Purpose: Children with histologically diagnosed high-risk medulloblastoma, supratentorial primitive neuroectodermal tumor of the CNS (CNS-PNET), and pineoblastoma (PBL) have had poor survival despite intensive treatment. We included these patients in this Children's Oncology Group trial. Molecular profiling later revealed tumor heterogeneity that was not detectable at protocol inception. Enrollment of patients with CNS-PNET/PBL was subsequently discontinued, and outcomes for this part of the study are reported here.
Patients and methods: In this phase III, four-arm prospective trial, consenting children age 3-22 years with newly diagnosed CNS-PNET were randomly assigned (1:1) to receive carboplatin during radiation and/or adjuvant isotretinoin after standard intensive therapy. Primary outcome measure was event-free survival (EFS) in the intent-to-treat population. Molecular tumor classification was retrospectively completed using DNA methylation profiling.
Results: Eighty-five participants with institutionally diagnosed CNS-PNETs/PBLs were enrolled. Of 60 patients with sufficient tissue, 31 were nonpineal in location, of which 22 (71%) represented tumors that were not intended for trial inclusion, including 18 high-grade gliomas (HGGs), two atypical teratoid rhabdoid tumors, and two ependymomas. Outcomes across tumor types were strikingly different. Patients with supratentorial embryonal tumors/PBLs exhibited 5-year EFS and overall survival of 62.8% (95% CI, 43.4% to 82.2%) and 78.5% (95% CI, 62.2% to 94.8%), respectively, whereas patients with molecularly classified HGG had EFS and overall survival of 5.6% (95% CI, 0% to 13.0%) and 12.0% (95% CI, 0% to 24.7%), respectively. Neither carboplatin, nor isotretinoin significantly altered outcomes for all patients. Survival for patients with HGG was similar to that of historic studies that avoid craniospinal irradiation and intensive chemotherapy.
Conclusion: For patients with CNS-PNET/PBL, prognosis is considerably better than previously assumed when molecularly confirmed HGGs are removed. Identification of molecular HGGs may spare affected children from unhelpful intensive treatment. This trial highlights the challenges of a histology-based diagnosis for pediatric brain tumors and indicates that molecular profiling should become a standard component of initial diagnosis.