Breast Cancer Radiation Therapy and the Risk of Acute Coronary Events: Insights From a Process-Oriented Model.

PURPOSE: Acute coronary events (ACEs) are considered the most important side effect of radiation therapy (RT) for breast cancer, but underlying mechanisms still have to be identified. Process-oriented models mathematically describe the development of disease and provide a link between mechanisms and subsequent risk. Here, this link is exploited to learn about the underlying mechanisms from the observed age-time patterns of ACE risk. METHODS AND MATERIALS: A process-oriented model of atherosclerosis and subsequent ACEs was applied to a contemporary breast cancer cohort of 810 patients with measurements of coronary artery calcification. Patients with prior ischemic heart disease were excluded. The process-oriented model describes disease development as a series of different stages. Different variants of the model were fitted to the data. In each variant, one stage was assumed to be accelerated in relation to mean heart dose. RESULTS: During a mean follow-up of 9.1 years, 25 ACEs occurred. The model reproduced the prevalence and associated risk of coronary calcifications. Mean heart dose significantly improved the fit only when implemented as affecting a late stage of atherosclerosis on already-existing complicated lesions (achieving P = .007). This can be understood by atherosclerosis being a slowly progressing disease. Therefore, an increase in ACEs a few years after RT requires advanced atherosclerosis at the time of RT. CONCLUSIONS: Risk of ACE increases within a few years in patients with advanced atherosclerosis at RT. Therefore, patients should be assessed for cardiovascular risk, and older patients need to be considered for heart-sparing techniques.

Validation of separate multi-atlases for auto segmentation of cardiac substructures in CT-scans acquired in deep inspiration breath hold and free breathing.

BACKGROUND AND PURPOSE: Developing NTCP-models for cardiac complications after breast cancer (BC) radiotherapy requires cardiac dose-volume parameters for many patients. These can be obtained by using multi-atlas based automatic segmentation (MABAS) of cardiac structures in planning CT scans. We investigated the relevance of separate multi-atlases for deep inspiration breath hold (DIBH) and free breathing (FB) CT scans. MATERIALS AND METHODS: BC patients scanned in DIBH (n = 10) and in FB (n = 20) were selected to create separate multi-atlases consisting of expert panel delineations of the whole heart, atria and ventricles. The accuracy of atlas-generated contours was validated with expert delineations in independent datasets (n = 10 for DIBH and FB) and reported as Dice coefficients, contour distances and dose-volume differences in relation to interobserver variability of manual contours. Dependency of MABAS contouring accuracy on breathing technique was assessed by validation of a FB atlas in DIBH patients and vice versa (cross-validation). RESULTS: For all structures the FB and DIBH atlases resulted in Dice coefficients with their respective reference contours ≥ 0.8 and average contour distances ≤ 2 mm smaller than slice thickness of (CTs). No significant differences were found for dose-volume parameters in volumes receiving relevant dose levels (WH, LV and RV). Accuracy of the DIBH atlas was at least similar to, and for the ventricles better than, the interobserver variation in manual delineation. Cross-validation between breathing techniques showed a reduced MABAS performance. CONCLUSION: Multi-atlas accuracy was at least similar to interobserver delineation variation. Separate atlases for scans made in DIBH and FB could benefit atlas performance because accuracy depends on breathing technique.

The Importance of Radiation Dose to the Atherosclerotic Plaque in the Left Anterior Descending Coronary Artery for Radiation-Induced Cardiac Toxicity of Breast Cancer Patients?

