Effects of Recombinant α1-Microglobulin on Early Proteomic Response in Risk Organs after Exposure to 177Lu-Octreotate.

Recombinant α1-microglobulin (A1M) is proposed as a protector during 177Lu-octreotate treatment of neuroendocrine tumors, which is currently limited by bone marrow and renal toxicity. Co-administration of 177Lu-octreotate and A1M could result in a more effective treatment by protecting healthy tissue, but the radioprotective action of A1M is not fully understood. The aim of this study was to examine the proteomic response of kidneys and bone marrow early after 177Lu-octreotate and/or A1M administration. Mice were injected with 177Lu-octreotate and/or A1M, while control mice received saline or A1M vehicle solution. Bone marrow, kidney medulla, and kidney cortex were sampled after 24 h or 7 d. The differential protein expression was analyzed with tandem mass spectrometry. The dosimetric estimation was based on 177Lu activity in the kidney. PHLDA3 was the most prominent radiation-responsive protein in kidney tissue. In general, no statistically significant difference in the expression of radiation-related proteins was observed between the irradiated groups. Most canonical pathways were identified in bone marrow from the 177Lu-octreotate+A1M group. Altogether, a tissue-dependent proteomic response followed exposure to 177Lu-octreotate alone or together with A1M. Combining 177Lu-octreotate with A1M did not inhibit the radiation-induced protein expression early after exposure, and late effects should be further studied.

Dual beam-current transformer design for monitoring and reporting of electron ultra-high dose rate (FLASH) beam parameters.

PURPOSE: To investigate the usefulness and effectiveness of a dual beam-current transformer (BCTs) design to monitor and record the beam dosimetry output and energy of pulsed electron FLASH (eFLASH) beams in real-time, and to inform on the usefulness of this design for future eFLASH beam control. METHODS: Two BCTs are integrated into the head of a FLASH Mobetron system, one located after the primary scattering foil and the other downstream of the secondary scattering foil. The response of the BCTs was evaluated individually to monitor beam output as a function of dose, scattering conditions, and ability to capture physical beam parameters such as pulse width (PW), pulse repetition frequency (PRF), and dose per pulse (DPP), and in combination to determine beam energy using the ratio of the lower-to-upper BCT signal. RESULTS: A linear relationship was observed between the absorbed dose measured on Gafchromic film and the BCT signals for both the upper and lower BCT (R2  > 0.99). A linear relationship was also observed in the BCT signals as a function of the number of pulses delivered regardless of the PW, DPP, or PRF (R2  > 0.99). The lower-to-upper BCT ratio was found to correlate strongly with the energy of the eFLASH beam due to differential beam attenuation caused by the secondary scattering foil. The BCTs were also able to provide accurate information about the PW, PRF, energy, and DPP for each individual pulse delivered in real-time. CONCLUSION: The dual BCT system integrated within the FLASH Mobetron was shown to be a reliable monitoring system able to quantify accelerator performance and capture all essential physical beam parameters on a pulse-by-pulse basis, and the ratio between the two BCTs was strongly correlated with beam energy. The fast signal readout and processing enables the BCTs to provide real-time information on beam output and energy and is proposed as a system suitable for accurate beam monitoring and control of eFLASH beams.

Characterization of the Plastic Scintillator Detector System Exradin W2 in a High Dose Rate Flattening-Filter-Free Photon Beam.

(1) Background: The Exradin W2 is a commercially available scintillator detector designed for reference and relative dosimetry in small fields. In this work, we investigated the performance of the W2 scintillator in a 10 MV flattening-filter-free photon beam and compared it to the performance of ion chambers designed for small field measurements. (2) Methods: We measured beam profiles and percent depth dose curves with each detector and investigated the linearity of each system based on dose per pulse (DPP) and pulse repetition frequency. (3) Results: We found excellent agreement between the W2 scintillator and the ion chambers for beam profiles and percent depth dose curves. Our results also showed that the two-voltage method of calculating the ion recombination correction factor was sufficient to correct for the ion recombination effect of ion chambers, even at the highest DPP. (4) Conclusions: These findings show that the W2 scintillator shows excellent agreement with ion chambers in high DPP conditions.

