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Risk of age-related macular degeneration in patients with prostate cancer: a nationwide, population-based cohort study
Annals of Oncology 28: 2575–2580, 2017 doi:10.1093/annonc/mdx402 Published online 24 July 2017
ORIGINAL ARTICLE
Risk of age-related macular degeneration in patients with prostate cancer: a nationwide, population-based cohort study S.-Y. Lin1,2, C.-L. Lin3,4, C.-H. Chang5, H.-C. Wu5, C.-H. Lin6 & C.-H. Kao7,8,9* 1 Institute of Clinical Medical Science, China Medical University College of Medicine, Taichung; 2Division of Nephrology and Kidney Institute; 3Management Office for Health Data, China Medical University Hospital, Taichung; 4College of Medicine, China Medical University, Taichung; 5Departments of Urology; 6Family Medicine, China Medical University Hospital, Taichung; 7Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung; 8Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung; 9Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
*Correspondence to: Prof. Chia-Hung Kao, Graduate Institute of Clinical Medical Science and School of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 404, Taiwan. Tel: þ886-4-22052121 ext. 7412; Fax: þ886-4-22336174; E-mail: [email protected]
Background: Prostate cancer (PC) can be related to increased systemic oxidative stress and dihydrotestosterone level, which are also reported to be involved in the pathogenesis of age-related macular degeneration (AMD). We conducted a cohort study to determine whether patients with PC have an increased risk of AMD. Patients and methods: Data were collected from the Taiwan Longitudinal Health Insurance Database for the 1999–2010 period. The study PC cohort comprised 22 084 patients aged 18 years with a first diagnosis of PC. The comparison cohort consisted of age-, occupation-, and urbanization level-matched patients at a ratio of 1 : 1. The primary outcome was the incidence of AMD, which was evaluated using Kaplan–Meier survival analysis and proportional hazards modeling. Results: The mean follow-up periods (standard deviation) for the patients with AMD in the age-, occupation-, and urbanization level-matched PC cohort and non-PC cohorts were 4.69 (2.90) and 5.51 (2.82) years. The mean age of the PC cohort was 73.9 years and that of the non-PC cohort was 73.2 years, with approximately 85.9% of the patients aged >65 years. The PC cohort had a higher risk of AMD than did the propensity score-matched non-PC cohort with an adjusted hazard ratio of 1.25 (95% confidence interval, 1.12–1.39). Compared with PC cohort receiving no injection hormone therapy, the PC cohort receiving injection hormone therapy had a lower risk of AMD (adjusted hazard ratio, 0.56; 95% confidence interval, 0.41–0.76). Conclusion: PC is associated with an increased risk of AMD. Patients with PC receiving injected form of androgen deprivation therapy had a lower risk of AMD than patients with PC not receiving injected form of androgen-deprivation therapy. Key words: prostate cancer, age-related macular degeneration, cohort study
Introduction Age-related macular degeneration (AMD) is the leading cause of blindness worldwide [1]. The most common clinical features of AMD are impairment of the central vision and metamorphopsia [2]. Choroidal neovascularization and geographic atrophy are two classic ophthalmoscopic hallmarks of AMD. Intravitreal bevacizumab or ranibizumab, high doses of vitamins C and E, b-carotene, and zinc supplements can help delay the progression of AMD [3, 4]. However, until now, no curative treatment of AMD has existed. Embryonic stem cell therapies [5] and several
neuroprotective agents have shown potential and remain under clinical investigation [6, 7]. Thus, identifying the risk factors of AMD would be the most effective strategy for lowering the incidence of AMD. Current major risk factors of AMD include smoking, cardiovascular diseases, and genetic influences, including complement polymorphism and lipid, angiogenetic, and extracellular matrix pathways [1]. Oxidative stress and inflammatory processes also play roles in the pathogenesis of AMD [8]. Dihyrotestosterone, a metabolite of testosterone, was shown to have a protective effect in mouse embryonic stem cells [9].
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Original article
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However, animal studies have shown that dihyrotestosterone can induce oxidative stress [10, 11]. In clinical aspects, dihydrotestosterone has been associated with the development and progression of PC [12, 13]. No clinical population-based studies have investigated the risk of AMD in PC patients. Whether the risks of AMD would lessen if PC patients received androgen-deprivation therapy is unknown. Therefore, we used the National Health Insurance Research Database (NHIRD), a database representing the Taiwanese population, to test our hypothesis that patients with PC have an increased risk of AMD and that the risk of AMD decreases after androgen-deprivation therapy.
Methods Data source This population-based retrospective cohort study was conducted using the NHIRD of the Taiwan National Health Insurance (NHI) program. The NHI program was launched on 1 March 1995 and now covers approximately 99% of the 23.74 million people living in Taiwan. The NHIRD and NHI program have been thoroughly described in previous studies [14–17]. Diagnostic codes based on the International Classification of Diseases (ICD)-9-CM were retrieved using the NHIRD. This study was evaluated and approved by the Institutional Review Board of China Medical University and Hospital (CMUH104-REC2-115-CR1).
diagnoses or coding, they are liable for severe penalties. Many studies have utilized the NHIRD as a research resource [14–17]. Therefore, the diagnoses adapted in this study should be highly reliable.
