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The challenge of saturation at the high dose rate employed in FLASH radiotherapy and the lack of real-time 2D and 3D dosimeters create an opportunity for the use of plastic scintillators. This study presents the development of an online dosimetric system designed for electron FLASH radiotherapy applications: an array of dosimeters, made by plastic scintillating fibers, each one coupled to an optical fiber, was evaluated as a proof-of-concept using a LINAC providing 9 MeV electrons, at the Centro Pisano Flash Radiotherapy. Signal linearity was established up to 10 Gy/pulse, with a pulse duration of 4 μ s. We also measured the signal variation across the beam profile using different applicators (30 mm, 50 mm and 100 mm in diameters) and we developed a geometrical model that accounts for the different amount of dose absorbed by the plastic scintillating fibers and the optical fibers. By fitting this model to the data, we estimated both the inter-calibration factors of the dosimeters, as well as the intrinsic ratio (i.e. for equal irradiated volumes) of spurious light in the optical fiber respect to the scintillation, which is equal to (4.7 ± 0. 1 s t a t. ± 1. 0 s y s t. ) %. • Dosimeters made by an array of plastic scintillating fibers tested with a FLASH beam. • Beam profile measured with an array of five dosimeters. • New calibration method to equalize response and subtract spurious signal. [ABSTRACT FROM AUTHOR]

• SICA detectors allow real-time dose and dose rate monitoring during FLASH experiments. • Per-delivery data enable dose cohort regrouping and regression based on actual delivered dose. • High spatiotemporal resolution information is important to ensure FLASH experiments are robust to future dose rate definitions, especially for PBS proton irradiations. • Large cohorts of mice and long-term in vivo data are crucial for preclinical and clinical FLASH studies. To investigate quality assurance (QA) techniques for in vivo dosimetry and establish its routine uses for proton FLASH small animal experiments with a saturated monitor chamber. 227 mice were irradiated at FLASH or conventional (CONV) dose rates with a 250 MeV FLASH-capable proton beamline using pencil beam scanning to characterize the proton FLASH effect on abdominal irradiation and examining various endpoints. A 2D strip ionization chamber array (SICA) detector was positioned upstream of collimation and used for in vivo dose monitoring during irradiation. Before each irradiation series, SICA signal was correlated with the isocenter dose at each delivered dose rate. Dose, dose rate, and 2D dose distribution for each mouse were monitored with the SICA detector. Calibration curves between the upstream SICA detector signal and the delivered dose at isocenter had good linearity with minimal R2 values of 0.991 (FLASH) and 0.985 (CONV), and slopes were consistent for each modality. After reassigning mice, standard deviations were less than 1.85 % (FLASH) and 0.83 % (CONV) for all dose levels, with no individual subject dose falling outside a ± 3.6 % range of the designated dose. FLASH fields had a field-averaged dose rate of 79.0 ± 0.8 Gy/s and mean local average dose rate of 160.6 ± 3.0 Gy/s. In vivo dosimetry allowed for the accurate detection of variation between the delivered and the planned dose. In vivo dosimetry benefits FLASH experiments through enabling real-time dose and dose rate monitoring allowing mouse cohort regrouping when beam fluctuation causes delivered dose to vary from planned dose. [ABSTRACT FROM AUTHOR]

FLASH-radiotherapy (FLASH-RT) is an emerging modality that uses ultra-high dose rates of radiation to enable curative doses to the tumor while preserving normal tissue. The biological studies showed the potential of FLASH-RT to revolutionize radiotherapy cancer treatments. However, the complex biological basis of FLASH-RT is not fully known yet. Within this context, our aim is to get deeper insights into the biomolecular mechanisms underlying FLASH-RT through Fourier Transform Infrared Microspectroscopy (FTIRM). C57Bl/6J female mice were whole brain irradiated at 10 Gy with the eRT6-Oriatron system. 10 Gy FLASH-RT was delivered in 1 pulse of 1. 8 μ s and conventional irradiations at 0.1 Gy/s. Brains were sampled and prepared for analysis 24 h post-RT. FTIRM was performed at the MIRAS beamline of ALBA Synchrotron. Infrared raster scanning maps of the whole mice brain sections were collected for each sample condition. Hyperspectral imaging and Principal Component Analysis (PCA) were performed in several regions of the brain. PCA results evidenced a clear separation between conventional and FLASH irradiations in the 1800–950 cm−1 region, with a significant overlap between FLASH and Control groups. An analysis of the loading plots revealed that most of the variance accounting for the separation between groups was associated to modifications in the protein backbone (Amide I). This protein degradation and/or conformational rearrangement was concomitant with nucleic acid fragmentation/condensation. Cluster separation between FLASH and conventional groups was also present in the 3000–2800 cm−1 region, being correlated with changes in the methylene and methyl group concentrations and in the lipid chain length. Specific vibrational features were detected as a function of the brain region. This work provided new insights into the biomolecular effects involved in FLASH-RT through FTIRM. Our results showed that beyond nucleic acid investigations, one should take into account other dose-rate responsive molecules such as proteins, as they might be key to understand FLASH effect. • This study explores the capabilities of FTIRM to investigate FLASH-RT • FTIRM allowed to rebuild the action of FLASH-RT on normal brain at 24 h • FLASH-RT induces differences in protein signature compared to conventional dose-rates • FLASH-RT induces reduced nucleic acid damage compared to conventional irradiations • Dose-rate responsive molecules such as proteins might be key to understand FLASH-RT [ABSTRACT FROM AUTHOR]

