Significance: Ultra-high dose-rate (≥100 Gy⋅s ⁻¹ ) irradiation, termed FLASH radiotherapy, affords some remarkable (if not unexpected) normal tissue sparing in the irradiated brain when compared with conventional dose rates (0.07–0.1 Gy⋅s ⁻¹ ) used in clinical practice. Radiation-induced neurocognitive deficits, persistent neuroinflammation, and the structural degradation of mature neurons, typical of conventional dose-rate exposures, were resolved significantly in a preclinical mouse model exposed to FLASH radiotherapy. These benefits persisted over a 6-mon postirradiation interval and were caused, in part, by a mechanism involving reduced reactive oxygen species. Since normal tissue injury during and following radiotherapy dictates the maximum tolerated dose, the capability to ameliorate these adverse side effects holds significant promise for improving therapeutic outcome for cancer survivors worldwide.

Purpose: Recent data have shown that single-fraction irradiation delivered to the whole brain in less than tenths of a second using FLASH radiotherapy (FLASH-RT), does not elicit neurocognitive deficits in mice. This observation has important clinical implications for the management of invasive and treatment-resistant brain tumors that involves relatively large irradiation volumes with high cytotoxic doses. Experimental Design: Therefore, we aimed at simultaneously investigating the antitumor efficacy and neuroprotective benefits of FLASH-RT 1-month after exposure, using a well-characterized murine orthotopic glioblastoma model. As fractionated regimens of radiotherapy are the standard of care for glioblastoma treatment, we incorporated dose fractionation to simultaneously validate the neuroprotective effects and optimized tumor treatments with FLASH-RT. Results: The capability of FLASH-RT to minimize the induction of radiation-induced brain toxicities has been attributed to the reduction of reactive oxygen species, casting some concern that this might translate to a possible loss of antitumor efficacy. Our study shows that FLASH and CONV-RT are isoefficient in delaying glioblastoma growth for all tested regimens. Furthermore, only FLASH-RT was found to significantly spare radiation-induced cognitive deficits in learning and memory in tumor-bearing animals after the delivery of large neurotoxic single dose or hypofractionated regimens. Conclusions: The present results show that FLASH-RT delivered with hypofractionated regimens is able to spare the normal brain from radiation-induced toxicities without compromising tumor cure. This exciting capability provides an initial framework for future clinical applications of FLASH-RT. See related commentary by Huang and Mendonca, p. 662