Nonsteroidal Anti-Inflammatory Drugs and Risk of Esophageal and Gastric Cancer

444 Cancer Epidemiology, Biomarkers & Prevention Nonsteroidal Anti-inflammatory Drugs and Risk of Esophageal and Gastric Cancer

Mats Lindblad,1 Jesper Lagergren,1,2 and Luis A. Garcıá Rodrı´guez 3 1Department of Surgical Sciences, Karolinska University Hospital and 2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; and 3Centro Espanõl de Investigacioń Farmacoepidemiologica, Madrid, Spain

Abstract

Introduction: Nonsteroidal anti-inflammatory drugs (NSAID) esophageal (OR, 0.82; 95% CI, 0.57-1.18) and gastric cancer might reduce risks of esophageal and gastric cancer, but (OR, 0.65; 95% CI, 0.44-0.94), whereas long-term aspirin users previous studies are limited and provide somewhat might be at decreased risk of esophageal cancer (OR, 0.76; conflicting results. 95% CI, 0.53-1.08), but not of gastric cancer (OR, 1.09; 95% CI, Methods: We tested these associations in a prospective, 0.82-1.45). All estimates of reduced risk were weakened in nested case-control study based on the General Practitioners the 2 years lag time analysis except the association between Research Database, including over 2 million persons in the nonaspirin NSAIDs long-term users and gastric cancer. United Kingdom between 1994 and 2001. In multivariate Potentially protective effects were suggestive of being more analyses we calculated odds ratios (OR) with 95% confidence marked among subjects with a history of UGI disorders. intervals (95% CI). Data were stratified by history of upper Conclusions: Nonaspirin NSAIDs long-term use was associ- gastrointestinal (UGI) disorders and recalculated using 2 ated with a reduced risk of gastric cancer, whereas no other years lag time on data (i.e., excluding all information 2 years studied associations could be firmly established. Our results before index date). suggest that UGI disorders could distort the associations, Results: Among 4,340,207 person-years of follow-up, we although we could not show this with statistical significance. identified 909 patients with esophageal cancer and 1,023 If such bias was to be true, the previously reported inverse patients with gastric cancer. We randomly selected 10,000 associations might, at least partly, be explained by lack of control subjects. Overall analysis suggested that long-term appropriate adjustment for such disorders. (Cancer Epide- users of nonaspirin NSAIDs were at reduced risks of miol Biomarkers Prev 2005;14(2):444–50)

Introduction

The hypothesis that nonsteroidal anti-inflammatory drugs dysplasia among users of celecoxib, a cyclooxygenase-2 (NSAID) prevent gastrointestinal cancers is gaining support. enzyme inhibitor, in a population at high risk of esophageal Mechanisms involving NSAIDs inhibitory effect on the cyclo- squamous cell carcinoma (24). With regard to gastric cancer, oxygenase-2 enzyme’s production of various prostaglandins, case-control studies have reported a reduced risk in the range resulting in modulation of inflammation and immunores- of 20% to 70% among users of NSAIDs (13, 14, 16, 17, 25, 26). ponse, induction of cell apoptosis, and inhibition of angiogen- A few cohort studies have reported results in support of a esis have been suggested (1). The majority of epidemiologic protective effect (20, 22, 27), whereas others have not (28, 29). studies have addressed colorectal cancer (2-10). The relation Our aim was to test whether use of aspirin and nonaspirin between NSAIDs and upper gastrointestinal (UGI) cancers has NSAIDs reduces risk of esophageal or gastric cancer in a been less studied, and the results are partly conflicting. Two prospective, nested case-control study conducted in the recent reviews conclude that, although the data are limited in General Practitioner Research Database (GPRD). This database several aspects, a synthesis of existing studies support an has been used in a previous study (17) conducted between inverse association between use of aspirin or nonaspirin 1993 and 1995 in testing the association between NSAID and NSAIDs and risk of esophageal cancer (11, 12), equally strong cancer. However, these two studies differ considerably in in both main histologic types (11). Pooled estimates of seven design with regard to study period, efforts of case validation case-control (13-19) and two cohort studies (20, 21) showed and tumor classification, drug exposure definitions, and in the that ‘‘any’’ exposure to aspirin or nonaspirin NSAIDs carried a extent of adjustments for potential confounding factors, 43% reduced risk of esophageal cancer (11). All studies did not including UGI disorders. support a negative association, however (16). Furthermore, a large cohort study indicated an increased risk of esophageal carcinoma among patients with rheumatoid arthritis, who Materials and Methods presumably used NSAIDs in a vast majority (22). Nevertheless, clinical trials testing the potential prevention of esophageal The GPRD. The GPRD has been described in detail else- cancer by the use of NSAIDs have already been initiated (23). where (17, 30). In brief, this database consists of computer- One randomized, double blind, placebo-controlled trial did not based information from over two million patients visiting detect any regression in the severity of squamous cell GPs in the United Kingdom. Prescriptions from participating GPs are computer linked to the GPRD. The GPs also prospectively supply information regarding the patients, including demographics, details from the visits, diagnoses Received 6/22/04; revised 8/29/04; accepted 9/7/04. from referrals to specialist doctors and hospital admissions, Grant support: AstraZeneca Sverige AB and Swedish Cancer Society. results from laboratory tests, and indications for new courses The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. of drug therapy. A modification of the Oxford Medical Section 1734 solely to indicate this fact. Information System classification system is used to code Requests for reprints: Mats Lindblad, Department of Surgery, P9: 03, Karolinska University diagnoses, and a dictionary based on data from the Hospital, SE-171 76 Stockholm, Sweden. Phone: 46-8-517-70-000; Fax: 46-8-33-15-87. E-mail: [email protected] Prescription Pricing Authority is used to code drugs. Data Copyright D 2005 American Association for Cancer Research. are sent anonymously to the Medicines and Healthcare

