Estrogen supplements are associated with a decreased coronary
artery disease risk in patients with cervical cancer after treatment: A
nationwide population-based retrospective cohort study
Running Title: Coronary artery disease and cervical cancer
Li-Min Sun, MD,1 Ji-An Liang, MD,2,3 Shih-Ni Chang, MS,4,5,6 Fung-Chang Sung,
PhD,5,7 Chih-Hsin Muo, MS,5,7 and Chia-Hung Kao, MD,3,8
1Department of Radiation Oncology, Zuoying Armed Forces General Hospital,
Kaohsiung, Taiwan
2Department of Radiation Oncology, 7Management Office for Health Data, and 8Department of Nuclear Medicine and PET Center, China Medical University
Hospital, Taichung, Taiwan
3School of Medicine, College of Medicine, 4The Ph.D. Program for Cancer Biology
and Drug Discovery, and 5Institute of Environmental Health, College of Public
Health, China Medical University, Taichung, Taiwan
6Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
Li-Min Sun and Chih-Hsin Muo contributed equally to this work. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Corresponding author: Dr. Chia-Hung Kao, Department of Nuclear Medicine and PET Center, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung 404, Taiwan. Tel.: +886 4 22052121x7412; Fax.: +886 4 22336174. E-mail: [email protected]
Conflicts of interest.
The authors declare that they have no conflict of interest or financial interest invested in this work, either collectively or individually.
Acknowledgement.
This work was supported by study grants (DMR-101–061 and DMR-101–080) from our hospital, and from the Clinical Trial and Research Center of the Taiwanese Department of Health (DOH101-TD-B-111–004), as well as from Taiwan’s Department of Health Cancer Research Center for Excellence (DOH101-TD-C-111– 005). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
ABSTRACT
Background: The purpose of this study was to explore the possible association between coronary artery disease (CAD) risk and cervical cancer.
Methods: We used data from the National Health Insurance system of Taiwan to address the research topic. The exposure cohort contained 728 patients with cervical cancer. Each cancer patient was randomly frequency-matched with 4 participants by age, index-month, and index-year from the general population who did not have a cancer history before the index date (control group). Cox’s proportion hazard regression analyses were conducted to estimate the relationship between cervical cancer and CAD risk.
Results: Among patients with cervical cancer, the overall risk for developing CADs was significantly lower than that of the control group [adjusted hazard ratio (aHR): 0.57, 95% confidence interval (95% CI): 0.41—0.79]. Further analyses revealed that the lower risk was observed only in patients with older age (aHR: 0.57, 95% CI: 0.40 —0.82), a shorter follow-up duration (aHR: 0.47, 95% CI: 0.31—0.72), or with estrogen supplements (aHR: 0.39, 95% CI: 0.22—0.68).
Conclusions: The findings from this population-based study suggest that estrogen supplements are associated with a decreased CAD risk in patients with cervical cancer. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Keywords: Coronary artery diseases; cervical cancer; estrogen; population-based study.
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INTRODUCTION
Cancer has been the leading cause of death in Taiwan since 1982, and the age-adjusted incidence rate has increased steadily since then (1). Because of earlier detection, improved diagnostic methods, more effective treatment, improved clinical follow-up after treatment, and an aging population, the proportion of long-term survivors is rising (2). Consequently, surveillance and monitoring of cancer survivors has become a critical issue, not only for disease control, but also for cancer treatment and treatment-related health problems (3).
Cardiovascular disease is the second leading cause of death in Taiwan (4). Cancer and cardiovascular disease will be a continuously major healthcare burden to Taiwanese society, and the related issues have aroused concern in the public health. Previous research has revealed higher risks for cardiovascular disease in survivors of some types of cancer; and treatment-related complications, as well as shared daily life risk factors, may contribute to cardiovascular disease (5–9). We are interested in exploring whether any possible link exists between these 2 major public health threats. Cervical cancer, which is more commonly seen in developing rather than developed countries, is the fifth most common malignancy among Taiwanese women, with an age-adjusted incidence rate of 11.8 per 100 000 women in 2008 (1). Little information is available regarding cardiovascular disease risk among cervical cancer 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
patients. Madurd et al. discovered that an increased risk of developing a myocardial infarction was observed in a cohort of cervical cancer patients (10). Assuming that the coronary artery disease (CAD) risk is also higher among Taiwanese women with cervical cancer, we designed a population-based retrospective cohort study to explore this possibility using the database from the National Health Insurance (NHI) system of Taiwan.
METHODS
Data resources
This nationwide cohort study was based on the claims data of the universal health insurance program of Taiwan. This insurance program was implemented in 1995, covering more than 96% of the country’s population and had contracted with 97% of the hospitals and clinics in Taiwan by the end of 1996. We used claims data from the National Health Insurance Research Database (NHIRD), consisting of registries and claims reported by contracted health care facilities. The NHIRD is managed by the National Health Research Institute (NHRI) in Taiwan, an autonomous organization established by the government and under the supervision of the Department of Health. We used data subsets composed of one million insurants selected by NHRI using a systematically random sampling method in 2000, from the entire population 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
(approximately 23 million) of enrollees in the insurance program between March 1995 and December 2000. After creating the data subsets in 2000, it was updated approximately every other year for additional medical records in the subsequent years until December 31, 2009. A more detailed description of the NHIRD was previously described (11).
