Characterization and commissioning of a Leksell Gamma Knife ICON system for framed and frameless stereotactic radiosurgery.

PURPOSE: The Leksell Gamma Knife Icon unit (IU) was introduced recently as an upgrade to the Perfexion unit (PU) at our Gamma Knife practice. In the current study, we sought mainly to characterize dosimetry and targeting accuracy of the IU treatment deliveries using both invasive frame and frameless treatment workflows. METHODS: Relative output factors were measured by delivering single-shot 4, 8 and 16 mm radiation profiles in the manufacturer's acrylonitrile butadiene styrene spherical phantom in coronal and sagittal planes using EBT3 film. Resultant dosimetry was compared with the manufacturer's dose calculation and derived output factors were compared with the manufacturer's published value. Geometric consistency of stereotactic coordinates based on cone-beam computed tomography (CBCT) versus the traditional conventional CT-based method was characterized using a rigid phantom containing nine fiducial indicators over four separate trials. End-to-end (E2E) testing using EBT3 film was designed to evaluate both dosimetric and geometric accuracy for hypothetical framed and frameless workflows. RESULTS: Relative output factors as measured by the manufacturer were independently confirmed using EBT3 film measurements to within 2%. The mean 3D radial discrepancy in stereotactic space between CBCT and CT-based definition over the sampled locations in our rigid geometry phantom was demonstrated to be between 0.40 mm and 0.56 mm over the set of trials, larger than prior reported values. E2E performed in 2D demonstrates sub-mm (and typically < 0.5 mm) accuracy for framed and frameless workflows; geometric accuracy of framed treatments using CBCT-defined stereotactic coordinates was shown to be slightly improved in comparison with those defined using conventional CT. Furthermore, in phantom, frameless workflows exhibited better accuracy than framed workflows for fractionated treatments, despite large magnitudes of introduced interfraction setup error. Accuracy of dosimetric delivery was confirmed in terms of qualitative comparisons of dose profiles and in terms of 2D gamma pass rates based on 1%/1 mm criteria. CONCLUSION: The IU was commissioned for clinical use of frameless and framed treatment protocols. The present study outlines an extensive E2E methodology for confirmation of dosimetric and geometric treatment accuracy.

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.

Clinical implementation of respiratory-gated spot-scanning proton therapy: An efficiency analysis of active motion management.

PURPOSE: The aim of this work is to describe the clinical implementation of respiratory-gated spot-scanning proton therapy (SSPT) for the treatment of thoracic and abdominal moving targets. The experience of our institution is summarized, from initial acceptance and commissioning tests to the development of standard clinical operating procedures for simulation, motion assessment, motion mitigation, treatment planning, and gated SSPT treatment delivery. MATERIALS AND METHODS: A custom respiratory gating interface incorporating the Real-Time Position Management System (RPM, Varian Medical Systems, Inc., Palo Alto, CA, USA) was developed in-house for our synchrotron-based delivery system. To assess gating performance, a motion phantom and radiochromic films were used to compare gated vs nongated delivery. Site-specific treatment planning protocols and conservative motion cutoffs were developed, allowing for free-breathing (FB), breath-holding (BH), or phase-gating (Ph-G). Room usage efficiency of BH and Ph-G treatments was retrospectively evaluated using beam delivery data retrieved from our record and verify system and DICOM files from patient-specific quality assurance (QA) procedures. RESULTS: More than 70 patients were treated using active motion management between the launch of our motion mitigation program in October 2015 and the end date of data collection of this study in January 2018. During acceptance procedures, we found that overall system latency is clinically-suitable for Ph-G. Regarding room usage efficiency, the average number of energy layers delivered per minute was <10 for Ph-G, 10-15 for BH and ≥15 for FB, making Ph-G the slowest treatment modality. When comparing to continuous delivery measured during pretreatment QA procedures, the median values of BH treatment time were extended from 6.6 to 9.3 min (+48%). Ph-G treatments were extended from 7.3 to 13.0 min (+82%). CONCLUSIONS: Active motion management has been crucial to the overall success of our SSPT program. Nevertheless, our conservative approach has come with an efficiency cost that is more noticeable in Ph-G treatments and should be considered in decision-making.

