52 Chapter 4 These findings suggest that worse OS can be caused by radiation dose to both organs at risk, but the biological mechanism remains unknown. Given the prognostic significance of a heart dose parameter in the radiation pneumonitis patient group, and not in the whole group, a possible explanation can be found in the physiological interaction of the heart and lungs. In preclinical studies, this interaction between heart and lung irradiation was objectified. Combining radiation on heart and lungs resulted in a synergistic effect on cardiopulmonary toxicity in rats. On pathologic examinations this interaction seemed to be caused by small vascular damage in lung tissue and perivascular fibrosis in heart tissue, resulting in pulmonary hypertension and reduced diastolic function [24,25]. Clinically, worse OS rates after (higher dose) thoracic radiotherapy despite better local control also suggests underreported toxicity, perhaps even unrecognized toxicity [10,24]. In several (SEER) database studies, higher cardiac death rates were reported in distal tumours and with the use of “older radiotherapy techniques” suggesting radiation induced toxicity of the heart [12,25–27]. More recent publications, like ours, are able to present DVH data on different critical organs and its relation to overall survival. Although several papers have been published on the correlation of cardiac dose with OS, there are reasons to be cautious of increasing the dose to the lungs in an attempt to spare the heart. The correlations found with cardiac dose in the literature might have been a reflection of the absence of cardiac toxicity models while lung toxicity models have been available for a longer period of time, resulting in strict planning criteria for the V20 of the lungs and the mean lung dose. Furthermore, in several of the earlier mentioned trials, not only the dose to the heart but total dose to the lungs was predictive for OS as well [11,16,28–30]. Altogether it is important to consider both heart and lungs as organs at risk in the treatment of thoracic indications. Especially in VMAT or IMRT techniques, cardiac dose reduction will be at the expense of a higher lung dose. Proton therapy on the other hand can reduce both the radiation dose to the heart and lungs. In a recent trial randomizing between photon and proton CRT, a significant reduction of treatment related complications was seen; the total toxicity score was 2.3 times lower after proton radiotherapy, compared to IMRT treated patients[31]. Therefore, it is preferable to combine both heart and lung DVH parameters in these prediction models. These models should originate from prospective data and be validated in independent cohorts to be robust against institutional differences. A further understanding of the mechanisms behind these toxicities can facilitate
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