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.

Dose and dose rate dependence of the tissue sparing effect at ultra-high dose rate studied for proton and electron beams using the zebrafish embryo model.

PURPOSE: A better characterization of the dependence of the tissue sparing effect at ultra-high dose rate (UHDR) on physical beam parameters (dose, dose rate, radiation quality) would be helpful towards a mechanistic understanding of the FLASH effect and for its broader clinical translation. To address this, a comprehensive study on the normal tissue sparing at UHDR using the zebrafish embryo (ZFE) model was conducted. METHODS: One-day-old ZFE were irradiated over a wide dose range (15-95 Gy) in three different beams (proton entrance channel, proton spread out Bragg peak and 30 MeV electrons) at UHDR and reference dose rate. After irradiation the ZFE were incubated for 4 days and then analyzed for four different biological endpoints (pericardial edema, curved spine, embryo length and eye diameter). RESULTS: Dose-effect curves were obtained and a sparing effect at UHDR was observed for all three beams. It was demonstrated that proton relative biological effectiveness and UHDR sparing are both relevant to predict the resulting dose response. Dose dependent FLASH modifying factors (FMF) for ZFE were found to be compatible with rodent data from the literature. It was found that the UHDR sparing effect saturates at doses above âˆ¼ 50 Gy with an FMF of âˆ¼ 0.7-0.8. A strong dose rate dependence of the tissue sparing effect in ZFE was observed. The magnitude of the maximum sparing effect was comparable for all studied biological endpoints. CONCLUSION: The ZFE model was shown to be a suitable pre-clinical high-throughput model for radiobiological studies on FLASH radiotherapy, providing results comparable to rodent models. This underlines the relevance of ZFE studies for FLASH radiotherapy research.

Biological-equivalent-dose-based integrated optimization framework for fast-energy-switching Bragg peak FLASH-RT using single-beam-per-fraction.

BACKGROUNDS: When comparing the delivery of all beams per fraction (ABPF) to single beam per fraction (SBPF), it is observed that SBPF not only helps meet the FLASH dose threshold but also mitigates the uncertainty with beam switching in the FLASH effect. However, SBPF might lead to a higher biological equivalent dose in 2 Gy (EQD2) for normal tissues. PURPOSE: This study aims to develop an EQD2-based integrated optimization framework (EQD2-IOF), encompassing robust dose, delivery efficiency, and beam orientation optimization (BOO) for Bragg peak FLASH plans using the SBPF treatment schedule. The EQD2-IOF aims to enhance both dose sparing and the FLASH effect. METHODS: A superconducting gantry was employed for fast energy switching within 27 ms, while universal range shifters were utilized to improve beam current in the implementation of FLASH plans with five Bragg peak beams. To enhance dose delivery efficiency while maintaining plan quality, a simultaneous dose and spot map optimization (SDSMO) algorithm for single field optimization was incorporated into a Bayesian optimization-based auto-planning algorithm. Subsequently, a BOO algorithm based on Tabu search was developed to select beam angle combinations (BACs) for 10 lung cases. To simultaneously consider dose sparing and FLASH effect, a quantitative model based on dose-dependent dose modification factor (DMF) was used to calculate FLASH-enhanced dose distribution. The EQD2-IOF plan was compared to the plan optimized without SDSMO using BAC selected by a medical physicist (Manual plan) in the SBPF treatment schedule. Meanwhile, the mean EQD2 in the normal tissue was evaluated for the EQD2-IOF plan in both SBPF and ABPF treatment schedules. RESULTS: No significant difference was found in D2% and D98% of the target between EQD2-IOF plans and Manual Plans. When using a minimum DMF of 0.67 and a dose threshold of 4 Gy, EQD2-IOF plans showed a significant reduction in FLASH-enhanced EQD2mean of the ipsilateral lung and normal tissue by 10.5% and 11.5%, respectively, compared to Manual plans. For normal tissues that received a dose greater than 70% of the prescription dose, using a minimum DMF of 0.7 for FLASH sparing compensated for the increase in EQD2mean resulting from replacing ABPF with SBPF schedules. CONCLUSIONS: The EQD2-IOF can automatically optimize SBPF FLASH-RT plans to achieve optimal sparing of normal tissues. With an energy switching time of 27 ms, the loss of fractionate repairing using SBPF schedules in high-dose regions can be compensated for by the FLASH effect. However, when an energy switching time of 500 ms is utilized, the SBPF schedule needs careful consideration, as the FLASH effect diminishes with longer irradiation time.

