Clinical Practice Guideline Medulloblastoma - Alberta Health Services
Clinical Practice Guideline Medulloblastoma - Alberta Health Services
Clinical Practice Guideline Medulloblastoma - Alberta Health Services
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MEDULLOBLASTOMA<br />
Date Developed: August, 2010<br />
CLINICAL PRACTICE GUIDELINE CNS-008<br />
The recommendations contained in this guideline are a consensus of the <strong>Alberta</strong> Provincial CNS Tumour Team<br />
synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature.<br />
Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in<br />
the context of individual clinical circumstances to direct care.
BACKGROUND<br />
CLINICAL PRACTICE GUIDELINE CNS-008<br />
<strong>Medulloblastoma</strong> is the most common brain tumour in children, accounting for 15 to 30 percent of all<br />
pediatric cancers of the central nervous system (CNS); in adults, however, the tumour is quite rare,<br />
accounting for only one to three percent of all primary brain tumours. 1-3 Because of it’s rarity in the adult<br />
population, most published reports in adults with medulloblastoma involve limited and select populations,<br />
and are retrospective analyses conducted over several decades with varying diagnostic procedures and<br />
treatment protocols. Based on the assumption that adult tumours have the same properties as those in<br />
children, adult patients with medulloblastoma are often given treatment protocols according to therapies<br />
developed for children with similarly staged disease at diagnosis. 4,5 However, important histologic and<br />
phenotypic differences have been identified between pediatric and adult medulloblastoma patients. In<br />
addition, radiologic differences have also been identified: adult tumours involve the lateral cerebellar<br />
hemispheres, while pediatric tumours most often occur in the vermis. 6-7 Further, late relapse, which occurs<br />
only rarely in pediatric tumours, occurs more frequently among adult patients with medulloblastoma.<br />
Reported survival rates for adult medulloblastoma vary in the literature. In a recent large, multicentre<br />
study, Padovani et al. retrospectively reviewed the outcomes of 253 adult patients treated for<br />
medulloblastoma between 1975 and 2004, and reported five- and ten-year overall survival rates of 72 and<br />
55 percent, respectively. 6 When low- and high-risk patients were compared, the ten-year overall survival<br />
rates were 62 and 49 percent (p=0.03). 7 Lower five-year survival rates were reported in an unselected,<br />
population-based study published by Roldán et al. 8 In this study, the <strong>Alberta</strong> Cancer Registry database<br />
was used to identify all cases of medulloblastoma occurring in Southern <strong>Alberta</strong> during a 21 year period,<br />
and five-year survival rates were reported to be 44.1 percent for patients over the age of sixteen, and 55.7<br />
percent for those under the age of sixteen. 8 The authors reported that these rates were more in line with<br />
those of other population-based studies. In addition, the survival curves in this analysis did not “level off”,<br />
suggesting that the patients had a lifetime risk of recurrence. 8 A recent analysis of 454 patients in the<br />
Surveillance, Epidemiology, and End Results (SEER) database in the United States reported five- and tenyears<br />
survival rates of 64.9 and 52.1 percent, respectively, for adult patients diagnosed with<br />
medulloblastoma between 1973 and 2004. 9 Multivariate analysis identified that diagnosis after the 1980s,<br />
age of diagnosis before 20 years, gross total resection, and treatment with radiotherapy were all<br />
associated with better survival. 9<br />
The most commonly reported symptoms of medulloblastoma at initial diagnosis are associated with<br />
increased intracranial pressure and cerebellar dysfunction. In the Roldán et al. study, headache (80%),<br />
nausea and vomiting (78%), and ataxia (73%) were most commonly identified; 8 similar symptoms and<br />
rates have been reported in retrospective series from France, India, and the MD Anderson Cancer Center<br />
in the United States. 4,10,11<br />
GUIDELINE QUESTIONS<br />
What is the optimal management strategy for adult patients with medulloblastoma?
