Back to the Future: Very High-Energy Electrons (VHEEs) and Their Potential Application in Radiation Therapy
30 Sep 2021-Cancers (Multidisciplinary Digital Publishing Institute (MDPI))-Vol. 13, Iss: 19, pp 4942
TL;DR: In this paper, a review of the current knowledge on very high energy electron (VHEE) radiotherapy is presented, with a synthesis of the studies that have been published on various experimental and simulation works.
Abstract: The development of innovative approaches that would reduce the sensitivity of healthy tissues to irradiation while maintaining the efficacy of the treatment on the tumor is of crucial importance for the progress of the efficacy of radiotherapy. Recent methodological developments and innovations, such as scanned beams, ultra-high dose rates, and very high-energy electrons, which may be simultaneously available on new accelerators, would allow for possible radiobiological advantages of very short pulses of ultra-high dose rate (FLASH) therapy for radiation therapy to be considered. In particular, very high-energy electron (VHEE) radiotherapy, in the energy range of 100 to 250 MeV, first proposed in the 2000s, would be particularly interesting both from a ballistic and biological point of view for the establishment of this new type of irradiation technique. In this review, we examine and summarize the current knowledge on VHEE radiotherapy and provide a synthesis of the studies that have been published on various experimental and simulation works. We will also consider the potential for VHEE therapy to be translated into clinical contexts.
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TL;DR: An overview of the principles underlying FLASH radiotherapy is provided and the challenges along the path towards its clinical application are discussed, including the need for a better understanding of the biological mechanisms, optimization of parameters and technological challenges.
43 citations
TL;DR: A newly designed 2D strip-segmented ionization chamber array (SICA) with high spatial and temporal resolution is characterized and compared with measurements using parallel-plate ion chambers, a 2D scintillator camera, Gafchromic films, and a Faraday Cup.
Abstract: PURPOSE
Experimental measurements of 2D dose rate distributions in proton pencil beam scanning (PBS) FLASH radiation therapy (RT) are currently lacking. In this study, we characterize a newly designed 2D strip-segmented ionization chamber array (SICA) with high spatial and temporal resolution and demonstrate its applications in a modern proton PBS delivery system at both conventional and ultra-high dose rates.
METHODS
A dedicated research beamline of the Varian ProBeam system was employed to deliver a 250 MeV proton PBS beam with nozzle currents up to 215 nA. In the research and clinical beamlines, the spatial, temporal, and dosimetric performance of the SICA was characterized and compared with measurements using parallel-plate ion chambers (IBA PPC05 and PTW Advanced Markus chamber), a 2D scintillator camera (IBA Lynx), Gafchromic films (EBT-XD), and a Faraday Cup. A novel reconstruction approach was proposed to enable the measurement of 2D dose and dose rate distributions using such a strip-type detector.
RESULTS
The SICA demonstrated a position accuracy of 0.12 ± 0.02 mm at a 20 kHz sampling rate (50 μs per event) and a linearity of R2 > 0.99 for both dose and dose rate with nozzle beam currents ranging from 1 nA to 215 nA. The 2D dose comparison to the film measurement resulted in a gamma passing rate of 99.8% (2 mm/2%). A measurement-based proton PBS 2D FLASH dose rate distribution was compared to simulation results and showed a gamma passing rate of 97.3% (2 mm/2%).
CONCLUSIONS
The newly designed SICA demonstrated excellent spatial, temporal, and dosimetric performance and is well suited for commissioning, quality assurance (QA), and a wide range of clinical applications in proton PBS clinical and FLASH radiotherapy. This article is protected by copyright. All rights reserved.
9 citations
TL;DR: In this article , the authors investigated the potential immune response generated by FLASH-RT in a high dose of proton therapy in an orthotopic glioma rat model and showed that FLASH proton radiation therapy offers a neuro-protective effect even at high doses while mounting an effective lymphoid immune response in the tumor.
