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Objective: A favorable effect of ultra-high dose rate (FLASH) radiation on normal tissue-sparing has been indicated in several preclinical studies. In these studies, the adverse effects of radiation damage were reduced without compromising tumor control. Most studies of proton FLASH investigate these effects within the entrance of a proton beam. However, the real advantage of proton therapy lies in the Spread-out Bragg Peak (SOBP), which allows for giving a high dose to a target with a limited dose to healthy tissue at the entrance of the beam. Therefore, a clinically relevant investigation of the FLASH effect would be of healthy tissues within a SOBP. Our study quantified the tissue-sparing effect of FLASH radiation on acute and late toxicity within an SOBP in a murine model. Material/Methods: Radiation-induced damage was assessed for acute and late toxicity in the same mice following irradiation with FLASH (Field dose rate of 60 Gy/s) or conventional (CONV, 0.34 Gy/s) dose rates. The right hindleg of unanesthetized female CDF1 mice was irradiated with single-fraction doses between 19.9-49.7 Gy for CONV and 30.4-65.9 Gy for FLASH with 5-8 mice per dose. The leg was placed in the middle of a 5 cm SOBP generated from a mono-energetic beam using a 2D range modulator. Acute skin toxicity quantified by hair loss, moist desquamation and toe separation was monitored daily within 29 days post-treatment. Late toxicity of fibrotic development measured by leg extendibility was monitored biweekly until 30 weeks post-treatment. Results: Comparison of acute skin toxicity following radiation indicated a tissuesparing effect of FLASH compared to conventional single-fraction radiation with a mean protection ratio of 1.40 (1.35-1.46). Fibrotic development similarly indicated normal tissue sparing with a 1.18 (1.17-1.18) protection ratio. The acute skin toxicity tissue sparing was similar to data from entrance-beam irradiations of Sørensen et al. (4). Conclusion: Full dose-response curves for acute and late toxicity after CONV and FLASH radiation were obtained. Radiation within the SOBP retains the normal-tissue-sparing effect of FLASH with a dose-modifying factor of 40% for acute skin damage and 18% for fibrotic development. [ABSTRACT FROM AUTHOR]

Background: The spatial and temporal dose rate distribution of pencil beam scanning (PBS) proton therapy is important in ultra-high dose rate (UHDR) or FLASH irradiations. Validation of the temporal structure of the dose rate is crucial for quality assurance and may be performed using detectors with high temporal resolution and large dynamic range. Purpose: To provide time-resolved in vivo dose rate measurements using a scintillator-based detector during proton PBS pre-clinical mouse experiments with dose rates ranging from conventional to UHDR. Methods: All irradiations were performed at the entrance plateau of a 250 MeV PBS proton beam. A detector system with four fiber-coupled ZnSe:O inorganic scintillators and 20 μs temporal resolution was used for dose rate measurements.The system was first characterized in terms of precision and stem signal. The detector precision was determined through repeated irradiations with the same field. The stem signal contribution was quantified by irradiating two of the detector probes alongside a bare fiber (fiber without a coupled scintillator). Next, the detector system was calibrated against an ionization chamber (IC) with all four detector probes and the IC placed in a water bath at 2 cm depth. A scan pattern covering 9.6 × 9.6 cm was used. Multiple irradiations with different requested nozzle currents provided instantaneous dose rates at the detector positions in the range of 7–1270 Gy/s. The correspondence of the detector signal (in Volts) to the instantaneous dose rate (in Gy/s) was found.The instantaneous dose rate was calculated from the beam current and the spot-to-detector distance assuming a Gaussian beam profile at distances up to 8 mm from the spot. Afterwards, the calibrated system was used in vivo, in mouse experiments, where mouse legs were irradiated with a constant dose and varying field dose rates of 0.7–87.5 Gy/s. The instantaneous dose rate was measured for each delivered spot and the delivered dose was determined as the integrated instantaneous dose rate. The spot dose profile and PBS dose rate map were calculated. The dose contamination to neighbouring mice were measured together with the upper limit of the dose to the mouse body. Results: The detectors showed high precision with ≤0.4% fluctuations in the measured dose. The stem signal exceeded 10% for spots <5 mm from the optical fiber and >18 mm from the scintillator.It contributed up to 0.2% to the total dose, which was considered negligible. All four detectors showed a non-linear relation between signal and instantaneous dose rate, which was modelled with a polynomial response function. In the mouse experiments, the measured scintillator dose showed 1.8% fluctuations, independent of the field dose rate.The in vivo measured spot dose profile had tails that deviated from a Gaussian profile with measurable dose contributions from spots up to 85 mm from the detector. Neighbour mouse irradiation contributed ∼1% of the total mouse dose. The upper limit of the mouse body dose was 6% of the mouse leg dose. Conclusions: A fiber-coupled inorganic scintillator-based detector system can provide high precision in vivo measurements of the instantaneous dose rate if correction for the non-linear dose rate dependency is applied. [ABSTRACT FROM AUTHOR]