Radiotherapy (RT) has been shown to be a cornerstone of both palliative and curative tumor care. RT has generally been reported to be sharply restricted by ionizing radiation (IR)-induced toxicity, thereby constraining the control effect of RT on tumor growth. FLASH-RT is the delivery of ultra-high dose rate (UHDR) several orders of magnitude higher than what is presently used in conventional RT (CONV-RT). The FLASH-RT clinical trials have been designed to examine the UHDR deliverability, the effectiveness of tumor control, the dose tolerance of normal tissues, and the consistency of treatment effects across several institutions. Although it is still in its infancy, FLASH-RT has been demonstrated to have potential to rival current RT in terms of safety. Multiple studies have indicated that the adoption of FLASH-RT is very limited, and the incorporation of this new method into routine clinical RT will necessitate the use of precise dosimetry techniques and reproducible equipment that enable the reliable and robust measurements of doses and dose rates. The purpose of this work aims to highlight the advantages of this technology, the potential biological mechanisms underpinning the FLASH-RT effect, and the major challenges that need to be tackled in the clinical transfer of FLASH-RT. Accumulating preclinical data have indicated that radiolytic oxygen depletion contributes, at least in part, to the FLASH-RT effect; However, the precise scope of this contribution is still being validated by emerging experimental evidence. It has been reported that FLASH-RT could revolutionize pediatric oncology by minimizing normal tissue complications. Nevertheless, translating preclinical murine electron data into scalable human models demands rigorous future research. Moreover, widespread clinical application is hindered by stringent technological demands, imprecise dose distribution, and shallow depth penetration of electron-based RT. Although proton-based FLASH-RT dose rates have been experimentally evaluated, investigations remain restricted to small target volumes. In conclusion, despite current translational hurdles, decreasing technological costs and growing datasets provide an optimistic outlook for the widespread accessibility of FLASH-RT in both human and veterinary oncology.

This published study was supported by the Russian Science Foundation (project No. 24-45-20002).

Keywords:

Ionizing radiation; conventional radiotherapy; FLASH radiotherapy; ultra-high dose rate.