Multiple studies have confirmed that the risk of CVM among cancer patients varies considerably in different countries. In a population-based study of 21634 adult cancer patients, Ye et al. concluded that the risk of CVM has no significant differences between cancer patients and the general population in Australian (SMR: 0.97; 95% CI: 0.90–1.04) . Oh et al. reported that compared with the general population in Korea, cancer patients have a lower risk of developing CVM (men, SMR: 0.73; 95% CI: 0.70–0.75; women, SMR: 0.83; 95% CI: 0.80–0.87), although they found a 20-fold increase in CVM among cancer patients from 2000 to 2016 . Sturgeon et al. confirmed that the risk of CVM among 28 of types cancer patients was significantly increased by contrast with that of the general population in the United States, especially in the first year after diagnosis (SMR: 3.93; 95% CI: 3.89–3.97) . A recent study based on the SEER database showed that 1680 (5.6%) NENs patients died from heart diseases and 545 (1.8%) NENs patients died from other CVD (hypertension without heart disease, cerebrovascular diseases, atherosclerosis, aortic aneurysm and dissection, and other diseases of arteries/arterioles/capillaries), with SMRs of 2.31 (95%CI: 2.20–2.42) and 2.36 (95%CI: 2.17–2.57), respectively . Most NENs are primarily located in the GEP (67.5%) and bronchopulmonary system (25.3%) ; however, the 5-year overall survival rates between GEP-NENs (74.7%) and bronchopulmonary NENs (33.7%) patients were significantly different [7, 30]. These findings suggested NENs patients had various natures and characteristics depend on different primary sites. Hence, we focus exclusively on the GEP-NENs in the present study.
In this study, we comprehensively assessed the risk of all causes of death among more than 42 thousand GEP-NENs patients from the SEER database, and found the risk of CVM in GEP-NENs patients was 20% higher than that of the general US population (SMR: 1.20; 95%CI: 1.14–1.26).
According to the competing risk analyses, we found that the CM of CVD was the lowest among all causes of death including primary cancer, other cancer and other non-cancer disease.
In addition, we identified age of diagnosis, race, Hispanic origin, gender, martial status, year of diagnosis, grade, education level, region, SEER stage, primary site, surgery and chemotherapy were independent predictors of CVM in GEP-NENs patients.
NENs were previously known as carcinoid tumours, in which approximately 50% of patients developed carcinoid syndrome . Around 60% NENs patients with carcinoid syndrome developed carcinoid heart disease (CHD) which was characterized by development of valvular dysfunction, in particular right heart failure . In addition, several researches have found that NENs patients are prone to depression and anxiety [33, 34], which may aggravate state of cardiovascular physiology [15, 35]. These results may explain the high risk of CVM in patients with NENs to some extent.
In terms of the time after cancer diagnosis, we confirmed that GEP-NENs patients within the first two-month after diagnosis had the highest risk of CVM (SMR: 3.64; 95% CI: 3.05–4.30). This finding was similar to previous conclusions reported by Sturgeon et al. and Zaorsky et al. [8, 36]. Moreover, Ye et al. and Fang et al. showed that the recent diagnosis of cancer could be a major psychological stressor and lead to a negative effect on cardiovascular physiology [15, 26, 35]. These results suggested that psychiatric evaluation and psychological support could be indispensable for GEP-NENs patients with recent diagnosis of cancer. In terms of age at diagnosis, we observed that the CM of CVD steadily increased with the age at diagnosis. This phenomenon resembled previous findings reported by Weberpals et al. and Ye et al. [16, 26]. In general, death from primary cancer was the most common cause of death in cancer patients; however, the CM of CVD exceeded that of primary cancer in patients aged ≥ 65 during follow-up time (Fig. 3C and D). These results implied that surveillance efforts should not only include assessment of primary cancer but also control of modifiable risk factors for CVD in elderly cancer patients. In terms of primary site, we observed that pancreas NENs patients and small intestine NENs patients had the lowest (4.12%) and highest (13.26%) CM of CVD, respectively. One possible reason was that CHD occurs most frequently in small intestine NENs patients, accounting for 72% . Another plausible explanation was that pancreas NENs patients had so advanced tumor stage that they might have not enough life expectancy to die of CVD [28, 37, 38], which may be explainable for the lower risk of CVM in patients with grade III/IV (HR: 0.701; 95%CI: 0.533–0.923) or distant tumor stage (HR: 0.456; 95%CI: 0.382–0.544).
The multivariate competing risk analysis was used to identify independent indicators of CVM in GEP-NENs patients in current study. We found that aged patients at diagnosis were inclined to die due to CVD (HR: 4.799; 95%CI: 4.313–5.341). Interestingly, patients with younger age at diagnosis (≤ 39 years) had the highest SMR 3.20 (95%CI: 1.93–4.99), which similar with the results reported by Zaorsky et al. . Male patients had a high probability of CVM compare with female patients, as previous reports of colorectal cancer and non-Hodgkin’s lymphoma [13, 39]. A plausible reason is that males have worse health behaviors, such as smoking and drinking, which were confirmed as independent risk factors of CVD [40–42]. Our study showed that Black patients were significantly associated with the higher CVM risk compared with other races. Although patients with different ethnicities had a difference in receiving cancer therapy in the United States, this difference alone cannot explain the discrepancies of cancer patients in death due to non-cancer causes . Hence, further investigations on this subject remained warranted. Patients with unmarried status showed propensity to die of CVD in contrast to married patients, as previously reported in non-Hodgkin’s lymphoma . A reasonable explanation was that married patients were more likely to feel cared for and encouraged and supported physically and spiritually in contrast to unmarried patients . Other studies also had revealed that marriage could help to improve cardiovascular, endocrine, immune function and cancer prognosis [45–47]. Sturgeon et al. reported that individuals with low socioeconomic status were prone to have a high risk of CVM in cancer survivors . In our study, patients with low education level commonly gave rise to higher risk of CVM, which was consistent with results of prior studies [15, 21].
In the present study, a majority (76.8%) of patients underwent surgery, 10.3% patients received chemotherapy, and only 2.3% patients received radiotherapy. Notably, multivariate analysis indicated that patients received chemotherapy had a reduced CVM risk compared with patients not received chemotherapy. This result seemed to be inconsistent with the known cardiotoxic effect of chemotherapy, but conformed with the finding reported by Low et al. . A possible reason was that patients who received chemotherapy have not enough life expectancy to occur CVM events (median survival time: chemotherapy 18 months vs surgery 61 months). We concluded that patients without surgery had an increased CVM risk compared with patients received surgery, which was consistent to the results from prior studies [13, 14, 44]. In respect of radiotherapy, prior study reported that radiation-induced macrovascular damages accelerated age-related atherosclerosis and microvascular damages, and reduced capillary density , however, radiotherapy was not an independent predictor for CVM in our study. In the SEER program, radiotherapy was defined as the first-course radiation treatment but lack of detailed regimen. Therefore, further investigation is required to clarify the effect of radiotherapy on the risk of CVM in patients with GEP-NENs.
Limitations still exist in our study. First, some information associated with CVD were not available in the SEER registry, such as comorbidities, smoking and alcohol use, doses of radiotherapy and chemotherapy agents. Second, this study is a retrospective study, which might lead to a potential selection bias in the participants. Third, causes of death may be subject to misclassification ascertained from death certificates, and there was evidence indicating that causes on death certificates about CVM may be overestimated .