Cancer Epidemiol Biomarkers Prev 2005;14(2). February 2005 Downloaded from cebp.aacrjournals.org on September 28, 2021. © 2005 American Association for Cancer Research. Cancer Epidemiology, Biomarkers & Prevention 445 products Regulatory Agency, which organizes the informa- whereas past use represents whenever the most recent tion in the GPRD for research purposes. Validation studies of prescription for that drug was issued at least 1 year before the GPRD have found that >90 % of all referrals are entered index date. Among current users, the duration of drug use into the GPs computer with a diagnosis code that reflects the was calculated adding the periods of ‘‘consecutive’’ prescrip- specialist’s diagnosis (31-33). These validation studies did not tions, defined as an interval of <6 months between two address the completeness or misclassification of exposure prescriptions of the same drug. Duration was grouped into variables, however. A recent study validated the information three levels (<1, 1-3, or >3 years). The latter duration category on tobacco smoking status in the GPRD finding that record- was defined as long-term use. Daily dose of nonaspirin ings of current and former use were 79% and 29%, NSAIDs was categorized as low medium or high for each respectively, of expected rates according to a population- individual drug (see Appendix 1), whereas daily dose of based survey (34). aspirin was grouped into three levels (up to 75 mg, >75 but z Study Cohort. In the GPRD, we identified all patients ages <300 mg, and 300 mg). 40 to 84 years during the study period, January 1994 through Analysis. In cohort analyses, we calculated the incidence December 2001. Patients became members of the study cohort rates by dividing the total number of observed cases by the on the date when they met the criteria of at least 2 years of corresponding total person-time followed up in each age and enrollment with the GP and at least 1 year of computerized sex specific strata. We used Poisson regression to estimate prescription history. Patients with any cancer recorded in the relative risk and 95% confidence interval (95% CI; ref. 35). In GPRD before this start date were excluded. nested case-control analyses (i.e., the main analyses), we used unconditional logistic regression to calculate odds ratios (OR) Follow-up. The members of the study cohort were followed up until the earliest occurrence of any of the following end with 95% CIs. In this study design, the OR is an unbiased estimator of the incidence rate ratio. All estimates of risk points: (a) detection of an esophageal or gastric cancer, (b) detection of any other cancer, (c) age of 85 years, (d) death, or were adjusted for the following potential confounding factors: (e) end of study period (December 31, 2001). age (in 10-year categories), sex, calendar year, smoking status (categorized into nonsmokers, ex-smokers, current smokers, Identification of Case Subjects. The computerized search or unknown), alcohol use (categorized into 0-2, 3-16, 16-34, of the study cohort identified 2,128 patients with a diagnosis >34 units per day, or unknown), body mass index (BMI) in code indicating an esophageal or gastric cancer during kg/m2 (categorized into <20, 20-25, 26-30, >30, or unknown), follow-up. One investigator (M.L.) reviewed all computerized and a history of UGI disorders (yes or no). UGI disorders was patient profiles to verify and further classify all tumors. To defined as any of the following events recorded up to 6 avoid bias, all exposure information was removed before the months before index date: gastroesophageal reflux disease, start of this review. Patients were excluded from further peptic ulcer, dyspepsia, or prescription of acid suppressing analyses if (a) the tumor was benign; (b) the site of the drugs (i.e., proton pump inhibitors or H2-receptor blockers). primary cancer was unknown; (c) the tumor was a metastasis; Stratified