MEDULLOBLASTOMA Effective Date: March, 2014

Transcription

MEDULLOBLASTOMA Effective Date: March, 2014
CLINICAL PRACTICE GUIDELINE CNS-008
Version 3
MEDULLOBLASTOMA
Effective Date: March, 2014
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.
CLINICAL PRACTICE GUIDELINE CNS-008
Version 3
BACKGROUND
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 its 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
ten-years 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
1. What are the recommended management strategies for adult patients with newly diagnosed
medulloblastoma?
2. What are the recommended management strategies for adult patients with relapsed or recurrent
medulloblastoma?
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DEVELOPMENT AND REVISION HISTORY
This guideline was reviewed and endorsed by the Alberta Provincial Central Nervous System (CNS)
Tumour Team. Members of the Alberta Provincial CNS Tumour Team include medical oncologists,
pediatric oncologists, neuro-oncologists, radiation oncologists, surgical oncologists, nurses, pathologists,
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.
This guideline was originally developed in August, 2010, and was revised in February, 2013 and March,
2014.
SEARCH STRATEGY
Medical journal articles were searched using the Medline (1950 to November Week 4, 2012), EMBASE
(1980 to November Week 4, 2012), Cochrane Database of Systematic Reviews (3rd Quarter, 2012), 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, or were not available through the library system. A review of the relevant existing practice
guidelines for medulloblastoma was also conducted by searching the websites of the American Society of
Clinical Oncology (ASCO), Australian Cancer Network, British Columbia Cancer Agency (BCCA), Cancer
Care Nova Scotia, Cancer Care Ontario (CCO), European Society for Medical Oncology (ESMO),
National Comprehensive Cancer Network National Guidelines Clearinghouse, National Institute for Health
and Clinical Excellence (NICE), National Cancer Institute (NCI), and the Scottish Intercollegiate
Guidelines Network (SIGN).
An updated literature search was conducted in January, 2014 following the same search strategy as
described above.
TARGET POPULATION
The recommendations outlined in this guideline apply to adults over the age of 16 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 clinical trials is encouraged.
2. Prior to initiating therapy, an MRI of the brain and total spine should be performed within 72 hours
postoperatively, given the risk of seeding throughout the craniospinal axis. Lumbar cerebrospinal fluid
(CSF) cytology should also be performed, either pre-operatively if safe or 2-3 weeks post-operatively;
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the MRI should precede lumbar CSF sampling to avoid false positive interpretations of imaging data.
3. Adult patients with T1, T2, T3a and M0 disease who undergo a total or near-total resection (< 1.5 cm2)
are classified as having average-risk disease. In contrast, adult patients with T3b or T4 plus M1 to M3
disease plus postoperative residual tumours are classified as having high-risk disease.
Treatment for Newly Diagnosed Patients:
4. Maximal safe surgical resection followed by postoperative radiotherapy and possibly concurrent and/or
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.
5. 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. Adjuvant chemotherapy may allow for use of
lower craniospinal radiation doses of 23.4Gy.
6. 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,
concurrent and/or adjuvant chemotherapy may be considered for select 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. Decisions should be made on an individual basis for each patient,
and should be discussed and planned at multidisciplinary Tumour Board meetings.
Follow-up:
7. 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.
Treatment for Recurrent Patients:
8. Patients with disseminated disease should be managed with chemotherapy, focal radiation where
indicated, and best supportive care. Fit patients with localized recurrence should undergo maximum
safe re-resection, and may be offered re-irradiation or high-dose chemotherapy with autologous stem
cell transplantation. Decisions should be made on an individual basis for each patient, and should be
discussed and planned at multidisciplinary Tumour Board meetings.
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 clinical trials is encouraged (recommendation #1).
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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 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
lumbar CSF cytology, either pre-operatively if safe, or two to three weeks post-operatively
(recommendation #2).15 Because the use of either spinal MRI or lumbar CSF alone has been associated
with a rate of false negatives as high as 20 percent, both spinal MRI and lumbar CSF are ideal.16 A
lumbar puncture may introduce imaging artifacts, therefore the MRI should precede lumbar CSF.13
Staging and Classification
Historically, adult medulloblastoma has been clinically staged according to the Chang staging definitions
for tumour and metastases parameters; a modified Chang Staging System, is described in Table 1.17
Table 1. Modified Chang Staging System for Medulloblastoma
Tumour Classification
T1
T2
T3a
T3b
T4
Metastasis Classification
M0
M1
M2
M3
M4
17
Description
greatest tumour dimension <3cm
greatest tumour dimension >3cm
greatest tumour dimension >3cm with spread into the aqueduct of Sylvius and/or foramen of
Luschka, cerebral subarachnoid space, third or lateral ventricles
greatest tumour dimension >3cm with unequivocal spread into the brainstem; for T3b, surgical
staging may be used in the absence of involvement at imaging
greatest tumour dimension >3cm with spread beyond the aqueduct of Sylvius and/or the
foramen magnum
Description
no evidence of gross subarachnoid or hematogenous metastasis
microscopic tumour cells in cerebrospinal fluid
gross nodular seeding in cerebellum
gross nodular seeding in spinal subarachnoid space
metastasis beyond cerebrospinal axis
While the “T” component of this classification system has little prognostic value, the “M” component
remains vital for determining the appropriate risk-adapted treatment protocols for adult patients. More
recently, average- and high-risk classification has been identified to be an important factor in treatment
decisions as well as a prognostic indicator in several studies, although the definition of average- and highrisk is variable.5,6,18 According to the Chang criteria, average-risk patients are those that have T1, T2, T3a
and M0 disease, and have totally or near totally resected disease (< 1.5 cm2) following surgery. In
contrast, high-risk patients are those that have T3b or T4 plus M1 to M3 disease, and do have
postoperative residual tumours (recommendation #3).5 In their retrospective study of adult patients with
medulloblastoma, Padovani and colleagues defined high-risk patients as those with metastatic disease
and/or CSF involvement and/or macroscopic residual tumour after surgery, while the standard-risk
patients had none of these risk factors.6 In comparison, the Children’s Oncology Group defines averagerisk patients as those with any T-stage who have totally or near totally resected disease (< 1.5 cm2)
following surgery and no metastases, while high-risk patients have greater than 1.5 cm2 residual disease
following surgery and/or metastatic disease.19
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Histology and Molecular Classification
Medulloblastoma is described as malignant and invasive, and is classified by the World Health
Organization (WHO) as a grade IV tumour.20 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.20 In general, the large-cell
and anaplastic subtypes appear to be associated with the worst prognosis.21
A recent consensus statement published by Taylor and colleagues proposed nomenclature for four
molecular subgroups of medulloblastoma: Wnt, Sonic Hedgehog (SHH), Group 3, and Group 4.22 This
statement was supplemented by an international meta-analysis of 550 patients from seven studies, and
described distinct differences with respect to transcriptome, DNA copy-number aberrations,
demographics, and survival of patients in each of the four subtypes.23 A recently published comprehensive
review of adult medulloblastoma suggests that SHH tumours are most common in adult patients,
comprising about two-thirds of adult medulloblastoma cases.24
Standard histologic reporting for medulloblastoma includes documentation of tumour nodularity, necrosis,
mitoses, apoptosis, cell size, nuclear wrapping, 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.21,25 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,21,25-27 but are not considered standard
tests in Alberta at the present time.
