216 Research paper
Allopurinol and the incidence of bladder cancer: a Taiwan national retrospective cohort study Chung-Jen Chena,*, Ming-Chia Hsiehd,*, Wei-Ting Liaob,*, Ya-Ting Chanc and Shun-Jen Changc Our aim is to investigate the risk association between allopurinol use and cancer incidence among gout patients using clinical evidence. Newly diagnosed male patients with gout, 20 years or older, were included after excluding those who had a diagnosis of type 2 diabetes, and were followed up for 12 years in a retrospective cohort study of one million outpatients of a national database. The gout patients were matched to male controls by age and first diagnosis date of gout disease. We then estimated the risk associations between incident cancers and duration of allopurinol use by Cox hazard regression, age-adjusted standardized incidence ratio, and incidence per 1000 person-years. A total of 24 050 gout patients and 76 129 controls were included. The incidence of all-cause cancers for gout patients and controls was 8.26 cases and 7.49 cases/1000 person-years, respectively; it was markedly increased in gout patients who used allopurinol for over 90 days. The hazard ratio of allcause cancers was 1.21 (95% confidence interval = 1.03–1.42, P = 0.019) after adjustment for age and 2.26 for bladder cancer (95% confidence interval = 1.32–3.87, P = 0.003) on comparing those who
used allopurinol for over 90 days with nonusers. Meanwhile, other cancers did not show the same significant result. We concluded that those who used allopurinol for a long duration had a higher occurrence of both bladder cancer and all-cause cancers in clinical evidence. European Journal of Cancer Prevention 25:216–223 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Introduction
levels; thus, the causal association between the use of allopurinol and incident cancers is an important issue.
Allopurinol was developed as an inhibitor of xanthine oxidase in the 1960s, and was used to decrease both urate levels in plasma and the occurrence of acute gout. Recently, studies have shown that gout has an association with cancers (Boffetta et al., 2009; Kuo et al., 2012), especially kidney cancer bladder cancer, and prostate cancer (Loeb and Harris, 2008; Chen, 2014). Well-known risk factors for both gout and cancer may include obesity, hyperglycemia, heavy alcohol use as well as inflammation syndrome (Bianchini et al., 2002; Aggarwal and Gehlot, 2009; Greer and Whitcomb, 2009; Noroozian et al., 2014). In particular, inflammation has been well documented to be related to several cancers (Coussens and Werb, 2002; Balkwill and Coussens, 2004), including colorectal cancer (McMillan et al., 2003), pancreatic cancer (Jamieson et al., 2005; Greer and Whitcomb, 2009), urinary bladder cancer (Hilmy et al., 2005), and renal clear cell cancer (Lamb et al., 2006). Furthermore, about one-third of gout patients use allopurinol for the management of uric acid
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.eurjcancerprev.com). 0959-8278 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
European Journal of Cancer Prevention 2016, 25:216–223 Keywords: all-cause cancers, allopurinol, bladder cancer, hypouricemia agent Departments of aInternal Medicine, bBiotechnology, College of Life Science, Kaohsiung Medical University, cDepartment of Kinesiology, Health and Leisure Studies, National University of Kaohsiung, Kaohsiung and dDepartment of Internal Medicine, Division of Endocrinology and Metabolism, Changhua Christian Hospital, Changhua, Taiwan Correspondence to Shun-Jen Chang, PhD, National University of Kaohsiung, No. 700, Kaohsiung University Rd., Nanzih District, 811, Kaohsiung City, Taiwan Tel: + 886 7 5916679; fax: + 886 7 5919264; e-mail: [email protected] *Chung-Jen Chen, Ming-Chia Hsieh and Wei-Ting Liao contributed equally to the writing of this article. Received 17 January 2015 Accepted 18 February 2015
Many studies have shown that allopurinol enhances the occurrence of bladder cancer in animal models. Wang et al. (1976) showed that bladder cancer could be synergistically induced by both formamide and allopurinol treatment in rats. Furthermore, Fukushima et al. (1983) reported the enhancing effect of allopurinol on bladder cancer onset in male F334 rats; in the same year, Ito et al. (1983) confirmed the enhancing effect of allopurinol on bladder cancer onset in rats. However, with the aim of reducing serum uric acid level in the management of gout, relatively little attention has been paid to the relationship between the use of allopurinol and cancer in clinical evidence, and the widespread use of the drug was intended to reduce uric acid levels in gout patients. Allopurinol is used widely to reduce serum uric acid levels for the management of gout disease; even though accumulating evidence supports the relationship between development of cancer and allopurinol use, the clinical evidence remains unclear. Whether gout itself or allopurinol use affects the development of cancers should be studied. Here, we designed a retrospective cohort study to explore the causal association between the use of DOI: 10.1097/CEJ.0000000000000161
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
Allopurinol and bladder cancer Chen et al. 217
allopurinol and incident cancers in gout patients by analysis of national clinical outpatient records.
Materials and methods Study sample
The National Health Insurance Research Database (NHIRD) provided longitudinal cohort data on one million patients – about 5% of the total population of Taiwan – from the health insurance database from 1998 to 2011. The approval for analysis of the database was obtained from the Institutional Review Board of Changhua Christian Hospital (CCH IRB 121213). NHIRD provides disease diagnosis codes, following the International Classification of Diseases, Ninth Revision (ICD-9), and medical prescriptions. The outpatient database included records from 1998 to 2011, and the selection process is shown in Fig. 1. Participants included men who were 20 years of age or older, and we identified gout patients using the ICD-9 code 274, with the first date of diagnosis of gout after January 2000. Those who had a diagnosis of gout between 1998 and 1999 were excluded to ensure that they were new gout patients. The diagnosis was then further confirmed by continuous prescriptions of antigout medications three times. The control group included patients without a diagnosis of gout from 1998 to 2011. Those who had a diagnosis of diabetes (ICD-9: 250) and any cancers (ICD-9: 140–208) within 12 months after enrollment were excluded from the study. All participants from the inclusion date of the first diagnosis to 2011 were followed up. We randomly selected three to four nongout controls to match each gout patient by age as well as the same year and month of enrollment. This matching process ensures that the follow-up time was the same at baseline, and avoids confounding effects from sex and age on the outcome of the diseases. Usage of hypouricemia agents, such as allopurinol and benzbromarone, was estimated within 3 years after the onset of gout. The comorbidities of gout were defined for those who had a diagnosis within 1 year after enrollment, such as obesity (ICD-9: 278), hyperlipidemia (ICD-9: 272), and hypertension (ICD-9: 4010, 4011, 4019). The endpoint was the occurrence of all-cause cancers after 1 year of enrollment for all participants. Statistical analyses
The hazard ratio (HR), standardized incidence ratio (SIR), and 95% confidence intervals (95% CI) after adjustment for age were estimated to determine the risk ratio of incident all-cause cancers between gout and control groups and between those who used allopurinol (or benzbromarone) for over 90 days and nonusers. The t-test was used to estimate the mean difference for age and follow-up time, and the χ2-test was used to estimate the differences in frequency for obesity, hyperlipidemia, hypertension, and all-cause cancers between gout patients and controls.
