Solid-State Detector for FLASH Radiotherapy: Dosimetric Applications and Emerging Concepts

Objective. The successful implementation of FLASH radiotherapy in clinical settings, with typical dose rates >40 Gy s−1, requires accurate real-time dosimetry. Approach. Silicon carbide (SiC) p–n diode dosimeters designed for the stringent requirements of FLASH radiotherapy have been fabricated and characterized in an ultra-high pulse dose rate electron beam. The circular SiC PiN diodes were fabricated at IMB-CNM (CSIC) in 3 μm epitaxial 4H-SiC. Their characterization was performed in PTB’s ultra-high pulse dose rate reference electron beam. The SiC diode was operated without external bias voltage. The linearity of the diode response was investigated up to doses per pulse (DPP) of 11 Gy and pulse durations ranging from 3 to 0.5 μs. Percentage depth dose measurements were performed in ultra-high dose per pulse conditions. The effect of the total accumulated dose of 20 MeV electrons in the SiC diode sensitivity was evaluated. The temperature dependence of the response of the SiC diode was measured in the range 19 °C–38 °C. The temporal response of the diode was compared to the time-resolved beam current during each electron beam pulse. A diamond prototype detector (flashDiamond) and Alanine measurements were used for reference dosimetry. Main results. The SiC diode response was independent both of DPP and of pulse dose rate up to at least 11 Gy per pulse and 4 MGy s−1, respectively, with tolerable deviation for relative dosimetry (<3%). When measuring the percentage depth dose under ultra-high dose rate conditions, the SiC diode performed comparably well to the reference flashDiamond. The sensitivity reduction after 100 kGy accumulated dose was <2%. The SiC diode was able to follow the temporal structure of the 20 MeV electron beam even for irregular pulse estructures. The measured temperature coefficient was (–0.079 ± 0.005)%/°C. Significance. The results of this study demonstrate for the first time the suitability of silicon carbide diodes for relative dosimetry in ultra-high dose rate pulsed electron beams up to a DPP of 11 Gy per pulse.

Background: Radiotherapy (RT) plays a major role in eradicating residual disease in primary breast cancer (BC) and in palliating metastatic BC. While conventional RT (≤0.03 Gy/s) is effective, it often causes significant normal tissue toxicity—such as skin inflammation—limiting treatment intensity and patient quality of life. FLASH RT, a newer approach delivering ultra-high dose rates (&amp;gt;40 Gy/s), has shown similar tumor control with reduced normal tissue damage (the “FLASH effect”). However, the mechanism by which FLASH spares normal tissue and supresses tumor growth remains poorly understood. Ionizing radiation activates the cGAS-STING pathway through DNA damage, triggering proinflammatory cytokine production and tissue inflammation. Recent reports suggest that FLASH RT also activates the cGAS-STING pathway. In this study, we explored the role of the cGAS-STING pathway in mediating the effects of FLASH and CONV RT on tumor eradication and tissue toxicity using cGAS KO mice, to better understand the contribution of the host cGAS pathway to the FLASH effect and tumor suppression. Aim: This study aims to systematically compare the therapeutic efficacy and normal tissue toxicity of FLASH vs CONV RT in a syngeneic BC mouse model and to elucidate the role of the cGAS pathway in mediating radiation-induced inflammation and tumor response. Methods: PYMT117 BC cells were orthotopically injected into the 3rd mammary fat pad of 6-8-week-old female C57BL/6 and cGAS KO mice. Once tumors reached ∼50 mm3, mice received a single 30 Gy dose of either FLASH or CONV RT. Tumor growth was monitored every other day with calipers, and mice were observed for skin toxicity (inflammation, cracking). Euthanasia was performed based on tumor burden or skin damage. Tumor volumes were analyzed using two-way ANOVA followed by Tukey’s post hoc test. Skin toxicity was graded (0-6). Each strain was analyzed separately, and p &amp;lt; 0.05 was considered significant. Results: Both FLASH and CONV RT significantly reduced tumor volume (p &amp;lt; 0.001, two-way ANOVA), with tumors becoming undetectable by day 14 post-irradiation compared to controls. Tumor recurrence began around day 25 in all treated groups. In C57BL6 mice, CONV RT showed a trend towards better tumor control with smaller recurrent tumors and some complete responses but caused severe skin toxicity, including inflammation and cracking, requiring euthanasia by day 50 (toxicity score: 6). FLASH RT, while slightly less effective in long-term tumor control, greatly reduced skin toxicity, with only mild lesions in 3 out of 10 mice (score: 4) in C57BL6 mice. Notably, cGAS KO mice showed no visible skin toxicity in either treatment group (score: 0). Conclusion: FLASH RT significantly reduces normal tissue toxicity compared to CONV RT, offering better tolerability with minimal skin damage. Although CONV RT showed stronger initial tumor control, its use was limited by severe skin toxicity. The absence of toxicity in cGAS KO mice suggests the cGAS pathway plays a key role in radiation-induced inflammation. These findings support FLASH RT as a promising, less toxic alternative and highlight the potential of targeting cGAS to improve radiotherapy outcomes in BC. Citation Format: B. Verma, A. Mutahar, S. Melamenidis, R. Verma, K. Casey, K. Horst, E. Graves, M. Clarke, B. Loo, F. Dirbas. Tumor response to ultra high dose rate radiation (FLASH) vs. conventional radiotherapy in normal and cGAS-knockout mice [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-07-10.