Technical Note: Extended field-of-view (FOV) MRI distortion determination through multi-positional phantom imaging.

Comprehensive characterization of geometric distortions for MRI simulators and MRI-guided treatment delivery systems is typically performed with large phantoms that are costly and unwieldy to handle. Here we propose an easily implementable methodology for MR distortion determination of the entire imaging space of the scanner through the use of a compact commercially available distortion phantom. The MagphanRT phantom was scanned at several locations within a MR scanner. From each scan, an approximate location of the phantom was determined from a subset of the fiducial spheres. The fiducial displacements were determined, and a displacement field was fitted to the displacement data using the entire multi-scan data set. An orthogonal polynomial expansion fitting function was used that had been augmented to include independent rigid-body transformations for each scan. The rigid-body portions of the displacement field were thereafter discarded, and the resultant fit then represented the distortion field. Multi-positional scans of the phantom were used successfully to determine the distortion field with extended coverage. A single scan of the phantom covered 20 cm in its smallest dimension. By stitching together overlapping scans we extended the distortion measurements to 30 cm. No information about the absolute location or orientation of each scan was required. The method, termed the Multi-Scan Expansion (MSE) method, can be easily applied for larger field-of-views (FOVs) by using a combination of larger phantom displacements and more scans. The implementation of the MSE method allows for distortion determination beyond the physical limitations of the phantom. The method is scalable to the user's needs and does not require any specialized equipment. This approach could open up for easier determination of the distortion magnitude at distances further from the scanner's isocenter. This is especially important in the newly proposed methodologies of MR-only simulation in RT and in adaptive replanning in MR linac systems.

Clinical impact of the VOLO optimizer on treatment plan quality and clinical treatment efficiency for CyberKnife.

With the recent CyberKnife treatment planning system (TPS) upgrade from Precision 1.0 to Precision 2.0, the new VOLO optimizer was released for plan optimization. The VOLO optimizer sought to overcome some of the limitations seen with the Sequential optimizer from previous TPS versions. The purpose of this study was to investigate the clinical impact of the VOLO optimizer on treatment plan quality and clinical treatment efficiency as compared to the Sequential optimizer. Treatment plan quality was evaluated in four categories of patients: Brain Simple (BS), Brain Complex (BC), Spine Complex (SC), and Prostate (PC). A total of 60 treatment plans were compared using both the Sequential and VOLO optimizers with Iris and MLC collimation with the same clinical constraints. Metrics evaluated included estimated treatment time, monitor units (MUs) delivered, conformity index (CI), and gradient index (GI). Furthermore, the clinical impact of the VOLO optimizer was evaluated through statistical analysis of the patient population treated during the 4 months before (n = 297) and 4 months after (n = 285) VOLO introduction. Significant MU and time reductions were observed for all four categories planned. MU reduction ranged from -14% (BS Iris) to -52% (BC MLC), and time reduction ranged from -11% (BS Iris) to -22% (BC MLC). The statistical analysis of patient population before and after VOLO introduction for patients using 6D Skull tracking with fixed cone, 6D Skull tracking with Iris, and Xsight Spine tracking with Iris were -4.6%, -22.2%, and -17.8% for treatment time reduction, -1.1%, -22.0%, and -28.4% for beam reduction and -3.2%, -21.8%, and -28.1% for MU reduction, respectively. The VOLO optimizer maintains or improves the plan quality while decreases the plan complexity and improves treatment efficiency. We anticipate an increase in patient throughput with the introduction of the VOLO optimizer.

The amount of injected 177Lu-octreotate strongly influences biodistribution and dosimetry in C57BL/6N mice.

