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In proton therapy dose calculation, Monte Carlo (MC) simulations are superior in accuracy but more time consuming, compared to analytical calculations. Graphic processing units (GPUs) are effective in accelerating MC simulations but may suffer thread divergence and racing condition in GPU threads that degrades the computing performance due to the generation of secondary particles during nuclear reactions.A novel concept of virtual particle (VP) MC (VPMC) is proposed to avoid simulating secondary particles in GPU-accelerated proton MC dose calculation and take full advantage of the computing power of GPU.Neutrons and gamma rays were ignored as escaping from the human body; doses of electrons, heavy ions, and nuclear fragments were locally deposited; the tracks of deuterons were converted into tracks of protons. These particles, together with primary and secondary protons, are considered to be the realistic particles. Histories of primary and secondary protons were replaced by histories of multiple VPs. Each VP corresponded to one proton (either primary or secondary). A continuous-slowing-down-approximation model, an ionization model, and a large angle scattering event model corresponding to nuclear interactions were developed for VPs by generating probability distribution functions (PDFs) based on simulation results of realistic particles using MCsquare. For efficient calculations, these PDFs were stored in the Compute Unified Device Architecture textures. VPMC was benchmarked with TOPAS and MCsquare in phantoms and with MCsquare in 13 representative patient geometries. Comparisons between the VPMC calculated dose and dose measured in water during patient-specific quality assurance (PSQA) of the selected 13 patients were also carried out. Gamma analysis was used to compare the doses derived from different methods and calculation efficiencies were also compared.Integrated depth dose and lateral dose profiles in both homogeneous and inhomogeneous phantoms all matched well among VPMC, TOPAS, and MCsquare calculations. The 3D-3D gamma passing rates with a criterion of 2%/2 mm and a threshold of 10% was 98.49% between MCsquare and TOPAS and 98.31% between VPMC and TOPAS in homogeneous phantoms, and 99.18% between MCsquare and TOPAS and 98.49% between VPMC and TOPAS in inhomogeneous phantoms, respectively. In patient geometries, the 3D-3D gamma passing rates with 2%/2 mm/10% between dose distributions from VPMC and MCsquare were 98.56 ± 1.09% in patient geometries. The 2D-3D gamma analysis with 3%/2 mm/10% between the VPMC calculated dose distributions and the 2D measured planar dose distributions during PSQA was 98.91 ± 0.88%. VPMC calculation was highly efficient and took 2.84 ± 2.44 s to finish for the selected 13 patients running on four NVIDIA Ampere GPUs in patient geometries.VPMC was found to achieve high accuracy and efficiency in proton therapy dose calculation.

To evaluate the accuracy of the RayStation Monte Carlo dose engine (RayStation MC) in modeling small-field block apertures in proton pencil beam scanning. Furthermore, we evaluate the suitability of MCsquare as a second check for RayStation MC.We have enhanced MCsquare to model block apertures. To test the accuracy of both RayStation MC and the newly enhanced MCsquare, we compare the dose predictions of each to in-water dose measurements obtained using diode detectors and radiochromic film. Nine brass apertures with openings of 1, 2, 3, 4, and 5 cm and either 2 cm or 4 cm thickness were used in the irradiation of a water phantom. Two measurement setups were used, one with a range shifter and 119.7 MeV proton beam energy and the other with no range shifter and 147 MeV proton beam energy. To further test the validity of RayStation MC and MCsquare in modeling block apertures and to evaluate MCsquare as a second check tool, 10 small-field (average target volume 8.3 cmComparing to the absolute dose measurements in water, RayStation MC differed by 1.2% ± 1.0% while MCsquare differed by -1.8% ± 3.7% in the plateau region of a pristine Bragg peak. Compared to the in-water film measurements, RayStation MC and MCsquare both performed well with an average 2D-3D gamma passing rate of 99.4% and 99.7% (3%/3 mm), respectively. A t-test comparing the agreement with the film measurements between RayStation MC and MCsquare suggested that the relative spatial dose distributions calculated by MCsquare and RayStation MC were statistically indistinguishable. Directly comparing the dose calculations between MCsquare and RayStation MC over 10 patients resulted in an average 3D-3D gamma passing rates of 98.5% (3%/3 mm) and 94.1% (2%/2 mm), respectively.The validity of RayStation MC algorithm for use with patient-specific apertures has been expanded to include small apertures. MCsquare has been enhanced to model apertures and was found to be an adequate second check of RayStation MC in this scenario.

Purpose Due to the employment of quadratic programming using soft constraints to implement dose volume constraints and the "trial-and-error" procedure needed to achieve a clinically acceptable plan, conventional dose volume constraints (upper limit) are not adequately effective in controlling small and isolated hot spots in the dose/linear energy transfer (LET) distribution. Such hot spots can lead to adverse events. In order to mitigate the risk of brain necrosis, one of the most clinically significant adverse events in patients receiving intensity-modulated proton therapy (IMPT) for base of skull (BOS) cancer, we propose per-voxel constraints to minimize hot spots in LET-guided robust optimization. Methods and materials Ten BOS cancer patients treated with IMPT were carefully selected by meeting one of the following conditions: 1) diagnosis of brain necrosis during follow-up; 2) considered high risk for brain necrosis by not meeting dose constraints to the brain. An optimizing structure (BrainOPT) and an evaluating structure (BrainROI) that both contained the aforementioned hot dose regions in the brain were generated for optimization and evaluation, respectively. Two plans were generated for every patient: one using conventional dose-only robust optimization, the other using LET-guided robust optimization. The impact of LET was integrated into the optimization via a term of extra biological dose (xBD). A novel optimization tool of per-voxel constraints to control small and isolated hot spots in either the dose, LET, or combined (dose/LET) distribution was developed and used to minimize dose/LET hot spots of the selected structures. Indices from dose-volume histogram (DVH) and xBD dose-volume histogram (xBDVH) were used in the plan evaluation. A newly developed tool of the dose-LET-volume histogram (DLVH) was also adopted to illustrate the underlying mechanism. Wilcoxon signed-rank test was used for statistical comparison of the DVH and xBDVH indices between the conventional dose-only and the LET-guided robustly optimized plans. Results Per-voxel constraints effectively and efficiently minimized dose hot spots in both dose-only and LET-guided robust optimization and LET hot spots in LET-guided robust optimization. Compared to the conventional dose-only robust optimization, the LET-guided robust optimization could generate plans with statistically lower xBD hot spots in BrainROI (VxBD,50Gy[RBE], P = 0.009; VxBD,60Gy[RBE], P = 0.025; xBD1cc, P = 0.017; xBD2cc, P = 0.022) with comparable dose coverage, dose hot spots in the target, and dose hot spots in BrainROI. DLVH analysis indicated that LET-guided robust optimization could either reduce LET at the same dose level or redistribute high LET from high dose regions to low dose regions. Conclusion Per-voxel constraint is a powerful tool to minimize dose/LET hot spots in IMPT. The LET-guided robustly optimized plans outperformed the conventional dose-only robustly optimized plans in terms of xBD hot spots control. This article is protected by copyright. All rights reserved.