Taking Care with FLASH Radiation Therapy

FLASH: Current status and the transition to clinical use.

PurposeThe ultra-high dose rate (UHDR) radiation shows promise in eradicating tumors while reducing normal tissue toxicities. However, the biological outcomes of UHDR are influenced by various factors, particularly the mean dose rate and instantaneous dose rate. Additionally, the UHDR response at large field sizes is lacking. This study aimed to explore the impact of different dose rate combinations on gastrointestinal biological outcomes following total-body irradiations (TBI) and to examine the involved molecular signaling pathways.MethodFemale C57BL6/J mice received 10 Gy TBI using three modes: ultra-high mean and ultra-high instantaneous dose rate irradiation (HH mode), low mean and ultra-high instantaneous dose rate irradiation (LH mode), and low mean and low instantaneous dose rate irradiation (LL mode). Mice were euthanized at 3 h and 48 h post irradiation to assess acute normal tissue damage and perform transcriptome sequencing. Furthermore, a subset of mice was monitored for 30 days to evaluate survival.ResultsWe found that when the instantaneous dose rate is sufficiently high (> 105 Gy/s), both ultra-high or low mean dose rate irradiation reduced mice mortality, myelosuppression, DNA damage, and cell apoptosis. The survival probabilities 30 days after 10 Gy TBI were 4/7, 4/6, and 0/6 in the HH, LH, and LL groups, respectively. Myelosuppression was lower at 3 h and 48 h post HH and LH irradiations than LL irradiation. The better regulated inflammatory response was evident at 48 h post HH and LH irradiation compared to LL irradiation. Additionally, DNA damages and cell apoptosis in the intestinal tissue were significantly reduced after HH and LH irradiations compared to LL irradiation. Transcriptome sequencing of intestinal tissues revealed that HH irradiation activated immune response pathways and suppressed mitochondrial related pathways compared to LL irradiation.ConclusionOur findings underscore the pivotal role of instantaneous dose rate in reducing radiation damages. When the instantaneous dose rate is sufficiently high (> 105 Gy/s), both ultra-high or low mean dose rate irradiation (HH and LH mode) reduced mice mortality, myelosuppression, DNA damage, and cell apoptosis. Understanding these dose rate effects and biological responses are crucial for optimizing radiotherapy strategies and exploring the potential benefits of UHDR irradiation.

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. 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. SiC PiN junction detectors, recently realized and provided by STLab company, with different active areas (ranging from 4.5 to 10mm2) and thicknesses (10-20µm), were irradiated using 9MeV 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. The study revealed a linear response for the different SiC detectors employed up to 21Gy/pulse for SiC detectors with 4.5 mm2/10µm 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. 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.

