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CLINICAL PRACTICE GUIDELINE CNS-008Version 3

MEDULLOBLASTOMA

Effective Date: March, 2014

The recommendations contained in this guideline are a consensus of the Alberta Provincial CNS Tumour Teamsynthesis 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 thecontext of individual clinical circumstances to direct care.

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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.

1-3Because 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 andtreatment protocols. Based on the assumption that adult tumours have the same properties as those inchildren, adult patients with medulloblastoma are often given treatment protocols according to therapiesdeveloped for children with similarly staged disease at diagnosis.

4,5However, important histologic and

phenotypic differences have been identified between pediatric and adult medulloblastoma patients. Inaddition, radiologic differences have also been identified: adult tumours involve the lateral cerebellarhemispheres, while pediatric tumours most often occur in the vermis.

6,7Further, 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, multicentrestudy, Padovaniet al.retrospectively reviewed the outcomes of 253 adult patients treated formedulloblastoma between 1975 and 2004, and reported five- and ten-year overall survival rates of 72 and55 percent, respectively.

6When low- and high-risk patients were compared, the ten-year overall survival

rates were 62 and 49 percent (p=0.03).7Lower five-year survival rates were reported in an unselected,

population-based study published by Roldnet al.8In 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 55.7percent for those under the age of sixteen.

8The 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.

8A 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 withmedulloblastoma between 1973 and 2004.

9Multivariate analysis identified that diagnosis after the 1980s,

age of diagnosis before 20 years, gross total resection, and treatment with radiotherapy were allassociated with better survival.

9

The most commonly reported symptoms of medulloblastoma at initial diagnosis are associated withincreased intracranial pressure and cerebellar dysfunction. In the Roldn et al. study, headache (80%),nausea and vomiting (78%), and ataxia (73%) were most commonly identified;

8similar symptoms and

rates have been reported in retrospective series from France, India, and the MD Anderson Cancer Centerin the United States.

4,10,11

GUIDELINE QUESTIONS

1. What are the recommended management strategies for adult patients with newly diagnosedmedulloblastoma?

2. What are the recommended management strategies for adult patients with relapsed or recurrentmedulloblastoma?

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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 fromthe Alberta Provincial CNS Tumour Team and a Knowledge Management Specialist from the GuidelineUtilization Resource Unit. A detailed description of the methodology followed during the guidelinedevelopment process can be found in theGuideline 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 (3 rdQuarter, 2012), andPubMed electronic databases; the references and bibliographies of articles identified through thesesearches were scanned for additional sources. The MeSH heading Medulloblastoma was combined withthe search terms Surgery, Radiotherapy, Drug Therapy, Therapy, and Follow-up Studies. Theresults were limited to adults, practice guidelines, systematic reviews, meta-analyses, comparativestudies, multicentre studies, randomized controlled trials, and clinical trials. Articles were excluded fromthe review if they: addressed medulloblastoma in pediatric or adolescent patients, had a non-Englishabstract, or were not available through the library system. A review of the relevant existing practiceguidelines for medulloblastoma was also conducted by searching the websites of the American Society ofClinical Oncology (ASCO), Australian Cancer Network, British Columbia Cancer Agency (BCCA), CancerCare 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 IntercollegiateGuidelines Network (SIGN).

An updated literature search was conducted in January, 2014 following the same search strategy asdescribed above.

TARGET POPULATION

The recommendations outlined in this guideline apply to adults over the age of 16 years diagnosed withmedulloblastoma. Different principles may apply to pediatric patients.

RECOMMENDATIONS

Evaluation and Workup:

1. Evaluation and management of adult patients with medulloblastoma should be discussed and plannedwithin 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 hourspostoperatively, 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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Prior to initiating therapy, an MRI of the brain and total spine is recommended, as this is an important toolfor accurate staging of the tumour, particularly when the tumour extends beyond the posterior fossa andinto the spinal spaces.

12,13Postoperative neuro-imaging with MRI will help to quantify residual disease,

and is recommended within 72 hours following surgical resection.12-14

Medulloblastoma tumours in adultpatients are associated with a high likelihood for craniospinal seeding and spread through thecerebrospinal fluid (CSF). Therefore, when safe to do so, the workup of adult patients should includelumbar CSF cytology, either pre-operatively if safe, or two to three weeks post-operatively(recommendation #2).

