In this nationwide study, we found that the risk factors associated with PAD were similar in both cohorts except for adjuvant RT that was negligible in the young age group, but positive in the older group. In our study population, the young patients accounted for 47% of the total (894/1,889), which is much higher than that reported in Western populations (2, 5). Among the survivors, hypertension, advanced age, and HRT for longer than 180 days per year were more hazardous than RT.
PAD in the general population usually appears after the age of 50 years, and the prevalence then increases with age (21). This trend was also observed in the UC survivors in the present study. RT is a known cause of cardiovascular morbidity and mortality. The long-term effects on vascular endothelial damage and the possible mechanism of ionizing radiation on the progression of atherosclerotic plaque have been reported (22, 23). Although studies on the late vascular effects induced by RT have been performed in preclinical models, no clear correlations between individual changes and their time course after conventional fractionated RT have been identified. Accordingly, further studies are needed to investigate whether RT for UC increases the risk of PAD. In our analysis, RT did not cause PAD to occur earlier, but it increased the incidence of PAD in the older patients. People over 65 years of age often have multiple cardiovascular risk factors, and atherosclerosis can be accelerated by radiation (24).
In this study, we found that HRT was more associated with an increased risk of PAD than RT. A previous study reported that estrogen can regulate injury-induced chemokines and oxidative stress and that it has a vascular protective effect, but that it has no vascular protective effects on aging blood vessels (25). The “timing hypothesis” suggests that because the estrogen signaling pathway in older women has changed, estrogen has no vascular protective effect in patients with subclinical vascular diseases (25). Compared with the slow decline of estrogen levels in natural menopause over time, bilateral oophorectomy for UC treatment can lead to a sudden decrease in estrogen and menopause. This dramatic decline in estrogen has been associated with a higher cardiometabolic risk (26, 27). This may explain why HRT does not have a protective effect in UC patients, and even showed toxic effects on blood vessels in this study.
In this study, the UC survivors all had common risk factors for lower limb PAD, such as smoking, obesity, hypertension, and diabetes. Previous studies have reported that hypertension is a major risk factor for PAD regardless of age (2). In addition, the prevalence of PAD has been shown to increase with age and to be higher in people with metabolic syndrome and diabetes (15). We also found that the influence of diabetes and hyperlipidemia was more prominent in the young group. This may be because young UC patients usually have type I endometrial cancer, which is associated with obesity and metabolic syndrome. These are common risk factors for symptomatic PAD and can lead to chronic atherosclerosis (4, 15)
There are several strengths to this study. The first study examining RT effect on long-term UC survivors, and the use of a nationwide database allowed for a large sample size, homogeneous population, and long follow-up period. In addition, we could evaluate the temporal relationship regarding the use of HRT. Nevertheless, the major limitation is that data on other covariates including body mass index, use of contraceptives, self-pay medications, reproductive history, smoking status, details of treatment such as volume of radiation are not provided in NHIRD. We also lacked information of histology and staging at the initial diagnosis, which are major factors for survival. However, endometrial adenocarcinoma comprises approximately 90% of all UC (4) and we only included patients who had surgery alone or surgery combined with adjuvant RT, which are the main treatments for loco-regional disease.