Impact of Scattering Foil Composition on Electron Energy Distribution in a Clinical Linear Accelerator Modified for FLASH Radiotherapy: A Monte Carlo Study.

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

FLASH Effect Is Not Always Induced by Ultra-high Dose-rate Proton Irradiation Under Hypoxic Conditions.

BACKGROUND/AIM: Pre-clinical studies have shown that irradiation with electrons at an ultra-high dose-rate (FLASH) spares normal tissue while maintaining tumor control. However, most in vitro experiments with protons have been conducted using a non-clinical irradiation system in normoxia alone. This study evaluated the biological response of non-tumor and tumor cells at different oxygen concentrations irradiated with ultra-high dose-rate protons using a clinical system and compared it with the conventional dose rate (CONV). MATERIALS AND METHODS: Non-tumor cells (V79) and tumor cells (U-251 and A549) were irradiated with 230 MeV protons at a dose rate of >50 Gy/s or 0.1 Gy/s under normoxic or hypoxic (<2%) conditions. The surviving fraction was analyzed using a clonogenic cell survival assay. RESULTS: No significant difference in the survival of non-tumor or tumor cells irradiated with FLASH was observed under normoxia or hypoxia compared to the CONV. CONCLUSION: Proton irradiation at a dose rate above 40 Gy/s, the FLASH dose rate, did not induce a sparing effect on either non-tumor or tumor cells under the conditions examined. Further studies are required on the influence of various factors on cell survival after FLASH irradiation.

Radiation safety of ultra-high dose rate electron accelerators for FLASH radiotherapy.

BACKGROUND: An ultra-high dose rate (UHDR) electron accelerator for FLASH radiotherapy (RT) produces very intense bremsstrahlung by the interaction of the electron beam with objects both inside and outside of the accelerator. The bremsstrahlung dose per pulse is typically 1-2 orders of magnitude larger than that of conventional RT x-ray treatment of the same energy, and for electron energies above 10 MeV, the bremsstrahlung produces substantially more induced radioactivity outside the accelerator than for conventional RT. Therefore, a thorough radiation safety assessment is mandatory prior to the operation of a UHDR electron accelerator. PURPOSE: To evaluate the radiation safety of a prototype FLASH-enabled Varian TrueBeam accelerator and to develop a general framework for assessment of all key radiation safety properties of a UHDR electron accelerator for FLASH RT. METHODS: Production of bremsstrahlung and induced radioactivity by a UHDR electron accelerator is modeled by various analytical methods. The analytical modeling is compared with National Institute of Standards and Technology (NIST) bremsstrahlung yield data as well as measurements of primary bremsstrahlung outside the bunker and induced radioactivity of irradiated thick targets for a FLASH-enabled 16 MeV Varian TrueBeam electron accelerator. In addition, the analytical modeling is complemented by measurements of secondary bremsstrahlung inside/outside the bunker and neutrons at the maze entrance. RESULTS: Calculated bremsstrahlung yields deviate maximum 8.5% from NIST data, and all measurements of primary bremsstrahlung and induced radioactivity agree with calculations, validating the analytical tools. In addition, it is found that scattering foil bremsstrahlung dominates primary bremsstrahlung and the main source of secondary bremsstrahlung is the irradiated object outside the accelerator. It follows that primary and secondary bremsstrahlung outside the bunker can be calculated using the same simple formalism as that used for conventional RT. Measured primary bremsstrahlung tenth-value layers for concrete of the simple formalism are in good agreement with NCRP and IAEA data, while measured secondary bremsstrahlung tenth-value layers for concrete are considerably lower than NCRP and IAEA data. All calculations and measurements form a general framework for assessment of all key radiation safety properties of a UHDR electron accelerator. CONCLUSIONS: The FLASH-enabled Varian TrueBeam accelerator is safe for normal operation (max. 99 pulses per irradiation) in a bunker designed for at least 15 MV conventional x-ray treatment unless the UHDR workload is much larger than the x-ray workload. A similar finding applies to other UHDR electron accelerators. However, during beam tuning, radiation survey, or other tests with extended irradiation time, the UHDR workload may become very large, necessitating the implementation of additional safety measures.

