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Non-steroidal anti-inflammatory drugs, anti-acid drugs and passive smoking as impact factors for esophageal and gastric adenocarcinomas

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Non-steroidal anti-inflammatory drugs, anti-acid drugs and passive smoking as impact factors for esophageal and gastric adenocarcinomas

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Content NON-STEROIDAL ANTI-INFLAMMATORY DRUGS, ANTI-ACID DRUGS AND PASSIVE SMOKING AS IMPACT FACTORS FOR ESOPHAGEAL AND GASTRIC ADENOCARCINOMAS by Lei Duan A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PREVENTIVE MEDICINE) August 2008 Copyright 2008 Lei Duan ii Acknowledgements I wish to thank my committee members (Drs. Anna Wu, Kim Reynolds, and Parakrama Chandrasoma) and my committee chair (Drs. Leslie Bernstein and Chih-Ping Chou) for their encouragement, guidance, advice, support, and for helping me establish the foundation upon which I now stand on. Dr. Wu, thank you for your understanding and insightful comments. To Dr. Reynolds for challenging me with questions that extended my knowledge on measurement reliability. Thank you Dr. Chandrasoma for your commitment as my outside member and bringing in your expertise of pathology. Dr. Chou, thank you for making my introduction into biostatistics fun, inspiring me with various statistical techniques, and always thinking of me when opportunities arose. To Dr. Bernstein, thank you for mentoring me all the way through, for editing my paper, for directing me in research, and for always being there when I need help. I have learned so much under your guidance, by your example, and from your words. Thank you so much. I would also like to thank all of my fellow students, researchers and staff at IPR, Norris, and City of Hope, for providing inspiration ideas and prompt support. I thank you all for your contribution to this degree. Finally I would like to thank my husband, Jie Yao, and my parents, Sanyuan Duan and Guozhen Tao, for their endless support, love and belief in me. iii Table of Contents Acknowledgements ii List of Tables iv List of Figures v Abstracts vi Chapter 1: Background 1 Chapter 2: Non-Steroidal Anti-Inflammatory Drugs and Risk of Esophageal and Gastric Adenocarcinomas 28 Chapter 3: Antacid use and Risk of Esophageal and Gastric Adenocarcinomas 57 Chapter 4: Passive smoking and Risk of Esophageal and Gastric Adenocarcinomas 80 Chapter 5: Conclusion 92 References 97 Appendix A 106 Appendix B 107 iv List of Tables Table 1.1: Age-adjusted incidence rates. 4 Table 1.2: Summary of epidemiological studies on antacid use. 13 Table 1.3: Meta-analysis of H2-receptor antagonists. 15 Table 1.4: Summary of epidemiological studies on aspirin use. 20 Table 2.1: Characteristics of case patients and control subjects. 47 Table 2.2: Multivariable ORs and 95% CIs for use of aspirin. 49 Table 2.3: Multivariable ORs and 95% CIs for use of aspirin, using never users as the reference group. 51 Table 2.4: Multivariable ORs and 95% CIs for use of aspirin, by history of UGI disorders. 52 Table 2.5: Multivariable ORs and 95% CIs for use of aspirin using never users as the reference group, by history of UGI disorders. 55 Table 3.1: Demographic characteristics. 75 Table 3.2: Multivariable ORs and 95% CIs for antacid use. 76 Table 3.3: ORs for OTC acid neutralizing agent use, by history of UGI disorders. 77 Table 3.4: ORs for number of different antacid use among irregular users. 79 Table 4.1. Demographic characteristics of nonsmoking subjects. 89 Table 4.2. ORs for active and passive smoking history among male. 90 Table 4.3. ORs for smoking history among female. 90 Table 4.4. ORs for passive smoking among non-smoking male. 91 v List of Figures Figure 1.1: Anatomy of the esophagus and gastric junction. 2 Figure 1.2: Secular trends in the age-adjusted incidence rates of carcinomas of the esophagus and gastric cardia of non-Latino white males in Los Angeles County 1972-1997. 5 Figure 1.3: Normal anatomy showing the lower esophagus. 8 Figure 1.4: Anatomy showing the lower esophagus with frequent reflux. 8 Figure 1.5: Anatomy showing the lower esophagus with severe reflux. 9 vi Abstracts A dramatic increase in the incidence of esophageal adenocarcinoma has been observed in the United States and Western Europe during the past 3 decades. Likewise, a similar pattern of incidence although of smaller magnitude has also been observed for adenocarcinomas of the gastric cardia over the same period. Compared to 30 years ago, the rates of esophageal adenocarcinoma have increased more than 350%. In contrast, the incidence rates of the squamous cell carcinoma of the esophagus and adenocarcinoma of the distal stomach have remained static or even decreased. The underlying reasons for the increase in the incidence of adenocarcinoma of the esophagus and gastric cardia remain mostly unknown. Evidence suggests environmental exposures and host factors may play a very important role in this change. Studies have evaluated behavioral factors like tobacco and alcohol consumption, diet, obesity and physical activity as risk factors for many types of cancers as well as for adenocarcinomas of the esophagus and gastric cardia. While the existence of some medical conditions, such as Helicobacter pylori infection, Barrett’s esophagus and gastro-esophageal reflux disease, and medications that were used to treat these diseases may be uniquely related with the risk of adenocarcinomas of the esophagus and gastric cardia. This project examined the impact of behavioral factors, medical / biological factors and their interaction on the risk of esophageal and gastric adenocarcinomas. Specifically, we focused on passive smoking as a behavioral vii factor, and non-steroidal anti-inflammatory drugs and gastric acid suppression drugs as two medical / biological factors. Three studies were undertaken, Study One: Non-Steroidal Anti-Inflammatory Drugs and Risk of Esophageal and Gastric Adenocarcinomas in Los Angeles County, Study Two: Antacid Drugs and Risk of Esophageal and Gastric Adenocarcinomas in Los Angeles County, and Study Three: Passive smoking and Risk of Esophageal and Gastric Adenocarcinomas in Los Angeles County, to evaluate the risk factors and protective factors for these cancers. This study used the data from a population-based case-control study lead by Dr. Leslie Bernstein. Incident cancer cases for this study were identified by the USC Cancer Surveillance Program (CSP). 1 Chapter 1: Background 1. Esophagus and Esophageal Cancer The esophagus is the muscular tube that connects the throat to the stomach and allows food to enter the stomach for digestion. Esophageal cancer is malignancy of the esophagus. The esophagus usually has a squamous epithelium. The most common histological type of esophageal cancer is the squamous cell carcinoma (SCC), historically, adenocarcinoma is less frequent (Pera, Cameron et al. 1993). Their distributions in the esophagus are different. SCC can occur anywhere and occur equally though out the esophagus, while adenocarcinomas are more likely to occur in the lower esophagus. 2. Cancer at Gastric Cardia Cardia is an anatomical term representing the junction between the esophagus and stomach. Gastric cardia is the part of the stomach immediately adjacent to and surrounding the cardiac opening of the oesophagus (Hetzel, Dent et al. 1988). At the cardia, the epithelium of the esophagus transits into gastric mucosa, distinguished by the presence of the cardiac glands. 2 Histologicaly, cancer at the gastric and gastric cardia are all adenocarcinomas. Figure 1.1 Anatomy of the esophagus and gastric junction. 3 3. Epidemiology of Esophageal and Gastric Adenocarcinomas Overall the incidence and mortality rates of stomach carcinoma around the world have largely been reduced in the past 50 years. Factors that may contribute to the decrease include: better refrigeration; reduced consumption of salted, smoked, and chemically preserved foods; increased intake of fruit and vegetables; and a greater use of antibiotics that can reduce Helicobacter pylori infection. Similarly, incidence rates of esophageal SCC have decreased largely due to decline in smoking. However, incidence of esophageal adenocarcinomas has increased dramatically over last three decades, with a relatively smaller parallel increase in the incidence of adenocarcinomas at the gastric cardia during the same time period. Compared to 30 years ago, the rates of esophageal adenocarcinoma have increased more than 350% (Bernstein 1999). Currently, esophageal cancer is the seventh leading cause of cancer death worldwide. The striking increase in incidence has been more pronounced for white males whose rates of esophageal adenocarcinoma are 3-4 times greater than those of black males and at least 8 times higher than those of white females (Table 1) (Bernstein 1999). The secular trends in the age-adjusted incidence rates of carcinomas of the esophagus and gastric cardia among non-Latino white males in Los Angeles County 1972-1997 (Figure 2) suggest the majority of the increase in the incidence of this cancer occurred somewhat during early to mid-1970s, and then increased gradually over the time. We hypothesize that environmental changes and host factors play a role in the etiology of these tumors and may explain the markedly different demographic 4 profiles. We propose to investigate the risk factors in a population-based case-control study that was conducted in Los Angeles in 1990s’. Table 1.1. Age-adjusted incidence rates of adenocarcinomas of the esophagus (EAC) and gastric cardia (GCA) per 100,000 population by race/ethnicity. Los Angeles County, 1972-1997. Number of cases given in parentheses (Original Table1 in (Bernstein 2003)). Racial/ethnic group Esophagus Gastric cardia Ratio (GCA/EAC) Males Non-Hispanic white 1.7 (1,008) 3.1 (1,865) 1.8 Hispanic white 1.7 (180) 2.6 (280) 1.5 Black 0.5 (45) 1.4 (109) 2.8 Chinese 0.6 (9) 2.0 (31) 3.3 Japanese 0.9 (14) 3.1 (49) 3.4 Filipino 0.3 (5) 1.1 (18) 3.7 Korean - (1) 2.1 (19) - All races 1.5 (1,263) 2.7 (2,391) 1.8 Females Non-Hispanic white 0.2 (213) 0.6 (503) 3.0 Hispanic white 0.2 (23) 0.7 (95) 3.5 Black 0.2 (22) 0.4 (45) 2.0 Chinese - (1) 0.6 (11) - Japanese - (2) 0.3 (5) - Filipino - (1) 0.7 (11) - Korean - (0) 1.1 (13) - All races 0.2 (263) 0.6 (690) Note: rates not presented if fewer than 5 cases 5 Figure 1.2. Secular trends in the age-adjusted incidence rates of carcinomas of the esophagus and gastric cardia of non-Latino white males in Los Angeles County 1972-1997. Incidence rates adjusted to the 1970 US population (Original Fig 1 in (Bernstein 2003) ). 