A Target-Level Oxygen Fixation Extension of the LPL Model Explains Oxygen-Mediated Flash Trends
Abstract
Purpose
To develop a mechanistic extension of the classical Lethal and Potentially Lethal (LPL) model that explains oxygen-mediated ultra-high dose rate (FLASH) sparing without prescribing dose-rate–dependent radiosensitivity.
Methods
We introduce an explicit precursor lesion population whose fate is governed by competing oxygen-dependent fixation versus restitution/repair. Fixation kinetics are coupled to a time-varying DNA target-level oxygen tension, pO2(t), which decreases via radiolytic depletion during irradiation and recovers by diffusion toward a baseline pO2,0. Oxygen enhancement is modeled with an exponential dependence on a fixation-rate parameter, ω, so that oxygen modulates lesion fixation kinetics rather than radiosensitivity parameters. Model parameters are constrained so that, in the low dose-rate limit, the formulation reduces to the conventional LPL model and recovers standard survival behavior.
Results
For baseline pO2,0 in the physiologic hypoxia range, FLASH depletion drives pO2(t) across the steep portion of the oxygen enhancement response, suppressing fixation and increasing survival. At 10 Gy, the sparing metric Λ = ln (SFFLASH/SFCONV) reaches approximately 0.33 for the reference parameter set. In contrast, sparing is negligible for baseline conditions that are near-anoxic (pO2,0 ≈ 0.2 mmHg) or well oxygenated (pO2,0 ≥ 30 mmHg). Predicted sparing decreases as delivery duration approaches the oxygen recovery timescale, linking pulse structure to the magnitude of sparing.
Conclusion
An LPL-consistent, target-level oxygen fixation framework predicts maximal FLASH sparing within a physiologic hypoxia window consistent with stem-cell niches and provides quantitative constraints for clinically relevant FLASH delivery parameters.