Treatment for Newly Diagnosed Patients
Surgery. Maximal safe surgical resection followed by postoperative radiotherapy and possibly adjuvant
chemotherapy is the recommended treatment strategy for adult patients with medulloblastoma
(recommendation #4). 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.3,6,8,9,28,29 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<0.01).28 In addition, only one of 17 patients who underwent complete
total resection experienced failure in the posterior fossa, whereas ten of 15 patients who underwent a less
than complete resection experienced failure in the posterior fossa.28 Similarly, in a retrospective review of
53 adult patients with medulloblastoma, del Charco et al. reported that absolute survival rates at five years
after biopsy alone, subtotal excision, and gross total excision were 43, 67, and 78 percent, respectively
(p=0.04), and posterior fossa control rates were 27, 89, and 83 percent, respectively (p=0.004).29
Radiotherapy. Postoperative radiotherapy is the standard of care for the treatment of adult patients with
medulloblastoma. The reported five-year overall survival rates for adult patients with medulloblastoma
treated with craniospinal irradiation range from 58 to 84 percent.3,4,6,30,31 In the pediatric setting, there has
been a recent shift to a reduction in the craniospinal radiation dose, in an effort to prevent or reduce the
negative neurocognitive effects of radiation on the developing brain.32-35 However, a dose of 36-40Gy to
the spinal axis appears to be well tolerated in adults, with no major acute or late effects reported in the
literature to date.3,31,36 In their retrospective review of 156 adult patients, Carrie et al. reported that 36Gy to
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the craniospinal axis was well tolerated and had a statistically significant positive effect on prognosis
(p=0.003).3 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 craniospinal 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<0.0001, respectively).6 In multivariate analysis, a radiotherapy dose
less than 50Gy to the posterior fossa was negatively associated with overall survival (RR=2.7, 95% CI 3.05.8; p=0.009).6 In a recent retrospective analysis, Balducci and colleagues presented the long-term
outcomes of 13 adult patients treated with postoperative radiotherapy over a 20 year period.31 The median
dose to the brain was 40 Gy (range 34.5-44) and to the posterior fossa was 55 Gy (range 50.4-55.8);
eleven patients also received a dose of 30 Gy on the spinal cord. The ten-year rates of local control,
overall survival, and disease-free survival were 91%, 76%, and 84%, respectively. A recent retrospective
review of 40 adult medulloblastoma patients compared proton craniospinal irradiation (CSI) with
conventional photon CSI and found that patients treated with proton CSI experienced less treatmentrelated morbidity, including less acute gastrointestinal and hematologic toxicities.37 Members of the
Alberta Provincial CNS Tumour Team recommend that postoperative radiotherapy to the entire
craniospinal axis at a total dose of 36-40Gy/20 fractions, followed by a posterior fossa boost to 54-55.8Gy
should be administered to all adult patients with medulloblastoma. Sites of gross disease elsewhere in the
craniospinal axis should be boosted to at least 40Gy. Concurrent chemotherapy, as described below, may
allow for use of lower craniospinal radiation doses of 23.4Gy, but only for adult patients with average risk
disease (recommendation #5).
Chemotherapy. Beginning in the early 1990’s, several randomized clinical trials reported that treatment
with chemotherapy resulted in improved survival for children with high-risk medulloblastoma, and these
children demonstrated better survival when compared to their low-risk counterparts who were not treated
with chemotherapy.19,38-41 As a result, it became standard to treat all children with medulloblastoma with
chemotherapy in addition to radiotherapy. In contrast to childhood medulloblastoma, the role of
chemotherapy in adult patients with medulloblastoma is less clear. Recent publications suggest that the
biology of adult medulloblastoma might closely resemble the Sonic Hedgehog (SHH) pediatric subtype of
medulloblastoma;22-24 thus, based on extrapolation from the pediatric literature, adjuvant chemotherapy
may be considered for adults with high-risk disease, and also for the treatment of recurrence
(recommendation #6). Although there is currently no strong evidence to support a specific chemotherapy
regimen for adults, treatment toxicity may be an important factor to take into consideration in this
population. In a retrospective review of toxicities for 56 adolescents treated for medulloblastoma, Tabori
and colleagues reported significant grade 2 or higher neurotoxicity and ototoxicity in 71% and 45% of
patients treated with chemotherapy, respectively.42 Apart from two recent prospective trials,5,43 most of the
published reports addressing chemotherapy in the adult population are small, retrospective, involve
patients diagnosed and treated more than 30 years ago, involve a variety of chemotherapy drugs or
regimens, and include both low-risk and high-risk populations. Table 2 summarizes the results from a
selection of the largest of these published trials of adjuvant chemotherapy in adult patients with
medulloblastoma.