4. Risk or Protective Factors 1). Medical Conditions i). Helicobacter pylori infection Helicobacter pylori infection is a common cause of chronic gastritis (Graham 1989), and may be a major factor in the pathogenesis of peptic ulcer disease (Peterson 1991). The organism lives under the mucosal layer lining the stomach, but does not actually invade the mucosa. In order to protect itself from acid and pepsin secretions of the stomach, H. pylori secrete an enzyme that can neutralize stomach acid. The mucosal layer becomes thin and the stomach 6 lining is more vulnerable to acid and pepsin due the activities of H. pylori. In this manner, a chronic inflammation in the stomach lining may develop and eventually may progresses to atrophic gastritis, which predisposes to precancerous changes in the stomach. Numerous studies have found that H. pylori may contribute to increased risk of stomach cancer. And, in fact, the geographic prevalence of H. pylori infection appears to be positively correlated with stomach cancer risk. In 1994, the International Agency for Research on Cancer classified Helicobacter pylori as a class I human carcinogen (IARC 1994). From the participants in the Los Angeles study, Wu et al. estimated the association between H. pylori infection and esophageal gastric adenocarcinomas, and the findings consistently confirmed that H. pylori infection may increase the risk (Wu, Crabtree et al. 2003). ii). Gastroesophageal reflux and Barrett’s esophagus Normally, the lower esophageal sphincter relaxes to allow the food to pass from the esophagus into the stomach. However, when the lower esophageal sphincter loses its function, food and gastric juice may back up into the esophagus, and this is called ‘reflux’. Unlike the stomach lining, the esophagus lining does not have a mucosal layer which can protect it from the erosion of the gastric acid. Periodically reflux may cause erosive esophagitis. In the long term this results in GERD, which has been found as the main cause of BE (Winters, Spurling et al. 1987), a condition in which columnar-cells replace the native squamous-cell epithelium of the esophageal lining (Spechler and Goyal 1986). BE can progress through stages of metaplasia, and in turn, is considered 7 the major risk factor for esophageal adenocarcinomas and for lesions occurring at the gastroesophageal junction. Most esophageal adenocarcinomas arise in Barrett’s epithelium. In current practice BE can be diagnosed only by endoscopy, and only people who have visible changes under endoscopy will be further histologically confirmed by biopsy (Mahue-Giangreco and Berstein 2001). Around 10-20% of adults in the United States experience heartburn at least weekly (Nebel, Fornes et al. 1976; Romero, Cameron et al. 1997; Cohen and Parkman 1999), while 0.8%-3.9% of patients undergoing upper endoscopy are diagnosed with BE (Kim, Weissfeld et al. 1997). The prevalence estimates of GERD and BE are likely to be underestimated, since most patients may ignore the relatively minor symptoms of heartburn (Spechler and Goyal 1986; Mendes de Almeida, Chaves et al. 1997; Cohen and Parkman 1999; Morales and Sampliner 1999), and, frequently, BE patients report no symptoms until malignancy develops (Mahue-Giangreco and Berstein 2001; Chandrasoma and Demeester 2006). There is ongoing debate whether GERD patients should undergo biopsy when they have no visible changes under endoscopy. This would permit recognition of the cellular change at the early stage in the reflux to adenocarcinoma sequence (Chandrasoma and Demeester 2006). Figure 3-5 shows the progression from reflux to BE. 8 Figure 1.3. Normal anatomy showing the lower esophagus (Chandrasoma and Demeester 2006). Figure 1.4. Anatomy showing the lower esophagus with frequent reflux (Chandrasoma and Demeester 2006). Original FIGURE 11.24 With repeated and frequent exposures of the distal esophageal squamous epithelium, damage does not heal sufficiently and gastric molecules gain access to the basal region where it induces columnar metaplasia. 9 Figure 1.5. Anatomy showing the lower esophagus with severe reflux (Chandrasoma and Demeester 2006). Original FIGURE 11.27 Severe reflux disease with near complete loss of the abdominal part of the sphincter. Epidemiologic studies are mainly consistent with regard to the impact of GERD on risk of upper gastrointestinal cancers, though the number of studies is limited. In 1995, Chow et al. reported a two-fold increased risk of adenocarcinoma of the gastric cardia and esophagus combined in patients with GERD symptoms (Chow, Finkle et al. 1995). In a Swedish study, Lagergren et al. found approximately an 8-fold increased risk of esophageal adenocarcinoma and a two-fold increased risk of adenocarcinoma at the gastric cardia among persons with recurrent symptoms of GERD. These results suggested that the more frequent, more severe, and longer lasting the symptoms of reflux, the greater is the risk (Lagergren, Bergstrom et al. 1999). Farrow et al. reported similar findings among the participants in a more recent US study (Farrow, Vaughan et al. 2000), except they did not observe any association with cancer at gastric cardia (Farrow, Vaughan et al. 2000). 10 2). Anti-acid drugs In the late 1970s, histamine2-receptor (H2) antagonist drugs, including ranitidine, cimetidine, famotidine, and nizatidine, were introduced to the market and became widely used in the treatment of BE, GERD and peptic ulcers. H2-receptor antagonists are competitive inhibitors of histamine at the parietal cell H2 receptor. Gastric acid secretion is suppressed if the parietal cell H2 receptor is not bound with histamine in the stomach (wikipedia). However, patients receiving H2-receptor antagonists treatments have been reported to have an increased concentration of N-nitrosamines in the stomach (Elder, Ganguli et al. 1979; Reed, Smith et al. 1981). Experimental studies have shown that cimetidine is itself nitrosated in the stomach to form nitrocimetidine, which shares a similar chemical structure with the potent carcinogen N-nitroso-N-methylntroguannidine (MNNG) (Foster, Jarman et al. 1980). As a result, there have been concerns that gastric acid suppression, particularly by these drugs, is associated with increased risk of esophageal and gastric adenocarcinomas. Epidemiological studies, both case-control (La Vecchia, Negri et al. 1990; Chow, Finkle et al. 1995; Johnson, Jick et al. 1996; Farrow, Vaughan et al. 2000; Suleiman, Harrison et al. 2000; Rodriguez, Lagergren et al. 2006) and cohort studies (Moller, Lindvig et al. 1989; Colin-Jones, Langman et al. 1991; Moller, Nissen et al. 1992) in design, have investigated the possible positive association between the use of H2-receptor antagonists and the risk of esophageal and gastric adenocarcinomas (Table 2). However, the results are inconsistent. Despite an initial increase in risk of gastric cancer within 1 year of exposure to 11 H2-recepor antagonists, Moller et al. (Moller, Lindvig et al. 1989; Moller, Nissen et al. 1992) found this effect disappearing with more prolonged observation. On the contrary, although the post-marketing surveillance report of H2-recepor antagonist use in United Kingdom (Colin-Jones, Langman et al. 1991; Beresford, Colin-Jones et al. 1998) did not support an increased risk of developing esophageal and gastric cancer from cimetidine treatment, the study observed an unexpected rise in esophageal cancer deaths after 7 to 8 years of follow-up (Colin-Jones, Langman et al. 1991; Beresford, Colin-Jones et al. 1998). Farrow and her colleagues found that individuals with long-standing GERD were at increased risk of esophageal adenocarcinomas, no matter whether the symptoms were treated with H2 blockers or not(Farrow, Vaughan et al. 2000). Conversely, in the Swedish case-control study, Lagergren et al. reported a nearly 3-fold higher risk among persons who used medications for reflux symptoms at least 5 years prior to study than among those who took no medication (Lagergren, Bergstrom et al. 1999). The author of this dissertation conducted a meta-analysis on this topic (Duan, Ma et al. 2008). In summary, the author found that H2-recepor antagonist use was associated with an increased risk of esophageal cancer, but not with cancer at the gastric cardia or distal stomach (Duan, Ma et al. 2008). The summary odds ratio (OR) by cancer subsite showed that subjects with the highest duration of H2 receptor antagonist use had 68% higher risk of esophageal cancer (summary OR = 1.68; 95% confidence interval (CI) = 1.10 – 2.57), but no increased risk was detected for cancers of the gastric cardia and distal stomach (summary OR = 0.81; 12 95% CI= 0.55-1.19) (Table 3) (Duan, Ma et al. 2008). However, the issue remains that we are not able to tell if the increased risk is truly caused by the medication or is just a sign of severe conditions, especially when existing evidence comes from populations with different social and environmental backgrounds, and given that esophageal and gastric carcinogenesis are multi-factorial and multi-step processes (Correa 1992). 13 Table 1.2. Summary of epidemiological studies on antacid use and risk of esophageal and gastric cancer. Study Design + Sample size Exposure (antacid drugs) Covariates Outcome Moller, 1989 Population based cohort Sample size=16739 Cimetidine Esophagus & Stomach La Vecchia, 1990 Hospital-based case-control (northern Italy) # of case=563 # of control=1501 H2-receptor antagonists Age, sex, area of residence, education, smk Gastric cancer Colin-Jones, 1990 Cohort 9928 cimetidine 71 Adenocarcinoma of stomach 22 Adenocarcinoma of Esophageal or gastric cardia + 5 unknown histology 13 squamous cell cancers of esophageal Moller, 1992 Population based cohort cimetidine Gastric cancer Chow, 1995 Medical record-based case-control case 196/ control 196 H2 (cimetidine, ranitidine, famotidine, and nizatidine) Anticholinergics Up to 1 year before diagnosis Race, smk, BMI and with or without composite conditions Adenocarcinoma of Esophageal and gastric cardia Johnson, 1996 Pharmacy-based case-control 113/452 H2-receptor antagonists 8 or more prescriptions Up to 2 years before diagnosis Crude (time since first use) None/2-4yrs/5-yrs/>=10 (conditional logistic) Gastric cancer 13 14 Table 1.2, Continued. Suleiman, 2000 Case-control 56/56 H2-receptor antagonists Up to 2 years before diagnosis Never/< 1yr/>1 yr Social class (conditional logistic) Cardio-oesophageal adenocarcinoma Farrow, 2000 Population-based case-control (293+221+261+368) /695 H2-receptor antagonists At least once a week for 1 month or more 0/1-47months/48+month No lag/2 yr lag/ 5 yrlag GERD +age, center, sex, cig smk, history of ulcer, BMI. Hiatal hernia is adjusted for Esophagus in addition. Esophageal adenocarcinoma Esophageal squamous cell carcinoma Gastric cardia adenocaarcinoma Non-cardia gastric adenocarcinoma Rodriguez, 2006 Nested-case-control (UK) (287+195+327)/10000 H2+PPI Never/past/current Current [< 1yr / 1-3 yr/ >3 yr] 1 year lag time Current user adjusted Esophageal adenocarcinoma Gastric cardia adenocaarcinoma Non-cardia gastric adenocarcinoma 14 15 Table 1.3. H2-receptor antagonists and risk of cancer at esophagus, gastric cardia and distal stomach. (Duan, Ma et al. 2008) Study No. of cases/no. of non-cases No. of exposure levels Non-use Highest exposure level RR (95% CI) for highest versus lowest exposure level Esophageal cancer Moller, 1989 6/16739 - - - 1.14 (0.27-2.95) Farrow, 2000 21/33 3 Never user 48+ months 1.30 (0.60-2.80) Rodriguez, 2006 18/268 5 Never user current > 3 years 2.10 (1.20-3.68) Summary OR: 1.68 (1.10-2.57) Gastric cardia Farrow, 2000 6/33 3 Never user 48+ months 0.70 (0.30-1.80) Rodriguez, 2006 6/268 5 Never user current > 3 years 0.73 (0.30-1.76) Summary OR: 0.72 (0.38-1.34) Cardio-oesophageal adenocarcinoma (AEC) Chow, 1995 16/4 4 Never user ≥ 4 prescriptions 1.80 (0.50-6.70) Suleiman, 2000 4/3 3 Never user > 1 year 2.56 (0.17-38.09) Summary OR: 1.92 (0.60-6.20) 15 16 Table 1.3, continued. Distal stomach Farrow, 2000 17/33 3 Never user 48+ months 0.80 (0.40-1.70) Rodriguez, 2006 12/268 5 Never user current > 3 years 0.93 (0.48-1.80) Summary OR: 0.87 (0.53-1.42) Stomach cancer Moller, 1992 134/16739 - - - 3.11 (2.43-3.97) La Vecchia, 1990 36/59 2 Never user Ever user 1.80 (1.20-2.80) Johnson, 1996 113/452 2 Never user Ever user 2.00 (1.00-3.90) Summary OR: 2.35 (1.57-3.52) † Summary OR: Cardia + Distal Gastric + Stomach 1.32 (0.80-2.19) † Summary OR: Esophagus + Cardia +AEC 1.33 (0.95-1.87) Summary OR: Cardia + Distal Gastric 0.81 (0.55-1.19) Summary OR: All cohort studies 2.25 (0.90-5.64) Summary OR: All case-control studies 1.39 (1.11-1.74) Summary OR: All studies 1.44 (1.00-2.06) † † OR and 95%CI are based on random effect model since p-value for homogeineity test is less than 0.1. Test for heterogeneity among all esophageal studies: P=0.487. Test for heterogeneity among all cardia studies: P=0.948. Test for heterogeneity among all AEC studies: P=0.818 Test for heterogeneity among all distal stomach studies: P=0.763. Test for heterogeneity among all stomach studies: P=0.064. Test for heterogeneity among all cardia, distal gastric and stomach studdies: P<0.001. Test for heterogeneity among all esophageal, cardia and AEC studies: P=0.340. Test for heterogeneity among all cardia and distal gastric studies: P=0.955. Test for heterogeneity among all cohort studies: P=0.107. Test for heterogeneity among all case-control studies: P=0.165. Test for heterogeneity among all studies: P<0.001. 