Radiobiology of the FLASH effect

Radiation exposures at ultrahigh dose rates (UHDRs) at several orders of magnitude greater than in current clinical radiotherapy (RT) have been shown to manifest differential radiobiological responses compared to conventional (CONV) dose rates. This has led to studies investigating the application of UHDR for therapeutic advantage (FLASH-RT) that have gained significant interest since the initial discovery in 2014 that demonstrated reduced lung toxicity with equivalent levels of tumor control compared with conventional dose-rate RT. Many subsequent studies have demonstrated the potential protective role of FLASH-RT in normal tissues, yet the underlying molecular and cellular mechanisms of the FLASH effect remain to be fully elucidated. Here, we summarize the current evidence of the FLASH effect and review FLASH-RT studies performed in preclinical models of normal tissue response. To critically examine the underlying biological mechanisms of responses to UHDR radiation exposures, we evaluate in vitro studies performed with normal and tumor cells. Differential responses to UHDR versus CONV irradiation recurrently involve reduced inflammatory processes and differential expression of pro- and anti-inflammatory genes. In addition, frequently reduced levels of DNA damage or misrepair products are seen after UHDR irradiation. So far, it is not clear what signal elicits these differential responses, but there are indications for involvement of reactive species. Different susceptibility to FLASH effects observed between normal and tumor cells may result from altered metabolic and detoxification pathways and/or repair pathways used by tumor cells. We summarize the current theories that may explain the FLASH effect and highlight important research questions that are key to a better mechanistic understanding and, thus, the future implementation of FLASH-RT in the clinic.