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Table 2. Review of Select Studies of Adults with Medulloblastoma Treated with Adjuvant Chemotherapy
Study
N
Rao,
44
2014
363
Median
Age
not
reported
prospective
trial
Friedrich,
45
2013
Adjuvant Chemotherapy Regimen(s)
Radiation Doses
Outcomes
Regimen A:
2
Day 0=CCNU (75 mg/m )
2
Day 0=cisplatin (75 mg/m )
2
Day 0, 7, 14=VCR (1.5 mg/m ; max. 2
mg)
Regimen B:
2
Day 0=cisplatin (75 mg/m )
2
Day 0, 7, 14=VCR (1.5 mg/m ; max. 2
mg)
2
Day 21, 22=cyclophosphamide (1 mg/m )
2
lomustine orally (75 mg/m ) + vincristine
2
intravenous (1.5 mg/m ; max. 2 mg) +
cisplatin infusion over 6 h after CSI (70
2
mg/m )
Craniospinal: 2,340 cGy
Posterior fossa boost:
3,240 cGy
Total: 5,580 cGy
180 cGy/day; 5
days/week
• 8-yr EFS=78.2 ± 2.6%
• 8-year OS=83.9 ±
2.4%
Craniospinal: 35.2 Gy
Posterior fossa boost:
55.2 Gy
• 4-year EFS=68 ± 7%
• 4-year OS=89 ± 5%
• Peripheral neuropathy
(74%) and
haematotoxicity
(55%) appear to be
more common in
adults than children
• Histological subtype
and tumour location
identified as risk
factors
• 5-yr OS rate=80%
• 10-yr OS rate=55.8%
• 5-yr OS rates for
standard- vs. high-risk
patients=69.8% vs.
50% (p=0.0063)
• extent of surgery and
desmoplastic vs.
classic variant were
not predictive of
survival
• 5-yr PFS rate=57.6%
• 18/28 patients
developed recurrence
• 5-yr OS rate=78%
• 10-yr OS rate=30%
• adjuvant therapy did
not significantly
impact survival
• Mean OS=59.8
months CT-treated
vs. 41.4 months no
CT (p=0.15)
• 5-yr OS rates=80%
standard-risk patients
vs. 73% high-risk
patients (p=NS)
70
28.5 yrs
28
27 yrs
cisplatin (45 mg/m days 1-3) + etoposide
2
(120 mg/m , days 1-3) every 4 wks x 3
cycles
Craniospinal: 36 Gy
Posterior fossa boost:
53.2–60 Gy (median=54
Gy)
25
30 yrs
Ertas,
47
2008
29
not
reported
N=1: vincristine + CCNU + prednisone
N=6: cisplatin/etoposide alternating with
vincristine/ cyclophosphamide
N=1: vincristine + CCNU
N=4: other protocols
N=11: procarbazine + CCNU + vincristine
Brandes,
5
2007
36
26 yrs
Craniospinal: 23.4 –
28.8 Gy (n=3) or 35 –
39.6 Gy (n=16)
Posterior fossa boost:
50–56 Gy
Whole brain: 40 Gy
Spine: 36 Gy
Posterior fossa boost:
10–14 Gy
Craniospinal: 36 Gy (20
fractions of 1.8 Gy/5
fractions/week)
Posterior fossa boost:
18.8 Gy (in 10 fractions
up to total of 54.8 Gy)
prospective
trial
Silvani,
43
2012
2
prospective
trial
Ang, 2008
46
prospective
trial
N=10 standard-risk patients: treated with
RT alone
N=26 high-risk patients: treated with RT +
CT
•
pre-1995: nitrogen mustard +
vincristine + prednisone +
procarbazine
•
post-1995: cisplatin + etoposide +
cyclophosphamide
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Study
N
Adjuvant Chemotherapy Regimen(s)
Radiation Doses
Outcomes
253
Median
Age
29 yrs
Padovani,
6
2007
N=146: heterogeneous adjuvant CT
regimens (8 drugs in 1 day regimen;
carboplatin + etoposide)
Brain: 35 Gy
Spine: 35 Gy
Posterior fossa boost: 54
Gy
Herrlinger,
48
2005
34
24.5 yrs
N=8: vincristine + CCNU + cisplatin or
carboplatin
N=7: methotrexate alone or methotrexate
+
vincristine based protocols
N=5: other protocols
Abacioglu,
49
2002
30
27 yrs
N=10 high-risk patients: varying
combinations of procarbazine + CCNU +
vincristine
RT only
Brain: 35 Gy
Spine: 35.5 Gy
Posterior fossa boost: 55
Gy
CT+RT
Brain: 35.2 Gy
Spine: 35.1 Gy
Posterior fossa boost:
57.8 Gy
Brain: 40 Gy (1.8–2 Gy
fractions/day)
Spine: 36 Gy (1.4–1.8
Gy fractions/day)
Posterior fossa boost: 54
Gy
• 5-yr OS rate=71% CT
vs. 73% no CT
• 10-yr OS =58% CT
vs. 53% no CT
(p=NS)
• 5-yr OS rate=84% CT
vs. 75% no CT
• 10-yr OS rate=84%
CT vs. 41% no CT
• Median survival=NR
for CT patients vs.