BACKGROUND: (177)Lu-octreotate therapy has proven to give favorable results after treatment of patients with neuroendocrine tumors. Much focus has been on the binding and uptake of (177)Lu-octreotate in tumor tissue, but biodistribution properties in normal tissues is still not fully understood, and the effect of receptor saturation may be important. The aim of this study was to investigate the influence of the amount of (177)Lu-octreotate on the biodistribution of (177)Lu-octreotate in normal tissues in mice. MATERIAL AND METHODS: C57BL/6N female mice were intravenously injected with 0.1-150 MBq (177)Lu-octreotate (0.039 µg peptide/MBq). The mice were killed 0.25 h to 14 days after injection by cardiac puncture under anesthesia. Activity concentration was determined in blood, bone marrow, kidneys, liver, lungs, pancreas, and spleen, and mean absorbed doses were calculated. RESULTS: The activity concentration varied with time and amount of injected activity. At 4-8 h after injection, a local maximum in activity concentration was found for liver, lungs, pancreas, and spleen. With the exception for the lower injected activities (0.1-1 MBq), the overall highest uptake was found in the kidneys (%IA/g). Large variations were found and the activity concentration in kidneys was 11-23%IA/g at 4 h, and 0.22-1.9%IA/g at 7 days after injection. Furthermore, a clear reduction in activity concentration with increased injected activity was observed for lungs, pancreas and spleen. CONCLUSION: The activity concentration in all tissues investigated was strongly influenced by the amount of (177)Lu-octreotate injected. Large differences in mean absorbed dose per unit injected activity were found between low (0.1-1 MBq, 0.0039-0.039 µg) and moderate amounts (5-45 MBq, 0.2-1.8 µg). Furthermore, the results clearly showed the need for better ways to estimate absorbed dose to bone marrow other than methods based on a single blood sample analysis. Since the absorbed dose to critical organs will limit the amount of (177)Lu-octreotate administered, these findings must be taken into consideration when optimizing this type of therapy.

Technical note: High-dose and ultra-high dose rate (UHDR) evaluation of Al2 O3 :C optically stimulated luminescent dosimeter nanoDots and powdered LiF:Mg,Ti thermoluminescent dosimeters for radiation therapy applications.

BACKGROUND: Dosimetry in ultra-high dose rate (UHDR) electron beamlines poses a significant challenge owing to the limited usability of standard dosimeters in high dose and high dose-per-pulse (DPP) applications. PURPOSE: In this study, Al2 O3 :C nanoDot optically stimulated luminescent dosimeters (OSLDs), single-use powder-based LiF:Mg,Ti thermoluminescent dosimeters (TLDs), and Gafchromic EBT3 film were evaluated at extended dose ranges (up to 40 Gy) in conventional dose rate (CONV) and UHDR beamlines to determine their usability for calibration and dose verification in the setting of FLASH radiation therapy. METHODS: OSLDs and TLDs were evaluated against established dose-rate-independent Gafchromic EBT3 film with regard to the potential influence of mean dose rate, instantaneous dose rate, and DPP on signal response. The dosimeters were irradiated at CONV or UHDR conditions on a 9-MeV electron beam. Under UHDR conditions, different settings of pulse repetition frequency (PRF), pulse width (PW), and pulse amplitude were used to characterize the individual dosimeters' response in order to isolate their potential dependencies on dose, dose rate, and DPP. RESULTS: The OSLDs, TLDs, and Gafchromic EBT3 film were found to be suitable at a dose range of up to 40 Gy without any indication of saturation in signal. The response of OSLDs and TLDs in UHDR conditions were found to be independent of mean dose rate (up to 1440 Gy/s), instantaneous dose rate (up to 2 MGy/s), and DPP (up to 7 Gy), with uncertainties on par with nominal values established in CONV beamlines (± 4%). In cross-comparing the response of OSLDs, TLDs and Gafchromic film at dose rates of 0.18-245 Gy/s, the coefficient of variation or relative standard deviation in the measured dose between the three dosimeters (inter-dosimeter comparison) was found to be within 2%. CONCLUSIONS: We demonstrated the dynamic range of OSLDs, TLDs, and Gafchromic film to be suitable up to 40 Gy, and we developed a protocol that can be used to accurately translate the measured signal in each respective dosimeter to dose. OSLDs and powdered TLDs were shown to be viable for dosimetric measurement in UHDR beamlines, providing dose measurements with accuracies on par with Gafchromic EBT3 film and their concurrent use demonstrating a means for redundant dosimetry in UHDR conditions.

