Evaluating the Impact of Bowel Gas Variations for Wilms' Tumor in Pediatric Proton Therapy.

(1) Background: Proton therapy, a precise form of radiation treatment, can be significantly affected by variations in bowel content. The purpose was to identify the most beneficial gantry angles that minimize deviations from the treatment plan quality, thus enhancing the safety and efficacy of proton therapy for Wilms' tumor patients. (2) Methods: Thirteen patients with Wilms' tumor, enrolled in the SJWT21 clinical trial, underwent proton therapy. The variations in bowel gas were systematically monitored using daily Cone Beam Computed Tomography (CBCT) imaging. Air cavities identified in daily CBCT images were analyzed to construct daily verification plans and measure water equivalent path length (WEPL) changes. A worst-case scenario simulation was conducted to identify the safest beam angles. (3) Results: The study revealed a maximum decrease in target dose (ΔD100%) of 8.0%, which corresponded to a WEPL variation (ΔWEPL) of 11.3 mm. The average reduction in target dose, denoted as mean ΔD100%, was found to be 2.8%, with a standard deviation (SD) of 3.2%. The mean ΔWEPL was observed as 3.3 mm, with an SD of 2.7 mm. The worst-case scenario analysis suggested that gantry beam angles oriented toward the patient's right and posterior aspects from 110° to 310° were associated with minimized WEPL discrepancies. (4) Conclusions: This study comprehensively evaluated the influence of bowel gas variability on treatment plan accuracy and proton range uncertainties in pediatric proton therapy for Wilms' tumor.

Novel Monthly Quality Assurance Regimen and 5-Year Analysis Using a Proton Metrology System.

Purpose: To develop a novel, monthly quality assurance (QA) regimen for a proton therapy system that uses 2 custom phantoms, each housing a commercial scintillator detector and a charge-coupled device camera. The novel metrology system assessed QA trends at a pediatric proton therapy center from 2018 to 2022. Materials and Methods: The measurement system was designed to accommodate horizontal and vertical positioning of the commercial device and to enable gantry and couch isocentricity measurements (using a star shot procedure), proton spot profile verification, and imaging and radiation congruence tests to be performed simultaneously in the dual-phantom setup. Gantry angles and proton beam energies were varied and alternated each month, using gantry angles of 0°, 30°, 60°, 90°, 120°, 150°, and 180° and discrete beam energies of 69.4, 84.5, 100, 139.1, 180.4, 200.4, and 221.3 MeV after radiographic verification. A total of 1176 individual monthly QA measurements of gantry and couch isocentricity, spot size, and congruence were analyzed. Results: Gantry and couch star shot measurements showed beam isocentricities of 0.3 ± 0.2 mm and 0.2 ± 0.2 mm, respectively, which were within the threshold of 1.0 mm. Spot sizes for each discrete energy were within the threshold of ± 10% of the baseline values for all 3 proton rooms. The imaging and radiation coincidence test results for the 1176 individual monthly QA measurements were 0.5 mm for the 50th percentile and 1.2 mm (the clinical threshold) for the 97.6th percentile. Conclusions: Integrating a commercial device with custom phantoms improved the quality of proton system checks compared with previous methods using radiochromic films, loose ball bearings, and foam. The scheme of alternating beam angles with discrete energies in the monthly QA-enabled, clinically meaningful verification of beam energy and gantry angle combinations while the machine performance and accuracy were being checked.

Interplay Effect of Splenic Motion for Total Lymphoid Irradiation in Pediatric Proton Therapy.

