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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., (© 2024. The Author(s), under exclusive licence to Japanese Society of Radiological Technology and Japan Society of Medical Physics.)

Flash radiotherapy is a kind of radiotherapy method using ultra-high dose rate radiation. Compared with the traditional dose rate radiotherapy, it has unique radiobiological advantages. In this paper, the principle of flash radiotherapy, the process and results of biological experiments are summarized. At the same time, the advantages and challenges of flash radiotherapy are analyzed, and the future clinical application is prospected.

FLASH radiotherapy (FLASH-RT) is a technology that could modify the way radiotherapy is delivered in the future. This technique involves the ultra-fast delivery of radiotherapy at dose rates several orders of magnitude higher than those currently used in routine clinical practice. This very short time of exposure leads to the striking observation of relative protection of normal tissues that are exposed to FLASH-RT as compared with conventional dose rate radiotherapy. Here we summarise the current knowledge about the FLASH effect and provide a synthesis of the observations that have been reported on various experimental animal models (mice, zebrafish, pig, cats), various organs (lung, gut, brain, skin) and by various groups across 40 years of research. We also propose possible mechanisms for the FLASH effect, as well as possible paths for clinical application., (Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Normal tissue sparing from radiation damage upon ultra-high dose rate irradiation, known as the FLASH effect with an equivalent tumor response, has been widely reported in murine skin models, and translation of this type of radiotherapy to humans has already begun, with skin sparing being a primary outcome expected. Methods: This study reviews the status of the field, focusing on the proposed mechanisms and skin response assays, outlining what has become known in terms of input parameters that might control the magnitude of the FLASH effect. Results: Murine studies have largely focused on acute damage responses, developing over 3–8 weeks, to single doses of FLASH versus conventional dose rate (CDR), suggesting that at dose rates above tens of Gray per second, with a total dose of more than 20 Gy, the FLASH effect is induced. Fractionated delivery appears to be possible, although fraction sizes >17 Gy appear to be needed for sparing efficacy. The interplay between the dose rate and total dose per fraction remains to be fully elucidated. Oxygen is a modulator of efficacy, with both hypoxia and hyperoxia diminishing the effect of FLASH. Measurement of transient changes in oxygen levels is possible and may be a marker of treatment efficacy. Conclusion: Taken together, murine skin data provide important information for translational studies, despite the associated limitations. Studies of later-term sparing effects, as well as studies on pig skin, are needed to take the next step in assessing translational FLASH efficacy. The control of biological factors, such as tissue oxygenation, may be required to understand and control the response. [ABSTRACT FROM AUTHOR]

Simple Summary: Ultrahigh-dose-rate therapy, known as FLASH radiotherapy (RT), is an emerging cancer treatment technique that offers similar tumor control to conventional RT but with the enhanced protection of normal tissue through the FLASH-sparing effect. Preclinical studies on animals and cell lines show promising results. This is significant for patients with recurrent tumors and reirradiation cases, where conventional RT has high toxicity rates. FLASH-RT can potentially improve tumor control while reducing side effects and preserving quality of life. Among the FLASH modalities, proton therapy stands out for its superior dosimetric and delivery characteristics, making it a safe and effective option for human malignancies. Despite its potential, proton Bragg peak FLASH for HN cancer remains underexplored, and this review highlights the novel proton conformal FLASH techniques, which allow for high-quality plans while minimizing radiation exposure to critical organs at risk (OARs) for HN cancer reirradiation. Ultrahigh-dose-rate therapy, also known as FLASH radiotherapy (RT), is an emerging technique that is garnering significant interest in cancer treatment due to its potential to revolutionize therapy. This method can achieve comparable tumor control to conventional-dose-rate RT while offering the enhanced protection of normal tissue through the FLASH-sparing effect. This innovative technique has demonstrated promising results in preclinical studies involving animals and cell lines. Particularly noteworthy is its potential application in treating head and neck (HN) cancers, especially in patients with challenging recurrent tumors and reirradiation cases, where the toxicity rates with conventional radiotherapy are high. Such applications aim to enhance tumor control while minimizing side effects and preserving patients' quality of life. In comparison to electron or photon FLASH modalities, proton therapy has demonstrated superior dosimetric and delivery characteristics and is a safe and effective FLASH treatment for human malignancies. Compared to the transmission proton FLASH, single-energy Bragg peak FLASH is a novel delivery method that allows highly conformal doses to targets and minimal radiation doses to crucial OARs. Proton Bragg peak FLASH for HN cancer has still not been well studied. This review highlights the significance of proton FLASH in enhancing cancer therapy by examining the advantages and challenges of using it for HN cancer reirradiation. [ABSTRACT FROM AUTHOR]

Radiotherapy is an important treatment for many unresectable advanced malignant tumors, and radiotherapy-associated inflammatory reactions to radiation and other toxic side effects are significant reasons which reduce the quality of life and survival of patients. FLASH-radiotherapy (FLASH-RT), a prominent topic in recent radiation therapy research, is an ultra-high dose rate treatment known for significantly reducing therapy time while effectively targeting tumors. This approach minimizes radiation side effects on at-risk organs and maximally protects surrounding healthy tissues. Despite decades of preclinical exploration and some notable achievements, the mechanisms behind FLASH effects remain debated. Standardization is still required for the type of FLASH-RT rays and dose patterns. This review addresses the current state of FLASH-RT research, summarizing the biological mechanisms behind the FLASH effect. Additionally, it examines the impact of FLASH-RT on immune cells, cytokines, and the tumor immune microenvironment. Lastly, this review will discuss beam characteristics, potential clinical applications, and the relevance and applicability of FLASH-RT in treating advanced cancers. [ABSTRACT FROM AUTHOR]

