100 Chapter 7 The aim of this study was therefore, to test the hypothesis that the levels of these biomarkers increase after radiation therapy in a dose dependent way and to test if these biomarkers are predictive for clinical cardiac events . Materials & Methods To be eligible for this study, patients had to have histologically proven EC and to be planned for curatively intended neoadjuvant chemoradiotherapy (neoCRT), definitive chemoradiotherapy (dCRT) or radiotherapy (dRT) alone. The study was approved by the local ethical review board (clinicaltrial.gov NCT02481778) and written informed consent was obtained in all patients. Blood samples were taken before commencing treatment, at the last day of radiotherapy, and during follow up visits at 4 weeks, 6 months, and 1 and 2 years after completion of treatment (Figure 1). HS-TNT and NT-ProBNP concentrations in serum were measured and the results were blinded for the treating physicians to minimize the risk of bias in selecting patients for different treatment options and the scoring of clinical events. Treatment was given according to our institutional standard which are in line with European guidelines [24]. Next to target volumes, the lungs, the heart and its substructures were contoured according to previously published guidelines by Feng et al. [25]. Dosimetric parameters were extracted from the treatment planning system for each patient including maximum, mean and the V-values in 5 Gy bins. All patients were included in our standard follow up program in which details of treatment, (cardiac) comorbidities, use of medication and all cardiopulmonary events are scored according to the common terminology criteria of adverse events (CTCAE) version 5. In addition to clinical visits, patients were contacted by phone by a research nurse to assess the EORTC quality of life questionnaires (LC-13, OES-18, and ACE-27) during follow up. Stable and pre-existing comorbidities were not registered as cardiac events during follow up. Non-tumor related death was analysed as a surrogate for toxicity as the exact cause of death is often not recognized as toxicity. The primary endpoint was change in NT-ProBNP between baseline and 1 year after treatment, as we want to evaluate whether there is a dose-dependent rise of NT proBNP. Our sample size calculation was therefore based on a 0.9% increase of NTProBNP per Gray mean heart dose (MHD). Estimating a 15% standard deviation in NT-ProBNP levels and an expected standard deviation of 7 Gy in MHD, 52 patients were needed at one year (90% power). With a 70% survival at 1 year and a 10% dropout because of poor clinical condition 87 patients were required.
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