(1) Background: The most significant cause of an unacceptable deviation from the planned dose during respiratory motion is the interplay effect. We examined the correlation between the magnitude of splenic motion and its impact on plan quality for total lymphoid irradiation (TLI); (2) Methods: Static and 4D CT images from ten patients were used for interplay effect simulations. Patients' original plans were optimized based on the average CT extracted from the 4D CT and planned with two posterior beams using scenario-based optimization (±3 mm of setup and ±3% of range uncertainty) and gradient matching at the level of mid-spleen. Dynamically accumulated 4D doses (interplay effect dose) were calculated based on the time-dependent delivery sequence of radiation fluence across all phases of the 4D CT. Dose volume parameters for each simulated treatment delivery were evaluated for plan quality; (3) Results: Peak-to-peak splenic motion (≤12 mm) was measured from the 4D CT of ten patients. Interplay effect simulations revealed that the ITV coverage of the spleen remained within the protocol tolerance for splenic motion, ≤8 mm. The D100% coverage for ITV spleen decreased from 95.0% (nominal plan) to 89.3% with 10 mm and 87.2% with 12 mm of splenic motion; (4) Conclusions: 4D plan evaluation and robust optimization may overcome problems associated with respiratory motion in proton TLI treatments. Patient-specific respiratory motion evaluations are essential to confirming adequate dosimetric coverage when proton therapy is utilized.

Monitoring of Interfractional Proton Range Verification and Dosimetric Impact Based on Daily CBCT for Pediatric Patients with Pelvic Tumors.

(1) Background: Synthetic CT images of the pelvis were generated from daily CBCT images to monitor changes in water equivalent path length (WEPL) and determine the dosimetric impact of anatomy changes along the proton beam's path; (2) Methods: Ten pediatric patients with pelvic tumors treated using proton therapy with daily CBCT were included. The original planning CT was deformed to the same-day CBCT to generate synthetic CT images for WEPL comparison and dosimetric evaluation; (3) Results: WEPL changes of 20 proton fields at the distal edge of the CTV ranged from 0.1 to 12 mm with a median of 2.5 mm, and 75th percentile of 5.1 mm for (the original CT-rescanned CT) and ranged from 0.3 to 10.1 mm with a median of 2.45 mm and 75th percentile of 4.8 mm for (the original CT-synthetic CT). The dosimetric impact was due to proton range pullback or overshoot, which led to reduced coverage in CTV Dmin averaging 12.1% and 11.3% in the rescanned and synthetic CT verification plans, respectively; (4) Conclusions: The study demonstrated that synthetic CT generated by deforming the original planning CT to daily CBCT can be used to quantify proton range changes and predict adverse dosimetric scenarios without the need for excessive rescanned CT scans during large interfractional variations in adaptive proton therapy of pediatric pelvic tumors.

A hybrid method of correcting CBCT for proton range estimation with deep learning and deformable image registration.

Objective. This study aimed to develop a novel method for generating synthetic CT (sCT) from cone-beam CT (CBCT) of the abdomen/pelvis with bowel gas pockets to facilitate estimation of proton ranges.Approach. CBCT, the same-day repeat CT, and the planning CT (pCT) of 81 pediatric patients were used for training (n= 60), validation (n= 6), and testing (n= 15) of the method. The proposed method hybridizes unsupervised deep learning (CycleGAN) and deformable image registration (DIR) of the pCT to CBCT. The CycleGAN and DIR are respectively applied to generate the geometry-weighted (high spatial-frequency) and intensity-weighted (low spatial-frequency) components of the sCT, thereby each process deals with only the component weighted toward its strength. The resultant sCT is further improved in bowel gas regions and other tissues by iteratively feeding back the sCT to adjust incorrect DIR and by increasing the contribution of the deformed pCT in regions of accurate DIR.Main results. The hybrid sCT was more accurate than deformed pCT and CycleGAN-only sCT as indicated by the smaller mean absolute error in CT numbers (28.7 ± 7.1 HU versus 38.8 ± 19.9 HU/53.2 ± 5.5 HU;P≤ 0.012) and higher Dice similarity of the internal gas regions (0.722 ± 0.088 versus 0.180 ± 0.098/0.659 ± 0.129;P≤ 0.002). Accordingly, the hybrid method resulted in more accurate proton range for the beams intersecting gas pockets (11 fields in 6 patients) than the individual methods (the 90th percentile error in 80% distal fall-off, 1.8 ± 0.6 mm versus 6.5 ± 7.8 mm/3.7 ± 1.5 mm;P≤ 0.013). The gamma passing rates also showed a significant dosimetric advantage by the hybrid method (99.7 ± 0.8% versus 98.4 ± 3.1%/98.3 ± 1.8%;P≤ 0.007).Significance. The hybrid method significantly improved the accuracy of sCT and showed promises in CBCT-based proton range verification and adaptive replanning of abdominal/pelvic proton therapy even when gas pockets are present in the beam path.

