Association Between Nonsteroidal Anti-Inflammatory Drugs and Colorectal Cancer: a Population-Based Case–Control Study

Published OnlineFirst April 25, 2018; DOI: 10.1158/1055-9965.EPI-17-0876

Research Article Cancer Epidemiology, Biomarkers Association between Nonsteroidal Anti- & Prevention Inﬂammatory Drugs and Colorectal Cancer: A Population-Based Case–Control Study Chun-Nan Kuo1,2, Jen-Jung Pan3, Ya-Wen Huang4, Hui-Ju Tsai4,5, and Wei-Chiao Chang1,2,6,7

Abstract

Background: COX-2 overexpression may contribute to Results: A total of 65,208 colorectal cancer cases and 65,208 colorectal cancer occurrence. Aspirin and nonsteroidal anti- matched controls were identified. Patients with aspirin use had a inflammatory drugs (NSAIDs) can reduce colorectal cancer recur- lower risk of colorectal cancer compared with nonusers [adjusted rence, but the efficacy of primary prevention in Asian populations OR (AOR) ¼ 0.94, 95% confidence interval (CI) ¼ 0.90–0.99]. is still elusive. Thus, we examined the primary preventive efficacy NSAID use was associated with lower incidence of colorectal of aspirin and NSAIDs on colorectal cancer incidence in Taiwan. cancer (AOR ¼ 0.96; 95% CI ¼ 0.92–1.00). When examining Methods: A nested case–control study was conducted using colon or rectal cancer, similar decreased risks were observed. the National Health Insurance Research Database (NHIRD) in Patients taking more cumulative days of NSAIDs use tended to Taiwan. We identified patients with diagnosis of colorectal cancer experience a more protective effect on colorectal cancer, but no from 2005 to 2013 in the Registry of Catastrophic Illness Patient dose–response effects were noted. Database. We selected patients without colorectal cancer from the Conclusions: Aspirin and NSAIDs were associated with a Longitudinal Health Insurance Database as the controls and reduced risk of colorectal cancer development among a study matched them with cases. NSAID exposure was defined as at least cohort in an Asian population. two prescriptions 13 to 48 months prior to the index date. Impact: This study provided a possible chemoprevention for Conditional logistic regression models were performed to eval- colorectal cancer in an Asian population. Cancer Epidemiol Biomarkers uate the association between NSAID use and colorectal cancer. Prev; 27(7); 1–9. 2018 AACR.

Introduction dence and death are even higher in Taiwan than in the Western world (4). Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely It is known that the mechanisms by which the enzymes or COX used as symptomatic treatment for conditions such as acute pain, cause inflammation are related to inhibition of the formation of chronic inflammatory, and degenerative joint diseases (1). Gen- prostaglandins, prostacyclins, and thromboxanes (5). Previous erally, NSAIDs are divided into nonselective and selective NSAIDs studies have documented that COX-2 plays an important role in depending on whether or not the inhibitory target is on COX-2 the pathogenesis of colorectal cancer (6, 7). Given the association selectivity. Colorectal cancer is the third deadliest cancer between COX-2 and colorectal cancer, many studies have inves- in America (2), and also the second most common cancer in tigated the efficacy of NSAIDs as chemoprevention for colorectal Taiwan (3). The age-standardized rates of colorectal cancer inci- cancer. For example, several studies have shown that aspirin reduces the recurrence of adenomatous polyps among patients – 1Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical Univer- with a history of colorectal cancer (8 10). However, other ran- sity, Taipei, Taiwan. 2Department of Pharmacy, Wan Fang Hospital, Taipei domized trials failed to show that low-dose aspirin given as Medical University, Taipei, Taiwan. 3Division of Gastroenterology and Hepatol- primary prevention lowered the risk of colorectal cancer (11, 12). ogy, Department of Medicine, The University of Arizona, Tucson, Arizona. Although, numerous studies have examined the role of aspirin 4Institute of Population Health Sciences, National Health Research Institutes, 5 or NSAIDs on colorectal cancer chemoprevention, data regarding Miaoli, Taiwan. Department of Pediatrics, Feinberg School of Medicine, primary prevention among Asian populations are still unclear. Northwestern University, Chicago, Illinois. 6Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Furthermore, dose and duration response data are also limited. To Medical University, Taipei, Taiwan. 7Center for Biomarkers and Biotech Drugs, extend our understanding in this area, we conducted a nested Kaohsiung Medical University, Kaohsiung, Taiwan. case–control study to examine the primary preventive efficacy of Corresponding Authors: Hui-Ju Tsai, Division of Biostatistics and Bioinformat- aspirin and NSAIDs on colorectal cancer incidence in a large ics, Institute of Population Health Sciences National Health Research Institutes, nationwide population-based cohort in Taiwan. Zhunan, Miaoli 35053, Taiwan. Phone: 886-3724-6166, ext. 36150; Fax: 886- 3758-6467; E-mail: [email protected]; and Wei-Chiao Chang, Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Materials and Methods Taiwan. Phone: 8862-2736-1661, ext. 6188; E-mail: [email protected] Data source doi: 10.1158/1055-9965.EPI-17-0876 The data used in this study were derived from the National 2018 American Association for Cancer Research. Health Insurance Research Database (NHIRD) in Taiwan. The

