High-Dose Chemotherapy Plus Autologous Stem Cell Transplantation Compared With Intermediate-Dose Chemotherapy Plus Autologous Stem Cell Transplantation With or Without Isotretinoin in Treating Young Patients With Recurrent High-Grade Gliomas

OBJECTIVES:

• Compare the event-free survival and overall survival of pediatric patients with recurrent high-grade gliomas treated with a single course of high-dose carboplatin, etoposide, and thiotepa and autologous stem cell transplantation vs multiple courses of intermediate-dose carboplatin and thiotepa and autologous stem cell transplantation with or without isotretinoin.
• Compare the number of hospital days and time to engraftment in patients treated with these regimens.
• Compare the toxic death rate in patients treated with these regimens.
• Compare the tolerability of isotretinoin in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to pathologic diagnosis (glioblastoma multiforme vs anaplastic astrocytoma vs other high-grade glioma).

• Chemotherapy and autologous stem cell reinfusion (ASCR): Patients are randomized to 1 of 2 treatment arms.

• Arm I (high-dose chemotherapy and ASCR): Patients receive high-dose chemotherapy comprising carboplatin IV over 4 hours on days -8 to -6; thiotepa IV over 3 hours and etoposide IV over 3 hours on days -5 to -3; and filgrastim (G-CSF) IV or subcutaneously (SC) once daily beginning on day 1 and continuing until blood counts recover. Autologous peripheral blood stem cells (PBSC) or bone marrow are reinfused on day 0.
• Arm II (intermediate-dose chemotherapy and ASCR): Patients receive intermediate-dose chemotherapy comprising carboplatin IV over 4 hours and thiotepa IV over 3 hours on days 1-2 and G-CSF IV or SC once daily beginning on day 4 and continuing until blood counts recover. Autologous PBSC or bone marrow are reinfused on day 3. Treatment repeats every 28 days for a total of 3 courses.
• Maintenance therapy: After recovery from chemotherapy (approximately day 30 post-transplantation), all patients are further randomized to 1 of 2 maintenance arms.

• Arm I: Patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for a total of 6 courses.
• Arm II: Patients do not receive maintenance therapy. In all arms, treatment continues in the absence of disease progression.

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

PROJECTED ACCRUAL: A total of 80-150 patients (40-75 per treatment arm) will be accrued for this study within 5 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of 1 of the following high-grade gliomas:

• Glioblastoma multiforme
• Anaplastic astrocytoma
• Gliosarcoma
• Disease in first relapse
• No primary brainstem or spinal cord gliomas
• No secondary glioblastomas arising after prior treatment for a non-glial tumor
• Prior local radiotherapy of 5,000-6,000 cGy required
• Less than 1.5 cm of residual gadolinium-enhancing tumor in maximal cross-sectional diameter by MRI
• No metastatic tumor by spinal MRI

PATIENT CHARACTERISTICS:

Age

• Under 21 at diagnosis

Performance status

• Lansky 50-100% OR
• Karnofsky 50-100%

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 500/mm^3
• Platelet count ≥ 100,000/mm^3 (transfusion independent)

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST or ALT < 2.5 times ULN

Renal

• Glomerular filtration rate ≥ 60 mL/min AND/OR
• Creatinine clearance ≥ 60 mL/min

Cardiovascular

• Shortening fraction ≥ 27% by echocardiogram OR
• Ejection fraction ≥ 50% by MUGA

Pulmonary

• No dyspnea at rest
• No exercise intolerance
• Pulse oximetry > 94%

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• More than 4 weeks since prior chemotherapy
• No prior thiotepa
• No prior myeloablative chemotherapy

Endocrine therapy

• No concurrent corticosteroids

Radiotherapy

• See Disease Characteristics
• More than 8 weeks since prior radiotherapy
• No prior craniospinal radiotherapy

Surgery

• Not specified