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Non-steroidal anti-inflammatory drugs and risk of esophageal and gastric adenocarcinomas in Los Angeles county

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Non-steroidal anti-inflammatory drugs and risk of esophageal and gastric adenocarcinomas in Los Angeles county

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Content NON-STEROIDAL ANTI-INFLAMMATORY DRUGS AND RISK OF ESOPHAGEAL AND GASTRIC ADENOCARCINOMAS IN LOS ANGELES COUNTY by Lei Duan A Thesis Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE (BIOSTATISTICS) May 2007 Copyright 2007 Lei Duan ii Dedication To my parents, Sanyuan Duan & Guozhen Tao, my husband, Jie Yao, for their support and understanding iii Acknowledgements This work was done under the direction and supervision of my guidance committee chair, Dr. Leslie Bernstein. I would like to give my gratitude and appreciation to Dr. Bernstein for her invaluable guidance and support provided throughout the course of my research and the writing of my papers. Meanwhile, I would also like to extend my enormous thanks and gratitude to my guidance committee co-chair, Dr. Chih- Ping Chou, for his comprehensive guidance and insight throughout my graduate study at USC. I would also like to extend my appreciation to other member of my guidance committee, Dr. Anna Wu for her advice and suggestions throughout the course of my research and in the preparation of this manuscript. I would like to express my most sincere appreciation to my husband, Jie Yao, for his understanding and support. Special appreciation also goes to friends, Yan Zhou, Bella Feng, and Huiyan Ma, for their accompany and support throughout my life at United States. iv Table of Contents Dedication ii Acknowledgements iii List of Tables v Abstract vi Introduction 1 Methods 4 Interview Methods 7 Statistical Analysis 9 Results 12 Discussion 20 Bibliography 26 Appendices 29 v List of Tables Table 1: Selected characteristics of esophageal and gastric adenocarcinoma case patients and control subjects, Los Angeles County 12 Table 2: Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) for use of aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) in relation to esophageal, gastric cardia and distal gastric adenocarcinomas 16 Table 3: Multivariable odds ratios (ORs) and 95% confidence intervals (CI) for use of aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) in relation to esophageal, gastric cardia and distal gastric adenocarcinomas, by history of upper gastrointestinal tract (UGI) disorders 18 vi Abstract Non-steroidal anti-inflammatory drug (NSAID) use has been consistently associated with reduced risks of colon cancer, but epidemiologic data are inconsistent for stomach and esophageal adenocarcinomas. Furthermore, data on potential confounding effects by upper gastrointestinal tract (UGI) disorders are limited. We sought to clarify these relationships in a large population-based case-control study. This study recruited newly diagnosed patients with esophageal adenocarcinoma (n=220), gastric cardia adenocarcinoma (n=277), or distal gastric adenocarcinoma (n=441), and 1356 control subjects in Los Angeles County. Evidence were found to support a reduction in risk of esophageal and distal gastric adenocarcinomas associated with at least five years of regular use of aspirin and other NSAIDs in individuals with and without a history of UGI disorders. It suggests that daily use provides the greatest protection. NSAID use does not affect risk of adenocarcinomas of the gastric cardia. 1 Introduction Since the late 1980s, evidence has accumulated to suggest that aspirin and other non- steroidal anti-inflammatory drug (NSAID) use may reduce cancer risk (Vainio and Morgan 1998; Baron and Sandler 2000; Vainio and Morgan 2000; Bosetti, Gallus et al. 2002; Baron 2003; Harris, Beebe-Donk et al. 2005). The hypothesized mechanism is that NSAIDs are able to inhibit the enzyme, cyclo-oxygenase, which is key in prostaglandin synthesis. One subtype of this enzyme, cyclo-oxygenase 2 (COX-2), is usually absent from normal mucosa, but overexpressed in gastrointestinal cancer tissue as well as in premalignant GI lesions (Langman, Cheng et al. 2000; Dai and Wang 2006). High concentrations of prostaglandins have been shown to promote cellular proliferation and tumor growth, suppress immune systems, and induce angiogenesis (Husain, Szabo et al. 2002). Thus, NSAIDs may protect against GI cancers by inhibiting COX-2, which in turn suppresses prostaglandin synthesis (Sugawa, Takekuma et al. 1997; Husain, Szabo et al. 2002). NSAID use has been consistently associated with reduced risks of colon cancer (Baron and Sandler 2000; Baron 2003). In contrast, epidemiologic data for the association between stomach and esophageal adenocarcinomas and NSAID use are inconsistent (Vainio and Morgan 2000). Findings from several case-control studies indicate up to 70% reduced risk of gastric cancer among NSAID users (Farrow, 2 Vaughan et al. 1998; Coogan, Rosenberg et al. 2000; Langman, Cheng et al. 2000), but results from cohort studies are less consistent, with some supporting a protective effect (Thun, Namboodiri et al. 1993; Sorensen, Friis et al. 2003), while others do not (Friis, Sorensen et al. 2003). Gridley and colleagues observed an increased risk of esophageal cancer in a large cohort of patients with rheumatoid arthritis, who mostly presumably used NSAIDs (Gridley, McLaughlin et al. 1993). A recent meta- analysis of eight case-control studies and one cohort study indicated that aspirin and other NSAIDs users were at reduced risk of non-cardia gastric cancers, but not of gastric cancer at the cardia (Wang, Huang et al. 2003). In considering the impact of NSAIDs on risk of upper gastrointenstinal (UGI) cancers, it is important to consider how use of NSAIDs might be influenced by history of UGI disorders which are related to risk of these cancers. Results reported thus far are scant and conflicting (Farrow, Vaughan et al. 1998; Zaridze, Borisova et al. 1999; Akre, Ekstrom et al. 2001). We investigated the association between use of aspirin and other NSAIDs and the risk of adenocarcinomas of the esophagus and stomach using data from a large population-based case-control study conducted in Los Angeles County, California. We sought to clarify whether these drugs were associated with decreased risk of adenocarcinoma of the esophagus, gastric cardia or distal stomach and whether the 3 risk for individuals with a history of UGI disorders differed from that for individuals with no history of UGI disorders. 4 Methods The study population and study design have been previously described (Wu, Wan et al. 2001; Wu, Crabtree et al. 2003; Wu, Tseng et al. 2003). Briefly, patients included in this analysis are men and women aged 30-74 years with histologically confirmed adenocarcinomas of the esophagus, gastric cardia, or distal stomach, who had no prior history of a cancer at any of these sites. These patients were identified by the Los Angeles County Cancer Surveillance Program (CSP), the population-based cancer registry covering all Los Angeles County residents. We included patients who were newly diagnosed with first incident esophageal adenocarcinoma (Internal Classification of Disease for Oncology [ICOD] C15.0-C15.9) or gastric cardia adenocarcinoma (ICOD C16.0) between 1992 and 1997 and patients newly diagnosed with distal gastric cancer (ICOD C16.1-C16.6, C16.8-C16.9) between 1992 and 1994. We identified 1716 eligible patients (429 with esophageal adenocarcinomas (EA)/500 with ardenocarcinomas of the gastric cardia (GCA) / 787 with distal gastric adenocarcinomas (DGA); numbers for the three tumor types are shown separated by slashes in the description below). We conducted in-person interviews with patients or with their next-of-kin (NOK) when patients were unable to be interviewed due to death or illness. We were unable to obtain interviews for 769 patients: 315 (92 5 EA/88 GCA /135 DGA) had died or were too ill to be interviewed and did not have a NOK available for interview; physicians denied permission to contact 171 (50/37/84) patients largely because the patients were too ill; 144 (30 EA /51 GCA /63 DGA) patients could not be located; and 139 (34 EA /46GCA /59 DGA) patients did not wish to participate. We completed interviews with the remaining 947 cases patients (55% (947/1716) of those identified and 77% (947/(1716-315-171)) of those approached; 77% for esophageal adenocarcinoma, 74% for gastric cardia, and 78% for distal gastric cancers). We excluded 9 case patients for whom information on NSAID drug use was incomplete. A total of 938 cases patients and 1356 control subjects are included in the analyses presented. Age, gender, and race distributions did not differ between the case patients we interviewed and those we were unable to interview. Control subjects were matched individually to interviewed case patients on gender, race, and age (± 5 years). Whenever possible, we sought two control subjects for each case patient to increase the statistical power of the study. Control subjects had no diagnosis of stomach or esophageal carcinoma. Control subjects were identified within the neighborhoods of the interviewed case patients. Each neighborhood control subject was sought using an algorithm indicating the sequence of residences to be contacted based on the residential address of the case patient. This sequence eliminates the blocks immediately surrounding the residence of the case patient. If 6 the first identified eligible matched control subject refused to participate, the second identified eligible control subject in the sequence was invited, and so on. Of the 947 case patients interviewed, 528 had 1 participating control subject, 382 had 2 or more participating control subjects, and 37 had no eligible control subjects identified within their neighborhoods. The study was approved by the Institutional Review Board of the Keck School of Medicine of the University of Southern California. Written informed consent was obtained from each study participant before interview. 7 Interview methods Cases and their matching controls were interviewed by the same interviewer in almost all instances. NOK interviews accounted for 269 of the 938 interviews with case patients (65 EA/ 85 GCA/119 DGA). Although it was not feasible to blind the interviewers to case (or NOK) or control status, interviewers (and study participants) were not aware of the study hypotheses. A reference date was defined as one year before the date of diagnosis of the case patient. This same reference date was used for each patient’s matched control subject. We used a structured questionnaire that we developed specifically for the current study. It included questions on lifetime smoking habits, lifetime use of all types of alcoholic beverages, weight at ages 20 and 40 years and on the reference date, and height. In addition, we asked detailed questions regarding personal and family history of various non-malignant diseases and conditions of the gastrointestinal tract and use of antacid drugs. With regard to the exposures interest in the current study, the respondents were asked if they ever regularly took aspirin, non-aspirin NSAIDs, acetaminophen, codeine, or other types of pain relievers. A detailed list of such drugs was used. Participants who used at least 2 pills per week for one month of any of the NSAIDs for pain relief were defined as a regular user of that drug. For users of NSAIDS, we recorded details of medication use, such as ages started and stopped 8 taking the medication, total duration of use (in days, weeks, months, or years) and frequency of use (pills per day, week, or month) of each drug use each drug that a participant used regularly. 