16 17 3). Non-steroidal anti-inflammatory drugs Since the late 1980s, evidence has accumulated to suggest that aspirin and other NSAID use reduces cancer risk (Schreinemachers and Everson 1994; Vainio and Morgan 1998; Vainio and Morgan 2000; Bosetti, Gallus et al. 2002; Sorensen, Friis et al. 2003). 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 intestinal mucosa, but is overexpressed in premalignant and malignant gastrointestinal cancers (Harris, Beebe-Donk et al. 2005; Dai and Wang 2006). High concentrations of prostaglandins have been shown to promote cellular proliferation and tumor growth, suppress the immune system, and induce angiogenesis (Husain, Szabo et al. 2002). Thus, NSAIDs may protect against UGI cancers by inhibiting COX-2, which in turn suppresses prostaglandin synthesis (Husain, Szabo et al. 2002). NSAID use has been associated with reduced risks of a number of cancers, although results are considered to be most consistent for colon cancer (Schreinemachers and Everson 1994; Baron and Sandler 2000; Bosetti, Gallus et al. 2002; Baron 2003). Recent studies have demonstrated NSAID use reduces the risk of esophageal adenocarcinoma (Thun, Namboodiri et al. 1993; Funkhouser and Sharp 1995; Farrow, Vaughan et al. 1998; Langman, Cheng et al. 2000; Suleiman, Harrison et al. 2000; Anderson, Johnston et al. 2006). Three recent meta-analyses that included both case-control studies and cohort studies indicated that aspirin and other NSAID users were at reduced risk of esophageal 18 squamous cell carcinoma, esophageal adenocarcinoma, and non-cardia gastric adenocarcinomas, but not at reduced risk of gastric cardia cancers (Corley, Kerlikowske et al. 2003; Gonzalez-Perez, Garcia Rodriguez et al. 2003; Wang, Huang et al. 2003). As we discussed in the previous section, infection with H. pylori, or presence of BE, hiatal hernia and reflux symptoms are independent risk factors for esophageal and gastric adenocarcinomas in this study population (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 the relationship between NSAID use and esophageal and gastric adenocarcinomas. Case-control studies conducted in Russia and Sweden evaluated risk patterns with adjustment for a history of H. pylori infection; both studies found that an inverse association with distal gastric cancer existed only among subjects who were H. pylori positive (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 an inverse association between current non-aspirin NSAID users and risk of esophageal and gastric adenocarcinomas in analyses restricted to subjects with no history of UGI disorders (Farrow, Vaughan et al. 1998). Another case-control study of gastric and esophageal adenocarcinomas found that long-term use (>3 years) of NSAIDs decreased the risk of all gastric cancers 19 combined more among subjects with UGI disorders than among those with no UGI disorders although this difference did not reach statistical significance (Lindblad, Lagergren et al. 2005). Most previous studies of the relationship between NSAID use and risk of esophageal or gastric cancer have defined the reference group as individuals whose NSAID use history falls below a certain threshold (Farrow, Vaughan et al. 1998; Zaridze, Borisova et al. 1999; Akre, Ekstrom et al. 2001; Gammon, Terry et al. 2004; Tsibouris, Hendrickse et al. 2004; Vaughan, Dong et al. 2005; Anderson, Johnston et al. 2006), similar to our approach where the reference group consisted of individuals whose had never used at least two NSAID pills per week for a month (Table 4). Two studies have separated irregular users from never users (Coogan, Rosenberg et al. 2000; Lindblad, Lagergren et al. 2005), but neither separated adenocarcinomas of the esophagus from squamous cell carcinomas nor did either study segregate gastric cancers by site. Coogan et al (Coogan, Rosenberg et al. 2000) found that both regular use and irregular use of NSAIDs were associated with reduced risk of stomach cancers, but observed no impact on esophageal cancer risk. Lindblad et al (Lindblad, Lagergren et al. 2005) observed that long-term use of non-aspirin NSAIDs was associated with a reduced risk of gastric cancer, but not esophageal cancer; further, no associations with aspirin use were noted. 20 Table 1.4. Summary of epidemiological studies on aspirin and risk of esophageal and gastric cancers. Study Exposure Sub site Histological Type Confounder Major Finding Farrow, 1998 (Farrow, Vaughan et al. 1998) 1) Reference time: 1 year before interview. 2-5 years lag before R. 2) Current user defined as taking the drug at the reference date, and former users otherwise. 3) Ever use defined as at least once per week for 6 months or more. (Ever vs. otherwise) esophageal adenocarcinoma / gastric cardia adeno. / non-cardia gastric adeno. esophageal adenocarcinoma / esophageal squamous cell carcinoma age, gender, study center, respond type (self or NOK), smoking, SES, BMI, and UGI 1) Current user of aspirin were at reduced risk of esophageal adeno., and non-cardia gastric adeno. 2) Risk was similar reduced for non-aspirin NSAID. 3) The association remained when restricted to UGI-. Zaridze, 1999 (Zaridze, Borisova et al. 1999) Regular use was defined as use at least 2 days a week for 6 months or more. (Regular vs. No-regular) cardia vs. non-cardia age, education 1) Use of aspirin and other NSAID were associated with protection against cancer of the stomach. 2) Aspirin does not affect gastric cardia. 3) No reduction with aspirin or other NSAID among H pylori -. 20 21 Table 1.4, Continued. Akre, 2001 (Akre, Ekstrom et al. 2001) 1) Reference time: 2 years before interview. 2) Multiple drug user data was not record for drug specific dose. 3) Ever user defined as ever use the medication with a frequency equal or exceeding one tablet per month. (Ever vs. otherwise) Cancer of the gastric cardia was defined as an adenocarcinoma with its centre located within 1cm proximal and 2 cm distal to the gastro-oesophageal junction (Misumi et al, 1989). intestinal/diffuse/mixed SES, smoking, H. pylori, intake of fruit and vegetables, UGI history (either diagnose or ever use H2 blocker 1) Users of aspirin had a moderately reduced risk of gastric cancer compared to never users. 2) The risk reduction was apparent for both cardia (0.6, 0.3-1.1) and non-cardia (0.8, 0.3-1.0) tumors. 3) No association was observed between gastric cancer risk and non-aspirin NSAIDs or other studied pain relievers. 4) Risk reduction is higher among H. pylori positive than negative, though the difference is not significant. 21 22 Table 1.4, Continued. Lindblad, 2005 (Lindblad, Lagergren et al. 2005) 1) Nonuse vs. ever use (Pure never). Nonuse represent no recorded use and ever use is defined as any recorded use of that drug. 2) Ever users were further grouped into current or past users. Current user was defined as when prescriptions for that drug were issued within the year before index date. esophageal /gastric sex, age, smoking, alcohol consumption, BMI and calendar year, and UGI 1) Non-aspirin NSAIDs long-term use was associated with a reduced risk of gastric cancer, whereas no other studied associations could be firmly established. 2) Among UGI-, the association approach to null, whereas among UGI+, the negative association reinforced. Anderson，2006 (Anderson, Johnston et al. 2006) 1） Aspirin or NSAID at least once weekly for >=6 month. Reflux esophagitis/ Barrett’s esophagus / esophageal adenocarcinoma Sex, age at interview, education, job type, smoking, alcohol, BMI (5 years before interview), and location. Stratified by GER symptoms. 1) Use of aspirin and NSAID were associated with reduced risk of Barrett’s esophagus and esophageal adenocarcinoma. 22 23 Table 1.4, Continued. Coogan, 2000 (Coogan, Rosenberg et al. 2000) 1) Regular /Nonregular/ Never. Regular use defined as use for at least 4 days/week for at least 3 months that had been initiated 1 year before refer 2) Regular users were divided into continuing use (continued into the year before admission) and discontinued use (last use at least 1 year before admission). Esophagus / Stomach Age, sex, interview year, center, race, religion, cigarettes, family history of digestive cancer, education, and alcohol consumption. 1) Regular use of NSAID (including aspirin and other) and continuing use was associated with reduced OR for stomach. 2) OR for more than 5 years use of NSAID was also significant for stomach. Vaughan, 2005 (cohort study) (Vaughan, Dong et al. 2005) 1) Aspirin and non-aspirin NSAID 2) Regular use defined as at least once a week for 6 months or more 3) Current user / former user / never user (=no regular user) Barrett’s esophagus HR doe esophageal adenocarcinoma for current users at baseline or afterwards was 0.2 (0.1-0.4) compared with never user. 23 24 Table 1.4, Continued. Langman, 2000 (Langman, Cheng et al. 2000) 1) No. of prescriptions. 0/1/2-6/>=7. Prescription NSAIDs only. (reference group= 0 prescription) 2) Data on prescription for aspirin and non-aspirin NSAIDs were extracted for the 13-36 months before diagnosis. Esophagus / Stomach No specific type, cancer overall Findings supports the protective effect at esophagus and stomach Tsibouris, 2004 (Tsibouris, Hendrickse et al. 2004) 1) Subjects consuming NSAIDs at least once a week for the 10-year period were considered as NSAIDs user. If they consumed NSAIDs everyday for at least 2 years during the 10-year period, they will be considered as daily user. Barrett’s esophagus patients adenocarcinoma 24 25 Table 1.4, Continued. Thun, 1993 (cohort study) (Thun, Namboodiri et al. 1993) 1) How many times in the last month have you used the following medications? 2) How long (in years) have you used them? 3) The first category listed was Aspirin, Bufferin, and Anacin and the second was acetaminophen esophagus, stomach, colon, and rectum Our data suggest that regular, prolonged use of aspirin may reduce the risk of fatal cancer of the esophagus, stomach, colon, and rectum. Funkhouser, 1995 (cohort study) (Funkhouser and Sharp 1995) Use aspirin in last 30 days Esophageal carcinoma Cheng, 2000 (Cheng, Sharp et al. 2000) Ever take aspirin daily for as long as a month Esophageal adenocarcinoma in women Not significant. 