Proton FLASH effects on mouse skin at different oxygen tensions.

Objective. Irradiation at FLASH dose rates (>40 Gy s-1) has received great attention due to its reported normal tissue sparing effect. The FLASH effect was originally observed in electron irradiations but has since been shown to also occur with both photon and proton beams. Several mechanisms have been proposed to explain the tissue sparing at high dose rates, including effects involving oxygen, such as depletion of oxygen within the irradiated cells. In this study, we investigated the protective role of FLASH proton irradiation on the skin when varying the oxygen concentration.Approach. Our double scattering proton system provided a 1.2 × 1.6 cm2elliptical field at a dose rate of ∼130 Gy s-1. The conventional dose rate was ∼0.4 Gy s-1. The legs of the FVB/N mice were marked with two tattooed dots and fixed in a holder for exposure. To alter the skin oxygen concentration, the mice were breathing pure oxygen or had their legs tied to restrict blood flow. The distance between the two dots was measured to analyze skin contraction over time.Main results. FLASH irradiation mitigated skin contraction by 15% compared to conventional dose rate irradiation. The epidermis thickness and collagen deposition at 75 d following 25 to 30 Gy exposure suggested a long-term protective function in the skin from FLASH irradiation. Providing the mice with oxygen or reducing the skin oxygen concentration removed the dose-rate-dependent difference in response.Significance. FLASH proton irradiation decreased skin contraction, epidermis thickness and collagen deposition compared to standard dose rate irradiations. The observed oxygen-dependence of the FLASH effect is consistent with, but not conclusive of, fast oxygen depletion during the exposure.

Transformative Technology for FLASH Radiation Therapy.

The general concept of radiation therapy used in conventional cancer treatment is to increase the therapeutic index by creating a physical dose differential between tumors and normal tissues through precision dose targeting, image guidance, and radiation beams that deliver a radiation dose with high conformality, e.g., protons and ions. However, the treatment and cure are still limited by normal tissue radiation toxicity, with the corresponding side effects. A fundamentally different paradigm for increasing the therapeutic index of radiation therapy has emerged recently, supported by preclinical research, and based on the FLASH radiation effect. FLASH radiation therapy (FLASH-RT) is an ultra-high-dose-rate delivery of a therapeutic radiation dose within a fraction of a second. Experimental studies have shown that normal tissues seem to be universally spared at these high dose rates, whereas tumors are not. While dose delivery conditions to achieve a FLASH effect are not yet fully characterized, it is currently estimated that doses delivered in less than 200 ms produce normal-tissue-sparing effects, yet effectively kill tumor cells. Despite a great opportunity, there are many technical challenges for the accelerator community to create the required dose rates with novel compact accelerators to ensure the safe delivery of FLASH radiation beams.

Modeling of scavenging systems in water radiolysis with Geant4-DNA.