Ultra-high dose rate radiotherapy with electrons and protons has shown potential for cancer treatment by effectively targeting tumors while sparing healthy tissues (FLASH effect). This study aimed to investigate the potential FLASH sparing effect of ultra-high-dose rate helium ion irradiation, focusing on acute brain injury and subcutaneous tumor response in a preclinical in vivo setting. Raster-scanned helium ion beams were used to compare the effects of standard dose rate (SDR at 0.2 Gy/s) and FLASH (at 141 Gy/s) radiotherapy on healthy brain tissue. Irradiation-induced brain injury was studied in C57BL/6 mice via DNA damage response, using nuclear γH2AX as a marker for double-strand breaks (DSB). The integrity of neurovascular and immune compartments was assessed through CD31 + microvascular density and activation of microglia/macrophages. Iba1+ ramified and CD68 + phagocytic microglia/macrophages were quantified, along with the expression of inducible nitric oxide synthetase (iNOS). Tumor response to SDR (0.2 Gy/s) and FLASH (250 Gy/s) radiotherapy was evaluated in A549 carcinoma model, using tumor volume and Kaplan-Meier survival as endpoints. The results showed that helium FLASH radiotherapy significantly reduced acute brain tissue injury compared to SDR, evidenced by lower levels of DSB and preserved neurovascular endothelium. Additionally, FLASH radiotherapy reduced neuroinflammatory signals compared to SDR, as indicated by fewer CD68+ iNOS+ microglia/macrophages. FLASH radiotherapy achieved tumor control comparable to that of SDR radiotherapy. This study is the first to report the FLASH sparing effect of raster scanning helium ion radiotherapy in vivo, highlighting its potential for neuroprotection and effective tumor control.

FLASH radiotherapy is an innovative technique that delivers radiation at ultra-high dose rates (UHDR), offering tumour control comparable to conventional (CONV) radiotherapy while significantly reducing normal tissue toxicity. Here we aim to determine the effects of FLASH compared to CONV radiotherapy in muscle-invasive bladder cancer (MIBC) models. Using an in-house 6 MeV linear accelerator able to deliver electron beam at UHDR or CONV dose rate, we employed clonogenic survival assays, RNA sequencing (RNA-seq), and in vivo tumour growth analyses using MBT2 cells and C3H MIBC models. Both subcutaneous and orthotopic tumour models were used to assess tumour response, survival and treatment-related toxicity as demonstrated by weight loss. Clonogenic analysis demonstrated comparable cancer cell survival between FLASH and CONV irradiation in vitro. RNA-seq analysis of in vitro irradiated cells revealed similar gene expression at 5 Gy but significant transcriptional divergence at 10 Gy. Intestinal organoids exhibited preserved growth after FLASH compared with CONV irradiation, consistent with a normal tissue sparing effect. In subcutaneous models, FLASH and CONV radiotherapy exhibited similar tumour responses. However, in the orthotopic model, FLASH radiotherapy enabled dose escalation, significantly extending survival at 15 Gy (p = 0.02) and 17.5 Gy (p = 0.004). Dose rate (100 vs 106 Gy/s) did not significantly affect survival. The benefit of single-fraction FLASH was not retained with fractionated (3 × 7.3 Gy) delivery. FLASH radiotherapy demonstrates significant potential for treating MIBC, offering enhanced survival through effective dose escalation. These findings support continued investigation into optimal FLASH parameters and its clinical application.

