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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. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: Ultra‐high dose rate irradiation (≥40 Gy/s, FLASH) has been shown to reduce normal tissue toxicity, while maintaining tumor control compared to conventional dose‐rate radiotherapy. The radiolytic oxygen (O2) depletion (ROD) resulting from FLASH has been proposed to explain the normal tissue protection effect; however, in vivo experiments have not confirmed that FLASH induced global tissue hypoxia. Nonetheless, the experiments reported are based on volume‐averaged measurement, which have inherent limitations in detecting microscopic phenomena, including the potential preservation of stem cells niches due to local FLASH‐induced O2 depletion. Computational modeling offers a complementary approach to understand the ROD caused by FLASH at the microscopic level. Purpose: We developed a comprehensive model to describe the spatial and temporal dynamics of O2 consumption and transport in response to irradiation in vivo. The change of oxygen enhancement ratio (OER) was used to quantify and investigate the FLASH effect as a function of physiological and radiation parameters at microscopic scale. Methods: We considered time‐dependent O2 supply and consumption in a 3D cylindrical geometry, incorporating blood flow linking the O2 concentration ([O2]) in the capillary to that within the tissue through the Hill equation, radial and axial diffusion of O2, metabolic and zero‐order radiolytic O2 consumption, and a pulsed radiation structure. Time‐evolved distributions of [O2] were obtained by numerically solving perfusion‐diffusion equations. The model enables the computation of dynamic O2 distribution and the relative change of OER (δROD) under various physiological and radiation conditions in vivo. Results: Initial [O2] level and the subsequent changes during irradiation determined δROD distribution, which strongly depends on physiological parameters, i.e., intercapillary spacing, ultimately determining the tissue area with enhanced radioresistance. We observed that the δROD/FLASH effect is affected by and sensitive to the interplay effect among physiological and radiation parameters. It renders that the FLASH effect can be tissue environment dependent. The saturation of FLASH normal tissue protection upon dose and dose rate was shown. Beyond ∼60 Gy/s, no significant decrease in radiosensitivity within tissue region was observed. In turn, for a given dose rate, the change of radiosensitivity became saturated after a certain dose level. Pulse structures with the same dose and instantaneous dose rate but with different delivery times were shown to have distinguishable δROD thus tissue sparing, suggesting the average dose rate could be a metric assessing the FLASH effect and demonstrating the capability of our model to support experimental findings. Conclusion: On a macroscopic scale, the modeling results align with the experimental findings in terms of dose and dose rate thresholds, and it also indicates that pulse structure can vary the FLASH effect. At the microscopic level, this model enables us to examine the spatially resolved FLASH effect based on physiological and irradiation parameters. Our model thus provides a complementary approach to experimental methods for understanding the underlying mechanism of FLASH radiotherapy. Our results show that physiological conditions can potentially determine the FLASH efficacy in tissue protection. The FLASH effect may be observed under optimal combination of physiological parameters, not limited to radiation conditions alone. [ABSTRACT FROM AUTHOR]

This study conducts a comparative analysis of cystamine (RSSR), a disulfide, and cysteamine (RSH), its thiol monomer, to evaluate their efficacy as radioprotectors and antioxidants under high linear energy transfer (LET) and high-dose-rate irradiation conditions. It examines their interactions with reactive primary species produced during the radiolysis of the aqueous ferrous sulfate (Fricke) dosimeter, offering insights into the mechanisms of radioprotection and highlighting their potential to enhance the therapeutic index of radiation therapy, particularly in advanced techniques like FLASH radiotherapy. Using Monte Carlo multi-track chemical modeling to simulate the radiolytic oxidation of ferrous to ferric ions in Fricke-cystamine and Fricke-cysteamine solutions, this study assesses the radioprotective and antioxidant properties of these compounds across a variety of irradiation conditions. Concentrations were varied in both aerated (oxygen-rich) and deaerated (hypoxic) environments, simulating conditions akin to healthy tissue and tumors. Both cystamine and cysteamine demonstrate radioprotective and strong antioxidant properties. However, their effectiveness varies significantly depending on the concentration employed, the conditions of irradiation, and whether or not environmental oxygen is present. Specifically, excluding potential in vivo toxicity, cysteamine substantially reduces the adverse effects of ionizing radiation under aerated, low-LET conditions at concentrations above ~1 mM. However, its efficacy is minimal in hypoxic environments, irrespective of the concentration used. Conversely, cystamine consistently offers robust protective effects in both oxygen-rich and oxygen-poor conditions. The distinct protective capacities of cysteamine and cystamine underscore cysteamine's enhanced potential in radiotherapeutic settings aimed at safeguarding healthy tissues from radiation-induced damage while effectively targeting tumor tissues. This differential effectiveness emphasizes the need for personalized radioprotective strategies, tailored to the specific environmental conditions of the tissue involved. Implementing such approaches is crucial for optimizing therapeutic outcomes and minimizing collateral damage in cancer treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Ultrahigh-dose-rate therapy, known as FLASH radiotherapy (RT), is an emerging cancer treatment technique that offers similar tumor control to conventional RT but with the enhanced protection of normal tissue through the FLASH-sparing effect. Preclinical studies on animals and cell lines show promising results. This is significant for patients with recurrent tumors and reirradiation cases, where conventional RT has high toxicity rates. FLASH-RT can potentially improve tumor control while reducing side effects and preserving quality of life. Among the FLASH modalities, proton therapy stands out for its superior dosimetric and delivery characteristics, making it a safe and effective option for human malignancies. Despite its potential, proton Bragg peak FLASH for HN cancer remains underexplored, and this review highlights the novel proton conformal FLASH techniques, which allow for high-quality plans while minimizing radiation exposure to critical organs at risk (OARs) for HN cancer reirradiation. Ultrahigh-dose-rate therapy, also known as FLASH radiotherapy (RT), is an emerging technique that is garnering significant interest in cancer treatment due to its potential to revolutionize therapy. This method can achieve comparable tumor control to conventional-dose-rate RT while offering the enhanced protection of normal tissue through the FLASH-sparing effect. This innovative technique has demonstrated promising results in preclinical studies involving animals and cell lines. Particularly noteworthy is its potential application in treating head and neck (HN) cancers, especially in patients with challenging recurrent tumors and reirradiation cases, where the toxicity rates with conventional radiotherapy are high. Such applications aim to enhance tumor control while minimizing side effects and preserving patients' quality of life. In comparison to electron or photon FLASH modalities, proton therapy has demonstrated superior dosimetric and delivery characteristics and is a safe and effective FLASH treatment for human malignancies. Compared to the transmission proton FLASH, single-energy Bragg peak FLASH is a novel delivery method that allows highly conformal doses to targets and minimal radiation doses to crucial OARs. Proton Bragg peak FLASH for HN cancer has still not been well studied. This review highlights the significance of proton FLASH in enhancing cancer therapy by examining the advantages and challenges of using it for HN cancer reirradiation. [ABSTRACT FROM AUTHOR]