Validation of clinical acceptability of deep-learning-based automated segmentation of organs-at-risk for head-and-neck radiotherapy treatment planning.

Introduction: Organ-at-risk segmentation for head and neck cancer radiation therapy is a complex and time-consuming process (requiring up to 42 individual structure, and may delay start of treatment or even limit access to function-preserving care. Feasibility of using a deep learning (DL) based autosegmentation model to reduce contouring time without compromising contour accuracy is assessed through a blinded randomized trial of radiation oncologists (ROs) using retrospective, de-identified patient data. Methods: Two head and neck expert ROs used dedicated time to create gold standard (GS) contours on computed tomography (CT) images. 445 CTs were used to train a custom 3D U-Net DL model covering 42 organs-at-risk, with an additional 20 CTs were held out for the randomized trial. For each held-out patient dataset, one of the eight participant ROs was randomly allocated to review and revise the contours produced by the DL model, while another reviewed contours produced by a medical dosimetry assistant (MDA), both blinded to their origin. Time required for MDAs and ROs to contour was recorded, and the unrevised DL contours, as well as the RO-revised contours by the MDAs and DL model were compared to the GS for that patient. Results: Mean time for initial MDA contouring was 2.3 hours (range 1.6-3.8 hours) and RO-revision took 1.1 hours (range, 0.4-4.4 hours), compared to 0.7 hours (range 0.1-2.0 hours) for the RO-revisions to DL contours. Total time reduced by 76% (95%-Confidence Interval: 65%-88%) and RO-revision time reduced by 35% (95%-CI,-39%-91%). All geometric and dosimetric metrics computed, agreement with GS was equivalent or significantly greater (p<0.05) for RO-revised DL contours compared to the RO-revised MDA contours, including volumetric Dice similarity coefficient (VDSC), surface DSC, added path length, and the 95%-Hausdorff distance. 32 OARs (76%) had mean VDSC greater than 0.8 for the RO-revised DL contours, compared to 20 (48%) for RO-revised MDA contours, and 34 (81%) for the unrevised DL OARs. Conclusion: DL autosegmentation demonstrated significant time-savings for organ-at-risk contouring while improving agreement with the institutional GS, indicating comparable accuracy of DL model. Integration into the clinical practice with a prospective evaluation is currently underway.

Comparative analysis of traditional and coiled fiducials implanted during EUS for pancreatic cancer patients receiving stereotactic body radiation therapy.

BACKGROUND: EUS-guided fiducial placement facilitates image-guided radiation therapy (IGRT). OBJECTIVE: To compare 2 types of commercially available fiducials for technical success, complications, visibility, and migration. DESIGN: Retrospective, single-center, comparative study. SETTING: Tertiary-care medical center. INTERVENTIONS: Traditional fiducials (TFs) (5-mm length, 0.8-mm diameter) and Visicoil fiducials (VFs) (10-mm length, 0.35-mm diameter) were compared. Fiducials were placed using linear 19-gauge (for TFs) or 22-gauge (for VFs) needles. A subjective visualization scoring system (0-2; 0 = not visible, 1 = barely visible, 2 = clearly visible) was used to assess visibility on CT. Fiducial migration was calculated as a change in interfiducial distance. MAIN OUTCOME MEASUREMENTS: Technical success, complications, visibility, and migration of 2 types of fiducials. RESULTS: Thirty-nine patients with locally advanced pancreatic cancer underwent EUS-guided placement of 103 fiducials (77 TFs, 26 VFs). The mean number of fiducials placed per patient was 2.66 (standard deviation 0.67) for the 19-gauge needle and 2.60 (standard deviation 0.70) for the 22-gauge needle (P = .83). No intra- or postprocedural complications were encountered. The median visibility score for TFs was significantly better than that for VFs, both when scores of 0 were and were not included (2.00, interquartile range [IQR] 2.00-2.00 vs 1.75, IQR 1.50-2.00, P = .009 and 2.00, IQR 2.00-2.00 vs 2.00, IQR 1.50-2.00, P < .0001, respectively). The mean migration was not significantly different between the 2 types of fiducials (0.8 mm [IQR 0.4-1.6 mm] for TFs vs 1.3 mm [IQR 0.6-1.5 mm] for VFs; P = .72). LIMITATIONS: Retrospective, nonrandomized design. CONCLUSIONS: Visibility was significantly better for TFs compared with VFs. The degree of fiducial migration was not significantly different for TFs and VFs. There was no significant difference in the mean number of fiducials placed, indicating a similar degree of technical difficulty for TF and VF deployment.

