The goal of radiation therapy is to provide the highest probability of tumor control while minimizing normal tissue toxicity. Recently, it has been discovered that ultra-high dose rates of ionizing radiation may preferentially spare normal tissue over tumor tissue. This effect, referred to as FLASH radiotherapy, has been observed in various animal models as well as, more recently, in a human patient. This effect may be related to the cell sparing found in vitro at ultra-high dose rates of photons and electrons dating back to the 1960s. Conditions representative of physiologic oxygen were found to be essential for this process to occur. However, there is no conclusive data on whether this effect occurs with protons, as all results to date have been in cells irradiated at ambient oxygen conditions. There have been no ultra-high dose-rate experiments with heavy ions, which would be relevant to the implementation of FLASH to carbon-ion therapy. These basic science results are critical in guiding this rapidly advancing field, since clinical particle therapy machines capable of FLASH dose rates have already been promoted for protons. To help ensure FLASH radiotherapy is reliable and maximally effective, the radiobiology must keep ahead of the clinical implementation to help guide it. In this context, in vitro and in vivo proton and heavy ion experiments involving FLASH dose rates need to be performed to evaluate not only short-term consequences, but also sequelae related to long-term health risks. Critical to these future studies is consideration of relevant oxygen tensions at the time of irradiation, as well as appropriate in silico modeling to assist in understanding the initial physicochemical events.

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