Background:Preclinical investigations studies have shown that FLASH radiotherapy (FLASH-RT), delivering radiation in ultra-high dose rates (UHDR), preserves healthy tissue and reduces toxicity, all while maintaining an effective tumor response compared to conventional radiotherapy (CONV-RT), the combined biological benefit was termed as “FLASH effect”. However, the mechanisms responsible for this effect remain unclear. Research demonstrated that oxygen concentration contributes to the FLASH effect, and it has been hypothesized that Fenton reaction might play a role in the “FLASH effect”.Purpose:We propose to investigate the effect of ultra-high dose rate (UHDR), compared to conventional dose rates (CONV), on the Fenton reaction by studying the radiolysis of Fricke solution. The study will focus on how dose, dose rate, and initial oxygen concentration influence the activation of the Fenton reaction.Methods and Materials:TOPAS-nBio version 2.0 was used to simulate the radiolysis of the Fricke system. A cubic water phantom of 3μm side was irradiated by 300MeV protons on one of its edges. For UHDR, a proton field (1.5×1.5μm2) was delivered in a single pulse of 1ns width. The protons were accumulated until reached 5Gy or 10Gy absorbed dose. For CONV, the independent history approach was used to mimic 60Co irradiation. For both dose-rates, oxygen concentrations representative of hypoxic and normoxic tissues (10–250μM) were simulated. The G-value for oxidant ions G(Fe3+) and ΔG-value of Fenton reaction (H2O2 + Fe2+→ Fe3++•OH+OH−) were scored. The simulations ended after G(Fe3+) achieved steady-state, and calculated yields were compared with published data.Results:For CONV, G(Fe3+) agreed with ICRU-report 34 data by (0.97±0.1) %. For UHDR, G(Fe3+) agreed with ICRU data by (1.24±0.1)% and (0.92±0.1)% for 5Gy and 10Gy, respectively. Notably, UHDR at 10 Gy reduced the occurrence of Fenton reactions by (1.0±0.1)% and (11.5±0.1)% at initial oxygen concentrations of 250 μM and 10 μM, respectively. In consequence, UHDR decreased G(Fe3+) by (1.8±0.1)% and (12.5±0.1)% at these oxygen levels. Additionally, increasing the absorbed dose to 15 Gy and 20 Gy at low oxygen (10 μM), UHDR further reduced the ΔG-value by (15.7±0.1)% and (18.6±0.1)%, respectively. The decrease was driven by intertrack effects present in UHDR pulses and its impact on the scavenging effect that oxygen had over hydrogen radicals.Conclusions:UHDR reduces the yield of Fe3+ (G(Fe3+)) and significantly impacts Fenton reactions, particularly at low oxygen concentrations, while showing minimal effects at higher oxygen levels. This effect becomes more pronounced at higher dose thresholds, such as 10–20 Gy. This emphasizes the important role of the initial oxygen concentration in UHDR and its influence on the Fenton reaction, a mechanism that may contribute to elucidate the FLASH effect.

FLASH radiotherapy (FLASH-RT) that uses an ultra-high dose rate (UHDR) radiation is emerging as an effective cancer treatment modality but the biological effects of UHDR are not fully understood. In this study, biological effects induced by conventional dose rate (CDR; 1 Gy/min) and UHDR (600 Gy/s) were evaluated in human peripheral blood lymphocytes of 10 donors at two different radiation doses (3 Gy and 8 Gy) of 9 MeV electrons. Cytogenetic analysis revealed that the unstable chromosome aberrations (dicentrics, rings and fragments) were reduced by 1.5–twofold after UHDR exposure (600 Gy/s) relative to CDR (1 Gy/min) at both radiation doses (3 Gy and 8 Gy). A similar trend was observed for the stable chromosome aberrations (insertions, balanced and unbalanced translocations) detected by fluorescence in situ hybridization (FISH) using a cocktail of DNA probes for chromosomes 1, 2 and 4. Pooled data indicated that the translocations (color junctions) were reduced by 40–50% in 600 Gy/s irradiated lymphocytes at both 3 Gy and 8 Gy doses relative to CDR. In corroboration, genome wide analysis of translocations by the multicolor FISH technique revealed reduced yields of chromosome exchange events after UHDR compared to CDR of electrons. In agreement with inter-chromosomal aberrations, intra-chromosomal aberrations detected by multicolor BAND analysis of chromosome 1 also showed reduced yields of different aberrations (inversions, insertions, and p- and q arm translocations) after UHDR exposure relative to CDR. Quantitative modeling of dicentrics and translocations, utilizing the linear-quadratic formalism with polynomial regression (inverse-variance weighting) and quantile regression, revealed significant dose response reductions at 600 Gy/s versus 1 Gy/min. In agreement with the reduced yields of unstable and stable chromosome aberrations, UHDR of electrons resulted in a modest increase in leukocyte viability and reduced BAX protein expression. Further molecular studies using well defined human cell model systems are required for gaining insight into the cellular DNA repair mechanisms for UHDR radiation.