Research participants Figure 1 shows the selection procedure of study participants. We established two types of cohorts from prostate cancer (ICD-9-CM code 185) newly diagnosed in 2000–2008. The first date of diagnosis of PC was defined as the index date. Patients under 20 years old, with another form of cancer (ICD-9-CM codes 140–184, 186–208) and macular degeneration (ICD-9-CM code 362.5) before the index date, or with incomplete demographic information were excluded. The first cohort type comprised 22 084 patients with PC and 22 065 patients without PC, who were frequency matched by age, occupation, urbanization level, and index year using the same exclusion criteria. We calculated propensity scores by using logistic regression to estimate the probability of the disease assignment. Baseline variables used for calculating the propensity score included PC diagnosis year, age, occupation, urbanization level, and comorbidities. For the second cohort type, we selected 19 624 patients with PC and 19 624 patients without PC, matched by the propensity score. Comorbidities included diabetes (ICD-9-CM 250), hypertension (ICD-9-CM 401–405), hyperlipidemia (ICD-9-CM 272), coronary artery disease (CAD) (ICD-9-CM 410–414), stroke (ICD-9-CM 430–438), end-stage renal disease (ICD-9-CM 585), chronic obstructive pulmonary disease (COPD) (ICD-9-CM 491, 492, 496), myopia (ICD-9-CM 367.1, 360.21), vitreous floaters (ICD-9-CM 379.24), congenital hyperthyroidism (ICD-9-CM 243), acquired hypothyroidism (ICD-9-CM 244), and hyperthyroidism (ICD-9-CM 242). To minimize potential surveillance bias, frequency of medical visits was adjusted as one confounding factor.
Accuracy of the NHIRD This study used the NHIRD as its data source. The NHIRD covers a highly representative sample of the Taiwanese population because the reimbursement policy is universal and operated by a single payer, the government of Taiwan. All insurance claims are scrutinized by medical reimbursement specialists and through peer review according to the standard diagnostic criteria. If doctors or hospitals make the wrong Newly diagnosed prostate cancer (PC) patients in 2000-2008 (N= 24 464)
Outcome measurement and treatments Each of the study participants was followed until macular degeneration, withdrawal from the NHI program, or 31 December 2011. We also considered PC-related treatments, including hormone therapy, radiotherapy, chemotherapy, and prostatectomy.
General population without PC patients
Exclusion: 1. With another form of cancer (N= 1399) 2. With a history of macular degeneration (N= 979)
Using the same exclusion criteria as the PC cohort. Frequency matched with age, occupation, urbanization level, and index year of PC.
3. Age younger than 20 years (N= 2)
Non-PC cohort N= 22065
PC cohort N=22 084
Propensity score matching
PC cohort N=19 624
Non-PC cohort N= 19624
Figure 1. Flow chart dipicting the selection procedure of the study participants.
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Table 1. Demographic characteristics and comorbidities in cohorts with and without prostate cancer by age-, occupation-, and urbanization level matched and propensity score matched Age, occupation, and urbanization level matched Variable
P valuea
Prostate cancer No N 5 22 065
Age, years 64 3106 (14.1) >65 18 959 (85.9) Means (SD)b 73.2 (8.63) Frequency of medical visits/per year, means (SD)b 23.4 (19.5) Occupation White collar 9276 (42.0) Blue collar 8078 (36.6) Othersc 4711 (21.4) Urbanization leveld 1 (highest) 6328 (28.7) 2 6084 (27.6) 3 3439 (15.6) 4 (lowest) 6214 (28.2) Comorbidity Diabetes 3779 (17.1) Hypertension 13 490 (61.1) Hyperlipidemia 5720 (25.9) CAD 7537 (34.2) Stroke 2540 (11.5) ESRD 138 (0.63) COPD 9580 (43.4) Myopia 79 (0.36) Vitreous floaters 283 (1.28) Hypothyroidism 78 (0.35) Hyperthyroidism 163 (0.74) Hormone therapy Oral Injection Treatment Radiotherapy Chemotherapy Prostatectomy
Yes N 5 22 084
Propensity score matched Prostate cancer No N 5 19 624
Yes N 5 19 624
0.97 3106 (14.1) 18 978 (85.9) 73.9 (8.34) 28.7 (20.1)
0.001 0.001 0.99
9289 (42.1) 8080 (36.6) 4715 (21.4)
0.001 2421 (12.3) 2940 (15.0) 17 203 (87.7) 16 684 (85.0) 73.7 (8.40) 73.7 (8.45) 24.4 (19.7) 27.5 (19.4) 8198 (41.8) 7225 (36.8) 4201 (21.4)
8195 (41.8) 7243 (36.9) 4186 (21.3)
5600 (28.5) 5376 (27.4) 3074 (15.7) 5574 (28.4)
5602 (28.6) 5375 (27.4) 3086 (15.7) 5561 (28.3)
0.99 6333 (28.6) 6085 (27.6) 3441 (15.6) 6225 (28.2) 3855 (17.5) 15 254 (69.1) 7631 (34.6) 9613 (43.5) 2313 (10.5) 91 (0.41) 10 779 (48.8) 118 (0.53) 371 (1.68) 126 (0.57) 15 (0.07)
0.36 <0.001 <0.001 <0.001 <0.001 0.002 <0.001 0.006 <0.001 <0.001 <0.001
P valuea
0.66 0.001 0.98
0.99
3418 (17.4) 3451 (17.6) 12 945 (66.0) 12 938 (65.9) 5633 (28.7) 5760 (29.4) 7413 (37.8) 7538 (38.4) 2177 (11.1) 2173 (11.1) 86 (0.44) 91 (0.46) 9072 (46.2) 9070 (46.2) 79 (0.40) 91 (0.46) 278 (1.42) 263 (1.34) 65 (0.33) 72 (0.37) 15 (0.08) 15 (0.08)
16 129 (73.0) 2988 (13.5)
14 332 (73.0) 2672 (13.6)
8347 (37.8) 2695 (12.2) 9256 (41.9)
7375 (37.6) 2446 (12.5) 8303 (42.3)
0.66 0.94 0.16 0.19 0.95 0.71 0.98 0.36 0.52 0.55 0.99
a
Comparison between prostate cancer and control. Student’s t-test. c Other occupations included primarily retired, unemployed, or low income populations. d The urbanization level was categorized by the population density of the residential area into four levels, with level 1 as the most urbanized and level 4 as the least urbanized. CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; ESRD, end-stage renal disease. b
Statistical analysis The baseline distributions of sociodemographic characteristics and comorbidities were compared between the PC and non-PC cohorts using the v2 test for categorical variables and Student’s t-test for continuous variables. To assess the difference in the cumulative incidence curve of macular degeneration between the two cohorts, Kaplan–Meier analysis and a log-rank test were used. We calculated the overall incidence density of macular degeneration for each cohort and used univariable and multivariable Cox proportional hazards regression models to measure the
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hazard ratios (HRs) and 95% confidence interval (CI) of macular degeneration for the PC cohorts compared with the non-PC cohorts. Furthermore, we considered death a competing risk for estimating the risk of macular degeneration. We did so using the Fine–Gray model, which extends the standard univariable and multivariable Cox proportional-hazard regression model. The multivariable models were simultaneously adjusted for age, occupation, and urbanization level and the comorbidities of diabetes, hypertension, hyperlipidemia, CAD, stroke, end-stage renal disease, COPD, myopia, vitreous floaters, hypothyroidism, and hyperthyroidism. SAS (version 9.4 for Windows; SAS
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Annals of Oncology significantly higher in the PC cohort than in the age-, occupation-, and urbanization level-matched non-PC cohort (adjusted sub-HR, 1.24; 95% CI, 1.11–1.38) (Table 3). Similar results were observed for propensity score-matching, where the PC cohort had a 1.25-fold higher risk of developing macular degeneration than the non-PC cohort. Compared with the PC cohort receiving no injection hormone therapy, the PC cohort receiving injection hormone therapy had a lower risk of macular degeneration. The PC cohort receiving oral hormone therapy appeared to have a lower risk of macular degeneration than the PC cohort receiving no oral hormone therapy although the difference was not statistically significant (Table 4).
