Oxygen dynamics in FLASH radiotherapy

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Project Abstract Oxygen sensing with high precision & high spatial localization can provide new insights into the action and effects of ultra-high dose rate (UHDR) radiation therapy (RT), known as FLASH-RT. When compared to RT delivered at conventional dose rates (C-RT), FLASH-RT has been shown to inflict lower radiobiological damage to normal tissues while still preserving the same tumor killing efficacy. This enhanced selectivity has become known as the ‘FLASH’ effect. Oxygen (O2) has been suggested to underpin the FLASH effect, with several theories centered on increased consumption of oxygen upon application of UHDR radiation. However, our in vitro and in vivo oxygen measurements using the phosphorescence quenching method were the first to show that compared to C-RT, FLASH-RT leads not to higher, but actually lower O2 consumption per unit radiation dose. Additionally, we have been the first to establish that the oxygen consumption rate during FLASH-RT is dependent upon the baseline oxygen level within tissue, indicating that the oxygen fixation effect may be oxygen dependent. Based on these results, we hypothesize that the FLASH effect originates not from fast depletion of oxygen and radiobiological hypoxia, but rather from a dose rate dependent oxygen enhancement ratio (OER) from differences in oxygen consumption and damage fixation between FLASH-RT vs C-RT. This original hypothesis can be tested only with accurate measurement of the acute change in oxygen partial pressure (pO2), as an indirect biomarker of the oxygen fixation happening. If this is via variation in peroxyl formation, measurement of pO2 is an ideal surrogate of changes in DNA damage from variations in dose rate delivery parameters. In this project we will develop a unique high-resolution O2 imaging method to track and optimize the FLASH efficacy by combining phosphorescence quenching oximetry in vivo with Cherenkov Excited Luminescence Imaging (CELI) to dynamically quantify oxygen in tissues with spatial resolution of ~1 mm. In CELI, X-ray beams of RT generate localized optical field, which excites phosphorescence deep within tissues, and the phosphorescence, imaged with external detectors, reflects tissue oxygenation. This work will pioneer a new approach to oxygen measurements in RT and will provide mechanistic insight into FLASH radiochemistry with the important potential to optimize the radiobiological efficacy of FLASH-RT. The teams and resources at Wisconsin, Dartmouth and UPenn are unparalleled in their experimental potential for this project, and the work will provide fundamentally new capabilities in guidance of RT, with guidance by key consultants. The components of our work have been based upon high impact publication of original in vivo data with both electrons and protons. The fundamental insights that can be gained here are very timely, as the search for the origins of the FLASH effect in normal tissue is happening now. As we find ways to understand the mechanisms, that can help us optimize its effect, and test the dose rate beam delivery and oxygenation conditions for tissues that lead to its optimization.