Abstract: FLASH radiation therapy (FLASH-RT) is a promising radiation technique that uses ultrahigh doses of radiation to increase the therapeutic window of the treatment. FLASH-RT has been observed to provide normal tissue sparing at high dose rates and similar tumor control compared with conventional RT, yet the biological processes governing these radiobiological effects are still unknown. In this study, we sought to investigate the potential immune response generated by FLASH-RT in a high dose of proton therapy in an orthotopic glioma rat model.We cranially irradiated rats with a single high dose (25 Gy) using FLASH dose rate proton irradiation (257 ± 2 Gy/s) or conventional dose rate proton irradiation (4 ± 0.02 Gy/s). We first assessed the protective FLASH effect that resulted in our setup through behavioral studies in naïve rats. This was followed by a comprehensive analysis of immune cells in blood, healthy tissue of the brain, and tumor microenvironment by flow cytometry.Proton FLASH-RT spared memory impairment produced by conventional high-dose proton therapy and induced a similar tumor infiltrating lymphocyte recruitment. Additionally, a general neuroinflammation that was similar in both dose rates was observed.Overall, this study demonstrated that FLASH proton therapy offers a neuro-protective effect even at high doses while mounting an effective lymphoid immune response in the tumor.
7 citations
TL;DR: In this paper , the authors present a review of the TPS developments in high-energy electron (HEE) and very high energy electron (VHEE, 50-250 MeV) beam models, characteristics, and future FLASH applications.
6 citations
TL;DR: In this paper , the mechanism of the FLASH effect is discussed, which is likely the combined results of the recombination effect, oxygen depletion effect and immune sparing effect, and three RT technologies, namely FLASH RT, proton therapy and spatially fractionated RT (SFRT), are singled out for the era of immunotherapy.
4 citations
References
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TL;DR: The results suggest that FLASH radiation may be a viable option for treating lung tumors and reduce the occurrence and severity of early and late complications affecting normal tissue.
Abstract: In vitro studies suggested that sub-millisecond pulses of radiation elicit less genomic instability than continuous, protracted irradiation at the same total dose. To determine the potential of ultrahigh dose-rate irradiation in radiotherapy, we investigated lung fibrogenesis in C57BL/6J mice exposed either to short pulses (≤500 ms) of radiation delivered at ultrahigh dose rate (≥40 Gy/s, FLASH) or to conventional dose-rate irradiation (≤0.03 Gy/s, CONV) in single doses. The growth of human HBCx-12A and HEp-2 tumor xenografts in nude mice and syngeneic TC-1 Luc + orthotopic lung tumors in C57BL/6J mice was monitored under similar radiation conditions. CONV (15 Gy) triggered lung fibrosis associated with activation of the TGF-b (transforming growth factor–b) cascade, whereas no complications developed after doses of FLASH below 20 Gy for more than 36 weeks after irradiation. FLASH irradiation also spared normal smooth muscle and epithelial cells from acute radiation-induced apoptosis, which could be reinduced by administrationofsystemicTNF-a(tumornecrosisfactor–a)beforeirradiation.Incontrast,FLASHwasasefficientasCONVinthe repression of tumor growth. Together, these results suggest that FLASH radiotherapy might allow complete eradication of lung tumors and reduce the occurrence and severity of early and late complications affecting normal tissue.
696 citations
University of Michigan1, Ottawa Hospital2, University of California, Los Angeles3, Mayo Clinic4, University of California, San Francisco5, National Research Council6, Stanford University7, University of Texas MD Anderson Cancer Center8, Fox Chase Cancer Center9, Carleton University10, McGill University11, Virginia Commonwealth University12
TL;DR: The purpose of this report is to set out the salient issues associated with clinical implementation and experimental verification of MC dose algorithms, and to provide the framework upon which to build a comprehensive program for commissioning and routine quality assurance of MC-based treatment planning systems.
