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 to 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 swift carbon ions, under FLASH 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.

Generation of ultrafast, transient, highly acidic pH spikes in the radiolysis of water at very high dose rates: relevance for FLASH radiotherapy

“…We used a modified version of our Monte Carlo track-chemistry computer code IONLYS-IRT 15 to simulate the radiolysis of deaerated or aerated water at ambient temperature by 300-MeV irradiating protons under conditions of high dose rates. This code has been described in detail elsewhere, 42,43,53 and only its most essential features are given below.…”

“…24 Under these conditions, the increase in the density of primary events favors the occurrence of inter-track radical-radical D r a f t combination/recombination reactions in the solution, thus leading to lower radical and higher molecular yields. 24,42,43,53 As noted above, the influence of dissolved molecular oxygen on the time profiles of G(H 3 O + ) and G(OH  ) begins to set in at ~0.1-1 s regardless of N. This is easily explained, because in the radiolysis of aerated water, O 2 scavenges the primary radicals e  aq and H • atoms on the microsecond time scale, 66 and converts them to superoxide anion (O 2 • ) and hydroperoxyl (HO 2 • ) radicals, according to 2,3,19 (4…”

The current status of FLASH particle therapy: a systematic review

“…The representation of experimental carbon-FLASH literature, in a radiobiological context, is sparse, with only six papers fitting the systematic criteria of this review. Two of these papers, authored by Zakaria et al [ 12 , 86 ], outline the potential anti-tumour benefits of carbon FLASH in silico . Monte Carlo simulations produced 3-dimensional track segments of low and high LET carbon ions to draw comparisons between their energy deposition profiles.…”

“…Additional simulation work explores the interaction of multiple interacting carbon ion tracks, instantaneous irradiations, and the effect these have upon radiolytic oxygen consumption and peroxide ion formation. At the highest dose rate utilised of approximately 10 10 Gy/s, 300 MeV/nucleon (~ 11.6 keV/µm) carbon ions consumed 90% of oxygen present in solution, suggesting that carbon ions at FLASH dose rates are capable of inducing transient intracellular hypoxia [ 86 ]. Intriguingly, they also show that peroxide ion formation increases with increasing dose rate, and draw comparison to previous work conducted by Montay-Gruel et al [ 36 ] where lower concentrations of H 2 O 2 were produced at ~ 1000 Gy/s compared to ~ 0.1 Gy/s.…”