15Because the use of eitherspinal MRI or lumbar CSF alone has been associated

with a rate of false negatives as high as 20 percent, bothspinal MRI and lumbar CSF are ideal.16

Alumbar 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 definitionsfor tumour and metastases parameters; a modified Chang Staging System, is described in Table 1.

17

Table 1.Modified Chang Staging System for Medulloblastoma17

Tumour Classification Description

T1 greatest tumour dimension 3cm

T3a greatest tumour dimension >3cm with spread into the aqueduct of Sylvius and/or foramen ofLuschka, cerebral subarachnoid space, third or lateral ventricles

T3b greatest tumour dimension >3cm with unequivocal spread into the brainstem; for T3b, surgicalstaging may be used in the absence of involvement at imaging

T4 greatest tumour dimension >3cm with spread beyond the aqueduct of Sylvius and/or theforamen 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 cerebellumM3 gross nodular seeding in spinal subarachnoid space

M4 metastasis beyond cerebrospinal axis

While the T component of this classification system has little prognostic value, the M componentremains vital for determining the appropriate risk-adapted treatment protocols for adult patients. Morerecently, average- and high-risk classification has been identified to be an important factor in treatmentdecisions as well as a prognostic indicator in several studies, although the definition of average- and high-risk is variable.

5,6,18According 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 havepostoperative residual tumours (recommendation #3).

5In 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-riskpatients had none of these risk factors.

6In comparison, the Childrens Oncology Group defines average-

risk 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 cm2residual disease

following surgery and/or metastatic disease.19

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Histology and Molecular Classif ication

Medulloblastoma is described as malignant and invasive, and is classified by the World Health

Organization (WHO) as a grade IV tumour.20In addition to the classic type of medulloblastoma, fourhistologic subtypes have also been identified (desmoplastic/nodular type, medulloblastoma with extensivenodularity, anaplastic medulloblastoma, large-cell medulloblastoma), and recent publications stress theimportance of these histologic subtypes in the prognosis of medulloblastoma.

20In 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 fourmolecular subgroups of medulloblastoma: Wnt, Sonic Hedgehog (SHH), Group 3, and Group 4.

22This

statement was supplemented by an international meta-analysis of 550 patients from seven studies, anddescribed distinct differences with respect to transcriptome, DNA copy-number aberrations,demographics, and survival of patients in each of the four subtypes.

23A 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 -catenin, may also be required for determining prognosis and ruling out medulloblastoma mimics.

21,25Other

specialized molecular tests, including those for MYC-C and MYC-N amplification, and loss of chromosome17p, may allow a more accurate prediction of disease prognosis,

21,25-27but 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 adjuvantchemotherapy 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 visibletumour, as several studies have correlated outcome with the extent of resection and the amount ofresidual tumour.

3,6,8,9,28,29In 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 significantlybetter 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

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the craniospinal axis was well tolerated and had a statistically significant positive effect on prognosis(p=0.003).

3The 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 Padovaniet al., a craniospinal radiation dose

greater than 30Gy and a posterior fossa radiation dose greater than 50Gy both correlated significantlywith overall survival (p=0.0054 and p

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Table 2. Review of Select Studies of Adults with Medulloblastoma Treated with Adjuvant ChemotherapyStudy N Median

Age

Adjuvant Chemotherapy Regimen(s) Radiation Doses Outcomes

Rao,201444

prospectivetrial

363 notreported Regimen A:Day 0=CCNU (75 mg/m2)

Day 0=cisplatin (75 mg/m2)

Day 0, 7, 14=VCR (1.5 mg/m2; max. 2

mg)Regimen B:Day 0=cisplatin (75 mg/m

2)

Day 0, 7, 14=VCR (1.5 mg/m2; max. 2

mg)Day 21, 22=cyclophosphamide (1 mg/m

2)

Craniospinal: 2,340 cGyPosterior fossa boost:3,240 cGyTotal: 5,580 cGy180 cGy/day; 5days/week

8-yr EFS=78.2 2.6 8-year OS=83.9

2.4%

Friedrich,2013

45

prospectivetrial

70 28.5 yrs lomustine orally (75 mg/m ) + vincristineintravenous (1.5 mg/m

2; max. 2 mg) +

cisplatin infusion over 6 h after CSI (70mg/m

2)

