Understanding the FLASH effect to unravel the potential of ultra-high dose rate irradiation

Abstract

A reemergence of research implementing radiation delivery at ultra-high dose rates (UHDRs) has triggered intense interest in the radiation sciences and has opened a new field of investigation in radiobiology. Much of the promise of UHDR irradiation involves the FLASH effect, an in vivo biological response observed to maintain anti-tumor efficacy without the normal tissue complications associated with standard dose rates. The FLASH effect has been validated primarily, using intermediate energy electron beams able to deliver high doses (>7 Gy) in a very short period of time (<200 ms), but has also been found with photon and proton beams. The clinical implications of this new area of research are highly significant, as FLASH radiotherapy (FLASH-RT) has the potential to enhance the therapeutic index, opening new possibilities for eradicating radio-resistant tumors without toxicity. As pioneers in this field, our group has developed a multidisciplinary research team focused on investigating the mechanisms and clinical translation of the FLASH effect. Here, we review the field of UHDR, from the physico-chemical to the biological mechanisms.

Graphical Abstract

Keywords:

• Ultra-high dose rate
• FLASH-RT
• ROS
• plasmid
• pre-clinical models

Acknowledgements

The authors thank Charles Limoli for discussions in the preparation of this MS as well as help with English edition. We would like to thank Jonathan Ollivier for the help doing zebrafish experiments as well as Benoit Petit for the animal handling. We would like to thank the team of Institute of Radiation Physics (IRA, CHUV) especially François Bochud, Claude Bailat, Pascal Froidevaux, Jerome Damet, Raphael Moeckli, Veljko Grilj, Patrik Jorge Gonçalves and Jean-François Germond for the development of the physics part of the FLASH-RT program at CHUV as well as Jean Bourhis for his support. We would like to thank the Epalinges Animal Facility for the animal care-taking as well as Francesca Amati at the zebrafish facility. Figures were created with BioRender.com.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The FLASH studies are supported by a grant from the Fond National Suisse Synergia Grant [FNS CRS II5_186369], ISREC Foundation thanks to Biltema Donation and NIH Program Project Grant PO1CA244091. HK salary is supported by FNS Synergia Grant [FNS CRS II5_186369], AA by NIH Program Project Grant PO1CA244091. This work is also supported by the Fondation ISREC and Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung.

Notes on contributors

Houda Kacem

Houda Kacem, PhD Student Research interest I am investigating the oxygen contribution and production of reactive oxygen species after FLASH irradiation in cell free systems and biological systems such as normal/tumor cells and zebrafish model. Background I'm a chemist by training. I have graduated from the international Erasmus Master's program SERP+, at the University of Paris-Saclay (France) and the University of Porto (Portugal).

Aymeric Almeida

Aymeric Almeida, PhD Student Research interest I'm investigating the anti tumor immune response and downstream immune cascade, activated or not, in lung tumor, glioblastoma and normal tissue after irradiation at ultra high dose rate (FLASH). Background I studied at l'Université Claude Bernard Lyon where I obtained my bachelor in physiology and subsequently did a Masters in Immunology & Cancer at the University of Lausanne.

Nicolas Cherbuin

Nicolas Cherbuin, Technician RTT Research interest I have an interest in research for the benefit of radiation protection of patients, workers and the public, and therefore involved in projects ranging from radiobiology to occupational dosimetry monitoring. Background with a Bachelor's in Medical Radiology Technics study (HES-SO, HESAV) gained in 2008, I worked in the Service of nuclear medicine of the Lausanne University Hospital, particularly working on radiation therapies. In 2014, I moved to the hospital's Institute of radiation physics, as a scientific collaborator and radiation protection expert. I completed the joint HES-SO/UNIL Master's in Health Sciences in 2021, in the course of which I had the chance to begin an ongoing collaboration with the Vozenin Lab.

Marie-Catherine Vozenin

Marie-Catherine Vozenin, PhD Associate professor in the service of Radio-oncology, CHUV/UNIL Head of the radio-Oncology Laboratory, CHUV Adjunct Professor, University of California Irvine Research interest: The research project that I develop with my team aim at finding innovative tools able to protect normal tissue and enhance tumor control. In this context, we have developed a novel of modality of radiation therapy called FLASH radiotherapy that minimizes normal tissue toxicity and eradicates tumors in various organs including the brain, lung and skin, and in various species including mice, zebrafish, pigs and cats. Much of our recent work has focused on investigating the entirely different biological response induced after FLASH exposure. Importantly, we have worked to secure the translation of FLASH-RT into clinical trials for human patient with cancer.