analyses were done by sex, age (<70, or >70 years), (d) the patient had another, concurrent, cancer; (e) the cancer UGI disorders (yes or no), and by use of health services was first diagnosed before the start date in the study cohort; during the 2 years before index date. The use of health or (f) the histologic diagnosis was not adenocarcinoma or services was defined as recorded visits to the GP, referrals, or squamous cell carcinoma. For a sample of 1,280 (60%) hospitalizations. To further evaluate the influence of proto- consecutive case patients, identified by the computerized pathic bias (i.e., reversed causality due to that the use of a search, the GPs were asked to provide information on the site drug might be determined by early symptoms of a, yet and histology of the tumor and to send available paper-based undetected, cancer), all main analyses were recalculated information (e.g., operation and pathology reports, letters using 2 years of lag time (i.e., only including information from specialists) related to the diagnosis. We received recorded at least 2 years before index date). complementary information on 993 (78%) of these patients, Ethics. The Scientific and Ethical Advisory Group in the resulting in an additional exclusion of 2.7 % of the computer- United Kingdom approved the study. detected cases. Because the effect of this additional exclusion review was negligible, we did not request complementary information from the GPs for the remaining computer- detected case subjects. Index date was set to be the date Results when the tumor was first recorded or when the manual review revealed an earlier date of diagnosis. Study Participants. Among 4,340,207 person-years of follow-up, we identified 2,128 patients with esophageal or Selection of Control Subjects. A date within the study gastric cancer and 10,000 control subjects. The manual review period was generated at random for each of the members of revealed 85 patients with a concurrent cancer or a cancer the entire source cohort. If this random date was included in diagnosed before the start of the study, 38 patients with the eligible person-time for that cohort member, we used this other or unknown site of their primary cancer, 28 patients random date as the index date and marked that person as an with a benign esophageal or gastric tumor, and 27 patients eligible control subject. Thereafter, a total of 10,000 controls, with a tumor of other histology than adenocarcinoma or free of cancer, were randomly selected and frequency matched squamous cell carcinoma. After exclusion of these 178 by sex, age (within 1 year), and same calendar year from the patients (8%), 1,950 case patients remained for final analysis. pool of eligible controls. The number of 10,000 controls was The manual review rendered a change of the tumor site from chosen as being close to five controls per case, a ratio esophageal to gastric in 74 (8%) patients and from gastric to considered to bring close to as much information as any other esophageal in 14 (2%) patients. Thereafter, the tumor site was ratio greater than it. classified as esophageal in 909 patients, as gastric in 1,023, Definition of the Drug Exposure. Any drug exposure whereas in 18 patients it was impossible to discern whether before index date was considered. We classified exposure for the site was esophageal or gastric. The median time of each drug into nonuse or ever use. Nonuse represented no follow-up between first drug prescription and index date was recorded use and ever use was defined as any recorded use similar between cases (2,235 days) and controls (2,200 days). of that drug. Ever users were further grouped into current or As presented in Table 1, the distribution of potential past users. Current use was defined as when prescriptions for confounding variables was even among case patients and that drug were issued within the year before index date, control subjects.