Cumulative incidence of macular degeneration
0.08 Without prostate cancer With prostate cancer Log-rank test: P-value<0.001 0.06
0.04
0.02
Discussion
0 0
2 4 6 8 10 Time to macular degeneration (years)
12
Figure 2. Cumulative incidence of macular degeneration with and without prostate cancer in the age-, occupation-, and urbanization level-matched cohorts. Institute Inc., Cary, NC) was used for all data analyses, with P < 0.05 being considered significant for a two-tailed test.
Results The baseline sociodemographic factors, comorbidity, hormone therapy, and treatment of the patients in the PC and non-PC cohorts are presented in Table 1. The patients in the PC cohort registered a higher frequency of medical visits than did those in the non-PC cohort. The mean age of the PC cohorts was 73.9 years and that of the non-PC cohorts was 73.2 years, with approximately 85.9% of the patients aged 65 years, 42% holding white-collar jobs, and 56% residing in urban areas. Comorbidities, including hypertension, hyperlipidemia, CAD, COPD, myopia, vitreous floaters, and hypothyroidism were more prevalent in the first PC cohort. The proportions of patients with PC receiving treatment of oral hormone therapy, prostatectomy, and radiotherapy were 73.0%, 41.9%, and 37.8%, respectively. As for the second cohort type, the propensity score-matched PC and non-PC cohorts were similar in all baseline sociodemographic factors and comorbidities. Figure 2 shows the cumulative incidence of macular degeneration curves and reveals that the curve for PC patients was significantly higher than that for the non-PC cohort in the age-, occupation-, and urbanization level-matched cohorts (P < 0.001). The mean follow-up periods (standard deviation) for the patients with macular degeneration in the age-, occupation-, and urbanization level-matched PC and non-PC cohorts were 4.69 (2.90) and 5.51 (2.82) years, respectively (Table 2). The overall incidence density of macular degeneration was higher in the PC cohort than in the frequency-matched non-PC cohort (7.24 versus 5.38 per 1000 person-years) with an adjusted HR of 1.20 (95% CI, 1.08–1.34). The PC cohort had a higher risk of macular degeneration than the propensity score-matched non-PC cohort with an adjusted HR of 1.18 (95% CI, 1.05–1.32). After adjusting for all confounding factors in the competing risk regression model, the risk of macular degeneration remained
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This cohort study showed an association between patients with PC and AMD. Patients with PC who received androgendeprivation therapy, especially injection form, had a lower risk of AMD compared with the patients with PC who did not receive injected androgen-deprivation therapy. There are several explanations for this finding. AMD and PC might have the same etiology. Low dietary intake of certain carotenoid-containing fruits and vegetables was found to be associated with higher risks of PC and AMD [18]. Further, oxidative stress resulting both from diet and PC [19, 20] could contribute to the development of AMD. Until now, no significant data have shown that androgen levels or male characteristics are related to a higher risk of AMD. Li et al. [21] observed that men had greater choroidal thickness than women, which might be related to the risk of AMD. However, their study did not provide direct evidence of a link between men and AMD. In another aspect, Defay et al. determined that hormone replacement therapy for women aged older than 60 years provided no protective effect against AMD [22]. Because PC risk is not closely related to high serum androgen concentrations [23], sex steroids could not fully account for the association between PC and AMD. Another notable finding is that androgen-deprivation therapy was associated with a lower risk of AMD. Nishiyama et al. determined that dihydrotestosterone levels in serum decreased to approximately 7.5% after androgen-deprivation therapy [24]. Although no research has identified a clear association between dihydrotestosterone levels and AMD risk, studies have determined that testosterone deficiency is related to insulin resistance, increased oxidative stress, and metabolic syndrome [25, 26], which are known AMD risk factors. Thus, future studies must clarify the mechanism by which androgen-deprivation therapy is associated with a lower risk of AMD. Some limitations were present in this study. First, we had no information regarding family histories of AMD among the patients. Second, detailed information regarding blood pressure levels, glucose control, cholesterol levels, cigarette smoking habits, fresh vegetable and artificial fat consumption, and obesity, all of which are factors related to AMD, was unavailable. Third, information about histology, staging, pattern of relapse, and pattern of progression of PC were unobtainable using NHIRD. Besides, there was also no specified information in NHIRD about precise extent of surgery, type of lymph node dissection, and serum baseline levels of testosterone for PC patients. Asymptomatic PC could also be missed
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Table 2. Incidence and hazard ratio of macular degeneration in patients with prostate cancer compared with those without prostate cancer by type of matching between study cohorts
Person-years Follow-up time (years) Macular degeneration Event Rate Crude HR (95% CI) Adjusted HR (95% CI)
Age, occupation, and urbanization level matched
Propensity score matched
Prostate cancer
Prostate cancer
No
Yes
No
Yes
(N ¼ 22 065) 121 676 5.51 6 2.82
(N ¼ 22 084) 103 484 4.69 6 2.90
(N ¼ 19 624) 107 986 5.50 6 2.82
(N ¼ 19 624) 91 872 4.68 6 2.91
655 5.38 1 (Reference) 1 (Reference)
749 7.24 1.34 (1.21, 1.49)*** 1.20 (1.08, 1.34)***
607 5.62 1 (Reference) 1 (Reference)
629 6.85 1.22 (1.09, 1.37)*** 1.18 (1.05, 1.32)**
Rate: incidence rate, per 1000 person-years; Crude HR: relative hazard ratio; Adjusted HR: multivariable analysis including age, occupation, urbanization level, frequency of medical visits, comorbidities of diabetes, hypertension, hyperlipidemia, coronary artery disease, stroke, end-stage renal disease, chronic obstructive pulmonary disease, myopia, vitreous floaters, hypothyroidism, and hyperthyroidism. **P < 0.01; ***P < 0.001. CI, confidence interval; HR, hazard ratio.
