|
1
|
Battestini M, Missiaggia M, Bolzoni S, Cordoni FG, Scifoni E. A multiscale radiation biophysical stochastic model describing the cell survival response at ultra-high dose rate under different oxygenations and radiation qualities. Radiother Oncol 2025; 207:110895. [PMID: 40233874 DOI: 10.1016/j.radonc.2025.110895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 03/25/2025] [Accepted: 04/09/2025] [Indexed: 04/17/2025]
Abstract
BACKGROUND AND PURPOSE While the advantages of ultra-high dose-rate (UHDR) irradiation have been well highlighted experimentally, the biological mechanism underlying the FLASH effect is still unclear and highly debated. The aim of this work is to reproduce the main in-vitro UHDR experiments and to try to explain the different in-vivo response between healthy tissues and tumors, developing a fully consistent radiation biophysical model for UHDR regime. MATERIALS AND METHODS We developed the MultiScale Generalized Stochastic Microdosimetric Model (MS-GSM2), a multi-stage extension of the GSM2, which is a probabilistic model describing the time evolution of the lesions in an irradiated cell nucleus. We coupled the slow DNA damage evolution with the fast chemical reaction kinetics, including the impact of the redox environment. RESULTS The MS-GSM2 can investigate the combined effects of chemical species, DNA damage formation and time evolution. We demonstrate that the MS-GSM2 predictions are coherent with the in-vitro UHDR experimental results across various oxygenation levels, and radiation qualities. We analyze the role of the chemical environmental conditions of the irradiated medium, i.e. oxygenation, and scavengers concentration, discussing possible factors that can attenuate or level out the dose rate dependence of the cell survival, to understand the differential effect that occurs in-vivo between normal tissue and tumor. CONCLUSION The MS-GSM2 can accurately describe multiple aspects of the FLASH effect and be consistent with the main evidence from the in-vitro experiments with different types of radiation and oxygenations. Our model proposes a consistent explanation for the differential outcomes observed in normal tissues and tumors, in-vivo and in-vitro.
Collapse
Affiliation(s)
- Marco Battestini
- Department of Physics, University of Trento 38123 Trento, Italy; Trento Institute for Fundamental Physics and Applications (TIFPA), National Institute for Nuclear Physics (INFN), 38123 Trento, Italy
| | - Marta Missiaggia
- Trento Institute for Fundamental Physics and Applications (TIFPA), National Institute for Nuclear Physics (INFN), 38123 Trento, Italy; Radiation Oncology Department, University of Miami FL, 33136 Miami, USA
| | - Sara Bolzoni
- Department of Physics, University of Trento 38123 Trento, Italy
| | - Francesco G Cordoni
- Trento Institute for Fundamental Physics and Applications (TIFPA), National Institute for Nuclear Physics (INFN), 38123 Trento, Italy; Department of Civil, Environmental and Mechanical Engineering, University of Trento 38123 Trento, Italy.
| | - Emanuele Scifoni
- Trento Institute for Fundamental Physics and Applications (TIFPA), National Institute for Nuclear Physics (INFN), 38123 Trento, Italy
| |
Collapse
|
|
2
|
Chaoui M, Tayalati Y, Bouhali O, Ramos-Méndez J. Monte Carlo track-structure simulation of the impact of Ultra-Hight Dose Rate and oxygen concentration on the Fenton reaction. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.05.13.652705. [PMID: 40463020 PMCID: PMC12132385 DOI: 10.1101/2025.05.13.652705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/11/2025]
Abstract
Background Preclinical investigations studies have shown that FLASH radiotherapy (FLASH-RT), delivering radiation in ultra-high dose rates (UHDR), preserves healthy tissue and reduces toxicity, all while maintaining an effective tumor response compared to conventional radiotherapy (CONV-RT), the combined biological benefit was termed as "FLASH effect". However, the mechanisms responsible for this effect remain unclear. Research demonstrated that oxygen concentration contributes to the FLASH effect, and it has been hypothesized that Fenton reaction might play a role in the "FLASH effect". Purpose We propose to investigate the effect of ultra-high dose rate (UHDR), compared to conventional dose rates (CONV), on the Fenton reaction by studying the radiolysis of Fricke solution. The study will focus on how dose, dose rate, and initial oxygen concentration influence the activation of the Fenton reaction. Methods and Materials TOPAS-nBio version 2.0 was used to simulate the radiolysis of the Fricke system. A cubic water phantom of 3μm side was irradiated by 300MeV protons on one of its edges. For UHDR, a proton field (1.5×1.5μm2) was delivered in a single pulse of 1ns width. The protons were accumulated until reached 5Gy or 10Gy absorbed dose. For CONV, the independent history approach was used to mimic 60Co irradiation. For both dose-rates, oxygen concentrations representative of hypoxic and normoxic tissues (10-250μM) were simulated. The G-value for oxidant ions G(Fe3+) and ΔG-value of Fenton reaction (H2O2 + Fe2+→ Fe3++•OH+OH-) were scored. The simulations ended after G(Fe3+) achieved steady-state, and calculated yields were compared with published data. Results For CONV, G(Fe3+) agreed with ICRU-report 34 data by (0.97±0.1) %. For UHDR, G(Fe3+) agreed with ICRU data by (1.24±0.1)% and (0.92±0.1)% for 5Gy and 10Gy, respectively. Notably, UHDR at 10 Gy reduced the occurrence of Fenton reactions by (1.0±0.1)% and (11.5±0.1)% at initial oxygen concentrations of 250 μM and 10 μM, respectively. In consequence, UHDR decreased G(Fe3+) by (1.8±0.1)% and (12.5±0.1)% at these oxygen levels. Additionally, increasing the absorbed dose to 15 Gy and 20 Gy at low oxygen (10 μM), UHDR further reduced the ΔG-value by (15.7±0.1)% and (18.6±0.1)%, respectively. The decrease was driven by intertrack effects present in UHDR pulses and its impact on the scavenging effect that oxygen had over hydrogen radicals. Conclusions UHDR reduces the yield of Fe3+ (G(Fe3+)) and significantly impacts Fenton reactions, particularly at low oxygen concentrations, while showing minimal effects at higher oxygen levels. This effect becomes more pronounced at higher dose thresholds, such as 10-20 Gy. This emphasizes the important role of the initial oxygen concentration in UHDR and its influence on the Fenton reaction, a mechanism that may contribute to elucidate the FLASH effect.
Collapse
Affiliation(s)
- M. Chaoui
- Faculty of Sciences, University Mohammed V in Rabat, Morocco
| | - Y. Tayalati
- Faculty of Sciences, University Mohammed V in Rabat, Morocco
- School of applied and Engineering physics, Mohammed VI Polytechnic University, Ben Guerir, Morocco
| | - O. Bouhali
- Electrical Engineering, College of Science and Engineering, Hamad Bin Khalifa University Doha, Qatar
| | - J. Ramos-Méndez
- Department of Radiation Oncology, University of California, San Francisco, USA
| |
Collapse
|
|
3
|
Kuipers ME, van Liefferinge F, van der Wal E, Rovituso M, Slats AM, Hiemstra PS, Van Doorn-Wink KC. Effect of FLASH proton therapy on primary bronchial epithelial cell organoids. Clin Transl Radiat Oncol 2025; 52:100927. [PMID: 39968050 PMCID: PMC11833640 DOI: 10.1016/j.ctro.2025.100927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 01/21/2025] [Accepted: 01/28/2025] [Indexed: 02/20/2025] Open
Abstract
Purpose The effects of conventional (CONV) and FLASH proton therapy on primary bronchial epithelial cell (PBEC) organoids from individuals with chronic obstructive pulmonary disease (COPD) were investigated. The primary objective was to compare the effect of FLASH and CONV on COPD PBEC organoids with a focus on DNA damage, organoid formation, and gene expression. Methods PBECs were obtained from six COPD donors, cultured as three-dimensional (3D) organoids and exposed to 2 and 8 Gy CONV and FLASH proton radiation at the Holland Proton Therapy Center. DNA damage was assessed by γH2AX staining. Organoid formation capacity was assessed by counting the organoids formed after reseeding irradiated cells at 24 h and 7 days. Bulk RNA sequencing (RNAseq) and qPCR analyses were performed to identify pathways and differences in the radiation response. Results γH2AX foci analysis showed a significant dose-dependent increase in DNA damage at 1 h for both CONV and FLASH treatments, without differences between the two modalities. Organoid formation assays revealed a dose-dependent decrease in organoid formation capacity at 24 h for both treatments. At 7 days, 2 Gy FLASH-treated samples showed significantly reduced organoid formation compared to 2 Gy CONV (p = 0.008). RNAseq identified CONV and FLASH-induced changes in expression of DNA-damage response and apoptosis pathway genes. A dose-dependent upregulation of MDM2, GDF15, DDB2, BAX, P21, AEN and a decrease in MKi67 expression was confirmed by qPCR analysis. Conclusion No significant differences were found in DNA damage or gene expression profiles between CONV and FLASH. The organoid formation assay showed a prolonged detrimental effect in the FLASH-treated organoids, suggesting a more complex interaction of FLASH with lung epithelial cells. The results of this study contribute to the advancement of robust in vitro human lung models for investigating the mechanisms of action of FLASH, potentially facilitating the treatment of NSCLC patients with proton FLASH therapy.
Collapse
Affiliation(s)
- Merian E. Kuipers
- Leiden University Medical Center (LUMC), Department of Pulmonology, C02-Q, Albinusdreef 2 2333 ZA Leiden, the Netherlands
| | - Floriane van Liefferinge
- Leiden University Medical Center (LUMC), Department of Pulmonology, C02-Q, Albinusdreef 2 2333 ZA Leiden, the Netherlands
| | - Ernst van der Wal
- Holland Proton Therapy Center (HollandPTC), Huismansingel 4 2629 JH Delft, the Netherlands
| | - Marta Rovituso
- Holland Proton Therapy Center (HollandPTC), Huismansingel 4 2629 JH Delft, the Netherlands
| | - Annelies M. Slats
- Leiden University Medical Center (LUMC), Department of Pulmonology, C02-Q, Albinusdreef 2 2333 ZA Leiden, the Netherlands
| | - Pieter S. Hiemstra
- Leiden University Medical Center (LUMC), Department of Pulmonology, C02-Q, Albinusdreef 2 2333 ZA Leiden, the Netherlands
| | - Krista C.J. Van Doorn-Wink
- Holland Proton Therapy Center (HollandPTC), Huismansingel 4 2629 JH Delft, the Netherlands
- Leiden University Medical Center (LUMC), Department of Radiotherapy, K01-P, Albinusdreef 2 2333 ZA Leiden, the Netherlands
| |
Collapse
|
|
4
|
Yang XX, Luo H, Zhang JJ, Ge H, Ge L. Clinical translation of ultra-high dose rate flash radiotherapy: Opportunities, challenges, and prospects. World J Radiol 2025; 17:105722. [PMID: 40309475 PMCID: PMC12038406 DOI: 10.4329/wjr.v17.i4.105722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 03/09/2025] [Accepted: 03/25/2025] [Indexed: 04/22/2025] Open
Abstract
Ultra-high dose rate flash radiotherapy (FLASH-RT) has attracted wide attention in the field of radiotherapy in recent years. For FLASH-RT, radiation is delivered at a very high dose rate [usually thousands of times compared with conventional radiotherapy (CONV-RT)] in an extremely short time. This novel irradiation technique shows a protective effect on normal tissues, also known as the flash effect. At the same time, FLASH-RT is comparable to CONV-RT in terms of tumor-killing efficacy. As basic research dedicates to uncover the mechanisms by which FLASH-RT reduces radiation-induced normal tissue damage, clinical trials of FLASH-RT have been gradually conducted worldwide. This article systematically reviews the evidence of the feasibility and safety of FLASH-RT in clinical practice and offers insights into the future translation of this technology in clinic.
Collapse
Affiliation(s)
- Xiang-Xiang Yang
- Department of Medical Imaging, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Hui Luo
- Department of Radiation Oncology, Henan Cancer Hospital, Zhengzhou 450003, Henan Province, China
| | - Jia-Jun Zhang
- Department of Medical Imaging, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Heng Ge
- Department of Oncology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Liang Ge
- Department of Medical Imaging, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, Henan Province, China
| |
Collapse
|
|
5
|
Zheng D, Preuss K, Milano MT, He X, Gou L, Shi Y, Marples B, Wan R, Yu H, Du H, Zhang C. Mathematical modeling in radiotherapy for cancer: a comprehensive narrative review. Radiat Oncol 2025; 20:49. [PMID: 40186295 PMCID: PMC11969940 DOI: 10.1186/s13014-025-02626-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 03/17/2025] [Indexed: 04/07/2025] Open
Abstract
Mathematical modeling has long been a cornerstone of radiotherapy for cancer, guiding treatment prescription, planning, and delivery through versatile applications. As we enter the era of medical big data, where the integration of molecular, imaging, and clinical data at both the tumor and patient levels could promise more precise and personalized cancer treatment, the role of mathematical modeling has become even more critical. This comprehensive narrative review aims to summarize the main applications of mathematical modeling in radiotherapy, bridging the gap between classical models and the latest advancements. The review covers a wide range of applications, including radiobiology, clinical workflows, stereotactic radiosurgery/stereotactic body radiotherapy (SRS/SBRT), spatially fractionated radiotherapy (SFRT), FLASH radiotherapy (FLASH-RT), immune-radiotherapy, and the emerging concept of radiotherapy digital twins. Each of these areas is explored in depth, with a particular focus on how newer trends and innovations are shaping the future of radiation cancer treatment. By examining these diverse applications, this review provides a comprehensive overview of the current state of mathematical modeling in radiotherapy. It also highlights the growing importance of these models in the context of personalized medicine and multi-scale, multi-modal data integration, offering insights into how they can be leveraged to enhance treatment precision and patient outcomes. As radiotherapy continues to evolve, the insights gained from this review will help guide future research and clinical practice, ensuring that mathematical modeling continues to propel innovations in radiation cancer treatment.
