Using experimentally-guided multi-scale modeling to determining the mechanism of FLASH tissue sparing

点击翻译按钮获取中文摘要

Abstract FLASH irradiations, irradiations with dose rates >40 Gy/s, have been shown to greatly reduce radiation damage for normal tissue while not affecting tumor control. This sparing effect was demonstrated in multiple animal models, mostly using electron FLASH irradiations. The pre- clinical data generated a strong push to translate FLASH radiation therapy (RT) into the clinic. Only a few human patients have so far been treated with FLASH-RT. The first patient, a single cutaneous lymphoma lesion was treated with electron FLASH-RT. Recently, Varian an- nounced the first clinical trial of proton FLASH-RT (phase 1) and treated the first patients with symptomatic bone metastases. Yet many questions remain unanswered. Most significantly, the underlying mechanism of FLASH induced sparing of healthy tissue still remain elusive. As corollary, the constraints im- posed on the clinical parameters (e.g. dose, dose rate and time within and between treatment fields) to induce the FLASH tissue sparing effect are still not determined. While there are many experimental efforts currently being pursued, my team has worked on understanding FLASH both from an experimental as well as theoretical point of view. Our ex- perimental preliminary data show proton FLASH tissue sparing in intestine, brain and skin. Our theoretical preliminary data include modeling oxygen depletion and simulations of radi- ochemistry using TOPAS-nBio, a mechanistic Monte Carlo framework developed by our group. Our central hypothesis is that the FLASH effect is caused by a combination of (stem) cells in a low-oxygen niche and long-lived (µs to ms) daughter products of chemical reactions involving oxygen. We propose an interplay between experiments and modeling to determine the under- lying mechanism of FLASH-RT tissue sparing by employing TOPAS-nBio to investigate the involved chemical reactions based on their intrinsic time features. We propose to test the hypothesis and validate the model with the following aims: SA 1: Investigate the mechanisms of proton FLASH-RT 1. Conduct multi-scale experiments to guide the modeling efforts. 2. Model the mechanism and chemical processes at relevant time scales in TOPAS-nBio. SA 2: Validate the model and determine clinical parameters for FLASH tissue sparing.