Cancer Epidemiol Biomarkers Prev 2005;14(2). February 2005 Downloaded from cebp.aacrjournals.org on September 28, 2021. © 2005 American Association for Cancer Research. 446 NSAIDs and Esophageal and Gastric Cancer

Table 1. Basic characteristics and distribution of potential confounding factors among cases and controls

Characteristic Controls, Esophageal cancer, Gastric cancer, All cases*, n (%) n (%) n (%) n (%)

Total 10,000 909 1,023 1,950 Sex Male 6,713 (67.1) 604 (66.4) 698 (68.2) 1,315 (67.4) Female 3,287 (32.9) 305 (33.6) 325 (31.8) 635 (32.6) Age (y) 40-59 1,669 (16.7) 153 (16.8) 158 (15.4) 313 (16.0) 60-69 2,615 (26.2) 248 (27.3) 255 (24.9) 507 (26.0) 70-79 4,060 (40.6) 360 (39.6) 435 (42.5) 803 (41.2) 80-84 1,656 (16.6) 148 (16.3) 175 (17.1) 327 (16.8) Tobacco smoking status Nonsmoker 5,443 (54.4) 416 (45.8) 481 (47.0) 906 (46.5) Ex-smoker 987 (9.9) 97 (10.7) 127 (12.4) 227 (11.6) Smoker 1,714 (17.1) 233 (25.6) 241 (23.6) 476 (24.4) Unknown 1,856 (18.6) 163 (17.9) 174 (17.0) 341 (17.5) Alcohol (units/d) 0-2 4,188 (41.9) 351 (38.6) 455 (44.5) 813 (41.7) 3-15 2,033 (20.3) 195 (21.4) 203 (19.8) 402 (20.6) 16-34 661 (6.6) 71 (7.8) 74 (7.2) 146 (7.5) >34 216 (2.2) 34 (3.7) 18 (1.8) 52 (2.7) Unknown 2,902 (29.0) 258 (28.4) 273 (26.7) 537 (27.5) BMI (kg/m2) <20 245 (2.4) 38 (4.2) 35 (3.4) 73 (3.7) 20-25 3,425 (34.2) 282 (31.0) 363 (35.5) 649 (33.3) 26-30 2,468 (24.7) 225 (24.8) 251 (24.5) 481 (24.7) >30 744 (7.4) 67 (7.4) 79 (7.7) 147 (7.5) Unknown 3,118 (31.2) 297 (32.7) 295 (28.8) 600 (30.8) Calendar year Before 1995 2,719 (27.2) 237 (26.1) 274 (26.8) 518 (26.6) 1995 2,055 (20.6) 183 (20.1) 205 (20.0) 389 (20.0) 1996-1997 3,208 (32.1) 280 (30.8) 320 (31.3) 606 (31.1) After 1997 2,018 (20.2) 209 (23.0) 224 (21.9) 437 (22.4) UGI disorders Never 6,713 (67.1) 569 (62.6) 554 (54.2) 1,137 (58.3) Ever 3,287 (32.9) 340 (37.4) 469 (45.8) 813 (41.7)

*Includes 909 cases of esophageal cancer, 1,023 cases of gastric cancer and 18 cases undefined if esophageal or gastric cancer.

Incidence Rates. The crude incidence rates for esophageal cancer (OR, 0.82; 95% CI, 0.57-1.18) and a 35% reduced risk of cancer was 20.9/100,000 person-years and for gastric cancer gastric cancer (OR, 0.65; 95% CI, 0.44-0.94). No clear dose- 23.6/100,000 person-years. Age- and sex specific relative risks response relation was found. Among long-term users who had of esophageal and gastric cancer are presented in Table 2. The used low-medium and high daily doses, respectively, ORs age and sex distributions were similar between patients with were 0.70 (95% CI, 0.42-1.18) and 0.96 (95% CI, 0.59-1.55) esophageal and gastric cancer. There was a clear male for esophageal cancer, and 0.53 (95% CI, 0.31-0.92) and 0.78 predominance and an increasing incidence by age in both (95% CI, 0.47-1.27) for gastric cancer. There was no apparent these types of cancer (Table 2). difference in OR between adenocarcinoma (OR, 0.59; 95% CI, 0.29-1.22) and squamous cell carcinoma (OR, 0.59; 95% CI, Nonaspirin NSAIDs. The overall analyses revealed that use 0.21-1.64) of the esophagus among long-term users, whereas in of nonaspirin NSAIDs was inversely associated with risk of the group of esophageal cancers without a defined histologic both esophageal and gastric cancer (Table 3). Long-term users classification in the database there was no association (OR, of nonaspirin NSAIDs were at 18% reduced risk of esophageal 1.02; 95% CI, 0.65-1.59). No important changes of the results

Table 2. Crude sex- and age-specific incidence rates and incidence rate ratios of esophageal cancer and gastric cancer

Variable Person-years Esophageal cancer Gastric cancer

n Incidence rate Incidence rate ratio n Incidence rate Incidence rate ratio (per 100,000 (95 % CI) (per 100,000 (95% CI) person-years) person-years)

Total 4,340,207 909 20.9 1,023 23.6 Sex Female 2,300,962 305 13.3 1.00 (reference) 325 14.1 1.00 (reference) Male 2,039,245 604 29.6 2.51 (2.18-2.88) 698 34.2 2.75 (2.41-3.15) Age groups (y) 40-49 1,315,159 35 2.7 1.00 (reference) 43 3.3 1.00 (reference) 50-59 1,163,475 118 10.1 3.73 (2.56-5.45) 115 9.9 3.11 (2.19-4.43) 60-69 924,320 248 26.8 9.98 (7.00-14.22) 255 27.6 8.55 (6.17-11.86) 70-79 725,970 360 49.6 19.23 (13.58-27.21) 435 59.9 19.41 (14.14-26.65) >80 211,283 148 70.0 28.23 (19.49-40.88) 175 82.8 28.62 (20.42-40.13)

