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FLASH Radiotherapy: From Benchwork to a New Paradigm-Shifting Radiotherapy
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FLASH Radiotherapy: From Benchwork to a New Paradigm-Shifting Radiotherapy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 November 2023) | Viewed by 10221

Special Issue Editors

Dr. Melpo Christofidou-Solomidou

E-Mail Website
Guest Editor
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Interests: antioxidants; inflammation; lung fibrosis; oxidative stress; radiotherapy; radiation medical countermeasures; radiation toxicity; space radiation; genomics; metabolomics
Special Issues, Collections and Topics in MDPI journals
Dr. Anastasia Velalopoulou

E-Mail Website
Guest Editor
Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Interests: carcinogenesis; FLASH radiotherapy; protons; radiotherapy-induced normal tissue toxicities; radiation-induced immune responses

Special Issue Information

Dear Colleagues,

Among technological advances in the field of radiation oncology, FLASH radiotherapy, with a single, ultra-high dose rate > 40 Gy/sec, intrigued researchers by sparing normal tissues from radiation-induced toxicities while being equipotently efficient in tumor growth delay compared to conventional radiotherapy. FLASH radiotherapy rapidly evolved as a very promising radiotherapeutic candidate for clinical translation thanks to a wealth of studies worldwide, with the first patient being treated in 2018 and the first clinical trial being launched in 2020. Nevertheless, the crucial question regarding its underlying mechanisms responsible for the differential responses between tumors and normal tissues remains unanswered. This Special Issue of IJMS aims to provide a comprehensive overview of the FLASH radiotherapy studies, using all current irradiation systems along with prototypes, and will focus on the mechanistic aspects of the so-called “FLASH effect” and the differential responses between healthy and tumor tissues.

Dr. Melpo Christofidou-Solomidou
Dr. Anastasia Velalopoulou
Guest Editors

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Keywords

  • FLASH radiotherapy
  • FLASH effect
  • radiation
  • irradiation
  • tumor
  • toxicity
  • genomics
  • miRNA transcriptomics
  • metabolomics

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Published Papers (3 papers)

