Prospective Trial of Functional Lung Avoidance Radiation Therapy for Lung Cancer: Quality of Life Report.

PURPOSE: A novel form of lung function imaging has been developed that uses 4-dimensional computed tomography (4DCT) data to generate lung ventilation images (4DCT-ventilation). Functional avoidance uses 4DCT-ventilation to reduce doses to functional lung with the aim of reducing pulmonary side effects. A phase 2, multicenter 4DCT-ventilation functional avoidance clinical trial was completed. The purpose of this work was to quantify changes in patient-reported outcomes (PROs) for patients treated with functional avoidance and determine which metrics are predictive of PRO changes. MATERIALS AND METHODS: Patients with locally advanced lung cancer receiving curative-intent radiation therapy were accrued. Each patient had a 4DCT-ventilation image generated using 4DCT data and image processing. PRO instruments included the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire administered pretreatment; at the end of treatment; and at 3, 6, and 12 months posttreatment. Using the FACT-Trial Outcome Index and the FACT-Lung Cancer Subscale results, the percentage of clinically meaningful declines (CMDs) were determined. A linear mixed-effects model was used to determine which patient, clinical, dose, and dose-function metrics were predictive of PRO decline. RESULTS: Of the 59 patients who completed baseline PRO surveys. 83% had non-small cell lung cancer, with 75% having stage 3 disease. The median dose was 60 Gy in 30 fractions. CMD FACT-Trial Outcome Index decline was 46.3%, 38.5%, and 26.8%, at 3, 6, and 12 months, respectively. CMD FACT-Lung Cancer Subscale decline was 33.3%, 33.3%, and 29.3%, at 3, 6, and 12 months, respectively. Although an increase in most dose and dose-function parameters was associated with a modest decline in PROs, none of the results were significant (all P > .053). CONCLUSIONS: The current work presents an innovative combination of use of functional avoidance and PRO assessment and is the first report of PROs for patients treated with prospective 4DCT-ventilation functional avoidance. Approximately 30% of patients had clinically significant decline in PROs at 12 months posttreatment. The study provides additional data on outcomes with 4DCT-ventilation functional avoidance.

Clinical and Dosimetric Impact of 2D kV Motion Monitoring and Intervention in Liver Stereotactic Body Radiation Therapy.

Purpose: Positional errors resulting from motion are a principal challenge across all disease sites in radiation therapy. This is particularly pertinent when treating lesions in the liver with stereotactic body radiation therapy (SBRT). To achieve dose escalation and margin reduction for liver SBRT, kV real-time imaging interventions may serve as a potential solution. In this study, we report results of a retrospective cohort of liver patients treated using real-time 2D kV-image guidance SBRT with emphasis on the impact of (1) clinical workflow, (2) treatment accuracy, and (3) tumor dose. Methods and Materials: Data from 33 patients treated with 41 courses of liver SBRT were analyzed. During treatment, planar kV images orthogonal to the treatment beam were acquired to determine treatment interventions, namely treatment pauses (ie, adequacy of gating thresholds) or treatment shifts. Patients were shifted if internal markers were >3 mm, corresponding to the PTV margin used, from the expected reference condition. The frequency, duration, and nature of treatment interventions (ie, pause vs shift) were recorded, and the dosimetric impact associated with treatment shifts was estimated using a machine learning dosimetric model. Results: Of all fractions delivered, 39% required intervention, which took on average 1.9 ± 1.6 minutes and occurred more frequently in treatments lasting longer than 7 minutes. The median realignment shift was 5.7 mm in size, and the effect of these shifts on minimum tumor dose in simulated clinical scenarios ranged from 0% to 50% of prescription dose per fraction. Conclusion: Real-time kV-based imaging interventions for liver SBRT minimally affect clinical workflow and dosimetrically benefit patients. This potential solution for addressing positional errors from motion addresses concerns about target accuracy and may enable safe dose escalation and margin reduction in the context of liver SBRT.

Evaluation of variables predicting PFT changes for lung cancer patients treated on a prospective 4DCT-ventilation functional avoidance clinical trial.

