Simulation study of protoacoustics as a real-time in-line dosimetry tool for FLASH proton therapy.

BACKGROUND: Applying ultra-high dose rates to radiation therapy, otherwise known as FLASH, has been shown to be just as effective while sparing more normal tissue compared to conventional radiation therapy. However, there is a need for a dosimeter that is able to detect such high instantaneous dose, particularly in vivo. To fulfill this need, protoacoustics is introduced, which is an in vivo range verification method with submillimeter accuracy. PURPOSE: The purpose of this work is to demonstrate the feasibility of using protoacoustics as a method of in vivo real-time monitoring during FLASH proton therapy and investigating the resulting protoacoustic signal when dose per pulse and pulsewidth are varied through multiple simulation studies. METHODS: The dose distribution of a proton pencil beam was calculated through a Monte Carlo toolbox, TOPAS. Next, the k-Wave toolbox in MATLAB was used for performing protoacoustic simulations, where the initial proton dose deposition was inputted to model acoustic propagations, which were also used for reconstructions. Simulations involving the manipulation of the dose per pulse and pulsewidth were performed, and the temporal and spatial resolution for protoacoustic reconstructions were investigated as well. A 3D reconstruction was performed with a multiple beam spot profile to investigate the spatial resolution as well as determine the feasibility of 3D imaging with protoacoustics. RESULTS: Our results showed consistent linearity in the increasing dose-per-pulse, even up to rates considered for FLASH. The simulations and reconstructions were performed for a range of pulsewidths from 0.1 to 10 µs. The results show the characteristics of the proton beam after convolving the protoacoustic signal with the varying pulsewidths. 3D reconstruction was successfully performed with each beam being distinguishable using an 8 cm × 8 cm planar array. These simulation results show that measurements using protoacoustics has the potential for in vivo dosimetry in FLASH therapy during patient treatments in real time. CONCLUSION: Through this simulation study, the use of protoacoustics in FLASH therapy was verified and explored through observations of varying parameters, such as the dose per pulse and pulsewidth. 2D and 3D reconstructions were also completed. This study shows the significance of using protoacoustics and provides necessary information, which can further be explored in clinical settings.

Two-dimensional oxygen-diffusion modelling for FLASH proton therapy with pencil beam scanning-Impact of diffusive tissue properties, dose, dose rate and scan patterns.

Objective.Oxygen depletion is generally believed to play an important role in the FLASH effect-a differential reduction of the radiosensitivity of healthy tissues, relative to that of the tumour under ultra-high dose-rate (UHDR) irradiation conditions. In proton therapy (PT) with pencil-beam scanning (PBS), the deposition of dose, and, hence, the degree of (radiolytic) oxygen depletion varies both spatially and temporally. Therefore, the resulting oxygen concentration and the healthy-tissue sparing effect through radiation-induced hypoxia varies both spatially and temporally as well.Approach.We propose and numerically solve a physical oxygen diffusion model to study these effects and their dependence on tissue parameters and the scan pattern in pencil-beam delivery. Since current clinical FLASH PT (FLASH-PT) is based on 250 MeV shoot-through (transmission) beams, for which dose and dose rate (DR) hardly vary with depth compared to the variation transverse to the beam axis, we focus on the two-dimensional case. We numerically integrate the model to obtain the oxygen concentration in each voxel as a function of time and extract voxel-based and spatially and temporarily integrated metrics for oxygen (FLASH) enhanced dose. Furthermore, we evaluate the impact on oxygen enhancement of standard pencil-beam delivery patterns and patterns that were optimised on dose-rate. Our model can contribute to the identification of tissue properties and pencil-beam delivery parameters that are critical for FLASH-PT and it may be used for the optimisation of FLASH-PT treatment plans and their delivery.Main results.(i) the diffusive properties of oxygen are critical for the steady state concentration and therefore the FLASH effect, even more so in two dimensions when compared to one dimension. (ii) The FLASH effect through oxygen depletion depends primarily on dose and less on other parameters. (iii) At a fixed fraction dose there is a slight dependence on DR. (iv) Scan patterns optimised on DR slightly increase the oxygen induced FLASH effect.Significance.To our best knowledge, this is the first study assessing the impact of scan-pattern optimization (SPO) in FLASH-PT with PBS on a biological FLASH model. While the observed impact of SPO is relatively small, a larger effect is expected for larger target volumes. A better understanding of the FLASH effect and the role of oxygen (depletion) therein is essential for the further development of FLASH-PT with PBS, and SPO.

