FLASH Radiotherapy Research Articles

A comprehensive investigation of the performance of a commercial scintillator system for applications in electron FLASH radiotherapy.

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. 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 100Hz, to determine its feasibility for use in UHDR electron beamlines. 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. The W2 scintillator demonstrated mean dose rate independence and linearity as a function of integrated dose and DPP for DPP ≤ 1.5Gy (R2>0.99) and PRF ≤ 90Hz. At DPP>1.5Gy, 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<1.5Gy, 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. The Exradin W2 scintillator can provide output measurements that are both dose rate independent and linear in response if the DPP is kept ≤1.5Gy (corresponding to a mean dose rate up to 290Gy/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>1.5Gy, the W2 scintillator's response becomes nonlinear, likely due to limitations in the electrometer related to the high signal intensity.

First Monte Carlo beam model for ultra-high dose rate radiotherapy with a compact electron LINAC.

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. 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. 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. 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 2mm/3%. With the criteria of 2mm/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. 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.

FLASH radiotherapy for the treatment of symptomatic bone metastases in the thorax (FAST-02): protocol for a prospective study of a novel radiotherapy approach

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

A prototype scintillator real-time beam monitor for ultra-high dose rate radiotherapy.

FLASH Radiotherapy (RT) is an emergent cancer RT modality where an entire therapeutic dose is delivered at more than 1000 times higher dose rate than conventional RT. For clinical trials to be conducted safely, a precise and fast beam monitor that can generate out-of-tolerance beam interrupts is required. This paper describes the overall concept and provides results from a prototype ultra-fast, scintillator-based beam monitor for both proton and electron beam FLASH applications. A FLASH Beam Scintillator Monitor (FBSM) is being developed that employs a novel proprietary scintillator material. The FBSM has capabilities that conventional RT detector technologies are unable to simultaneously provide: (1) large area coverage; (2) a low mass profile; (3) a linear response over a broad dynamic range; (4) radiation hardness; (5) real-time analysis to provide an IEC-compliant fast beam-interrupt signal based on true two-dimensional beam imaging, radiation dosimetry and excellent spatial resolution. The FBSM uses a proprietary low mass, less than 0.5mm water equivalent, non-hygroscopic, radiation tolerant scintillator material (designated HM: hybrid material) that is viewed by high frame rate CMOS cameras. Folded optics using mirrors enable a thin monitor profile of ∼10cm. A field programmable gate array (FPGA) data acquisition system generates real-time analysis on a time scale appropriate to the FLASH RT beam modality: 100-1000Hz for pulsed electrons and 10-20kHz for quasi-continuous scanning proton pencil beams. An ion beam monitor served as the initial development platform for this work and was tested in low energy heavy-ion beams (86Kr+26 and protons). A prototype FBSM was fabricated and then tested in various radiation beams that included FLASH level dose per pulse electron beams, and a hospital RT clinic with electron beams. Results presented in this report include image quality, response linearity, radiation hardness, spatial resolution, and real-time data processing. The HM scintillator was found to be highly radiation damage resistant. It exhibited a small 0.025%/kGy signal decrease from a 216 kGy cumulative dose resulting from continuous exposure for 15 min at a FLASH compatible dose rate of 237Gy/s. Measurements of the signal amplitude versus beam fluence demonstrate linear response of the FBSM at FLASH compatible dose rates of >40Gy/s. Comparison with commercial Gafchromic film indicates that the FBSM produces a high resolution 2D beam image and can reproduce a nearly identical beam profile, including primary beam tails. The spatial resolution was measured at 35-40µm. Tests of the firmware beta version show successful operation at 20000Hz frame rate or 50 µs/frame, where the real-time analysis of the beam parameters is achieved in less than 1 µs. The FBSM is designed to provide real-time beam profile monitoring over a large active area without significantly degrading the beam quality. A prototype device has been staged in particle beams at currents of single particles up to FLASH level dose rates, using both continuous ion beams and pulsed electron beams. Using a novel scintillator, beam profiling has been demonstrated for currents extending from single particles to 10 nA currents. Radiation damage is minimal and even under FLASH conditions would require ≥50 kGy of accumulated exposure in a single spot to result in a 1% decrease in signal output. Beam imaging is comparable to radiochromic films, and provides immediate images without hours of processing. Real-time data processing, taking less than 50 µs (combined data transfer and analysis times), has been implemented in firmware for 20kHz frame rates for continuous proton beams.

