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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]

Definition: Flash radiotherapy (Flash-RT) is an innovative technique used in radiotherapy for cancer treatment because it delivers an extremely high dose of radiation (>40 Gy/s) to the tumour in a very short period of time, typically within a fraction of a second. This ultra-fast delivery of radiation distinguishes Flash-RT from conventional radiotherapy, which typically involves the delivery of radiation over a longer time period, often several minutes. Studies conducted in cell and preclinical models suggested that Flash-RT may spare normal tissues from radiation-related side effects, such as skin toxicity, gastrointestinal complications, and damage to organs-at-risk. This is believed to be due to the unique normal tissue response to the ultra-high dose rate. Nevertheless, while Flash-RT shows promising results in preclinical and early clinical studies, one should note that the technique is still in the early stages of development. This entry provides a comprehensive exploration of the immense potentials of Flash-RT, covering its background, mechanisms, radiation sources, recent experimental findings based on cell and preclinical models, and future prospects. It aims to provide valuable insights into this innovative radiotherapy technology for anyone interested in the subject. [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]

Background: The potential reduction of normal tissue toxicities during FLASH radiotherapy (FLASH‐RT) has inspired many efforts to investigate its underlying mechanism and to translate it into the clinic. Such investigations require experimental platforms of FLASH‐RT capabilities. Purpose: To commission and characterize a 250 MeV proton research beamline with a saturated nozzle monitor ionization chamber for proton FLASH‐RT small animal experiments. Methods: A 2D strip ionization chamber array (SICA) with high spatiotemporal resolution was used to measure spot dwell times under various beam currents and to quantify dose rates for various field sizes. An Advanced Markus chamber and a Faraday cup were irradiated with spot‐scanned uniform fields and nozzle currents from 50 to 215 nA to investigate dose scaling relations. The SICA detector was set up upstream to establish a correlation between SICA signal and delivered dose at isocenter to serve as an in vivo dosimeter and monitor the delivered dose rate. Two off‐the‐shelf brass blocks were used as apertures to shape the dose laterally. Dose profiles in 2D were measured with an amorphous silicon detector array at a low current of 2 nA and validated with Gafchromic films EBT‐XD at high currents of up to 215 nA. Results: Spot dwell times become asymptotically constant as a function of the requested beam current at the nozzle of greater than 30 nA due to the saturation of monitor ionization chamber (MIC). With a saturated nozzle MIC, the delivered dose is always greater than the planned dose, but the desired dose can be achieved by scaling the MU of the field. The delivered doses exhibit excellent linearity with R2>0.99${R^2} > 0.99$ with respect to MU, beam current, and the product of MU and beam current. If the total number of spots is less than 100 at a nozzle current of 215 nA, a field‐averaged dose rate greater than 40 Gy/s can be achieved. The SICA‐based in vivo dosimetry system achieved excellent estimates of the delivered dose with an average (maximum) deviation of 0.02 Gy (0.05 Gy) over a range of delivered doses from 3 to 44 Gy. Using brass aperture blocks reduced the 80%‐20% penumbra by 64% from 7.55 to 2.75 mm. The 2D dose profiles measured by the Phoenix detector at 2 nA and the EBT‐XD film at 215 nA showed great agreement, with a gamma passing rate of 95.99% using 1 mm/2% criterion. Conclusion: A 250 MeV proton research beamline was successfully commissioned and characterized. Challenges due to the saturated monitor ionization chamber were mitigated by scaling MU and using an in vivo dosimetry system. A simple aperture system was designed and validated to provide sharp dose fall‐off for small animal experiments. This experience can serve as a foundation for other centers interested in implementing FLASH radiotherapy preclinical research, especially those equipped with a similar saturated MIC. [ABSTRACT FROM AUTHOR]

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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.

Glioma has received considerable attention because of its potential of inducing high rates of morbidity, disability, and mortality. FLASH radiotherapy (FLASH-RT) has emerged as a popular topic in current research because of its ability to protect normal tissues. The present review summarized the current development of FLASH-RT in both the central nervous system and glioblastomas, explored the potential mechanisms underlying FLASH-RT-mediated protective effects on the central nervous system, and revealed the advantages of this new technique for glioma therapy. This study highlights the benefits and challenges of the present research and provides a reference for future research.

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]

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. [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]

FLASH (ultra-high dose rate) radiotherapy spares normal tissue while keeping tumor control. However, the mechanism of the FLASH effect remains unclear and may have consequences beyond the irradiated area. We reanalyze the available results of ultra-high-dose-rate-related experiments to find out the key points of the mechanism of the FLASH effect. Then, we present a hypothesis on the mechanism of the FLASH effect: FLASH beams generate a high transient concentration of peroxyl radicals leading to a high fraction of radical recombination, which results in less oxidation damage to normal tissue. For the cells containing higher concentrations of antioxidants, the fractions of radical recombination are smaller because the antioxidants compete to react with peroxyl radicals. Therefore the damages by different dose rate beams differ slightly in this condition. Since some tumors contain a higher level of antioxidants, this may be the reason for the loss of the protective effect in tumors irradiated by FLASH beams. The high concentration of antioxidants in tumors results in slight radiolytic oxygen consumption, and consequently the protective effect observed in in vitro experiment cannot be observed in in vivo experiment. To quantitatively elaborate our hypothesis, a kinetic model is implemented to simulate the reactions induced by irradiation. Two parameters are defined to abstractly study the factors affecting the reaction, such as dose rate, antioxidants, total dose and reaction rate constants. We find that the explanation of the difference between in vivo and in vitro experiments is crucial to understanding the mechanism of the FLASH effect. Our hypothesis agrees with the results of related experiments. Based on the kinetic model, the effects of these factors on the FLASH effect are quantitatively investigated. [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.