The Circular Electron–Positron Collider (CEPC) in China can also work as an excellent powerful synchrotron light source, which can generate high-quality synchrotron radiation. This synchrotron radiation has potential advantages in the medical field as it has a broad spectrum, with energies ranging from visible light to X-rays used in conventional radiotherapy, up to several megaelectronvolts. FLASH radiotherapy is one of the most advanced radiotherapy modalities. It is a radiotherapy method that uses ultra-high dose rate irradiation to achieve the treatment dose in an instant; the ultra-high dose rate used is generally greater than 40 Gy s−1, and this type of radiotherapy can protect normal tissues well. In this paper, the treatment effect of CEPC synchrotron radiation for FLASH radiotherapy was evaluated by simulation. First, a Geant4 simulation was used to build a synchrotron radiation radiotherapy beamline station, and then the dose rate that the CEPC can produce was calculated. A physicochemical model of radiotherapy response kinetics was then established, and a large number of radiotherapy experimental data were comprehensively used to fit and determine the functional relationship between the treatment effect, dose rate and dose. Finally, the macroscopic treatment effect of FLASH radiotherapy was predicted using CEPC synchrotron radiation through the dose rate and the above-mentioned functional relationship. The results show that the synchrotron radiation beam from the CEPC is one of the best beams for FLASH radiotherapy.

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

Background: The extremely fast delivery of doses with ultra high dose rate (UHDR) beams necessitates the investigation of novel approaches for real‐time dosimetry and beam monitoring. This aspect is fundamental in the perspective of the clinical application of FLASH radiotherapy (FLASH‐RT), as conventional dosimeters tend to saturate at such extreme dose rates. Purpose: This study aims to experimentally characterize newly developed silicon carbide (SiC) detectors of various active volumes at UHDRs and systematically assesses their response to establish their suitability for dosimetry in FLASH‐RT. Methods: SiC PiN junction detectors, recently realized and provided by STLab company, with different active areas (ranging from 4.5 to 10 mm2) and thicknesses (10–20 µm), were irradiated using 9 MeV UHDR pulsed electron beams accelerated by the ElectronFLASH linac at the Centro Pisano for FLASH Radiotherapy (CPFR). The linearity of the SiC response as a function of the delivered dose per pulse (DPP), which in turn corresponds to a specific instantaneous dose rate, was studied under various experimental conditions by measuring the produced charge within the SiC active layer with an electrometer. Due to the extremely high peak currents, an external customized electronic RC circuit was built and used in conjunction with the electrometer to avoid saturation. Results: The study revealed a linear response for the different SiC detectors employed up to 21 Gy/pulse for SiC detectors with 4.5 mm2/10 µm active area and thickness. These values correspond to a maximum instantaneous dose rate of 5.5 MGy/s and are indicative of the maximum achievable monitored DPP and instantaneous dose rate of the linac used during the measurements. Conclusions: The results clearly demonstrate that the developed devices exhibit a dose‐rate independent response even under extreme instantaneous dose rates and dose per pulse values. A systematic study of the SiC response was also performed as a function of the applied voltage bias, demonstrating the reliability of these dosimeters with UHDR also without any applied voltage. This demonstrates the great potential of SiC detectors for accurate dosimetry in the context of FLASH‐RT. [ABSTRACT FROM AUTHOR]

The Circular Electron–Positron Collider (CEPC) in China can also work as an excellent powerful synchrotron light source, which can generate high‐quality synchrotron radiation. This synchrotron radiation has potential advantages in the medical field as it has a broad spectrum, with energies ranging from visible light to X‐rays used in conventional radiotherapy, up to several megaelectronvolts. FLASH radiotherapy is one of the most advanced radiotherapy modalities. It is a radiotherapy method that uses ultra‐high dose rate irradiation to achieve the treatment dose in an instant; the ultra‐high dose rate used is generally greater than 40 Gy s−1, and this type of radiotherapy can protect normal tissues well. In this paper, the treatment effect of CEPC synchrotron radiation for FLASH radiotherapy was evaluated by simulation. First, a Geant4 simulation was used to build a synchrotron radiation radiotherapy beamline station, and then the dose rate that the CEPC can produce was calculated. A physicochemical model of radiotherapy response kinetics was then established, and a large number of radiotherapy experimental data were comprehensively used to fit and determine the functional relationship between the treatment effect, dose rate and dose. Finally, the macroscopic treatment effect of FLASH radiotherapy was predicted using CEPC synchrotron radiation through the dose rate and the above‐mentioned functional relationship. The results show that the synchrotron radiation beam from the CEPC is one of the best beams for FLASH radiotherapy. [ABSTRACT FROM AUTHOR]

Irradiations at Ultra-High Dose Rate (UHDR) regimes, exceeding 40 Gy/s in single fractions lasting less than 200 ms, have shown an equivalent antitumor effect compared to conventional radiotherapy with reduced harm to normal tissues. This work details the hardware and software modifications implemented to deliver 10 MeV UHDR electron beams with a linear accelerator Elekta SL 18 MV and the beam characteristics obtained. GafChromic EBT XD films and an Advanced Markus chamber were used for dosimetry characterization, while a silicon sensor assessed the machine's beam pulses stability and repeatability. The dose per pulse, average dose rate and instantaneous dose rate in the pulse were evaluated for four experimental settings, varying the source-to-surface distance and the beam collimation, i.e., with and without the use of a cylindrical applicator. The results showed a dose per pulse from 0.6 Gy to a few tens of Gy and an average dose rate up to 300 Gy/s. The obtained results demonstrate the possibility to perform in vitro radiobiology experiments and test new technologies for beam monitoring and dosimetry at the upgraded LINAC, thus contributing to the electron UHDR research field. [ABSTRACT FROM AUTHOR]

