Deciphering Time-Dependent DNA Damage Complexity, Repair, and Oxygen Tension: A Mechanistic Model for FLASH-Dose-Rate Radiation Therapy

Abstract

Irradiation with ultra-high dose-rates (FLASH) has reemerged as a promising radiotherapy approach to effectively lower potential damage burden on normal tissue without sacrificing tumor control; however, the large number of recent FLASH studies are conducted under vastly different experimental conditions and circumstances i.e. investigated biological endpoint, radiation quality and environmental oxygen level, with unverified biological mechanisms of action and unexplored interplay effect of the main dependencies. To facilitate radiobiological investigation of FLASH phenomena and assessment of clinical applicability, we present an extension of the mechanistic radiobiological model "XXX" († MODELX). The dynamic (time-dependent) extension of MODELX is developed here incorporating fundamental temporal mechanisms necessary for dose-rate effect prediction, i.e. DNA damage repair kinetics (DDRK), oxygen depletion and re-oxygenation during irradiation. Model performance in various experimental conditions is validated based on a large panel of in-vitro and in-vivo data from the literature. Impact of dose, dose-rate, oxygen tension, tissue-type, beam quality and DDRK is analyzed. MODELX adequately reproduces dose-, dose-rate and oxygen tension-dependent influence on cell killing. For the studied systems, results indicate that the extent of cell/tissue sparing effect, if present at all, strongly depends on DDRK and beam quality used for reference conventional irradiation. A validated mechanistic framework for predicting clinically relevant end-points comparing conventional and FLASH high-dose-rate effect has been successfully established, relying on time-dependent processing of radiation-induced damage classes taking into account variable oxygen tension. Highlighted by MODELX itself, the multi-dimensional nature of this relative sparing effect using high dose-rate radiation compared to conventional means underlines the importance of robust quantification of biophysical characteristics and consistent/well-documented experimental conditions both in-vitro and in-vivo prior to clinical translation. To further elucidate underlying mechanisms and appraise clinical viability, MODELX can provide reliable prediction for biophysical investigations of radiotherapy using ultra-high dose-rate.