Table 3. Association between use of nonaspirin NSAIDs and aspirin and the risk of esophageal or gastric cancer estimated in ORs

Exposure Controls Esophageal cancer Gastric cancer All cases*

n (%) n (%) OR (95% CI) n (%) OR (95% CI) n (%) OR (95% CI)

Total 10,000 909 1,023 1,950 Nonaspirin NSAIDs Never use 4,703 (47.0) 446 (49.1) 1.00 (reference) 504 (49.3) 1.00 (reference) 960 (49.2) 1.00 (reference) Ever use 5,297 (53.0) 463 (50.9) 0.91 (0.79-1.04) 519 (50.7) 0.88 (0.78-1.01) 990 (50.8) 0.90 (0.81-0.99) Current use 2,209 (22.1) 202 (22.2) 0.95 (0.80-1.13) 200 (19.6) 0.83 (0.70-0.99) 406 (20.8) 0.89 (0.78-1.01) Current use <3 y 1,762 (17.6) 167 (18.4) 0.98 (0.81-1.19) 168 (16.4) 0.87 (0.73-1.05) 338 (17.3) 0.93 (0.81-1.07) Current use z3 y 447 (4.5) 35 (3.8) 0.82 (0.57-1.18) 32 (3.1) 0.65 (0.44-0.94) 68 (3.5) 0.73 (0.56-0.95) Aspirin Never use 8,251 (82.5) 753 (82.8) 1.00 (reference) 806 (78.8) 1.00 (reference) 1,576 (80.8) 1.00 (reference) Ever use 1,749 (17.5) 156 (17.2) 0.96 (0.79-1.15) 519 (50.7) 1.15 (0.98-1.36) 374 (19.2) 1.05 (0.93-1.20) Current use 1,406 (14.1) 120 (13.2) 0.93 (0.76-1.15) 174 (17.0) 1.17 (0.97-1.39) 295 (15.1) 1.05 (0.91-1.21) Current use <3 y 893 (8.9) 85 (9.4) 1.03 (0.81-1.31) 114 (11.1) 1.21 (0.98-1.49) 199 (10.2) 1.11 (0.94-1.31) Current use z3 y 513 (5.1) 35 (3.8) 0.76 (0.53-1.08) 60 (5.9) 1.09 (0.82-1.45) 96 (4.9) 0.94 (0.74-1.18)

NOTE: All data adjusted for sex, age, smoking, alcohol consumption, BMI, calendar year, and UGI disorders. *Includes 909 cases of esophageal cancer, 1,023 cases of gastric cancer, and 18 cases undefined if esophageal or gastric cancer.

were found when we repeated all basic analyses using the overall analysis (Table 5). Using data without lag time, duration of drug exposure as the total cumulative time of we found that among subjects without UGI disorders, the drug use (data not shown). The results were not materially negative association slightly approached the null among altered after exclusion of persons who also had used aspirin nonaspirin NSAIDs long-term users, whereas among subjects (data not shown). with UGI disorders, the negative association was reinforced In analyses of exposure recorded at least 2 years before (Table 5). This finding was more pronounced when using index date (i.e., 2 years lag time), the association between the 2 years lag time data and extended to encompass also nonaspirin NSAIDs and risk of esophageal and gastric cancer the association with aspirin long-term use (Table 5). were virtually unchanged among ever users (data not shown). However, the differences between the two strata of UGI Long-term use of nonaspirin NSAIDs was not associated with disorder, in their association to use of NSAIDs, never esophageal cancer (OR, 0.98; 95% CI, 0.66-1.43), whereas the reached the level of statistical significance. Analyses of each inverse association remained for gastric cancer (OR, 0.59; 95% separate UGI disorder (i.e., gastroesophageal reflux disease, CI, 0.37-0.92). peptic ulcer, dyspepsia, or prescription of acid suppressing Aspirin. Users of aspirin with >3 years of duration were drugs) rendered similar results as the composite variable associated with a decreased risk of esophageal cancer (OR, 0.76; (data not shown). 95% CI, 0.53-1.08), but no reduction in risk was found for gastric Influence of Other Potential Confounding Variables. cancer (Table 3). Among persons who used daily doses of 75, Stratification by sex and age did not reveal any clear effect 150, and z300 mg, ORs for esophageal cancer were 0.79 (95% modification (data not shown). The number of GP visits during CI, 0.47-1.33), 0.86 (95% CI, 0.46-1.61), and 0.60 (95% CI, 0.29- the 2 years before index date revealed weakly increased risks of 1.23), respectively. Among long-term users, there were no esophageal and moderately increased risks of gastric cancer. major differences between esophageal adenocarcinoma (OR, Using zero to two GP visits as reference, the ORs for esophageal 0.75; 95% CI, 0.41-1.36) and squamous cell carcinoma (OR, 0.87; and gastric cancer, respectively, were in three to five GP visits 95% CI, 0.35-2.16). No important changes of results were found 1.27 (95% CI, 1.01-1.59) and 1.56 (95% CI, 1.22-1.99), and more in analyses using duration as the total cumulative time of drug use (data not shown). Furthermore, the results did not change importantly after exclusion of nonaspirin NSAIDs users (data Table 4. Association between UGI disorders and use not shown). In analyses with 2 years lag time, current use of of nonaspirin NSAIDs and aspirin among study control aspirin was associated with a decreased risk of esophageal subjects cancer (OR, 0.75; 95% CI, 0.58-0.97) but not gastric cancer (OR, 1.17; 95% CI, 0.95-1.45). Among long-term current users of Drug use Never UGI UGI aspirin, no association with esophageal cancer (OR, 0.99; 95% disorders disorder CI, 0.65-1.51) or gastric cancer (OR, 1.04; 95% CI, 0.71-1.54) was observed. n (%) n (%) OR (95 % CI)