Craniospinal: 35.2 GyPosterior fossa boost:55.2 Gy

4-year EFS=68 7%

4-year OS=89 5%

Peripheral neuropat(74%) andhaematotoxicity

(55%) appear to bemore common inadults than children

Histological subtypeand tumour locationidentified as riskfactors

Silvani,2012

43

prospectivetrial

28 27 yrs cisplatin (45 mg/m days 1-3) + etoposide(120 mg/m

2, days 1-3) every 4 wks x 3

cycles

Craniospinal: 36 GyPosterior fossa boost:53.260 Gy (median=54Gy)

5-yr OS rate=80%

10-yr OS rate=55.8%

5-yr OS rates forstandard- vs. high-ripatients=69.8% vs.50% (p=0.0063)

extent of surgery andesmoplastic vs.classic variant werenot predictive ofsurvival

5-yr PFS rate=57.6%

18/28 patientsdeveloped recurrenc

Ang, 2008 25 30 yrs N=1: vincristine + CCNU + prednisoneN=6: cisplatin/etoposide alternating withvincristine/ cyclophosphamideN=1: vincristine + CCNUN=4: other protocols

Craniospinal: 23.4 28.8 Gy (n=3) or 35 39.6 Gy (n=16)Posterior fossa boost:5056 Gy

5-yr OS rate=78%

10-yr OS rate=30%

adjuvant therapy didnot significantlyimpact survival

Ertas,2008

47

29 notreported

N=11: procarbazine + CCNU + vincristine Whole brain: 40 GySpine: 36 GyPosterior fossa boost:

1014 Gy

Mean OS=59.8months CT-treatedvs. 41.4 months no

CT (p=0.15)Brandes,2007

5

prospectivetrial

36 26 yrs N=10 standard-risk patients: treated withRT aloneN=26 high-risk patients: treated with RT +CT

pre-1995: nitrogen mustard +vincristine + prednisone +procarbazine

post-1995:cisplatin + etoposide +cyclophosphamide

Craniospinal: 36 Gy (20fractions of 1.8 Gy/5fractions/week)Posterior fossa boost:18.8 Gy (in 10 fractionsup to total of 54.8 Gy)

5-yr OS rates=80%standard-risk patienvs. 73% high-riskpatients (p=NS)

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Study N Median

Age


Padovani,2007

6

253 29 yrs N=146: heterogeneous adjuvant CTregimens (8 drugs in 1 day regimen;carboplatin + etoposide)

Brain: 35 GySpine: 35 GyPosterior fossa boost: 54Gy

5-yr OS rate=71% Cvs. 73% no CT

10-yr OS =58% CTvs. 53% no CT(p=NS)

Herrlinger,2005

48

34 24.5 yrs N=8: vincristine + CCNU + cisplatin orcarboplatinN=7: methotrexate alone or methotrexate+vincristine based protocolsN=5: other protocols

RT onlyBrain: 35 GySpine: 35.5 GyPosterior fossa boost: 55GyCT+RTBrain: 35.2 GySpine: 35.1 GyPosterior fossa boost:57.8 Gy

5-yr OS rate=84% Cvs. 75% no CT

10-yr OS rate=84%CT vs. 41% no CT

Median survival=NRfor CT patients vs.101 mos for patientsnot treated with CT(RR=1.89, 95% CI0.95-4.86; p=0.068)

Abacioglu,

200249

30 27 yrs N=10 high-risk patients: varying

combinations of procarbazine + CCNU +vincristine

Brain: 40 Gy (1.82 Gy

fractions/day)Spine: 36 Gy (1.41.8Gy fractions/day)Posterior fossa boost: 54Gy

5-yr OS rate=65%

8-yr OS rate=51% 5-yr DFS rate=69%

CT vs. 60% no CT(p=NS)

Greenberg,2001

5017 23 yrs N=10: weekly vincristine followed by

cisplatin + CCNU + vincristine (Packerprotocol)N=7: cisplatin/etoposide alternating withvincristine/ cyclophosphamide (POGprotocol)

Craniospinal: 36 GyPosterior fossa boost:53.260 Gy

Median OS=36 mosPacker protocol vs.57 mos POG protoc(p=0.058)

