Clinical Practice Guideline Medulloblastoma - Alberta Health Services

MEDULLOBLASTOMA
Date Developed: August, 2010
CLINICAL PRACTICE GUIDELINE CNS-008
The recommendations contained in this guideline are a consensus of the Alberta Provincial CNS Tumour Team
synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature.
Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in
the context of individual clinical circumstances to direct care.

BACKGROUND
CLINICAL PRACTICE GUIDELINE CNS-008
Medulloblastoma is the most common brain tumour in children, accounting for 15 to 30 percent of all
pediatric cancers of the central nervous system (CNS); in adults, however, the tumour is quite rare,
accounting for only one to three percent of all primary brain tumours. 1-3 Because of it’s rarity in the adult
population, most published reports in adults with medulloblastoma involve limited and select populations,
and are retrospective analyses conducted over several decades with varying diagnostic procedures and
treatment protocols. Based on the assumption that adult tumours have the same properties as those in
children, adult patients with medulloblastoma are often given treatment protocols according to therapies
developed for children with similarly staged disease at diagnosis. 4,5 However, important histologic and
phenotypic differences have been identified between pediatric and adult medulloblastoma patients. In
addition, radiologic differences have also been identified: adult tumours involve the lateral cerebellar
hemispheres, while pediatric tumours most often occur in the vermis. 6-7 Further, late relapse, which occurs
only rarely in pediatric tumours, occurs more frequently among adult patients with medulloblastoma.
Reported survival rates for adult medulloblastoma vary in the literature. In a recent large, multicentre
study, Padovani et al. retrospectively reviewed the outcomes of 253 adult patients treated for
medulloblastoma between 1975 and 2004, and reported five- and ten-year overall survival rates of 72 and
55 percent, respectively. 6 When low- and high-risk patients were compared, the ten-year overall survival
rates were 62 and 49 percent (p=0.03). 7 Lower five-year survival rates were reported in an unselected,
population-based study published by Roldán et al. 8 In this study, the Alberta Cancer Registry database
was used to identify all cases of medulloblastoma occurring in Southern Alberta during a 21 year period,
and five-year survival rates were reported to be 44.1 percent for patients over the age of sixteen, and 55.7
percent for those under the age of sixteen. 8 The authors reported that these rates were more in line with
those of other population-based studies. In addition, the survival curves in this analysis did not “level off”,
suggesting that the patients had a lifetime risk of recurrence. 8 A recent analysis of 454 patients in the
Surveillance, Epidemiology, and End Results (SEER) database in the United States reported five- and tenyears
survival rates of 64.9 and 52.1 percent, respectively, for adult patients diagnosed with
medulloblastoma between 1973 and 2004. 9 Multivariate analysis identified that diagnosis after the 1980s,
age of diagnosis before 20 years, gross total resection, and treatment with radiotherapy were all
associated with better survival. 9
The most commonly reported symptoms of medulloblastoma at initial diagnosis are associated with
increased intracranial pressure and cerebellar dysfunction. In the Roldán et al. study, headache (80%),
nausea and vomiting (78%), and ataxia (73%) were most commonly identified; 8 similar symptoms and
rates have been reported in retrospective series from France, India, and the MD Anderson Cancer Center
in the United States. 4,10,11
GUIDELINE QUESTIONS
What is the optimal management strategy for adult patients with medulloblastoma?

