Modelling small block aperture in an in-house developed GPU-accelerated Monte Carlo-based dose engine for pencil beam scanning proton therapy.

Purpose. To enhance an in-house graphic-processing-unit accelerated virtual particle (VP)-based Monte Carlo (MC) proton dose engine (VPMC) to model aperture blocks in both dose calculation and optimization for pencil beam scanning proton therapy (PBSPT)-based stereotactic radiosurgery (SRS).Methods and materials. A module to simulate VPs passing through patient-specific aperture blocks was developed and integrated in VPMC based on simulation results of realistic particles (primary protons and their secondaries). To validate the aperture block module, VPMC was first validated by an opensource MC code, MCsquare, in eight water phantom simulations with 3 cm thick brass apertures: four were with aperture openings of 1, 2, 3, and 4 cm without a range shifter, while the other four were with same aperture opening configurations with a range shifter of 45 mm water equivalent thickness. Then, VPMC was benchmarked with MCsquare and RayStation MC for 10 patients with small targets (average volume 8.4 c.c. with range of 0.4-43.3 c.c.). Finally, 3 typical patients were selected for robust optimization with aperture blocks using VPMC.Results. In the water phantoms, 3D gamma passing rate (2%/2 mm/10%) between VPMC and MCsquare was 99.71 ± 0.23%. In the patient geometries, 3D gamma passing rates (3%/2 mm/10%) between VPMC/MCsquare and RayStation MC were 97.79 ± 2.21%/97.78 ± 1.97%, respectively. Meanwhile, the calculation time was drastically decreased from 112.45 ± 114.08 s (MCsquare) to 8.20 ± 6.42 s (VPMC) with the same statistical uncertainties of ~0.5%. The robustly optimized plans met all the dose-volume-constraints (DVCs) for the targets and OARs per our institutional protocols. The mean calculation time for 13 influence matrices in robust optimization by VPMC was 41.6 s and the subsequent on-the-fly 'trial-and-error' optimization procedure took only 71.4 s on average for the selected three patients.Conclusion. VPMC has been successfully enhanced to model aperture blocks in dose calculation and optimization for the PBSPT-based SRS.

Beam mask and sliding window-facilitated deep learning-based accurate and efficient dose prediction for pencil beam scanning proton therapy.

BACKGROUND: Accurate and efficient dose calculation is essential for on-line adaptive planning in proton therapy. Deep learning (DL) has shown promising dose prediction results in photon therapy. However, there is a scarcity of DL-based dose prediction methods specifically designed for proton therapy. Successful dose prediction method for proton therapy should account for more challenging dose prediction problems in pencil beam scanning proton therapy (PBSPT) due to its sensitivity to heterogeneities. PURPOSE: To develop a DL-based PBSPT dose prediction workflow with high accuracy and balanced complexity to support on-line adaptive proton therapy clinical decision and subsequent replanning. METHODS: PBSPT plans of 103 prostate cancer patients (93 for training and the other 10 for independent testing) and 83 lung cancer patients (73 for training and the other 10 for independent testing) previously treated at our institution were included in the study, each with computed tomography scans (CTs), structure sets, and plan doses calculated by the in-house developed Monte-Carlo dose engine (considered as the ground truth in the model training and testing). For the ablation study, we designed three experiments corresponding to the following three methods: (1) Experiment 1, the conventional region of interest (ROI) (composed of targets and organs-at-risk [OARs]) method. (2) Experiment 2, the beam mask (generated by raytracing of proton beams) method to improve proton dose prediction. (3) Experiment 3, the sliding window method for the model to focus on local details to further improve proton dose prediction. A fully connected 3D-Unet was adopted as the backbone. Dose volume histogram (DVH) indices, 3D Gamma passing rates with a criterion of 3%/3 mm/10%, and dice coefficients for the structures enclosed by the iso-dose lines between the predicted and the ground truth doses were used as the evaluation metrics. The calculation time for each proton dose prediction was recorded to evaluate the method's efficiency. RESULTS: Compared to the conventional ROI method, the beam mask method improved the agreement of DVH indices for both targets and OARs and the sliding window method further improved the agreement of the DVH indices (for lung cancer, CTV D98 absolute deviation: 0.74 ± 0.18 vs. 0.57 ± 0.21 vs. 0.54 ± 0.15 Gy[RBE], ROI vs. beam mask vs. sliding window methods, respectively). For the 3D Gamma passing rates in the target, OARs, and BODY (outside target and OARs), the beam mask method improved the passing rates in these regions and the sliding window method further improved them (for prostate cancer, targets: 96.93% ± 0.53% vs. 98.88% ± 0.49% vs. 99.97% ± 0.07%, BODY: 86.88% ± 0.74% vs. 93.21% ± 0.56% vs. 95.17% ± 0.59%). A similar trend was also observed for the dice coefficients. This trend was especially remarkable for relatively low prescription isodose lines (for lung cancer, 10% isodose line dice: 0.871 ± 0.027 vs. 0.911 ± 0.023 vs. 0.927 ± 0.017). The dose predictions for all the testing cases were completed within 0.25 s. CONCLUSIONS: An accurate and efficient deep learning-augmented proton dose prediction framework has been developed for PBSPT, which can predict accurate dose distributions not only inside but also outside ROI efficiently. The framework can potentially further reduce the initial planning and adaptive replanning workload in PBSPT.

