reanastomosis to
contralateral
mainstem bronchus
* carinal reconstruction with moderate amount of airway resected →
trachea anastomosed end to end with either right or left mainstem
bronchus, with the contralateral bronchus reimplanted into side of
trachea (upper right diagram = more commonly used technique)

NON SMALL CELL LUNG CARCINOMA
Summary of treatment approach. V.
More advanced stage IIIB and stage IV disease
* RT to symptomatic local sites;
* CT for ambulatory pts (consider CT, cetuximab and
bevacizumab for selected pts);
* chest tube drainage of large malignant pleural
effusions;
* consider resection of primary tumor and isolated brain
or adrenal metastases

* limited stage (good performance status) = combination
CT + chest RT;
* extensive stage (good performance status) =
combination CT;
- complete responders (all stages): prophylactic cranial
RT;
* poor - performance - status pts (all stages):
- modified - dose combination CT;
- palliative RT
SMALL CELL LUNG CARCINOMA
Summary of treatment approach

* palliative radiotherapy for brain metastases, spinal cord
compression, weight - bearing lytic bony lesions,
symptomatic local lesions (nerve paralyses, obstructed
airway, hemoptysis not responding to CT);
* appropriate diagnosis and treatment of other medical
problems and supportive care;
* encouragement to stop smoking;
* entrance into clinical trial
LUNG CARCINOMA
All pts

TREATMENT BY STAGE
OF NON SMALL CELL LUNG
CARCINOMA

TREATMENT BY STAGE
OF NON SMALL CELL LUNG
CARCINOMA
LOCALIZED
OR LOCALLY ADVANCED DISEASE
(STAGES I, II and nonbulky IIIA)

STAGES I - II

STAGE I

STAGE I (T1a - b, N0, M0)
* T1 = ≤ 3 cm in greatest dimension, surrounded by lung or
visceral pleura, without bronchoscopic evidence of
invasion more proximal than lobar bronchus (i.e., not in
main bronchus):
- T1a = ≤ 2 cm in greatest dimension;
- T1b = > 2 - ≤ 3 cm in greatest dimension

STAGE I NON - SMALL CELL LUNG CANCER
* stage IA = T ≤ 2 cm surrounded by lung or visceral pleura, without
bronchoscopic evidence of invasion more proximal than lobar bronchus
(i.e., not in main bronchus); N0; M0;
* stage IB = - T > 2 - ≤ 3 cm + as for stage IA

STAGE II

STAGE IIA. I. T1a - T1b, N1, M0
* T1a, N1, M0 : T1a = < 2 cm, surrounded by lung or
visceral pleura, without bronchoscopic evidence of
invasion more proximal than lobar bronchus (i.e., not in
main bronchus); N1 (metastasis to ipsilateral peribronchial
and / or ipsilateral hilar lymph nodes, and intrapulmonary
nodes involved by direct extension of primary tumor); M0
* T1b, N1, M0: T1b = > 2 - ≤ 3 cm + as above; N1; M0

STAGE IIA. II. (T2a, N1, M0; T2b, N0, M0)
* T2a, N1, M0: T2a = > 3 - ≤ 5 cm or with any of following
features: involves main bronchus ≥ 2 cm distal to carina;
invades visceral pleura (PL1 or PL2); associated with
atelectasis or obstructive pneumonitis extended to hilar
region but not involving entire lung; N1 (metastasis to
ipsilateral peribronchial and / or ipsilateral hilar lymph
nodes, and intrapulmonary nodes involved by direct
extension of primary tumor); M0
* T2b, N0, M0: T2b = > 5 - ≤ 7 cm + as above; N0; M0

STAGE IIA (T1a - T1b, N1, M0; T2a, N1, M0; T2b, N0, M0)

STAGE IIB (T2b, N1, M0; T3, N0, M0)
* T2b, N1, M0: T2b = > 5 - ≤ 7 cm or with any of following:
involves main bronchus; ≥ 2 cm distal to carina; invades
visceral pleura (PL1 or PL2); associated with atelectasis or
obstructive pneumonitis not involving entire lung; N1
(metastasis to ipsilateral peribronchial and / or ipsilateral
hilar lymph nodes, and intrapulmonary nodes involved by
direct extension of primary tumor); M0
* T3, N0, M0: T3 = > 7 cm or directly invading any of following:
parietal pleural (PL3), chest wall (including superior sulcus
tumors), diaphragm, phrenic nerve, mediastinal pleura or
parietal pericardium; tumor in main bronchus (< 2 cm from
carina but without involvement of carina); associated
atelectasis or obstructive pneumonitis of entire lung or
separate tumor nodules in same lobe; N0; M0