DEVELOPMENT
CLINICAL PRACTICE GUIDELINE CNS-008
This guideline was reviewed and endorsed by the Alberta Provincial CNS Tumour Team. Members of the
Alberta Provincial CNS Tumour Team include medical oncologists, radiation oncologists, surgical
oncologists, neurosurgeons, nurses, neuropathologists, and pharmacists. Evidence was selected and
reviewed by a working group comprised of members from the Alberta Provincial CNS Tumour Team and a
Knowledge Management Specialist from the Guideline Utilization Resource Unit. A detailed description of
the methodology followed during the guideline development process can be found in the Guideline
Utilization Resource Unit Handbook.
SEARCH STRATEGY
Medical journal articles were searched using the Medline (1950 to March Week 4, 2010), EMBASE (1980
to March Week 4, 2010), Cochrane Database of Systematic Reviews (1 st Quarter, 2010), and PubMed
electronic databases; the references and bibliographies of articles identified through these searches were
scanned for additional sources. The MeSH heading Medulloblastoma was combined with the search terms
“Surgery”, “Radiotherapy”, “Drug Therapy”, “Therapy”, and “Follow-up Studies”. The results were limited to
adults, practice guidelines, systematic reviews, meta-analyses, comparative studies, multicentre studies,
randomized controlled trials, and clinical trials. Articles were excluded from the review if they: addressed
medulloblastoma in pediatric or adolescent patients, had a non-English abstract, were not available
through the library system, or were case studies involving less than 5 patients. A review of the relevant
existing practice guidelines for medulloblastoma was also conducted by accessing the practice guidelines
on the websites of the British Columbia Cancer Agency (BCCA) and the National Cancer Institute (NCI).
TARGET POPULATION
The recommendations outlined in this guideline apply to adults over the age of 18 years diagnosed with
medulloblastoma. Different principles may apply to pediatric patients.
RECOMMENDATIONS
Evaluation and Workup:
1. Evaluation and management of adult patients with medulloblastoma should be discussed and planned
within a multidisciplinary tumour team. Whenever possible, participation in a clinical trial is
encouraged.
2. The initial workup should include cerebrospinal fluid (CSF) cytology if safe, and an MRI of the brain
and total spine, given the risk of seeding throughout the craniospinal axis.
Treatment:
3. Maximal safe surgical resection followed by postoperative radiotherapy and possibly adjuvant
chemotherapy is the recommended treatment algorithm for adult patients with medulloblastoma. An
attempt should be made to excise as much as possible of the grossly visible tumour.
4. Postoperative radiotherapy to the entire craniospinal axis to a dose of 36-40Gy, followed by a posterior
fossa boost to 54-55.8Gy should be administered. Sites of gross disease elsewhere in the craniospinal
axis should be boosted to at least 40Gy. Concurrent chemotherapy may allow for use of lower
craniospinal radiation doses of 23.4Gy.

CLINICAL PRACTICE GUIDELINE CNS-008
5. In contrast to childhood medulloblastoma, the role of chemotherapy in adult patients with
medulloblastoma is less clear. Based on extrapolation from the pediatric literature, however, adjuvant
chemotherapy may be considered for adults with high-risk disease, and also for the treatment of
recurrence. There is currently no strong evidence to support a specific chemotherapy regimen in
adults.
Follow-up:
6. Long term follow-up (5 to 10 years) is recommended following completion of therapy, due to the
potential for late recurrence, as well as neurocognitive, neuroendocrine, thyroid, pulmonary, cardiac,
gastrointestinal, renal, and reproductive late effects.
DISCUSSION
Evaluation and Workup
Combined modality therapy, including surgery, radiotherapy, and possibly chemotherapy is the standard of
care for both children and adult patients with medulloblastoma. Therefore, evaluation and management
should be discussed and planned with a multidisciplinary team of clinicians. Whenever possible, patient
participation in a clinical trial is encouraged (recommendation #1).
Prior to initiating therapy, an MRI of the brain and total spine is recommended, as this is an important tool
for accurate staging of the tumour, particularly when the tumour extends beyond the posterior fossa and
into the spinal spaces. 12,13 Postoperative neuro-imaging with MRI will help to quantify residual disease,
and is recommended within 72 hours to two weeks following surgical resection. 12-14 Medulloblastoma
tumours in adult patients are associated with a high likelihood for craniospinal seeding and spread through
the cerebrospinal fluid (CSF). Therefore, when safe to do so, the workup of adult patients should include
CSF cytology (recommendation #2). 15
Staging and Classification
Historically, medulloblastoma has been clinically staged according to the Chang staging definitions for
tumour and metastases parameters, described in Table 1. 16
Table 1. Chang Staging System for Medulloblastoma 16
Tumour Classification Description
T1 greatest tumour dimension 3cm
T3a greatest tumour dimension >3cm with spread into the aqueduct of Sylvius and/or foramen of
Luschka, cerebral subarachnoid space, third or lateral ventricles
T3b greatest tumour dimension >3cm with unequivocal spread into the brainstem; for T3b, surgical
staging may be used in the absence of involvement at imaging
T4 greatest tumour dimension >3cm with spread beyond the aqueduct of Sylvius and/or the foramen
magnum
Metastasis Classification Description
M0 no evidence of gross subarachnoid or hematogenous metastasis
M1 microscopic tumour cells in cerebrospinal fluid
M2 gross nodular seeding in cerebellum
M3 gross nodular seeding in spinal subarachnoid space
M4 metastasis beyond cerebrospinal axis