A comprehensive investigation of the performance of a commercial scintillator system for applications in electron FLASH radiotherapy.

BACKGROUND: Dosimetry in ultra-high dose rate (UHDR) beamlines is significantly challenged by limitations in real-time monitoring and accurate measurement of beam output, beam parameters, and delivered doses using conventional radiation detectors, which exhibit dependencies in ultra-high dose-rate (UHDR) and high dose-per-pulse (DPP) beamline conditions. PURPOSE: In this study, we characterized the response of the Exradin W2 plastic scintillator (Standard Imaging, Inc.), a water-equivalent detector that provides measurements with a time resolution of 100 Hz, to determine its feasibility for use in UHDR electron beamlines. METHODS: The W2 scintillator was exposed to an UHDR electron beam with different beam parameters by varying the pulse repetition frequency (PRF), pulse width (PW), and pulse amplitude settings of an electron UHDR linear accelerator system. The response of the W2 scintillator was evaluated as a function of the total integrated dose delivered, DPP, and mean and instantaneous dose rate. To account for detector radiation damage, the signal sensitivity (pC/Gy) of the W2 scintillator was measured and tracked as a function of dose history. RESULTS: The W2 scintillator demonstrated mean dose rate independence and linearity as a function of integrated dose and DPP for DPP ≤ 1.5 Gy (R2 > 0.99) and PRF ≤ 90 Hz. At DPP > 1.5 Gy, nonlinear behavior and signal saturation in the blue and green signals as a function of DPP, PRF, and integrated dose became apparent. In the absence of Cerenkov correction, the W2 scintillator exhibited PW dependence, even at DPP values <1.5 Gy, with a difference of up to 31% and 54% in the measured blue and green signal for PWs ranging from 0.5 to 3.6 µs. The change in signal sensitivity of the W2 scintillator as a function of accumulated dose was approximately 4%/kGy and 0.3%/kGy for the measured blue and green signal responses, respectively, as a function of integrated dose history. CONCLUSION: The Exradin W2 scintillator can provide output measurements that are both dose rate independent and linear in response if the DPP is kept ≤1.5 Gy (corresponding to a mean dose rate up to 290 Gy/s in the used system), as long as proper calibration is performed to account for PW and changes in signal sensitivity as a function of accumulated dose. For DPP > 1.5 Gy, the W2 scintillator's response becomes nonlinear, likely due to limitations in the electrometer related to the high signal intensity.

Evaluation of ion chamber response for applications in electron FLASH radiotherapy.

Ion chambers are required for calibration and reference dosimetry applications in radiation therapy (RT). However, exposure of ion chambers in ultra-high dose rate (UHDR) conditions pertinent to FLASH-RT leads to severe saturation and ion recombination, which limits their performance and usability. The purpose of this study was to comprehensively evaluate a set of commonly used commercially available ion chambers in RT, all with different design characteristics, and use this information to produce a prototype ion chamber with improved performance in UHDR conditions as a first step toward ion chambers specific for FLASH-RT. The Advanced Markus and Exradin A10, A26, and A20 ion chambers were evaluated. The chambers were placed in a water tank, at a depth of 2 cm, and exposed to an UHDR electron beam at different pulse repetition frequency (PRF), pulse width (PW), and pulse amplitude settings on an IntraOp Mobetron. Ion chamber responses were investigated for the various beam parameter settings to isolate their dependence on integrated dose, mean dose rate and instantaneous dose rate, dose-per-pulse (DPP), and their design features such as chamber type, bias voltage, and collection volume. Furthermore, a thin parallel-plate (TPP) prototype ion chamber with reduced collector plate separation and volume was constructed and equally evaluated as the other chambers. The charge collection efficiency of the investigated ion chambers decreased with increasing DPP, whereas the mean dose rate did not affect the response of the chambers (± 1%). The dependence of the chamber response on DPP was found to be solely related to the total dose within the pulse, and not on mean dose rate, PW, or instantaneous dose rate within the ranges investigated. The polarity correction factor (Ppol ) values of the TPP prototype, A10, and Advanced Markus chambers were found to be independent of DPP and dose rate (± 2%), while the A20 and A26 chambers yielded significantly larger variations and dependencies under the same conditions. Ion chamber performance evaluated under different irradiation conditions of an UHDR electron beam revealed a strong dependence on DPP and a negligible dependence on the mean and instantaneous dose rates. These results suggest that modifications to ion chambers design to improve their usability in UHDR beamlines should focus on minimizing DPP effects, with emphasis on optimizing the electric field strength, through the construction of smaller electrode separation and larger bias voltages. This was confirmed through the production and evaluation of a prototype ion chamber specifically designed with these characteristics.

