Pediatric High-Grade Glioma Patterns of Failure by Molecular Subgroup

Abstract

Pediatric high-grade gliomas (HGG), which include WHO Grades III and IV astrocytomas, are molecularly diverse as characterized by their mutations and histopathological features. There has been little progress over the last few decades in improving pediatric HGG outcomes, with published median survivals ranging from 9-15 months. We hypothesize that tumor molecular subgroup may be associated with survival outcomes and patterns of failure after definitive radiation therapy (RT). Medical records, pathology reports, RT plans and follow up brain MRIs for pediatric patients treated for HGG from 2006 to 2019 at a single institution were reviewed. Inclusion criteria were age 18 or younger, biopsy-proven WHO Grade III or IV astrocytoma, received at least 1 post-treatment MRI, and either already had molecular subgroup classification or had tissue available for further testing. Molecular testing is ongoing; genes in our molecular assay include, but are not limited to, Histone H3, PTEN, EGFR, BRAF and PDGFRA. Patients in this study were treated with fractionated volumetric modulated arc radiotherapy using a simultaneous integrated boost, 54 Gy to the T2/FLAIR signal abnormality plus margin, and 60 Gy to the T1 post-contrast abnormality, resection cavity, or any gross residual disease plus a margin, all in 30 fractions. Kaplan-Meier method was used to estimate overall survival (OS) and progression free survival (PFS). Univariate Cox proportional hazards models were fit for patient characteristics. Failure is characterized as local, marginal or distant. 39 patients with a median age at diagnosis of 11.2 years (range 3.7 – 18.3) met inclusion criteria, 29 with WHO Grade IV and 10 with WHO Grade III disease. Median survival was 10.4 months (95% CI 7.5, 17.2), with a 24-month survival of 25.4% (13.1%, 39.7%). Median PFS was 6.5 months (3.9, 10.1) with a 12-month PFS of 30.8% (17.3%, 45.4%). On univariate analysis, neither OS nor PFS were associated with any recorded patient characteristic including GTV size, age at diagnosis, type of surgery, receipt of chemotherapy or cumulative RT dose. 8 patients had distant failures; 6 had marginal failures. The remaining patients who had progressed prior to last analysis failed locally. Of the 8 patients with distant failure, 6 had leptomeningeal disease (LMD). Half of the patients with LMD had PTEN deletions. 5 of the 8 patients with distant failures had MIB-1 staining results, all with values below or equal to 50%. Additional molecular testing for patients in the entire cohort is ongoing and will be correlated with patterns of failure and survival. Pediatric high-grade gliomas are comprised of diverse mutational signatures, which may be associated with tumor aggressiveness and potential for treatment response. Molecular phenotyping of pediatric high-grade gliomas may provide valuable prognostic information that could inform treatment decision-making.