PURPOSE To measure diode sensitivity degradation (DSD) induced by cumulative proton dose delivered to a commercial daily quality assurance (QA) device. METHODS At our institution, six Daily QA 3 (DQA3, Sun Nuclear Corporation, Melbourne, FL, USA) devices have been used for daily proton pencil beam scanning QA in four proton gantry rooms over a span of 4 years. DQA3 diode counts were cross-calibrated using a homogenous field with a known dose of 1 Gy. The DSD rate (ΔR%/100 Gy) was calculated using linear regression on time-series plots of diode counts and an estimate of cumulative dose per year based on the cross-calibration. The effect of DSD on daily QA spot position measurements was quantified by converting DSD to baseline spot position shift. RESULTS The average dose delivered to the four inner DQA3 diodes was 104 ± 5 Gy/year, and the rate of DSD was -5.1% ± 1.0/100 Gy with the exception of one DQA3 device that had a significantly higher rate of DSD (-12%/100 Gy). The R2 s of the linear fit to time-series plots were between 0.92 and 0.98. The DSD rates were not constant but decreases with accumulated doses. The four center diodes, which received 40% of the cumulative dose received by inner diodes, had a DSD rate of -7.2% ± 0.9/100 Gy. For our daily QA program, 1 year of DSD was equivalent to a 0.2 mm shift in spot position. CONCLUSIONS The DSD rate of DQA3 diodes determined by long-term proton daily QA data was about -5%/100 Gy, which is more than 10 times greater than the reported DSD rate from photon irradiation. DQA3 diodes may be used for daily proton QA programs, provided that they are recalibrated at an appropriate frequency that should be determined specifically for different daily QA programs.

We proposed a novel tool-a dose linear energy transfer (LET)-volume histogram (DLVH)-and performed an exploratory study to investigate rectal bleeding in prostate cancer treated with intensity modulated proton therapy.The DLVH was constructed with dose and LET as 2 axes, and the normalized volume of the structure was contoured in the dose-LET plane as isovolume lines. We defined the DLVH index, DLv%(d,l) (ie, v% of the structure) to have a dose of ≥d Gy and an LET of ≥l keV/μm, similar to the dose-volume histogram index Dv%. Nine patients with prostate cancer with rectal bleeding (Common Terminology Criteria for Adverse Events grade ≥2) were included as the adverse event group, and 48 patients with no complications were considered the control group. A P value map was constructed by comparison of the DLVH indices of all patients between the 2 groups using the Mann-Whitney U test. Dose-LET volume constraints (DLVCs) were derived based on the P value map with a manual selection procedure facilitated by Spearman's correlation tests. The obtained DLVCs were further cross-validated using a multivariate support vector machine (SVM)-based normal tissue complication probability (NTCP) model with an independent testing data set composed of 8 adverse event and 13 control patients.We extracted 2 DLVC constraints. One DLVC was obtained, Vdose/LETboundary:2.5keVμmat 75 Gy to 3.2keVμmat8.65Gy1.27% (DLVC1), revealing a high LET volume effect. The second DLVC, V(72.2Gy,0keVμm)2.23% (DVLC2), revealed a high dose volume effect. The SVM-based NTCP model with 2 DLVCs provided slightly superior performance than using dose only, with an area under the curve of 0.798 versus 0.779 for the testing data set.Our results demonstrated the importance of rectal "hot spots" in both high LET (DLVC1) and high dose (DLVC2) in inducing rectal bleeding. The SVM-based NTCP model confirmed the derived DLVCs as good predictors for rectal bleeding when intensity modulated proton therapy is used to treat prostate cancer.

In this review article, we review the 3 important aspects of linear-energy-transfer (LET) in intensity-modulated proton therapy (IMPT) for head and neck (H&N) cancer management. Accurate LET calculation methods are essential for LET-guided plan evaluation and optimization, which can be calculated either by analytical methods or by Monte Carlo (MC) simulations. Recently, some new 3D analytical approaches to calculate LET accurately and efficiently have been proposed. On the other hand, several fast MC codes have also been developed to speed up the MC simulation by simplifying nonessential physics models and/or using the graphics processor unit (GPU)–acceleration approach. Some concepts related to LET are also briefly summarized including (1) dose-weighted versus fluence-weighted LET; (2) restricted versus unrestricted LET; and (3) microdosimetry versus macrodosimetry. LET-guided plan evaluation has been clinically done in some proton centers. Recently, more and more studies using patient outcomes as the biological endpoint have shown a positive correlation between high LET and adverse events sites, indicating the importance of LET-guided plan evaluation in proton clinics. Various LET-guided plan optimization methods have been proposed to generate proton plans to achieve biologically optimized IMPT plans. Different optimization frameworks were used, including 2-step optimization, 1-step optimization, and worst-case robust optimization. They either indirectly or directly optimize the LET distribution in patients while trying to maintain the same dose distribution and plan robustness. It is important to consider the impact of uncertainties in LET-guided optimization (ie, LET-guided robust optimization) in IMPT, since IMPT is sensitive to uncertainties including both the dose and LET distributions. We believe that the advancement of the LET-guided plan evaluation and optimization will help us exploit the unique biological characteristics of proton beams to improve the therapeutic ratio of IMPT to treat H&N and other cancers.

Purpose The development of collimating technologies has become a recent focus in pencil beam scanning (PBS) proton therapy to improve the target conformity and healthy tissue sparing through field-specific or energy-layer–specific collimation. Given the growing popularity of collimators for low-energy treatments, the purpose of this work was to summarize the recent literature that has focused on the efficacy of collimators for PBS and highlight the development of clinical and preclinical collimators. Materials and Methods The collimators presented in this work were organized into 3 categories: per-field apertures, multileaf collimators (MLCs), and sliding-bar collimators. For each case, the system design and planning methodologies are summarized and intercompared from their existing literature. Energy-specific collimation is still a new paradigm in PBS and the 2 specific collimators tailored toward PBS are presented including the dynamic collimation system (DCS) and the Mevion Adaptive Aperture. Results Collimation during PBS can improve the target conformity and associated healthy tissue and critical structure avoidance. Between energy-specific collimators and static apertures, static apertures have the poorest dose conformity owing to collimating only the largest projection of a target in the beam's eye view but still provide an improvement over uncollimated treatments. While an external collimator increases secondary neutron production, the benefit of collimating the primary beam appears to outweigh the risk. The greatest benefit has been observed for low- energy treatment sites. Conclusion The consensus from current literature supports the use of external collimators in PBS under certain conditions, namely low-energy treatments or where the nominal spot size is large. While many recent studies paint a supportive picture, it is also important to understand the limitations of collimation in PBS that are specific to each collimator type. The emergence and paradigm of energy-specific collimation holds many promises for PBS proton therapy.