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National Health Insurance (NHI) program in Taiwan was nac, aceclofenac, acemetacin, nabumetone, diclofenac, etodo- launched in 1995 and the NHIRD has been released for research lac, ketorolac, sulindac, and tolmetin; (v) enolic acid deriva- purposes since 1998. NHIRD has collected demographic char- tives: piroxicam, meloxicam, and tenoxicam; (vi) anthranilic: acteristics, outpatient visits and inpatient claims data, and pre- flufenamic, mefenamic, niflumic, and tolfenamic; and (vii) scription records and disease diagnoses for approximately 99% of sulphonailide: nimesulide. the entire population of 23 million people residing in Taiwan. However, the data in NHIRD before 2001 were not comprehen- NSAID exposure sive for research purpose. Therefore, in this study, we set 2005 as In this study, we examined the long-term effects of NSAID index year and evaluated 4-year exposure duration for cases in (including aspirin, selective, and nonselective NSAIDs) use. 2005, starting from 2001. Specifically, we defi ned users, recent or former users were based on a previous population-based case–control Demark study Cases of colorectal cancer and matched controls (14). We accounted for the duration of exposure to NSAID use The incident cases of colorectal cancer were defined as patients that was between 13 months and 48 months prior to the index diagnosed with colorectal cancer from 2005–2013 (ICD-9-CM date. Study participants were categorized on the basis of their codes: 153 and 154) who were identified from the Registry of NSAID exposure status. First, patients exposed to NSAIDs were Catastrophic Illness Patient Database (RCIPD). The date of the classified as users (definedasatleasttwoprescriptionsof first diagnosed record of colorectal cancer was defined as the index NSAIDs during the 13–48 months prior to the index date) or date. In detail, patients were mandated to have histologic, radio- nonusers. Patients with only one prescription would be exclud- graphic, and/or pathologic confirmations for cancer diagnosis ed from the subsequent analyses. Next, we classified patients before catastrophic illness certificates were issued and included in as recent users (defined as at least two prescriptions of NSAIDs the RCIPD. Of note, in this study, we did not include those with in the 13–24 months prior to the index date), former users in situ malignancies because such early-stage diseases do not (defined as at least two prescriptions of NSAIDs in the 25–48 qualify for catastrophic illness certificates and hence are not months prior to the index date, but not in the 13–24 months captured by the RCIPD. As we intended to analyze the association prior to the index date), or nonusers. Furthermore, we grouped between NSAID and colorectal cancer incidence, we excluded patients into continuous users (definedasatleasttwoprescrip- nearly 80,000 cases before the year 2005. tions of NSAIDs per months and continuing for over 6 months For each case, we randomly selected one control from the in the period of 13–48 months prior to the index date), Longitudinal Health Insurance Database for the year 2005 noncontinuous users (defined as not meeting the criteria of (LHID2005) who did not have a colorectal cancer diagnosis at continuous use, but with identified prescriptions of aspirin or the time when the matched case was diagnosed with colorectal NSAIDs in the period of 13–48 months prior to the index date), cancer. The LHID2005 is a subset derived from the NHIRD and or nonusers (14). includes medical claims data of 1,000,000 individuals randomly sampled from the 2005 NHI Registry for Beneficiaries. Previous Adjustment of potential confounding factors studies have reported that there is no difference of distributions in We took into account the potential confounding effects age and gender between LHID 2005 and NHIRD (13). Therefore, caused by comorbid medical disorders, concomitant medica- the LHID2005 is representative of the original NHIRD. We then tion use, and health service utilization; and adjusted for these applied risk set sampling and randomly selected one control from factors in the subsequent analytical models. In detail, comorbid the LHID2005 without having a colorectal cancer diagnosis at the medical disorders included: type 2 diabetes mellitus, alcohol- time of matching colorectal cancer case. The controls were ism, chronic pulmonary disease, asthma, migraines, rheumatic matched with the cases by age, sex, and index year. Controls were diseases, cardiovascular diseases (e.g., acute myocardial infarc- assigned the same index date as their matched cases. Of note, the tion, ischemic heart disease, congestive heart failure, and atrial exclusion criteria were as follows: (i) less than 30 years old or over flutter), and cerebrovascular disease; and concomitant drugs 85 years old on the first diagnostic date of colorectal cancer; (ii) included: bisphosphonates, statins, antidepressants, angioten- previous diagnosis of cancer (ICD-9 codes: 140–208) or benign sin converting enzyme inhibitors/angiotensin receptor block- lesions (ICD-9 code: 210–239) prior to 2005; (iii) diagnosis of ers, and hormone replacement agents. Health service utiliza- ulcerative colitis (ICD-9 code: 556), familial adenomatous poly- tion was computed using the number of ambulatory visits and posis (ICD-9 code: 211.3) or Crohn disease (ICD-9 code: 555) hospitalizations during 2003 and 2004. prior to 2005; and/or (iv) participation in the NHI program less than 4 years before the index date. In addition, for controls, Statistical analysis subjects with colorectal cancer diagnosed prior to 2005 were Descriptive statistics for the colorectal cancer cases and matched excluded. controls are presented as counts and corresponding percentages, or by mean and the corresponding SD for demographic and Utilization of NSAIDs clinical characteristics, comorbid medical disorders, concomitant We identified information related to NSAID use from pre- medication use, and health service utilization. The Student t test scription records in the NHIRD including types of prescribed was used for testing continuous variables and the c2 test was used medication, time of prescription, and duration of drug supply for testing discrete variables, separately, to compare demographic and dosage. NSAIDs were classified as follows: (i) aspirin; (ii) and clinical characteristics between colorectal cancer cases and selective COX-2 inhibitors: celecoxib, etoricoxib, and rofecoxib; matched controls. Conditional logistic regression models (with (iii) propionic acid derivatives: ibuprofen, naproxen, ketopro- and without covariate adjustment) were carried out to evaluate fen, fenbufen, fenoprofen, alminoprofen, flurbiprofen, and the association between NSAID use (aspirin and selective and tiaprofenic; (iv) acetic acid derivatives: indomethacin, alclofe- nonselective NSAIDs) and colorectal cancer, based on NSAID