101 mos for patients
not treated with CT
(RR=1.89, 95% CI
0.95-4.86; p=0.068)
• 5-yr OS rate=65%
• 8-yr OS rate=51%
• 5-yr DFS rate=69%
CT vs. 60% no CT
(p=NS)
Greenberg,
50
2001
17
23 yrs
N=10: weekly vincristine followed by
cisplatin + CCNU + vincristine (Packer
protocol)
N=7: cisplatin/etoposide alternating with
vincristine/ cyclophosphamide (POG
protocol)
Craniospinal: 36 Gy
Posterior fossa boost:
53.2–60 Gy
Kunschner,
4
2001
28
30.5 yrs
NA
Chan,
28
2000
32
25.5 yrs
N=1: thioguanine + procarbazine +
dibromodulcitol + CCNU + vincristine
N=4: cyclophosphamide + etoposide +
cisplatin
N=1: methotrexate + nitrogen mustard +
vincristine + prednisone + procarbazine
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 yrs
Brain: 39.6 Gy
Spine: 38.4 Gy
Posterior fossa boost:
55.8 Gy
47
28 yrs
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
N=11 standard-risk patients:
procarbazine + hydroxyurea (+ CCNU in
• Median OS=36 mos
Packer protocol vs.
57 mos POG protocol
(p=0.058)
• Toxicity moderately
severe with Packer
protocol
• No significant
difference in OS
demonstrated
between the patients
treated with CT vs. no
CT
• 5-yr OS rate=83%
• 8-yr OS rate=45%
• CT adversely
associated with rate
of posterior fossa
control (p=0.03)
• Patients treated with
CT presented with
more advanced Mstage than patients
treated with RT alone
• 5-yr OS rate=58%
• No effect of CT on
survival or posterior
fossa control
Brain: 33.9 Gy
Spine: 31.1 Gy
• 5-yr OS rate=81%
standard-risk patients
Le, 1997
Prados,
18
1995
30
Craniospinal: 36 Gy
Posterior fossa boost: 55
Gy
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Study
N
Median
Age
Adjuvant Chemotherapy Regimen(s)
Radiation Doses
one patient)
N=21 high-risk patients: nitrosoureabased combination chemotherapy
Primary site: 55.4 Gy
Outcomes
•
•
Carrie,
3
1994
156
28 yrs
N=31: vincristine + BCNU + procarbazine
+ hydroxyurea + cisplatin + cytarabine +
methotrexate
N=29: vincristine + CCNU or BCNU
N=9: ifosfamide + cisplatin + vincristine
N=6: other protocols
Brain: 35 Gy
Spine: 35 Gy
Posterior fossa boost: 55
Gy
•
•
•
•
vs. 54% high-risk
patients (p=0.03)
Adjuvant CT
associated with
longer survival
(p=0.03)
Lack of adjuvant CT
associated with
shorter time to tumour
progression (p=0.05)
5-yr OS rate=66% CT
vs. 57% no CT
(p=NS)
10-yr OS rate=52%
CT vs. 43% no CT
(p=NS)
No significant
difference in survival
between different CT
regimens
CT appeared to be
much more toxic in
this adult series than
in children
Abbreviations: BCNU=carmustine, CCNU=lomustine, CI=95% confidence interval, CT=chemotherapy, DFS=disease-free survival, NR=not reached,
NS=not statistically significant, OS=overall survival, POG=Pediatric Oncology Group, RT=radiotherapy, RR=relative risk.
The use of concurrent chemotherapy and radiotherapy followed by adjuvant chemotherapy has also been
described in the literature. Douglas et al. treated 33 pediatric and adults patients with average risk disease
using concurrent vincristine and reduced-dose cranial spinal irradiation (23.4 Gy) plus a conformal tumour
bed boost, followed by eight cycles of adjuvant chemotherapy (vincristine, cisplatin, and lomustine or
cyclophosphamide).32 They reported an estimated 5-year disease free survival rate of 86 percent, as well
as estimated 5-year disease free posterior fossa control and primary tumour bed control rates of 94
percent.
A recent randomized trial of medulloblastoma patients aged 3 to 21 years evaluated EFS after receiving
chemotherapy before radiation (n=112) or after radiation (n=112).51 Patients received either 7-weeks of
cisplatin and VP-16 followed by chemoRT then 28 weeks of vincristine/cyclophosphamide (arm 1) or
chemoRT followed by 7-weeks of cisplatin and VP-16 then 28 weeks of vincristine/cyclophosphamide
(arm 2). The study authors reported a 5-year EFS of 66 percent in the arm 1 group and 70 percent in the
arm 2 group (p=0.54); 5-year OS in the two groups was 73.1 percent and 76.1 percent, respectively
(p=0.47). Five-year EFS did not differ significantly between the two groups in this study. These results do
not support the use of neoadjuvant chemotherapy for medulloblastoma in children.
The use of temozolomide as an alternative to some of the older chemotherapy regimens has recently
shown favourable results with improved efficacy and reduced adverse effects in adult patients with both
newly diagnosed and recurrent medulloblastoma.52-56
Prospective randomized studies are required to more definitively address whether the combination of
concurrent and adjuvant chemotherapy is an effective treatment for adults with medulloblastoma, and if
so, which chemotherapy regimens are most effective. At the present time, it is reasonable to treat select
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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.
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.28 Riffaud et al. reported a recurrence rate of 41 percent, with a median time to first recurrence
of 4.2 years (range 0.7–18 years).10 Similarly, in one of the only prospective studies 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 In a review of 23 patients aged 2 to
40 years with extra-CNS medulloblastoma metastases, Eberhart and colleagues reported that only four
cases were identified at diagnosis, while the remaining cases of recurrence or metastasis appeared up to
11 years after the initial diagnosis.57
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 #7). 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.
