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Background Purpose Methods Results Conclusion FLASH radiotherapy is an emerging treatment modality using ultra‐high dose rate beams. Much effort has been made to develop suitable dosimeters for reference dosimetry, yet the spatial beam characteristics must also be characterized to enable computerized treatment planning, as well as quality control and service of a treatment delivery device. In conventional radiation therapy, this is commonly achieved by beam profile scans in a water phantom using a point detector. In ultra‐high dose rate beams, the delivered dose needed for a set of beam profile scans may exceed the regulatory dose limit specified for a typical treatment room, or degrade components of the scanning system and scanning detector. Point detector scans also cannot quantify the pulse‐to‐pulse stability of a beam profile. Detector arrays can overcome these challenges, but to date, no detector arrays suitable for ultra‐high dose rate beams are commercially available.The study presents the development and characterization of a two‐dimensional detector array for measuring pulse‐resolved spatial fluence distributions in real‐time and temporal structure of intra‐pulse dose rate of ultra‐high pulsed dose rate (UHPDR) electron beams used in FLASH radiotherapy.The performance of the SunPoint 1 diode was evaluated by measuring the response of the EDGE Detector in a 20 MeV UHPDR electron beam with a dose per pulse of 0.04 Gy – 6 Gy at a pulse duration of 1 µs or 1.9 µs, and instantaneous dose rates of 0.040 – 3.2 MGy·s−1. Based on the findings regarding a suitable signal acquisition technique, a PROFILER 2 detector array made of SunPoint 1 diodes was then modified by minimizing trace resistance, applying a reverse bias, and implementing an RC component to each diode to optimize the transfer of the collected charge during a pulse. The resultant “FLASH Profiler” was then tested in the same UHPDR electron beam.The FLASH Profiler exhibited a linear response within ± 3% deviation over the investigated dose per pulse range. The FLASH Profiler array showed good agreement with the absolute dose measured using a flashDiamond point detector and an integrating current transformer for dose‐per‐pulse values of up to 6 Gy. The FLASH Profiler was able to measure lateral beam profiles in real‐time and on a single‐pulse basis. The ability to capture and display the profiles during steering of UHPDR beams was demonstrated. The SunPoint 1 diode was able to measure the pulse duration and the intra‐pulse dose rate with a time resolution of 4 ns.The FLASH Profiler could be used for characterizing UHPDR electron beams and facilitating quality control and beam steering service of electron FLASH irradiators. [ABSTRACT FROM AUTHOR]

Background Purpose Methods Results Conclusions Pre‐clinical studies demonstrate that delivering a high dose at a high dose rate result in less toxicity while maintaining tumor control, known as the FLASH effect. In proton therapy, clinical trials have started using 250 MeV transmission beams and more trials are foreseen. A novel aspect of FLASH treatments, compared to conventional radiotherapy, is the importance of dose rate next to dose and geometry. Therefore, to ensure the safety and quality of FLASH treatments, patient‐specific dose‐rate verification before treatment is an important additional prerequisite. Various definitions of dose rate have been reported, however, the scanning proton beam (PBS) dose rate definition of Folkerts 2020 is currently the most used. It is the ratio between delta dose (ΔD) and delta time (Δt), subject to a predefined threshold, for a given position. Gafchromic film is a widely available detector used to perform relative and absolute integrated dose measurements. Since the response time of film is in the order of micro seconds it could also be suitable for pre‐treatment verification of FLASH proton therapy.Development of a patient‐specific pre‐treatment verification procedure for FLASH proton therapy based on time resolved film dosimetry. The detector design is presented and validated using three tests.A dedicated setup was built that holds a Gafchromic film and a high‐speed camera to record the film during the irradiations. The red color channel of the camera's readings was converted into optical density (OD) and an OD‐to‐dose calibration curve was applied to determine the relative dose accumulation over time. To undo the film measurement (film response) of the post‐irradiation coloration process, it is assumed that each dose deposit (pulse) results in a similar film response function. The convolution of the film response function over the pulse provides the film response. First the film response function was obtained by fitting this parameter onto a known film response and corresponding pulse. Post‐irradiation coloration correction was performed by deconvoluting all film measurement by the obtained film response function. From the integral of each measured pulse, the Δt was obtained. Several validation tests were conducted: compare the Δt film measurement to a reference detector, exclude that revisiting spots result in an unwanted artefact on the dose accumulation measurement and thereby Δt, and compare Δt distributions of film measurement and simulation (local gamma evaluation, criteria 10%/2 mm) for nine QA fields (dose values; 12, 15, and 20 Gy, and, nozzle currents; 25, 120, and 215 nA). A similar analysis was performed for three dose optimized treatment beams, with and without scan patterns optimized on local dose rate.Good agreement was found for Δt comparing film to the reference detector, but for Δt values smaller than ∼20 ms the error becomes larger (≥15%). Dose accumulation measured with film over time from a single spot is independent of whether the dose is delivered at once, twice or thrice. All gamma evaluations resulted in a gamma pass rate of ≥90%.Time resolved film dosimetry to perform patient‐specific pre‐treatment verification in FLASH proton therapy is feasible. [ABSTRACT FROM AUTHOR]

Background Purpose Methods Results Conclusions Ultra‐high dose rate (UHDR/FLASH) irradiations, along with particle minibeam therapy (PMBT) are both emerging as promising alternatives to current radiotherapy techniques thanks to their improved healthy tissue sparing and similar tumor control.Monte Carlo (MC) modeling of a commercial machine delivering 5–7 MeV electrons at UHDR. This model was used afterward to compare measurements against simulations for an experimental setup combining both FLASH and PMBT modalities.We modeled the main accelerator elements with TOPAS3.8/Geant4.10.07.p03, optimized the electron source parameters, and subsequently benchmarked this geometry against measurements. Minibeam experiments were performed by delivering 7 MeV electrons at UHDR on three different 65‐mm thick brass collimators as manufactured for protons with a 400‐µm slit width: single slit, 5 slits with a center‐to‐center (CTC) distance of 4 mm and 9 slits with CTC of 2 mm. Finally, complementary simulations were run by changing critical PMBT collimator parameters to assess their specific impact on peak‐to‐valley dose ratio (PVDR) as well as on the Bremsstrahlung photon contribution to the total dose.Percentage depth dose (PDD) distributions and lateral dose profiles showed a good agreement between simulations and measurements, with a maximum discrepancy of less than 4%. With the PMBT collimators in place, discrepancies between simulated and measured dose profiles, lateral and in‐depth in peaks and valleys, were within 3%. High PVDR between 5 and 26 were observed until 4 mm in the phantom. During the experiments, a mean dose rate of 167 Gy/s and an instantaneous dose rate of 1.2 × 105 Gy/s were obtained for the FLASH‐minibeam setup. PMBT collimator parameters need to be optimized to maximize PVDR while limiting Bremsstrahlung photon contribution to the total dose.The validation of the MC model and the configuration of an electron FLASH‐minibeam setup were successfully completed, paving the way for future radiobiological investigations. [ABSTRACT FROM AUTHOR]

Background: High‐energy transmission beams (TBs) are currently the main delivery method for proton pencil beam scanning ultrahigh dose‐rate (UHDR) FLASH radiotherapy. TBs place the Bragg‐peaks behind the target, outside the patient, making delivery practical and achievement of high dose‐rates more likely. However, they lead to higher integral dose compared to conventional intensity‐modulated proton therapy (IMPT), in which Bragg‐peaks are placed within the tumor. It is hypothesized that, when energy changes are not required and high beam currents are possible, Bragg‐peak‐based beams can not only achieve more conformal dose distributions than TBs, but also have more FLASH‐potential. Purpose: This works aims to verify this hypothesis by taking three different Bragg‐peak‐based delivery techniques and comparing them with TB and IMPT‐plans in terms of dosimetry and FLASH‐potential for single‐fraction lung stereotactic body radiotherapy (SBRT). Methods: For a peripherally located lung target of various sizes, five different proton plans were made using "matRad" and inhouse‐developed algorithms for spot/energy‐layer/beam reduction and minimum monitor unit maximization: (1) IMPT‐plan, reference for dosimetry, (2) TB‐plan, reference for FLASH‐amount, (3) pristine Bragg‐peak plan (non‐depth‐modulated Bragg‐peaks), (4) Bragg‐peak plan using generic ridge filter, and (5) Bragg‐peak plan using 3D range‐modulated ridge filter. Results: Bragg‐peak‐based plans are able to achieve sufficient plan quality and high dose‐rates. IMPT‐plans resulted in lowest OAR‐dose and integral dose (also after a FLASH sparing‐effect of 30%) compared to both TB‐plans and Bragg‐peak‐based plans. Bragg‐peak‐based plans vary only slightly between themselves and generally achieve lower integral dose than TB‐plans. However, TB‐plans nearly always resulted in lower mean lung dose than Bragg‐peak‐based plans and due to a higher amount of FLASH‐dose for TB‐plans, this difference increased after including a FLASH sparing‐effect. Conclusion: This work indicates that there is no benefit in using Bragg‐peak‐based beams instead of TBs for peripherally located, UHDR stereotactic lung radiotherapy, if lung dose is the priority. [ABSTRACT FROM AUTHOR]

Background Purpose Methods Results Conclusion FLASH radiation therapy (RT) offers a promising avenue for the broadening of the therapeutic index. However, to leverage the full potential of FLASH in the clinical setting, an improved understanding of the biological principles involved is critical. This requires the availability of specialized equipment optimized for the delivery of conventional (CONV) and ultra‐high dose rate (UHDR) irradiation for preclinical studies. One method to conduct such preclinical radiobiological research involves adapting a clinical linear accelerator configured to deliver both CONV and UHDR irradiation.We characterized the dosimetric properties of a clinical linear accelerator configured to deliver ultra‐high dose rate irradiation to two anatomic sites in mice and for cell‐culture FLASH radiobiology experiments.Delivered doses of UHDR electron beams were controlled by a microcontroller and relay interfaced with the respiratory gating system. We also produced beam collimators with indexed stereotactic mouse positioning devices to provide anatomically specific preclinical treatments. Treatment delivery was monitored directly with an ionization chamber, and charge measurements were correlated with radiochromic film measurements at the entry surface of the mice. The setup for conventional dose rate irradiation utilized the same collimation system but at increased source‐to‐surface distance. Monte Carlo simulations and film dosimetry were used to characterize beam properties and dose distributions.The mean electron beam energies before the flattening filter were 18.8 MeV (UHDR) and 17.7 MeV (CONV), with corresponding values at the mouse surface of 17.2 and 16.2 MeV. The charges measured with an external ion chamber were linearly correlated with the mouse entrance dose. The use of relay gating for pulse control initially led to a delivery failure rate of 20% (± 1 pulse); adjustments to account for the linac latency improved this rate to < 1/20. Beam field sizes for two anatomically specific mouse collimators (4 × 4 cm2 for whole‐abdomen and 1.5 × 1.5 cm2 for unilateral lung irradiation) were accurate within < 5% and had low radiation leakage (< 4%). Normalizing the dose at the center of the mouse (∼0.75 cm depth) produced UHDR and CONV doses to the irradiated volumes with > 95% agreement.We successfully configured a clinical linear accelerator for increased output and developed a robust preclinical platform for anatomically specific irradiation, with highly accurate and precise temporal and spatial dose delivery, for both CONV and UHDR irradiation applications. [ABSTRACT FROM AUTHOR]