STAGE IIB (T2b, N1, M0; T3, N0, M0)

STAGE II NON - SMALL CELL LUNG CANCER
*e.g., stage IIA = T1b,
N1, M0: T1b = > 2 - ≤ 3
cm; N1 (metastasis to
ipsilateral peribronchial
and / or ipsilateral
hilar lymph nodes);
M0);
* e.g., stage IIB = T3,
N0, M0: T3 = > 7 cm or
directly invading any of
following: parietal
pleural / chest wall (a),
diaphragm (b), phrenic
nerve, mediastinal
pleura (c) or parietal
pericardium (d); tumor
in main bronchus (< 2
cm from carina but
without involvement of
carina) (e);
associated atelectasis or obstructive pneumonitis of
entire lung or separate tumor nodules in same lobe; N0;
M0

TREATMENT BY STAGE
STAGES I - II NSCLC. I. Surgery
* pulmonary resection (pneunomectomy, lobectomy or
segmental, wedge or sleeve resection) = treatment of
choice for pts who can tolerate operation;
- with complete resection possible, 5 - yr survival for N0
disease ~ 60 - 80% (depending on size of tumor) and ~ 50%
for N1 disease (hilar node involvement);
* adjuvant chemotherapy after curative surgery for Stage II
disease;
- clinical trials of radiation therapy after curative surgery
for Stage II disease

TREATMENT BY STAGE
STAGES I - II NSCLC. II. Surgery
* extent of resection = surgical judgment based on
findings at exploration;
- in general, conservative resection encompassing
all known tumor → survival = that obtained with more
extensive procedures;
- → lobectomy preferred to pneumonectomy [and to
wedge resections and segmentectomies (↑ rate of
local relapse)]

TREATMENT BY STAGE
STAGES I - II NSCLC. III. Surgery
* pneumonectomy reserved for pts with tumors
involving multiple lobes (T3A) or very central tumors and
only be performed in pts with excellent pulmonary
reserve;
- in addition, pts undergoing right - sided
pneumonectomy after induction chemotherapy and
radiation therapy → high mortality rate = be carefully
selected before surgery;
- wedge resection and segmentectomy (potentially by
video assisted thoracic surgery, VATS) reserved for pts
with poor pulmonary reserve and small peripheral lesions

RIGHT PNEUMONECTOMY

RIGHT PNEUMONECTOMY

RIGHT LOBECTOMY

TREATMENT BY STAGE
STAGES I - II NSCLC. IV. Surgery
Lobectomy vs limited resection
* ↓ in local recurrence for pts treated with lobectomy compared with
pts treated with limited excision
but no significant difference in overall survival
(Ginsberg RJ & Rubinstein LV Ann Thorac Surg 95)

* from Cochrane Collaboration
group review, including 11
randomized trials of 1.910 pts who
underwent surgical interventions for
early stage (I - IIIA) NSCLC, 4 - yr
survival superior in pts with
resectable stage I - IIIA who
underwent resection and “Complete
ipsilateral Mediastinal Lymph Node
Dissection” (CMLND) compared with
those who underwent resection and
lymph node sampling (3 hilar + 3
mediastinal nodes) (p = .005)
TREATMENT BY STAGE
STAGES I - II NSCLC. V. Surgery
Surgery for localized disease (stages I - IIIa)
* disease - free survival with lymph node sampling vs systematic
sampling (CMLND) (Gajra A et al JCO 21; 1029, 2003)

WEDGE RESECTION OF LUNG CANCER
* part of lung lobe containing cancer
and small amount of healthy tissue around removed

WEDGE RESECTION OF
LUNG CANCER
* wedge resections and
segmentectomies, potentially
by VATS (Video - Assisted
Thoracic Surgery via
thoracoscopy, not usually
used for curative LC resection)
for pts with poor pulmonary
reserve and small peripheral
lesions

VIDEO - ASSISTED THORACIC SURGERY
- video - assisted thoracic surgery (VATS) via
thoracoscopy not usually used for curative lung cancer
resection, but useful for peripheral lung nodules in pts
with stage I disease and poor lung function;
- VATS advocated to ↓ postoperative impairment of lung
function, pain, length of hospital stay and recovery time
(but randomized, controlled trials not confirm advantages)
→ open thoracotomy still preferred surgical approach to
curative resection of lung cancer

VIDEO - ASSISTED THORACIC SURGERY
* for peripheral lung nodules in
pts with stage I disease and poor
lung function