Purpose To demonstrate that variation in chemical composition has a negligible effect on the mapping curve from relative electron density (RED) to proton stopping power ratio (SPR), and to establish the theoretical framework of using Megavoltage (MV) computed tomography (CT), instead of kilovoltage (kV) dual energy CT, to accurately estimate proton SPR. Methods A simulation study was performed to evaluate the effect of chemical composition variation on kVCT number and proton SPR. The simulation study involved both reference and simulated human tissues. The reference human tissues, together with their physical densities and chemical compositions, came from the ICRP publication 23. The simulated human tissues were created from the reference human tissues assuming that elemental percentage weight followed a Gaussian distribution. For all tissues, kVCT number and proton SPR were obtained through (a) theoretical calculation from tissue’s physical density and chemical composition which served as the ground truth, and (b) estimation from RED using the calibration curves established from the stoichiometric method. Deviations of the estimated values from the calculated values were quantified as errors in using RED to estimate kVCT number and proton SPR. Results Given a chemical composition variation of 5% (1σ) of the nominal percentage weights, the total estimation error of using RED to estimate kVCT number was 0.34%, 0.62%, and 0.77% and the total estimation error of using RED to estimate proton SPR was 0.30%, 0.22%, and 0.16% for fat tissues, non‐fat soft tissues and bone tissues, respectively. Conclusion Chemical composition had a negligible effect on the method of using RED to determine proton SPR. RED itself is sufficient to accurately determine proton SPR. MVCT number maintains a superb linear relationship with RED because it is highly dominated by Compton scattering. Therefore, MVCT has great potential in reducing the proton range uncertainty.

PURPOSE Intensity-modulated proton therapy (IMPT) is sensitive to uncertainties from patient setup and proton beam range, as well as interplay effect. In addition, respiratory motion may vary from cycle to cycle, and also from day to day. These uncertainties can severely degrade the original plan quality and potentially affect patient's outcome. In this work, we developed a new tool to comprehensively consider the impact of all these uncertainties and provide plan robustness evaluation under them. METHODS We developed a comprehensive plan robustness evaluation tool that considered both uncertainties from patient setup and proton beam range, as well as respiratory motion simultaneously. To mimic patients' respiratory motion, the time spent in each phase was randomly sampled based on patient-specific breathing pattern parameters as acquired during the four-dimensional (4D)-computed tomography (CT) simulation. Spots were then assigned to one specific phase according to the temporal relationship between spot delivery sequence and patients' respiratory motion. Dose in each phase was calculated by summing contributions from all the spots delivered in that phase. The final 4D dynamic dose was obtained by deforming all doses in each phase to the maximum exhalation phase. Three hundred (300) scenarios (10 different breathing patterns with 30 different setup and range uncertainty scenario combinations) were calculated for each plan. The dose-volume histograms (DVHs) band method was used to assess plan robustness. Benchmarking the tool as an application's example, we compared plan robustness under both three-dimensional (3D) and 4D robustly optimized IMPT plans for 10 nonrandomly selected patients with non-small cell lung cancer. RESULTS The developed comprehensive plan robustness tool had been successfully applied to compare the plan robustness between 3D and 4D robustly optimized IMPT plans for 10 lung cancer patients. In the presence of interplay effect with uncertainties considered simultaneously, 4D robustly optimized plans provided significantly better CTV coverage (D95% , P = 0.002), CTV homogeneity (D5% -D95% , P = 0.002) with less target hot spots (D5% , P = 0.002), and target coverage robustness (CTV D95% bandwidth, P = 0.004) compared to 3D robustly optimized plans. Superior dose sparing of normal lung (lung Dmean , P = 0.020) favoring 4D plans and comparable normal tissue sparing including esophagus, heart, and spinal cord for both 3D and 4D plans were observed. The calculation time for all patients included in this study was 11.4 ± 2.6 min. CONCLUSION A comprehensive plan robustness evaluation tool was successfully developed and benchmarked for plan robustness evaluation in the presence of interplay effect, setup and range uncertainties. The very high efficiency of this tool marks its clinical adaptation, highly practical and versatile nature, including possible real-time intra-fractional interplay effect evaluation as a potential application for future use.

Purpose To commission an open source Monte Carlo (MC) dose engine, “MCsquare” for a synchrotron‐based proton machine, integrate it into our in‐house C++‐based I/O user interface and our web‐based software platform, expand its functionalities, and improve calculation efficiency for intensity‐modulated proton therapy (IMPT). Methods We commissioned MCsquare using a double Gaussian beam model based on in‐air lateral profiles, integrated depth dose of 97 beam energies, and measurements of various spread‐out Bragg peaks (SOBPs). Then we integrated MCsquare into our C++‐based dose calculation code and web‐based second check platform “DOSeCHECK.” We validated the commissioned MCsquare based on 12 different patient geometries and compared the dose calculation with a well‐benchmarked GPU‐accelerated MC (gMC) dose engine. We further improved the MCsquare efficiency by employing the computed tomography (CT) resampling approach. We also expanded its functionality by adding a linear energy transfer (LET)‐related model‐dependent biological dose calculation. Results Differences between MCsquare calculations and SOBP measurements were

To develop an online graphic processing unit (GPU)-accelerated Monte Carlo-based adaptive radiation therapy (ART) workflow for pencil beam scanning (PBS) proton therapy to address interfraction anatomical changes in patients treated with PBS.A four-step workflow was developed using our in-house developed GPU-accelerated Monte Carlo-based treatment planning system to implement online Monte Carlo-based ART for PBS. The first step conducts diffeomorphic demon-based deformable image registration (DIR) to propagate contours on the initial planning CT (pCT) to the verification CT (vCT) to form a new structure set. The second step performs forward dose calculation of the initial plan on the vCT with the propagated contours after manual approval (possible modifications involved). The third step triggers a reoptimization of the plan depending on whether the verification dose meets the clinical requirements or not. A robust evaluation will be done for both the verification plan in the second step and the reopotimized plan in the third step. The fourth step involves a two-stage (before and after delivery) patient-specific quality assurance (PSQA) of the reoptimized plan. The before-delivery PSQA is to compare the plan dose to the dose calculated using an independent fast open-source Monte Carlo code, MCsquare. The after-delivery PSQA is to compare the plan dose to the dose recalculated using the log file (spot MU, spot position, and spot energy) collected during the delivery. Jaccard index (JI), dice similarity coefficients (DSCs), and Hausdorff distance (HD) were used to assess the quality of the propagated contours in the first step. A commercial plan evaluation software, ClearCheck™, was integrated into the workflow to carry out efficient plan evaluation. 3D Gamma analysis was used during the fourth step to ensure the accuracy of the plan dose from reoptimization. Three patients with three different disease sites were chosen to evaluate the feasibility of the online ART workflow for PBS.For all three patients, the propagated contours were found to have good volume conformance [JI (lowest-highest: 0.833-0.983) and DSC (0.909-0.992)] but suboptimal boundary coincidence [HD (2.37-20.76 mm)] for organs-at-risk. The verification dose evaluated by ClearCheck™ showed significant degradation of the target coverage due to the interfractional anatomical changes. Reoptimization on the vCT resulted in great improvement of the plan quality to a clinically acceptable level. 3D Gamma analyses of PSQA confirmed the accuracy of the plan dose before delivery (mean Gamma index = 98.74% with a threshold of 2%/2 mm/10%), and after delivery based on the log files (mean Gamma index = 99.05% with a threshold of 2%/2 mm/10%). The average time cost for the complete execution of the workflow was around 858 s, excluding the time for manual intervention.The proposed online ART workflow for PBS was demonstrated to be efficient and effective by generating a reoptimized plan that significantly improved the plan quality.

