br The left ventricular ejection fraction
The left ventricular ejection fraction (LVEF) by echo-cardiography is the cornerstone of LV systolic function assessment in clinical practice. However, LVEF can un-derestimate actual cardiac damage because of the compensatory reserve of the myocardium that enables adequate ventricular outcome even in the presence of dysfunctional myocytes.7 Global longitudinal systolic strain (GLS) is an echocardiographic technique that detects and quantifies subclinical and subtle disturbances in LV systolic function and can thus be considered as an early marker for radiation-induced cardiac damage.8 This is particularly relevant because the latency time for symp-tomatic radiation-induced cardiovascular diseases is rela-tively long. These early markers may be helpful to identify patients at risk for major cardiac events who may benefit from preventive strategies.
The aim of this study was to assess the relationship between radiation dose to the LV and radiation dose to the coronary Riboflavin phosphate and LV systolic and diastolic function in BC survivors treated with RT based on individual planned 3-dimensional (3D) dose distributions and computed to-mography (CT) information.
Methods and Materials
The Department of General Practice of the University Medical Center Groningen (UMCG) performed a cross-sectional, population-based study to assess the frequency of cardiac dysfunction in female BC survivors in a primary care setting.9 Patients were included if they received a diagnosis of BC stage I to III and had no disease activity for at least 5 years after treatment. Information could be extracted from electronic patient records of 1 of 80 participating primary care physi-cians (PCPs) in the northern Netherlands region. Patients were excluded if they had metastatic disease at the time of BC diagnosis, had a history of other malignancies, or received prior chemotherapy or RT treatment of other malignancies. The main study included 350 BC survivors treated from 1988 to 2011. All 350 patients underwent echocardiography. Because of the inclusion criteria of the main study with the date of treatment mostly in the pre-CT era, patients were only selected when CT-based RT treatment planning data were available. Therefore, our total study population was composed of 109 BC survivors treated with RT from 2005 to 2011.
All patients were treated with breast-conserving surgery followed by adjuvant RT. Patients with node-positive dis-ease and patients who were high risk and node negative were treated with adjuvant systemic treatment including endocrine therapy, according to the national guidelines.
Citizens of the Netherlands are registered in an electronic record of a PCP. The PCP captures all information
394 van den Bogaard et al. International Journal of Radiation Oncology Biology Physics
according to the International Classification of Primary Care.10 Relevant data were collected using the International Classification of Primary Care codes for cardiovascular risk factors (dyslipidemia, hypertension, and diabetes mellitus) and cardiovascular disease (heart failure, ischemic heart disease, acute myocardial infarction, coronary artery scle-rosis, atrial fibrillation, [supra]ventricular tachycardia, and nonrheumatic valve disease).
Detailed information about patient characteristics, tumor characteristics, systemic BC therapy (including chemo-therapy, endocrine therapy, or Trastuzumab), and follow-up data were retrieved from hospital charts. The baseline date was defined as the date of BC diagnosis. The censoring date was defined as the date of the echocardiographic assess-ment. The medical ethics committee of the UMCG approved the study, which was registered at ClinicalTrials. gov (ID:NCT01904331).9
All 109 patients were treated with 3D conformal RT using CT-based treatment planning.11 At the time of inclusion, cardiac sparing using breath-holding techniques was not yet implemented. Therefore, none of the patients were treated with a breath-hold technique. The reported doses are therefore higher than the typical cardiac exposure with modern planning and cardioprotective techniques.12 The prescribed dose was 50.4 Gy delivered in 28 fractions to the whole breast with a simultaneous integrated boost of 14.0 or 16.8 Gy to a boost volume in the same 28 fractions, depending on pathological risk factors.
To analyze the relationship between cardiac function of the LV and incidental cardiac irradiation, contouring was performed of the LV and coronary arteries, responsible for the oxygenation of the LV. The LV was contoured using a multiatlas automatic segmentation tool based on the de-lineations by Feng et al (Mirada RTx [version 1.6]; Mirada Medical, Oxford, UK).13 The contouring of the coronary arteries, including the left main coronary artery (LMCA), left anterior descending coronary artery, circumflex coro-nary artery (CX), and right coronary artery, was based on a recently published cardiac contouring guideline by Duane et al14 and was done manually by 1 observer (example of a 3D reconstruction is shown in Fig. 1). After cardiac sub-structure delineation, the individual radiation dose to these substructures was recalculated using the original treatment plan. As a final step for this study, dose-volume histogram (DVH) parameters of the cardiac substructures were extracted from the treatment planning system (Pinnacle [version 9.1]; Philips Radiation Oncology, Fitchburg, WI).