VIDEO - ASSISTED THORACIC SURGERY
* also used for diagnostic purposes
to examine pleural surface and cavity
and biopsy peripheral lung nodules or
accessible mediastinal nodes (and to
drain and treat large malignant
effusions)

OVERALL OUTCOME OF SURGERY IN NSCLC. I.
(STAGES I, II and nonbulky IIIA)
* overall, complete pulmonary resection = treatment of
choice in pts with:
- stages IA, IB, IIA and IIB (T1 - 2, N0 - 1) disease;
- stage IIIA (T3, N0 - 1 + T1 - 3, N2) with favorable age,
cardiopulmonary function and anatomy (from team
approach, involving pulmonary medicine, thoracic surgery,
medical and radiation oncology);
[- neoadjuvant chemotherapy ± radiotherapy shrinks local
tumor and treats micrometastases → surgical resection
safer and more effective in “selected pts”]

OVERALL OUTCOME OF SURGERY IN NSCLC. II.
(STAGES I, II and nonbulky IIIA)
* 43% (43 / 100) of pts with NSCLC undergo
thoracotomy:
- 76% (= 33 / 43 pts): “curative resection”;
- 12%: explored only for disease extent, and
- 12%: palliative procedure with known disease left
behind;
* 30 - day hospital mortality = 3 and 6% for lobectomy
and pneumonectomy, respectively

OVERALL OUTCOME OF SURGERY IN NSCLC. III.
(STAGES I, II and nonbulky IIIA)
* overall, ~ 30% of pts (~ 10 / 33 pts) treated with
“curative resection” survive 5 yrs [~ 15% (5 pts)
survive for 10 yrs];
- most pts ultimately die of metastatic disease
(usually within 5 yrs from surgery)

OVERALL OUTCOME OF SURGERY IN NSCLC. IV.
(STAGES I, II and nonbulky IIIA)
* for stage IIIA, 5 - yr survival for N1 and N2 disease = ~
50% and 20%, respectively;
* however, technically resectable only 20% of pts with N2
disease (most pts discovered with N2 disease at
thoracotomy)

TREATMENT BY STAGE
STAGES I - II NSCLC. VI.
Radiotherapy with curative intent
* pts with stage I or II disease refusing surgery or not
candidates for pulmonary resection considered for
radiation therapy with curative intent (based on extent of
disease and volume of chest requiring irradiation);
* pts with malignant pleural effusion or cardiac
involvement not candidates for curative radiation
treatment;
- long - term survival for pts with all stages of LC who
receive radiation with curative intent ~ 20%

TREATMENT BY STAGE
STAGES I - II NSCLC. VII.
Radiotherapy with curative intent
* usually midplane doses of 55 - 60 mGy (5500 - 6000
rad, either split course or continuous fraction
radiotherapy);
- major concern: amount of lung parenchyma and
other thoracic organs (spinal cord, heart and
esophagus) included in treatment plan;
* deleterious effects of radiation on pulmonary
function often hampers treatment in pts with major
underlying pulmonary disease

TREATMENT BY STAGE
STAGES I - II NSCLC. VIII.
Radiotherapy with curative intent: side effects
Esophagitis
* most common side
effect of curative thoracic
radiation = acute
radiation esophagitis
during treatment, usually
self - limited

TREATMENT BY STAGE
STAGES I - II NSCLC. IX.
Radiotherapy with curative intent: side effects
* other side effects include fatigue, radiation myelitis
(spinal cord injury may be permanent, but usually
avoided by careful treatment planning) and radiation
pneumonitis (sometimes progressing to pulmonary
fibrosis)

TREATMENT BY STAGE
STAGES I - II NSCLC. X.
Radiotherapy with curative intent: side effects
Radiation pneumonitis
* risk proportional to dose
of radiation and volume of
lung within radiation field;
- full clinical syndrome
(dyspnea, fever, and
radiographic infiltrate
corresponding to treatment
port) in 5% of cases and
treated with glucocorticoids

RADIATION PNEUMONITIS

RADIATION PNEUMONITIS
* CT findings: a) homogeneous
slight increase in attenuation (2 - 4
mos after therapy); b) patchy
consolidation (1 - 12 mos after
therapy); c) non - uniform discrete
consolidation (most common; 3 mos
to 10 yrs after therapy)

TREATMENT BY STAGE
STAGES I - II NSCLC. XI.
Radiotherapy with curative intent
* Continuous Hyperfractionated, Accelerated RT
(CHART) = delivery of 36 treatments of 1.5 Gy 3 times /
day for 12 consecutive days (total dose of 54 Gy);
- 2 - yr survival rate > 20 - 30% (with more esophagites);
* brachytherapy (local radiotherapy delivered by placing
radioactive "seeds" in catheter into tumor bed) delivers ↑
local dose with sparing surrounding normal tissue