PURPOSE: This paper presents the capabilities of the Geant4-DNA Monte Carlo toolkit to simulate water radiolysis with scavengers using the step-by-step (SBS) or the independent reaction times (IRT) methods. It features two examples of application areas: (1) computing the escape yield of H2O2 following a 60Co γ-irradiation and (2) computing the oxygen depletion in water irradiated with 1 MeV electrons. METHODS: To ease the implementation of the chemical stage in Geant4-DNA, we developed a user interface that helps define the chemical reactions and set the concentration of scavengers. The first application area example required two computational steps to perform water radiolysis using NO2- and NO3- as scavengers and a 60Co irradiation. The oxygen depletion computation technique for the second application area example consisted of simulating track segments of 1 MeV electrons and determining the radio-induced loss and gain of oxygen molecules. RESULTS: The production of H2O2 under variable scavenging levels is consistent with the literature; the mean relative difference between the SBS and IRT methods is 7.2 % ± 0.5 %. For the oxygen depletion 1 µs post-irradiation, the mean relative difference between both methods is equal to 9.8 % ± 0.3 %. The results in the microsecond scale depend on the initial partial pressure of oxygen in water. In addition, the computed oxygen depletions agree well with the literature. CONCLUSIONS: The Geant4-DNA toolkit makes it possible to simulate water radiolysis in the presence of scavengers. This feature offers perspectives in radiobiology, with the possibility of simulating cell-relevant scavenging mechanisms.

Modeling ultra-high dose rate electron and proton FLASH effect with the physicochemical approach.

Objective. A physicochemical model built on the radiochemical kinetic theory was recently proposed in (Labarbeet al2020) to explain the FLASH effect. We performed extensive simulations to scrutinize its applicability for oxygen depletion studies and FLASH-related experiments involving both proton and electron beams.Approach. Using the dose and beam delivery parameters for each FLASH experiment, we numerically solved the radiochemical rate equations comprised of a set of coupled nonlinear ordinary differential equations to obtain the area under the curve (AUC) of radical concentrations.Main results. The modeled differences in AUC induced by ultra-high dose rates appeared to correlate well with the FLASH effect. (i) For the whole brain irradiation of mice performed in (Montay-Gruelet al2017), the threshold dose rate values for memory preservation coincided with those at which AUC started to decrease much less rapidly. (ii) For the proton pencil beam scanning FLASH of (Cunninghamet al2021), we found linear correlations between radicals' AUC and the biological endpoints: TGF-ß1, leg contracture and plasma level of cytokine IL-6. (iii) Compatible with the findings of the proton FLASH experiment in (Kimet al2021), we found that radicals' AUC at the entrance and mid-Spread-Out Bragg peak regions were highly similar. In addition, our model also predicted ratios of oxygen depletionG-values between normal and UHDR irradiation similar to those observed in (Caoet al2021) and (El Khatibet al2022).Significance. Collectively, our results suggest that the normal tissue sparing conferred by UHDR irradiation may be due to the lower degree of exposure to peroxyl and superoxide radicals. We also found that the differential effect of dose rate on the radicals' AUC was less pronounced at lower initial oxygen levels, a trait that appears to align with the FLASH differential effect on normal versus tumor tissues.

Absence of Tissue-Sparing Effects in Partial Proton FLASH Irradiation in Murine Intestine.

Ultra-high dose rate irradiation has been reported to protect normal tissues more than conventional dose rate irradiation. This tissue sparing has been termed the FLASH effect. We investigated the FLASH effect of proton irradiation on the intestine as well as the hypothesis that lymphocyte depletion is a cause of the FLASH effect. A 16 × 12 mm2 elliptical field with a dose rate of ~120 Gy/s was provided by a 228 MeV proton pencil beam. Partial abdominal irradiation was delivered to C57BL/6j and immunodeficient Rag1-/-/C57 mice. Proliferating crypt cells were counted at 2 days post exposure, and the thickness of the muscularis externa was measured at 280 days following irradiation. FLASH irradiation did not reduce the morbidity or mortality of conventional irradiation in either strain of mice; in fact, a tendency for worse survival in FLASH-irradiated mice was observed. There were no significant differences in lymphocyte numbers between FLASH and conventional-dose-rate mice. A similar number of proliferating crypt cells and a similar thickness of the muscularis externa following FLASH and conventional dose rate irradiation were observed. Partial abdominal FLASH proton irradiation at 120 Gy/s did not spare normal intestinal tissue, and no difference in lymphocyte depletion was observed. This study suggests that the effect of FLASH irradiation may depend on multiple factors, and in some cases dose rates of over 100 Gy/s do not induce a FLASH effect and can even result in worse outcomes.

Fractionated FLASH radiation in xenografted lung tumors induced FLASH effect at a split dose of 2 Gy.