Development of a log file analysis tool for proton patient QA, system performance tracking, and delivered dose reconstruction.

PURPOSE/OBJECTIVE(S): To describe a log file-based patient-specific quality assurance (QA) method and develop an in-house tool for system performance tracking and dose reconstruction in pencil-beam scanning proton therapy that can be used for pre-treatment plan review. MATERIALS/METHODS: The software extracts beam-specific information from the treatment delivery log file and automatically compares the monitor units (MU), lateral position, and size of each spot against the intended values in the treatment plan to identify any discrepancies in the beam delivery. The software has been used to analyze 992 patients, 2004 plans, 4865 fields, and more than 32 million proton spots from 2016 to 2021. The composite doses of 10 craniospinal irradiation (CSI) plans were reconstructed based on the delivered spots and compared with the original plans as an offline plan review method. RESULTS: Over the course of 6 years, the proton delivery system has proved stable in delivering patient QA fields with proton energies of 69.4-221.3 MeV and an MU range of 0.003-1.473 MU per spot. The planned mean and standard deviation (SD) of the energy and spot MU were 114.4 ± 26.4 MeV and 0.010 ± 0.009 MU, respectively. The mean and SD of the differences in MU and position between the delivered and planned spots were 9.56 × 10-8 ± 2.0 × 10-4 MU and 0.029/-0.007 ± 0.049/0.044 mm on the X/Y-axis for random differences and 0.005/0.125 ± 0.189/0.175 mm on the X/Y-axis for systematic differences. The mean and SD of the difference between the commissioning and delivered spot sizes were 0.086/0.089 ± 0.131/0.166 mm on the X/Y-axis. CONCLUSION: A tool has been developed to extract crucial information about the performance of the proton delivery and monitor system and provide a dose reconstruction based on delivered spots for quality improvement. Each patient's plan was verified before treatment to ensure accurate and safe delivery within the delivery tolerance of the machine.

Treatment-planning approaches to intensity modulated proton therapy and the impact on dose-weighted linear energy transfer.

PURPOSE: We quantified the effect of various forward-based treatment-planning strategies in proton therapy on dose-weighted linear energy transfer (LETd). By maintaining the dosimetric quality at a clinically acceptable level, we aimed to evaluate the differences in LETd among various treatment-planning approaches and their practicality in minimizing biologic uncertainties associated with LETd. METHOD: Eight treatment-planning strategies that are achievable in commercial treatment-planning systems were applied on a cylindrical water phantom and four pediatric brain tumor cases. Each planning strategy was compared to either an opposed lateral plan (phantom study) or original clinical plan (patient study). Deviations in mean and maximum LETd from clinically acceptable dose distributions were compared. RESULTS: In the phantom study, using a range shifter and altering the robust scenarios during optimization had the largest effect on the mean clinical target volume LETd, which was reduced from 4.5 to 3.9 keV/µm in both cases. Variations in the intersection angle between beams had the largest effect on LETd in a ring defined 3 to 5 mm outside the target. When beam intersection angles were reduced from opposed laterals (180°) to 120°, 90°, and 60°, corresponding maximum LETd increased from 7.9 to 8.9, 10.9, and 12.2 keV/µm, respectively. A clear trend in mean and maximum LETd variations in the clinical cases could not be established, though spatial distribution of LETd suggested a strong dependence on patient anatomy and treatment geometry. CONCLUSION: Changes in LETd from treatment-plan setup follow intuitive trends in a controlled phantom experiment. Anatomical and other patient-specific considerations, however, can preclude generalizable strategies in clinical cases. For pediatric cranial radiation therapy, we recommend using opposed lateral treatment fields to treat midline targets.

Three-dimensional dose and LETD prediction in proton therapy using artificial neural networks.