Radiotherapy is an important treatment for many unresectable advanced malignant tumors, and radiotherapy-associated inflammatory reactions to radiation and other toxic side effects are significant reasons which reduce the quality of life and survival of patients. FLASH-radiotherapy (FLASH-RT), a prominent topic in recent radiation therapy research, is an ultra-high dose rate treatment known for significantly reducing therapy time while effectively targeting tumors. This approach minimizes radiation side effects on at-risk organs and maximally protects surrounding healthy tissues. Despite decades of preclinical exploration and some notable achievements, the mechanisms behind FLASH effects remain debated. Standardization is still required for the type of FLASH-RT rays and dose patterns. This review addresses the current state of FLASH-RT research, summarizing the biological mechanisms behind the FLASH effect. Additionally, it examines the impact of FLASH-RT on immune cells, cytokines, and the tumor immune microenvironment. Lastly, this review will discuss beam characteristics, potential clinical applications, and the relevance and applicability of FLASH-RT in treating advanced cancers. [ABSTRACT FROM AUTHOR]

Background: Dosimetry in pre‐clinical FLASH studies is essential for understanding the beam delivery conditions that trigger the FLASH effect. Resolving the spatial and temporal characteristics of proton pencil beam scanning (PBS) irradiations with ultra‐high dose rates (UHDR) requires a detector with high spatial and temporal resolution. Purpose: To implement a novel camera‐based system for time‐resolved two‐dimensional (2D) monitoring and apply it in vivo during pre‐clinical proton PBS mouse irradiations. Methods: Time‐resolved 2D beam monitoring was performed with a scintillation imaging system consisting of a 1 mm thick transparent scintillating sheet, imaged by a CMOS camera. The sheet was placed in a water bath perpendicular to a horizontal PBS proton beam axis. The scintillation light was reflected through a system of mirrors and captured by the camera with 500 frames per second (fps) for UHDR and 4 fps for conventional dose rates. The raw images were background subtracted, geometrically transformed, flat field corrected, and spatially filtered. The system was used for 2D spot and field profile measurements and compared to radiochromic films. Furthermore, spot positions were measured for UHDR irradiations. The measured spot positions were compared to the planned positions and the relative instantaneous dose rate to equivalent fiber‐coupled point scintillator measurements. For in vivo application, the scintillating sheet was placed 1 cm upstream the right hind leg of non‐anaesthetized mice submerged in the water bath. The mouse leg and sheet were both placed in a 5 cm wide spread‐out Bragg peak formed from the mono‐energetic proton beam by a 2D range modulator. The mouse leg position within the field was identified for both conventional and FLASH irradiations. For the conventional irradiations, the mouse foot position was tracked throughout the beam delivery, which took place through repainting. For FLASH irradiations, the delivered spot positions and relative instantaneous dose rate were measured. Results: The pixel size was 0.1 mm for all measurements. The spot and field profiles measured with the scintillating sheet agreed with radiochromic films within 0.4 mm. The standard deviation between measured and planned spot positions was 0.26 mm and 0.35 mm in the horizontal and vertical direction, respectively. The measured relative instantaneous dose rate showed a linear relation with the fiber‐coupled scintillator measurements. For in vivo use, the leg position within the field varied between mice, and leg movement up to 3 mm was detected during the prolonged conventional irradiations. Conclusions: The scintillation imaging system allowed for monitoring of UHDR proton PBS delivery in vivo with 0.1 mm pixel size and 2 ms temporal resolution. The feasibility of instantaneous dose rate measurements was demonstrated, and the system was used for validation of the mouse leg position within the field. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

BackgroundNormal 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.MethodsThis 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.ResultsMurine 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.ConclusionTaken 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.

Abstract Ultra-high dose rate (UHDR) irradiation has been shown to have a sparing effect on healthy tissue, an effect known as ‘FLASH’. This effect has been studied across several radiation modalities, including photons, protons and clinical energy electrons, however, very little data is available for the effect of FLASH with Very High Energy Electrons (VHEE). pBR322 plasmid DNA was used as a biological model to measure DNA damage in response to Very High Energy Electron (VHEE) irradiation at conventional (0.08 Gy/s), intermediate (96 Gy/s) and ultra-high dose rates (UHDR, (2 × 109 Gy/s) at the CERN Linear Electron Accelerator (CLEAR) user facility. UHDRs were used to determine if the biological FLASH effect could be measured in the plasmid model, within a hydroxyl scavenging environment. Two different concentrations of the hydroxyl radical scavenger Tris were used in the plasmid environment to alter the proportions of indirect damage, and to replicate a cellular scavenging capacity. Indirect damage refers to the interaction of ionising radiation with molecules and species to generate reactive species which can then attack DNA. UHDR irradiated plasmid was shown to have significantly reduced amounts of damage in comparison to conventionally irradiated, where single strand breaks (SSBs) was used as the biological endpoint. This was the case for both hydroxyl scavenging capacities. A reduced electron energy within the VHEE range was also determined to increase the DNA damage to pBR322 plasmid. Results indicate that the pBR322 plasmid model can be successfully used to explore and test the effect of UHDR regimes on DNA damage. This is the first study to report FLASH sparing with VHEE, with induced damage to pBR322 plasmid DNA as the biological endpoint. UHDR irradiated plasmid had reduced amounts of DNA single-strand breaks (SSBs) in comparison with conventional dose rates. The magnitude of the FLASH sparing was a 27% reduction in SSB frequency in a 10 mM Tris environment and a 16% reduction in a 100 mM Tris environment.

Optical fibres are gaining popularity for relative dosimetry in proton therapy due to their spatial resolution and ability for near real-time acquisition. For FLASH proton therapy, these fibres need to handle higher dose rates and larger doses than for conventional proton dose rates. We developed a multi-point fibre sensor embedded in a 3D-printed phantom which can measure the profile of a FLASH proton beam. Seven PMMA fibres of 1 mm diameter were embedded in a custom 3D-printed plastic phantom of the same density as the fibres. The phantom was placed in a proton beam with FLASH dose rates at the TRIUMF Proton Therapy Research Centre (PTRC). The sensor was exposed to different proton energies, 13.5 MeV, 19 MeV and 40.4 MeV, achieved by adding PMMA bolus in front of the phantom and three different beam currents, varying the dose rates from 7.5 to 101 Gy/s. The array was able to record beam profiles in both transverse and axial directions in relative agreement with measurements from EBT-XD radiochromic films (transverse) and Monte Carlo simulations (axial). A decrease in light output over time was observed, which might be caused by radiation damage in the matrix of the fibre and characterised by an exponential decay function. [ABSTRACT FROM AUTHOR]