Study sample
This study design featured a study cohort and comparison cohort. We used the code of International Classification of Disease Diagnoses, Ninth revision (ICD-9-CM) to identify 869 patients with newly diagnosed cervical cancer (ICD-9-CM 180) from January 2000 to December 2008. We excluded patients who had other malignant cancer history (ICD-9-CM 140–208, n=28) or had a history of CADs (ICD-9-CM 410–414, n=113) before index date. The index date for the patients with cervical cancer was the date of their first medical visit. After the inclusion and exclusion criteria were satisfied, our study cohort included 728 participants with cervical cancer. For the comparison group, we randomly selected 4 enrollees without a history of cervical cancer, with frequency matching of the case group by age, index-month, and index-year, using the same exclusion criteria in the same period.
Study end point
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Using the unique patient identification number, we linked study participants to the registry for inpatient and outpatient claims data to identify new diagnoses of CADs as the outcome of this study. To ensure the validity of the diagnosis, only new patients with at least 3 CAD diagnoses to make sure a correct diagnoses during the follow-up period after the index date were eligible end points in the study cohort. We calculated person-years for each study participant until the CAD was diagnosed, or until December 31, 2009, for those censored for loss to follow-up, death, termination of insurance, or other causes.
In addition, we also searched for hypertension (ICD-9-CM: 401–405), diabetes mellitus (ICD-9-CM: 250), and hyperlipidemia (ICD-9-CM: 272) as co-morbidities at the baseline.
Statistical analysis
We compared the distributions of age and co-morbidities between cancer patients and non-cancer patients, and statistical significance was tested using the chi-square test. We also calculated the incidence density with person-years using these variables in the study cohort and comparison cohort. The univariate and multivariate Cox’s proportion hazard regression analyses were used to estimate the effects of cervical cancer on the risk of CADs, adjusting for variables that were significantly related to cervical cancer from the prior chi-square analyses. The effects of estrogen 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
supplements were then assessed using Cox’s proportion hazard regression model. The hazard ratio (HR) and 95% confidence interval (CI) were calculated in the model.
All analyses were performed using SAS statistical software (Version 9.1 for Windows; SAS Institute, Inc., Cary, NC, USA). Results were considered to be statistically significant when two-tailed P-values were less than .05.
RESULTS
Table 1 compares distributions of age and co-morbidities between the cervical cancer cohort and the comparison cohort. Compared with the study cohort, the comparison cohort was more prevalent to have hyperlipidemia (16.4% vs. 12.9%, P = .02).
Table 2 presents the incidence densities and HR of CADs according to age and follow-up duration. Overall, the incidence rate of CADs in the study cohort was lower than in the comparison cohort (11.6 vs. 21.5 per 1,000 person-years). The comparison cohort of 50 years of age or older had the highest incidence (33.5 per 1,000 person-years).
The multivariate analysis for Cox’s proportional regression model revealed that the risk of CADs was significantly lower in the cancer cohort than in the non-cancer cohort (HR = 0.57, 95% CI = 0.41—0.79 (Table 2). Compared with the non-cancer 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
cohort of patients ≥ 50 years of age, the HR of CADs significantly decreased in patients with cervical cancer (HR = 0.57, 95% CI = 0.40—0.82) (Table 2). For the stratified analyses by follow-up duration, the HR of developing CADs was significantly lower in the cancer cohort within 3 years after the index date (HR=0.47, 95% CI=0.31–0.72).
Furthermore, the stratification analysis of estrogen supplements regarding the risk of CADs in association with cervical cancer is presented in Table 3. Compared with the non-cancer cohort, the HR of CADs was lower in cancer patients. Remarkably, the lowest estimated risk was noted in patients who had estrogen supplements (HR = 0.39, 95% CI = 0.22—0.68) (Table 3).
DISCUSSION
We assumed that patients with cervical cancer have a higher risk of developing CADs when compared to the general population without cancer. However, the results from this population-based cohort study indicated a reverse trend and showed that the overall CAD risk was significantly lower in the cervical cancer cohort. Sub-analyses revealed that the significantly lower risks were only seen in the patient group with older age, shorter follow-up duration, or estrogen supplement.
The age-adjusted cancer incidence rate in Taiwan has increased steadily, and in 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
2008, 297 new cases per 100,000 individuals resulted in the general population (1). This trend is different from that of the U.S., where data from Surveillance Epidemiology and End Results showed that the overall cancer incidence rate decreased by 0.7% per year between 1999 and 2006 (12). Because cancer continues to be a public health challenge in Taiwan, it has come to the attention of the government, resulting in population-based investigations regarding cancer-preventive epidemiology, as well as quality of life issues for cancer survivors. The NHI program provides comprehensive healthcare coverage, and the NHIRD contains data on ambulatory service records, hospital service records, and prescription claims. This database enabled us to select and examine patients who represented the underlying population. Previously, we used the data to evaluate the risk of malignancy for patients with various possible risk factors (e.g., diseases or medications), and discovered some compelling findings, which have been published or accepted for publication (13–15). Because of the advance in cancer diagnosis and treatment, increasingly more cancer victims can now survive longer. We also aim to explore the risk of developing particular types of disease among the increasing number of cancer survivors. The current study used a similar design with a reverse direction (cancer is a risk factor instead of an end point) in attempting to determine whether survivors of cervical cancer are at a higher risk of developing CADs.