CLINICAL PRACTICE GUIDELINE CNS-008
More recently, low- and high-risk classification has been identified to be an important factor in treatment
decisions as well as a prognostic indicator in several studies. 5,6,17 Low-risk patients are those that have T1,
T2, T3a and M0 disease, and have totally or near totally resected disease (< 1.5 cm 2 ) following surgery. In
contrast, high-risk patients are those that have T3b or T4 and M1 to M3 disease, and do have
postoperative residual tumours. 5
Histology
Medulloblastoma is described as malignant and invasive, and is classified by the World Health
Organization (WHO) as a grade IV tumour. 18 In addition to the classic type of medulloblastoma, four
histologic subtypes have also been identified (desmoplastic/nodular type, medulloblastoma with extensive
nodularity, anaplastic medulloblastoma, large-cell medulloblastoma), and recent publications stress the
importance of these histologic subtypes in the prognosis of medulloblastoma. 18 In general, the large-cell
and anaplastic subtypes appear to be associated with the worst prognosis. 19
Standard histologic reporting for medulloblastoma includes documentation of tumour necrosis, mitoses,
apoptosis, cell size, nuclear wrapping, nodularity, and large cell and anaplastic distribution.
Immunohistochemical tests, such as those for expression or mutation of p53, INI 1, Her2/neu, and βcatenin,
may also be required for determining prognosis and ruling out medulloblastoma mimics. 19,20 Other
specialized molecular tests, including those for MYC-C and MYC-N amplification, and loss of chromosome
17p, may allow a more accurate prediction of disease prognosis, 19-22 but are not considered standard tests
in Alberta at the present time.
Treatment
Surgery. Maximal safe surgical resection followed by postoperative radiotherapy and possibly adjuvant
chemotherapy is the recommended treatment strategy for adult patients with medulloblastoma
(recommendation #3). An attempt should be made to excise as much as possible of grossly visible
tumour, as several studies have correlated outcome with the extent of resection and the amount of
residual tumour. 3,6,8,9,23,24 In a retrospective review of 32 adult patients with medulloblastoma confined to
the craniospinal axis, Chan et al. reported that the five year disease-free survival rate was significantly
better for patients who underwent complete total resection versus a less than complete resection (89% vs.
27%; RR=10.9, 95% CI 2.73-80.8; p

CLINICAL PRACTICE GUIDELINE CNS-008
The authors also reported a trend to longer event-free survival for doses higher than 50Gy to the posterior
fossa (p=0.09). In the series reported by Padovani et al., a spinal radiation dose greater than 30Gy and a
posterior fossa radiation dose greater than 50Gy both correlated significantly with overall survival
(p=0.0054 and p

Study N Median
Age (yrs)
Abacioglu et
al., 2002 39
30 27 N=10 high-risk patients: varying combinations
of procarbazine + CCNU + vincristine
Greenberg et
al., 2001 40
Kunschner et
al., 2001 4
Chan et al.,
2000 23
Le et al.,
1997 25
Prados et al.,
1995 17
Carrie et al.,
1994 3
Chemotherapy Regimen(s) Outcomes
17 23 N=10: weekly vincristine followed by cisplatin
+ CCNU + vincristine (Packer protocol)
N=7: cisplatin/etoposide alternating with
vincristine/ cyclophosphamide (POG protocol)
28 30.5 N=1: thioguanine + procarbazine +
dibromodulcitol + CCNU + vincristine
N=4: cyclophosphamide + etoposide +
cisplatin
N=1: methotrexate + nitrogen mustard +
vincristine + prednisone + procarbazine
32 25.5 N=16: cisplatin + vincristine
N=4: cisplatin + vincristine +
cyclophosphamide + etoposide
N=1: cisplatin + vincristine +
cyclophosphamide
N=1: cisplatin + vincristine + etoposide
N=1: vincristine + CCNU
34 23 N=12: procarbazine + hydroxyurea
N=5: cisplatin + CCNU + vincristine
N=2: CCNU + vincristine + procarbazine +
hydroxyurea
N=2: thioguanine + procarbazine +
dibromodulcitol + CCNU + vincristine
N=1: CCNU + hydroxyurea
N=1: cytarabine
47 28 N=11 low-risk patients: procarbazine +
hydroxyurea (+ CCNU in one patient)
N=21 high-risk patients: nitrosourea-based
combination chemotherapy
156 28 N=31: vincristine + BCNU + procarbazine +
hydroxyurea + cisplatin + cytarabine +
methotrexate
N=29: vincristine + CCNU or BCNU
N=9: ifosfamide + cisplatin + vincristine
N=6: other protocols
CLINICAL PRACTICE GUIDELINE CNS-008
5-year OS rate = 65%; 8-year OS rate = 51%
5-year DFS rate = 69% CT versus 60% no
CT (p=not significant)
Median OS = 36 months Packer protocol
versus 57 months POG protocol (p=0.058)
Toxicity during Packer protocol treatment was
moderately severe
No significant difference in OS demonstrated
between the patients treated with CT versus
no CT
5-year OS rate = 83%; 8-year OS rate = 45%
The use of CT was adversely associated with
rate of posterior fossa control (p=0.03)
Patients who received CT presented with
more advanced M-stage than patients treated
with RT alone
5-year OS rate = 58%
No effect of CT on survival or posterior fossa
control
5-year OS rates = 81% low-risk patients
versus 54% high-risk patients (p=0.03)
Treatment with adjuvant CT associated with
longer survival (p=0.03)
Lack of adjuvant CT associated with shorter
time to tumour progression (p=0.05)
5-year OS rate = 66% CT versus 57% no CT
(p=not significant)
10-year OS rate = 52% CT versus 43% no
CT (p=not significant)
No significant difference in survival between
different CT regimens
CT appeared to be much more toxic in this
adult series than in children
Abbreviations: CCNU=lomustine, OS=overall survival, CT=chemotherapy, RT=radiotherapy, RR=relative risk, CI=confidence interval, DFS=disease-free
survival, POG=Pediatric Oncology Group, BCNU=carmustine.
Prospective randomized studies are required to more definitively address whether primary adjuvant
chemotherapy is effective in the treatment of adults with medulloblastoma. At the present time, it seems
reasonable to treat high-risk adult patients with the chemotherapy protocols which have been shown to be
effective through randomized clinical trials in the pediatric population. Decisions should be made on an
individual basis for each patient, and should be discussed and planned at multidisciplinary tumour board
meetings.