Characterizing devices for validation of dose, dose rate, and LET in ultra high dose rate proton irradiations.

BACKGROUND: Ultra high dose rate (UHDR) radiotherapy using ridge filter is a new treatment modality known as conformal FLASH that, when optimized for dose, dose rate (DR), and linear energy transfer (LET), has the potential to reduce damage to healthy tissue without sacrificing tumor killing efficacy via the FLASH effect. PURPOSE: Clinical implementation of conformal FLASH proton therapy has been limited by quality assurance (QA) challenges, which include direct measurement of UHDR and LET. Voxel DR distributions and LET spectra at planning target margins are paramount to the DR/LET-related sparing of organs at risk. We hereby present a methodology to achieve experimental validation of these parameters. METHODS: Dose, DR, and LET were measured for a conformal FLASH treatment plan involving a 250-MeV proton beam and a 3D-printed ridge filter designed to uniformly irradiate a spherical target. We measured dose and DR simultaneously using a 4D multi-layer strip ionization chamber (MLSIC) under UHDR conditions. Additionally, we developed an "under-sample and recover (USRe)" technique for a high-resolution pixelated semiconductor detector, Timepix3, to avoid event pile-up and to correct measured LET at high-proton-flux locations without undesirable beam modifications. Confirmation of these measurements was done using a MatriXX PT detector and by Monte Carlo (MC) simulations. RESULTS: MC conformal FLASH computed doses had gamma passing rates of >95% (3 mm/3% criteria) when compared to MatriXX PT and MLSIC data. At the lateral margin, DR showed average agreement values within 0.3% of simulation at 100 Gy/s and fluctuations ∼10% at 15 Gy/s. LET spectra in the proximal, lateral, and distal margins had Bhattacharyya distances of <1.3%. CONCLUSION: Our measurements with the MLSIC and Timepix3 detectors shown that the DR distributions for UHDR scenarios and LET spectra using USRe are in agreement with simulations. These results demonstrate that the methodology presented here can be used effectively for the experimental validation and QA of FLASH treatment plans.

Definition of dose rate for FLASH pencil-beam scanning proton therapy: A comparative study.

BACKGROUND: FLASH proton therapy has the potential to reduce side effects of conventional proton therapy by delivering a high dose of radiation in a very short period of time. However, significant progress is needed in the development of FLASH proton therapy. Increasing the dose rate while maintaining dose conformality may involve the use of advanced beam-shaping technologies and specialized equipment such as 3D patient-specific range modulators, to take advantage of the higher transmission efficiency at the highest energy available. The dose rate is an important factor in FLASH proton therapy, but its definition can vary because of the uneven distribution of the dose over time in pencil-beam scanning (PBS). PURPOSE: Highlight the distinctions, both in terms of concept and numerical values, of the various definitions that can be established for the dose rate in PBS proton therapy. METHODS: In an in silico study, five definitions of the dose rate, namely the PBS dose rate, the percentile dose rate, the maximum percentile dose rate, the average dose rate, and the dose averaged dose rate (DADR) were analyzed first through theoretical comparison, and then applied to a head and neck case. To carry out this study, a treatment plan utilizing a single energy level and requiring the use of a patient-specific range modulator was employed. The dose rate values were compared both locally and by means of dose rate volume histograms (DRVHs). RESULTS: The PBS dose rate, the percentile dose rate, and the maximum percentile dose are definitions that are specifically designed to take into account the time structure of the delivery of a PBS treatment plan. Although they may appear similar, our study shows that they can vary locally by up to 10%. On the other hand, the DADR values were approximately twice as high as those of the PBS, percentile, and maximum percentile dose rates, since the DADR disregards the periods when a voxel does not receive any dose. Finally, the average dose rate can be defined in various ways, as discussed in this paper. The average dose rate is found to be lower by a factor of approximately 1/2 than the PBS, percentile, and maximum percentile dose rates. CONCLUSIONS: We have shown that using different definitions for the dose rate in FLASH proton therapy can lead to variations in calculated values ranging from a few percent to a factor of two. Since the dose rate is a critical parameter in FLASH radiation therapy, it is essential to carefully consider the choice of definition. However, to make an informed decision, additional biological data and models are needed.