Objectives:

FLASH radiotherapy is gaining traction at the pre-clinical and clinical levels, and increasing data generated using diverse model systems continues to substantiate the capability of this innovative irradiation modality to spare normal tissue injury while maintaining anti-tumor efficacy. While the diversity of tumors found to respond equally to dose rate modulation and the breadth of normal tissue sparing observed across multiple organ sites attests to the potential clinical utility of FLASH-RT, it has also confounded efforts to identify a common mechanism/s of action.

Results:

To date, traditional tenets of radiobiology have fallen short of providing unifying explanations able to account for the tumoricidal and normal tissue outcomes that define the FLASH effect. The extent that radiation chemistry, DNA damage and repair, oxygen depletion, blood volume and/or immune contributions are differentially affected by dose rate modulation will be discussed.

Conclusion(s):

Alternative concepts involving non-DNA targets, structural predeterminants and metabolic alterations will be proffered along with some provocative new insights based on unpublished data in efforts to stimulate discussion and move the field of FLASH radiotherapy safely forward toward clinical translation with deeper mechanistic insight.