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The special request data LHID 2005 CRC1 cases in 2001–2013 (n = 1,000,000) (n = 177,790)

Exclude cases: Exclude subjects: Were diagnosed with cancer* prior to 2005 Were diagnosed with cancer* prior to 2005 (n = 80,372) (n = 12,611) Age <30 or >85 y in the index date Were diagnosed with CRC (n = 4,663) (n = 6,126) Age <30 or >85 y in 2005 (n = 478,671) Were diagnosed with Were diagnosed with IBD (n = 870) IBD (n = 2,598) FAP (n = 16,864) FAP (n = 20,081) Crohn disease (n = 5,104) Crohn disease (n = 30,104) <4 y coverage before the index date (n = 2,522)

CRC cases age between 30 and 85 At risk for CRC age between 30 and in 2005–2013 85 (n = 65,932) (n = 451,272)

1:1 matching by birth year, gender, and index year

CRC cases Controls (n = 65,208) (n = 65,208)

NSAIDs NSAIDs Aspirin Aspirin NSAIDs NSAIDs Aspirin Aspirin Nonusers users Nonusers users Nonusers users Nonusers users (n = 10,092) (n = 48,463) (n = 49,095) (n = 13,541) (n = 9,783) (n = 49,284) (n = 49,170) (n = 13,521)

Figure 1. Flow diagram of inclusion/exclusion criteria for the study population. Note: CRC, colorectal cancer; IBD, inflammatory bowel disease; FAP, familial adenomatous polyposis; and Crohn disease., Any cancer diagnosis except nonmelanoma skin cancer. exposure status, various drug classes, number of cumulative use Results days, and defined daily dose (DDD), which was defined as "the A total of 130,416 study participants (65,208 colorectal assumed maintenance dose per day for a drug used for its main cancer cases and 65,208 matched controls) with cases diagnosed indication." If patients took two or more classes of NSAIDs at the between January 1, 2005, and December 31, 2013, were includ- same time, we defined those patients as combined users. In this ed. Figure 1 shows the detailed flow chart for identification of the study, most subjects taking aspirin dose less than 100 mg per day, study participants. Demographic and clinical characteristics of the only less than 0.5% of aspirin users took dose over 100 mg per study participants are presented in Table 1. The mean age was day. For NSAIDs, we used the data in WHO Collaborating Centre 65.61 12.14 years in both groups, and 43.3% were females. for Drug Statistics Methodology (https://www.whocc.no/) as the The number of prescriptions for aspirin and NSAIDs, separately, source to reference of DDD of NSAIDs examined in this study and concomitant drugs and comorbidities are also provided (15). In addition, the definition of "user" might not precisely in Table 1. capture users of aspirin/ NSAIDs, we further grouped participants Table 2 presents the association between NSAID use and based on number of prescriptions, that is, nonusers versus parti- colorectal cancer. Aspirin use was inversely associated with cipants with more than 12 prescriptions. We then assessed the colorectal cancer compared withitscounterparts[AOR¼ association between aspirin/ NSAID use and colorectal cancer 0.94, 95% confidence interval (CI): 0.90–0.99]. When further based on this definition as a sensitivity analysis. The covariates stratifying study participants to non-, recent-, and former aspi- that were adjusted in the analytical models are listed above. P rin users, similar associations were found (adjusted OR ¼ 0.98; values less than 0.05 were declared to be statistically significant. 95% CI, 0.93–1.02 for recent users and AOR ¼ 0.85; 95% CI, All analyses were conducted using SAS version 9.2 for Windows 0.79–0.92 for former users). Continuous use of aspirin was (SAS Institute). associated with lower colorectal cancer risk significantly (adjusted OR ¼ 0.89; 95% CI, 0.83–0.97). NSAID use was Ethics approval also associated with a decreased risk of colorectal cancer com- The Institutional Review Board of the National Health Research pared with its counterparts (AOR ¼ 0.96; 95% CI, 0.92–1.00). Institutes, Taiwan approved the study protocol. Similarly, when stratifying participants to nonuser, recent- and