Population-attributable fraction
This is the proportion by which the incidence of all-cause cancers or bladder cancer in the gout population would theoretically be reduced if they did not use allopurinol for over 90 days. PAF ¼
Ip Iu 100 % ; Ip
where Ip and Iu are the incidences of all-cause cancers in the gout population (Ip) and those who did not use allopurinol (Iu), respectively. Exposed-attributable fraction
This is the proportion by which the incidence of all-cause cancers in allopurinol users for over 90 days would theoretically be reduced if drug use was stopped. EAF ¼
Ie Iu 100 % ; Ie
where Ie is the incidence of all-cause cancers or bladder cancer in those using allopurinol for over 90 days. Furthermore, the incidences of all-cause cancers and specific cancer per 1000 person-years were estimated. The Cox regression model was used to estimate the HR and the log-rank test was used to estimate the significance for the cumulative hazard rate using SAS program (v9.3; SAS Institute Inc., Cary, North Carolina, USA) after mining the national outpatient records using the PERL (v5.8; free download) program. At a P value less than 0.05, a difference was considered to be significant.
Results A total of 24 050 new gout patients and 76 129 controls were included from the outpatient database from 2000 to 2011. The mean ages were 44.63 (± 14.84) and 44.74 (± 14.69) for gout patients and controls, respectively; the mean ages were not significantly different (P = 0.287; Table 1). In terms of the incidence of cancers among all participants, 6.68% of gout patients showed incident allcause cancers compared with 6.43% of controls; the HR adjusted by age was 1.08, and it showed a significant association (95% CI = 1.02–1.15, P = 0.006). Furthermore, we analyzed the HR between specific cancers and gout disease. The results showed that gout patients had a higher risk of developing bladder cancer after adjustment for age (HR = 1.28, 95% CI = 1.01–1.62, P = 0.041; Table 1), but the other cancers listed in Table 1 did not show the same significant evidence for gout disease (all P > 0.05). Supplementary Fig. 1 (http://www.gouthyperur icemia.com/changsj/ejcp/supplemental_figure_1.tiff) lists the significant difference in the cumulative hazard rate curve between gout patients and controls (log-rank test, P = 0.014).
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
218 European Journal of Cancer Prevention 2016, Vol 25 No 3
Fig. 1
One million outpatients cover years 1998 − 2011
Inclusion criteria Male and age ≥ 20 years
Gout patients
Nongout patients
Include those with first diagnosis from year 2000
No gout diagnosis from years 1998 − 2011
Exclusion criteria Diagnosis of DM and cancers within 1 year after enrollment Matching criteria (1) Age (2) Year and month of enrollment (3) Ratio 1 : 3−4
Gout patients
Nongout patients
(n = 24 050)
(controls) (n = 76 129)
Days of using allopurinol within 3 years after gout onset
0 day n = 16 829
1−90 days n = 5502
>90 days n = 1719
New all-cause cancer n = 1092 (6.49%)
n = 337 (6.13%)
n = 177 (10.30%)
n = 4893 (6.43%)
The flow chart of selection of the sample population. First, we selected those who were male and 20 years or older as the target population, and selected gout patients with first date of diagnosis of gout after January 2000. The control group included patients without a diagnosis of gout from 1998 to 2011. Those who had a diagnosis of diabetes and any cancers within 12 months after enrollment were excluded from the study. We then randomly selected three to four nongout controls to match each patient with gout by age, and year and month of enrollment. Furthermore, the gout patients were divided into three groups according to the duration of allopurinol use, which was estimated within 3 years after gout onset.
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
Allopurinol and bladder cancer Chen et al. 219
Table 1
Associations between gout patients and controls in basic characteristics and all-cause cancers
Variables N Age (mean ± SD) (years) Follow-up time for all-cause cancers (mean ± SD) (months) All-cause cancer Yes No Nasopharynx cancer Yes No Lung cancer Yes No Brain cancer Yes No Pancreas cancer Yes No Prostate cancer Yes No Stomach cancer Yes No Thyroid cancer Yes No Non-Hodgkin’s lymphoma Yes No Oral cancer Yes No Kidney cancer Yes No Hepatoma Yes No Esophageal cancer Yes No Colorectal cancer Yes No Bladder cancer Yes No
aHR (95% CI)
P-valuesa
Gout [n (%)]
Control [n (%)]
24 050 44.63 ± 14.84 100.70 ± 29.72
76 129 44.74 ± 14.69 103.00 ± 29.18
1606 (6.68) 22 444 (93.32)
4893 (6.43) 71 236 (93.57)
1.08 (1.02–1.15) 1.0
0.006
89 (0.37) 23 961 (99.63)
255 (0.33) 75 874 (99.67)
1.14 (0.89–1.45)
0.299
210 (0.87) 23 840 (99.13)
640 (0.84) 75 489 (99.16)
1.09 (0.93–1.27) 1.0
0.301
25 (0.10) 24 025 (99.90)
95 (0.12) 76 034 (99.88)
0.87 (0.56–1.35) 1.0
0.527
29 (0.12) 24 021 (99.88)
86 (0.11) 76 043 (99.89)
1.12 (0.74–1.71) 1.0
0.591
225 (0.94) 23 825 (99.05)
698 (0.92) 75 431 (99.08)
1.05 (0.90–1.22) 1.0
0.554
48 (0.20) 24 002 (99.80)
206 (0.27) 75 923 (99.73)
0.77 (0.56–1.05) 1.0
0.097
17 (0.07) 24 033 (99.93)
45 (0.06) 76 084 (99.94)
1.23 (0.70–2.14) 1.0
0.474
34 (0.14) 24 016 (99.86)
143 (0.19) 75 986 (99.81)
0.79 (0.54–1.14) 1.0
0.205
160 (0.67) 23 890 (99.33)
448 (0.59) 75 681 (99.41)
1.17 (0.98–1.40) 1.0
0.087
64 (0.27) 23 986 (99.73)
170 (0.22) 75 959 (99.78)
1.24 (0.93–1.66) 1.0
0.141
253 (1.05) 23 797 (98.95)
754 (0.99) 75 375 (99.01)
1.11 (0.96–1.28) 1.0
0.165
39 (0.16) 24 011 (99.84)
122 (0.16) 76 007 (99.84)
1.07 (0.75–1.53) 1.0
0.719
315 (1.31) 23 735 (98.69)
958 (1.26) 75 171 (98.74)
1.08 (0.95–1.23) 1.0
0.233
95 (0.40) 23 955 (99.60)
243 (0.32) 75 886 (99.68)
1.28 (1.01–1.62) 1.0
0.041
0.287 < 0.001
Those who had a diagnosis of type 2 diabetes within 1 year of enrollment were excluded. aHR, adjusted hazard ratio; CI, confidence interval. The hazard ratio adjusted for age.
a
A total of 6499 new all-cause cancer cases were observed in gout patients and nongout controls; for those gout patients who used allopurinol for 0 day, 1–90 days, and more than 90 days and nongout controls, the numbers of new all-cause cancer were 1092, 337, 177, and 4893 cases, respectively (Fig. 1). The mean age of the participants who developed cancer was 55.60 (± 13.97) years, compared with 43.96 (± 14.48) years for those who did not. In terms of the comorbidity effect on the incident cancers, variables of age and gout disease had a significantly higher risk of incident all-cause cancers (P < 0.001 and 0.006, respectively), but the obesity comorbidity did not show the same results (P = 0.689; Table 2).