Introduction: FLASH proton therapy (FLASH-PT) requires ultra-high dose rate (= 40 Gy/s) protons to be delivered in a short timescale whilst conforming to a patient-specific target. This study investigates the feasibility and constraints of Bragg peak FLASH-PT treatment planning, and compares the in silico results produced to plans for intensity modulated proton therapy (IMPT). Materials and method: Bragg peak FLASH-PT and IMPT treatment plans were generated for bone (n=3), brain (n=3), and lung (n=4) targets using the MIROpt research treatment planning system and the Conformal FLASH library developed by Applications SA from the open-source version of UCLouvain. FLASH-PT beams were simulated using monoenergetic spot-scanned protons traversing through a conformal energy modulator, a range shifter, and an aperture. A dose rate constraint of = 40 Gy/s was included in each FLASH-PT plan optimisation. Results: Space limitations in the FLASH-PT adapted beam nozzle imposed a maximum target width constraint, excluding 4 cases from the study. FLASH-PT plans did not satisfy the imposed target dose constraints (D95% = 95% and D2%= 105%) but achieved clinically acceptable doses to organs at risk (OARs). IMPT plans adhered to all target and OAR dose constraints. FLASH-PT plans showed a reduction in both target homogeneity (p < 0.001) and dose conformity (nonsignificant) compared to IMPT. Conclusion: Without accounting for a sparing effect, IMPT plans were superior in target coverage, dose conformity, target homogeneity, and OAR sparing compared to FLASH-PT. Further research is warranted in treatment planning optimisation and beam delivery for clinical implementation of Bragg peak FLASH-PT. [ABSTRACT FROM AUTHOR]

Abstract Background FLASH 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. Methods This 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. Discussion This 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. Registration ClinicalTrials.gov NCT05524064.

The article discusses the potential benefits of ultra-high dose rate irradiation, known as FLASH radiotherapy, in cancer treatment. FLASH-RT has been shown to reduce radiation-induced toxicity on normal tissues while maintaining similar antitumor effects as conventional radiotherapy. However, there are technological challenges in designing stable radiation sources and developing accurate dosimetric protocols for FLASH-RT. Additionally, the biological mechanisms underlying the FLASH effect are not yet fully understood. The article presents a multidisciplinary approach involving technological advancements, dosimetry, radiobiological experiments, and in silico simulations to further investigate and optimize FLASH-RT for clinical implementation. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

FLASH radiotherapy (FLASH-RT) has great potential to improve patient outcomes. It delivers radiation doses at an ultra-high dose rate (UHDR: ≥ 40 Gy/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 (0.01−0.40 Gy/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. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer is one of the most diagnosed cancers in men. While it can be successfully treated with radiotherapy (RT), patients often leave treatment with previously healthy organs affected by radiation. This work assessed a novel ultra-high dose rate FLASH proton therapy technique for the treatment of prostate cancers. We were able to generate clinically viable Bragg peak FLASH treatment plans for prostate cancer patients previously treated with conventional proton RT. Feasible prostate treatment quality was observed with all constraints for organs at risk (OARs) being met while maintaining an ultra-high dose rate. 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. [ABSTRACT FROM AUTHOR]

Purpose: Most current research toward ultra‐high dose rate (FLASH) radiation is conducted with advanced proton and electron accelerators, which are of limited accessibility to basic laboratory research. An economical alternative to charged particle accelerators is to employ high‐capacity rotating anode x‐ray tubes to produce kilovoltage x‐rays at FLASH dose rates at short source‐to‐surface distances (SSD). This work describes a comprehensive dosimetric evaluation of a rotating anode x‐ray tube for potential application in laboratory FLASH study. Methods and materials: A commercially available high‐capacity fluoroscopy x‐ray tube with 75 kW input power was implemented as a potential FLASH irradiator. Radiochromic EBT3 film and thermoluminescent dosimeters (TLDs) were used to investigate the effects of SSD and field size on dose rates and depth‐dose characteristics in kV‐compatible solid water phantoms. Custom 3D printed accessories were developed to enable reproducible phantom setup at very short SSD. Open and collimated radiation fields were assessed. Results: Despite the lower x‐ray energy and short SSD used, FLASH dose rates above 40 Gy/s were achieved for targets up to 10‐mm depth in solid water. Maximum surface dose rates of 96 Gy/s were measured in the open field at 47 mm SSD. A non‐uniform high‐to‐low dose gradient was observed in the planar dose distribution, characteristic of anode heel effects. With added collimation, beams up to 10‐mm diameter with reasonable uniformity can be produced. Typical 80%–20% penumbra in the collimated x‐ray FLASH beams were less than 1 mm at 5‐mm depth in phantom. Ramp‐up times at the maximum input current were less than 1 ms. Conclusion: Our dosimetric characterization demonstrates that rotating anode x‐ray tube technology is capable of producing radiation beams in support of preclinical FLASH radiobiology research. [ABSTRACT FROM AUTHOR]

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

No tumor group can be irresponsive to chemotherapy, especially radiotherapy, when applied in sufficient doses. However, in most cases, it is not possible to give effective doses that can destroy the tumor due to side effects and damage that may occur in healthy, normal tissues. Although current technological possibilities transmit the rays to the target area and protect the surrounding healthy tissues and organs much more effectively than before, there is a need for more studies and scientific content on this subject. FLASH-RT has theoretical advantages over conventional radiotherapy. Giving radiation in small, daily doses helps protect healthy cells by giving more time to repair. However, new research shows that there may be a way to deliver radiation at record speeds while sparing healthy tissue. FLASH (ultra-high dose rate radiotherapy), an innovative technique, uses electrons to target tumors while minimizing damage to healthy tissue. More importantly, FLASH is claimed to achieve these effects in less than a second, which can exponentially shorten the duration of radiation sessions. Recent studies indicated how using proton radiation instead of electrons or photons and other technical tweaks could turn FLASH into a powerful tool that can deliver radiation in milliseconds. Significant technological advances are needed to generate FLASH photons, potentially protons, very high energy electrons, and heavy ions. Such radiation sources will allow the required dose distribution to be obtained at more immense depths inside the human body, where most tumors occur. [ABSTRACT FROM AUTHOR]

IntroductionFLASH proton therapy (FLASH-PT) requires ultra-high dose rate (≥ 40 Gy/s) protons to be delivered in a short timescale whilst conforming to a patient-specific target. This study investigates the feasibility and constraints of Bragg peak FLASH-PT treatment planning, and compares the in silico results produced to plans for intensity modulated proton therapy (IMPT).Materials and methodBragg peak FLASH-PT and IMPT treatment plans were generated for bone (n=3), brain (n=3), and lung (n=4) targets using the MIROpt research treatment planning system and the Conformal FLASH library developed by Applications SA from the open-source version of UCLouvain. FLASH-PT beams were simulated using monoenergetic spot-scanned protons traversing through a conformal energy modulator, a range shifter, and an aperture. A dose rate constraint of ≥ 40 Gy/s was included in each FLASH-PT plan optimisation.ResultsSpace limitations in the FLASH-PT adapted beam nozzle imposed a maximum target width constraint, excluding 4 cases from the study. FLASH-PT plans did not satisfy the imposed target dose constraints (D95% ≥ 95% and D2%≤ 105%) but achieved clinically acceptable doses to organs at risk (OARs). IMPT plans adhered to all target and OAR dose constraints. FLASH-PT plans showed a reduction in both target homogeneity (p < 0.001) and dose conformity (non-significant) compared to IMPT.ConclusionWithout accounting for a sparing effect, IMPT plans were superior in target coverage, dose conformity, target homogeneity, and OAR sparing compared to FLASH-PT. Further research is warranted in treatment planning optimisation and beam delivery for clinical implementation of Bragg peak FLASH-PT.