A successful proton beam therapy (PBT) center relies heavily on the proper function and maintenance of a proton beam therapy machine. However, when a PBT machine is non-operational, a proton facility is hindered with delays that can potentially lead to inferior treatment outcome due to treatment interruption. This article reports a viable solution for a photon back-up plan in a proton down event.The implementation of a workflow for which proton plans are converted to photon plans so that patients can be treated using photons has been a successful strategy to reduce delays and mitigate its effect on patient care. This workflow was established through collaboration of physicians, physicists, dosimetrists, therapists, nurses, and schedulers.A tiered system established by disease site, number of fractions, and individualized circumstances is used to prioritize patients. Proton-photon backup planning strategy and physics check details were described. This article provides an overview of workflow of conversion of PBT to photon when the PBT machine is down. Specific needs of patients undergoing proton beam therapy are addressed.

Purpose To validate breast tissue expander metallic port (MP) models in a commercial treatment planning system (TPS) in proton pencil beam scanning (PBS) treatments for breast cancer patients with breast tissue expanders. Methods and materials Three types of MPs taken out of a Mentor CPX4, a Natrelle 133, and a PMT Integra breast tissue expanders and a 650cc saline filled Mentor CPX4 expander were placed on top of acrylic slabs, and scanned using a Siemens Somatom Definition AS Open RT CT scanner. Structure templates for each of the MPs were designed within Eclipse TPS. The CT numbers for the metallic parts were overridden to reflect measured or calculated relative proton stopping powers (RPSPs). Mock targets were contoured in acrylic to represent post-mastectomy chest-wall radiation therapy (PMRT) targets. Plans with different beam incident angles were optimized using the Eclipse TPS to deliver uniform prescription dose to the target using Hitachi Probeat-V PBS beams. Eclipse calculated doses and an in-house Monte Carlo (MC) code calculated doses were compared to the measured Gafchromic EBT3 film doses in acrylic. Results TPS/MC and film dose comparison results showed that: 1) 3%/2mm/10% threshold Gamma pass rates were better than 90.8% in the acrylic target region for all plans; 2) comparing TPS and film doses for the individual beam plans in the MP dose shadow areas, the area with dose difference above 5% ((ΔA)5%) ranged from 1.1cm2 to 5.0cm2 , and the maximum dose difference ((ΔD)0.01cm2 ) ranged from 12.5% to 25.0%; 3) comparing MC and film doses for the individual beam plans in the MP dose shadow areas, the (ΔA)5% varied from 1.1cm2 to 2.9cm2 and (ΔD)0.01cm2 varied from 8.5% to 24.2%; 4) for a plan composed of three individual beams treating through the Mentor CPX4 expander, the TPS (ΔA)5% was less than 0.13cm2 , and the (ΔD)0.01cm2 was less than 6% in the MP dose shadow areas. Conclusions It is feasible to treat patients with tissue expanders using multiple PBS beams using a structure template with CT number overridden to represent the measured/calculated RPSP for MPs for PBS treatment planning. MC dose was more accurate than analytical dose in the areas with high dose gradient caused by the density heterogeneity of the breast tissue expander MPs. This article is protected by copyright. All rights reserved.

Purpose The dose-averaged linear energy transfer (LETd ) for intensity-modulated proton therapy (IMPT) calculated by one-dimensional (1D) analytical models deviates from more accurate but time-consuming Monte Carlo (MC) simulations. We developed a fast hybrid three-dimensional (3D) analytical LETd calculation that is more accurate than 1D analytical model. Methods We used the Geant4 MC code to generate 3D LETd distributions of monoenergetic proton beams in water for all energies and used a customized error function to fit the LETd lateral profiles at various depths to the MC simulation. The 3D LETd calculation kernel was a lookup table of these fitted coefficients, and LETd was determined directly from spot energies and voxel coordinates during analytical dose calculations. We validated our new method by comparing the calculated LETd distributions to MC results using 3D Gamma index analysis with 3%/2 mm criteria in 12 patient geometries. The significance of the improvement in Gamma index analysis passing rates over the 1D analytical model was determined using the Wilcoxon rank-sum test. Results The passing rate of 3D Gamma analysis comparing LETd distributions from the hybrid 3D method and the 1D method to MC simulations was significantly improved from 94.0% ± 2.5% to 98.0% ± 1.0% (P = 0.0003). The typical time to calculate dose and LETd simultaneously using an Intel Xeon E5-2680 2.50 GHz workstation was approximately 2.5 min. Conclusions Our new method significantly improved the LETd calculation accuracy compared to the 1D method while maintaining significantly shorter calculation time even comparing with the GPU-based fast MC code.