PURPOSE: Functional avoidance radiotherapy uses functional imaging to reduce pulmonary toxicity by designing radiotherapy plans that reduce doses to functional regions of the lung. A phase-II, multi-center, prospective study of 4DCT-ventilation functional avoidance was completed. Pre and post-treatment pulmonary function tests (PFTs) were acquired and assessed pulmonary function change. This study aims to evaluate which clinical, dose and dose-function factors predict PFT changes for patients treated with 4DCT-ventilation functional avoidance radiotherapy. MATERIALS AND METHODS: 56 patients with locally advanced lung cancer receiving radiotherapy were accrued. PFTs were obtained at baseline and three months following radiotherapy and included forced expiratory volume in 1-second (FEV1), forced vital capacity (FVC), and FEV1/FVC. The ability of patient, clinical, dose (lung and heart), and dose-function metrics (metrics that combine dose and 4DCT-ventilation-based function) to predict PFT changes were evaluated using univariate and multivariate linear regression. RESULTS: Univariate analysis showed that only dose-function metrics and the presence of chronic obstructive pulmonary disease (COPD) were significant (p<0.05) in predicting FEV1 decline. Multivariate analysis identified a combination of clinical (immunotherapy status, presence of thoracic comorbidities, smoking status, and age), along with lung dose, heart dose, and dose-function metrics in predicting FEV1 and FEV1/FVC changes. CONCLUSION: The current work evaluated factors predicting PFT changes for patients treated in a prospective functional avoidance radiotherapy study. The data revealed that lung dose- function metrics could predict PFT changes, validating the significance of reducing the dose to the functional lung to mitigate the decline in pulmonary function and providing guidance for future clinical trials.

Fiducial Markers Allow Accurate and Reproducible Delivery of Liver Stereotactic Body Radiation Therapy.

Fiducial markers are utilized for image guided radiotherapy (IGRT) alignment during the delivery of liver stereotactic body radiosurgery (SBRT). There are limited data demonstrating the impact of matching fiducials on the accuracy of liver SBRT. This study quantifies the benefit of fiducial-based alignment and improvements in inter-observer reliability. Nineteen patients with 24 liver lesions were treated with SBRT. Target localization was performed using fiducial markers on cone-beam computed tomography (CBCT). Each CBCT procedure was retrospectively realigned to match both the liver edge and fiducial markers. The shifts were recorded by seven independent observers. Inter-observer variability was analyzed by calculating the mean error and uncertainty for the set-up. The mean absolute Cartesian error observed from fiducial and liver edge-based alignment was 1.5 mm and 5.3 mm, respectively. The mean uncertainty from fiducial and liver edge-based alignment was 1.8 mm and 4.5 mm, respectively. An error of 5 mm or greater was observed 50% of the time when aligning to the liver surface versus 5% of the time when aligning to fiducial markers. Aligning to the liver edge significantly increased the error, resulting in increased shifts when compared to alignment to fiducials. Tumors of 3 cm or farther from the liver dome had higher mean errors when aligned without fiducials (4.8 cm vs. 4.4 cm, p = 0.003). Our data support the use of fiducial markers for safer and more accurate liver SBRT.

Phase 1 Dose Escalation Study of SBRT Using 3 Fractions for Locally Advanced Pancreatic Cancer.

PURPOSE: The optimal dose and fractionation of stereotactic body radiation therapy (SBRT) for locally advanced pancreatic cancer (LAPC) have not been defined. Single-fraction SBRT was associated with more gastrointestinal toxicity, so 5-fraction regimens have become more commonly employed. We aimed to determine the safety and maximally tolerated dose of 3-fraction SBRT for LAPC. METHODS AND MATERIALS: Two parallel phase 1 dose escalation trials were conducted from 2016 to 2019 at Memorial Sloan Kettering Cancer Center and University of Colorado. Patients with histologically confirmed LAPC without distant progression after at least 2 months of induction chemotherapy were eligible. Patients received 3-fraction linear accelerator-based SBRT at 3 dose levels, 27, 30, and 33 Gy, following a modified 3+3 design. Dose-limiting toxicity, defined as grade ≥3 gastrointestinal toxicity within 90 days, was scored by National Cancer Institute Common Terminology Criteria for Adverse Events, version 4. The secondary endpoints included cumulative incidence of local failure (LF) and distant metastasis (DM), as well as progression-free and overall survival PFS and OS, respectively, toxicity, and quality of life (QoL) using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and the pancreatic cancer-specific QLQ-PAN26 questionnaire. RESULTS: Twenty-four consecutive patients were enrolled (27 Gy: 9, 30 Gy: 8, 33 Gy: 7). The median (range) age was 67 (52-79) years, and 12 (50%) had a head/uncinate tumor location, with a median tumor size of 3.8 (1.1-11) cm and CA19-9 of 60 (1-4880) U/mL. All received chemotherapy for a median of 4 (1.4-10) months. There were no grade ≥3 toxicities. Two-year rates (95% confidence interval) of LF, DM, PFS, and OS were 31.7% (8.6%-54.8%), 70.2% (49.7%-90.8%), 20.8% (4.6%-37.1%), and 29.2% (11.0%-47.4%), respectively. Three- and 6-month QoL assessment showed no detriment. CONCLUSIONS: For select patients with LAPC, dose escalation to 33 Gy in 3 fractions resulted in no dose-limiting toxicities, no detriments to QoL, and disease outcomes comparable with conventional RT. Further exploration of SBRT schemes to maximize tumor control while enabling efficient integration with systemic therapy is warranted.