Irradiations at Ultra-High Dose Rate (UHDR) regimes, exceeding 40 Gy/s in single fractions lasting less than 200 ms, have shown an equivalent antitumor effect compared to conventional radiotherapy with reduced harm to normal tissues. This work details the hardware and software modifications implemented to deliver 10 MeV UHDR electron beams with a linear accelerator Elekta SL 18 MV and the beam characteristics obtained. GafChromic EBT XD films and an Advanced Markus chamber were used for dosimetry characterization, while a silicon sensor assessed the machine’s beam pulses stability and repeatability. The dose per pulse, average dose rate and instantaneous dose rate in the pulse were evaluated for four experimental settings, varying the source-to-surface distance and the beam collimation, i.e., with and without the use of a cylindrical applicator. The results showed a dose per pulse from 0.6 Gy to a few tens of Gy and an average dose rate up to 300 Gy/s. The obtained results demonstrate the possibility to perform in vitro radiobiology experiments and test new technologies for beam monitoring and dosimetry at the upgraded LINAC, thus contributing to the electron UHDR research field.

Recently, as the clinically positive biological effects of ultra-high dose rate (UHDR) radiation beams have been revealed, interest in flash radiation therapy has increased. Generally, FLASH preclinical experiments are performed using UHDR electron beams generated by linear accelerators. Real-time monitoring of UHDR beams is required to deliver the correct dose to a sample. However, it is difficult to use typical transmission-type ionization chambers for primary beam monitoring because there is no suitable electrometer capable of reading high pulsed currents, and collection efficiency is drastically reduced in pulsed radiation beams with ultra-high doses. In this study, a monitoring method using bremsstrahlung photons generated by irradiation devices and a water phantom was proposed. Charges collected in an ionization chamber located at the back of a water phantom were analyzed using the bremsstrahlung tail on electron depth dose curves obtained using radiochromic films. The dose conversion factor for converting a monitored charge into a delivered dose was determined analytically for the Advanced Markus® chamber and compared with experimentally determined values. It is anticipated that the method proposed in this study can be useful for monitoring sample doses in UHDR electron beam irradiation.

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

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.

Radiotherapy (RT) is performed in approximately 75% of patients with cancer, and its efficacy is often hampered by the low tolerance of the surrounding normal tissues. Recent advancements have demonstrated the potential to widen the therapeutic window using “very short” radiation treatment delivery (from a conventional dose rate between 0.5 Gy/min and 2 Gy/min to more than 40 Gy/s) causing a significant increase of normal tissue tolerance without varying the tumor effect. This phenomenon is called “FLASH Effect (FE)” and has been discovered by using electrons. Although several physical, dosimetric, and radiobiological aspects need to be clarified, current preclinical “in vivo” studies have reported a significant protective effect of FLASH RT on neurocognitive function, skin toxicity, lung fibrosis, and bowel injury. Therefore, the current radiobiological premises lay the foundation for groundbreaking potentials in clinical translation, which could be addressed to an initial application of Low Energy Electron FLASH (LEE) for the treatment of superficial tumors to a subsequent Very High Energy Electron FLASH (VHEE) for the treatment of deep tumors. Herein, we report a clinical investigational scenario that, if supported by preclinical studies, could be drawn in the near future. [ABSTRACT FROM AUTHOR]

To rapidly assess healthy tissue toxicities induced by new anti-cancer therapies (i.e., radiation alone or in combination with drugs), there is a critical need for relevant and easy-to-use models. Consistent with the ethical desire to reduce the use of animals in medical research, we propose to monitor lung toxicity using an ex vivo model. Briefly, freshly prepared organotypic lung slices from mice were irradiated, with or without being previously exposed to chemotherapy, and treatment toxicity was evaluated by analysis of cell division and viability of the slices. When exposed to different doses of radiation, this ex vivo model showed a dose-dependent decrease in cell division and viability. Interestingly, monitoring cell division was sensitive enough to detect a sparing effect induced by FLASH radiotherapy as well as the effect of combined treatment. Altogether, the organotypic lung slices can be used as a screening platform to rapidly determine in a quantitative manner the level of lung toxicity induced by different treatments alone or in combination with chemotherapy while drastically reducing the number of animals. Translated to human lung samples, this ex vivo assay could serve as an innovative method to investigate patients' sensitivity to radiation and drugs. [ABSTRACT FROM AUTHOR]

Flash radiotherapy (Flash-RT) is an innovative technique used in radiotherapy for cancer treatment because it delivers an extremely high dose of radiation (>40 Gy/s) to the tumour in a very short period of time, typically within a fraction of a second. This ultra-fast delivery of radiation distinguishes Flash-RT from conventional radiotherapy, which typically involves the delivery of radiation over a longer time period, often several minutes. Studies conducted in cell and preclinical models suggested that Flash-RT may spare normal tissues from radiation-related side effects, such as skin toxicity, gastrointestinal complications, and damage to organs-at-risk. This is believed to be due to the unique normal tissue response to the ultra-high dose rate. Nevertheless, while Flash-RT shows promising results in preclinical and early clinical studies, one should note that the technique is still in the early stages of development. This entry provides a comprehensive exploration of the immense potentials of Flash-RT, covering its background, mechanisms, radiation sources, recent experimental findings based on cell and preclinical models, and future prospects. It aims to provide valuable insights into this innovative radiotherapy technology for anyone interested in the subject.

