Low Dose Fractionated Radiation Therapy As a Chemo-Potentiator of Temozolomide for Recurrent Anaplastic Astrocytoma and Glioblastoma: A Single-Arm Phase I/II Trial

Abstract

Purpose: Preclinical and clinical studies suggest low-dose fractionated radiotherapy (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 (HGG).

Methods and material: 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 chemoradiotherapy and adjuvant temozolomide were enrolled. Radiotherapy consisted of 0.5 Gy twice daily fractions with concurrent temozolomide on days 1-5 of a 28-day cycle for 6 cycles, and adjuvant temozolomide for 6 cycles. MRI was performed every 2 months after initiating LDFRT. The Phase 1 primary e`ndpoint was acute hematologic toxicity. The Phase 2 primary endpoint was 1-year overall survival (OS), with a lower bound of 80% CI >28.6% (historical control). Secondary endpoints included pseudoprogression incidence.

Results: Preclinical - LDFRT-mediated temozolomide potentiation appears more effective than 2 Gy-mediated potentiation.

Clinical: - Thirty patients were enrolled from 2013-2021; 80% had recurrent glioblastoma and 90% were ECOG 0-1. Amongst patients with molecular data, 61% were MGMT-methylated and 23% were IDH-mutant. Median RT dose was 30 Gy (range, 28.5-30). Median follow-up was 9.5 months (range, 0.1-66.3). One-year OS was 34.5% (95% CI 20.9-57.0; lower bound of 80% CI=24.8%). 77% experienced pseudoprogression (median dose 10 Gy; range, 6-30), corresponding with improved OS (HR=0.12, 95% CI 0.03-0.40; P<0.01) versus no pseudoprogression.

Conclusions: 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 re-irradiation. 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.

Keywords: glioblastoma; low-dose fractionated radiotherapy; pseudoprogression; re-irradiation; temozolomide.