An in-silico study of conventional and FLASH radiotherapy iso-effectiveness: Radiolytic oxygen depletion and its potential impact on tumor control probability

Abstract: FLASH radiotherapy (FLASH-RT) has shown the potential to spare normal tissue while seemingly maintaining the effectiveness of conventional radiotherapy (CONV-RT). It has been suggested that the protective effect arises from the radiolytic oxygen depletion (ROD) caused by FLASH-RT, but it is not entirely clear why this protective effect is not observed in tumors. Iso-effectiveness has been experimentally observed in time-volume curves of preclinical tumors irradiated with FLASH and conventional radiotherapy, but it may not translate to clinical trials, where tumor control probability (TCP) is typically the investigated endpoint. In this work, we used mathematical models to investigate the iso-effectiveness of FLASH-RT/CONV-RT on tumors, focusing on the role of ROD. We used a spatiotemporal reaction-diffusion model, including ROD, to simulate tumor oxygenation. From those oxygen distributions we obtained surviving fractions (SFs), using the linear-quadratic model with oxygen enhancement ratios (OER). We then used the calculated SFs to describe the evolution of preclinical tumor volumes through a mathematical model of tumor response. We also calculated TCPs using the Poisson-LQ approach. Our study suggests that ROD causes differences in SF between FLASH-RT and CONV-RT, especially in low $\alpha$/$\beta$ and poorly oxygenated cells. These changes do not lead to significant differences in the evolution of preclinical tumors. However, when extrapolating this effect to TCP curves, we observed important differences between both techniques (TCP is lower in FLASH-RT). Nonetheless, it cannot be discarded that other effects not modeled in this work could contribute to tumor control and maintain the iso-effectiveness of FLASH-RT.