Collapse
Affiliation(s)
- Dandan Zheng
- Department of Radiation Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Box 647, Rochester, NY, 14642, USA.
| | | | - Michael T Milano
- Department of Radiation Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Box 647, Rochester, NY, 14642, USA
| | - Xiuxiu He
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Lang Gou
- Department of Radiation Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Box 647, Rochester, NY, 14642, USA
| | - Yu Shi
- School of Biological Sciences, University of Nebraska Lincoln, Lincoln, USA
| | - Brian Marples
- Department of Radiation Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Box 647, Rochester, NY, 14642, USA
| | - Raphael Wan
- Department of Radiation Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Box 647, Rochester, NY, 14642, USA
| | - Hongfeng Yu
- Department of Computer Science, University of Nebraska Lincoln, Lincoln, USA
| | - Huijing Du
- Department of Mathematics, University of Nebraska Lincoln, Lincoln, USA
| | - Chi Zhang
- School of Biological Sciences, University of Nebraska Lincoln, Lincoln, USA
| |
Collapse
|
|
6
|
Tinganelli W, Puspitasari-Kokko A, Sokol O, Helm A, Simoniello P, Schuy C, Lerchl S, Eckert D, Oppermann J, Rehm A, Janssen S, Engel D, Moeller R, Romano R, Horst F, Boscolo D, Fournier C, Durante M, Weber U. FLASH Bragg-Peak Irradiation With a Therapeutic Carbon Ion Beam: First In Vivo Results. Int J Radiat Oncol Biol Phys 2025; 121:1282-1292. [PMID: 39608612 DOI: 10.1016/j.ijrobp.2024.11.089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 10/22/2024] [Accepted: 11/10/2024] [Indexed: 11/30/2024]
Abstract
PURPOSE In recent years, ultra-high dose rate (UHDR) irradiation has emerged as a promising innovative approach to cancer treatment. Characteristic feature of this regimen, commonly referred to as FLASH effect, demonstrated primarily for electrons, photons, or protons, is the improved normal tissue sparing, whereas the tumor control is similar to the one of the conventional dose-rate (CDR) treatments. The FLASH mechanism is, however, unknown. One major question is whether this effect is maintained when using densely ionizing (high-LET) heavy nuclei. METHODS MATERIALS Here, we report the effects of 20 Gy UHDR heavy ion irradiation in clinically relevant conditions, ie, at high-LET in the spread-out Bragg peak of a 12C beam using an osteosarcoma mouse model. RESULTS We show that UHDR irradiation was less toxic in the normal tissue compared with CDR while maintaining tumor control. The immune activation was also comparable in UHDR and CDR groups. Both UHDR and CDR exposures steered the metagenome toward a balanced state. CONCLUSIONS These results suggest that the UHDR irradiations can improve the safety and effectiveness of heavy ion therapy, and provide a crucial benchmark for current mechanistic FLASH models. However, additional experiments are needed to validate these findings across other animal and tumor models.
Collapse
Affiliation(s)
- Walter Tinganelli
- GSI Helmholtzzentrum für Schwerionenforschung, Biophysics Department, Darmstadt, Germany
| | | | - Olga Sokol
- GSI Helmholtzzentrum für Schwerionenforschung, Biophysics Department, Darmstadt, Germany
| | - Alexander Helm
- GSI Helmholtzzentrum für Schwerionenforschung, Biophysics Department, Darmstadt, Germany
| | - Palma Simoniello
- Department of Science and Technology, University of Naples Parthenope, Naples, Italy
| | - Christoph Schuy
- GSI Helmholtzzentrum für Schwerionenforschung, Biophysics Department, Darmstadt, Germany
| | - Sylvie Lerchl
- GSI Helmholtzzentrum für Schwerionenforschung, Biophysics Department, Darmstadt, Germany
| | - Denise Eckert
- GSI Helmholtzzentrum für Schwerionenforschung, Biophysics Department, Darmstadt, Germany
| | - Julius Oppermann
- GSI Helmholtzzentrum für Schwerionenforschung, Biophysics Department, Darmstadt, Germany
| | - Anna Rehm
- Algorithmic Bioinformatics, Justus Liebig University, Giessen, Germany
| | - Stefan Janssen
- Algorithmic Bioinformatics, Justus Liebig University, Giessen, Germany
| | - Denise Engel
- German Aerospace Center, Institute of Aerospace Medicine, Radiation Biology Department, Aerospace Microbiology, Cologne/Köln, Germany
| | - Ralf Moeller
- German Aerospace Center, Institute of Aerospace Medicine, Radiation Biology Department, Aerospace Microbiology, Cologne/Köln, Germany
| | - Rossana Romano
- Department of Science and Technology, University of Naples Parthenope, Naples, Italy
| | - Felix Horst
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany
| | - Daria Boscolo
- GSI Helmholtzzentrum für Schwerionenforschung, Biophysics Department, Darmstadt, Germany
| | - Claudia Fournier
- GSI Helmholtzzentrum für Schwerionenforschung, Biophysics Department, Darmstadt, Germany
| | - Marco Durante
- GSI Helmholtzzentrum für Schwerionenforschung, Biophysics Department, Darmstadt, Germany; Department of Physics, Institute of Condensed Matter Physics, Technische Universität Darmstadt, Darmstadt, Germany; Department of Physics "Ettore Pancini," University Federico II, Naples, Italy.
| | - Uli Weber
- GSI Helmholtzzentrum für Schwerionenforschung, Biophysics Department, Darmstadt, Germany; Life Science Engineering Department, Technische Hochschule Mittelhessen, Gießen, Germany
| |
Collapse
|
|
7
|
Chaoui M, Bouhali O, Tayalati Y. FLASH radiotherapy: technical advances, evidence of the FLASH effect and mechanistic insights. Biomed Phys Eng Express 2025; 11:022003. [PMID: 40043321 DOI: 10.1088/2057-1976/adbcb1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 03/05/2025] [Indexed: 03/18/2025]
Abstract
Cancer is one of the leading causes of death worldwide, responsible for nearly 10 million deaths in 2020, with approximately 50% of patients receiving radiation therapy as part of their treatment (Baskaret al2012). Preclinical investigations studies have shown that FLASH radiotherapy (FLASH-RT), delivering radiation in ultra-high dose rates (UHDR), preserves healthy tissue integrity and reduces toxicity, all while maintaining an effective tumor response compared to conventional radiotherapy (CONV-RT), the combined biological benefit was termed as FLASH effect. This article comprehensively surveys pertinent research conducted within FLASH-RT, explores the facilities used in this realm, delves into hypothesized mechanism perspectives, and addresses the challenges to trigger the FLASH effect. In addition, we discuss the potential prospects of FLASH-RT and examine the obstacles that require resolution before its clinical implementation can become a reality.
Collapse
Affiliation(s)
- Mustapha Chaoui
- Faculty of Sciences, University Mohammed V in Rabat, Morocco
| | - Othmane Bouhali
- Electrical Engineering, College of Science and Engineering, Hamad Bin Khalifa University Doha, Qatar
| | - Yahya Tayalati
- Faculty of Sciences, University Mohammed V in Rabat, Morocco
- Institute of Applied Physics, Mohammed VI Polytechnic University, Ben Guerir, Morocco
| |
Collapse
|
|
8
|
Huang J, Cheng J, Shi B, Du X, Tang S, Lin B, Mo J, Yan F, Luo S, Yang H. Ultra‑high dose rate (FLASH) treatment: A novel radiotherapy modality (Review). Mol Clin Oncol 2025; 22:23. [PMID: 39885864 PMCID: PMC11775888 DOI: 10.3892/mco.2025.2818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 12/05/2024] [Indexed: 02/01/2025] Open
Abstract
Ultra-high dose rate radiotherapy defined as FLASH radiotherapy is a potential technology to improve local tumor therapeutic gain ratio. It relies on linear accelerator capable of delivering large doses in a single microsecond pulse (>40 Gy/sec). This therapy would lead to sparing of normal tissue which has been termed the FLASH effect. As significant reduction of radiation-induced toxicity, a greater dose of FLASH radiotherapy could be administered in tumor region. Some evidences prove the relation between FLASH effect and oxygen. Yet, the underlying physicochemical and biological mechanism remain to be fully demonstrated. The current hypotheses that may explain the normal and tumor tissue different response were We summarized and the future direction of study and clinic implementation was proposed.
Collapse
Affiliation(s)
- Junqi Huang
- Department of Orthopaedics, Mianyang Central Hospital, Mianyang, Sichuan 621000, P.R. China
| | - Jiajia Cheng
- Department of Orthopaedics, Mianyang Central Hospital, Mianyang, Sichuan 621000, P.R. China
| | - Bo Shi
- Department of Orthopaedics, Mianyang Central Hospital, Mianyang, Sichuan 621000, P.R. China
| | - Xiaobo Du
- Department of Orthopaedics, Mianyang Central Hospital, Mianyang, Sichuan 621000, P.R. China
| | - Shitian Tang
- Department of Orthopaedics, Mianyang Central Hospital, Mianyang, Sichuan 621000, P.R. China
| | - Binwei Lin
- Department of Orthopaedics, Mianyang Central Hospital, Mianyang, Sichuan 621000, P.R. China
| | - Jun Mo
- Department of Orthopaedics, Mianyang Central Hospital, Mianyang, Sichuan 621000, P.R. China
| | - Fenglin Yan
- Department of Orthopaedics, Mianyang Central Hospital, Mianyang, Sichuan 621000, P.R. China
| | - Shunyu Luo
- Department of Orthopaedics, Mianyang Central Hospital, Mianyang, Sichuan 621000, P.R. China
| | - Heng Yang
- Department of Orthopaedics, Mianyang Central Hospital, Mianyang, Sichuan 621000, P.R. China
| |
Collapse
|
|
9
|
Pikes G, Dass J, Gill S, Ebert M, Reynolds M, Rowshanfarzad P. Monte Carlo in the mechanistic modelling of the FLASH effect: a review. Phys Med Biol 2025; 70:02TR02. [PMID: 39746308 DOI: 10.1088/1361-6560/ada51a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 01/02/2025] [Indexed: 01/04/2025]
Abstract
FLASH radiotherapy employs ultra-high dose rates of>40Gy s-1, which may reduce normal tissue complication as compared to conventional dose rate treatments, while still ensuring the same level of tumour control. The potential benefit this can offer to patients has been the cause of great interest within the radiation oncology community, but this has not translated to a direct understanding of the FLASH effect. The oxygen depletion and inter-track interaction hypotheses are currently the leading explanations as to the mechanisms behind FLASH, but these are still not well understood, with many questions remaining about the exact underpinnings of FLASH and the treatment parameters required to optimally induce it. Monte Carlo simulations may hold the key to unlocking the mystery behind FLASH, allowing for analysis of the underpinning mechanisms at a fundamental level, where the interactions between individual radiation particles, DNA strands and chemical species can be studied. Currently, however, there is still a great deal of disagreement in simulation findings and the importance of the different mechanisms they support. This review discusses current studies into the mechanisms of FLASH using the Monte Carlo method. The simulation parameters and results for all major investigations are provided. Discussion primarily revolves around the oxygen depletion and inter-track interactions hypotheses, though other, more novel, theories are also mentioned. A general list of recommendations for future simulations is provided, informed by the articles discussed. This review highlights some of the useful parameters and simulation methodologies that may be required to finally understand the FLASH effect.
Collapse
Affiliation(s)
- Gavin Pikes
- School of Physics, Mathematics & Computing, University of Western Australia, Crawley, Western Australia, Australia
- Centre for Advanced Technologies in Cancer Research (CATCR), Perth, Western Australia, Australia
- Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
| | - Joshua Dass
- Centre for Advanced Technologies in Cancer Research (CATCR), Perth, Western Australia, Australia
- Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
| | - Suki Gill
- Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
| | - Martin Ebert
- School of Physics, Mathematics & Computing, University of Western Australia, Crawley, Western Australia, Australia
- Centre for Advanced Technologies in Cancer Research (CATCR), Perth, Western Australia, Australia
- Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
| | - Mark Reynolds
- School of Physics, Mathematics & Computing, University of Western Australia, Crawley, Western Australia, Australia
| | - Pejman Rowshanfarzad
- School of Physics, Mathematics & Computing, University of Western Australia, Crawley, Western Australia, Australia
- Centre for Advanced Technologies in Cancer Research (CATCR), Perth, Western Australia, Australia
| |
Collapse
|
|
10
|
D-Kondo JN, Borys D, Ruciński A, Brzozowska B, Masilela TAM, Grochowska-Tatarczak M, Węgrzyn M, Ramos-Mendez J. Effect of FLASH dose-rate and oxygen concentration in the production of H 2O 2in cellular-like media versus water: a Monte Carlo track-structure study. Phys Med Biol 2025; 70:025014. [PMID: 39746310 DOI: 10.1088/1361-6560/ada517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 01/02/2025] [Indexed: 01/04/2025]
Abstract
Objective. To study the effect of dose-rate in the time evolution of chemical yields produced in pure water versus a cellular-like environment for FLASH radiotherapy research.Approach.A version of TOPAS-nBio with Tau-Leaping algorithm was used to simulate the homogenous chemistry stage of water radiolysis using three chemical models: (1) liquid water model that considered scavenging ofeaq-, H•by dissolved oxygen; (2) Michaels & Hunt model that considered scavenging of•OH,eaq‒, and H•by biomolecules existing in cellular environment; (3) Wardman model that considered model 2) and the non-enzymatic antioxidant glutathione (GSH). H2O2concentrations at conventional and FLASH dose-rates were compared with published measurements. Model 3) was used to estimate DNA single-strand break (SSB) yields and compared with published data. SSBs were estimated from simulated yields of DNA hydrogen abstraction and attenuation factors to account for the scavenging capacity of the medium. The simulation setup consisted of monoenergetic protons (100 MeV) delivered in pulses at conventional (0.2857Gy s-1) and FLASH (500Gy s-1) dose rates. Dose varied from 5-20 Gy, and oxygen concentration from 10µM-1 mM.Main Results.At the steady state, for model (1), H2O2concentration differed by 81.5%± 4.0% between FLASH and conventional dose-rates. For models (2) and (3) the differences were within 8.0%± 4.8%, and calculated SSB yields agreed with published data within 3.8%± 1.2%. A maximum oxygen concentration difference of 60% and 50% for models (2) and (3) between conventional and FLASH dose-rates was found between 2 × 106and 9 × 1013ps for 20 Gy of absorbed dose.Significance.The findings highlight the importance of developing more advanced cellular models to account for both the chemical and biological factors that comprise the FLASH effect. It was found that differences between pure water and cellular environment models were significant and extrapolating results between the two should be avoided. Observed differences call for further experimental investigation.
Collapse
Affiliation(s)
- J Naoki D-Kondo
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, United States of America
| | - Damian Borys
- Department of Systems Biology and Engineering, Silesian University of Technology, Gliwice, Poland
| | | | | | - Thongchai A M Masilela
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, United States of America
| | | | - Magdalena Węgrzyn
- Department of Systems Biology and Engineering, Silesian University of Technology, Gliwice, Poland
| | - José Ramos-Mendez
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, United States of America
| |
Collapse
|
|
11
|
Geirnaert F, Kerkhove L, Montay-Gruel P, Gevaert T, Dufait I, De Ridder M. Exploring the Metabolic Impact of FLASH Radiotherapy. Cancers (Basel) 2025; 17:133. [PMID: 39796760 PMCID: PMC11720285 DOI: 10.3390/cancers17010133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 12/30/2024] [Accepted: 12/31/2024] [Indexed: 01/13/2025] Open
Abstract
FLASH radiotherapy (FLASH RT) is an innovative modality in cancer treatment that delivers ultrahigh dose rates (UHDRs), distinguishing it from conventional radiotherapy (CRT). FLASH RT has demonstrated the potential to enhance the therapeutic window by reducing radiation-induced damage to normal tissues while maintaining tumor control, a phenomenon termed the FLASH effect. Despite promising outcomes, the precise mechanisms underlying the FLASH effect remain elusive and are a focal point of current research. This review explores the metabolic and cellular responses to FLASH RT compared to CRT, with particular focus on the differential impacts on normal and tumor tissues. Key findings suggest that FLASH RT may mitigate damage in healthy tissues via altered reactive oxygen species (ROS) dynamics, which attenuate downstream oxidative damage. Studies indicate the FLASH RT influences iron metabolism and lipid peroxidation pathways differently than CRT. Additionally, various studies indicate that FLASH RT promotes the preservation of mitochondrial integrity and function, which helps maintain apoptotic pathways in normal tissues, attenuating damage. Current knowledge of the metabolic influences following FLASH RT highlights its potential to minimize toxicity in normal tissues, while also emphasizing the need for further studies in biologically relevant, complex systems to better understand its clinical potential. By targeting distinct metabolic pathways, FLASH RT could represent a transformative advance in RT, ultimately improving the therapeutic window for cancer treatment.
