Characteristics and Outcomes of Patients With IDH-Mutant Grade 2 and 3 Gliomas After Deferred or Adjuvant Radiotherapy

Abstract

Background and objectives: Current treatment guidelines for patients with isocitrate dehydrogenase (IDH)-mutant (IDHm) glioma recommend radiation (XRT) and chemotherapy after surgery in most cases based on studies in which XRT was compared with XRT plus chemotherapy. Although XRT has been shown to improve time to tumor progression, there has never been a controlled study in this population in which adjuvant XRT (aXRT) demonstrated superior overall survival (OS) over initial observation. The aim of this study was to evaluate the effect of timing of XRT on survival in IDHm-glioma.

Methods: We performed a retrospective observational cohort study, comprising a cohort of adult patients with grade 2 or 3 IDHm-gliomas seen at 2 academic centers (University of Washington and Stanford University) between 2007 and 2022 (identified through research data registries). The main comparison of interest was patients who received XRT within 3 months of diagnosis and before progression, that is, as adjuvant treatment (aXRT), versus those who did not have aXRT (deferred XRT, dXRT). The primary outcome measures were median progression-free survival and OS. Survival analysis was performed through multivariable Cox proportional hazard modeling, propensity matching, and subset analysis.

Results: A total of 450 eligible patients were identified (mean age 39.7 years; 41% female). The median survival of the combined cohort was 19.1 years (25th-75th percentiles 9.75-27.8 years). 47.1% of patients received aXRT. Patients with aXRT demonstrated similar time to next intervention (hazard ratio [HR] 0.83, 95% CI 0.65-1.07) but showed a markedly diminished OS compared with the dXRT cohort (HR of death 2.90, 95% CI 1.9-4.42, p < 0.001). This shorter OS with aXRT was appreciated in all assessed subgroups, including patients considered high risk by grade, age, and extent of resection. This shorter OS was also consistent in multivariable analysis and in propensity-matched cohorts.

Discussion: Although retrospective, the marked OS difference between aXRT and dXRT groups suggests that aXRT may be not be as beneficial as what was once thought, especially regarding long-term survival. These results also offer justification for the use of a dXRT group in studies assessing adjuvant treatments, as well as a reconsideration of the current treatment paradigm for these patients, especially given the recent introduction of IDH inhibitors.

Figure 1. Kaplan-Meier Curves for OS and TNI

Kaplan-Meier curves comparing aXRT and dXRT for (A) OS in all patients, (B) TNI in all patients, (C) OS in a propensity-matched cohort, (D) TNI in a propensity-matched cohort, (E) OS in a cohort of high-risk patients, (F) TNI in a cohort of high-risk patients, (G) OS in a cohort of patients with residual disease after surgery, and (H) TNI in a cohort of patients with residual disease after surgery. In all curves, a hazard ratio of death is provided using log-rank tests. The lines represent the Kaplan-Meier curves, and the shaded regions represent the lower and upper limits of the 95% CIs for survival estimates. aXRT = adjuvant radiation therapy; dXRT = deferred radiation therapy (no adjuvant radiation therapy); high-risk = patients with either grade 3 tumors, grade 2 tumors with residual disease after surgery, or grade 2 tumors with gross total resection but older than 40 years; OS = overall survival; TNI = time to next intervention.

Figure 2. Overall Survival Univariate Subset Analysis Comparing Adjuvant vs Deferred XRT

This figure demonstrates univariate analysis for each subset cohort of patients listed on the left as well as for the overall population. Each hazard ratio of death (for adjuvant XRT relative to deferred XRT) and its corresponding 95% CI are shown, with corresponding values listed on the right. XRT = radiation therapy.