What is the role of oxygen in FLASH radiotherapy using electron beams?

OBJECTIVE: To evaluate the role of oxygen in the FLASH effect during electron beam radiotherapy, aiming to understand mechanisms that enable normal tissue sparing at ultra-high dose rates. METHODS: A systematic literature review was conducted, analyzing 27 studies involving mathematical models and experimental approaches (in silico, in vitro, ex vivo, and in vivo) related to the use of electron beams in FLASH radiotherapy. RESULTS: The studies indicate that optimal normal tissue sparing occurs at oxygen concentrations up to 7 % during irradiation at dose rates ≥ 40 Gy/s. The FLASH effect is associated with partial oxygen depletion, radical-radical recombination, modulation of apoptosis and post-irradiation repopulation, and varying antioxidant responses between normal and tumor tissues. SIGNIFICANCE AND CONCLUSION: Understanding oxygen's role is crucial for optimizing FLASH protocols, especially in electron beam applications. These findings support the development of radiotherapy strategies that minimize normal tissue toxicity while maintaining tumor control. The FLASH effect is likely governed by a combination of beam physics and biological factors, particularly oxygen availability and oxidative stress balance. This equilibrium influences DNA damage and cellular recovery, making oxygen a key modulator of the FLASH response.