Influence of UGI Disorders. A history of UGI disorders 6,713 3,287 increased the risk of both esophageal cancer (OR, 1.20; 95% Nonaspirin NSAIDs CI, 1.04-1.39) and gastric cancer (OR, 1.69; 95% CI, 1.48-1.92) Never use 3,358 (50.0) 1,345 (40.9) 1.00 (reference) after adjustment for all other potential confounding variables Ever use 3,355 (50.0) 1,942 (59.1) 1.41 (1.29-1.54) listed in the Materials and Methods section. In analyses with Current use 1,431 (21.3) 778 (23.7) 1.31 (1.18-1.46) Current use <3 y 1,158 (17.2) 604 (18.4) 1.27 (1.13-1.43) 2 years lag time, there were still increased risks of both Current use z3 y 273 (4.1) 174 (5.3) 1.48 (1.21-1.81) esophageal cancer (OR, 1.19; 95% CI, 1.02-1.38) and gastric Aspirin cancer (OR, 1.27; 95% CI, 1.11-1.46). Among control subjects, Never use 5,754 (85.7) 2,497 (76.0) 1.00 (reference) UGI disorders was linked with increased use of both Ever use 959 (14.3) 790 (24.0) 1.72 (1.55-1.92) nonaspirin NSAIDs and aspirin (Table 4). When we Current use 798 (11.9) 608 (18.5) 1.59 (1.41-1.79) excluded adjustment for UGI disorders in the model, the Current use <3 y 504 (7.5) 389 (11.8) 1.64 (1.42-1.89) Current use z3 y 294 (4.4) 219 (6.7) 1.51 (1.26-1.82) risk estimates only increased slightly (data not shown). When stratifying the analysis by UGI disorders, ORs for NOTE: UGI disorders are ever peptic ulcer or dyspepsia or reflux disease or acid both esophageal and gastric cancer changed compared with suppressing drugs.

Table 5. Analysis stratified by UGI disorders

Exposure No lag time, OR (95% CI) [no. cases] Two years lag time, OR (95% CI) [no. cases]

Esophageal cancer Gastric cancer All cases* Esophageal cancer Gastric cancer All cases*

