Interpretable Machine Learning for Choosing Radiation Dose-volume Constraints on Cardio-pulmonary Substructures Associated with Overall Survival in NRG Oncology RTOG 0617.

PURPOSE: Our objective was to use interpretable machine learning for choosing dose-volume constraints on cardiopulmonary substructures (CPSs) associated with overall survival (OS) in radiation therapy for locally advanced non-small cell lung cancer. METHODS AND MATERIALS: A total of 428 patients with non-small cell lung cancer were randomly divided into training/validation/test subsets (n = 230/149/49) in Radiation Therapy Oncology Group 0617. Manual or automated contouring was performed to segment CPSs, including heart, atria, ventricles, aorta, left/right ventricle/atrium (LV+RV+LA+RA), inferior/superior vena cava, pulmonary artery, and pericardium. Peri (pericardium-heart), rest (heart-[LV+RV+LA+RA]), clinical target volume (CTV), and lungs-CTV contours were also obtained. Dose-volume histogram features were extracted, including minimum/mean dose to the hottest x% volume (Dx%[Gy]/MOHx%[Gy]), minimum/mean/maximum dose, percent volume receiving at least xGy (VxGy[%]), and overlapping volume of each CPS with planning target volume (PTV_Voverlap[%]). Clinical parameters were collected from the National Clinical Trials Network/Community oncology research program data archive. Feature selection was performed using a series of multiblock sparse partial least squares regression, stability selection supervised principal component analysis, and Boruta. Explainable boosting machine (EBM) was trained using a conditional survival distribution-based approach for imputing censored data, treating survival analysis as a regression problem. Harrell's C-index was used to evaluate OS discrimination performance of EBM, Cox proportional hazards (CPH), random survival forest, extreme gradient boosting survival embeddings, and CPH deep neural network (DeepSurv) models in the test set. Dose-volume constraints were selected using the binary change point detection algorithm in Shapley additive explanations-based partial dependence functions. RESULTS: Selected features included LA_V60Gy(%), pericardium_D30%(Gy), lungs-CTV_PTV_Voverlap(%), RA_V55Gy(%), and received_cons_chemo. All models ranked LA_V60Gy(%) as the most important feature. EBM achieved the best performance for predicting OS, followed by extreme gradient boosting survival embeddings, random survival forest, DeepSurv, and CPH (C-index = 0.653, 0.646, 0.642, 0.638, and 0.632). EBM global explanations suggested that LA_V60Gy(%) < 25.6, lungs-CTV_PTV_Voverlap(%) < 1.1, pericardium_D30%(Gy) < 18.9, RA_V55Gy(%) < 19.5, and received_cons_chemo = 'Yes' for improved OS. CONCLUSIONS: EBM can be used to discriminate OS while also guiding dose-volume constraint selection for optimal management of cardiac toxicity in lung cancer radiation therapy.

Implementation of Machine Learning Models to Ensure Radiotherapy Quality for Multicenter Clinical Trials: Report from a Phase III Lung Cancer Study.

The outcome of the patient and the success of clinical trials involving RT is dependent on the quality assurance of the RT plans. Knowledge-based Planning (KBP) models using data from a library of high-quality plans have been utilized in radiotherapy to guide treatment. In this study, we report on the use of these machine learning tools to guide the quality assurance of multicenter clinical trial plans. The data from 130 patients submitted to RTOG1308 were included in this study. Fifty patient cases were used to train separate photon and proton models on a commercially available platform based on principal component analysis. Models evaluated 80 patient cases. Statistical comparisons were made between the KBP plans and the original plans submitted for quality evaluation. Both photon and proton KBP plans demonstrate a statistically significant improvement of quality in terms of organ-at-risk (OAR) sparing. Proton KBP plans, a relatively emerging technique, show more improvements compared with photon plans. The KBP proton model is a useful tool for creating proton plans that adhere to protocol requirements. The KBP tool was also shown to be a useful tool for evaluating the quality of RT plans in the multicenter clinical trial setting.