This study investigates how scattering foil materials and sampling holder placement affect electron energy distribution in electron beams from a modified medical linear accelerator for FLASH radiotherapy. We analyze electron energy spectra at various positions—ionization chamber, mirror, and jaw—to evaluate the impact of Cu, Pb-Cu, Pb, and Ta foils. Our findings show that close proximity to the source intensifies the dependence of electron energy distribution on foil material, enabling precise beam control through material selection. Monte Carlo simulations are effective for designing foils to achieve desired energy distributions. Moving the sampling holder farther from the source reduces foil material influence, promoting more uniform energy spreads, particularly in the 0.5–10 MeV range for 12 MeV electron beams. These insights emphasize the critical role of tailored material selection and sampling holder positioning in optimizing electron energy distribution and fluence intensity for FLASH radiotherapy research, benefiting both experimental design and clinical applications. [ABSTRACT FROM AUTHOR]

BackgroundNormal tissue sparing from radiation damage upon ultra-high dose rate irradiation, known as the FLASH effect with an equivalent tumor response, has been widely reported in murine skin models, and translation of this type of radiotherapy to humans has already begun, with skin sparing being a primary outcome expected.MethodsThis study reviews the status of the field, focusing on the proposed mechanisms and skin response assays, outlining what has become known in terms of input parameters that might control the magnitude of the FLASH effect.ResultsMurine studies have largely focused on acute damage responses, developing over 3–8 weeks, to single doses of FLASH versus conventional dose rate (CDR), suggesting that at dose rates above tens of Gray per second, with a total dose of more than 20 Gy, the FLASH effect is induced. Fractionated delivery appears to be possible, although fraction sizes >17 Gy appear to be needed for sparing efficacy. The interplay between the dose rate and total dose per fraction remains to be fully elucidated. Oxygen is a modulator of efficacy, with both hypoxia and hyperoxia diminishing the effect of FLASH. Measurement of transient changes in oxygen levels is possible and may be a marker of treatment efficacy.ConclusionTaken together, murine skin data provide important information for translational studies, despite the associated limitations. Studies of later-term sparing effects, as well as studies on pig skin, are needed to take the next step in assessing translational FLASH efficacy. The control of biological factors, such as tissue oxygenation, may be required to understand and control the response.

BackgroundUltrahigh dose-rate radiotherapy (FLASH-RT) affords improvements in the therapeutic index by minimizing normal tissue toxicities without compromising antitumor efficacy compared to conventional dose-rate radiotherapy (CONV-RT). To investigate the translational potential of FLASH-RT to a human pediatric medulloblastoma brain tumor, we used a radiosensitive juvenile mouse model to assess adverse long-term neurological outcomes.MethodsCohorts of 3-week-old male and female C57Bl/6 mice exposed to hypofractionated (2 × 10 Gy, FLASH-RT or CONV-RT) whole brain irradiation and unirradiated controls underwent behavioral testing to ascertain cognitive status four months posttreatment. Animals were sacrificed 6 months post-irradiation and tissues were analyzed for neurological and cerebrovascular decrements.ResultsThe neurological impact of FLASH-RT was analyzed over a 6-month follow-up. FLASH-RT ameliorated neurocognitive decrements induced by CONV-RT and preserved synaptic plasticity and integrity at the electrophysiological (long-term potentiation), molecular (synaptophysin), and structural (Bassoon/Homer-1 bouton) levels in multiple brain regions. The benefits of FLASH-RT were also linked to reduced neuroinflammation (activated microglia) and the preservation of the cerebrovascular structure, by maintaining aquaporin-4 levels and minimizing microglia colocalized to vessels.ConclusionsHypofractionated FLASH-RT affords significant and long-term normal tissue protection in the radiosensitive juvenile mouse brain when compared to CONV-RT. The capability of FLASH-RT to preserve critical cognitive outcomes and electrophysiological properties over 6-months is noteworthy and highlights its potential for resolving long-standing complications faced by pediatric brain tumor survivors. While care must be exercised before clinical translation is realized, present findings document the marked benefits of FLASH-RT that extend from synapse to cognition and the microvasculature.

More than 70% of tumor patients require radiotherapy. Medical electron linear accelerators are important high-end radiotherapy equipment for tumor radiotherapy. With the application of artificial intelligence technology in medical electron linear accelerator, radiotherapy has evolved from ordinary radiotherapy to today’s intelligent radiotherapy. This study introduces the development history, working principles and system composition of medical electron linear accelerators. It outlines the key technologies for improving the performance of medical linear electron accelerators, including beam control, multi-leaf collimator, guiding technology and dose evaluation. It also looks forward to the development trend of major radiotherapy technologies, such as biological guided radiotherapy, FLASH radiotherapy and intelligent radiotherapy, which provides references for the development of medical electron linear accelerators.

