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Background: Radiation with high dose rate (FLASH) has shown to reduce toxicities to normal tissues around the target and maintain tumor control with the same amount of dose compared to conventional radiation. This phenomenon has been widely studied in electron therapy, which is often used for shallow tumor treatment. Proton therapy is considered a more suitable treatment modality for deep-seated tumors. The feasibility of FLASH proton therapy has recently been demonstrated by a series of pre- and clinical trials. One of the challenges is to efficiently generate wide enough dose distributions in both lateral and longitudinal directions to cover the entire tumor volume. The goal of this paper is to introduce a set of automatic FLASH proton beam optimization algorithms developed recently., Purpose: To develop a fast and efficient optimizer for the design of a passive scattering proton FLASH radiotherapy delivery at The University of Texas MD Anderson Proton Therapy Center, based on the fast dose calculator (FDC)., Methods: A track-repeating algorithm, FDC, was validated versus Geant4 simulations and applied to calculate dose distributions in various beamline setups. The design of the components was optimized to deliver homogeneous fields with well-defined diameters between 11.0 and 20.5 mm, as well as a spread-out Bragg peak (SOBP) with modulations between 8.5 and 39.0 mm. A ridge filter, a high-Z material scatterer, and a collimator with range compensator were inserted in the beam path, and their shapes and sizes were optimized to spread out the Bragg peak, widen the beam, and reduce the penumbra. The optimizer was developed and tested using two proton energies (87.0 and 159.5 MeV) in a variety of beamline arrangements. Dose rates of the optimized beams were estimated by scaling their doses to those of unmodified beams., Results: The optimized 87.0-MeV beams, with a distance from the beam pipe window to the phantom surface (window-to-surface distance [WSD]) of 550 mm, produced an 8.5-mm-wide SOBP (proximal 90% to distal 90% of the maximum dose); 14.5, 12.0, and 11.0-mm lateral widths at the 50%, 80%, and 90% dose location, respectively; and a 2.5-mm penumbra from 80% to 20% in the lateral profile. The 159.5-MeV beam had an SOBP of 39.0 mm and lateral widths of 20.5, 15.0, and 12.5 mm at 50%, 80%, and 90% dose location, respectively, when the WSD was 550 mm. Wider lateral widths were obtained with increased WSD. The SOBP modulations changed when the ridge filters with different characteristics were inserted. Dose rates on the beam central axis for all optimized beams (other than the 87.0-MeV beam with 2000-mm WSD) were above that needed for the FLASH effect threshold (40 Gy/s) except at the very end of the depth dose profile scaling with a dose rate of 1400 Gy/s at the Bragg peak in the unmodified beams. The optimizer was able to instantly design the individual beamline components for each of the beamline setups, without the need of time intensive iterative simulations., Conclusion: An efficient system, consisting of an optimizer and an FDC have been developed and validated in a variety of beamline setups, comprising two proton energies, several WSDs, and SOBPs. The set of automatic optimization algorithms produces beam shaping element designs efficiently and with excellent quality., (© 2022 American Association of Physicists in Medicine.)

Objective . Irradiation with ultra-high dose rates (>40 Gy s -1 ), also known as FLASH irradiation, has the potential to shift the paradigm of radiation therapy because of its reduced toxicity to normal tissues compared to that of conventional irradiations. The goal of this study was to (1) achieve FLASH irradiation conditions suitable for pre-clinical i n vitro and in vivo biology experiments using our synchrotron-based proton beamline and (2) commission the FLASH irradiation conditions achieved. Approach . To achieve these suitable FLASH conditions, we made a series of adaptations to our proton beamline, including modifying the spill length and size of accelerating cycles, repurposing the reference monitor for dose control, and expanding the field size with a custom double-scattering system. We performed the dosimetric commissioning with measurements using an Advanced Markus chamber and EBT-XD films as well as with Monte Carlo simulations. Main results . Through adaptations, we have successfully achieved FLASH irradiation conditions, with an average dose rate of up to 375 Gy s -1 . The Advanced Markus chamber was shown to be appropriate for absolute dose calibration under our FLASH conditions with a recombination factor ranging from 1.002 to 1.006 because of the continuous nature of our synchrotron-based proton delivery within a spill. Additionally, the absolute dose measured using the Advanced Markus chamber and EBT-XD films agreed well, with average and maximum differences of 0.32% and 1.63%, respectively. We also performed a comprehensive temporal analysis for FLASH spills produced by our system, which helped us identify a unique relationship between the average dose rate and the dose in our FLASH irradiation. Significance. We have established a synchrotron-based proton FLASH irradiation platform with accurate and precise dosimetry that is suitable for pre-clinical biology experiments. The unique time structure of the FLASH irradiation produced by our synchrotron-based system may shed new light onto the mechanism behind the FLASH effect., (© 2022 Institute of Physics and Engineering in Medicine.)

