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

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 toWorld Health Organization consensus molecular subgroups of medulloblastoma. DESIGN, SETTING, AND PARTICIPANTS A randomized clinical phase 3 trialwas 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 pointwas 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-cm(2) 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.