25 26 5). Smoking and Passive Smoking Cigarette smoking has been established as a cause of squamous cell carcinoma at the esophagus (2002). Now substantial evidence from all over the world indicates that it also plays a role in the development of esophageal and gastric adenocarcinomas, however, for these the magnitude of risk associated with cigarette smoking is lower than that observed for squamous cell esophageal cancers (2002). In three US studies, ex-smokers and current smokers were both at approximately 2-fold increased risk of esophageal or gastric cardia adenocarcinoma, and the elevated risk appears to persist for up to 30 years after cessation of smoking (Vaughan, Davis et al. 1995; Gammon, Schoenberg et al. 1997; Wu, Wan et al. 2001). In a Swedish case-control study, Lagergren et al. (Lagergren, Bergstrom et al. 2000) found a comparable increase in risk of esophageal adenocarcinoma, but a relatively higher risk for adenocarcinoma of the gastric cardia. Cigarette smoking may slow gastric emptying, alter acid secretion, and more importantly, the condensation product from cigarette includes N-nitroso compounds, which are known carcinogens and may damage the esophagus and gastric mucosa (1987; Bernstein 2003). All of these may in turn cause cellular changes that are at risk for progresses to carcinoma. Passive smoking (also called involuntary smoking) refers to being exposed to secondhand tobacco smoke, which is a mixture of exhaled mainstream smoke and sidestream smoke released from the smouldering cigarette or other smoking device (cigar, pipe, bidi, etc.) and diluted with ambient air (2002). Passive smokers may inhale carcinogens as well as other toxic components. Over the 27 past 20-30 years, numerous studies have shown that exposure to passive smoking increases the risk of of lung cancer in non-smokers (2002). However, the data on the association between passive smoking and gastrointestinal cancers are limited. 28 Chapter 2: Non-Steroidal Anti-Inflammatory Drugs and Risk of Esophageal and Gastric Adenocarcinomas in Los Angeles County Introduction Since the late 1980s, evidence has accumulated to suggest that aspirin and other non-steroidal anti-inflammatory drug (NSAID) use reduces cancer risk (Schreinemachers and Everson 1994; Vainio and Morgan 1998; Vainio and Morgan 2000; Bosetti, Gallus et al. 2002; Sorensen, Friis et al. 2003). 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 intestinal mucosa, but it is overexpressed in premalignant (Harris, Beebe-Donk et al. 2005; Dai and Wang 2006) and malignant gastrointestinal cancers. High concentrations of prostaglandins have been shown to promote cellular proliferation and tumor growth, suppress the immune system, 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 (Husain, Szabo et al. 2002). NSAID use has been associated with reduced risks for a number of cancers, although results are considered to be most consistent for colon cancer(Schreinemachers and Everson 1994; Baron and Sandler 2000; Bosetti, Gallus et al. 2002; Baron 2003). Recent studies have demonstrated NSAID use 29 reduces the risk of esophageal adenocarcinoma (Thun, Namboodiri et al. 1993; Funkhouser and Sharp 1995; Farrow, Vaughan et al. 1998; Langman, Cheng et al. 2000; Suleiman, Harrison et al. 2000; Anderson, Johnston et al. 2006). Three recent meta-analyses that included both case-control studies and cohort studies indicated that aspirin and other NSAID users were at reduced risk of esophageal squamous cell carcinoma, esophageal adenocarcinoma, and non-cardia gastric adenocarcinomas, but not at reduced risk of gastric cardia cancers (Corley, Kerlikowske et al. 2003; Gonzalez-Perez, Garcia Rodriguez et al. 2003; 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 tumor types. However, few studies have adequately controlled for UGI conditions and results are conflicting (Farrow, Vaughan et al. 1998; Zaridze, Borisova et al. 1999; Akre, Ekstrom et al. 2001; Lindblad, Lagergren et al. 2005). 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 the nature of the association between these drugs and risk of adenocarcinoma of the esophagus, gastric cardia or distal stomach and whether the risk patterns differ depending on history of non-malignant UGI disorders. 30 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; Vigen, Bernstein et al. 2006; Wu, Tseng et al. 2007). 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 Los Angeles County. We included patients who were newly diagnosed with first incident esophageal adenocarcinoma (Internal Classification of Disease for Oncology [ICDO] C15.0-C15.9) or gastric cardia adenocarcinoma (ICDO C16.0) between 1992 and 1997 and patients newly diagnosed with distal gastric cancer (ICDO C16.1-C16.6, C16.8-C16.9) between 1992 and 1994. We identified 1716 eligible patients (429 esophageal adenocarcinomas (EA)/500 ardenocarcinomas of the gastric cardia (GCA) / 787 distal gastric adenocarcinomas (DGA); numbers for the three tumor sites 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 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 EA/37 GCA /84 DGA) patients largely because the 31 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, sex, 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 sex, 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 in the neighborhoods of the interviewed case patients. Each neighborhood control subject was sought using a systematic 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 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 one control subject, 382 had two or more control subjects, and 37 had no eligible control subjects identified. 32 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. Interview method Case patients and their matching control subjects 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 case patient’s matched control subject. We used a structured questionnaire that we developed specifically for this 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 of interest in this analysis, we explicitly listed 20 over-the-counter and 45 prescription brand-name analgesics in the questionnaire. For each of the listed 33 medications, we first asked the subject whether they had ever used the drug. If the answer was ‘no’, the subjects was defined as a non-user. If the answer was ‘yes’, the subject was further asked if he or she had ever taken the drug two or more times a week for 1 month or longer. If the answer was no, the subject was classified as an ‘irregular user’. Otherwise, the subject was defined as a ‘regular user’ and we further asked about the ages at first and last use, duration of use, usual frequency and dosage of use, and the primary reason for each use. We also asked the subjects if they had used any analgesics that were not on our list and recorded the drug name and details of use if the subject had used the medication ‘regularly’. All of the medications in the study were categorized into the following groups based on their components: aspirin, non-aspirin NSAIDs, acetaminophen, or prescription medications not included in these categories. We focus this report on reported use of aspirin and non-aspirin NSAIDs. 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 (46 types of drug) [All NSAID containing drugs with any reported use are listed in the appendix]. We also created combined NSAIDs variables (duration and frequency of aspirin plus non-aspirin NSAIDs). 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. The 34 no regular use category was further divided into never users and irregular users for some analyses. Frequency of regular use was grouped into three levels (0, 2-<7, ≥ 7 pills per week). Because early symptoms of cancer patients might affect their NSAIDs use, we excluded from the calculation of total duration and frequency of use any drugs that were first taken within the interval beginning 1 year before the reference date for both case patients and control subjects, which is two years before diagnosis for case patients and the same date for their matched control subjects. A similar approach was used to create variables for acetaminophen use. Polychotomous logistic regression was used to compute the odds ratios (ORs), as estimates of the relative risk, and corresponding 95% confidence intervals (CIs) for adenocarcinomas of the esophagus, gastric cardia, and distal stomach simultaneously in relation to duration and frequency of each type of drug use. We used all control subjects in this analysis to maximize statistical power, and adjusted for the matching factors in our analysis. In our previous study (Wu, Tseng et al. 2007), this approach provided more precise estimates of the ORs, and 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+ years), sex (male/female), race (Non-Latino White, African-American, Latino-American, Asian-American), birthplace (US born, non-US born), 35 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 (<25, 25-29.9, 30+ kg/m 2 ’), history (no/yes) of upper gastrointestinal tract disorders (including gastric ulcer, duodenal ulcer, unspecified type of ulcer, gastritis, hiatal hernia, 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) 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 data collected from NOK subjects. Risk estimates were not materially different from the results presented below based on all subjects combined (i.e., self-respondents and NOK subjects). 36 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 years (standard error (SE) =9.4) for patients with esophageal adenocarcinoma, 60.8 years (SE=10.2) for patients with adenocarcinoma of the gastric cardia, and 60.4 years (SE=11.5) for patients distal gastric adenocarcinoma; control subjects were, on average, 59.5 years (SE=11.2) at their assigned reference age. Among control subjects, 73.7% were male, compared with 90.9% of patients with esophageal adenocarcinoma, 83.4% of patients with gastric cardia adenocarcinoma, and 59% of the distal gastric cancer patients. Non-Latino Whites represented 62% of those with esophageal adenocarcinoma, 77.3% of those with gastric cardia adenocarcinoma, and 30.2% of those with distal gastric adenocarcinoma. For all three tumor sites, 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 2 summarizes the associations between regular use of aspirin, non-aspirin NSAIDs and any NSAIDs and each tumor site. Regular use of aspirin for at least five years was associated with approximately 40% reduced risk of distal gastric adenocarcinoma (adjusted OR=0.58; 95 % CI, 0.36-0.92). Both short-term (< 5 years) and longer-term ( > 5 years) 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 37 (adjusted 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). The dose-response effect was strengthened when aspirin and non-aspirin NSAIDs use were examined together (p-trend=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 (Table 2). Among those who took NSAIDs for more than 5 years the OR was 0.60 (95% CI, 0.38-0.95) relative to individuals who had not used any NSAID drug regularly and the dose response effect was statistically significant (p-trend=0.04). 