TREATMENT BY STAGE
STAGES I - II NSCLC. XII.
Radiotherapy with curative intent
* beside potentially curative, radiotherapy may
control primary tumor and preventing symptoms
related to local spreading and increase quality and
length of life of non - cured pts

TREATMENT BY STAGE
STAGES I - II NSCLC. XIII.
* pts with resected stage IA NSCLC receive no other
therapy but are at high risk of recurrence (~ 2 - 3% / yr) or
developing second primary lung cancer → follow these pts
with CT scans for first 5 yrs and consider entering onto
early detection and chemoprevention studies

TREATMENT BY STAGE
STAGES I - II NSCLC. XIV. Adjuvant chemotherapy. I.
* meta - analysis of > 4300 pts → trend toward ↑ survival
of ~ 5% at 5 yrs with cisplatin - based adjuvant therapy (p
= .08);
- however, from 3 subsequent randomized studies → no
significant survival advantage despite addition of more
"modern" postoperative adjuvant chemotherapy regimens;
- still however, since then at least 5 additional randomized
trials and two meta - analyses → survival benefit in
response to postoperative adjuvant - based therapy
→ adjuvant chemotherapy now routinely recommended in
NSCLC pts with good performance status and stage IIA - B
disease (though with modest beneficial effects)

Randomized studies of adjuvant chemotherapy in NSCLC
Study Treatment No. of pts 5-Year
Survival
(%)
ECOG 3590
(II–IIIA)
ALPI
(I–IIIA)
Big Lung Trial
(I–IIIB)
IALT
(IB–IIIA)
UFT
(IA–IB)
Surgery RT
vs. Surgery + post- op concurrent RT + cis / etoposide
Surgery alone
vs. Surgery + post- op mitomycin / vindesine / cisplatin
Surgery alone
vs. Surgery + post- op chemotherapy a
Surgery alone
vs. Surgery + post- op Cis + VP16 / vinca
Surgery alone
vs. Surgery + post- op UFT
CALGB IB (ASCO 06) Surgery alone
vs. Surgery + post- op carbo / paclitaxel
NCI-C
(IB–II)
ANITA
(IB, - IIIA)
Surgery alone
vs. Surgery + post- op Cis / vinorelbine
Surgery alone
vs. Surgery + post- op Cis / vinorelbine
242
246
603
606
189
192
405
361
488
469
172
172
241
241
433
407
39%
33%
51%
43%
Median
Survival
39 mos vs.
38 mos
NR 33 mos
34 mos
40%
44.5%
85%
88%
57%
59%
54%
69%
43%
51%
p Value
0.56
NR 0.59
0.90
NR < 0.03
NR 0.04
78 mos
95 mos
73 mos
94 mos
44 mos
66 mos
0.10
0.04
0.017

TREATMENT BY STAGE
STAGES I - II NSCLC. XV. Adjuvant chemotherapy. II.
* role of adjuvant chemotherapy for stage IB disease
undefined;
- subset analysis of randomized studies → no benefit in
pts with stage IB;
- one trial focusing on IB disease and using carboplatin
and paclitaxel (one of most commonly used regimens for
advanced disease) → 20% ↓ in death (ns)
→ pts with stage IB (T1b N0, M0) NSCLC not routinely
given adjuvant therapy

Adjuvant chemotherapy
Postoperative UFT (uracil - tegafur) in stage I adenocarcinoma
Nakagawa M et al Ann Oncol 16; 75, 2005
* post - operative UFT does not significantly ↑ survival of
pathological stage I NSCLC [UFT ↑ survival of pT1 pts (T1a - b, N0,
M0, p = .036), but not of pT2 pts]

Adjuvant chemotherapy. IIter.
Postoperative UFT (uracil - tegafur) in
stage I adenocarcinoma
* 999 pts with completely resected T1 - 2
N0M0 adenocarcinoma randomized (1994 -
97) between oral UFT for 2 yrs and no CT;
- 5 - yr OS ↑ in UFT with respect to
control - arm due to greatly ↑ OS of pts
with T2 disease (T2, N0, M0) in UFT arm
(84.9 vs 73.5%) (p = .005) (no # among pts
with T1 disease)
Kato H et al NEJM 2004

TREATMENT BY STAGE
STAGES I - II NSCLC. XVI. Neodjuvant chemotherapy
* no evidence of # in overall survival with neo - adjuvant
chemotherapy