Collapse
Affiliation(s)
- Febe Geirnaert
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (F.G.); (L.K.); (T.G.); (I.D.)
| | - Lisa Kerkhove
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (F.G.); (L.K.); (T.G.); (I.D.)
| | - Pierre Montay-Gruel
- Radiation Oncology Department, Iridium Netwerk, 2610 Antwerp, Belgium;
- Antwerp Research in Radiation Oncology (AreRO), Center for Oncological Research (CORE), University of Antwerp, 2020 Antwerp, Belgium
| | - Thierry Gevaert
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (F.G.); (L.K.); (T.G.); (I.D.)
| | - Inès Dufait
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (F.G.); (L.K.); (T.G.); (I.D.)
| | - Mark De Ridder
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (F.G.); (L.K.); (T.G.); (I.D.)
| |
Collapse
|
|
12
|
Wang Y, Qi SN, Bi N, Li YX. FLASH radiotherapy combined with immunotherapy: From biological mechanisms to blockbuster therapeutics. Transl Oncol 2025; 51:102183. [PMID: 39613524 PMCID: PMC11629542 DOI: 10.1016/j.tranon.2024.102183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 09/19/2024] [Accepted: 10/29/2024] [Indexed: 12/01/2024] Open
Abstract
FLASH ultra-high dose rate radiotherapy (RT) can effectively exert the protective effect on normal tissue and reduce the risk of treatment-related toxicity, without compromising the killing effect on tumor tissue, resulting in a significant differential biological effect between tumor control and normal tissue damage, namely the FLASH effect. To date, the precise biological details of the FLASH effect remain uncertain. The currently mainstream mechanisms proposed by the academic community include the transient oxygen depletion hypothesis, free radical hypothesis, immune protection hypothesis, and DNA integrity hypothesis, which have attracted increasing attention in recent years. Based on these theoretical principles and numerous investigations on the FLASH effect in vivo and in vitro, the combined application of FLASH and immune checkpoint inhibitors (ICIs) has been considered synergistic and potentially practical. The primary underlying basis is that FLASH might actively preserve the number and function of circulating immune cells, thereby enhancing the efficacy of immune cell-mediated immunotherapy. Meanwhile, FLASH RT could activate the tumor immune microenvironment and transform "cold'' tumors into ''hot'' ones, consequently boosting local and systemic anti-tumor immunity and expanding the therapeutic benefits of ICIs. Moreover, FLASH might attenuate immunoinflammatory responses and minimize the incidence of radiation-related adverse events, allowing for the potentially safer and promising clinical application of combing FLASH RT with ICI therapy. Nevertheless, data on this treatment modality is currently lacking, and several barriers remain to be addressed, including the logistical bottlenecks, technical hurdles, limited availability, and unclear biological mechanisms. Further research is warranted in the future.
Collapse
Affiliation(s)
- Yu Wang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China
| | - Shu-Nan Qi
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China.
| | - Nan Bi
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China; State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Ye-Xiong Li
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China.
| |
Collapse
|
|
13
|
Li M, Zhou S, Dong G, Wang C. Emergence of FLASH‑radiotherapy across the last 50 years (Review). Oncol Lett 2024; 28:602. [PMID: 39493433 PMCID: PMC11529378 DOI: 10.3892/ol.2024.14735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 09/02/2024] [Indexed: 11/05/2024] Open
Abstract
A novel radiotherapy (RT) approach termed FLASH-RT, which irradiates areas at ultra-high dose rates, is of current interest to medical researchers. FLASH-RT can maintain equivalent antitumor effects while sparing healthy tissue compared with conventional RT (CONV-RT), which uses low dose rates. The sparing effect on healthy tissue after FLASH-RT is known as the FLASH effect. Owing to the FLASH effect, FLASH-RT can raise the maximum tolerable dose to control tumor growth or eradicate the tumor and provide a new strategy for clinical RT. However, definitive irradiation conditions for reproducing the FLASH effect and the biological mechanism of the FLASH effect have not yet been fully elucidated. The efficacy of FLASH-RT is controversial despite its successful application in clinical RT. The present review recapitulates the progression of FLASH-RT and critically comments on the hypothesis of the FLASH effect. In addition, the review expounds on the current issues with regard to the differential phenomena between in vitro and in vivo studies, and elaborates on the challenges for the application of FLASH-RT that need to be addressed in the future.
Collapse
Affiliation(s)
- Menghua Li
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China
- Department of Biochemistry, Basic Medical College of Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Sen Zhou
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China
| | - Guofu Dong
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China
- Department of Biochemistry, Basic Medical College of Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Changzhen Wang
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China
- Department of Biochemistry, Basic Medical College of Anhui Medical University, Hefei, Anhui 230032, P.R. China
| |
Collapse
|
|
14
|
Scarmelotto A, Delprat V, Michiels C, Lucas S, Heuskin AC. The oxygen puzzle in FLASH radiotherapy: A comprehensive review and experimental outlook. Clin Transl Radiat Oncol 2024; 49:100860. [PMID: 39381632 PMCID: PMC11458961 DOI: 10.1016/j.ctro.2024.100860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/05/2024] [Accepted: 09/10/2024] [Indexed: 10/10/2024] Open
Abstract
FLASH radiotherapy is attracting increasing interest because it maintains tumor control while inflicting less damage to normal tissues compared to conventional radiotherapy. This sparing effect, the so-called FLASH effect, is achieved when radiation is delivered at ultra-high dose rates (≥40 Gy/s). Although the FLASH effect has already been demonstrated in several preclinical models, a complete mechanistic description explaining why tumors and normal tissues respond differently is still missing. None of the current hypotheses fully explains the experimental evidence. A common point between many of these is the role of oxygen, which is described as a major factor, either through transient hypoxia in the form of dissolved molecules, or reactive oxygen species (ROS). Therefore, this review focuses on both forms of this molecule, retracing old and more recent theories, while proposing new mechanisms that could provide a complete description of the FLASH effect based on preclinical and experimental evidence. In addition, this manuscript describes a set of experiments designed to provide the FLASH community with new tools for exploring the post-irradiation fate of ROS and their potential biological implications.
Collapse
Affiliation(s)
- Andrea Scarmelotto
- Laboratory for Analysis by Nuclear Reaction (LARN), Namur Research Institute for Life Sciences (NARILIS), University of Namur, Rue de Bruxelles 61, B-5000 Namur, Belgium
| | - Victor Delprat
- Laboratory for Analysis by Nuclear Reaction (LARN), Namur Research Institute for Life Sciences (NARILIS), University of Namur, Rue de Bruxelles 61, B-5000 Namur, Belgium
| | - Carine Michiels
- Unité de Recherche en Biologie Cellulaire (URBC), Namur Research Institute For Life Sciences (NARILIS), University of Namur, Rue de Bruxelles 61, B-5000 Namur, Belgium
| | - Stéphane Lucas
- Laboratory for Analysis by Nuclear Reaction (LARN), Namur Research Institute for Life Sciences (NARILIS), University of Namur, Rue de Bruxelles 61, B-5000 Namur, Belgium
- Ion Beam Application (IBA), Chemin du Cyclotron, 6, B-1348 Louvain-La-Neuve, Belgium
| | - Anne-Catherine Heuskin
- Laboratory for Analysis by Nuclear Reaction (LARN), Namur Research Institute for Life Sciences (NARILIS), University of Namur, Rue de Bruxelles 61, B-5000 Namur, Belgium
| |
Collapse
|
|
15
|
Zhang T, Stengl C, Derksen L, Palskis K, Koritsidis K, Zink K, Adeberg S, Major G, Weishaar D, Theiß U, Jin J, Spadea MF, Theodoridou E, Hesser J, Baumann KS, Seco J. Analysis of hydrogen peroxide production in pure water: Ultrahigh versus conventional dose-rate irradiation and mechanistic insights. Med Phys 2024; 51:7439-7452. [PMID: 39092902 DOI: 10.1002/mp.17335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 07/16/2024] [Accepted: 07/16/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Ultrahigh dose-rate radiation (UHDR) produces less hydrogen peroxide (H2O2) in pure water, as suggested by some experimental studies, and is used as an argument for the validity of the theory that FLASH spares the normal tissue due to less reactive oxygen species (ROS) production. In contrast, most Monte Carlo simulation studies suggest the opposite. PURPOSE We aim to unveil the effect of UHDR on H2O2 production in pure water and its underlying mechanism, to serve as a benchmark for Monte Carlo simulation. We hypothesized that the reaction of solvated electrons (e aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ ) removing hydroxyl radicals (•OH), the precursor of H2O2, is the reason why UHDR leads to a lower G-value (molecules/100 eV) for H2O2 (G[H2O2]), because: 1, the third-order reaction betweene aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ and •OH is more sensitive to increased instantaneous ROS concentration by UHDR than a two-order reaction of •OH self-reaction producing H2O2; 2,e aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ has two times higher diffusion coefficient and higher reaction rate constant than that of •OH, which meanse aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ would dominate the competition for •OH and benefit more from the inter-track effect of UHDR. Meanwhile, we also experimentally verify the theory of long-lived radicals causing lower G(H2O2) in conventional irradiation, which is mentioned in some simulation studies. METHODS AND MATERIALS H2O2 was measured by Amplex UltraRed assay. 430.1 MeV/u carbon ions (50 and 0.1 Gy/s), 9 MeV electrons (600 and 0.62 Gy/s), and 200 kV x-ray tube (10 and 0.1 Gy/s) were employed. For three kinds of water (real hypoxic: 1% O2; hypoxic: 1% O2 and 5% CO2; and normoxic: 21% O2), unbubbled and bubbled samples with N2O, the scavenger ofe aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ , were irradiated by carbon ions and electrons with conventional and UHDR at different absolute dose levels. Normoxic water dissolved with sodium nitrate (NaNO3), another scavenger ofe aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ , and bubbled with N2O was irradiated by x-ray to verify the results of low-LET electron beam. RESULTS UHDR leads to a lower G(H2O2) than conventional irradiation. O2 and CO2 can both increase G(H2O2). N2O increases G(H2O2) of both UHDR and conventional irradiation and eliminates the difference between them for carbon ions. However, N2O decreases G(H2O2) in electron conventional irradiation but increases G(H2O2) in the case of UHDR, ending up with no dose-rate dependency of G(H2O2). Three-spilled carbon UHDR does not have a lower G(H2O2) than one-spilled UHDR. However, the electron beam shows a lower G(H2O2) for three-spilled UHDR than for one-spilled UHDR. Normoxic water with N2O or NaNO3 can both eliminate the dose rate dependency of H2O2 production for x-ray. CONCLUSIONS UHDR has a lower G(H2O2) than the conventional irradiation for both high LET carbon and low LET electron and x-ray beams. Both scavengers fore aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ , N2O and NaNO3, eliminate the dose-rate dependency of G(H2O2), which suggestse aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ is the reason for decreased G(H2O2) for UHDR. Three-spilled UHDR versus one-spilled UHDR indicates that the assumption of residual radicals reducing G(H2O2) of conventional irradiation may only be valid for low LET electron beam.
Collapse
Affiliation(s)
- Tengda Zhang
- Division of Biomedical Physics in Radiation Oncology, German Cancer Research Center, Heidelberg, Germany
- MIISM, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Christina Stengl
- Division of Medical Physics in Radiation Oncology, German Cancer Research Center, Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Larissa Derksen
- University of Applied Sciences, Institute of Medical Physics and Radiation Protection, Giessen, Germany
| | - Kristaps Palskis
- CERN, Geneva, Switzerland
- Riga Technical University, Riga, Latvia
| | - Konstantinos Koritsidis
- Division of Biomedical Physics in Radiation Oncology, German Cancer Research Center, Heidelberg, Germany
- Faculty of Physics, The Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Klemens Zink
- University of Applied Sciences, Institute of Medical Physics and Radiation Protection, Giessen, Germany
- Department of Radiotherapy and Radiation Oncology, Marburg University Hospital, Marburg, Germany
- Marburg Ion-Beam Therapy Center (MIT), Marburg, Germany
| | - Sebastian Adeberg
- Department of Radiotherapy and Radiation Oncology, Marburg University Hospital, Marburg, Germany
- Marburg Ion-Beam Therapy Center (MIT), Marburg, Germany
- Universitäres Centrum für Tumorerkrankungen (UCT) Frankfurt - Marburg, Marburg, Germany
| | - Gerald Major
- Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany
- Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - David Weishaar
- University of Applied Sciences, Institute of Medical Physics and Radiation Protection, Giessen, Germany
| | - Ulrike Theiß
- Marburg Ion-Beam Therapy Center (MIT), Marburg, Germany
- Department of Radiotherapy and Radiation Oncology, Philipps-University, Marburg, Germany
| | - Jing Jin
- State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, CAMS and PUMC, Shenzhen, China
| | - Maria Francesca Spadea
- Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany
| | - Elpida Theodoridou
- Division of Biomedical Physics in Radiation Oncology, German Cancer Research Center, Heidelberg, Germany
- Faculty of Physics, The Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Jürgen Hesser
- MIISM, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Interdisciplinary Center for Scientific Computing (IWR), Central Institute for Computer Engineering (ZITI), CZS Heidelberg Center for Model-Based AI, Heidelberg University, Heidelberg, Germany
| | - Kilian-Simon Baumann
- University of Applied Sciences, Institute of Medical Physics and Radiation Protection, Giessen, Germany
- Department of Radiotherapy and Radiation Oncology, Marburg University Hospital, Marburg, Germany
- Marburg Ion-Beam Therapy Center (MIT), Marburg, Germany
| | - Joao Seco
- Division of Biomedical Physics in Radiation Oncology, German Cancer Research Center, Heidelberg, Germany
- Department of Physics and Astronomy, Heidelberg University, Heidelberg, Germany
| |
Collapse
|
|
16
|
Wanstall HC, Korysko P, Farabolini W, Corsini R, Bateman JJ, Rieker V, Hemming A, Henthorn NT, Merchant MJ, Santina E, Chadwick AL, Robertson C, Malyzhenkov A, Jones RM. VHEE FLASH sparing effect measured at CLEAR, CERN with DNA damage of pBR322 plasmid as a biological endpoint. Sci Rep 2024; 14:14803. [PMID: 38926450 PMCID: PMC11208499 DOI: 10.1038/s41598-024-65055-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 06/17/2024] [Indexed: 06/28/2024] Open
Abstract
Ultra-high dose rate (UHDR) irradiation has been shown to have a sparing effect on healthy tissue, an effect known as 'FLASH'. This effect has been studied across several radiation modalities, including photons, protons and clinical energy electrons, however, very little data is available for the effect of FLASH with Very High Energy Electrons (VHEE). pBR322 plasmid DNA was used as a biological model to measure DNA damage in response to Very High Energy Electron (VHEE) irradiation at conventional (0.08 Gy/s), intermediate (96 Gy/s) and ultra-high dose rates (UHDR, (2 × 109 Gy/s) at the CERN Linear Electron Accelerator (CLEAR) user facility. UHDRs were used to determine if the biological FLASH effect could be measured in the plasmid model, within a hydroxyl scavenging environment. Two different concentrations of the hydroxyl radical scavenger Tris were used in the plasmid environment to alter the proportions of indirect damage, and to replicate a cellular scavenging capacity. Indirect damage refers to the interaction of ionising radiation with molecules and species to generate reactive species which can then attack DNA. UHDR irradiated plasmid was shown to have significantly reduced amounts of damage in comparison to conventionally irradiated, where single strand breaks (SSBs) was used as the biological endpoint. This was the case for both hydroxyl scavenging capacities. A reduced electron energy within the VHEE range was also determined to increase the DNA damage to pBR322 plasmid. Results indicate that the pBR322 plasmid model can be successfully used to explore and test the effect of UHDR regimes on DNA damage. This is the first study to report FLASH sparing with VHEE, with induced damage to pBR322 plasmid DNA as the biological endpoint. UHDR irradiated plasmid had reduced amounts of DNA single-strand breaks (SSBs) in comparison with conventional dose rates. The magnitude of the FLASH sparing was a 27% reduction in SSB frequency in a 10 mM Tris environment and a 16% reduction in a 100 mM Tris environment.