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Table 1. Demographic and clinical characteristics among study participants Controls (n ¼ 65,208) Cases (n ¼ 65,208) P Demographic characteristics Age (year; mean SD) 65.61 12.14 65.61 12.14 1.00 Gender (n,%) Males 36,964 (56.69) 36,964 (56.69) 1.00 Females 28,244 (43.31) 28,244 (43.31) Number of prescriptions for aspirin (n,%) 0–1 49,170 (75.40) 49,095 (75.29) 0.66 2–12 6,112 (9.37) 6,036 (9.26) 13–24 3,077 (4.72) 3,167 (4, 86) 25 4,332 (6.64) 4,338 (6.65) Number of prescriptions for NSAIDs (n,%) 0–1 9,783 (15.00) 10,092 (15.48) <0.01 2–12 32,240 (49.44) 32,758 (50.24) 13–24 9,452 (14.50) 8,970 (13.76) 25 7,592 (11.64) 6,735 (10.33) Clinical characteristics Concomitant drugs (n,%) Statins 8,947 (13.72) 9,072 (13.91) 0.32 Antidepressants 5,164 (7.92) 5,607 (8.60) <0.01 ACEIs or ARBs 16,733 (25.66) 18,088 (27.74) <0.01 Bisphosphonates 93 (0.14) 70 (0.11) 0.07 Hormone replacement therapy 1,250 (1.92) 1,319 (2.02) 0.17 Comorbidity (n,%) T2DM 12,141 (18.62) 15,502 (23.77) <0.01 Alcoholism 120 (0.18) 192 (0.29) <0.01 COPD or asthma 5,888 (9.03) 6,445 (9.88) <0.01 Migraine 692 (1.06) 665 (1.02) 0.46 Rheumatic, soft tissue, or connective tissue disease 22,503 (34.51) 21,878 (33.55) <0.01 AMI/ischemic heart disease 8,475 (13.00) 9,161 (14.05) <0.01 Congestive heart failure 852 (1.31) 1,163 (1.78) <0.01 Atrial ﬂutter 2,135 (3.27) 2,430 (3.73) <0.01 Cerebrovascular disease 6,291 (9.65) 6,639 (10.18) <0.01 NOTE: The signiﬁcance of bold values is P < 0.05. Abbreviations: ACEIs/ARBs: angiotensin converting-enzyme inhibitors/angiotensin receptor blockers; AMI: acute myocardial infarction; COPD: chronic obstructive pulmonary disease; T2DM: type 2 diabetes mellitus.

former users or to nonuser, and continuous and noncontinu- reduce the risk of colorectal cancer (AOR ¼ 0.93; 95% CI, ous users, significant beneficial effects were found on colorectal 0.89–0.98). No associations were found when examining indi- cancer (AOR ¼ 0.94; 95% CI, 0.89–0.98 for recent users and vidual classes of NSAID use (Table 4). AOR ¼ 0.67; 95% CI, 0.63–0.73 for continuous users). In We further separated cases to patients with colon cancer or addition, when we further grouped participants based on rectal cancer. Table 5 shows aspirin use reduced the risk of rectal number of prescription, no significant association was found cancer (AOR ¼ 0.91; 95% CI, 0.85–0.98), but not colon cancer for aspirin users with >12 prescriptions (AOR ¼ 1.01; 95% CI, (AOR ¼ 0.97; 95% CI, 0.91–1.03). The use of NSAIDs did not 0.95–1.06), compared with aspirin users with >2 prescriptions reduce the risk of colon cancer or rectal cancer, however, signif- (AOR ¼ 0.94; 95% CI, 0.90–0.99). Whereas for NSAID users, icant beneficial effects of NSAID use in continuous users were more strong significant association was found for NSAID users found on both colon and rectal cancers (AOR ¼ 0.61; 95% CI, >12 prescriptions (AOR ¼ 0.78; 95% CI, 0.74–0.83), compared 0.55–0.67 for colon cancer and AOR ¼ 0.78; 95% CI, 0.69–0.87 with NSAID users with >2 prescriptions (AOR ¼ 0.96; 95% CI, for rectal cancer). 0.92–1.00). When investigating cumulative use days and DDD, a signif- Discussion icantly reduced colorectal cancer risk was observed among NSAID users (Table 3). Specifically, patients who took NSAIDS From the results of this nationwide population-based case– for more cumulative days tended to have a more reduced control study, our data demonstrate that taking aspirin or NSAIDs colorectal cancer risk (AOR ¼ 0.96; 95% CI, 0.92–1.01 for is associated with a lower incidence of colorectal cancer compared 1–365 days; AOR ¼ 0.71; 95% CI, 0.64–0.78 for 366–730 days; with nonuse in Taiwanese population. Importantly, the protective AOR ¼ 0.60; 95% CI, 0.52–0.70 for more than 730 days; Ptrend effect was even stronger when the cumulative duration of NSAID < 0 3). However, no dose–response effects were found for the use was longer. However, we did not identify a dose response use of NSAIDs (Table 3). partially due to moderate protective effect of aspirin or NSAIDs on Furthermore, we assessed the associations between different colorectal cancer or sample size constraint. NSAID classes and colorectal cancer. Table 4 shows a significant The chemopreventive efficacy of aspirin for colorectal cancer beneficial effect on colorectal cancer among patients with a has been examined in several previous studies. In randomized combined use of selective and nonselective NSAIDs (AOR ¼ controlled studies for high-risk populations, previous studies 0.81; 95% CI, 0.76–0.87). In addition, the combined use of showed conclusive results that aspirin reduced colorectal cancer various nonselective NSAIDs was also found to significantly risk by 19% to 40% (8–10, 16). The treatment duration ranged