The article discusses the potential benefits of ultra-high dose rate irradiation, known as FLASH radiotherapy, in cancer treatment. FLASH-RT has been shown to reduce radiation-induced toxicity on normal tissues while maintaining similar antitumor effects as conventional radiotherapy. However, there are technological challenges in designing stable radiation sources and developing accurate dosimetric protocols for FLASH-RT. Additionally, the biological mechanisms underlying the FLASH effect are not yet fully understood. The article presents a multidisciplinary approach involving technological advancements, dosimetry, radiobiological experiments, and in silico simulations to further investigate and optimize FLASH-RT for clinical implementation. [Extracted from the article]

Background: FLASH therapy is a treatment technique in which radiation is delivered at ultra-high dose rates (≥ 40 Gy/s). The first-in-human FAST-01 clinical trial demonstrated the clinical feasibility of proton FLASH in the treatment of extremity bone metastases. The objectives of this investigation are to assess the toxicities of treatment and pain relief in study participants with painful thoracic bone metastases treated with FLASH radiotherapy, as well as workflow metrics in a clinical setting. Methods: This single-arm clinical trial is being conducted under an FDA investigational device exemption (IDE) approved for 10 patients with 1–3 painful bone metastases in the thorax, excluding bone metastases in the spine. Treatment will be 8 Gy in a single fraction administered at ≥ 40 Gy/s on a FLASH-enabled proton therapy system delivering a single transmission proton beam. Primary study endpoints are efficacy (pain relief) and safety. Patient questionnaires evaluating pain flare at the treatment site will be completed for 10 consecutive days post-RT. Pain response and adverse events (AEs) will be evaluated on the day of treatment and on day 7, day 15, months 1, 2, 3, 6, 9, and 12, and every 6 months thereafter. The outcomes for clinical workflow feasibility are the occurrence of any device issues as well as time on the treatment table. Discussion: This prospective clinical trial will provide clinical data for evaluating the efficacy and safety of proton FLASH for palliation of bony metastases in the thorax. Positive findings will support the further exploration of FLASH radiation for other clinical indications including patient populations treated with curative intent. Registration: ClinicalTrials.gov NCT05524064. [ABSTRACT FROM AUTHOR]

Major strides have been made in the development of FLASH radiotherapy (FLASH RT) in the last ten years, but there are still many obstacles to overcome for transfer to the clinic to become a reality. Although preclinical and first-in-human clinical evidence suggests that ultra-high dose rates (UHDRs) induce a sparing effect in normal tissue without modifying the therapeutic effect on the tumor, successful clinical translation of FLASH-RT depends on a better understanding of the biological mechanisms underpinning the sparing effect. Suitable in vitro studies are required to fully understand the radiobiological mechanisms associated with UHDRs. From a technical point of view, it is also crucial to develop optimal technologies in terms of beam irradiation parameters for producing FLASH conditions. This review provides an overview of the research progress of FLASH RT and discusses the potential challenges to be faced before its clinical application. We critically summarize the preclinical evidence and in vitro studies on DNA damage following UHDR irradiation. We also highlight the ongoing developments of technologies for delivering FLASH-compliant beams, with a focus on laser-driven plasma accelerators suitable for performing basic radiobiological research on the UHDR effects. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer is one of the most diagnosed cancers in men. While it can be successfully treated with radiotherapy (RT), patients often leave treatment with previously healthy organs affected by radiation. This work assessed a novel ultra-high dose rate FLASH proton therapy technique for the treatment of prostate cancers. We were able to generate clinically viable Bragg peak FLASH treatment plans for prostate cancer patients previously treated with conventional proton RT. Feasible prostate treatment quality was observed with all constraints for organs at risk (OARs) being met while maintaining an ultra-high dose rate. Bragg peak FLASH radiotherapy (RT) uses a distal tracking method to eliminate exit doses and can achieve superior OAR sparing. This study explores the application of this novel method in stereotactic body radiotherapy prostate FLASH-RT. An in-house platform was developed to enable intensity-modulated proton therapy (IMPT) planning using a single-energy Bragg peak distal tracking method. The patients involved in the study were previously treated with proton stereotactic body radiotherapy (SBRT) using the pencil beam scanning (PBS) technique to 40 Gy in five fractions. FLASH plans were optimized using a four-beam arrangement to generate a dose distribution similar to the conventional opposing beams. All of the beams had a small angle of two degrees from the lateral direction to increase the dosimetry quality. Dose metrics were compared between the conventional PBS and the Bragg peak FLASH plans. The dose rate histogram (DRVH) and FLASH metrics of 40 Gy/s coverage (V40Gy/s) were investigated for the Bragg peak plans. There was no significant difference between the clinical and Bragg peak plans in rectum, bladder, femur heads, large bowel, and penile bulb dose metrics, except for Dmax. For the CTV, the FLASH plans resulted in a higher Dmax than the clinical plans (116.9% vs. 103.3%). For the rectum, the V40Gy/s reached 94% and 93% for 1 Gy dose thresholds in composite and single-field evaluations, respectively. Additionally, the FLASH ratio reached close to 100% after the application of the 5 Gy threshold in composite dose rate assessment. In conclusion, the Bragg peak distal tracking method can yield comparable plan quality in most OARs while preserving sufficient FLASH dose rate coverage, demonstrating that the ultra-high dose technique can be applied in prostate FLASH SBRT. [ABSTRACT FROM AUTHOR]