PURPOSE: To explore the minimum split dose of FLASH radiotherapy (FLASH). MATERIAL AND METHODS: Lungs of nude mice were used to verify the capacity of normal tissue sparing of FLASH, while tumor-bearing nude mice were used to evaluate the curative power. Xenografted tumor models were established in Balb/c-nu mice using A549 cells at a concentration of 5×106/100 µL. With the same total dose (20 Gy), the dose rate of FLASH was 200 Gy/s when conventional radiotherapy(CONV) was 0.033 Gy/s. Two schemes of FLASH irradiations were applied: single pulse (FLASH1) and ten pulses (FLASH10). Then, according to the different tissue types and irradiation schemes, mice were divided into eight groups: Control-T, CONV-T, FLASH1-T, FLASH10-T (T for tumor) and Control-L, CONV-L, FLASH1-L, FLASH10-L (L for lung). Evaluation of FLASH effect was based on the changes in tumor volume and pathological analysis of tumor and lung tissues before and after irradiation. RESULTS: Compared to control group, the mean volume of tumors in nude mice increased slowly or decreased after irradiation with both FLASH and CONV (Control-T: 233.6±55.19 mm3, CONV-T: 146.1±50.62 mm3, FLASH1-T: 148±18.83 mm3, FLASH10-T: 119.1±50.62 mm3, p ≤ .05) . Tumor cells of irradiated groups had similar degrees of dissolution damage and inflammation, while the acute radiation pneumonia induced by FLASH was less severe. The pulmonary pathology of FLASH1-L and FLASH10-L were similar, and only a few neutrophils were observed. In addition to inflammatory cells, slight thickening of alveolar septum and obvious interstitial hemorrhage were also observed in the CONV-L group. CONCLUSION: The FLASH effect was successfully reproduced in both single and fractionated irradiation, with 2 Gy being the minimum split dose to achieve the FLASH effect in existing experiments. It is suggested that the transient oxygen depletion might not be the only mechanism behind the FLASH effect.

Flash Therapy for Cancer: A Potentially New Radiotherapy Methodology.

In traditional treatment modalities and standard clinical practices, FLASH radiotherapy (FL-RT) administers radiation therapy at an exceptionally high dosage rate. When compared to standard dose rate radiation therapy, numerous preclinical investigations have demonstrated that FL-RT provides similar benefits in conserving normal tissue while maintaining equal antitumor efficacy, a phenomenon possible due to the 'FLASH effect' (FE) of FL-RT. The methodologies involve proton radiotherapy, intensity-modulated radiation treatment, and managing high-throughput damage by radiation to solid tissues. Recent results from animal studies indicate that FL-RT can reduce radiation-induced tissue damage, significantly enhancing anticancer potency. Focusing on the potential benefits of FL proton beam treatment in the years to come, this review details the FL-RT research that has been done so far and the existing theories illuminating the FL effects. This subject remains of interest, with many issues still needing to be answered. We offer a brief review to emphasize a few of the key efforts and difficulties in moving FL radiation research forward. The existing research state of FL-RT, its affecting variables, and its different specific impacts are presented in this current review. Key topics discussed include the biochemical mechanism during FL therapy, beam sources for FL therapy, the FL effect on immunity, clinical and preclinical studies on the protective effect of FL therapy, and parameters for effective FL therapy.

3D-conformal very-high energy electron therapy as candidate modality for FLASH-RT: A treatment planning study for glioblastoma and lung cancer.