Background: The mechanism responsible for the FLASH effect remains undetermined yet critical to the clinical translation of FLASH radiotherapy. The potential role of intertrack interactions in the FLASH effect, arising from the high spatio-temporal concentrations of particle tracks at UHDRs, has been widely discussed but its influence is unknown.Methods: We construct an analytical model of the distribution, diffusive evolution, and chemical interaction of particle tracks in an irradiated target. We fit parameters of the model to Monte Carlo (MC) simulations of electron tracks, and include the effects of scavenging capacities of different target media. We compare the model’s predictions to MC simulations of many interacting electron tracks, and use the comparison to predict the prevalence of intertrack interactions in the parameter space where the FLASH effect is observed in vivo, and where differential reactive species (RS) yields have been observed in aqua.Results: MC simulations of interacting electron tracks demonstrate negligible changes in RS yields at 12 Gy both in oxygenated water and in cellular scavenging conditions, but significant changes at 58 Gy in oxygenated water. The model fits well to the simulation data, and predicts that pulse doses >90Gy delivered in 0.5 μs would be necessary for intertrack interactions to affect RS yields in cellular scavenging conditions, and >13Gy in 0.5 μs for water at 4% O2. The model defines optimal beam parameters (e.g., dose, pulse width, LET) to maximize intertrack interactions, and indicates that decreasing the pulse width of electron pulses further below ≈0.5 μs has no effect on intertrack interactions.Conclusion: The results of the MC simulations indicate that intertrack interactions do not play a role in the parameters space where the FLASH effect is observed. However, potentially critical limitations in the simulations performed provide the possibility that intertrack interactions occur much more readily than predicted. More accurate simulations, as well as experimental characterization of RS yields across the pulse parameter space, are necessary to more confidently confirm or deny the role of intertrack interactions in the FLASH effect.

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.

Purpose: In recent years, the FLASH effect, in which ultrahigh dose rate (UHDR) radiotherapy (RT) can significantly reduce toxicity to normal tissue while maintaining antitumor efficacy, has been verified in many studies and even applied in human clinical cases. This work evaluates whether a room-temperature radio-frequency (RF) linear accelerator (linac) system can produce UHDR high-energy X-rays exceeding a dose rate of 40 Gy/s at a clinical source-surface distance (SSD), exploring the possibility of a compact and economical clinical FLASH RT machine suitable for most hospital treatment rooms. Methods: A 1.65 m long S-band backward-traveling-wave (BTW) electron linac was developed to generate high-current electron beams, supplied by a commercial klystron-based power source. A tungsten-copper electron-to-photon conversion target for UHDR X-rays was designed and optimized with Monte Carlo (MC) simulations using Geant4 and thermal finite element analysis (FEA) simulations using ANSYS. EBT3 and EBT-XD radiochromic films, which were calibrated with a clinical machine Varian VitalBeam,were used for absolute dose measurements. A PTW ionization chamber detector was used to measure the relative total dose and a plane-parallel ionization chamber detector was used to measure the relative normalized dose of each pulse. Results: The BTW linac generated 300-mA-pulse-current 11 MeV electron beams with 29 kW mean beam power, and the conversion target could sustain this high beam power within a maximum irradiation duration of 0.75 s.The mean energy of the produced X-rays was 1.66 MeV in the MC simulation. The measured flat-filter-free (FFF) maximum mean dose rate of the room-temperature linac exceeded 80 Gy/s at an SSD of 50 cm and 45 Gy/s at an SSD of 67.9 cm, both at a 2.1 cm depth of the water phantom. The FFF radiation fields at 50 cm and 67.9 cmSSD at a 2.1 cm depth of the water phantom showed Gaussian-like distributions with 14.3 and 20 cm full-width at half -maximum (FWHM) values, respectively. Conclusion: This work demonstrated the feasibility of UHDR X-rays produced by a room-temperature RF linac, and explored the further optimization of system stability. It shows that a simple and compact UHDR X-ray solution can be facilitated for both FLASH-RT scientific research and clinical applications. [ABSTRACT FROM AUTHOR]

Ultra-high dose rate (UHDR) beams for FLASH radiotherapy present significant dosimetric challenges. Although novel approaches for decreasing or correcting ion recombination in ionization chambers are being proposed, applicability of ionimetric dosimetry to UHDR beams is still under investigation. Solid-state sensors have been recently investigated as a valuable alternative for real-time measurements, especially for relative dosimetry and beam monitoring. Among them, Silicon Carbide (SiC) represents a very promising candidate, compromising between the maturity of Silicon and the robustness of diamond. Its features allow for large area sensors and high electric fields, required to avoid ion recombination in UHDR beams. In this study, we present simulations and experimental measurements with the low energy UHDR electron beams accelerated with the ElectronFLASH machine developed by the SIT Sordina company (IT). The response of a newly developed 1 × 1 cm2 SiC sensor in charge as a function of the dose-per-pulse and its radiation hardness up to a total delivered dose of 90 kGy, was investigated during a dedicated experimental campaign, which is, to our knowledge, the first characterization ever done of SiC with UHDR-pulsed beams accelerated by a dedicated ElectronFLASH LINAC. Results are encouraging and show a linear response of the SiC detector up to 2 Gy/pulse and a variation in the charge per pulse measured for a cumulative delivered dose of 90 kGy, within ±0.75%. [ABSTRACT FROM AUTHOR]

(1) Background: cystamine and its reduced form cysteamine have radioprotective/antioxidant effects in vivo. In this study, we use an in vitro model system to examine the behavior of cystamine towards the reactive primary species produced during the radiolysis of the Fricke dosimeter under high dose-rate irradiation conditions. (2) Methods: our approach was to use the familiar radiolytic oxidation of ferrous to ferric ions as an indicator of the radioprotective/antioxidant capacity of cystamine. A Monte Carlo computer code was used to simulate the multi-track radiation-induced chemistry of aerated and deaerated Fricke-cystamine solutions as a function of dose rate while covering a large range of cystamine concentrations. (3) Results: our simulations revealed that cystamine provides better protection at pulsed dose rates compared to conventional, low-dose-rate irradiations. Furthermore, our simulations confirmed the radical-capturing ability of cystamine, clearly indicating the strong antioxidant profile of this compound. (4) Conclusion: assuming that these findings can be transposable to cells and tissues at physiological pH, it is suggested that combining cystamine with FLASH-RT could be a promising approach to further enhance the therapeutic ratio of cancer cure. [ABSTRACT FROM AUTHOR]

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]

Radiotherapy (RT) is one of the important modalities for cancer treatments. Mounting evidence suggests that the host immune system is involved in the tumor cell killing during RT, and future RT technology development should aim to minimize radiation dose to the immune system while maintaining a sufficient dose to the tumor. A brief history of RT technology development is first summarized. Three RT technologies, namely FLASH RT, proton therapy, and spatially fractionated RT (SFRT), are singled out for the era of immunotherapy. Besides the technical aspects, the mechanism of FLASH effect is discussed, which is likely the combined results of the recombination effect, oxygen depletion effect and immune sparing effect. The proton therapy should have the advantage of causing much less immune damage in comparison to X-ray based RT due to the Bragg peak. However, the relative biological effectiveness (RBE) uncertainty and range uncertainty may hinder the translation of this advantage into clinical benefit. Research approaches to overcome these two technical hurdles are discussed. Various SFRT approaches and their application are reviewed. These approaches are categorized as single-field 1D/2D SFRT, multi-field 3D SFRT and quasi-3D SFRT techniques. A 3D SFRT approach, which is achieved by placing the Bragg peak of a proton 2D SFRT field in discrete depths, may have special potential because all 3 technologies (FLASH RT, proton therapy and SFRT) may be used in this approach.