Silicon carbide detectors for dosimetry and monitoring of ultra-high dose rate beams

FLASH radiotherapy, which employs ultra-high dose rate (UHDR) beams with a mean dose rate > 40 Gy/s and a total irradiation time < 200 ms to treat tumors, exhibits remarkable ability to spare healthy tissue while maintaining the same efficiency in treating tumors. However, UHDR presents challenges in dosimetry and beam monitoring, as the dosimeters recommended for conventional radiotherapy, i.e. the ionization chambers, show saturation at such high dose rates and dose delivered per pulse and hence cannot be employed for accurate dosimetry in the future clinical transition of FLASH radiotherapy. This implies the need to develop alternative techniques and dosimeters able to sustain the peculiar conditions of the UHDR beams. This study investigates the feasibility of using a new generation of Silicon Carbide (SiC) detectors for the measurement of the instantaneous dose rate of UHDR electron beams. An experimental investigation was conducted with the ElectronFLASH linac developed by the SIT Sordina company and able to accelerate 7 and 9 MeV electron pulsed beams at FLASH regimes. The signalsproduced in the SiC detectors were acquired and compared with the signals detected by the monitoring system currently mounted along the LINAC, i.e. two AC current transformers supplied by the Bergoz company. The main purpose of the experiment was to demonstrate the capability of the developed SiC detector to measure the single pulse duration and waveform with high time resolution and accuracy. The test was performed by using both 7 and 9 MeV electron beams and has shown promising results.

O 40 - Commissioning a 250 MeV research beamline for proton FLASH radiotherapy preclinical experiments

O 40 - Commissioning a 250 MeV research beamline for proton FLASH radiotherapy preclinical experiments

Digital twins in dosimetry and radiotherapy, a survey and some applications

Digital Twins (DTs) are emerging as a powerful tool in several applications, including Dosimetry and Radiotherapy (RT). Indeed, DTs have increased their effectiveness, up to the point that can be considered as virtual replicas of physical objects, processes, or systems. Through predictive modeling, DTs can determine optimal doses in radiation therapy, assist in defining personalized treatment schedules for individual patients, and monitor treatment responses. Moreover, DTs play a pivotal role in designing radioisotope production processes in the field of nuclear medicine. This can help to ensure the most effective treatment possible while minimizing the risk of side effects.As a frontier case example, DTs can be employed in the analysis of a possible new source for flash radiotherapy worth with respect to their effectiveness parameters like Radio-Biological Effectiveness (RBE) or cell Surviving Fraction (SF). Flash techniques involve the delivery of a high dose of radiation in a short time, reducing damage to surrounding healthy tissue while possibly increasing damage to malignant cells. DTs could be used to simulate and collect data about particle interactions with the treated tissues, optimizing the treatment and leading to improved outcomes.The most powerful tools that can be applied in DTs development are the Monte Carlo (MC) codes, particularly those with the highest capability of a detailed material/geometry description through an automatized spatial discretization approach like the one based on Unstructured Mesh (UM), allowing a common mathematical domain for both particle/radiation transport and thermal, fluid-dynamics and mechanical simulations. What comes out from various kind of applications is a common ground in terms of data management, phase space identification, simulation tools, that can be easily recognized even if spanning from cell response to technological devices, making realistic the perspective of the setup of general optimization procedures.

Dose Rate Effects on Hydrated Electrons, Hydrogen Peroxide, and a OH Radical Molecular Probe Under Clinical Energy Protons.

We report the dose rate dependence of radiation chemical yields (G value) of water radiolysis products under clinical energy protons (230 MeV) to understand mechanisms of the FLASH radiotherapy performed at ultra-high dose rate (>40 Gy/s). The G value of 7-hydoroxy-coumarin-3-carboxylic acid (7OH-C3CA) produced by reactions of coumarin-3-carboxylic acid (C3CA) with OH radicals and oxygen is evaluated by fluorescence method. Also, those of hydrated electrons and hydrogen peroxide are derived by absorption method using Saltzman and Ghomley techniques, respectively. Both G values of 7OH-C3CA and hydrated electrons decrease with increasing dose rate. The relative evolution of 7OH-C3CA is -39 ± 2% between 0.1 and 50 Gy/s. This value is higher than that of hydrated electrons, measured at -21 ± 4%. The G value of hydrogen peroxide in ultra-pure water also decreases with increasing dose rate. In comparison to these findings, we represent the increase of the G value of hydrogen peroxide with increasing dose rate in the mixture solution of MeOH and NaNO3, which act as scavengers of OH radicals and hydrated electrons, respectively, that decompose hydrogen peroxide. This finding indicates that a complex track structure can be expected with increasing dose rate and the reduction of OH radicals by forming hydrogen peroxide would be related to the sparing effect of healthy tissues.