BACKGROUND: Pre-clinical ultra-high dose rate (UHDR) electron irradiations on time scales of 100 ms have demonstrated a remarkable sparing of brain and lung tissues while retaining tumor efficacy when compared to conventional dose rate irradiations. While clinically-used gantries and intensity modulation techniques are too slow to match such time scales, novel very-high energy electron (VHEE, 50-250 MeV) radiotherapy (RT) devices using 3D-conformed broad VHEE beams are designed to deliver UHDR treatments that fulfill these timing requirements. PURPOSE: To assess the dosimetric plan quality obtained using VHEE-based 3D-conformal RT (3D-CRT) for treatments of glioblastoma and lung cancer patients and compare the resulting treatment plans to those delivered by standard-of-care intensity modulated photon RT (IMRT) techniques. METHODS: Seven glioblastoma patients and seven lung cancer patients were planned with VHEE-based 3D-CRT using 3 to 16 coplanar beams with equidistant angular spacing and energies of 100 and 200 MeV using a forward planning approach. Dose distributions, dose-volume histograms, coverage (V95% ) and homogeneity (HI98% ) for the planning target volume (PTV), as well as near-maximum doses (D2% ) and mean doses (Dmean ) for organs-at-risk (OAR) were evaluated and compared to clinical IMRT plans. RESULTS: Mean differences of V95% and HI98% of all VHEE plans were within 2% or better of the IMRT reference plans. Glioblastoma plan dose metrics obtained with VHEE configurations of 200 MeV and 3-16 beams were either not significantly different or were significantly improved compared to the clinical IMRT reference plans. All OAR plan dose metrics evaluated for VHEE plans created using 5 beams of 100 MeV were either not significantly different or within 3% on average, except for Dmean for the body, Dmean for the brain, D2% for the brain stem, and D2% for the chiasm, which were significantly increased by 1, 2, 6, and 8 Gy, respectively (however below clinical constraints). Similarly, the dose metrics for lung cancer patients were also either not significantly different or were significantly improved compared to the reference plans for VHEE configurations with 200 MeV and 5 to 16 beams with the exception of D2% and Dmean to the spinal canal (however below clinical constraints). For the lung cancer cases, the VHEE configurations using 100 MeV or only 3 beams resulted in significantly worse dose metrics for some OAR. Differences in dose metrics were, however, strongly patient-specific and similar for some patient cases. CONCLUSIONS: VHEE-based 3D-CRT may deliver conformal treatments to simple, mostly convex target shapes in the brain and the thorax with a limited number of critical adjacent OAR using a limited number of beams (as low as 3 to 7). Using such treatment techniques, a dosimetric plan quality comparable to that of standard-of-care IMRT can be achieved. Hence, from a treatment planning perspective, 3D-conformal UHDR VHEE treatments delivered on time scales of 100 ms represent a promising candidate technique for the clinical transfer of the FLASH effect.

FLASH ultra-high dose rates in radiotherapy: preclinical and radiobiological evidence.

PURPOSE: Flash radiotherapy (FLASH-RT) is currently being regarded as the next breakthrough in radiation treatment of cancer, delivering ultrahigh radiation doses in a very short time, and sparing normal tissues from detrimental injury. Here we review the current evidence on the preclinical findings as well as the radiobiological mechanisms underlying the FLASH effect. We also briefly examine the scenario of available technologies for delivering FLASH dose-rates for research and their implications for future clinical use. CONCLUSIONS: Preclinical studies report that the FLASH-RT reduces radiation-induced toxicity whilst maintaining an equivalent tumor response across different animal models. However, the molecular radiobiology underlying FLASH effect is not fully understood and further experiments are necessary to understand the biological response. Future studies also includes the design of a FLASH delivery system able to produce beams appropriate for treatment of tumors with ultra-high dose rates. All these research activities will greatly benefit from a multidisciplinary collaboration across biology, physics and clinical oncology, increasing the potential of a rapid clinical translation of FLASH-RT.

Ultra-high dose rate electron beams and the FLASH effect: From preclinical evidence to a new radiotherapy paradigm.

In their seminal paper from 2014, Fauvadon et al. coined the term FLASH irradiation to describe ultra-high-dose rate irradiation with dose rates greater than 40 Gy/s, which results in delivery times of fractions of a second. The experiments presented in that paper were performed with a high-dose-per-pulse 4.5 MeV electron beam, and the results served as the basis for the modern-day field of FLASH radiation therapy (RT). In this article, we review the studies that have been published after those early experiments, demonstrating the robust effects of FLASH RT on normal tissue sparing in preclinical models. We also outline the various irradiation parameters that have been used. Although the robustness of the biological response has been established, the mechanisms behind the FLASH effect are currently under investigation in a number of laboratories. However, differences in the magnitude of the FLASH effect between experiments in different labs have been reported. Reasons for these differences even within the same animal model are currently unknown, but likely has to do with the marked differences in irradiation parameter settings used. Here, we show that these parameters are often not reported, which complicates large multistudy comparisons. For this reason, we propose a new standard for beam parameter reporting and discuss a systematic path to the clinical translation of FLASH RT.