The FRIDA INFN project characterized thin silicon sensors for monitoring electron FLASH beams, showing a response linearity up to ∼ 10 Gy/pulse on 9 MeV electrons. The use of segmented silicon configurations could provide the spatial resolution useful in Spatially Fractionated Radiotherapy (SFRT). Within the MIRO INFN project, a strip sensor integrated with a multichannel readout chip is being developed and tested for monitoring FLASH and SFRT electron and proton beams. One hundred and twenty-eight strips are independently read by two front-end TERA chips. Preliminary tests were performed on 6–10 MeV electron beams at the LINAC at Physics Department of the University of Torino, with and without using a tungsten minibeam collimator, and on 62–226 MeV proton beams at CNAO (Pavia). The capability to spatially resolve electron and proton beams at conventional dose-rates has been proved. [ABSTRACT FROM AUTHOR]

The purpose of this study is to systematically study and analyse the dose calibration and measurement of the alanine/electron spin resonance dosimetry system in FLASH radiotherapy. The dose calibration curve of the alanine dosimeter ranged from 0 to 50 Gy, and the best linear fit to the data shows a correlation coefficient close to 1. In the stability experiment, the preset irradiation values for the alanine dosimeter and radiochromic film were 14.34 Gy and 13.38 Gy, respectively, and the results of a stability experiment results showed that the alanine dosimeter exhibited superior stability, compared with radiochromic film, with a deviation of less than 1% in repeated measurements. The results of X-ray FLASH irradiation experiments on mice showed that the maximum standard errors of the alanine dosimeter between the measured results and the preset dose values were 4.57% (chest experiment) and 3.22% (abdomen experiment), whereas those for the radiochromic film were 6.03% (chest experiment) and 6.50% (abdomen experiment). Additionally, X-ray and electron-beam FLASH radiotherapy experiments on mice verified that the alanine dosimeter showed no dose-rate dependence and provided more accurate measurement results compared to the radiochromic film. • Alanine dosimeters show high stability and accuracy in FLASH radiotherapy dosimetry. • Calibration curves show strong linear correlation, ensuring reliable measurements. • Potential for alanine dosimeters to enhance precision in FLASH radiotherapy. • The FLASH radiotherapy experiments highlight the dose rate independence of the response of alanine dosimeters. [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]

To rapidly assess healthy tissue toxicities induced by new anti-cancer therapies (i.e., radiation alone or in combination with drugs), there is a critical need for relevant and easy-to-use models. Consistent with the ethical desire to reduce the use of animals in medical research, we propose to monitor lung toxicity using an ex vivo model. Briefly, freshly prepared organotypic lung slices from mice were irradiated, with or without being previously exposed to chemotherapy, and treatment toxicity was evaluated by analysis of cell division and viability of the slices. When exposed to different doses of radiation, this ex vivo model showed a dose-dependent decrease in cell division and viability. Interestingly, monitoring cell division was sensitive enough to detect a sparing effect induced by FLASH radiotherapy as well as the effect of combined treatment. Altogether, the organotypic lung slices can be used as a screening platform to rapidly determine in a quantitative manner the level of lung toxicity induced by different treatments alone or in combination with chemotherapy while drastically reducing the number of animals. Translated to human lung samples, this ex vivo assay could serve as an innovative method to investigate patients’ sensitivity to radiation and drugs.

• Deeper understanding of the charge collection efficiency of ionization chambers. • Simulation of the charge collection efficiency including charge multiplication. • Application of ionization chambers under ultra-high dose rate electron beams. • Promising tool for real-time dosimetry in FLASH radiotherapy. Investigating and understanding of the underlying mechanisms affecting the charge collection efficiency (CCE) of vented ionization chambers under ultra-high dose rate pulsed electron radiation. This is an important step towards real-time dosimetry with ionization chambers in FLASH radiotherapy. Parallel-plate ionization chambers (PPIC) with three different electrode distances were build and investigated with electron beams with ultra-high dose-per-pulse (DPP) up to 5.4 Gy. The measurements were compared with simulations. The experimental determination of the CCE was done by comparison against the reference dose based on alanine dosimetry. The numerical solution of a system of partial differential equations taking into account charge creations by the radiation, their transport and reaction in an applied electric field was used for the simulations of the CCE and the underlying effects. A good agreement between the experimental results and the simulated CCE could be achieved. The recombination losses found under ultra-high DPP could be attributed to a temporal and spatial charge carrier imbalance and the associated electric field distortion. With ultra-thin electrode distances down to 0.25 mm and a suitable chamber voltage, a CCE greater than 99 % could be achieved under the ultra-high DPP conditions investigated. Well-guarded ultra-thin PPIC are suited for real-time dosimetry under ultra-high DPP conditions. This allows dosimetry also for FLASH RT according to common codes of practice, traceable to primary standards. The numerical approach used allows the determination of appropriate correction factors beyond the DPP ranges where established theories are applicable to account for remaining recombination losses. [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]

