Outcome of Children With Metastatic Medulloblastoma Treated With Carboplatin During Craniospinal Radiotherapy: A Children's Oncology Group Phase I/II Study

Abstract

A B S T R A C T PurposeWe 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 (Mϩ) MB. Patients and MethodsAfter 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). ResultsIn 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 ϫ 30 was determined to be the RP2D of carboplatin. Twenty-nine (36%) of 81 patients with Mϩ 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 Ϯ SE and progression-free survival Ϯ SE for Mϩ patients treated at the RP2D on regimen A was 82% Ϯ 9% and 71% Ϯ 11% versus 68% Ϯ 10% and 59% Ϯ 10% on regimen B (P ϭ .36). There was no difference in survival by M stage. Anaplasia was a negative predictor of outcome. ConclusionThe use of carboplatin as a radiosensitizer is a promising strategy for patients with Mϩ MB. Early progression should be confirmed by biopsy.

Radiation Necrosis in Pediatric Patients with Brain Tumors Treated with Proton Radiotherapy

“…For example, as chemosensitizers, temozolomide and bevacizumab have been used concurrently with radiation therapy in high-grade gliomas, and carboplatin has been studied as a radiation sensitizer with medulloblastomas and other CNS tumors. [19][20][21][22] In addition, chemotherapeutics such as anthracycline and doxorubicin are commonly avoided during radiation and can even remotely result in radiation recall with a later insult. 23 Finally, there are many chemotherapeutics that may have direct CNS toxicity such as methotrexate and ifosfamide, which could potentiate CNS radiation necrosis.…”

Survival of children with medulloblastoma in Canada diagnosed between 1990 and 2009 inclusive

“…Other factors shown to influence survival include histological subtype, age at diagnosis, and therapy utilized. The majority of publications on survival of medulloblastoma describe results of clinical trials, which have stringent eligibility criteria that necessarily influence the survival data [5][6][7][8][9]. As well, the majority of medulloblastoma studies are for specific age ranges, usually over age 3 or under age 3, and not for the whole population of affected children.…”

Misdiagnosing recurrent medulloblastoma: the danger of examination and imaging without histological confirmation

“…5,24 There is also evidence to suggest that standard or highdose chemo therapy can injure the normal brain, 9 and there appears to be a compounding effect when radiation therapy and che motherapy are used together. 3,14,15,17,20 In a Phase I/II study evaluating the use of carboplatin during radiation therapy in patients with medulloblastoma, the authors found 4 metastatic patients with early progression of leptome ningeal disease who were longterm survivors following palliative chemotherapy alone. The authors, in retrospect, stated that these patients were not believed to have true progressive disease.…”

“…The authors, in retrospect, stated that these patients were not believed to have true progressive disease. 15 Additionally, there is increased evidence of clini cal and radiographic therapyrelated alterations as a re sult of the more frequent use of highdose chemotherapy combined with radiation therapy for pediatric brain tu mors. 16,25 Our patient was observed to have clinical symp toms and radiographic changes more than a year after therapy.…”