Bragatston study protocol: a multicentre cohort study on automated quantification of cardiovascular calcifications on radiotherapy planning CT scans for cardiovascular risk prediction in patients with breast cancer

Introduction Cardiovascular disease (CVD) is an important cause of death in breast cancer survivors. Some breast cancer treatments including anthracyclines, trastuzumab and radiotherapy can increase the risk of CVD, especially for patients with pre-existing CVD risk factors. Early identification of patients at increased CVD risk may allow switching to less cardiotoxic treatments, active surveillance or treatment of CVD risk factors. One of the strongest independent CVD risk factors is the presence and extent of coronary artery calcifications (CAC). In clinical practice, CAC are generally quantified on ECGtriggered cardiac CT scans. Patients with breast cancer treated with radiotherapy routinely undergo radiotherapy planning CT scans of the chest, and those scans could provide the opportunity to routinely assess CAC before a potentially cardiotoxic treatment. The Bragatston study aims to investigate the association between calcifications in the coronary arteries, aorta and heart valves (hereinafter called ‘cardiovascular calcifications’) measured automatically on planning CT scans of patients with breast cancer and CVD risk. Methods and analysis In a first step, we will optimise and validate a deep learning algorithm for automated quantification of cardiovascular calcifications on planning CT scans of patients with breast cancer. Then, in a multicentre cohort study (University Medical Center Utrecht, Utrecht, Erasmus MC Cancer Institute, Rotterdam and Radboudumc, Nijmegen, The Netherlands), the association between cardiovascular calcifications measured on planning CT scans of patients with breast cancer (n≈16 000) and incident (non-)fatal CVD events will be evaluated. To assess the added predictive value of these calcifications over traditional CVD risk factors and treatment characteristics, a case-cohort analysis will be performed among all cohort members diagnosed with a CVD event during follow-up (n≈200) and a random sample of the baseline cohort (n≈600). Ethics and dissemination The Institutional Review Boards of the participating hospitals decided that the Medical R

Learning coronary artery calcium scoring in coronary CTA from non-contrast CT using unsupervised domain adaptation

Deep learning methods have demonstrated the ability to perform accurate coronary artery calcium (CAC) scoring. However, these methods require large and representative training data hampering applicability to diverse CT scans showing the heart and the coronary arteries. Training methods that accurately score CAC in cross-domain settings remains challenging. To address this, we present an unsupervised domain adaptation method that learns to perform CAC scoring in coronary CT angiography (CCTA) from non-contrast CT (NCCT). To address the domain shift between NCCT (source) domain and CCTA (target) domain, feature distributions are aligned between two domains using adversarial learning. A CAC scoring convolutional neural network is divided into a feature generator that maps input images to features in the latent space and a classifier that estimates predictions from the extracted features. For adversarial learning, a discriminator is used to distinguish the features between source and target domains. Hence, the feature generator aims to extract features with aligned distributions to fool the discriminator. The network is trained with adversarial loss as the objective function and a classification loss on the source domain as a constraint for adversarial learning. In the experiments, three data sets were used. The network is trained with 1,687 labeled chest NCCT scans from the National Lung Screening Trial. Furthermore, 200 labeled cardiac NCCT scans and 200 unlabeled CCTA scans were used to train the generator and the discriminator for unsupervised domain adaptation. Finally, a data set containing 313 manually labeled CCTA scans was used for testing. Directly applying the CAC scoring network trained on NCCT to CCTA led to a sensitivity of 0.41 and an average false positive volume 140 mm3/scan. The proposed method improved the sensitivity to 0.80 and reduced average false positive volume of 20 mm3/scan. The results indicate that the unsupervised domain adaptation approach enables automatic CAC scoring in contrast enhanced CT while learning from a large and diverse set of CT scans without contrast. This may allow for better utilization of existing annotated data sets and extend the applicability of automatic CAC scoring to contrast-enhanced CT scans without the need for additional manual annotations. The code is publicly available at https://github.com/qurAI-amsterdam/CACscoringUsingDomainAdaptation

AI-Based Quantification of Planned Radiation Therapy Dose to Cardiac Structures and Coronary Arteries in Patients With Breast Cancer