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Research

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15 pages, 1543 KiB  
Article
Comet Assay Profiling of FLASH-Induced Damage: Mechanistic Insights into the Effects of FLASH Irradiation
by Christian R. Cooper, Donald J. L. Jones, George D. D. Jones and Kristoffer Petersson
Int. J. Mol. Sci. 2023, 24(8), 7195; https://doi.org/10.3390/ijms24087195 - 13 Apr 2023
Cited by 5 | Viewed by 2158
Abstract
Numerous studies have demonstrated the normal tissue-sparing effects of ultra-high dose rate ‘FLASH’ irradiation in vivo, with an associated reduction in damage burden being reported in vitro. Towards this, two key radiochemical mechanisms have been proposed: radical–radical recombination (RRR) and transient oxygen depletion [...] Read more.
Numerous studies have demonstrated the normal tissue-sparing effects of ultra-high dose rate ‘FLASH’ irradiation in vivo, with an associated reduction in damage burden being reported in vitro. Towards this, two key radiochemical mechanisms have been proposed: radical–radical recombination (RRR) and transient oxygen depletion (TOD), with both being proposed to lead to reduced levels of induced damage. Previously, we reported that FLASH induces lower levels of DNA strand break damage in whole-blood peripheral blood lymphocytes (WB-PBL) ex vivo, but our study failed to distinguish the mechanism(s) involved. A potential outcome of RRR is the formation of crosslink damage (particularly, if any organic radicals recombine), whilst a possible outcome of TOD is a more anoxic profile of induced damage resulting from FLASH. Therefore, the aim of the current study was to profile FLASH-induced damage via the Comet assay, assessing any DNA crosslink formation as a putative marker of RRR and/or anoxic DNA damage formation as an indicative marker of TOD, to determine the extent to which either mechanism contributes to the “FLASH effect”. Following FLASH irradiation, we see no evidence of any crosslink formation; however, FLASH irradiation induces a more anoxic profile of induced damage, supporting the TOD mechanism. Furthermore, treatment of WB-PBLs pre-irradiation with BSO abrogates the reduced strand break damage burden mediated by FLASH exposures. In summary, we do not see any experimental evidence to support the RRR mechanism contributing to the reduced damage burden induced by FLASH. However, the observation of a greater anoxic profile of damage following FLASH irradiation, together with the BSO abrogation of the reduced strand break damage burden mediated by FLASH, lends further support to TOD being a driver of the reduced damage burden plus a change in the damage profile mediated by FLASH. Full article
(This article belongs to the Special Issue FLASH Radiotherapy: From Benchwork to a New Paradigm-Shifting Radiotherapy)
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12 pages, 1835 KiB  
Article
Do We Preserve Tumor Control Probability (TCP) in FLASH Radiotherapy? A Model-Based Analysis
by Hans Liew, Stewart Mein, Thomas Tessonnier, Amir Abdollahi, Jürgen Debus, Ivana Dokic and Andrea Mairani
Int. J. Mol. Sci. 2023, 24(6), 5118; https://doi.org/10.3390/ijms24065118 - 7 Mar 2023
Cited by 4 | Viewed by 2685
Abstract
Reports of concurrent sparing of normal tissue and iso-effective treatment of tumors at ultra-high dose-rates (uHDR) have fueled the growing field of FLASH radiotherapy. However, iso-effectiveness in tumors is often deduced from the absence of a significant difference in their growth kinetics. In [...] Read more.
Reports of concurrent sparing of normal tissue and iso-effective treatment of tumors at ultra-high dose-rates (uHDR) have fueled the growing field of FLASH radiotherapy. However, iso-effectiveness in tumors is often deduced from the absence of a significant difference in their growth kinetics. In a model-based analysis, we investigate the meaningfulness of these indications for the clinical treatment outcome. The predictions of a previously benchmarked model of uHDR sparing in the “UNIfied and VERSatile bio response Engine” (UNIVERSE) are combined with existing models of tumor volume kinetics as well as tumor control probability (TCP) and compared to experimental data. The potential TCP of FLASH radiotherapy is investigated by varying the assumed dose-rate, fractionation schemes and oxygen concentration in the target. The developed framework describes the reported tumor growth kinetics appropriately, indicating that sparing effects could be present in the tumor but might be too small to be detected with the number of animals used. The TCP predictions show the possibility of substantial loss of treatment efficacy for FLASH radiotherapy depending on several variables, including the fractionation scheme, oxygen level, and DNA repair kinetics. The possible loss of TCP should be seriously considered when assessing the clinical viability of FLASH treatments. Full article
(This article belongs to the Special Issue FLASH Radiotherapy: From Benchwork to a New Paradigm-Shifting Radiotherapy)
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Review

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17 pages, 900 KiB  
Review
FLASH Radiotherapy: Expectations, Challenges, and Current Knowledge
by Andrea Borghini, Luca Labate, Simona Piccinini, Costanza Maria Vittoria Panaino, Maria Grazia Andreassi and Leonida Antonio Gizzi
Int. J. Mol. Sci. 2024, 25(5), 2546; https://doi.org/10.3390/ijms25052546 - 22 Feb 2024
Cited by 10 | Viewed by 4397
Abstract
Major strides have been made in the development of FLASH radiotherapy (FLASH RT) in the last ten years, but there are still many obstacles to overcome for transfer to the clinic to become a reality. Although preclinical and first-in-human clinical evidence suggests that [...] Read more.
Major strides have been made in the development of FLASH radiotherapy (FLASH RT) in the last ten years, but there are still many obstacles to overcome for transfer to the clinic to become a reality. Although preclinical and first-in-human clinical evidence suggests that ultra-high dose rates (UHDRs) induce a sparing effect in normal tissue without modifying the therapeutic effect on the tumor, successful clinical translation of FLASH-RT depends on a better understanding of the biological mechanisms underpinning the sparing effect. Suitable in vitro studies are required to fully understand the radiobiological mechanisms associated with UHDRs. From a technical point of view, it is also crucial to develop optimal technologies in terms of beam irradiation parameters for producing FLASH conditions. This review provides an overview of the research progress of FLASH RT and discusses the potential challenges to be faced before its clinical application. We critically summarize the preclinical evidence and in vitro studies on DNA damage following UHDR irradiation. We also highlight the ongoing developments of technologies for delivering FLASH-compliant beams, with a focus on laser-driven plasma accelerators suitable for performing basic radiobiological research on the UHDR effects. Full article
(This article belongs to the Special Issue FLASH Radiotherapy: From Benchwork to a New Paradigm-Shifting Radiotherapy)
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