The minimal FLASH sparing effect needed to compensate the increase of radiobiological damage due to hypofractionation for late‐reacting tissues

Purpose Normal tissue (NT) sparing by ultra‐high dose rate (UHDR) irradiations compared to conventional dose rate (CONV) irradiations while being isotoxic to the tumor has been termed “FLASH effect” and has been observed when large doses per fraction (d ≳ 5 Gy) have been delivered. Since hypofractionated treatment schedules are known to increase toxicities of late‐reacting tissues compared to normofractionated schedules for many clinical scenarios at CONV dose rates, we developed a formalism based on the biologically effective dose (BED) to assess the minimum magnitude of the FLASH effect needed to compensate the loss of late‐reacting NT sparing when reducing the number of fractions compared to a normofractionated CONV treatment schedule while remaining isoeffective to the tumor. Methods By requiring the same BED for the tumor, we derived the “break‐even NT sparing weighting factor” WBE for the linear‐quadratic (LQ) and LQ‐linear (LQ‐L) models for an NT region irradiated at a relative dose r (relative to the prescribed dose per fraction d to the tumor). WBE was evaluated numerically for multiple values of d and r, and for different tumor and NT α/β‐ratios. WBE was compared against currently available experimental data on the magnitude of the NT sparing provided by the FLASH effect for single fraction doses. Results For many clinically relevant scenarios, WBE decreases steeply initially for d > 2 Gy for late‐reacting tissues with (α/β)NT ≈ 3 Gy, implying that a significant NT sparing by the FLASH effect (between 15% and 30%) is required to counteract the increased radiobiological damage experienced by late‐reacting NT for hypofractionated treatments with d 10–15 G