Ultra-high Dose Research Articles

RBIO-02. DEVELOPMENT OF FLASH-CAR RADIOIMMUNOTHERAPY FOR PEDIATRIC BRAIN TUMORS

Abstract Pediatric brain tumors including medulloblastoma and high-grade glioma are generally refractory to T cell-based immunotherapy, largely due to an immune-hostile microenvironment infiltrated extensively with immunosuppressive macrophages. Ultra-high dose rate (FLASH) radiotherapy holds promise for treating solid tumors, given the potential lower toxicity in normal tissues and possible favorable impact on tumor immunity. Using a genetically engineered mouse model of medulloblastoma and glioma, we show that FLASH radiation stimulates pro-inflammatory polarization in tumor macrophages. Single-cell transcriptome analysis shows that FLASH proton beam radiation skews macrophages towards proinflammatory phenotypes and increases T cell infiltration in the medulloblastoma model. Further bulk transcriptome analyses reveal that FLASH radiation reduces peroxisome proliferator-activated receptor (PPAR)-γ and arginase-1 expression and inhibits immunosuppressive macrophage polarization under stimulus-inducible conditions. Mechanistically, FLASH radiation abrogates lipid oxidase expression and oxidized low-density lipid (oxLDL) generation to reduce PPARγ activity, while standard radiation induces reactive oxygen species (ROS)-dependent PPARγ activation in macrophages. Notably, FLASH radiotherapy improves infiltration and activation of chimeric antigen receptor (CAR) T cells and sensitizes tumors to GD2 CAR T immunotherapy in the autochthonous medulloblastoma and syngeneic glioma models. These findings suggest that FLASH radiotherapy may reprogram macrophage lipid metabolism to reverse tumor immunosuppression and that combination FLASH-CAR radioimmunotherapy may offer exciting opportunities for treatment of pediatric brain tumor.

RBIO-03. A SMALL ANIMAL RADIATION RESEARCH PLATFORM (FLASH-SARRP) TO MEASURE IMMUNOLOGICAL EFFECT OF ULTRA HIGH DOSE RATE (FLASH) RADIOTHERAPY

Abstract Patients who undergo radiation therapy (RT), particularly fractionated courses, often develop lymphopenia. Clinical outcome for various cancer types, including brain tumors, identifies lymphopenia as a negative prognostic factor. The mechanism for RT induced lymphopenia is unclear. Simulated models suggest the volume of blood flowing through a radiation field could play a crucial role in death of radiosensitive lymphocytes. FLASH RT is ultrahigh dose rate administration of RT, >100 times faster dose rate than standard RT that has been observed to improve the therapeutic ratio in preclinical models by preferential normal tissue sparing. Hypothesized mechanisms include chemical reactions depleting oxygen in well oxygenated normal cells creating radioresistance, differing pro-inflammatory signaling impacting tumor and normal tissue, and less impact on circulating immune cells consequent to decreased proportion exposed during a treatment session which may enhance antineoplastic response. We designed the novel FLASH kV x-ray cabinet system for preclinical laboratory research (FLASH-SARRP) to deliver ultra-high dose rates up to 100 Gy/s as well as conventional dose rates of 1.0 Gy/s to facilitate comparative studies. A custom designed docking system was developed to reproducibly position and immobilize mouse for stereotactic radiation of the brain. Dose and dose rate measurements were performed with calibrated Gafchromic EBT3 film in solid water with 0.025 mm additional copper filter. FLASH-SARRP system delivered kV x-rays at an average dose-rate of 79.2±2.1Gy/s corresponding to 10 mm depth in the immobilized mouse brain. For the delivery of 15 Gy, treatment duration was 0.2 seconds for FLASH RT administration whereas it was 244 seconds for conventional dose rate. We successfully designed a high-precision platform to study partial brain x-ray FLASH effects in mice and studies are ongoing to assess differential impact on normal brain tissue, circulating cytokines, and immune cell populations for single dose and fractionated administration of FLASH and standard radiotherapy.

Oxygen consumption measurements at ultra-high dose rate over a wide LET range.