Interpretable machine learning for predicting pathologic complete response in patients treated with chemoradiation therapy for rectal adenocarcinoma.

Purpose: Pathologic complete response (pCR) is a critical factor in determining whether patients with rectal cancer (RC) should have surgery after neoadjuvant chemoradiotherapy (nCRT). Currently, a pathologist's histological analysis of surgical specimens is necessary for a reliable assessment of pCR. Machine learning (ML) algorithms have the potential to be a non-invasive way for identifying appropriate candidates for non-operative therapy. However, these ML models' interpretability remains challenging. We propose using explainable boosting machine (EBM) to predict the pCR of RC patients following nCRT. Methods: A total of 296 features were extracted, including clinical parameters (CPs), dose-volume histogram (DVH) parameters from gross tumor volume (GTV) and organs-at-risk, and radiomics (R) and dosiomics (D) features from GTV. R and D features were subcategorized into shape (S), first-order (L1), second-order (L2), and higher-order (L3) local texture features. Multi-view analysis was employed to determine the best set of input feature categories. Boruta was used to select all-relevant features for each input dataset. ML models were trained on 180 cases from our institution, with 37 cases from RTOG 0822 clinical trial serving as the independent dataset for model validation. The performance of EBM in predicting pCR on the test dataset was evaluated using ROC AUC and compared with that of three state-of-the-art black-box models: extreme gradient boosting (XGB), random forest (RF) and support vector machine (SVM). The predictions of all black-box models were interpreted using Shapley additive explanations. Results: The best input feature categories were CP+DVH+S+R_L1+R_L2 for all models, from which Boruta-selected features enabled the EBM, XGB, RF, and SVM models to attain the AUCs of 0.820, 0.828, 0.828, and 0.774, respectively. Although EBM did not achieve the best performance, it provided the best capability for identifying critical turning points in response scores at distinct feature values, revealing that the bladder with maximum dose >50 Gy, and the tumor with maximum2DDiameterColumn >80 mm, elongation <0.55, leastAxisLength >50 mm and lower variance of CT intensities were associated with unfavorable outcomes. Conclusions: EBM has the potential to enhance the physician's ability to evaluate an ML-based prediction of pCR and has implications for selecting patients for a "watchful waiting" strategy to RC therapy.

A comparison of two methodologies for radiotherapy treatment plan optimization and QA for clinical trials.

BACKGROUND AND PURPOSE: The efficacy of clinical trials and the outcome of patient treatment are dependent on the quality assurance (QA) of radiation therapy (RT) plans. There are two widely utilized approaches that include plan optimization guidance created based on patient-specific anatomy. This study examined these two techniques for dose-volume histogram predictions, RT plan optimizations, and prospective QA processes, namely the knowledge-based planning (KBP) technique and another first principle (FP) technique. METHODS: This analysis included 60, 44, and 10 RT plans from three Radiation Therapy Oncology Group (RTOG) multi-institutional trials: RTOG 0631 (Spine SRS), RTOG 1308 (NSCLC), and RTOG 0522 (H&N), respectively. Both approaches were compared in terms of dose prediction and plan optimization. The dose predictions were also compared to the original plan submitted to the trials for the QA procedure. RESULTS: For the RTOG 0631 (Spine SRS) and RTOG 0522 (H&N) plans, the dose predictions from both techniques have correlation coefficients of >0.9. The RT plans that were re-optimized based on the predictions from both techniques showed similar quality, with no statistically significant differences in target coverage or organ-at-risk sparing. The predictions of mean lung and heart doses from both methods for RTOG1308 patients, on the other hand, have a discrepancy of up to 14 Gy. CONCLUSIONS: Both methods are valuable tools for optimization guidance of RT plans for Spine SRS and Head and Neck cases, as well as for QA purposes. On the other hand, the findings suggest that KBP may be more feasible in the case of inoperable lung cancer patients who are treated with IMRT plans that have spatially unevenly distributed beam angles.