Nonaspirinc NSAIDs long-term use Overall b 0.82 (0.57-1.18) [35] 0.65 (0.44-0.94) [32] 0.73 (0.56-0.95) [68] 0.98 (0.66-1.43) [31] 0.59 (0.37-0.92) [21] 0.77 (0.57-1.04) [53] Never UGI disorderb 0.85 (0.52-1.38) [19] 0.67 (0.40-1.13) [16] 0.77 (0.54-1.11) [36] 1.19 (0.74-1.92) [20] 0.72 (0.41-1.26) [14] 0.95 (0.66-1.38) [35] UGI disorder 0.76 (0.44-1.32) [16] 0.57 (0.33-0.98) [16] 0.65 (0.44-0.97) [32] 0.65 (0.34-1.25) [11] 0.39 (0.18-0.87) [7] 0.51 (0.30-0.86) [18] Aspirin long-termc use Overall b 0.76 (0.53-1.08) [35] 1.09 (0.82-1.45) [60] 0.94 (0.74-1.18) [96] 0.99 (0.65-1.51) [25] 1.04 (0.71-1.54) [30] 1.00 (0.74-1.35) [55] Never UGI disorderb 0.74 (0.45-1.21) [18] 1.17 (0.78-1.74) [29] 0.94 (0.68-1.30) [47] 1.04 (0.61-1.80) [15] 1.22 (0.76-1.98) [20] 1.12 (0.77-1.63) [35] UGI disorder 0.77 (0.46-1.29) [17] 1.01 (0.68-1.51) [31] 0.93 (0.67-1.29) [49] 0.83 (0.42-1.65) [10] 0.77 (0.39-1.52) [10] 0.80 (0.48-1.32) [20]

NOTE: ORs of esophageal, gastric cancer, and combined (all cases) among long-term users of nonaspirin NSAIDs and long-term users of aspirin, respectively, compared with nonusers. Results both without lag time and with 2 years of lag time are presented. *Includes 909 cases of esophageal cancer, 1,023 cases of gastric cancer, and 18 cases undefined if esophageal or gastric cancer. cAll data adjusted for sex, age, smoking, alcohol consumption, BMI, calendar year and UGI disorders. bAll data adjusted for sex, age, smoking, alcohol consumption, BMI, and calendar year.

than five GP visits 1.25 (95% CI, 1.03-1.53) and 1.86 (95% CI, be negligible, especially when the exposure of interest is 1.50-2.29). After stratification by GP visits (0-5 versus >5), a long term (36). Another limitation is that the computerized weak negative interaction, when combining use of analgesics database started in the late 1980s and therefore lacks and more frequent visits was found (data not shown). information before that period. Consequently, the lag-time analyses were inherently less precise when evaluating the role of long-term duration of drug use. Furthermore, our Discussion definitions of current use and long-term use are arbitrary and the data collection regarding the long-term usage (i.e., This study identifies an inverse association between long-term current use of at least 3 years) probably includes many use of nonaspirin NSAIDs and risk of gastric cancer, which subjects with <5 years of use, which might dilute the group seemed to be stronger among subjects with a history of UGI of ‘‘true’’ long-term users. Yet, this should not interfere disorders. No other associations were firmly identified after importantly with our results, because consistency has been adjustment for potential confounding, neither with nonaspirin high among previous studies of the association between NSAIDS nor aspirin. NSAIDs and gastrointestinal cancers despite major hetero- The main advantages of our study are the large sample geneous exposure definitions (12). We also assessed, in a size and the prospectively assessed exposure data, with subanalysis, the role of total cumulative exposure of detailed information on dates and types of drug use and NSAIDs (aspirin and nonaspirin NSAIDs), without finding medical data, including UGI disorders. The recordings in any important differences with the main analysis. Similarly, the database are based on the GPs’ routine medical care. the GPRD lacks information regarding the presence of This renders a degree of missing values and misclassifica- medical disorders (e.g., UGI disorders) occurring earlier tion that, in some of the potential confounders, could differ than the beginning of the computerized database, which between cases and controls. We found that the missing might introduce residual confounding. values were evenly distributed between cases and controls, Although data are somewhat conflicting, the majority of however. This implies that the exposure information was previous studies support an inverse association between use equally good for cases and controls. Furthermore, because of aspirin or nonaspirin NSAIDs and risk of esophageal and the information regarding potential confounders was gastric cancer (13, 14, 16-18, 20-22, 25-27). In most studies, recorded prospectively, before the occurrence of any cancer, personal interviews or self-administered questionnaires any possible exposure misclassification should mainly be were employed, however (14-16, 19, 25, 26). Problems with nondifferential and could, at the most, slightly dilute the such retrospective data collection are nondifferential mis- risk estimates. A potential weakness of our study is the case classification, and more importantly, differential misclassi- ascertainment, because there was no cancer registry for fication. Retrospective data collection is particularly prone identification of case patients. Previous studies of the to recall bias, because it relies heavily on the subject’s diagnoses assessed in the GPRD have shown good validity, ability to recall past drug exposure, especially when however (32, 33). Furthermore, our manual review of all duration of use is the main interest. This ability of recalling computer-selected cases together with the review of addi- might be influenced by the newly verified cancer among tional information provided by the GP in a large sample of cases. Most of our risk estimates did not bear statistical cases should have reduced tumor misclassification. Another significance, which could be due to insufficient numbers of source of error was that the GPRD does not contain subjects, but the point estimates in our study were in line adequate information regarding some potential confounding with previous results. However, the protective effects factors, including dietary habits, education, or familiar weakened when restricting the analysis to persons without antecedents. However, it is unlikely that any of these UGI disorders. Only three previous studies attempted to factors could explain our results, as they will most likely adjust their results for UGI disorders (14, 25, 26). In a U.S. be shared equally between users and nonusers of NSAIDs. population-based case-control study, there was no change We did not have access to Helicobacter pylori status, which in the protective effect of aspirin or NSAIDs on the risk of possibly could have an influence on the use of NSAIDs. On esophageal or gastric cancer in analyses restricted to sub- the other hand, we had access to data regarding several jects without UGI disorders (14). Two case-control studies of other, and possibly more important variables, including UGI aspirin and gastric cancer in Russia (25), and in Sweden disorders. We were unable to capture exposure to widely (26), adjusted for UGI disorders and found that the negative available over-the-counter anti-inflammatory drugs, but the association was compelled to H. pylori –positive subjects, impact of this possible error has previously been reported to however.