The role of radiolytic oxygen consumption for the in-vitro "Ultra-High Dose Rate" (UHDR) sparing and in-vivo FLASH effect is subject to active debate, but data on key dependencies such as the radiation quality are lacking. The influence of "dose-averaged Linear Energy Transfer" (LETd) and dose rate on radiolytic oxygen consumption was investigated by monitoring the oxygen concentration during irradiation with electrons, protons, helium, carbon, and oxygen ions at UHDR and "Standard Dose Rates" (SDR). Sealed "Bovine Serum Albumin" (BSA) 5% samples were exposed to 15Gy of electrons and protons, and for the first time helium, carbon, and oxygen ions with LETd values of 1, 5.4, 14.4, 65, and 100.3keV/µm, respectively, delivered at mean dose rates of either 0.3-0.4Gy/s for SDR or approximately 100Gy/s for UHDR. The Oxylite (Oxford Optronics) system allowed measurements of the oxygen concentration before and after irradiation to calculate the oxygen consumption rate. The oxygen consumption rate was found to decrease with increasing LETd from 0.351mmHg/Gy for low LET electrons to 0.1796mmHg/Gy for high LET oxygen ions at SDR and for UHDR from 0.317 to 0.1556mmHg/Gy, respectively. A higher consumption rate for SDR irradiation compared to the corresponding UHDR irradiation persisted for all particle types. The measured consumption rates demonstrate a distinct LETd dependence. The obtained dataset, encompassing a wide range of LETd values, could serve as a benchmark for Monte Carlo simulations, which may aid in enhancing our comprehension of oxygen-related mechanisms after irradiations. Ultimately, they could help assess the viability of different hypotheses regarding UHDR sparing mechanisms and the FLASH effect. The found LETd dependence underscores the potential of heavy ion therapy, wherein elevated consumption rates in adjacent normal tissue offer protective benefits, while leaving tumor regions with generally higher "Linear Energy Transfer" (LET) vulnerable.

Investigating ultra-high dose rate water radiolysis using the Geant4-DNA toolkit and a Geant4 model of the Oriatron eRT6 electron linac

Ultra-high dose rate FLASH radiotherapy, a promising cancer treatment approach, offers the potential to reduce healthy tissue damage during radiotherapy. As the mechanisms underlying this process remain unknown, several hypotheses have been proposed, including the altered production of radio-induced species under ultra-high dose rate (UHDR) conditions. This study explores realistic irradiation scenarios with various dose-per-pulse and investigates the role of pulse temporal structure. Using the Geant4 toolkit and its Geant4-DNA extension, we modeled the Oriatron eRT6 linac, a FLASH-validated electron beam, and conducted simulations covering four distinct dose-per-pulse scenarios – 0.17 Gy, 1 Gy, 5 Gy, and 10 Gy – all featuring a 1.8 µs pulse duration. Results show close agreement between simulated and experimental dose profiles in water, validating the eRT6 model for Geant4-DNA simulations. We observed important changes in the temporal evolution of certain species, such as the earlier fall in hydroxyl radicals (\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^{ \\bullet } \ ext{O}\ ext{H}$$\\end{document}) and reduced production and lifetime of superoxide (\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\ ext{O}}_{2}^{{\\bullet\\:}-}$$\\end{document}) with higher dose-per-pulse levels. The pulse temporal structure did not influence the long-term evolution of species. Our findings encourage further investigation into different irradiation types, such as multi-pulse configurations, and emphasize the need to add components in water to account for relevant cellular processes.

Study of a gel dosimeter based on Ag nanoparticles for applications in radiation therapy with synchrotron X-rays at ultrahigh dose rate compared to 60Co γ-rays

A silver nitrate (AgNO3) gel was developed and evaluated as a dosimeter for synchrotron X-ray-based studies in microbeam radiation therapy (MRT) and FLASH radiation therapy. The gel was irradiated at the European Synchrotron Radiation Facility (ID17 Biomedical beamline) with a continuous X-ray spectrum in the 50-600 keV range and a dose rate of 11.6kGy/s. The spectrophotometric response after irradiation at this beamline was compared with the response at a conventional 60Co γ-ray source providing a dose rate of 0.27 Gy/s. Ag+ ions in the gel dosimeter undergo reduction to Ago nanoparticles, as detected at 450 nm, which is a surface plasmon resonance band. The intensity of this band increased linearly with increasing absorbed dose up to 100 Gy, and improved with the addition of glycerol. The gel dosimeter exhibited the lowest detectable dose (LDD) of 75.9% lower and a dose deposition of 76% higher for ID17 beamline irradiation than for 60Co irradiation. The theoretical relative response HQ,Qo for the gel irradiated at the synchrotron was 1.70, which is in close agreement with the experimental relative response FQ,Qo = 1.76. These results confirm the dose enhancement in the gel irradiated with orthovoltage X-rays. The good properties of the silver nitrate gel, together with its increased sensitivity to orthovoltage X-ray irradiation and modest overall uncertainty of 5.8% (2σ), confirm that the gel is a valid dosimeter for measurements at ultrahigh dose rates for synchrotron radiotherapy. The dosimeter is also a promising candidate for dose enhancement factor measurements in nanoparticle-based radiotherapy techniques.