Purpose: The purpose of this work is to develop and evaluate an automatic deep learning method for segmentation of cardiac chambers and large arteries, and localization of the 3 main coronary arteries in radiation therapy planning on computed tomography (CT). In addition, a second purpose is to determine the planned radiation therapy dose to cardiac structures for breast cancer therapy. Methods and Materials: Eighteen contrast-enhanced cardiac scans acquired with a dual-layer-detector CT scanner were included for method development. Manual reference annotations of cardiac chambers, large arteries, and coronary artery locations were made in the contrast scans and transferred to virtual noncontrast images, mimicking noncontrast-enhanced CT. In addition, 31 noncontrast-enhanced radiation therapy treatment planning CTs with corresponding dose-distribution maps of breast cancer cases were included for evaluation. For reference, cardiac chambers and large vessels were manually annotated in two 2-dimensional (2D) slices per scan (26 scans, totaling 52 slices) and in 3-dimensional (3D) scan volumes in 5 scans. Coronary artery locations were annotated on 3D imaging. The method uses an ensemble of convolutional neural networks with 2 output branches that perform 2 distinct tasks: (1) segmentation of the cardiac chambers and large arteries and (2) localization of coronary arteries. Training was performed using reference annotations and virtual noncontrast cardiac scans. Automatic segmentation of the cardiac chambers and large vessels and the coronary artery locations was evaluated in radiation therapy planning CT with Dice score (DSC) and average symmetrical surface distance (ASSD). The correlation between dosimetric parameters derived from the automatic and reference segmentations was evaluated with R2. Results: For cardiac chambers and large arteries, median DSC was 0.76 to 0.88, and the median ASSD was 0.17 to 0.27 cm in 2D slice evaluation. 3D evaluation found a DSC of 0.87 to 0.93 and an ASSD of 0.07 to 0.10 cm. Median DSC of the coronary artery locations ranged from 0.80 to 0.91. R2 values of dosimetric parameters were 0.77 to 1.00 for the cardiac chambers and large vessels, and 0.76 to 0.95 for the coronary arteries. Conclusions: The developed and evaluated method can automatically obtain accurate estimates of planned radiation dose and dosimetric parameters for the cardiac chambers, large arteries, and coronary arteries

AI-Based Radiation Dose Quantification for Estimation of Heart Disease Risk in Breast Cancer Survivors After Radiation Therapy

Purpose: To investigate whether the dose planned for cardiac structures is associated with the risk of heart disease (HD) in patients with breast cancer treated with radiation therapy, and whether this association is modified by the presence of coronary artery calcification (CAC). Methods and Materials: Radiation therapy planning computed tomographic (CT) scans and corresponding dose distribution maps of 5561 patients were collected, 5300 patients remained after the exclusion of ineligible patients and duplicates; 1899 patients received their CT scan before 2011, allowing long follow-up. CAC was detected automatically. Using an artificial intelligence–based method, the cardiac structures (heart, cardiac chambers, large arteries, 3 main coronary arteries) were segmented. The planned radiation dose to each structure separately and to the whole heart were determined. Patients were assigned to a low-, medium-, or high-dose group based on the dose to the respective heart structure. Information on HD hospitalization and mortality was obtained for each patient. The association of planned radiation dose to cardiac structures with risk of HD was investigated in patients with and without CAC using Cox proportional hazard analysis in the long follow-up population. Tests for interaction were performed. Results: After a median follow-up of 96.0 months (interquartile range, 84.2-110.4 months) in the long follow-up group, 135 patients were hospitalized for HD or died of HD. If the dose to a structure increased 1 Gy, the relative HD risk increased by 3% to 11%. The absolute increase in HD risk was substantially higher in patients with CAC (event-ratelow-dose = 14-15 vs event-ratehigh-dose = 15-34 per 1000 person-years) than in patients without CAC (event-ratelow-dose = 6-8 vs event-ratehigh-dose = 5-17 per 1000 person-years). No interaction between CAC and radiation dose was found. Conclusions: Radiation exposure of cardiac structures is associated with increased risk of HD. Automatic segmentation of cardiac structures enables spatially localized dose estimation, which can aid in the prevention of radiation therapy–induced cardiac damage. This could be especially valuable in patients with breast cancer and CAC

Coronary artery calcifications on breast cancer radiotherapy planning CT scans and cardiovascular risk: What do patients want to know?

Background: Coronary artery calcifications (CAC) is a strong predictor of cardiovascular disease (CVD), which can be automatically quantified on routine breast radiotherapy planning computed tomography (CT) scans. Around 8% of patients have (very) high CAC scores and corresponding increased risks of CVD. Aim: This study explores whether, how, and under what conditions women with breast cancer want to be informed about their CAC-based CVD risk. Methods: A cross-sectional survey study was conducted in a random sample of UMBRELLA, a prospective breast cancer cohort. Participants (n = 79) filled out a questionnaire about their knowledge on the CVD risk following breast cancer, their interest in being informed about their CVD risk based on CAC score, and preferences on how they would want to receive this information. Results: Most participants (66%) were not aware that the presence of CAC indicates an increased CVD risk. Participants indicated that they were not or only slightly aware of the risk of treatment-induced cardiotoxicity (48%), and that the risk of cardiotoxicity was higher in patients with pre-existing CVD risk factors (82%). The vast majority (90%) indicated that they want to be informed about in increased CAC-based CVD risk. Conclusions: The majority of patients with breast cancer wants to be informed about their CAC-based CVD risk. With the majority of patients with breast cancer undergoing radiotherapy, and with low cost and automated options for accurate CAC measurement in planning CT scans, it is important to develop strategies to manage patients with an increased CAC-based risk of CVD

Bragatston study protocol: a multicentre cohort study on automated quantification of cardiovascular calcifications on radiotherapy planning CT scans for cardiovascular risk prediction in patients with breast cancer

