The effect of common dental fixtures on treatment planning and delivery for head and neck intensity modulated proton therapy.

PURPOSE: Proton treatment plan perturbation by common dental fixtures such as amalgams (Am) and porcelain-fused-to-metal (PFM) crowns has, to date, been uncharacterized. Previous studies have been conducted to determine the physical effect of these materials within the beam path for single spots, but their effects on complex treatment plans and clinical anatomy have not yet been quantified. The present manuscript aims to study the effect of Am and PFM fixtures on proton treatment planning in a clinical setting. METHODS: An anthropomorphic phantom with removable tongue, maxilla, and mandible modules was simulated on a clinical computed tomography (CT) scanner. Spare maxilla modules were modified to include either a 1.5 mm depth central groove occlusal amalgam (Am) or a porcelain-fused-to-metal (PFM) crown, implanted on the first right molar. Modified tongue modules were 3D printed to accommodate several axial or sagittal oriented pieces of EBT-3 film. Clinically representative spot-scanning proton plans were generated in Eclipse v.15.6 using the proton convolution superposition (PCS) algorithm v.15.6.06 using a multi-field optimization (MFO) technique with the goal of delivering a uniform 54 Gy dose to a clinical target volume (CTV) typical of a base-of-tongue (BoT) treatment. A typical geometric beam arrangement of two anterior oblique (AO) beams and a posterior beam was employed. Plans optimized without any material overrides were delivered to the phantom A) without implants; B) with Am fixture; or C) with PFM crown. Plans were also reoptimized and delivered with inclusion of material overrides to equate relative stopping power of the fixture with that of a previously measured result. RESULTS: Plans exhibit slightly greater dose weight towards AO beams. The optimizer accounted for inclusion of fixture overrides by increasing beam weights to the beam closest to the implant. Film measurements exhibited cold spots directly within the beam path through the fixture in plans with and without overridden materials. Cold spots were somewhat mitigated in plans including overridden materials in the structure set but were not entirely eliminated. Cold spots associated with Am and PFM fixtures were quantified at 17% and 14% for plans without overrides, respectively, and 11% and 9% with using Monte Carlo simulation. Compared with film measurements and Monte Carlo simulation, the treatment planning system underestimates the dose shadowing effect in plans including material overrides. CONCLUSIONS: Dental fixtures create a dose shadowing effect directly in line with the beam path through the material. This cold spot is partially mitigated by overriding the material to measured relative stopping powers. Due to uncertainties in modeling perturbation through the fixture, the magnitude of the cold spot is underestimated using the institutional TPS when compared to measurement and MC simulation.

Design of a 3D patient-specific collision avoidance virtual framework for half-gantry proton therapy system.

INTRODUCTION: This study presents a comprehensive collision avoidance framework based on three-dimension (3D) computer-aided design (CAD) modeling, a graphical user interface (GUI) as peripheral to the radiation treatment planning (RTP) environment, and patient-specific plan parameters for intensity-modulated proton therapy (IMPT). METHODS: A stand-alone software application was developed leveraging the Varian scripting application programming interface (API) for RTP database object accessibility. The Collision Avoider software models the Hitachi ProBeat-V half gantry design and the Kuka robotic couch with triangle mesh structures. Patient-specific plan parameters are displayed in the collision avoidance software for potential proximity evaluation. The external surfaces of the patients and the immobilization devices are contoured based on computed tomography (CT) images. A "table junction-to-CT-origin" (JCT) measurement is made for every patient at the time of CT simulation to accurately provide reference location of the patient contours to the treatment couch. Collision evaluations were performed virtually with the program during treatment planning to prevent four major types of collisional events: collisions between the gantry head and the treatment couch, gantry head and the patient's body, gantry head and the robotic arm, and collisions between the gantry head and the immobilization devices. RESULTS: The Collision Avoider software was able to accurately model the proton treatment delivery system and the robotic couch position. Commonly employed clinical beam configuration and JCT values were investigated. Brain and head and neck patients require more complex gantry and patient positioning system configurations. Physical measurements were performed to validate 3D CAD model geometry. Twelve clinical proton treatment plans were used to validate the accuracy of the software. The software can predict all four types of collisional events in our clinic since its full implementation in 2020. CONCLUSION: A highly efficient patient-specific collision prevention program for scanning proton therapy has been successfully implemented. The graphical program has provided accurate collision detection since its inception at our institution.

