OBJECTIVES:

Primary

- Determine whether carboplatin radiosensitization increases long-term, event-free
survival of pediatric patients with newly diagnosed, previously untreated, high-risk
medulloblastoma or supratentorial primitive neuroectodermal tumors.

- Determine whether isotretinoin increases long-term, event-free survival of these
patients.

Secondary

- Compare residual disease response to radiotherapy alone versus radiotherapy and
carboplatin in these patients.

- Identify molecular prognostic indicators suitable for patient stratification in future
trials.

OUTLINE: This is a randomized, open-label, factorial-designed, multicenter study. Patients
are stratified according to location of disease and dissemination status (M0 medulloblastoma
with > 1.5 cm² residual tumor vs M+ medulloblastoma vs M0 supratentorial primitive
neuroectodermal tumor [SPNET] with < 1.5 cm² residual tumor vs M0 SPNET with > 1.5 cm²
residual tumor vs M+ SPNET vs M0 diffusely anaplastic medulloblastoma ). Patients are
randomized to 1 of 4 treatment arms.

- Arm I (standard chemoradiotherapy and standard maintenance therapy):

- Chemoradiotherapy: Patients undergo radiotherapy once daily on days 1-5, 8-12,
15-19, 22-26, 29-33, and 36-40 and receive vincristine IV over 1 minute on days 1,
8, 15, 22, 29, and 36. Six weeks after completion of chemoradiotherapy, patients
proceed to maintenance therapy.

- Maintenance therapy: Patients receive cisplatin IV over 6 hours on day 1,
vincristine IV over 1 minute on days 1 and 8, and cyclophosphamide IV over 1 hour
on days 2 and 3. Patients also receive filgrastim (G-CSF) subcutaneously (SC) or
IV beginning on day 4 and continuing until blood counts recover (at least 10
days). Treatment repeats every 28 days for a total of 6 courses in the absence of
disease progression or unacceptable toxicity.

- Arm II (standard chemoradiotherapy plus carboplatin and standard maintenance therapy):

- Chemoradiotherapy: Patients receive carboplatin IV over 15 minutes once daily on
days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40 and undergo radiotherapy and
receive vincristine as in arm I. Six weeks after completion of chemoradiotherapy,
patients proceed to maintenance therapy.

- Maintenance therapy: Patients receive maintenance therapy as in arm I.

- Arm III (standard chemoradiotherapy, standard maintenance therapy plus isotretinoin,
and continuation therapy with isotretinoin):

- Chemoradiotherapy: Patients undergo chemoradiotherapy as in arm I. Six weeks after
completion of chemoradiotherapy, patients proceed to maintenance therapy.

- Maintenance therapy: Patients receive oral isotretinoin twice daily on day 1 and
days 16-28 and cisplatin, vincristine, cyclophosphamide, and G-CSF as in arm I
maintenance therapy. Treatment repeats every 28 days for a total of 6 courses in
the absence of disease progression or unacceptable toxicity. Patients then proceed
to continuation therapy.

- Continuation therapy: Patients receive oral isotretinoin twice daily on days
15-28. Treatment repeats every 28 days for up to 6 courses in the absence of
disease progression or unacceptable toxicity.

- Arm IV (standard chemoradiotherapy plus carboplatin, standard maintenance therapy plus
isotretinoin, and continuation therapy with isotretinoin):

- Chemoradiotherapy: Patients undergo chemoradiotherapy as in arm II. Six weeks
after completion of chemoradiotherapy, patients proceed to maintenance therapy.

- Maintenance therapy: Patients receive maintenance therapy as in arm III. Patients
then proceed to continuation therapy.

- Continuation therapy: Patients receive continuation therapy as in arm III. After
completion of study treatment, patients are followed up periodically for up to 10
years.

PROJECTED ACCRUAL: A total of 300 patients will be accrued for this study.