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      The FLASH effect—an evaluation of preclinical studies of ultra-high dose rate radiotherapy

      systematic-review

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          Abstract

          FLASH radiotherapy (FLASH-RT) is a novel radiotherapy approach based on the use of ultra-high dose radiation to treat malignant cells. Although tumours can be reduced or eradicated using radiotherapy, toxicities induced by radiation can compromise healthy tissues. The FLASH effect is the observation that treatment delivered at an ultra-high dose rate is able to reduce adverse toxicities present at conventional dose rates. While this novel technique may provide a turning point for clinical practice, the exact mechanisms underlying the causes or influences of the FLASH effect are not fully understood. The study presented here uses data collected from 41 experimental investigations (published before March 2024) of the FLASH effect. Searchable databases were constructed to contain the outcomes of the various experiments in addition to values of beam parameters that may have a bearing on the FLASH effect. An in-depth review of the impact of the key beam parameters on the results of the experiments was carried out. Correlations between parameter values and experimental outcomes were studied. Pulse Dose Rate had positive correlations with almost all end points, suggesting viability of FLASH-RT as a new modality of radiotherapy. The collective results of this systematic review study suggest that beam parameter qualities from both FLASH and conventional radiotherapy can be valuable for tissue sparing and effective tumour treatment.

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          Most cited references48

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          Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice.

          In vitro studies suggested that sub-millisecond pulses of radiation elicit less genomic instability than continuous, protracted irradiation at the same total dose. To determine the potential of ultrahigh dose-rate irradiation in radiotherapy, we investigated lung fibrogenesis in C57BL/6J mice exposed either to short pulses (≤ 500 ms) of radiation delivered at ultrahigh dose rate (≥ 40 Gy/s, FLASH) or to conventional dose-rate irradiation (≤ 0.03 Gy/s, CONV) in single doses. The growth of human HBCx-12A and HEp-2 tumor xenografts in nude mice and syngeneic TC-1 Luc(+) orthotopic lung tumors in C57BL/6J mice was monitored under similar radiation conditions. CONV (15 Gy) triggered lung fibrosis associated with activation of the TGF-β (transforming growth factor-β) cascade, whereas no complications developed after doses of FLASH below 20 Gy for more than 36 weeks after irradiation. FLASH irradiation also spared normal smooth muscle and epithelial cells from acute radiation-induced apoptosis, which could be reinduced by administration of systemic TNF-α (tumor necrosis factor-α) before irradiation. In contrast, FLASH was as efficient as CONV in the repression of tumor growth. Together, these results suggest that FLASH radiotherapy might allow complete eradication of lung tumors and reduce the occurrence and severity of early and late complications affecting normal tissue.
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            The Advantage of FLASH Radiotherapy Confirmed in Mini-pig and Cat-cancer Patients

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              Irradiation in a flash: Unique sparing of memory in mice after whole brain irradiation with dose rates above 100Gy/s.

              This study shows for the first time that normal brain tissue toxicities after WBI can be reduced with increased dose rate. Spatial memory is preserved after WBI with mean dose rates above 100Gy/s, whereas 10Gy WBI at a conventional radiotherapy dose rate (0.1Gy/s) totally impairs spatial memory.
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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/2578307Role: Role: Role: Role: Role:
                URI : https://loop.frontiersin.org/people/869406Role: Role: Role: Role:
                URI : https://loop.frontiersin.org/people/815892Role: Role: Role:
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                22 April 2024
                2024
                : 14
                : 1340190
                Affiliations
                [1] 1 Department of Physics, Imperial College London , London, United Kingdom
                [2] 2 Science and Technology Facilities Council (STFC), Rutherford Appleton Laboratory , Oxford, United Kingdom
                [3] 3 Institut Curie, Universite Paris-Saclay, Centre national de la recherche scientifique (CNRS) UMR3347, Inserm U1021, Signalisation radiobiologie et cancer , Orsay, France
                [4] 4 Universite Paris-Saclay, Centre national de la recherche scientifique (CNRS) UMR3347, Inserm U1021, Signalisation radiobiologie et cancer , Orsay, France
                Author notes

                Edited by: Kevin Prise, Queen’s University Belfast, United Kingdom

                Reviewed by: Angelica Facoetti, National Center of Oncological Hadrontherapy, Italy

                Ralph Eric Vatner, University of Cincinnati, United States

                *Correspondence: Josie May McGarrigle, jmm119@ 123456ic.ac.uk ; Kenneth Richard Long, k.long@ 123456imperial.ac.uk ; Yolanda Prezado, yolanda.prezado@ 123456curie.fr
                Article
                10.3389/fonc.2024.1340190
                11071325
                38711846
                73c62546-077c-40a2-a22e-2c0e5987131e
                Copyright © 2024 McGarrigle, Long and Prezado

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 17 November 2023
                : 20 March 2024
                Page count
                Figures: 6, Tables: 9, Equations: 8, References: 49, Pages: 12, Words: 5629
                Funding
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The work described here was carried out within the joint National de la Recherche Scientifique (CNRS)-Imperial College London (ICL) International Research Centre. The research was made possible by grants from CNRS, ICL and the UKRI Science and Technology Facilities Council and received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (Grant Agreement No 817908).
                Categories
                Oncology
                Systematic Review
                Custom metadata
                Radiation Oncology

                Oncology & Radiotherapy
                ultra-high dose rate irradiation,ultra-high dose rate,flash-rt,normal-tissue sparing,flash,radiotherapy,therapeutic index,radiation - adverse effects

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