Efficacy of Carboplatin and Isotretinoin in Children With High-risk Medulloblastoma: A Randomized Clinical Trial From the Children's Oncology Group

Abstract

Importance: Brain tumors are the leading cause of disease-related death in children. Medulloblastoma is the most common malignant embryonal brain tumor, and strategies to increase survival are needed.

Objective: To evaluate therapy intensification with carboplatin as a radiosensitizer and isotretinoin as a proapoptotic agent in children with high-risk medulloblastoma in a randomized clinical trial and, with a correlative biology study, facilitate planned subgroup analysis according to World Health Organization consensus molecular subgroups of medulloblastoma.

Design, setting, and participants: A randomized clinical phase 3 trial was conducted from March 2007 to September 2018. Analysis was completed in September 2020. Patients aged 3 to 21 years with newly diagnosed high-risk medulloblastoma from Children's Oncology Group institutions within the US, Canada, Australia, and New Zealand were included. High-risk features included metastasis, residual disease, or diffuse anaplasia.

Interventions: Patients were randomized to receive 36-Gy craniospinal radiation therapy and weekly vincristine with or without daily carboplatin followed by 6 cycles of maintenance chemotherapy with cisplatin, cyclophosphamide, and vincristine with or without 12 cycles of isotretinoin during and following maintenance.

Main outcomes and measures: The primary clinical trial end point was event-free survival, using the log-rank test to compare arms. The primary biology study end point was molecular subgroup classification by DNA methylation array.

Results: Of 294 patients with medulloblastoma, 261 were evaluable after central radiologic and pathologic review; median age, 8.6 years (range, 3.3-21.2); 183 (70%) male; 189 (72%) with metastatic disease; 58 (22%) with diffuse anaplasia; and 14 (5%) with greater than 1.5-cm2 residual disease. For all participants, the 5-year event-free survival was 62.9% (95% CI, 55.6%-70.2%) and overall survival was 73.4% (95% CI, 66.7%-80.1%). Isotretinoin randomization was closed early owing to futility. Five-year event-free survival was 66.4% (95% CI, 56.4%-76.4%) with carboplatin vs 59.2% (95% CI, 48.8%-69.6%) without carboplatin (P = .11), with the effect exclusively observed in group 3 subgroup patients: 73.2% (95% CI, 56.9%-89.5%) with carboplatin vs 53.7% (95% CI, 35.3%-72.1%) without (P = .047). Five-year overall survival differed by molecular subgroup (P = .006): WNT pathway activated, 100% (95% CI, 100%-100%); SHH pathway activated, 53.6% (95% CI, 33.0%-74.2%); group 3, 73.7% (95% CI, 61.9%-85.5%); and group 4, 76.9% (95% CI, 67.3%-86.5%).

Conclusions and relevance: In this randomized clinical trial, therapy intensification with carboplatin improved event-free survival by 19% at 5 years for children with high-risk group 3 medulloblastoma. These findings further support the value of an integrated clinical and molecular risk stratification for medulloblastoma.

Trial registration: ClinicalTrials.gov Identifier: NCT00392327.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Jaju reported receiving grants from National Institutes of Health (NIH)/Children’s Oncology Group (COG) during the conduct of the study; receiving grants from Incyte Corporation outside the submitted work; and owning Gilead Sciences stock. Dr Walsh reported receiving personal fees from Novo Nordisk and Cogstate consulting unrelated to this project outside the submitted work. Dr Pollack reported receiving grants from the NIH during the conduct of the study. Dr Northcott reported receiving grants from The Brain Tumor Charity, St Baldrick's Foundation, and National Cancer Institute during the conduct of the study. Dr Olson reported receiving grants from the NIH during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. All 294 Patients With Medulloblastoma Enrolled in the Children’s Oncology Group ACNS0332 Study

aSecond randomization to isotretinoin maintenance included 56 patients in the arm without carboplatin and 58 patients in the arm with carboplatin before closure of the isotretinoin randomization based on futility analysis. Study chair exclusions were for patients deemed to be ineligible owing to timing of start of therapy (n = 6), staging/extent of disease (n = 2), and disease type/histologic characteristics (n = 1). Central pathologic review exclusions were for tumors determined not to be medulloblastoma (n = 6) or not to have diffuse anaplastic histologic characteristics (n = 8). Central radiologic review exclusion was for residual disease less than 1.5-cm2, including gross total resection (n = 7) or near-total resection (n = 3).

Figure 2.. Event-Free Survival (EFS) and Overall Survival (OS) (n = 261)

A, Survival for all eligible patients. B, Survival for eligible patients by randomization to carboplatin.

Figure 3.. Molecular Classification of Medulloblastoma (MB)

A, Molecular classification of patients with MB. A single patient clinically and histologically classified as having MB was found to have molecular subgrouping consistent with pineoblastoma. B, Uniform manifold approximation and projection (UMAP) plot depicting molecular classification of evaluated MB tumors (n = 231) according to subgroup. C, Heatmap (OncoPrint) summary of recurrently altered genes, chromosomal alteration, clinical characteristics, and randomization of patients with available whole-exome sequencing data (n = 189). NGS, next-generation sequencing; SHH, medulloblastoma, SHH pathway activated; SNV, single-nucleotide variant; WNT, medulloblastoma, WNT pathway activated.

Figure 4.. Event-Free Survival (EFS) of 231 Patients With Medulloblastoma Receiving vs Not Receiving Carboplatin

Classification of subgroups WNT pathway activated, log-rank P = .50 (A); SHH pathway activated, log-rank P = .28; (B); group 3, log-rank P = .047; (C); and group 4, log-rank P = .45 (D).