The current status of preclinical proton FLASH radiation and future directions

Abstract

We review the current status of proton FLASH experimental systems, including preclinical physical and biological results. Technological limitations on preclinical investigation of FLASH biological mechanisms and determination of clinically relevant parameters are discussed. A review of the biological data reveals no reproduced proton FLASH effect in vitro and a significant in vivo FLASH sparing effect of normal tissue toxicity observed with multiple proton FLASH irradiation systems. Importantly, multiple studies suggest little or no difference in tumor growth delay for proton FLASH when compared to conventional dose rate proton radiation. A discussion follows on future areas of development with a focus on the determination of the optimal parameters for maximizing the therapeutic ratio between tumor and normal tissue response and ultimately clinical translation of proton FLASH radiation.

Future Developments in Charged Particle Therapy: Improving Beam Delivery for Efficiency and Efficacy

“…Furthermore, as ensuring precise beam delivery and positioning is difficult, transmission or ‘ shoot-through ’ FLASH ( 186 ) with protons is performed where exploitation of the BP may be considered redundant to maintain a high, effective mean dose rate whilst also resulting in the FLASH effect ( 184 ). Several transmission studies have been reported ( 177 , 178 , 187 ) as this method is achievable with current technologies. This bypasses the need for additional beam modification devices, minimizing range uncertainties and delivery requirements.…”

Comparing radiolytic production of H2O2 and development of Zebrafish embryos after ultra high dose rate exposure with electron and transmission proton beams

“…The FLASH effect has been primarily studied in vivo models with electron beams of intermediate energy [2] and reproduced with other beams including proton beams at 60-160 Gy/s [3][4][5][6][7]. Electron beams are pulsed whereas proton beams are quasicontinuous; this inherent difference in temporal beam structure dictates major differences in instantaneous dose rates that might impact early physico-chemical and biological outcomes.…”

A roadmap to clinical trials for FLASH

“…Other papers in this issue highlight the variety of radiotherapy types used to deliver UHDR to date: electrons, photons, protons, and light ions. [47][48][49] Multimodality clinical trials will require careful consideration of machine capabilities, differences in dose prescriptions, radiobiology, etc. Early clinical trials would optimally be powered to see if different FLASH modalities caused different outcomes using patients as their own controls if possible.…”

“…Other papers in this issue highlight the variety of radiotherapy types used to deliver UHDR to date: electrons, photons, protons, and light ions 47‐49 . Multi‐modality clinical trials will require careful consideration of machine capabilities, differences in dose prescriptions, radiobiology, etc.…”