Efficacy of Carboplatin and Isotretinoin in Children With High-risk Medulloblastoma

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 PARTICIPANTSA 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 MEASURESThe 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. RESULTSOf 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 RELEVANCEIn 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.

Radiotherapy in Medulloblastoma—Evolution of Treatment, Current Concepts and Future Perspectives

“…Being a constant work in progress, new disease subgroups and risks groups have been implemented in the analysis of ongoing clinical trials concerning therapy reduction in low-risk and treatment intensification in high-risk patients. Concerning the latter, a prospective randomized trial for high-risk patients from the Children’s Oncology Group involving concomitant Carboplatin during radiotherapy showed a survival benefit in the Carboplatin arm in group 3 patients only [ 86 ].…”

SIOP PNET5 MB Trial: History and Concept of a Molecularly Stratified Clinical Trial of Risk-Adapted Therapies for Standard-Risk Medulloblastoma

“…Haematological toxicity was dose-limiting while ototoxicity was acceptable. This regimen resulted in a favourable 5-year PFS rate of 71% and was the basis for the later randomised phase III Children’s Oncology Group ACNS-0332 study [ 70 ]. Recently, this study has demonstrated an improvement of EFS by 19% at 5-years for children with high-risk group 3 medulloblastoma receiving concurrent carboplatin during 36 Gy craniospinal irradiation.…”

Molecular Subgroup Is the Strongest Predictor of Medulloblastoma Outcome in a Resource-Limited Country

“…Indeed, our findings suggest that when correcting for subgroup, comparable outcomes can be achieved, and subgroup-specific strategies can and should be implemented in LMIC settings. Specifically, recent studies from the Children's Oncology Group have suggested that carboplatin radiosensitization significantly improves outcome in metastatic group 3 34 and reductions in radiotherapy to 18 Gy have poor survivals restricted to group 4, 35 suggesting that subgroup-specific therapies should not be restricted to HICs. Although a limitation for many LMIC centers is lack of a constant twinning partner, we would advocate for protocol implementation in LMIC centers to ensure uniform staging, and being cognizant of the risks of delaying therapy, specifically developing protocols unique to the limitations of each center.…”