As gout patients had a higher risk associated with incident all-cause cancers, we aimed to determine the effect of hypouricemia agents on the development of incident cancers. Supplementary Fig. 2 (http://www.gouthyperur icemia.com/changsj/ejcp/supplemental_figure_2.tiff) shows the incidences of all-cause cancers among gout patients who used allopurinol or benzbromarone. There was a marked increase in incident all-cause cancers for participants who used allopurinol for over 90 days, but the same phenomenon was not observed in benzbromarone users. The incidences of all-cause cancers per 1000 person-years are shown for different durations of allopurinol or benzbromarone use (Supplementary Table 1 http://www.gou
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
220 European Journal of Cancer Prevention 2016, Vol 25 No 3
Table 2
Hazard ratios of all-cause cancers estimated from adjustment for age, gout disease, and obesity
Variables N Age (mean ± SD) (years) Gout disease Yes No Obesity Yes No
All-cause cancers [n (%)]
Noncancer [n (%)]
HR (95% CI)
P-values
aHR (95% CI)a
P-values
6499 (6.49) 55.60 (13.97)
93 680 (93.51) 43.96 (14.48)
1.05 (1.05–1.05)
< 0.001
1.05 (1.05–1.05)
< 0.001
1606 (24.71) 4893 (75.29)
22 444 (23.96) 71 236 (76.04)
1.07 (1.02–1.14) 1.0
0.014
1.08 (1.02–1.15) 1.0
0.006
14 (0.22) 6485 (99.78)
212 (0.23) 93 468 (99.77)
1.11 (0.66–1.88) 1.0
0.689
–
–
Those who had a diagnosis of type 2 diabetes within 1 year of enrollment was excluded. aHR, adjusted hazard ratio; CI, confidence interval; HR, hazard ratio. a The HR was estimated by adjustment of the other variables.
thyperuricemia.com/changsj/ejcp/supplemental_table_1.pdf). The incidences of all-cause cancers for gout patients and nongout controls were 8.26 cases and 7.49 cases/1000 person-years, respectively; meanwhile, the incidences in gout patients who used allopurinol for over 90 days and nonusers were 11.90 cases and 7.87 cases, respectively. According to the aforementioned incidences of all-cause cancers, we estimated population-attributable fraction and EAR to be 4.72 and 36.87%, respectively. This means that if all gout patients did not use allopurinol for over 90 days, 4.72 and 36.87% of all-cause cancers would be eliminated from the population of gout patients and those using allopurinol for over 90 days, respectively. The age-adjusted SIR of incident all-cause cancers for gout patients who used allopurinol for over 90 days was 1.51 compared with nonusers (95% CI = 1.28–1.78, P < 0.05). This means that those who used allopurinol for over 90 days had 1.51 times greater risk of developing allcause cancers compared with nonusers (all P < 0.05), but the use of benzbromarone for over 90 days did not show the same significant result (data not shown). Thus, we divided these gout patients into three groups on the basis of the duration of allopurinol or benzbromarone use: (a) nonusers (0 days), (b) 1–90 days of use, and (c) over 90 days of use. The HR of incident allcause cancers among those who used allopurinol for over 90 days compared with 1–90 days or nonusers are listed in Table 3. On comparing those who used allopurinol for over 90 days with nonusers, the HR was 1.21 (95% CI = 1.03–1.42, P = 0.019) after adjustment for age. Furthermore, on comparing those who used allopurinol for 1–90 days with nonusers, the HR was 0.90 (0.80–1.02, P = 0.092). HRs did not show any significant association when applying the above method to analyze benzbromarone use (P > 0.05). The cumulative hazard rate curve of all-cause cancers among participants with different durations of allopurinol use is shown in Supplementary Fig. 3 (http://www.gouthy peruricemia.com/changsj/ejcp/supplemental_figure_3.tiff). Gout patients using allopurinol for over 90 days had a higher cumulative hazard rate of incident all-cause cancers compared with nonusers (P < 0.001). Furthermore, there
was a significantly higher association between those who used allopurinol for 1–90 days and nonusers (P = 0.020). The HR after adjustment for age was also applied to evaluate specific cancers in allopurinol users. The results showed that those using allopurinol for over 90 days had a 2.26 times higher risk of incident bladder cancer compared with nonusers (0 day) (HR = 2.26, 95% CI = 1.32–3.87, P = 0.003; Table 4). However, other cancers listed in Table 4 did not show the same significant hazard risk between these two groups (all P > 0.05). Furthermore, in terms of the cumulative hazard risk of incident bladder cancer, Fig. 2 shows that those who used allopurinol for over 90 days had a higher cumulative hazard risk compared with nonusers among gout patients (P < 0.001). The age-adjusted SIR also showed a 3.12 times higher risk of incident bladder cancer for those using allopurinol for over 90 days compared with nonusers. However, 1–90-day allopurinol users and nonusers did not show any significant association (P = 0.337).
Discussion Our study provides evidence that gout patients have a higher incidence of all-cause cancers compared with nongout controls. Importantly, those who used allopurinol for over 90 days had a higher incidence of bladder cancer compared with nonusers. In terms of the effect of hypouricemia agents, such as allopurinol and benzbromarone, on the occurrence of cancers, benzbromarone users did not show the same significant result as the allopurinol users. Moreover, to avoid confounding effects on the occurrence of cancer, we excluded those who had been diagnosed with type 2 diabetes within 1 year of enrollment because diabetes is a risk factor for cancer (Zelenko and Gallagher, 2014). Furthermore, we selected all male participants and matched the gout patients and nongout controls to the same age and diagnosis date to avoid confounding results. However, there were many risk factors associated with bladder cancer that were not avoided in the current study such as smoking, education, or intake of vitamin C (Erdurak et al., 2014; Ryu et al., 2014), as the outpatient data did not provide sufficient information on these behaviors.
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
Allopurinol and bladder cancer Chen et al. 221
Table 3
Hazard ratios of incident all-cause cancers on different days of use of allopurinol or benzbromarone among gout patients Days of use of gout treatment medicine [n (%)]
Allopurinol N Age (mean ± SD) (years) All-cause cancers Yes No Benzbromarone N Age (mean ± SD) (years) All-cause cancers Yes No
0 day
1–90 days
> 90 days
aHR (95% CI)a
P-values
aHR (95% CI)b
P-values
16 829 (69.98) 44.48 ± 14.68
5502 (22.88) 43.61 ± 14.77
1719 (7.15) 49.27 ± 15.75
1.05 (1.04–1.05)
< 0.001
1.05 (1.04–1.05)
< 0.001
1092 (6.49) 15 737 (93.51)
337 (6.13) 5165 (93.87)
177 (10.30) 1542 (89.70)
0.90 (0.80–1.02) 1.0
0.092
1.21 (1.03–1.42) 1.0
0.019
11 056 (45.97) 44.71 ± 14.78
8648 (35.96) 43.40 ± 14.68
4346 (18.07) 46.86 ± 15.03
1.05 (1.04–1.05)
< 0.001
1.05 (1.04–1.05)
< 0.001
710 (6.42) 10 346 (93.58)
569 (6.58) 8079 (93.42)
327 (7.52) 4019 (92.48)
1.03 (0.92–1.14) 1.0
0.666
0.98 (0.86–1.12) 1.0
0.769
aHR, adjusted hazard ratio; CI, confidence interval. Hazard ratios were estimated between groups who used allopurinol or benzbromarone for 1–90 and 0 days after adjustment for age. Hazard ratios were estimated between groups who used allopurinol for > 90 days and 0 day after adjustment for age.
