Assessment of FLASH Radiation Doses Using Polycrystalline Alanine Powder as a Passive Dosimeter.

Framework for Quality Assurance of Ultrahigh Dose Rate Clinical Trials Investigating FLASH Effects and Current Technology Gaps

Taking Care with FLASH Radiation Therapy

Scanning Proton FLASH Irradiation Using a Synchrotron Accelerator: Effects on Cultured Cells and Differences by Irradiation Positions

FLASH radiation therapy (FLASH-RT) reference dosimetry to obtain traceability, repeatability and stability of irradiations cannot be performed with conventional dosimetric methods, such as monitor chambers or ionization chambers. Until now, only passive dosimeters have provided the necessary dosimetric data. Alanine dosimetry is accurate; however, to be used for FLASH-RT in biological experiments and for clinical transfer to humans, the reading time needs to be reduced, while preserving a maximum deviation to the reference of ±2%. Optimization of alanine dosimetry was based on the acquisition of electron paramagnetic resonance (EPR) spectra with a Bruker spectrometer. Reading parameters such as the conversion time, the number of scans, the time constant, the microwave power and the modulation amplitude of the magnetic field were optimized as a trade-off between the signal-to-noise ratio (SNR) and the reading time of one measurement using the reference 10.1 Gy alanine pellet. After optimizing the parameters, we compared the doses measured with alanine pellets up to 100 Gy with the reference doses, and then determined the number of measurements necessary to get a difference lower than ±2%. A low-dose alanine pellet of 4.9 Gy was also measured to evaluate the quality of the optimization for doses lower than 10 Gy. The optimization of the Bruker default parameters made it possible to reduce the reading time for one measurement from 5.6 to 2.6 min. That reduction was not at the cost of the SNR because it was kept comparable to the default parameters. Three measurements were enough to obtain a maximum dose deviation to the reference of 1.8% for the range of 10-100 Gy. The total reading time for the three measurements was 7.8 min (3 × 2.6 min). For lower doses such as 4.9 Gy, three measurements led to a deviation greater than 5%. By increasing the number of measurements to five, the average difference to the reference dose was reduced to less than 5% with a total reading time increased to 13.0 min. For doses between 10 Gy and 100 Gy, the optimized acquisition parameters made it possible to keep the average differences between the reference and the measured doses below ±2%, for a reading time of 7.8 min. This enabled an accurate and fast dose determination for biological preparations as part of FLASH-beam irradiations.

Objective. FLASH radiation therapy with ultrahigh dose rates (UHDR) has the potential to reduce damage to normal tissue while maintaining anti-tumor efficacy. However, rapid and precise dose distribution measurements remain difficult for FLASH radiation therapy with proton beams. To solve this problem, we performed luminescence imaging of water following irradiation by a UHDR proton beam captured using a charge-coupled device camera. Approach. We used 60 MeV proton beams with dose rates of 0.03–837 Gy s−1 from a cyclotron. Therapeutic 139.3 MeV proton beams with dose rates of 0.45–4320 Gy s−1 delivered by a synchrotron-based proton therapy system were also tested. The luminescent light intensity induced by the UHDR beams was compared with that produced by conventional beams to compare the dose rate dependency of the light intensity and its profile. Main results. Luminescence images of water were clearly visualized under UHDR conditions, with significantly shorter exposure times than those with conventional beams. The light intensity was linearly proportional to the delivered dose, which is similar to that of conventional beams. No significant dose-rate dependency was observed for 0.03–837 Gy s−1. The light-intensity profiles of the UHDR beams agreed with those of conventional beams. The results did not differ between accelerators (synchrotron or cyclotron) and beam energies. Significance. Luminescence imaging of water is achievable with UHDR proton beams as well as with conventional beams. The proposed method should be suitable for rapid and easy quality assurance investigations for proton FLASH therapy, because it facilitates real-time, filmless measurements of dose distributions, and is useful for rapid feedback.

FLASH radiation therapy (RT) offers a promising avenue for the broadening of the therapeutic index. However, to leverage the full potential of FLASH in the clinical setting, an improved understanding of the biological principles involved is critical. This requires the availability of specialized equipment optimized for the delivery of conventional (CONV) and ultra-high dose rate (UHDR) irradiation for preclinical studies. One method to conduct such preclinical radiobiological research involves adapting a clinical linear accelerator configured to deliver both CONV and UHDR irradiation. We characterized the dosimetric properties of a clinical linear accelerator configured to deliver ultra-high dose rate irradiation to two anatomic sites in mice and for cell-culture FLASH radiobiology experiments. Delivered doses of UHDR electron beams were controlled by a microcontroller and relay interfaced with the respiratory gating system. We also produced beam collimators with indexed stereotactic mouse positioning devices to provide anatomically specific preclinical treatments. Treatment delivery was monitored directly with an ionization chamber, and charge measurements were correlated with radiochromic film measurements at the entry surface of the mice. The setup for conventional dose rate irradiation utilized the same collimation system but at increased source-to-surface distance. Monte Carlo simulations and film dosimetry were used to characterize beam properties and dose distributions. The mean electron beam energies before the flattening filter were 18.8 MeV (UHDR) and 17.7 MeV (CONV), with corresponding values at the mouse surface of 17.2 and 16.2 MeV. The charges measured with an external ion chamber were linearly correlated with the mouse entrance dose. The use of relay gating for pulse control initially led to a delivery failure rate of 20% (±1 pulse); adjustments to account for the linac latency improved this rate to<1/20. Beam field sizes for two anatomically specific mouse collimators (4 × 4 cm2 for whole-abdomen and 1.5 × 1.5 cm2 for unilateral lung irradiation) were accurate within<5% and had low radiation leakage (<4%). Normalizing the dose at the center of the mouse (∼0.75cm depth) produced UHDR and CONV doses to the irradiated volumes with>95% agreement. We successfully configured a clinical linear accelerator for increased output and developed a robust preclinical platform for anatomically specific irradiation, with highly accurate and precise temporal and spatial dose delivery, for both CONV and UHDR irradiation applications.