Table 3. Incidence and SHR of macular degeneration in patients with prostate cancer compared with those without prostate cancer using the competing-risks regression models by type of matching between study cohorts Competing-risks regression models Prostate cancer No (N 5 22 065) Age, occupation, and urbanization level matched Macular degeneration Crude SHR (95% CI) 1 (Reference) Adjusted SHR (95% CI) 1 (Reference) Propensity score matched Macular degeneration Crude SHR (95% CI) 1 (Reference) Adjusted SHR (95% CI) 1 (Reference)
Yes (N 5 22 084)
1.37 (1.23, 1.52)*** 1.24 (1.11, 1.38)***
Acknowledgement 1.28 (1.14, 1.43)*** 1.25 (1.12, 1.39)***
Crude SHR: relative SHR. Adjusted SHR: multivariable analysis including age, occupation, urbanization level, frequency of medical visits, and comorbidities of diabetes, hypertension, hyperlipidemia, coronary artery disease , stroke, end-stage renal disease, chronic obstructive pulmonary disease, myopia, vitreous floaters, hypothyroidism, and hyperthyroidism. ***P < 0.001. CI, confidence interval; SHR, subhazard ratio.
diagnosed or under-estimated while this study was based on registered NHIRD. Fourth, the database comprised data on a primarily Taiwanese population; consequently, the findings might not be generalizable to other populations. Finally, information regarding
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the genetic variations regulating inflammation, which are factors related to AMD, was unavailable. Furthermore, the propensity score matching method is important for cohorts with high risks of complications and/or mortality. In the present study, we proved that the results were approximately similar between cohort sets with and without propensity score matching. We agree that it is possible there are uncontrolled confounders not solved. In conclusion, our study findings indicate that PC is associated with the risk of developing AMD. Patients with PC who were receiving injected androgen-deprivation therapy had a lower risk than others of developing AMD. This finding provides an impetus for clinicians to closely monitor the retinas of patients with PC to detect AMD early.
We very appreciate English language editing by Prof. FungChang Sung, PhD, for the revised manuscript.
Funding This study was supported in part by Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW106-TDU-B-212-113 004), China Medical University Hospital, Academia Sinica Taiwan Biobank Stroke Biosignature Project (BM10601010036), Taiwan Clinical Trial Consortium for Stroke (MOST 106-2321-B-039-005), Tseng-Lien Lin Foundation, Taichung, Taiwan (no grant numbers apply), Taiwan Brain Disease Foundation, Taipei, Taiwan (no grant numbers apply), and Katsuzo and Kiyo AoshimaMemorial Funds, Japan (no grant numbers apply). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.
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Table 4. Comparisons of incidence, and hazard ratios of macular degeneration by different treatment of prostate cancer among prostate cancer by propensity score matched Variable
Event
PY
Rate
Crude HR (95% CI)
Adjusted HR (95% CI)
Crude HR (95% CI)
Adjusted HR (95% CI)
Non-PC cohort Hormone therapy Oral No Yes Injection No Yes
607
107 985
5.62
1 (Reference)
1 (Reference)
210 419
25 115 66 757
8.36 6.28
1.49 (1.28, 1.75)*** 1.12 (0.99, 1.27)
1.39 (1.19, 1.63)*** 1.09 (0.96, 1.24)
1 (Reference) 0.75 (0.64, 0.89)***
1 (Reference) 0.86 (0.72, 1.02)
585 44
79 151 12 721
7.39 3.46
1.32 (1.18, 1.48)*** 0.62 (0.45, 0.84)**
1.25 (1.12, 1.40)*** 0.65 (0.48, 0.88)**
1 (Reference) 0.47 (0.35, 0.64)***
1 (Reference) 0.56 (0.41, 0.76)***
Rate: incidence rate, per 1000 person-years; Crude HR: relative hazard ratio; Adjusted HR: multivariable analysis including age, occupation, urbanization level, frequency of medical visits, comorbidities of diabetes, hypertension, hyperlipidemia, coronary artery disease, stroke, end-stage renal disease, chronic obstructive pulmonary disease, myopia, vitreous floaters, hypothyroidism, hyperthyroidism, hormone therapy, radiotherapy, chemotherapy and prostatectomy;. **P < 0.01, ***P < 0.001. CI, confidence interval; PC, prostate cancer.
