Timing of Adjuvant Radiotherapy and Survival Analysis for Molecularly Defined Low Grade Glioma

Abstract

<h3>Purpose/Objective(s)</h3> The optimal treatment for patients with diffuse low-grade glioma (LGG) is controversial. Level I evidence support the use of radiotherapy (RT) for histologic LGG, but incorporation of molecular biomarkers in the WHO classification compels additional investigation to define the optimal treatment and timing of RT. We hypothesized molecularly defined LGG (IDH-mutant astrocytoma [astro] and IDH-mutant, 1p/19q-codeleted oligodendrogliomas [oligo]) have different survival outcomes following early vs delayed RT, knowledge that may guide RT in the context of resection and chemotherapy. <h3>Materials/Methods</h3> We performed a retrospective analysis of adult patients who were newly diagnosed with a WHO Grade 2 IDH-mutant astro or IDH-mutant, 1p/19q-codel oligo and had initial resection at a single institution from Jan 1998 to Nov 2017. Wilcoxon rank sum and Chi-squared tests were used to compare continuous and categorical variables between cohorts, respectively. Survival analysis was performed using the Kaplan-Meier method. Patients without clinical progression or death were censored at last follow-up date. Pre-operative and post-operative tumor volumes were quantified using 3D Slicer and defined as the T2 FLAIR hyperintense lesion to calculate extent of resection (EOR). <h3>Results</h3> 392 patients (202 astro, 190 oligo) were analyzed with a median follow up of 9.3 yr (95% CI: 8.19–10.16). Median overall survival (OS) was 13.0 yr for astro (95% CI: 11.4 – 18.6) and not reached for oligo (95% CI: 19.9 – NA). 168 patients (42.8%) received RT during their treatment course, with the majority (84%) treated at time of first disease progression. Chemotherapy was used in 81.7% of patients who received RT (TMZ in 90.3% of cases). The median RT dose was 54 Gy (range: 40 – 60 Gy). RT was more likely for astro (51.0%) than for oligo (34.2%) (p < 0.001), and a lower median EOR was associated with RT (88% vs 95%; p = 0.017). RT was not associated with increased OS for astro (p = 0.12) or oligo (p = 0.31) for all comers. For patients < 40 yr of age who had subtotal resections of astros (< 85% EOR), RT increased median OS with a trend toward significance when compared to no RT (13.1 yr [95% CI: 7.3 – NA] vs 9.1 yr [95% CI: 5.4 – NA], p = 0.1). RT within 1 yr of diagnosis was associated with improved median PFS compared to patients who received RT after 1 yr for astro (7.0 yr [95% CI: 5.5 – NA] vs 3.6 yr [95% CI: 2.9 – 4.8], p < 0.001), but not for oligo (p = 0.4). RT within 1 yr of diagnosis increased subsequent survival following RT for astro (median 12.9 yr [95% CI: 7.9 – NA] vs 4.4 yr [95% CI: 3.4 – 8.5], p < 0.001), with a trend toward improvement for oligo (p = 0.08). Patients with astro < 40 yr of age exhibited the greatest improvement in subsequent survival following RT, when RT was delivered within 1 yr of diagnosis (0 recorded deaths out of n = 12, p = 0.001). <h3>Conclusion</h3> Retrospective data from a single institution support the use of early RT for patients < 40 yr of age with molecularly-defined astrocytomas. RT may also improve OS in this population after subtotal resection.