Pulsed Reduced Dose Rate Re-Irradiation for Recurrent Grade 4 Gliomas: A Retrospective Analysis of Safety and Efficacy

Abstract

Despite maximal treatment, nearly all patients with grade 4 gliomas develop recurrent disease. Treatment options for these patients are limited and overall survival is poor. Re-irradiation may be considered in certain patients, though risk of side effects often limits the effective dose able to be delivered. Pulsed reduced dose rate (PRDR) radiation is a treatment technique that reduces effective dose rate and increases treatment time allowing for intrafraction repair. Here, we report safety and efficacy of PRDR re-irradiation for recurrent grade 4 gliomas. We performed a retrospective review of patients treated with PRDR between 2001 and 2022. Patients were treated with reduced dose rate radiation delivered in 0.2 Gy pulses every 3 minutes in 2 Gy daily fractions. Both 3D conformal and step and shoot IMRT radiation plans were utilized. Toxicities were evaluated based on Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria. Kaplan Meier analysis was used to calculate overall survival (OS). Cox regression analysis was performed for multivariate analysis. A total of 168 grade 4 glioma patients treated with PRDR re-irradiation were identified. The median age was 55 years old. The median initial radiation dose was 60 Gy (range 36 Gy - 72 Gy) and the median PRDR dose was 54 Gy (range 37.5 - 60 Gy). Seventy percent of patients received systemic therapy for recurrent disease prior to PRDR, while 30% received PRDR as first treatment for recurrent disease (or following re-resection without other treatment). The median survival following PRDR was 6.3 months. Multivariate analysis showed time since initial radiation of 14+ months (HR 0.66, p = 0.005, 95% CI 0.44 - 0.98), pre-PRDR use of steroids (HR 1.78, p = 0.005, 95% CI 1.2 - 2.66), and Karnofsky performance status of 70 or greater to be a significant predictor of survival (HR = 0.6, p = 0.008, 95% CI 0.44 - 0.98). No grade 4 or 5 toxicity was noted. Grade 3 new onset seizures was noted in 6% of patients, all subsequently controlled with medication. The most common grade 1-2 side effect after treatment was fatigue. In this large, retrospective cohort, PRDR re-irradiation for recurrent grade 4 gliomas was well tolerated with low rates of grade 3 toxicity. Overall survival outcomes were encouraging, especially in heavily pre-treated patients. Prospective studies are ongoing to further evaluate the efficacy of PRDR for recurrent glioma treatment.