Introduction
Cancer and cardiovascular disease (CVD) are major public health problems with rising incidence rates in developed countries [
1‐
4]. In 2015, approximately 3.1 million individuals in Japan had cancer, and more than 862,000 new cases are diagnosed annually [
3]. Separately, the number of outpatients with left ventricular dysfunction (LVD) was 979,000 in 2005 and is predicted to increase gradually as the population ages, reaching 1.3 million by 2030 [
4].
CVD is endemic among cancer patients; hypertension, atrial fibrillation (AF), ischemic heart disease (IHD), venous thromboembolism (VTE), LVD, and heart failure (HF) are common comorbidities [
5,
6]. This is attributable to common risk factors shared by cancer and CVD (e.g., aging, smoking, diabetes, obesity, and physical inactivity), neoplastic effects on the cardiovascular system, chemotherapy- and radiotherapy-induced cardiovascular toxicities, and longer life expectancies [
1,
3,
6‐
9].
CVD-related comorbidities are a persistent burden on cancer patients [
5‐
7]. CVD causes acute HF, myocardial infarction, pulmonary thromboembolism, stroke, cardiogenic shock, syncope, and arrhythmia; these can be lethal or lead to serious disabilities. CVDs often relapse, and some cause major adverse cardiovascular events (MACEs); they also often interrupt the patient’s cancer treatment. Some anticancer drugs are contraindicated to avoid CVD and MACE, resulting in insufficient treatment and a worse prognosis. For example, anthracycline and trastuzumab are withheld for LVD patients, while bevacizumab is withheld for VTE patients. Curative surgery may be abandoned in favor of palliative surgery or radiotherapy. In our registry, the 5-year survival rate was 64.0% for all cancer patients and 44.2% for cancer patients with CVD [
6]. Comorbidities with AF, VTE, and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) elevation were significantly associated with mortality [
6].
The number of cancer patients in Japan is estimated to increase to 3.5 million by 2025 [
3]. The future disease burden may be further complicated by comorbidities associated with CVD and may vary among cancer types. Predicting the CVD epidemic can help to anticipate future resource needs among cancer-treating institutions. However, to our knowledge, no predictive studies have been performed on this issue in Japan. Therefore, we conducted a retrospective study at our cancer center hospital to predict the impact of CVD on cancer patients over the next 20 years.
Discussion
Japan is projected to face an HF pandemic [
4,
14,
15] and cancer epidemic [
3] in the coming 2 decades owing to an aging population. Therefore, we predicted the future number of cancer patients with CVD. Our study revealed the following new observations: (1) the total number of Japanese cancer patients with CVD was 253,000 in 2015, and is expected to increase rapidly by 30,000 by 2020, peaking at 313,000 in 2030–2034; (2) the CVD population will be predominantly men (2.5-fold the number of women) and ≥ 75 years of age; (3) the growth rate in the number of cancer patients ≥ 75 years will be greater in women than in men; hence, the growth rate in cancer patients with CVD will also be greater in women; and (4) therefore, cancer patients in 2035 will be older and more likely to have CVD than those in 2015, especially women.
While cancer patients with CVD will continue to be predominantly male (2.5 times the number of female patients), female patients will experience greater increases in the rate of cancer with CVD. While rates of cancer without CVD will increase 1.16-fold between 2015 and 2035, cancer with CVD rates will increase 1.29-fold. The odds ratio, which is the relative ratio between increasing rates of cancer with vs without CVD, will be 1.11 (Table
2). Breast and uterine cancers show the highest odds ratios at 1.30 and 1.15, respectively. Therefore, healthcare practitioners caring for female (i.e., breast and gynecological) cancers should prepare to treat CVD, especially LVD and VTE.
The cancer/CVD epidemic will persist in a decremental phase in Japan after 2005 owing to the aging population. As cancer and CVD are more common in individuals aged over 75 years, cancer centers will be obliged to improve medical care for CVD as well. Cancer patients in 2035 will be older and more likely to have CVD than cancer patients in 2015, especially among women. Japan is projected to face an epidemic of cancer with CVD; as a history of CVD is a strong predictor of relapse or MACE, cancer healthcare practitioners should recognize CVD presence and history. However, the appropriate management of CVD may be deficient owing to unawareness of its existence, failure of patients to mention CVD history (e.g., because of cognitive impairment), communication lapses between hospitals, and shorter medical record storage periods. Electronic medical records containing information on both CVD and cancer should be available at cancer centers.
Cancer and CVD incident cases have increased in the US owing to the aging Caucasian population [
16,
17]. Cancer patients with CVD are prevalent [
5] owing to the longer survival rates of patients with both diseases [
18]. The prevalence of HF in patients aged 66 years or older with breast cancer, colorectal cancer, lung cancer, and prostatic cancer were 6.9%, 11.6%, 12.4% and 5.7%, respectively [
5]. Although precise comparisons with previously published data are not feasible because of the different methods of assessment and cohort types, our cancer patients may have a lower prevalence of CVD than the US cohort (Supplementary Table 2). However, a future epidemic of cancer with CVD in Japan will likely occur given that Japan has the most rapidly aging population among developed countries [
2,
3].
A number of limitations must also be considered. First, this pilot study was retrospective and observational; a prospective study would be preferable for the precise assessment of CVD burden on cancer patients. Second, this was a single-center study; the incidence rates of some cancers differ in Japan (e.g., stomach cancer), and Niigata Cancer Center Hospital may not be a representative Japanese cancer center. However, no single representative hospital has been selected to study the prevalence of cancer with CVD in Japan to date; thus, our hospital is the closest to realizing this goal owing to its suitable population size, average number of cancer patients at each type, and proper diagnosis by cardiologists. Furthermore, the CVD/cancer deaths (ratios) in 2014 in Niigata city and Japan overall were 153/292 (0.524) and 157/294 (0.535), respectively [
19]. The ratio in Niigata city was the 15th closest to the overall ratio in Japan, which encompassed 47 prefectures and 21 major cities. CVD and cancer death in Niigata were sufficiently close to the nationwide average that our study can be deemed representative of the country. Third, CVD diagnoses were influenced by access to electrocardiography, echocardiography, vascular echo, CT, and NT-proBNP measurement; the identification of CVD in all cancer patients was not feasible. Moreover, there is a possibility that the actual prevalence of CVD in cancer patients was underestimated because of selection bias arising from the fact that patients with latent CVD in our hospital are not identified simply because of their non-referral to those examinations. Fourth, both our own public data and those of the National Center were based on past-year surveys. With advancing therapies and improved prognoses, future extrapolations may be modified. However, because survival rates in the future promise to improve with advancing anticancer and anti-CVD therapies, the actual number of patients living with cancer and CVD cannot be lower than our projection; in other words, it is highly unlikely that our projection is overestimated.
In conclusion, as cancer patients in Japan progressively age, comorbid CVD is expected to increase in prevalence in the near future. Cancer care providers should prepare the medical system for CVD management. The rapid growth of CVD in women with cancer should be recognized, especially in those with breast cancer and gynecological cancers.
Acknowledgements
We are indebted to Chika Sekine and Tomomi Fujita (cancer registry) for their superb assistance with the datasets; Sumika Ishigaki, Satoko Sakakibara, Chika Yumoto, Megumi Kira, Mitsue Hashidate, Keiko Henmi (echocardiography laboratory) for performing electrocardiography, echocardiography, and vascular echo; Naho Sasaki, Masaki Yoshino, Mayuko Ohtaki, and Naoko Kurematsu (Department of Pharmacology) for pharmacological information; and Dr. Yoshinobu Okada for treating cancer patients with CVD.
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