Comparison of Radiation Therapy Regimens in Combination With Chemotherapy in Treating Young Patients With Newly Diagnosed Standard-Risk Medulloblastoma

PRIMARY OBJECTIVES:

I. Compare event-free survival (EFS) of pediatric patients (3 to 7 years of age) with newly
diagnosed standard-risk medulloblastoma treated with standard-dose versus (vs.) reduced-dose
craniospinal radiotherapy (SDCSI vs. LDCSI).

II. Compare EFS of patients (3-21 years of age) treated with standard-dose craniospinal
radiotherapy and posterior fossa boost vs tumor bed boost radiotherapy in combination with
this chemotherapy regimen.

SECONDARY OBJECTIVES:

I. Compare overall survival (OS) of pediatric patients (3-7 years of age) with newly
diagnosed standard-risk medulloblastoma treated with SDCSI vs. LDCSI.

II. Compare OS of patients (3-21 years of age) with newly diagnosed standard-risk
medulloblastoma treated with PFRT vs. IFRT.

III. To evaluate patterns of failure in patients treated with an irradiation boost volume
smaller than conventional posterior fossa volumes.

IV. To reduce the cognitive, auditory, and endocrinologic effects of treatment of
average-risk medulloblastoma by reducing the dose of craniospinal irradiation therapy.

V. To determine if the audiologic and endocrinologic toxicity will be reduced with the use of
limited tumor boost volume irradiation compared to patients treated with conventional target
volumes of radiation.

VI. Develop an optimal gene expression medulloblastoma outcome predictor, validated
prospectively in a multi-institution randomized clinical trial.

VII. To improve compliance with long-term quality of life (QoL) and functional status data
submission by educating institutional nurses to administer and submit for analysis a battery
of four instruments (Behavior Assessment System for Children- 2nd Edition (BASC-2), Adaptive
Behavior Assessment System - 2nd Edition (ABAS-II), Behavior Rating Inventory of Executive
Function (BRIEF) and PedsQLTM 4.0).

OUTLINE: Patients 3-7 years of age are randomized to 1 of 4 arms (Arm I-IV). Patients 8-21
years of age are randomized to 1 of 2 arms (Arm V or VI).

Within 31 days after definitive surgery, all patients begin therapy. Patients undergo
radiation therapy with doses according to their Arm randomization on days 1-5, 8-12, 15-19,
22-26, 29-33, 36-40, and 43-47 (weeks 0-6). All patients receive vincristine intravenously
(IV) over 1 minute (or infusion via minibag as per institutional policy) on days 8, 15, 22,
29, 36, and 43 (weeks 1-6).

ARM I: Patients 3-7 years of age undergo lowered dose craniospinal irradiation (LDCSI) with
involved-field radiation therapy (IFRT) boost.

ARM II: Patients 3-7 years of age undergo LDCSI with whole posterior fossa radiation therapy
(PFRT) boost.

ARM III: Patients 3-7 years of age undergo standard dose craniospinal irradiation (SDCSI)
with IFRT boost.

ARM IV: Patients 3-7 years of age undergo SDCSI with PFRT boost.

ARM V: Patients 8-21 years of age undergo SDCSI with IFRT boost.

ARM VI: Patients 8-21 years of age undergo SDCSI with PFRT boost.

MAINTENANCE CHEMOTHERAPY: Beginning 4 weeks after completion of chemoradiotherapy, patients
receive 2 different regimens of maintenance chemotherapy for a total of 9 courses. Each
course in regimen A is 6 weeks (42 days) in duration. Each course in regimen B is 4 weeks (28
days) in duration.

REGIMEN A (courses 1, 2, 4, 5, 7, and 8): Patients receive lomustine orally and cisplatin IV
over 6 hours on day 1 and vincristine IV on days 1, 8, and 15 of weeks 11, 17, 27, 33, 43,
and 49.

REGIMEN B (courses 3, 6, and 9): Patients receive cyclophosphamide IV over 1 hour on days 1
and 2 and vincristine IV on days 1 and 8 of weeks 23, 39, and 55.

Treatment continues in the absence of disease progression or unacceptable toxicity. Quality
of life is assessed at 3-6 months after completion of radiotherapy and at 3-4 years after
study entry. Neurocognitive function may also be assessed.

Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then
annually thereafter.

Inclusion Criteria:

- Histologically confirmed medulloblastoma located in the posterior fossa

- Standard-risk disease

- Minimal volume, non-disseminated disease, defined by the following:

- Residual tumor ≤ 1.5 cm^2 confirmed by MRI with contrast imaging within 21 days
after surgery

- No metastatic disease in the head, spine, or cerebrospinal fluid (CSF) confirmed
by both of the following:

- Enhanced MRI of the spine within 5 days before surgery OR within 28 days
after surgery

- Negative cytological examination of CSF after surgery, but before study
enrollment

- Brain stem involvement allowed

- Performance status - Karnofsky 50-100% (> 16 years of age)

- Performance status - Lansky 30-100% (≤ 16 years of age)

- Absolute neutrophil count > 1,500/uL

- Platelet count > 100,000/uL (transfusion independent)

- Hemoglobin > 10 g/dL (transfusions allowed)

- Bilirubin < 1.5 times upper limit of normal (ULN) for age

- AST or ALT < 1.5 times ULN for age

- Creatinine clearance OR radioisotope glomerular filtration rate >= 70 mL/min/1.73m^2
or a serum creatinine based on age/gender as follows:

Age Maximum Serum Creatine (mg/dL)

- 1month to < 6 months male: 0.4 female: 0.4

- 6 months to <1 year male: 0.5 female: 0.5

- 1 year to < 2 years male: 0.6 female: 0.6

- 2 to < 6 years male: 0.8 female: 0.8

- 6 to < 10 years male: 1 female: 1

- 10 to < 13 years male: 1.2 female: 1.2

- 13 to < 16 years male: 1.5 female: 1.4

- >= 16 years male: 1.7 female: 1.4

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No prior chemotherapy

- Prior corticosteroids allowed

- No prior radiotherapy