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

Abstract

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.

Invited Review: DNA methylation‐based classification of paediatric brain tumours

“…Even though we would definitely not recommend this as routine practice, this may in some cases help to at least retrieve some information from material where standard fixation was accidentally not performed. A further example of the ensuing versatility comes from the retrospective analysis of the tumour material of the COG ACNS0332 trial on CNS primitive neuroectodermal tumours (PNETs) . DNA methylation profiling was initially not planned and for many of the cases only archived haematoxylin and eosin or immunohistochemically stained slides were available.…”

Pineoblastoma in children less than six years of age: The Head Start I, II, and III experience

“…They subsequently received six cycles of maintenance chemotherapy with or without adjuvant isotretinoin 25 . All patients were alive at the time of publication with a median OS of 72.3 months (range, 24.8‐106.6 months) 25 . This strongly suggests the benefit of CSI in improving survival outcomes in children three years of age or older with pineoblastoma.…”

“…Eleven of the 12 patients experienced PD 24 . In the Children's Oncology Group (COG) ACNS0332 trial, eight of 29 patients with pineoblastoma were between three and six years of age with a median age of 3.45 years (range, 3‐5.9 years) 25 . These eight patients received upfront surgical resection followed by CSI of 36 Gy with a tumor bed boost to 55.8 Gy combined with vincristine with or without carboplatin radiosensitization.…”

“…These eight patients received upfront surgical resection followed by CSI of 36 Gy with a tumor bed boost to 55.8 Gy combined with vincristine with or without carboplatin radiosensitization. They subsequently received six cycles of maintenance chemotherapy with or without adjuvant isotretinoin 25 . All patients were alive at the time of publication with a median OS of 72.3 months (range, 24.8‐106.6 months) 25 .…”

“…The COG 99701 trial found that GTR was a positive prognostic factor among older patients with local disease 30 . The recent ACNS0332 trial showed that patients with supratentorial primitive neuroectodermal tumor (CNS‐PNET) and pineoblastoma with residual disease greater than 1.5 cm 2 had better OS compared with patients with residual disease less than 1.5 cm 2 25 . Therefore, we recommend pursuing an upfront maximal surgical resection and a second‐look surgical resection early into the induction chemotherapy phase whenever deemed safe and feasible.…”