Contains fulltext : 208554.pdf (publisher's version ) (Open Access)INTRODUCTION: Cardiovascular disease (CVD) is an important cause of death in breast cancer survivors. Some breast cancer treatments including anthracyclines, trastuzumab and radiotherapy can increase the risk of CVD, especially for patients with pre-existing CVD risk factors. Early identification of patients at increased CVD risk may allow switching to less cardiotoxic treatments, active surveillance or treatment of CVD risk factors. One of the strongest independent CVD risk factors is the presence and extent of coronary artery calcifications (CAC). In clinical practice, CAC are generally quantified on ECG-triggered cardiac CT scans. Patients with breast cancer treated with radiotherapy routinely undergo radiotherapy planning CT scans of the chest, and those scans could provide the opportunity to routinely assess CAC before a potentially cardiotoxic treatment. The Bragatston study aims to investigate the association between calcifications in the coronary arteries, aorta and heart valves (hereinafter called 'cardiovascular calcifications') measured automatically on planning CT scans of patients with breast cancer and CVD risk. METHODS AND ANALYSIS: In a first step, we will optimise and validate a deep learning algorithm for automated quantification of cardiovascular calcifications on planning CT scans of patients with breast cancer. Then, in a multicentre cohort study (University Medical Center Utrecht, Utrecht, Erasmus MC Cancer Institute, Rotterdam and Radboudumc, Nijmegen, The Netherlands), the association between cardiovascular calcifications measured on planning CT scans of patients with breast cancer (n approximately 16 000) and incident (non-)fatal CVD events will be evaluated. To assess the added predictive value of these calcifications over traditional CVD risk factors and treatment characteristics, a case-cohort analysis will be performed among all cohort members diagnosed with a CVD event during follow-up (n approximately 200) and a random sample of the baseline cohort (n approximately 600). ETHICS AND DISSEMINATION: The Institutional Review Boards of the participating hospitals decided that the Medical Research Involving Human Subjects Act does not apply. Findings will be published in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: NCT03206333

Identification of Risk of Cardiovascular Disease by Automatic Quantification of Coronary Artery Calcifications on Radiotherapy Planning CT Scans in Patients With Breast Cancer

Importance: Cardiovascular disease (CVD) is common in patients treated for breast cancer, especially in patients treated with systemic treatment and radiotherapy and in those with preexisting CVD risk factors. Coronary artery calcium (CAC), a strong independent CVD risk factor, can be automatically quantified on radiotherapy planning computed tomography (CT) scans and may help identify patients at increased CVD risk. Objective: To evaluate the association of CAC with CVD and coronary artery disease (CAD) in patients with breast cancer. Design, Setting, and Participants: In this multicenter cohort study of 15915 patients with breast cancer receiving radiotherapy between 2005 and 2016 who were followed until December 31, 2018, age, calendar year, and treatment-adjusted Cox proportional hazard models were used to evaluate the association of CAC with CVD and CAD. Exposures: Overall CAC scores were automatically extracted from planning CT scans using a deep learning algorithm. Patients were classified into Agatston risk categories (0, 1-10, 11-100, 101-399, >400 units). Main Outcomes and Measures: Occurrence of fatal and nonfatal CVD and CAD were obtained from national registries. Results: Of the 15915 participants included in this study, the mean (SD) age at CT scan was 59.0 (11.2; range, 22-95) years, and 15879 (99.8%) were women. Seventy percent (n = 11179) had no CAC. Coronary artery calcium scores of 1 to 10, 11 to 100, 101 to 400, and greater than 400 were present in 10.0% (n = 1584), 11.5% (n = 1825), 5.2% (n = 830), and 3.1% (n = 497) respectively. After a median follow-up of 51.2 months, CVD risks increased from 5.2% in patients with no CAC to 28.2% in patients with CAC scores higher than 400. After adjustment, CVD risk increased with higher CAC score (hazard ratio [HR]CAC = 1-10 = 1.1; 95% CI, 0.9-1.4; HRCAC = 11-100 = 1.8; 95% CI, 1.5-2.1; HRCAC = 101-400 = 2.1; 95% CI, 1.7-2.6; and HRCAC>400 = 3.4; 95% CI, 2.8-4.2). Coronary artery calcium was particularly strongly associated with CAD (HRCAC>400 = 7.8; 95% CI, 5.5-11.2). The association between CAC and CVD was strongest in patients treated with anthracyclines (HRCAC>400 = 5.8; 95% CI, 3.0-11.4) and patients who received a radiation boost (HRCAC>400 = 6.1; 95% CI, 3.8-9.7). Conclusions and Relevance: This cohort study found that coronary artery calcium on breast cancer radiotherapy planning CT scan results was associated with CVD, especially CAD. Automated CAC scoring on radiotherapy planning CT scans may be used as a fast and low-cost tool to identify patients with breast cancer at increased risk of CVD, allowing implementing CVD risk-mitigating strategies with the aim to reduce the risk of CVD burden after breast cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT03206333