A phenomenological model of proton FLASH oxygen depletion effects depending on tissue vasculature and oxygen supply.

Introduction: Radiation-induced oxygen depletion in tissue is assumed as a contributor to the FLASH sparing effects. In this study, we simulated the heterogeneous oxygen depletion in the tissue surrounding the vessels and calculated the proton FLASH effective-dose-modifying factor (FEDMF), which could be used for biology-based treatment planning. Methods: The dose and dose-weighted linear energy transfer (LET) of a small animal proton irradiator was simulated with Monte Carlo simulation. We deployed a parabolic partial differential equation to account for the generalized radiation oxygen depletion, tissue oxygen diffusion, and metabolic processes to investigate oxygen distribution in 1D, 2D, and 3D solution space. Dose and dose rates, particle LET, vasculature spacing, and blood oxygen supplies were considered. Using a similar framework for the hypoxic reduction factor (HRF) developed previously, the FEDMF was derived as the ratio of the cumulative normoxic-equivalent dose (CNED) between CONV and UHDR deliveries. Results: Dynamic equilibrium between oxygen diffusion and tissue metabolism can result in tissue hypoxia. The hypoxic region displayed enhanced radio-resistance and resulted in lower CNED under UHDR deliveries. In 1D solution, comparing 15 Gy proton dose delivered at CONV 0.5 and UHDR 125 Gy/s, 61.5% of the tissue exhibited ≥20% FEDMF at 175 µm vasculature spacing and 18.9 µM boundary condition. This percentage reduced to 34.5% and 0% for 8 and 2 Gy deliveries, respectively. Similar trends were observed in the 3D solution space. The FLASH versus CONV differential effect remained at larger vasculature spacings. A higher FLASH dose rate showed an increased region with ≥20% FEDMF. A higher LET near the proton Bragg peak region did not appear to alter the FLASH effect. Conclusion: We developed 1D, 2D, and 3D oxygen depletion simulation process to obtain the dynamic HRF and derive the proton FEDMF related to the dose delivery parameters and the local tissue vasculature information. The phenomenological model can be used to simulate or predict FLASH effects based on tissue vasculature and oxygen concentration data obtained from other experiments.

Characterization of a high-resolution 2D transmission ion chamber for independent validation of proton pencil beam scanning of conventional and FLASH dose delivery.

INTRODUCTION: Ultra-high dose rate (FLASH) radiotherapy has become a popular research topic with the potential to reduce normal tissue toxicities without losing the benefit of tumor control. The development of FLASH proton pencil beam scanning (PBS) delivery requires accurate dosimetry despite high beam currents with correspondingly high ionization densities in the monitoring chamber. In this study, we characterized a newly designed high-resolution position sensing transmission ionization chamber with a purpose-built multichannel electrometer for both conventional and FLASH dose rate proton radiotherapy. METHODS: The dosimetry and positioning accuracies of the ion chamber were fully characterized with a clinical scanning beam. On the FLASH proton beamline, the cyclotron output current reached up to 350 nA with a maximum energy of 226.2 MeV, with 210 ± 3 nA nozzle pencil beam current. The ion recombination effect was characterized under various bias voltages up to 1000 V and different beam intensities. The charge collected by the transmission ion chamber was compared with the measurements from a Faraday cup. RESULTS: Cross-calibrated with an Advanced Markus chamber (PTW, Freiburg, Germany) in a uniform PBS proton beam field at clinical beam setting, the ion chamber calibration was 38.0 and 36.7 GyE·mm2 /nC at 100 and 226.2 MeV, respectively. The ion recombination effect increased with larger cyclotron current at lower bias voltage while remaining ≤0.5 ± 0.5% with ≥200 V of bias voltage. Above 200 V, the normalized ion chamber readings demonstrated good linearity with the mass stopping power in air for both clinical and FLASH beam intensities. The spot positioning accuracy was measured to be 0.10 ± 0.08 mm in two orthogonal directions. CONCLUSION: We characterized a transmission ion chamber system under both conventional and FLASH beam current densities and demonstrated its suitability for use as a proton pencil beam dose and spot position delivery monitor under FLASH dose rate conditions.

Current delivery limitations of proton PBS for FLASH.

PURPOSE: Proton Pencil Beam Scanning (PBS) is an attractive solution to realize the advantageous normal tissue sparing elucidated from FLASH high dose rates. The mechanics of PBS spot delivery will impose limitations on the effective field dose rate for PBS. METHODS: This study incorporates measurements from clinical and FLASH research beams on uniform single energy and the spread-out Bragg Peak PBS fields to extrapolate the PBS dose rate to high cyclotron beam currents 350, 500, and 800 nA. The impact of the effective field dose rate from cyclotron current, spot spacing, slew time and field size were studied. RESULTS: When scanning magnet slew time and energy switching time are not considered, single energy effective field FLASH dose rate (≥40 Gy/s) can only be achieved with less than 4 × 4 cm2 fields when the cyclotron output current is above 500 nA. Slew time and energy switching time remain the limiting factors for achieving high effective dose rate of the field. The dose rate-time structures were obtained. The amount of the total dose delivered at the FLASH dose rate in single energy layer and volumetric field was also studied. CONCLUSION: It is demonstrated that while it is difficult to achieve FLASH dose rate for a large field or in a volume, local FLASH delivery to certain percentage of the total dose is possible. With further understanding of the FLASH radiobiological mechanism, this study could provide guidance to adapt current clinical multi-field proton PBS delivery practice for FLASH proton radiotherapy.