Purpose: Ultra‐high‐dose‐rate irradiation, also known as FLASH, has been shown to improve the therapeutic ratio of radiation therapy (RT). The mechanism behind this effect has been partially explained by the radiochemical oxygen depletion (ROD) hypothesis, which attributes the protection of the normal tissue to the induction of transient hypoxia by ROD. To better understand the contribution of oxygen to the FLASH effect, it is necessary to measure oxygen (O2) in vivo during FLASH irradiation. This study's goal is to determine the temporal resolution required to accurately measure the rapidly changing oxygen concentration immediately after FLASH irradiation. Methods: We conducted a computational simulation of oxygen dynamics using a real vascular model that was constructed from a public fluorescence microscopy dataset. The dynamic distribution of oxygen tension (po2) during and after FLASH RT was modeled by a partial differential equation (PDE) considering oxygen diffusion, metabolism, and ROD. The underestimation of ROD due to oxygen recovery was evaluated assuming either complete or partial depletion, and a range of possible values for parameters such as oxygen diffusion, consumption, vascular po2 and vessel density. Result: The O2 concentration recovers rapidly after FLASH RT. Assuming a temporal resolution of 0.5 s, the estimated ROD is only 50.7% and 36.7% of its actual value in cases of partial and complete depletion, respectively. Additionally, the underestimation of ROD is highly dependent on the vascular density. To estimate ROD rate with 90% accuracy, temporal resolution on the order of milliseconds is required considering the uncertainty in parameters involved, especially, the diverse vascular density of the tissue. Conclusion: The rapid recovery of O2 poses a great challenge for in vivo ROD measurements during FLASH RT. Temporal resolution on the order of milliseconds is recommended for ROD measurements in the normal tissue. Further work is warranted to investigate whether the same requirements apply to tumors, given their irregular vasculature. [ABSTRACT FROM AUTHOR]

Purpose: FLASH radiotherapy (RT) is an emerging technique in which beams with ultra‐high dose rates (UH‐DR) and dose per pulse (UH‐DPP) are used. Commercially available active real‐time dosimeters have been shown to be unsuitable in such conditions, due to severe response nonlinearities. In the present study, a novel diamond‐based Schottky diode detector was specifically designed and realized to match the stringent requirements of FLASH‐RT. Methods: A systematic investigation of the main features affecting the diamond response in UH‐DPP conditions was carried out. Several diamond Schottky diode detector prototypes with different layouts were produced at Rome Tor Vergata University in cooperation with PTW‐Freiburg. Such devices were tested under electron UH‐DPP beams. The linearity of the prototypes was investigated up to DPPs of about 26 Gy/pulse and dose rates of approximately 1 kGy/s. In addition, percentage depth dose (PDD) measurements were performed in different irradiation conditions. Radiochromic films were used for reference dosimetry. Results: The response linearity of the diamond prototypes was shown to be strongly affected by the size of their active volume as well as by their series resistance. By properly tuning the design layout, the detector response was found to be linear up to at least 20 Gy/pulse, well into the UH‐DPP range conditions. PDD measurements were performed by three different linac applicators, characterized by DPP values at the point of maximum dose of 3.5, 17.2, and 20.6 Gy/pulse, respectively. The very good superimposition of three curves confirmed the diamond response linearity. It is worth mentioning that UH‐DPP irradiation conditions may lead to instantaneous detector currents as high as several mA, thus possibly exceeding the electrometer specifications. This issue was properly addressed in the case of the PTW UNIDOS electrometers. Conclusions: The results of the present study clearly demonstrate the feasibility of a diamond detector for FLASH‐RT applications. [ABSTRACT FROM AUTHOR]

Purpose: This work aims to study the dose and ultra-high-dose rate characteristics of transmission proton pencil beam scanning (PBS) FLASH radiotherapy (RT) for hypofractionation liver cancer based on the parameters of a commercially available proton system operating under FLASH mode. Methods and Materials: An in-house treatment planning software (TPS) was developed to perform intensity-modulated proton therapy (IMPT) FLASH-RT planning. Single-energy transmission proton PBS plans of 4.5 Gy × 15 fractions were optimized for seven consecutive hepatocellular carcinoma patients, using 2 and 5 fields combined with 1) the minimum MU/spot chosen between 100 and 400, and minimum spot time (MST) of 2 ms, and 2) the minimum MU/spot of 100, and MST of 0.5 ms, based upon considerations in target uniformities, OAR dose constraints, and OAR FLASH dose rate coverage. Then, the 3D average dose rate distribution was calculated. The dose metrics for the mean dose of Liver-GTV and other major OARs were characterized to evaluate the dose quality for the different combinations of field numbers and minimum spot times compared to that of conventional IMPT plans. Dose rate quality was evaluated using 40 Gy/s volume coverage (V40Gy/s). Results: All plans achieved favorable and comparable target uniformities, and target uniformity improved as the number of fields increased. For OARs, no significant dose differences were observed between plans of different field numbers and the same MST. For plans using shorter MST and the same field numbers, better sparing was generally observed in most OARs and was statistically significant for the chest wall. However, the FLASH dose rate coverage V40Gy/s was increased by 20% for 2-field plans compared to 5-field plans in most OARs with 2-ms MST, which was less evident in the 0.5-ms cases. For 2-field plans, dose metrics and V40Gy/s of select OARs have large variations due to the beam angle selection and variable distances to the targets. The transmission plans generally yielded inferior dosimetric quality to the conventional IMPT plans. Conclusion: This is the first attempt to assess liver FLASH treatment planning and demonstrates that it is challenging for hypofractionation with smaller fractional doses (4.5 Gy/fraction). Using fewer fields can allow higher minimum MU/spot, resulting in higher OAR FLASH dose rate coverages while achieving similar plan quality compared to plans with more fields. Shorter MST can result in better plan quality and comparable or even better FLASH dose rate coverage. [ABSTRACT FROM AUTHOR]

