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Original Investigation
July 22, 2021

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

Author Affiliations
  • 1Cancer and Blood Disorders Center, Seattle Children’s, Seattle, Washington
  • 2Department of Pediatrics, University of Washington School of Medicine, Seattle
  • 3Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 4Center for Neuroscience and Behavioral Health, Children’s National Hospital, Washington, DC
  • 5Department of Biostatistics, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 6Department of Developmental Neurobiology, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 7Department of Radiology, Ann and Robert H. Lurie Children’s Hospital, Chicago, Illinois
  • 8Department of Radiology, NYP/Weill Cornell Medical Center, New York, New York
  • 9Sidney Kimmel Cancer Center, Department of Pathology, Johns Hopkins University, Baltimore, Maryland
  • 10Division of Neuropsychology, Children’s National Hospital, Washington, DC
  • 11Pediatric Hematology/Oncology, UT Health San Antonio, San Antonio, Texas
  • 12Department of Radiation Oncology, Washington University School of Medicine, St Louis, Missouri
  • 13Center for Cancer and Blood Disorders, Children’s National Hospital, Washington, DC
  • 14Department of Oncology, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 15Department of Neurosurgery, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania
  • 16Pediatric Hematology & Oncology, Nationwide Children’s Hospital, Columbus, Ohio
JAMA Oncol. 2021;7(9):1313-1321. doi:10.1001/jamaoncol.2021.2224
Key Points

Question  Does carboplatin during radiotherapy or isotretinoin during maintenance chemotherapy improve survival in children with high-risk medulloblastoma?

Findings  In this randomized clinical trial including 261 children with medulloblastoma, isotretinoin was not found to improve survival. The addition of carboplatin during radiotherapy improved survival from 54% to 73% only for children with high-risk group 3 medulloblastoma.

Meaning  The findings of this randomized clinical trial indicate that prospective molecular and clinical risk stratification for medulloblastoma is necessary because the addition of carboplatin during radiotherapy is recommended for high-risk group 3 medulloblastoma, but not for other molecular subgroups.


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

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