Characterization of a novel time-resolved, real-time scintillation dosimetry system for ultra-high dose rate radiation therapy applications.

Background: Scintillation dosimetry has promising qualities for ultra-high dose rate (UHDR) radiotherapy (RT), but no system has shown compatibility with mean dose rates (DR-) above 100 Gy/s and doses per pulse (Dp) exceeding 1.5 Gy typical of UHDR (FLASH)-RT. The aim of this study was to characterize a novel scintillator dosimetry system with the potential of accommodating UHDRs. Methods and Materials: A thorough dosimetric characterization of the system was performed on an UHDR electron beamline. The system's response as a function of dose, DR-,Dp, and the pulse dose rate DRp was investigated, together with the system's dose sensitivity (signal per unit dose) as a function of dose history. The capabilities of the system for time-resolved dosimetric readout were also evaluated. Results: Within a tolerance of ±3%, the system exhibited dose linearity and was independent of DR- and Dp within the tested ranges of 1.8-1341 Gy/s and 0.005-7.68 Gy, respectively. A 6% reduction in the signal per unit dose was observed as DRp was increased from 8.9e4-1.8e6 Gy/s. Additionally, the dose delivered per integration window of the continuously sampling photodetector had to remain between 0.028 and 11.64 Gy to preserve a stable signal response per unit dose. The system accurately measured Dp of individual pulses delivered at up to 120 Hz. The day-to-day variation of the signal per unit dose at a reference setup varied by up to ±13% but remained consistent (<±2%) within each day of measurements and showed no signal loss as a function of dose history. Conclusions: With daily calibrations and DRp specific correction factors, the system reliably provides real-time, millisecond-resolved dosimetric measurements of pulsed conventional and UHDR beams from typical electron linacs, marking an important advancement in UHDR dosimetry and offering diverse applications to FLASH-RT and related fields.

Development of novel ionization chambers for reference dosimetry in electron flash radiotherapy.

BACKGROUND: Reference dosimetry in ultra-high dose rate (UHDR) beamlines is significantly hindered by limitations in conventional ionization chamber design. In particular, conventional chambers suffer from severe charge collection efficiency (CCE) degradation in high dose per pulse (DPP) beams. PURPOSE: The aim of this study was to optimize the design and performance of parallel plate ion chambers for use in UHDR dosimetry applications, and evaluate their potential as reference class chambers for calibration purposes. Three chamber designs were produced to determine the influence of the ion chamber response on electrode separation, field strength, and collection volume on the ion chamber response under UHDR and ultra-high dose per pulse (UHDPP) conditions. METHODS: Three chambers were designed and produced: the A11-VAR (0.2-1.0 mm electrode gap, 20 mm diameter collector), the A11-TPP (0.3 mm electrode gap, 20 mm diameter collector), and the A30 (0.3 mm electrode gap, 5.4 mm diameter collector). The chambers underwent full characterization using an UHDR 9 MeV electron beam with individually varied beam parameters of pulse repetition frequency (PRF, 10-120 Hz), pulse width (PW, 0.5-4 µs), and pulse amplitude (0.01-9 Gy/pulse). The response of the ion chambers was evaluated as a function of the DPP, PRF, PW, dose rate, electric field strength, and electrode gap. RESULTS: The chamber response was found to be dependent on DPP and PW, and these dependencies were mitigated with larger electric field strengths and smaller electrode spacing. At a constant electric field strength, we measured a larger CCE as a function of DPP for ion chambers with a smaller electrode gap in the A11-VAR. For ion chambers with identical electrode gap (A11-TPP and A30), higher electric field strengths were found to yield better CCE at higher DPP. A PW dependence was observed at low electric field strengths (500 V/mm) for DPP values ranging from 1 to 5 Gy at PWs ranging from 0.5 to 4 µs, but at electric field strengths of 1000 V/mm and higher, these effects become negligible. CONCLUSION: This study confirmed that the CCE of ion chambers depends strongly on the electrode spacing and the electric field strength, and also on the DPP and the PW of the UHDR beam. A significant finding of this study is that although chamber performance does depend on PW, the effect on the CCE becomes negligible with reduced electrode spacing and increased electric field. A CCE of ≥95% was achieved for DPPs of up to 5 Gy with no observable dependence on PW using the A30 chamber, while still achieving an acceptable performance in conventional dose rate beams, opening up the possibility for this type of chamber to be used as a reference class chamber for calibration purposes of electron FLASH beamlines.