• The generation of High energy X-ray FLASH by the PARTER system and its physical properties were confirmed. • This study reports the first demonstration of the FLASH effect triggered by high energy X-rays on a platform called PARTER. • The study provides a basis for future scientific research and clinical application of HEX in FLASH radiotherapy. This study aimed to evaluate whether high-energy X-rays (HEXs) of the PARTER (platform for advanced radiotherapy research) platform built on CTFEL (Chengdu THz Free Electron Laser facility) can produce ultrahigh dose rate (FLASH) X-rays and trigger the FLASH effect. EBT3 radiochromic film and fast current transformer (FCT) devices were used to measure absolute dose and pulsed beam current of HEXs. Subcutaneous tumor-bearing mice and healthy mice were treated with sham, FLASH, and conventional dose rate radiotherapy (CONV), respectively to observe the tumor control efficiency and normal tissue damage. The maximum dose rate of HEXs of PARTER was up to over 1000 Gy/s. Tumor-bearing mice experiment showed a good result on tumor control (p < 0.0001) and significant difference in survival curves (p < 0.005) among the three groups. In the thorax-irradiated healthy mice experiment, there was a significant difference (p = 0.038) in survival among the three groups, with the risk of death decreased by 81% in the FLASH group compared to that in the CONV group. The survival time of healthy mice irradiated in the abdomen in the FLASH group was undoubtedly higher (62.5% of mice were still alive when we stopped observation) than that in the CONV group (7 days). This study confirmed that HEXs of the PARTER system can produce ultrahigh dose rate X-rays and trigger a FLASH effect, which provides a basis for future scientific research and clinical application of HEX in FLASH radiotherapy. [ABSTRACT FROM AUTHOR]

PurposeThis work aims to study the dose and ultra-high-dose rate characteristics of transmission proton pencil beam scanning (PBS) FLASH radiotherapy (RT) for hypofractionation liver cancer based on the parameters of a commercially available proton system operating under FLASH mode.Methods and MaterialsAn in-house treatment planning software (TPS) was developed to perform intensity-modulated proton therapy (IMPT) FLASH-RT planning. Single-energy transmission proton PBS plans of 4.5 Gy × 15 fractions were optimized for seven consecutive hepatocellular carcinoma patients, using 2 and 5 fields combined with 1) the minimum MU/spot chosen between 100 and 400, and minimum spot time (MST) of 2 ms, and 2) the minimum MU/spot of 100, and MST of 0.5 ms, based upon considerations in target uniformities, OAR dose constraints, and OAR FLASH dose rate coverage. Then, the 3D average dose rate distribution was calculated. The dose metrics for the mean dose of Liver-GTV and other major OARs were characterized to evaluate the dose quality for the different combinations of field numbers and minimum spot times compared to that of conventional IMPT plans. Dose rate quality was evaluated using 40 Gy/s volume coverage (V40Gy/s).ResultsAll plans achieved favorable and comparable target uniformities, and target uniformity improved as the number of fields increased. For OARs, no significant dose differences were observed between plans of different field numbers and the same MST. For plans using shorter MST and the same field numbers, better sparing was generally observed in most OARs and was statistically significant for the chest wall. However, the FLASH dose rate coverage V40Gy/s was increased by 20% for 2-field plans compared to 5-field plans in most OARs with 2-ms MST, which was less evident in the 0.5-ms cases. For 2-field plans, dose metrics and V40Gy/s of select OARs have large variations due to the beam angle selection and variable distances to the targets. The transmission plans generally yielded inferior dosimetric quality to the conventional IMPT plans.ConclusionThis is the first attempt to assess liver FLASH treatment planning and demonstrates that it is challenging for hypofractionation with smaller fractional doses (4.5 Gy/fraction). Using fewer fields can allow higher minimum MU/spot, resulting in higher OAR FLASH dose rate coverages while achieving similar plan quality compared to plans with more fields. Shorter MST can result in better plan quality and comparable or even better FLASH dose rate coverage.

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%.

FLASH radiotherapy (FLASH-RT) delivers radiation treatment at an ultra-high dose rate that is several orders of magnitude higher than current clinical practice. In multiple preclinical studies, FLASH-RT has shown consistent normal tissue sparing effects while preserving equivalent antitumour activity in comparison with conventional dose rate radiation treatment. This is known as the 'FLASH effect'. Given the recent research interest in combining hypofractionated radiotherapy with immunotherapy to try to improve clinical outcomes, there is an intriguing clinical question as to whether FLASH irradiation may be a rational partner to combine with immune modulating drugs? To better predict the synergistic effect of both modalities, here we review the biological mechanisms of how FLASH differentially impacts the immune landscape, including circulating immune cells, tumour microenvironment and the inflammatory response. In order to make recommendations for future research, we summarise all published studies that investigated the immune modulatory effects of FLASH-RT and further explore the scientific reasons for combining FLASH with immunotherapy for potential clinical applications. [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]

FLASH Radiotherapy (RT) delivers an average dose-rate >40 Gy/s in less than 200 ms with extremely high instantaneous dose-rates, and preclinical studies demonstrated a tumoricidal effect comparable to conventional RT with an increased sparing effect on healthy tissues (FLASH effect). Within the INFN-FRIDA project, we are exploring thin silicon sensors and polycrystalline CVD diamond (pCVD) sensors as real-time beam monitors for electron and proton FLASH beams. Planar silicon sensors were first tested on conventional electron beams and subsequently on high-dose electron beams (ElectronFLASH machine, funded by the Pisa Foundation). Diamond, due to some of its properties including radiation resistance, could also be a viable alternative for monitoring FLASH beams. The first tests were carried out in Turin, and the sensor response was studied in terms of polarization voltage, integrated charge, charge collection efficiency and sensitivity. [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]