9 Statistical analysis Total duration and frequency of aspirin and non-aspirin NSAIDs use were calculated by summing all use of the same class of medication for each person. Drugs that did not contain aspirin or other NSAIDs were excluded. [All NSAID containing drugs with any reported use are listed in the appendix]. Considering the small number of subjects at certain drug exposure levels, we created a combined NSAIDs variable (aspirin and non-aspirin NSAIDs) to increase the stability of the exposure measure. Duration of use was categorized as no regular use, less than 5 years of regular use, and at least 5 years of regular use for aspirin, non-aspirin NSAIDs and all NSAIDs combined. Frequency of use was grouped into three levels (0, 2-7, 7 pills per week). We excluded from the calculation of total duration and frequency of use any drugs that were first taken within the interval beginning 2 years before diagnosis for cases and the reference date for controls. Polychotomous logistic regression was used to compute the odds ratios (ORs), as estimates of the relative risk, and corresponding 95% confidence intervals (CIs) for adenocarcinomous of the esophagus, gastric cardia, and distal stomach simultaneously in relation to duration and frequency of each type of drug use. We used all controls in this analysis to maximize statistical power, and adjusted for the matching factors in our analysis. In prior analyses, this approach provided more 10 precise estimates of the ORs, but the magnitude of the ORs was consistent with those obtained in separate conditional logistic regression analyses that preserved the original case-control match within each cancer site. In multivariable analyses, we adjusted for age (39, 40-49, 50-59, 60-69, 70+), sex (male/female), race (White, African-American, Latino-American, Asian-American), birthplace (US born, non-US born), education (less than high school, high school, some college, college graduate or higher), smoking status (never smoker, ex-smoker, current smoker), body mass index (BMI) at reference age (normal=<25 kg/m 2 , overweight=25-29.9 kg/m 2 , obese=30+ kg/m 2 ’), history of upper gastrointestinal tract disorders (including gastric ulcer, duodenal ulcer, unspecified type of ulcer, gastritis, hiatal, esophagitis, Barrett's esophagus, gastroesophageal reflux disease, excess acid or gastric hyperacidity, and other diseases of the stomach), and antacid use (never/ever). A test for trend across ordinal categories of duration and frequency of use was performed for each type of cancer to evaluate the dose-response effects. We constructed a one degree-of-freedom likelihood ratio test to assess homogeneity of trends in duration of NSAID use among individuals who had a history of UGI disorders and those who did not. We conducted these analyses separately for each type of cancer using unconditional logistic regression comparing a multivariable model that fit two trend variables (one for each category of UGI disorder history) 11 with a multivariable model that fit a single trend variable for all subjects. The p- values reported for trend tests and for the test for homogeneity of trends are two- sided. For validity purposes, we repeated all statistical analyses excluding NOK data. Risk estimates were not materially different from the results presented below based on self and NOK reports. 12 Results Selected characteristics of each of the three groups of case patients and the control subjects are summarized in Table 1. The mean ages at diagnosis were 61.2 (standard error (SE) =9.4) for patients with esophageal adenocarcinoma, 60.8 (SE=10.2) for patients with adenocarcinoma of the gastric cardia, and 60.4 (SE=11.5) for patients distal gastric adenocarcinoma; control subjects were 59.5 (SE=11.2) at their assigned reference age. Among control subjects, 73.7% were male, compared with 90.9% of patients with esophageal adenacarcinoma, 83.4% of patients with gastric cardia adenocarcinoma, and 59% of the distal gastric cancer patients. Whites represented 62% of those with esophageal adenacarcinoma, 77.3% of those with gastric cardia adenocarcinoma, and 30.2% of those with distal gastric adenocarcinoma. For all three tumor types, case patients tended to have lower education than control subjects. Current smoking, history of UGI disorders, and antacid use were more common among case patients than control subjects. Table 1. Selected characteristics of esophageal and gastric adenocarcinoma case patients and control subjects, Los Angeles County. Patients with Control subjects Esophageal adenocarcinoma Gastric cardia adenocarcinoma Distal gastric adenocarcinoma (n=1356) (n=220) (n=277) (n=441) Age <40 98 (7.2) 9 (4.1) 13 (4.7) 29 (6.6) 40-49 194 (14.3) 14 (6.4) 23 (8.3) 50 (11.3) 50-59 345 (25.4) 56 (25.5) 73 (26.4) 91 (20.6) 60-69 463 (34.1) 95 (43.2) 108 (39.0) 153 (34.7) >70 256 (18.9) 46 (20.9) 60 (21.7) 118 (26.7) 13 Table 1. Continued Patients with Control subjects Esophageal adenocarcinoma Gastric cardia adenocarcinoma Distal gastric adenocarcinoma (n=1356) (n=220) (n=277) (n=441) Sex Men 999 (73.7) 200 (90.9) 231 (83.4) 260 (59.0) Women 357 (26.3) 20 (9.1) 46 (16.6) 181 (41.0) Race Non-Latino White 841 (62.0) 171 (77.3) 210 (75.8) 133 (30.2) African-American 90 (6.6) 3 (1.4) 10 (3.6) 54 (12.2) Latino-American 308 (22.7) 39 (17.7) 40 (14.4) 169 (38.3) Asian-American 117 (8.6) 7 (3.2) 17 (6.1) 85 (19.3) Birthplace US born 1011 (74.6) 184 (83.6) 211 (76.2) 217 (49.2) Non-US born 345 (25.4) 36 (16.4) 66 (23.8) 224 (50.8) Education <High school 252 (18.6) 48 (21.8) 53 (19.1) 184 (41.7) High school 252 (18.6) 50 (22.8) 68 (24.6) 96 (21.8) Some college 392 (28.9) 63 (28.6) 86 (31.1) 83 (18.8) College graduate or higher 460 (33.9) 59 (26.8) 70 (25.3) 78 (17.7) Smoking Status Never smoker 540 (39.8) 48 (21.8) 78 (28.2) 183(41.5) Ex-smoker 588 (43.4) 105 (47.7) 123 (44.4) 169 (38.3) Current 228 (16.8) 67 (30.5) 76 (27.4) 89 (20.2) Body mass index (kg/m2) * Normal 558 (41.2) 66 (30.0) 88 (31.2) 189 (42.9) Overweight 555 (40.9) 91 (41.4) 110 (39.7) 126 (28.6) Obese 218(16.1) 55 (25.0) 68 (24.6) 78 (17.7) Upper GI disease history Yes 362 (26.7) 103 (46.8) 110 (39.7) 143 (32.4) No 994 (73.3) 117 (53.2) 167 (60.3) 298 (67.6) Antacid use Never 973 (71.8) 136 (61.8) 193 (69.7) 282 (64.7) Ever 382 (28.2) 84 (38.2) 84 (30.3) 154 (35.3) * at reference date (one year prior to case patient’s date of diagnosis; control subject has reference date of the case patient to whom he or she was initially matched) 14 Table 2 summarizes the associations between regular use of aspirin, non-aspirin NSAIDs and any NSAIDs and each tumor type. Regular use of aspirin for at least five years was associated with approximately 40% reduced risk of distal gastric adenocarcinoma (OR=0.58; 95CI, 0.36-0.92). Both short-term (< 5 years) and longer-term regular use of non-aspirin NSAIDs were associated with lower risk of distal gastric adenocarcinoma, although the confidence interval for longer term use did not exclude 1.0 (OR=0.63; 95% CI, 0.41-0.97 for < 5 yrs use and OR=0.54; 95% CI, 0.24-1.20 for > 5 yrs use). Nonetheless, this dose-response effect was strengthened when aspirin and non-aspirin NSAIDs use were examined together (Trend test p=0.01). The OR for adenocarcinoma of the esophagus was significantly decreased for participants who took aspirin or non-aspirin NSAIDs with a greater reduction for non-aspirin NSAIDS than for aspirin. Among those who took NSAIDs for more than 5 years the OR was 0.60 relative to individuals who had not used any NSAID drug regularly (95% CI, 0.38-0.95) and the dose response effect was statistically significant (Trend test p=0.04). NSAID use was not associated with risk of adenocarcinoma of the gastric cardia. Similar risk patterns were observed when we evaluated frequency of use. Statistically significant inverse relationships with increasing number of pills used per week were observed for the risk of adenocarcinomas of the esophagus and the distal stomach in relation to use of non-aspirin NSAIDs. A roughly 50% decline in the 15 OR associated with use of at least 7 pills per week of non-aspirin NSAIDs was observed for adenocarcinomas of the esophagus (OR=0.53; 95%CI, 0.31-0.89) and distal stomach (OR=0.51; 95% CI, 0.33-0.79). 16 Table 2. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) for use of aspirin and non- aspirin non-steroidal anti-inflammatory drugs (NSAIDs) in relation to esophageal, gastric cardia and distal gastric adenocarcinomas. Exposure Control Esophageal adenocarcinoma Gastric cardia adenocarcinoma Distal Gastric adenocarcinoma n n OR a (95% CI) n OR a (95% CI) n OR a (95% CI) Duration Aspirin No regular use 1037 168 1.00—reference 200 1.00—reference 375 1.00—reference < 5 years 148 26 0.98 (0.62-1.57) 40 1.30 (0.88-1.94) 39 1.00 (0.67-1.49) 5 years 170 25 0.77 (0.48-1.23) 35 0.95 (0.63-1.42) 25 0.58 (0.36-0.92) p-trend 0.30 0.86 0.04 Non-Aspirin NSAID No regular use 1140 193 1.00—reference 237 1.00—reference 399 1.00—reference < 5 years 160 20 0.69(0.42-1.16) 26 0.74 (0.47-1.17) 32 0.63 (041-0.97) 5 years 55 5 0.37 (0.14-0.97) 12 0.86 (0.44-1.67) 8 0.54 (0.24-1.20) p-trend 0.02 0.28 0.02 Any NSAID No regular use 927 155 1.00—reference 176 1.00—reference 353 1.00—reference < 5 years 219 38 0.94 (0.63-1.41) 55 1.25 (0.88-1.78) 52 0.80 (0.55-1.10) 5 years 210 26 0.60 (0.38-0.95) 44 0.96 (0.66-1.40) 34 0.61 (0.40-0.92) p-trend 0.04 0.86 0.01 Tablet per week Aspirin No regular use 1038 168 1.00—reference 200 1.00—reference 375 1.00—reference 2-7 pills/wk 85 14 1.07 (0.58-1.99) 18 1.10 (0.64-1.90) 21 0.97 (0.57-1.65) 7 pills/wk 231 37 0.81 (0.54-1.21) 57 1.12 (0.80-1.58) 43 0.71 (0.49-1.04) p-trend 0.35 0.49 0.09 Non-Aspirin NSAID No regular use 1140 193 1.00—reference 239 1.00—reference 399 1.00—reference 2-7 pills/wk 32 6 1.01 (0.40-2.55) 3 0.40 (0.12-1.34) 10 1.28 (0.58-2.85) 7 pills/wk 182 19 0.53 (0.31-0.89) 33 0.79 (0.52-1.19) 30 0.51 (0.33-0.79) p-trend 0.02 0.18 0.01 Any NSAID No regular use 929 155 1.00—reference 178 1.00—reference 353 1.00—reference 2-7 pills/wk 96 17 1.10 (0.61-1.90) 20 1.05 (0.62-1.77) 24 0.95 (0.58-1.57) 7 pills/wk 330 47 0.70 (0.48-1.01) 77 1.10 (0.80-1.48) 62 0.63 (0.46-0.88) p-trend 0.07 0.59 0.01 * Participants who used at least 2 pills per week for one month of any of the NSAIDs for pain relief were defined as a regular user of that drug. a Adjusted for age, sex, race, birthplace, education, smoking status, BMI (at reference age), UGI history and Antacid use in a polychotomous logistic regression models. 17 Because we suspected that use of aspirin or non-aspirin NSAIDs might have been affected by gastrointestinal tract disorders that are also risk factors for these cancers, we conducted analyses separately among participants with and without a history of UGI disorders (Table 3). No heterogeneity of trends was observed between individuals with and without this history. Compared to persons with no regular use of any NSAID drug, the ORs for distal gastric adenocarcinomas among NSAIDs users of at least 5 years was similar for those with and without a history of UGI disorders (OR=0.52, 95%CI, 0.27-1.00; and OR=0.62,%95CI, 0.36-1.06, respectively). For esophageal adenocarcinomas, more than five years of NSAIDs use was associated with lower risk regardless whether or not participants had a UGI disorder history, but neither the risk estimates nor the trend tests achieved statistical significance. 