Background and Aims

FLASH radiotherapy [1], has emerged in the latest years as a promising new avenue for therapeutic use of radiation. It has been collected experimental evidence that FLASH irradiations are able to spare normal tissue being equally efficient for tumour control. Besides this evidence, the mechanism at the basis of FLASH effect remain to date largely unknown.

[1]Favaudon,V.ScienceTranslationalMedicine(2014)

Methods

The Generalized Stochastic Microdosimetric Model (GSM2),[2], is a probabilistic model that describes the time-evolution of the DNA damages in a cell nucleus from microdosimetric principles. Among the most relevant strengths there is the capability of efficiently treat the several levels of spatio-temporal stochasticity happening during a protracted irradiation. We derive a multiscale GSM2 coupling the DNA damage evolution with fast reaction kinetics accounting for radical formations, oxygen consumption and re-oxygenation happening during a given dose delivery time structure.The resulting multiscale GSM2 describes the coupled evolution of the multiscale system composed by DNA damage and fast Reactive Oxygen Species (ROS).

[2]Cordoni,F.Phys.Rev.E(2021).

Results

Via simulations of proton energy deposition in a microscopic volume using TOPAS-nBIO, we study the combined effects of ROS and the time evolution of DNA damages, assessing the resulting cell-survival curve at different beam structures and oxygenation conditions. We show how the multiscale GSM2 is able to justify the empirical patterns of Double Stand Breaks (DSB) yields and normal tissue sparring typical of FLASH radiotherapy, [3].

[3]Buonanno,M,et.al.RadiotherapyAndOncology(2019).

Conclusions

We extended GSM2 coupling DNA damage to fast ROS kinetics to reproduce the suppression of DSB yields and normal tissue sparing typical of FLASH radiotherapy.

Background and Aims

Since the oxygen depletion hypothesis has been recently challenged, the setup of a new joint project dedicated to an alternative mechanistic explanation of the FLASH effect, presently submitted to the Italian Association for Cancer Research (AIRC), will be presented. Our approach is a bottom up analysis linking radiation chemical based radicals description and DNA damage modeling studies. This should enable us to predict the irradiation parameters of absolute dose, and dose rate for which the effect could be verified.

Methods

We will develop point-like and two dimensional optical based methods for FLASH real time dosimetry using Cerenkov and radioluminescence light.

In a second phase a multiscale mechanistic description of ultrahigh dose rate induced damage including oxygen interplay and reactive oxygen species production and reactions will be developed. Our approach is based on chemical track structure Monte Carlo simulations and dedicated extensions of analytical biophysical models.

Results

We expect to obtain:

-Real time dosimetric methods to monitor FLASH beams for cells and mice irradiations. The same methods can be also translated to monitor FLASH delivery to human patients.

-A refined mechanistic description of the FLASH effect starting from basic radiation chemistry concepts in a biological environment. We will also provide in vitro and in vivo validation tests using two types of FLASH beams.

Conclusions

This work will contribute to unraveling the basic biological mechanisms of the FLASH effect and, at the same time, it will provide accurate real time dosimetric tools not available at the moment.