Proton FLASH Irradiation Using a Synchrotron Accelerator: Differences by Irradiation Positions.

To establish an ultra-high dose rate (UHDR) radiation system using a synchrotron proton beam accelerator and to compare the effects by irradiation positions on cultured cells and chick embryos. Protons for UHDR were obtained by applying high-frequency power at much higher levels than usual to extract all protons within approximately 50 ms. Subsequently, monitoring with a Faraday cup was performed immediately after synchrotron extraction and the waveform was adjusted accordingly. Four cultured tumor lines, two normal cell lines, and chick embryos were used. Ultra-high dose-rate radiation (UHDR-RT) at 6-18 Gy (200-300 Gy/s, single exposure) and conventional dose-rate radiation (Conv-RT) at 6-18 Gy (3 Gy/s) were administered to the 1-cm spread-out Bragg peak (SOBP) and the plateau region preceding SOBP. Following irradiation, disparities in cell growth rates and cell cycle progression were assessed, and cell survival was evaluated via colony assay. Chick embryos were also examined for survival. UHDR-RT was achieved at a range of 40 to 800 Gy/s, encompassing both plateau and peak phases. In vitro studies demonstrated similar cell-killing effects between UHDR-RT and Conv-RT in cancer cells. Significant apoptotic effects and G2 arrest were observed during the cell cycle under peak UHDR-RT conditions. The FLASH effect was not observed in normal single cells under normal atmospheric conditions. Stronger cell-killing effects were noted in V79 spheroids exposed to peak UHDR-RT than peak Conv-RT. Moreover, in chick embryos, an increase in survival rate, indicative of the FLASH effect, was observed. The FLASH effect was also achieved with UHDR-RT using a synchrotron proton beam accelerator in chick embryos. The cell-killing effects in cancer cells were higher with peak UHDR-RT which may be due to the higher linear energy transfer at the SOBP.

Dosimetry for FLASH and other non-standard radiotherapy sources

We review current dosimetry practices for non-standard radiotherapy sources. We classify radiotherapy sources as established, variations of established, or novel. Our review concentrates on novel sources including ultra-high dose-rate (FLASH) sources and some that have yet to be used for clinical radiotherapy. Factors which differentiate non-standard sources include dose-rate, temporal pulse structure, spatial fractionation, focusing, the presence of magnetic fields, and energy range. For the most part we exclude techniques which use materials inside the tumor to modify the dose. Dosimetry techniques include ionization chambers, film, alanine, calorimetry, and solid-state detectors. We review dosimetry only, neglecting other issues such as beam monitoring, patient delivery systems and treatment planning.

Effects of high-dose glucose oxidase on broiler growth performance, antioxidant function, and intestinal microbiota in broilers.

Glucose oxidase (GOD) has been investigated as a potential additive for enhancing intestinal health and growth performance in poultry. However, limited research exists on the effects of ultra-high doses of GOD in practical poultry production. This study aimed to investigate the impact of high dietary GOD levels on broiler growth performance, antioxidant capacity, and intestinal microbiota. A total of 400 healthy, 1-day-old, slow-growing broiler chickens were randomly assigned to four treatment groups. The control group was fed a standard basal diet, while the other groups (G1, G2, and G3) were fed the basal diet supplemented with 4 U/g, 20 U/g, and 100 U/g of VTR GOD, respectively. The results showed that a dose of 100 U/g GOD significantly improved the final body weight and average daily feed intake (ADFI) (p < 0.05). Additionally, the G3 group exhibited a marked increase in glutathione peroxidase (GSH-Px) activity (p < 0.05), reflecting enhanced antioxidant function. Gut morphology remained intact across all groups, indicating no adverse effects on intestinal barrier integrity. Microbiota analysis revealed significant increases (p < 0.05) in Firmicutes and Verrucomicrobiota abundance at the phylum level in the GOD-supplemented groups. Moreover, GOD treatments significantly increased the abundance of Faecalibacterium, Mucispirllum, and CHKCI001 at the genus level. Metabolic function predictions suggested that high-dose GOD supplementation enriched carbohydrate metabolism, particularly starch and sucrose metabolism. Correlation analysis indicated that Faecalibacterium and CHCKI001 were two bacteria strongly influenced by GOD supplementation and were associated with enhanced growth performance and improved gut health. In conclusion, high-dose GOD supplementation had no adverse effects and demonstrated significant benefits, promoting both growth performance and gut health in broilers.

