110 Chapter 7 underwent nCRT followed by an esophagectomy, had better overall survival, and higher (post-operative) complication rates. Although we can’t perform these subgroup analyses, this suggest surgery plays an important role in toxicity rates within this patient group. Regarding the effect of chemotherapy, the vast majority, 94% of the patients, was treated with a combination therapy and although we know chemotherapy is potentially cardiotoxic[28], we can’t draw any conclusions on the role that chemotherapy played in the toxicity rates. Furthermore, for the same reasons, we were also not able to correct for known risk factors for cardiac events, like hypertension, diabetes, and age. Nonetheless, worse recovery of HS-TNT was seen amongst patients with cardiac event history at baseline. Moreover, cardiac event history was found to be a confounding factor in the multivariable longitudinal analysis of the rise of HS-TNT, which impacted the radiation dose response effect. Both findings are in line with the papers of e.g. Banfill, Wang and Atkins et al [2,5,29]. They found a significant dose effect relationship for cardiac death in patients with a cardiac event history as opposed to patients without a cardiac event history. This may be explained by worse recovery of myocardial tissue damage after thoracic irradiation for patients with a cardiac event history. In this paper we did not find significant associations between DVH parameters and the combined cardiac toxicities instead of the (too low number of) separate events. Clearly these toxicities originate from different biological mechanisms, which may relate different to the radiation dose distribution to (subregions of) the heart. So for future studies, combining toxicities as an endpoint in NTCP modelling is therefore not a solution for low numbers of the separate events. There are several reasons for the fact that we found significant correlations between cardiac blood biomarkers with radiotherapy dose parameters as well as with clinical events, while others did not [15–23](Supplementary data, Table1). First, our baseline values were not affected by prior chemotherapy. Second, as compared to breast cancer patients treated with radiotherapy, more cardiac damage can be expected in esophageal cancer patients because of the higher radiation dose to the heart and lungs, as they are in close proximity to the tumor. Furthermore, we were able to perform longitudinal analyses for radiotherapy dose effects linked to clinical events during follow up. Blood biomarkers can be an important tool, not only for baseline risk assessment and decision-making on preventive measures, but also to select patients for multimodality treatment and/or radiation technique (e.g., proton therapy). Additional studies are warranted to explore the added value of cardiac blood biomarkers on a
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