Characterizing Pulmonary Function Test Changes for Patients With Lung Cancer Treated on a 2-Institution, 4-Dimensional Computed Tomography-Ventilation Functional Avoidance Prospective Clinical Trial.

Purpose: Four-dimensional computed tomography (4DCT)-ventilation-based functional avoidance uses 4DCT images to generate plans that avoid functional regions of the lung with the goal of reducing pulmonary toxic effects. A phase 2, multicenter, prospective study was completed to evaluate 4DCT-ventilation functional avoidance radiation therapy. The purpose of this study was to report the results for pretreatment to posttreatment pulmonary function test (PFT) changes for patients treated with functional avoidance radiation therapy. Methods and Materials: Patients with locally advanced lung cancer receiving chemoradiation were accrued. Functional avoidance plans based on 4DCT-ventilation images were generated. PFTs were obtained at baseline and 3 months after chemoradiation. Differences for PFT metrics are reported, including diffusing capacity for carbon monoxide (DLCO), forced expiratory volume in 1 second (FEV1), and forced vital capacity (FVC). PFT metrics were compared for patients who did and did not experience grade 2 or higher pneumonitis. Results: Fifty-six patients enrolled on the study had baseline and posttreatment PFTs evaluable for analysis. The mean change in DLCO, FEV1, and FVC was -11.6% ± 14.2%, -5.6% ± 16.9%, and -9.0% ± 20.1%, respectively. The mean change in DLCO was -15.4% ± 14.4% for patients with grade 2 or higher radiation pneumonitis and -10.8% ± 14.1% for patients with grade <2 radiation pneumonitis (P = .37). The mean change in FEV1 was -14.3% ± 22.1% for patients with grade 2 or higher radiation pneumonitis and -3.9% ± 15.4% for patients with grade <2 radiation pneumonitis (P = .09). Conclusions: The current work is the first to quantitatively characterize PFT changes for patients with lung cancer treated on a prospective functional avoidance radiation therapy study. In comparison with patients treated with standard thoracic radiation planning, the data qualitatively show that functional avoidance resulted in less of a decline in DLCO and FEV1. The presented data can help elucidate the potential pulmonary function improvement with functional avoidance radiation therapy.

Cardiac metabolic changes on 18 F-positron emission tomography after thoracic radiotherapy predict for overall survival in esophageal cancer patients.

PURPOSE: Heart doses have been shown to be predictive of cardiac toxicity and overall survival (OS) for esophageal cancer patients. There is potential for functional imaging to provide valuable cardiac information. The purpose of this study was to evaluate the cardiac metabolic dose-response using 18 F-deoxyglucose (FDG)-PET and to assess whether standard uptake value (SUV) changes in the heart were predictive of OS. METHODS: Fifty-one patients with esophageal cancer treated with radiation who underwent pre- and post-treatment FDG-PET scans were retrospectively evaluated. Pre- and post-treatment PET-scans were rigidly registered to the planning CT for each patient. Pre-treatment to post-treatment absolute mean SUV (SUVmean) changes in the heart were calculated to assess dose-response. A dose-response curve was generated by binning each voxel in the heart into 10 Gy dose-bins and analyzing the SUVmean changes in each dose-bin. Multivariate cox proportional hazard models were used to assess whether pre-to-post treatment cardiac SUVmean changes predicted for OS. RESULTS: The cardiac dose-response curve demonstrated a trend of increasing cardiac SUV changes as a function of dose with an average increase of 0.044 SUV for every 10 Gy dose bin. In multivariate analysis, disease stage and SUVmean change in the heart were predictive (p < 0.05) for OS. CONCLUSIONS: Changes in pre- to post-treatment cardiac SUV were predictive of OS with patients having a higher pre- to post-treatment cardiac SUV change surviving longer.

Population-level and individual-level explainers for propensity score matching in observational studies.