Optimizing Gantry Breakpoint Angles in Proton Therapy: Enhancing Efficiency and Patient Experience.

Purpose: The breakpoint for a 360° radiotherapy gantry is typically positioned at 180°. This arbitrary setting has not been systematically evaluated for efficiency and may cause redundant gantry rotation and extended setup times. Our study aimed to identify an optimal gantry breakpoint angle for a full-gantry proton therapy system, with the goal of minimizing gantry movement. Materials and Methods: We analyzed 70 months of clinically delivered proton therapy plans (9152 plans, 131 883 fractions), categorizing them by treatment site and mapping the fields from a partial-gantry to full-gantry orientation. For each delivered fraction, we computed the minimum total gantry rotation angle as a function of gantry breakpoint position, which was varied between 0° and 360° in 1° steps. This analysis was performed separately within the entire plan cohort and individual treatment sites, both with and without the capability of over-rotating 10° past the breakpoint from either direction (20° overlap). The optimal gantry breakpoint was identified as one which resulted in a low average gantry rotation per fraction. Results: Considering mechanical constraints, 130° was identified as a reasonable balance between increased gantry-rotation efficiency and practical treatment considerations. With a 20° overlap, this selection reduced the average gantry rotation by 41.4° per fraction when compared to the standard 180° breakpoint. Disease site subgroups showed the following reduction in average gantry rotation: gastrointestinal 192.2°, thoracic 56.3°, pediatric 44.9°, genitourinary 19.9°, central nervous system 10.7°, breast 2.8°, and head and neck 0.1°. Conclusion: For a full-gantry system, a breakpoint of 130° generally outperforms the conventional 180° breakpoint. This reduction is particularly impactful for gastrointestinal, pediatric, and thoracic sites, which constitute a significant proportion of cases at our center. The adjusted breakpoint could potentially streamline patient delivery, alleviate mechanical wear, and enhance treatment precision by reducing the likelihood of patient movement during delivery.

Radiation Dose Sensitivity of Subregions of the Larynx to Patient-Reported Swallowing Outcomes.

Purpose: To assess any correlation between swallowing dysfunction and radiation dose to 5 subregions of the larynx. Methods and Materials: A cohort of 136 patients with head and neck cancer, treated with either photon or proton radiation therapy, was assessed using an endpoint of patient-reported swallowing scores, evaluated with the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-H&N35 survey, within 1 month after treatment. Five subregions of the larynx were contoured, and dosimetric metrics were extracted for each subregion as well as the total larynx. Univariate and multivariate logistic regression statistical analyses were used to determine statistical correlation with the dose metrics and clinical variables. Univariate regression models were statistically compared using a non-nested model test. Results: Under univariate analysis, unilateral versus bilateral nodal irradiation (P = .004), concurrent chemotherapy (P = .007), and surgery (P = .015) were statistically significant predictors of poor swallowing score. Unilateral versus bilateral irradiation was statistically significant under multivariate analysis (P = .039). The epiglottis was the most predictive subregion of swallowing score, with a majority (21 of 25) of dosimetric variables being identified as statistically significant. The maximum dose to the epiglottis was the most significant dosimetric variable tested for poor swallowing score in both univariate (P = .003) and multivariate (P = .051) analyses. Comparison of univariate models indicated a general preference for epiglottic variables with the mean dose to the epiglottis being preferred at a statistically significant level in many cases. Conclusions: These results show the relatively increased sensitivity of the epiglottis compared with the rest of the larynx when considering patient-reported decrements in quality-of-life swallowing score and support both the inclusion of the epiglottis in standard larynx contours and the assessment of the epiglottis dose during plan evaluation. Our data suggest that keeping the mean and max doses to the epiglottis <20 to 37 Gy and <53 to 60 Gy, respectively, will reduce swallowing difficulties.

Impact of radiation dose distribution on nutritional supplementation needs in head and neck cancer radiotherapy: a voxel-based machine learning approach.