Dose delivery reproducibility for PBS proton treatment of breast cancer patients with and without mask immobilization.

BACKGROUND: Setup reproducibility of the tissue in the proton beam path is critical in maintaining the planned clinical target volume (CTV) dose coverage and sparing the organs at risk (OAR). In this study, we retrospectively evaluated radiation therapy dose reproducibility for proton pencil beam scanning (PBS) treatment of breast cancer patients with and without mask immobilization. METHODS: Ninety-four patients treated between January 2019 and September 2022 with at least one verification CT scan (V-CT) in treatment position were included for this study. All patients were set up with arms up using the Orfit AIO patient positioning system, with (69 patients) or without (25 patients) mask immobilization in chin, neck, shoulder, upper arm, and chest areas. Two to three enface or near enface single field uniform dose PBS beams were optimized using a commercial treatment planning system. Prescription doses were 25 to 60 GyRBE in 5 to 45 fractions. Treatment plan doses re-calculated on V-CTs were compared to the corresponding planned doses. Cumulative doses were also calculated for patients with at least 3 V-CTs by deform and weighted sum doses from V-CTs to corresponding P-CTs. CTV D95%, ipsilateral-lung V40%, esophagus D0.01cc, and heart mean dose were evaluated and reported as percentages of prescription doses. Differences were large dose deteriorations (LDD) if: (1) CTV (V-CT/cumulative D95%) - (Planned D95%) < - 5%; or (2) Ipsilateral-lung (V-CT/cumulative V40%) - (Planned V40%) > 5%; or (3) Esophagus (V-CT/cumulative D0.01cc) - (Planned D0.01cc) > 10%; or (4) Heart (V-CT/cumulative mean) - (Planned mean) > 1.5%. RESULTS: On average, V-CT/cumulative and planned CTV/OAR dose parameter differences were less than 2.2%/1.7% and 3.4%/3.7% for masked and maskless patients, respectively. The percentages of patients with at least one CTV or OAR V-CT/cumulative dose LDD were 20.3%/25.0% and 72.0%/54.0% for masked and maskless patients, respectively. CONCLUSIONS: On average, masked/maskless setups achieved delivered and planned CTV/OAR dose parameters agreed within 2.2%/3.7% for PBS treatment of breast cancer patients in this study. Maskless patients had higher rate of CTV/OAR LDDs compared to masked patients. Dosimetric differences large enough to raise clinical concerns in either group were able to be addressed with replannings.

Beam mask and sliding window-facilitated deep learning-based accurate and efficient dose prediction for pencil beam scanning proton therapy.

PURPOSE: To develop a DL-based PBSPT dose prediction workflow with high accuracy and balanced complexity to support on-line adaptive proton therapy clinical decision and subsequent replanning. METHODS: PBSPT plans of 103 prostate cancer patients and 83 lung cancer patients previously treated at our institution were included in the study, each with CTs, structure sets, and plan doses calculated by the in-house developed Monte-Carlo dose engine. For the ablation study, we designed three experiments corresponding to the following three methods: 1) Experiment 1, the conventional region of interest (ROI) method. 2) Experiment 2, the beam mask (generated by raytracing of proton beams) method to improve proton dose prediction. 3) Experiment 3, the sliding window method for the model to focus on local details to further improve proton dose prediction. A fully connected 3D-Unet was adopted as the backbone. Dose volume histogram (DVH) indices, 3D Gamma passing rates, and dice coefficients for the structures enclosed by the iso-dose lines between the predicted and the ground truth doses were used as the evaluation metrics. The calculation time for each proton dose prediction was recorded to evaluate the method's efficiency. RESULTS: Compared to the conventional ROI method, the beam mask method improved the agreement of DVH indices for both targets and OARs and the sliding window method further improved the agreement of the DVH indices. For the 3D Gamma passing rates in the target, OARs, and BODY (outside target and OARs), the beam mask method can improve the passing rates in these regions and the sliding window method further improved them. A similar trend was also observed for the dice coefficients. In fact, this trend was especially remarkable for relatively low prescription isodose lines. The dose predictions for all the testing cases were completed within 0.25s.