Precis: The exclusion of unmatched observations in propensity score matching has implications for the generalizability of causal effects. Machine learning methods can help to identify how the study population differs from the unmatched subpopulation. Background: There has been widespread use of propensity scores in evaluating the effect of cancer treatments on survival, particularly in administrative databases and cancer registries. A byproduct of certain matching schemes is the exclusion of observations. Borrowing an analogy from clinical trials, one can view these exclusions as subjects that do not satisfy eligibility criteria. Methods: Developing identification rules for these "data-driven eligibility criteria" in observational studies on both population and individual levels helps to ascertain the population on which causal effects are being made. This article presents a machine learning method to determine the representativeness of causal effects in two different datasets from the National Cancer Database. Results: Decision trees reveal that groups with certain features have a higher probability of inclusion in the study population than older patients. In the first dataset, younger age categories had an inclusion probability of at least 0.90 in all models, while the probability for the older category ranged from 0.47 to 0.65. Most trees split once more on an even higher age at a lower node, suggesting that the oldest patients are the least likely to be matched. In the second set of data, both age and surgery status were associated with inclusion. Conclusion: The methodology presented in this paper underscores the need to consider exclusions in propensity score matching procedures as well as complementing matching with other propensity score adjustments.

The role of concomitant chemoradiotherapy versus radiation alone in T1-3N0 HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma.

OBJECTIVE: To evaluate the role of curative intent concurrent chemoradiation (CCRT) vs radiation (RT) alone for T1-T3N0 HPV-positive and HPV-negative oropharyngeal squamous cell cancer (OPSCC). METHODS: The NCDB was queried for patients diagnosed between 2010 and 2017 with cT1-3N0M0 OPSCC treated with definitive RT or CCRT. Univariable analysis (UVA) and multivariable analysis (MVA) Cox regression analysis was performed with OS as the endpoint. Propensity score matching (PSM) 1:1 was performed. Interaction test to assess heterogeneity of treatment effect. RESULTS: A total of 2830 patients were queried. On MVA, CCRT was associated with improved OS for T3N0 tumors (HR 0.49; 95% CI 0.39-0.63) but not for T1N0 (HR 1.43; 95% CI 0.99-2.07) and T2N0 (HR 0.92; 95% CI 0.75-1.13). For T3 patients, CCRT improved OS for HPV-negative (HR 0.43; 95% CI 0.31-0.59) and HPV-positive tumors (HR 0.39; 95% CI 0.25-0.61). After PSM, CCRT was not statistically different to RT for patients with T1-2N0 HPV-negative tumors (HR 1.10; 95% CI 0.85-1.43; p = 0.48) and T1-2N0 HPV-positive tumors (HR 1.15; 95% CI 0.79-1.68; p = 0.45). After PSM, CCRT improved OS compared to RT alone for patients with T3N0 HPV-negative (HR 0.43; 95% CI 0.31-0.59; p < 0.01) and HPV-positive tumors (HR 0.39; 95 %CI 0.25-0.61; p < 0.01). CONCLUSIONS: CCRT is associated with improved OS in HPV-positive and HPV-negative T3N0 OPSCC. RT alone vs. CCRT demonstrated similar OS for T1-T2N0 OPSCC for both HPV negative and HPV positive tumors.

Results of a Multi-Institutional Phase 2 Clinical Trial for 4DCT-Ventilation Functional Avoidance Thoracic Radiation Therapy.

PURPOSE: Radiation pneumonitis remains a major limitation in the radiation therapy treatment of patients with lung cancer. Functional avoidance radiation therapy uses functional imaging to reduce pulmonary toxic effects by designing radiation therapy plans that reduce doses to functional regions of the lung. Lung functional imaging has been developed that uses 4-dimensional computed tomography (4DCT) imaging to calculate 4DCT-based lung ventilation (4DCT-ventilation). A phase 2 multicenter study was initiated to evaluate 4DCT-ventilation functional avoidance radiation therapy. The study hypothesis was that functional avoidance radiation therapy could reduce the rate of grade ≥2 radiation pneumonitis to 12% compared with a 25% historical rate, with the trial being positive if ≤16.4% of patients experienced grade ≥2 pneumonitis. METHODS AND MATERIALS: Lung cancer patients receiving curative-intent radiation therapy (prescription doses of 45-75 Gy) and chemotherapy were accrued. Patient 4DCT scans were used to generate 4DCT-ventilation images. The 4DCT-ventilation images were used to generate functional avoidance plans that reduced doses to functional portions of the lung while delivering the prescribed tumor dose. Pneumonitis was evaluated by a clinician at 3, 6, and 12 months after radiation therapy. RESULTS: Sixty-seven evaluable patients were accrued between April 2015 and December 2019. The median prescription dose was 60 Gy (range, 45-66 Gy) delivered in 30 fractions (range, 15-33 fractions). The average reduction in the functional volume of lung receiving ≥20 Gy with functional avoidance was 3.5% (range, 0%-12.8%). The median follow-up was 312 days. The rate of grade ≥2 radiation pneumonitis was 10 of 67 patients (14.9%; 95% upper CI, 24.0%), meeting the phase 2 criteria. CONCLUSIONS: 4DCT-ventilation offers an imaging modality that is convenient and provides functional imaging without an extra procedure necessary. This first report of a multicenter study of 4DCT-ventilation functional avoidance radiation therapy provided data showing that the trial met phase 2 criteria and that evaluation in a phase 3 study is warranted.