Objectives: To investigate the relationship between nutritional supplementation and radiation dose to the pharyngeal constrictor muscles and larynx for head and neck (HN) cancer patients undergoing radiotherapy. Methods: We retrospectively analyzed radiotherapy (RT) dose for 231 HN cancer patients, focusing on the pharyngeal constrictors and larynx. We defined nutritional supplementation as feeding tube utilization or >10% weight loss from baseline within 90 days after radiotherapy completion. Using deformable image registration (DIR), we mapped each patient's anatomical structures to a reference coordinate system, and corresponding deformations were applied to dose matrices. Voxel doses were utilized as features for ridge logistic regression models, optimized through 5-fold cross-validation. Model performance was assessed with area under the curve of a receiver operating curve (AUC) and F1 score. We built and compared models using 1) pharyngeal constrictor voxels, 2) larynx voxels, 3) clinical factors and mean regional dose metrics, and 4) clinical factors and dose-volume histogram metrics. Test set AUCs were compared among the models, and feature importance was evaluated. Results: DIR of the pharyngeal constrictors and larynx yielded mean Dice coefficients of 0.80 and 0.84, respectively. Pharyngeal constrictors voxels and larynx voxel models had AUC of 0.88 and 0.82, respectively. Voxel-based dose modeling identified the superior to middle regions of the pharyngeal constrictors and the superior region of larynx as most predictive of feeding tube use/weight loss. Univariate analysis found treatment setting, treatment laterality, chemotherapy, baseline dysphagia, weight, and socioeconomic status predictive of outcome. An aggregated model using mean doses of pharyngeal constrictors and larynx subregions had an AUC of 0.87 and the model using conventional DVH metrics had an AUC of 0.85 with p-value of 0.04. Feature importance calculations from the regional dose model indicated that mean doses to the superior-middle pharyngeal constrictor muscles followed by mean dose to the superior larynx were most predictive of nutritional supplementation. Conclusions: Machine learning modeling of voxel-level doses enables identification of subregions within organs that correlate with toxicity. For HN radiotherapy, doses to the superior-middle pharyngeal constrictors are most predictive of feeding tube use/weight loss followed by the doses to superior portion of the larynx.

Physical characterization of therapeutic proton delivery through common dental materials.

PURPOSE: Dental fixtures are commonplace in an aging, radiation treatment population. The current, local standard of practice in particle therapy is to employ treatment geometries to avoid delivery through implanted dental fixtures. The present study aims to observe the physical effect of delivering therapeutic proton beams through common dental fixture materials as prelude to an eventual goal of assessing the feasibility of using treatment geometries not specified for avoidance of oral implants. A sampling of common dental materials was selected based on prosthodontic consult and was evaluated in terms of relative stopping power and three-dimensional (3D) dose perturbation. METHODS: Amalgams, porcelain-fused-to-metal (PFM) crowns consisting of zirconia and non-noble base metals, and lithium disilicate implants were chosen for analysis. Theoretical stopping power (S) and mass stopping power (S/ρ) were calculated using the Stopping and Range of Ions in Matter (SRIM) application, basing stoichiometric compositions of each fixture on published materials data. S and S/ρ were calculated for a range of historically available compositions of amalgams from 1900 until the current era. The perturbance of S and S/ρ as a function of clinically relevant ranges of amalgam compositions for the modern era was analyzed. Water equivalent thickness (WET) and relative stopping power (Srel ) of each material was measured for a clinical spot-scanning proton beam with monoenergies of 159.9 and 228.8 MeV with a multi-layer ionization chamber (MLIC). Subsequently, 3D dose perturbation was assessed by delivering proton beams through a custom phantom designed to simulate both en-face and on-edge treatment geometries through the selected materials. A treatment plan mimicking the experimental delivery was constructed in the institutional treatment planning system and calculated using TOPAS-based Monte Carlo simulation (MCS). Experimental results were used to validate the MCS. Finally, treatment planning system (TPS) outputs were compared to MCS to determine the accuracy of the dose calculation model. RESULTS: Historical compositions of amalgams ranged in S from 44.8 to 42.9 MeV/cm, with the greatest deviation being observed for the 1900-1959 era. Deviation as a function of amalgam composition from the modern era was most sensitive to proportion of Hg, accounting for deviations up to -4.2% at the greatest clinically relevant concentration. S/ρ was not found to vary greatly between each porcelain and metal alloy material for PFM type crowns. Relative stopping powers ranged between 1.3 and 5.4 for all studied materials, suggesting substantial changes in proton range with respect to water. Film measurements of pristine spots confirm dose perturbance and shortening of proton range, with an upstream shift of each Bragg peak being observed directly behind the installed fixture. At high energies, cold spots were found in all cases directly behind each material feature with a medial fill-in of dose occurring distally. Qualitative agreement of spot perturbance was confirmed between film measurements and MCS. Finally, when comparing integrated depth doses (IDD) by summing over all axial directions, good agreement is observed between TPS and MCS. CONCLUSIONS: All dental materials studied substantially perturbed the dosimetry of pristine proton spots both in terms of WET/Srel as well as the spatial distribution of dose. Proton range was quantifiably shortened, and each dental material affected a cold spot directly behind the object with medial dose back-filling was observed distally. MCS and Eclipse dose calculations exhibited good agreement with measurements, suggesting that treatment planning without employing avoidance strategies may be possible with further investigation.