Treatment for Recurrent Patients
Published trials addressing the treatment of disease recurrence in adult patients with medulloblastoma are
limited mostly to small case series and retrospective reviews. Treatments described in the literature most
often involve re-resection combined with chemotherapy and re-irradiation,28,48,53,58-60 but re-irradiation
alone4 and chemotherapy alone5 have also been reported. It is difficult to compare treatment responses at
the time of recurrence across these studies however, due to the wide variety of chemotherapeutic agents
and treatment schedules reported. In their published guidance, the National Comprehensive Cancer
Network (NCCN) recommends that patients with disseminated disease should be managed with
chemotherapy or best supportive care including focal radiation, where indicated, while patients with
localized brain recurrences should be treated with maximum safe re-resection, followed by chemotherapy
and/or additional radiotherapy.61 For patients who have not previously received chemotherapy, the NCCN
recommends the use of high-dose cyclophosphamide/etoposide, carboplatin/etoposide/
cyclophosphamide, or cisplatin/etoposide/ cyclophosphamide. For patients previously treated with
chemotherapy, they recommend the use of high-dose cyclophosphamide/ etoposide, oral etoposide, or
temozolomide.61
The NCCN also lists high-dose chemotherapy followed by autologous stem cell transplantation as an
option following re-resection.61 To date, there have been 12 publications involving 61 adults patients with
recurrent medulloblastoma treated with high-dose chemotherapy followed by stem-cell transplantation.62-74
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The majority of these studies have been case reports, case series, or retrospective reviews, and patient
characteristics such as the degree of disease progression at recurrence, first versus later recurrence, and
the fitness of the patients varies across studies. In addition, both high-dose and salvage chemotherapy
regimens have varied across studies, limiting the comparability of the results. In the only publication to
include a comparison group, Gill et al. reported that patients treated with high-dose chemotherapy and
autologous stem cell transplantation at recurrence had a better overall survival than a group of historical
controls treated with conventional chemotherapy at recurrence (3.47 years vs. 2 years, p=0.04).66 A
recent systematic review on the management of recurrent medulloblastoma in the adult population found
similar results.75
Based on our interpretation of the existing literature combined with our expert opinion, the Alberta
Provincial CNS Tumour Team members recommend that patients with disseminated disease should be
managed with chemotherapy, focal radiation where indicated, and best supportive care. Fit patients with
localized recurrence should undergo maximum safe re-resection, and may be offered re-irradiation or
high-dose chemotherapy with autologous stem cell transplantation. Decisions should be made on an
individual basis for each patient, and should be discussed and planned at multidisciplinary Tumour Board
meetings (recommendation #8).
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CLINICAL PRACTICE GUIDELINE CNS-008
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GLOSSARY OF ABBREVIATIONS
Acronym
ASCT
BCNU
CCNU
CI
CNS
CSF
CSI
CT
DFS
EFS
Gy
MRI
OS
POG
RR
RT
SEER
SHH
WHO
Description
autologous stem cell transplantation
carmustine
lomustine
confidence interval
central nervous system
cerebrospinal fluid
craniospinal irradiation
chemotherapy
disease-free survival
event-free survival
gray
magnetic resonance imaging
overall survival
Pediatric Oncology Group
relative risk
radiotherapy
Surveillance, Epidemiology, and End Results database
sonic hedgehog
World Health Organization
DISSEMINATION
•
•
•
Present 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 CancerControl Alberta.
MAINTENANCE
A formal review of the guideline will be conducted at the Annual Provincial Meeting in 2015. 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. CancerControl Alberta
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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REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Brandes AA, Paris MK. Review of the prognostic factors in medulloblastoma of children and adults. Crit Rev
Oncol Hematol 2004 May;50(2):121-128.
Bloom HJ, Bessell EM. Medulloblastoma in adults: a review of 47 patients treated between 1952 and 1981. Int J
Radiat Oncol Biol Phys 1990 Apr;18(4):763-772.
Carrie C, Lasset C, Alapetite C, Haie-Meder C, Hoffstetter S, Demaille MC, et al. Multivariate analysis of
prognostic factors in adult patients with medulloblastoma. Retrospective study of 156 patients. Cancer 1994 Oct
15;74(8):2352-2360.
Kunschner LJ, Kuttesch J, Hess K, Yung WK. Survival and recurrence factors in adult medulloblastoma: the
M.D. Anderson Cancer Center experience from 1978 to 1998. Neuro Oncol 2001 Jul;3(3):167-173.
Brandes AA, Franceschi E, Tosoni A, Blatt V, Ermani M. Long-term results of a prospective study on the
treatment of medulloblastoma in adults. Cancer 2007 Nov 1;110(9):2035-2041.
Padovani L, Sunyach MP, Perol D, Mercier C, Alapetite C, Haie-Meder C, et al. Common strategy for adult and
pediatric medulloblastoma: a multicenter series of 253 adults. Int J Radiat Oncol Biol Phys 2007 Jun
1;68(2):433-440.
Giordana MT, Cavalla P, Dutto A, Borsotti L, Chio A, Schiffer D. Is medulloblastoma the same tumor in children
and adults? J Neurooncol 1997 Nov;35(2):169-176.
Roldan G, Brasher P, Vecil G, Senger D, Rewcastle B, Cairncross G, et al. Population-based study of
medulloblastoma: outcomes in Alberta from 1975 to 1996. Can J Neurol Sci 2008 May;35(2):210-215.
Lai R. Survival of patients with adult medulloblastoma: a population-based study. Cancer 2008 Apr
1;112(7):1568-1574.