Rigid and Deformable Image Registration for Radiation Therapy: A Self-Study Evaluation Guide for NRG Oncology Clinical Trial Participation.

PURPOSE: The registration of multiple imaging studies to radiation therapy computed tomography simulation, including magnetic resonance imaging, positron emission tomography-computed tomography, etc. is a widely used strategy in radiation oncology treatment planning, and these registrations have valuable roles in image guidance, dose composition/accumulation, and treatment delivery adaptation. The NRG Oncology Medical Physics subcommittee formed a working group to investigate feasible workflows for a self-study credentialing process of image registration commissioning. METHODS AND MATERIALS: The American Association of Physicists in Medicine (AAPM) Task Group 132 (TG132) report on the use of image registration and fusion algorithms in radiation therapy provides basic guidelines for quality assurance and quality control of the image registration algorithms and the overall clinical process. The report recommends a series of tests and the corresponding metrics that should be evaluated and reported during commissioning and routine quality assurance, as well as a set of recommendations for vendors. The NRG Oncology medical physics subcommittee working group found incompatibility of some digital phantoms with commercial systems. Thus, there is still a need to provide further recommendations in terms of compatible digital phantoms, clinical feasible workflow, and achievable thresholds, especially for future clinical trials involving deformable image registration algorithms. Nine institutions participated and evaluated 4 commonly used commercial imaging registration software and various versions in the field of radiation oncology. RESULTS AND CONCLUSIONS: The NRG Oncology Working Group on image registration commissioning herein provides recommendations on the use of digital phantom/data sets and analytical software access for institutions and clinics to perform their own self-study evaluation of commercial imaging systems that might be employed for coregistration in radiation therapy treatment planning and image guidance procedures. Evaluation metrics and their corresponding values were given as guidelines to establish practical tolerances. Vendor compliance for image registration commissioning was evaluated, and recommendations were given for future development.

Offline Quality Assurance for Intensity Modulated Radiation Therapy Treatment Plans for NRG-HN001 Head and Neck Clinical Trial Using Knowledge-Based Planning.

PURPOSE: This study aimed to investigate whether a disease site-specific, multi-institutional knowledge based-planning (KBP) model can improve the quality of intensity modulated radiation therapy treatment planning for patients enrolled in the head and neck NRG-HN001clinical trial and to establish a threshold of improvements of treatment plans submitted to the clinical trial. METHODS AND MATERIALS: Fifty treatment plans for patients enrolled in the NRG-HN001 clinical trial were used to build a KBP model; the model was then used to reoptimize 50 other plans. We compared the dosimetric parameters of the submitted and KBP reoptimized plans. We compared differences between KBP and submitted plans for single- and multi-institutional treatment plans. RESULTS: Mean values for the dose received by 95% of the planning target volume (PTV_6996) and for the maximum dose (D0.03cc) of PTV_6996 were 0.5 Gy and 2.1 Gy higher in KBP plans than in the submitted plans, respectively. Mean values for D0.03cc to the brain stem, spinal cord, optic nerve_R, optic nerve_L, and chiasm were 2.5 Gy, 1.9 Gy, 6.4 Gy, 6.6 Gy, and 5.7 Gy lower in the KBP plans than in the submitted plans. Mean values for Dmean to parotid_R and parotid_L glands were 2.2 Gy and 3.8 Gy lower in KBP plans, respectively. In 33 out of 50 KBP plans, we observed improvements in sparing of at least 7 organs at risk (OARs) (brain stem, spinal cord, optic nerves (R & L), chiasm, and parotid glands [R & L]). A threshold of improvement of OARs sparing of 5% of the prescription dose was established for providing the quality assurance results back to the treating institution. CONCLUSIONS: A disease site-specific, multi-institutional, clinical trial-based KBP model improved sparing of OARs in a large number of reoptimized plans submitted to the NRG-HN001 clinical trial, and the model is being used as an offline quality assurance tool.

Automated Quality Assurance of OAR Contouring for Lung Cancer Based on Segmentation With Deep Active Learning.