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 nearly 50% decline in the 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) (Table 2). The observed association between any NSAID use and risk of adenocarcinomas at each site was strengthened when we restricted our reference group to never users (Table 3). The ORs for esophageal adenocarcinoma and distal gastric adenocarcinoma were significantly decreased among irregular users as well as short-term (< 5 years) and longer term NSAID users. Interestingly, we also 38 found reduced ORs for adenocarcinoma of the gastric cardia among study participants who were irregular as well as regular NSAID users. 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 4). No heterogeneity of trends was observed between individuals with or 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 those without a history of UGI disorders (OR=0.52, 95% CI, 0.27-1.00; and OR=0.62,95% CI, 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 of these risk estimates nor the trend tests achieved statistical significance. In Table 5, we show risk by history of UGI disorders in logistic regression models where the reference group was restricted to participants who reported never using NSAIDs. As was observed in Table 4, we see no heterogeneity of effects by UGI disorder status, with irregular NSAID users also at lower risk for cancer at each of the three subsites than never users. We further assessed whether risk differed between current users, those who were NSAID users on the reference date (that is, one year prior to the case patient’s date of diagnosis and a comparable date for the control subjects), and other users. 39 We found that current users and former users both had reduced ORs for adenocarcinomas of the esophagus and distal stomach and that these results did not differ statistically (results not shown). Moving the date on which subjects were defined as current users back to three years prior to the case patients’ diagnosis date, did not produce different results for current users and former users. In order to rule out differential reporting of NSAID use by case patients and control subjects, we also studied the association between acetaminophen use and risk of adenocarcinomas at each site. In a multivariate analysis that included NSAID use, no statistically significant association between acetaminophen use and risk of adenocarcinomas of the esophagus, gastric cardia or distal stomach cancers was observed (results not shown). 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 statistically significant dose response effects for both tumor sites. Regular NSAID use was unrelated to risk of adenocarcinomas of the gastric cardia. In this study, a regular user was one who had taken at least two NSAID pills a week for a month. Changing the reference group from those with no regular NSAID 40 use to never users strengthened these relationships, but also uncovered lower risks among individuals who were in the irregular user category In addition, risk of gastric cardia adenocarcinomas was significantly reduced in the analysis using non users as the reference group. A history of UGI disorders did not modify these effects as none of the tests for homogeneity of trends was statistically significant. We excluded any drugs initiated in the 2 years before the patients’ diagnoses or the equivalent date for control subjects as symptoms experienced by case patients prior to their diagnoses could have influenced their use of NSAID drugs. We reanalyzed our data including drug use initiated during this time period, and our results were essentially the same as those presented here. Our results on regular NSAID use support previous results suggesting that NSAID use is inversely associated with risk of adenocarcinomas of the esophagus and stomach (Corley, Kerlikowske et al. 2003; Wang, Huang et al. 2003; Harris, Beebe-Donk et al. 2005). As suggested by Anderson (Anderson, Johnston et al. 2006), NSAIDs may impact the early stage of the inflammation-metaplasia-adenocarcinoma sequence in the esophagus. NSAID use can reduce inflammation by inhibiting cyclooxygenase 2 (COX-2）enzyme production. Overexpression of COX-2 has been found in a range of esophageal conditions including reflux esophagitis (Hamoui, Peters et al. 2004), dysplasia (Shirvani, Ouatu-Lascar et al. 2000), Barrett’s esophagus (Shirvani, Ouatu-Lascar et al. 2000; Abdalla, Sanderson et al. 2005), and esophageal adenocarcinomas (Shirvani, Ouatu-Lascar et al. 2000; Souza, Shewmake et al. 2000; Hamoui, 41 Peters et al. 2004). Overexpression of COX-2 and increased prostaglandin secretion have also been found to be involved in the growth and metastasis of gastric cancer (Chen, Liu et al. 2001). Studies also suggest COX-2 inhibitors can reduce cell growth and decrease cell proliferation in Barrett’s esophagus (Husain, Szabo et al. 2002), in spite of the onset of COX-2 overexpression in the early stages of development of Barrett’s esophagus (Kandil, Tanner et al. 2001; Buttar, Wang et al. 2002), and that they suppress growth of gastric cancer in a human gastric cancer cell line (Tsuji, Kawano et al. 1996; Sawaoka, Kawano et al. 1998). Three previous studies suggest that current users of NSAIDs are at lower risk of esophageal or distal gastric adenocarcinomas than those who never used NSAIDs (Farrow, Vaughan et al. 1998; Coogan, Rosenberg et al. 2000; Vaughan, Dong et al. 2005). In these three studies, current users were defined as subjects who reported taking the medications at the study’s reference date (i.e., that date was 1 year before interview for controls and the earlier of 1 year before interview or diagnosis date for cases), all other users were considered former users. Former NSAID use was also associated with decreased risk of esophageal or distal gastric adenocarcinomas, but the risk reductions were not statistically significant. The authors question whether their findings are artifactual because individuals with early symptoms of cancer might have stopped using NSAIDs. In our study, the associations did not differ between current and past NSAIDs users. And our analysis where former users ceased use at least three years prior to the diagnosis date suggest that the effect of NSAIDs, if true, may persist at least three years 42 after cessation of NSAID use. Prior studies that have evaluated frequency of use have not observed that daily use has greater impact on risk of UGI cancers (Farrow, Vaughan et al. 1998; Vaughan, Dong et al. 2005). In one prospective study, the authors found no relation between frequency of NSAID use and risk of esophageal adenocarcinoma (Vaughan, Dong et al. 2005). In a case-control study, the risk of esophageal and distal gastric adenocarcinoma was lower among subjects who took one aspirin pill per day, but no risk reduction was noted for users of non-aspirin NSAIDs (Farrow, Vaughan et al. 1998). We found that risk reduction for esophageal and distal gastric adenocarcinomas was restricted to regular NSAID users who took at least seven pills per week. This suggests that daily use of an aspirin or other NSAID drug may be optimal for use in cancer prevention for those at high risk for esophageal or distal gastric adenocarcinomas. However, the lack of any effect among those who were considered as regular users but had less frequent use is at odds with our finding that irregular use is associated with lower UGI cancer risk, an inconsistency we are unable to explain. Infection with Helicobacter pylori (H. pylori), Barrett’s esophagus, hiatal hernia and reflux symptoms are independent risk factors for esophageal and gastric adenocarcinomas in this study population (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 43 contraindicated. However, few epidemiological studies have considered a history of UGI disorders when examining the relationship between NSAID use and esophageal and gastric adenocarcinomas. Case-control studies conducted in Russia and Sweden evaluated risk patterns with adjustment for a history of H. pylori infection; both studies found that an inverse association with distal gastric cancer existed only among subjects who were H. pylori positive (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 an inverse association between current non-aspirin NSAID users and risk of esophageal and gastric adenocarcinomas in analyses restricted to subjects with no history of UGI disorders (Farrow, Vaughan et al. 1998). Another case-control study of gastric and esophageal adenocarcinomas found that long-term use (>3 years) of NSAIDs decreased the risk of all gastric cancers combined more among subjects with UGI disorders than among those with no UGI disorders although this difference did not reach statistical significance (Lindblad, Lagergren et al. 2005). Our findings showed a clear pattern of decreasing ORs for distal gastric adenocarcinomas with increasing duration and frequency of NSAID use among persons with and without 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. We 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 44 NSAID formulations were available only by prescription; at the time this study was conducted, many were just becoming available as over-the-counter pain relievers. One speculation is that when non-aspirin NSAIDs were used by our study subjects, they were used at the higher doses available only by prescription, yielding effective doses of non-aspirin NSAIDs that may have been greater than those for aspirin products. Further, indications for use of non-aspirin NSAIDs may have differed from those for aspirin. Aspirin and non-aspirin NSAIDs differ in that aspirin is believed to mainly inhibit the COX-1 enzyme, while most non-aspirin NSAID mainly influence COX-2 (Tarnawski and Caves 2004). Most previous studies of the relationship between NSAID use and risk of esophageal or gastric cancer have defined the reference group as individuals whose NSAID use history falls below a certain threshold (Farrow, Vaughan et al. 1998; Zaridze, Borisova et al. 1999; Akre, Ekstrom et al. 2001; Gammon, Terry et al. 2004; Tsibouris, Hendrickse et al. 2004; Vaughan, Dong et al. 2005; Anderson, Johnston et al. 2006), similar to our approach where the reference group consisted of individuals whose had never used at least two NSAID pills per week for a month. Two studies have separated irregular users from never users (Coogan, Rosenberg et al. 2000; Lindblad, Lagergren et al. 2005), but neither separated adenocarcinomas of the esophagus from squamous cell carcinomas nor did either study segregate gastric cancers by site. Coogan et al (Coogan, Rosenberg et al. 2000) found that both regular use and irregular use of NSAIDs were associated with reduced risk of stomach cancers, but observed no impact on esophageal cancer risk. Lindblad et al (Lindblad, Lagergren et al. 2005) observed that 45 long-term use of non-aspirin NSAIDs was associated with a reduced risk of gastric cancer, but not esophageal cancer; further, no associations with aspirin use were noted. We found similar reductions in risk for irregular users, short-term users, and longer-term users when restricting the reference group to persons with no use. This observation calls into question whether NSAIDs are responsible for the reduction in risk of these cancers, or whether non-users differ is some heretofore undefined way from NSAID users that is predictive of risk. 