A phenomenological model of proton FLASH oxygen depletion effects depending on tissue vasculature and oxygen supply.

Introduction: Radiation-induced oxygen depletion in tissue is assumed as a contributor to the FLASH sparing effects. In this study, we simulated the heterogeneous oxygen depletion in the tissue surrounding the vessels and calculated the proton FLASH effective-dose-modifying factor (FEDMF), which could be used for biology-based treatment planning. Methods: The dose and dose-weighted linear energy transfer (LET) of a small animal proton irradiator was simulated with Monte Carlo simulation. We deployed a parabolic partial differential equation to account for the generalized radiation oxygen depletion, tissue oxygen diffusion, and metabolic processes to investigate oxygen distribution in 1D, 2D, and 3D solution space. Dose and dose rates, particle LET, vasculature spacing, and blood oxygen supplies were considered. Using a similar framework for the hypoxic reduction factor (HRF) developed previously, the FEDMF was derived as the ratio of the cumulative normoxic-equivalent dose (CNED) between CONV and UHDR deliveries. Results: Dynamic equilibrium between oxygen diffusion and tissue metabolism can result in tissue hypoxia. The hypoxic region displayed enhanced radio-resistance and resulted in lower CNED under UHDR deliveries. In 1D solution, comparing 15 Gy proton dose delivered at CONV 0.5 and UHDR 125 Gy/s, 61.5% of the tissue exhibited ≥20% FEDMF at 175 µm vasculature spacing and 18.9 µM boundary condition. This percentage reduced to 34.5% and 0% for 8 and 2 Gy deliveries, respectively. Similar trends were observed in the 3D solution space. The FLASH versus CONV differential effect remained at larger vasculature spacings. A higher FLASH dose rate showed an increased region with ≥20% FEDMF. A higher LET near the proton Bragg peak region did not appear to alter the FLASH effect. Conclusion: We developed 1D, 2D, and 3D oxygen depletion simulation process to obtain the dynamic HRF and derive the proton FEDMF related to the dose delivery parameters and the local tissue vasculature information. The phenomenological model can be used to simulate or predict FLASH effects based on tissue vasculature and oxygen concentration data obtained from other experiments.

Changes in Radical Levels as a Cause for the FLASH effect: Impact of beam structure parameters at ultra-high dose rates on oxygen depletion in water.

The influence of different average and bunch dose rates in electron beams on the FLASH effect was investigated. The present study measures O2 content in water at different beam pulse patterns and finds strong correlation with biological data, strengthening the hypothesis of radical-related mechanisms as a reason for the FLASH effect.

The minimal FLASH sparing effect needed to compensate the increase of radiobiological damage due to hypofractionation for late-reacting tissues.