This paper reports the development of dosimeters based on plastic scintillating fibers imaged by a charge-coupled device camera, and their performance evaluation through irradiations with the electron Flash research accelerator located at the Centro Pisano Flash Radiotherapy. The dosimeter prototypes were composed of a piece of plastic scintillating fiber optically coupled to a clear optical fiber which transported the scintillation signal to the readout systems (an imaging system and a photodiode). The following properties were tested: linearity, capability to reconstruct the percentage depth dose curve in solid water and to sample in time the single beam pulse. The stem effect contribution was evaluated with three methods, and a proof-of-concept one-dimensional array was developed and tested for online beam profiling. Results show linearity up to 10 Gy per pulse, and good capability to reconstruct both the timing and spatial profiles of the beam, thus suggesting that plastic scintillating fibers may be good candidates for low-energy electron Flash dosimetry. • Flash radiotherapy may be groundbreaking for improving cancer treatment. • Conventional dosimeters do not function properly in the Flash regime. • Dosimeters based on plastic scintillating fibers were developed and characterized. • No quenching or energy dependence was observed in the Flash regime. • The beam time structure could be properly sampled. [ABSTRACT FROM AUTHOR]

• Conformal and targeted irradiation of mice can be performed without image guidance. • The end-to-end validation of methodology has been performed on a dead mouse. • Respiration's impact was studied 65 MeV protons lateral and posterior irradiations. • OC-1 radiochromic films can be used to check treatment planning. As part of translational research projects, mice may be irradiated on radiobiology platforms such as the one at the ARRONAX cyclotron. Generally, these platforms do not feature an integrated imaging system. Moreover, in the context of ultra-high dose-rate radiotherapy (FLASH-RT), treatment planning should consider potential changes in the beam characteristics and internal movements in the animal. A patient-like set-up and methodology has been implemented to ensure target coverage during conformal irradiations of the brain, lungs and intestines. In addition, respiratory cycle amplitudes were quantified by fluoroscopic acquisitions on a mouse, to ensure organ coverage and to assess the impact of respiration during FLASH-RT using the 4D digital phantom MOBY. Furthermore, beam incidence direction was studied from mice µCBCT and Monte Carlo simulations. Finally, in vivo dosimetry with dose-rate independent radiochromic films (OC-1) and their LET dependency were investigated. The immobilization system ensures that the animal is held in a safe and suitable position. The geometrical evaluation of organ coverage, after the addition of the margins around the organs, was satisfactory. Moreover, no measured differences were found between CONV and FLASH beams enabling a single model of the beamline for all planning studies. Finally, the LET-dependency of the OC-1 film was determined and experimentally verified with phantoms, as well as the feasibility of using these films in vivo to validate the targeting. The methodology developed ensures accurate and reproducible preclinical irradiations in CONV and FLASH-RT without in-room image guidance in terms of positioning, dose calculation and in vivo dosimetry. [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.

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]

The quality of treatment delivery as prescribed in radiotherapy is exceptionally important. One element that helps provide quality assurance is the ability to carry out time-resolved radiotherapy dose measurements. Reports on doped silica optical fibers scintillators using radioluminescence (RL) based radiotherapy dosimetry have indicated merits, especially regarding robustness, versatility, wide dynamic range, and high spatial resolution. Topping the list is the ability to provide time-resolved measurements, alluding to pulse-by-pulse dosimetry. For effective time-resolved dose measurements, high temporal resolution is enabled by high-speed electronics and scintillator material offering sufficiently fast rise and decay time. In the present work, we examine the influence of Ge doping on the RL response of Ge-doped silica optical fiber scintillators. We particularly look at the size of the Ge-doped core relative to the fiber diameter, and its associated effects as it is adjusted from single-mode fiber geometry to a large core-to-cladding ratio structure. The primary objective is to produce a structure that facilitates short decay times with a sufficiently large yield for time-resolved dosimetry. RL characterization was carried out using a high-energy clinical X-ray beam (6 MV), delivered by an Elekta Synergy linear accelerator located at the Advanced Medical and Dental Institute, Universiti Sains Malaysia (USM). The Ge-doped silica optical fiber scintillator samples, fabricated using chemical vapor deposition methods, comprised of large core and small core optical fiber scintillators with high and low core-to-cladding ratios, respectively. Accordingly, these samples having different Ge-dopant contents offer distinct numbers of defects in the amorphous silica network. Responses were recorded for six dose-rates (between 35 MU/min and 590 MU/min), using a photomultiplier tube setup with the photon-counting circuit capable of gating time as small as 1 μs. The samples showed linear RL response, with differing memory and afterglow effects depending on its geometry. Samples with a large core-to-cladding ratio showed a relatively short decay time (2 matrix, thereby reducing phosphorescence effects. This is a desirable feature of scintillating glass materials that enables avoiding the pulse pile-up effect, especially in high dose-rate applications. These results demonstrate the potential of Ge-doped optical-fiber scintillators, with a large core-to-cladding ratio for use in time-resolved radiation dosimetry.