Riffaud L, Saikali S, Leray E, Hamlat A, Haegelen C, Vauleon E, et al. Survival and prognostic factors in a series
of adults with medulloblastomas. J Neurosurg 2009 Sep;111(3):478-487.
Lal P, Nagar YS, Kumar S, Singh S, Maria Das KJ, Narayan SL, et al. Medulloblastomas: clinical profile,
treatment techniques and outcome - an institutional experience. Indian J Cancer 2002 Jul-Sep;39(3):97-105.
Brandes AA, Palmisano V, Monfardini S. Medulloblastoma in adults: clinical characteristics and treatment.
Cancer Treat Rev 1999 Feb;25(1):3-12.
Eisenstat DD. Clinical management of medulloblastoma in adults. Expert Rev Anticancer Ther 2004
Oct;4(5):795-802.
Merchant TE, Pollack IF, Loeffler JS. Brain tumors across the age spectrum: biology, therapy, and late effects.
Semin Radiat Oncol 2010 Jan;20(1):58-66.
Gajjar A, Fouladi M, Walter AW, Thompson SJ, Reardon DA, Merchant TE, et al. Comparison of lumbar and
shunt cerebrospinal fluid specimens for cytologic detection of leptomeningeal disease in pediatric patients with
brain tumors. J Clin Oncol 1999 Jun;17(6):1825-1828.
Fouladi M, Gajjar A, Boyett JM, Walter AW, Thompson SJ, Merchant TE, et al. Comparison of CSF cytology
and spinal magnetic resonance imaging in the detection of leptomeningeal disease in pediatric medulloblastoma
or primitive neuroectodermal tumor. J Clin Oncol 1999 Oct;17(10):3234-3237.
Chang CH, Housepian EM, Herbert C,Jr. An operative staging system and a megavoltage radiotherapeutic
technic for cerebellar medulloblastomas. Radiology 1969 Dec;93(6):1351-1359.
Prados MD, Warnick RE, Wara WM, Larson DA, Lamborn K, Wilson CB. Medulloblastoma in adults. Int J
Radiat Oncol Biol Phys 1995 Jul 15;32(4):1145-1152.
Zeltzer PM, Boyett JM, Finlay JL, Albright AL, Rorke LB, Milstein JM, et al. Metastasis stage, adjuvant
treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the
Children's Cancer Group 921 randomized phase III study. J Clin Oncol 1999 Mar;17(3):832-845.
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of
tumours of the central nervous system. Acta Neuropathol 2007 Aug;114(2):97-109.
Gulino A, Arcella A, Giangaspero F. Pathological and molecular heterogeneity of medulloblastoma. Curr Opin
Oncol 2008 Nov;20(6):668-675.
Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, et al. Molecular subgroups of
medulloblastoma: the current consensus. Acta Neuropathol 2012 Apr;123(4):465-472.
Page 14 of 17
CLINICAL PRACTICE GUIDELINE CNS-008
Version 3
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
Kool M, Korshunov A, Remke M, Jones DT, Schlanstein M, Northcott PA, et al. Molecular subgroups of
medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of
WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol 2012 Apr;123(4):473-484.
Remke M, Hielscher T, Northcott PA, Witt H, Ryzhova M, Wittmann A, et al. Adult medulloblastoma comprises
three major molecular variants. J Clin Oncol 2011 Jul 1;29(19):2717-2723.
Pizer BL, Clifford SC. The potential impact of tumour biology on improved clinical practice for medulloblastoma:
progress towards biologically driven clinical trials. Br J Neurosurg 2009 Aug;23(4):364-375.
Korshunov A, Remke M, Werft W, Benner A, Ryzhova M, Witt H, et al. Adult and pediatric medulloblastomas
are genetically distinct and require different algorithms for molecular risk stratification. J Clin Oncol 2010 Jun
20;28(18):3054-3060.
Lamont JM, McManamy CS, Pearson AD, Clifford SC, Ellison DW. Combined histopathological and molecular
cytogenetic stratification of medulloblastoma patients. Clin Cancer Res 2004 Aug 15;10(16):5482-5493.
Chan AW, Tarbell NJ, Black PM, Louis DN, Frosch MP, Ancukiewicz M, et al. Adult medulloblastoma:
prognostic factors and patterns of relapse. Neurosurgery 2000 Sep;47(3):623-31; discussion 631-2.
del Charco JO, Bolek TW, McCollough WM, Maria BL, Kedar A, Braylan RC, et al. Medulloblastoma: time-dose
relationship based on a 30-year review. Int J Radiat Oncol Biol Phys 1998 Aug 1;42(1):147-154.
Le QT, Weil MD, Wara WM, Lamborn KR, Prados MD, Edwards MS, et al. Adult medulloblastoma: an analysis
of survival and prognostic factors. Cancer J Sci Am 1997 Jul-Aug;3(4):238-245.
Balducci M, Chiesa S, Chieffo D, Manfrida S, Dinapoli N, Fiorentino A, et al. The role of radiotherapy in adult
medulloblastoma: long-term single-institution experience and a review of the literature. J Neurooncol 2012
Jan;106(2):315-323.
Douglas JG, Barker JL, Ellenbogen RG, Geyer JR. Concurrent chemotherapy and reduced-dose cranial spinal
irradiation followed by conformal posterior fossa tumor bed boost for average-risk medulloblastoma: efficacy
and patterns of failure. Int J Radiat Oncol Biol Phys 2004 Mar 15;58(4):1161-1164.
Deutsch M, Thomas PR, Krischer J, Boyett JM, Albright L, Aronin P, et al. Results of a prospective randomized
trial comparing standard dose neuraxis irradiation (3,600 cGy/20) with reduced neuraxis irradiation (2,340
cGy/13) in patients with low-stage medulloblastoma. A Combined Children's Cancer Group-Pediatric Oncology
Group Study. Pediatr Neurosurg 1996;24(4):167-176; discussion 176-7.