First experimental validation of silicon-based sensors for monitoring ultra-high dose rate electron beams

Monitoring Ultra-High Dose Rate (UHDR) beams is one of the multiple challenges posed by the emergent FLASH radiotherapy. Technologies (i.e., gas-filled ionization chambers) nowadays used in conventional radiotherapy are no longer effective when applied to UHDR regimes, due to the recombination effect they are affected by, and the time required to collect charges. Exploiting the expertise in the field of silicon sensors’ applications into clinics, the medical physics group of the University and INFN Torino is investigating thin silicon sensors as possible candidates for UHDR beam monitoring, exploiting their excellent spatial resolution and well-developed technology. Silicon sensors of 30 and 45 µm active thicknesses and 0.25, 1 and 2 mm2 active areas were tested at the SIT ElectronFlash machine (CPFR, Pisa) on 9 MeV electron beams, featuring a pulse duration of 4 µs, a frequency of 1 Hz, and a dose-per-pulse ranging from 1.62 to 10.22 Gy/pulse. The silicon sensors were positioned at the exit of the ElectronFlash applicator, after a solid water build-up slab, and were readout both with an oscilloscope and with a multi-channel front-end readout chip (TERA08). A response linearity extending beyond 10 Gy/pulse was demonstrated by comparison with a reference dosimeter (FlashDiamond), thus fulfilling the first requirement of a potential application in UHDR beam monitoring.

FLASH Radiotherapy: Expectations, Challenges, and Current Knowledge.

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

Pencil Beam Scanning Proton Bragg Peak Conformal FLASH in Prostate Cancer Stereotactic Body Radiotherapy.

Bragg peak FLASH radiotherapy (RT) uses a distal tracking method to eliminate exit doses and can achieve superior OAR sparing. This study explores the application of this novel method in stereotactic body radiotherapy prostate FLASH-RT. An in-house platform was developed to enable intensity-modulated proton therapy (IMPT) planning using a single-energy Bragg peak distal tracking method. The patients involved in the study were previously treated with proton stereotactic body radiotherapy (SBRT) using the pencil beam scanning (PBS) technique to 40 Gy in five fractions. FLASH plans were optimized using a four-beam arrangement to generate a dose distribution similar to the conventional opposing beams. All of the beams had a small angle of two degrees from the lateral direction to increase the dosimetry quality. Dose metrics were compared between the conventional PBS and the Bragg peak FLASH plans. The dose rate histogram (DRVH) and FLASH metrics of 40 Gy/s coverage (V40Gy/s) were investigated for the Bragg peak plans. There was no significant difference between the clinical and Bragg peak plans in rectum, bladder, femur heads, large bowel, and penile bulb dose metrics, except for Dmax. For the CTV, the FLASH plans resulted in a higher Dmax than the clinical plans (116.9% vs. 103.3%). For the rectum, the V40Gy/s reached 94% and 93% for 1 Gy dose thresholds in composite and single-field evaluations, respectively. Additionally, the FLASH ratio reached close to 100% after the application of the 5 Gy threshold in composite dose rate assessment. In conclusion, the Bragg peak distal tracking method can yield comparable plan quality in most OARs while preserving sufficient FLASH dose rate coverage, demonstrating that the ultra-high dose technique can be applied in prostate FLASH SBRT.