a
b
This study evaluated the effect of allopurinol or benzbromarone use on the development of incident cancers. Both allopurinol and benzbromarone are hypouricemia agents that are used in the management of gout. Those using allopurinol for over 90 days had a significantly higher incidence of all-cause cancers and bladder cancer, but the users of benzbromarone did not show the same result, even though it has the same effect of reducing serum uric acid (Murrell and Rapeport, 1986). It can be postulated that the higher incidence of cancer observed in gout patients or allopurinol users is not because of the effect of reduced uric acid levels although uric acid has an anticarcinogenic effect (Peden et al., 1990). Chemical carcinogenesis is a multistage process usually recognized as initiation, promotion, and progression that results from chemical–cellular interactions at the tissue/organ level. Initiation of cancer is triggered by genetic or epigenetic changes (Sharma et al., 2010). Once a selective survival/ growth advantage is gained by the transformed cells (promotion), progression, invasion, and metastasis may follow (Bartkova et al., 2005). Here, we showed the causal effect of allopurinol on the occurrence of bladder cancer, and propose allopurinol as a potential cancer-promoting agent. Several animal studies strongly support our current findings. In 1976, Wang et al. (1976) showed that bladder cancer could be synergistically induced by both N-[4-(5-nitro-2-furyl)2-thiazolyl] formamide (FANFT) and allopurinol treatment in rats, even in situations whereas allopurinol use alone did not induce bladder cancer. Furthermore, Fukushima et al. (1983) reported the enhancing effect of allopurinol on the induction of bladder cancer in male F334 rats; in the same year, Ito et al. (1983) confirmed the enhancing effect of allopurinol on the induction of bladder cancer. Here, we reported that gout patients who used allopurinol, but not benzbromarone, had a higher risk of developing bladder cancer. However, not all gout treatment agents that contribute toward cancer formation are mutagens because chemical carcinogenesis is a multistage
process, that is, initiation (mutagenic), promotion (nonmutagenic), and progression (Evan and Vousden, 2001). On the basis of the present knowledge, allopurinol did not show obvious mutagenicity that contributed toward cancer initiation in humans. However, evidence from animal models indicates that allopurinol has a cancer-promoting activity under cancer-initiating FANFT exposure (Wang et al., 1976). Our results show that allopurinol may contribute toward bladder cancer formation because of its cancer-promoting activity. In general, the cancerpromoting process of a carcinogen requires repeated exposure over a period of time after a mutagenic initiation (Baxter et al., 1991; Evan and Vousden, 2001). In our study, we showed that those who used allopurinol for over 90 days had a higher incidence of bladder cancer compared with nonusers among gout patients, which further supports the possibility of allopurinol as a cancerpromoting agent after repeated exposure. Allopurinol is the drug used most widely to lower the level of urate in blood and, therefore, to decrease the number of repeated gout attacks. Allopurinol is rapidly and extensively metabolized to oxypurinol, and the hypouricemic efficacy of allopurinol is mainly because of this metabolite. Both allopurinol and oxypurinol are structural analogues of the purine bases hypoxanthine and xanthine, and competitively bind to xanthine oxidase, thereby inhibiting the xanthine oxidase stimulated synthesis of uric acid. Oxypurinol has a longer elimination half-life than allopurinol and is eliminated unchanged in urine (Murrell and Rapeport, 1986). However, to our knowledge, we did not find any evidence of oxypurinol related to cancer initiation or promotion. The associations between bladder cancer and allopurinol, oxypurinol, or its metabolite need to be further confirmed. Although Wang et al. (1976) have clearly shown an enhancing effect of allopurinol on bladder cancer induced by FANFT in an animal experiment, they did not report the mechanism involved. The active metabolite of allopurinol is
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
222 European Journal of Cancer Prevention 2016, Vol 25 No 3
Age-adjusted hazard ratios of specific cancers between those who used allopurinol for over 90 days and nonusers (0 days) among gout patients
Table 4
Fig. 2
0.016
Use of allopurinol (days)
Nasopharynx cancer Yes 10 (0.58) No 1709 (99.42) Lung cancer Yes 23 (1.34) No 1696 (98.66) Brain cancer Yes 1 (0.06) No 1718 (99.94) Pancreas cancer Yes 2 (0.12) No 1717 (99.88) Prostate cancer Yes 30 (1.75) No 1689 (98.25) Stomach cancer Yes 5 (0.29) No 1714 (99.71) Thyroid cancer Yes 0 (0.00) No 1719 (100) Non-Hodgkin’s lymphoma Yes 4 (0.23) No 1715 (99.77) Oral cancer Yes 19 (1.11) No 1700 (98.89) Kidney cancer Yes 7 (0.41) No 1712 (99.59) Hepatoma Yes 21 (1.22) No 1698 (98.78) Esophageal cancer Yes 6 (0.35) No 1713 (99.65) Colorectal cancer Yes 35 (2.04) No 1684 (97.96) Bladder cancer Yes 18 (1.05) No 1701 (98.95)
0
aHR (95% CI)
P-values
63 (0.37) 16 766 (99.63)
1.40 (0.71–2.73) 1.0
0.330
147 (0.87) 16 682 (99.13)
1.04 (0.66–1.61) 1.0
0.875
20 (0.12) 16 809 (99.88)
0.40 (0.05–2.98) 1.0
0.370
20 (0.12) 16 809 (99.88)
0.70 (0.16–3.00)
0.626
146 (0.87) 16 683 (99.13)
1.29 (0.87–1.91)
0.212
33 (0.20) 16 796 (99.80)
0.99 (0.38–2.54)
0.980
13 (0.08) 16 816 (99.92)
–
26 (0.15) 16 803 (99.85)
1.20 (0.42–3.46) 1.0
0.736
106 (0.63) 16 723 (99.37)
1.47 (0.90–2.40) 1.0
0.126
39 (0.23) 16 790 (99.77)
1.30 (0.58–2.92) 1.0
0.527
179 (1.06) 16 650 (98.94)
0.89 (0.57–1.41) 1.0
0.625
26 (0.15) 16 803 (99.85)
1.67 (0.68–4.10) 1.0
0.259
214 (1.27) 16 615 (98.73)
1.14 (0.80–1.64) 1.0
0.470
53 (0.31) 16 776 (99.69)
2.26 (1.32–3.87) 1.0
0.003
Cumulative hazard rate
> 90
Use allopurinol >90 days Use allopurinol 1−90 days Without use allopurinol
0.014 0.012 0.010 0.008 0.006 0.004 0.002 0.000 0
Those who used allopurinol for 1–90 days were not included in the table. aHR, adjusted hazard ratio; CI, confidence interval; –, not estimated because of zero events.
