Standard Chemotherapy in Treating Young Patients with Medulloblastoma or Other Central Nervous System Embryonal Tumors

Summary

Objectives

PRIMARY OBJECTIVES:
I. To determine, in a prospective randomized clinical trial, whether dose-intensive tandem consolidation, in a randomized comparison with single cycle consolidation, provides an event-free survival (EFS) and overall survival (OS) benefit for high-risk patients (non-Wnt and non-Shh subgroups) with medulloblastoma, and for all patients with central nervous system (CNS) embryonal tumors completing “Head Start 4” induction.
II. To further determine whether the additional labor-intensity (duration of hospitalizations and short-term and long-term morbidities) associated with the tandem treatment is justified by the improvement in outcome.

SECONDARY OBJECTIVES:
I. To determine if reduction in the number of induction chemotherapy cycles from five to three for molecularly high-risk medulloblastoma (non-Shh/non-Wnt) and CNS embryonal tumors who achieve a complete response (CR) after three cycles of induction therapy results in equivalent 3-year EFS.
II. To determine molecular subtypes of medulloblastoma at diagnosis.
III. Determine whether dose-intensive and dose-compressed induction chemotherapy, risk-adapted based upon the absence of detectable residual disease (after 3 induction chemotherapy cycles) and low risk medulloblastoma biology (Shh or Wnt sub-groups, with the exception of anaplastic/large cell Shh) results in equivalent patient outcomes (3-year EFS and OS) with subsequent single cycle marrow-ablative chemotherapy consolidation regimen (compared to historical controls from “Head Start II” and “Head Start III” and other studies).
IV. To assess the rate of response to sequential dose-intensive and dose-compressed induction chemotherapy followed by marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHPCR) for children with medulloblastoma and other CNS embryonal tumors enrolled on the “Head Start 4” study utilizing a uniform treatment regimen.
V. To determine the proportion of patients with each histopathological disease type of CNS embryonal tumor (desmoplastic/nodular medulloblastoma, classic medulloblastoma, anaplastic/large cell medulloblastoma; pineoblastoma and non-pineal region supratentorial embryonal tumors) cured without the need of CNS irradiation.
VI. To determine the prevalence and severity of therapy-related hearing loss between study arms as a function of cumulative dosing of cisplatin (three versus five cycles during Induction) and AuHPCR (one versus three tandem transplants in Consolidation) and to evaluate Distortion Product Oto-acoustic Emissions (DPOAE) as an early predictor of hearing loss to identified at-risk patients.
VII. To determine the long-term endocrine functions and physical growth, as well as incidence of development of second neoplasms, in children treated on this protocol.
VIII. To compare the toxicity and quality of life (QoL) effects of single versus tandem HDCx cycles.
IX. To establish a “Head Start 4” repository of clinical, radiographic and biologic specimens, including nucleic acids derived from these specimens, for future genomic, biologic, and pharmacologic research.
X. To determine if prognostic biomarkers of irradiation-free progression-free survival can be identified from deoxyribonucleic acid (DNA) copy number profiling (Oncoscan), gene expression profiling (e.g. MBL31 gene, MBL nanostring-22 gene assay and whole exome sequencing and methylation profiling) collected in “Head Start 4”.
XI. To determine if the 5-gene detection signature (MBL5-cerebrospinal fluid [CSF]) assay performed on cerebrospinal fluid (CSF) samples will improve prediction of outcome in the context of imaging, patho-biologic and clinical variables for patients enrolled in “Head Start 4”.
XII. To identify exosomal microRNAs in the CSF specific for medulloblastoma at diagnosis and to determine if decrease/disappearance of such CSF MiRNAs correlates with radiographic documentation of response to induction and consolidation therapies, and correlates with event-free survival.
XIII. To prospectively evaluate neurocognitive functioning, adjustment, and quality of life in children with brain tumors receiving treatment with “Head Start 4”.
XIV. To assess CNS myelin load, gray and white matter volumes and structural integrity with brain imaging techniques, and include the impact of socioeconomic status, home environment, parenting, and parent distress as factors that may directly affect or moderate risk.

OUTLINE:
INDUCTION PHASE: Patients undergo molecular testing for risk stratification. Patients receive cisplatin intravenously (IV) over 6 hours on day 1, vincristine sulfate IV on days 1, 8, and 15, etoposide IV over 2 hours and cyclophopsphamide IV over 1 hour on days 2 and 3, and methotrexate IV over 4 hours on day 4. Treatment repeats every 21-28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients with no evidence of residual tumor following recovery from the third cycle of induction chemotherapy proceed directly to the consolidation phase of treatment. Patients with positive lumbar cerebral spinal fluid (CSF) cytology or unresectable residual viable tumor or residual radiographic abnormalities consistent with residual tumor but not deemed able to be biopsied, receive up to 2 additional induction cycles.

CONSOLIDATION PHASE: Low risk patients (determined by molecular testing) undergo a single cycle chemotherapy. High risk patients are randomized to 1 of 2 arms.

CONSOLIDATION PHASE SINGLE CYCLE CHEMOTHERAPY: Patients receive carboplatin IV over 4 hours on days -8 to -6, and thiotepa IV over 3 hours and etoposide IV over 3 hours on days -5 to -3. Patients undergo stem cell transplant on day 0.

CONSOLIDATION PHASE TANDEM 3 CYCLE CHEMOTHERAPY: Patients receive carboplatin IV over 4 hours and thiotepa IV over 3 hours on days -4 to -3. Patients undergo stem cell transplant on day 0. Following recovery from the first cycle, about 21-28 days, treatment repeats for up to 3 total cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 6 weeks and once a month in the first year, every 3 months in the second and third years, every 4-6 months in the fourth year, and annually after 5 years.