PURPOSE: Radiation-induced acute coronary events (ACEs) may occur as a treatment-related late adverse effect of breast cancer (BC) radiation. However, the underlying mechanisms behind this radiation-induced cardiac disease remain to be determined. The objective of this study was to test the hypothesis that radiation dose to calcified atherosclerotic plaques in the left anterior descending coronary artery (LAD) is a better predictor for ACEs than radiation dose to the whole heart or left ventricle in patients with BC treated with radiation therapy. METHODS AND MATERIALS: The study cohort consisted of 910 patients with BC treated with postoperative radiation therapy after breast-conserving surgery. In total, 163 patients had an atherosclerotic plaque in the LAD. The endpoint was the occurrence of an ACE after treatment. For each individual patient, the mean heart dose, volume of the left ventricle receiving ≥5 Gy (LV-V5), mean LAD dose, and mean dose to calcified atherosclerotic plaques in the LAD, if present, were acquired based on planning computed tomography scans. Cox regression analysis was used to analyze the effects on the cumulative incidence of ACEs. RESULTS: The median follow-up time was 9.2 years (range, 0.1-14.3 years). In total, 38 patients (4.2%) developed an ACE during follow-up. For patients with an atherosclerotic plaque (n = 163), the mean dose to the atherosclerotic plaque was the strongest predictor for ACEs, even after correction for cardiovascular risk factors (hazard ratio [HR], 1.269; 95% CI, 1.090-1.477; P = .002). The LV-V5 was associated with ACEs in patients without atherosclerotic plaques in the LAD (n = 680) (HR, 1.021; 95% CI, 1.003-1.039; P = .023). CONCLUSIONS: The results of this study suggest that radiation dose to pre-existing calcified atherosclerotic plaques in the LAD is strongly associated with the development of ACEs in patients with BC.

Development and evaluation of an auto-segmentation tool for the left anterior descending coronary artery of breast cancer patients based on anatomical landmarks.

This study describes the development and evaluation of an auto-segmentation tool for the left anterior descending coronary artery (LAD), on non-contrast planning computed tomography scans of breast cancer patients. The dosimetric parameters of the auto-segmented LAD contours are highly correlated with those of manual contours (R2-values ≥0.89).

Cardiac Function After Radiation Therapy for Breast Cancer.

PURPOSE: The main purpose of this study was to test the hypothesis that incidental cardiac irradiation is associated with changes in cardiac function in breast cancer (BC) survivors treated with radiation therapy (RT). METHODS AND MATERIALS: We conducted a cross-sectional study consisting of 109 BC survivors treated with RT between 2005 and 2011. The endpoint was cardiac function, assessed by echocardiography. Systolic function was assessed with the left ventricular ejection fraction (LVEF) (n = 107) and the global longitudinal strain (GLS) of the left ventricle (LV) (n = 52). LV diastolic dysfunction (n = 109) was defined by e' at the lateral and septal region, which represents the relaxation velocity of the myocardium. The individual calculated RT dose parameters of the LV and coronary arteries were collected from 3-dimensional computed tomography-based planning data. Univariable and multivariable analysis using forward selection was performed to identify the best predictors of cardiac function. Robustness of selection was assessed using bootstrapping. The resulting multivariable linear regression model was presented for the endpoints of systolic and diastolic function. RESULTS: The median time between BC diagnosis and echocardiography was 7 years. No relation between RT dose parameters and LVEF was found. In the multivariable analysis for the endpoint GLS of the LV, the maximum dose to the left main coronary artery was most often selected across bootstrap samples. For decreased diastolic function, the most often selected model across bootstrap samples included age at time of BC diagnosis and hypertension at baseline. Cardiac dose-volume histogram parameters were less frequently selected for this endpoint. CONCLUSIONS: This study shows an association between individual cardiac dose distributions and GLS of the LV after RT for BC. No relation between RT dose parameters and LVEF was found. Diastolic function was most associated with age and hypertension at time of BC diagnosis. Further research is needed to make definitive conclusions.

Is the coronary artery calcium score associated with acute coronary events in breast cancer patients treated with radiotherapy?

