Adjuvant Chemoradiotherapy within One Year of Resection for Molecularly Defined Astrocytoma

Abstract

Treatments for diffuse low-grade gliomas (LGG) are controversial. Level I evidence supports the use of adjuvant radiotherapy (RT) and PCV chemotherapy for histologic LGG, but integration of molecular biomarkers in recent WHO classification and the emergence of temozolomide chemotherapy for gliomas necessitates additional investigation of the optimal treatment and timing of postoperative interventions. We hypothesized molecularly-defined LGG (IDH-mutant astrocytoma (astro) and IDH-mutant, 1p/19q-codeleted oligodendroglioma (oligo)) may have different clinical outcomes following adjuvant RT (aRT) with chemotherapy (aRT+chemo) vs observation or chemo alone. A retrospective analysis of consecutive adult patients diagnosed with WHO Grade 2 astrocytoma or oligodendroglioma who underwent initial resection at a single institution from January 1998 to November 2017 was performed. Wilcoxon rank sum and Chi-squared tests were used to compare continuous and categorical variables, respectively. Survival analyses were performed using the Kaplan-Meier method and Cox proportional hazards models. Patients without clinical progression or death were censored at the date of last follow-up. Pre-operative and post-operative T2 FLAIR hyperintense tumor volumes were quantified using 3D Slicer to calculate extent of resection (EOR). A total of 342 patients with molecularly-defined LGG (178 astro, 164 oligo) were identified with a median follow up of 9.1 yr. 171 (50%) patients received RT during their treatment course, of which 31 (18%) were treated with aRT within 1 year of diagnosis. The median aRT dose was 54 Gy (range: 40-60 Gy). aRT was more likely for astro (58%) vs oligo (41%, p = 0.001) and for patients who had resections with lower median EOR (88% vs 95%, p = 0.014). 53 patients (15%) were treated with chemo alone, and 136 patients (40%) were treated with aRT+chemo. Temozolomide was used for 161 patients (85%). For astro, aRT+chemo was associated with longer PFS (median 14.9 yr) compared to observation (4.8 yr, p = 0.05), aRT without chemo (5.2 yr, p = 0.01), or chemo alone (4.7 yr, p = 0.02). For oligo, aRT+chemo was associated with longer PFS (median not reached) compared to aRT without chemo (1.6 yr, p = 0.03), but not when compared to observation (median not reached, p = 0.47), or chemo alone (7.9 yr, p = 0.45). Multivariate analysis showed preoperative tumor volume, EOR, and aRT+chemo (but not aRT or chemo alone) were independently associated with astro PFS compared to observation. Propensity matching based on pre-operative tumor volume, EOR, and age demonstrated longer astro PFS after aRT+chemo (14.9 yr) compared to observation or chemo alone (4.5 yr, p = 0.015), without significant difference in OS (18.2 vs. 11.5 yr, p = 0.40). Retrospective data from a single institution support the use of adjuvant radiotherapy with chemotherapy for patients with molecular astrocytomas, while the role of this approach for oligodendrogliomas is unclear in this cohort.