TREATMENT BY STAGE. STAGE I - IIIA NSCLC. XVIbis.
NEOADJUVANT CHEMOTHERAPY
Preoperative chemotherapy in pts with resectable NSCLC: results of
the MRC LU22 / NVALT 2 / EORTC 08012 multicentre randomised
trial and update of systematic review (International Standard
Randomised Controlled Trial, no. ISRCTN25582437). I.
Gilligan D et al Lancet 2007; 369: 1929
Background: although surgery is best chance of cure for pts with
NSCLC, overall 5 - yr survival modest → improvements;
- in 1990s, from small trials reporting striking results with neo -
adjuvant chemotherapy → randomised trial designed to investigate
whether, in pts with operable NSCLC of any stage, outcomes be ↑ by
platinum - based chemotherapy before surgery
Methods: pts randomised to surgery alone (S) or 3 cycles of
platinum - based chemotherapy → surgery (CT - S);
- primary outcome = overall survival, analysed on an intention - to -
treat basis

idem. II.
Gilligan D et al Lancet 2007; 369: 1929
Results. I.: 519 pts randomised (S: 261, CT - S: 258) from 70 centres
in UK, Netherlands, Germany and Belgium (61% = clinical stage I,
31% = stage II and 7% = stage III);
- neo - adjuvant chemotherapy feasible (75% of pts had all 3 cycles
of chemotherapy), resulted in good response rate (49%) and downstaging
in 31% of pts and did not alter type or completeness of
surgery (lobectomy: S : 56%, CT - S: 60%, complete resection: S:
80%, CT - S: 82%), with post - operative complications not ↑ in CT - S
group and no impairment of quality of life

idem. III.
Gilligan D et al Lancet 2007; 369: 1929
- Results. II.: however, no benefit in
overall survival (p = .86)
- Interpretation: no evidence of # in
overall survival with neo - adjuvant
chemotherapy

TREATMENT BY STAGE
STAGES I - II NSCLC. XVII. Adjuvant radiotherapy
* after apparent complete resection, postoperative
adjuvant radiation therapy → not ↑ survival (and actually
detrimental to survival in N0 and N1 disease)

TREATMENT BY STAGE. XVIII.
Superior sulcus or Pancoast tumors. I.
* NSCLC of superior pulmonary sulcus (producing
Pancoast's syndrome) behave # than LC at other sites and
usually treated with combined radiotherapy and surgery

TREATMENT BY STAGE. XIX.
Superior sulcus or Pancoast tumors. II.
* usual preoperative staging procedures (including
mediastinoscopy and CT and PET scans) for tumor extent
and neurologic examination (and sometimes nerve
conduction studies) to document involvement or
impingement of nerves in region;
- with mediastinoscopy negative → curative approaches
be used in treating Pancoast's syndrome despite its
apparent locally invasive nature

TREATMENT BY STAGE. XX.
Superior sulcus or Pancoast tumors. III.
* best results with employing concurrent preoperative
irradiation [30 Gy in 10 treatments] and cisplatin and
etoposide → en bloc resection of tumor and involved chest
wall 3 - 6 wks later (65% of thoracotomy specimens →
complete response or minimal residual microscopic
disease on pathologic evaluation);
- 2 - yr survival = 55% for all eligible pts and = 70% for pts
with complete resection

TREATMENT BY STAGE. XXI.
Superior sulcus or Pancoast tumors. IV.
* as alternatives (as needed from pt conditions):
- radiation therapy alone;
- surgery alone (selected cases);
- clinical trials of combined modality therapy

TREATMENT BY STAGE. XXII.
NSCLC with T3, N0 Disease (Stage IIB)
* subset of T3, N0 disease not presenting as Pancoast
tumor (initially considered stage III disease, but with #
natural history and treatment strategy than stage III N2
disease) now considered as stage IIB;
- pts with peripheral chest wall invasion → resection of
involved ribs and underlying lung (chest wall defects then
repaired with chest wall musculature or Marlex mesh and
methylmethacrylate);
- 5 - yr survival = 35 - 50% (adjuvant chemotherapy usually
recommended)

STAGE III

TREATMENT BY STAGE. XXIII.
STAGE III NSCLC. I.
* treatment of still “locally advanced NSCLC” (with
involvement of mediastinal lymph nodes, N2 - N3) = one of
most controversial issues in management of LC;
- treatment options include local therapy (surgery or
radiation therapy) combined with systemic chemotherapy
to control micrometastases