Radiotherapy is an important treatment for many unresectable advanced malignant tumors, and radiotherapy-associated inflammatory reactions to radiation and other toxic side effects are significant reasons which reduce the quality of life and survival of patients. FLASH-radiotherapy (FLASH-RT), a prominent topic in recent radiation therapy research, is an ultra-high dose rate treatment known for significantly reducing therapy time while effectively targeting tumors. This approach minimizes radiation side effects on at-risk organs and maximally protects surrounding healthy tissues. Despite decades of preclinical exploration and some notable achievements, the mechanisms behind FLASH effects remain debated. Standardization is still required for the type of FLASH-RT rays and dose patterns. This review addresses the current state of FLASH-RT research, summarizing the biological mechanisms behind the FLASH effect. Additionally, it examines the impact of FLASH-RT on immune cells, cytokines, and the tumor immune microenvironment. Lastly, this review will discuss beam characteristics, potential clinical applications, and the relevance and applicability of FLASH-RT in treating advanced cancers.

ABSTRACTFocal radiation therapy (RT) has attracted considerable attention as a combinatorial partner for immunotherapy (IT), largely reflecting a well-defined, predictable safety profile and at least some potential for immunostimulation. However, only a few RT-IT combinations have been tested successfully in patients with cancer, highlighting the urgent need for an improved understanding of the interaction between RT and IT in both preclinical and clinical scenarios. Every year since 2016, ImmunoRad gathers experts working at the interface between RT and IT to provide a forum for education and discussion, with the ultimate goal of fostering progress in the field at both preclinical and clinical levels. Here, we summarize the key concepts and findings presented at the Sixth Annual ImmunoRad conference.

The FLASH effect is a radiobiological phenomenon that has garnered considerable interest in the clinical field. Pre-clinical experimental studies have highlighted its potential to reduce side effects on healthy tissues while maintaining isoeffectiveness on tumor tissues, thus widening the therapeutic window and enhancing the effectiveness of radiotherapy. The FLASH effect is achieved through the administration of the complete therapeutic radiation dose within a brief time frame, shorter than 200 milliseconds, and, therefore, utilizing remarkably high average dose rates above at least 40 Gy/s. Despite its potential in radiotherapy, the radiobiological mechanisms governing this effect and its quantitative relationship with temporal parameters of the radiation beam, such as dose-rate, dose-per-pulse, and average dose-rate within the pulse, remain inadequately elucidated. A more profound comprehension of these underlying mechanisms is imperative to optimize the clinical application and translation of the FLASH effect into routine practice. Due to the aforementioned factors, the undertaking of quantitative radiobiological investigations becomes imperative, necessitating the utilization of sophisticated and adaptable apparatus capable of generating radiation beams with exceedingly high dose-rates and dose-per-pulse characteristics. This study presents a comprehensive account of the design and operational capabilities of a Linear Accelerator (LINAC) explicitly tailored for FLASH radiotherapy research purposes. Termed the “ElectronFlash” (EF) LINAC, this specialized system employs a low-energy configuration (7 and 9 MeV) and incorporates a triode gun. The EF LINAC is currently operational at the Centro Pisano FLASH Radiotherapy (CPFR) facility located in Pisa, Italy. Lastly, this study presents specific instances exemplifying the LINAC’s adaptability, enabling the execution of hitherto unprecedented experiments. By enabling independent variations of the temporal parameters of the radiation beam implicated in the FLASH effect, these experiments facilitate the acquisition of quantitative data concerning the effect’s dependence on these specific parameters. This novel approach hopefully contributes to a more comprehensive understanding of the FLASH effect, shedding light on its intricate radiobiological behavior and offering valuable insights for optimizing its clinical implementation.

Radiotherapy (RT) is performed in approximately 75% of patients with cancer, and its efficacy is often hampered by the low tolerance of the surrounding normal tissues. Recent advancements have demonstrated the potential to widen the therapeutic window using “very short” radiation treatment delivery (from a conventional dose rate between 0.5 Gy/min and 2 Gy/min to more than 40 Gy/s) causing a significant increase of normal tissue tolerance without varying the tumor effect. This phenomenon is called “FLASH Effect (FE)” and has been discovered by using electrons. Although several physical, dosimetric, and radiobiological aspects need to be clarified, current preclinical “in vivo” studies have reported a significant protective effect of FLASH RT on neurocognitive function, skin toxicity, lung fibrosis, and bowel injury. Therefore, the current radiobiological premises lay the foundation for groundbreaking potentials in clinical translation, which could be addressed to an initial application of Low Energy Electron FLASH (LEE) for the treatment of superficial tumors to a subsequent Very High Energy Electron FLASH (VHEE) for the treatment of deep tumors. Herein, we report a clinical investigational scenario that, if supported by preclinical studies, could be drawn in the near future.

Background: FLASH radiotherapy (RT) is a novel method for delivering ionizing radiation, which has been shown in preclinical studies to have a normal tissue sparing effect and to maintain anticancer efficacy as compared to conventional RT. Treatment of head and neck tumors with conventional RT is commonly associated with severe toxicity, hence the normal tissue sparing effect of FLASH RT potentially makes it especially advantageous for treating oral tumors. In this work, the objective was to study the adverse effects of dogs with spontaneous oral tumors treated with FLASH RT. Methods: Privately-owned dogs with macroscopic malignant tumors of the oral cavity were treated with a single fraction of ≥30Gy electron FLASH RT and subsequently followed for 12 months. A modified conventional linear accelerator was used to deliver the FLASH RT. Results: Eleven dogs were enrolled in this prospective study. High grade adverse effects were common, especially if bone was included in the treatment field. Four out of six dogs, who had bone in their treatment field and lived at least 5 months after RT, developed osteoradionecrosis at 3-12 months post treatment. The treatment was overall effective with 8/11 complete clinical responses and 3/11 partial responses. Conclusion: This study shows that single-fraction high dose FLASH RT was generally effective in this mixed group of malignant oral tumors, but the risk of osteoradionecrosis is a serious clinical concern. It is possible that the risk of osteonecrosis can be mitigated through fractionation and improved dose conformity, which needs to be addressed before moving forward with clinical trials in human cancer patients. [ABSTRACT FROM AUTHOR]