CLINICAL PRACTICE GUIDELINE CNS-008
Future directions. Several recent studies have shown that salvage therapy with combination
chemotherapy may be of benefit in adults with recurrent medulloblastoma. 4,10 The use of temozolomide as
an alternative to some of the older chemotherapy regimens has also recently shown favourable results
with improved efficacy and reduced adverse effects in adult patients with both newly diagnosed and
recurrent medulloblastoma. 41-43 Another approach is combination chemotherapy after radiotherapy with a
reduced craniospinal axis dose (23.4Gy), or radiotherapy plus concurrent vincristine. 26,44
Follow-up
In their population-based review of adult patients with medulloblastoma in Alberta, Roldán et al. reported a
50 percent survival rate at five years, and noted that the estimated survival curves did not level off,
suggesting that these patients have a lifetime risk of tumour recurrence, and should not be considered
“cured”. 8 Late relapses in adult patients with medulloblastoma have also been documented in several
other studies. Chan et al. reported that 59 percent of all recurrences in their series occurred more than two
years after completion of treatment, and 29 percent occurred more than five years after the completion of
treatment. 23 Riffaud et al. reported a recurrences rate of 41 percent, with a median time to first recurrence
of 4.2 years (range 0.7–18 years). 10 Similarly, in the only prospective study published to date, Brandes et
al. reported that the risk of recurrence increased markedly after seven years of follow-up for low-risk adult
patients, and after ten years for high-risk adult patients. 5
Due to the potential for late recurrences, the Alberta CNS Tumour Team members recommend a minimum
of five to ten years of follow-up for adult patients with medulloblastoma (recommendation #6). In particular,
monitoring and surveillance should be focused on neurocognitive, neuroendocrine, thyroid, pulmonary,
cardiac, gastrointestinal, renal, and reproductive system late effects. 14 An MRI of the brain and full spine
with gadolinium enhancement should be obtained every three to six months for the first two years of
follow-up, and every year thereafter. The final discharge of the patient to their family physician will be at
the discretion of the treating oncologist.
GLOSSARY OF ABBREVIATIONS
Acronym Description
BCNU carmustine
CCNU lomustine
CI confidence interval
CNS central nervous system
CSF cerebrospinal fluid
CT chemotherapy
DFS disease-free survival
Gy gray
MRI magnetic resonance imaging
OS overall survival
POG Pediatric Oncology Group
RR relative risk
RT radiotherapy
SEER Surveillance, Epidemiology, and End Results database
WHO World Health Organization

DISSEMINATION
CLINICAL PRACTICE GUIDELINE CNS-008
Present and review the guideline at the local and provincial tumour team meetings and weekly rounds.
Post the guideline on the Alberta Health Services website.
Send an electronic notification of the new guideline to all members of Alberta Health Services, Cancer
Care.
MAINTENANCE
A formal review of the guideline will be conducted at the next Annual Provincial Meeting in October 2011.
If critical new evidence is brought forward before that time, however, the guideline working group
members will revise and update the document accordingly.
CONFLICT OF INTEREST
Participation of members of the Alberta Provincial CNS Tumour Team in the development of this guideline
has been voluntary and the authors have not been remunerated for their contributions. There was no
direct industry involvement in the development or dissemination of this guideline. Alberta Health Services
– Cancer Care recognizes that although industry support of research, education and other areas is
necessary in order to advance patient care, such support may lead to potential conflicts of interest. Some
members of the Alberta Provincial CNS Tumour Team are involved in research funded by industry or have
other such potential conflicts of interest. However the developers of this guideline are satisfied it was
developed in an unbiased manner.
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