Characterization of Transgenic NSG-SGM3 Mouse Model of Precision Radiation-Induced Chronic Hyposalivation.

Regenerative medicine holds promise to cure radiation-induced salivary hypofunction, a chronic side effect in patients with head and neck cancers, therefore reliable preclinical models for salivary regenerative outcome will promote progress towards therapies. In this study, our objective was to develop a cone beam computed tomography-guided precision ionizing radiation-induced preclinical model of chronic hyposalivation using immunodeficient NSGSGM3 mice. Using a Schirmer's test based sialagogue-stimulated saliva flow kinetic measurement method, we demonstrated significant differences in hyposalivation specific to age, sex, precision-radiation dose over a chronic (6 months) timeline. NSG-SMG3 mice tolerated doses from 2.5 Gy up to 7.5 Gy. Interestingly, 5-7.5 Gy had similar effects on stimulated-saliva flow (∼50% reduction in young female at 6 months after precision irradiation over sham-treated controls), however, >5 Gy led to chronic alopecia. Different groups demonstrated characteristic saliva fluctuations early on, but after 5 months all groups nearly stabilized stimulated-saliva flow with low-inter-mouse variation within each group. Further characterization revealed precision-radiation-induced glandular shrinkage, hypocellularization, gland-specific loss of functional acinar and glandular cells in all major salivary glands replicating features of human salivary hypofunction. This model will aid investigation of human cell-based salivary regenerative therapies.

Evaluation of a New, Highly Flexible Radiofrequency Coil for MR Simulation of Patients Undergoing External Beam Radiation Therapy.

PURPOSE: To evaluate the performance of a new, highly flexible radiofrequency (RF) coil system for imaging patients undergoing MR simulation. METHODS: Volumetric phantom and in vivo images were acquired with a commercially available and prototype RF coil set. Phantom evaluation was performed using a silicone-filled humanoid phantom of the head and shoulders. In vivo assessment was performed in five healthy and six patient subjects. Phantom data included T1-weighted volumetric imaging, while in vivo acquisitions included both T1- and T2-weighted volumetric imaging. Signal to noise ratio (SNR) and uniformity metrics were calculated in the phantom data, while SNR values were calculated in vivo. Statistical significance was tested by means of a non-parametric analysis of variance test. RESULTS: At a threshold of p = 0.05, differences in measured SNR distributions within the entire phantom volume were statistically different in two of the three paired coil set comparisons. Differences in per slice average SNR between the two coil sets were all statistically significant, as well as differences in per slice image uniformity. For patients, SNRs within the entire imaging volume were statistically significantly different in four of the nine comparisons and seven of the nine comparisons performed on the per slice average SNR values. For healthy subjects, SNRs within the entire imaging volume were statistically significantly different in seven of the nine comparisons and eight of the nine comparisons when per slice average SNR was tested. CONCLUSIONS: Phantom and in vivo results demonstrate that image quality obtained from the novel flexible RF coil set was similar or improved over the conventional coil system. The results also demonstrate that image quality is impacted by the specific coil configurations used for imaging and should be matched appropriately to the anatomic site imaged to ensure optimal and reproducible image quality.

Tumor-Derived Extracellular Vesicles Predict Clinical Outcomes in Oligometastatic Prostate Cancer and Suppress Antitumor Immunity.