Objective. Ultra-high-dose-rate radiotherapy, referred to as FLASH therapy, has been demonstrated to reduce the damage of normal tissue as well as inhibiting tumor growth compared with conventional dose-rate radiotherapy. The transient hypoxia may be a vital explanation for sparing the normal tissue. The heterogeneity of oxygen distribution for different doses and dose rates in the different radiotherapy schemes are analyzed. With these results, the influence of doses and dose rates on cell survival are evaluated in this work. Approach. The two-dimensional reaction–diffusion equations are used to describe the heterogeneity of the oxygen distribution in capillaries and tissue. A modified linear quadratic model is employed to characterize the surviving fraction at different doses and dose rates. Main results. The reduction of the damage to the normal tissue can be observed if the doses exceeds a minimum dose threshold under the ultra-high-dose-rate radiation. Also, the surviving fraction exhibits the 'plateau effect' under the ultra-high dose rates radiation, which signifies that within a specific range of doses, the surviving fraction either exhibits minimal variation or increases with the dose. For a given dose, the surviving fraction increases with the dose rate until tending to a stable value, which means that the protection in normal tissue reaches saturation. Significance. The emergence of the 'plateau effect' allows delivering the higher doses while minimizing damage to normal tissue. It is necessary to develop appropriate program of doses and dose rates for different irradiated tissue to achieve more efficient protection. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most prevalent form of cancer worldwide and is projected to affect one in every eight American women over their lifetimes; radiation therapy (RT) is utilized for most breast cancer patients' treatments. Our study aimed to evaluate a novel Bragg peak, ultra-high dose rate (FLASH), proton radiotherapy (PRT) technique that can potentially decrease radiotherapy toxicities. Clinically viable Bragg peak FLASH treatment plans were generated for breast cancer patients who were treated with conventional PRT. Across dosimetric standards of care for healthy and cancerous tissues, we observed feasible breast cancer treatment delivery and high plan quality while maintaining an ultra-high dose rate. Therefore, delivering proton FLASH-RT for breast cancer may reduce toxicities and improve the therapeutic ratio. Bragg peak FLASH-RT can deliver highly conformal treatment and potentially offer improved normal tissue protection for radiotherapy patients. This study focused on developing ultra-high dose rate (≥40 Gy × RBE/s) intensity-modulated proton therapy (IMPT) for hypofractionated treatment of early-stage breast cancer. A novel tracking technique was developed to enable pencil beaming scanning (PBS) of single-energy protons to adapt the Bragg peak (BP) to the target distally. Standard-of-care PBS treatment plans of consecutively treated early-stage breast cancer patients using multiple energy layers were reoptimized using this technique, and dose metrics were compared between single-energy layer BP FLASH and conventional IMPT plans. FLASH dose rate coverage by volume (V40Gy/s) was also evaluated for the FLASH sparing effect. Distal tracking can precisely stop BP at the target distal edge. All plans (n = 10) achieved conformal IMPT-like dose distributions under clinical machine parameters. No statistically significant differences were observed in any dose metrics for heart, ipsilateral lung, most ipsilateral breast, and CTV metrics (p > 0.05 for all). Conventional plans yielded slightly superior target and skin dose uniformities with 4.5% and 12.9% lower dose maxes, respectively. FLASH-RT plans reached 46.7% and 61.9% average-dose rate FLASH coverage for tissues receiving more than 1 and 5 Gy plan dose total under the 250 minimum MU condition. Bragg peak FLASH-RT techniques achieved comparable plan quality to conventional IMPT while reaching adequate dose rate ratios, demonstrating the feasibility of early-stage breast cancer clinical applications. [ABSTRACT FROM AUTHOR]

Definition: Flash radiotherapy (Flash-RT) is an innovative technique used in radiotherapy for cancer treatment because it delivers an extremely high dose of radiation (>40 Gy/s) to the tumour in a very short period of time, typically within a fraction of a second. This ultra-fast delivery of radiation distinguishes Flash-RT from conventional radiotherapy, which typically involves the delivery of radiation over a longer time period, often several minutes. Studies conducted in cell and preclinical models suggested that Flash-RT may spare normal tissues from radiation-related side effects, such as skin toxicity, gastrointestinal complications, and damage to organs-at-risk. This is believed to be due to the unique normal tissue response to the ultra-high dose rate. Nevertheless, while Flash-RT shows promising results in preclinical and early clinical studies, one should note that the technique is still in the early stages of development. This entry provides a comprehensive exploration of the immense potentials of Flash-RT, covering its background, mechanisms, radiation sources, recent experimental findings based on cell and preclinical models, and future prospects. It aims to provide valuable insights into this innovative radiotherapy technology for anyone interested in the subject. [ABSTRACT FROM AUTHOR]

Simple Summary: FLASH radiotherapy (RT) delivering ultra-high dose rate radiation can reduce normal tissue toxicity while effectively treating tumors. However, implementing FLASH RT in clinical settings faces challenges like limited depth penetration and complex treatment planning. Monte Carlo simulation is a valuable tool to optimize FLASH RT. Radiation detectors, including diamond detectors like microDiamond and ionization chambers, play a crucial role in accurately measuring dose delivery. Moreover, optically stimulated luminescence dosimeters and radiochromic films are used for validation. Advancements are being made to improve detector accuracy in FLASH RT. Further research is needed to refine treatment planning and detector performance for widespread FLASH RT implementation, which can potentially revolutionize cancer treatment. Radiotherapy (RT) using ultra-high dose rate (UHDR) radiation, known as FLASH RT, has shown promising results in reducing normal tissue toxicity while maintaining tumor control. However, implementing FLASH RT in clinical settings presents technical challenges, including limited depth penetration and complex treatment planning. Monte Carlo (MC) simulation is a valuable tool for dose calculation in RT and has been investigated for optimizing FLASH RT. Various MC codes, such as EGSnrc, DOSXYZnrc, and Geant4, have been used to simulate dose distributions and optimize treatment plans. Accurate dosimetry is essential for FLASH RT, and radiation detectors play a crucial role in measuring dose delivery. Solid-state detectors, including diamond detectors such as microDiamond, have demonstrated linear responses and good agreement with reference detectors in UHDR and ultra-high dose per pulse (UHDPP) ranges. Ionization chambers are commonly used for dose measurement, and advancements have been made to address their response nonlinearities at UHDPP. Studies have proposed new calculation methods and empirical models for ion recombination in ionization chambers to improve their accuracy in FLASH RT. Additionally, strip-segmented ionization chamber arrays have shown potential for the experimental measurement of dose rate distribution in proton pencil beam scanning. Radiochromic films, such as GafchromicTM EBT3, have been used for absolute dose measurement and to validate MC simulation results in high-energy X-rays, triggering the FLASH effect. These films have been utilized to characterize ionization chambers and measure off-axis and depth dose distributions in FLASH RT. In conclusion, MC simulation provides accurate dose calculation and optimization for FLASH RT, while radiation detectors, including diamond detectors, ionization chambers, and radiochromic films, offer valuable tools for dosimetry in UHDR environments. Further research is needed to refine treatment planning techniques and improve detector performance to facilitate the widespread implementation of FLASH RT, potentially revolutionizing cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Several studies have shown pencil beam scanning (PBS) proton therapy is a feasible and safe modality to deliver conformal and ultra‐high dose rate (UHDR) FLASH radiation therapy. However, it would be challenging and burdensome to conduct the quality assurance (QA) of the dose rate along with conventional patient‐specific QA (psQA). Purpose: To demonstrate a novel measurement‐based psQA program for UHDR PBS proton transmission FLASH radiotherapy (FLASH‐RT) using a high spatiotemporal resolution 2D strip ionization chamber array (SICA). Methods: The SICA is a newly designed open‐air strip‐segmented parallel plate ionization chamber, which is capable of measuring spot position and profile through 2 mm‐spacing‐strip electrodes at a 20 kHz sampling rate (50 μs per event) and has been characterized to exhibit excellent dose and dose rate linearity under UHDR conditions. A SICA‐based delivery log was collected for each irradiation containing the measured position, size, dwell time, and delivered MU for each planned spot. Such spot‐level information was compared with the corresponding quantities in the treatment planning system (TPS). The dose and dose rate distributions were reconstructed on patient CT using the measured SICA log and compared to the planned values in volume histograms and 3D gamma analysis. Furthermore, the 2D dose and dose rate measurements were compared with the TPS calculations of the same depth. In addition, simulations using different machine‐delivery uncertainties were performed, and QA tolerances were deduced. Results: A transmission proton plan of 250 MeV for a lung lesion was planned and measured in a dedicated ProBeam research beamline (Varian Medical System) with a nozzle beam current between 100 to 215 nA. The worst gamma passing rates for dose and dose rate of the 2D SICA measurements (four fields) compared to TPS prediction (3%/3 mm criterion) were 96.6% and 98.8%, respectively, whereas the SICA‐log reconstructed 3D dose distribution achieved a gamma passing rate of 99.1% (2%/2 mm criterion) compared to TPS. The deviations between SICA measured log, and TPS were within 0.3 ms for spot dwell time with a mean difference of 0.069 ± 0.11 s, within 0.2 mm for spot position with a mean difference of −0.016 ± 0.03 mm in the x‐direction, and −0.036 ± 0.059 mm in the y‐direction, and within 3% for delivered spot MUs. Volume histogram metric of dose (D95) and dose rate (V40Gy/s) showed minimal differences, within less than 1%. Conclusions: This work is the first to describe and validate an all‐in‐one measurement‐based psQA framework that can fulfill the goals of validating the dose rate accuracy in addition to dosimetric accuracy for proton PBS transmission FLASH‐RT. The successful implementation of this novel QA program can provide future clinical practice with more confidence in the FLASH application. [ABSTRACT FROM AUTHOR]

