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Purpose: Preclinical studies indicate a normal tissue sparing effect when ultra-high dose rate (FLASH) radiation is used, while tumor response is maintained. This differential response has promising perspectives for improved clinical outcome. This study investigates tumor control and normal tissue toxicity of pencil beam scanning (PBS) proton FLASH in a mouse model., Methods and Materials: Tumor bearing hind limbs of non-anaesthetized CDF1 mice were irradiated in a single fraction with a PBS proton beam using either conventional (CONV) dose rate (0.33-0.63 Gy/s field dose rate, 244 MeV) or FLASH (71-89 Gy/s field dose rate, 250 MeV). 162 mice with a C3H mouse mammary carcinoma subcutaneously implanted in the foot were irradiated with physical doses of 40-60 Gy (8-14 mice per dose point). The endpoints were tumor control (TC) assessed as no recurrent tumor at 90 days after treatment, the level of acute moist desquamation (MD) to the skin of the foot within 25 days post irradiation, and radiation induced fibrosis (RIF) within 24 weeks post irradiation., Results: TCD 50 (dose for 50% tumor control) was similar for CONV and FLASH with values (and 95% confidence intervals) of 49.1 (47.0-51.4) Gy for CONV and 51.3 (48.6-54.2) Gy for FLASH. RIF analysis was restricted to mice with tumor control. Both endpoints showed distinct normal tissue sparing effect of proton FLASH with MDD 50 (dose for 50% of mice displaying moist desquamation) of <40.1 Gy for CONV and 52.3 (50.0-54.6) Gy for FLASH, (dose modifying factor at least 1.3) and FD 50 (dose for 50% of mice displaying fibrosis) of 48.6 (43.2-50.8) Gy for CONV and 55.6 (52.5-60.1) Gy for FLASH (dose modifying factor of 1.14)., Conclusions: FLASH had the same tumor control as CONV, but reduced normal tissue damage assessed as acute skin damage and radiation induced fibrosis., Competing Interests: Conflict of interest statement This study presented in this manuscript is partly funded by Varian. Two co-authors are co-inventors on a patent-application filled with application number 63257211 and EFS ID: 44064136, which contains parts of the data included in the manuscript., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Key factors in FLASH treatments are the ultra-high dose rate (UHDR) and the time structure of the beam delivery. Measurement of the time structure in pencil beam scanning (PBS) proton FLASH treatments is challenging for many types of detectors since high temporal resolution is needed. In this study, a fast scintillator detector system was developed and used to measure the individual spot durations as well as the time when the beam moves between two positions (transition duration) during PBS proton FLASH and UHDR treatments. The spot durations were compared with machine log-file recordings., Methods: A detector system based on inorganic scintillating crystals was developed. The system consisted of four detector probes made of a sub-millimeter ZnSe:O crystal that was coupled via an optical fiber to an optical reader with 50 kHz sampling rate. The detector system was used in two experiments, both performed with a PBS proton beam with 250 MeV beam energy and 215 nA requested nozzle beam current. The sampling rate enabled multiple measurements during each spot delivery and during the beam transition between spots. First, the detector was tested in a phantom experiment, where a total of 305 scan sequences were delivered to the four detectors. The number of spots delivered without beam interruption in a single scan sequence ranged from one to 35. The spot duration and transition duration were measured for each individual spot. Secondly, the detector system was used in vivo in preclinical experiments with FLASH irradiation of mouse legs placed in the entrance plateau of the beam. A single detector was placed 1 cm downstream of the irradiated mouse leg. The mouse dose ranged from 30.5 to 44.2 Gy and the field consisted of 35 spots. The spot durations as well as the mean dose rate (field dose divided by the measured field duration) for each mouse were determined using the detector and then compared with the corresponding log files., Results: The phantom experiment showed that the logged total duration of an uninterrupted spot sequence was consistently shorter than the measured duration with a difference of -0.252 ms (95% confidence interval: [-0.255, -0.249 ms]). This corresponded to 0.05%-0.07% of the spot sequence duration in the mice experiments. For individual spots, the mean ± 1SD difference between logged and measured spot duration was -0.39 ± 0.05 ms for the first spot in a sequence, 0.13 ± 0.04 ms for the last spot in a sequence, and -0.0017 ± 0.09 ms for the intermediate spots in a sequence. The measured spot transition durations were 0.20 ± 0.04 ms (5.1 mm horizontal steps) and 0.50 ± 0.04 ms (5.0 mm vertical steps). For the mouse experiments, the mean dose rate calculated from the measured field duration was 84.1-92.5 Gy/s. It agreed with log files with a root mean square difference of 0.02 Gy/s., Conclusions: Fiber-coupled scintillator detectors were designed with sufficient temporal resolution to measure the spot and transition duration during PBS proton UHDR deliveries. Their small volume makes them feasible for in vivo use in preclinical FLASH studies. The logged spot durations were in excellent agreement with measurements but showed small systematic errors in the logged duration for the first and last spot in a sequence., (© 2022 American Association of Physicists in Medicine.)