Collapse
Affiliation(s)
- Hannah C Wanstall
- Department of Physics and Astronomy, Faculty of Science and Engineering, University of Manchester, Schuster Building, Oxford Road, Manchester, M13 9PL, UK.
- Manchester Academic Health Science Centre, Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK.
- Daresbury Laboratory, The Cockcroft Institute, Daresbury, Warrington, WA4 4AD, UK.
| | - Pierre Korysko
- University of Oxford, Oxford, OX1 2JD, UK
- CERN, Geneva, 1211, Geneva 23, Switzerland
| | | | | | | | - Vilde Rieker
- CERN, Geneva, 1211, Geneva 23, Switzerland
- University of Oslo, 0316, Oslo, Norway
| | - Abigail Hemming
- Manchester Academic Health Science Centre, Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK
| | - Nicholas T Henthorn
- Manchester Academic Health Science Centre, Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, School of Medical Sciences, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK
| | - Michael J Merchant
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, School of Medical Sciences, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK
| | - Elham Santina
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, School of Medical Sciences, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK
| | - Amy L Chadwick
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, School of Medical Sciences, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK
| | | | | | - Roger M Jones
- Department of Physics and Astronomy, Faculty of Science and Engineering, University of Manchester, Schuster Building, Oxford Road, Manchester, M13 9PL, UK
- Daresbury Laboratory, The Cockcroft Institute, Daresbury, Warrington, WA4 4AD, UK
| |
Collapse
|
|
17
|
Chow JCL, Ruda HE. Mechanisms of Action in FLASH Radiotherapy: A Comprehensive Review of Physicochemical and Biological Processes on Cancerous and Normal Cells. Cells 2024; 13:835. [PMID: 38786057 PMCID: PMC11120005 DOI: 10.3390/cells13100835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/09/2024] [Accepted: 05/11/2024] [Indexed: 05/25/2024] Open
Abstract
The advent of FLASH radiotherapy (FLASH-RT) has brought forth a paradigm shift in cancer treatment, showcasing remarkable normal cell sparing effects with ultra-high dose rates (>40 Gy/s). This review delves into the multifaceted mechanisms underpinning the efficacy of FLASH effect, examining both physicochemical and biological hypotheses in cell biophysics. The physicochemical process encompasses oxygen depletion, reactive oxygen species, and free radical recombination. In parallel, the biological process explores the FLASH effect on the immune system and on blood vessels in treatment sites such as the brain, lung, gastrointestinal tract, skin, and subcutaneous tissue. This review investigated the selective targeting of cancer cells and the modulation of the tumor microenvironment through FLASH-RT. Examining these mechanisms, we explore the implications and challenges of integrating FLASH-RT into cancer treatment. The potential to spare normal cells, boost the immune response, and modify the tumor vasculature offers new therapeutic strategies. Despite progress in understanding FLASH-RT, this review highlights knowledge gaps, emphasizing the need for further research to optimize its clinical applications. The synthesis of physicochemical and biological insights serves as a comprehensive resource for cell biology, molecular biology, and biophysics researchers and clinicians navigating the evolution of FLASH-RT in cancer therapy.
Collapse
Affiliation(s)
- James C. L. Chow
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1X6, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, ON M5T 1P5, Canada
| | - Harry E. Ruda
- Centre of Advance Nanotechnology, Faculty of Applied Science and Engineering, University of Toronto, Toronto, ON M5S 3E4, Canada;
- Department of Materials Science and Engineering, University of Toronto, Toronto, ON M5S 3E4, Canada
| |
Collapse
|
|
18
|
Giannini N, Gadducci G, Fuentes T, Gonnelli A, Di Martino F, Puccini P, Naso M, Pasqualetti F, Capaccioli S, Paiar F. Electron FLASH radiotherapy in vivo studies. A systematic review. Front Oncol 2024; 14:1373453. [PMID: 38655137 PMCID: PMC11035725 DOI: 10.3389/fonc.2024.1373453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 03/15/2024] [Indexed: 04/26/2024] Open
Abstract
FLASH-radiotherapy delivers a radiation beam a thousand times faster compared to conventional radiotherapy, reducing radiation damage in healthy tissues with an equivalent tumor response. Although not completely understood, this radiobiological phenomenon has been proved in several animal models with a spectrum of all kinds of particles currently used in contemporary radiotherapy, especially electrons. However, all the research teams have performed FLASH preclinical studies using industrial linear accelerator or LINAC commonly employed in conventional radiotherapy and modified for the delivery of ultra-high-dose-rate (UHDRs). Unfortunately, the delivering and measuring of UHDR beams have been proved not to be completely reliable with such devices. Concerns arise regarding the accuracy of beam monitoring and dosimetry systems. Additionally, this LINAC totally lacks an integrated and dedicated Treatment Planning System (TPS) able to evaluate the internal dose distribution in the case of in vivo experiments. Finally, these devices cannot modify dose-time parameters of the beam relevant to the flash effect, such as average dose rate; dose per pulse; and instantaneous dose rate. This aspect also precludes the exploration of the quantitative relationship with biological phenomena. The dependence on these parameters need to be further investigated. A promising advancement is represented by a new generation of electron LINAC that has successfully overcome some of these technological challenges. In this review, we aim to provide a comprehensive summary of the existing literature on in vivo experiments using electron FLASH radiotherapy and explore the promising clinical perspectives associated with this technology.
Collapse
Affiliation(s)
- Noemi Giannini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Tuscany, Italy
- Centro Pisano Multidisciplinare Sulla Ricerca e Implementazione Clinica Della Flash Radiotherapy (CPFR), University of Pisa, Pisa, Italy
| | - Giovanni Gadducci
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Tuscany, Italy
- Centro Pisano Multidisciplinare Sulla Ricerca e Implementazione Clinica Della Flash Radiotherapy (CPFR), University of Pisa, Pisa, Italy
| | - Taiusha Fuentes
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Tuscany, Italy
- Centro Pisano Multidisciplinare Sulla Ricerca e Implementazione Clinica Della Flash Radiotherapy (CPFR), University of Pisa, Pisa, Italy
| | - Alessandra Gonnelli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Tuscany, Italy
- Centro Pisano Multidisciplinare Sulla Ricerca e Implementazione Clinica Della Flash Radiotherapy (CPFR), University of Pisa, Pisa, Italy
| | - Fabio Di Martino
- Centro Pisano Multidisciplinare Sulla Ricerca e Implementazione Clinica Della Flash Radiotherapy (CPFR), University of Pisa, Pisa, Italy
- Unit of Medical Physics, Azienda Ospedaliero-Universitaria Pisana, Pisa, Tuscany, Italy
- National Institute of Nuclear Physics (INFN)-section of Pisa, Pisa, Tuscany, Italy
| | - Paola Puccini
- Department of Radiation Oncology, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Tuscany, Italy
| | - Monica Naso
- Department of Radiation Oncology, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Tuscany, Italy
| | - Francesco Pasqualetti
- Department of Radiation Oncology, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Tuscany, Italy
| | - Simone Capaccioli
- Centro Pisano Multidisciplinare Sulla Ricerca e Implementazione Clinica Della Flash Radiotherapy (CPFR), University of Pisa, Pisa, Italy
- Department of Physics, University of Pisa, Pisa, Tuscany, Italy
| | - Fabiola Paiar
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Tuscany, Italy
- Centro Pisano Multidisciplinare Sulla Ricerca e Implementazione Clinica Della Flash Radiotherapy (CPFR), University of Pisa, Pisa, Italy
- Department of Radiation Oncology, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Tuscany, Italy
| |
Collapse
|
|
19
|
Shiraishi Y, Matsuya Y, Fukunaga H. Possible mechanisms and simulation modeling of FLASH radiotherapy. Radiol Phys Technol 2024; 17:11-23. [PMID: 38184508 DOI: 10.1007/s12194-023-00770-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 12/01/2023] [Accepted: 12/02/2023] [Indexed: 01/08/2024]
Abstract
FLASH radiotherapy (FLASH-RT) has great potential to improve patient outcomes. It delivers radiation doses at an ultra-high dose rate (UHDR: ≥ 40 Gy/s) in a single instant or a few pulses. Much higher irradiation doses can be administered to tumors with FLASH-RT than with conventional dose rate (0.01-0.40 Gy/s) radiotherapy. UHDR irradiation can suppress toxicity in normal tissues while sustaining antitumor efficiency, which is referred to as the FLASH effect. However, the mechanisms underlying the effects of the FLASH remain unclear. To clarify these mechanisms, the development of simulation models that can contribute to treatment planning for FLASH-RT is still underway. Previous studies indicated that transient oxygen depletion or augmented reactions between secondary reactive species produced by irradiation may be involved in this process. To discuss the possible mechanisms of the FLASH effect and its clinical potential, we summarized the physicochemical, chemical, and biological perspectives as well as the development of simulation modeling for FLASH-RT.
Collapse
Affiliation(s)
- Yuta Shiraishi
- Graduate School of Health Sciences, Hokkaido University, N12 W5 Kita-Ku, Sapporo, Hokkaido, 060-0812, Japan
- Faculty of Health Sciences, Japan Healthcare University, 3-11-1-50 Tsukisamu-Higashi, Toyohira-Ku, Sapporo, Hokkaido, 062-0053, Japan
| | - Yusuke Matsuya
- Faculty of Health Sciences, Hokkaido University, N12 W5 Kita-Ku, Sapporo, Hokkaido, 060-0812, Japan
| | - Hisanori Fukunaga
- Faculty of Health Sciences, Hokkaido University, N12 W5 Kita-Ku, Sapporo, Hokkaido, 060-0812, Japan.
| |
Collapse
|
|
20
|
Cordoni FG. A spatial measure-valued model for radiation-induced DNA damage kinetics and repair under protracted irradiation condition. J Math Biol 2024; 88:21. [PMID: 38285219 PMCID: PMC10824812 DOI: 10.1007/s00285-024-02046-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 10/01/2023] [Accepted: 12/27/2023] [Indexed: 01/30/2024]
Abstract
In the present work, we develop a general spatial stochastic model to describe the formation and repair of radiation-induced DNA damage. The model is described mathematically as a measure-valued particle-based stochastic system and extends in several directions the model developed in Cordoni et al. (Phys Rev E 103:012412, 2021; Int J Radiat Biol 1-16, 2022a; Radiat Res 197:218-232, 2022b). In this new spatial formulation, radiation-induced DNA damage in the cell nucleus can undergo different pathways to either repair or lead to cell inactivation. The main novelty of the work is to rigorously define a spatial model that considers the pairwise interaction of lesions and continuous protracted irradiation. The former is relevant from a biological point of view as clustered lesions are less likely to be repaired, leading to cell inactivation. The latter instead describes the effects of a continuous radiation field on biological tissue. We prove the existence and uniqueness of a solution to the above stochastic systems, characterizing its probabilistic properties. We further couple the model describing the biological system to a set of reaction-diffusion equations with random discontinuity that model the chemical environment. At last, we study the large system limit of the process. The developed model can be applied to different contexts, with radiotherapy and space radioprotection being the most relevant. Further, the biochemical system derived can play a crucial role in understanding an extremely promising novel radiotherapy treatment modality, named in the community FLASH radiotherapy, whose mechanism is today largely unknown.
Collapse
|
|
21
|
Rudigkeit S, Schmid TE, Dombrowsky AC, Stolz J, Bartzsch S, Chen CB, Matejka N, Sammer M, Bergmaier A, Dollinger G, Reindl J. Proton-FLASH: effects of ultra-high dose rate irradiation on an in-vivo mouse ear model. Sci Rep 2024; 14:1418. [PMID: 38228747 PMCID: PMC10791610 DOI: 10.1038/s41598-024-51951-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 01/11/2024] [Indexed: 01/18/2024] Open
Abstract
FLASH-radiotherapy may provide significant sparing of healthy tissue through ultra-high dose rates in protons, electrons, and x-rays while maintaining the tumor control. Key factors for the FLASH effect might be oxygen depletion, the immune system, and the irradiated blood volume, but none could be fully confirmed yet. Therefore, further investigations are necessary. We investigated the protective (tissue sparing) effect of FLASH in proton treatment using an in-vivo mouse ear model. The right ears of Balb/c mice were irradiated with 20 MeV protons at the ion microprobe SNAKE in Garching near Munich by using three dose rates (Conv = 0.06 Gy/s, Flash9 = 9.3 Gy/s and Flash930 = 930 Gy/s) at a total dose of 23 Gy or 33 Gy. The ear thickness, desquamation, and erythema combined in an inflammation score were measured for 180 days. The cytokines TGF-β1, TNF-α, IL1α, and IL1β were analyzed in the blood sampled in the first 4 weeks and at termination day. No differences in inflammation reactions were visible in the 23 Gy group for the different dose rates. In the 33 Gy group, the ear swelling and the inflammation score for Flash9 was reduced by (57 ± 12) % and (67 ± 17) % and for Flash930 by (40 ± 13) % and (50 ± 17) % compared to the Conv dose rate. No changes in the cytokines in the blood could be measured. However, an estimation of the irradiated blood volume demonstrates, that 100-times more blood is irradiated when using Conv compared to using Flash9 or Flash930. This indicates that blood might play a role in the underlying mechanisms in the protective effect of FLASH.