Background Purpose Methods Results Conclusion Reference dosimetry in ultra‐high dose rate (UHDR) beamlines is significantly hindered by limitations in conventional ionization chamber design. In particular, conventional chambers suffer from severe charge collection efficiency (CCE) degradation in high dose per pulse (DPP) beams.The aim of this study was to optimize the design and performance of parallel plate ion chambers for use in UHDR dosimetry applications, and evaluate their potential as reference class chambers for calibration purposes. Three chamber designs were produced to determine the influence of the ion chamber response on electrode separation, field strength, and collection volume on the ion chamber response under UHDR and ultra‐high dose per pulse (UHDPP) conditions.Three chambers were designed and produced: the A11‐VAR (0.2–1.0 mm electrode gap, 20 mm diameter collector), the A11‐TPP (0.3 mm electrode gap, 20 mm diameter collector), and the A30 (0.3 mm electrode gap, 5.4 mm diameter collector). The chambers underwent full characterization using an UHDR 9 MeV electron beam with individually varied beam parameters of pulse repetition frequency (PRF, 10–120 Hz), pulse width (PW, 0.5–4 µs), and pulse amplitude (0.01–9 Gy/pulse). The response of the ion chambers was evaluated as a function of the DPP, PRF, PW, dose rate, electric field strength, and electrode gap.The chamber response was found to be dependent on DPP and PW, and these dependencies were mitigated with larger electric field strengths and smaller electrode spacing. At a constant electric field strength, we measured a larger CCE as a function of DPP for ion chambers with a smaller electrode gap in the A11‐VAR. For ion chambers with identical electrode gap (A11‐TPP and A30), higher electric field strengths were found to yield better CCE at higher DPP. A PW dependence was observed at low electric field strengths (500 V/mm) for DPP values ranging from 1 to 5 Gy at PWs ranging from 0.5 to 4 µs, but at electric field strengths of 1000 V/mm and higher, these effects become negligible.This study confirmed that the CCE of ion chambers depends strongly on the electrode spacing and the electric field strength, and also on the DPP and the PW of the UHDR beam. A significant finding of this study is that although chamber performance does depend on PW, the effect on the CCE becomes negligible with reduced electrode spacing and increased electric field. A CCE of ≥95% was achieved for DPPs of up to 5 Gy with no observable dependence on PW using the A30 chamber, while still achieving an acceptable performance in conventional dose rate beams, opening up the possibility for this type of chamber to be used as a reference class chamber for calibration purposes of electron FLASH beamlines. [ABSTRACT FROM AUTHOR]

Background: Although the FLASH radiotherapy (FLASH) can improve the sparing of organs‐at‐risk (OAR) via the FLASH effect, it is generally a tradeoff between the physical dose coverage and the biological FLASH coverage, for which the concept of FLASH effective dose (FED) is needed to quantify the net improvement of FLASH, compared to the conventional radiotherapy (CONV). Purpose: This work will develop the first‐of‐its‐kind treatment planning method called simultaneous dose and dose rate optimization via dose modifying factor modeling (SDDRO‐DMF) for proton FLASH that directly optimizes FED. Methods: SDDRO‐DMF models and optimizes FED using FLASH dose modifying factor (DMF) models, which can be classified into two categories: (1) the phenomenological model of the FLASH effect, such as the FLASH effectiveness model (FEM); (2) the mechanistic model of the FLASH radiobiology, such as the radiolytic oxygen depletion (ROD) model. The general framework of SDDRO‐DMF will be developed, with specific DMF models using FEM and ROD, as a demonstration of general applicability of SDDRO‐DMF for proton FLASH via transmission beams (TB) or Bragg peaks (BP) with single‐field or multi‐field irradiation. The FLASH dose rate is modeled as pencil beam scanning dose rate. The solution algorithm for solving the inverse optimization problem of SDDRO‐DMF is based on iterative convex relaxation method. Results: SDDRO‐DMF is validated in comparison with IMPT and a state‐of‐the‐art method called SDDRO, with demonstrated efficacy and improvement for reducing the high dose and the high‐dose volume for OAR in terms of FED. For example, in a SBRT lung case of the dose‐limiting factor that the max dose of brachial plexus should be no more than 26 Gy, only SDDRO‐DMF met this max dose constraint; moreover, SDDRO‐DMF completely eliminated the high‐dose (V70%) volume to zero for CTV10mm (a high‐dose region as a 10 mm ring expansion of CTV). Conclusion: We have proposed a new proton FLASH optimization method called SDDRO‐DMF that directly optimizes FED using phenomenological or mechanistic models of DMF, and have demonstrated the efficacy of SDDO‐DMF in reducing the high‐dose volume or/and the high‐dose value for OAR, compared to IMPT and a state‐of‐the‐art method SDDRO. [ABSTRACT FROM AUTHOR]

Background: Ultra‐high‐dose‐rate (UHDR) electron beams have been commonly utilized in FLASH studies and the translation of FLASH Radiotherapy (RT) to the clinic. The EDGE diode detector has potential use for UHDR dosimetry albeit with a beam energy dependency observed. Purpose: The purpose is to present the electron beam response for an EDGE detector in dependence on beam energy, to characterize the EDGE detector's response under UHDR conditions, and to validate correction factors derived from the first detailed Monte Carlo model of the EDGE diode against measurements, particularly under UHDR conditions. Methods: Percentage depth doses (PDDs) for the UHDR Mobetron were measured with both EDGE detectors and films. A detailed Monte Carlo (MC) model of the EDGE detector has been configured according to the blueprint provided by the manufacturer under an NDA agreement. Water/silicon dose ratios of EDGE detector for a series of mono‐energetic electron beams have been calculated. The dependence of the water/silicon dose ratio on depth for a FLASH relevant electron beam was also studied. An analytical approach for the correction of PDD measured with EDGE detectors was established. Results: Water/silicon dose ratio decreased with decreasing electron beam energy. For the Mobetron 9 MeV UHDR electron beam, the ratio decreased from 1.09 to 1.03 in the build‐up region, maintained in range of 0.98–1.02 at the fall‐off region and raised to a plateau in value of 1.08 at the tail. By applying the corrections, good agreement between the PDDs measured by the EDGE detector and those measured with film was achieved. Conclusions: Electron beam response of an UHDR capable EDGE detector was derived from first principles utilizing a sophisticated MC model. An analytical approach was validated for the PDDs of UHDR electron beams. The results demonstrated the capability of EDGE detector in measuring PDDs of UHDR electron beams. [ABSTRACT FROM AUTHOR]

Background: Cyclotron‐based proton therapy systems utilize the highest proton energies to achieve an ultra‐high dose rate (UHDR) for FLASH radiotherapy. The deep‐penetrating range associated with this high energy can be modulated by inserting a uniform plate of proton‐stopping material, known as a range shifter, in the beam path at the nozzle to bring the Bragg peak within the target while ensuring high proton transport efficiency for UHDR. Aluminum has been recently proposed as a range shifter material mainly due to its high compactness and its mechanical properties. A possible drawback lies in the fact that aluminum has a larger cross‐section of producing secondary neutrons compared to conventional plastic range shifters. Accordingly, an increase in secondary neutron contamination was expected during the delivery of range‐modulated FLASH proton therapy, potentially heightening neutron‐induced carcinogenic risks to the patient. Purpose: We conducted neutron dosimetry using simulations and measurements to evaluate excess dose due to neutron exposure during UHDR proton irradiation with aluminum range shifters compared to plastic range shifters. Methods: Monte Carlo simulations in TOPAS were performed to investigate the secondary neutron production characteristics with aluminum range shifter during 225 MeV single‐spot proton irradiation. The computational results were validated against measurements with a pair of ionization chambers in an out‐of‐field region (≤$\le$ 30 cm) and with a Proton Recoil Scintillator‐Los Alamos rem meter in a far‐out‐of‐field region (0.5–2.5 m). The assessments were repeated with solid water slabs as a surrogate for the conventional range shifter material to evaluate the impact of aluminum on neutron yield. The results were compared with the International Electrotechnical Commission (IEC) standards to evaluate the clinical acceptance of the secondary neutron yield. Results: For a range modulation up to 26 cm in water, the maximum simulated and measured values of out‐of‐field secondary neutron dose equivalent per therapeutic dose with aluminum range shifter were found to be (0.57±0.02)mSv/Gy$(0.57\pm 0.02)\ \text{mSv/Gy}$ and (0.46±0.04)mSv/Gy$(0.46\pm 0.04)\ \text{mSv/Gy}$, respectively, overall higher than the solid water cases (simulation: (0.332±0.003)mSv/Gy$(0.332\pm 0.003)\ \text{mSv/Gy}$; measurement: (0.33±0.03)mSv/Gy$(0.33\pm 0.03)\ \text{mSv/Gy}$). The maximum far out‐of‐field secondary neutron dose equivalent was found to be (8.8±0.5$8.8 \pm 0.5$) μSv/Gy$\umu {\rm Sv/Gy}$ and (1.62±0.02$1.62 \pm 0.02$) μSv/Gy$\umu {\rm Sv/Gy}$ for the simulations and rem meter measurements, respectively, also higher than the solid water counterparts (simulation: (3.3±0.3$3.3 \pm 0.3$) μSv/Gy$\umu {\rm Sv/Gy}$; measurement: (0.63±0.03$0.63 \pm 0.03$) μSv/Gy$\umu {\rm Sv/Gy}$). Conclusions: We conducted simulations and measurements of secondary neutron production under proton irradiation at FLASH energy with range shifters. We found that the secondary neutron yield increased when using aluminum range shifters compared to conventional materials while remaining well below the non‐primary radiation limit constrained by the IEC regulations. [ABSTRACT FROM AUTHOR]

Background: FLASH radiotherapy based on ultra‐high dose rate (UHDR) is actively being studied by the radiotherapy community. Dedicated UHDR electron devices are currently a mainstay for FLASH studies. Purpose: To present the first Monte Carlo (MC) electron beam model for the UHDR capable Mobetron (FLASH‐IQ) as a dose calculation and treatment planning platform for preclinical research and FLASH‐radiotherapy (RT) clinical trials. Methods: The initial beamline geometry of the Mobetron was provided by the manufacturer, with the first‐principal implementation realized in the Geant4‐based GAMOS MC toolkit. The geometry and electron source characteristics, such as energy spectrum and beamline parameters, were tuned to match the central‐axis percentage depth dose (PDD) and lateral profiles for the pristine beam measured during machine commissioning. The thickness of the small foil in secondary scatter affected the beam model dominantly and was fine tuned to achieve the best agreement with commissioning data. Validation of the MC beam modeling was performed by comparing the calculated PDDs and profiles with EBT‐XD radiochromic film measurements for various combinations of applicators and inserts. Results: The nominal 9 MeV electron FLASH beams were best represented by a Gaussian energy spectrum with mean energy of 9.9 MeV and variance (σ) of 0.2 MeV. Good agreement between the MC beam model and commissioning data were demonstrated with maximal discrepancy < 3% for PDDs and profiles. Hundred percent gamma pass rate was achieved for all PDDs and profiles with the criteria of 2 mm/3%. With the criteria of 2 mm/2%, maximum, minimum and mean gamma pass rates were (100.0%, 93.8%, 98.7%) for PDDs and (100.0%, 96.7%, 99.4%) for profiles, respectively. Conclusions: A validated MC beam model for the UHDR capable Mobetron is presented for the first time. The MC model can be utilized for direct dose calculation or to generate beam modeling input required for treatment planning systems for FLASH‐RT planning. The beam model presented in this work should facilitate translational and clinical FLASH‐RT for trials conducted on the Mobetron FLASH‐IQ platform. [ABSTRACT FROM AUTHOR]

Background: Plane‐parallel ionization chambers are the recommended secondary standard systems for clinical reference dosimetry of electrons. Dosimetry in high dose rate and dose‐per‐pulse (DPP) is challenging as ionization chambers are subject to ion recombination, especially when dose rate and/or DPP is increased beyond the range of conventional radiotherapy. The lack of universally accepted models for correction of ion recombination in UDHR is still an issue as it is, especially in FLASH‐RT research, which is crucial in order to be able to accurately measure the dose for a wide range of dose rates and DPPs. Purpose: The objective of this study was to show the feasibility of developing an Artificial Intelligence model to predict the ion‐recombination factor—ksat for a plane‐parallel Advanced Markus ionization chamber for conventional and ultra‐high dose rate electron beams based on machine parameters. In addition, the predicted ksat of the AI model was compared with the current applied analytical models for this correction factor. Methods: A total number of 425 measurements was collected with a balanced variety in machine parameter settings. The specific ksat values were determined by dividing the output of the reference dosimeter (optically stimulated luminescence [OSL]) by the output of the AM chamber. Subsequently, a XGBoost regression model was trained, which used the different machine parameters as input features and the corresponding ksat value as output. The prediction accuracy of this regression model was characterized by R2‐coefficient of determination, mean absolute error and root mean squared error. In addition, the model was compared with the Two‐Voltage (TVA) method and empirical Petersson model for 19 different dose‐per‐pulse values ranging from conventional to UDHR regimes. The Akiake Information criterion (AIC) was calculated for the three different models. Results: The XGBoost regression model reached a R2‐score of 0.94 on the independent test set with a MAE of 0.067 and RMSE of 0.106. For the additional 19 random data points, the ksat values predicted by the XGBoost model showed to be in agreement, within the uncertainties, with the ones determined by the Petersson model and better than the TVA method for doses per pulse >3.5 Gy with a maximum deviation from the ground truth of 14.2%, 16.7%, and −36.0%, respectively, for DPP >4 Gy. Conclusion: The proposed method of using AI for ksat determination displays efficiency. For the investigated DPPs, the ksat values obtained with the XGBoost model were in concurrence with the ones obtained with the current available analytical models within the boundaries of uncertainty, certainly for the DPP characterizing UDHR. But the overall performance of the AI model, taking the number of free parameters into account, lacked efficiency. Future research should optimize the determination of the experimental ksat, and investigate the determination the ksat for DPPs higher than the ones investigated in this study, while also evaluating the prediction of the proposed XGBoost model for UDHR machines of different centers. [ABSTRACT FROM AUTHOR]