Randomized phase II selection trial of FLASH and conventional radiotherapy for patients with localized cutaneous squamous cell carcinoma or basal cell carcinoma: A study protocol

BackgroundCutaneous basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most prevalent skin cancers in western countries. Surgery is the standard of care for these cancers and conventional external radiotherapy (CONV-RT) with conventional dose rate (0.03–0.06 Gy/sec) represents a good alternative when the patients or tumors are not amenable to surgery but routinely generates skin side effects. Low energy electron FLASH radiotherapy (FLASH-RT) is a new form of radiotherapy exploiting the biological advantage of the FLASH effect, which consists in delivering radiation dose in milliseconds instead of minutes in CONV-RT. In pre-clinical studies, when compared to CONV-RT, FLASH-RT induced a robust, reproducible and remarkable sparing of the normal healthy tissues, while the efficacy on tumors was preserved. In this context, we aim to prospectively evaluate FLASH-RT versus CONV-RT with regards to toxicity and oncological outcome in localized cutaneous BCC and SCC. MethodsThis is a randomized selection, non-comparative, phase II study of curative FLASH-RT versus CONV-RT in patients with T1-T2 N0 M0 cutaneous BCC and SCC. Patients will be randomly allocated to low energy electron FLASH-RT (dose rate: 220–270 Gy/s) or to CONV-RT arm. Small lesions (T1) will receive a single dose of 22 Gy and large lesions (T2) will receive 30 Gy in 5 fractions of 6 Gy over two weeks.The primary endpoint evaluates safety at 6 weeks after RT through grade ≥ 3 toxicity and efficacy through local control rate at 12 months. Approximately 60 patients in total will be randomized, considering on average 1–2 lesions and a maximum of 3 lesions per patients corresponding to the total of 96 lesions required. FLASH-RT will be performed using the Mobetron® (IntraOp, USA) with high dose rate functionality.LANCE (NCT05724875) is the first randomized trial evaluating FLASH-RT and CONV-RT in a curative setting.

A spatial measure-valued model for radiation-induced DNA damage kinetics and repair under protracted irradiation condition

In the present work, we develop a general spatial stochastic model to describe the formation and repair of radiation-induced DNA damage. The model is described mathematically as a measure-valued particle-based stochastic system and extends in several directions the model developed in Cordoni et al. (Phys Rev E 103:012412, 2021; Int J Radiat Biol 1–16, 2022a; Radiat Res 197:218–232, 2022b). In this new spatial formulation, radiation-induced DNA damage in the cell nucleus can undergo different pathways to either repair or lead to cell inactivation. The main novelty of the work is to rigorously define a spatial model that considers the pairwise interaction of lesions and continuous protracted irradiation. The former is relevant from a biological point of view as clustered lesions are less likely to be repaired, leading to cell inactivation. The latter instead describes the effects of a continuous radiation field on biological tissue. We prove the existence and uniqueness of a solution to the above stochastic systems, characterizing its probabilistic properties. We further couple the model describing the biological system to a set of reaction–diffusion equations with random discontinuity that model the chemical environment. At last, we study the large system limit of the process. The developed model can be applied to different contexts, with radiotherapy and space radioprotection being the most relevant. Further, the biochemical system derived can play a crucial role in understanding an extremely promising novel radiotherapy treatment modality, named in the community FLASH radiotherapy, whose mechanism is today largely unknown.

Beam control system and output fine-tuning for safe and precise delivery of FLASH radiotherapy at a clinical linear accelerator.

We have previously adapted a clinical linear accelerator (Elekta Precise, Elekta AB) for ultra-high dose rate (UHDR) electron delivery. To enhance reliability in future clinical FLASH radiotherapy trials, the aim of this study was to introduce and evaluate an upgraded beam control system and beam tuning process for safe and precise UHDR delivery. The beam control system is designed to interrupt the beam based on 1) a preset number of monitor units (MUs) measured by a monitor detector, 2) a preset number of pulses measured by a pulse-counting diode, or 3) a preset delivery time. For UHDR delivery, an optocoupler facilitates external control of the accelerator's thyratron trigger pulses. A beam tuning process was established to maximize the output. We assessed the stability of the delivery, and the independent interruption capabilities of the three systems (monitor detector, pulse counter, and timer). Additionally, we explored a novel approach to enhance dosimetric precision in the delivery by synchronizing the trigger pulse with the charging cycle of the pulse forming network (PFN). Improved beam tuning of gun current and magnetron frequency resulted in average dose rates at the dose maximum at isocenter distance of >160 Gy/s or >200 Gy/s, with or without an external monitor chamber in the beam path, respectively. The delivery showed a good repeatability (standard deviation (SD) in total film dose of 2.2%) and reproducibility (SD in film dose of 2.6%). The estimated variation in DPP resulted in an SD of 1.7%. The output in the initial pulse depended on the PFN delay time. Over the course of 50 measurements employing PFN synchronization, the absolute percentage error between the delivered number of MUs calculated by the monitor detector and the preset MUs was 0.8 ± 0.6% (mean ± SD). We present an upgraded beam control system and beam tuning process for safe and stable UHDR electron delivery of hundreds of Gy/s at isocenter distance at a clinical linac. The system can interrupt the beam based on monitor units and utilize PFN synchronization for improved dosimetric precision in the dose delivery, representing an important advancement toward reliable clinical FLASH trials.