Analysis of the Rate of Re-planning in Spot-Scanning Proton Therapy.

Purpose: Finite proton range affords improved dose conformality of radiation therapy when patient regions-of-interest geometries are well characterized. Substantial changes in patient anatomy necessitate re-planning (RP) to maintain effective, safe treatment. Regularly planned verification scanning (VS) is performed to ensure consistent treatment quality. Substantial resources, however, are required to conduct an effective proton plan verification program, which includes but is not limited to, additional computed tomography (CT) scanner time and dedicated personnel: radiation therapists, medical physicists, physicians, and medical dosimetrists. Materials and Methods: Verification scans (VSs) and re-plans (RPs) of 711 patients treated with proton therapy between June 2015 and June 2018 were studied. All treatment RP was performed with the intent to maintain original plan integrity and coverage. The treatments were classified by anatomic site: brain, craniospinal, bone, spine, head and neck (H&N), lung or chest, breast, prostate, rectum, anus, pelvis, esophagus, liver, abdomen, and extremity. Within each group, the dates of initial simulation scan, number of VSs, number of fractions completed at the time of VS, and the frequency of RP were collected. Data were analyzed in terms of rate of RP and individual likelihood of RP. Results: A total of 2196 VSs and 201 RPs were performed across all treatment sites. H&N and lung or chest disease sites represented the largest proportion of plan modifications in terms of rate of re-plan (RoR: 54% and 58%, respectively) and individual likelihood of RP on a per patient basis (likelihood of RP [RP%]: 46% and 39%, respectively). These sites required RP beyond 4 weeks of treatment, suggesting continued benefit for frequent, periodic VS. Disease sites in the lower pelvis demonstrated a low yield for RP per VS (0.01-0.02), suggesting that decreasing VS frequency, particularly late in treatment, may be reasonable. Conclusions: A large degree of variation in RoR and individual RP% was observed between anatomic treatment sites. The present retrospective analysis provides data to help develop anatomic site-based VS protocols.

An accelerated threshold-based back-projection algorithm for compton camera image reconstruction.

PURPOSE: Compton camera imaging (CCI) systems are currently under investigation for radiotherapy dose reconstruction and verification. The ability of such a system to provide real-time images during dose delivery will be limited by the computational speed of the image reconstruction algorithm. In this work, the authors present a fast and simple method by which to generate an initial back-projected image from acquired CCI data, suitable for use in a filtered back-projection algorithm or as a starting point for iterative reconstruction algorithms, and compare its performance to the current state of the art. METHODS: Each detector event in a CCI system describes a conical surface that includes the true point of origin of the detected photon. Numerical image reconstruction algorithms require, as a first step, the back-projection of each of these conical surfaces into an image space. The algorithm presented here first generates a solution matrix for each slice of the image space by solving the intersection of the conical surface with the image plane. Each element of the solution matrix is proportional to the distance of the corresponding voxel from the true intersection curve. A threshold function was developed to extract those pixels sufficiently close to the true intersection to generate a binary intersection curve. This process is repeated for each image plane for each CCI detector event, resulting in a three-dimensional back-projection image. The performance of this algorithm was tested against a marching algorithm known for speed and accuracy. RESULTS: The threshold-based algorithm was found to be approximately four times faster than the current state of the art with minimal deficit to image quality, arising from the fact that a generically applicable threshold function cannot provide perfect results in all situations. The algorithm fails to extract a complete intersection curve in image slices near the detector surface for detector event cones having axes nearly parallel to the image plane. This effect decreases the sum of the image, thereby also affecting the mean, standard deviation, and SNR of the image. All back-projected events associated with a simulated point source intersected the voxel containing the source and the FWHM of the back-projected image was similar to that obtained from the marching method. CONCLUSIONS: The slight deficit to image quality observed with the threshold-based back-projection algorithm described here is outweighed by the 75% reduction in computation time. The implementation of this method requires the development of an optimum threshold function, which determines the overall accuracy of the method. This makes the algorithm well-suited to applications involving the reconstruction of many large images, where the time invested in threshold development is offset by the decreased image reconstruction time. Implemented in a parallel-computing environment, the threshold-based algorithm has the potential to provide real-time dose verification for radiation therapy.

