Research progresses on FLASH radiotherapy and its application for the treatment of digestive system tumors

Abstract Over the past decades, advances in technique have turned radiotherapy into a precise and effective modality for cancer treatment. Nevertheless, the biological effect on organs surrounding the tumor target area is a main dose-limiting element in radiotherapy, e.g., doses are restricted by lethal intestinal tissue toxicity for many pelvic or abdominal cancer radiotherapy. Consequently, minimizing the damage to normal tissues has become a focal point in radiotherapy research. Recently, ionizing radiation delivered at ultra-high dose rates (also termed FLASH-RT) has emerged in the field. Preclinical studies in a variety of animal models have shown that FLASH-RT can control tumors while minimizing normal tissue toxicity compared to conventional radiotherapy (CONV-RT), which broadens the therapeutic window of radiotherapy. In this review, we summarize the present speculations on the biological mechanisms underlying the FLASH effects, including oxygen depletion hypothesis, mitochondria hypothesis, genome stability hypothesis, immunomodulation hypothesis, and so on. Furthermore, we summarize the main data supporting the clinical translation of FLASH-RT, and discuss its relevance and applicability in the treatment of digestive system tumors.