PURPOSE: SABR has demonstrated clinical benefit in oligometastatic prostate cancer. However, the risk of developing new distant metastatic lesions remains high, and only a minority of patients experience durable progression-free response. Therefore, there is a critical need to identify which patients will benefit from SABR alone versus combination SABR and systemic agents. Herein we provide, to our knowledge, the first proof-of-concept of circulating prostate cancer-specific extracellular vesicles (PCEVs) as a noninvasive predictor of outcomes in oligometastatic castration-resistant prostate cancer (omCRPC) treated with SABR. METHODS AND MATERIALS: We analyzed the levels and kinetics of PCEVs in the peripheral blood of 79 patients with omCRPC at baseline and days 1, 7, and 14 after SABR using nanoscale flow cytometry and compared with baseline values from cohorts with localized and widely metastatic prostate cancer. The association of omCRPC PCEV levels with oncological outcomes was determined with Cox regression models. RESULTS: Levels of PCEVs were highest in mCRPC followed by omCRPC and were lowest in localized prostate cancer. High PCEV levels at baseline predicted a shorter median time to distant recurrence (3.5 vs 6.6 months; P = .0087). After SABR, PCEV levels peaked on day 7, and median overall survival was significantly longer in patients with elevated PCEV levels (32.7 vs 27.6 months; P = .003). This suggests that pretreatment PCEV levels reflect tumor burden, whereas early changes in PCEV levels after treatment predict response to SABR. In contrast, radiomic features of 11C-choline positron emission tomography and computed tomography before and after SABR were not predictive of clinical outcomes. Interestingly, PCEV levels and peripheral tumor-reactive CD8 T cells (TTR; CD8+ CD11ahigh) were correlated. CONCLUSIONS: This original study demonstrates that circulating PCEVs can serve as prognostic and predictive markers to SABR to identify patients with "true" omCRPC. In addition, it provides novel insights into the global crosstalk, mediated by PCEVs, between tumors and immune cells that leads to systemic suppression of immunity against CRPC. This work lays the foundation for future studies to investigate the underpinnings of metastatic progression and provide new therapeutic targets (eg, PCEVs) to improve SABR efficacy and clinical outcomes in treatment-resistant CRPC.

Preclinical Risk Evaluation of Normal Tissue Injury With Novel Radiosensitizers.

Genotoxic damage induced by radiation triggers a highly coordinated DNA damage response, and molecular inhibitors of key nodes within this complex response network can profoundly enhance the antitumor efficacy of radiation. This is especially true for drugs targeting the catalytic subunit of DNA-dependent protein kinase, which is a core component of the nonhomologous end-joining DNA repair pathway, and ataxia telangiectasia mutated, which coordinates cell cycle arrest, apoptosis, and DNA repair functionalities after radiation exposure. Unlike the more modest in vitro radiosensitizing effects seen with classic sensitizing agents such as cisplatin, 5-fluorouracil, or taxanes, DNA-dependent protein kinase or ataxia telangiectasia mutated inhibitors provide much more robust sensitizing effects in vitro, as might be anticipated from targeting these key DNA repair modulators. However, patients with homozygous inactivating mutations of ataxia telangiectasia mutated or mice with homozygous defects in DNA-dependent protein kinase (severe combined immunodeficiency) have profoundly enhanced acute normal tissue radiation reactions. Therefore, there is significant potential that the combination of small molecule inhibitors of these kinases with radiation could cause similar dose-limiting acute normal tissue toxicities. Similarly, although less understood, inhibition of these DNA repair response pathways could markedly increase the risk of late radiation toxicities. Because these potent radiosensitizers could be highly useful to improve local control of otherwise radiation-resistant tumors, understanding the potential for elevated risks of radiation injury is essential for optimizing therapeutic ratio and developing safe and informative clinical trials. In this review, we will discuss 2 straightforward models to assess the potential for enhanced mucosal toxicity in the oral cavity and small intestine established in our laboratories. We also will discuss similar strategies for evaluating potential drug-radiation interactions with regard to increased risks of debilitating late effects.

Executive Summary of Clinical and Technical Guidelines for Esophageal Cancer Proton Beam Therapy From the Particle Therapy Co-Operative Group Thoracic and Gastrointestinal Subcommittees.

