A FLASH model of radiolytic oxygen depletion and reactive oxygen species for differential tumor and normal-tissue response

ObjectiveFLASH-RT can potentially improve the sparing of normal tissues while preserving the tumoricidal efficiency, owing to the radiation with ultra-high dose rate. However, the FLASH mechanism remains to be solved. A popular FLASH model is based on radiolytic oxygen depletion (ROD), which explains for radiation protection of normal tissues under FLASH-RT. However, ROD does not explain the preservation of tumoricidal efficiency for tumors. This work will develop a ROS+ROD FLASH model that can explain the differential tumor and normal-tissue response. ApproachThe new FLASH model utilizes reactive oxygen species (ROS) in addition to ROD, and takes into account that ROS level decreases during FLASH-RT. Specifically, the differential-equation model takes into account that the basic ROS level is lower during FLASH-RT and the degeneration rates of ROS are different in tumor cells and healthy cells. Based on this ROS+ROD FLASH model, the surviving fractions of tumor and normal cells are respectively compared between conventional radiotherapy (CONV-RT) and FLASH-RT. Main resultsWhile ROD alone does not distinguish the response of tumors and normal tissues to FLASH-RT, the proposed new FLASH model based on ROD and ROS successfully explained the differential response of tumors and normal tissues to FLASH-RT, i.e., the preserved tumoricidal capability, which cannot be explained by ROD alone, and the extra normal-tissue protection owing to the ultra-high dose rate. SignificanceSince the ROS level decreases slower in tumors than in normal tissues, during FLASH-RT, ROS decreases more in normal tissue, thus can get more protection. By incorporating ROS in addition to ROD, the new FLASH model can not only recover all results by previous FLASH model with ROD alone, but also explain the differential response: preserved lethality of FLASH-RT to tumors and improved protection to normal tissues.