FLASH: New intersection of physics, chemistry, biology, and cancer medicine

Ultrahigh dose rate, FLASH radiotherapy has emerged as one of the most promising innovations over the past decade in the field of radiation oncology, with the potential to eradicate radiation resistant primary tumors and improve the therapeutic outcome for cancer patients. FLASH is based on delivering radiation doses at ultrahigh dose rates (UHDR; $>40\mathrm{Gy}/\mathrm{s}$), more than 1000 times faster than irradiation at conventional dose rates (CONV). The experimental evidence demonstrating the differential effect of dose rate modulation on tumors and normal tissue is reviewed. Preclinical data consistently show that the antitumor efficacy of cytotoxic doses is not dependent on dose rate, but in normal tissues UHDR significantly reduces normal tissue toxicities compared to CONV, as observed in vivo. These observations define the FLASH effect. The FLASH effect has been reported to occur when using single or hypofractionated dose regimens in several experimental animal models (mice, rat, zebrafish, pig, and cats) and in multiple organs (lung, skin, gut, and brain) by numerous groups worldwide. Note that the FLASH effect has been demonstrated with electron, photon, and hadron (proton and heavier ion) beams. The current status and future technological development are reviewed, with an emphasis on critical beam parameters, future beam modalities, and prerequisites for safe clinical translation in terms of dosimetry, radioprotection, and treatment planning systems. Mechanistic investigations at the physicochemical and biological levels are presented, as are strategies to support and initiate clinical translation. This comprehensive review provides multidisciplinary radiation scientists with a road map of the technological, physical, chemical, biological, and clinical considerations that have made FLASH topical. These considerations are presented with a realistic and practical backdrop of the limitations and challenges that lie ahead.