Discordance in acute gastrointestinal toxicity between synchrotron-based proton and linac-based electron ultra-high dose rate irradiation.

Purpose: Proton FLASH has been investigated using cyclotron and synchrocyclotron beamlines but not synchrotron beamlines. We evaluated the impact of dose rate (ultra-high [UHDR] vs. conventional [CONV]) and beam configuration (shoot-through [ST] vs. spread-out-Bragg-peak [SOBP]) on acute radiation-induced gastrointestinal toxicity (RIGIT) in mice. We also compared RIGIT between synchrotron-based protons and linac-based electrons with matched mean dose rates. Methods and Materials: We administered abdominal irradiation (12-14 Gy single fraction) to female C57BL/6J mice with an 87 MeV synchrotron-based proton beamline (2 cm diameter field size as a lateral beam). Dose rates were 0.2 Gy/s (S-T pCONV), 0.3 Gy/s (SOBP pCONV), 150 Gy/s (S-T pFLASH), and 230 Gy/s (SOBP pFLASH). RIGIT was assessed by the jejunal regenerating crypt assay and survival. We also compared responses to proton [pFLASH and pCONV] with responses to electron CONV (eCONV, 0.4 Gy/s) and electron FLASH (eFLASH, 188-205 Gy/s). Results: The number of regenerating jejunal crypts at each matched dose was lowest for pFLASH (similar between S-T and SOBP), greater and similar between pCONV (S-T and SOBP) and eCONV, and greatest for eFLASH. Correspondingly, mice that received pFLASH SOBP had the lowest survival rates (50% at 50 days), followed by pFLASH S-T (80%), and pCONV SOBP (90%), but 100% of mice receiving pCONV S-T survived (log-rank P = 0.047 for the four groups). Conclusions: Our findings are consistent with an increase in RIGIT after synchrotron-based pFLASH versus pCONV. This negative proton-specific FLASH effect versus linac-based electron irradiation underscores the importance of understanding the physical and biological factors that will allow safe and effective clinical translation.

Pulmonary interstitial lymphography: A prospective trial with potential impact on stereotactic ablative radiotherapy planning for early-stage lung cancer.

This prospective feasibility trial investigated pulmonary interstitial lymphography to identify thoracic primary nodal drainage (PND). A post-hoc analysis of nodal recurrences was compared with PND for patients with early-stage lung cancer; larger studies are needed to establish correlation. Exploratory PND-inclusive stereotactic ablative radiotherapy plans were assessed for dosimetric feasibility.

Navigating the Critical Translational Questions for Implementing FLASH in the Clinic.