On the acceptance, commissioning, and quality assurance of electron FLASH units.

FLASH or ultra-high dose rate (UHDR) radiation therapy (RT) has gained attention in recent years for its ability to spare normal tissues relative to conventional dose rate (CDR) RT in various preclinical trials. However, clinical implementation of this promising treatment option has been limited because of the lack of availability of accelerators capable of delivering UHDR RT. Commercial options are finally reaching the market that produce electron beams with average dose rates of up to 1000Gy/s. We established a framework for the acceptance, commissioning, and periodic quality assurance (QA) of electron FLASH units and present an example of commissioning. A protocol for acceptance, commissioning, and QA of UHDR linear accelerators was established by combining and adapting standards and professional recommendations for standard linear accelerators based on the experience with UHDR at four clinical centers that use different UHDR devices. Non-standard dosimetric beam parameters considered included pulse width, pulse repetition frequency, dose per pulse, and instantaneous dose rate, together with recommendations on how to acquire these measurements. The 6- and 9-MeV beams of an UHDR electron device were commissioned by using this developed protocol. Measurements were acquired with a combination of ion chambers, beam current transformers (BCTs), and dose-rate-independent passive dosimeters. The unit was calibrated according to the concept of redundant dosimetry using a reference setup. This study provides detailed recommendations for the acceptance testing, commissioning, and routine QA of low-energy electron UHDR linear accelerators. The proposed framework is not limited to any specific unit, making it applicable to all existing eFLASH units in the market. Through practical insights and theoretical discourse, this document establishes a benchmark for the commissioning of UHDR devices for clinical use.

Major contributors to FLASH sparing efficacy emerge from murine skin studies: dose rate, total dose per fraction, anesthesia and oxygenation.

Normal tissue sparing from radiation damage upon ultra-high dose rate irradiation, known as the FLASH effect with an equivalent tumor response, has been widely reported in murine skin models, and translation of this type of radiotherapy to humans has already begun, with skin sparing being a primary outcome expected. This study reviews the status of the field, focusing on the proposed mechanisms and skin response assays, outlining what has become known in terms of input parameters that might control the magnitude of the FLASH effect. Murine studies have largely focused on acute damage responses, developing over 3-8 weeks, to single doses of FLASH versus conventional dose rate (CDR), suggesting that at dose rates above tens of Gray per second, with a total dose of more than 20 Gy, the FLASH effect is induced. Fractionated delivery appears to be possible, although fraction sizes >17 Gy appear to be needed for sparing efficacy. The interplay between the dose rate and total dose per fraction remains to be fully elucidated. Oxygen is a modulator of efficacy, with both hypoxia and hyperoxia diminishing the effect of FLASH. Measurement of transient changes in oxygen levels is possible and may be a marker of treatment efficacy. Taken together, murine skin data provide important information for translational studies, despite the associated limitations. Studies of later-term sparing effects, as well as studies on pig skin, are needed to take the next step in assessing translational FLASH efficacy. The control of biological factors, such as tissue oxygenation, may be required to understand and control the response.

Mesoporous Microneedles Enabled Localized Controllable Delivery of Stimulator of Interferon Gene Agonist Nanoexosomes for FLASH Radioimmunotherapy against Breast Cancer.