Modelling small block aperture in an in-house developed GPU-accelerated Monte Carlo-based dose engine for pencil beam scanning proton therapy.

Purpose: To enhance an in-house graphic-processing-unit (GPU) accelerated virtual particle (VP)-based Monte Carlo (MC) proton dose engine (VPMC) to model aperture blocks in both dose calculation and optimization for pencil beam scanning proton therapy (PBSPT)-based stereotactic radiosurgery (SRS). Methods and Materials: A module to simulate VPs passing through patient-specific aperture blocks was developed and integrated in VPMC based on simulation results of realistic particles (primary protons and their secondaries). To validate the aperture block module, VPMC was first validated by an opensource MC code, MCsquare, in eight water phantom simulations with 3cm thick brass apertures: four were with aperture openings of 1, 2, 3, and 4cm without a range shifter, while the other four were with same aperture opening configurations with a range shifter of 45mm water equivalent thickness. Then, VPMC was benchmarked with MCsquare and RayStation MC for 10 patients with small targets (average volume 8.4 cc with range of 0.4 - 43.3 cc). Finally, 3 typical patients were selected for robust optimization with aperture blocks using VPMC. Results: In the water phantoms, 3D gamma passing rate (2%/2mm/10%) between VPMC and MCsquare was 99.71±0.23%. In the patient geometries, 3D gamma passing rates (3%/2mm/10%) between VPMC/MCsquare and RayStation MC were 97.79±2.21%/97.78±1.97%, respectively. Meanwhile, the calculation time was drastically decreased from 112.45±114.08 seconds (MCsquare) to 8.20±6.42 seconds (VPMC) with the same statistical uncertainties of ~0.5%. The robustly optimized plans met all the dose-volume-constraints (DVCs) for the targets and OARs per our institutional protocols. The mean calculation time for 13 influence matrices in robust optimization by VPMC was 41.6 seconds and the subsequent on-the-fly "trial-and-error" optimization procedure took only 71.4 seconds on average for the selected three patients. Conclusion: VPMC has been successfully enhanced to model aperture blocks in dose calculation and optimization for the PBSPT-based SRS.

Technical note: Comprehensive evaluations of gantry and couch rotation isocentricities for implementing proton stereotactic radiosurgery.

BACKGROUND: Mechanical accuracy should be verified before implementing a proton stereotactic radiosurgery (SRS) program. Linear accelerator (Linac)-based SRS systems often use electronic portal imaging devices (EPIDs) to verify beam isocentricity. Because proton therapy systems do not have EPID, beam isocentricity tests of proton SRS may still rely on films, which are not efficient. PURPOSE: To validate that our proton SRS system meets mechanical precision requirements and to present an efficient method to evaluate the couch and gantry's rotational isocentricity for our proton SRS system. METHODS: A dedicated applicator to hold brass aperture for proton SRS system was designed. The mechanical precision of the system was tested using a metal ball and film for 11 combinations of gantry and couch angles. A more efficient quality assurance (QA) procedure was developed, which used a scintillator device to replace the film. The couch rotational isocentricity tests were performed using orthogonal kV x-rays with the couch rotated isocentrically to five positions (0°, 315°, 270°, 225°, and 180°). At each couch position, the distance between the metal ball in kV images and the imaging isocenter was measured. The gantry isocentricity tests were performed using a cone-shaped scintillator and proton beams at five gantry angles (0°, 45°, 90°, 135°, and 180°), and the isocenter position and the distance of each beam path to the isocenter were obtained. Daily QA procedure was performed for 1 month to test the robustness and reproducibility of the procedure. RESULTS: The gantry and couch rotational isocentricity exhibited sub-mm precision, with most measurements within ±0.5 mm. The 1-month QA results showed that the procedure was robust and highly reproducible to within ±0.2 mm. The gantry isocentricity test using the cone-shaped scintillator was accurate and sensitive to variations of ±0.2 mm. The QA procedure was efficient enough to be completed within 30 min. The 1-month isocentricity position variations were within 0.5 mm, which demonstrating that the overall proton SRS system was stable and precise. CONCLUSION: The proton SRS Winston-Lutz QA procedure using a cone-shaped scintillator was efficient and robust. We were able to verify radiation delivery could be performed with sub-mm mechanical precision.