1 Table 3. Multivariable odds ratios (ORs) and 95% confidence intervals (CI) for use of aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) in relation to esophageal, gastric cardia and distal gastric adenocarcinomas, by history of upper gastrointestinal tract (UGI) disorders. Esophageal Cardia UGI disorders No UGI disorders UGI disorders No UGI disorders Exposure Number of cases/ controls OR a (95%CI) Number of cases/ controls OR a (95%CI) Number of cases/ controls OR a (95%CI) Number of cases/ controls OR a (95%CI) Aspirin No regular use 82/262 1.0 (referent) 86/775 1.0 (referent) 76/262 1.0 (referent) 124/775 1.0 (referent) < 5 years 9/45 0.64(0.29-1.42) 17/103 1.52 (0.85-2.74) 22/45 1.59 (0.87-2.90) 18/103 1.02 (0.58-1.77) 5 years 11/55 0.72 (0.34-1.49) 14/115 0.90 (0.48-1.68) 12/55 0.75 (0.37-1.51) 23/115 1.07 (0.64-1.78) p-trend 0.24 0.89 0.84 0.80 P for heterogeneity of trends 0.32 0.75 Non-Aspirin NSAID No regular use 85/281 1.0 (referent) 108/859 1.0 (referent) 88/281 1.0 (referent) 149/859 1.0 (referent) < 5 years 12/59 0.87 (0.42-1.80) 8/101 0.60 (0.28-1.30) 14/59 0.91(0.47-1.77) 12/101 0.61 (0.32-1.16) 5 years 4/21 0.51 (0.16-1.60) 1/34 0.22(0.03-1.70) 8/21 1.05 (0.43-2.54) 4/34 0.66 (0.22-1.94) p-trend 0.25 0.05* 0.96 0.13 P for heterogeneity of trends 0.38 0.27 Any NSAID No regular use 73/224 1.0 (referent) 82/703 1.0 (referent) 64/224 1.0 (referent) 112/703 1.0 (referent) < 5 years 17/69 0.86 (0.46-1.62) 21/150 1.16 (0.68-1.98) 29/69 1.57 (0.91-2.70) 26/150 1.02 (0.63-1.64) 5 years 12/69 0.59 (0.29-1.19) 14/141 0.71 (0.38-1.33) 17/69 0.83 (0.44-1.54) 27/141 1.03 (0.64-1.67) p-trend 0.14 0.44 0.94 0.88 P for heterogeneity of trends 0.53 0.88 18 2 Table 3. Continued Distal UGI disorders No UGI disorders Exposure Number of cases/ controls OR a (95%CI) Number of cases/ controls OR a (95%CI) Aspirin No regular use 114/262 1.0 (referent) 261/775 1.0 (referent) < 5 years 19/45 1.19 (0.64-2.24) 20/103 0.88 (0.51-1.50) 5 years 10/55 0.44 (0.20-0.96) 15/115 0.63 (0.34-1.15) p-trend 0.10 0.13 P for heterogeneity of trends 0.75 Non-Aspirin NSAID No regular use 127/281 1.0 (referent) 272/859 1.0 (referent) < 5 years 12/59 0.39 (0.19-0.79) 20/101 0.81 (0.47-1.39) 5 years 4/21 0.43 (0.14-1.40) 4/34 0.58 (0.19-1.72) p-trend 0.01* 0.22 P for heterogeneity of trends 0.20 Any NSAID No regular use 106/224 1.0 (referent) 247/703 1.0 (referent) < 5 years 22/69 0.68 (0.38-1.22) 30/150 0.81 (0.51-1.27) 5 years 15/69 0.52 (0.27-1.00) 19/141 0.62 (0.36-1.06) p-trend 0.03* 0.06 P for heterogeneity of trends 0.60 Note: UGI=upper gastrointestinal tract symptoms (including gastric ulcer, duodenal ulcer, unspecified type of ulcer, gastritis, hiatal, esophagitis, Barrett's esophagus, gastroesophageal reflux disease, Excess acid or gastric hyperacidity and other disease of stomach). a Adjusted for age, sex, race, birthplace, education, smoking status, BMI (at reference age), UGI history and Antacid use in unconditional logistic regression models. 19 20 Discussion Regular use of aspirin and non-aspirin NSAIDs was associated with decreased risk of distal gastric adenocarcinomas, and use of non-aspirin NSAIDs was associated with a decreased risk of esophageal adenocarcinoma in multivariable models that included adjustment for UGI disorders and other potential confounding factors. Combining the two classes of NSAIDS produced marked dose response effects for both types of cancer. A history of UGI disorders did not modify these effects as none of the tests for heterogeneity of trends was statistically significant. NSAID use was unrelated to risk of adenocarcinomas of the gastric cardia. We excluded any drugs initiated in the 2 years before the patients’ diagnoses or the control subjects’ reference dates as symptoms experienced by case patients prior to their diagnoses could have influenced their use of NSAID drugs. Inclusion of drug use initiated during this two year period did not alter our findings. Infection with Helicobacter pylori (H. pylori), Barrett’s esophagus, hiatal hernia and reflux symptoms are independent risk factors of esophageal and gastric adenocarcinomas (Wu, Crabtree et al. 2003; Wu, Tseng et al. 2003; Anderson, Johnston et al. 2006). Presence of these and other upper gastrointestinal conditions, can influence the use of NSAIDs (Sugawa, Takekuma et al. 1997); in fact, for a number of these conditions, NSAID use is contraindicated. However, few epidemiological studies have considered a history of UGI disorders when examining 21 the relationship between NSAID use and esophageal and gastric adenocarcinomas. Two case-control studies conducted in Russia and Sweden evaluated risk adjusted for a history of UGI disorders and found that an inverse association existed only among subjects with an H. pylori infection (Zaridze, Borisova et al. 1999; Akre, Ekstrom et al. 2001). In contrast, in a U.S. population-based case-control study, Farrow and her colleagues observed a reduction in risk in analyses restricted to subjects with no history of UGI disorders (Farrow, Vaughan et al. 1998). Another recent case-control study found thatlong-term use (>3 years) of NSAIDs decreased the risk of gastric cancer more among subjects with UGI disorders than among those with no UGI disorders; this difference did not reach statistical significance (Lindblad, Lagergren et al. 2005). Consistently, our findings showed a clear pattern of decreasing ORs for distal gastric adenocarcinomas with increasing NSAID use among persons with a history of UGI disorders as well as those who did not have a history of UGI disorders. Similarly, no differences were observed in the risk patterns of esophageal adenocarcinoma in the two subgroups defined by presence or absence of a history of UGI disorders, although in these subgroup analyses, confidence intervals for the risk estimates included 1.0. After subgrouping the data, the number of exposed cases and controls was limited, thereby influencing the statistical power for these comparisons. 