Purpose: Ensuring high-quality data for clinical trials in radiotherapy requires the generation of contours that comply with protocol definitions. The current workflow includes a manual review of the submitted contours, which is time-consuming and subjective. In this study, we developed an automated quality assurance (QA) system for lung cancer based on a segmentation model trained with deep active learning. Methods: The data included a gold atlas with 36 cases and 110 cases from the "NRG Oncology/RTOG 1308 Trial". The first 70 cases enrolled to the RTOG 1308 formed the candidate set, and the remaining 40 cases were randomly assigned to validation and test sets (each with 20 cases). The organs-at-risk included the heart, esophagus, spinal cord, and lungs. A preliminary convolutional neural network segmentation model was trained with the gold standard atlas. To address the deficiency of the limited training data, we selected quality images from the candidate set to be added to the training set for fine-tuning of the model with deep active learning. The trained robust segmentation models were used for QA purposes. The segmentation evaluation metrics derived from the validation set, including the Dice and Hausdorff distance, were used to develop the criteria for QA decision making. The performance of the strategy was assessed using the test set. Results: The QA method achieved promising contouring error detection, with the following metrics for the heart, esophagus, spinal cord, left lung, and right lung: balanced accuracy, 0.96, 0.95, 0.96, 0.97, and 0.97, respectively; sensitivity, 0.95, 0.98, 0.96, 1.0, and 1.0, respectively; specificity, 0.98, 0.92, 0.97, 0.94, and 0.94, respectively; and area under the receiving operator characteristic curve, 0.96, 0.95, 0.96, 0.97, and 0.94, respectively. Conclusions: The proposed system automatically detected contour errors for QA. It could provide consistent and objective evaluations with much reduced investigator intervention in multicenter clinical trials.

Comparative Effectiveness of Proton vs Photon Therapy as Part of Concurrent Chemoradiotherapy for Locally Advanced Cancer.

Importance: Concurrent chemoradiotherapy is the standard-of-care curative treatment for many cancers but is associated with substantial morbidity. Concurrent chemoradiotherapy administered with proton therapy might reduce toxicity and achieve comparable cancer control outcomes compared with conventional photon radiotherapy by reducing the radiation dose to normal tissues. Objective: To assess whether proton therapy in the setting of concurrent chemoradiotherapy is associated with fewer 90-day unplanned hospitalizations (Common Terminology Criteria for Adverse Events, version 4 [CTCAEv4], grade ≥3) or other adverse events and similar disease-free and overall survival compared with concurrent photon therapy and chemoradiotherapy. Design, Setting, and Participants: This retrospective, nonrandomized comparative effectiveness study included 1483 adult patients with nonmetastatic, locally advanced cancer treated with concurrent chemoradiotherapy with curative intent from January 1, 2011, through December 31, 2016, at a large academic health system. Three hundred ninety-one patients received proton therapy and 1092, photon therapy. Data were analyzed from October 15, 2018, through February 1, 2019. Interventions: Proton vs photon chemoradiotherapy. Main Outcomes and Measures: The primary end point was 90-day adverse events associated with unplanned hospitalizations (CTCAEv4 grade ≥3). Secondary end points included Eastern Cooperative Oncology Group (ECOG) performance status decline during treatment, 90-day adverse events of at least CTCAEv4 grade 2 that limit instrumental activities of daily living, and disease-free and overall survival. Data on adverse events and survival were gathered prospectively. Modified Poisson regression models with inverse propensity score weighting were used to model adverse event outcomes, and Cox proportional hazards regression models with weighting were used for survival outcomes. Propensity scores were estimated using an ensemble machine-learning approach. Results: Among the 1483 patients included in the analysis (935 men [63.0%]; median age, 62 [range, 18-93] years), those receiving proton therapy were significantly older (median age, 66 [range, 18-93] vs 61 [range, 19-91] years; P < .01), had less favorable Charlson-Deyo comorbidity scores (median, 3.0 vs 2.0; P < .01), and had lower integral radiation dose to tissues outside the target (mean [SD] volume, 14.1 [6.4] vs 19.1 [10.6] cGy/cc × 107; P < .01). Baseline grade ≥2 toxicity (22% vs 24%; P = .37) and ECOG performance status (mean [SD], 0.62 [0.74] vs 0.68 [0.80]; P = .16) were similar between the 2 cohorts. In propensity score weighted-analyses, proton chemoradiotherapy was associated with a significantly lower relative risk of 90-day adverse events of at least grade 3 (0.31; 95% CI, 0.15-0.66; P = .002), 90-day adverse events of at least grade 2 (0.78; 95% CI, 0.65-0.93; P = .006), and decline in performance status during treatment (0.51; 95% CI, 0.37-0.71; P < .001). There was no difference in disease-free or overall survival. Conclusions and Relevance: In this analysis, proton chemoradiotherapy was associated with significantly reduced acute adverse events that caused unplanned hospitalizations, with similar disease-free and overall survival. Prospective trials are warranted to validate these results.