Intensity-Modulated Proton Therapy (IMPT) Treatment of Angiosarcoma of the Face and Scalp.

PURPOSE: To successfully plan and treat a patient with diffuse angiosarcoma involving the face and scalp with intensity-modulated proton therapy (IMPT) before surgical resection. MATERIALS AND METHODS: A patient presented to the radiation oncology department for preoperative treatment of an angiosarcoma diffusely involving the face and scalp. A 4-field IMPT technique was used to create a homogeneous dose distribution to the entire target volume while sparing underlying critical structures from toxicity and low-dose spread. A custom Monte Carlo optimizer was necessary to achieve treatment goals. Biological dose was evaluated with a linear energy transfer-based biological enhancement model. Robustness criteria were evaluated per department standard. The patient was successfully planned and treated according to clinical goals. RESULTS: The patient successfully completed the course of IMPT and was able to undergo surgical resection. Pathology indicated no presence of angiosarcoma. CONCLUSION: IMPT using a custom Monte Carlo optimizer is a suitable radiation therapy treatment option for patients with diffuse angiosarcoma of the scalp and face.

Oncologic Outcomes for Head and Neck Skin Malignancies Treated with Protons.

PURPOSE: Radiation therapy (RT) is the standard treatment for patients with inoperable skin malignancies of the head and neck region (H&N), and as adjuvant treatment post surgery in patients at high risk for local or regional recurrence. This study reports clinical outcomes of intensity-modulated proton therapy (IMPT) for these malignancies. MATERIALS AND METHODS: We retrospectively reviewed cases involving 47 patients with H&N malignancies of the skin (squamous cell, basal cell, melanoma, Merkel cell, angiosarcoma, other) who underwent IMPT for curative intent between July 2016 and July 2019. Overall survival was estimated via Kaplan-Meier analysis, and oncologic outcomes were reported as cumulative incidence with death as a competing risk. RESULTS: The 2-year estimated local recurrence rate, regional recurrence rate, local regional recurrence rate, distant metastasis rate, and overall survival were 11.1% (95% confidence interval [CI], 4.1%-30.3%), 4.4% (95% CI, 1.1%-17.4%), 15.5% (95% CI, 7%-34.3%), 23.4% (95% CI, 5.8%-95.5%), and 87.2% (95% CI, 75.7%-100%), respectively. No patient was reported to have a grade 3 or higher adverse event during the last week of treatment or at the 3-month follow-up visit. CONCLUSION: IMPT is safe and effective in the treatment of skin malignancies of the H&N.

Uncertainty analysis of a Compton camera imaging system for radiation therapy dose reconstruction.

PURPOSE: Improved radiotherapy dose delivery techniques over the past decade have increased the necessity for accurate, independent verification of delivered dose. Compton camera imaging (CCI) systems may have the potential to quantitatively reconstruct three-dimensional dose delivered to the patient with little or no a priori information. METHODS: In this work, the adequacy of a Compton camera imaging system for application to radiotherapy dose reconstruction is explored using analytical models of system spatial and dosimetric resolution. The effects of scatter and absorption detector energy resolution, initial photon energy, and detector separation distance on system performance were calculated with the goal of determining whether current detector technology is adequate for such an application. RESULTS: Results indicate that the energy and spatial resolutions associated with current Si and Ge double-sided strip detectors in a planar configuration is sufficient to determine dose deposition to within an average of 1.9 mm and 2.5%. Minimum values of less than 0.5 mm and 1% are achievable under certain conditions. As the energy of the photon incident on the patient increases from 1.0 to 10 MeV, system performance improves at the expense of the range of patient and detector scattering angles over which the system is capable of reconstructing dose deposition to within the acceptable upper limits of 5 mm and 5%. System performance also improves with increasing distance between the scatter and absorption detectors, but is acceptable throughout the range of values likely to be associated with a gantry-mounted system (2-20 cm). CONCLUSIONS: The results indicate that Compton camera imaging systems based on current solid-state detector technology have the potential to provide independent verification of dose delivered to a patient during radiation therapy. Further consideration must be given to detector efficiency and image reconstruction algorithms for this application of CCI systems.