Air-vented ionization chambers have been the secondary standard for radiation dosimetry since the origins of radiation metrology. However, the feasibility of their use in ultra-high dose rate pulsed beams has been a matter of discussion, as large losses are caused by ion recombinations and no suitable theoretical model is available for their correction. The theories developed by Boag and his contemporaries since the 1950s, which have provided the standard ion recombination correction factor in clinical dosimetry, do not provide an accurate description when used under the limit conditions of ultra-high dose rates (UHDRs). Moreover, the high-ion recombination effects of ionization chambers under extreme dose-rate applications are an obstacle to the development of adequate dosimetry standards. In this article, the charge carrier transport equations within a parallel plate ionization chamber (PPIC) have been solved numerically with a double aim. First, this numerical model provides a more accurate tool that can be used to evaluate ion recombination correction for established PPICs in pulsed ultra-high dose rate regimes. Second, studying the chamber behavior in detail allow as to explore the limits of new chamber designs in order to improve their performance under UHDRs. The model presented here has been tested by measuring the instantaneous current of one unit of a Roos chamber (i.e., the time-resolved current during and after the irradiation pulse under UHDR conditions) and comparing these results with the absolute value of the simulated current. The experimental data show consistent agreement with the results obtained using the numerical model. The experimental instantaneous current reveals effects such as the variation of the free electron fraction with the dose per pulse that are supported by the numerical model but cannot be explained in the framework of Boag's theory. Numerical solutions of the charge carrier released and transport in ionization chambers are able to estimate the effects observed when PPICs are irradiated with ultra-high dose rate beams and to provide new insight into processes related to recombination losses at UHDRs. These models can be reliably extended to include regions where current analytical solutions are not valid. An agreement of better than 5 % between the experimental and simulated effective free electron fraction is found. We were able to reproduce the instantaneous current from a Roos chamber. The discrepancies observed between the experimental data and the numerical simulations can be attributed to the uncertainty about the transport parameters involved in the calculation. • Numerical method to describe air ionization chambers at UHDR. • Free electron fraction as a function of dose per pulse and electrode distance. • Instantaneous current, ion collection time, free electron fraction for Roos chamber. • Comparative study of numerical and analytical models. • Effect of the time pulse structure on charge collection efficiency. [ABSTRACT FROM AUTHOR]

Simple Summary: The excellent preservation of normal tissue function after high dose rate radiotherapy has been shown in pre-clinical studies. Normal tissue in the tumor environment is well preserved even after target doses of several hundred Gy while reliably destroying the tumor cells. These results have triggered the establishment of appropriate research structures at the synchrotron PETRA III on the DESY campus in Hamburg, Germany. Dose rates of hundreds of Gy/s can be achieved, compared to 6–20 Gy/min in clinical radiotherapy. We describe the design, development, key parameters, and first use of a mobile insert for high dose rate radiotherapy research, a new research instrument at P61A, the first polychromatic beamline of PETRA III. The data obtained at the end station P61A will support the international interdisciplinary effort to improve radiotherapy concepts for patients with malignant tumors that are considered radioresistant with the currently established clinical radiotherapy techniques. High dose rate radiotherapies such as FLASH and microbeam radiotherapy (MRT) both have developed to the stage of first veterinary studies within the last decade. With the development of a new research tool for high dose rate radiotherapy at the end station P61A of the synchrotron beamline P61 on the DESY campus in Hamburg, we increased the research capacity in this field to speed up the translation of the radiotherapy techniques which are still experimental, from bench to bedside. At P61, dose rates of several hundred Gy/s can be delivered. Compared to dedicated biomedical beamlines, the beam width available for MRT experiments is a very restrictive factor. We developed two model systems specifically to suit these specific technical parameters and tested them in a first set of experiments. [ABSTRACT FROM AUTHOR]

FLASH radiotherapy, or the delivery of a dose at an ultra-high dose rate (>40 Gy/s), has recently emerged as a promising tool to enhance the therapeutic index in cancer treatment. The remarkable sparing of normal tissues and equivalent tumor control by FLASH irradiation compared to conventional dose rate irradiation—the FLASH effect—has already been demonstrated in several preclinical models and even in a first patient with T-cell cutaneous lymphoma. However, the biological mechanisms responsible for the differential effect produced by FLASH irradiation in normal and cancer cells remain to be elucidated. This is of great importance because a good understanding of the underlying radiobiological mechanisms and characterization of the specific beam parameters is required for a successful clinical translation of FLASH radiotherapy. In this review, we summarize the FLASH investigations performed so far and critically evaluate the current hypotheses explaining the FLASH effect, including oxygen depletion, the production of reactive oxygen species, and an altered immune response. We also propose a new theory that assumes an important role of mitochondria in mediating the normal tissue and tumor response to FLASH dose rates. [ABSTRACT FROM AUTHOR]

Purpose: The transmission proton FLASH technique delivers high doses to the normal tissue distal to the target, which is less conformal compared to the Bragg peak technique. To investigate FLASH radiotherapy (RT) planning using single‐energy Bragg peak beams with a similar beam arrangement as clinical intensity‐modulated proton therapy (IMPT) in a liver stereotactic body radiation therapy (SBRT) and to characterize the plan quality, dose sparing of organs‐at‐risk (OARs), and FLASH dose rate percentage. Materials and methods: An in‐house platform was developed to enable inverse IMPT‐FLASH planning using single‐energy Bragg peaks. A universal range shifter and range compensators were utilized to effectively align the Bragg peak to the distal edge of the target. Two different minimum MU settings of 400 and 800 MU/spot (Bragg‐400 MU and Bragg‐800 MU) plans were investigated on 10 consecutive hepatocellular carcinoma patients previously treated by IMPT–SBRT to evaluate the FLASH dose and dose rate coverage for OARs. The IMPT–FLASH using single‐energy Bragg peaks delivered 50 Gy in five fractions with similar or identical beam arrangement to the clinical IMPT–SBRT plans. NRG GI003 dose constraint metrics were used. Three dose rate calculation methods, including average dose rate (ADR), dose threshold dose rate (DTDR), and dose‐ADR (DADR), were all studied. Results: The novel spot map optimization can fulfill the inverse planning using single‐energy Bragg peaks. All the Bragg peak FLASH plans achieved similar results for the liver‐gross tumor volume (GTV) Dmean and heart D0.5cm3${D_{0.5\,{\rm{c}}{{\rm{m}}^3}}}$, compared to SBRT–IMPT. The Bragg‐800 MU plans resulted in 18.3% higher clinical target volume (CTV) D2cm3${D_{2\,{\rm{c}}{{\rm{m}}^{\rm{3}}}}}$ compared with SBRT (p < 0.05), and no significant difference was found between Bragg‐400 MU and SBRT plans. For the CTV Dmax, SBRT plans resulted in 10.3% (p < 0.01) less than Bragg‐400 MU plans and 16.6% (p < 0.01) less than Bragg‐800 MU plans. The Bragg‐800 MU plans generally achieved higher ADR, DADR, and DTDR dose rates than Bragg‐400 MU plans, and DADR mostly led to the highest V40 Gy/s compared to other dose rate calculation methods, whereas ADR led to the lowest. The lower dose rate portions in certain OARs are related to the lower dose deposited due to the farther distances from targets, especially in the penumbra of the beams. Conclusion: Single‐energy Bragg peak IMPT–FLASH plans eliminate the exit dose in normal tissues, maintaining comparable dose metrics to the conventional IMPT–SBRT plans, while achieving a sufficient FLASH dose rate for liver cancers. This study demonstrates the feasibility of and sufficiently high dose rate when applying the Bragg peak FLASH treatment for a liver cancer hypofractionated FLASH therapy. The advancement of this novel method has the potential to optimize treatment for liver cancer patients. [ABSTRACT FROM AUTHOR]

