Transient hypoxia in water irradiated by swift carbon ions at ultra-high dose rates: implication for FLASH carbon-ion therapy

Abstract

Large doses of ionizing radiation delivered to tumors at ultra-high dose rates (i.e., in a few milliseconds) paradoxically spare the surrounding healthy tissue while preserving anti-tumor activity (compared with conventional radiotherapy delivered at much lower dose rates). This new modality is known as “FLASH radiotherapy” (FLASH-RT). Although the molecular mechanisms underlying FLASH-RT are not yet fully understood, it has been suggested that radiation delivered at high dose rates spares normal tissue via oxygen depletion followed by subsequent radioresistance of the irradiated tissue. To date, FLASH-RT has been studied using electrons, photons, and protons in various basic biological experiments, pre-clinical studies, and recently in a human patient. However, the efficacy of heavy ions, such as energetic carbon ions, under FLASH-RT conditions remains unclear. Given that living cells and tissues consist mainly of water, we set out to study, from a pure radiation chemistry perspective, the effects of ultra-high dose rates on the transient yields and concentrations of radiolytic species formed in water irradiated by 300-MeV per nucleon carbon ions (LET ∼ 11.6 keV/µm). This mimics irradiation in the “plateau” region of the depth–dose distribution of ions, i.e., in the “normal” tissue region in which the LET is rather low. We used Monte Carlo simulations of multiple, simultaneously interacting radiation tracks together with an “instantaneous pulse” irradiation model. Our calculations show a pronounced oxygen depletion around 0.2 μs, strongly suggesting, as with electrons, photons, and protons, that irradiation with energetic carbon ions at ultra-high dose rates is suitable for FLASH-RT.