BACKGROUND AND PURPOSE: The main objective of this study was to test whether pre-treatment coronary artery calcium (CAC) was associated with the cumulative incidence of acute coronary events (ACE) among breast cancer (BC) patients treated with postoperative radiotherapy (RT). MATERIAL AND METHODS: The study population consisted of 939 consecutive female BC patients treated with RT. The association between CAC and ACE was tested using Cox-proportional hazard models. Known risk factors for ACE and the mean heart dose (MHD), collected from three-dimensional computed tomography planning data, were tested for confounding. RESULTS: CAC scores varied from 0 to 2,859 (mean 27.3). The 9-year cumulative incidence of ACE was 3.2%, this was significantly associated with the pre-treatment CAC score. After correction for confounders, age, history of ischemic heart disease, diabetes, Body Mass Index ≥30, MHD, hypercholesterolemia and hypertension, the hazard ratio for ACE for the low and the combined intermediate and high CAC score category were 1.42 (95%CI: 0.49-4.17; p = 0.519) and 4.95 (95%CI: 1.69-14.53; p = 0.004) respectively, compared to the CAC zero category. CONCLUSIONS: High pre-treatment CAC is associated with ACE in BC patients treated with postoperative RT, even after correction for confounding factors such as MHD.

Validation and Modification of a Prediction Model for Acute Cardiac Events in Patients With Breast Cancer Treated With Radiotherapy Based on Three-Dimensional Dose Distributions to Cardiac Substructures.

Purpose A relationship between mean heart dose (MHD) and acute coronary event (ACE) rate was reported in a study of patients with breast cancer (BC). The main objective of our cohort study was to validate this relationship and investigate if other dose-distribution parameters are better predictors for ACEs than MHD. Patients and Methods The cohort consisted of 910 consecutive female patients with BC treated with radiotherapy (RT) after breast-conserving surgery. The primary end point was cumulative incidence of ACEs within 9 years of follow-up. Both MHD and various dose-distribution parameters of the cardiac substructures were collected from three-dimensional computed tomography planning data. Results The median MHD was 2.37 Gy (range, 0.51 to 15.25 Gy). The median follow-up time was 7.6 years (range, 0.1 to 10.1 years), during which 30 patients experienced an ACE. The cumulative incidence of ACE increased by 16.5% per Gy (95% CI, 0.6 to 35.0; P = .042). Analysis showed that the volume of the left ventricle receiving 5 Gy (LV-V5) was the most important prognostic dose-volume parameter. The most optimal multivariable normal tissue complication probability model for ACEs consisted of LV-V5, age, and weighted ACE risk score per patient (c-statistic, 0.83; 95% CI, 0.75 to 0.91). Conclusion A significant dose-effect relationship was found for ACEs within 9 years after RT. Using MHD, the relative increase per Gy was similar to that reported in the previous study. In addition, LV-V5 seemed to be a better predictor for ACEs than MHD. This study confirms the importance of reducing exposure of the heart to radiation to avoid excess risk of ACEs after radiotherapy for BC.

Diagnosing perforated appendicitis in pediatric patients: a new model.

OBJECTIVE: Studies have investigated sensitivity and specificity of symptoms and tests for diagnosing appendicitis in children. Less is known with regard to the predictive value of these symptoms and tests with respect to the severity of appendicitis. The aim of this study was to determine the predictive value of patient's characteristics and tests for discriminating between perforated and nonperforated appendicitis in children. PATIENTS AND METHODS: Pediatric patients who underwent an appendectomy at Spaarne Hospital Hoofddorp, the Netherlands, between January 1, 2009 and December 31, 2013, were included. Baseline patient's characteristics, history, physical examination, laboratory data and results of ultrasounds were collected. Univariate and multivariate logistic regressions were used to determine predictors of perforation. RESULTS: In total, 375 patients were included in this study of which 97 children (25.9%) had significant signs of perforation. Univariate analysis showed that age, duration of complaints, temperature, vomiting, CRP, WBC, different findings on ultrasound and the diameter of the appendix were good predictors of a perforated appendicitis. The final multivariate prediction model included temperature, CRP, clearly visible appendix and free fluids on ultrasound and diameter of the appendix and resulted in an area under the curve (AUC) of 0.91 showing sensitivity and specificity of respectively 85.2% and 81.2%. CONCLUSION: This prediction model can be used for identification of 'high-risk' children for a perforated appendicitis and might be helpful to prevent complications and longer hospitalization by bringing these children to theater earlier.