A physicochemical model of reaction kinetics supports peroxyl radical recombination as the main determinant of the FLASH effect.

Abstract

FLASH radiotherapy, a technique based on delivering large doses in a single fraction at the micro/millisecond timescale, spares normal tissues from late radiation-induced toxicity, in an oxygen-dependent process, whilst keeping full anti-tumor efficiency. We present a theoretical model taking into account the kinetics of formation and decay of reactive oxygen species, in particular of organic peroxyl radicals ROO^. formed by addition of O₂ to primary carbon-centred radicals R^. and known to play a major role at the origin radio-induced complications. The model focuses on the time-dependent evolution of radiolytic products in living matter exposed to continuous irradiation at dose-rates in the range 10^-3-10⁷Gy·s^-1. The 9 differential rate equations resulting from the radiolytic and enzymatic reactions network were solved using the published values of these reactions rate constants in a cellular environment. The model suggests a correlation between the area-under-the-curve of time-evolving [ROO^.] and the probability of normal tissue complications. The model does not lend weight to the hypothesis of transient oxygen depletion as a main determinant of FLASH but rather suggests a major role of radical-radical recombination. The model gives support to the reduction of ROO^. lifetime as the main root of FLASH and compares favorably with published experimental results. We conclude that any process - in this case radical recombination - that shortens the lifetime or limits the radiolytic yield of ROO^. is likely to protect normoxic tissues against the deleterious effects of radiation.