Clinical translation of FLASH radiotherapy: Why and how?

•FLASH-RT a paradigm-shifting method of delivering doses within an extremely short irradiation time.•FLASH-RT is a promising new tool to enhance the differential effect between tumors and normal tissues.•The consistency of the preclinical data clinical justifies transfer of FLASH-RT.•The most relevant parameters for FLASH are the combination of dose, dose-rate within the pulse, and overall time of irradiation.•A first proof of concept could be done with low-energy electrons and further tested with VHEE, protons and X-rays. Over the past decades, technological advances have transformed radiation therapy (RT) into a precise and powerful treatment for cancer patients. Nevertheless, the treatment of radiation-resistant tumors is still restricted by the dose-limiting normal tissue complications. In this context, FLASH-RT is emerging in the field. Consisting of delivering doses within an extremely short irradiation time, FLASH-RT has been identified as a promising new tool to enhance the differential effect between tumors and normal tissues. Indeed, preclinical studies on various animal models and a veterinarian clinical trial have recently shown that compared to conventional dose-rate RT, FLASH-RT could control tumors while minimizing normal tissue toxicity. In the present review, we summarize the main data supporting the clinical translation of FLASH-RT and explore its feasibility, the key irradiation parameters and the potential technologies needed for a successful clinical translation.