• ERBB2 protein expression in patients with progression-free survival 2 years after study completion [ Designated as safety issue: No ]
  
• Effects of a computer-based training system compared to the current standard of care as measured by reading decoding composite score 2 years after study completion [ Designated as safety issue: No ]
  
• Treatment failure in the posterior fossa of patients undergoing reduced-dose radiotherapy approximately 2 years after study completion [ Designated as safety issue: No ]
  

• Correlate protein and/or mRNA expression , amplification, or deletion of several oncogenes and tumor suppressor genes in tumor tissue with histopathological subtype, clinical characteristics, and clinical outcome approx. 2 years after study completion [ Designated as safety issue: No ]
  
• Medulloblastoma histopathologic classification compared to clinical disease behavior approximately 2 years after study completion [ Designated as safety issue: No ]
  
• Generate microarray gene expression profiles of primary tumors by identifying novel genes important in medulloblastoma tumorgenesis [ Designated as safety issue: No ]
  
• Correlate gene expression profiles with specific molecular characteristics, tumor pathology, and clinical outcome approximately 2 years after study completion [ Designated as safety issue: No ]
  
• Tissue microarrays for future analysis of molecular genetic alterations [ Designated as safety issue: No ]
  
• Incidence of mitochondrial DNA mutations in tumor tissue and cerebrospinal fluid (CSF) from serial CSF specimens [ Designated as safety issue: No ]
  
• Correlate mutations with histopathological subtype, demographic and clinical characteristics, and clinical outcome approximately 2 years after study completion [ Designated as safety issue: No ]
  
• Incidence of GSTM1, GSTT1, and GSTP1 polymorphisms and GST protein expression in pediatric medulloblastomas tumor tissue and correlate presence with histopathological subtype, demographic, and clinical characteristics, and clinical outcome [ Designated as safety issue: No ]
  
• High resolution maps of regions of chromosome gain and loss in tumor samples [ Designated as safety issue: No ]
  
• Pharmacokinetics (PK) of cyclophosphamide and metabolites (e.g., hydroxycyclophosphamide) as measured by various PK parameters [ Designated as safety issue: No ]
  
• Effect of cyclophosphamide and metabolite PK, including clearance and auto-induction response, on pharmacodynamic outcome of event-free survival after completion of accrual [ Designated as safety issue: No ]
  
• Correlation of pharmacogenetic variation in drug metabolizing enzymes and drug transporters with PK, including clearance and auto-induction response, and with pharmacodynamics of cyclophosphamide and its metabolites [ Designated as safety issue: No ]
  
• Neurochemical etiology of impaired neurocognitive functioning observed after treatment as measured by various neurotransmitters in serial CSF specimens approximately 2 years after study completion [ Designated as safety issue: No ]
  
• Novel tumor suppressor genes important for the pathogenesis of medulloblastoma by combining the inhibition of nonsense mediated mRNA decay and microarray gene expression patterns [ Designated as safety issue: No ]
  
• Changes in neuropsych. perform. by Woodcock Johnson-III Tests of Achievement & Cognitive Abilities, Continuous Perform. Test, Coping Resp. Inventory, Family Environment Scale, Child Behavior Chklst., & Behav. Rating Inventory of Executive Func. [ Designated as safety issue: No ]
  
• Correlate changes in neuropsychological performance with risk group, age at diagnosis, and parent measures approx. 2 years after study completion [ Designated as safety issue: No ]
  
• Neurotoxic differences among the average-risk group and the high-risk group as measured by annual qMRI and fMRI scans [ Designated as safety issue: Yes ]
  
• Develop or refine novel models relating impact of treatment on neurocognitive performance to quantitative and functional neuroimaging measures approximately 2 years after study completion [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary

• Correlate ERBB2 protein expression in tumors with progression-free survival of patients with medulloblastoma, supratentorial primitive neuroectodermal tumor, or atypical teratoid rhabdoid tumor treated with radiotherapy, high-dose cisplatin, vincristine, and cyclophosphamide, and autologous stem cell rescue.
• Determine the neurocognitive outcome in patients treated with this regimen.

Secondary

• Monitor patients receiving a reduced radiotherapy dose for treatment failure in the posterior fossa.

OUTLINE: This is a multicenter study. Patients are stratified according to disease risk (high-risk disease vs average-risk disease).

Patients in both strata undergo peripheral blood stem cell or bone marrow harvest.

• Stratum 1 (high-risk group):

  • Radiotherapy: Patients undergo craniospinal radiotherapy once daily 5 days a week for 6 weeks.
  • High-dose chemotherapy and autologous stem cell transplantation (SCT): Six weeks after the completion of radiotherapy, patients receive high-dose chemotherapy comprising vincristine IV followed by cisplatin IV over 6 hours on day -4 and cyclophosphamide IV over 1 hour on days -3 and -2. Patients undergo autologous SCT on day 0. Patients receive filgrastim (G-CSF) subcutaneously beginning on day 1 and continuing until blood counts recover. Patients receive vincristine IV on day 6. High-dose chemotherapy and autologous SCT repeat every 4 weeks for 3 additional courses in the absence of unacceptable toxicity.

• Stratum 2 (average-risk group):

  • Radiotherapy: Patients undergo craniospinal radiotherapy as in stratum 1, but at a lower dose.
  • High-dose chemotherapy and autologous SCT: Patients receive high-dose chemotherapy, autologous SCT, G-CSF, and post-transplantation vincristine as in stratum 1.

Some patients undergo a neuropsychology assessment at baseline, before chemotherapy, and then annually for 5 years.

After completion of study therapy, patients are followed every 3 months until month 30 (2.5 years) after diagnosis and then every 6 months until month 72 (6 years) after diagnosis.

PROJECTED ACCRUAL: A total of 164 patients will be accrued for this study within 5.5 years.