Reirradiation vs. Systemic Therapy vs. Combination Therapy for Recurrent High-Grade Glioma: A Meta-Analysis of Survival and Toxicity

Abstract

To compare the effects of reirradiation, systemic therapy and combination therapy (reirradiation + systemic therapy) on overall survival (OS), progression-free survival (PFS) and adverse effects (AEs) in patients with recurrent high-grade glioma (rHGG). A search was performed on PubMed, Scopus, Embase and CENTRAL on 18 March 2022, and repeated on 1 November 2022. Studies comparing OS, PFS and AEs in patients with rHGG, and encompassing the following four groups were included; reirradiation vs systemic therapy, combination therapy vs systemic therapy, combination therapy vs reirradiation, and reirradiation + bevacizumab-based systemic therapy vs reirradiation +/- non-bevacizumab-based systemic therapy. Risk of bias was assessed using the Cochrane RoB 2 tool for randomized control trials (RCTs) and the ROBINS-I tool for non-randomized studies. The logHR and SE (logHR) for OS and PFS, and logRR and SE (logRR) for AEs were extracted or estimated if not reported. Meta-analyses were performed for each comparator group using a random effects model. Subgroup analysis was performed on only RCTs if ≥ 2 studies were available. Thirty-three studies comprising of 2201 participants were included. In the reirradiation vs systemic therapy group, there was no difference in PFS (2 studies, 185 participants; HR 0.87 (95% CI 0.61-1.22)) and OS (3 studies, 237 participants; HR 0.94 (95% CI 0.67-1.31)). In the combination therapy vs systemic therapy group, combination therapy improved PFS (6 studies, 605 participants; HR = 0.70 (95% CI 0.59-0.82)) and OS (6 studies, 537 participants; HR 0.73 (95% CI 0.56-0.96)), and there was no difference in grade 3+ AEs (4 studies, 398 participants; RR 1.03 (95% CI 0.57-1.86)). Subgroup analysis of only RCTs (2 studies, 205 participants) similarly showed no difference in grade 3+ AEs (RR 1.13 (95% CI 0.71-1.82)), though no significant improvements in PFS (HR 0.51 (95% CI 0.22-1.19)) or OS (HR 0.90 (95% CI 0.65-1.26)) were demonstrated. In the combination therapy vs reirradiation group, combination therapy improved PFS (5 studies, 259 participants; HR 0.50 (95% CI 0.37-0.69)) and OS (13 studies, 713 participants; HR 0.59 (95% CI 0.47-0.74)). In the reirradiation + bevacizumab-based systemic therapy vs reirradiation +/- non-bevacizumab-based systemic therapy group, combining reirradiation with bevacizumab improved PFS (2 studies, 104 participants; HR 0.46 (95% CI 0.27-0.77)) and OS (5 studies, 256 participants; HR 0.42 (95% CI 0.24-0.72)), and reduced radionecrosis (RN) (5 studies, 353 participants; RR 0.17 (95% CI 0.06-0.48)). Combination therapy may improve OS and PFS with acceptable toxicity in select patients with rHGG. Further RCTs comparing systemic therapy to combination therapy, particularly with bevacizumab-based systemic therapy, are needed. The limitations of previous RCTs must be addressed; namely inadequate accrual of appropriate patients, and exclusion of FLAIR abnormalities from target delineation.