Background and Purpose: Preclinical studies indicate a normal tissue sparing effect using ultra-high dose rate (FLASH) radiation with comparable tumor response. Most data so far are based on electron beams with limited utility for human treatments. This study validates the effect of proton FLASH delivered with pencil beam scanning (PBS) in a mouse leg model of acute skin damage and quantifies the normal tissue sparing factor, the FLASH factor, through full dose response curves., Materials and Methods: The right hind limb of CDF1 mice was irradiated with a single fraction of proton PBS in the entrance plateau of either a 244 MeV conventional dose rate field or a 250 MeV FLASH field. In total, 301 mice were irradiated in four separate experiments, with 7-21 mice per dose point. The endpoints were the level of acute moist desquamation to the skin of the foot within 25 days post irradiation., Results: The field duration and field dose rate were 61-107 s and 0.35-0.40 Gy/s for conventional dose rate and 0.35-0.73 s and 65-92 Gy/s for FLASH. Full dose response curves for five levels of acute skin damage for both conventional and FLASH dose rate revealed a distinct normal tissue sparing effect with FLASH: across all scoring levels, a 44-58% higher dose was required to give the same biological response with FLASH as compared to the conventional dose rate., Conclusions: The normal tissue sparing effect of PBS proton FLASH was validated. The FLASH factor was quantified through full dose response curves., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Preclinical studies have shown a preferential normal tissue sparing effect of FLASH radiation therapy with ultra-high dose rates. The aim of the present study was to use a murine model of acute skin toxicity to investigate the biologic effect of varying dose rates, time structure, and introducing pauses in the dose delivery. The right hind limbs of nonanaesthetized mice were irradiated in the entrance plateau of a pencil beam scanning proton beam with 39.3 Gy. Experiment 1 was with varying field dose rates (0.7-80 Gy/s) without repainting, experiment 2 was with varying field dose rates (0.37-80 Gy/s) with repainting, and in experiment 3, the dose was split into 2, 3, 4, or 6 identical deliveries with 2-minute pauses. In total, 320 mice were included, with 6 to 25 mice per group. The endpoints were skin toxicity of different levels up to 25 days after irradiation. The dose rate 50 , which is the dose rate to induce a response in 50% of the animals, depended on the level of skin toxicity, with the higher toxicity levels displaying a FLASH effect at 0.7-2 Gy/s. Repainting resulted in higher toxicity for the same field dose rate. Splitting the dose into 2 deliveries reduced the FLASH effect, and for 3 or more deliveries, the FLASH effect was almost abolished for lower grades of toxicity. The dose rate that induced a FLASH effect varied for different skin toxicity levels, which are characterized by a differing degree of sensitivity to radiation dosage. Conclusions on a threshold for the dose rate needed to obtain a FLASH effect can therefore be influenced by the dose sensitivity of the used endpoint. Splitting the total dose into more deliveries compromised the FLASH effect. This can have an impact for fractionation as well as for regions where 2 or more FLASH fields overlap within the same treatment session. [ABSTRACT FROM AUTHOR]