TREATMENT BY STAGE. XXIV.
STAGE III NSCLC. II.
* interpretation of results clouded by a no. of issues,
including changing diagnostic techniques, variation of
staging systems and # pt populations, with tumors ranging
from “nonbulky stage IIIA” (clinical N1 nodes, with N2
nodes discovered only at time of surgery, despite negative
mediastinoscopy) to “bulky N2 stage IIIA” (enlarged
adenopathy clearly visible on chest x - rays or multiple
nodal level involvement) to clearly inoperable “stage IIIB
disease”
→ team approach involving pulmonary medicine, thoracic
surgery and medical and radiation oncology essential for
management of these pts

STAGE IIIA

STAGE IIIA. I. (T1a, N2, M0; T1b, N2, M0)
* T1a, N2, M0: T1a = < 2 cm, surrounded by lung or visceral
pleura, without bronchoscopic evidence of invasion more
proximal than the lobar bronchus (i.e., not in main
bronchus); N2 (metastasis to ipsilateral mediastinal and /
or subcarinal lymph nodes); M0
* T1b, N2, M0: T1b = > 2 - ≤ 3 cm + as above; N2; M0

STAGE IIIA. II. T3, N1, M0; T3, N2, M0
* T3, N1, M0: T3 = > 7 cm or directly invading any of
following: parietal pleural (PL3), chest wall (including
superior sulcus tumors), diaphragm, phrenic nerve,
mediastinal pleura or parietal pericardium; tumor in main
bronchus < cm from carina but without involvement of
carina); associated atelectasis or obstructive pneumonitis
of entire lung or separate tumor nodule(s) in same lobe;
N1 (metastasis to ipsilateral peribronchial and / or
ipsilateral hilar lymph nodes, and intrapulmonary nodes
involved by direct extension of primary tumor); M0
* T3, N2, M0: T3 = as above; N2 (metastasis to ipsilateral
mediastinal and / or subcarinal lymph nodes(s); M0

STAGE IIIA. IV. (T4, N0, M0; T4, N1, M0)
* T4, N0, M0: T4 = any size invading any of following:
mediastinum, heart, great vessels, trachea, recurrent
laryngeal nerve, esophagus, vertebral body, carina or
separate tumor nodule(s) in different ipsilateral lobe; N0;
M0
* T4, N1, M0: T4 = as above; N1 (metastasis to ipsilateral
peribronchial and / or ipsilateral hilar lymph nodes, and
intrapulmonary nodes involved by direct extension of
primary tumor); M0

STAGE IIIA
(T1a - T1b, N2, M0; T3, N1 - N2 M0; T4, N0 - N1, M0)

STAGE IIIA NON - SMALL CELL LUNG CANCER
* e.g., Stage III A: T3, N1, M0: T3
= > 7 cm or directly invading any
of following: tumor in main
bronchus (< 2 cm from carina but
without involvement of carina) (a);
parietal pleura / chest wall (b);
diaphragm (c); mediastinal pleura
or parietal pericardium (e);
phrenic nerve; associated
atelectasis or obstructive
pneumonitis of entire lung or
separate tumor nodule(s) in same
lobe; N1 (metastasis to ipsilateral
peribronchial and / or ipsilateral
hilar lymph nodes, and
intrapulmonary nodes involved by
direct extension of primary
tumor); M0

TREATMENT BY STAGE. XXV.
STAGE IIIA NSCLC. I.
Options
* options:
- resection → postoperative radiation + chemotherapy for
N2 disease;
- neoadjuvant chemotherapy → resection, or
- neoadjuvant chemo - radiotherapy → resection

TREATMENT BY STAGE. XXVI.
Stage IIIA (N2 disease) NSCLC. II.
Surgery
* surgery for Stage IIIA (N2 disease) controversial;
- for pts with N2 disease with "minimal
disease" (involvement of only 1 node with microscopic foci,
usually discovered at thoracotomy or mediastinoscopy)
and ? for more common pts with "advanced bulky
disease” (preoperatively obvious on CT scan);
[- pts with incidental finding of N2 disease at time of
resection need adjuvant chemotherapy]

TREATMENT BY STAGE. XXVII.
STAGE II - IIIA NSCLC. III.
ADJUVANT CHEMOTHERAPY
* overall, possible, modest ↑ survival with
adjuvant chemotherapy after apparently complete
resection