22 Our results in combination with those in the literature suggest that NSAID use protects against adenocarcinomas of the esophagus and distal stomach. As suggested by Anderson (Anderson, Johnston et al. 2006), NSAIDs may impact the early stage of the inflammation-metaplasia-adenocarcinoma sequence for the esophagus. NSAID use can reduce inflammation by inhibiting cyclooxygenase 2 enzyme production. This can result in an increase in the apoptotic response, reduced cell growth, and decreased cell proliferation (Husain, Szabo et al. 2002). We found no evidence of a differential effect according to the individual’s history of UGI disorders, despite the fact that those with UGI disorders may be less likely to use aspirin or other NSAIDs. We also observed greater risk reduction for distal gastric tumors and esophageal adenocarcinomas associated with non-aspirin NSAIDs than with aspirin use, but the number of exposed individuals was small. For many years, non-aspirin NSAID formulations were available only by prescription; one speculation is that effective doses of non-aspirin NSAIDs may have been greater than those for aspirin products, and as prescription formulations, these drugs may have been taken more regularly when prescribed than aspirin was. Prior studies that have evaluated frequency of use have not observed that daily use had a greater impact on risk of UGI cancers (Farrow, Vaughan et al. 1998; Vaughan, Dong et al. 2005). Our results showed a 30% to 40% reduction in risk of esophageal 23 and distal gastric adenocarcinoma associated for individuals who took at least 7 NSAID pills per week. Our data suggest that daily use of an aspirin or other NSAID drug may be optimal for use in cancer prevention in those at high risk for esophageal and distal gastric adenocarcinomas. We and others find no relationship between NSAID use and adenocarcinomas of the gastric cardia (Wang, Huang et al. 2003). The incidence patterns of cancers of the gastric cardia differ from those in the more distal stomach as the incidence of gastric cardia cancers has increased over the past two decades, despite an overall decrease in incidence of gastric cancer overall and of distal gastric cancers, specifically (Blot, Devesa et al. 1991). The increase in incidence for esophageal adenocarcinomas has been far greater than that for cardia tumors, yet the two cancers share some risk factors. We have previously shown similar risk estimates for the two cancer subsites related to current smoking, duration of smoking, age started smoking, and body mass index in this study population (Wu reference). Although a number of UGI tract disorders, particularly reflux symptoms and hiatal hernia, are risk factors for both esophageal and gastric cardia cancers, their associations with risk are much greater for esophageal adenocarcinoma (other Wu paper). These conditions do not influence risk of distal gastric cancers. Thus, the lack of any impact of NSAIDs on gastric cardia cancers, but an effect on esophageal and distal gastric adenocarcinomas is puzzling. Although Gammon (Gammon, Terry et al. 2004) has suggested that 24 NSAIDs use is associated with lower risk of all UGI cancers that overexpress cyclin D1, their results for cyclin D1-positive gastric cardia cancers were not definitive . Gammon’s report on cyclin D1 overexpression was based on a subset of 55% of the original case patient population participating in a population-based case-control study conducted in 3 locations in the U.S.. In a prior publication, based on the total study population, they found no impact of NSAIDs on adenocarcinomas of the gastric cardia (Farrow, Vaughan et al. 1998). Our study has several limitations. Our overall response rate was modest. Only 55% of the eligible case patients completed the interview, and they tended to have an earlier stage of disease at diagnosis than the patients who were not included (Wu, Crabtree et al. 2003; Wu, Tseng et al. 2003). NOK interviews accounted for 29% of the patient reports in this study. One would expect less accurate reporting of NSAID use by NOK. However, our results did not appear to be affected by NOK interviews, as whether these were excluded from the analyses, our results were quite similar. We based our exposure measures on self-reports. It is difficult to validate over-the- counter medication use which comprised a majority of the exposures in this study and we did not validate the use of prescription analgesic medications. We did, however, ask extensive questions regarding the details of each NSAID medication used regularly; for example, if the medication required a prescription, we recorded the starting and stoping dates, frequency of use and the name of the physician who 25 prescribed the drug. For over-the-counter drugs, we recorded almost the same thing except the information about the physician and prescription. Unfortunately, we did not document the dose of the medications; we did record the frequency of use in pills per day, week, or month over each exposure time period. The number of regular NSAIDs users in this study was not substantial, particularly after stratifying by history of UGI symptoms. In summary, this large, population-based case-control study indicates that aspirin and other NSAIDs are associated with reduced risk of esophageal and distal gastric adenocarcinomas and that risk declines in a dose-response manner. These relationships are evident among individuals with and without a history of upper UGI disorders or symptoms. 