The immunosuppressive nature of the tumor microenvironment (TME) contributes to radioresistance, thereby impairing the effectiveness of radiotherapy as a therapeutic intervention. Activation through the stimulator of interferon genes (STING) pathway shows potential in modulating immunogenicity. However, the therapeutic efficacy of STING agonists might be restricted by off-target effects and potential cytotoxicity. In this work, nanoexosomes (EXOs) loaded within porous microneedles were employed for precise delivery of the STING agonist MSA-2 (MEM) to the tumor site. Leveraging the enhanced tumor penetration enabled by microneedles, EXOs can be continually released and accumulate within deep residual tumors. Once internalized, these EXOs release the encapsulated MSA-2, facilitating the activation of the STING pathway upon exposure to ultrahigh dose-rate (FLASH) irradiation. This strategy elevates the type I interferon level, promotes dendric cell maturation, and modulates the immunosuppressive TME, showing efficient antitumor efficacy in both primary/metastatic tumors. Furthermore, the induction of a potent immune response effectively prevented tumor recurrence. The combination of EXO-loaded microneedles with FLASH radiotherapy resulted in minimal systemic side effects, attributed to precise drug delivery and radioprotection conferred by FLASH. Altogether, the strategic design of EXO-loaded microneedles holds promise for enhancing MSA-2 delivery, thereby mitigating the radioresistant tumor microenvironment through STING cascade activation-mediated immunotherapy, consequently optimizing the outcomes of FLASH radiotherapy.

High-throughput, low-cost FLASH: irradiation of Drosophila melanogaster with low-energy X-rays using time structures spanning conventional and ultrahigh dose rates.

FLASH radiotherapy is an emerging technique in radiation oncology that may improve clinical outcomes by reducing normal tissue toxicities. The physical radiation characteristics needed to induce the radiobiological benefits of FLASH are still an active area of investigation. To determine the dose rate, range of doses and delivery time structure necessary to trigger the FLASH effect, Drosophila melanogaster were exposed to ultrahigh dose rate (UHDR) or conventional radiotherapy dose rate (CONV) 120-kVp X-rays. A conventional X-ray tube outfitted with a shutter system was used to deliver 17- to 44-Gy doses to third-instar D. melanogaster larvae at both UHDR (210Gy/s) and CONV (0.2-0.4Gy/s) dose rates. The larvae were then tracked through development to adulthood and scored for eclosion and lifespan. Larvae exposed to UHDR eclosed at higher rates and had longer median survival as adults compared to those treated with CONV at the same doses. Eclosion rates at 24Gy were 68% higher for the UHDR group (P<0.05). Median survival from 22Gy was >22days for UHDR and 17days for CONV (P<0.01). Two normal tissue-sparing effects were observed for D. melanogaster irradiated with UHDR 120-kVp X-rays. The effects appeared only at intermediate doses and may be useful in establishing the dose range over which the benefits of FLASH can be obtained. This work also demonstrates the usefulness of a high-throughput fruit fly model and a low-cost X-ray tube system for radiobiological FLASH research.

Implementation and validation of a very-high-energy electron model in the matRad treatment planning system.

While electron beams of up to 20 MeV are commonly used in radiotherapy, the use of very-high-energy electrons (VHEEs) in the range of 100-200 MeV is now becoming a realistic option thanks to the recent advancements in accelerator technology. Indeed, VHEE offers several clinically attractive features and can be delivered using various conformation methods (including scanning, collimation, and focussing) at ultra-high dose rates. To date, there is a lack of research tools for fast simulation of treatment plans using VHEE beams. This work aims to implement and validate a simple and fast dose calculation algorithm based on the Fermi-Eyges theory of multiple Coulomb scattering for VHEE radiation therapy, with energies up to 200 MeV. A treatment planning system (TPS) toolkit with VHEE modality would indeed allow for further preclinical investigations, including treatment plan optimization and evaluation, and thus contribute to the gradual introduction of VHEE radiotherapy in clinical practice. A VHEE pencil beam scanning double Gaussian model was introduced into the open-source TPS matRad environment along with new functions and options dedicated to VHEE dose calculations. Various geometries and field configurations were then calculated in matRad (up to 200 MeV and 15×15 cm2, with complex bone or lung heterogeneities) and the results were compared to Monte Carlo simulations in the TOPAS/Geant4 toolkit. Two types of beam model (divergent or focused) were also tested. Examples of clinical treatment plans were computed, and the results were compared between the two codes. VHEE modality was fully implemented in matRad with GUI capabilities while preserving all original TPS features. New relevant options such as the importation of specific spot-lists or adjustment of the lateral dose calculation cutoff to optimize the calculation speed were validated. Single spot and square field dose distributions were validated in water alone as well as in clinically relevant inhomogeneities. Dose maps from the VHEE model in matRad were in good agreement with TOPAS (2D gamma index [2%/1mm] with passing rates superior to 90%, <6% mean dose differences), except for large interface heterogeneities. This work describes the implementation of a simple but efficient VHEE simulation model in matRad. A few configurations were studied in order to validate the model against accurate Monte Carlo simulations, demonstrating its usefulness for carrying out preliminary studies involving VHEE radiotherapy.