oxypurinol. Garewal et al. (1983) studied the effect of oxypurinol, the major metabolite of allopurinol, on 5-FU cytotoxicity against human tumor cell lines using a soft agar clonogenic assay. For both colon and breast cancer cell lines, 5-FU cytotoxicity was enhanced in the presence of oxypurinol. It has been noted that patients treated with cytotoxic agents for nonmalignant conditions are also at an increased risk of developing a malignancy, which implies that these agents may have oncogenic potential (Sieber, 1977). Taken together, oxypurinol might have the potential to promote the development of bladder cancer in patients with long-term use of allopurinol. To date, information on the mechanisms of allopurinol in the promotion of bladder cancer is very limited and further investigations are awaited. In conclusion, by limiting sex and matching age, month, and year of first diagnosis, we found novel clinical evidence that those who use allopurinol for over 90 days
20
40
60 80 100 120 Follow time (months)
140
160
Cumulative hazard rate of incident bladder cancer. Those who used allopurinol for over 90 days had a higher cumulative hazard risk of bladder cancer compared with nonusers among gout patients (log-rank test, P
Allopurinol and the incidence of bladder cancer: a Taiwan national retrospective cohort study Chung-Jen Chena,*, Ming-Chia Hsiehd,*, Wei-Ting Liaob,*, Ya-Ting Chanc and Shun-Jen Changc Our aim is to investigate the risk association between allopurinol use and cancer incidence among gout patients using clinical evidence. Newly diagnosed male patients with gout, 20 years or older, were included after excluding those who had a diagnosis of type 2 diabetes, and were followed up for 12 years in a retrospective cohort study of one million outpatients of a national database. The gout patients were matched to male controls by age and first diagnosis date of gout disease. We then estimated the risk associations between incident cancers and duration of allopurinol use by Cox hazard regression, age-adjusted standardized incidence ratio, and incidence per 1000 person-years. A total of 24 050 gout patients and 76 129 controls were included. The incidence of all-cause cancers for gout patients and controls was 8.26 cases and 7.49 cases/1000 person-years, respectively; it was markedly increased in gout patients who used allopurinol for over 90 days. The hazard ratio of allcause cancers was 1.21 (95% confidence interval = 1.03–1.42, P = 0.019) after adjustment for age and 2.26 for bladder cancer (95% confidence interval = 1.32–3.87, P = 0.003) on comparing those who
used allopurinol for over 90 days with nonusers. Meanwhile, other cancers did not show the same significant result. We concluded that those who used allopurinol for a long duration had a higher occurrence of both bladder cancer and all-cause cancers in clinical evidence. European Journal of Cancer Prevention 25:216–223 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Introduction
levels; thus, the causal association between the use of allopurinol and incident cancers is an important issue.
Allopurinol was developed as an inhibitor of xanthine oxidase in the 1960s, and was used to decrease both urate levels in plasma and the occurrence of acute gout. Recently, studies have shown that gout has an association with cancers (Boffetta et al., 2009; Kuo et al., 2012), especially kidney cancer bladder cancer, and prostate cancer (Loeb and Harris, 2008; Chen, 2014). Well-known risk factors for both gout and cancer may include obesity, hyperglycemia, heavy alcohol use as well as inflammation syndrome (Bianchini et al., 2002; Aggarwal and Gehlot, 2009; Greer and Whitcomb, 2009; Noroozian et al., 2014). In particular, inflammation has been well documented to be related to several cancers (Coussens and Werb, 2002; Balkwill and Coussens, 2004), including colorectal cancer (McMillan et al., 2003), pancreatic cancer (Jamieson et al., 2005; Greer and Whitcomb, 2009), urinary bladder cancer (Hilmy et al., 2005), and renal clear cell cancer (Lamb et al., 2006). Furthermore, about one-third of gout patients use allopurinol for the management of uric acid
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.eurjcancerprev.com). 0959-8278 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
European Journal of Cancer Prevention 2016, 25:216–223 Keywords: all-cause cancers, allopurinol, bladder cancer, hypouricemia agent Departments of aInternal Medicine, bBiotechnology, College of Life Science, Kaohsiung Medical University, cDepartment of Kinesiology, Health and Leisure Studies, National University of Kaohsiung, Kaohsiung and dDepartment of Internal Medicine, Division of Endocrinology and Metabolism, Changhua Christian Hospital, Changhua, Taiwan Correspondence to Shun-Jen Chang, PhD, National University of Kaohsiung, No. 700, Kaohsiung University Rd., Nanzih District, 811, Kaohsiung City, Taiwan Tel: + 886 7 5916679; fax: + 886 7 5919264; e-mail: [email protected] *Chung-Jen Chen, Ming-Chia Hsieh and Wei-Ting Liao contributed equally to the writing of this article. Received 17 January 2015 Accepted 18 February 2015
Many studies have shown that allopurinol enhances the occurrence of bladder cancer in animal models. Wang et al. (1976) showed that bladder cancer could be synergistically induced by both formamide and allopurinol treatment in rats. Furthermore, Fukushima et al. (1983) reported the enhancing effect of allopurinol on bladder cancer onset in male F334 rats; in the same year, Ito et al. (1983) confirmed the enhancing effect of allopurinol on bladder cancer onset in rats. However, with the aim of reducing serum uric acid level in the management of gout, relatively little attention has been paid to the relationship between the use of allopurinol and cancer in clinical evidence, and the widespread use of the drug was intended to reduce uric acid levels in gout patients. Allopurinol is used widely to reduce serum uric acid levels for the management of gout disease; even though accumulating evidence supports the relationship between development of cancer and allopurinol use, the clinical evidence remains unclear. Whether gout itself or allopurinol use affects the development of cancers should be studied. Here, we designed a retrospective cohort study to explore the causal association between the use of DOI: 10.1097/CEJ.0000000000000161
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
Allopurinol and bladder cancer Chen et al. 217
allopurinol and incident cancers in gout patients by analysis of national clinical outpatient records.
Materials and methods Study sample
The National Health Insurance Research Database (NHIRD) provided longitudinal cohort data on one million patients – about 5% of the total population of Taiwan – from the health insurance database from 1998 to 2011. The approval for analysis of the database was obtained from the Institutional Review Board of Changhua Christian Hospital (CCH IRB 121213). NHIRD provides disease diagnosis codes, following the International Classification of Diseases, Ninth Revision (ICD-9), and medical prescriptions. The outpatient database included records from 1998 to 2011, and the selection process is shown in Fig. 1. Participants included men who were 20 years of age or older, and we identified gout patients using the ICD-9 code 274, with the first date of diagnosis of gout after January 2000. Those who had a diagnosis of gout between 1998 and 1999 were excluded to ensure that they were new gout patients. The diagnosis was then further confirmed by continuous prescriptions of antigout medications three times. The control group included patients without a diagnosis of gout from 1998 to 2011. Those who had a diagnosis of diabetes (ICD-9: 250) and any cancers (ICD-9: 140–208) within 12 months after enrollment were excluded from the study. All participants from the inclusion date of the first diagnosis to 2011 were followed up. We randomly selected three to four nongout controls to match each gout patient by age as well as the same year and month of enrollment. This matching process ensures that the follow-up time was the same at baseline, and avoids confounding effects from sex and age on the outcome of the diseases. Usage of hypouricemia agents, such as allopurinol and benzbromarone, was estimated within 3 years after the onset of gout. The comorbidities of gout were defined for those who had a diagnosis within 1 year after enrollment, such as obesity (ICD-9: 278), hyperlipidemia (ICD-9: 272), and hypertension (ICD-9: 4010, 4011, 4019). The endpoint was the occurrence of all-cause cancers after 1 year of enrollment for all participants. Statistical analyses
The hazard ratio (HR), standardized incidence ratio (SIR), and 95% confidence intervals (95% CI) after adjustment for age were estimated to determine the risk ratio of incident all-cause cancers between gout and control groups and between those who used allopurinol (or benzbromarone) for over 90 days and nonusers. The t-test was used to estimate the mean difference for age and follow-up time, and the χ2-test was used to estimate the differences in frequency for obesity, hyperlipidemia, hypertension, and all-cause cancers between gout patients and controls.