Background: Dosimetry in ultra‐high dose rate (UHDR) beamlines is significantly challenged by limitations in real‐time monitoring and accurate measurement of beam output, beam parameters, and delivered doses using conventional radiation detectors, which exhibit dependencies in ultra‐high dose‐rate (UHDR) and high dose‐per‐pulse (DPP) beamline conditions. Purpose: In this study, we characterized the response of the Exradin W2 plastic scintillator (Standard Imaging, Inc.), a water‐equivalent detector that provides measurements with a time resolution of 100 Hz, to determine its feasibility for use in UHDR electron beamlines. Methods: The W2 scintillator was exposed to an UHDR electron beam with different beam parameters by varying the pulse repetition frequency (PRF), pulse width (PW), and pulse amplitude settings of an electron UHDR linear accelerator system. The response of the W2 scintillator was evaluated as a function of the total integrated dose delivered, DPP, and mean and instantaneous dose rate. To account for detector radiation damage, the signal sensitivity (pC/Gy) of the W2 scintillator was measured and tracked as a function of dose history. Results: The W2 scintillator demonstrated mean dose rate independence and linearity as a function of integrated dose and DPP for DPP ≤ 1.5 Gy (R2 > 0.99) and PRF ≤ 90 Hz. At DPP > 1.5 Gy, nonlinear behavior and signal saturation in the blue and green signals as a function of DPP, PRF, and integrated dose became apparent. In the absence of Cerenkov correction, the W2 scintillator exhibited PW dependence, even at DPP values <1.5 Gy, with a difference of up to 31% and 54% in the measured blue and green signal for PWs ranging from 0.5 to 3.6 µs. The change in signal sensitivity of the W2 scintillator as a function of accumulated dose was approximately 4%/kGy and 0.3%/kGy for the measured blue and green signal responses, respectively, as a function of integrated dose history. Conclusion: The Exradin W2 scintillator can provide output measurements that are both dose rate independent and linear in response if the DPP is kept ≤1.5 Gy (corresponding to a mean dose rate up to 290 Gy/s in the used system), as long as proper calibration is performed to account for PW and changes in signal sensitivity as a function of accumulated dose. For DPP > 1.5 Gy, the W2 scintillator's response becomes nonlinear, likely due to limitations in the electrometer related to the high signal intensity. [ABSTRACT FROM AUTHOR]

Background: The conventional theories and methods of determining the ion recombination correction factor, such as Boag theory and the related two voltage method and Jaffé plot extrapolation, do not seem to yield accurate results in FLASH /high dose per pulse (DPP) beams (>$>$10 mGy DPP). This is due to the presence of a large free electron fraction that distorts the electric field inside the chamber sensitive volume. To understand the influence of these effects on the ion recombination correction factor and to develop new expressions for it, it is necessary to re‐visit the underlying physics. Purpose: To present a mathematical procedure to develop an analytical expression for the ion recombination correction factor. The expression is the basis for an extrapolation method so the correction factor can be determined in a clinical setting. Methods: A semi‐analytical solution method, the homotopy perturbation method (HPM), is used to solve the partial differential equations (PDEs) describing the charge carrier physics, including space charge and free electrons. The electron velocity and attachment rate are modeled as functions of the electric field strength. An expression for the charge collection efficiency and ion recombination correction factor are developed. A fit procedure based on this expression is used to compare it to measured data from previously published articles. Another fit procedure using a general equation is also proposed and compared to the data. Results: The series obtained for the charge collection efficiency and the ion recombination correction factor are determined to be asymptotic series and the optimal truncation established. The ion recombination correction factor exhibits a 1/V2$1/V^2$ dependency due to the free electron presence. The fit using this expression agrees well with measured data as long as (1) the DPP is below 1 Gy for chambers with a 1 mm plate separation and (2) when the DPP is below 3 Gy for chambers with a 0.5 mm plate separation. In these DPP ranges, the deviation between measured and fit value did not exceed 6%. In both chamber cases the voltage range where the fit applies decreases as DPP increases. The general equation yielded comparable results. Conclusions: The HPM was shown to be applicable to a complex system of PDEs and generate meaningful and novel solutions, as they include both space charge and free electrons. The HPM also lends itself to other chamber geometries. The fit procedure was also shown to yield accurate results for the ion recombination correction up to the 1 Gy DPP level. [ABSTRACT FROM AUTHOR]

Background: Dosimetry in ultra‐high dose rate (UHDR) electron beamlines poses a significant challenge owing to the limited usability of standard dosimeters in high dose and high dose‐per‐pulse (DPP) applications. Purpose: In this study, Al2O3:C nanoDot optically stimulated luminescent dosimeters (OSLDs), single‐use powder‐based LiF:Mg,Ti thermoluminescent dosimeters (TLDs), and Gafchromic EBT3 film were evaluated at extended dose ranges (up to 40 Gy) in conventional dose rate (CONV) and UHDR beamlines to determine their usability for calibration and dose verification in the setting of FLASH radiation therapy. Methods: OSLDs and TLDs were evaluated against established dose‐rate–independent Gafchromic EBT3 film with regard to the potential influence of mean dose rate, instantaneous dose rate, and DPP on signal response. The dosimeters were irradiated at CONV or UHDR conditions on a 9‐MeV electron beam. Under UHDR conditions, different settings of pulse repetition frequency (PRF), pulse width (PW), and pulse amplitude were used to characterize the individual dosimeters' response in order to isolate their potential dependencies on dose, dose rate, and DPP. Results: The OSLDs, TLDs, and Gafchromic EBT3 film were found to be suitable at a dose range of up to 40 Gy without any indication of saturation in signal. The response of OSLDs and TLDs in UHDR conditions were found to be independent of mean dose rate (up to 1440 Gy/s), instantaneous dose rate (up to 2 MGy/s), and DPP (up to 7 Gy), with uncertainties on par with nominal values established in CONV beamlines (± 4%). In cross‐comparing the response of OSLDs, TLDs and Gafchromic film at dose rates of 0.18–245 Gy/s, the coefficient of variation or relative standard deviation in the measured dose between the three dosimeters (inter‐dosimeter comparison) was found to be within 2%. Conclusions: We demonstrated the dynamic range of OSLDs, TLDs, and Gafchromic film to be suitable up to 40 Gy, and we developed a protocol that can be used to accurately translate the measured signal in each respective dosimeter to dose. OSLDs and powdered TLDs were shown to be viable for dosimetric measurement in UHDR beamlines, providing dose measurements with accuracies on par with Gafchromic EBT3 film and their concurrent use demonstrating a means for redundant dosimetry in UHDR conditions. [ABSTRACT FROM AUTHOR]

Background: Radiotherapy with charged particles at high dose and ultra‐high dose rate (uHDR) is a promising technique to further increase the therapeutic index of patient treatments. Dose rate is a key quantity to predict the so‐called FLASH effect at uHDR settings. However, recent works introduced varying calculation models to report dose rate, which is susceptible to the delivery method, scanning path (in active beam delivery) and beam intensity. Purpose: This work introduces an analytical dose rate calculation engine for raster scanned charged particle beams that is able to predict dose rate from the irradiation plan and recorded beam intensity. The importance of standardized dose rate calculation methods is explored here. Methods: Dose is obtained with an analytical pencil beam algorithm, using pre‐calculated databases for integrated depth dose distributions and lateral penumbra. Dose rate is then calculated by combining dose information with the respective particle fluence (i.e., time information) using three dose‐rate‐calculation models (mean, instantaneous, and threshold‐based). Dose rate predictions for all three models are compared to uHDR helium ion beam (145.7 MeV/u, range in water of approximatively 14.6 cm) measurements performed at the Heidelberg Ion Beam Therapy Center (HIT) with a diamond‐detector prototype. Three scanning patterns (scanned or snake‐like) and four field sizes are used to investigate the dose rate differences. Results: Dose rate measurements were in good agreement with in‐silico generated distributions using the here introduced engine. Relative differences in dose rate were below 10% for varying depths in water, from 2.3 to 14.8 cm, as well as laterally in a near Bragg peak area. In the entrance channel of the helium ion beam, dose rates were predicted within 7% on average for varying irradiated field sizes and scanning patterns. Large differences in absolute dose rate values were observed for varying calculation methods. For raster‐scanned irradiations, the deviation between mean and threshold‐based dose rate at the investigated point was found to increase with the field size up to 63% for a 10 mm × 10 mm field, while no significant differences were observed for snake‐like scanning paths. Conclusions: This work introduces the first dose rate calculation engine benchmarked to instantaneous dose rate, enabling dose rate predictions for physical and biophysical experiments. Dose rate is greatly affected by varying particle fluence, scanning path, and calculation method, highlighting the need for a consensus among the FLASH community on how to calculate and report dose rate in the future. The here introduced engine could help provide the necessary details for the analysis of the sparing effect and uHDR conditions. [ABSTRACT FROM AUTHOR]

Background: The recent rediscovery of the FLASH effect, a normal tissue sparing phenomenon observed in ultra‐high dose rate (UHDR) irradiations, has instigated a surge of research endeavors aiming to close the gap between experimental observation and clinical treatment. However, the dependences of the FLASH effect and its underpinning mechanisms on beam parameters are not well known, and large‐scale in vivo studies using murine models of human cancer are needed for these investigations. Purpose: To commission a high‐throughput, variable dose rate platform providing uniform electron fields (≥15 cm diameter) at conventional (CONV) and UHDRs for in vivo investigations of the FLASH effect and its dependences on pulsed electron beam parameters. Methods: A murine whole‐thoracic lung irradiation (WTLI) platform was constructed using a 1.3 cm thick Cerrobend collimator forming a 15 × 1.6 cm2 slit. Control of dose and dose rate were realized by adjusting the number of monitor units and couch vertical position, respectively. Achievable doses and dose rates were investigated using Gafchromic EBT‐XD film at 1 cm depth in solid water and lung‐density phantoms. Percent depth dose (PDD) and dose profiles at CONV and various UHDRs were also measured at depths from 0 to 2 cm. A radiation survey was performed to assess radioactivation of the Cerrobend collimator by the UHDR electron beam in comparison to a precision‐machined copper alternative. Results: This platform allows for the simultaneous thoracic irradiation of at least three mice. A linear relationship between dose and number of monitor units at a given UHDR was established to guide the selection of dose, and an inverse‐square relationship between dose rate and source distance was established to guide the selection of dose rate between 20 and 120 Gy·s−1. At depths of 0.5 to 1.5 cm, the depth range relevant to murine lung irradiation, measured PDDs varied within ±1.5%. Similar lateral dose profiles were observed at CONV and UHDRs with the dose penumbrae widening from 0.3 mm at 0 cm depth to 5.1 mm at 2.0 cm. The presence of lung‐density plastic slabs had minimal effect on dose distributions as compared to measurements made with only solid water slabs. Instantaneous dose rate measurements of the activated copper collimator were up to two orders of magnitude higher than that of the Cerrobend collimator. Conclusions: A high‐throughput, variable dose rate platform has been developed and commissioned for murine WTLI electron FLASH radiotherapy. The wide field of our UHDR‐enabled linac allows for the simultaneous WTLI of at least three mice, and for the average dose rate to be modified by changing the source distance, without affecting dose distribution. The platform exhibits uniform, and comparable dose distributions at CONV and UHDRs up to 120 Gy·s−1, owing to matched and flattened 16 MeV CONV and UHDR electron beams. Considering radioactivation and exposure to staff, Cerrobend collimators are recommended above copper alternatives for electron FLASH research. This platform enables high‐throughput animal irradiation, which is preferred for experiments using a large number of animals, which are required to effectively determine UHDR treatment efficacies. [ABSTRACT FROM AUTHOR]

