FLASH Radiotherapy is faster than a heartbeat: A compartmental model to illustrate the interplay between tissue oxygen perfusion and ultra-high dose rate effects

Abstract Ultra-high-dose-rate therapy enhances the protection of normal tissues and reduces side effects while effectively controlling tumors. This biological phenomenon is called the FLASH effect, and when observed, therapy is called FLASH Radiotherapy (FLASH-RT). Various hypotheses have been proposed to explain how ultra-high dose rates achieve these effects under different conditions, with the impact of tissue oxygen perfusion still needing further investigation. FLASH-RT involves brief exposure to radiation, which results in fewer heartbeats occurring during the irradiation period, which could lead to reduced tissue oxygen perfusion occurring during the treatment timeframe. Therefore, we developed a compartmental model to simulate oxygen transfer and its interaction with radiation. The proposed model consists of three compartments: 1) the heart and arteries; 2) the irradiated brain’s blood vessels and capillaries; and 3) the irradiated brain tissue. We employed a system of differential equations, incorporating experimental data from in vivo oxygen measurements using the Oxyphor probe in the brain, to fit the model parameters to the experimental results. This model shows how dose rate and oxygen perfusion could influence chemical processes such as lipid peroxidation, potentially leading to differential biological effects. Our analysis of lipid peroxidation as a function of dose rate revealed a sigmoidal dose-rate-response curve that correlates well with several published biological response datasets. Our results indicate that the differential chemical effects of FLASH-RT compared with conventional dose rates may depend on factors such as oxygen perfusion, consumption, and tissue oxygen tension. This suggests that the temporal dynamics of oxygen could play a crucial role in enhancing the therapeutic window for FLASH-RT treatments. Furthermore, it suggests that the magnitude of some observed FLASH effects may vary across tissues or tumors and across experimental models, given differential oxygen dynamics.