Collapse
Affiliation(s)
- Sarah Rudigkeit
- Institute of Applied Physics and Measurement Technologies, Universität der Bundeswehr München, Neubiberg, Germany
| | - Thomas E Schmid
- Institute of Radiation Medicine (IRM), Helmholtz Zentrum München, Neuherberg, Germany
- Department of Radiooncology, School of Medicine, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Annique C Dombrowsky
- Institute of Radiation Medicine (IRM), Helmholtz Zentrum München, Neuherberg, Germany
| | - Jessica Stolz
- Institute of Radiation Medicine (IRM), Helmholtz Zentrum München, Neuherberg, Germany
| | - Stefan Bartzsch
- Institute of Radiation Medicine (IRM), Helmholtz Zentrum München, Neuherberg, Germany
- Department of Radiooncology, School of Medicine, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Ce-Belle Chen
- Centre for Ion Beam Applications, Department of Physics, National University of Singapore, Singapore, Singapore
- Singapore Synchrotron Light Source, National University of Singapore, Singapore, Singapore
| | - Nicole Matejka
- Institute of Applied Physics and Measurement Technologies, Universität der Bundeswehr München, Neubiberg, Germany
| | - Matthias Sammer
- Institute of Applied Physics and Measurement Technologies, Universität der Bundeswehr München, Neubiberg, Germany
| | - Andreas Bergmaier
- Institute of Applied Physics and Measurement Technologies, Universität der Bundeswehr München, Neubiberg, Germany
| | - Günther Dollinger
- Institute of Applied Physics and Measurement Technologies, Universität der Bundeswehr München, Neubiberg, Germany
| | - Judith Reindl
- Institute of Applied Physics and Measurement Technologies, Universität der Bundeswehr München, Neubiberg, Germany.
| |
Collapse
|
|
22
|
Shiraishi Y, Matsuya Y, Kusumoto T, Fukunaga H. Modeling for predicting survival fraction of cells after ultra-high dose rate irradiation. Phys Med Biol 2023; 69:015017. [PMID: 38056015 DOI: 10.1088/1361-6560/ad131b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 12/06/2023] [Indexed: 12/08/2023]
Abstract
Objective. FLASH radiotherapy (FLASH-RT) with ultra-high dose rate (UHDR) irradiation (i.e. > 40 Gy s-1) spares the function of normal tissues while preserving antitumor efficacy, known as the FLASH effect. The biological effects after conventional dose rate-radiotherapy (CONV-RT) with ≤0.1 Gy s-1have been well modeled by considering microdosimetry and DNA repair processes, meanwhile modeling of radiosensitivities under UHDR irradiation is insufficient. Here, we developed anintegrated microdosimetric-kinetic(IMK)model for UHDR-irradiationenabling the prediction of surviving fraction after UHDR irradiation.Approach.TheIMK model for UHDR-irradiationconsiders the initial DNA damage yields by the modification of indirect effects under UHDR compared to CONV dose rate. The developed model is based on the linear-quadratic (LQ) nature with the dose and dose square coefficients, considering the reduction of DNA damage yields as a function of dose rate.Main results.The estimate by the developed model could successfully reproduce thein vitroexperimental dose-response curve for various cell line types and dose rates.Significance.The developed model would be useful for predicting the biological effects under the UHDR irradiation.
Collapse
Affiliation(s)
- Yuta Shiraishi
- Graduate school of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan
- Faculty of Health Sciences, Japan Healthcare University, 3-11-1-50 Tsukisamu-higashi, Toyohira-ku, Sapporo, Hokkaido, 062-0053, Japan
| | - Yusuke Matsuya
- Faculty of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan
- Nuclear Science and Engineering Center, Japan Atomic Energy Agency, 2-4 Shirakata, Tokai, Ibaraki, 319-1195, Japan
| | - Tamon Kusumoto
- National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan
| | - Hisanori Fukunaga
- Faculty of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan
| |
Collapse
|
|
23
|
Gupta S, Inman JL, De Chant J, Obst-Huebl L, Nakamura K, Costello SM, Marqusee S, Mao JH, Kunz L, Paisley R, Vozenin MC, Snijders AM, Ralston CY. A Novel Platform for Evaluating Dose Rate Effects on Oxidative Damage to Peptides: Toward a High-Throughput Method to Characterize the Mechanisms Underlying the FLASH Effect. Radiat Res 2023; 200:523-530. [PMID: 38014573 PMCID: PMC10754258 DOI: 10.1667/rade-23-00131.1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 10/05/2023] [Indexed: 11/29/2023]
Abstract
High dose rate radiation has gained considerable interest recently as a possible avenue for increasing the therapeutic window in cancer radiation treatment. The sparing of healthy tissue at high dose rates relative to conventional dose rates, while maintaining tumor control, has been termed the FLASH effect. Although the effect has been validated in animal models using multiple radiation sources, it is not yet well understood. Here, we demonstrate a new experimental platform for quantifying oxidative damage to protein sidechains in solution as a function of radiation dose rate and oxygen availability using liquid chromatography mass spectrometry. Using this reductionist approach, we show that for both X-ray and electron sources, isolated peptides in solution are oxidatively modified to different extents as a function of both dose rate and oxygen availability. Our method provides an experimental platform for exploring the parameter space of the dose rate effect on oxidative changes to proteins in solution.
Collapse
Affiliation(s)
- Sayan Gupta
- Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720
| | - Jamie L. Inman
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720
| | - Jared De Chant
- Accelerator Technology and Applied Physics Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720
| | - Lieselotte Obst-Huebl
- Accelerator Technology and Applied Physics Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720
| | - Kei Nakamura
- Accelerator Technology and Applied Physics Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720
| | - Shawn M. Costello
- Biophysics Graduate Program, Department of Chemistry; California Institute for Quantitative Biosciences, University of California, Berkeley, Califormia; Chan Zuckerberg Biohub, San Francisco, California
| | - Susan Marqusee
- Department of Molecular and Cell Biology, Department of Chemistry; California Institute for Quantitative Biosciences, University of California, Berkeley, Califormia; Chan Zuckerberg Biohub, San Francisco, California
| | - Jian-Hua Mao
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720
| | - Louis Kunz
- University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Ryan Paisley
- University Hospital and University of Lausanne, Lausanne, Switzerland
| | | | - Antoine M. Snijders
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720
| | - Corie Y. Ralston
- Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720
| |
Collapse
|
|
24
|
Siddique S, Ruda HE, Chow JCL. FLASH Radiotherapy and the Use of Radiation Dosimeters. Cancers (Basel) 2023; 15:3883. [PMID: 37568699 PMCID: PMC10417829 DOI: 10.3390/cancers15153883] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 07/27/2023] [Accepted: 07/27/2023] [Indexed: 08/13/2023] Open
Abstract
Radiotherapy (RT) using ultra-high dose rate (UHDR) radiation, known as FLASH RT, has shown promising results in reducing normal tissue toxicity while maintaining tumor control. However, implementing FLASH RT in clinical settings presents technical challenges, including limited depth penetration and complex treatment planning. Monte Carlo (MC) simulation is a valuable tool for dose calculation in RT and has been investigated for optimizing FLASH RT. Various MC codes, such as EGSnrc, DOSXYZnrc, and Geant4, have been used to simulate dose distributions and optimize treatment plans. Accurate dosimetry is essential for FLASH RT, and radiation detectors play a crucial role in measuring dose delivery. Solid-state detectors, including diamond detectors such as microDiamond, have demonstrated linear responses and good agreement with reference detectors in UHDR and ultra-high dose per pulse (UHDPP) ranges. Ionization chambers are commonly used for dose measurement, and advancements have been made to address their response nonlinearities at UHDPP. Studies have proposed new calculation methods and empirical models for ion recombination in ionization chambers to improve their accuracy in FLASH RT. Additionally, strip-segmented ionization chamber arrays have shown potential for the experimental measurement of dose rate distribution in proton pencil beam scanning. Radiochromic films, such as GafchromicTM EBT3, have been used for absolute dose measurement and to validate MC simulation results in high-energy X-rays, triggering the FLASH effect. These films have been utilized to characterize ionization chambers and measure off-axis and depth dose distributions in FLASH RT. In conclusion, MC simulation provides accurate dose calculation and optimization for FLASH RT, while radiation detectors, including diamond detectors, ionization chambers, and radiochromic films, offer valuable tools for dosimetry in UHDR environments. Further research is needed to refine treatment planning techniques and improve detector performance to facilitate the widespread implementation of FLASH RT, potentially revolutionizing cancer treatment.
Collapse
Affiliation(s)
- Sarkar Siddique
- Department of Physics, Toronto Metropolitan University, Toronto, ON M5B 2K3, Canada;
| | - Harry E. Ruda
- Centre of Advance Nanotechnology, Faculty of Applied Science and Engineering, University of Toronto, Toronto, ON M5S 3E4, Canada;
- Department of Materials Science and Engineering, University of Toronto, Toronto, ON M5S 3E4, Canada
| | - James C. L. Chow
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1X6, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, ON M5T 1P5, Canada
| |
Collapse
|
|
25
|
Atkinson J, Bezak E, Le H, Kempson I. The current status of FLASH particle therapy: a systematic review. Phys Eng Sci Med 2023; 46:529-560. [PMID: 37160539 DOI: 10.1007/s13246-023-01266-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 04/20/2023] [Indexed: 05/11/2023]
Abstract
Particle therapies are becoming increasingly available clinically due to their beneficial energy deposition profile, sparing healthy tissues. This may be further promoted with ultra-high dose rates, termed FLASH. This review comprehensively summarises current knowledge based on studies relevant to proton- and carbon-FLASH therapy. As electron-FLASH literature presents important radiobiological findings that form the basis of proton and carbon-based FLASH studies, a summary of key electron-FLASH papers is also included. Preclinical data suggest three key mechanisms by which proton and carbon-FLASH are able to reduce normal tissue toxicities compared to conventional dose rates, with equipotent, or enhanced, tumour kill efficacy. However, a degree of caution is needed in clinically translating these findings as: most studies use transmission and do not conform the Bragg peak to tumour volume; mechanistic understanding is still in its infancy; stringent verification of dosimetry is rarely provided; biological assays are prone to limitations which need greater acknowledgement.
Collapse
Affiliation(s)
- Jake Atkinson
- Future Industries Institute, University of South Australia, Mawson Lakes, South Australia, 5095, Australia
| | - Eva Bezak
- Cancer Research Institute, University of South Australia, Adelaide, South Australia, 5000, Australia
- Department of Physics, University of Adelaide, North Terrace, Adelaide, South Australia, 5000, Australia
| | - Hien Le
- Department of Radiation Oncology, Royal Adelaide Hospital, Adelaide, 5000, Australia
| | - Ivan Kempson
- Future Industries Institute, University of South Australia, Mawson Lakes, South Australia, 5095, Australia.
| |
Collapse
|
|
26
|
Froidevaux P, Grilj V, Bailat C, Geyer WR, Bochud F, Vozenin MC. FLASH irradiation does not induce lipid peroxidation in lipids micelles and liposomes. Radiat Phys Chem Oxf Engl 1993 2023. [DOI: 10.1016/j.radphyschem.2022.110733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
|
|
27
|
Liew H, Mein S, Tessonnier T, Abdollahi A, Debus J, Dokic I, Mairani A. Do We Preserve Tumor Control Probability (TCP) in FLASH Radiotherapy? A Model-Based Analysis. Int J Mol Sci 2023; 24:5118. [PMID: 36982185 PMCID: PMC10049554 DOI: 10.3390/ijms24065118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/01/2023] [Accepted: 03/02/2023] [Indexed: 03/30/2023] Open
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 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.
Collapse
Affiliation(s)
- Hans Liew
- Clinical Cooperation Unit Translational Radiation Oncology, German Cancer Consortium (DKTK) Core-Center Heidelberg, National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Division of Molecular and Translational Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), 69120 Heidelberg, Germany
- Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Oncology (NCRO), Heidelberg University Hospital and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Stewart Mein
- Clinical Cooperation Unit Translational Radiation Oncology, German Cancer Consortium (DKTK) Core-Center Heidelberg, National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Division of Molecular and Translational Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), 69120 Heidelberg, Germany
- Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Oncology (NCRO), Heidelberg University Hospital and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104-6303, USA
| | - Thomas Tessonnier
- Heidelberg Ion-Beam Therapy Center (HIT), Department of Radiation Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Amir Abdollahi
- Clinical Cooperation Unit Translational Radiation Oncology, German Cancer Consortium (DKTK) Core-Center Heidelberg, National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Division of Molecular and Translational Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), 69120 Heidelberg, Germany
- Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Oncology (NCRO), Heidelberg University Hospital and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Jürgen Debus
- Division of Molecular and Translational Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), 69120 Heidelberg, Germany
- Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Oncology (NCRO), Heidelberg University Hospital and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Department of Radiation Oncology, Heidelberg Institute of Radiation Oncology (HIRO), University Hospital Heidelberg, National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany
- Clinical Cooperation Unit Radiation Oncology, German Cancer Consortium (DKTK) Core-Center Heidelberg, National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Ivana Dokic
- Clinical Cooperation Unit Translational Radiation Oncology, German Cancer Consortium (DKTK) Core-Center Heidelberg, National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Division of Molecular and Translational Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), 69120 Heidelberg, Germany
- Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Oncology (NCRO), Heidelberg University Hospital and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Andrea Mairani
- Heidelberg Ion-Beam Therapy Center (HIT), Department of Radiation Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany
- Medical Physics Unit, National Centre of Oncological Hadrontherapy (CNAO), 27100 Pavia, Italy
| |
Collapse
|
|
28
|
Lv Y, Lv Y, Wang Z, Lan T, Feng X, Chen H, Zhu J, Ma X, Du J, Hou G, Liao W, Yuan K, Wu H. FLASH radiotherapy: A promising new method for radiotherapy. Oncol Lett 2022; 24:419. [PMID: 36284652 PMCID: PMC9580247 DOI: 10.3892/ol.2022.13539] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/10/2022] [Indexed: 11/06/2022] Open
Abstract
Among the treatments for malignant tumors, radiotherapy is of great significance both as a main treatment and as an adjuvant treatment. Radiation therapy damages cancer cells with ionizing radiation, leading to their death. However, radiation-induced toxicity limits the dose delivered to the tumor, thereby constraining the control effect of radiotherapy on tumor growth. In addition, the delayed toxicity caused by radiotherapy significantly harms the physical and mental health of patients. FLASH-RT, an emerging class of radiotherapy, causes a phenomenon known as the 'FLASH effect', which delivers radiotherapy at an ultra-high dose rate with lower toxicity to normal tissue than conventional radiotherapy to achieve local tumor control. Although its mechanism remains to be fully elucidated, this modality constitutes a potential new approach to treating malignant tumors. In the present review, the current research progress of FLASH-RT and its various particular effects are described, including the status of research on FLASH-RT and its influencing factors. The hypothetic mechanism of action of FLASH-RT is also summarized, providing insight into future tumor treatments.