Abstract: The Monte Carlo (MC) method has been shown through many research studies to calculate accurate dose distributions for clinical radiotherapy, particularly in heterogeneous patient tissues where the effects of electron transport cannot be accurately handled with conventional, deterministic dose algorithms. Despite its proven accuracy and the potential for improved dose distributions to influence treatment outcomes, the long calculation times previously associated with MC simulation rendered this method impractical for routine clinical treatment planning. However, the development of faster codes optimized for radiotherapy calculations and improvements in computer processor technology have substantially reduced calculation times to, in some instances, within minutes on a single processor. These advances have motivated several major treatment planning system vendors to embark upon the path of MC techniques. Several commercial vendors have already released or are currently in the process of releasing MC algorithms for photon and/or electron beam treatment planning. Consequently, the accessibility and use of MC treatment planning algorithms may well become widespread in the radiotherapy community. With MC simulation, dose is computed stochastically using first principles; this method is therefore quite different from conventional dose algorithms. Issues such as statistical uncertainties, the use of variance reduction techniques, theability to account for geometric details in the accelerator treatment head simulation, and other features, are all unique components of a MC treatment planning algorithm. Successful implementation by the clinical physicist of such a system will require an understanding of the basic principles of MC techniques. The purpose of this report, while providing education and review on the use of MC simulation in radiotherapy planning, is to set out, for both users and developers, the salient issues associated with clinical implementation and experimental verification of MC dose algorithms. As the MC method is an emerging technology, this report is not meant to be prescriptive. Rather, it is intended as a preliminary report to review the tenets of the MC method and to provide the framework upon which to build a comprehensive program for commissioning and routine quality assurance of MC-based treatment planning systems.
591 citations
TL;DR: In this article, the authors used the large difference in ionization potentials between successive ionization states of trace atoms for injecting electrons into a laser-driven wakefield, where a mixture of helium and trace amounts of nitrogen gas was used.
Abstract: A method, which utilizes the large difference in ionization potentials between successive ionization states of trace atoms, for injecting electrons into a laser-driven wakefield is presented. Here a mixture of helium and trace amounts of nitrogen gas was used. Electrons from the K shell of nitrogen were tunnel ionized near the peak of the laser pulse and were injected into and trapped by the wake created by electrons from majority helium atoms and the L shell of nitrogen. The spectrum of the accelerated electrons, the threshold intensity at which trapping occurs, the forward transmitted laser spectrum, and the beam divergence are all consistent with this injection process. The experimental measurements are supported by theory and 3D OSIRIS simulations.
422 citations
TL;DR: The results confirmed the potential advantage of FLASH-RT and provide a strong rationale for further evaluating FLash-RT in human patients.
Abstract: Purpose: Previous studies using FLASH radiotherapy (RT) in mice showed a marked increase of the differential effect between normal tissue and tumors. To stimulate clinical transfer, we evaluated whether this effect could also occur in higher mammals. Experimental Design: Pig skin was used to investigate a potential difference in toxicity between irradiation delivered at an ultrahigh dose rate called “FLASH-RT” and irradiation delivered at a conventional dose rate called “Conv-RT.” A clinical, phase I, single-dose escalation trial (25–41 Gy) was performed in 6 cat patients with locally advanced T2/T3N0M0 squamous cell carcinoma of the nasal planum to determine the maximal tolerated dose and progression-free survival (PFS) of single-dose FLASH-RT. Results: Using, respectively, depilation and fibronecrosis as acute and late endpoints, a protective effect of FLASH-RT was observed (≥20% dose-equivalent difference vs. Conv-RT). Three cats experienced no acute toxicity, whereas 3 exhibited moderate/mild transient mucositis, and all cats had depilation. With a median follow-up of 13.5 months, the PFS at 16 months was 84%. Conclusions: Our results confirmed the potential advantage of FLASH-RT and provide a strong rationale for further evaluating FLASH-RT in human patients. See related commentary by Harrington, p. 3
403 citations
TL;DR: This study shows for the first time that normal brain tissue toxicities after WBI can be reduced with increased dose rate.
363 citations