Objective. Beam current transformers (BCT) are promising detectors for real-time beam monitoring in ultra-high dose rate (UHDR) electron radiotherapy. However, previous studies have reported a significant sensitivity of the BCT signal to changes in source-to-surface distance (SSD), field size, and phantom material which have until now been attributed to the fluctuating levels of electrons backscattered within the BCT. The purpose of this study is to evaluate this hypothesis, with the goal of understanding and mitigating the variations in BCT signal due to changes in irradiation conditions. Approach. Monte Carlo simulations and experimental measurements were conducted with a UHDR-capable intra-operative electron linear accelerator to analyze the impact of backscattered electrons on BCT signal. The potential influence of charge accumulation in media as a mechanism affecting BCT signal perturbation was further investigated by examining the effects of phantom conductivity and electrical grounding. Finally, the effectiveness of Faraday shielding to mitigate BCT signal variations is evaluated. Main Results. Monte Carlo simulations indicated that the fraction of electrons backscattered in water and on the collimator plastic at 6 and 9 MeV is lower than 1%, suggesting that backscattered electrons alone cannot account for the observed BCT signal variations. However, our experimental measurements confirmed previous findings of BCT response variation up to 15% for different field diameters. A significant impact of phantom type on BCT response was also observed, with variations in BCT signal as high as 14.1% when comparing measurements in water and solid water. The introduction of a Faraday shield to our applicators effectively mitigated the dependencies of BCT signal on SSD, field size, and phantom material. Significance. Our results indicate that variations in BCT signal as a function of SSD, field size, and phantom material are likely driven by an electric field originating in dielectric materials exposed to the UHDR electron beam. Strategies such as Faraday shielding were shown to effectively prevent these electric fields from affecting BCT signal, enabling reliable BCT-based electron UHDR beam monitoring., (Creative Commons Attribution license.)

Ultrahigh dose-rate (FLASH) radiotherapy is an emerging technology with excellent therapeutic effects and low biological toxicity. However, tumor recurrence largely impede the effectiveness of FLASH therapy. Overcoming tumor recurrence is crucial for practical FLASH applications. Here, we prepared an agarose-based thermosensitive hydrogel containing a mild photothermal agent (TPE-BBT) and a glutaminase inhibitor (CB-839). Within nanoparticles, TPE-BBT exhibits aggregation-induced emission peaked at 900 nm, while the unrestricted molecular motions endow TPE-BBT with a mild photothermy generation ability. The balanced photothermal effect and photoluminescence are ideal for phototheranostics. Upon 660-nm laser irradiation, the temperature-rising effect softens and hydrolyzes the hydrogel to release TPE-BBT and CB-839 into the tumor site for concurrent mild photothermal therapy and chemotherapy, jointly inhibiting homologous recombination repair of DNA. The enhanced FLASH radiotherapy efficiently kills the tumor tissue without recurrence and obvious systematic toxicity. This work deciphers the unrestricted molecular motions in bright organic fluorophores as a source of photothermy, and provides novel recurrence-resistant radiotherapy without adverse side effects., Competing Interests: 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., (© 2024 The Authors.)

Objective. The successful implementation of FLASH radiotherapy in clinical settings, with typical dose rates >40 Gy s -1 , requires accurate real-time dosimetry. Approach. Silicon carbide (SiC) p-n diode dosimeters designed for the stringent requirements of FLASH radiotherapy have been fabricated and characterized in an ultra-high pulse dose rate electron beam. The circular SiC PiN diodes were fabricated at IMB-CNM (CSIC) in 3 μ m epitaxial 4H-SiC. Their characterization was performed in PTB's ultra-high pulse dose rate reference electron beam. The SiC diode was operated without external bias voltage. The linearity of the diode response was investigated up to doses per pulse (DPP) of 11 Gy and pulse durations ranging from 3 to 0.5 μ s. Percentage depth dose measurements were performed in ultra-high dose per pulse conditions. The effect of the total accumulated dose of 20 MeV electrons in the SiC diode sensitivity was evaluated. The temperature dependence of the response of the SiC diode was measured in the range 19 °C-38 °C. The temporal response of the diode was compared to the time-resolved beam current during each electron beam pulse. A diamond prototype detector (flashDiamond) and Alanine measurements were used for reference dosimetry. Main results. The SiC diode response was independent both of DPP and of pulse dose rate up to at least 11 Gy per pulse and 4 MGy s -1 , respectively, with tolerable deviation for relative dosimetry (<3%). When measuring the percentage depth dose under ultra-high dose rate conditions, the SiC diode performed comparably well to the reference flashDiamond. The sensitivity reduction after 100 kGy accumulated dose was <2%. The SiC diode was able to follow the temporal structure of the 20 MeV electron beam even for irregular pulse estructures. The measured temperature coefficient was (-0.079 ± 0.005)%/°C. Significance. The results of this study demonstrate for the first time the suitability of silicon carbide diodes for relative dosimetry in ultra-high dose rate pulsed electron beams up to a DPP of 11 Gy per pulse., (Creative Commons Attribution license.)