Disclosure All authors have declared no conflicts of interest.
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ORIGINAL ARTICLE
Risk of age-related macular degeneration in patients with prostate cancer: a nationwide, population-based cohort study S.-Y. Lin1,2, C.-L. Lin3,4, C.-H. Chang5, H.-C. Wu5, C.-H. Lin6 & C.-H. Kao7,8,9* 1 Institute of Clinical Medical Science, China Medical University College of Medicine, Taichung; 2Division of Nephrology and Kidney Institute; 3Management Office for Health Data, China Medical University Hospital, Taichung; 4College of Medicine, China Medical University, Taichung; 5Departments of Urology; 6Family Medicine, China Medical University Hospital, Taichung; 7Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung; 8Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung; 9Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
*Correspondence to: Prof. Chia-Hung Kao, Graduate Institute of Clinical Medical Science and School of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 404, Taiwan. Tel: þ886-4-22052121 ext. 7412; Fax: þ886-4-22336174; E-mail: [email protected]
Background: Prostate cancer (PC) can be related to increased systemic oxidative stress and dihydrotestosterone level, which are also reported to be involved in the pathogenesis of age-related macular degeneration (AMD). We conducted a cohort study to determine whether patients with PC have an increased risk of AMD. Patients and methods: Data were collected from the Taiwan Longitudinal Health Insurance Database for the 1999–2010 period. The study PC cohort comprised 22 084 patients aged 18 years with a first diagnosis of PC. The comparison cohort consisted of age-, occupation-, and urbanization level-matched patients at a ratio of 1 : 1. The primary outcome was the incidence of AMD, which was evaluated using Kaplan–Meier survival analysis and proportional hazards modeling. Results: The mean follow-up periods (standard deviation) for the patients with AMD in the age-, occupation-, and urbanization level-matched PC cohort and non-PC cohorts were 4.69 (2.90) and 5.51 (2.82) years. The mean age of the PC cohort was 73.9 years and that of the non-PC cohort was 73.2 years, with approximately 85.9% of the patients aged >65 years. The PC cohort had a higher risk of AMD than did the propensity score-matched non-PC cohort with an adjusted hazard ratio of 1.25 (95% confidence interval, 1.12–1.39). Compared with PC cohort receiving no injection hormone therapy, the PC cohort receiving injection hormone therapy had a lower risk of AMD (adjusted hazard ratio, 0.56; 95% confidence interval, 0.41–0.76). Conclusion: PC is associated with an increased risk of AMD. Patients with PC receiving injected form of androgen deprivation therapy had a lower risk of AMD than patients with PC not receiving injected form of androgen-deprivation therapy. Key words: prostate cancer, age-related macular degeneration, cohort study
Introduction Age-related macular degeneration (AMD) is the leading cause of blindness worldwide [1]. The most common clinical features of AMD are impairment of the central vision and metamorphopsia [2]. Choroidal neovascularization and geographic atrophy are two classic ophthalmoscopic hallmarks of AMD. Intravitreal bevacizumab or ranibizumab, high doses of vitamins C and E, b-carotene, and zinc supplements can help delay the progression of AMD [3, 4]. However, until now, no curative treatment of AMD has existed. Embryonic stem cell therapies [5] and several
neuroprotective agents have shown potential and remain under clinical investigation [6, 7]. Thus, identifying the risk factors of AMD would be the most effective strategy for lowering the incidence of AMD. Current major risk factors of AMD include smoking, cardiovascular diseases, and genetic influences, including complement polymorphism and lipid, angiogenetic, and extracellular matrix pathways [1]. Oxidative stress and inflammatory processes also play roles in the pathogenesis of AMD [8]. Dihyrotestosterone, a metabolite of testosterone, was shown to have a protective effect in mouse embryonic stem cells [9].
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However, animal studies have shown that dihyrotestosterone can induce oxidative stress [10, 11]. In clinical aspects, dihydrotestosterone has been associated with the development and progression of PC [12, 13]. No clinical population-based studies have investigated the risk of AMD in PC patients. Whether the risks of AMD would lessen if PC patients received androgen-deprivation therapy is unknown. Therefore, we used the National Health Insurance Research Database (NHIRD), a database representing the Taiwanese population, to test our hypothesis that patients with PC have an increased risk of AMD and that the risk of AMD decreases after androgen-deprivation therapy.
Methods Data source This population-based retrospective cohort study was conducted using the NHIRD of the Taiwan National Health Insurance (NHI) program. The NHI program was launched on 1 March 1995 and now covers approximately 99% of the 23.74 million people living in Taiwan. The NHIRD and NHI program have been thoroughly described in previous studies [14–17]. Diagnostic codes based on the International Classification of Diseases (ICD)-9-CM were retrieved using the NHIRD. This study was evaluated and approved by the Institutional Review Board of China Medical University and Hospital (CMUH104-REC2-115-CR1).
diagnoses or coding, they are liable for severe penalties. Many studies have utilized the NHIRD as a research resource [14–17]. Therefore, the diagnoses adapted in this study should be highly reliable.