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 complete reporting of NSAID use by NOK. However, our results did not appear to be affected by NOK interviews and were similar when NOK were excluded from the analyses. In this and other studies published to date, results are based on self or NOK reports on NSAID use. It is not feasible to validate over-the-counter medication use and it is also difficult to validate the use of prescription analgesic medications. We did, however, ask extensive questions regarding each NSAID medication used regularly by asking about the starting and stopping dates, frequency of use and the name of the physician who prescribed the drug (for prescription medications). We did not ask about specific doses of the medications used but we recorded the frequency of use in pills per day, week, or month over each exposure time period. In addition, the number of regular 46 NSAIDs users in this study was not substantial, which reduced the statistical power in our more detailed analyses that stratified by history of UGI symptoms. Similarly, the small number of regular users limited the possibility of testing for heterogeneity of effects by race. In summary, this large, population-based case-control study indicates that regular use of aspirin and other NSAIDs is associated with reduced risk of esophageal and distal gastric adenocarcinomas and that, in analyses comparing regular to irregular or non users, risk declines with increasing duration of use. These relationships are evident among individuals with and without a history of upper UGI disorders or symptoms. 47 Table 2.1. Selected characteristics of esophageal and gastric adenocarcinoma case patients and control subjects, Los Angeles County. 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) 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) 47 48 Table 2.1., continued. 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/m 2 ) * 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) 48 49 Table 2.2. 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 (0.41-0.97) ≥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 49 50 Table 2.2., continued. Tablet per week Aspirin No regular use 1038 168 - 1.0 - 200 - 1.0 - 375 - 1.0 - 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 - 1.0 - 239 - 1.0 - 399 - 1.0 - 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 - 1.0 - 178 - 1.0 - 353 - 1.0 - 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 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 multivariable polychotomous logistic regression models. 50 51 Table 2.3. 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. using never users as the reference group. Control Esophageal adenocarcinoma Gastric cardia adenocarcinoma Distal gastric adenocarcinoma Exposure n n OR a (95% CI) n OR a (95% CI) n OR a (95% CI) Any NSAID Never use 160 36 - 1.0 - 50 - 1.0 - 145 - 1.0 - No regular use 767 119 0.55 (0.35-0.87) 126 0.45 (0.30-0.67) 208 0.47 (0.35-0.64) < 5 years of regular use 219 38 0.58 (0.34-1.00) 55 0.66 (0.42-1.06) 52 0.45 (0.30-0.68) ≥5 years of regular use 210 26 0.37 (0.20-0.66) 44 0.50 (0.31-0.82) 34 0.34 (0.22-0.55) p-trend < 0.01 0.24 < 0.01 a Adjusted for age, sex, race, birthplace, education, smoking status, BMI (at reference age), UGI history and antacid use in a multivariable polychotomous logistic regression models. 51 52 Table 2.4. 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 adenocarcinoma 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 82/262 - 1.0 - 86/775 - 1.0 - < 5 years 9/45 0.64(0.29-1.42) 17/103 1.52 (0.85-2.74) ≥5 years 11/55 0.72 (0.34-1.49) 14/115 0.90 (0.48-1.68) p-trend 0.24 0.89 P for heterogeneity of trends 0.32 Non-Aspirin NSAID No regular use 85/281 - 1.0 - 108/859 - 1.0 - < 5 years 12/59 0.87 (0.42-1.80) 8/101 0.60 (0.28-1.30) ≥5 years 4/21 0.51 (0.16-1.60) 1/34 0.22(0.03-1.70) p-trend 0.25 0.05* P for heterogeneity of trends 0.38 Any NSAID No regular use 73/224 - 1.0 - 82/703 - 1.0 - < 5 years 17/69 0.86 (0.46-1.62) 21/150 1.16 (0.68-1.98) ≥5 years 12/69 0.59 (0.29-1.19) 14/141 0.71 (0.38-1.33) p-trend 0.14 0.44 P for heterogeneity of trends 0.53 52 53 Table 2.4., continued. Gastric cardia adenocarcinoma 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 76/262 - 1.0 - 124/775 - 1.0 - < 5 years 22/45 1.59 (0.87-2.90) 18/103 1.02 (0.58-1.77) ≥5 years 12/55 0.75 (0.37-1.51) 23/115 1.07 (0.64-1.78) p-trend 0.84 0.80 P for heterogeneity of trends 0.75 Non-Aspirin NSAID No regular use 88/281 - 1.0 - 149/859 - 1.0 - < 5 years 14/59 0.91(0.47-1.77) 12/101 0.61 (0.32-1.16) ≥5 years 8/21 1.05 (0.43-2.54) 4/34 0.66 (0.22-1.94) p-trend 0.96 0.13 P for heterogeneity of trends 0.27 Any NSAID No regular use 64/224 - 1.0 - 112/703 - 1.0 - < 5 years 29/69 1.57 (0.91-2.70) 26/150 1.16 (0.68-1.98) ≥5 years 17/69 0.83 (0.44-1.54) 27/141 0.71 (0.38-1.33) p-trend 0.94 0.44 P for heterogeneity of trends 0.88 53 54 Distal gastric adenocarcinoma 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 - 261/775 - 1.0 - < 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 - 272/859 - 1.0 - < 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 - 247/703 - 1.0 - < 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 multivariable unconditional logistic regression models. Table 2.4., continued. 54 55 Table 2.5. 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 using never users as the reference group. Esophageal adenocarcinoma UGI disorders No UGI disorders Exposure Number of cases/ controls OR a (95% CI) Number of cases/ controls OR a (95% CI) Any NSAID Never used 18/35 - 1.0 - - 1.0 - No regular use 55/189 0.45 (0.23-0.90) 64/578 0.65 (0.36-1.17) < 5 years of regular use 17/69 0.40 (0.18-0.91) 21/150 0.80 (0.39-1.62) ≥5 years of regular use 12/69 0.27 (0.11-0.64) 14/141 0.47 (0.22-1.03) p-trend <0.01 0.17 P for heterogeneity of trends 0.44 55 56 Table 2.5., continued. Gastric cardia adenocarcinoma Distal gastric adenocarcinoma UGI disorders No UGI disorders UGI disorders No UGI disorders 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) 18/35 - 1.0 - 32/125 - 1.0 - 37/35 - 1.0 - 108/125 - 1.0 - 46/189 0.40 (0.20-0.78) 80/578 0.48 (0.30-0.77) 69/189 0.52 (0.29-0.94) 139/578 0.46 (0.32-0.65) 29/69 0.73 (0.35-1.54) 26/150 0.58 (0.32-1.06) 22/69 0.43 (0.21-0.88) 30/150 0.47 (0.28-0.77) 17/69 0.40 (0.18-0.90) 27/141 0.57 (0.31-1.04) 15/69 0.35 (0.16-0.76) 19/141 0.34 (0.19-0.61) 0.41 0.37 0.01 <0.01 0.94 0.96 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 a multivariable polychotomous logistic regression models. 56 57 Chapter 3: Antacid Drug Use and Risk of Esophageal and Gastric Adenocarcinomas in Los Angeles County Introduction Histamine2-receptor antagonists (H2-blockers) and proton pump inhibitors (PPIs) were introduced to the market, in the late 1970s and 1980s correspondingly, and became widely used in the treatment of acid-peptic disorders such as peptic ulcer disease, gastroesophageal reflux disease (GERD) and acute stress ulcers. H2-receptor antagonists are competitive inhibitors of histamine binding at the parietal cell H2 receptor. Gastric acid secretion is suppressed if the parietal cell H2 receptor is not bound with histamine in the stomach (2005). PPIs suppress gastric acid secretion by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system of the gastric parietal cell (Chong and Ensom 2003). Because PPIs target the terminal-step in acid production, they are significantly more effective than H2-blockers in reducing gastric acid secretion. These drugs do not permanently change the acid milieu; although they raise gastric pH and provide rapid relief of symptoms; evidence of this impermanence is that erosive esophagitis recurrs in most patients within six months after discontinuing the drug therapy (Hetzel, Dent et al. 1988). Therefore, chronic maintenance therapy is generally required. Although today, some doses of these drugs are available without prescription, initially all required prescription. Some concerns have been expressed that long term gastric acid suppression, 58 particularly by H2 receptor antagonists, may be associated with increased risk of esophageal and gastric adenocarcinomas (Bernstein 2003). Some epidemiological studies, both prospective studies and retrospective studies, have attempted to evaluate associations of H2 receptor antagonists and PPIs with esophageal and gastric adenocarcinoma risk (Moller, Lindvig et al. 1989; La Vecchia, Negri et al. 1990; Colin-Jones, Langman et al. 1991; Moller, Nissen et al. 1992; Chow, Finkle et al. 1995; Johnson, Jick et al. 1996; Beresford, Colin-Jones et al. 1998; Lagergren, Bergstrom et al. 1999; Farrow, Vaughan et al. 2000; Suleiman, Harrison et al. 2000; Rodriguez, Lagergren et al. 2006), but the results have not been consistent. Although some investigators have reported positive associations between antacid drug use and increased risk of gastric cancer (La Vecchia, Negri et al. 1990; Moller, Nissen et al. 1992; Johnson, Jick et al. 1996) or esophageal cancer (Suleiman, Harrison et al. 2000; Rodriguez, Lagergren et al. 2006), others find no effect (Chow, Finkle et al. 1995; Beresford, Colin-Jones et al. 1998; Lagergren, Bergstrom et al. 1999; Farrow, Vaughan et al. 2000). Only one study stratified participants according to whether or not they had severe GERD (Farrow, Vaughan et al. 2000). It is important to consider the effect of GERD when examing the association between antacid use and risk of esophageal and gastric adenocarcinomas since GERD itself is a strong independent risk factor for adenocarcinomas of the esophagus and gastric cardia (Chow, Finkle et al. 1995; Lagergren, Bergstrom et al. 1999; Farrow, Vaughan et al. 2000; Wu, Tseng et al. 2003). We have explored the association between use of antacid drugs and risk of 59 esophageal and gastric adenocarcinomas using data from a large population-based case-control study conducted among residents of Los Angeles County. To understand any observed association better and to assess confounding of results by indication for use of the drug, we have investigated the relationship separately in groups with a history of UGI disorders and those without such a history. Methods Study Population. The details of the study population and study design have been described elsewhere (Wu, Wan et al. 2001; Wu, Crabtree et al. 2003; Wu, Tseng et al. 2003; Wu, Fu et al. 2005; Wu, Tseng et al. 2007; Duan, Ma et al. 2008). Basically, incident cancer cases for this study were identified by the USC Cancer Surveillance Program (CSP). This cancer registry covers the ethnically diverse Los Angeles County population of more than 9.5 million people. Case patients who were newly diagnosed with first incident esophageal adenocarcinoma (International Classification of Disease for Oncology code C15.0-C15.9), gastric cardia adenocarcinoma (code C16.0) or distal gastric adenocarcinoma (codes C16.1-C16.6 and C16.8-C16.9) between 1992 and 1997 were identified and contacted for participation. Control subjects were matched individually to each case patient on sex, race, age ( + 5 years), and neighborhood of residence. To increase the statistical power, we sought two control subjects for each case patient whenever possible. Of the 938 case patients interviewed, 523 had one control subjects, 381 had two or more control subjects, and 34 had no eligible control subjects identified for an overall total of 1356 control subjects. An experienced interviewer conducted the 60 in-person interview at the interviewees’ home or other convenient locations. Next-of-kin were interviewed when case patients were unable to be interviewed due to death or illness. Although it was not feasible to blind the interviewers