Background: Ultra‐high dose rate radiation (UHDR) is being explored by researchers in promise of advancing radiation therapy treatments. Purpose: This work presents the commissioning of Varian's Flash Extension for research (FLEX) conversion of a Clinac to deliver UHDR electrons. Methods: A Varian Clinac iX with the FLEX conversion was commissioned for non‐clinical research use with 16 MeV UHDR (16H) energy. This involved addition of new hardware, optimizing the electron gun voltages, radiofrequency (RF) power, and steering coils in order to maximize the accelerated electron beam current, sending the beam through custom scattering foils to produce the UHDR with 16H beam. Profiles and percent depth dose (PDD) measurements for 16H were obtained using radiochromic film in a custom vertical film holder and were compared to 16 MeV conventional electrons (16C). Dose rate and dose per pulse (DPP) were calculated from measured dose in film. Linearity and stability were assessed using an Advanced Markus ionization chamber. Results: Energies for 16H and 16C had similar beam quality based on PDD measurements. Measurements at the head of the machine (61.3 cm SSD) with jaws set to 10×10 cm2 showed the FWHM of the profile as 7.2 cm, with 3.4 Gy as the maximum DPP and instantaneous dose rate of 8.1E5 Gy/s. Measurements at 100 cm SSD with 10 cm standard cone showed the full width at half max (FWHM) of the profile as 10.5 cm, 1.08 Gy as the maximum DPP and instantaneous dose rate of 2.E5 Gy/s. Machine output with number of pulses was linear (R = 1) from 1 to 99 delivered pulses. Output stability was measured within ±1% within the same session and within ±2% for daily variations. Conclusions: The FLEX conversion of the Clinac is able to generate UHDR electron beams which are reproducible with beam properties similar to clinically used electrons at 16 MeV. Having a platform which can quickly transition between UHDR and conventional modes (<1 min) can be advantageous for future research applications. [ABSTRACT FROM AUTHOR]

Background: The first clinical trials to assess the feasibility of FLASH radiotherapy in humans have started (FAST‐01, FAST‐02) and more trials are foreseen. To increase comparability between trials it is important to assure treatment quality and therefore establish a standard for machine quality assurance (QA). Currently, the AAPM TG‐224 report is considered as the standard on machine QA for proton therapy, however, it was not intended to be used for ultra‐high dose rate (UHDR) proton beams, which have gained interest due to the observation of the FLASH effect. Purpose: The aim of this study is to find consensus on practical guidelines on machine QA for UHDR proton beams in transmission mode in terms of which QA is required, how they should be done, which detectors are suitable for UHDR machine QA, and what tolerance limits should be applied. Methods: A risk assessment to determine the gaps in the current standard for machine QA was performed by an international group of medical physicists. Based on that, practical guidelines on how to perform machine QA for UHDR proton beams were proposed. Results: The risk assessment clearly identified the need for additional guidance on temporal dosimetry, addressing dose rate (constancy), dose spillage, and scanning speed. In addition, several minor changes from AAPM TG‐224 were identified; define required dose rate levels, the use of clinically relevant dose levels, and the use of adapted beam settings to minimize activation of detector and phantom materials or to avoid saturation effects of specific detectors. The final report was created based on discussions and consensus. Conclusions: Consensus was reached on what QA is required for UHDR scanning proton beams in transmission mode for isochronous cyclotron‐based systems and how they should be performed. However, the group discussions also showed that there is a lack of high temporal resolution detectors and sufficient QA data to set appropriate limits for some of the proposed QA procedures. [ABSTRACT FROM AUTHOR]

Background: The possible emergence of the FLASH effect—the sparing of normal tissue while maintaining tumor control—after irradiations at dose‐rates exceeding several tens of Gy per second, has recently spurred a surge of studies attempting to characterize and rationalize the phenomenon. Investigating and reporting the dose and instantaneous dose‐rate of ultra‐high dose‐rate (UHDR) particle radiotherapy beams is crucial for understanding and assessing the FLASH effect, towards pre‐clinical application and quality assurance programs. Purpose: The purpose of the present work is to investigate a novel diamond‐based detector system for dose and instantaneous dose‐rate measurements in UHDR particle beams. Methods: Two types of diamond detectors, a microDiamond (PTW 60019) and a diamond detector prototype specifically designed for operation in UHDR beams (flashDiamond), and two different readout electronic chains, were investigated for absorbed dose and instantaneous dose‐rate measurements. The detectors were irradiated with a helium beam of 145.7 MeV/u under conventional and UHDR delivery. Dose‐rate delivery records by the monitoring ionization chamber and diamond detectors were studied for single spot irradiations. Dose linearity at 5 cm depth and in‐depth dose response from 2 to 16 cm were investigated for both measurement chains and both detectors in a water tank. Measurements with cylindrical and plane‐parallel ionization chambers as well as Monte‐Carlo simulations were performed for comparisons. Results: Diamond detectors allowed for recording the temporal structure of the beam, in good agreement with the one obtained by the monitoring ionization chamber. A better time resolution of the order of few μs was observed as compared to the approximately 50 μs of the monitoring ionization chamber. Both diamonds detectors show an excellent linearity response in both delivery modalities. Dose values derived by integrating the measured instantaneous dose‐rates are in very good agreement with the ones obtained by the standard electrometer readings. Bragg peak curves confirmed the consistency of the charge measurements by the two systems. Conclusions: The proposed novel dosimetric system allows for a detailed investigation of the temporal evolution of UHDR beams. As a result, reliable and accurate determinations of dose and instantaneous dose‐rate are possible, both required for a comprehensive characterization of UHDR beams and relevant for FLASH effect assessment in clinical treatments. [ABSTRACT FROM AUTHOR]

Background: Beam scanning is a useful technique for the treatment of large tumors when the primary beam size is limited, which is the case with radiation beams used in FLASH radiotherapy. Purpose: To optimize beam scanning as a dose delivery method for FLASH radiotherapy, it is necessary to first understand the effects of beam scanning on the FLASH effect. To do so, biological FLASH experiments need to be done using defined beam parameters with beam scanning and compared to the situation without beam scanning. In this regard, we propose implementation of a simple slit scanning system with an electron FLASH beam to obtain a scanned radiation field that closely resembles a static field. Methods: A pulsed electron linear accelerator (linac) was used in combination with a scanning slit system in order to simulate a scanned electron beam. Three configurations that produced homogeneous lateral profiles and high enough doses per pulse for FLASH experiments were established. The optimal scanning parameters were found for each configuration by examining the flatness of the obtained lateral dose profiles. Using the optimal scanning parameters, the scanned FLASH beams were dosimetrically characterized and compared to non‐scanned open field beam. Results: A final electron FLASH beam scanning configuration was found for a 1 mm wide slit at a distance of 350 mm from the linac and a 2 mm wide slit at distances of 350 and 490 mm from the linac. The lateral profiles for these final configurations were found to have a homogeneity that is comparable to the open field profiles. The percentage depth dose (PDD) values found for these final configurations closely matched (by a few percentage) the PDD of the open field beam. Conclusions: Three electron FLASH beam scanning configurations achieved by the motorized slit system were found to produce radiation fields similar to a non‐scanned open field electron beam. These final configurations can therefore be used in future biological FLASH experiments to compare to non‐scanned beam experiments in order to optimize beam scanning as a technique permitting the treatment of larger tumors with FLASH radiotherapy. [ABSTRACT FROM AUTHOR]

Ion chambers are required for calibration and reference dosimetry applications in radiation therapy (RT). However, exposure of ion chambers in ultra‐high dose rate (UHDR) conditions pertinent to FLASH‐RT leads to severe saturation and ion recombination, which limits their performance and usability. The purpose of this study was to comprehensively evaluate a set of commonly used commercially available ion chambers in RT, all with different design characteristics, and use this information to produce a prototype ion chamber with improved performance in UHDR conditions as a first step toward ion chambers specific for FLASH‐RT. The Advanced Markus and Exradin A10, A26, and A20 ion chambers were evaluated. The chambers were placed in a water tank, at a depth of 2 cm, and exposed to an UHDR electron beam at different pulse repetition frequency (PRF), pulse width (PW), and pulse amplitude settings on an IntraOp Mobetron. Ion chamber responses were investigated for the various beam parameter settings to isolate their dependence on integrated dose, mean dose rate and instantaneous dose rate, dose‐per‐pulse (DPP), and their design features such as chamber type, bias voltage, and collection volume. Furthermore, a thin parallel‐plate (TPP) prototype ion chamber with reduced collector plate separation and volume was constructed and equally evaluated as the other chambers. The charge collection efficiency of the investigated ion chambers decreased with increasing DPP, whereas the mean dose rate did not affect the response of the chambers (± 1%). The dependence of the chamber response on DPP was found to be solely related to the total dose within the pulse, and not on mean dose rate, PW, or instantaneous dose rate within the ranges investigated. The polarity correction factor (Ppol) values of the TPP prototype, A10, and Advanced Markus chambers were found to be independent of DPP and dose rate (± 2%), while the A20 and A26 chambers yielded significantly larger variations and dependencies under the same conditions. Ion chamber performance evaluated under different irradiation conditions of an UHDR electron beam revealed a strong dependence on DPP and a negligible dependence on the mean and instantaneous dose rates. These results suggest that modifications to ion chambers design to improve their usability in UHDR beamlines should focus on minimizing DPP effects, with emphasis on optimizing the electric field strength, through the construction of smaller electrode separation and larger bias voltages. This was confirmed through the production and evaluation of a prototype ion chamber specifically designed with these characteristics. [ABSTRACT FROM AUTHOR]

This paper studies how to implement Flash data programming for AMOLED display module products through eDP interface. eDP interface is an internal digital interface based on DisplayPort architecture and protocol, which has the advantages of high transmission rate and low power consumption, but is not suitable for transmitting non‐image or video data. Therefore, AMOLED display modules usually need additional interfaces to write key data (such as Demura, Gamma and TCON firmware) into Flash chips, which brings some problems of data transmission interference, unreliability and inefficiency. To solve these problems, this paper proposes a new operation method, which repackages the data to be written, converts them into images, sends them to TCON through eDP interface, and then TCON analyzes the images, extracts the valid data, and starts programming for Flash. This paper divides the whole process into three steps, and verifies the feasibility and effectiveness of the method through experiments. This method effectively solves the problem of data programming, simplifies the production process, and improves the speed and reliability of programming. [ABSTRACT FROM AUTHOR]

Purpose: The increased normal tissue tolerance for FLASH radiotherapy (FLASH‐RT), as compared to conventional radiotherapy, was first observed in ultra‐high dose rate electron beams. Initial clinical trials in companion animals have revealed a high risk of developing osteoradionecrosis following high‐dose single‐fraction electron FLASH‐RT, which may be related to inhomogeneities in the dose distribution. In the current study, we aim to evaluate the possibilities of intensity‐modulated electron FLASH‐RT in a clinical setting to ensure a homogeneous dose distribution in future veterinary and human clinical trials. Methods: Our beam model in the treatment planning system electronRT (.decimal, LLC, Sanford, FL, USA) was based on a 10‐MeV electron beam from a clinical linear accelerator used to treat veterinary patients with FLASH‐RT in a clinical setting. In electronRT, the beam can be intensity‐modulated using tungsten island blocks in the electron block cutout, and range‐modulated using a customized bolus with variable thickness. Modulations were first validated in a heterogeneous phantom by comparing measured and calculated dose distributions. To evaluate the impact of intensity modulation in superficial single‐fraction FLASH‐RT, a treatment planning study was conducted, including eight canine cancer patient cases with simulated tumors in the head‐and‐neck region. For each case, treatment plans with and without intensity modulation were created for a uniform bolus and a range‐modulating bolus. Treatment plans were evaluated using a target dose homogeneity index (HI), a conformity index (CI), the near‐maximum dose outside the target (D2%,Body−PTV${D_{2{\mathrm{\% }},{\mathrm{\ Body}} - {\mathrm{PTV}}}}$), and the near‐minimum dose to the target (D98%${D_{98\% }}$). Results: By adding intensity modulation to plans with a uniform bolus, the HI could be improved (p = 0.017). The combination of a range‐modulating bolus and intensity modulation provided a further significant improvement of the HI as compared to using intensity modulation in combination with a uniform bolus (p = 0.036). The range‐modulating bolus also improved the CI compared to using a uniform bolus, both with an open beam (p = 0.046) and with intensity modulation (p = 0.018), as well as increased the D98%${D_{98\% }}$ (p = 0.036 with open beam and p = 0.05 with intensity modulation) and reduced the median D2%,Body−PTV${D_{2\% ,{\mathrm{\ Body}} - {\mathrm{PTV}}}}$ (not significant). Conclusions: By using intensity‐modulated electron FLASH‐RT in combination with range‐modulating bolus, the target dose homogeneity and conformity in canine patients with simulated tumors in complex areas in the head‐and‐neck region could be improved. By utilizing this technique, we hope to decrease the dose outside the target volume and avoid hot spots in future clinical electron FLASH‐RT studies, thereby reducing the risk of radiation‐induced toxicity. [ABSTRACT FROM AUTHOR]