Purpose Approximate dose calculation methods were used in the nominal dose distribution and the perturbed dose distributions due to uncertainties in a commercial treatment planning system (CTPS) for robust optimization in intensity-modulated proton therapy (IMPT). We aimed to investigate whether the approximations influence plan quality, robustness, and interplay effect of the resulting IMPT plans for the treatment of locally advanced lung cancer patients. Materials and methods Ten consecutively treated locally advanced nonsmall cell lung cancer (NSCLC) patients were selected. Two IMPT plans were created for each patient using our in-house developed TPS, named "Solo," and also the CTPS, EclipseTM (Varian Medical Systems, Palo Alto, CA, USA), respectively. The plans were designed to deliver prescription doses to internal target volumes (ITV) drawn by a physician on averaged four-dimensional computed tomography (4D-CT). Solo plans were imported back to CTPS, and recalculated in CTPS for fair comparison. Both plans were further verified for each patient by recalculating doses in the inhalation and exhalation phases to ensure that all plans met clinical requirements. Plan robustness was quantified on all phases using dose-volume-histograms (DVH) indices in the worst-case scenario. The interplay effect was evaluated for every plan using an in-house developed software, which randomized starting phases of each field per fraction and accumulated dose in the exhalation phase based on the patient's breathing motion pattern and the proton spot delivery in a time-dependent fashion. DVH indices were compared using Wilcoxon rank-sum test. Results Compared to the plans generated using CTPS on the averaged CT, Solo plans had significantly better target dose coverage and homogeneity (normalized by the prescription dose) in the worst-case scenario [ITV D95% : 98.04% vs 96.28%, Solo vs CTPS, P = 0.020; ITV D5% -D95% : 7.20% vs 9.03%, P = 0.049] while all DVH indices were comparable in the nominal scenario. On the inhalation phase, Solo plans had better target dose coverage and cord Dmax in the nominal scenario [ITV D95% : 99.36% vs 98.45%, Solo vs CTPS, P = 0.014; cord Dmax : 20.07 vs 23.71 Gy(RBE), P = 0.027] with better target coverage and cord Dmax in the worst-case scenario [ITV D95% : 97.89% vs 96.47%, Solo vs CTPS, P = 0.037; cord Dmax : 24.57 vs 28.14 Gy(RBE), P = 0.037]. On the exhalation phase, similar phenomena were observed in the nominal scenario [ITV D95% : 99.63% vs 98.87%, Solo vs CTPS, P = 0.037; cord Dmax : 19.67 vs 23.66 Gy(RBE), P = 0.039] and in the worst-case scenario [ITV D95% : 98.20% vs 96.74%, Solo vs CTPS, P = 0.027; cord Dmax : 23.47 vs 27.93 Gy(RBE), P = 0.027]. In terms of interplay effect, plans generated by Solo had significantly better target dose coverage and homogeneity, less hot spots, and lower esophageal Dmean , and cord Dmax [ITV D95% : 101.81% vs 98.68%, Solo vs CTPS, P = 0.002; ITV D5% -D95% : 2.94% vs 7.51%, P = 0.002; cord Dmax : 18.87 vs 22.29 Gy(RBE), P = 0.014]. Conclusions Solo-generated IMPT plans provide improved cord sparing, better target robustness in all considered phases, and reduced interplay effect compared with CTPS. Consequently, the approximation methods currently used in commercial TPS programs may have space for improvement in generating optimal IMPT plans for patient cases with locally advanced lung cancer.

Background Esophageal carcinoma is the eighth most common cancer in the world. Volumetric-modulated arc therapy (VMAT) is widely used to treat distal esophageal carcinoma due to high conformality to the target and good sparing of organs at risk (OAR). It is not clear if small-spot intensity-modulated proton therapy (IMPT) demonstrates a dosimetric advantage over VMAT. In this study, we compared dosimetric performance of VMAT and small-spot IMPT for distal esophageal carcinoma in terms of plan quality, plan robustness, and interplay effects. Methods 35 distal esophageal carcinoma patients were retrospectively reviewed; 19 patients received small-spot IMPT and the remaining 16 of them received VMAT. Both plans were generated by delivering prescription doses to clinical target volumes (CTVs) on phase-averaged 4D-CT's. The dose-volume-histogram (DVH) band method was used to quantify plan robustness. Software was developed to evaluate interplay effects with randomized starting phases for each field per fraction. DVH indices were compared using Wilcoxon rank-sum test. For fair comparison, all the treatment plans were normalized to have the same CTVhigh D95% in the nominal scenario relative to the prescription dose. Results In the nominal scenario, small-spot IMPT delivered statistically significantly lower liver Dmean and V30Gy[RBE] , lung Dmean , heart Dmean compared with VMAT. CTVhigh dose homogeneity and protection of other OARs were comparable between the two treatments. In terms of plan robustness, the IMPT and VMAT plans were comparable for kidney V18Gy[RBE] , liver V30Gy[RBE] , stomach V45Gy[RBE] , lung Dmean , V5Gy[RBE] , and V20Gy[RBE] , cord Dmax and D 0.03 c m 3 , liver Dmean , heart V20Gy[RBE] , and V30Gy[RBE] , but IMPT was significantly worse for CTVhigh D95% , D 2 c m 3 , and D5% -D95% , CTVlow D95% , heart Dmean , and V40Gy[RBE] , requiring careful and experienced adjustments during the planning process and robustness considerations. The small-spot IMPT plans still met the standard clinical requirements after interplay effects were considered. Conclusions Small-spot IMPT decreases doses to heart, liver, and total lung compared to VMAT as well as achieves clinically acceptable plan robustness. Our study supports the use of small-spot IMPT for the treatment of distal esophageal carcinoma.

Objective. To investigate synchrotron-based proton pencil beam scanning (PBS) beam delivery time (BDT) using novel continuous scanning mode. Approach. A BDT calculation model was developed for the Hitachi particle therapy system. The model was validated against the measured BDT of 36 representative clinical proton PBS plans with discrete spot scanning (DSS) in the current Hitachi proton therapy system. BDTs were calculated with the next generation using Mayo Clinic Florida system operating parameters for conventional DSS, and novel dose driven continuous scanning (DDCS). BDTs of DDCS with and without Break Spots were investigated. Main results. For DDCS without Break Spots, the use of Stop Ratio to control the transit dose largely reduced the beam intensity and consequently, severely prolonged the BDT. DDCS with Break Spots was able to maintain a sufficiently high beam intensity while controlling transit dose. In DDCS with Break Spots, tradeoffs were made between beam intensity and number of Break Spots. Therefore, BDT decreased with increased beam intensity but reached a plateau for beam intensity larger than 10 MU s−1. Averaging over all clinical plans, BDT was reduced by 10% for DDCS with Break Spots compared to DSS. Significance. DDCS with Break Spots reduced BDT. DDCS has the potential to further reduce BDT under the ideal scenario which requests both stable beam intensity extraction and accurately modelling the transit dose. Further investigation is warranted.

PURPOSE The multiple energy extraction (MEE) delivery technique for synchrotron-based proton delivery systems reduces beam delivery time by decelerating the beam multiple times during one accelerator spill, but this might cause additional plan quality degradation due to intrafractional motion. We seek to determine whether MEE causes significantly different plan quality degradation compared to single energy extraction (SEE) for lung cancer treatments due to the interplay effect. METHODS Ten lung cancer patients treated with IMPT at our institution were nonrandomly sampled based on a representative range of tumor motion amplitudes, tumor volumes, and respiratory periods. Dose-volume histogram (DVH) indices from single-fraction SEE and MEE four-dimensional (4D) dynamic dose distributions were compared using the Wilcoxon signed-rank test. Distributions of monitor units (MU) to breathing phases were investigated for features associated with plan quality degradation. SEE and MEE DVH indices were compared in fractionated deliveries of the worst-case patient treatment scenario to evaluate the impact of fractionation. RESULTS There were no clinically significant differences in target mean dose, target dose conformity, or dose to organs-at-risk between SEE and MEE in single-fraction delivery. Three patients had significantly worse dose homogeneity with MEE compared to SEE (single-fraction mean D5% -D95% increased by up to 9.6% of prescription dose), and plots of MU distribution to breathing phases showed synchronization patterns with MEE but not SEE. However, after 30 fractions the patient in the worst-case scenario had clinically acceptable target dose homogeneity and coverage with MEE (mean D5% -D95% increased by 1% compared to SEE). CONCLUSIONS For some patients with breathing periods close to the mean spill duration, MEE resulted in significantly worse single-fraction target dose homogeneity compared to SEE due to the interplay effect. However, this was mitigated by fractionation, and target dose homogeneity and coverage were clinically acceptable after 30 fractions with MEE.