Purpose: We introduce a methodology to calculate the microdosimetric quantity dose-mean lineal energy for input into the microdosimetric kinetic model (MKM) to model the relative biological effectiveness (RBE) of proton irradiation experiments., Methods and Materials: The data from 7 individual proton RBE experiments were included in this study. In each experiment, the RBE at several points along the Bragg curve was measured. Monte Carlo simulations to calculate the lineal energy probability density function of 172 different proton energies were carried out with use of Geant4 DNA. We calculated the fluence-weighted lineal energy probability density function (f w (y)), based on the proton energy spectra calculated through Monte Carlo at each experimental depth, calculated the dose-mean lineal energy y D ¯ for input into the MKM, and then computed the RBE. The radius of the domain (r d ) was varied to reach the best agreement between the MKM-predicted RBE and experimental RBE. A generic RBE model as a function of dose-averaged linear energy transfer (LET D ) with 1 fitting parameter was presented and fit to the experimental RBE data as well to facilitate a comparison to the MKM., Results: Both the MKM and LET D -based models modeled the RBE from experiments well. Values for r d were similar to those of other cell lines under proton irradiation that were modeled with the MKM. Analysis of the performance of each model revealed that neither model was clearly superior to the other., Conclusions: Our 3 key accomplishments include the following: (1) We developed a method that uses the proton energy spectra and lineal energy distributions of those protons to calculate dose-mean lineal energy. (2) We demonstrated that our application of the MKM provides theoretical validation of proton irradiation experiments that show that RBE is significantly greater than 1.1. (3) We showed that there is no clear evidence that the MKM is better than LET D -based RBE models., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose Accurate modeling of the relative biological effectiveness ( RBE) of particle beams requires increased systematic in vitro studies with human cell lines with care towards minimizing uncertainties in biologic assays as well as physical parameters. In this study, we describe a novel high-throughput experimental setup and an optimized parameterization of the Monte Carlo (MC) simulation technique that is universally applicable for accurate determination of RBE of clinical ion beams. Clonogenic cell-survival measurements on a human lung cancer cell line (H460) are presented using proton irradiation. Methods Experiments were performed at the Heidelberg Ion Therapy Center (HIT) with support from the Deutsches Krebsforschungszentrum (DKFZ) in Heidelberg, Germany using a mono-energetic horizontal proton beam. A custom-made variable range selector was designed for the horizontal beam line using the Geant4 MC toolkit. This unique setup enabled a high-throughput clonogenic assay investigation of multiple, well defined dose and linear energy transfer ( LETs) per irradiation for human lung cancer cells (H460) cultured in a 96-well plate. Sensitivity studies based on application of different physics lists in conjunction with different electromagnetic constructors and production threshold values to the MC simulations were undertaken for accurate assessment of the calculated dose and the dose-averaged LET ( LETd). These studies were extended to helium and carbon ion beams. Results Sensitivity analysis of the MC parameterization revealed substantial dependence of the dose and LETd values on both the choice of physics list and the production threshold values. While the dose and LETd calculations using FTFP_BERT_LIV, FTFP_BERT_EMZ, FTFP_BERT_PEN and QGSP_BIC_EMY physics lists agree well with each other for all three ions, they show large differences when compared to the FTFP_BERT physics list with the default electromagnetic constructor. For carbon ions, the dose corresponding to the largest LETd value is observed to differ by as much as 78% between FTFP_BERT and FTFP_BERT_LIV. Furthermore, between the production threshold of 700 μm and 5 μm, proton dose varies by as much as 19% corresponding to the largest LETd value sampled in the current investigation. Based on the sensitivity studies, the FTFP_BERT physics list with the low energy Livermore electromagnetic constructor and a production threshold of 5 μm was employed for determining accurate dose and LETd. The optimized MC parameterization results in a different LETd dependence of the RBE curve for 10% SF of the H460 cell line irradiated with proton beam when compared with the results from a previous study using the same cell line. When the MC parameters are kept consistent between the studies, the proton RBE results agree well with each other within the experimental uncertainties. Conclusions A custom high-throughput, high-accuracy experimental design for accurate in vitro cell survival measurements was employed at a horizontal beam line. High sensitivity of the physics-based optimization establishes the importance of accurate MC parameterization and hence the conditioning of the MC system on a case-by-case basis. The proton RBE results from current investigations are observed to agree with a previous measurement made under different experimental conditions. This establishes the consistency of our experimental findings across different experiments and institutions. [ABSTRACT FROM AUTHOR]

