Dose Escalated Radiotherapy for Glioblastoma Multiforme: An International Systematic Review and Meta-Analysis of 22 Prospective Trials.

ABSTRACT Background Limited evidence is available on the utility of dose-escalated radiation therapy (DE-RT) +/- (TMZ) vs. standard-of-care RT (SoC-RT) for patients with newly diagnosed glioblastoma multiforme (GBM). We performed a systematic review/meta-analysis to compare overall survival (OS) and progression-free survival (PFS) between DE-RT and SoC-RT. Methods We utilized a PICOS/PRISMA/MOOSE selection criterion to identify studies. The primary and secondary outcomes were 1-year OS and 1-year PFS, respectively. Outcomes and comparisons were subdivided based on receipt of TMZ and MGMT status. DE-RT was defined based on equivalent dose (EQD2) calculations. Random effects meta-analyses using the Knapp-Hartung correction, arcsine transformation, and restricted maximum likelihood method were conducted. Meta-regression was used to compare therapeutic (e.g. DE-RT and/or TMZ) and pathologic characteristics (e.g. MGMT methylation status) using the Wald-type test Results Across 22 published studies, 2,198 patients with GBM were included; 507 received DE-RT. One-year OS following DE-RT alone was higher than SoC-RT alone (46.3% vs. 23.4%; p=0.02) as was 1-year PFS (17.9% vs. 5.3%; p=0.02). No significant difference in 1-year OS (73.2% vs. 64.4%; p=0.23) or 1-year PFS (44.5% vs. 44.3%; p=0.33) between DE-RT+TMZ and SoC-RT+TMZ was noted. No difference in 1-year OS was noted between DE-RT+TMZ and SoC-RT+TMZ in either MGMT methylated (83.2% vs. 73.2%; p=0.23) or MGMT unmethylated (72.6% vs. 50.6%; p=0.16) patients. Conclusions DE-RT alone resulted in superior PFS and OS vs. SoC-RT alone. DE-RT+TMZ did not lead to improved outcomes vs. SoC-RT+TMZ. No differential benefit based on MGMT status was found. Future studies are warranted to define which subgroups benefit most from DE-RT.