Presence of Orthopedic Residency Decreases Emergency Physician's Confidence in Orthopedic Procedures.

INTRODUCTION: At present, there exists no standard orthopedic training for emergency medicine (EM) residency programs. Varying residency environments including but not limited to volume, acuity, and competing residency programs will dictate the number of orthopedic procedures a resident is exposed to, ultimately dictating a graduate's comfort level with orthopedic procedures. Our study set out to investigate further whether training alongside an orthopedic residency affects an attending physician's perceived procedural comfort. METHODS: This is a cohort study utilizing a 14-question survey distributed to an online community of EM physicians to examine the relationship between training at a residence program alongside orthopedic residents, the utility of an elective orthopedic rotation, and the overall confidence in managing closed reductions. RESULTS: EM physicians trained at a program that also hosted an orthopedic residency were more likely to train at large academic tertiary care centers (78%). Forty-two percent of these respondents felt that the presence of an orthopedic residency had a negative impact on their overall orthopedic training. The remaining 58% felt that the orthopedic residency had a positive impact on their procedural skills. In our study, the overall mean comfort level was statistically significant (p-value = 0.0024) higher in those who trained without orthopedic residents (8.78) compared to those who trained alongside an orthopedic residency (7.61). Those who had an elective orthopedic rotation found it to be more beneficial if they did the rotation with an orthopedic residency (p-value = 0.0329). Those who reported a beneficial orthopedic rotation also reported a higher level of confidence in the management of non-fracture reductions (p < 0.011, ρ = .25). CONCLUSION: Seeing as though both training and practice environments for emergency physicians vary greatly across the country, every effort should be taken to ensure graduating residents are prepared to perform orthopedic procedures without the assistance of orthopedic surgeons. Irrespective of whether a program has in-house orthopedic residents or not, EM residents should take it upon themselves to maximize their time during residency to focus on these core competencies. Graduates at the greatest risk of having low confidence are trained at academic centers that also host orthopedic programs. One should be cognizant of this while going through their EM residency.

Factors predictive of 90-day mortality after surgical resection for oral cavity cancer: Development of a recursive partitioning analysis for risk stratification.

BACKGROUND: Factors that influence postoperative mortality (POM) have been identified, but a predictive model to guide clinicians treating oral cavity cancer (OCC) has not been well established. METHODS: Patients with OCC undergoing upfront surgical resection were included. Primary outcome was 90-day POM (90dPOM). RESULTS: 33 845 were identified using the National Cancer Database. Rate of 90dPOM was 3.2%. Predictors of higher 90dPOM include older age, higher comorbidity scores, nonprivate insurance, lower income, treatment in an academic facility, higher T- and N-classification, radical excision, and presence of positive margins. On RPA, two high-risk (90dPOM > 10%) patient subsets were identified: patients ≥80 years of age with T3-4 disease and patients <80 years, with any comorbidity and T3-4, N2-3 disease. CONCLUSIONS: We identified a subset of patients in this cohort who are at high risk for 90dPOM. These patients may warrant additional perioperative and postoperative monitoring in addition to better preoperative assessment and screening.

The Effects of Time to Treatment Initiation for Patients With Non-small-cell Lung Cancer in the United States.

BACKGROUND: The purpose of this study was to determine the effects of time from diagnosis to treatment (TTI) on survival in patients with nonmetastatic non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: The National Cancer Database was queried for patients with stages 1 to 3 NSCLC between 2004 and 2013. Patients with missing survival status/time, unknown TTI, or receipt of palliative therapy were excluded. Multivariable Cox proportional hazards modeling, logistic regression, and recursive partitioning analysis were performed to determine associated variables and survival outcomes. RESULTS: Altogether, 1,393,232 patients met inclusion criteria. The median follow-up was 36 months. The median TTI increased between 2004 and 2013 from 35 to 39 days (P < .001). On multivariable Cox proportional hazards modeling, TTI groups 31 to 60 days, 61 to 90 days, and > 90 days were independently related to poorer overall survival (OS) compared with TTI 1 to 30 days (hazard ratio, 1.04, 1.10, and 1.14; 95% confidence interval [CI], 1.02-1.06, 1.07-1.12, and 1.11-1.17, respectively; P < .001 for all). Recursive partitioning analysis revealed that TTI of ≤ 45 days was the most optimal threshold for survival (P < .001); patients with TTI ≤ 45 days had a median OS of 70.2 months (95% CI, 69.3-71.1 months) versus 61.5 months (95% CI, 60.5-62.4) (P < .001). There were significant disparities by age, race, ethnicity, and income for delayed (> 45 days) TTI (P < .001 for all). Subgroup analysis revealed that stage 1 and 2 patients with TTI > 45 days had a higher risk of mortality compared with TTI ≤ 45 days (hazard ratio, 1.15 and 1.05; 95% CI, 1.12-1.17 and 1.01-1.09, respectively) (P < .001). CONCLUSIONS: Increased TTI is independently associated with poorer survival in non-metastatic NSCLC. TTI ≤ 45 days is a clinically targetable time frame associated with improved outcomes and ought to be considered for patients with lung cancer undergoing definitive therapy.