Radiation therapy (RT) is an integral component of potentially curative management of esophageal cancer (EC). However, RT can cause significant acute and late morbidity due to excess radiation exposure to nearby critical organs, especially the heart and lungs. Sparing these organs from both low and high radiation dose has been demonstrated to achieve clinically meaningful reductions in toxicity and may improve long-term survival. Accruing dosimetry and clinical evidence support the consideration of proton beam therapy (PBT) for the management of EC. There are critical treatment planning and delivery uncertainties that should be considered when treating EC with PBT, especially as there may be substantial motion-related interplay effects. The Particle Therapy Co-operative Group Thoracic and Gastrointestinal Subcommittees jointly developed guidelines regarding patient selection, treatment planning, clinical trials, and future directions of PBT for EC.

Phase II Evaluation of Stereotactic Ablative Radiotherapy (SABR) and Immunity in 11C-Choline-PET/CT-Identified Oligometastatic Castration-Resistant Prostate Cancer.

PURPOSE: Outcomes for resistant metastatic castration-resistant prostate cancer (CRPC) are poor. Stereotactic ablative radiotherapy (SABR) induces antitumor immunity in clinical and preclinical studies, but immunologic biomarkers are lacking. PATIENTS AND METHODS: Eighty-nine patients with oligometastatic CRPC were identified by 11C-Choline-PET (Choline-PET) from August 2016 to December 2019 and treated with SABR. Prespecified coprimary endpoints were 2-year overall survival (OS) and PSA progression. Secondary endpoints included 2-year SABR-treated local failure and 6-month adverse events. Correlative studies included peripheral blood T-cell subpopulations before and after SABR. RESULTS: 128 lesions in 89 patients were included in this analysis. Median OS was 29.3 months, and 1- and 2-year OS were 96% and 80%, respectively. PSA PFS was 40% at 1 year and 21% at 2 years. Local PFS was 84.4% and 75.3% at 1 and 2 years, respectively, and no grade ≥3 AEs were observed. Baseline high levels of tumor-reactive T cells (TTR; CD8+CD11ahigh) predicted superior local, PSA, and distant PFS. Baseline high levels of effector memory T cells (TEM; CCR7-CD45RA-) were associated with improved PSA PFS. An increase in TTR at day 14 from baseline was associated with superior OS. CONCLUSIONS: This is the first comprehensive effector T-cell immunophenotype analysis in a phase II trial before and after SABR in CRPC. Results are favorable and support the incorporation of immune-based markers in the design of future randomized trials in patients with oligometastatic CRPC treated with SABR.

The emerging role of proton therapy for esophagus cancer.

Chemoradiotherapy (CRT) plays an essential role in the treatment of esophageal cancer as either curative or neoadjuvant therapy. When delivered with conventional photon-based techniques, multiple adjacent organs at risk including the heart, lungs, kidneys, liver, stomach, and bowel, receive considerable radiation dose which may contribute to acute and late adverse events (AEs). Proton beam therapy (PBT) offers a reduction in radiation exposure to these organs and potentially an improvement in the therapeutic ratio. Herein we discuss the emerging role of PBT for esophageal cancer, including rationale, treatment planning, early dosimetric and clinical comparisons of PBT with photon-based techniques, ongoing prospective trials, and potential areas of opportunity for the incorporation of PBT with the goal of improving outcomes for patients with esophageal cancer.

Managing treatment-related uncertainties in proton beam radiotherapy for gastrointestinal cancers.

In recent years, there has been rapid adaption of proton beam radiotherapy (RT) for treatment of various malignancies in the gastrointestinal (GI) tract, with increasing number of institutions implementing intensity modulated proton therapy (IMPT). We review the progress and existing literature regarding the technical aspects of RT planning for IMPT, and the existing tools that can help with the management of uncertainties which may impact the daily delivery of proton therapy. We provide an in-depth discussion regarding range uncertainties, dose calculations, image guidance requirements, organ and body cavity filling consideration, implanted devices and hardware, use of fiducials, breathing motion evaluations and both active and passive motion management methods, interplay effect, general IMPT treatment planning considerations including robustness plan evaluation and optimization, and finally plan monitoring and adaptation. These advances have improved confidence in delivery of IMPT for patients with GI malignancies under various scenarios.