TREATMENT BY STAGE. XXVIII.
STAGE I - IIIA NSCLC. IV. ADJUVANT THERAPY
Cisplatin - based adjuvant CT in resected stage I - IIIA LC
* 1867 radically operated pts (36%
stage I, 25% stage II, 39% stage IIIA)
randomized between receiving or not
receiving adjuvant cisplatin - based
CT;
- 2 - and 5 - yr disease - free survival
= 61 and 39% in CT arm vs 55 and
34% in control arm, respectively (p< .
003);
- 2 - and 5 - yr survival = 70 and 45%
in CT arm vs 67 and 40% in control
arm, respectively (p < .03);
- benefits more evident in stage III
disease
2004

TREATMENT BY STAGE. XXIX.
STAGE I - IIIA NSCLC. V.
ADJUVANT THERAPY
Cisplatin - based adjuvant CT in resected
stage I - IIIA LC
Pignon JP et al JCO 28; 3552, 2008
* from meta - analysis (5 large trials,
4,584 pts) on cisplatin - based
chemotherapy in pts with completely
resected NSCLC (stages IA = 8%, IB =
30%; II = 35%; IIIA = 27%) → 5 - yr
absolute benefit = 5.4%, mainly in stage
IIIA pts

Postoperative radio ± chemotherapy
(cisplatin + etoposide) in resected stage II - IIIA NSCLC
Keller S et al (for Eastern Cooperative Oncology Group) NEJM 343, 1217, 2000

TREATMENT BY STAGE. XXX.
STAGE IIIA NSCLC. III. NEOADJUVANT CHEMO RADIOTHERAPY
* no clear evidence suggests ↑ survival in pts with "bulky"
multilevel ipsilateral mediastinal nodes (N2) with surgery and either
pre - or post - operative chemotherapy compared with chemotherapy
plus radiation therapy

NEOADJUVANT CHEMOTHERAPY IN STAGES IB - IIIA
* randomized trial of neoadjuvant
CT (mitomycin, ifosfamide and
cisplatin) vs surgery alone in 355
pts with stages IB (37%) - II (16%) -
IIIA (47%) NSCLC;
- responders received two
postoperative cycles (and pT3 or
pN2 pts RT too);
* at a median follow up of 80
mos, benefit of neoadjuvant
therapy confined to pts with N0 -
N1 disease
Depierre A et al JCO 2002
A = PCT = primary CT +
surgery
B = PRS = surgery alone
p ns
p = .02

TREATMENT BY STAGE. XXXI.
STAGE IIIA NSCLC. IV. NEOADJUVANT CHEMO - RADIOTHERAPY
Improved results of induction chemoradiation before surgical
intervention for selected pts with stage IIIA - N2 NSCLC
Karl L et al J Thorac Cardiovasc Surg 134; 188, 2007
* Objective: optimal management of stage IIIA - N2 NSCLC
controversial → chemoradiation before surgical intervention for
selected pts with stage IIIA - N2 NSCLC → results after 7 yrs of
reported
Methods: retrospective study of 40 pts (25% T1, 62.5% T2, 7.5% T3,
and 5% T4) with biopsy - proved T1-3 N2 M0 lung cancer and good
performance status who underwent concurrent induction
chemoradiation (radiation therapy + 2 cycles of cisplatin and
etoposide) → lung resection → 2 further cycles of consolidation
chemotherapy

TREATMENT BY STAGE. XXXIbis.
STAGE IIIA NSCLC. IVbis. NEOADJUVANT CHEMO - RADIOTHERAPY
Improved results of induction chemoradiation before surgical
intervention for selected pts with stage IIIA - N2 NSCLC
Karl L et al J Thorac Cardiovasc Surg 134; 188, 2007
* Results: overall and disease - free
median survivals = 40 and 37.1 mos,
respectively (overall and disease - free
3 - yr survivals = 51.7% and 52.3%,
respectively)
- trend for ↑ overall survival in pts with
single node at mediastinoscopy;
Conclusion: chemoradiation before
pulmonary resection in carefully
selected pts with surgically resectable
stage IIIA (N2) NSCLC can lead to ↑
overall survival

TREATMENT BY STAGE. XXXII.
STAGE IIIA NSCLC. V. NEOADJUVANT CHEMO - RADIOTHERAPY
Concurrent versus sequential chemoradiotherapy with cisplatin and
vinorelbine in locally advanced NSCLC: a randomized study. I.
Zatloukal P et al Lung Cancer 46; 87, 2004
* Purpose: relative merits of concurrent chemoradiotherapy (CRT)
schedule vs sequential administration unclear;
- Pts and methods: 102 previously untreated pts with locally
advanced, stage IIIA (n = 15) or IIIB (n = 87) NSCLC randomized
between concurrent (arm A) or sequential (arm B) CRT (cisplatin and
vinorelbine + 60 Gy / 30 fractions for 6 wks)