Optimizing Coded Aperture Imaging techniques to allow for online tracking of fiducial markers with high-energy scattered radiation from treatment beam.

PURPOSE: Real-time visualization of target motion using fiducial markers during radiation therapy treatment will allow for more accurate dose delivery. The purpose of this study was to optimize techniques for online fiducial marker tracking by detecting the scattered treatment beam through coded aperture imaging (CAI). Coded aperture imaging is a novel imaging technique that can allow target tracking in real time during treatment, and do so without adding any additional radiation dose, by making use of the scattered treatment beam radiation. METHODS: Radiotherapy beams of various energies, incident on phantoms containing gold fiducial markers were modeled using MCNP6.2 Monte Carlo transport code. Orthogonal scatter radiographs were collected through a CAI geometry. After decoding the simulated radiograph data, the centroid location and FWHM/SNR of the fiducial signals were analyzed. The effects of properties related to the CA (rank, pattern, and physical dimensions), detector (dimensions and pixel count), position (CA and phantom), and the incident beam (spectrum and direction) were investigated. These variables were evaluated by quantifying the positional accuracy, resolution, and SNR of the fiducials' signal. The effects of phantom scatter and decoding artifacts were reduced via Fourier filtering to avoid treatment interruption and physical interaction with the coded mask. RESULTS: The method was able to accurately localize the markers to within 1 pixel of a simulated radiograph. A 10 × 10 × 2 cm tungsten mask was chosen to attenuate >99 % of incident scatter through opaque elements, while minimizing collimation artifacts which arise from vignetting of the coded radiograph. Clear separation of centroids from fiducial signals with 2.5 mm separation was maintained, and initial optimization of parameters has produced an aperture which decodes the location of multiple fiducial markers inside a human phantom properly with a high SNR in the final radiograph image. CONCLUSION: Current results show a proof of concept for a novel real-time imaging method. Coded aperture imaging is a promising technique for extracting the fiducial scatter signal from a broader Compton-scatter background. These results can be used to further optimize the CAI parameter space and guide fabrication and testing of a clinical device.

Technical Note: Deep Learning approach for automatic detection and identification of patient positioning devices for radiation therapy.

PURPOSE: Automatic detection and identification of setup devices, using a deep convolutional neural network (CNN) for real-time multiclass object detection, has the potential to reduce errors in the treatment delivery process by avoiding documentation errors. METHODS: A database of the setup device photos from the most recent 1200 patients treated at our institution was downloaded from the record and verify (R&V) system along with the corresponding setup notes. Images were manually labeled with bounding boxes of each device. A real-time object detection CNN using the "you only look once" (YOLOv2) architecture was trained using transfer learning of a pretrained CNN (ResNet50). The CNN was trained to detect and identify 11 of the most common treatment accessories used at our institution. RESULTS: Using transfer learning of a CNN for multiclass object detection, we are able to automatically detect and identify setup devices in photographs with an accuracy of 96%. CONCLUSIONS: Automation in radiation oncology has the potential to reduce risk. Automatic detection of setup devices is possible using a CNN and transfer learning. This work shows both the value of incident learning systems (ILS) in practice knowledge dissemination, and shows how automation of clinical processes and less reliance on manual documentation has the potential for risk reduction in radiation oncology treatments.

Evaluating Positron Emission Tomography-Based Functional Imaging Changes in the Heart After Chemo-Radiation for Patients With Lung Cancer.