Purpose: ³He ions may hold great potential for clinical therapy because of both their physical and biological properties. In this study, the authors investigated the physical properties, i.e., the depth-dose curves from primary and secondary particles, and the energy distributions of helium (³He) ions. A relative biological effectiveness (RBE) model was applied to assess the biological effectiveness on survival of multiple cell lines. Methods: In light of the lack of experimental measurements and cross sections, the authors used Monte Carlo methods to study the energy deposition of ³He ions. The transport of ³He ions in water was simulated by using three Monte Carlo codes--FLUKA, GEANT4, and MCNPX--for incident beams with Gaussian energy distributions with average energies of 527 and 699 MeV and a full width at half maximum of 3.3 MeV in both cases. The RBE of each was evaluated by using the repair-misrepair-fixation model. In all of the simulations with each of the three Monte Carlo codes, the same geometry and primary beam parameters were used. Results: Energy deposition as a function of depth and energy spectra with high resolution was calculated on the central axis of the beam. Secondary proton dose from the primary ³He beams was predicted quite differently by the three Monte Carlo systems. The predictions differed by as much as a factor of 2. Microdosimetric parameters such as dose mean lineal energy (yD), frequency mean lineal energy (yF), and frequency mean specific energy (zF) were used to characterize the radiation beam quality at four depths of the Bragg curve. Calculated RBE values were close to 1 at the entrance, reached on average 1.8 and 1.6 for prostate and head and neck cancer cell lines at the Bragg peak for both energies, but showed some variations between the different Monte Carlo codes. Conclusions: Although the Monte Carlo codes provided different results in energy deposition and especially in secondary particle production (most of the differences between the three codes were observed close to the Bragg peak, where the energy spectrum broadens), the results in terms of RBE were generally similar. [ABSTRACT FROM AUTHOR]

Simple Summary: Although particle therapy using protons and heavier ions has many inherent advantages when compared to x-rays for cancer treatment, numerous unknowns still exist in the radiobiology of particle therapy. Informative high-accuracy biological effects data are lacking and difficult to obtain. This study aimed to provide a novel high-throughput experimental method to more efficiently obtain large amounts of biophysical data of particle therapy and to correlate the biological responses with the physical characteristics of particle beams. Large amounts of high quality biophysical data are needed to improve current biological effects models but such data are lacking and difficult to obtain. The present study aimed to more efficiently measure the spatial distribution of relative biological effectiveness (RBE) of charged particle beams using a novel high-accuracy and high-throughput experimental platform. Clonogenic survival was selected as the biological endpoint for two lung cancer cell lines, H460 and H1437, irradiated with protons, carbon, and helium ions. Ion-specific multi-step microplate holders were fabricated such that each column of a 96-well microplate is spatially situated at a different location along a particle beam path. Dose, dose-averaged linear energy transfer (LETd), and dose-mean lineal energy (yd) were calculated using an experimentally validated Geant4-based Monte Carlo system. Cells were irradiated at the Heidelberg Ion Beam Therapy Center (HIT). The experimental results showed that the clonogenic survival curves of all tested ions were yd-dependent. Both helium and carbon ions achieved maximum RBEs within specific yd ranges before biological efficacy declined, indicating an overkill effect. For protons, no overkill was observed, but RBE increased distal to the Bragg peak. Measured RBE profiles strongly depend on the physical characteristics such as yd and are ion specific. [ABSTRACT FROM AUTHOR]

The physical properties of particles used in radiation therapy, such as protons, have been well characterized, and their dose distributions are superior to photon-based treatments. However, proton therapy may also have inherent biologic advantages that have not been capitalized on. Unlike photon beams, the linear energy transfer (LET) and hence biologic effectiveness of particle beams varies along the beam path. Selective placement of areas of high effectiveness could enhance tumor cell kill and simultaneously spare normal tissues. However, previous methods for mapping spatial variations in biologic effectiveness are time-consuming and often yield inconsistent results with large uncertainties. Thus the data needed to accurately model relative biological effectiveness to guide novel treatment planning approaches are limited. We used Monte Carlo modeling and high-content automated clonogenic survival assays to spatially map the biologic effectiveness of scanned proton beams with high accuracy and throughput while minimizing biological uncertainties. We found that the relationship between cell kill, dose, and LET, is complex and non-unique. Measured biologic effects were substantially greater than in most previous reports, and non-linear surviving fraction response was observed even for the highest LET values. Extension of this approach could generate data needed to optimize proton therapy plans incorporating variable RBE. [ABSTRACT FROM AUTHOR]