Background: FLASH proton therapy has the potential to reduce side effects of conventional proton therapy by delivering a high dose of radiation in a very short period of time. However, significant progress is needed in the development of FLASH proton therapy. Increasing the dose rate while maintaining dose conformality may involve the use of advanced beam‐shaping technologies and specialized equipment such as 3D patient‐specific range modulators, to take advantage of the higher transmission efficiency at the highest energy available. The dose rate is an important factor in FLASH proton therapy, but its definition can vary because of the uneven distribution of the dose over time in pencil‐beam scanning (PBS). Purpose: Highlight the distinctions, both in terms of concept and numerical values, of the various definitions that can be established for the dose rate in PBS proton therapy. Methods: In an in silico study, five definitions of the dose rate, namely the PBS dose rate, the percentile dose rate, the maximum percentile dose rate, the average dose rate, and the dose averaged dose rate (DADR) were analyzed first through theoretical comparison, and then applied to a head and neck case. To carry out this study, a treatment plan utilizing a single energy level and requiring the use of a patient‐specific range modulator was employed. The dose rate values were compared both locally and by means of dose rate volume histograms (DRVHs). Results: The PBS dose rate, the percentile dose rate, and the maximum percentile dose are definitions that are specifically designed to take into account the time structure of the delivery of a PBS treatment plan. Although they may appear similar, our study shows that they can vary locally by up to 10%. On the other hand, the DADR values were approximately twice as high as those of the PBS, percentile, and maximum percentile dose rates, since the DADR disregards the periods when a voxel does not receive any dose. Finally, the average dose rate can be defined in various ways, as discussed in this paper. The average dose rate is found to be lower by a factor of approximately 1/2 than the PBS, percentile, and maximum percentile dose rates. Conclusions: We have shown that using different definitions for the dose rate in FLASH proton therapy can lead to variations in calculated values ranging from a few percent to a factor of two. Since the dose rate is a critical parameter in FLASH radiation therapy, it is essential to carefully consider the choice of definition. However, to make an informed decision, additional biological data and models are needed. [ABSTRACT FROM AUTHOR]

Background: Ultra‐high dose rate (UHDR) FLASH beams typically deliver dose at rates of >40 Gy/sec. Characterization of these beams with respect to dose, mean dose rate, and dose per pulse requires dosimeters which exhibit high temporal resolution and fast readout capabilities. Purpose: A diode EDGE Detector with a newly designed electrometer has been characterized for use in an UHDR electron beam and demonstrated appropriateness for UHDR FLASH radiotherapy dosimetry. Methods: Dose linearity, mean dose rate, and dose per pulse dependencies of the EDGE Detector were quantified and compared with dosimeters including a W1 scintillator detector, radiochromic film, and ionization chamber that were irradiated with a 10 MeV UHDR beam. The dose, dose rate, and dose per pulse were controlled via an in‐house developed scintillation‐based feedback mechanism, repetition rate of the linear accelerator, and source‐to‐surface distance, respectively. Depth‐dose profiles and temporal profiles at individual pulse resolution were compared to the film and scintillation measurements, respectively. The radiation‐induced change in response sensitivity was quantified via irradiation of ∼5kGy. Results: The EDGE Detector agreed with film measurements in the measured range with varying dose (up to 70 Gy), dose rate (nearly 200 Gy/s), and dose per pulse (up to 0.63 Gy/pulse) on average to within 2%, 5%, and 1%, respectively. The detector also agreed with W1 scintillation detector on average to within 2% for dose per pulse (up to 0.78 Gy/pulse). The EDGE Detector signal was proportional to ion chamber (IC) measured dose, and mean dose rate in the bremsstrahlung tail to within 0.4% and 0.2% respectively. The EDGE Detector measured percent depth dose (PDD) agreed with film to within 3% and per pulse output agreed with W1 scintillator to within −6% to +5%. The radiation‐induced response decrease was 0.4% per kGy. Conclusions: The EDGE Detector demonstrated dose linearity, mean dose rate independence, and dose per pulse independence for UHDR electron beams. It can quantify the beam spatially, and temporally at sub millisecond resolution. It's robustness and individual pulse detectability of treatment deliveries can potentially lead to its implementation for in vivo FLASH dosimetry, and dose monitoring. [ABSTRACT FROM AUTHOR]

Background: The intensities (i.e., number of protons in monitor unit [MU]) of deliverable proton spots need to be either zero or meet a minimum‐MU (MMU) threshold, which is a nonconvex problem. Since the dose rate is proportionally associated with the MMU threshold, higher‐dose‐rate proton radiation therapy (RT) (e.g., efficient intensity modulated proton therapy (IMPT) and ARC proton therapy, and high‐dose‐rate‐induced FLASH effect needs to solve the MMU problem with larger MMU threshold, which however makes the nonconvex problem more difficult to solve. Purpose: This work will develop a more effective optimization method based on orthogonal matching pursuit (OMP) for solving the MMU problem with large MMU thresholds, compared to state‐of‐the‐art methods, such as alternating direction method of multipliers (ADMM), proximal gradient descent method (PGD), or stochastic coordinate descent method (SCD). Methods: The new method consists of two essential components. First, the iterative convex relaxation (ICR) method is used to determine the active sets for dose‐volume planning constraints and decouple the MMU constraint from the rest. Second, a modified OMP optimization algorithm is used to handle the MMU constraint: the non‐zero spots are greedily selected via OMP to form the solution set to be optimized, and then a convex constrained subproblem is formed and can be conveniently solved to optimize the spot weights restricted to this solution set via OMP. During this iterative process, the new non‐zero spots localized via OMP will be adaptively added to or removed from the optimization objective. Results: The new method via OMP is validated in comparison with ADMM, PGD and SCD for high‐dose‐rate IMPT, ARC, and FLASH problems of large MMU thresholds, and the results suggest that OMP substantially improved the plan quality from PGD, ADMM and SCD in terms of both target dose conformality (e.g., quantified by max target dose and conformity index) and normal tissue sparing (e.g., mean and max dose). For example, in the brain case, the max target dose for IMPT/ARC/FLASH was 368.0%/358.3%/283.4% respectively for PGD, 154.4%/179.8%/150.0% for ADMM, 134.5%/130.4%/123.0% for SCD, while it was <120% in all scenarios for OMP; compared to PGD/ADMM/SCD, OMP improved the conformity index from 0.42/0.52/0.33 to 0.65 for IMPT and 0.46/0.60/0.61 to 0.83 for ARC. Conclusions: A new OMP‐based optimization algorithm is developed to solve the MMU problems with large MMU thresholds, and validated using examples of IMPT, ARC, and FLASH with substantially improved plan quality from ADMM, PGD, and SCD. [ABSTRACT FROM AUTHOR]

Xuanfeng Ding, PhD I fully agree with my opponent that I "proton arc therapy does not deviate from the fundamental principles of the radiation therapy," i and the beauty of proton arc therapy is that our radiation oncology community could quickly adopt it for clinical use. Keywords: FLASH; Proton arc therapy EN FLASH Proton arc therapy 1 7 7 08/08/23 20230801 NES 230801 INTRODUCTION In the clinical practice of radiation oncology, we rely on precise dose calculation and deposition,[[1], [3]] high dose conformity[[4], [6]] to the target while lowering the dose to the adjacent Organs-At-Risk (OARs) as much as possible. The good part is that both developments will push our radiation treatment technology to its limits toward a new era of fast, efficient, precise, and effective personalized therapy. [Extracted from the article]

Background: During recent years FLASH radiotherapy (FLASH‐RT) has shown promising results in radiation oncology, with the potential to spare normal tissue while maintaining the antitumor effects. The high speed of the FLASH‐RT delivery increases the need for fast and precise motion monitoring to avoid underdosing the target. Surface guided radiotherapy (SGRT) uses surface imaging (SI) to render a 3D surface of the patient. SI provides real‐time motion monitoring and has a large scanning field of view, covering off‐isocentric positions. However, SI has so far only been used for human patients with conventional setup and treatment. Purpose: The aim of this study was to investigate the performance of SI as a motion management tool during electron FLASH‐RT of canine cancer patients. Methods: To evaluate the SI system's ability to render surfaces of fur, three fur‐like blankets in white, grey, and black were used to imitate the surface of canine patients and the camera settings were optimized for each blanket. Phantom measurements using the fur blankets were carried out, simulating respiratory motion and sudden shift. Respiratory motion was simulated using the QUASAR Respiratory Motion Phantom with the fur blankets placed on the phantom platform, which moved 10 mm vertically with a simulated respiratory period of 4 s. Sudden motion was simulated with an in‐house developed phantom, consisting of a platform which was moved vertically in a stepwise motion at a chosen frequency. For sudden measurements, 1, 2, 3, 4, 5, 6, 7, and 10 Hz were measured. All measurements were both carried out at the conventional source‐to‐surface distance (SSD) of 100 cm, and in the locally used FLASH‐RT setup at SSD = 70 cm. The capability of the SI system to reproduce the simulated motion and the sampling time were evaluated. As an initial step towards clinical implementation, the feasibility of SI for surface guided FLASH‐RT was evaluated for 11 canine cancer patients. Results: The SI camera was capable of rendering surfaces for all blankets. The deviation between simulated and measured mean peak‐to‐peak breathing amplitude was within 0.6 mm for all blankets. The sampling time was generally higher for the black fur than for the white and grey fur, for the measurement of both respiratory and sudden motion. The SI system could measure sudden motion within 62.5 ms and detect motion with a frequency of 10 Hz. The feasibility study of the canine patients showed that the SI system could be an important tool to ensure patient safety. By using this system we could ensure and document that 10 out of 11 canine patients had a total vector offset from the reference setup position <2 mm immediately before and after irradiation. Conclusions: We have shown that SI can be used for surface guided FLASH‐RT of canine patients. The SI system is currently not fast enough to interrupt a FLASH‐RT beam while irradiating but with the short sampling time sudden motion can be detected. The beam can therefore be held just prior to irradiation, preventing treatment errors such as underdosing the target. [ABSTRACT FROM AUTHOR]