PURPOSE: Studies have noted a link between radiation dose to the heart and overall survival (OS) for patients with lung cancer treated with chemoradiation. The purpose of this study was to characterize pre- to posttreatment cardiac metabolic changes using fluorodeoxyglucose/positron emission tomography (FDG-PET) images and to evaluate whether changes in cardiac metabolism predict for OS. METHODS AND MATERIALS: Thirty-nine patients enrolled in a functional avoidance prospective study who had undergone pre- and postchemoradiation FDG-PET imaging were evaluated. For each patient, the pretreatment and posttreatment PET/CTs were rigidly registered to the planning CT, dose, and structure set. PET-based metabolic dose-response was assessed by comparing pretreatment to posttreatment mean standardized uptake values (SUVmean) in the heart as a function of dose-bin. OS analysis was performed by comparing SUVmean changes for patients who were alive or had died at last follow-up and by using a multivariate model to assess whether pre- to posttreatment SUVmean changes were a predictor of OS. RESULTS: The dose-response curve revealed increasing changes in SUV as a function of cardiac dose with an average SUVmean increase of 1.7% per 10 Gy. Patients were followed for a median of 437 days (range, 201-1131 days). SUVmean change was significantly predictive of OS on multivariate analysis with a hazard ratio of 0.541 (95% confidence intervals, 0.312-0.937). Patients alive at follow-up had an average increase of 17.2% in cardiac SUVmean while patients that died had an average decrease in SUVmean decrease of 13.5% (P = .048). CONCLUSIONS: Our data demonstrated that posttreatment SUV changes in the heart were significant indicators of dose-response and predictors of OS. The present work is hypothesis generating and must be validated in an independent cohort. If validated, our data show the potential for cardiac metabolic changes to be an early predictor for clinical outcomes.

Simulation of x-ray-induced acoustic imaging for absolute dosimetry: Accuracy of image reconstruction methods.

PURPOSE: Three-dimensional in-vivo dose verification is one of the standing challenges in radiation therapy. X-ray-induced acoustic tomography has recently been proposed as an imaging method for use in in-vivo dosimetry. The aim of this study was to investigate the accuracy of reconstructing three-dimensional (3D) absolute dose using x-ray-induced acoustic tomography. We performed this investigation using two different tomographic dose reconstruction techniques. METHODS: Two examples of 3D dose reconstruction techniques for x-ray acoustic imaging are investigated. Dose distributions are calculated for varying field sizes using a clinical treatment planning system. The induced acoustic pressure waves which are generated by the increase in temperature due to the absorption of pulsed MV x-rays are simulated using an advanced numerical modeling package for acoustic wave propagation in the time domain. Two imaging techniques, back projection and iterative time reversal, are used to reconstruct the 3D dose distribution in a water phantom with open fields. Image analysis is performed and reconstructed depth dose curves from x-ray acoustic imaging are compared to the depth dose curves calculated from the treatment planning system. Calculated field sizes from the reconstructed dose profiles by back projection and time reversal are compared to the planned field size to determine their accuracy. The iterative time reversal imaging technique is also used to reconstruct dose in an example clinical dose distribution. Image analysis of this clinical test case is performed using the gamma passing rate. In addition, gamma passing rates are used to validate the stopping criteria in the iterative time reversal method. RESULTS: Water phantom simulations showed that back projection does not adequately reconstruct the shape and intensity of the depth dose. When compared to the depth of maximum dose calculated by a treatment planning system, the maximum dose depth by back projection is shifted deeper by 55 and 75 mm for 4 × 4 cm and 10 × 10 cm field sizes, respectively. The reconstructed depth dose by iterative time reversal accurately agrees with the planned depth dose for a 4 × 4 cm field size and is shifted deeper by 12 mm for the 10 × 10 cm field size. When reconstructing field sizes, the back projection method leads to 18% and 35% larger sizes for the 4 × 4 cm and 10 × 10 cm fields, respectively, whereas the iterative time reversal method reconstructs both field sizes with < 2% error. For the clinical dose distribution, we were able to reconstruct the dose delivered by a 1 degree sub-arc with a good accuracy. The reconstructed and planned doses were compared using gamma analysis, with> 96% gamma passing rate at 3%/2 mm. CONCLUSIONS: Our results show that the 3D x-ray acoustic reconstructed dose by iterative time reversal is considerably more accurate than the dose reconstructed by back projection. Iterative time reversal imaging has a potential for use in 3D absolute dosimetry.

The Effect of Time to Postoperative Radiation Therapy on Survival in Resected Merkel Cell Carcinoma.