Collapse
Affiliation(s)
- Yinghao Lv
- Department of Liver Surgery and Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, Sichuan University and Collaborative Innovation Center of Biotherapy, West China Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Yue Lv
- Department of Liver Surgery and Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, Sichuan University and Collaborative Innovation Center of Biotherapy, West China Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Zhen Wang
- Department of Liver Surgery and Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, Sichuan University and Collaborative Innovation Center of Biotherapy, West China Hospital, Chengdu, Sichuan 610000, P.R. China
- Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610000, P.R. China
| | - Tian Lan
- Department of Liver Surgery and Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, Sichuan University and Collaborative Innovation Center of Biotherapy, West China Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Xuping Feng
- Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610000, P.R. China
| | - Hao Chen
- Department of Liver Surgery and Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, Sichuan University and Collaborative Innovation Center of Biotherapy, West China Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Jiang Zhu
- Department of Liver Surgery and Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, Sichuan University and Collaborative Innovation Center of Biotherapy, West China Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Xiao Ma
- Department of Liver Surgery and Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, Sichuan University and Collaborative Innovation Center of Biotherapy, West China Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Jinpeng Du
- Department of Liver Surgery and Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, Sichuan University and Collaborative Innovation Center of Biotherapy, West China Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Guimin Hou
- Department of Liver Surgery and Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, Sichuan University and Collaborative Innovation Center of Biotherapy, West China Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Wenwei Liao
- Department of Liver Surgery and Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, Sichuan University and Collaborative Innovation Center of Biotherapy, West China Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Kefei Yuan
- Department of Liver Surgery and Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, Sichuan University and Collaborative Innovation Center of Biotherapy, West China Hospital, Chengdu, Sichuan 610000, P.R. China
- Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610000, P.R. China
| | - Hong Wu
- Department of Liver Surgery and Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, Sichuan University and Collaborative Innovation Center of Biotherapy, West China Hospital, Chengdu, Sichuan 610000, P.R. China
- Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610000, P.R. China
| |
Collapse
|
|
29
|
Kc S, Abolfath R. Towards the ionizing radiation induced bond dissociation mechanism in oxygen, water, guanine and DNA fragmentation: a density functional theory simulation. Sci Rep 2022; 12:19853. [PMID: 36400823 PMCID: PMC9674679 DOI: 10.1038/s41598-022-23727-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 11/04/2022] [Indexed: 11/19/2022] Open
Abstract
The radiation-induced damages in bio-molecules are ubiquitous processes in radiotherapy and radio-biology, and critical to space projects. In this study, we present a precise quantification of the fragmentation mechanisms of deoxyribonucleic acid (DNA) and the molecules surrounding DNA such as oxygen and water under non-equilibrium conditions using the first-principle calculations based on density functional theory (DFT). Our results reveal the structural stability of DNA bases and backbone that withstand up to a combined threshold of charge and hydrogen abstraction owing to simultaneously direct and indirect ionization processes. We show the hydrogen contents of the molecules significantly control the stability in the presence of radiation. This study provides comprehensive information on the impact of the direct and indirect induced bond dissociations and DNA damage and introduces a systematic methodology for fine-tuning the input parameters necessary for the large-scale Monte Carlo simulations of radio-biological responses and mitigation of detrimental effects of ionizing radiation.
Collapse
Affiliation(s)
- Santosh Kc
- Chemical and Materials Engineering, San José State University, San José, CA, 95192, USA.
| | - Ramin Abolfath
- Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, TX, 75031, USA.
| |
Collapse
|
|
30
|
Gao Y, Liu R, Chang C, Charyyev S, Zhou J, Bradley JD, Liu T, Yang X. A potential revolution in cancer treatment: A topical review of FLASH radiotherapy. J Appl Clin Med Phys 2022; 23:e13790. [PMID: 36168677 PMCID: PMC9588273 DOI: 10.1002/acm2.13790] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 07/08/2022] [Accepted: 09/01/2022] [Indexed: 11/26/2022] Open
Abstract
FLASH radiotherapy (RT) is a novel technique in which the ultrahigh dose rate (UHDR) (≥40 Gy/s) is delivered to the entire treatment volume. Recent outcomes of in vivo studies show that the UHDR RT has the potential to spare normal tissue without sacrificing tumor control. There is a growing interest in the application of FLASH RT, and the ultrahigh dose irradiation delivery has been achieved by a few experimental and modified linear accelerators. The underlying mechanism of FLASH effect is yet to be fully understood, but the oxygen depletion in normal tissue providing extra protection during FLASH irradiation is a hypothesis that attracts most attention currently. Monte Carlo simulation is playing an important role in FLASH, enabling the understanding of its dosimetry calculations and hardware design. More advanced Monte Carlo simulation tools are under development to fulfill the challenge of reproducing the radiolysis and radiobiology processes in FLASH irradiation. FLASH RT may become one of standard treatment modalities for tumor treatment in the future. This paper presents the history and status of FLASH RT studies with a focus on FLASH irradiation delivery modalities, underlying mechanism of FLASH effect, in vivo and vitro experiments, and simulation studies. Existing challenges and prospects of this novel technique are discussed in this manuscript.
Collapse
Affiliation(s)
- Yuan Gao
- Department of Radiation Oncology and Winship Cancer InstituteEmory UniversityAtlantaGeorgiaUSA
| | - Ruirui Liu
- Department of Radiation Oncology and Winship Cancer InstituteEmory UniversityAtlantaGeorgiaUSA
| | - Chih‐Wei Chang
- Department of Radiation Oncology and Winship Cancer InstituteEmory UniversityAtlantaGeorgiaUSA
| | - Serdar Charyyev
- Department of Radiation Oncology and Winship Cancer InstituteEmory UniversityAtlantaGeorgiaUSA
| | - Jun Zhou
- Department of Radiation Oncology and Winship Cancer InstituteEmory UniversityAtlantaGeorgiaUSA
| | - Jeffrey D. Bradley
- Department of Radiation Oncology and Winship Cancer InstituteEmory UniversityAtlantaGeorgiaUSA
| | - Tian Liu
- Department of Radiation Oncology and Winship Cancer InstituteEmory UniversityAtlantaGeorgiaUSA
| | - Xiaofeng Yang
- Department of Radiation Oncology and Winship Cancer InstituteEmory UniversityAtlantaGeorgiaUSA
| |
Collapse
|
|
31
|
Lin B, Huang D, Gao F, Yang Y, Wu D, Zhang Y, Feng G, Dai T, Du X. Mechanisms of FLASH effect. Front Oncol 2022; 12:995612. [PMID: 36212435 PMCID: PMC9537695 DOI: 10.3389/fonc.2022.995612] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022] Open
Abstract
FLASH radiotherapy (FLASH-RT) is a novel radiotherapy technology defined as ultra-high dose rate (≥ 40 Gy/s) radiotherapy. The biological effects of FLASH-RT include two aspects: first, compared with conventional dose rate radiotherapy, FLASH-RT can reduce radiation-induced damage in healthy tissue, and second, FLASH-RT can retain antitumor effectiveness. Current research shows that mechanisms of the biological effects of FLASH-RT are related to oxygen. However, due to the short time of FLASH-RT, evidences related to the mechanisms are indirect, and the exact mechanisms of the biological effects of FLASH-RT are not completely clear and some are even contradictory. This review focuses on the mechanisms of the biological effects of FLASH-RT and proposes future research directions.
Collapse
Affiliation(s)
- Binwei Lin
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, Department of Oncology, Mianyang Central Hospital, Mianyang, China
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Dan Huang
- Department of Radiology Mianyang Central Hospital, Mianyang, China
| | - Feng Gao
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, Department of Oncology, Mianyang Central Hospital, Mianyang, China
| | - Yiwei Yang
- Institute of Applied Electronics, China Academy of Engineering Physics, Mianyang, China
| | - Dai Wu
- Institute of Applied Electronics, China Academy of Engineering Physics, Mianyang, China
| | - Yu Zhang
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, Department of Oncology, Mianyang Central Hospital, Mianyang, China
| | - Gang Feng
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, Department of Oncology, Mianyang Central Hospital, Mianyang, China
| | - Tangzhi Dai
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, Department of Oncology, Mianyang Central Hospital, Mianyang, China
| | - Xiaobo Du
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, Department of Oncology, Mianyang Central Hospital, Mianyang, China
| |
Collapse
|
|
32
|
Van den Heuvel F, Vella A, Fiorini F, Brooke M, Hill M, Ryan A, Maughan T, Giaccia A. Using oxygen dose histograms to quantify voxelised ultra-high dose rate (FLASH) effects in multiple radiation modalities. Phys Med Biol 2022; 67:125001. [PMID: 35594854 PMCID: PMC9174700 DOI: 10.1088/1361-6560/ac71ef] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 04/15/2022] [Accepted: 05/20/2022] [Indexed: 11/12/2022]
Abstract
Purpose.To introduce a methodology to predict tissue sparing effects in pulsed ultra-high dose rate radiation exposures which could be included in a dose-effect prediction system or treatment planning system and to illustrate it by using three published experiments.Methods and materials.The proposed system formalises the variability of oxygen levels as an oxygen dose histogram (ODH), which provides an instantaneous oxygen level at a delivered dose. The histogram concept alleviates the need for a mechanistic approach. At each given oxygen level the oxygen fixation concept is used to calculate the change in DNA-damage induction compared to the fully hypoxic case. Using the ODH concept it is possible to estimate the effect even in the case of multiple pulses, partial oxygen depletion, and spatial oxygen depletion. The system is illustrated by applying it to the seminal results by Town (Nat. 1967) on cell cultures and the pre-clinical experiment on cognitive effects by Montay-Gruelet al(2017Radiother. Oncol.124365-9).Results.The proposed system predicts that a possible FLASH-effect depends on the initial oxygenation level in tissue, the total dose delivered, pulse length and pulse repetition rate. The magnitude of the FLASH-effect is the result of a redundant system, in that it will have the same specific value for a different combination of these dependencies. The cell culture data are well represented, while a correlation between the pre-clinical experiments and the calculated values is highly significant (p < 0.01).Conclusions. A system based only on oxygen related effects is able to quantify most of the effects currently observed in FLASH-radiation.
Collapse
Affiliation(s)
- Frank Van den Heuvel
- University of Oxford, Department of Oncology, Oxford, United Kingdom
- Radiation Oncology, Zuidwest Radiotherapeutic Institute, Vlissingen (Flushing), Zeeland, The Netherlands
| | - Anna Vella
- University of Oxford, Department of Oncology, Oxford, United Kingdom
- Oxford University Hospitals, Department of Hæmatology & Oncology, Oxford, United Kingdom
| | - Francesca Fiorini
- University of Oxford, Department of Oncology, Oxford, United Kingdom
- Rutherford Cancer Centre Thames Valley, Reading, United Kingdom
| | - Mark Brooke
- University of Oxford, Department of Oncology, Oxford, United Kingdom
| | - Mark Hill
- University of Oxford, Department of Oncology, Oxford, United Kingdom
| | - Anderson Ryan
- University of Oxford, Department of Oncology, Oxford, United Kingdom
| | - Tim Maughan
- University of Oxford, Department of Oncology, Oxford, United Kingdom
- Oxford University Hospitals, Department of Hæmatology & Oncology, Oxford, United Kingdom
| | - Amato Giaccia
- University of Oxford, Department of Oncology, Oxford, United Kingdom
| |
Collapse
|
|
33
|
Abolfath R, Baikalov A, Bartzsch S, Afshordi N, Mohan R. The effect of non-ionizing excitations on the diffusion of ion species and inter-track correlations in FLASH ultra-high dose rate radiotherapy. Phys Med Biol 2022; 67. [PMID: 35453139 DOI: 10.1088/1361-6560/ac69a6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 04/22/2022] [Indexed: 12/17/2022]
Abstract
Purpose. We present a microscopic mechanism that accounts for the outward burst of 'cold' ion species (IS) in a high-energy particle track due to coupling with 'hot' non-ion species (NIS). IS refers to radiolysis products of ionized molecules, whereas NIS refers to non-ionized excitations of molecules in a medium. The interaction is mediated by a quantized field of acoustic phonons, a channel that allows conversion of thermal energy of NIS to kinetic energy of IS, a flow of heat from the outer to the inner core of the track structure.Methods. We perform step-by-step Monte Carlo (MC) simulations of ionizing radiation track structures in water to score the spatial coordinates and energy depositions that form IS and NIS at atto-second time scales. We subsequently calculate the resulting temperature profiles of the tracks with MC track structure simulations and verify the results analytically using the Rutherford scattering formulation. These temperature profiles are then used as boundary conditions in a series of multi-scale atomistic molecular dynamic (MD) simulations that describe the sudden expansion and enhanced diffusive broadening of tracks initiated by the non-equilibrium spectrum of high-energy IS. We derive a stochastic coarse-grained Langevin equation of motion for IS from first-principle MD to describe the irreversible femto-second flow of thermal energy pumping from NIS to IS, mediated by quantized fields of acoustic phonons. A pair-wise Lennard-Jones potential implemented in a classical MD is then employed to validate the results calculated from the Langevin equation.Results. We demonstrate the coexistence of 'hot' NIS with 'cold' IS in the radiation track structures right after their generation. NIS, concentrated within nano-scale volumes wrapping around IS, are the main source of intensive heat-waves and the outward burst of IS due to femto-second time scale IS-NIS coupling. By comparing the transport of IS coupled to NIS with identical configurations of non-interacting IS in thermal equilibrium at room temperature, we demonstrate that the energy gain of IS due to the surrounding hot nanoscopic volumes of NIS significantly increases their effective diffusion constants. Comparing the average track separation and the time scale calculated for a deposited dose of 10 Gy and a dose rate of 40 Gy s-1, typical values used in FLASH ultra high dose rate (UHDR) experiments, we find that the sudden expansion of tracks and ballistic transport proposed in this work strengthens the hypothesis of inter-track correlations recently introduced to interpret mitigation of the biological responses at the FLASH-UHDR (Abolfathet al2020Med. Phys.47, 6551-6561).Conclusions. The much higher diffusion constants predicted in the present model suggest higher inter-track chemical reaction rates at FLASH-UHDR, as well as lower intra-track reaction rates. This study explains why research groups relying on the current Monte Carlo frameworks have reported negligible inter-track overlaps, simply because of underestimation of the diffusion constants. We recommend incorporation of the IS-NIS coupling and heat exchange in all MC codes to enable these tool-kits to appropriately model reaction-diffusion rates at FLASH-UHDR.Novelty. To introduce a hypothetical pathway of outward burst of radiolysis products driven by highly localized thermal spikes wrapping around them and to investigate the interplay of the non-equilibrium spatio-temporal distribution of the chemical activities of diffusive high-energy particle tracks on inter-track correlations at FLASH-UHDR.