• The single-energy Bragg planning can have IMPT-equivalent plan quality for lung cancers. • Both dose rate and dose thresholds were applied to evaluate the "FLASHness" for OARs.. • Single-field in a multiple-filed scheme for a hypofractionation regimen also can reach FLASH constraints. Pristine or single-energy Bragg peak IMPT can deliver highly conformal FLASH radiotherapy. To investigate the dosimetric characteristics between an advanced proton pencil beam scanning (PBS) Bragg peak FLASH technique and conventional PBS planning technique in lung tumors. To evaluate the "FLASHness" of single-field in a multiple-field delivery scheme for a hypofractionation regimen and move a step forward to clinical application. Single-energy PBS Bragg peak FLASH treatment plans were optimized based on a novel Bragg peak tracking technique to enable Bragg peaks to stop at the distal edge of the target. Inverse treatment planning using multiple-field optimization (MFO) can achieve sufficient FLASH dose rate and intensity-modulated proton therapy (IMPT)-equivalent dosimetric quality. The dose rate of organs-at-risk (OARs) and the target were calculated under FLASH machine parameters. A group of 10 consecutive lung SBRT patients was optimized to 34 Gy/fraction using a standard treatment of PBS technique with multiple energy layers as references to the Bragg peak plans. The dosimetric quality was compared between Bragg peak FLASH and conventional plans based on RTOG0915 dose metrics. FLASH dose rate ratios (V 40Gy/s) were calculated as a metric of the FLASH-sparing effect. For higher dose thresholds, the Bragg peak plans achieved greater V 40Gy/s FLASH coverage for all major OARs. The V40Gy/s was close to 100% for all OARs when the dose thresholds were > 5 Gy for full plan and single beam evaluations. The less "FLASHness" region was associated with a low dose distribution, mainly occurring in the PBS field penumbra region. The conventional IMPT treatment plans yielded slightly superior target dose uniformity with a D 2% (%) of 108.02% versus that of Bragg peak 300 MU plans of 111.81% (p < 0.01) and that of Bragg peak 1200 MU plans of 115.95% (p < 0.01). No significant difference in dose metrics was found between Bragg peak and IMPT treatment plans for the spinal cord, esophagus, heart, or lung-GTV (all p > 0.05). Hypofractionated lung Bragg peak plans can maintain comparable plan quality to conventional PBS while achieving sufficient FLASH dose rate coverage for major OARs for each field under the multiple-field delivery scheme. The novel Bragg peak FLASH technique has the potential to enhance lung cancer planning treatment outcomes compared to standard PBS treatment techniques. [ABSTRACT FROM AUTHOR]

• OAR sparing through FLASH may be achieved in clinically realistic lung treatments. • 30% FLASH enhancement outweighs loss of fractionation and conformality. • Dose and dose-rate thresholds within a beam are critical for clinical translatability. Besides a dose-rate threshold of 40–100 Gy/s, the FLASH effect may require a dose > 3.5–7 Gy. Even in hypofractioned treatments, with all beams delivered in each fraction (ABEF), most healthy tissue is irradiated to a lower fraction dose. This can be circumvented by single-beam-per-fraction (SBPF) delivery, with a loss of healthy tissue sparing by fractionation. We investigated the trade-off between FLASH and loss of fractionation in SBPF stereotactic proton therapy of lung cancer and determined break-even FLASH-enhancement ratios (FERs). Treatment plans for 12 patients were generated. GTV delineations were available and a 5 mm GTV-PTV margin was applied. Equiangular arrangements of 3, 5, 7, and 9 244 MeV proton transmission beams were used. To facilitate SBPF, the number of fractions was equal to the number of beams. Iso-effective fractionation schedules with a single field uniform dose prescription were used: D 95%,PTV = 100%D pres per beam. All plans were evaluated in terms of dose to lung and conformity of dose to target of FLASH-enhanced biologically equivalent dose (EQD2). Compared to ABEF, SBPF resulted in a median increase of EQD2 mean to healthy lung of 56%, 58%, 55% and 54% in plans with 3, 5, 7 and 9 fractions respectively and of 236%, 78%, 50% and 41% in V 100% EQD2 , quantifying conformity. This can be compensated for by FERs of at least 1.28, 1.32, 1.30 and 1.23 respectively for EQD2 mean and 1.29, 1.18, 1.28 and 1.15 for V 100%,EQD2. A FLASH effect outweighing the loss of fractionation in SBPF may be achieved in stereotactic lung treatments. The trade-off with fractionation depends on the conditions under which the FLASH effect occurs. Better understanding of the underlying biology and the impact of delivery conditions is needed. [ABSTRACT FROM AUTHOR]

• New planning approaches are needed to realise the FLASH effect in clinical practice. • The requirements of these planning approaches are still uncertain. • Recommendations are presented to facilitate future retrospective analysis. With increasing focus on the translation of the observed FLASH effect into clinical practice, this paper presents treatment planning considerations for its development using proton therapy. Potential requirements to induce a FLASH effect are discussed along with the properties of existing proton therapy delivery systems and the changes in planning and delivery approaches required to satisfy these prerequisites. For the exploration of treatment planning approaches for FLASH, developments in treatment planning systems are needed. Flexibility in adapting to new information will be important in such an evolving area. Variations in definitions, threshold values and assumptions can make it difficult to compare different published studies and to interpret previous studies in the context of new information. Together with the fact that much is left to be understood about the underlying mechanism behind the FLASH effect, a systematic and comprehensive approach to information storage is encouraged. Collecting and retaining more detailed information on planned and realised dose delivery as well as reporting the assumptions made in planning studies creates the potential for research to be revisited and re-evaluated in the light of future improvements in understanding. Forward thinking at the time of study development can help facilitate retrospective analysis. This, we hope, will increase the available evidence and accelerate the translation of the FLASH effect into clinical benefit. [ABSTRACT FROM AUTHOR]

