Explaining the Normal Tissue Sparing of Flash By Oxygen Fixation Hypothesis 📝

Author: Daisuke Kawahara, Yoichi Watanabe 👨‍🔬

Affiliation: Department of Radiation Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Department of Radiation Oncology, University of Minnesota Medical School 🌍

Abstract:

Purpose: To theoretically demonstrate that FLASH dose delivery leads to higher normal tissue sparing than conventional dose rates.
Methods: A two-component kinetic model was built for target and damaged cells. The target cell killing probability was calculated using the L-Q model. The FLASH dose delivery (flashRT) was assumed to kill target cells instantly. In contrast, the conventional dose rate (convRT) therapy constantly killed the target cells during irradiation. The cell killing rate of convRT was determined so that the number of surviving cells at the end of irradiation was the same as flashRT when there was no cell repair. The target cells could proliferate. Damaged cells were repaired or died at constant rates. The oxygen fixation hypothesis suggests hypoxia makes the damage repair less likely than in a normoxic environment. Thus, the repair rate depended on the amount of oxygen concentration in the tissue. Sets of ordinal differential equations were numerically solved to obtain the numbers of target cells for flashRT (Nf) and convRT (Nc) by varying the dose D and the oxygen concentration [O2]. The ratio of Nf and Nc was calculated at a fixed time after the start of treatment.
Results: Nf was 1.6 % larger than Nc at half a day post-irradiation for typical biological parameters and a 10-minute irradiation. The Nf-to-Nc ratio showed a sigmoidal curve-like increase with increasing dose. The threshold doses, for which the ratio reached half the maximum value, were 10 Gy and 18 Gy for [O2] = 1 % and 2 %, respectively.
Conclusion:: A theoretical study showed that more cells survive with flashRT than convRT after irradiation. Furthermore, hypoxia resulted in a lower threshold dose above which the sparing effects became significant. The model could offer the biological mechanism of published experimental results.

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