Research participants Figure 1 shows the selection procedure of study participants. We established two types of cohorts from prostate cancer (ICD-9-CM code 185) newly diagnosed in 2000–2008. The first date of diagnosis of PC was defined as the index date. Patients under 20 years old, with another form of cancer (ICD-9-CM codes 140–184, 186–208) and macular degeneration (ICD-9-CM code 362.5) before the index date, or with incomplete demographic information were excluded. The first cohort type comprised 22 084 patients with PC and 22 065 patients without PC, who were frequency matched by age, occupation, urbanization level, and index year using the same exclusion criteria. We calculated propensity scores by using logistic regression to estimate the probability of the disease assignment. Baseline variables used for calculating the propensity score included PC diagnosis year, age, occupation, urbanization level, and comorbidities. For the second cohort type, we selected 19 624 patients with PC and 19 624 patients without PC, matched by the propensity score. Comorbidities included diabetes (ICD-9-CM 250), hypertension (ICD-9-CM 401–405), hyperlipidemia (ICD-9-CM 272), coronary artery disease (CAD) (ICD-9-CM 410–414), stroke (ICD-9-CM 430–438), end-stage renal disease (ICD-9-CM 585), chronic obstructive pulmonary disease (COPD) (ICD-9-CM 491, 492, 496), myopia (ICD-9-CM 367.1, 360.21), vitreous floaters (ICD-9-CM 379.24), congenital hyperthyroidism (ICD-9-CM 243), acquired hypothyroidism (ICD-9-CM 244), and hyperthyroidism (ICD-9-CM 242). To minimize potential surveillance bias, frequency of medical visits was adjusted as one confounding factor.
Accuracy of the NHIRD This study used the NHIRD as its data source. The NHIRD covers a highly representative sample of the Taiwanese population because the reimbursement policy is universal and operated by a single payer, the government of Taiwan. All insurance claims are scrutinized by medical reimbursement specialists and through peer review according to the standard diagnostic criteria. If doctors or hospitals make the wrong Newly diagnosed prostate cancer (PC) patients in 2000-2008 (N= 24 464)
Outcome measurement and treatments Each of the study participants was followed until macular degeneration, withdrawal from the NHI program, or 31 December 2011. We also considered PC-related treatments, including hormone therapy, radiotherapy, chemotherapy, and prostatectomy.
General population without PC patients
Exclusion: 1. With another form of cancer (N= 1399) 2. With a history of macular degeneration (N= 979)
Using the same exclusion criteria as the PC cohort. Frequency matched with age, occupation, urbanization level, and index year of PC.
3. Age younger than 20 years (N= 2)
Non-PC cohort N= 22065
PC cohort N=22 084
Propensity score matching
PC cohort N=19 624
Non-PC cohort N= 19624
Figure 1. Flow chart dipicting the selection procedure of the study participants.
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Table 1. Demographic characteristics and comorbidities in cohorts with and without prostate cancer by age-, occupation-, and urbanization level matched and propensity score matched Age, occupation, and urbanization level matched Variable
P valuea
Prostate cancer No N 5 22 065
Age, years 64 3106 (14.1) >65 18 959 (85.9) Means (SD)b 73.2 (8.63) Frequency of medical visits/per year, means (SD)b 23.4 (19.5) Occupation White collar 9276 (42.0) Blue collar 8078 (36.6) Othersc 4711 (21.4) Urbanization leveld 1 (highest) 6328 (28.7) 2 6084 (27.6) 3 3439 (15.6) 4 (lowest) 6214 (28.2) Comorbidity Diabetes 3779 (17.1) Hypertension 13 490 (61.1) Hyperlipidemia 5720 (25.9) CAD 7537 (34.2) Stroke 2540 (11.5) ESRD 138 (0.63) COPD 9580 (43.4) Myopia 79 (0.36) Vitreous floaters 283 (1.28) Hypothyroidism 78 (0.35) Hyperthyroidism 163 (0.74) Hormone therapy Oral Injection Treatment Radiotherapy Chemotherapy Prostatectomy
Yes N 5 22 084
Propensity score matched Prostate cancer No N 5 19 624
Yes N 5 19 624
0.97 3106 (14.1) 18 978 (85.9) 73.9 (8.34) 28.7 (20.1)
0.001 0.001 0.99
9289 (42.1) 8080 (36.6) 4715 (21.4)
0.001 2421 (12.3) 2940 (15.0) 17 203 (87.7) 16 684 (85.0) 73.7 (8.40) 73.7 (8.45) 24.4 (19.7) 27.5 (19.4) 8198 (41.8) 7225 (36.8) 4201 (21.4)
8195 (41.8) 7243 (36.9) 4186 (21.3)
5600 (28.5) 5376 (27.4) 3074 (15.7) 5574 (28.4)
5602 (28.6) 5375 (27.4) 3086 (15.7) 5561 (28.3)
0.99 6333 (28.6) 6085 (27.6) 3441 (15.6) 6225 (28.2) 3855 (17.5) 15 254 (69.1) 7631 (34.6) 9613 (43.5) 2313 (10.5) 91 (0.41) 10 779 (48.8) 118 (0.53) 371 (1.68) 126 (0.57) 15 (0.07)
0.36 <0.001 <0.001 <0.001 <0.001 0.002 <0.001 0.006 <0.001 <0.001 <0.001
P valuea
0.66 0.001 0.98
0.99
3418 (17.4) 3451 (17.6) 12 945 (66.0) 12 938 (65.9) 5633 (28.7) 5760 (29.4) 7413 (37.8) 7538 (38.4) 2177 (11.1) 2173 (11.1) 86 (0.44) 91 (0.46) 9072 (46.2) 9070 (46.2) 79 (0.40) 91 (0.46) 278 (1.42) 263 (1.34) 65 (0.33) 72 (0.37) 15 (0.08) 15 (0.08)
16 129 (73.0) 2988 (13.5)
14 332 (73.0) 2672 (13.6)
8347 (37.8) 2695 (12.2) 9256 (41.9)
7375 (37.6) 2446 (12.5) 8303 (42.3)
0.66 0.94 0.16 0.19 0.95 0.71 0.98 0.36 0.52 0.55 0.99
a
Comparison between prostate cancer and control. Student’s t-test. c Other occupations included primarily retired, unemployed, or low income populations. d The urbanization level was categorized by the population density of the residential area into four levels, with level 1 as the most urbanized and level 4 as the least urbanized. CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; ESRD, end-stage renal disease. b
Statistical analysis The baseline distributions of sociodemographic characteristics and comorbidities were compared between the PC and non-PC cohorts using the v2 test for categorical variables and Student’s t-test for continuous variables. To assess the difference in the cumulative incidence curve of macular degeneration between the two cohorts, Kaplan–Meier analysis and a log-rank test were used. We calculated the overall incidence density of macular degeneration for each cohort and used univariable and multivariable Cox proportional hazards regression models to measure the
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hazard ratios (HRs) and 95% confidence interval (CI) of macular degeneration for the PC cohorts compared with the non-PC cohorts. Furthermore, we considered death a competing risk for estimating the risk of macular degeneration. We did so using the Fine–Gray model, which extends the standard univariable and multivariable Cox proportional-hazard regression model. The multivariable models were simultaneously adjusted for age, occupation, and urbanization level and the comorbidities of diabetes, hypertension, hyperlipidemia, CAD, stroke, end-stage renal disease, COPD, myopia, vitreous floaters, hypothyroidism, and hyperthyroidism. SAS (version 9.4 for Windows; SAS
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Annals of Oncology significantly higher in the PC cohort than in the age-, occupation-, and urbanization level-matched non-PC cohort (adjusted sub-HR, 1.24; 95% CI, 1.11–1.38) (Table 3). Similar results were observed for propensity score-matching, where the PC cohort had a 1.25-fold higher risk of developing macular degeneration than the non-PC cohort. Compared with the PC cohort receiving no injection hormone therapy, the PC cohort receiving injection hormone therapy had a lower risk of macular degeneration. The PC cohort receiving oral hormone therapy appeared to have a lower risk of macular degeneration than the PC cohort receiving no oral hormone therapy although the difference was not statistically significant (Table 4).
