BEST IN PHYSICS (THERAPY): Simulation of Dose-Rate Dependent Mechanisms of Lymphocyte Damage In Proton Flash Radiotherapy
Abstract
Purpose
Radiation-induced damage to circulating lymphocytes is increasingly recognized as a critical determinant of both normal tissue toxicity and antitumor immune responses. Differences in radiation delivery time between proton conventional and FLASH dose rates may lead to population-level effects in the highly radiosensitive lymphocyte pool, contributing to observed normal tissue sparing effects of FLASH radiotherapy. We incorporated FLASH and conventional experimental conditions into a murine lymphocyte circulation modeling framework to test this hypothesis and validated the model predictions using longitudinal peripheral blood lymphocyte data.
Methods
Fifteen mice received 13.5Gy x 3 fractions for proton conventional, FLASH, and control (no irradiation) experiments to the whole heart (using a 1cm circular collimator) guided with micro–Cone Beam CT. Complete Blood Counts (CBC) were taken two and three weeks post last fraction. A stochastic model of lymphocyte migration through the heart, lymphatics, and Secondary Lymphoid Organs (SLOs) was developed using Beekman et al.’s model. Lymphocyte migration and dose accumulation were tracked using the stochastic Gillespie algorithm, and linear-quadratic survival was compared to measured lymphocyte outcomes.
Results
Our model shows FLASH significantly reduces the number of irradiated lymphocytes (1.31% vs 75.5%) but delivers a higher mean dose (6.84±3.93Gy vs. 0.505±0.252Gy) amongst irradiated lymphocytes. Following a nadir at 2 weeks, FLASH lymphocyte counts appeared to recover more quickly than CONV (4.1±1.2 vs. 5.5±1.3 103/μl). Although follow-up experiments are planned for increased statistical power, the data is consistent with our simulated lymphocyte concentration.
Conclusion
This study explores possible mechanisms for proton FLASH radiotherapy lymphocyte sparing, incorporating the heart and SLOs to create a comprehensive tool for lymphocyte dosimetry. Our simulations that incorporate dose delivery timing to circulating lymphocytes revealed dose rate effects on the survival of lymphocyte populations during cardiac proton irradiation. These dynamics have the potential to be harnessed to better protect patients’ immune health.