Imprint materials for optical applications can have a multitude of different properties, dictated by the function they must fulfill. Apart from optical properties such as refractive index, wavelength-dependent transmission or scattering behavior, a frequently neglected parameter is the thermo-mechanical behavior. We will discuss the importance to balance all these properties to achieve the best performance in different application and production scenarios, based on simulations and experimental tests.

First focus when developing imprint materials for optical applications is on their optical properties. However other properties are also key. Here we focus on the thermo-mechanical properties of polymer-based imprint materials and their importance for various applications. Special emphasis will be put on thermo-mechanical stress induced by thermal mismatch. We’ll compare thermo-mechanical bulk properties of such materials with results from FEM simulations and experimental tests.

In order to better spare organs at risk in the head and neck, the application of proton beam therapy is of great interest. In this study we report the clinical utilization of a novel and robust scanning proton beam therapy treatment planning method called Individual Field Simultaneous Optimization (IFSO) that incorporates the advantages of field patching technique integrated with simultaneous optimization of multiple fields. A treatment planning intercomparison between a conventional Intensity Modulated Proton Therapy Treatment Plan with single target volume vs a split target volume utilizing IFSO method demonstrates superiority of IFSO with regards to sparing of organs at risk and plan robustness.

Purpose Radiation therapy for mesothelioma remains challenging, as normal tissue toxicity limits the amount of radiation that can be safely delivered to the pleural surfaces, especially radiation dose to the contralateral lung. The physical properties of proton therapy result in better sparing of normal tissues when treating the pleura, both in the postpneumonectomy setting and the lung-intact setting. Compared with photon radiation, there are dramatic reductions in dose to the contralateral lung, heart, liver, kidneys, and stomach. However, the tissue heterogeneity in the thorax, organ motion, and potential for changing anatomy during the treatment course all present challenges to optimal irradiation with protons. Methods The clinical data underlying proton therapy in mesothelioma are reviewed here, including indications, advantages, and limitations. Results The Particle Therapy Cooperative Group Thoracic Subcommittee task group provides specific guidelines for the use of proton therapy for mesothelioma. Conclusions This consensus report can be used to guide clinical practice, insurance approval, and future research.

Proton therapy is an expanding radiotherapy modality in the United States and worldwide. With the number of proton therapy centers treating patients increasing, so does the need for consistent, high-quality clinical commissioning practices. Clinical commissioning encompasses the entire proton therapy system's multiple components, including the treatment delivery system, the patient positioning system, and the image-guided radiotherapy components. Also included in the commissioning process are the x-ray computed tomography scanner calibration for proton stopping power, the radiotherapy treatment planning system, and corresponding portions of the treatment management system. This commissioning report focuses exclusively on intensity-modulated scanning systems, presenting details of how to perform the commissioning of the proton therapy and ancillary systems, including the required proton beam measurements, treatment planning system dose modeling, and the equipment needed.

Intensity-modulated proton therapy (IMPT) is known to be sensitive to patient setup and range uncertainty issues. Multiple robust optimization methods have been developed to mitigate the impact of these uncertainties. Here, we propose a new robust optimization method, which provides an alternative way of robust optimization in IMPT, and is clinically practical, which will enable users to control the balance between nominal plan quality and plan robustness in a user-defined fashion.We calculated nine individual dose distributions which corresponded to one nominal and eight extreme scenarios caused by patient setup and proton beam's range uncertainties. For each voxel, the normalized dose interval (NDI) is defined as the full dose range variation divided by the maximum dose in all uncertainty scenarios (NDI = [max - min dose]/max dose), which was then used to calculate the normalized dose interval volume histogram (NDIVH) curves. The areas under the NDIVH curves were used to quantify plan robustness. A normalized dose interval volume constraint (NDIVC) applied to the target was incorporated to specify the desired robustness which was user-defined. Users could then explore the trade-off between nominal plan quality and plan robustness by adjusting the position of the NDIVCs on the NDIVH curves freely. We benchmarked our method using one lung, five head and neck (HN), and three prostate cases by comparing our results to those derived using the voxel-wise worst-case robust optimization.Using the benchmark cases, our new method achieved quality IMPT plans comparable to those derived from the voxel-wise worst-case robust optimization for both nominal plan quality and plan robustness in general; even more conformal and more homogeneous target dose distributions in some cases, if proper NDIVCs were applied. The AUC under NDIVH, as a precise quantitative index of plan robustness, was consistent with DVH bandwidths. Additionally, we demonstrated the feasibility of adjusting the position of NDIVCs in the NDIVH curves which allowed users to explore the trade-off between nominal plan quality and plan robustness.The NDIVH-based robust optimization method provided a novel and individualized way of robust optimization in IMPT, and enables users to adjust the balance between nominal plan quality and plan robustness in a user-defined fashion. This method is applicable for continued improvement and developing the next generation of IMPT planning algorithms in the future.

Highlights • Whole-brain intensity modulated proton therapy capably spares hippocampal volumes. • Hippocampal avoidance whole-brain radiotherapy may benefit pediatric populations. • Intensity modulated proton therapy provides superior target-dose homogeneity relative to modulated x-rays., Background and purpose Intensity modulated proton therapy (IMPT) allows for modulation parameterized for individual beamlets by position, intensity, and depth. This modulation capability is ideally suited for sparing organs at risk intermediate of the radiation target, such as hippocampal volumes within the whole brain. This work compared IMPT relative to volumetric modulated arc therapy (VMAT) during hippocampal avoidance whole brain radiation therapy (HA WBRT). Materials and methods Ten adult and ten pediatric patients previously treated for central nervous system malignancies were identified. IMPT and VMAT treatment plans employing HA WBRT were generated for each patient, delivering 30 GyE (Gray Equivalent) in 10 fractions for adults and 36 GyE in 20 fractions for pediatrics. Dose indices, including dose volume histogram metrics and homogeneity index HI = [D5% − D95%]/[Dmean] × 100, were used to assess plan quality and describe target coverage and normal-tissue sparing. Results IMPT offered significant benefits relative to VMAT for hippocampal sparing. Hippocampal mean dose was reduced from 13.7 ± 0.8 Gy with VMAT to 5.4 ± 0.3 GyE using IMPT for pediatrics, and was reduced from 11.7 ± 0.9 Gy with VMAT to 4.4 ± 0.2 GyE using IMPT for adults. IMPT similarly lowered left hippocampal mean dose. Dose to 95% of the clinical target volume was statistically equivalent for both groups; however IMPT reduced the homogeneity index by roughly half. Conclusion This manuscript demonstrates that HA IMPT can match or exceed dosimetric benefits offered with modulated X-rays. Inclusion of IMPT in future prospective studies is warranted.