Background: The spatial and temporal dose rate distribution of pencil beam scanning (PBS) proton therapy is important in ultra-high dose rate (UHDR) or FLASH irradiations. Validation of the temporal structure of the dose rate is crucial for quality assurance and may be performed using detectors with high temporal resolution and large dynamic range. Purpose: To provide time-resolved in vivo dose rate measurements using a scintillator-based detector during proton PBS pre-clinical mouse experiments with dose rates ranging from conventional to UHDR. Methods: All irradiations were performed at the entrance plateau of a 250 MeV PBS proton beam. A detector system with four fiber-coupled ZnSe:O inorganic scintillators and 20 μs temporal resolution was used for dose rate measurements.The system was first characterized in terms of precision and stem signal. The detector precision was determined through repeated irradiations with the same field. The stem signal contribution was quantified by irradiating two of the detector probes alongside a bare fiber (fiber without a coupled scintillator). Next, the detector system was calibrated against an ionization chamber (IC) with all four detector probes and the IC placed in a water bath at 2 cm depth. A scan pattern covering 9.6 × 9.6 cm was used. Multiple irradiations with different requested nozzle currents provided instantaneous dose rates at the detector positions in the range of 7–1270 Gy/s. The correspondence of the detector signal (in Volts) to the instantaneous dose rate (in Gy/s) was found.The instantaneous dose rate was calculated from the beam current and the spot-to-detector distance assuming a Gaussian beam profile at distances up to 8 mm from the spot. Afterwards, the calibrated system was used in vivo, in mouse experiments, where mouse legs were irradiated with a constant dose and varying field dose rates of 0.7–87.5 Gy/s. The instantaneous dose rate was measured for each delivered spot and the delivered dose was determined as the integrated instantaneous dose rate. The spot dose profile and PBS dose rate map were calculated. The dose contamination to neighbouring mice were measured together with the upper limit of the dose to the mouse body. Results: The detectors showed high precision with ≤0.4% fluctuations in the measured dose. The stem signal exceeded 10% for spots <5 mm from the optical fiber and >18 mm from the scintillator.It contributed up to 0.2% to the total dose, which was considered negligible. All four detectors showed a non-linear relation between signal and instantaneous dose rate, which was modelled with a polynomial response function. In the mouse experiments, the measured scintillator dose showed 1.8% fluctuations, independent of the field dose rate.The in vivo measured spot dose profile had tails that deviated from a Gaussian profile with measurable dose contributions from spots up to 85 mm from the detector. Neighbour mouse irradiation contributed ∼1% of the total mouse dose. The upper limit of the mouse body dose was 6% of the mouse leg dose. Conclusions: A fiber-coupled inorganic scintillator-based detector system can provide high precision in vivo measurements of the instantaneous dose rate if correction for the non-linear dose rate dependency is applied. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the usefulness and effectiveness of a dual beam‐current transformer (BCTs) design to monitor and record the beam dosimetry output and energy of pulsed electron FLASH (eFLASH) beams in real‐time, and to inform on the usefulness of this design for future eFLASH beam control. Methods: Two BCTs are integrated into the head of a FLASH Mobetron system, one located after the primary scattering foil and the other downstream of the secondary scattering foil. The response of the BCTs was evaluated individually to monitor beam output as a function of dose, scattering conditions, and ability to capture physical beam parameters such as pulse width (PW), pulse repetition frequency (PRF), and dose per pulse (DPP), and in combination to determine beam energy using the ratio of the lower‐to‐upper BCT signal. Results: A linear relationship was observed between the absorbed dose measured on Gafchromic film and the BCT signals for both the upper and lower BCT (R2 > 0.99). A linear relationship was also observed in the BCT signals as a function of the number of pulses delivered regardless of the PW, DPP, or PRF (R2 > 0.99). The lower‐to‐upper BCT ratio was found to correlate strongly with the energy of the eFLASH beam due to differential beam attenuation caused by the secondary scattering foil. The BCTs were also able to provide accurate information about the PW, PRF, energy, and DPP for each individual pulse delivered in real‐time. Conclusion: The dual BCT system integrated within the FLASH Mobetron was shown to be a reliable monitoring system able to quantify accelerator performance and capture all essential physical beam parameters on a pulse‐by‐pulse basis, and the ratio between the two BCTs was strongly correlated with beam energy. The fast signal readout and processing enables the BCTs to provide real‐time information on beam output and energy and is proposed as a system suitable for accurate beam monitoring and control of eFLASH beams. [ABSTRACT FROM AUTHOR]

Purpose: The combined use of Bragg peak (BP) and shoot‐through (ST) beams has previously been shown to increase the normal tissue volume receiving FLASH dose rates while maintaining dose conformality compared to conventional intensity‐modulated proton therapy (IMPT) methods. However, the fixed beam optimization method has not considered the effects of beam orientation on the dose and dose rates. To maximize the proton FLASH effect, here, we incorporate dose rate objectives into our beam orientation optimization framework. Methods: From our previously developed group‐sparsity dose objectives, we add upper and lower dose rate terms using a surrogate dose‐averaged dose rate definition and solve using the fast‐iterative shrinking threshold algorithm. We compare the dosimetry for three head‐and‐neck cases between four techniques: (1) spread‐out BP IMPT (BP), (2) dose rate optimization using BP beams only (BP‐DR), (3) dose rate optimization using ST beams only (ST‐DR), and (4) dose rate optimization using combined BP and ST (BPST‐DR), with the goal of sparing organs at risk without loss of tumor coverage and maintaining high dose rate within a 10 mm region of interest (ROI) surrounding the clinical target volume (CTV). Results: For BP, BP‐DR, ST‐DR, and BPST‐DR, CTV homogeneity index and Dmax were found to be on average 0.886, 0.867, 0.687, and 0.936 and 107%, 109%, 135%, and 101% of prescription, respectively. Although ST‐DR plans were not able to meet dosimetric standards, BPST‐DR was able to match or improve either maximum or mean dose in the right submandibular gland, left and right parotids, constrictors, larynx, and spinal cord compared to BP plans. Volume of ROIs receiving greater than 40 Gy/s (Vγ0)${V_{\gamma 0}})$ was 51.0%, 91.4%, 95.5%, and 92.1% on average. Conclusions: The dose rate techniques, particularly BPST‐DR, were able to significantly increase dose rate without compromising physical dose compared with BP. Our algorithm efficiently selects beams that are optimal for both dose and dose rate. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this investigation is to evaluate the use of a probe‐format graphite calorimeter, Aerrow, as an absolute and relative dosimeter of high‐energy pulse dose rate (UHPDR) electron beams for in‐water reference and depth–dose‐type measurements, respectively. Methods: In this paper, the calorimeter system is used to investigate the potential influence of dose per pulses delivered up to 5.6 Gy, the number of pulses delivered per measurement, and its potential for relative measurement (depth–dose curve measurement). The calorimeter system is directly compared against an Advanced Markus ion chamber. The finite element method was used to calculate heat transfer corrections along the percentage depth dose of a 20‐MeV electron beam. Monte Carlo–calculated dose conversion factors necessary to calculate absorbed dose‐to‐water at a point from the measured dose‐to‐graphite are also presented. Results: The comparison of Aerrow against a fully calibrated Advanced Markus chamber, corrected for the saturation effect, has shown consistent results in terms of dose‐to‐water determination. The measured reference depth is within 0.5 mm from the expected value from Monte Carlo simulation. The relative standard uncertainty estimated for Aerrow was 1.06%, which is larger compared to alanine dosimetry (McEwen et al. https://doi.org/10.1088/0026‐1394/52/2/272) but has the advantage of being a real‐time detector. Conclusion: In this investigation, it was demonstrated that the Aerrow probe–type graphite calorimeter can be used for relative and absolute dosimetries in water in an UHPDR electron beam. To the author's knowledge, this is the first reported use of an absorbed dose calorimeter for an in‐water percentage depth–dose curve measurement. The use of the Aerrow in quasi‐adiabatic mode has greatly simplified the signal readout, compared to isothermal mode, as the resistance was directly measured with a high‐stability digital multimeter. [ABSTRACT FROM AUTHOR]

Background: Radiation with high dose rate (FLASH) has shown to reduce toxicities to normal tissues around the target and maintain tumor control with the same amount of dose compared to conventional radiation. This phenomenon has been widely studied in electron therapy, which is often used for shallow tumor treatment. Proton therapy is considered a more suitable treatment modality for deep‐seated tumors. The feasibility of FLASH proton therapy has recently been demonstrated by a series of pre‐ and clinical trials. One of the challenges is to efficiently generate wide enough dose distributions in both lateral and longitudinal directions to cover the entire tumor volume. The goal of this paper is to introduce a set of automatic FLASH proton beam optimization algorithms developed recently. Purpose: To develop a fast and efficient optimizer for the design of a passive scattering proton FLASH radiotherapy delivery at The University of Texas MD Anderson Proton Therapy Center, based on the fast dose calculator (FDC). Methods: A track‐repeating algorithm, FDC, was validated versus Geant4 simulations and applied to calculate dose distributions in various beamline setups. The design of the components was optimized to deliver homogeneous fields with well‐defined diameters between 11.0 and 20.5 mm, as well as a spread‐out Bragg peak (SOBP) with modulations between 8.5 and 39.0 mm. A ridge filter, a high‐Z material scatterer, and a collimator with range compensator were inserted in the beam path, and their shapes and sizes were optimized to spread out the Bragg peak, widen the beam, and reduce the penumbra. The optimizer was developed and tested using two proton energies (87.0 and 159.5 MeV) in a variety of beamline arrangements. Dose rates of the optimized beams were estimated by scaling their doses to those of unmodified beams. Results: The optimized 87.0‐MeV beams, with a distance from the beam pipe window to the phantom surface (window‐to‐surface distance [WSD]) of 550 mm, produced an 8.5‐mm‐wide SOBP (proximal 90% to distal 90% of the maximum dose); 14.5, 12.0, and 11.0‐mm lateral widths at the 50%, 80%, and 90% dose location, respectively; and a 2.5‐mm penumbra from 80% to 20% in the lateral profile. The 159.5‐MeV beam had an SOBP of 39.0 mm and lateral widths of 20.5, 15.0, and 12.5 mm at 50%, 80%, and 90% dose location, respectively, when the WSD was 550 mm. Wider lateral widths were obtained with increased WSD. The SOBP modulations changed when the ridge filters with different characteristics were inserted. Dose rates on the beam central axis for all optimized beams (other than the 87.0‐MeV beam with 2000‐mm WSD) were above that needed for the FLASH effect threshold (40 Gy/s) except at the very end of the depth dose profile scaling with a dose rate of 1400 Gy/s at the Bragg peak in the unmodified beams. The optimizer was able to instantly design the individual beamline components for each of the beamline setups, without the need of time intensive iterative simulations. Conclusion: An efficient system, consisting of an optimizer and an FDC have been developed and validated in a variety of beamline setups, comprising two proton energies, several WSDs, and SOBPs. The set of automatic optimization algorithms produces beam shaping element designs efficiently and with excellent quality. [ABSTRACT FROM AUTHOR]

FLASH radiotherapy (RT) is a novel technique in which the ultrahigh dose rate (UHDR) (≥40 Gy/s) is delivered to the entire treatment volume. Recent outcomes of in vivo studies show that the UHDR RT has the potential to spare normal tissue without sacrificing tumor control. There is a growing interest in the application of FLASH RT, and the ultrahigh dose irradiation delivery has been achieved by a few experimental and modified linear accelerators. The underlying mechanism of FLASH effect is yet to be fully understood, but the oxygen depletion in normal tissue providing extra protection during FLASH irradiation is a hypothesis that attracts most attention currently. Monte Carlo simulation is playing an important role in FLASH, enabling the understanding of its dosimetry calculations and hardware design. More advanced Monte Carlo simulation tools are under development to fulfill the challenge of reproducing the radiolysis and radiobiology processes in FLASH irradiation. FLASH RT may become one of standard treatment modalities for tumor treatment in the future. This paper presents the history and status of FLASH RT studies with a focus on FLASH irradiation delivery modalities, underlying mechanism of FLASH effect, in vivo and vitro experiments, and simulation studies. Existing challenges and prospects of this novel technique are discussed in this manuscript. [ABSTRACT FROM AUTHOR]

Purpose: To provide ultrahigh dose rate (UHDR) pencil beam scanning (PBS) proton dosimetry comparison of clinically used plane‐parallel ion chambers, PTW (Physikalisch‐Technische Werkstaetten) Advanced Markus and IBA (Ion Beam Application) PPC05, with a proton graphite calorimeter in a support of first in‐human proton FLASH clinical trial. Methods: Absolute dose measurement intercomparison of the plane‐parallel plate ion chambers and the proton graphite calorimeter was performed at 5‐cm water‐equivalent depth using rectangular 250‐MeV single‐layer treatment plans designed for the first in‐human FLASH clinical trial. The dose rate for each field was designed to remain above 60 Gy/s. The ion recombination effects of the plane‐parallel plate ion chambers at various bias voltages were also investigated in the range of dose rates between 5 and 60 Gy/s. Two independent model‐based extrapolation methods were used to calculate the ion recombination correction factors ks to compare with the two‐voltage technique from most widely used clinical protocols. Results: The mean measured dose to water with the proton graphite calorimeter across all the predefined fields is 7.702 ± 0.037 Gy. The average ratio over the predefined fields of the PTW Advanced Markus chamber dose to the calorimeter reference dose is 1.002 ± 0.007, whereas the IBA PPC05 chamber shows ∼3% higher reading of 1.033 ± 0.007. The relative differences in the ks values determined from between the linear and quadratic extrapolation methods and the two‐voltage technique for the PTW Advanced Markus chamber are not statistically significant, and the trends of dose rate dependence are similar. The IBA PPC05 shows a flat response in terms of ion recombination effects based on the ks values calculated using the two‐voltage technique. Differences in ks values for the PPC05 between the two‐voltage technique and other model‐based extrapolation methods are not statistically significant at FLASH dose rates. Some of the ks values for the PPC05 that were extrapolated from the three‐voltage linear method and the semiempirical model were reported less than unity possibly due to the charge multiplication effect, which was negligible compared to the volume recombination effect in FLASH dose rates. Conclusions: The absolute dose measurements of both PTW Advanced Markus and IBA PPC05 chambers are in a good agreement with the National Physical Laboratory graphite calorimeter reference dose considering overall uncertainties. Both ion chambers also demonstrate good reproducibility as well as stability as reference dosimeters in UHDR PBS proton radiotherapy. The dose rate dependency of the ion recombination effects of both ion chambers in cyclotron generated PBS proton beams is acceptable and therefore, both chambers are suitable to use in clinical practice for the range of dose rates between 5 and 60 Gy/s. [ABSTRACT FROM AUTHOR]

