Introduction
Cardiovascular disease (CVD) and cancer are the two major causes of mortality worldwide [
1,
2]. Recently, an increased risk of cancer development has been reported in patients affected by CVD, particularly acute coronary syndrome (ACS) [
3‐
6]. Variation in cancer incidence has been observed between urban and rural areas for several decades, with higher risk of cancer in urban populations [
7‐
9]. However, these differences diminished, and even inverted, over the past few years [
10‐
13].
To the best of our knowledge, these differences have never been reported in specific populations, such as patients with ACS. In the present study, we investigated the possible difference in malignancy risk in six geographic areas of the Veneto region in Italy in an unselected sample of patients discharged alive after an index hospitalization with ACS and followed up for 22 years. As a comparison, we report the risk of neoplasia in smokers and non-smokers in the same sample of patients.
Discussion
The main result of the ABC-7* Study on ACS is that urban-rural geographic areas have different long-term risk of malignancy, regarding the lack of difference in clinical and most of demographic characteristics between patients from rural and urban areas and even after controlling the survival models for age, gender, education level and main clinical features. This difference supports the hypothesis that the urban-rural geographic area is a strong independent effect modifier of malignancy risk in ACS patients.
Living in a rural area positively influences the probability of having cancer for patients in the northern province, meaning that those who live in the rural areas of this province have a greater risk of incurring neoplasia compared to citizens who live in the urban areas. In contrast, living in a rural area negatively affects the probability of having cancer in the southern province.
Notably, results from the present study also indicate that cancer risk in the north-rural area is even higher than the risk associated with tobacco smoking (Fig.
4), which is considered a leading preventable cause of cancer and cancer deaths [
21,
22], and strong evidences indicate that smoking significantly increases the risk of several malignancies [
23‐
25]. In a recent meta-analysis of 19 population-based prospective cohort studies included data for 897 021 European and American adults, current-smokers had a significantly higher overall risk of developing and dying from cancer (HR 1.44, 95 % CI 1.28–1.63 and HR 2.19, 95 % CI 1.83–2.63, respectively; P < 0.05, I
2 > 75 %) compared to never-smokers [
26], which is in concordance with our results based on smoking habits.
Urban-rural variation in cancer risk has been analyzed for several years to emphasize lifestyle dissimilarities, such as smoking and dietary habits, socioeconomic status, and exposures to other risk factors [
7,
27,
28]. Yet, homogeneous exposure to the most common risk factors in both urban and rural areas, particularly in developed Western European countries, has recently been reported to be a consequence of economic development, growing homogenization of lifestyle, and increased relocation opportunities [
27,
29]. Thus, several reports suggested that the differences in malignancy risk, as well as exposure to different risk factors seem to depend on health service accessibility, either diagnostic or therapeutic, and secondary prevention strategies, such as national screening programmes [
27,
30,
31]. Several reports have also documented an elevated cancer risk in the general population in rural communities compared to urban areas [
10‐
12,
30].
We also recently documented a higher long-term risk of malignancy in patients with ACS compared to the general population [
4]. In our patients, the incidence of cancer was similar in men and women, and higher in older patients than in younger patients [
4].
To the best of our knowledge, the present study is the first to report on the geographic distribution of malignancy in this specific population, ACS patients, with a very long follow-up and very few dropouts. In agreement with the medical knowledge, we found an association between malignancy risk and other important variables, such as age and smoking, but we also found an inverse association between malignancy risk in both urban and rural areas and serum cholesterol as in previous reports [
32,
33].
The explanation for the higher risk in the north-rural area in our cohort of patients, which resulted in approximately 3-times higher risk than in the north urban area, is not yet clear as both urban and rural areas share most of the clinical and of demographic characteristics. The level of higher education was lower in rural areas (Table
1), and it has been reported that education level inversely associated with cancer incidence [
34,
35]. Yet, adjustment for education level did not eliminates the risk differences of malignancy onset across the six geographic areas.
The six geographic areas considered in this analysis share the same national and regional primary healthcare services which are delivered by Health Districts, the operative branches of Local Health Units. Each Health District is responsible for planning and delivering health and social care based on population needs where a maximum of 1500 patients are assigned for each general practitioner. Moreover, recently the Veneto Region adopted a new primary care model, the Integrated Medical Group, where four or more general practitioners work together as well as with specialists, nurses and other health professionals and social workers to deliver a comprehensive array of people-centred services; ensure the effective management and care for chronic patients and take responsibility for community health [
36,
37]. Thus, it seems unlikely that differences in health system organization can justify the diverse risk of malignancy reported in the present paper. Although recent reports have suggested that the gradual convergence of environmental and economic factors and the changed lifestyle may have contributed to the observed difference in cancer risk, rural residents tend to be older, have a lower income, and less education than urban residents [
29,
38]. Gandinia et al. recently analysed data from 74,989 individuals aged > 35 years and living in 1442 Italian municipalities, who were recruited in 1999–2000 and followed up until 2008. In agreement with our results, they reported that the majority were living in rural areas with lower education level, and that the events of first hospital admission due to cardiovascular diseases or neoplasia were higher in rural residents [
39].
Notably, the north-rural area of the present study includes 86 % of the population living in the rural areas of the Prosecco Hills of Conegliano and Valdobbiadene (UNESCO cultural landscapes), whereas the north-urban area includes 100 % of the urban UNESCO population. On the other hand, these rural UNESCO areas overlap 78 % of the population of the north-rural area of the ABC 7* Study. This observation sheds light on the higher risk of malignancy in the UNESCO areas than the other geographic areas in the present study.
One of the biggest strengths of this study is derived from the long duration of follow-up with almost no dropouts. To the best of our knowledge, no previous studies have reported such a contrast in malignancy risk between urban and rural areas for a specific population.
Acknowledgements
The authors thank Paola Michelazzo, RN; Jessica Civiero, RN; and nurses from the emergency care units of Conegliano, Adria, and Bassano General Hospitals for their assistance with patient management. We thank Mario Baggio, RN; Daniela Donadel, RN; and Raffaella Frare, RN, for their help handling the data. We thank Renzo De Toni, Ph.D.; Patrizio Buttazzi, Ph.D.; and the general laboratory personnel for assistance collecting laboratory data.
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