FLASH radiotherapy for electrons and protons: roadmap towards the clinical introduction

Radiation therapy (RT) is a crucial component of cancer management, with most patients receiving RT at some point, often in combination with surgery or systemic treatments. Cell sparing at ultrahigh dose rates was found in in vitro cell survival fraction experiments dating back to the 1960s. In the 1970s, studies revealed an unexpected dose-rate effect on radiation-induced mortality in mice and a dose-rate-dependent response in rat skin. This effect was assumed to be affecting healthy and tumour tissue equally and was not pursued further. Decades later, this modality of RT was rediscovered using ultra-high dose-rate irradiation (average dose rate >40 Gy/s) and it was demonstrated that this improves the therapeutic ratio, sparing healthy tissue while being isoeffective for tumours. This effect is referred to as the FLASH effect. Currently, the first human trials using electron and proton beams are ongoing, although significant challenges remain in fully understanding the radiobiological and chemical mechanisms behind this phenomenon. This roadmap provides an overview of the current and future challenges of FLASH radiation therapy and outlines research directions to optimally advance the field and design future clinical trials: radiobiology of the FLASH effect, opportunities and beam parameters for the future in FLASH with electrons, intraoperative FLASH radiotherapy with electrons, ultra-high dose-rate dosimetry, opportunities for the future in FLASH with protons, FLASH treatment planning and machine QA with protons, clinical translation of FLASH with electrons and first experiences and challenges of initial proton FLASH trials.