Comparable survival in rats with intracranial glioblastoma irradiated with single-fraction conventional radiotherapy or FLASH radiotherapy.

Radiotherapy increases survival in patients with glioblastoma. However, the prescribed dose is limited by unwanted side effects on normal tissue. Previous experimental studies have shown that FLASH radiotherapy (FLASH-RT) can reduce these side effects. Still, it is important to establish an equal anti-tumor efficacy comparing FLASH-RT to conventional radiotherapy (CONV-RT). Fully immunocompetent Fischer 344 rats with the GFP-positive NS1 intracranial glioblastoma model were irradiated with CONV-RT or FLASH-RT in one fraction of 20 Gy, 25 Gy or 30 Gy. Animals were monitored for survival and acute dermal side effects. The brains were harvested upon euthanasia and tumors were examined post mortem. Survival was significantly increased in animals irradiated with CONV-RT and FLASH-RT at 20 Gy and 25 Gy compared to control animals. The longest survival was reached in animals irradiated with FLASH-RT and CONV-RT at 25 Gy. Irradiation at 30 Gy did not lead to increased survival, despite smaller tumors. Tumor size correlated inversely with irradiation dose, both in animals treated with CONV-RT and FLASH-RT. Acute dermal side effects were mild, but only a small proportion of the animals were alive for evaluation of those side effects. The dose response was similar for CONV-RT and FLASH-RT in the present model. Tumor size upon the time of euthanasia correlated inversely with the irradiation dose.

Streamlined pin-ridge-filter design for single-energy proton FLASH planning.

FLASH radiotherapy (FLASH-RT) with ultra-high dose rate has yielded promising results in reducing normal tissue toxicity while maintaining tumor control. Planning with single-energy proton beams modulated by ridge filters (RFs) has been demonstrated feasible for FLASH-RT. This study explored the feasibility of a streamlined pin-shaped RF (pin-RF) design, characterized by coarse resolution and sparsely distributed ridge pins, for single-energy proton FLASH planning. An inverse planning framework integrated within a treatment planning system was established to design streamlined pin RFs for single-energy FLASH planning. The framework involves generating a multi-energy proton beam plan using intensity-modulated proton therapy (IMPT) planning based on downstream energy modulation strategy (IMPT-DS), followed by a nested pencil-beam-direction-based (PBD-based) spot reduction process to iteratively reduce the total number of PBDs and energy layers along each PBD for the IMPT-DS plan. The IMPT-DS plan is then translated into the pin-RFs and the single-energy beam configurations for IMPT planning with pin-RFs (IMPT-RF). This framework was validated on three lung cases, quantifying the FLASH dose of the IMPT-RF plan using the FLASH effectiveness model. The FLASH dose was then compared to the reference dose of a conventional IMPT plan to measure the clinical benefit of the FLASH planning technique. The IMPT-RF plans closely matched the corresponding IMPT-DS plans in high dose conformity (conformity index of <1.2), with minimal changes in V7Gy and V7.4Gy for the lung (<3%) and small increases in maximum doses (Dmax) for other normal structures (<3.4Gy). Comparing the FLASH doses to the doses of corresponding IMPT-RF plans, drastic reductions of up to nearly 33% were observed in Dmax for the normal structures situated in the high-to-moderate-dose regions, while negligible changes were found in Dmax for normal structures in low-dose regions. Positive clinical benefits were seen in comparing the FLASH doses to the reference doses, with notable reductions of 21.4%-33.0% in Dmax for healthy tissues in the high-dose regions. However, in the moderate-to-low-dose regions, only marginal positive or even negative clinical benefit for normal tissues were observed, such as increased lung V7Gy and V7.4Gy (up to 17.6%). A streamlined pin-RF design was developed and its effectiveness for single-energy proton FLASH planning was validated, revealing positive clinical benefits for the normal tissues in the high dose regions. The coarsened design of the pin-RF demonstrates potential advantages, including cost efficiency and ease of adjustability, making it a promising option for efficient production.