Appropriate adjustment for UGI disorders should be of Appendix 1. Nonaspirin NSAIDs daily dose limits for great importance when investigating these associations, categorization into low-medium and high daily dose because patients who experience early symptoms from a Generic drug name Limit for low-medium Limit for high yet unrecognized UGI tumor may increase or decrease their daily dose (mg) daily dose (mg) use of NSAIDs (i.e., protopathic bias; refs. 11, 12, 23, 37). Furthermore, it might be crucial to consider interaction Ibuprofen V1,200 >1,200 between NSAIDs and known risk factors for the occurrence Diclofenac V100 >100 of esophageal or gastric cancer (i.e., reflux in esophageal Naproxen V750 >750 adenocarcinoma; ref. 38), or H. pylori infection and peptic Indomethacin V75 >75 ulcer disease in gastric cancer (39). Hence, the indication Piroxicam V10 >10 (or the contraindication) for treatment might act as a Ketoprofen V150 >150 confounder. These types of biases are common sources of Aceclofenac V100 >100 error in pharmacoepidemiology (40-42), a problem that has Acemetacin V120 >120 not been satisfactory addressed in the previous literature Apazonedihydrate V600 >600 (11, 12, 23, 37). Our data indicate that a history of UGI Diflunisal V750 >750 disorders is an independent risk factor for esophageal and Etodolac V400 >400 gastric cancer. Moreover, in agreement with previous studies Fenbufen V900 >900 (43-47), such disorders were linked with the use of Fenoprofen V1,200 >1,200 analgesics among our controls, representing the source Flurbiprofin V150 >150 population. Hence, if UGI disorders occur before NSAID Meloxicam V7.5 >7.5 use,theymayactasconfounders(42).Therefore,we Nabumetone V1,000 >1,000 attempted to adjust for UGI disorders in the analyses by Sulindac V200 >200 both logistic regression, stratification, and by changes of lag Tenoxicam V10 >10 time. Because we could not firmly establish the temporal Tiaprofenic V450 >450 relation between NSAID use and UGI disorders, the divergent results after stratification are complex to interpret. There are at least four alternative explanations. First, the use of NSAIDs might reduce the progression from UGI disorders References to esophageal and gastric cancers (i.e., UGI disorders are in 1. Thun MJ, Henley SJ, Patrono C. Nonsteroidal anti-inflammatory drugs as the causal chain). This would imply a true protective effect anticancer agents: mechanistic, pharmacologic, and clinical issues. J Natl of NSAIDs, stronger among subjects with UGI disorders. Cancer Inst 2002;94:252 – 66. Second, patients with a yet unrecognized esophageal or 2. Kune GA, Kune S, Watson LF. Colorectal cancer risk, chronic illnesses, operations, and medications: case control results from the Melbourne gastric cancer might be less prone to use NSAIDs because of Colorectal Cancer Study. 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Cancer Epidemiol Biomarkers Prev 2005;14(2). February 2005 Downloaded from cebp.aacrjournals.org on September 28, 2021. © 2005 American Association for Cancer Research. Nonsteroidal Anti-inflammatory Drugs and Risk of Esophageal and Gastric Cancer

Mats Lindblad, Jesper Lagergren and Luis A. García Rodríguez

Cancer Epidemiol Biomarkers Prev 2005;14:444-450.

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