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Modeling the impact of tissue oxygen profiles and oxygen depletion parameter uncertainties on biological response and therapeutic benefit of FLASH

Hongyu ZhuJan SchuemannQixian ZhangLeo E Gerweck
Jan 2022
FLASH radiation has been reported to efficiently suppress tumor growth whilesparing normal tissue, however, the mechanism of the differential tissuesparing effect is still not known. Oxygen has long been known to profoundlyimpact radiobiological responses, and radiolytic oxygen depletion has beenconsidered to be a possible cause or contributor to the FLASH phenomenon. Thiswork investigates the impact of tissue pO2 profiles, oxygen depletion per unitdose (g), and the oxygen concentration yielding half-maximal radiosensitization(k) in tumor and normal tissue. We developed a model that considers thedependent relationship between oxygen depletion and change of radiosensitivityduring FLASH irradiation. Cell survival was calculated based on the LQ-L modeland the radiosensitivity related parameters were adjusted while deliveringfractional doses of FLASH irradiation The model reproduced publishedexperimental data and was used to analyze the impact of parameter uncertaintieson the radiobiological responses. This study expands the oxygen depletionanalysis of FLASH to normal human tissue and tumor based on clinicallydetermined aggregate and individual patient pO2 profiles. The results show thatthe pO2 profile is the most essential factor that affects biological responseand analyses based on the median pO2 rather than the full pO2 profile can beunreliable and misleading. Additionally, the presence of a small fraction ofcells on the threshold of radiobiologic hypoxia substantially alters biologicalresponse to FLASH irradiation. We found that an increment in the k value isgenerally more protective of tumor than normal tissue due to a higher frequencyof lower pO2 values in tumors. Variation in the g value affects the dose atwhich oxygen depletion impacts response, but does not alter the dose dependentresponse trends, if the g value is identical in both tumor and normal tissue.