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Table 2. Association between NSAID use and colorectal cancer, grouped by different exposure status of NSAIDs Controls Cases Total Crude OR (95% CI) AORa (95% CI) Aspirin Users vs. nonusers Nonuserb 49,170 (78.43) 49,095 (78.38) 98,265 Reference Reference User 13,521 (21.57) 13,541 (21.62) 27,062 1.01 (0.98–1.04) 0.94c (0.90–0.99) Total 62,691 62,636 125,327 Recent or former users vs. nonusers Nonuser 49,170 (78.43) 49,095 (78.38) 98,265 Reference Reference Recent user 10,480 (16.72) 10,526 (16.81) 21,006 1.01 (0.98–1.04) 0.98 (0.93–1.02) Former user 3,041 (4.85) 3,015 (4.81) 6,056 1.00 (0.95–1.06) 0.85 (0.79–0.92) Total 62,691 62,636 125,327 Continuous or noncontinuous users vs. nonusers Nonuser 49,170 (78.43) 49,095 (78.38) 98,265 Reference Reference Continuous user 3,129 (4.99) 3,103 (4.95) 6,232 1.00 (0.95–1.05) 0.89 (0.83–0.97) Noncontinuous user 10,392 (16.58) 10,438 (16.66) 20,830 1.01 (0.98–1.04) 0.96 (0.91–1.00) Total 62,691 62,636 125,327 Subjects with >12 prescriptions vs. nonusers Nonuser 49,170 (78.43) 49,095 (78.38) 98,265 Reference Reference >12 prescriptions 7,409 (11.82) 7,505 (11.98) 14,914 1.02 (0.98–1.06) 1.01 (0.95–1.06) Total 56,579 56,600 113,179 NSAIDs Users vs. nonusers Nonuser 9,783 (16.56) 10,092 (17.24) 19,875 Reference Reference User 49,284 (83.44) 48,463 (82.76) 97,747 0.95 (0.92–0.98) 0.96 (0.92–1.00) Total 59,067 58,555 117,622 Recent or former users vs. nonusers Nonuser 9,783 (16.56) 10,092 (17.24) 19,875 Reference Reference Recent user 39,134 (66.25) 38,300 (65.41) 77,434 0.95 (0.92–0.98) 0.94 (0.89–0.98) Former user 10,150 (17.18) 10,163 (17.36) 20,313 0.97 (0.93–1.01) 1.02 (0.96–1.07) Total 59,067 58,555 117,622 Continuous or noncontinuous users vs. nonusers Nonuser 9,783 (16.56) 10,092 (17.24) 19,875 Reference Reference Continuous user 5,149 (8.72) 4,523 (7.72) 9,672 0.85 (0.80–0.89) 0.67 (0.63–0.73) Noncontinuous user 44,135 (74.72) 43,940 (75.04) 88,075 0.96 (0.93–1.00) 0.97 (0.93–1.01) Total 59,067 58,555 117,622 Subjects with >12 prescriptions vs. nonusers Nonuser 49,170 (78.43) 49,095 (78.38) 98,265 Reference Reference >12 prescriptions 17,044 (28.86) 15,705 (26.82) 32,749 0.88 (0.85–0.92) 0.78 (0.74–0.83) Total 26,827 25,797 52,624 aAdjusted covariates included: comorbid medical disorders (type 2 diabetes mellitus, alcoholism, chronic obstructive pulmonary disease, asthma, migraine, cardiovascular disease, cerebrovascular disease, acute myocardial infarction, ischemic heart disease, congestive heart failure, atrial flutter, and cerebrovascular disease), concomitant drugs (bisphosphonates, statins, antidepressants, angiotensin converting enzyme inhibitors/angiotensin receptor blockers, and hormone replacement agents), and health service utilization (ambulatory visits and inpatient visits). bStudy participants without aspirin or NSAID use were treated as the reference group. cSignificant results (P < 0.05) are in bold. from 1 to 2.5 years among these studies. However, these studies Previous studies have also documented the chemopreventive could not determine the optimal dose of aspirin. Sandler and efficacy of NSAID use for colorectal cancer. For example, previous colleagues reported that the daily use of 325 mg aspirin was randomized trials have reported that daily use of celecoxib for associated with a reduced incidence of colorectal adenomas in 3 years could reduce adenoma incidence in patients who had individuals with previous colorectal cancer (9). Baron and colon adenomas removed 3 years or 5 years prior (19, 20). Baron colleagues suggested that aspirin at a dose of 81 mg rather and colleagues showed that taking rofecoxib for 3 years than 325 mg showed a protective effect (8). In a nurse health among patients with a history of colon adenoma could reduce study, a lower incidence of colorectal cancer was found among adenoma recurrence, and a protective effect was found at the participants who took more than two 325 mg tablets of aspirin 1-year follow-up (21). In addition to selective NSAIDs, the efficacy weekly (17). Huang and colleagues suggested that the regular of nonselective NSAIDs was examined in a randomized trial. use of low-dose aspirin (50–150 mg per day) over at least 3.5 Takayama and colleagues examined the efficacy of sulindac and years could reduce the risk of colorectal cancer occurrence in found that taking a daily dose of 300 mg of sulindac for 2 months patients with high cardiovascular risks by 50% (18). On the could reduce colorectal cancer risk at a 1-year follow-up (22). In basis of data from the aforementioned studies, it is clear that another study, the regular use of more than 2 tablets of NSAIDs the long-term use of aspirin may have a preventive effect on weekly for 20 years showed primary preventive efficacy for colo- colorectal cancer, yet the optimal treatment duration and dose rectal cancer, with a more significant risk reduction in the group remain unclear. Therefore, further investigation of the protec- taking 6–14 tablets per week (23). Yang and colleagues suggested tive effects of aspirin as related to colorectal cancer is needed, that patients who used COX-2 inhibitors had a decreased risk of especially in Asian populations. colorectal cancer (24). Friis and colleagues reported that the