Population-attributable fraction
This is the proportion by which the incidence of all-cause cancers or bladder cancer in the gout population would theoretically be reduced if they did not use allopurinol for over 90 days. PAF ¼
Ip Iu 100 % ; Ip
where Ip and Iu are the incidences of all-cause cancers in the gout population (Ip) and those who did not use allopurinol (Iu), respectively. Exposed-attributable fraction
This is the proportion by which the incidence of all-cause cancers in allopurinol users for over 90 days would theoretically be reduced if drug use was stopped. EAF ¼
Ie Iu 100 % ; Ie
where Ie is the incidence of all-cause cancers or bladder cancer in those using allopurinol for over 90 days. Furthermore, the incidences of all-cause cancers and specific cancer per 1000 person-years were estimated. The Cox regression model was used to estimate the HR and the log-rank test was used to estimate the significance for the cumulative hazard rate using SAS program (v9.3; SAS Institute Inc., Cary, North Carolina, USA) after mining the national outpatient records using the PERL (v5.8; free download) program. At a P value less than 0.05, a difference was considered to be significant.
Results A total of 24 050 new gout patients and 76 129 controls were included from the outpatient database from 2000 to 2011. The mean ages were 44.63 (± 14.84) and 44.74 (± 14.69) for gout patients and controls, respectively; the mean ages were not significantly different (P = 0.287; Table 1). In terms of the incidence of cancers among all participants, 6.68% of gout patients showed incident allcause cancers compared with 6.43% of controls; the HR adjusted by age was 1.08, and it showed a significant association (95% CI = 1.02–1.15, P = 0.006). Furthermore, we analyzed the HR between specific cancers and gout disease. The results showed that gout patients had a higher risk of developing bladder cancer after adjustment for age (HR = 1.28, 95% CI = 1.01–1.62, P = 0.041; Table 1), but the other cancers listed in Table 1 did not show the same significant evidence for gout disease (all P > 0.05). Supplementary Fig. 1 (http://www.gouthyperur icemia.com/changsj/ejcp/supplemental_figure_1.tiff) lists the significant difference in the cumulative hazard rate curve between gout patients and controls (log-rank test, P = 0.014).
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
218 European Journal of Cancer Prevention 2016, Vol 25 No 3
Fig. 1
One million outpatients cover years 1998 − 2011
Inclusion criteria Male and age ≥ 20 years
Gout patients
Nongout patients
Include those with first diagnosis from year 2000
No gout diagnosis from years 1998 − 2011
Exclusion criteria Diagnosis of DM and cancers within 1 year after enrollment Matching criteria (1) Age (2) Year and month of enrollment (3) Ratio 1 : 3−4
Gout patients
Nongout patients
(n = 24 050)
(controls) (n = 76 129)
Days of using allopurinol within 3 years after gout onset
0 day n = 16 829
1−90 days n = 5502
>90 days n = 1719
New all-cause cancer n = 1092 (6.49%)
n = 337 (6.13%)
n = 177 (10.30%)
n = 4893 (6.43%)
The flow chart of selection of the sample population. First, we selected those who were male and 20 years or older as the target population, and selected gout patients with first date of diagnosis of gout after January 2000. The control group included patients without a diagnosis of gout from 1998 to 2011. Those who had a diagnosis of diabetes and any cancers within 12 months after enrollment were excluded from the study. We then randomly selected three to four nongout controls to match each patient with gout by age, and year and month of enrollment. Furthermore, the gout patients were divided into three groups according to the duration of allopurinol use, which was estimated within 3 years after gout onset.
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
Allopurinol and bladder cancer Chen et al. 219
Table 1
Associations between gout patients and controls in basic characteristics and all-cause cancers
Variables N Age (mean ± SD) (years) Follow-up time for all-cause cancers (mean ± SD) (months) All-cause cancer Yes No Nasopharynx cancer Yes No Lung cancer Yes No Brain cancer Yes No Pancreas cancer Yes No Prostate cancer Yes No Stomach cancer Yes No Thyroid cancer Yes No Non-Hodgkin’s lymphoma Yes No Oral cancer Yes No Kidney cancer Yes No Hepatoma Yes No Esophageal cancer Yes No Colorectal cancer Yes No Bladder cancer Yes No
aHR (95% CI)
P-valuesa
Gout [n (%)]
Control [n (%)]
24 050 44.63 ± 14.84 100.70 ± 29.72
76 129 44.74 ± 14.69 103.00 ± 29.18
1606 (6.68) 22 444 (93.32)
4893 (6.43) 71 236 (93.57)
1.08 (1.02–1.15) 1.0
0.006
89 (0.37) 23 961 (99.63)
255 (0.33) 75 874 (99.67)
1.14 (0.89–1.45)
0.299
210 (0.87) 23 840 (99.13)
640 (0.84) 75 489 (99.16)
1.09 (0.93–1.27) 1.0
0.301
25 (0.10) 24 025 (99.90)
95 (0.12) 76 034 (99.88)
0.87 (0.56–1.35) 1.0
0.527
29 (0.12) 24 021 (99.88)
86 (0.11) 76 043 (99.89)
1.12 (0.74–1.71) 1.0
0.591
225 (0.94) 23 825 (99.05)
698 (0.92) 75 431 (99.08)
1.05 (0.90–1.22) 1.0
0.554
48 (0.20) 24 002 (99.80)
206 (0.27) 75 923 (99.73)
0.77 (0.56–1.05) 1.0
0.097
17 (0.07) 24 033 (99.93)
45 (0.06) 76 084 (99.94)
1.23 (0.70–2.14) 1.0
0.474
34 (0.14) 24 016 (99.86)
143 (0.19) 75 986 (99.81)
0.79 (0.54–1.14) 1.0
0.205
160 (0.67) 23 890 (99.33)
448 (0.59) 75 681 (99.41)
1.17 (0.98–1.40) 1.0
0.087
64 (0.27) 23 986 (99.73)
170 (0.22) 75 959 (99.78)
1.24 (0.93–1.66) 1.0
0.141
253 (1.05) 23 797 (98.95)
754 (0.99) 75 375 (99.01)
1.11 (0.96–1.28) 1.0
0.165
39 (0.16) 24 011 (99.84)
122 (0.16) 76 007 (99.84)
1.07 (0.75–1.53) 1.0
0.719
315 (1.31) 23 735 (98.69)
958 (1.26) 75 171 (98.74)
1.08 (0.95–1.23) 1.0
0.233
95 (0.40) 23 955 (99.60)
243 (0.32) 75 886 (99.68)
1.28 (1.01–1.62) 1.0
0.041
0.287 < 0.001
Those who had a diagnosis of type 2 diabetes within 1 year of enrollment were excluded. aHR, adjusted hazard ratio; CI, confidence interval. The hazard ratio adjusted for age.
a
A total of 6499 new all-cause cancer cases were observed in gout patients and nongout controls; for those gout patients who used allopurinol for 0 day, 1–90 days, and more than 90 days and nongout controls, the numbers of new all-cause cancer were 1092, 337, 177, and 4893 cases, respectively (Fig. 1). The mean age of the participants who developed cancer was 55.60 (± 13.97) years, compared with 43.96 (± 14.48) years for those who did not. In terms of the comorbidity effect on the incident cancers, variables of age and gout disease had a significantly higher risk of incident all-cause cancers (P < 0.001 and 0.006, respectively), but the obesity comorbidity did not show the same results (P = 0.689; Table 2).
