121 Summarized discussion and future perspectives. In the second, more recent paper including oesophageal cancer patients, Cai et al. performed an analysis on risk factors for the arrhythmic patients (n=29) and found in multivariable analyses, next to the cardiac history, the LA V50 to be the best dosimetric parameter for arrhythmic events (HR 1.02, 95%CI [1.01-1.04])[18]. This means that the increase in volume (in %) of the left atrium receiving a dose of more than 50 Gy increases the risk on AF with 2%). The SA node is the so-called pacemaker regulating the heart frequency by the sympathetic and parasympathetic nervous system, the AV node seems even more important in the regulation of the heartbeat by delaying the electric impulses to the ventricles. It should be noted that information on the pathophysiology of AF in the general population is still unknown. The most quoted theory is that impulses from the SA node are overwhelmed by electric impulses originating from other parts of the atria. Fibrosis of the atrial walls seems to play a central role in the development of atrial fibrillation. Given the relatively high dose applied to the atria and the linear dose response relationship of the development of fibrosis as described in chapter 5, radiation-induced local fibrosis of the atria could play a role in the development of AF in these patients. In addition, local inflammatory reactions and ectopic foci are mentioned as possible factors for radiation-induced AF in cardiologic literature as well. For that reason, different parts of the atria might be susceptible for radiation-induced toxicity resulting in increased rates of atrial fibrillation [17–20]. These two papers reporting on the association of dose with substructures of the heart, suggest that the increased rate of AF is probably a local effect of the given radiation dose somewhere in the atria. The difference found in the paper including lung cancer patients [Song] as compared to the paper including oesophageal cancer patients, could be explained by the differences in dose distributions of lung cancer as compared to oesophageal cancer patients, as noted before. The oesophagus is located next to the left atrium (delineated in red, figure 1), whereas lungs are located next to the right atrium (delineated orange, figure 1). In order to be able to optimize radiation dose distributions, it becomes increasingly important to identify subregions within the heart that are most susceptible for radiation. Especially with more advanced techniques, like proton therapy, dose to specific cardiac regions, like the right atrium in oesophageal cancer patients can be avoided, whereas decreasing the mean dose to the left atrium remains challenging (Figure 1). Reduction of set up margins around the clinical target volume using daily 8
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