Outcome of children with metastatic medulloblastoma treated with carboplatin during craniospinal radiotherapy: a Children's Oncology Group Phase I/II study

Abstract

Purpose: We evaluated the feasibility of administering carboplatin as a radiosensitizer during craniospinal radiation therapy (CSRT) to patients with high-risk medulloblastomas (MBs) and supratentorial primitive neuroectodermal tumors, and we report the outcome in the subset with metastatic (M+) MB.

Patients and methods: After surgery, patients received 36 Gy CSRT with boosts to sites of disease. During radiation, patients received 15 to 30 doses of carboplatin (30-45 mg/m(2)/dose), along with vincristine (VCR) once per week for 6 weeks. Patients on regimen A received 6 months of maintenance chemotherapy (MC) with cyclophosphamide and VCR. Once the recommended phase II dose (RP2D) of carboplatin was determined, cisplatin was added to the MC (regimen B).

Results: In all, 161 eligible patients (median age, 8.7 years; range, 3.1 to 21.6 years) were enrolled. Myelosuppression was dose limiting and 35 mg/m(2)/dose × 30 was determined to be the RP2D of carboplatin. Twenty-nine (36%) of 81 patients with M+ MB had diffuse anaplasia. Four patients were taken off study within 11 months of completing radiotherapy for presumed metastatic progression and are long-term survivors following palliative chemotherapy. Excluding these four patients, 5-year overall survival ± SE and progression-free survival ± SE for M+ patients treated at the RP2D on regimen A was 82% ± 9% and 71% ± 11% versus 68% ± 10% and 59% ± 10% on regimen B (P = .36). There was no difference in survival by M stage. Anaplasia was a negative predictor of outcome.

Conclusion: The use of carboplatin as a radiosensitizer is a promising strategy for patients with M+ MB. Early progression should be confirmed by biopsy.

Fig 1.

Kaplan-Meier curves showing the overall survival (OS) and progression-free survival (PFS) of patients with centrally reviewed metastatic medulloblastoma treated on regimen A, excluding four patients who were felt to have had pseudoprogression. The numbers below the survival curves reflect the number of patients at risk at any given time point.

Fig 2.

Kaplan-Meier curves showing the overall survival (OS) and progression-free survival (PFS) of patients with centrally reviewed metastatic medulloblastoma treated at the recommended phase II dose of carboplatin on regimen A and regimen B. The numbers below the survival curves reflect the number of patients at risk at any given time point.

Fig 3.

Kaplan-Meier curves showing no significant difference in the overall survival of patients with centrally reviewed metastatic medulloblastoma based on M stage. The numbers below the survival curves reflect the number of patients at risk at any given time point.

Fig 4.

Kaplan-Meier curves showing the overall survival (OS) and progression-free survival (PFS) of patients with centrally reviewed metastatic medulloblastoma with and without anaplasia. The numbers below the survival curves reflect the number of patients at risk at any given time point.