Spiegler BJ, Bouffet E, Greenberg ML, Rutka JT, Mabbott DJ. Change in neurocognitive functioning after
treatment with cranial radiation in childhood. J Clin Oncol 2004 Feb 15;22(4):706-713.
Merchant TE, Kun LE, Krasin MJ, Wallace D, Chintagumpala MM, Woo SY, et al. Multi-institution prospective
trial of reduced-dose craniospinal irradiation (23.4 Gy) followed by conformal posterior fossa (36 Gy) and
primary site irradiation (55.8 Gy) and dose-intensive chemotherapy for average-risk medulloblastoma. Int J
Radiat Oncol Biol Phys 2008 Mar 1;70(3):782-787.
Smee RI, Williams JR. Medulloblastomas-primitive neuroectodermal tumours in the adult population. J Med
Imaging Radiat Oncol 2008 Feb;52(1):72-76.
Brown AP, Barney CL, Grosshans DR, McAleer MF, de Groot JF, Puduvalli VK, et al. Proton beam craniospinal
irradiation reduces acute toxicity for adults with medulloblastoma. Int J Radiat Oncol Biol Phys 2013 Jun
1;86(2):277-284.
Evans AE, Jenkin RD, Sposto R, Ortega JA, Wilson CB, Wara W, et al. The treatment of medulloblastoma.
Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine, and
prednisone. J Neurosurg 1990 Apr;72(4):572-582.
Tait DM, Thornton-Jones H, Bloom HJ, Lemerle J, Morris-Jones P. Adjuvant chemotherapy for
medulloblastoma: the first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I).
Eur J Cancer 1990 Apr;26(4):464-469.
Packer RJ, Sutton LN, Elterman R, Lange B, Goldwein J, Nicholson HS, et al. Outcome for children with
medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg 1994
Nov;81(5):690-698.
Packer RJ, Gajjar A, Vezina G, Rorke-Adams L, Burger PC, Robertson PL, et al. Phase III study of craniospinal
radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin
Oncol 2006 Sep 1;24(25):4202-4208.
Page 15 of 17
CLINICAL PRACTICE GUIDELINE CNS-008
Version 3
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
Tabori U, Sung L, Hukin J, Laperriere N, Crooks B, Carret AS, et al. Medulloblastoma in the second decade of
life: a specific group with respect to toxicity and management: a Canadian Pediatric Brain Tumor Consortium
Study. Cancer 2005 May 1;103(9):1874-1880.
Silvani A, Gaviani P, Lamperti E, Botturi A, Dimeco F, Franzini A, et al. Adult medulloblastoma: multiagent
chemotherapy with cisplatinum and etoposide: a single institutional experience. J Neurooncol 2012
Feb;106(3):595-600.
Nageswara Rao AA, Wallace DJ, Billups C, Boyett JM, Gajjar A, Packer RJ. Cumulative cisplatin dose is not
associated with event-free or overall survival in children with newly diagnosed average-risk medulloblastoma
treated with cisplatin based adjuvant chemotherapy: report from the Children's Oncology Group. Pediatr Blood
Cancer 2014 Jan;61(1):102-106.
Friedrich C, von Bueren AO, von Hoff K, Kwiecien R, Pietsch T, Warmuth-Metz M, et al. Treatment of adult
nonmetastatic medulloblastoma patients according to the paediatric HIT 2000 protocol: a prospective
observational multicentre study. Eur J Cancer 2013 Mar;49(4):893-903.
Ang C, Hauerstock D, Guiot MC, Kasymjanova G, Roberge D, Kavan P, et al. Characteristics and outcomes of
medulloblastoma in adults. Pediatr Blood Cancer 2008 Nov;51(5):603-607.
Ertas G, Ucer AR, Altundag MB, Durmus S, Calikoglu T, Ozbagi K, et al. Medulloblastoma/primitive
neuroectodermal tumor in adults: prognostic factors and treatment results: a single-center experience from
Turkey. Med Oncol 2008;25(1):69-72.
Herrlinger U, Steinbrecher A, Rieger J, Hau P, Kortmann RD, Meyermann R, et al. Adult medulloblastoma:
prognostic factors and response to therapy at diagnosis and at relapse. J Neurol 2005 Mar;252(3):291-299.
Abacioglu U, Uzel O, Sengoz M, Turkan S, Ober A. Medulloblastoma in adults: treatment results and prognostic
factors. Int J Radiat Oncol Biol Phys 2002 Nov 1;54(3):855-860.
Greenberg HS, Chamberlain MC, Glantz MJ, Wang S. Adult medulloblastoma: multiagent chemotherapy. Neuro
Oncol 2001 Jan;3(1):29-34.
Tarbell NJ, Friedman H, Polkinghorn WR, Yock T, Zhou T, Chen Z, et al. High-risk medulloblastoma: a pediatric
oncology group randomized trial of chemotherapy before or after radiation therapy (POG 9031). J Clin Oncol
2013 Aug 10;31(23):2936-2941.
Nicholson HS, Kretschmar CS, Krailo M, Bernstein M, Kadota R, Fort D, et al. Phase 2 study of temozolomide in
children and adolescents with recurrent central nervous system tumors: a report from the Children's Oncology
Group. Cancer 2007 Oct 1;110(7):1542-1550.
Durando X, Thivat E, Gilliot O, Irthum B, Verrelle P, Vincent C, et al. Temozolomide treatment of an adult with a
relapsing medulloblastoma. Cancer Invest 2007 Sep;25(6):470-475.