DEVELOPMENT<br />
CLINICAL PRACTICE GUIDELINE CNS-008<br />
This guideline was reviewed and endorsed by the <strong>Alberta</strong> Provincial CNS Tumour Team. Members of the<br />
<strong>Alberta</strong> Provincial CNS Tumour Team include medical oncologists, radiation oncologists, surgical<br />
oncologists, neurosurgeons, nurses, neuropathologists, and pharmacists. Evidence was selected and<br />
reviewed by a working group comprised of members from the <strong>Alberta</strong> Provincial CNS Tumour Team and a<br />
Knowledge Management Specialist from the <strong>Guideline</strong> Utilization Resource Unit. A detailed description of<br />
the methodology followed during the guideline development process can be found in the <strong>Guideline</strong><br />
Utilization Resource Unit Handbook.<br />
SEARCH STRATEGY<br />
Medical journal articles were searched using the Medline (1950 to March Week 4, 2010), EMBASE (1980<br />
to March Week 4, 2010), Cochrane Database of Systematic Reviews (1 st Quarter, 2010), and PubMed<br />
electronic databases; the references and bibliographies of articles identified through these searches were<br />
scanned for additional sources. The MeSH heading <strong>Medulloblastoma</strong> was combined with the search terms<br />
“Surgery”, “Radiotherapy”, “Drug Therapy”, “Therapy”, and “Follow-up Studies”. The results were limited to<br />
adults, practice guidelines, systematic reviews, meta-analyses, comparative studies, multicentre studies,<br />
randomized controlled trials, and clinical trials. Articles were excluded from the review if they: addressed<br />
medulloblastoma in pediatric or adolescent patients, had a non-English abstract, were not available<br />
through the library system, or were case studies involving less than 5 patients. A review of the relevant<br />
existing practice guidelines for medulloblastoma was also conducted by accessing the practice guidelines<br />
on the websites of the British Columbia Cancer Agency (BCCA) and the National Cancer Institute (NCI).<br />
TARGET POPULATION<br />
The recommendations outlined in this guideline apply to adults over the age of 18 years diagnosed with<br />
medulloblastoma. Different principles may apply to pediatric patients.<br />
RECOMMENDATIONS<br />
Evaluation and Workup:<br />
1. Evaluation and management of adult patients with medulloblastoma should be discussed and planned<br />
within a multidisciplinary tumour team. Whenever possible, participation in a clinical trial is<br />
encouraged.<br />
2. The initial workup should include cerebrospinal fluid (CSF) cytology if safe, and an MRI of the brain<br />
and total spine, given the risk of seeding throughout the craniospinal axis.<br />
Treatment:<br />
3. Maximal safe surgical resection followed by postoperative radiotherapy and possibly adjuvant<br />
chemotherapy is the recommended treatment algorithm for adult patients with medulloblastoma. An<br />
attempt should be made to excise as much as possible of the grossly visible tumour.<br />
4. Postoperative radiotherapy to the entire craniospinal axis to a dose of 36-40Gy, followed by a posterior<br />
fossa boost to 54-55.8Gy should be administered. Sites of gross disease elsewhere in the craniospinal<br />
axis should be boosted to at least 40Gy. Concurrent chemotherapy may allow for use of lower<br />
craniospinal radiation doses of 23.4Gy.
CLINICAL PRACTICE GUIDELINE CNS-008<br />
5. In contrast to childhood medulloblastoma, the role of chemotherapy in adult patients with<br />
medulloblastoma is less clear. Based on extrapolation from the pediatric literature, however, adjuvant<br />
chemotherapy may be considered for adults with high-risk disease, and also for the treatment of<br />
recurrence. There is currently no strong evidence to support a specific chemotherapy regimen in<br />
adults.<br />
Follow-up:<br />
6. Long term follow-up (5 to 10 years) is recommended following completion of therapy, due to the<br />
potential for late recurrence, as well as neurocognitive, neuroendocrine, thyroid, pulmonary, cardiac,<br />
gastrointestinal, renal, and reproductive late effects.<br />
DISCUSSION<br />
Evaluation and Workup<br />
Combined modality therapy, including surgery, radiotherapy, and possibly chemotherapy is the standard of<br />
care for both children and adult patients with medulloblastoma. Therefore, evaluation and management<br />
should be discussed and planned with a multidisciplinary team of clinicians. Whenever possible, patient<br />