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Table 3. Association between NSAID use and colorectal cancer, grouped by different cumulative days and DDD of NSAIDs Controls Cases Crude OR (95% CI) Adjusted ORa (95% CI) Aspirin Cumulative days Nonuserb 49,170 (78.43) 49,095 (78.38) Reference Reference 1–365 days 6,659 (10.62) 6,554 (10.46) 0.99 (0.95–1.03) 0.87c (0.83–0.92) 366–730 days 3,008 (4.80) 3,113 (4.97) 1.04 (0.99–1.10) 1.00 (0.93–1.08) >730 days 3,854 (6.15) 3,874 (6.18) 1.02 (0.97–1.07) 1.06 (0.98–1.13) d Total 62,691 62,636 Ptrend ¼ 0.53 NSAIDs Cumulative days Nonuser 9,783 (16.56) 10,092 (17.24) Reference Reference 1–365 days 46,029 (77.93) 45,715 (78.07) 0.96 (0.93–0.99) 0.96 (0.92–1.01) 366–730 days 2,330 (3.94) 2,028 (3.46) 0.83 (0.77–0.89) 0.71 (0.64–0.78) >730 days 925 (1.57) 720 (1.23) 0.74 (0.67–0.83) 0.60 (0.52–0.70) 3 Total 59,067 58,555 Ptrend <10 DDD Nonuser 9,783 (16.56) 10,092 (17.24) Reference Reference DDD 0.75 11,829 (20.03) 11,927 (20.37) 0.97 (0.93–1.01) 0.96 (0.91–1.02) 0.75 < DDD 1 14,008 (23.72) 13,615 (23.25) 0.95 (0.91–0.98) 0.93 (0.88–0.98) 1 < DDD 1.25 12,516 (21.19) 12,042 (20.57) 0.93 (0.89–0.97) 0.95 (0.90–1.00) 1.25 < DDD 10,931 (18.51) 10,879 (18.58) 0.97 (0.93–1.01) 0.99 (0.94–1.04)

Total 59,067 58,555 Ptrend ¼ 0.006 aAdjusted covariates: comorbid medical disorders (type 2 diabetes mellitus, alcoholism, chronic obstructive pulmonary disease, asthma, migraine, cardiovascular disease, cerebrovascular disease, acute myocardial infarction, ischemic heart disease, congestive heart failure, atrial ﬂutter and cerebrovascular disease), concomitant drugs (bisphosphonates, statins, antidepressants, angiotensin converting-enzyme inhibitors/angiotensin receptor blockers and hormone replacement agents), and health service utilization (ambulatory visits and inpatient visits). bStudy participants without aspirin or NSAID use were treated as the reference group. cSigniﬁcant results (P < 0.05) are in bold. dP values are obtained from the Cochran-Armitage trend test.

preventive effect was more obvious in the groups that took a dose On the other hand, some studies reported no association of greater than 0.3 DDD and had consistent use for more than 5 years aspirin or NSAID use with colorectal cancer. For example, in a (14). While most studies have evaluated the chemopreventive randomized controlled study of women taking 100 mg aspirin on efficacy of NSAIDs on colorectal cancer, only a limited number of alternative days for up to 10 years, no reduction in colorectal studies have reported on the primary preventive efficacy of cancer incidence was reported (12). In a prospective cohort study, NSAIDs on colorectal cancer. In line with these previous studies, no reduction of colorectal cancer risk was observed in male our results showed that patients who used NSAIDs showed participants regularly taking NSAIDs for 5 or more years (25). reduced colorectal cancer incidence. The efficacy was apparent in In Limburg study, taking 150 mg of sulindac twice daily for 6 groups of recent users and continuous users along with a duration months did not reduce colorectal cancer risk in patients with a response. previous diagnosis of colorectal cancer (26). Takayama and

Table 4. Association between NSAID use and colorectal cancer, grouped by different classes of NSAIDs Controls Cases Total COR (95% CI) AORa (95% CI) Selective vs. nonselective NSAIDs Nonuserb 9,783 (16.56) 10,092 (17.24) 19,875 Reference Reference Nonselective NSAIDs 41,249 (69.83) 41,035 (70.08) 82,284 0.96c (0.93–1.00) 0.97 (0.93–1.02) Selective NSAIDs 198 (0.34) 199 (0.34) 397 1.03 (0.84–1.28) 1.11 (0.83–1.48) Combinationd 7,837 (13.27) 7,229 (12.35) 15,066 0.89 (0.85–0.93) 0.81 (0.76–0.87) Total 59,067 58,555 117,622 Different classes of nonselective NSAIDs Nonuser 9,783 (16.56) 10,092 (17.24) 19,875 Reference Reference Propionic 1,484 (2.52) 1,593 (2.73) 3,077 1.06 (0.98–1.15) 1.11 (1.00–1.23) Acetic 5,201 (8.83) 5,296 (9.08) 10,497 0.98 (0.93–1.03) 1.01 (0.95–1.08) Enolic 409 (0.69) 410 (0.70) 819 0.96 (0.83–1.12) 1.00 (0.82–1.22) Anthranilic 1,796 (3.05) 1,961 (3.36) 3,757 1.05 (0.97–1.13) 1.05 (0.96–1.16) Sulphonailide 63 (0.11) 70 (0.12) 133 1.05 (0.74–1.50) 0.82 (0.51–1.32) Combinatione 40,133 (68.17) 38,934 (66.72) 79,067 0.94 (0.91–0.97) 0.93 (0.89–0.98) Total 58,869 58,356 117,225 aAdjusted covariates: comorbid medical disorders (type 2 diabetes mellitus, alcoholism, chronic obstructive pulmonary disease, asthma, migraine, cardiovascular disease, cerebrovascular disease, acute myocardial infarction, ischemic heart disease, congestive heart failure, atrial flutter, and cerebrovascular disease), concomitant drugs (bisphosphonates, statins, antidepressants, angiotensin converting-enzyme inhibitors/angiotensin receptor blockers, and hormone replacement agents), and health service utilization (ambulatory visits and inpatient visits). bStudy participants without NSAID use were treated as the reference group. cSignificant results (P < 0.05) are in bold. dCombination is defined as combined use of selective and nonselective NSAIDs. eCombination is defined as combined use of various classes of nonselective NSAIDs.

