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Purpose: Patient setup errors have been a primary concern impacting the dose delivery accuracy in radiation therapy. A robust treatment plan might mitigate the effects of patient setup errors. In this reported study, we aimed to evaluate the impact of translational and rotational errors on the robustness of linac‐based, single‐isocenter, coplanar, and non‐coplanar volumetric modulated arc therapy treatment plans for multiple brain metastases. Methods: Fifteen patients were retrospectively selected for this study with a combined total of 49 gross tumor volumes (GTVs). Single‐isocenter coplanar and non‐coplanar plans were generated first with a prescribed dose of 40 Gy in 5 fractions or 42 Gy in 7 fractions to cover 95% of planning target volume (PTV). Next, four setup errors (+1 and +2 mm translation, and +1° and +2° rotation) were applied individually to generate modified plans. Different plan quality evaluation metrics were compared between coplanar and non‐coplanar plans. 3D gamma analysis (3%/2 mm) was performed to compare the modified plans (+2 mm and +2° only) and the original plans. Paired t‐test was conducted for statistical analysis. Results: After applying setup errors, variations of all plan evaluation metrics were similar (p > 0.05). The worst case for V100% to GTV was 92.07% ± 6.13% in the case of +2 mm translational error. 3D gamma pass rates were > 90% for both coplanar (+2 mm and +2°) and the +2 mm non‐coplanar groups but was 87.40% ± 6.89% for the +2° non‐coplanar group. Conclusion: Translational errors have a greater impact on PTV and GTV dose coverage for both planning methods. Rotational errors have a greater negative impact on gamma pass rates of non‐coplanar plans. Plan evaluation metrics after applying setup errors showed that both coplanar and non‐coplanar plans were robust and clinically acceptable. [ABSTRACT FROM AUTHOR]

Objective: A newly developed GafchromicTM EBT4 film model was released recently. According to the vendor‐stated specifications, this new model maintains major features of its more recent predecessor, EBT3, but has a great improvement in the signal‐to‐noise ratio (SNR). The purpose of this study was to fully characterize the EBT4 model by testing its dose response dependence on beam energy using clinical photon and electron beams and validating its improvement in SNR. Methods: In the beam energy dependence experiments, 6 MV and 15 MV photon beams, 6 MeV, 12 MeV and 20 MeV electron beams, 120 kVp and two 250 kVp x‐ray beams (with different half‐layer values) were selected, representing different clinical beam energies and radiation types. In the noise and SNR analyses, only the 6 MV photon beam was selected as the representative to compare between EBT4 and EBT3 models. Results: The energy dependence test results showed that there was a slight difference (<2% at most dose levels) in the dose response among the clinical MV photons and MeV electrons. However, a large deviation (>10%) in the dose response was found for the 120 kVp x‐ray beam. For the two 250 kVp x‐ray beams, the difference in the dose response was moderate (<5%), but not negligible. The noise and SNR results showed a reduced noise and strengthened SNR in EBT4. Conclusion: We conclude that the EBT4 film has a minimal energy dependence for MV photon and MeV electron beams but has a notable energy dependence for kilovoltage x‐ray beams, and the vendor‐stated features of the reduced noise and improved SNR in EBT4 are validated. [ABSTRACT FROM AUTHOR]

Objective: To determine the effect of dose calculation accuracy on inverse linear energy transfer (LET) optimization for intensity‐modulated proton therapy, and to determine whether adding more beams would improve the plan robustness to different dose calculation engines. Methods: Two sets of intensity‐modulated proton therapy plans using two, four, six, and nine beams were created for 10 prostate cancer patients: one set was optimized with dose constraints (DoseOpt) using the pencil beam (PB) algorithm, and the other set was optimized with additional LET constraints (LETOpt) using the Monte Carlo (MC) algorithm. Dose distributions of DoseOpt plans were then recalculated using the MC algorithm, and the LETOpt plans were recalculated using the PB algorithm. Dosimetric indices of targets and critical organs were compared between the PB and MC algorithms for both sets of plans. Results: For DoseOpt plans, dose differences between the PB and MC algorithms were minimal. However, the maximum dose differences in LETOpt plans were 11.11% and 15.85% in the dose covering 98% and 2% (D2) of the clinical target volume, respectively. Furthermore, the dose to 1 cc of the bladder differed by 11.42 Gy (relative biological effectiveness). Adding more beams reduced the discrepancy in target coverage, but the errors in D2 of the structure were increased with the number of beams. Conclusion: High modulation of LET requires high dose calculation accuracy during the optimization and final dose calculation in the inverse treatment planning for intensity‐modulated proton therapy, and adding more beams did not improve the plan robustness to different dose calculation algorithms. [ABSTRACT FROM AUTHOR]