participation in a clinical trial is encouraged (recommendation #1).<br />
Prior to initiating therapy, an MRI of the brain and total spine is recommended, as this is an important tool<br />
for accurate staging of the tumour, particularly when the tumour extends beyond the posterior fossa and<br />
into the spinal spaces. 12,13 Postoperative neuro-imaging with MRI will help to quantify residual disease,<br />
and is recommended within 72 hours to two weeks following surgical resection. 12-14 <strong>Medulloblastoma</strong><br />
tumours in adult patients are associated with a high likelihood for craniospinal seeding and spread through<br />
the cerebrospinal fluid (CSF). Therefore, when safe to do so, the workup of adult patients should include<br />
CSF cytology (recommendation #2). 15<br />
Staging and Classification<br />
Historically, medulloblastoma has been clinically staged according to the Chang staging definitions for<br />
tumour and metastases parameters, described in Table 1. 16<br />
Table 1. Chang Staging System for <strong>Medulloblastoma</strong> 16<br />
Tumour Classification Description<br />
T1 greatest tumour dimension 3cm<br />
T3a greatest tumour dimension >3cm with spread into the aqueduct of Sylvius and/or foramen of<br />
Luschka, cerebral subarachnoid space, third or lateral ventricles<br />
T3b greatest tumour dimension >3cm with unequivocal spread into the brainstem; for T3b, surgical<br />
staging may be used in the absence of involvement at imaging<br />
T4 greatest tumour dimension >3cm with spread beyond the aqueduct of Sylvius and/or the foramen<br />
magnum<br />
Metastasis Classification Description<br />
M0 no evidence of gross subarachnoid or hematogenous metastasis<br />
M1 microscopic tumour cells in cerebrospinal fluid<br />
M2 gross nodular seeding in cerebellum<br />
M3 gross nodular seeding in spinal subarachnoid space<br />
M4 metastasis beyond cerebrospinal axis
CLINICAL PRACTICE GUIDELINE CNS-008<br />
More recently, low- and high-risk classification has been identified to be an important factor in treatment<br />
decisions as well as a prognostic indicator in several studies. 5,6,17 Low-risk patients are those that have T1,<br />
T2, T3a and M0 disease, and have totally or near totally resected disease (< 1.5 cm 2 ) following surgery. In<br />
contrast, high-risk patients are those that have T3b or T4 and M1 to M3 disease, and do have<br />
postoperative residual tumours. 5<br />
Histology<br />
<strong>Medulloblastoma</strong> is described as malignant and invasive, and is classified by the World <strong>Health</strong><br />
Organization (WHO) as a grade IV tumour. 18 In addition to the classic type of medulloblastoma, four<br />
histologic subtypes have also been identified (desmoplastic/nodular type, medulloblastoma with extensive<br />
nodularity, anaplastic medulloblastoma, large-cell medulloblastoma), and recent publications stress the<br />
importance of these histologic subtypes in the prognosis of medulloblastoma. 18 In general, the large-cell<br />
and anaplastic subtypes appear to be associated with the worst prognosis. 19<br />
Standard histologic reporting for medulloblastoma includes documentation of tumour necrosis, mitoses,<br />
apoptosis, cell size, nuclear wrapping, nodularity, and large cell and anaplastic distribution.<br />
Immunohistochemical tests, such as those for expression or mutation of p53, INI 1, Her2/neu, and βcatenin,<br />
may also be required for determining prognosis and ruling out medulloblastoma mimics. 19,20 Other<br />
specialized molecular tests, including those for MYC-C and MYC-N amplification, and loss of chromosome<br />
17p, may allow a more accurate prediction of disease prognosis, 19-22 but are not considered standard tests<br />
in <strong>Alberta</strong> at the present time.<br />
Treatment<br />
Surgery. Maximal safe surgical resection followed by postoperative radiotherapy and possibly adjuvant<br />
chemotherapy is the recommended treatment strategy for adult patients with medulloblastoma<br />
(recommendation #3). An attempt should be made to excise as much as possible of grossly visible<br />
tumour, as several studies have correlated outcome with the extent of resection and the amount of<br />
residual tumour. 3,6,8,9,23,24 In a retrospective review of 32 adult patients with medulloblastoma confined to<br />
the craniospinal axis, Chan et al. reported that the five year disease-free survival rate was significantly<br />