Cumulative incidence of macular degeneration
0.08 Without prostate cancer With prostate cancer Log-rank test: P-value<0.001 0.06
0.04
0.02
Discussion
0 0
2 4 6 8 10 Time to macular degeneration (years)
12
Figure 2. Cumulative incidence of macular degeneration with and without prostate cancer in the age-, occupation-, and urbanization level-matched cohorts. Institute Inc., Cary, NC) was used for all data analyses, with P < 0.05 being considered significant for a two-tailed test.
Results The baseline sociodemographic factors, comorbidity, hormone therapy, and treatment of the patients in the PC and non-PC cohorts are presented in Table 1. The patients in the PC cohort registered a higher frequency of medical visits than did those in the non-PC cohort. The mean age of the PC cohorts was 73.9 years and that of the non-PC cohorts was 73.2 years, with approximately 85.9% of the patients aged 65 years, 42% holding white-collar jobs, and 56% residing in urban areas. Comorbidities, including hypertension, hyperlipidemia, CAD, COPD, myopia, vitreous floaters, and hypothyroidism were more prevalent in the first PC cohort. The proportions of patients with PC receiving treatment of oral hormone therapy, prostatectomy, and radiotherapy were 73.0%, 41.9%, and 37.8%, respectively. As for the second cohort type, the propensity score-matched PC and non-PC cohorts were similar in all baseline sociodemographic factors and comorbidities. Figure 2 shows the cumulative incidence of macular degeneration curves and reveals that the curve for PC patients was significantly higher than that for the non-PC cohort in the age-, occupation-, and urbanization level-matched cohorts (P < 0.001). The mean follow-up periods (standard deviation) for the patients with macular degeneration in the age-, occupation-, and urbanization level-matched PC and non-PC cohorts were 4.69 (2.90) and 5.51 (2.82) years, respectively (Table 2). The overall incidence density of macular degeneration was higher in the PC cohort than in the frequency-matched non-PC cohort (7.24 versus 5.38 per 1000 person-years) with an adjusted HR of 1.20 (95% CI, 1.08–1.34). The PC cohort had a higher risk of macular degeneration than the propensity score-matched non-PC cohort with an adjusted HR of 1.18 (95% CI, 1.05–1.32). After adjusting for all confounding factors in the competing risk regression model, the risk of macular degeneration remained
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This cohort study showed an association between patients with PC and AMD. Patients with PC who received androgendeprivation therapy, especially injection form, had a lower risk of AMD compared with the patients with PC who did not receive injected androgen-deprivation therapy. There are several explanations for this finding. AMD and PC might have the same etiology. Low dietary intake of certain carotenoid-containing fruits and vegetables was found to be associated with higher risks of PC and AMD [18]. Further, oxidative stress resulting both from diet and PC [19, 20] could contribute to the development of AMD. Until now, no significant data have shown that androgen levels or male characteristics are related to a higher risk of AMD. Li et al. [21] observed that men had greater choroidal thickness than women, which might be related to the risk of AMD. However, their study did not provide direct evidence of a link between men and AMD. In another aspect, Defay et al. determined that hormone replacement therapy for women aged older than 60 years provided no protective effect against AMD [22]. Because PC risk is not closely related to high serum androgen concentrations [23], sex steroids could not fully account for the association between PC and AMD. Another notable finding is that androgen-deprivation therapy was associated with a lower risk of AMD. Nishiyama et al. determined that dihydrotestosterone levels in serum decreased to approximately 7.5% after androgen-deprivation therapy [24]. Although no research has identified a clear association between dihydrotestosterone levels and AMD risk, studies have determined that testosterone deficiency is related to insulin resistance, increased oxidative stress, and metabolic syndrome [25, 26], which are known AMD risk factors. Thus, future studies must clarify the mechanism by which androgen-deprivation therapy is associated with a lower risk of AMD. Some limitations were present in this study. First, we had no information regarding family histories of AMD among the patients. Second, detailed information regarding blood pressure levels, glucose control, cholesterol levels, cigarette smoking habits, fresh vegetable and artificial fat consumption, and obesity, all of which are factors related to AMD, was unavailable. Third, information about histology, staging, pattern of relapse, and pattern of progression of PC were unobtainable using NHIRD. Besides, there was also no specified information in NHIRD about precise extent of surgery, type of lymph node dissection, and serum baseline levels of testosterone for PC patients. Asymptomatic PC could also be missed
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Table 2. Incidence and hazard ratio of macular degeneration in patients with prostate cancer compared with those without prostate cancer by type of matching between study cohorts
Person-years Follow-up time (years) Macular degeneration Event Rate Crude HR (95% CI) Adjusted HR (95% CI)
Age, occupation, and urbanization level matched
Propensity score matched
Prostate cancer
Prostate cancer
No
Yes
No
Yes
(N ¼ 22 065) 121 676 5.51 6 2.82
(N ¼ 22 084) 103 484 4.69 6 2.90
(N ¼ 19 624) 107 986 5.50 6 2.82
(N ¼ 19 624) 91 872 4.68 6 2.91
655 5.38 1 (Reference) 1 (Reference)
749 7.24 1.34 (1.21, 1.49)*** 1.20 (1.08, 1.34)***
607 5.62 1 (Reference) 1 (Reference)
629 6.85 1.22 (1.09, 1.37)*** 1.18 (1.05, 1.32)**
Rate: incidence rate, per 1000 person-years; Crude HR: relative hazard ratio; Adjusted HR: multivariable analysis including age, occupation, urbanization level, frequency of medical visits, comorbidities of diabetes, hypertension, hyperlipidemia, coronary artery disease, stroke, end-stage renal disease, chronic obstructive pulmonary disease, myopia, vitreous floaters, hypothyroidism, and hyperthyroidism. **P < 0.01; ***P < 0.001. CI, confidence interval; HR, hazard ratio.