No tumor group can be irresponsive to chemotherapy, especially radiotherapy, when applied in sufficient doses. However, in most cases, it is not possible to give effective doses that can destroy the tumor due to side effects and damage that may occur in healthy, normal tissues. Although current technological possibilities transmit the rays to the target area and protect the surrounding healthy tissues and organs much more effectively than before, there is a need for more studies and scientific content on this subject. FLASH-RT has theoretical advantages over conventional radiotherapy. Giving radiation in small, daily doses helps protect healthy cells by giving more time to repair. However, new research shows that there may be a way to deliver radiation at record speeds while sparing healthy tissue. FLASH (ultra-high dose rate radiotherapy), an innovative technique, uses electrons to target tumors while minimizing damage to healthy tissue. More importantly, FLASH is claimed to achieve these effects in less than a second, which can exponentially shorten the duration of radiation sessions. Recent studies indicated how using proton radiation instead of electrons or photons and other technical tweaks could turn FLASH into a powerful tool that can deliver radiation in milliseconds. Significant technological advances are needed to generate FLASH photons, potentially protons, very high energy electrons, and heavy ions. Such radiation sources will allow the required dose distribution to be obtained at more immense depths inside the human body, where most tumors occur. [ABSTRACT FROM AUTHOR]

Radiotherapy (RT) is performed in approximately 75% of patients with cancer, and its efficacy is often hampered by the low tolerance of the surrounding normal tissues. Recent advancements have demonstrated the potential to widen the therapeutic window using “very short” radiation treatment delivery (from a conventional dose rate between 0.5 Gy/min and 2 Gy/min to more than 40 Gy/s) causing a significant increase of normal tissue tolerance without varying the tumor effect. This phenomenon is called “FLASH Effect (FE)” and has been discovered by using electrons. Although several physical, dosimetric, and radiobiological aspects need to be clarified, current preclinical “in vivo” studies have reported a significant protective effect of FLASH RT on neurocognitive function, skin toxicity, lung fibrosis, and bowel injury. Therefore, the current radiobiological premises lay the foundation for groundbreaking potentials in clinical translation, which could be addressed to an initial application of Low Energy Electron FLASH (LEE) for the treatment of superficial tumors to a subsequent Very High Energy Electron FLASH (VHEE) for the treatment of deep tumors. Herein, we report a clinical investigational scenario that, if supported by preclinical studies, could be drawn in the near future. [ABSTRACT FROM AUTHOR]

Background: FLASH radiotherapy (RT) is a novel method for delivering ionizing radiation, which has been shown in preclinical studies to have a normal tissue sparing effect and to maintain anticancer efficacy as compared to conventional RT. Treatment of head and neck tumors with conventional RT is commonly associated with severe toxicity, hence the normal tissue sparing effect of FLASH RT potentially makes it especially advantageous for treating oral tumors. In this work, the objective was to study the adverse effects of dogs with spontaneous oral tumors treated with FLASH RT. Methods: Privately-owned dogs with macroscopic malignant tumors of the oral cavity were treated with a single fraction of ≥30Gy electron FLASH RT and subsequently followed for 12 months. A modified conventional linear accelerator was used to deliver the FLASH RT. Results: Eleven dogs were enrolled in this prospective study. High grade adverse effects were common, especially if bone was included in the treatment field. Four out of six dogs, who had bone in their treatment field and lived at least 5 months after RT, developed osteoradionecrosis at 3-12 months post treatment. The treatment was overall effective with 8/11 complete clinical responses and 3/11 partial responses. Conclusion: This study shows that single-fraction high dose FLASH RT was generally effective in this mixed group of malignant oral tumors, but the risk of osteoradionecrosis is a serious clinical concern. It is possible that the risk of osteonecrosis can be mitigated through fractionation and improved dose conformity, which needs to be addressed before moving forward with clinical trials in human cancer patients. [ABSTRACT FROM AUTHOR]

