Current Views on Mechanisms of the FLASH Effect in Cancer Radiotherapy

TL;DR

This paper reviews current hypotheses and mechanisms behind the FLASH effect in radiotherapy, highlighting potential biological and physicochemical processes responsible for tumor sparing and normal tissue protection.

Contribution

It provides a comprehensive overview of existing theories and evidence on FLASH effect mechanisms, guiding future research directions in FLASH radiotherapy.

Findings

Summarizes main hypotheses including oxygen depletion and free radical reactions.

Connects biological and physicochemical mechanisms in a chronological framework.

Offers practical guidance for future investigations in FLASH-RT.

Abstract

FLASH radiotherapy (FLASH-RT) is a new modality of radiotherapy by delivering doses with ultra-high dose rates. FLASH-RT has the ability to suppress tumor growth while sparing normal tissues, known as the FLASH effect. Although FLASH effect has proved valid in various models by different ionizing radiations, the exact underlying mechanism is still unclear. This article summarizes mainstream hypotheses of FLASH effect at physicochemical and biological levels, including oxygen depletion and free radical reactions, nuclear and mitochondria damage, as well as immune response. These hypotheses contribute reasonable explanations to the FLASH effect, and are interconnected according to the chronological order of the organism's response to ionizing radiation. By collating the existing consensus, evidence, and hypotheses, this article provides a comprehensive overview of potential mechanisms of FLASH effect and practical guidance for future investigation in the field of FLASH-RT.