Shorter RT Schedule Linked to Worse Glioblastoma Survival

TOPLINEUltrahypofractionated radiotherapy for newly diagnosed glioblastoma was associated with shorter survival than standard fractionation, with median overall survival of 13 months vs 21 months. Radiation necrosis or pseudoprogression occurred about five times more often after ultrahypofractionation, although no grade 4-5 toxicities were observed. METHODOLOGYPrevious phase 2 evidence suggested ultrahypofractionation may offer survival outcomes similar to those of standard fractionation, with reduced treatment time and costs.In the current phase 3 open-label, randomized trial, researchers evaluated noninferiority of ultrahypofractionated temozolomide chemoradiation compared with standard fractionation in glioblastoma patients at eight radiotherapy centers in Netherlands.Overall, 135 adults with newly diagnosed histologically confirmed glioblastoma and Karnofsky Performance Status of 70 or higher were randomly assigned in a 1:1 ratio to receive either ultrahypofractionated radiotherapy (6 × 6 Gy in 2 weeks) or standard radiotherapy (30 × 2 Gy in 6 weeks), both with concurrent and six cycles of adjuvant temozolomide.Participants were stratified by MGMT promoter methylation status (methylated/unmethylated/unknown), age (< 70 vs ≥ 70 years), prior surgical procedure (biopsy/resection), and treatment center, with median follow-up of 24 months. Primary outcome was 2-year overall survival with a noninferiority margin defined as a hazard ratio (HR) of 1.2, while secondary outcomes included progression-free survival (PFS), radiation-induced toxicity, and use of dexamethasone or bevacizumab for treatment-related edema or necrosis. Enrollment stopped early due to slow accrual, with 135 of 474 planned patients enrolled, and all randomly assigned patients were included in intention-to-treat analyses. TAKEAWAYMedian overall survival was longer with standard radiotherapy than with ultrahypofractionated radiotherapy — 21 vs 13 months — with 1-year survival rates of 70.6% vs 52.2%, respectively (P < .001). Median PFS was 10 months in the standard-care arm vs 9 months ultrahypofractionated arm. Mortality risk was similar in the first 6 months (HR, 0.99; P = .99), but more than doubled in the ultrahypofractionated arm thereafter (HR, 2.54; P < .001). Radiation necrosis or pseudoprogression occurred in 47.8% of patients in the experimental arm vs 16.2% in the control arm (HR, 5.20). No grade 4-5 toxicities were observed in either treatment arm, with most adverse events being grade 1 or 2 in severity, though dexamethasone use was more frequent at 6-12 months in the ultrahypofractionated arm (60%-63% vs 31%-32%, P ≤ .006). IN PRACTICE“Noninferiority of the 6 × 6 Gy chemoradiation regimen could not be demonstrated,” the study authors concluded. “This ultrahypofractionated regimen was associated with inferior survival and increased radiation necrosis and, therefore, should not replace standard chemoradiation.”SOURCEThe study was led by Anouk M. de Jong, University Medical Center Utrecht in Utrecht, Netherlands. It was published online on August 8 in Radiotherapy and Oncology.LIMITATIONSThe study began during the COVID pandemic, which caused logistical delays and initial slow accrual, and patient enrollment was further limited by concurrent trials and other practical factors, resulting in early trial termination with only 135 of 474 planned patients enrolled, substantially reducing statistical power. The noninferiority design assumed proportional hazards, but the observed hazards were nonproportional, complicating interpretation of the prespecified HR-based noninferiority margin. Radiotherapy planning was performed according to a standardized protocol, but no central review of treatment plans was conducted, which may have introduced variability in treatment planning. MRI frequency and the use of advanced imaging were not mandated and varied according to local clinical practice, and although progression assessments were supported by dedicated neuroradiologic review and multidisciplinary confirmation, misclassification of progression, pseudoprogression, and radiation necrosis cannot be excluded.DISCLOSURESThe study received funding from ZonMw, The Netherlands Organisation for Health Research and Development, project number 852002028. ZonMw had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Joost J.C. Verhoeff disclosed receiving financial support from the Netherlands Organisation for Health Research and Development. Additional disclosures are noted in the original article.This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.