Effect of Ultrahigh Dose Rate on Biomolecular Radiation Damage.

Dose rate is one of the important parameters in radiation-induced biomolecular damage. The effects of dose rate have been known to modify radiation toxicity in biological systems. The rate and extent of sublethal DNA damage (e.g., base damage and single-strand breaks) repair and those of cell proliferation have been manifested by dose rate. However, the recent preclinical application of ultrahigh dose rate [(UHDR) ca. 40 Gy/s and higher] radiation modalities have been shown to lower the type and extent of radiation damage to biological systems. At these UHDR, radiation-induced physicochemical and chemical processes are expected to differ from those observed after irradiation at conventional dose rates (CONV). It is unclear whether these UHDR conditions can affect the quality (type) and quantity (extent) of biomolecular damage such as DNA lesions. Here, we comparatively study the influence of indirect effects of CONV and UHDR on the formation of DNA strand breaks and clustered damage including densely accumulated lesions in an aerated and an anoxic dilute aqueous solution of a plasmid DNA model under low and high hydroxyl radical (•OH) scavenging conditions. Aqueous solutions of purified supercoiled plasmid DNA (pUC19) were prepared in either air- or nitrogen-saturated conditions, with Tris buffer added as the radiation-produced •OH scavenger at low and high scavenging capacities. These DNA samples were irradiated using kV X-ray systems at CONV (0.1 Gy/s) and high dose rate (HDR, 25 Gy/s) as well as UHDR (55 and 125 Gy/s) under different scavenging and environmental conditions. DNA lesions including strand breaks and clustered damage including densely accumulated lesions were quantified by gel electrophoresis and the yields of these lesions were calculated from the dose-response curve. Non-DSB clustered damage including densely accumulated lesions were evaluated by treating DNAs using bacterial endonuclease enzymes (Fpg and Nth) prior to gel electrophoresis. UHDR of 55 and 125 Gy/s induced lower amounts of both isolated strand breaks and clustered DNA damage including densely accumulated lesions at doses >40 Gy in the presence of oxygen, compared to the abundance of these lesions induced by 0.1 and 25 Gy/s irradiation under the same dose conditions. Overall, the strand break and clustered damage including densely accumulated lesions yields decreased by factors of 1.3-3.5 after UHDR. We did not observe these differences either via •OH scavenging or by removing oxygen from the solution. In addition, our results point out that the inter-track recombination reactions did not contribute to the observed dose-rate effects on DNA damage. The effects of dose rate on DNA damage are highly dependent on the total dose, as expected, but also on the •OH scavenging capacity that is employed in the aqueous DNA solutions. These important variables may be relevant in biological systems as well. On a practical level, our in vitro plasmid DNA model, which permits to precisely vary the scavenging capacity and gassing conditions (air saturated vs. N2 saturated) can help to differentiate dose-rate effects on biomolecular damage. Our results indicate that the radical-radical reactions are important in understanding the dose-rate effect on DNA damage.

Emergence of FLASH‑radiotherapy across the last 50 years (Review).

A novel radiotherapy (RT) approach termed FLASH-RT, which irradiates areas at ultra-high dose rates, is of current interest to medical researchers. FLASH-RT can maintain equivalent antitumor effects while sparing healthy tissue compared with conventional RT (CONV-RT), which uses low dose rates. The sparing effect on healthy tissue after FLASH-RT is known as the FLASH effect. Owing to the FLASH effect, FLASH-RT can raise the maximum tolerable dose to control tumor growth or eradicate the tumor and provide a new strategy for clinical RT. However, definitive irradiation conditions for reproducing the FLASH effect and the biological mechanism of the FLASH effect have not yet been fully elucidated. The efficacy of FLASH-RT is controversial despite its successful application in clinical RT. The present review recapitulates the progression of FLASH-RT and critically comments on the hypothesis of the FLASH effect. In addition, the review expounds on the current issues with regard to the differential phenomena between in vitro and in vivo studies, and elaborates on the challenges for the application of FLASH-RT that need to be addressed in the future.