better for patients who underwent complete total resection versus a less than complete resection (89% vs.<br />
27%; RR=10.9, 95% CI 2.73-80.8; p
CLINICAL PRACTICE GUIDELINE CNS-008<br />
The authors also reported a trend to longer event-free survival for doses higher than 50Gy to the posterior<br />
fossa (p=0.09). In the series reported by Padovani et al., a spinal radiation dose greater than 30Gy and a<br />
posterior fossa radiation dose greater than 50Gy both correlated significantly with overall survival<br />
(p=0.0054 and p
Study N Median<br />
Age (yrs)<br />
Abacioglu et<br />
al., 2002 39<br />
30 27 N=10 high-risk patients: varying combinations<br />
of procarbazine + CCNU + vincristine<br />
Greenberg et<br />
al., 2001 40<br />
Kunschner et<br />
al., 2001 4<br />
Chan et al.,<br />
2000 23<br />
Le et al.,<br />
1997 25<br />
Prados et al.,<br />
1995 17<br />
Carrie et al.,<br />
1994 3<br />
Chemotherapy Regimen(s) Outcomes<br />
17 23 N=10: weekly vincristine followed by cisplatin<br />
+ CCNU + vincristine (Packer protocol)<br />
N=7: cisplatin/etoposide alternating with<br />
vincristine/ cyclophosphamide (POG protocol)<br />
28 30.5 N=1: thioguanine + procarbazine +<br />
dibromodulcitol + CCNU + vincristine<br />
N=4: cyclophosphamide + etoposide +<br />
cisplatin<br />
N=1: methotrexate + nitrogen mustard +<br />
vincristine + prednisone + procarbazine<br />
32 25.5 N=16: cisplatin + vincristine<br />
N=4: cisplatin + vincristine +<br />
cyclophosphamide + etoposide<br />
N=1: cisplatin + vincristine +<br />
cyclophosphamide<br />
N=1: cisplatin + vincristine + etoposide<br />
N=1: vincristine + CCNU<br />
34 23 N=12: procarbazine + hydroxyurea<br />
N=5: cisplatin + CCNU + vincristine<br />
N=2: CCNU + vincristine + procarbazine +<br />
hydroxyurea<br />
N=2: thioguanine + procarbazine +<br />
dibromodulcitol + CCNU + vincristine<br />
N=1: CCNU + hydroxyurea<br />
N=1: cytarabine<br />
47 28 N=11 low-risk patients: procarbazine +<br />
hydroxyurea (+ CCNU in one patient)<br />
N=21 high-risk patients: nitrosourea-based<br />
combination chemotherapy<br />
156 28 N=31: vincristine + BCNU + procarbazine +<br />
hydroxyurea + cisplatin + cytarabine +<br />
methotrexate<br />
N=29: vincristine + CCNU or BCNU<br />
N=9: ifosfamide + cisplatin + vincristine<br />
N=6: other protocols<br />
CLINICAL PRACTICE GUIDELINE CNS-008<br />
5-year OS rate = 65%; 8-year OS rate = 51%<br />
5-year DFS rate = 69% CT versus 60% no<br />
CT (p=not significant)<br />
Median OS = 36 months Packer protocol<br />
versus 57 months POG protocol (p=0.058)<br />
Toxicity during Packer protocol treatment was<br />
moderately severe<br />
No significant difference in OS demonstrated<br />
between the patients treated with CT versus<br />
no CT<br />
5-year OS rate = 83%; 8-year OS rate = 45%<br />
The use of CT was adversely associated with<br />
rate of posterior fossa control (p=0.03)<br />
Patients who received CT presented with<br />
more advanced M-stage than patients treated<br />
with RT alone<br />
5-year OS rate = 58%<br />
No effect of CT on survival or posterior fossa<br />
control<br />
5-year OS rates = 81% low-risk patients<br />
versus 54% high-risk patients (p=0.03)<br />
Treatment with adjuvant CT associated with<br />
longer survival (p=0.03)<br />
Lack of adjuvant CT associated with shorter<br />
time to tumour progression (p=0.05)<br />
5-year OS rate = 66% CT versus 57% no CT<br />
(p=not significant)<br />
10-year OS rate = 52% CT versus 43% no<br />
CT (p=not significant)<br />
No significant difference in survival between<br />
different CT regimens<br />
CT appeared to be much more toxic in this<br />
adult series than in children<br />
Abbreviations: CCNU=lomustine, OS=overall survival, CT=chemotherapy, RT=radiotherapy, RR=relative risk, CI=confidence interval, DFS=disease-free<br />
survival, POG=Pediatric Oncology Group, BCNU=carmustine.<br />
Prospective randomized studies are required to more definitively address whether primary adjuvant<br />
chemotherapy is effective in the treatment of adults with medulloblastoma. At the present time, it seems<br />
reasonable to treat high-risk adult patients with the chemotherapy protocols which have been shown to be<br />
effective through randomized clinical trials in the pediatric population. Decisions should be made on an<br />
individual basis for each patient, and should be discussed and planned at multidisciplinary tumour board<br />
meetings.