X‐ray diffraction from a solid crystal shows the wave nature of photons. It is an important electromagnetic (EM) physics process when X‐ray photons interact with a crystal. Bragg diffraction, often called Bragg reflection, is a special case of the general form of X‐ray diffraction, known as Laue diffraction. When the Bragg's law is met, the incident photon beam is reflected from the crystal plane behaving as a specular reflection at the Bragg angle. However, the Bragg reflection physical process has not been integrated into the general‐purpose Monte Carlo simulation toolkit Geant4 for particle physics. In the current study, we developed a new EM physical process class "G4CrystalBraggReflection" and a new EM physical model class "G4DarwinDynamicalModel" for modeling the Bragg reflection physical process within a crystal. We added the Bragg reflection physical process to the EM physics category of Geant4. The preliminary results of photon tracking in a silicon crystal slab have shown the feasibility of simulating the Bragg reflection process in addition to the standard EM processes in the framework of Geant4. [ABSTRACT FROM AUTHOR]

Background: Reliable estimates of radiation dose to bone marrow are critical to understanding the risk of radiation‐induced cancers. Although the medical internal radiation dose phantom is routinely used for dose estimation, bone marrow is not defined in the phantom. Consequently, methods of indirectly estimating bone marrow dose have been implemented based on dose to surrogate volumes or average dose to soft tissue. Methods: In this study, new bone marrow structures were implemented and evaluated to the medical internal radiation dose phantom in Geant4, offering improved fidelity. The dose equivalent to the bone marrow was calculated across medical, occupational, and space radiation exposure scenarios, and compared with results using prior indirect estimation methods. Conclusion: Our results show that bone marrow dose may be overestimated by up to a factor of three when using the traditional methods when compared with the improved fidelity medical internal radiation dose method, specifically at clinical x‐ray energies. [ABSTRACT FROM AUTHOR]

The EBT‐XD model of Gafchromic™ films has a broader optimal dynamic dose range, up to 40 Gy, compared with its predecessor models. This characteristic has made EBT‐XD films suitable for high‐dose applications, such as stereotactic body radiotherapy and stereotactic radiosurgery, as well as ultra‐high dose rate FLASH radiotherapy. The purpose of the current study was to characterize the dependence of EBT‐XD film response on linear energy transfer (LET) and dose rate of therapeutic protons from a synchrotron. A clinical spot‐scanning proton beam was used to study LET dependence at three dose‐averaged LET values of 1.0 keV/μm, 3.6 keV/μm, and 7.6 keV/μm. A research proton beamline was used to study dose rate dependence at 150 Gy/s in the FLASH mode and 0.3 Gy/s in the non‐FLASH mode. Film response data from dose‐averaged LET values of 0.9 keV/μm and 9.0 keV/μm of the proton FLASH beam were also compared. Film response data from a clinical 6‐MV photon beam were used as a reference. Both the gray value method and optical density (OD) method were used in film calibration. Calibration results using a specific OD calculation method and a generic OD calculation method were compared. The four‐parameter NIH Rodbard function and three‐parameter rational function were compared in fitting the calibration curves. Experimental results showed that the response of EBT‐XD film is proton LET dependent, but independent of dose rate. Goodness‐of‐fit analysis showed that using the NIH Rodbard function is superior for both protons and photons. Using the "specific OD + NIH Rodbard function" method for EBT‐XD film calibration is recommended. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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]

Purpose: The motivation of this study was to find and eliminate the cause of errors in dose-averaged linear energy transfer (LET) calculations from therapeutic protons in small targets, such as biological cell layers, calculated using the GEANT4 Monte Carlo code. Furthermore, the purpose was also to provide a recommendation to select an appropriate LET quantity from GEANT4 simulations to correlate with biological effectiveness of therapeutic protons. Methods: The authors developed a particle tracking step based strategy to calculate the average LET quantities (track-averaged LET, LETt and dose-averaged LET, LETd) using GEANT4 for different tracking step size limits. A step size limit refers to the maximally allowable tracking step length. The authors investigated how the tracking step size limit influenced the calculated LETt and LETd of protons with six different step limits ranging from 1 to 500 µm in a water phantom irradiated by a 79.7-MeV clinical proton beam. In addition, the authors analyzed the detailed stochastic energy deposition information including fluence spectra and dose spectra of the energy-deposition-per-step of protons. As a reference, the authors also calculated the averaged LET and analyzed the LET spectra combining the Monte Carlo method and the deterministic method. Relative biological effectiveness (RBE) calculations were performed to illustrate the impact of different LET calculation methods on the RBE-weighted dose. Results: Simulation results showed that the step limit effect was small for LETt but significant for LETd. This resulted from differences in the energy-deposition-per-step between the fluence spectra and dose spectra at different depths in the phantom. Using the Monte Carlo particle tracking method in GEANT4 can result in incorrect LETd calculation results in the dose plateau region for small step limits. The erroneous LETd results can be attributed to the algorithm to determine fluctuations in energy deposition along the tracking step in GEANT4. The incorrect LETd values lead to substantial differences in the calculated RBE. Conclusions: When the GEANT4 particle tracking method is used to calculate the average LET values within targets with a small step limit, such as smaller than 500 µm, the authors recommend the use of LETt in the dose plateau region and LETd around the Bragg peak. For a large step limit, i.e., 500 μm, LETd is recommended along the whole Bragg curve. The transition point depends on beam parameters and can be found by determining the location where the gradient of the ratio of LETd and LETt becomes positive. [ABSTRACT FROM AUTHOR]