Low-Dose Fractionated Radiation Therapy as a Chemopotentiator of Temozolomide for Recurrent Anaplastic Astrocytoma and Glioblastoma: A Single-Arm Phase 1/2 Trial.

Abstract

Preclinical and clinical studies suggest low-dose fractionated radiation therapy (LDFRT) is a chemopotentiator in several solid tumors. We evaluated chemopotentiation of temozolomide with LDFRT in glioblastoma and brain metastatic lung cancer cell lines, followed by a phase 1/2 trial assessing the safety/efficacy of LDFRT with concurrent/adjuvant temozolomide in patients with recurrent high-grade gliomas (HGGs). Preclinical-The temozolomide-potentiating effect of LDFRT was tested in glioblastoma and brain metastatic lung cancer cell lines with real-time cell electronic sensing system and flow cytometry. Clinical-Patients with recurrent HGG following standard-of-care chemoradiation therapy and adjuvant temozolomide were enrolled. Radiation therapy consisted of 0.5 Gy twice daily fractions with concurrent temozolomide on days 1 to 5 of a 28-day cycle for 6 cycles, and adjuvant temozolomide for 6 cycles. Magnetic resonance imaging was performed every 2 months after initiating LDFRT. The phase 1 primary endpoint was acute hematologic toxicity. The phase 2 primary endpoint was 1-year overall survival (OS), with a lower bound of 80% confidence interval > 28.6% (historical control). Secondary endpoints included pseudoprogression incidence. Preclinical-LDFRT-mediated temozolomide potentiation appears more effective than 2 Gy-mediated potentiation. Clinical-Thirty patients were enrolled from 2013 to 2021; 80% had recurrent glioblastoma and 90% were Eastern Cooperative Oncology Group 0-1. Among patients with molecular data, 61% were O-6-methylguanine-DNA methyltransferase-methylated and 23% were isocitrate dehydrogenase-mutant. Median RT dose was 30 Gy (range, 28.5-30 Gy). Median follow-up was 9.5 months (range, 0.1-66.3 months). One-year OS was 34.5% (95% confidence interval [CI], 20.9-57.0; lower bound of 80% CI = 24.8%). 77% experienced pseudoprogression (median dose 10 Gy; range, 6-30 Gy), corresponding with improved OS (HR, 0.12; 95% CI, 0.03-0.40; P < .01) versus no pseudoprogression. Preclinical work demonstrates the chemopotentiating effect of LDFRT. In our clinical trial, LDFRT with temozolomide was safe and well tolerated in patients with recurrent HGG receiving salvage reirradiation. Although the primary survival endpoint was not achieved, high pseudoprogression rates at low radiation doses support the principle of low-dose radiation hypersensitivity mediated by chemopotentiation and potentially immune-modulation.