The "FLASH effect" is an increased therapeutic index, that is, reduced normal tissue toxicity for a given degree of anti-cancer efficacy, produced by ultra-rapid irradiation delivered on time scales orders of magnitude shorter than currently conventional in the clinic for the same doses. This phenomenon has been observed in numerous preclinical in vivo tumor and normal tissue models. While the underlying biological mechanism(s) remain to be elucidated, a path to clinical implementation of FLASH can be paved by addressing several critical translational questions. Technological questions pertinent to each beam type (eg, electron, proton, photon) also dictate the logical progression of experimentation required to move forward in safe and decisive clinical trials. Here we review the available preclinical data pertaining to these questions and how they may inform strategies for FLASH cancer therapy clinical trials.

Redefining FLASH RT: the impact of mean dose rate and dose per pulse in the gastrointestinal tract.

Background: The understanding of how varying radiation beam parameter settings affect the induction and magnitude of the FLASH effect remains limited. Purpose: We sought to evaluate how the magnitude of radiation-induced gastrointestinal (GI) toxicity (RIGIT) depends on the interplay between mean dose rate (MDR) and dose per pulse (DPP). Methods: C57BL/6J mice were subjected to total abdominal irradiation (11-14 Gy single fraction) under conventional irradiation (low DPP and low MDR, CONV) and various combinations of DPP and MDR up to ultra-high-dose-rate (UHDR) beam conditions. The effects of DPP were evaluated for DPPs of 1-6 Gy while the total dose and MDR were kept constant; the effects of MDR were evaluated for the range 0.3- 1440 Gy/s while the total dose and DPP were kept constant. RIGIT was quantified in non-tumor-bearing mice through the regenerating crypt assay and survival assessment. Tumor response was evaluated through tumor growth delay. Results: Within each tested total dose using a constant MDR (>100 Gy/s), increasing DPP led to better sparing of regenerating crypts, with a more prominent effect seen at 12 and 14 Gy TAI. However, at fixed DPPs >4 Gy, similar sparing of crypts was demonstrated irrespective of MDR (from 0.3 to 1440 Gy/s). At a fixed high DPP of 4.7 Gy, survival was equivalently improved relative to CONV for all MDRs from 0.3 Gy/s to 104 Gy/s, but at a lower DPP of 0.93 Gy, increasing MDR produced a greater survival effect. We also confirmed that high DPP, regardless of MDR, produced the same magnitude of tumor growth delay relative to CONV using a clinically relevant melanoma mouse model. Conclusions: This study demonstrates the strong influence that the beam parameter settings have on the magnitude of the FLASH effect. Both high DPP and UHDR appeared independently sufficient to produce FLASH sparing of GI toxicity, while isoeffective tumor response was maintained across all conditions.

Recording and reporting of ultra-high dose rate "FLASH" delivery for preclinical and clinical settings.

Treatments at ultra-high dose rate (UHDR) have the potential to improve the therapeutic index of radiation therapy (RT) by sparing normal tissues compared to conventional dose rate irradiations. Insufficient and inconsistent reporting in physics and dosimetry of preclinical and translational studies may have contributed to a reproducibility crisis of radiobiological data in the field. Consequently, the development of a common terminology, as well as common recording, reporting, dosimetry, and metrology standards is required. In the context of UHDR irradiations, the temporal dose delivery parameters are of importance, and under-reporting of these parameters is also a concern.This work proposes a standardization of terminology, recording, and reporting to enhance comparability of both preclinical and clinical UHDR studies and and to allow retrospective analyses to aid the understanding of the conditions which give rise to the FLASH effect.

Dosimetric calibration of anatomy-specific ultra-high dose rate electron irradiation platform for preclinical FLASH radiobiology experiments.

BACKGROUND: 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. PURPOSE: 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. METHODS: 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. RESULTS: 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 (∼0.75 cm depth) produced UHDR and CONV doses to the irradiated volumes with > 95% agreement. CONCLUSION: 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.

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

Background & Purpose: 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 1000 Gy/s. We established a framework for the acceptance, commissioning, and periodic quality assurance (QA) of electron FLASH units and present an example of commissioning. Methods: 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. Results: 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. Conclusions: 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.

Multi-Institutional Audit of FLASH and Conventional Dosimetry With a 3D Printed Anatomically Realistic Mouse Phantom.