Objective. Ultra-high-dose-rate radiotherapy, referred to as FLASH therapy, has been demonstrated to reduce the damage of normal tissue as well as inhibiting tumor growth compared with conventional dose-rate radiotherapy. The transient hypoxia may be a vital explanation for sparing the normal tissue. The heterogeneity of oxygen distribution for different doses and dose rates in the different radiotherapy schemes are analyzed. With these results, the influence of doses and dose rates on cell survival are evaluated in this work. Approach. The two-dimensional reaction–diffusion equations are used to describe the heterogeneity of the oxygen distribution in capillaries and tissue. A modified linear quadratic model is employed to characterize the surviving fraction at different doses and dose rates. Main results. The reduction of the damage to the normal tissue can be observed if the doses exceeds a minimum dose threshold under the ultra-high-dose-rate radiation. Also, the surviving fraction exhibits the 'plateau effect' under the ultra-high dose rates radiation, which signifies that within a specific range of doses, the surviving fraction either exhibits minimal variation or increases with the dose. For a given dose, the surviving fraction increases with the dose rate until tending to a stable value, which means that the protection in normal tissue reaches saturation. Significance. The emergence of the 'plateau effect' allows delivering the higher doses while minimizing damage to normal tissue. It is necessary to develop appropriate program of doses and dose rates for different irradiated tissue to achieve more efficient protection. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most prevalent form of cancer worldwide and is projected to affect one in every eight American women over their lifetimes; radiation therapy (RT) is utilized for most breast cancer patients' treatments. Our study aimed to evaluate a novel Bragg peak, ultra-high dose rate (FLASH), proton radiotherapy (PRT) technique that can potentially decrease radiotherapy toxicities. Clinically viable Bragg peak FLASH treatment plans were generated for breast cancer patients who were treated with conventional PRT. Across dosimetric standards of care for healthy and cancerous tissues, we observed feasible breast cancer treatment delivery and high plan quality while maintaining an ultra-high dose rate. Therefore, delivering proton FLASH-RT for breast cancer may reduce toxicities and improve the therapeutic ratio. Bragg peak FLASH-RT can deliver highly conformal treatment and potentially offer improved normal tissue protection for radiotherapy patients. This study focused on developing ultra-high dose rate (≥40 Gy × RBE/s) intensity-modulated proton therapy (IMPT) for hypofractionated treatment of early-stage breast cancer. A novel tracking technique was developed to enable pencil beaming scanning (PBS) of single-energy protons to adapt the Bragg peak (BP) to the target distally. Standard-of-care PBS treatment plans of consecutively treated early-stage breast cancer patients using multiple energy layers were reoptimized using this technique, and dose metrics were compared between single-energy layer BP FLASH and conventional IMPT plans. FLASH dose rate coverage by volume (V40Gy/s) was also evaluated for the FLASH sparing effect. Distal tracking can precisely stop BP at the target distal edge. All plans (n = 10) achieved conformal IMPT-like dose distributions under clinical machine parameters. No statistically significant differences were observed in any dose metrics for heart, ipsilateral lung, most ipsilateral breast, and CTV metrics (p > 0.05 for all). Conventional plans yielded slightly superior target and skin dose uniformities with 4.5% and 12.9% lower dose maxes, respectively. FLASH-RT plans reached 46.7% and 61.9% average-dose rate FLASH coverage for tissues receiving more than 1 and 5 Gy plan dose total under the 250 minimum MU condition. Bragg peak FLASH-RT techniques achieved comparable plan quality to conventional IMPT while reaching adequate dose rate ratios, demonstrating the feasibility of early-stage breast cancer clinical applications. [ABSTRACT FROM AUTHOR]

Simple Summary: FLASH radiotherapy (RT) delivering ultra-high dose rate radiation can reduce normal tissue toxicity while effectively treating tumors. However, implementing FLASH RT in clinical settings faces challenges like limited depth penetration and complex treatment planning. Monte Carlo simulation is a valuable tool to optimize FLASH RT. Radiation detectors, including diamond detectors like microDiamond and ionization chambers, play a crucial role in accurately measuring dose delivery. Moreover, optically stimulated luminescence dosimeters and radiochromic films are used for validation. Advancements are being made to improve detector accuracy in FLASH RT. Further research is needed to refine treatment planning and detector performance for widespread FLASH RT implementation, which can potentially revolutionize cancer treatment. 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. [ABSTRACT FROM AUTHOR]

Background: Several studies have shown pencil beam scanning (PBS) proton therapy is a feasible and safe modality to deliver conformal and ultra‐high dose rate (UHDR) FLASH radiation therapy. However, it would be challenging and burdensome to conduct the quality assurance (QA) of the dose rate along with conventional patient‐specific QA (psQA). Purpose: To demonstrate a novel measurement‐based psQA program for UHDR PBS proton transmission FLASH radiotherapy (FLASH‐RT) using a high spatiotemporal resolution 2D strip ionization chamber array (SICA). Methods: The SICA is a newly designed open‐air strip‐segmented parallel plate ionization chamber, which is capable of measuring spot position and profile through 2 mm‐spacing‐strip electrodes at a 20 kHz sampling rate (50 μs per event) and has been characterized to exhibit excellent dose and dose rate linearity under UHDR conditions. A SICA‐based delivery log was collected for each irradiation containing the measured position, size, dwell time, and delivered MU for each planned spot. Such spot‐level information was compared with the corresponding quantities in the treatment planning system (TPS). The dose and dose rate distributions were reconstructed on patient CT using the measured SICA log and compared to the planned values in volume histograms and 3D gamma analysis. Furthermore, the 2D dose and dose rate measurements were compared with the TPS calculations of the same depth. In addition, simulations using different machine‐delivery uncertainties were performed, and QA tolerances were deduced. Results: A transmission proton plan of 250 MeV for a lung lesion was planned and measured in a dedicated ProBeam research beamline (Varian Medical System) with a nozzle beam current between 100 to 215 nA. The worst gamma passing rates for dose and dose rate of the 2D SICA measurements (four fields) compared to TPS prediction (3%/3 mm criterion) were 96.6% and 98.8%, respectively, whereas the SICA‐log reconstructed 3D dose distribution achieved a gamma passing rate of 99.1% (2%/2 mm criterion) compared to TPS. The deviations between SICA measured log, and TPS were within 0.3 ms for spot dwell time with a mean difference of 0.069 ± 0.11 s, within 0.2 mm for spot position with a mean difference of −0.016 ± 0.03 mm in the x‐direction, and −0.036 ± 0.059 mm in the y‐direction, and within 3% for delivered spot MUs. Volume histogram metric of dose (D95) and dose rate (V40Gy/s) showed minimal differences, within less than 1%. Conclusions: This work is the first to describe and validate an all‐in‐one measurement‐based psQA framework that can fulfill the goals of validating the dose rate accuracy in addition to dosimetric accuracy for proton PBS transmission FLASH‐RT. The successful implementation of this novel QA program can provide future clinical practice with more confidence in the FLASH application. [ABSTRACT FROM AUTHOR]