Comparative analysis of acute toxicities and patient reported outcomes between intensity-modulated proton therapy (IMPT) and volumetric modulated arc therapy (VMAT) for the treatment of oropharyngeal cancer.

BACKGROUND AND PURPOSE: IMPT improves normal tissue sparing compared to VMAT in treating oropharyngeal cancer (OPC). Our aim was to assess if this translates into clinical benefits. MATERIALS AND METHODS: OPC patients treated with definitive or adjuvant IMPT or VMAT from 2013 to 2018 were included. All underwent prospective assessment using patient-reported-outcomes (PROs) (EORTC-QLQ-H&N35) and provider-assessed toxicities (CTCAEv4.03). End-of-treatment and pretreatment scores were compared. PEG-tube use, hospitalization, and narcotic use were retrospectively collected. Statistical analysis used the Wilcoxon Rank-Sum Test with propensity matching for PROs/provider-assessed toxicities, and t-tests for other clinical outcomes. RESULTS: 46 IMPT and 259 VMAT patients were included; median follow-up was 12 months (IMPT) and 30 months (VMAT). Baseline characteristics were balanced except for age (p = 0.04, IMPT were older) and smoking (p < 0.01, 10.9% IMPT >20PYs, 29.3% VMAT). IMPT was associated with lower PEG placement (OR = 0.27; 95% CI: 0.12-0.59; p = 0.001) and less hospitalization ≤60 days post-RT (OR = 0.21; 95% CI:0.07-0.6, p < 0.001), with subgroup analysis revealing strongest benefits in patients treated definitively or with concomitant chemoradiotherapy (CRT). IMPT was associated with a relative risk reduction of 22.3% for end-of-treatment narcotic use. Patients reported reduced cough and dysgeusia with IMPT (p < 0.05); patients treated definitively or with CRT also reported feeling less ill, reduced feeding tube use, and better swallow. Provider-assessed toxicities demonstrated less pain and mucositis with IMPT, but more mucosal infection. CONCLUSION: IMPT is associated with improved PROs, reduced PEG-tube placement, hospitalization, and narcotic requirements. Mucositis, dysphagia, and pain were decreased with IMPT. Benefits were predominantly seen in patients treated definitively or with CRT.

The Importance of Verification CT-QA Scans in Patients Treated with IMPT for Head and Neck Cancers.

PURPOSE: To understand how verification computed tomography-quality assurance (CT-QA) scans influenced clinical decision-making to replan patients with head and neck cancer and identify predictors for replanning to guide intensity-modulated proton therapy (IMPT) clinical practice. PATIENTS AND METHODS: We performed a quality-improvement study by prospectively collecting data on 160 consecutive patients with head and neck cancer treated using spot-scanning IMPT who underwent weekly verification CT-QA scans. Kaplan-Meier estimates were used to determine the cumulative probability of a replan by week. Predictors for replanning were determined with univariate (UVA) and multivariate (MVA) Cox model hazard ratios (HRs). Logistic regression was used to determine odds ratios (ORs). P < .05 was considered statistically significant. RESULTS: Of the 160 patients, 79 (49.4%) had verification CT-QA scans, which prompted a replan. The cumulative probability of a replan by week 1 was 13.7% (95% confidence interval [CI], 8.82-18.9), week 2, 25.0% (95% CI, 18.0-31.4), week 3, 33.1% (95% CI, 25.4-40.0), week 4, 45.6% (95% CI, 37.3-52.8), and week 5 and 6, 49.4% (95% CI, 41.0-56.6). Predictors for replanning were sinonasal disease site (UVA: HR, 1.82, P = .04; MVA: HR, 3.64, P = .03), advanced stage disease (UVA: HR, 4.68, P < .01; MVA: HR, 3.10, P < .05), dose > 60 Gy equivalent (GyE; relative biologic effectiveness, 1.1) (UVA: HR, 1.99, P < .01; MVA: HR, 2.20, P < .01), primary disease (UVA: HR, 2.00 versus recurrent, P = .01; MVA: HR, 2.46, P = .01), concurrent chemotherapy (UVA: HR, 2.05, P < .01; MVA: not statistically significant [NS]), definitive intent treatment (UVA: HR, 1.70 versus adjuvant, P < .02; MVA: NS), bilateral neck treatment (UVA: HR, 2.07, P = .03; MVA: NS), and greater number of beams (5 beam UVA: HR, 5.55 versus 1 or 2 beams, P < .02; MVA: NS). Maximal weight change from baseline was associated with higher odds of a replan (≥3 kg: OR, 1.97, P = .04; ≥ 5 kg: OR, 2.13, P = .02). CONCLUSIONS: Weekly verification CT-QA scans frequently influenced clinical decision-making to replan. Additional studies that evaluate the practice of monitoring IMPT-treated patients with weekly CT-QA scans and whether that improves clinical outcomes are warranted.