As gout patients had a higher risk associated with incident all-cause cancers, we aimed to determine the effect of hypouricemia agents on the development of incident cancers. Supplementary Fig. 2 (http://www.gouthyperur icemia.com/changsj/ejcp/supplemental_figure_2.tiff) shows the incidences of all-cause cancers among gout patients who used allopurinol or benzbromarone. There was a marked increase in incident all-cause cancers for participants who used allopurinol for over 90 days, but the same phenomenon was not observed in benzbromarone users. The incidences of all-cause cancers per 1000 person-years are shown for different durations of allopurinol or benzbromarone use (Supplementary Table 1 http://www.gou
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
220 European Journal of Cancer Prevention 2016, Vol 25 No 3
Table 2
Hazard ratios of all-cause cancers estimated from adjustment for age, gout disease, and obesity
Variables N Age (mean ± SD) (years) Gout disease Yes No Obesity Yes No
All-cause cancers [n (%)]
Noncancer [n (%)]
HR (95% CI)
P-values
aHR (95% CI)a
P-values
6499 (6.49) 55.60 (13.97)
93 680 (93.51) 43.96 (14.48)
1.05 (1.05–1.05)
< 0.001
1.05 (1.05–1.05)
< 0.001
1606 (24.71) 4893 (75.29)
22 444 (23.96) 71 236 (76.04)
1.07 (1.02–1.14) 1.0
0.014
1.08 (1.02–1.15) 1.0
0.006
14 (0.22) 6485 (99.78)
212 (0.23) 93 468 (99.77)
1.11 (0.66–1.88) 1.0
0.689
–
–
Those who had a diagnosis of type 2 diabetes within 1 year of enrollment was excluded. aHR, adjusted hazard ratio; CI, confidence interval; HR, hazard ratio. a The HR was estimated by adjustment of the other variables.
thyperuricemia.com/changsj/ejcp/supplemental_table_1.pdf). The incidences of all-cause cancers for gout patients and nongout controls were 8.26 cases and 7.49 cases/1000 person-years, respectively; meanwhile, the incidences in gout patients who used allopurinol for over 90 days and nonusers were 11.90 cases and 7.87 cases, respectively. According to the aforementioned incidences of all-cause cancers, we estimated population-attributable fraction and EAR to be 4.72 and 36.87%, respectively. This means that if all gout patients did not use allopurinol for over 90 days, 4.72 and 36.87% of all-cause cancers would be eliminated from the population of gout patients and those using allopurinol for over 90 days, respectively. The age-adjusted SIR of incident all-cause cancers for gout patients who used allopurinol for over 90 days was 1.51 compared with nonusers (95% CI = 1.28–1.78, P < 0.05). This means that those who used allopurinol for over 90 days had 1.51 times greater risk of developing allcause cancers compared with nonusers (all P < 0.05), but the use of benzbromarone for over 90 days did not show the same significant result (data not shown). Thus, we divided these gout patients into three groups on the basis of the duration of allopurinol or benzbromarone use: (a) nonusers (0 days), (b) 1–90 days of use, and (c) over 90 days of use. The HR of incident allcause cancers among those who used allopurinol for over 90 days compared with 1–90 days or nonusers are listed in Table 3. On comparing those who used allopurinol for over 90 days with nonusers, the HR was 1.21 (95% CI = 1.03–1.42, P = 0.019) after adjustment for age. Furthermore, on comparing those who used allopurinol for 1–90 days with nonusers, the HR was 0.90 (0.80–1.02, P = 0.092). HRs did not show any significant association when applying the above method to analyze benzbromarone use (P > 0.05). The cumulative hazard rate curve of all-cause cancers among participants with different durations of allopurinol use is shown in Supplementary Fig. 3 (http://www.gouthy peruricemia.com/changsj/ejcp/supplemental_figure_3.tiff). Gout patients using allopurinol for over 90 days had a higher cumulative hazard rate of incident all-cause cancers compared with nonusers (P < 0.001). Furthermore, there
was a significantly higher association between those who used allopurinol for 1–90 days and nonusers (P = 0.020). The HR after adjustment for age was also applied to evaluate specific cancers in allopurinol users. The results showed that those using allopurinol for over 90 days had a 2.26 times higher risk of incident bladder cancer compared with nonusers (0 day) (HR = 2.26, 95% CI = 1.32–3.87, P = 0.003; Table 4). However, other cancers listed in Table 4 did not show the same significant hazard risk between these two groups (all P > 0.05). Furthermore, in terms of the cumulative hazard risk of incident bladder cancer, Fig. 2 shows that those who used allopurinol for over 90 days had a higher cumulative hazard risk compared with nonusers among gout patients (P < 0.001). The age-adjusted SIR also showed a 3.12 times higher risk of incident bladder cancer for those using allopurinol for over 90 days compared with nonusers. However, 1–90-day allopurinol users and nonusers did not show any significant association (P = 0.337).
Discussion Our study provides evidence that gout patients have a higher incidence of all-cause cancers compared with nongout controls. Importantly, those who used allopurinol for over 90 days had a higher incidence of bladder cancer compared with nonusers. In terms of the effect of hypouricemia agents, such as allopurinol and benzbromarone, on the occurrence of cancers, benzbromarone users did not show the same significant result as the allopurinol users. Moreover, to avoid confounding effects on the occurrence of cancer, we excluded those who had been diagnosed with type 2 diabetes within 1 year of enrollment because diabetes is a risk factor for cancer (Zelenko and Gallagher, 2014). Furthermore, we selected all male participants and matched the gout patients and nongout controls to the same age and diagnosis date to avoid confounding results. However, there were many risk factors associated with bladder cancer that were not avoided in the current study such as smoking, education, or intake of vitamin C (Erdurak et al., 2014; Ryu et al., 2014), as the outpatient data did not provide sufficient information on these behaviors.
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
Allopurinol and bladder cancer Chen et al. 221
Table 3
Hazard ratios of incident all-cause cancers on different days of use of allopurinol or benzbromarone among gout patients Days of use of gout treatment medicine [n (%)]
Allopurinol N Age (mean ± SD) (years) All-cause cancers Yes No Benzbromarone N Age (mean ± SD) (years) All-cause cancers Yes No
0 day
1–90 days
> 90 days
aHR (95% CI)a
P-values
aHR (95% CI)b
P-values
16 829 (69.98) 44.48 ± 14.68
5502 (22.88) 43.61 ± 14.77
1719 (7.15) 49.27 ± 15.75
1.05 (1.04–1.05)
< 0.001
1.05 (1.04–1.05)
< 0.001
1092 (6.49) 15 737 (93.51)
337 (6.13) 5165 (93.87)
177 (10.30) 1542 (89.70)
0.90 (0.80–1.02) 1.0
0.092
1.21 (1.03–1.42) 1.0
0.019
11 056 (45.97) 44.71 ± 14.78
8648 (35.96) 43.40 ± 14.68
4346 (18.07) 46.86 ± 15.03
1.05 (1.04–1.05)
< 0.001
1.05 (1.04–1.05)
< 0.001
710 (6.42) 10 346 (93.58)
569 (6.58) 8079 (93.42)
327 (7.52) 4019 (92.48)
1.03 (0.92–1.14) 1.0
0.666
0.98 (0.86–1.12) 1.0
0.769
aHR, adjusted hazard ratio; CI, confidence interval. Hazard ratios were estimated between groups who used allopurinol or benzbromarone for 1–90 and 0 days after adjustment for age. Hazard ratios were estimated between groups who used allopurinol for > 90 days and 0 day after adjustment for age.