26 Bibliography Akre, K., A. M. Ekstrom, et al. (2001). "Aspirin and risk for gastric cancer: a population-based case-control study in Sweden." Br J Cancer 84(7): 965-8. Anderson, L. A., B. T. Johnston, et al. (2006). "Nonsteroidal anti-inflammatory drugs and the esophageal inflammation-metaplasia-adenocarcinoma sequence." Cancer Res 66(9): 4975-82. Baron, J. A. (2003). "Epidemiology of non-steroidal anti-inflammatory drugs and cancer." Prog Exp Tumor Res 37: 1-24. Baron, J. A. and R. S. Sandler (2000). "Nonsteroidal anti-inflammatory drugs and cancer prevention." Annu Rev Med 51: 511-23. Blot, W. J., S. S. Devesa, et al. (1991). "Rising incidence of adenocarcinoma of the esophagus and gastric cardia." Jama 265(10): 1287-9. Bosetti, C., S. Gallus, et al. (2002). "Aspirin and cancer risk: an update to 2001." Eur J Cancer Prev 11(6): 535-42. Coogan, P. F., L. Rosenberg, et al. (2000). "Nonsteroidal anti-inflammatory drugs and risk of digestive cancers at sites other than the large bowel." Cancer Epidemiol Biomarkers Prev 9(1): 119-23. Dai, Y. and W. H. Wang (2006). "Non-steroidal anti-inflammatory drugs in prevention of gastric cancer." World J Gastroenterol 12(18): 2884-9. Farrow, D. C., T. L. Vaughan, et al. (1998). "Use of aspirin and other nonsteroidal anti-inflammatory drugs and risk of esophageal and gastric cancer." Cancer Epidemiol Biomarkers Prev 7(2): 97-102. Friis, S., H. T. Sorensen, et al. (2003). "A population-based cohort study of the risk of colorectal and other cancers among users of low-dose aspirin." Br J Cancer 88(5): 684-8. Gammon, M. D., M. B. Terry, et al. (2004). "Nonsteroidal anti-inflammatory drug use associated with reduced incidence of adenocarcinomas of the esophagus and gastric cardia that overexpress cyclin D1: a population-based study." Cancer Epidemiol Biomarkers Prev 13(1): 34-9. 27 Gridley, G., J. K. McLaughlin, et al. (1993). "Incidence of cancer among patients with rheumatoid arthritis." J Natl Cancer Inst 85(4): 307-11. Harris, R. E., J. Beebe-Donk, et al. (2005). "Aspirin, ibuprofen, and other non- steroidal anti-inflammatory drugs in cancer prevention: a critical review of non- selective COX-2 blockade (review)." Oncol Rep 13(4): 559-83. Husain, S. S., I. L. Szabo, et al. (2002). "NSAID inhibition of GI cancer growth: clinical implications and molecular mechanisms of action." Am J Gastroenterol 97(3): 542-53. Langman, M. J., K. K. Cheng, et al. (2000). "Effect of anti-inflammatory drugs on overall risk of common cancer: case-control study in general practice research database." Bmj 320(7250): 1642-6. Lindblad, M., J. Lagergren, et al. (2005). "Nonsteroidal anti-inflammatory drugs and risk of esophageal and gastric cancer." Cancer Epidemiol Biomarkers Prev 14(2): 444-50. Sorensen, H. T., S. Friis, et al. (2003). "Risk of cancer in a large cohort of nonaspirin NSAID users: a population-based study." Br J Cancer 88(11): 1687-92. Sugawa, C., Y. Takekuma, et al. (1997). "Bleeding esophageal ulcers caused by NSAIDs." Surg Endosc 11(2): 143-6. Thun, M. J., M. M. Namboodiri, et al. (1993). "Aspirin use and risk of fatal cancer." Cancer Res 53(6): 1322-7. Vainio, H. and G. Morgan (1998). "Non-steroidal anti-inflammatory drugs and the chemoprevention of gastrointestinal cancers." Scand J Gastroenterol 33(8): 785-9. Vainio, H. and G. Morgan (2000). "Non-steroidal anti-inflammatory drugs and chemoprevention of cancer." Ann Chir Gynaecol 89(3): 173-6. Vaughan, T. L., L. M. Dong, et al. (2005). "Non-steroidal anti-inflammatory drugs and risk of neoplastic progression in Barrett's oesophagus: a prospective study." Lancet Oncol 6(12): 945-52. Wang, W. H., J. Q. Huang, et al. (2003). "Non-steroidal anti-inflammatory drug use and the risk of gastric cancer: a systematic review and meta-analysis." J Natl Cancer Inst 95(23): 1784-91. 28 Wu, A. H., J. E. Crabtree, et al. (2003). "Role of Helicobacter pylori CagA+ strains and risk of adenocarcinoma of the stomach and esophagus." Int J Cancer 103(6): 815-21. Wu, A. H., C. C. Tseng, et al. (2003). "Hiatal hernia, reflux symptoms, body size, and risk of esophageal and gastric adenocarcinoma." Cancer 98(5): 940-8. Wu, A. H., P. Wan, et al. (2001). "A multiethnic population-based study of smoking, alcohol and body size and risk of adenocarcinomas of the stomach and esophagus (United States)." Cancer Causes Control 12(8): 721-32. Zaridze, D., E. Borisova, et al. (1999). "Aspirin protects against gastric cancer: results of a case-control study from Moscow, Russia." Int J Cancer 82(4): 473-6. 29 Appendix (Drug list) Compounds containing Aspirin Anacin APC tablets APC with Codeine Arthritis pain formula ASA Compounds Ascriptin Aspirin enteric Aspirin with Codeine Bayer aspirin Buffered aspirin Cama Darvon Compound Ecotrin Empirin compounds Empirin with Codeine Equagesic Fiorinal Fiorinal with Codeine Momentum Norgesic ot Norgesic Forte Percodan Synalogos Compounds containing non-aspirin NSAIDs Advil Aleve/Alleve Anaprox Ansaid Aprozen Clinoril Datpro Dolobidea Feldene Ibuprofen Indocin Indomethacin Lodine Meclomen Midol 200 Motrin Nalfon Naprosyn Nuprin Orudis Ponstel 30 Appendix (Drug list). Continued Relafen Salsalate Tolectin Voltaren