Proton beam radiotherapy for esophagus cancer: state of the art.

The majority of esophageal cancer patients are diagnosed with locoregionally confined disease, which is often amenable to curative intent therapy. Chemoradiotherapy (CRT) improves overall survival (OS) in stage II and III esophagus cancer in the neoadjuvant and definitive settings. Due to the close proximity of organs at risk (OARs), including lungs, heart, stomach, bowel, kidneys, and spinal cord, esophageal CRT can result in profound acute and late toxicities. Acute toxicities can include esophagitis, nausea, vomiting, fatigue, and cytopenias. Late complications may also occur months or years after completion of thoracic radiotherapy, including significant cardiac, pulmonary, liver, kidney, or bowel toxicities, which can be life-threatening or fatal. Photon-based radiotherapy exposes OARs to significant doses of radiation, whereas proton beam therapy (PBT) has unique physical properties, as it lacks an exit dose. This allows PBT to deliver, a more conformal dose to the target and minimize the volume of OARs exposed to radiation. This dosimetric advantage may portend an increased therapeutic ratio of CRT for esophagus cancer. The objective of this review is to discuss the evolution of photon and proton-based radiotherapy techniques, rationale, dosimetric and clinical studies comparing outcomes of photon- and proton-based techniques, ongoing prospective trials, and future directions of PBT as a means of reducing toxicity and improving oncologic outcomes for patients with esophagus cancer.

Imaging and Dosimetry Study of Inter-fraction Setup Error in a Murine Xenograft Flank Tumor Radiation Model.

Modern small animal irradiation platforms provide for accurate delivery of radiation under 3D image guidance. However, leveraging these improvements currently comes at the cost of lower-throughput experimentation. Herein, we characterized setup accuracy and dosimetric robustness for mock/sham irradiation of a murine xenograft flank tumor model using the X-RAD SmART+ with the vendor-supplied Monte Carlo (MC) treatment planning system (SmART ATP). The chosen beam arrangement was parallel-opposing using a 20 mm square collimator, aligned off-axis for ipsilateral lung sparing. Using a cohort of five mice imaged with cone beam computed tomography (CBCT) over five consecutive mock-irradiation fractions, we compared inter-fraction setup variability resulting from a vendor-supplied multi-purpose bed with anesthesia nose cone with a more complicated immobilization solution with an integrated bite block with nose cone and Styrofoam platform. A hypothetical "high-throughput" image-guidance scenario was investigated, wherein the day 1 stage coordinates (resulting from CBCT guidance) were applied on days 2-5. Daily inter-fraction setup errors were evaluated per specimen (days 2-5) using CBCT-derived offsets from day 1 stage coordinates. Using the CBCT images and Monte Carlo dose calculation, 3D dosimetric plan robustness was evaluated for the vendor-supplied immobilization solution, for both the high-throughput guidance scenario as well as for use of daily CBCT-based alignment. Inter-fraction setup offset magnitude was 3.6 (±1.5) mm for the vendor-supplied immobilization compared to 3.3 (±1.8) mm for the more complicated solution. For the vendor-supplied immobilization, we found that daily CBCT was needed to adequately cover the flank tumors dosimetrically, given our chosen treatment approach.

Low-Dose Image-Guided Pediatric CNS Radiation Therapy: Final Analysis From a Prospective Low-Dose Cone-Beam CT Protocol From a Multinational Pediatrics Consortium.

