Cumulative dose of chemotherapy and survival outcomes in children with average-risk medulloblastoma treated on Children's Oncology Group study ACNS0331.
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BACKGROUND: Although survival outcomes for average-risk (AR) medulloblastoma remain excellent, patients experience significant long-term toxicities. To evaluate the effect of therapy dose modifications among children with AR medulloblastoma, we examined the association of cumulative chemotherapy dose with overall survival (OS) and event-free survival (EFS) for patients treated on Children's Oncology Group (COG) study ACNS0331. METHODS: A cohort of children enrolled on ACNS0331 (medulloblastoma confirmed by methylation, received standard dose craniospinal radiation, and completed all cycles of chemotherapy) were evaluated for cumulative chemotherapy dose intensity continuously and categorically (≥75% or <75% of planned dose). Cox proportional hazards regression models were used to examine associations of proportion of planned chemotherapy received with outcome. A secondary analysis separately evaluated each of the 4 molecular subgroups: Wnt-activated (WNT), Sonic Hedgehog Activated (SHH), group 3 and group 4. RESULTS: Two hundred thirty-five children were followed for a median of 9.3 years (range, 7.0-10.4). Dose intensities of vincristine (VCR) and cisplatin showed the most variability (17% and 23.8% of patients received <75% of expected dosing, respectively). Molecular subgroup remained a significant predictor of outcome (EFS [P = .012] and OS [P = .008]). Cyclophosphamide and lomustine were not examined due to minimal dose variability. No significant differences in EFS or OS were found related to reduced dose intensity for VCR (P = .49 EFS, P = .52 OS) or cisplatin (P = .36 EFS, P = .35 OS) when analyzed independently. There was no difference in the effect of dose reductions by molecular subgroup. CONCLUSIONS: Moderate dose reductions of at least 25% in VCR and cisplatin do not significantly affect survival in AR medulloblastoma. Effects of larger dose reductions (>50%) or dose reductions in high-risk disease were not studied.