Comprehensive Genomic Analysis in NRG Oncology/RTOG 9802: A Phase III Trial of Radiation Versus Radiation Plus Procarbazine, Lomustine (CCNU), and Vincristine in High-Risk Low-Grade Glioma

Abstract

PURPOSE NRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375 ) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802. METHODS IDH1/2 mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and MGMT promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates. RESULTS Of the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were IDH-wild type, 43 (41%) were IDH-mutant/non-codeleted, and 37(35%) were IDH-mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32; P = .003; HR, 0.13; P < .001) and OS (HR, 0.38; P = .013; HR, 0.21; P = .029) in the IDH-mutant/non-codeleted and IDH-mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the IDH-wild-type subgroup. CONCLUSION This study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with IDH-mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.

EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood

“…The RTOG 9802 trial reported a major prolongation of OS with the addition of PCV polychemotherapy to radiotherapy (54 Gy), from 7.8 years to 13.3 years in patients with high-risk WHO grade 2 gliomas who were 18–39 years of age and had undergone a subtotal resection or biopsy or in those aged ≥40 years 75 . This benefit was reported across histological subgroups and, although cohort sizes were small, benefit was observed in patients with either IDH-mutant astrocytomas or oligodendrogliomas but not in those with IDH-wild-type tumours 87 . Thus, radiotherapy followed by PCV constitutes the standard of care for patients with WHO grade 2 IDH-mutant astrocytomas deemed to require post-surgical treatment.…”

A basic review on systemic treatment options in WHO grade II-III gliomas

“…Importantly, the large majority of IDH-mt gliomas present with MGMT methylation, resulting in limited additional predictive potential in IDH-mt gliomas [25]. This was also confirmed by a recently published post-hoc analysis on the RTOG 9802 trial, which is further discussed below [26]. However, in a subsequent analysis of the single-arm RTOG 0424 phase II trial investigating the addition of TMZ to radiotherapy only, MGMT was shown as an IDH-independent prognostic marker in high-risk WHO grade II glioma [27].…”

“…The benefit of adjuvant PCV was most pronounced in IDH-mt grade II gliomas for both OS (HR 0.43, p = 0.009) and PFS (HR = 0.36, p < 0.001). Recently, the results of a post-hoc analysis incorporating further genetic markers have been published [26]. Most importantly, the beneficial effect of adjuvant PCV remained significant in both IDH-mt/1p19q-codeleted oligodendroglioma and IDH-mt astrocytoma in terms of OS and PFS, whereas the addition of PCV had no effect in the IDH-wt subgroup.…”

High-dose radiation associated with improved survival in IDH-wildtype low-grade glioma

“…This negative result may be attributed to the heterogeneity of LGG, especially across the different molecular subgroups. As a most important biomarker, IDH mutation status deeply influences the pathophysiology of LGG, from survival to therapy response [ 2 , 15 ]. Tumors with IDH mutations, especially those accompanied by 1p/19q codeletion, may be sensitive to radiotherapy.…”