Hongeng S, Visudtibhan A, Dhanachai M, Laothamatus J, Chiamchanya S. Treatment of leptomeningeal
relapse of medulloblastoma with temozolomide. J Pediatr Hematol Oncol 2002 Oct;24(7):591-593.
Poelen J, Bernsen HJ, Prick MJ. Metastatic medulloblastoma in an adult; treatment with temozolomide. Acta
Neurol Belg 2007 Jun;107(2):51-54.
Korones DN, Smith A, Foreman N, Bouffet E. Temozolomide and oral VP-16 for children and young adults with
recurrent or treatment-induced malignant gliomas. Pediatr Blood Cancer 2006 Jul;47(1):37-41.
Eberhart CG, Cohen KJ, Tihan T, Goldthwaite PT, Burger PC. Medulloblastomas with systemic metastases:
evaluation of tumor histopathology and clinical behavior in 23 patients. J Pediatr Hematol Oncol 2003
Mar;25(3):198-203.
Bakst RL, Dunkel IJ, Gilheeney S, Khakoo Y, Becher O, Souweidane MM, et al. Reirradiation for recurrent
medulloblastoma. Cancer 2011 Nov 1;117(21):4977-4982.
Privitera G, Acquaviva G, Ettorre GC, Spatola C. Antiangiogenic therapy in the treatment of recurrent
medulloblastoma in the adult: case report and review of the literature. J Oncol 2009;2009:247873.
Menon G, Krishnakumar K, Nair S. Adult medulloblastoma: clinical profile and treatment results of 18 patients. J
Clin Neurosci 2008 Feb;15(2):122-126.
National Comprehensive Cancer Network. Central Nervous System Cancers. 2013;Version 2.
Dunkel IJ, Gardner SL, Garvin JH,Jr, Goldman S, Shi W, Finlay JL. High-dose carboplatin, thiotepa, and
etoposide with autologous stem cell rescue for patients with previously irradiated recurrent medulloblastoma.
Neuro Oncol 2010 Mar;12(3):297-303.
Page 16 of 17
CLINICAL PRACTICE GUIDELINE CNS-008
Version 3
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
Dunkel IJ, Boyett JM, Yates A, Rosenblum M, Garvin JH,Jr, Bostrom BC, et al. High-dose carboplatin, thiotepa,
and etoposide with autologous stem-cell rescue for patients with recurrent medulloblastoma. Children's Cancer
Group. J Clin Oncol 1998 Jan;16(1):222-228.
Grodman H, Wolfe L, Kretschmar C. Outcome of patients with recurrent medulloblastoma or central nervous
system germinoma treated with low dose continuous intravenous etoposide along with dose-intensive
chemotherapy followed by autologous hematopoietic stem cell rescue. Pediatr Blood Cancer 2009 Jul;53(1):3336.
Park JE, Kang J, Yoo KH, Sung KW, Koo HH, Lim do H, et al. Efficacy of high-dose chemotherapy and
autologous stem cell transplantation in patients with relapsed medulloblastoma: a report on the Korean Society
for Pediatric Neuro-Oncology (KSPNO)-S-053 study. J Korean Med Sci 2010 Aug;25(8):1160-1166.
Gill P, Litzow M, Buckner J, Arndt C, Moynihan T, Christianson T, et al. High-dose chemotherapy with
autologous stem cell transplantation in adults with recurrent embryonal tumors of the central nervous system.
Cancer 2008 Apr 15;112(8):1805-1811.
Secondino S, Pedrazzoli P, Schiavetto I, Basilico V, Bramerio E, Massimino M, et al. Antitumor effect of
allogeneic hematopoietic SCT in metastatic medulloblastoma. Bone Marrow Transplant 2008 Jul;42(2):131-133.
van den Berkmortel F, Gidding C, De Kanter M, Punt CJ. Severe encephalopathy after high-dose chemotherapy
with autologous stem cell support for brain tumours. Anticancer Res 2006 Jan-Feb;26(1B):729-733.
Zia MI, Forsyth P, Chaudhry A, Russell J, Stewart DA. Possible benefits of high-dose chemotherapy and
autologous stem cell transplantation for adults with recurrent medulloblastoma. Bone Marrow Transplant 2002
Nov;30(9):565-569.
Abrey LE, Rosenblum MK, Papadopoulos E, Childs BH, Finlay JL. High dose chemotherapy with autologous
stem cell rescue in adults with malignant primary brain tumors. J Neurooncol 1999 Sep;44(2):147-153.
Millot F, Delval O, Giraud C, Bataille B, Babin P, Germain T, et al. High-dose chemotherapy with hematopoietic
stem cell transplantation in adults with bone marrow relapse of medulloblastoma: report of two cases. Bone
Marrow Transplant 1999 Dec;24(12):1347-1349.
Graham ML, Herndon JE,2nd, Casey JR, Chaffee S, Ciocci GH, Krischer JP, et al. High-dose chemotherapy
with autologous stem-cell rescue in patients with recurrent and high-risk pediatric brain tumors. J Clin Oncol
1997 May;15(5):1814-1823.
Cottu PH, Giacchetti S, Mignot L, Epardeau B, Visot B, Extra JM, et al. High dose chemotherapy with stem-cell
transplantation in a metastatic medulloblastoma in an adult: a case report and review of the literature. J
Neurooncol 1994;18(1):19-23.
Lundberg JH, Weissman DE, Beatty PA, Ash RC. Treatment of recurrent metastatic medulloblastoma with
intensive chemotherapy and allogeneic bone marrow transplantation. J Neurooncol 1992 Jun;13(2):151-155.
Kostaras X, Easaw JC. Management of recurrent medulloblastoma in adult patients: a systematic review and
recommendations. J Neurooncol 2013 Oct;115(1):1-8.
Page 17 of 17