Purpose: FLASH radiotherapy (FLASH‐RT) is a novel irradiation modality with ultra‐high dose rates (>40 Gy/s) that have shown tremendous promise for its ability to enhance normal tissue sparing while maintaining comparable tumor cell eradication toconventional radiotherapy (CONV‐RT). Due to its extremely high dose rates, clinical translation of FLASH‐RT is hampered by risky delivery and current limitations in dosimetric devices, which cannot accurately measure, in real time, dose at deeper tissue. This work aims to investigate ionizing radiation acoustic imaging (iRAI) as a promising image‐guidance modality for real‐time deep tissue dose measurements during FLASH‐RT. The underlying hypothesis is that iRAI can enable mapping of dose deposition with respect to surrounding tissue with a single linear accelerator (linac) pulse precision in real time. In this work, the relationship between iRAI signal response and deposited dose was investigated as well as the feasibility of using a proof‐of‐concept dual‐modality imaging system of ultrasound and iRAI for treatment beam co‐localization with respect to underlying anatomy. Methods: Two experimental setups were used to study the feasibility of iRAI for FLASH‐RT using 6 MeV electrons from a modified Varian Clinac. First, experiments were conducted using a single element focused transducer to take a series of point measurements in a gelatin phantom, which was compared with independent dose measurements using GAFchromic film. Secondly, an ultrasound and iRAI dual‐modality imaging system utilizing a phased array transducer was used to take coregistered two‐dimensional (2D) iRAI signal amplitude images as well as ultrasound B‐mode images, to map the dose deposition with respect to surrounding anatomy in an ex vivo rabbit liver model with a single linac pulse precision. Results: Using a single element transducer, iRAI measurements showed a highly linear relationship between the iRAI signal amplitude and the linac dose per pulse (r2 = 0.9998) with a repeatability precision of 1% and a dose resolution error <2.5% in a homogenous phantom when compared to GAFchromic film dose measurements. These phantom results were used to develop a calibration curve between the iRAI signal response and the delivered dose per pulse. Subsequently, a normalized depth dose curve was generated that agreed with film measurements with an RMSE of 0.0243, using correction factors to account for deviations in measurement conditions with respect to calibration. Experiments on the ex‐vivo rabbit liver model demonstrated that a 2D iRAI image could be generated successfully from a single linac pulse, which was fused with the B‐mode ultrasound image to provide information about the beam position with respect to surrounding anatomy in real time. Conclusion: This work demonstrates the potential of using iRAI for real‐time deep tissue dosimetry in FLASH‐RT. Our results show that iRAI signals are linear with dose and can accurately map the delivered radiation dose with respect to soft tissue anatomy. With its ability to measure dose for individual linac pulses at any location within surrounding soft tissue while identifying where that dose is being delivered anatomically in real time, iRAI can be an indispensable tool to enable safe and efficient clinical translation of FLASH‐RT. [ABSTRACT FROM AUTHOR]

• Computer simulation showed a strong sparing effect on circulating immune cells. • Threshold FLASH dose rate consistent with reported FLASH dose rate in animal studies. • FLASH effect only with large dose per fraction. • Threshold FLASH dose rate for humans one order of magnitude less than that for mice. • Maybe not that challenging to develop a photon-based clinical FLASH-RT system. "FLASH" radiotherapy (RT) is a potential paradigm-changing RT technology with marked tumor killing and normal tissue sparing. However, the mechanism of the FLASH effect is not well understood. We hypothesize that the ultra-high dose rate FLASH-RT significantly reduces the killing of circulating immune cells which may partially contribute to the reported FLASH effect. This computation study directly models the effect of radiation dose rate on the killing of circulating immune cells. The model considers an irradiated volume that takes up A % of cardiac output and contains B % of total blood. The irradiated blood volume and dose were calculated for various A %, B %, blood circulation time, and irradiation time (which depends on the dose rate). The linear-quadratic model was used to calculate the extent of killing of circulating immune cells at ultra-high vs. conventional dose rates. A strong sparing effect on circulating blood cells by FLASH-RT was noticed; i.e., killing of circulating immune cells reduced from 90% to 100% at conventional dose rates to 5–10% at ultra-high dose rates. The threshold FLASH dose rate was determined to be ~40 Gy/s for mice in an average situation (A % = 50%), consistent with the reported FLASH dose rate in animal studies, and it was approximately one order of magnitude lower for humans than for mice. The magnitude of this sparing effect increased with the dose/fraction, reached a plateau at 30–50 Gy/fraction, and almost completely vanished at 2 Gy/fraction. We have calculated a strong sparing effect on circulating immune cells by FLASH-RT, which may contribute to the reported FLASH effects in animal studies. [ABSTRACT FROM AUTHOR]

• The first high-energy X-ray FLASH radiotherapy platform (PARTER) has been upgraded. • 6–8 MVs X-ray is available for FLASH irradiation at dose rate of 40–1000 Gy/s. • Treatment system and dosimetry were improved to provide verified high-performance FLASH X-rays. • The FLASH effect was demonstrated by numerous experiments using PARTER's MV X-rays. • The accelerator is being upgraded for FLASH irradiation at 80-cm SSD at the end of 2025. Recent studies indicated that ultrahigh dose rate (FLASH) radiation can reduce damage to normal tissue while maintaining anti-tumour activity compared to conventional dose rate (CONV) radiation. This paper provides a comprehensive description of the current status of the Platform for Advanced Radiotherapy Research (PARTER), which serves as the first experimental FLASH platform utilizing megavoltage X-rays and has facilitated numerous experiments. PARTER was established in 2019 based on a superconducting linac to support experimental FLASH studies using megavoltage X-rays. Continuous upgrades have been made to the accelerator, collimators, flattening filters, monitors, other auxiliary devices, and irradiation process in order to achieve optimal results. Passive and active dosimeters are employed for measuring dose distribution and to ensure traceability of radiation doses. The dose monitors and dosimeters demonstrate reliable performance with acceptable stability. At PARTER, the maximum mean dose rate is approximately 400 Gy/s at a surface-source distance of 20 cm (over 1000 Gy/s at smaller distances), with an instantaneous dose rate of approximately 8E5 Gy/s. Both passive and active dosimeters exhibit good linearity and agreement during FLASH X-ray irradiation. The monitors show good linearity to dose rate, with short-term fluctuations within 1.5 % for the diamond monitor. The discrepancy between measured absorbed dose and dose protocol is typically less than 4 %. The X-ray energy spectra on PARTER are comparable to those for megavoltage CONV linacs operating in flattening filter-free mode. The maximum field size of the FLASH beam is 4.5 cm × 4.5 cm. The FLASH dose profile demonstrates satisfactory flatness (1.04) and similar penumbra compared to clinical CONV linac, while the percentage depth dose curve of FLASH X-rays is steeper than that of the clinical megavoltage CONV X-ray. PARTER represents a pioneering platform for conducting megavolts FLASH X-ray irradiation in biological experiments. It effectively fulfills the requirements of preclinical research on megavoltage X-ray FLASH and undergoes continuous upgrades to meet increasingly demanding performance criteria. [ABSTRACT FROM AUTHOR]