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.

Purpose:Ultra-high dose rate (>40 Gy/s, FLASH) radiation therapy (RT) provides equivalent tumor control while reducing normal tissue toxicity relative to conventional dose rate (CONV) RT. However, the mechanisms underlying the observed FLASH effect are unknown. We hypothesized that the preservation of mitochondrial integrity in nontumorigenic cells by FLASH RT could be a key factor in reducing normal tissue toxicity and improving overall treatment outcomes.Methods:We examined mitochondrial health and function after CONV and FLASH in vitro, ex vivo, and in vivo through assays of metabolic flux, mitochondrial membrane potential, mitochondrial reactive oxygen species (ROS), mitochondrial DNA damage and copy number, mitochondrial morphology, and tumor growth and survival.Results:In in vitro assays, murine pancreatic cancer (PDAC) cells showed evidence of equal mitochondrial damage in response to CONV and FLASH, but nontumorigenic pancreatic cells were spared by FLASH. These results were recapitulated ex vivo, and mice treated with FLASH showed higher response rates and longer survival time than mice treated with CONV in an in vivo tumor model.Conclusions:Collectively, these results suggest that FLASH spares mitochondrial function in nontumorigenic cells, but not in PDAC cells, relative to CONV. The preservation of mitochondrial integrity in nontumorigenic cells may be a key mechanism underlying the reduced normal tissue toxicity observed with FLASH RT.

Point scintillator dosimetry in ultra-high dose rate electron “FLASH” radiation therapy: A first characterization

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

The Quasi-Adiabatic Graphite Calorimeter for Absolute Dosimetry in Ultrahigh Dose Rate FLASH X-Ray Radiation Therapy.

An aluminium calorimeter was investigated as a possible real-time dosimeter for electron beams with ultra-high dose per pulse (DPP) as clinical applied at FLASH radiation therapy (1.5 Gy/pulse). Ion chambers, the most widely used active dosimeter type in conventional external beam radiation therapy, suffer very large ion recombination losses at these conditions. Passive dosimeters, as e.g. alanine, are independent of dose rate but do not provide real-time readout. In this work it is shown that the response of alanine is independent of the DPP in the investigated ultra-high DPP range (up to 2.3 Gy/pulse). Alanine dose measurements were then used to determine the ion recombination correction for an Advanced Markus parallel-plate ion chamber at ultra-high DPP. Ion collection losses larger than 50 % were observed. Therefore, ion chambers are not considered suitable for accurate dosimetry in FLASH radiation therapy. As alternative an aluminium open-to-atmosphere calorimeter, operated in quasi-adiabatic mode was investigated at ultra-high DPP electron radiation. The beam pulse charge, and thus the DPP, was varied to evaluate the linearity of the calorimeter response in the DPP range between 0.3 and 1.8 Gy/pulse. On average, the standard deviation of the calorimeter response was 0.1 %. The response was proportional to the DPP in the investigated range. The average deviation of

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.

Immune Response following FLASH and Conventional Radiation in Diffuse Midline Glioma

Simple SummaryUltra-high dose rate radiation, widely nicknamed FLASH-RT, kills tumors without significantly damaging nearby normal tissues. This selective sparing of normal tissue by FLASH-RT tissue is called the FLASH effect. This review explores some of the proposed mechanisms of the FLASH effect and the current data that might support its use in pancreatic cancer. Since radiation for pancreatic cancer treatment is limited by GI toxicity issues and is a disease with one of the lowest five-year survival rates, FLASH-RT could have a large impact in the treatment of this disease with further study.Recent preclinical evidence has shown that ionizing radiation given at an ultra-high dose rate (UHDR), also known as FLASH radiation therapy (FLASH-RT), can selectively reduce radiation injury to normal tissue while remaining isoeffective to conventional radiation therapy (CONV-RT) with respect to tumor killing. Unresectable pancreatic cancer is challenging to control without ablative doses of radiation, but this is difficult to achieve without significant gastrointestinal toxicity. In this review article, we explore the propsed mechanisms of FLASH-RT and its tissue-sparing effect, as well as its relevance and suitability for the treatment of pancreatic cancer. We also briefly discuss the challenges with regard to dosimetry, dose rate, and fractionation for using FLASH-RT to treat this disease.