Trial Description

Children with histologically diagnosed high-risk medulloblastoma, supratentorial primitive neuro-ectodermal tumor of the CNS (CNS-PNET), and pineoblastoma (PBL) have had poor survival despite intensive treatment.  The Children’s Oncology Group (COG) study ACNS0332 was designed to test two approaches for treatment intensification for these patients: addition of carboplatin during irradiation and/or addition of isotretinoin to the adjuvant regimen. Carboplatin has demonstrated preclinical and clinical efficacy in these tumors and is well tolerated in children, whereas isotretinoin crosses the blood-brain barrier efficiently and is effective against preclinical models of medulloblastoma (MB).  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 reported.  Eighty-five participants with institutionally diagnosed CNS-PNETs/PBLs were enrolled. Of 60 patients with sufficient tissue, 31 were non-pineal 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. 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.  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.

Pre-operative and post-operative MRI scans of the brain with and without contrast and spinal MRI with and without contrast were required.  All scans underwent central review.

Trial Outcomes

Results of the trial have been reported in the following publication:

Hwang EI, Kool M, Burger PC, Capper D, Chavez L, Brabetz S, Williams-Hughes C, Billups C, Heier L, Jaju A, Michalski J, Li Y, Leary S, Zhou T, von Deimling A, Jones DTW, Fouladi M, Pollack IF, Gajjar A, Packer RJ, Pfister SM, Olson JM. Extensive Molecular and Clinical Heterogeneity in Patients With Histologically Diagnosed CNS-PNET Treated as a Single Entity: A Report From the Children's Oncology Group Randomized ACNS0332 Trial. J Clin Oncol. 2018 Oct 17:JCO2017764720. doi: 10.1200/JCO.2017.76.4720. Epub ahead of print. PMID: 30332335.