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Previous studies have endeavored to discover a higher risk of cardiovascular diseases in some types of cancer. Vaughn et al. and van den Belt-Dusebout et al. have reported a significantly higher risk of heart disease among long-term survivors of testicular cancer (6,16), suggesting that chemotherapy (CT) with cisplatin-based regimens and mediastinal radiotherapy (RT) are associated with this excess risk. Population-based cancer registry studies have shown increased mortality from myocardial infarction for patients who have undergone left-sided vs. right-sided breast cancer RT (17). Other previous studies have indicated that both anthracycline-based CT and RT are related to subsequent heart diseases in breast cancer patients (7,18). Radiotherapy (RT) also induced excess heart diseases in Hodgkin’s disease survivors, but the role of CT was very limited (19).
Data regarding cardiovascular disease risk and cervical cancer are sparse (10,20). Maduro et al. evaluated the risk of cardiovascular events in 277 patients with cervical cancer treated with RT or chemoradiation and found an increased risk for myocardial infarction. Whether this increased standardized incidence ratio is treatment-related or indicates a shared risk factor cannot be concluded. Our results unexpectedly revealed a significantly lower risk of CADs among Taiwanese women with cervical cancer. Comparing the presence of CAD risk factors between the 2 groups in Table 1, patients with cervical cancer had a significantly lower hyperlipidemia than did the general 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
population without cancer, which may have partially contributed to this result. Explaining why the significant difference is only seen in women ≥ 50 years or with a follow-up duration ≤ 3 years is difficult (Table 2). Only 5 CADs are in cervical cancer patients < 50 years, and the statistical significance is difficult to determine from a relatively small case number. One possible explanation for the lower risk of CADs in patients with follow-up duration ≤ 3 years is that cancer patients are usually eager to change their unhealthy behaviors (e.g., cigarette smoking, unhealthy diet, less regular exercise) immediately when they are diagnosed with cancer, and the change may decrease the risk of subsequent CADs. When cancer is controlled temporarily, patients are less likely to strictly follow the “more healthy” behaviors.
The estrogen supplement, by contrast, has a more plausible interpretation for the result shown in Table 3. Two observational studies have indicated that postmenopausal patients who receive hormone therapy (HT) have a lower rate of cardiovascular disease and cardiac death than those who do not receive it, thus suggesting the cardiovascular benefits of estrogen (21,22). Our result is compatible with this finding. Despite being randomized prospective primary and secondary prevention trials, the Heart and Estrogen/Progestin Replacement Study (HERS II) and the Women’s Health Initiative (WHI) have suggested that, contrary to expectations, HT may increase the risk of cardiovascular disease (23,24). The reasons for this 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
paradoxical characterization of HT as both beneficial and detrimental remain undetermined, but a new look at prospective data may indicate that HT has beneficial cardiovascular effects (25).
As the population from the current study is likely to have had surgical menopause and therefore start estrogen alone immediately at the onset of menopause, the newer information from the WHI indicated among postmenopausal women with prior hysterectomy followed up for 10.7 years, estrogen use for a median of 5.9 years was not associated with an increased or decreased risk of CADs (26). Monkey studies have shown that estrogen deficiency during the premenopausal stage is extremely relevant regarding the progression of atherosclerosis. After several postmenopausal years, however, studies have shown that estrogen has no beneficial effects on atherosclerosis progression and may, in fact, be deleterious (27). This observation may support our finding of shorter follow-up duration having a lower risk for CADs.
The current study still has limitations that must be addressed. First, the comparative analyses were not adjusted for potential confounders including smoking, drinking behavior, and some types of unhealthy choices because of the inherent shortcomings of the NHIRD database. Smoking is a well-known risk factor for CADs (28), and a higher proportion of smokers among cervical cancer patients has been observed (29). Other types of unhealthy choices could be risk factors for cervical cancer as well, and 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
could plausibly be associated with CADs. Second, the evidence derived from a cohort study is generally of lower methodological quality than that from randomized trials, because a cohort study design is subject to many biases related to adjustment for confounders. Despite our meticulous study design involving adequate control of confounding factors, a key limitation was that bias could still remain because of possible unmeasured or unknown confounders. Nevertheless, apart from these potential problems, the data on cervical cancer and CAD diagnosis were highly reliable.
In conclusion, this population-based retrospective cohort study unexpectedly discovered that patients with cervical cancer have a lower risk of developing subsequent CADs. The underlying mechanism remains unclear, and may be related to estrogen supplements. Additional large-scale studies are required to confirm our findings. 1 2 3 4 5 6 7 8 9 10 11 12 13
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