Conformality has been a key requirement in radiation therapy for cancer to minimize normal tissue toxicity while maintaining tumor control. Since 2014, there has been great interest in ultra‐high dose rate (UHDR), "FLASH," radiation therapy to enhance this therapeutic window. In multiple pre‐clinical studies, it was seen that normal tissue demonstrated less damage due to radiation of various modalities when the same dose was delivered at ultra‐high mean dose rates exceeding ∼40 Gy/s while tumor control remained indifferent to changes in dose rate. The scientific community has large‐scale interdisciplinary studies to investigate this potentially breakthrough technique to enhance treatment options for cancer. FLASH studies have been performed using a number of modalities and delivery techniques for many pre‐clinical models. There have been several studies reporting evidence of the FLASH effect as well as technological developments relating to UHDR studies. There is sustained interest and motivation for this topic as well as many questions that are yet to be answered. We provide a short overview to highlight some of the major work and challenges to advance research in FLASH radiotherapy. [ABSTRACT FROM AUTHOR]

Objective. To investigate the effects of respiratory motion on the delivered dose in the context of proton pencil beam scanning (PBS) transmission FLASH radiotherapy (FLASH-RT) by simulation and phantom measurements. Approach. An in-house simulation code was employed to perform in silico simulation of 2D dose distributions for clinically relevant proton PBS transmission FLASH-RT treatments. A moving simulation grid was introduced to investigate the impacts of various respiratory motion and treatment delivery parameters on the dynamic PBS dose delivery. A strip-ionization chamber array detector and an IROC motion platform were employed to perform phantom measurements of the 2D dose distribution for treatment fields similar to those used for simulation. Main results. Clinically relevant respiratory motion and treatment delivery parameters resulted in degradation of the delivered dose compared to the static delivery as translation and distortion. Simulation showed that the gamma passing rates (2 mm/2% criterion) and target coverage could drop below 50% and 80%, respectively, for certain scenarios if no mitigation strategy was used. The gamma passing rates and target coverage could be restored to more than 95% and 98%, respectively, for short beams delivered at the maximal inhalation or exhalation phase. The simulation results were qualitatively confirmed in phantom measurements with the motion platform. Significance. Respiratory motion could cause dose quality degradation in a clinically relevant proton PBS transmission FLASH-RT treatment if no mitigation strategy is employed, or if an adequate margin is not given to the target. Besides breath-hold, gated delivery can be an alternative motion management strategy to ensure high consistency of the delivered dose while maintaining minimal dose to the surrounding normal tissues. To the best of our knowledge, this is the first study on motion impacts in the context of proton transmission FLASH radiotherapy. [ABSTRACT FROM AUTHOR]

BackgroundFLASH radiotherapy (RT) is a novel method for delivering ionizing radiation, which has been shown in preclinical studies to have a normal tissue sparing effect and to maintain anticancer efficacy as compared to conventional RT. Treatment of head and neck tumors with conventional RT is commonly associated with severe toxicity, hence the normal tissue sparing effect of FLASH RT potentially makes it especially advantageous for treating oral tumors. In this work, the objective was to study the adverse effects of dogs with spontaneous oral tumors treated with FLASH RT.MethodsPrivately-owned dogs with macroscopic malignant tumors of the oral cavity were treated with a single fraction of ≥30Gy electron FLASH RT and subsequently followed for 12 months. A modified conventional linear accelerator was used to deliver the FLASH RT.ResultsEleven dogs were enrolled in this prospective study. High grade adverse effects were common, especially if bone was included in the treatment field. Four out of six dogs, who had bone in their treatment field and lived at least 5 months after RT, developed osteoradionecrosis at 3-12 months post treatment. The treatment was overall effective with 8/11 complete clinical responses and 3/11 partial responses.ConclusionThis study shows that single-fraction high dose FLASH RT was generally effective in this mixed group of malignant oral tumors, but the risk of osteoradionecrosis is a serious clinical concern. It is possible that the risk of osteonecrosis can be mitigated through fractionation and improved dose conformity, which needs to be addressed before moving forward with clinical trials in human cancer patients.

Focal radiation therapy (RT) has attracted considerable attention as a combinatorial partner for immunotherapy (IT), largely reflecting a well-defined, predictable safety profile and at least some potential for immunostimulation. However, only a few RT-IT combinations have been tested successfully in patients with cancer, highlighting the urgent need for an improved understanding of the interaction between RT and IT in both preclinical and clinical scenarios. Every year since 2016, ImmunoRad gathers experts working at the interface between RT and IT to provide a forum for education and discussion, with the ultimate goal of fostering progress in the field at both preclinical and clinical levels. Here, we summarize the key concepts and findings presented at the Sixth Annual ImmunoRad conference. [ABSTRACT FROM AUTHOR]

Treatments at ultra-high dose rate (UHDR) have the potential to improve the therapeutic index of radiation therapy (RT) by sparing normal tissues compared to conventional dose rate irradiations. Insufficient and inconsistent reporting in physics and dosimetry of preclinical and translational studies may have contributed to a reproducibility crisis of radiobiological data in the field. Consequently, the development of a common terminology, as well as common recording, reporting, dosimetry, and metrology standards is required. In the context of UHDR irradiations, the temporal dose delivery parameters are of importance, and under-reporting of these parameters is also a concern.This work proposes a standardization of terminology, recording, and reporting to enhance comparability of both preclinical and clinical UHDR studies and and to allow retrospective analyses to aid the understanding of the conditions which give rise to the FLASH effect. [ABSTRACT FROM AUTHOR]

