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.

The Therapeutic Potential of FLASH-RT for Pancreatic Cancer

“…First, most solid tumors are known to not be uniformly hypoxic, having both hypoxic and non-hypoxic compartments throughout the tumor [ 22 ]. Under the transient hypoxia hypothesis, this heterogeneity should then introduce a sparing effect also on tumors, which is not supported by the literature [ 9 ]. Second, in vitro studies of normal, non-immortalized cells have shown a sparing effect when irradiated in ambient air conditions (pO2 ≈ 159 mmHg) [ 23 , 24 , 25 , 26 ].…”

“…Regarding the former, FLASH-RT is a catchy nickname for the novel radiation treatment that uses ultra-high dose rates to deliver radiation therapy (RT). In conventional radiation therapy (CONV-RT) used in most of the world, the dose rate is generally <0.1 Gy/s, whereas the FLASH-RT dose rate is generally defined as a mean dose rate of ≥40 Gy/s [ 8 , 9 ]. A more precise definition is still being debated and will be important to define in order to ensure scientific rigor and to safeguard the clinical translation of FLASH-RT.…”

“…A more precise definition is still being debated and will be important to define in order to ensure scientific rigor and to safeguard the clinical translation of FLASH-RT. Moreover, a more mature definition of FLASH-RT should, at a minimum, include other interdependent parameters, such as dose, dose per pulse, instantaneous dose rate, and total duration of exposure [ 9 , 10 ].…”

Modeling interspur interactions as a potential mechanism of the FLASH effect

“…This biological effect, known as the FLASH effect, presents significant benefits to clinical radiotherapy applications. However, clinical application of the FLASH effect is currently hindered by an incomplete understanding of both the precise irradiation parameters necessary to elicit a reproducible FLASH effect as well as the underlying mechanisms [2,7,8].…”

Intra-Operative Electron Radiation Therapy: An Update of the Evidence Collected in 40 Years to Search for Models for Electron-FLASH Studies

“…Confirmed by different groups and on many preclinical models [ 3 , 4 ], the FLASH effect is defined as the combination of a relative absence of normal tissue toxicities compared to isodose of conventional dose rate RT combined with maintained anti-tumor efficacy. It has been observed after exposure of biological tissues to high doses in extremely short treatment times and with specific beam parameters including mean and instantaneous dose rates [ 5 ] mainly, using electrons [ 6 ], but also X-rays [ 7 ] and protons [ 8 ]. As transferring X-ray- and proton-FLASH into the clinics encounters numerous and important technological challenges, FLASH-RT using electrons is the logical first choice to being investigated for the transition from preclinical research to the first clinical applications.…”