FLASH radiotherapy is an emerging radiotherapy technique used to spare normal tissues. It employs ultra-high dose rate radiation beams over 40 Gy/s, which is significantly higher than those of conventional radiotherapy. In this study, a fiber-optic radiation sensor (FORS) was fabricated using a plastic scintillator, an optical filter, and a plastic optical fiber to measure the ultra-high dose rate electron beams over 40 Gy/s used in FLASH radiotherapy. The radiation-induced emissions, such as Cherenkov radiation and fluorescence generated in a transmitting optical fiber, were spectrally discriminated from the light outputs of the FORS. To evaluate the linearity and dose rate dependence of the FORS, the outputs of the fiber-optic radiation sensor were measured according to distances from an electron scattering device, and the results were compared with those of an ionization chamber and radiochromic films. Finally, the percentage depth doses were obtained using the FORS as a function of depth in a water phantom. This study found that ultra-high dose rate electron beams over 40 Gy/s could be measured in real time using a FORS.

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.

Background: Cutaneous basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most prevalent skin cancers in western countries. Surgery is the standard of care for these cancers and conventional external radiotherapy (CONV-RT) with conventional dose rate (0.03-0.06 Gy/sec) represents a good alternative when the patients or tumors are not amenable to surgery but routinely generates skin side effects. Low energy electron FLASH radiotherapy (FLASH-RT) is a new form of radiotherapy exploiting the biological advantage of the FLASH effect, which consists in delivering radiation dose in milliseconds instead of minutes in CONV-RT. In pre-clinical studies, when compared to CONV-RT, FLASH-RT induced a robust, reproducible and remarkable sparing of the normal healthy tissues, while the efficacy on tumors was preserved. In this context, we aim to prospectively evaluate FLASH-RT versus CONV-RT with regards to toxicity and oncological outcome in localized cutaneous BCC and SCC., Methods: This is a randomized selection, non-comparative, phase II study of curative FLASH-RT versus CONV-RT in patients with T1-T2 N0 M0 cutaneous BCC and SCC. Patients will be randomly allocated to low energy electron FLASH-RT (dose rate: 220-270 Gy/s) or to CONV-RT arm. Small lesions (T1) will receive a single dose of 22 Gy and large lesions (T2) will receive 30 Gy in 5 fractions of 6 Gy over two weeks.The primary endpoint evaluates safety at 6 weeks after RT through grade ≥ 3 toxicity and efficacy through local control rate at 12 months. Approximately 60 patients in total will be randomized, considering on average 1-2 lesions and a maximum of 3 lesions per patients corresponding to the total of 96 lesions required. FLASH-RT will be performed using the Mobetron® (IntraOp, USA) with high dose rate functionality.LANCE (NCT05724875) is the first randomized trial evaluating FLASH-RT and CONV-RT in a curative setting., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JB reports advisory role for Roche, BMS, MSD, Astra-Zeneca, Debiopharm, Nanobiotix, Merck and Mevion, Grant research with IntraOp, PMB and Theryq. RM receives a research grant from Accuray. All other authors have nothing to declare., (© 2024 The Author(s).)

Monte Carlo simulations of γ/fast electron-radiolysis of water show that the in situ formation of H 3 O+ temporarily renders each "native" isolated spur/track region very acidic. For pulsed (FLASH) irradiation with high dose rate, this early time, transient "acid-spike" response is shown to extend evenly across the entire irradiated volume. Since pH controls many cellular processes, this study highlights the need to consider these spikes of acidity in understanding the fundamental mechanisms underlying FLASH radiotherapy. [ABSTRACT FROM AUTHOR]

Objective . FLASH radiotherapy (FLASH-RT) with ultra-high dose rate (UHDR) irradiation (i.e. > 40 Gy s -1 ) spares the function of normal tissues while preserving antitumor efficacy, known as the FLASH effect. The biological effects after conventional dose rate-radiotherapy (CONV-RT) with ≤0.1 Gy s -1 have been well modeled by considering microdosimetry and DNA repair processes, meanwhile modeling of radiosensitivities under UHDR irradiation is insufficient. Here, we developed an integrated microdosimetric-kinetic ( IMK ) model for UHDR-irradiation enabling the prediction of surviving fraction after UHDR irradiation. Approach. The IMK model for UHDR-irradiation considers the initial DNA damage yields by the modification of indirect effects under UHDR compared to CONV dose rate. The developed model is based on the linear-quadratic (LQ) nature with the dose and dose square coefficients, considering the reduction of DNA damage yields as a function of dose rate. Main results. The estimate by the developed model could successfully reproduce the in vitro experimental dose-response curve for various cell line types and dose rates. Significance. The developed model would be useful for predicting the biological effects under the UHDR irradiation., (© 2023 Institute of Physics and Engineering in Medicine.)