• Oxygen depletion during irradiation was measured dynamically using a nanoparticle. • Oxygen depletion yields was measured at 200 Hz using a fiber-optic system. • Ultra-high dose rate radiation depleted 13% less oxygen than conventional radiation. • Radiochemical oxygen depletion is lower under hypoxic conditions, i.e., below 20 µM. The rapid depletion of oxygen during irradiation at ultra-high dose rate calls for tissue oximeters capable of high temporal resolution. This study demonstrates a water-soluble phosphorescent nanoprobe and fiber-coupled instrument, which together are used to measure the kinetics of oxygen depletion at 200 Hz during irradiation of in vitro solutions. [ABSTRACT FROM AUTHOR]

FLASH radiotherapy (FLASH-RT) is a novel radiotherapy technology defined as ultra-high dose rate (= 40 Gy/s) radiotherapy. The biological effects of FLASHRT 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. [ABSTRACT FROM AUTHOR]

Current radiotherapy facilities are standardized to deliver dose rates around 0.1–0.4 Gy/s in 2 Gy daily fractions, designed to deliver total accumulated doses to reach the tolerance limit of normal tissues undergoing irradiation. FLASH radiotherapy (FLASH‐RT), on the other hand, relies on facilities capable of delivering ultrahigh dose rates in large doses in a single microsecond pulse, or in a few pulses given over a very short time sequence. For example, most studies to date have implemented 4–6 MeV electrons with intra‐pulse dose rates in the range 106–107 Gy/s. The proposed dependence of the FLASH effect on oxygen tension has stimulated several theoretical models based on three different hypotheses: (i) Radiation‐induced transient oxygen depletion; (ii) cell‐specific differences in the ability to detoxify and/or recover from injury caused by reactive oxygen species; (iii) self‐annihilation of radicals by bimolecular recombination. This article focuses on the observations supporting or refuting these models in the frame of the chemical‐biological bases of the impact of oxygen on the radiation response of cell free, in vitro and in vivo model systems. [ABSTRACT FROM AUTHOR]

Preclinical studies have shown that radiotherapy treatments benefit from ultra-high dose rate (UHDR) irradiations. These trigger the FLASH-effect, resulting in a strong decrease in normal tissue toxicity with conserved tumor control probability, compared with conventional irradiations. However, the beam parameters to trigger the FLASH-effect and the radiobiological mechanisms behind it remain to be elucidated. A limiting factor in many studies is the lack of accurate real time dosimetry. In this work an innovative solution for 2D real time dosimetry in UHDR electron beams is presented and characterized. The in-house developed ImageDosis system consists of a scientific camera, with high temporal resolution, and a coating, containing 12% of Y 3 Al 5 O 12 :Ce 3 + as scintillating material. Reference dosimetry was performed by means of radiochromic film, and a (C 38 H 34 P 2)MnBr 4 point scintillator was used to validate the pulse discrimination properties of the ImageDosis system. Irradiations were performed in two centers (Antwerp and Orsay), with an ElectronFlash accelerator. The ImageDosis system was tested with varying number of pulses, pulse length, pulse repetition frequency (PRF) and energy. In addition, its temporal resolution and 2D properties were investigated. The ImageDosis system showed negligible dose, dose rate and energy dependence for doses up to 13 Gy and average dose rates up to 140 Gy/s, with a dose per pulse up to 2 Gy and a PRF up to 300 Hz. The system is capable of discriminating and measuring the dose of individual pulses and shows promising 2D characteristics that need further optimization. [Display omitted] • The YAG-based ImageDosis system is a promising tool for real time UHDR dosimetry. • The ImageDosis system has shown not to be dose rate dependent. • The ImageDosis system provides 2D characteristics that are relevant for FLASH-RT. • The ImageDosis system has shown not to be energy dependent. • The ImageDosis system is capable of measuring individual pulses. [ABSTRACT FROM AUTHOR]

TRIUMF has recently developed and implemented a workflow to design and fabricate application-specific ridge filters, which is a key upgrade to enable research using ultra-high (FLASH) dose rate beam delivery at its Proton Therapy Research Centre. These static ridge filters, called HEDGEHOGs, replace the rotating modulator wheels used to create a spread-out Bragg peak (SOBP) during conventional proton radiotherapy beam delivery, which are incompatible with the fast irradiation times of clinical doses at FLASH dose rates at TRIUMF. Initial beam commissioning of HEDGEHOGs demonstrated that they produce spread-out Bragg peaks matching their design parameters. Additional studies of some of the design parameters, including SOBP widths as well as different pin diameters and fabrication options (material, 3D printer technology) have now been completed. Based on those studies, the use of liquid medium printers (resin, jet) instead of filament printers is recommended. These studies also demonstrate that the lateral dose uniformity of the beam at 36.5 cm from the HEDGEHOG location is acceptable even with relatively large 7 mm base-diameter pins. The code base and workflow are made publicly available and can easily be adapted to other facilities. The feasibility of adapting the HEDGEHOG workflow to other beam lines or facilities was validated on a second proton beam line at the same facility at which the HEDGEHOG workflow was developed. [ABSTRACT FROM AUTHOR]