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Table 5. Association of NSAID use with colon or rectal cancer, grouped by different exposure status of NSAIDs (A) Colon cancer Controls Cases Total Adjusted ORa (95% CI) Aspirin Users vs. nonusers Nonuserb 28,211 (78.21) 29,087 (77.46) 57,298 Reference User 7,861 (21.79) 8,462 (22.64) 16,323 0.97 (0.91–1.03) Total 36,072 37,549 73,621 Recent or former users vs. nonusers Nonuser 28,211 (78.21) 29,087 (77.46) 57,298 Reference Recent user 6,086 (16.87) 6,607 (17.60) 12,693 1.01 (0.95–1.08) Former user 1,775 (4.92) 1,855 (4.94) 3,630 0.85c (0.77–0.94) Total 36,072 37,549 73,621 Continuous or noncontinuous users vs. nonusers Nonuser 28,211 (78.21) 29,087 (77.46) 57,298 Reference Continuous user 1,779 (4.99) 1,931 (5.14) 3,710 0.99 (0.89–1.09) Noncontinuous user 6,082 (16.58) 6,531 (17.39) 12,613 0.96 (0.91–1.03) Total 36,072 37,549 73,621 NSAIDs Users vs. nonusers Nonuser 5,187 (16.30) 5,963 (16.98) 11,150 Reference User 26,639 (83.70) 29,165 (83.02) 55,804 0.96 (0.91–1.02) Total 31,826 35,128 66,954 Recent or former users vs. nonusers Nonuser 5,187 (16.30) 5,963 (16.98) 11,150 Reference Recent user 21,226 (66.69) 23,032 (65.57) 44,258 0.94 (0.88–1.00) Former user 5,413 (17.01) 6,133 (17.46) 11,546 1.04 (0.97–1.12) Total 31,826 35,128 66,954 Continuous or noncontinuous users vs. nonusers Nonuser 5,187 (16.30) 5,963 (16.98) 11,150 Reference Continuous user 2,904 (9.12) 2,624 (7.47) 5,528 0.61 (0.55–0.67) Noncontinuous user 23,735 (74.58) 26,541 (75.56) 50,276 0.98 (0.92–1.04) Total 31,826 35,128 66,954

(B) Rectal cancer Controls Cases Total Adjusted ORa (95% CI) Aspirin Users vs. nonusers Nonuserb 18,348 (79.25) 19,170 (79.74) 37,518 Reference User 4,805 (20.75) 4,872 (20.26) 9,677 0.91c (0.85–0.98) Total 23,153 24,042 47,195 Recent or former users vs. nonusers Nonuser 18,348 (79.25) 19,170 (79.74) 37,518 Reference Recent user 3,745 (16.18) 3,744 (15.57) 7,489 0.93 (0.86–1.00) Former user 1,060 (4.58) 1,128 (4.69) 2,188 0.87 (0.78–0.98) Total 23,153 24,042 47,195 Continuous or noncontinuous users vs. nonusers Nonuser 18,348 (79.25) 19,170 (79.74) 37,518 Reference Continuous user 1,125 (4.86) 1,125 (4.68) 2,250 0.80 (0.71–0.90) Noncontinuous user 3,680 (15.89) 3,747 (15.59) 7,427 0.95 (0.88–1.02) Total 23,153 24,042 47,195 NSAIDs Users vs. nonusers Nonuser 3,395 (16.74) 3,960 (17.66) 7,355 Reference User 16,890 (83.26) 18,469 (82.34) 35,359 0.95 (0.88–1.01) Total 20,285 22,429 42,714 Recent or former users vs. nonusers Nonuser 3,395 (16.74) 3,960 (17.66) 7,355 Reference Recent user 13,359 (65.86) 14,594 (65.07) 27,953 0.93 (0.87–1.00) Former user 3,531 (17.41) 3,875 (17.28) 7,406 0.98 (0.91–1.07) Total 20,285 22,429 42,714 Continuous or noncontinuous users vs. nonusers Nonuser 3,395 (16.74) 3,960 (17.66) 7,355 Reference Continuous user 1,685 (8.31) 1,829 (8.15) 3,514 0.78 (0.69–0.87) Noncontinuous user 15,205 (74.96) 16,640 (74.19) 31,845 0.95 (0.89–1.02) Total 20,285 22,429 42,714 aAdjusted covariates included: comorbid medical disorders (type 2 diabetes mellitus, alcoholism, chronic obstructive pulmonary disease, asthma, migraine, cardiovascular disease, cerebrovascular disease, acute myocardial infarction, ischemic heart disease, congestive heart failure, atrial ﬂutter, and cerebrovascular disease), concomitant drugs (bisphosphonates, statins, antidepressants, angiotensin converting-enzyme inhibitors/angiotensin receptor blockers, and hormone replacement agents), and health service utilization (ambulatory visits and inpatient visits). bStudy participants without aspirin or NSAID use were treated as the reference group. cSigniﬁcant results (P < 0.05) are in bold.

