Ultra-high dose rate electron beams and the FLASH effect: From preclinical evidence to a new radiotherapy paradigm

Abstract

In their seminal paper from 2014, Fauvadon et al. coined the term FLASH irradiation to describe ultra-high-dose rate irradiation with dose rates greater than 40 Gy/s, which results in delivery times of fractions of a second. The experiments presented in that paper were performed with a high-dose-per-pulse 4.5 MeV electron beam, and the results served as the basis for the modern-day field of FLASH radiation therapy (RT). In this article, we review the studies that have been published after those early experiments, demonstrating the robust effects of FLASH RT on normal tissue sparing in preclinical models. We also outline the various irradiation parameters that have been used. Although the robustness of the biological response has been established, the mechanisms behind the FLASH effect are currently under investigation in a number of laboratories. However, differences in the magnitude of the FLASH effect between experiments in different labs have been reported. Reasons for these differences even within the same animal model are currently unknown, but likely has to do with the marked differences in irradiation parameter settings used. Here, we show that these parameters are often not reported, which complicates large multistudy comparisons. For this reason, we propose a new standard for beam parameter reporting and discuss a systematic path to the clinical translation of FLASH RT.

Keywords: FLASH effect; biological effects; dosimetry; electron FLASH; reporting system.

Figure 1:. Zebrafish embryos irradiated with the eRT6 electron beam FLASH did not show developmental retardation.

At 4 hours after fertilization, zebrafish embryos were irradiated and their development was analyzed 5 days later. Below: Normal development of zebrafish embryos (a) was altered following CONV irradiation (b) but not after FLASH irradiation (c) Right panel: dose response curve after CONV and FLASH-RT. Mean standard deviation and Mann-Whitney’s-test (at 10 Gy P < 0.01; at 11–12 Gy P < 0.001 (n =20 embryos/group).

Figure 2.. Clonogenic assays after irradiation with the eRT6 electron beam

Three tumor cell lines (human GBM U87, human cervix HeLa, murine GBM H454) and one normal cell line (HaCat) were irradiated with FLASH and CONV RT. No differences in clonogenic survival were measured between FLASH and CONV irradiation in cancer cell lines and one normal cell line (HaCat).