BACKGROUND: Lower-dose cone-beam computed tomography protocols for image-guided radiotherapy may permit target localization while minimizing radiation exposure. We prospectively evaluated a lower-dose cone-beam protocol for central nervous system image-guided radiotherapy across a multinational pediatrics consortium. METHODS: Seven institutions prospectively employed a lower-dose cone-beam computed tomography central nervous system protocol (weighted average dose 0.7 mGy) for patients ≤21 years. Treatment table shifts between setup with surface lasers versus cone-beam computed tomography were used to approximate setup accuracy, and vector magnitudes for these shifts were calculated. Setup group mean, interpatient, interinstitution, and random error were estimated, and clinical factors were compared by mixed linear modeling. RESULTS: Among 96 patients, with 2179 pretreatment cone-beam computed tomography acquisitions, median age was 9 years (1-20). Setup parameters were 3.13, 3.02, 1.64, and 1.48 mm for vector magnitude group mean, interpatient, interinstitution, and random error, respectively. On multivariable analysis, there were no significant differences in mean vector magnitude by age, gender, performance status, target location, extent of resection, chemotherapy, or steroid or anesthesia use. Providers rated >99% of images as adequate or better for target localization. CONCLUSIONS: A lower-dose cone-beam computed tomography protocol demonstrated table shift vector magnitude that approximate clinical target volume/planning target volume expansions used in central nervous system radiotherapy. There were no significant clinical predictors of setup accuracy identified, supporting use of this lower-dose cone-beam computed tomography protocol across a diverse pediatric population with brain tumors.

Quantifying the setup uncertainty of a stereotactic murine micro-image guided radiation therapy system.

OBJECTIVE:: Investigate the reproducibility of murine cranial positioning using solely a stereotactic stage, and quantify the potential improvements from the on-board image guidance of the X-RAD SmART irradiator. METHODS:: For intermouse reproducibility, athymic nude mice (N = 5, ×4 groups) were cranially fixed on a stereotactic stage. Each mouse was imaged via cone-beam CT (CBCT). A virtual isocenter target was placed in the brain, the stage shifted to that target, and the couch positions recorded. The mouse was removed from the stage and this process repeated twice (N=60 measurements). The first acquired CBCT coordinates (within each group of five mice) were used to define "stereotactic couch coordinates." CBCT shifts were calculated to quantify the accuracy of setup based on couch coordinates alone. For intramouse reproducibility, C57BL/6 mice (N=4) were imaged daily for 7 days. Each mouse had individual stereotactic coordinates defined from their first day of CBCT localization, and positional shifts required on the six subsequent days of imaging were quantified (N = 24 measurements). RESULTS:: The mean vector shift between stereotactic setup and CBCT alignment for inter and intramouse analysis was 0.78 ± 0.27 mm and 0.82 ± 0.34 mm, respectively. CONCLUSION:: Cranial irradiation that can permit positional uncertainties on the order of a millimeter can rely solely on stereotactic coordinates derived from a single daily CBCT. Irradiations of subregions requiring submillimeter accuracy require daily image guidance for each mouse. ADVANCES IN KNOWLEDGE:: This is the first investigation of stereotactic reproducibility using the X-RAD SmART and it suggests a method for increased efficiency in high-throughput experiments.

A Comparison of Patient-Reported Health-Related Quality of Life During Proton Versus Photon Chemoradiation Therapy for Esophageal Cancer.

PURPOSE: The purpose of this study was to compare Functional Assessment of Cancer Therapy-Esophagus (FACT-E) questionnaire changes during proton (PRT) or photon (XRT) chemoradiation therapy (CRT) for esophageal cancer (EC). METHODS AND MATERIALS: We reviewed patients enrolled in a prospective registry who received preoperative or definitive CRT for EC. Patients completed the FACT-E before CRT and during the last week of CRT. Analysis of variance testing was used to assess associations between patient and treatment characteristics and FACT-E score changes. RESULTS: One hundred twenty-five patients completed a baseline and posttreatment FACT-E; 63 received XRT and 62 received PRT. The mean age was 65 years; the PRT group was older (68 vs 64 years, P = .0063). The following characteristics were similar between cohorts: 83% male, 78% adenocarcinoma, and 89% stage II-III. The radiation therapy prescription dose was higher in the PRT group (≥50 Gy in 94% vs 67%, P < .0001), whereas the median clinical target volume was smaller in the PRT group (553 vs 668 cm3, P = .013). Most (96%) received concurrent weekly carboplatin-paclitaxel. The mean FACT-E score was 136.3 (standard deviation [SD] 21.0) at baseline and 119.6 (SD 24.8) post-CRT, with mean change of -16.7 (SD 19.8). Baseline scores were comparable between XRT and PRT groups (135.9 vs 136.7, P = .82). On univariate and multivariate analyses, less mean decline in FACT-E score was observed for PRT versus XRT (-12.7 vs -20.6, P = .026) and for trimodality versus definitive therapy (-13.0 vs -22.5, P = .008). CONCLUSIONS: For patients receiving CRT for EC, PRT was associated with less decline in FACT-E scores compared with XRT.