Purpose: Recent studies indicated that ultrahigh dose rate (FLASH) radiation can reduce damage to normal tissue while maintaining anti-tumour activity compared to conventional dose rate (CONV) radiation. This paper provides a comprehensive description of the current status of the Platform for Advanced Radiotherapy Research (PARTER), which serves as the first experimental FLASH platform utilizing megavoltage X-rays and has facilitated numerous experiments., Methods and Materials: PARTER was established in 2019 based on a superconducting linac to support experimental FLASH studies using megavoltage X-rays. Continuous upgrades have been made to the accelerator, collimators, flattening filters, monitors, other auxiliary devices, and irradiation process in order to achieve optimal results. Passive and active dosimeters are employed for measuring dose distribution and to ensure traceability of radiation doses., Results: The dose monitors and dosimeters demonstrate reliable performance with acceptable stability. At PARTER, the maximum mean dose rate is approximately 400 Gy/s at a surface-source distance of 20 cm (over 1000 Gy/s at smaller distances), with an instantaneous dose rate of approximately 8E5 Gy/s. Both passive and active dosimeters exhibit good linearity and agreement during FLASH X-ray irradiation. The monitors show good linearity to dose rate, with short-term fluctuations within 1.5% for the diamond monitor. The discrepancy between measured absorbed dose and dose protocol is typically less than 4%. The X-ray energy spectra on PARTER are comparable to those for megavoltage CONV linacs operating in flattening filter-free mode. The maximum field size of the FLASH beam is 4.5 cm × 4.5 cm. The FLASH dose profile demonstrates satisfactory flatness (1.04) and similar penumbra compared to clinical CONV linac, while the percentage depth dose curve of FLASH X-rays is steeper than that of the clinical megavoltage CONV X-ray., Conclusions: PARTER represents a pioneering platform for conducting megavolts FLASH X-ray irradiation in biological experiments. It effectively fulfills the requirements of preclinical research on megavoltage X-ray FLASH and undergoes continuous upgrades to meet increasingly demanding performance criteria., 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 © 2023. Published by Elsevier B.V.)

In traditional treatment modalities and standard clinical practices, FLASH radiotherapy (FL-RT) administers radiation therapy at an exceptionally high dosage rate. When compared to standard dose rate radiation therapy, numerous preclinical investigations have demonstrated that FL-RT provides similar benefits in conserving normal tissue while maintaining equal antitumor efficacy, a phenomenon possible due to the 'FLASH effect' (FE) of FL-RT. The methodologies involve proton radiotherapy, intensity-modulated radiation treatment, and managing high-throughput damage by radiation to solid tissues. Recent results from animal studies indicate that FL-RT can reduce radiation-induced tissue damage, significantly enhancing anticancer potency. Focusing on the potential benefits of FL proton beam treatment in the years to come, this review details the FL-RT research that has been done so far and the existing theories illuminating the FL effects. This subject remains of interest, with many issues still needing to be answered. We offer a brief review to emphasize a few of the key efforts and difficulties in moving FL radiation research forward. The existing research state of FL-RT, its affecting variables, and its different specific impacts are presented in this current review. Key topics discussed include the biochemical mechanism during FL therapy, beam sources for FL therapy, the FL effect on immunity, clinical and preclinical studies on the protective effect of FL therapy, and parameters for effective FL therapy., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Polevoy et al.)

• FLASH sparing in the brain can be achieved under standard fractionation. • Long-term potentiation (LTP) is sensitive to dose-rate modulation. • LTP measures synaptic plasticity and is impaired after CONV-RT but not FLASH-RT. Long-term potentiation (LTP) was used to gauge the impact of conventional and FLASH dose rates on synaptic transmission. Data collected from the hippocampus and medial prefrontal cortex confirmed significant inhibition of LTP after 10 fractions of 3 Gy (30 Gy total) conventional radiotherapy. Remarkably, 10x3Gy FLASH radiotherapy and unirradiated controls were identical and exhibited normal LTP. [ABSTRACT FROM AUTHOR]

The TRIUMF particle accelerator center in Vancouver, British Columbia, Canada houses a proton therapy beam line formerly used for the treatment of ocular cancer. This existing Proton Therapy Research Centre (PTRC) was upgraded to deliver protons at ultra-high dose rates which would be required for FLASH radiotherapy treatments. A peak dose rate of 110 Gy/s over an area of 20 mm 2 was delivered at a beam energy of 21 MeV. This was achieved by degrading the cyclotron extracted beam energy of 70 MeV using polymethyl methacrylate (PMMA) plates. In addition, a fast, versatile and reliable method for producing static ridge filters has been developed to spread the proton beam to the entirety of the target axially (i.e., in depth). FLASH dose rates were maintained with a spread-out Bragg peak of 0.5 cm. [ABSTRACT FROM AUTHOR]

• Presentation of the oxygen depletion and inter-track interactions hypotheses. • Proposition of key steps to study FLASH irradiation with the Geant4 toolkit. • Discussion on the importance of simulating the irradiation modality and beam structure. • Suggestion for the temporal extension of water radiolysis simulations. FLASH radiotherapy is a promising approach to cancer treatment that offers several advantages over conventional radiotherapy. With this novel technique, high doses of radiation are delivered in a short period of time, inducing the so-called FLASH effect – a phenomenon characterized by healthy tissue sparing without alteration of tumor control. The mechanisms behind the FLASH effect remain unknown. One way to approach this problem is to gain insight into the initial parameters that can distinguish FLASH from conventional irradiation by simulating particle transport in aqueous media using the general-purpose Geant4 Monte Carlo toolkit and its Geant4-DNA extension. This review article discusses the current status of Geant4 and Geant4-DNA simulations to investigate mechanisms underlying the FLASH effect, as well as the challenges faced in this research field. One of the primary challenges is to accurately simulate the experimental irradiation parameters. Another challenge is the temporal extension of the simulations. This review also focuses on two hypotheses to explain the FLASH effect – namely the oxygen depletion hypothesis and the inter-track interactions hypothesis – and discusses how the Geant4 toolkit can be used to investigate them. The aim of this review is to provide an overview of Geant4 and Geant4-DNA simulations for FLASH radiotherapy and to highlight the challenges that need to be overcome in order to better study the FLASH effect. [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]