to case (or next-of-kin) or control status, interviewers and study participants were not aware of the study hypotheses. Written informed consent was obtained from each study participant before interview. A total of 938 case patients [220 incident esophageal adenocarcinoma (EA) / 277 gastric cardia adenocarcinoma (GCA) / 441 distal gastric adenocarcinoma (DGA); numbers for the three tumor sites are shown separately with these abbreviations] and 1,356 control subjects are included in the current study. Next-of-kin interviews accounted for 269 of the 938 interviews with case patients (65EA/85GCA/119DGA). Measures. We developed a structured questionnaire specifically for this study that was administered during an in-person interview. The questionnaires obtained data up to a specified reference date, defined as the date that was one year before the date of diagnosis of the case patient; this same reference date was used for each case patient’s matched control subjects. The interview queried general background information such as ethnicity, marital status, birthplace, highest level of education, smoking history, lifetime use of all types of alcoholic beverages, usual diet, 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. We explicitly asked about 26 over-the-counter (OTC) and 19 prescription 61 brand-name antacid and related drugs in the questionnaire. For each of the listed medications, we first asked the participants whether they had ever used the drug before their reference date. If the answer was ‘no’, the participant was classified as a non-user. If the answer was ‘yes’, the participant was asked if he or she had ever taken the drug two or more times a week for one month or longer. If the answer was no, the participant was classified as an ‘irregular user’. Otherwise, the participant was defined as a ‘regular user’ and was further asked about ages at first and last use, duration of use, usual frequency and dosage of use, and the primary reason for each use. We also asked the participants if they had used any medications that were not on our list and recorded the drug name and details of use if the subject had used the medication ‘regularly’. All of the antacid medications in the study were categorized as requiring a prescription or as non-prescription. At the time the study was conducted, non-prescription (OTC) antacid drugs were limited to acid neutralizing agents (e.g., Tums, Pepto-Bismol, and Maalox); the majority of prescription antacids at that time were H2 receptor antagonists. Only a very small number of participants reported use of the PPI, which also required a prescription. To assess medical history, we provided a list of diseases, including heart disease, gastro-intestinal tract disorders and diabetes, and asked if the subject had any of those conditions diagnosed by a physician before the reference date. UGI related conditions that we queried included gastric ulcer, duodenal ulcer, gastritis, hiatal or diaphragmatic hernia, esophagitis, Barrett’s esophagus, gastroesophageal reflux disease, excess acid or gastric hyperacidity. If the response was yes to 62 any of the conditions, subjects were then asked their age at first diagnosis with the condition. In addition, participants were asked if they had experienced various symptoms including gas pain (in the stomach), sour stomach including acid indigestion and regurgitation, heartburn after meals, and trouble swallowing (feeling that solid food was sticking to their throats as it went down) before their reference date. If the response was positive, the frequency (daily, weekly, monthly, less than monthly) with which each symptom occurred and the age that the subject first experienced the symptom on a regular basis were recorded. Statistical Analysis. Participants were grouped as never users, irregular users or regular users of non-prescription acid neutralizing agents and of prescription acid suppressive drugs, separately. Among participants who reported regular use, duration of use of non-prescription acid neutralizing agents or prescription acid suppressive drugs was created by summing all durations of use of the same class of medication (prescription or non-prescription) for each person [All antacid drugs with any reported use are listed in Appendix A]. Categories for duration of regular antacid use (prescription or non-prescription) were <1 year, 1-3 years, and > 3 years of use. Because early symptoms of an upper gastrointestinal cancer may influence the use of antacid drugs, we have excluded from the calculation of total duration of use any drugs that were first taken in the year before a case or control participant’s reference date (for case patients, this therefore excludes drugs use that was initiated in the 2 years prior to the date of diagnosis). Additional analyses were conducted extending this exclusionary period to 3 years and to 5 years, respectively. 63 Polychotomous logistic regression was used to compute the odds ratios (ORs), as estimates of the relative risk, and corresponding 95% confidence intervals (CIs) for adenocarcinomas of the esophagus, gastric cardia, and distal stomach simultaneously in relation to use of non-prescription acid neutralizing agents or prescription acid suppressive drugs. In a previous study (Wu, Tseng et al. 2007), this approach provided more precise estimates of the ORs, and 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. Therefore, for the purpose of maximizing statistical power, we report results based on unconditional polychotomous logistic regression models with adjustments made for the matching variables in this analysis; this allowed us to use all control subjects in a single analysis. Forward stepwise logistic regression was used to select confounders from a list of variables, such as age (≤39, 40-49, 50-59, 60-69, 70+ years), sex (male/female), race (Non-Latino White vs. other), birthplace (US born, non-US born), smoking status (never smoker, ex-smoker, current smoker), body mass index (BMI) at reference age (<25, 25-29.9, 30+ kg/m 2 ’), history (no/yes) of UGI disorders diagnosed by physician (including gastric ulcer, duodenal ulcer, unspecified type of ulcer, gastritis, hiatal hernia, esophagitis, Barrett's esophagus, gastroesophageal reflux disease, excess acid or gastric hyperacidity, and other diseases of the stomach). A test for trend across ordinal categories of duration of use was performed for each type of cancer. 64 We constructed a 1 df likelihood ratio test to assess homogeneity of trends in duration of non-prescription acid neutralizing agent use among individuals who had a history of physician diagnosed UGI disorders and those who did not. With adjustment for prescription acid suppressive drug use and other confounding factors, we conducted the 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) 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 data collected from NOK subjects. Risk estimates were not materially different from the results based on all subjects combined (i.e., self-respondents and NOK subjects). Results Demographical characteristics of the study sample have been described previously (Duan, Ma et al. 2008). Briefly, the mean ages of cases at the reference date (one year before diagnosis) were 60.0 years (standard deviation (SD) =9.4) for patients with esophageal adenocarcinoma, 59.8 years (SD=10.2) for patients with adenocarcinoma of the gastric cardia, and 59.4 years (SD=11.5) for distal gastric adenocarcinoma patients; control subjects were, on average, 58.7 years (SD=11.5) at their reference dates. Among control subjects, 74% were male, compared with 91% of patients with esophageal adenocarcinoma, 83% of 65 patients with gastric cardia adenocarcinoma, and 59% of the distal gastric cancer patients. Non-Latino Whites represented 77% of those with esophageal adenocarcinoma, 76% of those with gastric cardia adenocarcinoma, and 30% of those with distal gastric adenocarcinoma. For all three tumor sites, case patients tended to have lower education and a higher percentage of current smokers than control subjects. 40% of case patients reported a history of UGI disorders diagnosed by physicians, compared with 27% of control subjects. These proportions became larger when self-reported UGI symptoms were considered. Participants who reported UGI symptoms accounted for 56% of case patients and 40% of control subjects in this study sample (Table 1). Regular use of non-prescription acid neutralizing agents for 1-3 years was associated with increased risk of esophageal adenocarcinoma (adjusted OR, 3.16; 95% CI, 1.39-7.20) after adjusting for prescription acid suppressive drug use and other confounding factors (Table 2). Among those who took non-prescription acid neutralizing agents for more than three years, the OR for esophageal adenocarcinoma increased to 6.32 (95% CI, 3.14-12.69, P trend <0.01). With duration of non-prescription acid neutralizing agent use in the statistical model, use of prescription acid suppressive drugs was unrelated to risk of esophageal adenocarcinoma. No strong effects on risk of cardia or distal gastric adenocarcinomas was observed for duration of use of either prescription acid suppressive drugs or non-prescription acid neutralizing agents. Conversely, irregular use of non-prescription acid neutralizing agents was associated with lower risk of gastric cardia (adjusted OR, 0.47; 95% CI, 0.30-0.72) and distal 66 gastric adenocarcinomas (adjusted OR, 0.48; 95% CI, 0.34-0.68). Because prior diagnosis of UGI disorders was also strongly associated with increased risk of adenocarcinomas for esophagus and gastric cardia (Wu, Tseng et al. 2003; Duan, Ma et al. 2008), and because presence of UGI disorders might influence frequency of antacid drug use, we conducted analyses separately among participants with and without a history of physician diagnosed UGI disorders (Table 3). After stratification of UGI disorders, we observed a modest difference in the dose response effects for non-prescription drug use between persons with UGI disorders and those without UGI disorders (p for homogeneity of trends = 0.07) although both trends for duration of use were statistically significant ((P trend <0.01). The increase in esophageal adenocarcinoma risk among long-term (> 3 year) users of non-prescription acid neutralizing agents was limited to participants without a history of physician diagnosed UGI disorders (adjusted OR, 10.89; 95% CI, 4.73-25.05). Although the adjusted ORs for 1-3 years and > 3 years of non-prescription antacid use among participants with a positive history of physician diagnosed UGI disorders were also greater than 1, the confidence intervals were wide and did not exclude 1.0 (adjusted OR, 2.01; 95% CI, 0.35-11.40 and adjusted OR, 3.19; 95% CI, 0.62-16.48 ). No significant increases in risk or dose-response effects were observed for adenocarcinomas of the gastric cardia or distal stomach. Irregular use of non-prescription acid neutralizing agents was associated with reduced OR for gastric cardia and gastric distal adenocarcinomas, but only for persons who had no history of physician diagnosed UGI disorders. Comparing non-users to 67 regular users, no heterogeneity in trend was observed across the UGI status at either cancer site. Because of the observation that gastric cardia and distal stomach adenocarcinoma risks were lower among irregular users of non-prescription acid neutralizing agents, we evaluated risk at these sites associated with the number of different non-prescription acid neutralizing agents that had been reported to have been used irregularly. The results show that the decrease in risk observed among irregular users is relative constant across increasing number of different acid neutralizing agents used irregularly (Table 4). All of the results presented in the current study exclude exposures that were initiated during the 1 year interval before each participant’s reference date. We also evaluated exposure using a longer lag time, excluding drugs that were first used 2 years before the reference date (3 years before diagnosis for a case) and 5 years before the reference date. The results of the 1, 2 and 5 year lags did not differ in any meaningful way (Results for the 2 and 5 year lag times not shown). Similarly, restricting the analyses to self-reported data only, that is, excluding data collected through next-of-kin interviews, did not differ from those presented which used all participant data although among those who participated in the interview directly, the odds ratios increased slightly when next-of-kin interviews were excluded (data not shown). 