Collimating individual beamlets in pencil beam scanning proton therapy, a dosimetric investigation.

The purpose of this work is to investigate collimating individual proton beamlets from a dosimetric perspective and to introduce a new device concept, the spot scanning aperture (SSA). The SSA consists of a thin aperture with a small cylindrical opening attached to a robotics system, which allows the aperture to follow and align with individual beamlets during spot delivery. Additionally, a range shifter is incorporated (source-side) for treating shallow depths. Since the SSA trims beamlets spot by spot, the patient-facing portion of the device only needs to be large enough to trim a single proton beamlet. The SSA has been modelled in an open-source Monte-Carlo-based dose engine (MCsquare) to characterize its dosimetric properties in water at depths between 0 and 10 cm while varying the following parameters: the aperture material, thickness, distance to the water phantom, distance between the aperture and attached range shifter, and the aperture opening radius. Overall, the SSA greatly reduced spot sizes for all the aperture opening radii that were tested (1 - 4 mm), especially in comparison with the extended range shifter (ranger shifter placed at 30 cm from patient); greater than 50% when placed less than 10 cm away from the patient at depths in water less than 50 mm. The peak to entrance dose ratio and linear energy transfer was found to depend on the thickness of the aperture and therefore the aperture material. Neutron production rates were also investigated and discussed.

Investigation of the impact of machine operating parameters on beam delivery time and its correlation with treatment plan characteristics for synchrotron-based proton pencil beam spot scanning system.

Purpose: To investigate the beam delivery time (BDT) reduction due to the improvement of machine parameters for Hitachi synchrotron-based proton PBS system. Methods: BDTs for representative treatment plans were calculated to quantitatively estimate the BDT improvement from our 2015 system at Mayo Clinic in Arizona to our system to be implemented in 2025 at Mayo Clinic in Florida, and to a hypothetical future system. To specifically assess how each incremental improvement in the operating parameters reduced the total BDT, for each plan, we simulated the BDT 10,368 times with various settings of the nine different operating parameters. The effect of each operating parameter on BDT reduction and its correlation with treatment plan characteristics were analyzed. The optimal number of multiple energy extraction (MEE) layers per spill for different systems was also investigated. Results: The median (range) decrease in BDT was 60% (56%-70%) from the 2015 to the 2025 system. The following incremental improvement in parameters of the 2015 system for the 2025 system played an important role in this decreased BDT: beam intensity (8 to 20 MU/s), recapture efficiency (50% to 80%), number of MEE layers per spill (4 to 8), scanning magnet preparation and verification time (1.9 to 0.95 msec), and MEE layer switch time (200 to 100 msec). Reducing the total spill change time and scanning magnet preparation and verification time from those of the 2025 system further reduced BDT in the hypothetical future system. 8 MEE layers per spill is optimal for a system with 50% recapture efficiency; 16 MEE layers per spill is optimal for a system with 80% recapture efficiency; and more than 16 MEE layers per spill is beneficial only for a system close to 100% recapture efficiency. Conclusions: We systematically studied the effect of each machine operating parameter on the reduction in total BDT and its correlation with treatment plan characteristics. Our findings will aid new and existing synchrotron-based proton beam therapy centers to make balanced decisions on BDT benefits vs. costs when considering machine upgrade or new system selection.

Technical note: Investigation of dose and LETd effect to rectum and bladder by using non-straight laterals in prostate cancer receiving proton therapy.