Purpose To compare dosimetric performance of volumetric-modulated arc therapy (VMAT) and small-spot intensity-modulated proton therapy for stage III non-small-cell lung cancer (NSCLC). Methods and materials A total of 24 NSCLC patients were retrospectively reviewed; 12 patients received intensity-modulated proton therapy (IMPT) and the remaining 12 received VMAT. Both plans were generated by delivering prescription doses to clinical target volumes (CTV) on averaged 4D-CTs. The dose-volume-histograms (DVH) band method was used to quantify plan robustness. Software was developed to evaluate interplay effects with randomized starting phases of each field per fraction. DVH indices were compared using Wilcoxon rank sum test. Results Compared with VMAT, IMPT delivered significantly lower cord Dmax , heart Dmean , and lung V5 Gy[ RBE ] with comparable CTV dose homogeneity, and protection of other OARs. In terms of plan robustness, the IMPT plans were statistically better than VMAT plans in heart Dmean , but were statistically worse in CTV dose coverage, cord Dmax , lung Dmean , and V5 Gy[ RBE ] . Other DVH indices were comparable. The IMPT plans still met the standard clinical requirements with interplay effects considered. Conclusions Small-spot IMPT improves cord, heart, and lung sparing compared to VMAT and achieves clinically acceptable plan robustness at least for the patients included in this study with motion amplitude less than 11 mm. Our study supports the usage of IMPT to treat some lung cancer patients.

Purpose: Multiple energy extraction (MEE) is a technology that was recently introduced by Hitachi for its spot-scanning proton treatment system, which allows multiple energies to be delivered in a single synchrotron spill. The purpose of this paper is to investigate how much beam delivery time (BDT) can be reduced with MEE compared with single energy extraction (SEE), in which one energy is delivered per spill. Methods and Materials: A recently developed model based on BDT measurements of our synchrotron's delivery performance was used to compute BDT. The total BDT for 2694 beam deliveries in a cohort of 79 patients treated at our institution was computed in both SEE and 9 MEE configurations to determine BDT reduction. The cohort BDT reduction was also calculated for hypothetical accelerators with increased deliverable charge and compared with the results of our current delivery system. Results: A vendor-provided MEE configuration with 4 energy layers per spill reduced the total BDT on average by 35% (41 seconds) compared with SEE, with up to 65% BDT reduction for individual fields. Adding an MEE layer reduced the total BDT by

Purpose The aim of this work was to develop an efficient daily quality assurance (QA) program with strict tolerance levels for pencil beam scanning (PBS) proton radiotherapy featuring simultaneous dosimetric testing on a single, nonuniform field. Methods A nonuniform field measuring beam output, proton range, and spot position was designed for delivery onto a Sun Nuclear Daily-QA 3 device. A custom acrylic block permitted simultaneous measurement of low- and high-energy proton ranges in addition to beam output. Sensitivities to output, range, and spot position were evaluated to quantitate the device's response. Reproducibility tests were used to identify and control sources of measurement error as well as to assess the QA procedure's robustness. This procedure was implemented in each of our four treatment rooms independently; 4-6 months of daily QA measurements were collected. Results The 1% output, 0.5 mm range, and 1.5 mm spot position tolerances derived from preliminary tests were tighter overall than tolerances found in the literature and equivalent to the limits used for proton system commissioning. The simplicity and automation of the procedure reduced the time required for daily QA to 10 min per treatment room, and competition for beam between multiple treatment rooms was minimized. Conclusions An efficient daily PBS QA procedure can be performed using a single, nonuniform field on a nondedicated QA device. A thorough quantitation of the device's response and careful control of measurement uncertainties allowed daily tolerances to match commissioning standards.

Purpose/Objective(s) High linear energy transfer (LET) radiotherapy may cause unexpected adverse events (AEs) in head and neck (H&N) cancer patients treated by intensity-modulated proton therapy (IMPT). In this exploratory study, we propose to investigate the effects of LET upon AEs in IMPT using dose-linear-energy-transfer volume histograms (DLVHs) and seed spots analysis. Materials/Methods We included 14 H&N patients with unanticipated CTCAEv4.0 grade≥3 AEs for analysis. The AE regions were contoured and the corresponding DLVHs of the AE regions were generated. DLVH was constructed with physical dose (Gy) and LET (keV/µm) as independent variables. The normalized volume of the structure was contoured as iso-volume lines in the dose-LET plane. All voxels in the structure were mapped into the dose-LET plane as dots to see how the dots with similar dose and LET were clustered. For seed spot analysis, we selected voxels at the top edge of the DLVH plots as critical voxels. Individually clustered critical voxels that are geometrically apart were considered as independent seed spots. Median dose/LET from seed spots were extracted. Bivariate-linear-regression models were established for all AEs. The dose and LET product (xBD) volume constraint of osteoradionecrosis was obtained using the receiver operating characteristic curve of 4 osteoradionecrosis patients and 15 additional independent control patients. Results Dose played a dominant role for in-field AEs such as hemorrhage and ulceration, while LET played an important role in out-of-field AEs such as osteoradionecrosis and mucositis. Intercept-free linear models between the reciprocal of dose and LET were found for different AEs. The corresponding xBD threshold values were included in Table 1. The xBD volume constraint of osteoradionecrosis was derived V (xBD≥275.18 Gy•keV/μm) Conclusion Our observations suggested that dose and LET can contribute to AEs in a complicated fashion. Using the intercept-free bivariate linear regression model, we found a LET-enhancing effect for all 6 AEs included in the study, substantiated by the positive slopes of the empirical dose-LET models. The xBD volume constraint of osteoradionecrosis was derived and showed good performance. We believe that both DLVH and seed spot analysis could be powerful tools for patient outcome studies in IMPT.