Initial experience with intensity modulated proton therapy for intact, clinically localized pancreas cancer: Clinical implementation, dosimetric analysis, acute treatment-related adverse events, and patient-reported outcomes.

PURPOSE: Pencil-beam scanning intensity modulated proton therapy (IMPT) may allow for an improvement in the therapeutic ratio compared with conventional techniques of radiation therapy delivery for pancreatic cancer. The purpose of this study was to describe the clinical implementation of IMPT for intact and clinically localized pancreatic cancer, perform a matched dosimetric comparison with volumetric modulated arc therapy (VMAT), and report acute adverse event (AE) rates and patient-reported outcomes (PROs) of health-related quality of life. METHODS AND MATERIALS: Between July 2016 and March 2017, 13 patients with localized pancreatic cancer underwent concurrent capecitabine or 5-fluorouracil-based chemoradiation therapy (CRT) utilizing IMPT to a dose of 50 Gy (radiobiological effectiveness: 1.1). A VMAT plan was generated for each patient to use for dosimetric comparison. Patients were assessed prospectively for AEs and completed PRO questionnaires utilizing the Functional Assessment of Cancer Therapy-Hepatobiliary at baseline and upon completion of CRT. RESULTS: There was no difference in mean target coverage between IMPT and VMAT (P > .05). IMPT offered significant reductions in dose to organs at risk, including the small bowel, duodenum, stomach, large bowel, liver, and kidneys (P < .05). All patients completed treatment without radiation therapy breaks. The median weight loss during treatment was 1.6 kg (range, 0.1-5.7 kg). No patients experienced grade ≥3 treatment-related AEs. The median Functional Assessment of Cancer Therapy-Hepatobiliary scores prior to versus at the end of CRT were 142 (range, 113-163) versus 136 (range, 107-173; P = .18). CONCLUSIONS: Pencil-beam scanning IMPT was feasible and offered significant reductions in radiation exposure to multiple gastrointestinal organs at risk. IMPT was associated with no grade ≥3 gastrointestinal AEs and no change in baseline PROs, but the conclusions are limited due to the patient sample size. Further clinical studies are warranted to evaluate whether these dosimetric advantages translate into clinically meaningful benefits.

Knowledge of endoscopic ultrasound-delivered fiducial composition and dimension necessary when planning proton beam radiotherapy.

BACKGROUND AND STUDY AIMS: Little consideration has been given to selection of endoscopic ultrasound-guided fiducials for proton radiotherapy and the resulting perturbations in the therapy dose and pattern. Our aim was to assess the impact of perturbations caused by six fiducials of different composition and dimensions in a phantom gel model. MATERIALS AND METHODS: The phantom was submerged in a water bath and irradiated with a uniform 10 cm × 10 cm field of 119.7 MeV monoenergetic spot scanning protons delivered through a 45 mm range shifter. The proton "Bragg Peak" was evaluated. RESULTS: Dose perturbations manifesting as dose reductions up to 30 % were observed. A carbon composite (1 × 5 mm) and gold (0.4 × 10 mm) fiducial with backload potential rather than dedicated EUS pre-loaded gold fiducial needles had the best performance in terms of minimizing the dose perturbation. CONCLUSIONS: Our data demonstrate that a carbon composite fiducial has a less untoward effect on proton therapy dose distribution than dedicated EUS pre-loaded gold fiducial needles. Such information is important to consider when selecting fiducials specifically for proton therapy.