PURPOSE: Challenges in proton therapy include identifying patients most likely to benefit; ensuring consistent, high-quality plans as its adoption becomes more widespread; and recognizing biological uncertainties that may be related to increased relative biologic effectiveness driven by linear energy transfer (LET). Knowledge-based planning (KBP) is a domain that may help to address all three. METHODS: Artificial neural networks were trained using 117 unique treatment plans and associated dose and dose-weighted LET (LETD ) distributions. The data set was split into training (n = 82), validation (n = 17), and test (n = 18) sets. Model performance was evaluated on the test set using dose- and LETD -volume metrics in the clinical target volume (CTV) and nearby organs at risk and Dice similarity coefficients (DSC) comparing predicted and planned isodose lines at 50%, 75%, and 95% of the prescription dose. RESULTS: Dose-volume metrics significantly differed (α = 0.05) between predicted and planned dose distributions in only one dose-volume metric, D2% to the CTV. The maximum observed root mean square (RMS) difference between corresponding metrics was 4.3 GyRBE (8% of prescription) for D1cc to optic chiasm. DSC were 0.90, 0.93, and 0.88 for the 50%, 75%, and 95% isodose lines, respectively. LETD -volume metrics significantly differed in all but one metric, L0.1cc of the brainstem. The maximum observed difference in RMS differences for LETD metrics was 1.0 keV/µm for L0.1cc to brainstem. CONCLUSIONS: We have devised the first three-dimensional dose and LETD -prediction model for cranial proton radiation therapy has been developed. Dose accuracy compared favorably with that of previously published models in other treatment sites. The agreement in LETD supports future investigations with biological doses in mind to enable the full potential of KBP in proton therapy.

Design of a novel 5-camera surface guidance system with multiple imaging isocenters.

PURPOSE/OBJECTIVE(S): Surface-guided radiation therapy (SGRT) can track the patient surface noninvasively to complement radiographic image-guided radiation therapy with a standard 3-camera system and a single radiation/image isocenter. Here we report the commissioning of a novel SGRT system that monitors three imaging isocenters locations in a proton half-gantry room with a unique 5-camera configuration. MATERIALS/METHODS: The proton half-gantry room has three image isocenters, designated ISO-0, ISO-1, and ISO-2, to cover various anatomical sites via a robotic ceiling-mounted cone-beam CT. Although ISO-0 and ISO-1 are used to image the cranium, head and neck, and thoracic regions, ISO-2 is often used to image body and extremity sites and contiguous craniospinal target volumes. The five-camera system was calibrated to the radiographic isocenter by using a stereotactic radiosurgery cube phantom for each image isocenter. RESULTS: The performance of this 5-camera system was evaluated for 6 degrees of freedom in three categories: (1) absolute setup accuracy relative to the radiographic kV image isocenter based on the DICOM reference; (2) relative shift accuracy based on a reference surface capture; and (3) isocenter tracking accuracy from one isocenter to another based on a reference surface capture. The evaluation revealed maximum deviations of 0.8, 0.2, and 0.6 mm in translation and 0.2°, 0.1°, and 0.1° in rotation for the first, second, and third categories, respectively. Comparing the dosimetry and latency with static and gated irradiation revealed a 0.1% dose difference and positional differences of 0.8 mm in X and 0.9 mm in Y with less than 50 ms temporal accuracy. CONCLUSION: The unique 5-camera system configuration provides SGRT at the treatment isocenter (ISO-0) and also imaging isocenter locations (ISO-0, ISO-1, and ISO-2) to ensure correct patient positioning before and after radiographic imaging, especially during transitions from the offset imaging isocenters to the treatment isocenter.

Pre- and Posttherapy Risk Factors for Vasculopathy in Pediatric Patients With Craniopharyngioma Treated With Surgery and Proton Radiation Therapy.