Liew and Mairani (2024 Phys. Med. Biol . 69 248001) commented on our previous reply to comments on our paper, 'Modeling for predicting survival fraction of cells after ultra-high dose rate irradiation'. We appreciate their comments on the choice of experimental data on DNA damage for cell survival and agree that the estimate of the dose-response curve on cell survival depends on the selection of DNA damage data. As an additional benchmark test, we compared the relative biological effectiveness (RBE) predicted using the recommended DNA damage data measured in normoxia with those reported in our original paper, and confirmed that the difference in RBE was less than 8%. Although our model allows for the estimation of cell survival and RBE under ultra-high dose rate (UHDR) irradiation, we highlight that a further accumulation of experimental data on DNA damage under UHDR irradiation is necessary for the further development of biophysical models concerning the mechanistical estimation of biological effects., (© 2024 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Objective. Clinical applications of FLASH radiotherapy require formulas to describe how the FLASH radiation features and other related factors determine the FLASH effect. Mathematical analysis of the models can connect the theoretical hypotheses with the radiobiological effect, which provides the foundation for establishing clinical application models. Moreover, experimental and clinical data can be used to explore the key factors through mathematical analysis. Approach. We abstract the complex models of the oxygen depletion hypothesis and radical recombination-antioxidants hypothesis into concise mathematical equations. The equations are solved to analyze how the radiation features and other factors influence the FLASH effect. Then we propose methodologies for determining the parameters in the models and utilizing the models to predict the FLASH effect. Main results. The formulas linking the physical, chemical and biological factors to the FLASH effect are obtained through mathematical derivation of the equation. The analysis indicates that the initial oxygen concentration, radiolytic oxygen consumption and oxygen recovery are key factors for the oxygen depletion hypothesis and that the level of antioxidants is the key factor for the radical recombination-antioxidants hypothesis. According to the model derivations and analysis, the methodologies for determining parameters and predicting the FLASH effect are proposed: (1) the criteria for data filtration, (2) the strategy of hybrid FLASH and conventional dose rate (CONV) irradiation to ensure the acquisition of effective experimental data across a wide dose range, (3) the pipelines of fitting parameters and predicting the FLASH effect. Significance. This study establishes the quantitative relationship between the FLASH effect and key factors. The derived formulas can be used to calculate the FLASH effect in future clinical FLASH radiotherapy. The proposed methodologies guide to obtain sufficient high-quality datasets and utilize them to predict the FLASH effect. Furthermore, this study indicates the key factors of the FLASH effect and offers clues to further explore the FLASH mechanism., (© 2024 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Background: Scintillation dosimetry has promising qualities for ultra-high dose rate (UHDR) radiotherapy (RT), but no system has shown compatibility with mean dose rates (DR‾) above 100 Gy/s and doses per pulse (D p ) exceeding 1.5 Gy typical of UHDR (FLASH)-RT. The aim of this study was to characterize a novel scintillation dosimetry system with the potential of accommodating UHDRs., Methods and Materials: We undertook a thorough dosimetric characterization of the system on an UHDR electron beamline. The system's response as a function of dose, DR‾, D p , and the pulse dose rate (DR p ) was investigated, as was the system's dose sensitivity (signal per unit dose) as a function of dose history. The capabilities of the system for time-resolved dosimetric readout were also evaluated., Results: Within a tolerance of ±3%, the system exhibited dose linearity and was independent of DR‾ and D p within the tested ranges of 1.8-1341 Gy/s and 0.005-7.68 Gy, respectively. A 6% reduction in the signal per unit dose was observed as DR p was increased from 8.9e4 to 1.8e6 Gy/s. The dose delivered per integration window of the continuously sampling photodetector had to remain between 0.028 and 11.56 Gy to preserve a stable signal response per unit dose. The system accurately measured D p of individual pulses delivered at up to 120 Hz. The day-to-day variation of the signal per unit dose in a reference setup varied by up to ±13% but remained consistent (<±2%) within each treatment day and showed no signal loss as a function of dose history., Conclusions: With daily calibrations and DR p -specific correction factors, the system reliably provides real-time, millisecond-resolved dosimetric measurements of pulsed conventional and UHDR beams from typical electron linacs, marking an important advancement in UHDR dosimetry and offering diverse applications to FLASH-RT and related fields., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Background and Purpose: Proton arc therapy and FLASH radiotherapy (FLASH-RT) each offer unique advantages in proton therapy. However, clinical translation of FLASH-RT faces challenges in defining and delivering high dose rates. We propose the use of proton FLASH-arc therapy (PFAT) to leverage the benefits of arc while addressing FLASH delivery concerns by spatially fractionating dose delivery to healthy tissue., Materials and Methods: Treatment plans for an abdominal phantom and a clinical brain case were designed in OpenTPS, using monoenergetic beams within a 360-degree gantry rotation. Beams were optimized to achieve target coverage while maximizing spatial fractionation in non-target regions. The temporal dose delivery to healthy-tissue voxels, or in specified organs-at-risk (OARs), was constrained via selective spot removal in the beamlets matrix. The dose, LET, number of spots per voxel, and voxel-wise average dose rate were calculated for each PFAT plan and compared to a corresponding IMPT scenario., Results: PFAT plans demonstrated comparable dose conformity to IMPT, with LET hotspots shifted towards the target center. The number of spots influencing healthy-tissue voxels was reduced, leading to regions of substantially higher dose rates in many points outside the target. OAR dose-rate optimization in the brain plan resulted in dose rates exceeding 40 Gy/s in the majority of points in the brainstem., Conclusion: The PFAT technique combines the advantages of FLASH and arc therapy, providing improved LET distributions and enhanced biological effect in the target, while achieving high dose rates in healthy tissue, thus reducing healthy tissue damage. This feasibility study demonstrates the capability of PFAT, setting the foundation for further optimization and application in diverse patient cases and complex geometries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective . This work aims to investigate the iso-effectiveness of conventional and FLASH radiotherapy on tumors through in-silico mathematical models. We focused on the role of radiolytic oxygen depletion (ROD), which has been argued as a possible factor to explain the FLASH effect. Approach . We used a spatiotemporal reaction-diffusion model, including ROD, to simulate tumor oxygenation and response. From those oxygen distributions we obtained surviving fractions (SFs) using the linear-quadratic (LQ) model with the oxygen enhancement ratios (OERs). We then employed the calculated SFs to describe the evolution of preclinical tumor volumes through a mathematical model of tumor response, and we also extrapolated those results to calculate tumor control probabilities (TCPs) using the Poisson-LQ approach. Main results . Our study suggests that the ROD effect may cause differences in SF between FLASH and conventional radiotherapy, especially in low α / β and poorly oxygenated cells. However, a statistical analysis showed that these changes in SF generally do not result in significant differences in the evolution of preclinical tumor growth curves when the sample size is small, because such differences in SF may not be noticeable in the heterogeneity of the population of animals. Nonetheless, when extrapolating this effect to TCP curves, we observed important differences between both techniques (TCP is lower in FLASH radiotherapy). When analyzing the response of tumors with heterogeneous oxygenations, differences in TCP are more important for well oxygenated tumors. This apparent contradiction with the results obtained for homogeneously oxygenated cells is explained by the complex interplay between the heterogeneity of tumor oxygenation, the OER effect, and the ROD effect. Significance . This study supports the experimentally observed iso-effectiveness of FLASH and conventional radiotherapy when analyzing the volume evolution of preclinical tumors (that are far from control). However, this study also hints that tumor growth curves may be less sensitive to small variations in SF than tumor control probability: ROD may lead to increased SF in FLASH radiotherapy, which while not large enough to cause significant differences in tumor growth curves, could lead to important differences in clinical TCPs. Nonetheless, it cannot be discarded that other effects not modeled in this work, like radiation-induced immune effects, can contribute to tumor control and maintain the iso-effectiveness of FLASH radiotherapy. The study of tumor growth curves may not be the ideal experiment to test the iso-effectiveness of FLASH, and experiments reporting TCP or D 50 may be preferred., (Creative Commons Attribution license.)