The biological effects of radiation dose to organs at risk surrounding tumor target volumes are a major dose-limiting constraint in radiotherapy. This can mean that the tumor cannot be completely destroyed, and the efficacy of radiotherapy will be decreased. Thus, ways to reduce damage to healthy tissue has always been a topic of particular interest in radiotherapy research. Modern radiotherapy technologies such as helical tomotherapy (HT), intensity-modulated radiation therapy (IMRT), and proton radiotherapy can reduce radiation damage to healthy tissues. Recent outcomes of animal experiments show that FLASH radiotherapy (FLASH-RT) can reduce radiation-induced damage in healthy tissue without decreasing antitumor effectiveness. The very short radiotherapy time compared to that of conventional dose-rate radiotherapy is another advantage of FLASH-RT. The first human patient received FLASH-RT in Switzerland in 2018. FLASH-RT may become one of the main radiotherapy technologies in clinical applications in the future. We summarize the history of the development of FLASH-RT, its mechanisms, its influence on radiotherapy, and its future. [ABSTRACT FROM AUTHOR]

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 n 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. [ABSTRACT FROM AUTHOR]

FLASH Radiotherapy is currently being studied and actively explored by medical and radiobiology communities as one of the most promising technological break-through in the future of cancer treatment as it could considerably improve the sparing of healthy tissues when compared to conventional radiotherapy. However, the FLASH effect activation mechanism still needs a thorough investigation before the characteristics of a therapeutic beam could be properly defined. In this manuscript, a new method for the on-line monitoring of therapeutic beams at FLASH intensities, based on air fluorescence and developed within the FlashDC project, is presented. [ABSTRACT FROM AUTHOR]

Simple Summary: As pencil beam scanning (PBS) proton therapy delivers doses via spot-scanning, the dose rate quantification is very different from the electron and scattering proton techniques in FLASH radiotherapy. Currently, there is no consensus on the definition of the PBS proton therapy dose rate calculation for normal tissues and targets. This study focuses on the dose rate quantification of organs-at-risk and target based on three proposed dose rate metrics using proton transmission beams. The differences in dose rate metrics have led a large variation for organs-at-risk dose rate assessment and may result in a different correlation expectation between dose rate and biological effects for pre-clinical experiments. An awareness of the differences in proton PBS dose rate calculation is important to design experiments and clinical trials to uncover FLASH-RT's biological and physiological mechanisms. To quantitatively assess target and organs-at-risk (OAR) dose rate based on three proposed proton PBS dose rate metrics and study FLASH intensity-modulated proton therapy (IMPT) treatment planning using transmission beams. An in-house FLASH planning platform was developed to optimize transmission (shoot-through) plans for nine consecutive lung cancer patients previously planned with proton SBRT. Dose and dose rate calculation codes were developed to quantify three types of dose rate calculation methods (dose-averaged dose rate (DADR), average dose rate (ADR), and dose-threshold dose rate (DTDR)) based on both phantom and patient treatment plans. Two different minimum MU/spot settings were used to optimize two different dose regimes, 34-Gy in one fraction and 45-Gy in three fractions. The OAR sparing and target coverage can be optimized with good uniformity (hotspot < 110% of prescription dose). ADR, accounting for the spot dwelling and scanning time, gives the lowest dose rate; DTDR, not considering this time but a dose-threshold, gives an intermediate dose rate, whereas DADR gives the highest dose rate without considering any time or dose-threshold. All three dose rates attenuate along the beam direction, and the highest dose rate regions often occur on the field edge for ADR and DTDR, whereas DADR has a better dose rate uniformity. The differences in dose rate metrics have led a large variation for OARs dose rate assessment, posing challenges to FLASH clinical implementation. This is the first attempt to study the impact of the dose rate models, and more investigations and evidence for the details of proton PBS FLASH parameters are needed to explore the correlation between FLASH efficacy and the dose rate metrics. [ABSTRACT FROM AUTHOR]

Major advances in high precision treatment delivery and imaging have greatly improved the tolerance of radiotherapy (RT); however, the selective sparing of normal tissue and the reduction of neurocognitive side effects from radiation-induced toxicities remain significant problems for pediatric patients with brain tumors. While the overall survival of pediatric patients afflicted with medulloblastoma (MB), the most common type primary brain cancer in children, remains high (≥80%), lifelong neurotoxic side-effects are commonplace and adversely impact patients' quality of life. To circumvent these clinical complications, we have investigated the capability of ultra-high dose rate FLASH-radiotherapy (FLASH-RT) to protect the radiosensitive juvenile mouse brain from normal tissue toxicities. Compared to conventional dose rate (CONV) irradiation, FLASH-RT was found to ameliorate radiation-induced cognitive dysfunction in multiple independent behavioral paradigms, preserve developing and mature neurons, minimize microgliosis and limit the reduction of the plasmatic level of growth hormone. The protective "FLASH effect" was pronounced, especially since a similar whole brain dose of 8 Gy delivered with CONV-RT caused marked reductions in multiple indices of behavioral performance (objects in updated location, novel object recognition, fear extinction, light-dark box, social interaction), reductions in the number of immature (doublecortin+) and mature (NeuN+) neurons and increased neuroinflammation, adverse effects that were not found with FLASH-RT. Our data point to a potentially innovative treatment modality that is able to spare, if not prevent, many of the side effects associated with long-term treatment that disrupt the long-term cognitive and emotional well-being of medulloblastoma survivors. [ABSTRACT FROM AUTHOR]