PURPOSE: Vasculopathy (VAS) is a significant complication associated with radiation therapy in patients treated for brain tumors. We studied the type, location, severity, timing, and resolution of VAS in children with craniopharyngioma treated with proton radiation therapy (PRT) and evaluated predictors of stenosis (STN) using a novel patient and imaging-based modeling approach. METHODS AND MATERIALS: Children with craniopharyngioma (n = 94) were treated with 54 Gy relative biological effectiveness PRT in a clinical trial, NCT01419067. We evaluated VAS type, location, severity, and resolution. VAS events were segmented and related to their location, operative corridor, PRT dose, and vascular territory to facilitate mixed effect logistic regression modeling of spatial predictors of STN events. RESULTS: Forty-five (47.9%) patients had 111 instances of confirmed VAS (pre-PRT n = 37, 33.3%). The median time to post-PRT VAS was 3.41 years (95% confidence interval, 1.86-6.11). STN events were observed post-PRT in 23.4% (n = 22) of patients. Post-PRT VAS was detected by cerebral angiogram in 9.6% (n = 9), severe in 4.3% (n = 4), and compensated on perfusion in 2.1% (n = 2). Revascularization was required for 5 (5.3%) patients. Postsurgical, pre-PRT VAS, and PRT dose to unperturbed vessels were predictive of STN. The effect of PRT on STN was negligible within the surgical corridor. CONCLUSIONS: VAS often precedes PRT and was the strongest predictor of post-PRT STN. The adverse effect of PRT on STN was only apparent in unperturbed vasculature beyond the operative corridor.

Monte Carlo framework for commissioning a synchrotron-based discrete spot scanning proton beam system and treatment plan verification.

This study aimed to develop a Monte Carlo (MC) framework for commissioning the narrow proton beams (spot size sigma, 5.2 mm 2 mm at isocenter for 69.4 MeV-221.3 MeV for the main beam option and 4.1 mm 1.3 mm for the minibeam option respectively) of a synchrotron-based proton therapy system and design an independent absolute dose calculation engine for intensity-modulated proton treatments. A proton therapy system (Hitachi PROBEAT-V) was simulated using divergent and convergent beam models at the nozzle entrance. The innovative source weighting scheme for the MC simulation with TOPAS (TOol for PArticle Simulations) was implemented using dose output data for the absolute dose calculations. The results of the MC simulation were compared to the experimental data, analyzed and used to commission the treatment planning system. Two MC models, divergent and convergent beams were implemented. The convergent beam model produced a high level of agreement when MC and measurements were analyzed. The beam ellipticity did not result in significant differences between MC simulated and treatment planning system calculated doses. A model of a synchrotron-based spot scanning proton therapy system has been developed and implemented in the TOPAS MC transport code framework. The dose computation engine is useful for treatment plan verification with primary and minibeam beam option.

Proton therapy delivery method affects dose-averaged linear energy transfer in patients.

The dosimetric advantages of proton therapy have led to its rapid proliferation in recent decades. This has been accompanied by a shift in technology from older units that deliver protons by passive scattering (PS) to newer units that increasingly use pencil-beam scanning (PBS). The biologic effectiveness of proton physical dose purportedly rises with increasing dose-weighted average linear energy transfer (LETD). The objective of this study was to determine the extent to which proton delivery methods affect LETD. We calculated LETDfrom simple, dosimetrically matched, and clinical treatment plans with TOPAS Monte-Carlo transport code. Simple treatment plans comprised single fields of PS and PBS protons in a water phantom. We performed simulations of matched and clinical treatment plans by using the treatment and anatomic data obtained from a cohort of children with craniopharyngioma who previously received PS or PBS proton therapy. We compared the distributions of LETDfrom PS and PBS delivery methods in clinically relevant ROIs. Wilcoxon signed-rank tests comparing single fields in water revealed that the LETDvalues from PBS were significantly greater than those from PS inside and outside the targeted volume (p < 0.01). Statistical tests comparing LETD-volume histograms from matched and clinical treatment plans showed that LETDwas generally greater for PBS treatment plans than for PS treatment plans (p < 0.05). In conclusion, the proton delivery method affects LETDboth inside and outside of the target volume. These findings suggest that PBS is more biologically effective than PS. Given the rapid expansion of PBS proton therapy, future studies are needed to confirm the applicability of treatment evaluation methods developed for PS proton therapy to those for modern PBS treatments to ensure their safety and effectiveness for the growing population of patients receiving proton therapy. This study uses data from two clinical trials: NCT01419067 and NCT02792582.

Automation of Monte Carlo-based treatment plan verification for proton therapy.