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Kuo et al.

colleagues found that taking 400 mg etodolac daily for 2 months NSAID use in patients who were in the very early stages of did not reduce colorectal cancer incidence at a 1-year follow-up colorectal cancer because they are not included in the RCIPD. (22). These inconsistent findings may be due to different exam- We also did not investigate the combined effect of drug-use timing ined doses, treatment durations, study populations, sample sizes, and drug-use cumulative duration due to considerable combina- and/or study designs. Our data provide supportive evidence that tion (or complex scenarios). Similarly, this may have underesti- there are beneficial effects of NSAID use on the primary preven- mated the effect of aspirin or NSAID use on colorectal cancer. tion of colorectal cancer in Asian population. However, due to Moreover, multiple testing was not taken into account in this inconclusive results, our findings should be interpreted with study. Sixth, the results for aspirin use observed in this study were caution. Further studies would be merited to confirm the findings inconsistent, as well as the duration of aspirin use, it was likely from this study. because the data of aspirin obtained from registry medical claims This study had several strengths. First, we identified cases from data might be imperfect, which might be in part explained the the RCIPD, which is part of the NHIRD. In Taiwan, once patients observed inconsistent results for aspirin use. Therefore, the results are diagnosed with a malignancy, they are considered to have should be interpreted with caution. catastrophic illness due to the need for intensive medical care. Because of this, we were able to ensure an accurate diagnosis of Conclusions colorectal cancer by identifying our studied participants from the The results of our study provide supportive evidence that the RCIPD. Second, a total of 130,416 patients were included in this use of aspirin or NSAID is associated with a reduced risk of study; this is a large sample size with sufficient power to allow us colorectal cancer incidence in Asian population. Unlike most fi to address the beneficial effects of NSAID use on the primary previous studies that have reported chemoprevention ef cacy of prevention of colorectal cancer. Third, we comprehensively and NSAID use on colorectal cancer, we demonstrate that NSAID use fi systematically investigated various conditions of NSAID use such has a chemoprevention ef cacy on colorectal cancer. Further as exposure status, cumulative use days, average daily dose, and investigation of the underlying regulatory mechanisms related fi individual drug structure classes, separately. Moreover, we to the observed bene cial effect of NSAID use on colorectal accounted for disease heterogeneity by examining the efficacy on cancer would be merited. colon and rectal cancers, separately. fl This study had a few limitations. First, our findings were similar Disclosure of Potential Con icts of Interest fl to previous observational studies from the western countries, but No potential con icts of interest were disclosed by the authors. with smaller effect. The observed smaller effect in this study may Authors' Contributions be due to the difference in genetic make-up or lifestyle-associated Conception and design: H.-J. Tsai, W.-C. Chang factors, such as smoking, exercise, and body mass index, since Analysis and interpretation of data (e.g., statistical analysis, biostatistics, majority of previous studies were conducted in the western computational analysis): C.-N. Kuo, J.-J. Pan, Y.-W. Huang, H.-J. Tsai countries. However, the information on genetic background or Writing, review, and/or revision of the manuscript: C.-N. Kuo, J.-J. Pan, some epidemiologic variables such as life style, smoking, alcohol, H.-J. Tsai, W.-C. Chang red meat consumption, obesity, and the familial history of colo- Study supervision: H.-J. Tsai, W.-C. Chang rectal cancer is not available in the NHIRD. Second, despite adjusting for several key confounders, our results are still likely Acknowledgments to be biased by unmeasured residual confounding factors. Third, H.-J. Tsai is supported in part by a grant from the National Health Research Institutes (PH-104-PP-14, PH-104-SP-05, PH-104-SP-16, PH-105- aspirin and NSAIDs are prescribed medications in Taiwan. SP-05, and PH-105-SP-04 to H.-J. Tsai; MOST105-2628-B-038-001-MY4 to According to the data in Taiwan's food and drug administration, W.-C. Chang). W.-C. Chang is supported by Taipei Medical University (105- 18 of 52 (34.6%) oral aspirin are over-the-counter (OTC) pro- 5807-002-400). Chun-Nan Kuo is supported by a grant (103-wf-eva-06) from ducts. Among NSAIDs, 66 of 174 (37.9%) oral ibuprofen are OTC Taipei Municipal Wanfang Hospital (managed by Taipei Medical University). products. A previous study in Taiwan has reported that few people We thank Tami R. Bartell at the Stanley Manne Children's Research Institute, would purchase OTC drugs when they felt sick because people Ann & Robert H. Lurie Children's Hospital of Chicago, for English editing. This study is based in part on data from the National Health Insurance preferred taking medication prescribed by trusted physicians; had Research Database provided by the Bureau of National Health Insurance, unsatisfied experience when purchasing OTC aspirin/NSAIDs Department of Health and managed by the National Health Research Institutes from pharmacy stores; or were lack of knowledge to self-purchase (registered numbers: 99081, 99136, 99287, 101014, NHRID-101-548, and which kinds of OTC aspirin/NSAIDs. Therefore, patients generally NHRID-105-046). The interpretation and conclusions contained herein do not seek medical help from medical professionals rather than inde- represent those of the Bureau of National Health Insurance, Department of pendently purchasing OTC drugs due to low medical costs in Health, or National Health Research Institutes. Taiwan (27). Hence, the percentage of study participants who were taking OTC aspirin or NSAIDs should have been small. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked Fourth, information regarding medication adherence or compli- advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate ance is not available in the NHIRD. However, medication adher- this fact. ence or compliance would most likely leads to an underestima- tion of the observed effect and would be in favor of a null Received September 28, 2017; revised December 6, 2017; accepted April 18, association. Fifth, we could not examine the effect of aspirin or 2018; published first April 25, 2018.

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Association between Nonsteroidal Anti-Inflammatory Drugs and Colorectal Cancer: A Population-Based Case −Control Study

Chun-Nan Kuo, Jen-Jung Pan, Ya-Wen Huang, et al.

Cancer Epidemiol Biomarkers Prev Published OnlineFirst April 25, 2018.

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