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.
DISEASE CHARACTERISTICS:
- Histologically confirmed diagnosis of medulloblastoma or supratentorial primitive neuroectodermal tumor (PNET)
- Newly diagnosed disease
- Previously untreated disease
- Meets 1 of the following criteria:
- M0 medulloblastoma with > 1.5 cm² residual tumor
- M+ medulloblastoma
- M0 or M+ supratentorial PNET (including pineoblastoma)
- Diffusely anaplastic medulloblastoma with any M-stage or residual tumor
- Must have undergone stereotactic biopsy or attempted neurosurgical resection of the tumor within the past 31 days
- The following procedures are required:
- Pre-operative MRI of the brain with and without contrast
- Post-operative (preferably within 72 hours after surgery) MRI of the brain with and without contrast**
- Spinal MRI with and without contrast within 10 days before surgery or 28 days after surgery
- Lumbar cerebrospinal fluid (CSF) cytological examination obtained pre-operatively or within 31 days after surgery*** NOTE: **Not required for patients with M2 or M3 disease or for patients who undergo stereotactic biopsy only
NOTE: ***If a spinal tap is contraindicated, and there is no ventricular CSF available, CSF cytology may be waived for patients with supratentorial tumors OR if there is documentation of spinal subarachnoid metastases (M3); patients with M1 disease must have either an intraoperative-positive CSF by lumbar puncture at the end of surgery OR a positive lumbar CSF obtained more than 7 days after surgery (to rule out surgically-induced false positives
- No M4 disease
PATIENT CHARACTERISTICS:
- Karnofsky performance status (PS) 30-100% (for patients > 16 years of age) OR Lansky PS 30-100% (for patients ≤ 16 years of age)
- Life expectancy > 8 weeks
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use 2 effective forms of contraception
- Creatinine normal OR creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR serum creatinine based on age and/or gender as follows:
- 0.4 mg/dL (1 month to < 6 months of age)
- 0.5 mg/dL (6 months to < 1 year of age)
- 0.6 mg/dL (1 to < 2 years of age)
- 0.8 mg/dL (2 to < 6 years of age)
- 1.0 mg/dL (6 to < 10 years of age)
- 1.2 mg/dL (10 to < 13 years of age)
- 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)
- 1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age)
- Bilirubin < 1.5 times upper limit of normal (ULN)
- AST and ALT < 2.5 times ULN (5 times ULN for patients on antiseizure medications)
- Absolute neutrophil count ≥ 1,000/mm³
- Platelet count ≥ 100,000/mm³ (transfusions not allowed)
- Hemoglobin ≥ 8 g/dL (transfusions allowed)
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- No prior chemotherapy or radiotherapy
- No other concurrent experimental therapy
- No concurrent isotretinoin for acne treatment
- No concurrent corticosteroids as an antiemetic during chemotherapy
Last updated: 11/03/2012
NCT ID: NCT00392327
IRB Number:07-004144
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