BACKGROUND: Parallel-opposed lateral beams are the conventional beam arrangements in proton therapy for prostate cancer. However, when considering linear energy transfer (LET) and RBE effects, alternative beam arrangements should be investigated. PURPOSE: To investigate the dose and dose averaged LET (LETd ) impact of using new beam arrangements rotating beams 5°-15° posteriorly to the laterals in prostate cancer treated with pencil-beam-scanning (PBS) proton therapy. METHODS: Twenty patients with localized prostate cancer were included in this study. Four proton treatment plans for each patient were generated utilizing 0°, 5°, 10°, and 15° posterior oblique beam pairs relative to parallel-opposed lateral beams. Dose-volume histograms (DVHs) from posterior oblique beams were analyzed. Dose-LETd -volume histogram (DLVH) was employed to study the difference in dose and LETd with each beam arrangement. DLVH indices, V ( d , l ) $V( {d,l} )$ , defined as the cumulative absolute volume that has a dose of at least d (Gy[RBE]) and a LETd of at least l (keV/µm), were calculated for both the rectum and bladder to the whole group of patients and two-sub groups with and without hydrogel spacer. These metrics were tested using Wilcoxon signed-rank test. RESULTS: Rotating beam angles from laterals to slightly posterior by 5°-15° reduced high LETd volumes while it increased the dose volume in the rectum and increased LETd in bladders. Beam angles rotated five degrees posteriorly from laterals (i.e., gantry in 95° and 265°) are proposed since they achieved the optimal balance of better LETd sparing and minimal dose increase in the rectum. A reduction of V(50 Gy[RBE], 2.6 keV/µm) from 7.41 to 3.96 cc (p < 0.01), and a slight increase of V(50 Gy[RBE], 0 keV/µm) from 20.1 to 21.6 cc (p < 0.01) were observed for the group without hydrogel spacer. The LETd sparing was less effective for the group with hydrogel spacer, which achieved the reduction of V(50 Gy[RBE], 2.6 keV/µm) from 4.28 to 2.10 cc (p < 0.01). CONCLUSIONS: Posterior oblique angle plans improved LETd sparing of the rectum while sacrificing LETd sparing in the bladder in the treatment of prostate cancer with PBS. Beam angle modification from laterals to slightly posterior may be a strategy to redistribute LETd and perhaps reduce rectal toxicity risks in prostate cancer patients treated with PBS. However, the effect is reduced for patients with hydrogel spacer.

Virtual particle Monte Carlo: A new concept to avoid simulating secondary particles in proton therapy dose calculation.

BACKGROUND: 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. PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: VPMC was found to achieve high accuracy and efficiency in proton therapy dose calculation.

Exploratory study of seed spots analysis to characterize dose and linear-energy-transfer effect in adverse event initialization of pencil-beam-scanning proton therapy.

BACKGROUND: Both dose and linear energy transfer (LET) could play a substantial role in adverse event (AE) initialization of cancer patients treated with pencil-beam-scanning (PBS) proton therapy. However, not all the voxels within the AE regions are directly induced from the dose and LET effect. It is important to study the synergistic effect of dose and LET in AE initialization by only including a subset of voxels that are dosimetrically important. PURPOSE: To perform exploratory investigation of the dose and LET effects upon AE initialization in PBS using seed spots analysis. METHODS: A total of 113 head-and-neck (H&N) cancer patients receiving curative PBS were included. Among them, 20 patients experienced unanticipated CTCAEv4.0 grade ≥3 AEs (AE group) and 93 patients did not (control group). Within the AE group, 13 AE patients were included in the seed spot analysis to derive the descriptive features of AE initialization and the remaining 7 mandible osteoradionecrosis patients and 93 control patients were used to derive the feature-based volume constraint of mandible osteoradionecrosis. The AE regions were contoured and the corresponding dose-LET volume histograms of AE regions were generated for all patients in the AE group. We selected high LET voxels (the highest 5% of each dose bin) with a range of moderate-to-high dose (≥∼40-Gy relative biological effectiveness) as critical voxels. Critical voxels that were contiguous with each other were grouped into clusters. Each cluster was considered a potential independent seed spot for AE initialization. Seed spots were displayed in a 2D dose-LET plane based on their mean dose and LET to derive the descriptive features of AE initialization. A volume constraint of mandible osteoradionecrosis was then established based on the extracted features using a receiver operating characteristic curve. RESULTS: The product of dose and LET (xBD) was found to be a descriptive feature of seed spots leading to AE initialization in this preliminary study. The derived xBD volume constraint for mandible osteoradionecrosis showed good performance with an area under curve of 0.87 (sensitivity of 0.714 and specificity of 0.807 in the leave-one-out cross-validation) for the very limited patient data included in this study. CONCLUSION: Our exploratory study showed that both dose and LET were observed to be important in AE initializations. The derived xBD volume constraint could predict mandible osteoradionecrosis reasonably well in the very limited H&N cancer patient data treated with PBS included in this study.