Toxicity moderatelysevere with Packerprotocol

Kunschner,2001

428 30.5 yrs N=1: thioguanine + procarbazine +

dibromodulcitol + CCNU + vincristineN=4: cyclophosphamide + etoposide +cisplatinN=1: methotrexate + nitrogen mustard +vincristine + prednisone + procarbazine

NA No significantdifference in OSdemonstratedbetween the patientstreated with CT vs. nCT

Chan,2000

28

32 25.5 yrs N=16 : cisplatin + vincristineN=4 : cisplatin + vincristine +cyclophosphamide + etoposideN=1 : cisplatin + vincristine +cyclophosphamideN=1 : cisplatin + vincristine + etoposideN=1 : vincristine + CCNU

Craniospinal: 36 GyPosterior fossa boost: 55Gy

5-yr OS rate=83%

8-yr OS rate=45%

CT adverselyassociated with rateof posterior fossacontrol (p=0.03)

Patients treated withCT presented withmore advanced M-stage than patients

treated with RT alonLe, 1997 34 23 yrs N=12: procarbazine + hydroxyurea

N=5: cisplatin + CCNU + vincristineN=2: CCNU + vincristine + procarbazine+ hydroxyureaN=2: thioguanine + procarbazine +dibromodulcitol + CCNU + vincristineN=1: CCNU + hydroxyureaN=1: cytarabine

Brain: 39.6 GySpine: 38.4 GyPosterior fossa boost:55.8 Gy

5-yr OS rate=58%

No effect of CT onsurvival or posteriorfossa control

Prados,1995

1847 28 yrs N=11 standard-risk patients:

procarbazine + hydroxyurea (+ CCNU inBrain: 33.9 GySpine: 31.1 Gy

5-yr OS rate=81%standard-risk patien

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Study N Median

Age


one patient)N=21 high-risk patients: nitrosourea-based combination chemotherapy

Primary site: 55.4 Gy vs. 54% high-riskpatients (p=0.03)

Adjuvant CTassociated withlonger survival(p=0.03)

Lack of adjuvant CTassociated withshorter time to tumoprogression (p=0.05

Carrie,1994

3156 28 yrs N=31: vincristine + BCNU + procarbazine

+ hydroxyurea + cisplatin + cytarabine +methotrexateN=29: vincristine + CCNU or BCNUN=9: ifosfamide + cisplatin + vincristineN=6: other protocols

Brain: 35 GySpine: 35 GyPosterior fossa boost: 55Gy

5-yr OS rate=66% Cvs. 57% no CT(p=NS)

10-yr OS rate=52%CT vs. 43% no CT(p=NS)

No significantdifference in survivabetween different CTregimens

CT appeared to bemuch more toxic inthis adult series thanin children

Abb revi ations: 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 beendescribed in the literature. Douglas et al.treated 33 pediatric and adults patients with average risk diseaseusing 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 orcyclophosphamide).

32They 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 94percent.

A recent randomized trial of medulloblastoma patients aged 3 to 21 years evaluated EFS after receivingchemotherapy before radiation (n=112) or after radiation (n=112).

51Patients received either 7-weeks of

cisplatin and VP-16 followed by chemoRT then 28 weeks of vincristine/cyclophosphamide (arm 1) orchemoRT 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 thearm 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 recentlyshown favourable results with improved efficacy and reduced adverse effects in adult patients with bothnewly diagnosed and recurrent medulloblastoma.

52-56

Prospective randomized studies are required to more definitively address whether the combination ofconcurrent and adjuvant chemotherapy is an effective treatment for adults with medulloblastoma, and ifso, 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 throughrandomized clinical trials in the pediatric population. Decisions should be made on an individual basis foreach 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, Roldnet al.reported a50 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 consideredcured.

8Late 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 twoyears after completion of treatment, and 29 percent occurred more than five years after the completion oftreatment.

28Riffaudet al.reported a recurrence rate of 41 percent, with a median time to first recurrence

of 4.2 years (range 0.718 years).10

Similarly, in one of the only prospective studies published to date,Brandeset 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 to40 years with extra-CNS medulloblastoma metastases, Eberhart and colleagues reported that only fourcases were identified at diagnosis, while the remaining cases of recurrence or metastasis appeared up to11 years after the initial diagnosis.