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.

Introduction: In the field of oncological treatments, FLASH Radiotherapy stands as a significant breakthrough. It is characterized by its rapid dose delivery, which shows promise in diminishing the typical negative side effects of radiation, yet still remains potent in tumor treatment. This review delves into current research to highlight the biological benefits, confront the technical complexities, and unravel the essential mechanisms that position FLASH - RT at the forefront of cancer therapy. Materials: FLASH Radiotherapy research evaluates various irradiation methods, including electron, photon, and proton beams, and their specific delivery techniques, like magnet switching in proton therapy. The exploration extends from cellular studies to animal models and initial human patient applications, showcasing FLASH - RT's versatility. We investigate its impact on tissue oxygenation, reactive oxygen species dynamics, DNA integrity, and immune system interactions to understand its nuanced effects on living tissues. This is augmented by examining theoretical models, particularly focusing on peroxyl radical recombination, to decode the FLASH effect's mechanisms. The review also contrasts FLASH - RT with conventional radiotherapy, noting differences in how normal and tumor tissues respond, and the role of redox biology. Results: Studies demonstrated FLASH - RT's capacity to spare normal tissues from late radiation - induced toxicity, an effect partly attributed to peroxyl radical recombination and the kinetics of reactive oxygen species. Clinical applications in various models, including canine cancer patients, showed promising outcomes. Technical challenges, particularly in proton therapy, were addressed, highlighting the necessity for specific dose rate requirements and delivery systems. A comprehensive model of reaction kinetics supported peroxyl radical recombination as a primary determinant of the FLASH effect, challenging the transient oxygen depletion hypothesis. Conclusions: FLASH - RT emerges as a paradigm - changing technology in radiation therapy, offering significant normal tissue sparing without compromising tumor control. Future developments and clinical translations of FLASH - RT are anticipated to revolutionize therapeutic approaches in oncology, necessitating further research into optimized delivery systems and a deeper understanding of its underlying mechanisms. [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]

Purpose: A diamond detector prototype was recently proposed by Marinelli et al. (Medical Physics 2022, https://doi.org/10.1002/mp.15473) for applications in ultrahigh‐dose‐per‐pulse (UH‐DPP) and ultrahigh‐dose‐rate (UH‐DR) beams, as used in FLASH radiotherapy (FLASH‐RT). In the present study, such so‐called flashDiamond (fD) was investigated from the dosimetric point of view, under pulsed electron beam irradiation. It was then used for the commissioning of an ElectronFlash linac (SIT S.p.A., Italy) both in conventional and UH‐DPP modalities. Methods: Detector calibration was performed in reference conditions, under 60Co and electron beam irradiation. Its response linearity was investigated in UH‐DPP conditions. For this purpose, the DPP was varied in the 1.2–11.9 Gy range, by changing either the beam applicator or the pulse duration from 1 to 4 μs. Dosimetric validation of the fD detector prototype was then performed in conventional modality, by measuring percentage depth dose (PDD) curves, beam profiles, and output factors (OFs). All such measurements were carried out in a motorized water phantom. The obtained results were compared with the ones from commercially available dosimeters, namely, a microDiamond, an Advanced Markus ionization chamber, a silicon diode detector, and EBT‐XD GAFchromic films. Finally, the fD detector was used to fully characterize the 7 and 9 MeV UH‐DPP electron beams delivered by the ElectronFlash linac. In particular, PDDs, beam profiles, and OFs were measured, for both energies and all the applicators, and compared with the ones from EBT‐XD films irradiated in the same experimental conditions. Results: The fD calibration coefficient resulted to be independent from the investigated beam qualities. The detector response was found to be linear in the whole investigated DPP range. A very good agreement was observed among PDDs, beam profiles, and OFs measured by the fD prototype and reference detectors, both in conventional and UH‐DPP irradiation modalities. Conclusions: The fD detector prototype was validated from the dosimetric point of view against several commercial dosimeters in conventional beams. It was proved to be suitable in UH‐DPP and UH‐DR conditions, for which no other commercial real‐time active detector is available to date. It was shown to be a very useful tool to perform fast and reproducible beam characterizations in standard clinical motorized water phantom setups. All of the previously mentioned demonstrate the suitability of the proposed detector for the commissioning of UH‐DR linac beams for preclinical FLASH‐RT applications. [ABSTRACT FROM AUTHOR]

