An integrated physico-chemical approach for explaining the differential impact of FLASH versus conventional dose rate irradiation on cancer and normal tissue responses

A computational model of radiolytic oxygen depletion during FLASH irradiation and its effect on the oxygen enhancement ratio

“…Several biological explanations have been advanced, including sparing of circulating immune cells due to the rapid treatment time, changes in chromatin remodeling, DNA damage repair kinetics, and inflammatory/anti-inflammatory cell signaling (Durante et al, 2018). Recently, the production of organic hydroperoxides and peroxyl radicals derived through lipid peroxidation chain reactions and higher levels of redox-active iron have been advanced as possible explanations for the differential sparing of normal tissue by FLASH radiation (Spitz et al, 2019).…”

“…Third, we assumed that the rate of ROD in tissue was similar to the rate reported in water and cell culture medium. Recently, it has been hypothesized that the rate of ROD may be 4 times higher in brain tissue than in water due to lipid peroxidation chain reactions and reactions driven by redox-active iron (Spitz et al, 2019). The computation model presented in this article can be used to estimate oxygen depletion in brain tissues based on the higher rate of ROD proposed by Spitz et al As shown in Figure 7, a higher ROD rate of 1.8 mmHg/Gy (equivalent to 2.5 μM/Gy) would be sufficient to protect cells from a single-fraction dose of 10 Gy for oxygen tension up to 20 mmHg.…”

“…Relative decrease in radiosensitivity due to ROD assuming ultra-high-dose-rate radiation (>100 Gy/s) and high ROD rate L = 1.8 mmHg/Gy as proposed by Spitz et al (2019).…”

FLASH radiotherapy: Newsflash or flash in the pan?

“…Given the nascent state of the field, a large portion of experimental observations to date remain preliminary and unpublished, and many questions remain unanswered particularly with respect to mechanism. While there are data suggesting a fundamental physical‐chemical effect, that is, radiochemical depletion of oxygen at FLASH dose rates, modulation of inflammatory cytokines, for example, TGF‐β and others, differential immunologic responses between tumor and normal tissues have also been observed. It remains to be determined if these are downstream effects rather than independent mechanisms.…”

FLASH irradiation enhances the therapeutic index of abdominal radiotherapy for the treatment of ovarian cancer

“…Moreover, the number of stool pellets excreted over 24 hours at day Previous studies have suggested that altered oxygen radiochemistry at extremely high dose rates may underlie the FLASH effect in vitro and in vivo 21,22 . Based on radiochemical modeling studies, a 10 Gy or greater dose of FLASH RT has the potential to deplete molecular oxygen in tissues at physiologic oxygen tensions, as oxygen rapidly reacts with radicals formed by radiolysis of water and other biomolecules (ROS) 23 . Perhaps especially in stem cell niches that may have baseline hypoxia, transient anoxia produced by FLASH but not conventional dose rate irradiation would result in reduced DNA double strand breaks caused by reduced oxygen-mediated fixation of DNA damage 24,25 .…”