A Deep Learning Model for Predicting Xerostomia Due to Radiation Therapy for Head and Neck Squamous Cell Carcinoma in the RTOG 0522 Clinical Trial.

PURPOSE: Xerostomia commonly occurs in patients who undergo head and neck radiation therapy and can seriously affect patients' quality of life. In this study, we developed a xerostomia prediction model with radiation treatment data using a 3-dimensional (3D) residual convolutional neural network (rCNN). The model can be used to guide radiation therapy to reduce toxicity. METHODS AND MATERIALS: A total of 784 patients with head and neck squamous cell carcinoma enrolled in the Radiation Therapy Oncology Group 0522 clinical trial were included in this study. Late xerostomia is defined as xerostomia of grade ≥2 occurring in the 12th month of radiation therapy. The computed tomography (CT) planning images, 3D dose distributions, and contours of the parotid and submandibular glands were included as 3D rCNN inputs. Comparative experiments were performed for the 3D rCNN model without 1 of the 3 inputs and for the logistic regression model. Accuracy, sensitivity, specificity, F-score, and area under the receiver operator characteristic curve were evaluated. RESULTS: The proposed model achieved promising prediction results. The performance metrics for 3D rCNN model with contour, CT images, and radiation therapy dose; 3D rCNN without contour; 3D rCNN without CT images; 3D rCNN without the dose; logistic regression with the dose and clinical parameters; and logistic regression without clinical parameters were as follows: accuracy: 0.76, 0.74, 0.73, 0.65, 0.64, and 0.56; sensitivity: 0.76, 0.72, 0.77, 0.59, 0.72, and 0.75; specificity: 0.76, 0.76, 0.71, 0.69, 0.59, and 0.43; F-score: 0.70, 0.68, 0.69, 0.56, 0.60, and 0.57; and area under the receiver operator characteristic curve: 0.84, 0.82, 0.78, 0.70, 0.74, and 0.68, respectively. CONCLUSIONS: The proposed model uses 3D rCNN filters to extract low- and high-level spatial features and to achieve promising performance. This is a potentially effective model for predicting objective toxicity for supporting clinical decision making.

A study of positioning orientation effect on segmentation accuracy using convolutional neural networks for rectal cancer.