PURPOSE: Independent calculations of proton therapy plans are an important quality control procedure in treatment planning. When using custom Monte Carlo (MC) models of the beamline, deploying the calculations can be laborious, time consuming, and require in-depth knowledge of the computational environment. We developed an automated framework to remove these barriers and integrate our MC model into the clinical workflow. MATERIALS AND METHODS: The Eclipse Scripting Application Programming Interface was used to initiate the automation process. A series of MATLAB scripts were then used for preprocessing of input data and postprocessing of results. Additional scripts were used to monitor the calculation process and appropriately deploy calculations to an institutional high-performance computing facility. The automated framework and beamline models were validated against 160 patient specific QA measurements from an ionization chamber array and using a ±3%/3 mm gamma criteria. RESULTS: The automation reduced the human-hours required to initiate and run a calculation to 1-2 min without leaving the treatment planning system environment. Validation comparisons had an average passing rate of 99.4% and were performed at depths ranging from 1 to 15 cm. CONCLUSION: An automated framework for running MC calculations was developed which enables the calculation of dose and linear energy transfer within a clinically relevant workflow and timeline. The models and framework were validated against patient specific QA measurements and exhibited excellent agreement. Before this implementation, execution was prohibitively complex for an untrained individual and its use restricted to a research environment.

Interplay Effect of Target Motion and Pencil-Beam Scanning in Proton Therapy for Pediatric Patients.

PURPOSE: To investigate the effect of interplay between spot-scanning proton beams and respiration-induced tumor motion on internal target volume coverage for pediatric patients. MATERIALS AND METHODS: Photon treatments for 10 children with representative tumor motions (1-13 mm superior-inferior) were replanned to simulate single-field uniform dose- optimized proton therapy. Static plans were designed by using average computed tomography (CT) data sets created from 4D CT data to obtain nominal dose distributions. The motion interplay effect was simulated by assigning each spot in the static plan delivery sequence to 1 of 10 respiratory-phase CTs, using the actual patient breathing trace and specifications of a synchrotron-based proton system. Dose distributions for individual phases were deformed onto the space of the average CT and summed to produce the accumulated dose distribution, whose dose-volume histogram was compared with the one from the static plan. RESULTS: Tumor motion had minimal impact on the internal target volume hot spot (D2), which deviated by <3% from the nominal values of the static plans. The cold spot (D98) was also minimally affected, except in 2 patients with diaphragmatic tumor motion exceeding 10 mm. The impact on tumor coverage was more pronounced with respect to the V99 rather than the V95. Decreases of 10% to 49% in the V99 occurred in multiple patients for whom the beam paths traversed the lung-diaphragm interface and were, therefore, more sensitive to respiration-induced changes in the water equivalent path length. Fractionation alone apparently did not mitigate the interplay effect beyond 6 fractions. CONCLUSION: The interplay effect is not a concern when delivering scanning proton beams to younger pediatric patients with tumors located in the retroperitoneal space and tumor motion of <5 mm. Children and adolescents with diaphragmatic tumor motion exceeding 10 mm require special attention, because significant declines in target coverage and dose homogeneity were seen in simulated treatments of such patients.

Rapid encoding of an internal model for imitative learning.

As in human infant speech development, vocal imitation in songbirds involves sensory acquisition and memorization of adult-produced vocal signals, followed by a protracted phase of vocal motor practice. The internal model of adult tutor song in the juvenile male brain, termed 'the template', is central to the vocal imitation process. However, even the most fundamental aspects of the template, such as when, where and how it is encoded in the brain, remain poorly understood. A major impediment to progress is that current studies of songbird vocal learning use protracted tutoring over days, weeks or months, complicating dissection of the template encoding process. Here, we take the key step of tightly constraining the timing of template acquisition. We show that, in the zebra finch, template encoding can be time locked to, on average, a 2 h period of juvenile life and based on just 75 s of cumulative tutor song exposure. Crucially, we find that vocal changes occurring on the day of training correlate with eventual imitative success. This paradigm will lead to insights on how the template is instantiated in the songbird brain, with general implications for deciphering how internal models are formed to guide learning of complex social behaviours.