Table 3. Incidence and SHR of macular degeneration in patients with prostate cancer compared with those without prostate cancer using the competing-risks regression models by type of matching between study cohorts Competing-risks regression models Prostate cancer No (N 5 22 065) Age, occupation, and urbanization level matched Macular degeneration Crude SHR (95% CI) 1 (Reference) Adjusted SHR (95% CI) 1 (Reference) Propensity score matched Macular degeneration Crude SHR (95% CI) 1 (Reference) Adjusted SHR (95% CI) 1 (Reference)
Yes (N 5 22 084)
1.37 (1.23, 1.52)*** 1.24 (1.11, 1.38)***
Acknowledgement 1.28 (1.14, 1.43)*** 1.25 (1.12, 1.39)***
Crude SHR: relative SHR. Adjusted SHR: multivariable analysis including age, occupation, urbanization level, frequency of medical visits, and comorbidities of diabetes, hypertension, hyperlipidemia, coronary artery disease , stroke, end-stage renal disease, chronic obstructive pulmonary disease, myopia, vitreous floaters, hypothyroidism, and hyperthyroidism. ***P < 0.001. CI, confidence interval; SHR, subhazard ratio.
diagnosed or under-estimated while this study was based on registered NHIRD. Fourth, the database comprised data on a primarily Taiwanese population; consequently, the findings might not be generalizable to other populations. Finally, information regarding
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the genetic variations regulating inflammation, which are factors related to AMD, was unavailable. Furthermore, the propensity score matching method is important for cohorts with high risks of complications and/or mortality. In the present study, we proved that the results were approximately similar between cohort sets with and without propensity score matching. We agree that it is possible there are uncontrolled confounders not solved. In conclusion, our study findings indicate that PC is associated with the risk of developing AMD. Patients with PC who were receiving injected androgen-deprivation therapy had a lower risk than others of developing AMD. This finding provides an impetus for clinicians to closely monitor the retinas of patients with PC to detect AMD early.
We very appreciate English language editing by Prof. FungChang Sung, PhD, for the revised manuscript.
Funding This study was supported in part by Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW106-TDU-B-212-113 004), China Medical University Hospital, Academia Sinica Taiwan Biobank Stroke Biosignature Project (BM10601010036), Taiwan Clinical Trial Consortium for Stroke (MOST 106-2321-B-039-005), Tseng-Lien Lin Foundation, Taichung, Taiwan (no grant numbers apply), Taiwan Brain Disease Foundation, Taipei, Taiwan (no grant numbers apply), and Katsuzo and Kiyo AoshimaMemorial Funds, Japan (no grant numbers apply). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.
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Table 4. Comparisons of incidence, and hazard ratios of macular degeneration by different treatment of prostate cancer among prostate cancer by propensity score matched Variable
Event
PY
Rate
Crude HR (95% CI)
Adjusted HR (95% CI)
Crude HR (95% CI)
Adjusted HR (95% CI)
Non-PC cohort Hormone therapy Oral No Yes Injection No Yes
607
107 985
5.62
1 (Reference)
1 (Reference)
210 419
25 115 66 757
8.36 6.28
1.49 (1.28, 1.75)*** 1.12 (0.99, 1.27)
1.39 (1.19, 1.63)*** 1.09 (0.96, 1.24)
1 (Reference) 0.75 (0.64, 0.89)***
1 (Reference) 0.86 (0.72, 1.02)
585 44
79 151 12 721
7.39 3.46
1.32 (1.18, 1.48)*** 0.62 (0.45, 0.84)**
1.25 (1.12, 1.40)*** 0.65 (0.48, 0.88)**
1 (Reference) 0.47 (0.35, 0.64)***
1 (Reference) 0.56 (0.41, 0.76)***
Rate: incidence rate, per 1000 person-years; Crude HR: relative hazard ratio; Adjusted HR: multivariable analysis including age, occupation, urbanization level, frequency of medical visits, comorbidities of diabetes, hypertension, hyperlipidemia, coronary artery disease, stroke, end-stage renal disease, chronic obstructive pulmonary disease, myopia, vitreous floaters, hypothyroidism, hyperthyroidism, hormone therapy, radiotherapy, chemotherapy and prostatectomy;. **P < 0.01, ***P < 0.001. CI, confidence interval; PC, prostate cancer.
Disclosure All authors have declared no conflicts of interest.
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