Background: Ultra‐high dose‐rate (UHDR) irradiations (>40 Gy/s) have recently garnered interest in radiotherapy (RT) as they can trigger the so‐called "FLASH" effect, namely a higher tolerance of normal tissues in comparison with conventional dose rates when a sufficiently high dose is delivered to the tissue. To transfer this to clinical RT treatments, adapted methods and practical tools for online dosimetry need to be developed. Ionization chambers remain the gold standards in RT but the charge recombination effects may be very significant at such high dose rates, limiting the use of some of these dosimeters. The reduction of the sensitive volume size can be an interesting characteristic to reduce such effects. Purpose: In that context, we have investigated the charge collection behavior of the recent IBA Razor™ Nano Chamber (RNC) in UHDR pulses to evaluate its potential interest for FLASH RT. Methods: In order to quantify the RNC ion collection efficiency (ICE), simultaneous dose measurements were performed under UHDR electron beams with dose‐rate‐independent Gafchromic™ EBT3 films that were used as the dose reference. A dose‐per‐pulse range from 0.01 to 30 Gy was investigated, varying the source‐to‐surface distance, the pulse duration (1 and 3 μs investigated) and the LINAC gun grid tension as irradiation parameters. In addition, the RNC measurements were corrected from the inherent beam shot‐to‐shot variations using an independent current transformer. An empirical logistic model was used to fit the RNC collection efficiency measurements and the results were compared with the Advanced Markus plane parallel ion chamber. Results: The RNC ICE was found to decrease as the dose‐per‐pulse increases, starting from doses above 0.2 Gy/pulse and down to 40% of efficiency at 30 Gy/pulse. The RNC resulted in a higher ICE for a given dose‐per‐pulse in comparison with the Markus chamber, with a measured efficiency found higher than 85 and 55% for 1 and 10 Gy/pulse, respectively, whereas the Markus ICE was of 60 and 25% for the same doses. However, the RNC shows a higher sensitivity to the pulse duration than the Advanced Markus chamber, with a lower efficiency found at 1 μs than at 3 μs, suggesting that this chamber could be more sensitive to the dose rate within the pulse. Conclusions: The results confirmed that the small sensitive volume of the RNC ensures higher ICE compared with larger chambers. The RNC was thus found to be a promising online dosimetry tool for FLASH RT and we proposed an ion recombination model to correct its response up to extreme dose‐per‐pulses of 30 Gy. [ABSTRACT FROM AUTHOR]

Background: Conventional air ionization chambers (ICs) exhibit ion recombination correction factors that deviate substantially from unity when irradiated with dose per pulse magnitudes higher than those used in conventional radiotherapy. This fact makes these devices unsuitable for the dosimetric characterization of beams in ultra‐high dose per pulse as used for FLASH radiotherapy. Purpose: We present the design, development, and characterization of an ultra‐thin parallel plate IC that can be used in ultra‐high dose rate (UHDR) deliveries with minimal recombination. Methods: The charge collection efficiency (CCE) of parallel plate ICs was modeled through a numerical solution of the coupled differential equations governing the transport of charged carriers produced by ionizing radiation. It was used to find out the optimal parameters for the purpose of designing an IC capable of exhibiting a linear response with dose (deviation less than 1%) up to 10 Gy per pulse at 4 μ$\umu$s pulse duration. As a proof of concept, two vented parallel plate IC prototypes have been built and tested in different ultra‐high pulse dose rate electron beams. Results: It has been found that by reducing the distance between electrodes to a value of 0.25 mm it is possible to extend the dose rate operating range of parallel plate ICs to ultra‐high dose per pulse range, at standard voltage of clinical grade electrometers, well into several Gy per pulse. The two IC prototypes exhibit behavior as predicted by the numerical simulation. One of the so‐called ultra‐thin parallel plate ionization chamber (UTIC) prototypes was able to measure up to 10 Gy per pulse, 4 μ$\umu$s pulse duration, operated at 300 V with no significant deviation from linearity within the uncertainties (ElectronFlash Linac, SIT). The other prototype was tested up to 5.4 Gy per pulse, 2.5 μ$\umu$s pulse duration, operated at 250 V with CCE higher than 98.6% (Metrological Electron Accelerator Facility, MELAF at Physikalisch‐Technische Bundesanstalt, PTB). Conclusions: This work demonstrates the ability to extend the dose rate operating range of ICs to ultra‐high dose per pulse range by reducing the spacing between electrodes. The results show that UTICs are suitable for measurement in UHDR electron beams. [ABSTRACT FROM AUTHOR]

At the present stage of scientific and technological progress, high-dose radiotherapy has become a common way to combat severe cancers. However, this treatment option is limited by normal tissues radiosensitivity. The developed technology of ultrashort pulse delivery of a dose of ionizing radiation to the zone of interest (FLASH radiotherapy) can achieve a high local control over tumor growth while sparing healthy tissues. This review summarizes the experimental findings supporting the possibility of transitioning to clinical studies of FLASH radiotherapy.

In this study, an electron-scattering device was fabricated to practically use the ultra-high dose rate electron beams for the FLASH preclinical research in Dongnam Institute of Radiological and Medical Sciences. The Dongnam Institute of Radiological and Medical Sciences has been involved in the investigation of linear accelerators for preclinical research and has recently implemented FLASH electron beams. To determine the geometry of the scattering device for the FLASH preclinical research with a 6-MeV linear accelerator, the Monte Carlo N-particle transport code was exploited. By employing the fabricated scattering device, the off-axis and depth dose distributions were measured with radiochromic films. The generated mean energy of electron beams via the scattering device was 4.3 MeV, and the symmetry and flatness of the off-axis dose distribution were 0.11% and 2.33%, respectively. Finally, the doses per pulse were obtained as a function of the source to surface distance (SSD); the measured dose per pulse varied from 4.0 to 0.2 Gy/pulse at an SSD range of 20–90 cm. At an SSD of 30 cm with a 100-Hz repetition rate, the dose rate was 180 Gy/s, which is sufficient for the preclinical FLASH studies.