Hybrid ultra-high and conventional dose rate treatments with electrons and photons for the clinical transfer of FLASH-RT to deep-seated targets: A treatment planning study

PurposeThis study explores the dosimetric feasibility and plan quality of hybrid ultra-high dose rate (UHDR) electron and conventional dose rate (CDR) photon (HUC) radiotherapy for treating deep-seated tumours with FLASH-RT. MethodsHUC treatment planning was conducted optimizing a broad UHDR electron beam (between 20–250 MeV) combined with a CDR VMAT for a glioblastoma, a pancreatic cancer, and a prostate cancer case. HUC plans were based on clinical prescription and fractionation schemes and compared against clinically delivered plans. Considering a HUC boost treatment for the glioblastoma consisting of a 15-Gy-single-fraction UHDR electron boost supplemented with VMAT, two scenarios for FLASH sparing were assessed using FLASH-modifying-factor-weighted doses. ResultsFor all three patient cases, HUC treatment plans demonstrated comparable dosimetric quality to clinical plans, with similar PTV coverage (V95% within 0.5 %), homogeneity, and critical OAR-sparing. At the same time, HUC plans delivered a substantial portion of the dose to the PTV (Dmedian of 50–69 %) and surrounding tissues at UHDR. For the HUC boost treatment of the glioblastoma, the first FLASH sparing scenario showed a moderate FLASH sparing magnitude (10 % for D2%,PTV) for the 15-Gy UHDR electron boost, while the second scenario indicated a more substantial sparing of brain tissues inside and outside the PTV (32 % for D2%,PTV, 31 % for D2%,Brain). ConclusionsFrom a planning perspective, HUC treatments represent a feasible approach for delivering dosimetrically conformal UHDR treatments, potentially mitigating technical challenges associated with delivering conformal FLASH-RT for deep-seated tumours. While further research is needed to optimize HUC fractionation and delivery schemes for specific patient cohorts, HUC treatments offer a promising avenue for the clinical transfer of FLASH-RT.

Dosimetric saturation effect study and correction calculation method of ionization chamber at ultra-high dose rate (FLASH)

Backgroundand Purpose: FLASH radiotherapy has aroused strong interest among researchers, but how to monitor dose in real time and lack of generally accepted ion correction model are one of the challenges. This study is based on previous research work, the dosimetric verification of FLASH ionization chamber was performed using a 200 keV electron beam irradiation platform at an ultra-high dose rate. At the same time, the finite element program is written to analyze and calculate the ion correction factor. In addition, the results are compared with the calculation results of Boag model. MethodsIn this study, the pressure of the sensitive volume in the detector was adjusted to 16 mbar for the purpose of dosimetry of dose rates in excess of 100 Gy/s. In order to monitor the response of the detector, the beam frequency and pulse width were adjusted accordingly. However, due to the saturation effect of the ionization chamber, the processes of electron ion pair drift, attachment, recombination and diffusion in the sensitive volume were modelled on the basis of the relevant physical principles. Finally, the correction factor was calculated by the finite element analysis. ResultsThe experimental results demonstrate that the FLASH ionization chamber is capable of meeting the requirements of dose measurement and beam monitoring of the electron beam at ultra-high dose rates. Furthermore, the analytical model is able to more accurately describe the saturation effect and calculate the correction factor. ConclusionIn this paper, the method of reducing air pressure is employed for the purpose of monitoring the dose of ultra-high dose rate. Simultaneously, the finite element method was employed to analyze the physical process of electron–ion pairs within the chamber and to calculate the ion correction factor analytically. A comparison with the Boag model indicates that the proposed approach is effective. However, the results exhibit a certain degree of divergence from experimental outcomes. This discrepancy may be attributed to the influence of the input parameters, which require further calibration to enhance the accuracy and the robustness of the model.

Oxygen Consumption In Vivo by Ultra-High Dose Rate Electron Irradiation Depends Upon Baseline Tissue Oxygenation