Purpose: This paper focused on the design and optimization of ridge filter–based intensity‐modulated proton therapy (IMPT), and its potential applications for FLASH. Differing from the standard pencil beam scanning (PBS) mode, no energy/layer switching is required and total treatment time can be shortened. Methods: Unique dose‐influence matrices were generated as a proton beam traverses through slabs of different thicknesses (i.e., modulation by different layers). To establish the references for comparison, conventional IMPT plans (single field) were created using a large‐scale nonlinear solver. The spot weights from the reference IMPT plans were used as inputs for optimizing the design of ridge filters. Two designs were evaluated: model A (static) and model B (dynamic). The ridge filter designs were first verified (by GEANT4 simulation) in a water phantom and then in an H&N case. A direct comparison was made between the GEANT4 simulation results of two models and their respective references, with regard to plan quality, dose‐averaged dose rate, and total treatment time. Results: In both the water phantom and the H&N case, two models are able to modulate dose distributions with high conformity, showing no significant difference relative to the reference plans. Dose rate–volume histograms suggest that in order to achieve a dose rate of 40 Gy/s over 90% PTV, the beam intensity needs to be 2.5 × 1011 protons/s for both models. For a fraction dose of 10 Gy, the total treatment time (including both irradiation time and dead time) can be shortened by a factor of 4.9 (model A) and 6.5 (model B), relative to the reference plans. Conclusion: Two proposed designs (both static and dynamic) can be used for PBS–IMPT requiring no layer switching. They are promising candidates for FLASH‐IMPT capable of reducing treatment time and achieving high dose rates while maintaining dose conformity simultaneously. [ABSTRACT FROM AUTHOR]

Higher dose rates, a trend for radiotherapy machines, can be beneficial in shortening treatment times for radiosurgery and mitigating the effects of motion. Recently, even higher doses (e.g., 100 times greater) have become targeted because of their potential to generate the FLASH effect (FE). We refer to these physical dose rates as ultra‐high (UHDR). The complete relationship between UHDR and the FE is unknown. But UHDR systems are needed to explore the relationship further and to deliver clinical UHDR treatments, where indicated. Despite the challenging set of unknowns, the authors seek to make reasonable assumptions to probe how existing and developing technology can address the UHDR conditions needed to provide beam generation capable of producing the FE in preclinical and clinical applications. As a preface, this paper discusses the known and unknown relationships between UHDR and the FE. Based on these, different accelerator and ionizing radiation types are then discussed regarding the relevant UHDR needs. The details of UHDR beam production are discussed for existing and potential future systems such as linacs, cyclotrons, synchrotrons, synchrocyclotrons, and laser accelerators. In addition, various UHDR delivery mechanisms are discussed, along with required developments in beam diagnostics and dose control systems. [ABSTRACT FROM AUTHOR]

The clinical translation of FLASH radiotherapy (RT) requires challenges related to dosimetry and beam monitoring of ultra‐high dose rate (UHDR) beams to be addressed. Detectors currently in use suffer from saturation effects under UHDR regimes, requiring the introduction of correction factors. There is significant interest from the scientific community to identify the most reliable solutions and suitable experimental approaches for UHDR dosimetry. This interest is manifested through the increasing number of national and international projects recently proposed concerning UHDR dosimetry. Attaining the desired solutions and approaches requires further optimization of already established technologies as well as the investigation of novel radiation detection and dosimetry methods. New knowledge will also emerge to fill the gap in terms of validated protocols, assessing new dosimetric procedures and standardized methods. In this paper, we discuss the main challenges coming from the peculiar beam parameters characterizing UHDR beams for FLASH RT. These challenges vary considerably depending on the accelerator type and technique used to produce the relevant UHDR radiation environment. We also introduce some general considerations on how the different time structure in the production of the radiation beams, as well as the dose and dose‐rate per pulse, can affect the detector response. Finally, we discuss the requirements that must characterize any proposed dosimeters for use in UDHR radiation environments. A detailed status of the current technology is provided, with the aim of discussing the detector features and their performance characteristics and/or limitations in UHDR regimes. We report on further developments for established detectors and novel approaches currently under investigation with a view to predict future directions in terms of dosimetry approaches, practical procedures, and protocols. Due to several on‐going detector and dosimetry developments associated with UHDR radiation environment for FLASH RT it is not possible to provide a simple list of recommendations for the most suitable detectors for FLASH RT dosimetry. However, this article does provide the reader with a detailed description of the most up‐to‐date dosimetric approaches, and describes the behavior of the detectors operated under UHDR irradiation conditions and offers expert discussion on the current challenges which we believe are important and still need to be addressed in the clinical translation of FLASH RT. [ABSTRACT FROM AUTHOR]

While FLASH radiation therapy is inspiring enthusiasm to transform the field, it is neither new nor well understood with respect to the radiobiological mechanisms. As FLASH clinical trials are designed, it will be important to ensure we can deliver dose consistently and safely to every patient. Much like hyperthermia and proton therapy, FLASH is a promising new technology that will be complex to implement in the clinic and similarly will require customized credentialing for multi‐institutional clinical trials. There is no doubt that FLASH seems promising, but many technologies that we take for granted in conventional radiation oncology, such as rigorous dosimetry, 3D treatment planning, volumetric image guidance, or motion management, may play a major role in defining how to use, or whether to use, FLASH radiotherapy. Given the extended time frame for patients to experience late effects, we recommend moving deliberately but cautiously forward toward clinical trials. In this paper, we review the state of quality assurance and safety systems in FLASH, identify critical pre‐clinical data points that need to be defined, and suggest how lessons learned from previous technological advancements will help us close the gaps and build a successful path to evidence‐driven FLASH implementation. [ABSTRACT FROM AUTHOR]

The increased radioresistence of healthy tissues when irradiated at very high dose rates (known as the Flash effect) is a radiobiological mechanism that is currently investigated to increase the therapeutic ratio of radiotherapy treatments. To maximize the benefits of the clinical application of Flash, a patient‐specific balance between different properties of the dose distribution should be found, that is, Flash needs to be one of the variables considered in treatment planning. We investigated the Flash potential of three proton therapy planning and beam delivery techniques, each on a different anatomical region. Based on a set of beam delivery parameters, on hypotheses on the dose and dose rate thresholds needed for the Flash effect to occur, and on two definitions of Flash dose rate, we generated exemplary illustrations of the capabilities of current proton therapy equipment to generate Flash dose distributions. All techniques investigated could both produce dose distributions comparable with a conventional proton plan and reach the Flash regime, to an extent that was strongly dependent on the dose per fraction and the Flash dose threshold. The beam current, Flash dose rate threshold, and dose rate definition typically had a more moderate effect on the amount of Flash dose in normal tissue. A systematic estimation of the impact of Flash on different patient anatomies and treatment protocols is possible only if Flash‐specific treatment planning features become readily available. Planning evaluation tools such as a voxel‐based dose delivery time structure, and the inclusion in the optimization cost function of parameters directly associated with Flash (e.g., beam current, spot delivery sequence, and scanning speed), are needed to generate treatment plans that are taking full advantage of the potential benefits of the Flash effect. [ABSTRACT FROM AUTHOR]

Purpose: The ARRONAX cyclotron facility offers the possibility to deliver proton beams from low to ultra‐high dose rates (UHDR). As a good control of the dosimetry is a prerequisite of UHDR experimentations, we evaluated in different conditions the usability and the dose rate dependency of several radiochromic films commonly used for dosimetry in radiotherapy. Methods: We compared the dose rate dependency of three types of radiochromic films: GAFchromic™ EBT3 and GAFchromic™ EBT‐XD (Ashland Inc., Wayne, NJ, USA), and OrthoChromic OC‐1 (OrthoChrome Inc., Hillsborough, NJ, USA), after proton irradiations at various mean dose rates (0.25, 40, 1500, and 7500 Gy/s) and for 10 doses (2–130 Gy). We also evaluated the dose rate dependency of each film considering beam structures, from single pulse to multiple pulses with various frequencies. Results: EBT3 and EBT‐XD films showed differences of response between conventional (0.25 Gy/s) and UHDR (7500 Gy/s) conditions, above 10 Gy. On the contrary, OC‐1 films did not present overall difference of response for doses except below 3 Gy. We observed an increase of the netOD with the mean dose rate for EBT3 and EBT‐XD films. OC‐1 films did not show any impact of the mean dose rate up to 7500 Gy/s, above 3 Gy. No difference was found based on the beam structure, for all three types of films. Conclusions: EBT3 and EBT‐XD radiochromic films should be used with caution for the dosimetry of UHDR proton beams over 10 Gy. Their overresponse, which increases with mean dose rate and dose, could lead to non‐negligible overestimations of the absolute dose. OC‐1 films are dose rate independent up to 7500 Gy/s in proton beams. Films response is not impacted by the beam structure. A broader investigation of the usability of OC‐1 films in UHDR conditions should be conducted at intermediate and higher mean dose rates and other beam energies. [ABSTRACT FROM AUTHOR]

Purpose: In proton therapy, the gantry, as the final part of the beamline, has a major effect on beam intensity and beam size at the isocenter. Most of the conventional beam optics of cyclotron‐based proton gantries have been designed with an imaging factor between 1 and 2 from the coupling point (CP) at the gantry entrance to the isocenter (patient location) meaning that to achieve a clinically desirable (small) beam size at isocenter, a small beam size is also required at the CP. Here we will show that such imaging factors are limiting the emittance which can be transported through the gantry. We, therefore, propose the use of large beam size and low divergence beam at the CP along with an imaging factor of 0.5 (2:1) in a new design of gantry beam optics to achieve substantial improvements in transmission and thus increase beam intensity at the isocenter. Methods: The beam optics of our gantry have been re‐designed to transport higher emittance without the need of any mechanical modifications to the gantry beamline. The beam optics has been designed using TRANSPORT, with the resulting transmissions being calculated using Monte Carlo simulations (BDSIM code). Finally, the new beam optics have been tested with measurements performed on our Gantry 2 at PSI. Results: With the new beam optics, we could maximize transmission through the gantry for a fixed emittance value. Additionally, we could transport almost four times higher emittance through the gantry compared to conventional optics, whilst achieving good transmissions through the gantry (>50%) with no increased losses in the gantry. As such, the overall transmission (cyclotron to isocenter) can be increased by almost a factor of 6 for low energies. Additionally, the point‐to‐point imaging inherent to the optics allows adjustment of the beam size at the isocenter by simply changing the beam size at the CP. Conclusion: We have developed a new gantry beam optics which, by selecting a large beam size and low divergence at the gantry entrance and using an imaging factor of 0.5 (2:1), increases the emittance acceptance of the gantry, leading to a substantial increase in beam intensity at low energies. We expect that this approach could easily be adapted for most types of existing gantries. [ABSTRACT FROM AUTHOR]

Purpose: Key factors in FLASH treatments are the ultra‐high dose rate (UHDR) and the time structure of the beam delivery. Measurement of the time structure in pencil beam scanning (PBS) proton FLASH treatments is challenging for many types of detectors since high temporal resolution is needed. In this study, a fast scintillator detector system was developed and used to measure the individual spot durations as well as the time when the beam moves between two positions (transition duration) during PBS proton FLASH and UHDR treatments. The spot durations were compared with machine log‐file recordings. Methods: A detector system based on inorganic scintillating crystals was developed. The system consisted of four detector probes made of a sub‐millimeter ZnSe:O crystal that was coupled via an optical fiber to an optical reader with 50 kHz sampling rate. The detector system was used in two experiments, both performed with a PBS proton beam with 250 MeV beam energy and 215 nA requested nozzle beam current. The sampling rate enabled multiple measurements during each spot delivery and during the beam transition between spots. First, the detector was tested in a phantom experiment, where a total of 305 scan sequences were delivered to the four detectors. The number of spots delivered without beam interruption in a single scan sequence ranged from one to 35. The spot duration and transition duration were measured for each individual spot. Secondly, the detector system was used in vivo in preclinical experiments with FLASH irradiation of mouse legs placed in the entrance plateau of the beam. A single detector was placed 1 cm downstream of the irradiated mouse leg. The mouse dose ranged from 30.5 to 44.2 Gy and the field consisted of 35 spots. The spot durations as well as the mean dose rate (field dose divided by the measured field duration) for each mouse were determined using the detector and then compared with the corresponding log files. Results: The phantom experiment showed that the logged total duration of an uninterrupted spot sequence was consistently shorter than the measured duration with a difference of −0.252 ms (95% confidence interval: [‐0.255, −0.249 ms]). This corresponded to 0.05%–0.07% of the spot sequence duration in the mice experiments. For individual spots, the mean ± 1SD difference between logged and measured spot duration was −0.39 ± 0.05 ms for the first spot in a sequence, 0.13 ± 0.04 ms for the last spot in a sequence, and −0.0017 ± 0.09 ms for the intermediate spots in a sequence. The measured spot transition durations were 0.20 ± 0.04 ms (5.1 mm horizontal steps) and 0.50 ± 0.04 ms (5.0 mm vertical steps). For the mouse experiments, the mean dose rate calculated from the measured field duration was 84.1–92.5 Gy/s. It agreed with log files with a root mean square difference of 0.02 Gy/s. Conclusions: Fiber‐coupled scintillator detectors were designed with sufficient temporal resolution to measure the spot and transition duration during PBS proton UHDR deliveries. Their small volume makes them feasible for in vivo use in preclinical FLASH studies. The logged spot durations were in excellent agreement with measurements but showed small systematic errors in the logged duration for the first and last spot in a sequence. [ABSTRACT FROM AUTHOR]

