Carboplatin Therapy Intensification Results in Improved 5-Year EFS in Pediatric High-Risk Group 3 Medulloblastoma

“In this prospective, randomized phase 3 clinical trial, we have not observed a sufficient benefit to recommend carboplatin or isotretinoin for all children with high-risk medulloblastoma. Although the study was initially intended to evaluate medulloblastoma as a single disease, biological insights have led to a contemporary picture of medulloblastoma as 4 molecularly distinct subgroups that may determine response to therapy and prognosis,” study researchers wrote.

The study initially enrolled 294 patients, 9 of whom were ineligible due to the timing of therapy, as well as an additional 24 patients who were ineligible due to retrospective central or central pathological assessment. The median duration of follow-up was 6.7 years. A total of 15 patients were lost to follow-up within 5 years. In addition, 261 patients were eligible for both prospective and retrospective central assessment.

At the time of enrollment, the median patient age was 8.6 years (range 3.3-21.2). A total of 72.4% (n = 189) of patients had metastatic disease and 22.2% (n = 58) had diffuse anaplasia. In addition, 5.4% (n = 14) of patients had residual disease of 1.5 cm2 or more.

Patients were randomized to receive 36 Gy of craniospinal radiation therapy plus weekly vincristine plus or minus daily carboplatin. This was followed by 6 cycles of maintenance chemotherapy with cisplatin, cyclophosphamide and vincristine plus or minus 12 cycles of isotretinoin (Absorica) and maintenance therapy.

Researchers discontinued isotretinoin because researchers believed it was unlikely to lead to a significant difference in EFS. The 5-year EFS with the use of isotretinoin was 68.6% (95% CI, 52.1%-85.1%) versus without isotretinoin was 67.8% (95% CI, 47.6%- 88.0%).

Among patients in the group 3 cohort with stage M0 disease (n = 20; 19 with anaplasia, 1 with residual), the 5-year EFS rate was 95.0% (95% CI, 84.2% 100%) and overall survival (OS) was 100% (95% CI, 100%-100%). In comparison, patients with metastatic disease achieved a 5-year EFS of 53.6% (95% CI, 37.9%-69.3%) and OS 64.9% (95% CI, 50.2%-79 .6%).

Patients with metastatic disease and group 3 medulloblastoma, the 5-year EFS with carboplatin was 64.8% (95% CI, 43.8%-85.8%) and the overall survival was 77.4% (95% CI , 58.8%-96.0%). In comparison, the 5-year EFS for without carboplatin was 40.3% (95% CI, 19.9%-60.7%; P = 0.45) and the OS was 51.2% (95% CI, 31.0%-71.4%; P = 0.046).

In addition, an association was established between MYC amplification or isochromosome 17 and inferior survival in patients with group 3 medulloblastoma. This translated to a 5-year EFS rate was 49.3% (95% CI, 29.5%-69 .1%) versus 73.6% among those who had no MYC amplification or isochromosome 17 (95% CI, 56.9%-90.3%; P = .01).

In terms of safety, haematological adverse reactions (AEs) appeared to be more noticeable in patients treated with carboplatin during the induction phase. This resulted in an increased risk of thrombocytopenia and febrile neutropenia. High toxicities of Grade 3 or greater were observed in greater than 5% of patients in the study. Grade 3 anaphylaxis of carboplatin was reported in 4 patients in the carboplatin arm.

Researchers also assessed 5-year EFS in several molecular subgroups treated with carboplatin, including WNT (92.9%; 95% CI, 75.7%-100%), SHH (49.6%; 95% CI, 27 .8%-71.4%), and group 4 65.6% (95% CI, 54.6% -76.6%).

“We saw a 19% higher survival exclusively in group 3 medulloblastoma patients who were randomized to receive more intensive chemoradiotherapy with concomitant carboplatin, and 25% higher survival for metastatic group 3 medulloblastoma patients. However, better survival comes at the cost of increased toxic effects. It is therefore appropriate to avoid therapy intensification in groups of patients who are not expected to benefit, especially in patients with group 4 WNT, SHH and medulloblastoma,” the study researchers concluded.


Leary SES, Packer RJ, Li Y, et al. Efficacy of carboplatin and isotretinoin in children with high-risk medulloblastoma: a randomized clinical trial of the Children’s Oncology Group. JAMA Oncology. Published online July 22, 2021. doi:10.1001/jamaoncol.2021.2224

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