CLINICAL PRACTICE GUIDELINE CNS-008<br />
Future directions. Several recent studies have shown that salvage therapy with combination<br />
chemotherapy may be of benefit in adults with recurrent medulloblastoma. 4,10 The use of temozolomide as<br />
an alternative to some of the older chemotherapy regimens has also recently shown favourable results<br />
with improved efficacy and reduced adverse effects in adult patients with both newly diagnosed and<br />
recurrent medulloblastoma. 41-43 Another approach is combination chemotherapy after radiotherapy with a<br />
reduced craniospinal axis dose (23.4Gy), or radiotherapy plus concurrent vincristine. 26,44<br />
Follow-up<br />
In their population-based review of adult patients with medulloblastoma in <strong>Alberta</strong>, Roldán et al. reported a<br />
50 percent survival rate at five years, and noted that the estimated survival curves did not level off,<br />
suggesting that these patients have a lifetime risk of tumour recurrence, and should not be considered<br />
“cured”. 8 Late relapses in adult patients with medulloblastoma have also been documented in several<br />
other studies. Chan et al. reported that 59 percent of all recurrences in their series occurred more than two<br />
years after completion of treatment, and 29 percent occurred more than five years after the completion of<br />
treatment. 23 Riffaud et al. reported a recurrences rate of 41 percent, with a median time to first recurrence<br />
of 4.2 years (range 0.7–18 years). 10 Similarly, in the only prospective study published to date, Brandes et<br />
al. reported that the risk of recurrence increased markedly after seven years of follow-up for low-risk adult<br />
patients, and after ten years for high-risk adult patients. 5<br />
Due to the potential for late recurrences, the <strong>Alberta</strong> CNS Tumour Team members recommend a minimum<br />
of five to ten years of follow-up for adult patients with medulloblastoma (recommendation #6). In particular,<br />
monitoring and surveillance should be focused on neurocognitive, neuroendocrine, thyroid, pulmonary,<br />
cardiac, gastrointestinal, renal, and reproductive system late effects. 14 An MRI of the brain and full spine<br />
with gadolinium enhancement should be obtained every three to six months for the first two years of<br />
follow-up, and every year thereafter. The final discharge of the patient to their family physician will be at<br />
the discretion of the treating oncologist.<br />
GLOSSARY OF ABBREVIATIONS<br />
Acronym Description<br />
BCNU carmustine<br />
CCNU lomustine<br />
CI confidence interval<br />
CNS central nervous system<br />
CSF cerebrospinal fluid<br />
CT chemotherapy<br />
DFS disease-free survival<br />
Gy gray<br />
MRI magnetic resonance imaging<br />
OS overall survival<br />
POG Pediatric Oncology Group<br />
RR relative risk<br />
RT radiotherapy<br />
SEER Surveillance, Epidemiology, and End Results database<br />
WHO World <strong>Health</strong> Organization
DISSEMINATION<br />
CLINICAL PRACTICE GUIDELINE CNS-008<br />
Present and review the guideline at the local and provincial tumour team meetings and weekly rounds.<br />
Post the guideline on the <strong>Alberta</strong> <strong>Health</strong> <strong>Services</strong> website.<br />
Send an electronic notification of the new guideline to all members of <strong>Alberta</strong> <strong>Health</strong> <strong>Services</strong>, Cancer<br />
Care.<br />
MAINTENANCE<br />
A formal review of the guideline will be conducted at the next Annual Provincial Meeting in October 2011.<br />
If critical new evidence is brought forward before that time, however, the guideline working group<br />
members will revise and update the document accordingly.<br />
CONFLICT OF INTEREST<br />
Participation of members of the <strong>Alberta</strong> Provincial CNS Tumour Team in the development of this guideline<br />
has been voluntary and the authors have not been remunerated for their contributions. There was no<br />
direct industry involvement in the development or dissemination of this guideline. <strong>Alberta</strong> <strong>Health</strong> <strong>Services</strong><br />
– Cancer Care recognizes that although industry support of research, education and other areas is<br />
necessary in order to advance patient care, such support may lead to potential conflicts of interest. Some<br />
members of the <strong>Alberta</strong> Provincial CNS Tumour Team are involved in research funded by industry or have<br />
other such potential conflicts of interest. However the developers of this guideline are satisfied it was<br />
developed in an unbiased manner.<br />
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29. Merchant TE, Kun LE, Krasin MJ, Jones-Wallace D, Chintagumpala MM, Woo SY, et al. A multi-institution prospective trial of<br />
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