Purpose: The Oriatron eRT6 is a linear accelerator (linac) used in FLASH preclinical studies able to reach dose rates ranging from conventional (CONV) up to ultrahigh (UHDR). This work describes the implementation of commercially available beam current transformers (BCTs) as online monitoring tools compatible with CONV and UHDR irradiations for preclinical FLASH studies. Methods: Two BCTs were used to measure the output of the Oriatron eRT6 linac. First, the correspondence between the set nominal beam parameters and those measured by the BCTs was checked. Then, we established the relationship between the total exit charge (measured by BCTs) and the absorbed dose to water. The influence of the pulse width (PW) and the pulse repetition frequency (PRF) at UHDR was characterized, as well as the short‐ and long‐term stabilities of the relationship between the exit charge and the dose at CONV and UHDR. Results: The BCTs were able to determine consistently the number of pulses, PW, and PRF. For fixed PW and pulse height, the exit charge measured from BCTs was correlated with the dose, and linear relationships were found with uncertainties of 0.5 % and 3 % in CONV and UHDR mode, respectively. Short‐ and long‐term stabilities of the dose‐to‐charge ratio were below 1.6 %. Conclusions: We implemented commercially available BCTs and demonstrated their ability to act as online beam monitoring systems to support FLASH preclinical studies with CONV and UHDR irradiations. The implemented BCTs support dosimetric measurements, highlight variations among multiple measurements in a row, enable monitoring of the physics parameters used for irradiation, and are an important step for the safety of the clinical translation of FLASH radiation therapy. [ABSTRACT FROM AUTHOR]

Purpose: In ultrahigh dose rate radiotherapy, the FLASH effect can lead to substantially reduced healthy tissue damage without affecting tumor control. Although many studies show promising results, the underlying biological mechanisms and the relevant delivery parameters are still largely unknown. It is unclear, particularly for scanned proton therapy, how treatment plans could be optimized to maximally exploit this protective FLASH effect. Materials and Methods: To investigate the potential of pencil beam scanned proton therapy for FLASH treatments, we present a phenomenological model, which is purely based on experimentally observed phenomena such as potential dose rate and dose thresholds, and which estimates the biologically effective dose during FLASH radiotherapy based on several parameters. We applied this model to a wide variety of patient geometries and proton treatment planning scenarios, including transmission and Bragg peak plans as well as single‐ and multifield plans. Moreover, we performed a sensitivity analysis to estimate the importance of each model parameter. Results: Our results showed an increased plan‐specific FLASH effect for transmission compared with Bragg peak plans (19.7% vs. 4.0%) and for single‐field compared with multifield plans (14.7% vs. 3.7%), typically at the cost of increased integral dose compared to the clinical reference plan. Similar FLASH magnitudes were found across the different treatment sites, whereas the clinical benefits with respect to the clinical reference plan varied strongly. The sensitivity analysis revealed that the threshold dose as well as the dose per fraction strongly impacted the FLASH effect, whereas the persistence time only marginally affected FLASH. An intermediate dependence of the FLASH effect on the dose rate threshold was found. Conclusions: Our model provided a quantitative measure of the FLASH effect for various delivery and patient scenarios, supporting previous assumptions about potentially promising planning approaches for FLASH proton therapy. Positive clinical benefits compared to clinical plans were achieved using hypofractionated, single‐field transmission plans. The dose threshold was found to be an important factor, which may require more investigation. [ABSTRACT FROM AUTHOR]

Radiation exposures at ultrahigh dose rates (UHDRs) at several orders of magnitude greater than in current clinical radiotherapy (RT) have been shown to manifest differential radiobiological responses compared to conventional (CONV) dose rates. This has led to studies investigating the application of UHDR for therapeutic advantage (FLASH‐RT) that have gained significant interest since the initial discovery in 2014 that demonstrated reduced lung toxicity with equivalent levels of tumor control compared with conventional dose‐rate RT. Many subsequent studies have demonstrated the potential protective role of FLASH‐RT in normal tissues, yet the underlying molecular and cellular mechanisms of the FLASH effect remain to be fully elucidated. Here, we summarize the current evidence of the FLASH effect and review FLASH‐RT studies performed in preclinical models of normal tissue response. To critically examine the underlying biological mechanisms of responses to UHDR radiation exposures, we evaluate in vitro studies performed with normal and tumor cells. Differential responses to UHDR versus CONV irradiation recurrently involve reduced inflammatory processes and differential expression of pro‐ and anti‐inflammatory genes. In addition, frequently reduced levels of DNA damage or misrepair products are seen after UHDR irradiation. So far, it is not clear what signal elicits these differential responses, but there are indications for involvement of reactive species. Different susceptibility to FLASH effects observed between normal and tumor cells may result from altered metabolic and detoxification pathways and/or repair pathways used by tumor cells. We summarize the current theories that may explain the FLASH effect and highlight important research questions that are key to a better mechanistic understanding and, thus, the future implementation of FLASH‐RT in the clinic. [ABSTRACT FROM AUTHOR]

FLASH radiotherapy is considered a new potential breakthrough in cancer treatment. Ultra‐high dose rates (>40 Gy/s) have been shown to reduce toxicity in the normal tissue without compromising tumor control, resulting in a widened therapeutic window. These high dose rates are more easily achievable in the clinic with charged particles, and clinical trials are, indeed, ongoing using electrons or protons. FLASH could be an attractive solution also for heavier ions such as carbon and could even enhance the therapeutic window. However, it is not yet known whether the FLASH effect will be the same as for sparsely ionizing radiation when densely ionizing carbons ions are used. Here we discuss the technical challenges in beam delivery and present a promising solution using 3D range‐modulators in order to apply ultra‐high dose rates (UHDR) compatible with FLASH with carbon ions. Furthermore, we will discuss the possible outcome of C‐ion therapy at UHDR on the level of the radiobiological and radiation chemical effects. [ABSTRACT FROM AUTHOR]

Purpose: In proton therapy, the potential of using high‐dose rates in the cancer treatment is being explored. High‐dose rates could improve efficiency and throughput in standard clinical practice, allow efficient utilization of motion mitigation techniques for moving targets, and potentially enhance normal tissue sparing due to the so‐called FLASH effect. However, high‐dose rates are difficult to reach when lower energy beams are applied in cyclotron‐based proton therapy facilities, because they result in large beam sizes and divergences downstream of the degrader, incurring large losses from the cyclotron to the patient position (isocenter). In current facilities, the emittance after the degrader is reduced using circular collimators; however, this does not provide an optimal matching to the acceptance of the following beamline, causing a low transmission for these energies. We, therefore, propose to use a collimation system, asymmetric in both beam size and divergence, resulting in symmetric emittance in both beam transverse planes as required for a gantry system. This new emittance selection, together with a new optics design for the following beamline and gantry, allows a better matching to the beamline acceptance and an improvement of the transmission. Methods: We implemented a custom method to design the collimator sizes and shape required to select high emittance, to be transported by the following beamline using new beam optics (designed with TRANSPORT) to maximize acceptance matching. For predicting the transmission in the new configuration (new collimators + optics), we used Monte Carlo simulations implemented in BDSIM, implementing a model of PSI Gantry 2 which we benchmarked against measurements taken in the current clinical scenario (circular collimators + clinical optics). Results: From the BDSIM simulations, we found that the new collimator system and matching beam optics results in an overall transmission from the cyclotron to the isocenter for a 70 MeV beam of 0.72%. This is an improvement of almost a factor of 6 over the current clinical performance (0.13% transmission). The new optics satisfies clinical beam requirements at the isocenter. Conclusions: We developed a new emittance collimation system for PSI's PROSCAN beamline which, by carefully selecting beam size and divergence asymmetrically, increases the beam transmission for low‐energy beams in current state‐of‐the‐art cyclotron‐based proton therapy gantries. With these improvements, we could predict almost 1% transmission for low‐energy beams at PSI's Gantry 2. Such a system could easily be implemented in facilities interested in increasing dose rates for efficient motion mitigation and FLASH experiments alike. [ABSTRACT FROM AUTHOR]

FLASH radiotherapy (FLASH‐RT) has gained attention as an ultra‐high dose rate RT in recent years. This treatment significantly shortens the time of RT and reduces the influence of tumor movement caused by breathing or other factors. In addition, it spares the surrounding normal tissues and organs while ensuring the anti‐tumor effect. With the efforts of scientific researchers and clinical staff, the FLASH effect has been successfully induced in electron, photon, and proton irradiation. Preliminary research has been carried out to explore its related mechanism. However, this has not yet been fully determined, although oxygen depletion was the proposed primary mechanism discovered. Due to the development of immunotherapy, studies on the involvement of the immune system in the FLASH effect have begun to attract attention. This study reviewed published experimental results to analyze and summarize the feasibility of FLASH‐RT widely used in clinical practice, and whether it could be combined with immune checkpoint inhibitors to guide therapy. [ABSTRACT FROM AUTHOR]

Purpose: To present an x‐ray tube system capable of in vitro ultrahigh dose‐rate (UHDR) irradiation of small < 0.3 mm samples and to characterize it by means of a plastic scintillation detector (PSD). Methods and materials: A conventional x‐ray tube was modified for the delivery of short UHDR irradiations. A beam shutter system with a sample holder was designed and installed in a close proximity of an x‐ray tube window to enable <1 s irradiations at UHDR. The dosimetry was performed with a small 0.5‐mm long 0.5‐mm in diameter PSD irradiated with 80, 100, and 120 kVp beams and beam currents of 1–37.5 mA. The PSD signal was recorded at frame rates of 20 and 50 fps for shutter exposure between 100 and 1125 ms. Irradiation reproducibility was studied with the PSD. The x‐ray tube irradiation setup was modeled with Monte Carlo (MC) and dose on a surface of a phantom was also measured with films. The effect of dose delivery uncertainty to 300‐μm spheroids due to positioning and spheroid size was evaluated. Results: MC simulations showed good agreement with PSD measurements acquired at both frame rates of 20 and 50 fps in terms of beam temporal profile. PSD‐measured dose exhibited excellent linearity as a function of instantaneous dose rate from 3.1 to 118.0 Gy/s as well as shutter exposure time from 100 and 1125 ms for all investigated beam energies. PSD absorbed dose for the 80, 100, and 120 kVp beams agreed with MC simulations to within 5%. The total delivered doses ranged from 0.4 Gy for a 1‐mA, 80 kVp beam, and 100 ms shutter exposure to 166.9 Gy for a 37.5‐mA, 80 kVp beam, and a 1125 ms exposure. PSD irradiation reproducibility was < 0.5%. Simulated and measured dose fall off agreed and it was steep along the axis of the shutter slit (1%/0.1 mm) and with depth (2%/0.1 mm at 1‐mm depth). Spheroid positioning uncertainty of 300 μm resulted in dose difference of < 3% for x and y shifts but up to 7% uncertainty for a z‐shift parallel to the beam axis. A 16% difference in spheroid size resulted in <5% dose difference in spheroid absorbed dose. Conclusions: We have presented a cost‐effective x‐ray tube‐based system with a beam shutter designed for in vitro UHDR delivery and reaching dose rates of up to 118.0 Gy/s. The described shutter system can be easily implemented at other institutions, which might enable new researchers to investigate the radiobiology of UHDR irradiations in vitro. [ABSTRACT FROM AUTHOR]