PURPOSE: Convolutional neural networks (CNN) have greatly improved medical image segmentation. A robust model requires training data can represent the entire dataset. One of the differing characteristics comes from variability in patient positioning (prone or supine) for radiotherapy. In this study, we investigated the effect of position orientation on segmentation using CNN. METHODS: Data of 100 patients (50 in supine and 50 in prone) with rectal cancer were collected for this study. We designed three sets of experiments for comparison: (a) segmentation using the model trained with data from the same orientation; (b) segmentation using the model trained with data from the opposite orientation; (c) segmentation using the model trained with data from both orientations. We performed fivefold cross-validation. The performance was evaluated on segmentation of the clinical target volume (CTV), bladder, and femurs with Dice similarity coefficient (DSC) and Hausdorff distance (HD). RESULTS: Compared with models trained on cases positioned in the same orientation, the models trained with cases positioned in the opposite orientation performed significantly worse (P < 0.05) on CTV and bladder segmentation, but had comparable accuracy for femurs (P > 0.05). The average DSC values were 0.74 vs 0.84, 0.85 vs 0.88, and 0.91 vs 0.91 for CTV, bladder, and femurs, respectively. The corresponding HD values (mm) were 16.6 vs 14.6, 8.4 vs 8.1, and 6.3 vs 6.3, respectively. The models trained with data from both orientations have comparable accuracy (P > 0.05), with average DSC of 0.84, 0.88, and 0.91 and HD of 14.4, 8.1, and 6.3, respectively. CONCLUSIONS: Orientation affects the accuracy for CTV and bladder, but has negligible effect on the femurs. The model trained from data combining both orientations performs as well as a model trained with data from the same orientation for all the organs. These observations can offer guidance on the choice of training data for accurate segmentation.

Technical Note: More accurate and efficient segmentation of organs-at-risk in radiotherapy with convolutional neural networks cascades.

PURPOSE: Manual delineation of organs-at-risk (OARs) in radiotherapy is both time-consuming and subjective. Automated and more accurate segmentation is of the utmost importance in clinical application. The purpose of this study is to further improve the segmentation accuracy and efficiency with a novel network named convolutional neural networks (CNN) Cascades. METHODS: CNN Cascades was a two-step, coarse-to-fine approach that consisted of a simple region detector (SRD) and a fine segmentation unit (FSU). The SRD first used a relative shallow network to define the region of interest (ROI) where the organ was located, and then, the FSU took the smaller ROI as input and adopted a deep network for fine segmentation. The imaging data (14,651 slices) of 100 head-and-neck patients with segmentations were used for this study. The performance was compared with the state-of-the-art single CNN in terms of accuracy with metrics of Dice similarity coefficient (DSC) and Hausdorff distance (HD) values. RESULTS: The proposed CNN Cascades outperformed the single CNN on accuracy for each OAR. Similarly, for the average of all OARs, it was also the best with mean DSC of 0.90 (SRD: 0.86, FSU: 0.87, and U-Net: 0.85) and the mean HD of 3.0 mm (SRD: 4.0, FSU: 3.6, and U-Net: 4.4). Meanwhile, the CNN Cascades reduced the mean segmentation time per patient by 48% (FSU) and 5% (U-Net), respectively. CONCLUSIONS: The proposed two-step network demonstrated superior performance by reducing the input region. This potentially can be an effective segmentation method that provides accurate and consistent delineation with reduced clinician interventions for clinical applications as well as for quality assurance of a multicenter clinical trial.

NCTN clinical trial standardization for radiotherapy through IROC and CIRO.

Evidence-based practice is the cornerstone of modern medicine. Randomized clinical trials across multiple institutions are the gold standard for modern evidence collection. National Cancer Trials Network (NCTN) instruments the clinical trials through the new infrastructure for improvements in cancer treatment. Radiation therapy is an integral component of cancer treatment and is involved in many of the NCTN clinical trials. Radiotherapy is experiencing exciting developments in new treatment modalities and multi-modality image guidance. One of NCTN network groups NRG Oncology brings together the research areas of the National Surgical Adjuvant Breast and Bowel Project (NSABP), the Radiation Therapy Oncology Group (RTOG), and the Gynecologic Oncology Group (GOG). The Imaging and Radiation Oncology Core (IROC) and Center for Innovation in Radiation Oncology(CIRO) of NRG Oncology complement each other's functions in development and implementation of the new radiotherapy and imaging technologies in clinical trials with standardization and other strategies for quality. The standardization process is the essential step to make the data collected for clinical trials of high quality, interoperable, and reusable.

Cascaded atrous convolution and spatial pyramid pooling for more accurate tumor target segmentation for rectal cancer radiotherapy.

