The effect of PORT on cardiac-related mortality is critical due to inadequately capturing the cardiac-related mortality risks in recent years. Our population-based analysis offers a holistic update on the cardiac-related mortality risks in ⅢA-N2 NSCLC patients who underwent PORT. To our knowledge, this is the first study concentrating on the incidence and trends of competing risk cardiac-related mortality in ⅢA-N2 NSCLC patients with long observation, and the results show that cardiac-related mortality has no association with PORT use between 1988 and 2016. And the incidence of cardiac-related modality has decreased over time.
Previous studies have demonstrated a benefit in local-regional control by using PORT but whether PORT could improve overall survival remains controversial[13–18]. The insignificant survival benefits with PORT could partially be explained by the early and late toxicities, including radiation esophagitis, radiation pneumonitis and radiation induced heart diseases. And cardiac-related mortality is one of the detrimental effect of PORT on survival. Several studies have reported increased cardiac-related mortality with PORT after surgery for stage I to Ⅲ NSCLC[19–21]. Lally et al[20] conducted the risk of cardiac-related mortality associated with PORT of resected NSCLC patients. It was demonstrated that PORT was associated with an increase in cardiac-related mortality independent of the expected effects of age, sex, and race between 1983 and 1988 by using SEER database. However, significant differences exist between Lally et al[20] and our study, given the substantial heterogeneity in patient selection, year of diagnosis and method of statistics analysis. First, in the study by Lally et al[20], a mixture of patients with varying stages (stage I to III) of resected NSCLC were included. In contrast, our study concentrated on ⅢA-N2 NSCLC patients, representing a population that is most likely to benefit from PORT. Second, the recruitment of patients included in Lally et al[20] went from 1983 to 1988 comparing with 1988 to 2016 in our study. Lastly, compared the results of study by Lally et al[20], our study used competing risk model to avoid overestimate cumulative survival rate and incorrectly evaluate the effects of covariates on the hazard ratio to the occurrence of the cardiac-related death event. This guaranteed the result's reliability of our study.
Our study found an approximate 3% cardiac-related mortality rate at 5 years experienced by all patients with ⅢA-N2 NSCLC who receive either PORT or Non-PORT. The insignificant difference of cardiac-related mortality observed between PORT and Non-PORT group in our study is probably due to the contemporary radiation techniques, limited volumes of radiation, suitable radiation doses and fraction sizes[22, 23]. Taken together, these factors likely decreased the volume of heart exposed to high dose radiation. Trials with contemporary radiation techniques demonstrated that there was no increase of death from intercurrent disease[24–28]. A serious of recently published non-randomized trials could not detect difference in cardiac-related mortality between patients receiving 3D-planned PORT group in comparison to Non-PORT group[14, 29, 30]. What’s more, the advances in lung cancer treatment could also explain the decrease of cardiac-related mortality over time (1988–2016). The trends are consistent with the analysis of Lally et al[20] and Haque et al[9]. Lally et al[20] demonstrated the decrease of cardiac-related mortality in resected NSCLC (1983–1993), while Haque et al[9] illustrated that the incidence of cardiac-related mortality has decreased over time in LA-NSCLC (1988–2014).
On univariate and multivariate analysis, our study confirmed that patients of older age, male patients, squamous cell lung cancer, earlier year of diagnosis and earlier T stage were more likely to have higher rates of cardiac-related mortality. This may be explained by the baseline risks of these subgroups rather than any relation to radiotherapy[31, 32]. This implies that patients with greater comorbidities or potential for longer survival may require extra attention to cardiac sparing[33]. Cardiac monitoring with imaging and routine involvement of cardiologist in the pre- and post-treatment care may be necessary for patients with cardiac-related mortality risk factor. Although there is no association between PORT use and cardiac-related mortality, cardiovascular issues such as cardiomyopathy, arterial disease, hypertension, and vascular and metabolic issues could manifest during or after therapy due to PORT-related toxicities. And we still encourage clinical attentiveness to cardiac-sparing radiotherapy and emphasize overall health through management of early and late cardiac toxicities. With increasing life expectancy of ⅢA-N2 NSCLC, further studies are needed in order to provide dosimetric correlates for cardiac toxicities, which is rarely reported in previous studies[34].
Several limitations should be acknowledged when interpreting our results. First, just as other studies derived from SEER database, our study is limited by the lack of important paramenters, such as the following: comorbid conditions, smoking history, chemotherapy utilization, radiation therapy dose, technique and target, which are potential confounders for our study. Second, there is an inherent weakness of selection bias in a population-based observational study. Third, the number of events was low, which limits the examination of multiple covariates.
These shortcomings notwithstanding, our study is still the largest retrospective study to address this important clinical question. What’s more, the large cohort of population-based patients provides sufficient power to detect relatively small increases in cardiac-related mortality for ⅢA-N2 NSCLC. We believe that PORT use is safe in ⅢA-N2 NSCLC patients, without worrying about cardiac-related mortality.