Background: The potential reduction of normal tissue toxicities during FLASH radiotherapy (FLASH‐RT) has inspired many efforts to investigate its underlying mechanism and to translate it into the clinic. Such investigations require experimental platforms of FLASH‐RT capabilities. Purpose: To commission and characterize a 250 MeV proton research beamline with a saturated nozzle monitor ionization chamber for proton FLASH‐RT small animal experiments. Methods: A 2D strip ionization chamber array (SICA) with high spatiotemporal resolution was used to measure spot dwell times under various beam currents and to quantify dose rates for various field sizes. An Advanced Markus chamber and a Faraday cup were irradiated with spot‐scanned uniform fields and nozzle currents from 50 to 215 nA to investigate dose scaling relations. The SICA detector was set up upstream to establish a correlation between SICA signal and delivered dose at isocenter to serve as an in vivo dosimeter and monitor the delivered dose rate. Two off‐the‐shelf brass blocks were used as apertures to shape the dose laterally. Dose profiles in 2D were measured with an amorphous silicon detector array at a low current of 2 nA and validated with Gafchromic films EBT‐XD at high currents of up to 215 nA. Results: Spot dwell times become asymptotically constant as a function of the requested beam current at the nozzle of greater than 30 nA due to the saturation of monitor ionization chamber (MIC). With a saturated nozzle MIC, the delivered dose is always greater than the planned dose, but the desired dose can be achieved by scaling the MU of the field. The delivered doses exhibit excellent linearity with R2>0.99${R^2} > 0.99$ with respect to MU, beam current, and the product of MU and beam current. If the total number of spots is less than 100 at a nozzle current of 215 nA, a field‐averaged dose rate greater than 40 Gy/s can be achieved. The SICA‐based in vivo dosimetry system achieved excellent estimates of the delivered dose with an average (maximum) deviation of 0.02 Gy (0.05 Gy) over a range of delivered doses from 3 to 44 Gy. Using brass aperture blocks reduced the 80%‐20% penumbra by 64% from 7.55 to 2.75 mm. The 2D dose profiles measured by the Phoenix detector at 2 nA and the EBT‐XD film at 215 nA showed great agreement, with a gamma passing rate of 95.99% using 1 mm/2% criterion. Conclusion: A 250 MeV proton research beamline was successfully commissioned and characterized. Challenges due to the saturated monitor ionization chamber were mitigated by scaling MU and using an in vivo dosimetry system. A simple aperture system was designed and validated to provide sharp dose fall‐off for small animal experiments. This experience can serve as a foundation for other centers interested in implementing FLASH radiotherapy preclinical research, especially those equipped with a similar saturated MIC. [ABSTRACT FROM AUTHOR]

Glioma has received considerable attention because of its potential of inducing high rates of morbidity, disability, and mortality. FLASH radiotherapy (FLASH-RT) has emerged as a popular topic in current research because of its ability to protect normal tissues. The present review summarized the current development of FLASH-RT in both the central nervous system and glioblastomas, explored the potential mechanisms underlying FLASH-RT-mediated protective effects on the central nervous system, and revealed the advantages of this new technique for glioma therapy. This study highlights the benefits and challenges of the present research and provides a reference for future research.

Conformality has been a key requirement in radiation therapy for cancer to minimize normal tissue toxicity while maintaining tumor control. Since 2014, there has been great interest in ultra‐high dose rate (UHDR), "FLASH," radiation therapy to enhance this therapeutic window. In multiple pre‐clinical studies, it was seen that normal tissue demonstrated less damage due to radiation of various modalities when the same dose was delivered at ultra‐high mean dose rates exceeding ∼40 Gy/s while tumor control remained indifferent to changes in dose rate. The scientific community has large‐scale interdisciplinary studies to investigate this potentially breakthrough technique to enhance treatment options for cancer. FLASH studies have been performed using a number of modalities and delivery techniques for many pre‐clinical models. There have been several studies reporting evidence of the FLASH effect as well as technological developments relating to UHDR studies. There is sustained interest and motivation for this topic as well as many questions that are yet to be answered. We provide a short overview to highlight some of the major work and challenges to advance research in FLASH radiotherapy. [ABSTRACT FROM AUTHOR]