Convolutional neural networks (CNNs) have become the state-of-the-art method for medical segmentation. However, repeated pooling and striding operations reduce the feature resolution, causing loss of detailed information. Additionally, tumors of different patients are of different sizes. Thus, small tumors may be ignored while big tumors may exceed the receptive fields of convolutions. The purpose of this study is to further improve the segmentation accuracy using a novel CNN (named CAC-SPP) with cascaded atrous convolution (CAC) and a spatial pyramid pooling (SPP) module. This work is the first attempt at applying SPP for segmentation in radiotherapy. We improved the network based on ResNet-101 yielding accuracy gains from a greatly increased depth. We added CAC to extract a high-resolution feature map while maintaining large receptive fields. We also adopted a parallel SPP module with different atrous rates to capture the multi-scale features. The performance was compared with the widely adopted U-Net and ResNet-101 with independent segmentation of rectal tumors for two image sets, separately: (1) 70 T2-weighted MR images and (2) 100 planning CT images. The results show that the proposed CAC-SPP outperformed the U-Net and ResNet-101 for both image sets. The Dice similarity coefficient values of CAC-SPP were 0.78 ± 0.08 and 0.85 ± 0.03, respectively, which were higher than those of U-Net (0.70 ± 0.11 and 0.82 ± 0.04) and ResNet-101 (0.76 ± 0.10 and 0.84 ± 0.03). The segmentation speed of CAC-SPP was comparable with ResNet-101, but about 36% faster than U-Net. In conclusion, the proposed CAC-SPP, which could extract high-resolution features with large receptive fields and capture multi-scale context yields, improves the accuracy of segmentation performance for rectal tumors.

Improving Quality and Consistency in NRG Oncology Radiation Therapy Oncology Group 0631 for Spine Radiosurgery via Knowledge-Based Planning.

PURPOSE: To use knowledge-based planning (KBP) as a method of producing high-quality, consistent, protocol-compliant treatment plans in a complex setting of spine stereotactic body radiation therapy on NRG Oncology Radiation Therapy Oncology Group (RTOG) 0631. METHODS AND MATERIALS: An internally developed KBP model was applied to an external validation cohort of 22 anonymized cases submitted under NRG Oncology RTOG 0631. The original and KBP plans were compared via their protocol compliance, target conformity and gradient index, dose to critical structures, and dose to surrounding normal tissues. RESULTS: The KBP model generated plans meeting all protocol objectives in a single optimization when tested on both internal and protocol-submitted NRG Oncology RTOG 0631 cases. Two submitted plans that were considered to have a protocol-unacceptable deviation were made protocol compliant through the use of the model. There were no statistically significant differences in protocol spinal cord metrics (D10% and D0.03cc) between the manually optimized plans and the KBP plans. The volume of planning target volume receiving prescription dose increased from 93.3% ± 3.2% to 98.3% ± 1.4% (P = .01) when using KBP. High-dose spillage to surrounding normal tissues (V105%) showed no significant differences (2.1 ± 7.3 cm3 for manual plans to 1.8 ± 0.6 cm3 with KBP), and dosimetric outliers with large amounts of spillage were eliminated through the use of KBP. Knowledge-based planning plans were also found to be significantly more consistent in several metrics, including target coverage and high dose outside of the target. CONCLUSION: Incorporation of KBP models into the clinical trial setting may have a profound impact on the quality of trial results, owing to the increase in consistency and standardization of planning, especially for treatment sites or techniques that are nonstandard.

A carbon nanotube field emission cathode with high current density and long-term stability.

Carbon nanotube (CNT) field emitters are now being evaluated for a wide range of vacuum electronic applications. However, problems including short lifetime at high current density, instability under high voltage, poor emission uniformity, and pixel-to-pixel inconsistency are still major obstacles for device applications. We developed an electrophoretic process to fabricate composite CNT films with controlled nanotube orientation and surface density, and enhanced adhesion. The cathodes have significantly enhanced macroscopic field emission current density and long-term stability under high operating voltages. The application of this CNT electron source for high-resolution x-ray imaging is demonstrated.