Collapse
Affiliation(s)
- Ramin Abolfath
- Department of Radiation Physics and Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 75031, United States of America
| | - Alexander Baikalov
- Technical University of Munich, Department of Physics, Garching, Germany.,Helmholtz Zentrum München GmbH, German Research Center for Environmental Health, Institute of Radiation Medicine, Neuherberg, Germany
| | - Stefan Bartzsch
- Helmholtz Zentrum München GmbH, German Research Center for Environmental Health, Institute of Radiation Medicine, Neuherberg, Germany.,Technical University of Munich, School of Medicine and Klinikum Rechts der Isar, Department of Radiation Oncology, Munich, Germany
| | | | - Radhe Mohan
- Department of Radiation Physics and Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 75031, United States of America
| |
Collapse
|
|
34
|
Chaudhary P, Gwynne DC, Odlozilik B, McMurray A, Milluzzo G, Maiorino C, Doria D, Ahmed H, Romagnani L, Alejo A, Padda H, Green J, Carroll D, Booth N, McKenna P, Kar S, Petringa G, Catalano R, Cammarata FP, Cirrone GAP, McMahon SJ, Prise KM, Borghesi M. Development of a portable hypoxia chamber for ultra-high dose rate laser-driven proton radiobiology applications. Radiat Oncol 2022; 17:77. [PMID: 35428301 PMCID: PMC9013042 DOI: 10.1186/s13014-022-02024-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 03/03/2022] [Indexed: 11/22/2022] Open
Abstract
Background There is currently significant interest in assessing the role of oxygen in the radiobiological effects at ultra-high dose rates. Oxygen modulation is postulated to play a role in the enhanced sparing effect observed in FLASH radiotherapy, where particles are delivered at 40–1000 Gy/s. Furthermore, the development of laser-driven accelerators now enables radiobiology experiments in extreme regimes where dose rates can exceed 109 Gy/s, and predicted oxygen depletion effects on cellular response can be tested. Access to appropriate experimental enviroments, allowing measurements under controlled oxygenation conditions, is a key requirement for these studies. We report on the development and application of a bespoke portable hypoxia chamber specifically designed for experiments employing laser-driven sources, but also suitable for comparator studies under FLASH and conventional irradiation conditions. Materials and methods We used oxygen concentration measurements to test the induction of hypoxia and the maintenance capacity of the chambers. Cellular hypoxia induction was verified using hypoxia inducible factor-1α immunostaining. Calibrated radiochromic films and GEANT-4 simulations verified the dosimetry variations inside and outside the chambers. We irradiated hypoxic human skin fibroblasts (AG01522B) cells with laser-driven protons, conventional protons and reference 225 kVp X-rays to quantify DNA DSB damage and repair under hypoxia. We further measured the oxygen enhancement ratio for cell survival after X-ray exposure in normal fibroblast and radioresistant patient- derived GBM stem cells. Results Oxygen measurements showed that our chambers maintained a radiobiological hypoxic environment for at least 45 min and pathological hypoxia for up to 24 h after disconnecting the chambers from the gas supply. We observed a significant reduction in the 53BP1 foci induced by laser-driven protons, conventional protons and X-rays in the hypoxic cells compared to normoxic cells at 30 min post-irradiation. Under hypoxic irradiations, the Laser-driven protons induced significant residual DNA DSB damage in hypoxic AG01522B cells compared to the conventional dose rate protons suggesting an important impact of these extremely high dose-rate exposures. We obtained an oxygen enhancement ratio (OER) of 2.1 ± 0.1 and 2.5 ± 0.1 respectively for the AG01522B and patient-derived GBM stem cells for X-ray irradiation using our hypoxia chambers. Conclusion We demonstrated the design and application of portable hypoxia chambers for studying cellular radiobiological endpoints after exposure to laser-driven protons at ultra-high dose, conventional protons and X-rays. Suitable levels of reduced oxygen concentration could be maintained in the absence of external gassing to quantify hypoxic effects. The data obtained provided indication of an enhanced residual DNA DSB damage under hypoxic conditions at ultra-high dose rate compared to the conventional protons or X-rays. Supplementary Information The online version contains supplementary material available at 10.1186/s13014-022-02024-3.
Collapse
|
|
35
|
Romano F, Bailat C, Jorge PG, Lerch MLF, Darafsheh A. Ultra‐high dose rate dosimetry: challenges and opportunities for FLASH radiation therapy. Med Phys 2022; 49:4912-4932. [PMID: 35404484 PMCID: PMC9544810 DOI: 10.1002/mp.15649] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 02/03/2022] [Accepted: 02/20/2022] [Indexed: 11/11/2022] Open
Affiliation(s)
- Francesco Romano
- Istituto Nazionale di Fisica Nucleare Sezione di Catania Catania Italy
| | - Claude Bailat
- Institute of Radiation Physics Lausanne University Hospital Lausanne University Switzerland
| | - Patrik Gonçalves Jorge
- Institute of Radiation Physics Lausanne University Hospital Lausanne University Switzerland
- Department of Radiation Oncology Lausanne University Hospital Lausanne Switzerland
- Radio‐Oncology Laboratory DO/CHUV Lausanne University Hospital Lausanne Switzerland
| | | | - Arash Darafsheh
- Department of Radiation Oncology Washington University School of Medicine St. Louis MO 63110 USA
| |
Collapse
|
|
36
|
Cui S, Pratx G. 3D computational model of oxygen depletion kinetics in brain vasculature during FLASH RT, and its implications for in vivo oximetry experiments. Med Phys 2022; 49:3914-3925. [PMID: 35393643 DOI: 10.1002/mp.15642] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 02/19/2022] [Accepted: 03/23/2022] [Indexed: 11/07/2022] Open
Abstract
PURPOSE Ultra-high dose rate irradiation, also known as FLASH, has been shown to improve the therapeutic ratio of radiation therapy (RT). The mechanism behind this effect has been partially explained by the radiochemical oxygen depletion (ROD) hypothesis, which attributes the protection of the normal tissue to the induction of transient hypoxia by ROD. To better understand the contribution of oxygen to the FLASH effect, it is necessary to measure oxygen (O2 ) in vivo during FLASH irradiation. This study's goal is to determine the temporal resolution required to accurately measure the rapidly changing oxygen concentration immediately after FLASH irradiation. METHODS We conducted a computational simulation of oxygen dynamics using a real vascular model that was constructed from a public fluorescence microscopy dataset. The dynamic distribution of oxygen tension (po2 ) during and after FLASH RT was modeled by a partial differential equation (PDE) considering oxygen diffusion, metabolism, and ROD. The underestimation of ROD due to oxygen recovery was evaluated assuming either complete or partial depletion, and a range of possible values for parameters such as oxygen diffusion, consumption, vascular po2 and vessel density. RESULT The O2 concentration recovers rapidly after FLASH RT. Assuming a temporal resolution of 0.5 s, the estimated ROD is only 50.7% and 36.7% of its actual value in cases of partial and complete depletion, respectively. Additionally, the underestimation of ROD is highly dependent on the vascular density. To estimate ROD rate with 90% accuracy, temporal resolution on the order of milliseconds is required considering the uncertainty in parameters involved, especially, the diverse vascular density of the tissue. CONCLUSION The rapid recovery of O2 poses a great challenge for in vivo ROD measurements during FLASH RT. Temporal resolution on the order of milliseconds is recommended for ROD measurements in the normal tissue. Further work is warranted to investigate whether the same requirements apply to tumors, given their irregular vasculature. This article is protected by copyright. All rights reserved.
Collapse
Affiliation(s)
- Sunan Cui
- Department of Radiation Oncology, Stanford University, Palo Alto, California, USA
| | - Guillem Pratx
- Department of Radiation Oncology, Stanford University, Palo Alto, California, USA
| |
Collapse
|
|
37
|
Friedl AA, Prise KM, Butterworth KT, Montay-Gruel P, Favaudon V. Radiobiology of the FLASH effect. Med Phys 2022; 49:1993-2013. [PMID: 34426981 DOI: 10.1002/mp.15184] [Citation(s) in RCA: 102] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 08/03/2021] [Accepted: 08/09/2021] [Indexed: 12/17/2022] Open
Abstract
Radiation exposures at ultrahigh dose rates (UHDRs) at several orders of magnitude greater than in current clinical radiotherapy (RT) have been shown to manifest differential radiobiological responses compared to conventional (CONV) dose rates. This has led to studies investigating the application of UHDR for therapeutic advantage (FLASH-RT) that have gained significant interest since the initial discovery in 2014 that demonstrated reduced lung toxicity with equivalent levels of tumor control compared with conventional dose-rate RT. Many subsequent studies have demonstrated the potential protective role of FLASH-RT in normal tissues, yet the underlying molecular and cellular mechanisms of the FLASH effect remain to be fully elucidated. Here, we summarize the current evidence of the FLASH effect and review FLASH-RT studies performed in preclinical models of normal tissue response. To critically examine the underlying biological mechanisms of responses to UHDR radiation exposures, we evaluate in vitro studies performed with normal and tumor cells. Differential responses to UHDR versus CONV irradiation recurrently involve reduced inflammatory processes and differential expression of pro- and anti-inflammatory genes. In addition, frequently reduced levels of DNA damage or misrepair products are seen after UHDR irradiation. So far, it is not clear what signal elicits these differential responses, but there are indications for involvement of reactive species. Different susceptibility to FLASH effects observed between normal and tumor cells may result from altered metabolic and detoxification pathways and/or repair pathways used by tumor cells. We summarize the current theories that may explain the FLASH effect and highlight important research questions that are key to a better mechanistic understanding and, thus, the future implementation of FLASH-RT in the clinic.
Collapse
Affiliation(s)
- Anna A Friedl
- Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
| | - Kevin M Prise
- Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
| | - Karl T Butterworth
- Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
| | - Pierre Montay-Gruel
- Department of Radiation Oncology, University of California at Irvine, Irvine, California, USA
| | - Vincent Favaudon
- Institut Curie, Inserm U 1021-CNRS UMR 3347, Université Paris-Saclay, PSL Research University, Centre Universitaire, Orsay, France
| |
Collapse
|
|
38
|
Kim MM, Darafsheh A, Schuemann J, Dokic I, Lundh O, Zhao T, Ramos-Méndez J, Dong L, Petersson K. Development of Ultra-High Dose-Rate (FLASH) Particle Therapy. IEEE TRANSACTIONS ON RADIATION AND PLASMA MEDICAL SCIENCES 2022; 6:252-262. [PMID: 36092270 PMCID: PMC9457346 DOI: 10.1109/trpms.2021.3091406] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Research efforts in FLASH radiotherapy have increased at an accelerated pace recently. FLASH radiotherapy involves ultra-high dose rates and has shown to reduce toxicity to normal tissue while maintaining tumor response in pre-clinical studies when compared to conventional dose rate radiotherapy. The goal of this review is to summarize the studies performed to-date with proton, electron, and heavy ion FLASH radiotherapy, with particular emphasis on the physical aspects of each study and the advantages and disadvantages of each modality. Beam delivery parameters, experimental set-up, and the dosimetry tools used are described for each FLASH modality. In addition, modeling efforts and treatment planning for FLASH radiotherapy is discussed along with potential drawbacks when translated into the clinical setting. The final section concludes with further questions that have yet to be answered before safe clinical implementation of FLASH radiotherapy.
Collapse
Affiliation(s)
- Michele M Kim
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Arash Darafsheh
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Jan Schuemann
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ivana Dokic
- Clinical Cooperation Unit Translational Radiation Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 460, Heidelberg, Germany
- Division of Molecular and Translational Radiation Oncology, Department of Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), Im Neuenheimer Feld 450, 69120 Heidelberg, Germany
- German Cancer Consortium (DKTK) Core-Center Heidelberg, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
- Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Oncology (NCRO), Heidelberg University and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 222, Heidelberg, Germany
| | - Olle Lundh
- Department of Physics, Lund University, Lund, Sweden
| | - Tianyu Zhao
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - José Ramos-Méndez
- Department of Radiation Oncology, University of California San Francisco, San Francisco, California, USA
| | - Lei Dong
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Kristoffer Petersson
- Department of Oncology, The Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom
- Radiation Physics, Department of Haematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden
| |
Collapse
|
|
39
|
Okoro CM, Schüler E, Taniguchi CM. The Therapeutic Potential of FLASH-RT for Pancreatic Cancer. Cancers (Basel) 2022; 14:cancers14051167. [PMID: 35267474 PMCID: PMC8909276 DOI: 10.3390/cancers14051167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/21/2022] [Accepted: 02/22/2022] [Indexed: 11/21/2022] Open
Abstract
Simple Summary Ultra-high dose rate radiation, widely nicknamed FLASH-RT, kills tumors without significantly damaging nearby normal tissues. This selective sparing of normal tissue by FLASH-RT tissue is called the FLASH effect. This review explores some of the proposed mechanisms of the FLASH effect and the current data that might support its use in pancreatic cancer. Since radiation for pancreatic cancer treatment is limited by GI toxicity issues and is a disease with one of the lowest five-year survival rates, FLASH-RT could have a large impact in the treatment of this disease with further study. Abstract Recent preclinical evidence has shown that ionizing radiation given at an ultra-high dose rate (UHDR), also known as FLASH radiation therapy (FLASH-RT), can selectively reduce radiation injury to normal tissue while remaining isoeffective to conventional radiation therapy (CONV-RT) with respect to tumor killing. Unresectable pancreatic cancer is challenging to control without ablative doses of radiation, but this is difficult to achieve without significant gastrointestinal toxicity. In this review article, we explore the propsed mechanisms of FLASH-RT and its tissue-sparing effect, as well as its relevance and suitability for the treatment of pancreatic cancer. We also briefly discuss the challenges with regard to dosimetry, dose rate, and fractionation for using FLASH-RT to treat this disease.
Collapse
Affiliation(s)
- Chidi M. Okoro
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Emil Schüler
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Correspondence: (E.S.); (C.M.T.)
| | - Cullen M. Taniguchi
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Correspondence: (E.S.); (C.M.T.)
| |
Collapse
|
|
40
|
Hu A, Qiu R, Wu Z, Zhang H, Li WB, Li J. A Computational Model for Oxygen Depletion Hypothesis in FLASH Effect. Radiat Res 2022; 197:175-183. [PMID: 34739052 DOI: 10.1667/rade-20-00260.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 09/23/2021] [Indexed: 11/03/2022]
Abstract
Experiments have reported low normal tissue toxicities during FLASH irradiation, but the mechanism has not been elaborated. Several hypotheses have been proposed to explain the mechanism. One hypothesis is oxygen depletion. We analyze the time-dependent change of oxygen concentration in the tissue to study the oxygen depletion hypothesis using a computational model. The effects of physical, chemical and physiological parameters on oxygen depletion were explored. The kinetic equation of the model is solved numerically using the finite difference method with rational boundary conditions. Results of oxygen distribution is supported by the experiments of oxygen-sensitivity electrodes and experiments on the expression and distribution of the hypoxia-inducible factors. The analysis of parameters shows that the steady-state oxygen distribution before irradiation is determined by the oxygen consumption rate of the tissue and the microvessel density. The change of oxygen concentration after irradiation has been found to follow a negative exponential function, and the time constant is mainly determined by the microvessel density. The change of oxygen during exposure increases with dose rate and tends to be saturated because of oxygen diffusion. When the dose rate is high enough, the same dose results in the same reduction of oxygen concentration regardless of dose rate. The analysis of the FLASH effect in the brain tissue based on this model does not support the explanation of the oxygen depletion hypothesis. The oxygen depletion hypothesis remains controversial because the oxygen in most normal tissues cannot be depleted to radiation resistance level by FLASH irradiation.