Automation of routine elements for spot-scanning proton patient-specific quality assurance.

PURPOSE: At our institution, all proton patient plans undergo patient-specific quality assurance (PSQA) prior to treatment delivery. For intensity-modulated proton beam therapy, quality assurance is complex and time consuming, and it may involve multiple measurements per field. We reviewed our PSQA workflow and identified the steps that could be automated and developed solutions to improve efficiency. METHODS: We used the treatment planning system's (TPS) capability to support C# scripts to develop an Eclipse scripting application programming interface (ESAPI) script and automate the preparation of the verification phantom plan for measurements. A local area network (LAN) connection between our measurement equipment and shared database was established to facilitate equipment control, measurement data transfer, and storage. To improve the analysis of the measurement data, a Python script was developed to automatically perform a 2D-3D γ-index analysis comparing measurements in the plane of a two-dimensional detector array with TPS predictions in a water phantom for each acquired measurement. RESULTS: Device connection via LAN granted immediate access to the plan and measurement information for downstream analysis using an online software suite. Automated scripts applied to verification plans reduced time from preparation steps by at least 50%; time reduction from automating γ-index analysis was even more pronounced, dropping by a factor of 10. On average, we observed an overall time savings of 55% in completion of the PSQA per patient plan. CONCLUSIONS: The automation of the routine tasks in the PSQA workflow significantly reduced the time required per patient, reduced user fatigue, and frees up system users from routine and repetitive workflow steps allowing increased focus on evaluating key quality metrics.

Technical Note: An efficient daily QA procedure for proton pencil beam scanning.

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.

Radiation binary targeted therapy for HER-2 positive breast cancers: assumptions, theoretical assessment and future directions.

A novel radiation targeted therapy is investigated for HER-2 positive breast cancers. The proposed concept combines two known approaches, but never used together for the treatment of advanced, relapsed or metastasized HER-2 positive breast cancers. The proposed radiation binary targeted concept is based on the anti HER-2 monoclonal antibodies (MABs) that would be used as vehicles to transport the nontoxic agent to cancer cells. The anti HER-2 MABs have been successful in targeting HER-2 positive breast cancers with high affinity. The proposed concept would utilize a neutral nontoxic boron-10 predicting that anti HER-2 MABs would assure its selective delivery to cancer cells. MABs against HER-2 have been a widely researched strategy in the clinical setting. The most promising antibody is Trastuzumab (Herceptin). Targeting HER-2 with the MAB Trastuzumab has been proven to be a successful strategy in inducing tumour regression and improving patient survival. Unfortunately, these tumours become resistant and afflicted women succumb to breast cancer. In the proposed concept, when the tumour region is loaded with boron-10 it is irradiated with neutrons (treatment used for head and neck cancers, melanoma and glioblastoma for over 40 years in Japan and Europe). The irradiation process takes less than an hour producing minimal side effects. This paper summarizes our recent theoretical assessments of radiation binary targeted therapy for HER-2 positive breast cancers on: the effective drug delivery mechanism, the numerical model to evaluate the targeted radiation delivery and the survey study to find the neutron facility in the world that might be capable of producing the radiation effect as needed. A novel method of drug delivery utilizing Trastuzumab is described, followed by the description of a computational Monte Carlo based breast model used to determine radiation dose distributions. The total flux and neutron energy spectra of five currently available neutron irradiation treatment facilities are examined for this application. The tumour boron concentrations and tumour to healthy tissue concentration ratios required to deliver 50 Gy-Eq to the tumour without exceeding 18 Gy-Eq in the skin are determined, as well as the associated therapeutic ratios. Discussion is provided to address the future research direction for assessing the feasibility of the proposed concept.

Clinical Implementation of a Proton Dose Verification System Utilizing a GPU Accelerated Monte Carlo Engine.