PURPOSE: We conducted a multi-institutional dosimetric audit between FLASH and conventional dose rate (CONV) electron irradiations by using an anatomically realistic 3-dimensional (3D) printed mouse phantom. METHODS AND MATERIALS: A computed tomography (CT) scan of a live mouse was used to create a 3D model of bony anatomy, lungs, and soft tissue. A dual-nozzle 3D printer was used to print the mouse phantom using acrylonitrile butadiene styrene (∼1.02 g/cm3) and polylactic acid (∼1.24 g/cm3) simultaneously to simulate soft tissue and bone densities, respectively. The lungs were printed separately using lightweight polylactic acid (∼0.64 g/cm3). Hounsfield units (HU), densities, and print-to-print stability of the phantoms were assessed. Three institutions were each provided a phantom and each institution performed 2 replicates of irradiations at selected anatomic regions. The average dose difference between FLASH and CONV dose distributions and deviation from the prescribed dose were measured with radiochromic film. RESULTS: Compared with the reference CT scan, CT scans of the phantom demonstrated mass density differences of 0.10 g/cm3 for bone, 0.12 g/cm3 for lung, and 0.03 g/cm3 for soft tissue regions. Differences in HU between phantoms were <10 HU for soft tissue and bone, with lung showing the most variation (54 HU), but with minimal effect on dose distribution (<0.5%). Mean differences between FLASH and CONV decreased from the first to the second replicate (4.3%-1.2%), and differences from the prescribed dose decreased for both CONV (3.6%-2.5%) and FLASH (6.4%-2.7%). Total dose accuracy suggests consistent pulse dose and pulse number, although these were not specifically assessed. Positioning variability was observed, likely due to the absence of robust positioning aids or image guidance. CONCLUSIONS: This study marks the first dosimetric audit for FLASH using a nonhomogeneous phantom, challenging conventional calibration practices reliant on homogeneous phantoms. The comparison protocol offers a framework for credentialing multi-institutional studies in FLASH preclinical research to enhance reproducibility of biologic findings.

Comprehensive evaluation and new recommendations in the use of Gafchromic EBT3 film.

BACKGROUND: Gafchromic film's unique properties of tissue-equivalence, dose-rate independence, and high spatial resolution make it an attractive choice for many dosimetric applications. However, complicated calibration processes and film handling limits its routine use. PURPOSE: We evaluated the performance of Gafchromic EBT3 film after irradiation under a variety of measurement conditions to identify aspects of film handling and analysis for simplified but robust film dosimetry. METHODS: The short- (from 5 min to 100 h) and long-term (months) film response was evaluated for clinically relevant doses of up to 50 Gy for accuracy in dose determination and relative dose distributions. The dependence of film response on film-read delay, film batch, scanner type, and beam energy was determined. RESULTS: Scanning the film within a 4-h window and using a standard 24-h calibration curve introduced a maximum error of 2% over a dose range of 1-40 Gy, with lower doses showing higher uncertainty in dose determination. Relative dose measurements demonstrated <1 mm difference in electron beam parameters such as depth of 50% of the maximum dose value (R50 ), independent of when the film was scanned after irradiation or the type of calibration curve used (batch-specific or time-specific calibration curve) if the same default scanner was used. Analysis of films exposed over a 5-year period showed that using the red channel led to the lowest variation in the measured net optical density values for different film batches, with doses >10 Gy having the lowest coefficient of variation (<1.7%). Using scanners of similar design produced netOD values within 3% after exposure to doses of 1-40 Gy. CONCLUSIONS: This is the first comprehensive evaluation of the temporal and batch dependence of Gafchromic EBT3 film evaluated on consolidated data over 8 years. The relative dosimetric measurements were insensitive to the type of calibration applied (batch- or time-specific) and in-depth time-dependent dosimetric signal behaviors can be established for film scanned outside of the recommended 16-24 h post-irradiation window. We generated guidelines based on our findings to simplify film handling and analysis and provide tabulated dose- and time-dependent correction factors to achieve this without reducing the accuracy of dose determination.