Investigation of beam delivery time for synchrotron-based proton pencil beam scanning system with novel scanning mode.

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.

GPU-accelerated Monte Carlo-based online adaptive proton therapy: A feasibility study.

PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSION: 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.

Implementation of Photon Treatment Back-up Workflow at a High-Volume Proton Center: Safety, Quality, and Patient Considerations.

PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS AND CONCLUSIONS: 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.

Technical note: Evaluation and second check of a commercial Monte Carlo dose engine for small-field apertures in pencil beam scanning proton therapy.

PURPOSE: 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. METHODS: 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 cm3 ) patient treatment plans were calculated by each dose engine followed by a statistical comparison. RESULTS: Comparing 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. CONCLUSION: 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.

Empirical Relative Biological Effectiveness (RBE) for Mandible Osteoradionecrosis (ORN) in Head and Neck Cancer Patients Treated With Pencil-Beam-Scanning Proton Therapy (PBSPT): A Retrospective, Case-Matched Cohort Study.

Purpose: To retrospectively investigate empirical relative biological effectiveness (RBE) for mandible osteoradionecrosis (ORN) in head and neck (H&N) cancer patients treated with pencil-beam-scanning proton therapy (PBSPT). Methods: We included 1,266 H&N cancer patients, of which, 931 patients were treated with volumetric-modulated arc therapy (VMAT) and 335 were treated with PBSPT. Among them, 26 VMAT and 9 PBSPT patients experienced mandible ORN (ORN group), while all others were included in the control group. To minimize the impact of the possible imbalance in clinical factors between VMAT and PBSPT patients in the dosimetric comparison between these two modalities and the resulting RBE quantification, we formed a 1:1 case-matched patient cohort (335 VMAT patients and 335 PBSPT patients including both the ORN and control groups) using the greedy nearest neighbor matching of propensity scores. Mandible dosimetric metrics were extracted from the case-matched patient cohort and statistically tested to evaluate the association with mandibular ORN to derive dose volume constraints (DVCs) for VMAT and PBSPT, respectively. We sought the equivalent constraint doses for VMAT so that the critical volumes of VMAT were equal to those of PBSPT at different physical doses. Empirical RBEs of PBSPT for ORN were obtained by calculating the ratio between the derived equivalent constraint doses and physical doses of PBSPT. Bootstrapping was further used to get the confidence intervals. Results: Clinical variables of age, gender, tumor stage, prescription dose, chemotherapy, hypertension or diabetes, dental extraction, smoking history, or current smoker were not statistically related to the incidence of ORN in the overall patient cohort. Smoking history was found to be significantly associated with the ORN incidence in PBSPT patients only. V40Gy[RBE], V50Gy[RBE], and V60Gy[RBE] were statistically different (p<0.05) between the ORN and control group for VMAT and PBSPT. Empirical RBEs of 1.58(95%CI: 1.34-1.64), 1.34(95%CI: 1.23-1.40), and 1.24(95%: 1.15-1.26) were obtained for proton dose at 40 Gy[RBE=1.1], 50 Gy[RBE=1.1] and 60 Gy[RBE=1.1], respectively. Conclusions: Our study suggested that RBEs were larger than 1.1 at moderate doses (between 40 and 60 Gy[RBE=1.1]) with high LET for mandible ORN. RBEs are underestimated in current clinical practice in PBSPT. The derived DVCs can be used for PBSPT plan evaluation and optimization to minimize the incidence rate of mandible ORN.

Per-voxel constraints to minimize hot spots in linear energy transfer-guided robust optimization for base of skull head and neck cancer patients in IMPT.

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; and (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,50 Gy[RBE], p = 0.009; VxBD,60 Gy[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.

Technical Note: Long-term monitoring of diode sensitivity degradation induced by proton irradiation.

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.

Technical Note: Clinical modeling and validation of breast tissue expander metallic ports in a commercial treatment planning system for proton therapy.

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 650 cc 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 postmastectomy 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%/2 mm/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 1.1 to 5.0 cm2 , and the maximum dose difference ([ΔD] 0.01 cm2 ) 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 1.1 to 2.9 cm2 and (ΔD) 0.01 cm2 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 0.13 cm2 , and the (ΔD) 0.01 cm2 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.

A Critical Review of LET-Based Intensity-Modulated Proton Therapy Plan Evaluation and Optimization for Head and Neck Cancer Management.

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.