PURPOSE: Normal tissue (NT) sparing by ultra-high dose rate (UHDR) irradiations compared to conventional dose rate (CONV) irradiations while being isotoxic to the tumor has been termed "FLASH effect" and has been observed when large doses per fraction (d ≳ 5 Gy) have been delivered. Since hypofractionated treatment schedules are known to increase toxicities of late-reacting tissues compared to normofractionated schedules for many clinical scenarios at CONV dose rates, we developed a formalism based on the biologically effective dose (BED) to assess the minimum magnitude of the FLASH effect needed to compensate the loss of late-reacting NT sparing when reducing the number of fractions compared to a normofractionated CONV treatment schedule while remaining isoeffective to the tumor. METHODS: By requiring the same BED for the tumor, we derived the "break-even NT sparing weighting factor" WBE for the linear-quadratic (LQ) and LQ-linear (LQ-L) models for an NT region irradiated at a relative dose r (relative to the prescribed dose per fraction d to the tumor). WBE was evaluated numerically for multiple values of d and r, and for different tumor and NT α/ß-ratios. WBE was compared against currently available experimental data on the magnitude of the NT sparing provided by the FLASH effect for single fraction doses. RESULTS: For many clinically relevant scenarios, WBE decreases steeply initially for d > 2 Gy for late-reacting tissues with (α/ß)NT ≈ 3 Gy, implying that a significant NT sparing by the FLASH effect (between 15% and 30%) is required to counteract the increased radiobiological damage experienced by late-reacting NT for hypofractionated treatments with d < 10 Gy compared to normofractionated treatments that are equieffective to the tumor. When using the LQ model with generic α/ß-ratios for tumor and late-reacting NT of (α/ß)T  = 10 Gy and (α/ß)NT  = 3 Gy, respectively, most currently available experimental evidence about the magnitude of NT sparing by the FLASH effect suggests no net NT sparing benefit for hypofractionated FLASH radiotherapy (RT) in the high-dose region when compared with WBE . Instead, clinical indications with more similar α/ß-ratios of the tumor and dose-limiting NT toxicities [i.e., (α/ß)T  ≈ (α/ß)NT ], such as prostate treatments, are generally less penalized by hypofractionated treatments and need consequently smaller magnitudes of NT sparing by the FLASH effect to achieve a net benefit. For strongly hypofractionated treatments (>10-15 Gy/fraction), the LQ-L model predicts, unlike the LQ model, a larger WBE suggesting a possible benefit of strongly hypofractionated FLASH RT, even for generic α/ß-ratios of (α/ß)T  = 10 Gy and (α/ß)NT  = 3 Gy. However, knowledge on the isoeffect scaling for high doses per fraction (≳10 Gy/fraction) and its modeling is currently limited and impedes accurate and reliable predictions for such strongly hypofractionated treatments. CONCLUSIONS: We developed a formalism that quantifies the minimal NT sparing by the FLASH effect needed to compensate for hypofractionation, based on the LQ and LQ-L models. For a given hypofractionated UHDR treatment scenario and magnitude of the FLASH effect, the formalism predicts if a net NT sparing benefit is expected compared to a respective normofractionated CONV treatment.

Beam pulse structure and dose rate as determinants for the flash effect observed in zebrafish embryo.

BACKGROUND AND PURPOSE: Continuing recent experiments at the research electron accelerator ELBE at the Helmholtz-Zentrum Dresden-Rossendorf the influence of beam pulse structure on the Flash effect was investigated. MATERIALS AND METHODS: The proton beam pulse structure of an isochronous cyclotron (UHDRiso) and a synchrocyclotron (UHDRsynchro) was mimicked at ELBE by quasi-continuous electron bunches at 13 MHz delivering mean dose rates of 287 Gy/s and 177 Gy/s and bunch dose rates of 106Gy/s and 109 Gy/s, respectively. For UHDRsynchro, 40 ms macro pulses at a frequency of 25 Hz superimposed the bunch delivery. For comparison, a maximum beam intensity (2.5 × 105 Gy/s mean and ∼109 Gy/s bunch dose rate) and a reference irradiation (of ∼8 Gy/min mean dose rate) were applied. Radiation induced changes were assessed in zebrafish embryos over four days post irradiation. RESULTS: Relative to the reference a significant protecting Flash effect was observed for all electron beam pulse regimes with less severe damage the higher the mean dose rate of the electron beam. Accordingly, the macro pulsing induced prolongation of treatment time at UHDRsynchro regime reduces the protecting effect compared to the maximum regime delivered at same bunch but higher mean dose rate. The Flash effect of the UHDRiso regime was confirmed at a clinical isochronous cyclotron comparing the damage induced by proton beams delivered at 300 Gy/s and ∼9 Gy/min. CONCLUSION: The recent findings indicate that the mean dose rate or treatment time are decisive for the normal tissue protecting Flash effect in zebrafish embryo.