Purpose: This study aimed to assess the impact of tissue oxygen levels on transient oxygen consumption induced by ultra-high dose rate (UHDR) electron radiation in murine flank and to examine the effect of dose rate variations on this relationship. Methods: Real-time oximetry using the phosphorescence quenching method and Oxyphor PdG4 molecular probe was employed. Continuous measurements were taken during radiation delivery on a UHDR-capable Mobetron linear accelerator (linac). Oxyphor PdG4 was administered into the subcutaneous tissue of the flank skin one hour before irradiation. Skin oxygen tension (pO2) was manipulated by adjusting oxygen content in the inhaled gas mixture and/or by vasculature compression. A skin surface radiation dose of 19.8±0.3Gy was verified using a calibrated semiconductor diode dosimeter. Dose rate was varied across the UHDR range by changing linac cone length and pulse repetition frequency (PRF). Results: The decrease in pO2 per unit dose during radiation delivery, termed oxygen consumption g-value (gO2, mmHg/Gy), was significantly influenced by tissue oxygen levels in the range 0-65mmHg under UHDR conditions. Within the 0-20mmHg range, gO2 exhibited a sharp increase with rising baseline pO2, plateauing at 0.26mmHg/Gy. Dose rate variations (mean values 25-1170Gy/s, per-pulse doses of 2.5-9.8Gy) were explored by varying both cone length and PRF (10-120Hz) with no significant changes in gO2. Conventional dose rate irradiation resulted in no discernible changes in pO2. Conclusions: The results show significant differences in the radiation-chemical effects of UHDR radiation between hypoxic and well-oxygenated tissues. Similar trends between earlier published in vitro and in vivo experiments presented herein suggest the chemical mechanisms driving the dependencies of gO2 on pO2 are similar, potentially underpinning the FLASH effect. Importantly, significant variations in baseline pO2 were observed in animals kept under identical conditions, underscoring the necessity to control and monitor tissue oxygen levels for preclinical investigations and future clinical applications of FLASH-RT.

The Radiosurgery Society Working Groups on GRID, LATTICE, Microbeam, and FLASH Radiotherapies: 2022 to 2023 Advancements Symposium and Subsequent Progress Made

PurposeSince the inaugural workshop “Understanding High-Dose, Ultra-High Dose Rate and Spatially Fractionated Radiotherapy.” hosted by the NCI and sponsored by the Radiosurgery Society (RSS), growing collaborations and investigations have ensued among experts, practitioners, and researchers. The RSS GRID, Lattice, Microbeam & FLASH (GLMF) Working Groups were formed as a framework for these efforts and have focused on advancing the understanding of the biology, technical/physical parameters, trial design, and clinical practice of these new radiation therapy modalities. Methods and MaterialsIn view of the steadily increasing clinical interest in SFRT and FLASH, a full-day symposium entitled “Advancements in GRID, LATTICE, and FLASH Radiotherapy Symposium” was established in 2022 that immediately preceded the RSS scientific meeting. This well-attended symposium focused on clinical, technical, and physics approaches for SFRT, while closely examining relevant radiobiological underpinnings. Practical clinical trial development was a highlighted discussion. An additional section reviewed proton therapy and other particle-based techniques for the delivery of GRID and Lattice therapy. A treatment planning and delivery tutorial for GRID, Lattice, and proton GRID/Lattice was directed towards the real-world considerations for the development of new clinical GRID or LATTICE programs. An overall similar approach was applied to the discussion of FLASH. This report summarizes the content of the first GLMF Symposium and related work of the RSS GLMF Working Groups in the field of heterogeneous and ultra-high dose rate irradiation, over approximately 2 years. ResultsThe GLMF Working Groups have continued to expand in membership and attendance, and several resultant trial concepts, research efforts, academic discussions, and peer-reviewed publications have followed as the number of institutions and practitioners utilizing SFRT and FLASH continues to grow. ConclusionsThe GLFM Working Groups and the RSS continue to demonstrate excellent progress in proliferating use of and improving understanding of SFRT and ultra-high dose rate radiotherapy techniques.

Simulation and commissioning of a Faraday cup for absolute charge measurements of very high-energy electrons in-air at PEER

The Pulsed Energetic Electrons for Research (PEER) beamline at the ANSTO Australian Synchrotron comprises a 100 MeV linac injector that is currently being developed for ultra-high dose-rate, very high-energy electron radiotherapy research. Previously, dosimetry studies discovered a lack of reliable charge measurement to the in-air end station, though no change in response was recorded in fast current transformer measurements, the only available diagnostic device for measuring charge. This work describes the process of simulating and then commissioning a purpose-built Faraday cup to ascertain absolute in-air charge measurements at PEER. By combining simulation data with experimental results, the PEER Faraday cup is shown to possess a primary electron capture efficiency of (99.22 ± 0.10)%, with a net capture efficiency due to secondary electron emission of (97.87 ± 0.24)%. These results show the PEER Faraday cup performs as intended and, when scaled against simulations, will be suitable for measuring absolute charge at PEER.