This in vitro study was undertaken to determine if ultrahigh dose rates could improve the radiation response of human tumors. Two cell lines, human glioma (U-87 MG), which is radioresistant, and human melanoma (HT-144), which is radiosensitive, were irradiated at ultrahigh and high dose rates under aerobic and anoxic conditions to determine if their oxygen enhancement ratios are modified by dose rate. In fact, the survival curves, and hence the oxygen enhancement ratios, were found to be independent of the dose rate. The oxygen enhancement ratio for glioma cells irradiated in plateau phase was 2.8 (+/- 0.3). The oxygen enhancement ratio was 2.7 (+/- 0.4) for melanoma cells in plateau phase and 2.8 (+/- 0.3) in exponential phase. These results indicate that there is no advantage in treating these tumors using ultrahigh dose rates instead of conventional dose rates.

Objective. Very high energy electrons (VHEE) in the range of 50–250 MeV are of interest for treating deep-seated tumours with FLASH radiotherapy (RT). This approach offers favourable dose distributions and the ability to deliver ultra-high dose rates (UHDR) efficiently. To make VHEE-based FLASH treatment clinically viable, a novel beam monitoring technology is explored as an alternative to transmission ionisation monitor chambers, which have non-linear responses at UHDR. This study introduces the fibre optic flash monitor (FOFM), which consists of an array of silica optical fibre-based Cherenkov sensors with a photodetector for signal readout. Approach. Experiments were conducted at the CLEAR facility at CERN using 200 MeV and 160 MeV electrons to assess the FOFM’s response linearity to UHDR (characterised with radiochromic films) required for FLASH radiotherapy. Beam profile measurements made on the FOFM were compared to those using radiochromic film and scintillating yttrium aluminium garnet (YAG) screens. Main results. A range of photodetectors were evaluated, with a complementary-metal-oxide-semiconductor (CMOS) camera being the most suitable choice for this monitor. The FOFM demonstrated excellent response linearity from 0.9 Gy/pulse to 57.4 Gy/pulse (R 2 = 0.999). Furthermore, it did not exhibit any significant dependence on the energy between 160 MeV and 200 MeV nor the instantaneous dose rate. Gaussian fits applied to vertical beam profile measurements indicated that the FOFM could accurately provide pulse-by-pulse beam size measurements, agreeing within the error range of radiochromic film and YAG screen measurements, respectively. Significance. The FOFM proves to be a promising solution for real-time beam profile and dose monitoring for UHDR VHEE beams, with a linear response in the UHDR regime. Additionally it can perform pulse-by-pulse beam size measurements, a feature currently lacking in transmission ionisation monitor chambers, which may become crucial for implementing FLASH radiotherapy and its associated quality assurance requirements.

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

Quality assurance (QA) for ultra-high dose rate (UHDR) irradiation is a crucial aspect in the emerging field of FLASH radiotherapy (FLASH-RT). This innovative treatment approach delivers radiation at UHDR, demanding careful adoption of QA protocols and procedures. A comprehensive understanding of beam properties and dosimetry consistency is vital to ensure the safe and effective delivery of FLASH-RT. To develop a comprehensive pre-treatment QA program for cyclotron-based proton pencil beam scanning (PBS) FLASH-RT. Establish appropriate tolerances for QA items based on this study's outcomes and TG-224 recommendations. A 250 MeV proton spot pattern was designed and implemented using UHDR with a 215nA nozzle beam current. The QA pattern that covers a central uniform field area, various spot spacings, spot delivery modes and scanning directions, and enabling the assessment of absolute, relative and temporal dosimetry QA parameters. A strip ionization chamber array (SICA) and an Advanced Markus chamber were utilized in conjunction with a 2cm polyethylene slab and a range (R80) verification wedge. The data have been monitored for over 3 months. The relative dosimetries were compliant with TG-224. The variations of temporal dosimetry for scanning speed, spot dwell time, and spot transition time were within±1mm/ms,±0.2 ms, and±0.2 ms, respectively. While the beam-to-beam absolute output on the same day reached up to 2.14%, the day-to-day variation was as high as 9.69%. High correlation between the absolute dose and dose rate fluctuations were identified. The dose rate of the central 5×5 cm2 field exhibited variations within 5% of the baseline value (155Gy/s) during an experimental session. A comprehensive QA program for FLASH-RT was developed and effectively assesses the performance of a UHDR delivery system. Establishing tolerances to unify standards and offering direction for future advancements in the evolving FLASH-RT field.

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 ∼40Gy/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.