Abstract (if available)

Abstract Non-steroidal anti-inflammatory drug (NSAID) use has been consistently associated with reduced risks of colon cancer, but epidemiologic data are inconsistent for stomach and esophageal adenocarcinomas. Furthermore, data on potential confounding effects by upper gastrointestinal tract (UGI) disorders are limited. We sought to clarify these relationships in a large population-based case-control study.

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Asset Metadata

Creator Duan, Lei (author)

Core Title Non-steroidal anti-inflammatory drugs and risk of esophageal and gastric adenocarcinomas in Los Angeles county

School Keck School of Medicine

Degree Master of Science

Degree Program Biostatistics

Publication Date 04/12/2009

Defense Date 04/01/2007

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag adenocarcinomas,esophageal,gastric,NSAIDs,OAI-PMH Harvest

Place Name Los Angeles (counties)

Language English

Advisor Bernstein, Leslie (committee chair), Chou, Chih-Ping (committee chair), Wu, Anna (committee member)

Creator Email lduan@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-m384

Unique identifier UC1331565

Identifier etd-Duan-20070412 (filename),usctheses-m40 (legacy collection record id),usctheses-c127-402748 (legacy record id),usctheses-m384 (legacy record id)

Legacy Identifier etd-Duan-20070412.pdf

Dmrecord 402748

Document Type Thesis

Rights Duan, Lei

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Repository Name Libraries, University of Southern California

Repository Location Los Angeles, California

Repository Email cisadmin@lib.usc.edu