OBJECTIVES: Delays from surgery to adjuvant radiation therapy (aRT) are associated with poorer prognosis in multiple neoplasms. Presently, no data exist for Merkel cell carcinoma (MCC). The authors sought to assess the time interval from surgery to aRT and effect on outcomes in MCC. MATERIALS AND METHODS: The National Cancer Database was queried for histologically confirmed nonmetastatic MCC status post resection and aRT diagnosed between 2004 and 2015 who received aRT within 24 weeks of surgery. Kaplan-Meier analysis assessed univariate overall survival (OS); multivariable Cox proportional hazards modeling assessed multivariate OS; χ and logistic regression assessed differences in baseline characteristics and predictors of delayed aRT. RESULTS: Of 5952 patients meeting criteria, 13% commenced aRT within 4 weeks, 48% between 4 and 7 weeks, 23% between 8 and 11 weeks, 11% between 12 and 15 weeks, and 6% between 16 and 24 weeks. There were no differences in OS on the basis of the surgery-aRT interval (P=0.99). Predictors of worse OS on the multivariate analysis included advanced age, greater comorbidities, male sex, lower regional income, earlier year of diagnosis, more advanced tumor and nodal staging, positive margins, head and neck location, and treatment at community facilities (P<0.05 for all). Factors predictive of delayed aRT were identified. Subset analyses on these factors, such as receipt of chemotherapy or positive lymph nodes, did not demonstrate that the timing of aRT affected survival (P≥0.37). CONCLUSION: This study of a contemporary national database revealed that delays from resection to aRT were not associated with survival in MCC, somewhat discordant from other malignancies such as squamous cell carcinoma.

Objective assessment of the effects of tumor motion in radiation therapy.

PURPOSE: Internal organ motion reduces the accuracy and efficacy of radiation therapy. However, there is a lack of tools to objectively (based on a medical or scientific task) assess the dosimetric consequences of motion, especially on an individual basis. We propose to use therapy operating characteristic (TOC) analysis to quantify the effects of motion on treatment efficacy for individual patients. We demonstrate the application of this tool with pancreatic stereotactic body radiation therapy (SBRT) clinical data and explore the origin of motion sensitivity. METHODS: The technique is described as follows. (a) Use tumor-motion data measured from patients to calculate the motion-convolved dose of the gross tumor volume (GTV) and the organs at risk (OARs). (b) Calculate tumor control probability (TCP) and normal tissue complication probability (NTCP) from the motion-convolved dose-volume histograms. (c) Construct TOC curves from TCP and NTCP models. (d) Calculate the area under the TOC curve (AUTOC) and use it as a figure of merit for treatment efficacy. We used tumor motion data measured from patients to calculate the relation between AUTOC and motion magnitude for 25 pancreatic SBRT treatment plans. Furthermore, to explore the driving factor of motion sensitivity of a given plan, we compared the dose distribution of motion-sensitive plans and motion-robust plans and studied the dependence of motion sensitivity to motion directions. RESULTS: Our technique is able to recognize treatment plans that are sensitive to motion. Under the presence of motion, the treatment efficacy of some plans changes from providing high tumor control and low risks of complications to providing no tumor control and high risks of side effects. Several treatment plans experience falloffs in AUTOC at a smaller magnitude of motion than other plans. In our dataset, a potential indicator of a motion-sensitive treatment plan is that the duodenum is in proximity to the tumor in the SI direction. CONCLUSIONS: The TOC framework can serve as a tool to quantify the effects of internal organ motion in radiation therapy. With pancreatic SBRT clinical data, we applied this tool to study the change in treatment efficacy induced by motion for individual treatment plans. This framework could potentially be used clinically to understand the effects of motion in an individual patient and to design a patient-specific motion management plan. This framework could also be used in research to evaluate different components of the treatment process, such as motion-management techniques, treatment-planning algorithms, and treatment margins.

Quantifying Allowable Motion to Achieve Safe Dose Escalation in Pancreatic SBRT.

PURPOSE: Tumor motion plays a key role in the safe delivery of stereotactic body radiation therapy (SBRT) for pancreatic cancer. The purpose of this study was to use tumor motion measured in patients to establish limits on motion magnitude for safe delivery of pancreatic SBRT and to help guide motion-management decisions in potential dose-escalation scenarios. METHODS AND MATERIALS: Using 91 sets of pancreatic tumor motion data, we calculated the motion-convolved dose of the gross tumor volume, duodenum, and stomach for 25 patients with pancreatic cancer. We derived simple linear or quadratic models relating motion to changes in dose and used these models to establish the maximum amount of motion allowable while satisfying error thresholds on key dose metrics. In the same way, we studied the effects of dose escalation and tumor volume on allowable motion. RESULTS: In our patient cohort, the mean (range) allowable motion for 33, 40, and 50 Gy to the planning target volume was 11.9 (6.3-22.4), 10.4 (5.2-19.1), and 9.0 (4.2-16.0) mm, respectively. The maximum allowable motion decreased as the dose was escalated and was smaller in patients with larger tumors. We found significant differences in allowable motion between the different plans, suggesting a patient-specific approach to motion management is possible. CONCLUSIONS: The effects of motion on pancreatic SBRT are highly variable among patients, and there is potential to allow more motion in certain patients, even in dose-escalated scenarios. In our dataset, a conservative limit of 6.3 mm would ensure safe treatment of all patients treated to 33 Gy in 5 fractions.