Collapse
Affiliation(s)
- Ankang Hu
- Department of Engineering Physics, Tsinghua University, Beijing, China
- Key Laboratory of Particle & Radiation Imaging, Tsinghua University, Ministry of Education, Beijing, China
| | - Rui Qiu
- Department of Engineering Physics, Tsinghua University, Beijing, China
- Key Laboratory of Particle & Radiation Imaging, Tsinghua University, Ministry of Education, Beijing, China
| | - Zhen Wu
- Department of Engineering Physics, Tsinghua University, Beijing, China
- Nuctech Company Limited, Beijing, China
| | - Hui Zhang
- Department of Engineering Physics, Tsinghua University, Beijing, China
- Key Laboratory of Particle & Radiation Imaging, Tsinghua University, Ministry of Education, Beijing, China
| | - Wei Bo Li
- Institute of Radiation Medicine, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH) Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
| | - Junli Li
- Department of Engineering Physics, Tsinghua University, Beijing, China
- Key Laboratory of Particle & Radiation Imaging, Tsinghua University, Ministry of Education, Beijing, China
| |
Collapse
|
|
41
|
Moon EJ, Petersson K, Oleina MM. The importance of hypoxia in radiotherapy for the immune response, metastatic potential and FLASH-RT. Int J Radiat Biol 2022; 98:439-451. [PMID: 34726575 PMCID: PMC7612434 DOI: 10.1080/09553002.2021.1988178] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE Hypoxia (low oxygen) is a common feature of solid tumors that has been intensely studied for more than six decades. Here we review the importance of hypoxia to radiotherapy with a particular focus on the contribution of hypoxia to immune responses, metastatic potential and FLASH radiotherapy, active areas of research by leading women in the field. CONCLUSION Although hypoxia-driven metastasis and immunosuppression can negatively impact clinical outcome, understanding these processes can also provide tumor-specific vulnerabilities that may be therapeutically exploited. The different oxygen tensions present in tumors and normal tissues may underpin the beneficial FLASH sparing effect seen in normal tissue and represents a perfect example of advances in the field that can leverage tumor hypoxia to improve future radiotherapy treatments.
Collapse
Affiliation(s)
- Eui Jung Moon
- MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK,Equal Contribution and to whom correspondence should be addressed. ; :
| | - Kristoffer Petersson
- MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK,Radiation Physics, Department of Haematology, Oncology and Radiation Physics, Skåne University Hospital, Sweden,Equal Contribution and to whom correspondence should be addressed. ; :
| | - Monica M. Oleina
- MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK,Equal Contribution and to whom correspondence should be addressed. ; :
| |
Collapse
|
|
42
|
Oxygen Depletion in Proton Spot Scanning: A Tool for Exploring the Conditions Needed for FLASH. RADIATION 2021. [DOI: 10.3390/radiation1040024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
FLASH radiotherapy is a rapidly developing field which promises improved normal tissue protection compared to conventional irradiation and no compromise on tumour control. The transient hypoxic state induced by the depletion of oxygen at high dose rates provides one possible explanation. However, studies have mostly focused on uniform fields of dose and there is a lack of investigation into the spatial and temporal variation of dose from proton pencil-beam scanning (PBS). A model of oxygen reaction and diffusion in tissue has been extended to simulate proton PBS delivery and its impact on oxygen levels. This provides a tool to predict oxygen effects from various PBS treatments, and explore potential delivery strategies. Here we present a number of case applications to demonstrate the use of this tool for FLASH-related investigations. We show that levels of oxygen depletion could vary significantly across a large parameter space for PBS treatments, and highlight the need for in silico models such as this to aid in the development and optimisation of FLASH radiotherapy.
Collapse
|
|
43
|
Zakaria AM, Colangelo NW, Meesungnoen J, Jay-Gerin JP. Transient hypoxia in water irradiated by swift carbon ions at ultra-high dose rates: implication for FLASH carbon-ion therapy. CAN J CHEM 2021. [DOI: 10.1139/cjc-2021-0110] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Large doses of ionizing radiation delivered to tumors at ultra-high dose rates (i.e., in a few milliseconds) paradoxically spare the surrounding healthy tissue while preserving anti-tumor activity (compared with conventional radiotherapy delivered at much lower dose rates). This new modality is known as “FLASH radiotherapy” (FLASH-RT). Although the molecular mechanisms underlying FLASH-RT are not yet fully understood, it has been suggested that radiation delivered at high dose rates spares normal tissue via oxygen depletion followed by subsequent radioresistance of the irradiated tissue. To date, FLASH-RT has been studied using electrons, photons, and protons in various basic biological experiments, pre-clinical studies, and recently in a human patient. However, the efficacy of heavy ions, such as energetic carbon ions, under FLASH-RT conditions remains unclear. Given that living cells and tissues consist mainly of water, we set out to study, from a pure radiation chemistry perspective, the effects of ultra-high dose rates on the transient yields and concentrations of radiolytic species formed in water irradiated by 300-MeV per nucleon carbon ions (LET ∼ 11.6 keV/µm). This mimics irradiation in the “plateau” region of the depth–dose distribution of ions, i.e., in the “normal” tissue region in which the LET is rather low. We used Monte Carlo simulations of multiple, simultaneously interacting radiation tracks together with an “instantaneous pulse” irradiation model. Our calculations show a pronounced oxygen depletion around 0.2 μs, strongly suggesting, as with electrons, photons, and protons, that irradiation with energetic carbon ions at ultra-high dose rates is suitable for FLASH-RT.
Collapse
Affiliation(s)
- Abdullah Muhammad Zakaria
- Département de médecine nucléaire et de radiobiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, 3001, 12ème Avenue Nord, Sherbrooke, QC J1H 5N4, Canada
| | - Nicholas W. Colangelo
- Department of Radiation Oncology, NYU Grossman School of Medicine, New York, NY, USA
| | - Jintana Meesungnoen
- Département de médecine nucléaire et de radiobiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, 3001, 12ème Avenue Nord, Sherbrooke, QC J1H 5N4, Canada
| | - Jean-Paul Jay-Gerin
- Département de médecine nucléaire et de radiobiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, 3001, 12ème Avenue Nord, Sherbrooke, QC J1H 5N4, Canada
| |
Collapse
|
|
44
|
Weber UA, Scifoni E, Durante M. FLASH radiotherapy with carbon ion beams. Med Phys 2021; 49:1974-1992. [PMID: 34318508 DOI: 10.1002/mp.15135] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 07/19/2021] [Accepted: 07/19/2021] [Indexed: 12/17/2022] Open
Abstract
FLASH radiotherapy is considered a new potential breakthrough in cancer treatment. Ultra-high dose rates (>40 Gy/s) have been shown to reduce toxicity in the normal tissue without compromising tumor control, resulting in a widened therapeutic window. These high dose rates are more easily achievable in the clinic with charged particles, and clinical trials are, indeed, ongoing using electrons or protons. FLASH could be an attractive solution also for heavier ions such as carbon and could even enhance the therapeutic window. However, it is not yet known whether the FLASH effect will be the same as for sparsely ionizing radiation when densely ionizing carbons ions are used. Here we discuss the technical challenges in beam delivery and present a promising solution using 3D range-modulators in order to apply ultra-high dose rates (UHDR) compatible with FLASH with carbon ions. Furthermore, we will discuss the possible outcome of C-ion therapy at UHDR on the level of the radiobiological and radiation chemical effects.
Collapse
Affiliation(s)
- Uli Andreas Weber
- Biophysics Department, GSI Helhmoltzzentrum für Schwerionenforschung, Darmstadt, Germany
| | - Emanuele Scifoni
- Istituto Nazionale di Fisica Nucleare (INFN), Trento Institute for Fundamental Physics and Applications (TIFPA), Trento, Italy
| | - Marco Durante
- Biophysics Department, GSI Helhmoltzzentrum für Schwerionenforschung, Darmstadt, Germany.,Institute of Condensed Matter Physics, Technische Universität Darmstadt, Darmstadt, Germany
| |
Collapse
|
|
45
|
Darafsheh A, Hao Y, Zhao X, Zwart T, Wagner M, Evans T, Reynoso F, Zhao T. Spread-out Bragg peak proton FLASH irradiation using a clinical synchrocyclotron: Proof of concept and ion chamber characterization. Med Phys 2021; 48:4472-4484. [PMID: 34077590 DOI: 10.1002/mp.15021] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 05/25/2021] [Accepted: 05/26/2021] [Indexed: 11/08/2022] Open
Abstract
PURPOSE The purpose of this work is to (a) demonstrate the feasibility of delivering a spread-out Bragg peak (SOBP) proton beam in ultra-high dose rate (FLASH) using a proton therapy synchrocyclotron as a major step toward realizing an experimental platform for preclinical studies, and (b) evaluate the response of four models of ionization chambers in such a radiation field. METHODS A clinical Mevion HYPERSCAN® synchrocyclotron was adjusted for ultra-high dose rate proton delivery. Protons with nominal energy of 230 MeV were delivered in pulses with temporal width ranging from 12.5 μs to 24 μs spanning from conventional to FLASH dose rates. A boron carbide absorber and a range modulator block were placed in the beam path for range modulation and creating an SOBP dose profile. The radiation field was defined by a brass aperture with 11 mm diameter. Two Faraday cups were used to determine the number of protons per pulse at various dose rates. The dosimetric response of two cylindrical (IBA CC04 and CC13) and two plane-parallel (IBA PPC05 and PTW Advanced Markus® ) ionization chambers were evaluated. The dose rate was measured using the plane-parallel ionization chambers. The integral depth dose (IDD) was measured with a PTW Bragg Peak® ionization chamber. The lateral beam profile was measured with EBT-XD radiochromic film. Monte Carlo simulation was performed in TOPAS as the secondary check for the measurements and as a tool for further optimization of the range modulators' design. RESULTS Faraday cups measurement showed that the maximum protons per pulse is 39.9 pC at 24 μs pulse width. A good agreement between the measured and simulated IDD and lateral beam profiles was observed. The cylindrical ionization chambers showed very high ion recombination and deemed not suitable for absolute dosimetry at ultra-high dose rates. The average dose rate measured using the PPC05 ionization chamber was 163 Gy/s at the pristine Bragg peak and 126 Gy/s at 1 cm depth for the SOBP beam. The SOBP beam range and modulation were measured 24.4 mm and 19 mm, respectively. The pristine Bragg peak beam had 25.6 mm range. Simulation results showed that the IDD and profile flatness can be improved by the cavity diameter of the range modulator and the number of scanned spots, respectively. CONCLUSIONS Feasibility of delivering protons in an SOBP pattern with >100 Gy/s average dose rate using a clinical synchrocyclotron was demonstrated. The dose heterogeneity can be improved through optimization of the range modulator and number of delivered spots. Plane-parallel chambers with smaller gap between electrodes are more suitable for FLASH dosimetry compared to the other ion chambers used in this work.
Collapse
Affiliation(s)
- Arash Darafsheh
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA
| | - Yao Hao
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA
| | - Xiandong Zhao
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA
| | | | | | | | - Francisco Reynoso
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA
| | - Tianyu Zhao
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA
| |
Collapse
|
|
46
|
Boscolo D, Scifoni E, Durante M, Krämer M, Fuss MC. May oxygen depletion explain the FLASH effect? A chemical track structure analysis. Radiother Oncol 2021; 162:68-75. [PMID: 34214612 DOI: 10.1016/j.radonc.2021.06.031] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 06/14/2021] [Accepted: 06/23/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND PURPOSE Recent observations in animal models show that ultra-high dose rate ("FLASH") radiation treatment significantly reduces normal tissue toxicity maintaining an equivalent tumor control. The dependence of this "FLASH" effect on target oxygenation has led to the assumption that oxygen "depletion" could be its major driving force. MATERIALS AND METHODS In a bottom-up approach starting from the chemical track evolution of 1 MeV electrons in oxygenated water simulated with the TRAX-CHEM Monte Carlo code, we determine the oxygen consumption and radiolytic reactive oxygen species production following a short radiation pulse. Based on these values, the effective dose weighted by oxygen enhancement ratio (OER) or the in vitro cell survival under dynamic oxygen pressure is calculated and compared to that of conventional exposures, at constant OER. RESULTS We find an excellent agreement of our Monte Carlo predictions with the experimental value for radiolytic oxygen removal from oxygenated water. However, the application of the present model to published radiobiological experiment conditions shows that oxygen depletion can only have a negligible impact on radiosensitivity through oxygen enhancement, especially at typical experimental oxygenations where a FLASH effect has been observed. CONCLUSION We show that the magnitude and dependence of the "oxygen depletion" hypothesis are not consistent with the observed biological effects of FLASH irradiation. While oxygenation plays an undoubted role in mediating the FLASH effect, we conclude that state-of-the-art radiation chemistry models do not support oxygen depletion and radiation-induced transient hypoxia as the main mechanism.
Collapse
Affiliation(s)
- Daria Boscolo
- GSI Helmholtzzentrum für Schwerionenforschung GmbH, Darmstadt, Germany
| | - Emanuele Scifoni
- Trento Institute for Fundamental Physics and Applications (TIFPA), National Institute for Nuclear Physics (INFN), Trento, Italy
| | - Marco Durante
- GSI Helmholtzzentrum für Schwerionenforschung GmbH, Darmstadt, Germany; Institut für Physik Kondensierter Materie, Technische Universität Darmstadt, Germany.
| | - Michael Krämer
- GSI Helmholtzzentrum für Schwerionenforschung GmbH, Darmstadt, Germany
| | - Martina C Fuss
- GSI Helmholtzzentrum für Schwerionenforschung GmbH, Darmstadt, Germany.
| |
Collapse
|
|
47
|
Marcu LG, Bezak E, Peukert DD, Wilson P. Translational Research in FLASH Radiotherapy-From Radiobiological Mechanisms to In Vivo Results. Biomedicines 2021; 9:181. [PMID: 33670409 PMCID: PMC7918545 DOI: 10.3390/biomedicines9020181] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 02/08/2021] [Accepted: 02/09/2021] [Indexed: 01/18/2023] Open
Abstract
FLASH radiotherapy, or the administration of ultra-high dose rate radiotherapy, is a new radiation delivery method that aims to widen the therapeutic window in radiotherapy. Thus far, most in vitro and in vivo results show a real potential of FLASH to offer superior normal tissue sparing compared to conventionally delivered radiation. While there are several postulations behind the differential behaviour among normal and cancer cells under FLASH, the full spectra of radiobiological mechanisms are yet to be clarified. Currently the number of devices delivering FLASH dose rate is few and is mainly limited to experimental and modified linear accelerators. Nevertheless, FLASH research is increasing with new developments in all the main areas: radiobiology, technology and clinical research. This paper presents the current status of FLASH radiotherapy with the aforementioned aspects in mind, but also to highlight the existing challenges and future prospects to overcome them.
Collapse
Affiliation(s)
- Loredana G Marcu
- Faculty of Informatics & Science, Department of Physics, University of Oradea, 410087 Oradea, Romania
- Cancer Research Institute and School of Health Sciences, University of South Australia, Adelaide, SA 5001, Australia
| | - Eva Bezak
- Cancer Research Institute and School of Health Sciences, University of South Australia, Adelaide, SA 5001, Australia
- School of Physical Sciences, Department of Physics, University of Adelaide, North Terrace, Adelaide, SA 5005, Australia
| | - Dylan D Peukert
- School of Civil, Environmental & Mining Engineering, University of Adelaide, North Terrace, Adelaide, SA 5005, Australia
- STEM, University of South Australia, Adelaide, SA 5001, Australia
| | - Puthenparampil Wilson
- STEM, University of South Australia, Adelaide, SA 5001, Australia
- Department of Radiation Oncology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia
| |
Collapse
|