Proton beam therapy (PBT) is a state-of-the-art radiotherapy treatment approach that uses focused proton beams for tumor ablation. A key advantage of this approach over conventional photon radiotherapy (XRT) is the unique dose deposition characteristic of protons, which results in superior healthy tissue sparing. This results in fewer unwanted side effects and improved outcomes for patients. Currently available dosimeters are intrinsic, complex, and expensive and are not routinely used to determine the dose delivered to the tumor. Here, we report a hydrogel-based plasmonic nanosensor for detecting clinical doses used in conventional and hyperfractionated proton beam radiotherapy. In this nanosensor, gold ions, encapsulated in a hydrogel, are reduced to gold nanoparticles following irradiation with proton beams. Formation of gold nanoparticles renders a color change to the originally colorless hydrogel. The intensity of the color can be used to calibrate the hydrogel nanosensor in order to quantify different radiation doses employed during proton treatment. The potential of this nanosensor for clinical translation was demonstrated using an anthropomorphic phantom mimicking a clinical radiotherapy session. The simplicity of fabrication, detection range in the fractionated radiotherapy regime, and ease of detection with translational potential makes this a first-in-kind plasmonic colorimetric nanosensor for applications in clinical proton beam therapy.

Monte Carlo (MC) simulation has been used to generate commissioning data for the beam modeling of treatment planning system (TPS). We have developed a method called radial projection (RP) for postprocessing of MC‐simulation‐generated data. We used the RP method to reduce the statistical uncertainty of the lateral profile of proton pencil beams with axial symmetry. The RP method takes advantage of the axial symmetry of dose distribution to use the mean value of multiple independent scores as the representative score. Using the mean as the representative value rather than any individual score results in substantial reduction in statistical uncertainty. Herein, we present the concept and step‐by‐step implementation of the RP method, as well as show the advantage of the RP method over conventional measurement methods for generating lateral profile. Lateral profiles generated by both methods were compared to demonstrate the uncertainty reduction qualitatively, and standard error comparison was performed to demonstrate the reduction quantitatively. The comparisons showed that statistical uncertainty was reduced substantially by the RP method. Using the RP method to postprocess MC data, the corresponding MC simulation time was reduced by a factor of 10 without quality reduction in the generated result from the MC data. We concluded that the RP method is an effective technique to increase MC simulation efficiency for generating lateral profiles for axially symmetric pencil beams.

Purpose To accurately model the beam delivery time (BDT) for a synchrotron-based proton spot scanning system using experimentally determined beam parameters. Methods A model to simulate the proton spot delivery sequences was constructed, and BDT was calculated by summing times for layer switch, spot switch, and spot delivery. Test plans were designed to isolate and quantify the relevant beam parameters in the operation cycle of the proton beam therapy delivery system. These parameters included the layer switch time, magnet preparation and verification time, average beam scanning speeds in x- and y-directions, proton spill rate, and maximum charge and maximum extraction time for each spill. The experimentally determined parameters, as well as the nominal values initially provided by the vendor, served as inputs to the model to predict BDTs for 602 clinical proton beam deliveries. The calculated BDTs (TBDT) were compared with the BDTs recorded in the treatment delivery log files (TLog): ∆t = TLog−TBDT. Results The experimentally determined average layer switch time for all 97 energies was 1.91 s (ranging from 1.9 to 2.0 s for beam energies from 71.3 to 228.8 MeV), average magnet preparation and verification time was 1.93 ms, the average scanning speeds were 5.9 m/s in x-direction and 19.3 m/s in y-direction, the proton spill rate was 8.7 MU/s, and the maximum proton charge available for one acceleration is 2.0 ± 0.4 nC. Some of the measured parameters differed from the nominal values provided by the vendor. The calculated BDTs using experimentally determined parameters matched the recorded BDTs of 602 beam deliveries (∆t = −0.49 ± 1.44 s), which were significantly more accurate than BDTs calculated using nominal timing parameters (∆t = −7.48 ± 6.97 s). Conclusions An accurate model for BDT prediction was achieved by using the experimentally determined proton beam therapy delivery parameters, which may be useful in modeling the interplay effect and patient throughput. The model may provide guidance on how to effectively reduce BDT and may be used to identifying deteriorating machine performance.

Background In treatment planning for intensity-modulated proton therapy (IMPT), we aim to deliver the prescribed dose to the target yet minimize the dose to adjacent healthy tissue. Mixed-integer programming (MIP) has been applied in radiation therapy to generate treatment plans. However, MIP has not been used effectively for IMPT treatment planning with dose-volume constraints. In this study, we incorporated dose-volume constraints in an MIP model to generate treatment plans for IMPT. Methods We created a new MIP model for IMPT with dose volume constraints. Two groups of IMPT treatment plans were generated for each of three patients by using MIP models for a total of six plans: one plan was derived with the Limited-memory Broyden–Fletcher–Goldfarb–Shanno (L-BFGS) method while the other plan was derived with our MIP model with dose-volume constraints. We then compared these two plans by dose-volume histogram (DVH) indices to evaluate the performance of the new MIP model with dose-volume constraints. In addition, we developed a model to more efficiently find the best balance between tumor coverage and normal tissue protection. Results The MIP model with dose-volume constraints generates IMPT treatment plans with comparable target dose coverage, target dose homogeneity, and the maximum dose to organs at risk (OARs) compared to treatment plans from the conventional quadratic programming method without any tedious trial-and-error process. Some notable reduction in the mean doses of OARs is observed. Conclusions The treatment plans from our MIP model with dose-volume constraints can meet all dose-volume constraints for OARs and targets without any tedious trial-and-error process. This model has the potential to automatically generate IMPT plans with consistent plan quality among different treatment planners and across institutions and better protection for important parallel OARs in an effective way.

This work is to show which is more relevant to cause local failures (LFs) due to patient setup uncertainty between the planning target volume (PTV) underdosage and the potential target underdosage subject to patient setup uncertainties in head and neck (H&N) cancer treated with volumetric‐modulated arc therapy (VMAT). Thirteen LFs in 10 H&N patients treated by VMAT were analyzed. Measures have been taken to minimize the chances of insufficient target delineation for these patients and the patients were clinically determined to have LF based on the PET/CT scan results by an experienced radiologist and then reviewed by a second experienced radiation oncologist. Two methods were used to identify the possible locations of LF due to underdosage: (a) examining the standard VMAT plan, in which the underdosed volume in the nominal dose distribution (UVN) was generated by subtracting the volumes receiving the prescription doses from PTVs, and (b) plan robustness analysis, in which in addition to the nominal dose distribution, six perturbed dose distributions were created by translating the CT iso‐center in three cardinal directions by the PTV margin. The coldest dose distribution was represented by the minimum of the seven doses in each voxel. The underdosed volume in the coldest dose distribution (UVC) was generated by subtracting the volumes receiving the prescription doses in the coldest dose distribution from the volumes receiving the prescription doses in the nominal dose distribution. UVN and UVC were subsequently examined for spatial association with the locations of LF. The association was tested using the binominal distribution and the Fisher's exact test of independence. We found that of 13 LFs, 11 were associated with UVCs (P = 0.011), while three were associated with UVNs (P = 0.99). We concluded that the possible target underdosage due to patient setup uncertainties appeared to be a more relevant factor associated with LF in VMAT for H&N cancer than the compromised PTV coverage at least for the patients included in this study.