TREATMENT BY STAGE. XXXIIbis
STAGE IIIA NSCLC. Vbis. NEOADJUVANT CHEMO - RADIOTHERAPY
Idem. II. Zatloukal P et al Lung Cancer 46; 87, 2004
- Results: overall survival
significantly longer in arm A vs
B (median survival = 11.9 vs 8.5
mos) (p = .024), as well as time
to progression (TTP) (16.6 vs
12.9 mos) and overall RR (80 vs
47%, p = 0.001);
- WHO G3 - 4 toxicity
(leucopenia and nausea /
vomiting) more frequent in arm
A than in B;
- Conclusion: concurrent CRT significantly benefits for response
rate, overall survival and time to progression over sequential CRT;
- concurrent CRT associated with higher toxicity

TREATMENT BY STAGE. XXXIII.
STAGE IIIA NSCLC. VI. NEOADJUVANT CHEMO - RADIOTHERAPY
Radiotherapy plus chemotherapy ± surgical resection for stage III
NSCLC: a phase III randomised controlled trial. I.
Albain KS et al Lancet 374; 379, 2009
* Background: phase II studies in pts with stage IIIA NSCLC with
ipsilateral mediastinal nodal metastases (N2) → feasibility of resection
after concurrent chemotherapy and radiotherapy with promising rates of
survival → phase III trial comparing concurrent chemotherapy and
radiotherapy followed by resection with standard concurrent
chemotherapy and definitive radiotherapy without resection
- Methods: pts with stage T1 - 3pN2 M0 NSCLC randomly assigned to
concurrent induction chemotherapy (2 cycles of cisplatin and etoposide
+ radiotherapy;
- with no progression, pts in “group 1 → resection” and pts in “group
2 → continued radiotherapy”;
- 2 additional cycles of cisplatin and etoposide given in both groups;
- primary endpoint = overall survival (OS), on intention to treat
(ClinicalTrials.gov, no. NCT00002550)

Idem. II
Albain KS et al Lancet 374; 379, 2009
* Findings: 202 pts (median age = 59 yrs)
assigned to group 1 and 194 (median age
= 61 yrs) to group 2;
- median OS (below) = 23,6 vs 22,2 mos
in groups 1 and 2 (p = .24), with pts alive
at 5 yrs = 37 and 24% in group 1 and 2,
respectively (p = .10);
- with N0 status at thoracotomy, median
OS = 34,4 mos;
- progression - free survival (PFS)
(above) better in group 1 (resection) than
in 2 (continue radiotherapy) (median =
12,8 vs 10,5 mos; p = .017, with pts
without disease progression at 5 yrs = 32
vs 13 %, respectively)

Idem. III.
Albain KS et al Lancet 374; 379, 2009
- G3 - 4 neutropenia and oesophagitis greater in group A than in B
(38 and 10% and 41 and 23%, respectively, with treatment related
deaths = 8 and 2%, respectively);
- OS ↑ for pts on lobectomy, but not pneumonectomy, vs
chemotherapy plus radiotherapy
* Interpretation: chemotherapy + radiotherapy ± resection
(preferably lobectomy: be considered, since treatment - related
mortality greater in surgery arm (8 vs. 2%), with majority of deaths in
pts undergoing pneumonectomy) options for pts with stage IIIA (N2)
NSCLC

TREATMENT BY STAGE. XXXIV.
STAGE IIIA NSCLC. VI. Bulky IIIA. I.
* pts with persistent histologic N2 disease following
neoadjuvant chemotherapy do particularly poorly, with
some oncologists concluding that surgery for bulky IIIA
disease be conducted only in pts with clearing of
mediastinal nodes following neoadjuvant therapy;
- main role of neoadjuvant chemotherapy = to control
micrometastatic disease;
- if macroscopically mediastinal disease still evident =
disease not sensitive to chemotherapy → unlikely that
microscopic disease will be controlled → surgical removal
of primary tumor after chemotherapy probably fruitless;
[- likewise, neoadjuvant chemotherapy generally not be
used to render inoperable disease operable]

TREATMENT BY STAGE. XXV.
STAGE IIIA NSCLC. IV. Bulky IIIA. II.
* exception to this approach = T4, N0 or T4, N1 (stage IIIB)
disease for which preoperative chemotherapy provides
enough tumor debulking to allow otherwise unresectable
disease to be resected (chemotherapy may allow chest wall
resection for direct extension of tumor, tracheal sleeve
pneumonectomy and sleeve lobectomy for lesions near
carina)