57

Due to the potential for late recurrences, the Alberta CNS Tumour Team members recommend aminimum of five to ten years of follow-up for adult patients with medulloblastoma (recommendation #7). Inparticular, monitoring and surveillance should be focused on neurocognitive, neuroendocrine, thyroid,pulmonary, cardiac, gastrointestinal, renal, and reproductive system late effects.

14An MRI of the brain and

full spine with gadolinium enhancement should be obtained every three to six months for the first twoyears of follow-up, and every year thereafter. The final discharge of the patient to their family physicianwill 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 arelimited mostly to small case series and retrospective reviews. Treatments described in the literature mostoften involve re-resection combined with chemotherapy and re-irradiation,

28,48,53,58-60but re-irradiation

alone4and chemotherapy alone

5have 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 agentsand treatment schedules reported. In their published guidance, the National Comprehensive CancerNetwork (NCCN) recommends that patients with disseminated disease should be managed withchemotherapy or best supportive care including focal radiation, where indicated, while patients withlocalized brain recurrences should be treated with maximum safe re-resection, followed by chemotherapy

and/or additional radiotherapy.61For patients who have not previously received chemotherapy, the NCCNrecommends the use of high-dose cyclophosphamide/etoposide, carboplatin/etoposide/cyclophosphamide, or cisplatin/etoposide/ cyclophosphamide. For patients previously treated withchemotherapy, they recommend the use of high-dose cyclophosphamide/ etoposide, oral etoposide, ortemozolomide.

61

The NCCN also lists high-dose chemotherapy followed by autologous stem cell transplantation as anoption following re-resection.

61To 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 patientcharacteristics such as the degree of disease progression at recurrence, first versus later recurrence, andthe 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 toinclude a comparison group, Gill et al.reported that patients treated with high-dose chemotherapy andautologous stem cell transplantation at recurrence had a better overall survival than a group of historicalcontrols treated with conventional chemotherapy at recurrence (3.47 years vs. 2 years, p=0.04).

66A

recent systematic review on the management of recurrent medulloblastoma in the adult population foundsimilar results.

75

Based on our interpretation of the existing literature combined with our expert opinion, the AlbertaProvincial CNS Tumour Team members recommend that patients with disseminated disease should bemanaged with chemotherapy, focal radiation where indicated, and best supportive care. Fit patients withlocalized recurrence should undergo maximum safe re-resection, and may be offered re-irradiation orhigh-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 Boardmeetings (recommendation #8).

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GLOSSARY OF ABBREVIATIONS

Acronym Descript ion

ASCT autologous stem cell transplantationBCNU carmustineCCNU lomustine

CI confidence intervalCNS central nervous system

CSF cerebrospinal fluidCSI craniospinal irradiation

CT chemotherapyDFS disease-free survival

EFS event-free survival

Gy grayMRI magnetic resonance imaging

OS overall survival

POG Pediatric Oncology GroupRR relative riskRT radiotherapy

SEER Surveillance, Epidemiology, and End Results databaseSHH sonic hedgehog

WHO 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 newevidence is brought forward before that time, however, the guideline working group members will reviseand update the document accordingly.

CONFLICT OF INTEREST

Participation of members of theAlberta Provincial CNS Tumour Team in the development of this guidelinehas been voluntary and the authors have not been remunerated for their contributions. There was nodirect 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 toadvance patient care, such support may lead to potential conflicts of interest. Some members of theAlberta Provincial CNS Tumour Team are involved in research funded by industry or have other suchpotential conflicts of interest. However the developers of this guideline are satisfied it was developed in anunbiased manner.

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Radiat Oncol Biol Phys 1990 Apr;18(4):763-772.3. 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 Oct15;74(8):2352-2360.

4. Kunschner LJ, Kuttesch J, Hess K, Yung WK. Survival and recurrence factors in adult medulloblastoma: theM.D. Anderson Cancer Center experience from 1978 to 1998. Neuro Oncol 2001 Jul;3(3):167-173.

5. Brandes AA, Franceschi E, Tosoni A, Blatt V, Ermani M. Long-term results of a prospective study on thetreatment of medulloblastoma in adults. Cancer 2007 Nov 1;110(9):2035-2041.

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