Technical note: A small animal irradiation platform for investigating the dependence of the FLASH effect on electron beam parameters.

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. To commission a high-throughput, variable dose rate platform providing uniform electron fields(≥15cm diameter) at conventional (CONV) and UHDRs for in vivo investigations of the FLASH effect and its dependences on pulsed electron beam parameters. A murine whole-thoracic lung irradiation (WTLI) platform was constructed using a 1.3cm 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 1cm 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 2cm. 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. 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 120Gy·s-1 . At depths of 0.5 to 1.5cm, 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 0.3mm at 0cm depth to 5.1mm at 2.0cm. 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. 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 120Gy·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.

The AsiDNA™ decoy mimicking DSBs protects the normal tissue from radiation toxicity through a DNA-PK/p53/p21-dependent G1/S arrest.

AsiDNA™, a cholesterol-coupled oligonucleotide mimicking double-stranded DNA breaks, was developed to sensitize tumour cells to radio- and chemotherapy. This drug acts as a decoy hijacking the DNA damage response. Previous studies have demonstrated that standalone AsiDNA™ administration is well tolerated with no additional adverse effects when combined with chemo- and/or radiotherapy. The lack of normal tissue complication encouraged further examination into the role of AsiDNA™ in normal cells. This research demonstrates the radioprotective properties of AsiDNA™. In vitro, AsiDNA™ induces a DNA-PK/p53/p21-dependent G1/S arrest in normal epithelial cells and fibroblasts that is absent in p53 deficient and proficient tumour cells. This cell cycle arrest improved survival after irradiation only in p53 proficient normal cells. Combined administration of AsiDNA™ with conventional radiotherapy in mouse models of late and early radiation toxicity resulted in decreased onset of lung fibrosis and increased intestinal crypt survival. Similar results were observed following FLASH radiotherapy in standalone or combined with AsiDNA™. Mechanisms comparable to those identified in vitro were detected both in vivo, in the intestine and ex vivo, in precision cut lung slices. Collectively, the results suggest that AsiDNA™ can partially protect healthy tissues from radiation toxicity by triggering a G1/S arrest in normal cells.

Preliminary study of low-pressure ionization chamber for online dose monitoring in FLASH carbon ion radiotherapy

The FLASH effect of carbon ion therapy has recently attracted significant attention from the scientific community. However, the radiobiological mechanism of the effect and the exact therapeutic conditions are still under investigation. Therefore, the dosimetry accuracy is critical for testing hypotheses about the effect and quantifying FLASH Radiotherapy. In this paper, the FLASH ionization chamber at low-pressure was designed, and its dose rate dependence was verified with the Faraday cup. In addition, the dose response was tested under the air pressure of the ionization chamber of 10 mbar, 80 mbar and 845 mbar, respectively. The results showed that when the pressure was 10 mbar, the dose linearity was verified and calibrated at the dose rate of ∼50 Gy s−1, and the residuals were less than 2%. In conclusion, the FLASH ionization chamber is a promising instrument for online dose monitoring.

Possible mechanisms and simulation modeling of FLASH radiotherapy.

FLASH radiotherapy (FLASH-RT) has great potential to improve patient outcomes. It delivers radiation doses at an ultra-high dose rate (UHDR: ≥ 40Gy/s) in a single instant or a few pulses. Much higher irradiation doses can be administered to tumors with FLASH-RT than with conventional dose rate (0.01-0.40Gy/s) radiotherapy. UHDR irradiation can suppress toxicity in normal tissues while sustaining antitumor efficiency, which is referred to as the FLASH effect. However, the mechanisms underlying the effects of the FLASH remain unclear. To clarify these mechanisms, the development of simulation models that can contribute to treatment planning for FLASH-RT is still underway. Previous studies indicated that transient oxygen depletion or augmented reactions between secondary reactive species produced by irradiation may be involved in this process. To discuss the possible mechanisms of the FLASH effect and its clinical potential, we summarized the physicochemical, chemical, and biological perspectives as well as the development of simulation modeling for FLASH-RT.