PURPOSE: To develop a clinical infrastructure that allows for routine Monte Carlo dose calculation verification of spot scanning proton treatment plans and includes a simple biological model to aid in normal tissue protection. MATERIALS AND METHODS: A graphical processing unit accelerated Monte Carlo dose engine was used as the calculation engine for dose verification on spot scanning proton plans. An infrastructure was built around this engine that allows for seamless exporting of treatment plans from the treatment planning system and importing of dose distribution from the Monte Carlo calculation via DICOM (digital imaging and communications in medicine). An easy-to-use Web-based interface was developed so that the application could be run from any computer. In addition to the standard relative biological effectiveness = 1.1 for proton therapy, a simple linear equation dependent on dose-weighted linear energy transfer was included. This was used to help detect possible high biological dose in critical structures. RESULTS: More than 270 patients were treated at our proton center in the first year of operation. Because most plans underwent multiple iterations before final approval, more than 1000 plans have been run through the system from multiple users with minimal downtime. The average time from plan export to importing of the Monte Carlo doses was less than 15 minutes. Treatment plans have been modified based on the nominal Monte Carlo dose or the biological dose. CONCLUSION: Monte Carlo dose calculation verification of spot scanning proton treatment plans is feasible in a clinical environment. The 3-dimensional dose verification, particularly near heterogeneities, has resulted in plan modifications. The biological dose data provides actionable feedback for end of range effects, especially in pediatric patients.

Analysis of automatic match results for cone-beam computed tomography localization of conventionally fractionated lung tumors.

PURPOSE: To evaluate the dependence of an automatic match process on the size of the user-defined region of interest (ROI), the structure volume of interest (VOI), and changes in tumor volume when using cone-beam computed tomography (CBCT) for tumor localization and to compare these results with a gold standard defined by a physician's manual match. METHODS AND MATERIALS: Daily CBCT images for 11 patients with lung cancer treated with conventionally fractionated radiation therapy were retrospectively matched to a reference CT image using the Varian On Board Imager software (Varian, Palo Alto, CA) and a 3-step automatic matching protocol. Matches were performed with 3 ROI sizes (small, medium, large), with and without a structure VOI (internal target volume [ITV] or planning target volume [PTV]) used in the last step. Additionally, matches were performed using an intensity range that isolated the bony anatomy of the spinal column. All automatic matches were compared with a manual match made by a physician. RESULTS: The CBCT images from 109 fractions were analyzed. Automatic match results depend on ROI size and the structure VOI. Compared with the physician's manual match, automatic matches using the PTV as the structure VOI and a small ROI resulted in differences ≥ 5 mm in 1.8% of comparisons. Automatic matches using no VOI and a large ROI differed by ≥ 5 mm in 30.3% of comparisons. Differences between manual and automatic matches using the ITV as the structure VOI increased as tumor size decreased during the treatment course. CONCLUSIONS: Users of automatic matching techniques should carefully consider how user-defined parameters affect tumor localization. Automatic matches using the PTV as the structure VOI and a small ROI were most consistent with a physician's manual match, and were independent of volumetric tumor changes.

Cutaneous sympathetic neural responses to body cooling in type 2 diabetes mellitus.

In humans, sympathetic vasoconstrictor nerves in the skin contribute to resting vascular tone and mediate reflex vasoconstrictor responses to body cooling. Although it is well recognized that type 2 diabetes mellitus (T2DM) is associated with peripheral neurovascular changes, it is unclear to what extent the thermal responsiveness of the cutaneous vasoconstrictor system is altered in individuals with relatively uncomplicated T2DM. We tested the hypothesis that skin sympathetic nerve activity (SSNA) is decreased at baseline and during body cooling in individuals with T2DM compared to healthy controls (C) of similar age and body size. We measured SSNA (microneurography) and skin blood flow (laser-Doppler flowmetry) in the innervated area in 8 T2DM and 12 C subjects at baseline and during 3-4min of rapid whole body cooling via a water-perfused suit. SSNA (total integrated activity) increased, and cutaneous vascular conductance decreased in both groups during body cooling (P<0.01 for both). However, SSNA was not different between groups during either baseline or body cooling conditions (P=NS). The deltas in SSNA between baseline and body cooling were similar between groups: T2DM: 55±27 and C: 57±12 units (P=NS). We conclude that reflex cutaneous sympathetic and vascular responses to rapid whole body cooling are preserved in relatively healthy individuals with T2DM.