a
b
This study evaluated the effect of allopurinol or benzbromarone use on the development of incident cancers. Both allopurinol and benzbromarone are hypouricemia agents that are used in the management of gout. Those using allopurinol for over 90 days had a significantly higher incidence of all-cause cancers and bladder cancer, but the users of benzbromarone did not show the same result, even though it has the same effect of reducing serum uric acid (Murrell and Rapeport, 1986). It can be postulated that the higher incidence of cancer observed in gout patients or allopurinol users is not because of the effect of reduced uric acid levels although uric acid has an anticarcinogenic effect (Peden et al., 1990). Chemical carcinogenesis is a multistage process usually recognized as initiation, promotion, and progression that results from chemical–cellular interactions at the tissue/organ level. Initiation of cancer is triggered by genetic or epigenetic changes (Sharma et al., 2010). Once a selective survival/ growth advantage is gained by the transformed cells (promotion), progression, invasion, and metastasis may follow (Bartkova et al., 2005). Here, we showed the causal effect of allopurinol on the occurrence of bladder cancer, and propose allopurinol as a potential cancer-promoting agent. Several animal studies strongly support our current findings. In 1976, Wang et al. (1976) showed that bladder cancer could be synergistically induced by both N-[4-(5-nitro-2-furyl)2-thiazolyl] formamide (FANFT) and allopurinol treatment in rats, even in situations whereas allopurinol use alone did not induce bladder cancer. Furthermore, Fukushima et al. (1983) reported the enhancing effect of allopurinol on the induction of bladder cancer in male F334 rats; in the same year, Ito et al. (1983) confirmed the enhancing effect of allopurinol on the induction of bladder cancer. Here, we reported that gout patients who used allopurinol, but not benzbromarone, had a higher risk of developing bladder cancer. However, not all gout treatment agents that contribute toward cancer formation are mutagens because chemical carcinogenesis is a multistage
process, that is, initiation (mutagenic), promotion (nonmutagenic), and progression (Evan and Vousden, 2001). On the basis of the present knowledge, allopurinol did not show obvious mutagenicity that contributed toward cancer initiation in humans. However, evidence from animal models indicates that allopurinol has a cancer-promoting activity under cancer-initiating FANFT exposure (Wang et al., 1976). Our results show that allopurinol may contribute toward bladder cancer formation because of its cancer-promoting activity. In general, the cancerpromoting process of a carcinogen requires repeated exposure over a period of time after a mutagenic initiation (Baxter et al., 1991; Evan and Vousden, 2001). In our study, we showed that those who used allopurinol for over 90 days had a higher incidence of bladder cancer compared with nonusers among gout patients, which further supports the possibility of allopurinol as a cancerpromoting agent after repeated exposure. Allopurinol is the drug used most widely to lower the level of urate in blood and, therefore, to decrease the number of repeated gout attacks. Allopurinol is rapidly and extensively metabolized to oxypurinol, and the hypouricemic efficacy of allopurinol is mainly because of this metabolite. Both allopurinol and oxypurinol are structural analogues of the purine bases hypoxanthine and xanthine, and competitively bind to xanthine oxidase, thereby inhibiting the xanthine oxidase stimulated synthesis of uric acid. Oxypurinol has a longer elimination half-life than allopurinol and is eliminated unchanged in urine (Murrell and Rapeport, 1986). However, to our knowledge, we did not find any evidence of oxypurinol related to cancer initiation or promotion. The associations between bladder cancer and allopurinol, oxypurinol, or its metabolite need to be further confirmed. Although Wang et al. (1976) have clearly shown an enhancing effect of allopurinol on bladder cancer induced by FANFT in an animal experiment, they did not report the mechanism involved. The active metabolite of allopurinol is
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
222 European Journal of Cancer Prevention 2016, Vol 25 No 3
Age-adjusted hazard ratios of specific cancers between those who used allopurinol for over 90 days and nonusers (0 days) among gout patients
Table 4
Fig. 2
0.016
Use of allopurinol (days)
Nasopharynx cancer Yes 10 (0.58) No 1709 (99.42) Lung cancer Yes 23 (1.34) No 1696 (98.66) Brain cancer Yes 1 (0.06) No 1718 (99.94) Pancreas cancer Yes 2 (0.12) No 1717 (99.88) Prostate cancer Yes 30 (1.75) No 1689 (98.25) Stomach cancer Yes 5 (0.29) No 1714 (99.71) Thyroid cancer Yes 0 (0.00) No 1719 (100) Non-Hodgkin’s lymphoma Yes 4 (0.23) No 1715 (99.77) Oral cancer Yes 19 (1.11) No 1700 (98.89) Kidney cancer Yes 7 (0.41) No 1712 (99.59) Hepatoma Yes 21 (1.22) No 1698 (98.78) Esophageal cancer Yes 6 (0.35) No 1713 (99.65) Colorectal cancer Yes 35 (2.04) No 1684 (97.96) Bladder cancer Yes 18 (1.05) No 1701 (98.95)
0
aHR (95% CI)
P-values
63 (0.37) 16 766 (99.63)
1.40 (0.71–2.73) 1.0
0.330
147 (0.87) 16 682 (99.13)
1.04 (0.66–1.61) 1.0
0.875
20 (0.12) 16 809 (99.88)
0.40 (0.05–2.98) 1.0
0.370
20 (0.12) 16 809 (99.88)
0.70 (0.16–3.00)
0.626
146 (0.87) 16 683 (99.13)
1.29 (0.87–1.91)
0.212
33 (0.20) 16 796 (99.80)
0.99 (0.38–2.54)
0.980
13 (0.08) 16 816 (99.92)
–
26 (0.15) 16 803 (99.85)
1.20 (0.42–3.46) 1.0
0.736
106 (0.63) 16 723 (99.37)
1.47 (0.90–2.40) 1.0
0.126
39 (0.23) 16 790 (99.77)
1.30 (0.58–2.92) 1.0
0.527
179 (1.06) 16 650 (98.94)
0.89 (0.57–1.41) 1.0
0.625
26 (0.15) 16 803 (99.85)
1.67 (0.68–4.10) 1.0
0.259
214 (1.27) 16 615 (98.73)
1.14 (0.80–1.64) 1.0
0.470
53 (0.31) 16 776 (99.69)
2.26 (1.32–3.87) 1.0
0.003
Cumulative hazard rate
> 90
Use allopurinol >90 days Use allopurinol 1−90 days Without use allopurinol
0.014 0.012 0.010 0.008 0.006 0.004 0.002 0.000 0
Those who used allopurinol for 1–90 days were not included in the table. aHR, adjusted hazard ratio; CI, confidence interval; –, not estimated because of zero events.
oxypurinol. Garewal et al. (1983) studied the effect of oxypurinol, the major metabolite of allopurinol, on 5-FU cytotoxicity against human tumor cell lines using a soft agar clonogenic assay. For both colon and breast cancer cell lines, 5-FU cytotoxicity was enhanced in the presence of oxypurinol. It has been noted that patients treated with cytotoxic agents for nonmalignant conditions are also at an increased risk of developing a malignancy, which implies that these agents may have oncogenic potential (Sieber, 1977). Taken together, oxypurinol might have the potential to promote the development of bladder cancer in patients with long-term use of allopurinol. To date, information on the mechanisms of allopurinol in the promotion of bladder cancer is very limited and further investigations are awaited. In conclusion, by limiting sex and matching age, month, and year of first diagnosis, we found novel clinical evidence that those who use allopurinol for over 90 days
20
40
60 80 100 120 Follow time (months)
140
160
Cumulative hazard rate of incident bladder cancer. Those who used allopurinol for over 90 days had a higher cumulative hazard risk of bladder cancer compared with nonusers among gout patients (log-rank test, P