68 Discussion In this large population-based case-control study, risk of esophageal adenocarcinoma increased with increasing duration of regular use of OTC acid neutralizing agents, but not with increasing duration of regular use of prescription acid suppressive drugs. No association with either type of drug was observed for adenocarcinomas of the gastric cardia or distal stomach. The substantially lower risks of gastric cardia and distal gastric adenocarcinomas observed among persons who used acid neutralizing agents irregularly was not explained by the number of such drugs that they used irregularly. The statistically significant trends in risk observed in Table 4 reflect the marked decrease that occurs with use of one drug relative to no use. Our findings of increased esophageal adenocarcinoma risk among regular users of non-prescription acid neutralizing agents and reduced risk of adenocarcinomas of the gastric cardia and distal stomach among irregular users of OTC acid neutralizing agents were restricted to persons who did not report any physician diagnosed UGI disorders. None of the tests for homogeneity of trends in duration of regular use comparing those with and without UGI disorders were statistically significant; these analyses excluded persons with irregular use. We did not observe that persons with UGI disorders had greater risk of esophageal adenocarcinoma with increasing duration of risk, which would have suggested that our observed association reflected confounding by indication. Nevertheless, it is possible that persons who did not have a physician diagnosed UGI disorder were taking non-prescription acid neutralizing agents for various 69 UGI symptoms. In the absence of acid neutralization or acid suppression, the degree of esophageal damage has been found to correlate with the degree of esophageal acid exposure through gastro-esophageal reflux (GERD) with esophageal 24-hour pH monitoring in humans (Robertson, Aldersley et al. 1987; Neumann and Cooper 1994). However, gastric acid is not the only substances that refluxes from the stomach into the esophagus. Animal studies have suggested that exposure to bile acid, a major component of duodenal juice which originates in duodenum and may reflux into the esophagus through duodenogastro-esophageal reflux (DGER), increase the risk of esophageal adenocarcinoma (Attwood, Smyrk et al. 1992; Ireland, Peters et al. 1996; Fein, Peters et al. 1998). In a rat model, duodenal juice refluxed into esophagus though DGER induced histological changes, from squamous-cell epithelium into columnar-cell epithelium, in the lining of the distal esophagus (Fein, Peters et al. 1998). Moreover, another animal study showed that the prevalence of esophageal adenocarcinoma increased as the amount of acid gastric juice that was permitted to reflux with duodenal juice into the esophagus decreased (Ireland, Peters et al. 1996), indicating that acid suppression therapy may be detrimental by encouraging esophageal metaplasia and tumorigenesis in subjects with DGER reflux. In humans, it has been shown that the degree of esophageal damage increases with increasing amount of DGER , with the highest DGER levels found in patients with Barrett’s esophagus (Todd, de Caestecker et al. 2003). With 24 hour ambulatory esophageal pH and bilirubin and gastric pH monitoring, 70 Marshall et al. have observed that most DGER takes place at night when the pH is between 4 and 7 (Marshall, Anggiansah et al. 1998). Based on previous laboratory findings, Todd et al. concluded that at pHs of 6 or greater, deconjugated bile acids, if refluxed into the esophagus, cause not only short-term damage to the esophageal mucosa, but also long-term damage to the cellular DNA (Todd, de Caestecker et al. 2003). Although acid suppressive drugs in the form of H2-receptor antagonists or PPIs allow symptom relief and promote endoscopic mucosa healing in GERD patients, they do not guarantee normalization of pH level at the gastro-esophageal junction nor do they prevent GERD or DGER (Chandrasoma and Demeester 2006). There is some disagreement about how well OTC acid neutralizing agents work in changing gastric pH. On the one hand, OTC acid neutralizing agents are believed to cause an immediate short-termincrease in the pH, which differs from the the long-lasting and profound effect of H2-receptor antagonists. On the other hand, OTC acid neutralizing agents are taken at the time of maximum symptoms when reflux is probably most intense in the patients, and OTC drugs may be taken at relatively large doses to provide the most rapid relief (Fordtran and Collyns 1966; Fordtran, Morawski et al. 1973), causing the gastric pH during to temporarily increase to levels that are much higher than those produced by H2-receptor antagonists (Engelhardt, Karl et al. 1985). According to the first postulate, the observed increase in risk of esophageal adenocarcinoma among regular users of long-term OTC acid neutralizing agents rather than H2-receptor antagonist users in this study would be explained by the fact that OTC acid 71 neutralizing agents provide less successful acid suppression than H2-receptor antagonists. Alternatively, if the second hypothesis is true, the observed association suggests that OTC acid neutralizing agents create a more alkaline condition in the stomach than H2-receptor antagonists at the time of maximum symptoms and reflux, and therefore more bile reflux may reach the distal esophagus. As we discussed above, the direct contact of alkaline duodenal bile that enters the lower esophagus can cause cell turnover and is potentially carcinogenic (Stamp 2006); further, it may promote progression of Barrett’s esophagus (Stein, Kauer et al. 1998; Chandrasoma and Demeester 2006). Although a number of epidemiological studies have investigated the possible positive association between the use of H 2 -receptor antagonists and the risk of gastric adenocarcinomas (Moller, Lindvig et al. 1989; La Vecchia, Negri et al. 1990; Moller, Nissen et al. 1992; Johnson, Jick et al. 1996; Farrow, Vaughan et al. 2000; Rodriguez, Lagergren et al. 2006), there has been limited research on whether the risk of esophageal adenocarcinoma is increased among users of H 2 -receptor antagonists or other antacids. In a recent case-control study, which was nested within a large prospective study in the UK, H2-recepor antagonist and PPI users were both at increased risk of esophageal adenocarcinoma; the association was limited to long-term current users of H2-recepor antagonist in the multivariable analysis that included GERD, hiatal hernia, peptic ulcer and dyspepsia (Rodriguez, Lagergren et al. 2006). This study was, however, based on a small number of cases and did not consider the use OTC acid neutralizing agents or acid suppressive drugs that were available 72 without prescription during their study period. In Sweden, Lagergren et al. reported a nearly 3-fold higher risk of esophageal adenocarcinoma among persons who used medications for reflux symptoms at least 5 years prior to study than among those who took no medication (Lagergren, Bergstrom et al. 1999). In a United States study, Chow et al. observed a fourfold higher risk of adenocarcinomas of the esophagus and gastric cardia in individuals who had four or more prescriptions for H 2 -receptor antagonists, but the association disappeared after adjusting for the predisposing conditions (Chow, Finkle et al. 1995). One of the drawbacks of that study, as well as many other earlier studies (Colin-Jones, Langman et al. 1991; Suleiman, Harrison et al. 2000), is that it did not separate esophageal adenocarcinomas from adenocarcinomas of the gastric cardia. Farrow and her colleagues investigated the separate associations between antacid use and adenocarcinomas of the esophagus, gastric cardia and distal stomach (Farrow, Vaughan et al. 2000). In this study, long-term use of OTC antacids was associated with increased risk of esophageal adenocarcinoma, but no statistically significant risk increase was observed for H2-blocker users, which is consistent with the results we report here. Our study represents one of the only two large population-based epidemiologic studies within U.S. that has been designed specifically to investigate further the etiologies of these tumor types. One strength of this study is the definition of the reference group. Instead of combining never users with irregular users as many other studies have done, our reference group is comprised of persons who have never used the antacids of interests. In addition, rather than simply 73 adjusting for GERD and other UGI symptoms in the analyses as most of other studies have done, we evaluated the risk estimates for antacid use separately among participants with and without a history of physician diagnosed UGI disorders. Further, our study allows comparison of risk estimates between OTC acid neutralizing agents and acid suppressive drugs; the former group has been rarely studied separately. Of interest is the reduced risk of distal gastric adenocarcinoma in individuals who irregularly used OTC acid neutralizing agents. After carefully studying the reported OTC acid neutralizing agents in this group used irregularly, we noticed that one of the most frequently used OTC acid neutralizing agents was Pepto-Bismol, which is used to protect the stomach lining from acid, but also kills H. pylori . Our analyses comparing irregular users of Pepto-Bismol to persons with no OTC antacid use found a reduction in risk of distal gastric cancer that was similar to that observed for other OTC antacid preparations. Limitations of this study include the recall bias, a modest response rate and the potential for less accurate reporting of exposures by next-of-kin; these have been described elsewhere (Duan, Ma et al. 2008). Next-of-kin interviews accounted for 29% of the patient reports in this study. Our results did not appear to be affected by next-of-kin interviews and were similar when next-of-kin were excluded from the analyses. Because of the strict criteria for reference group, the number of never users in this study was not substantial; in fact, we only had two patients with esophageal adenocarcinoma who had a history of UGI disorders 74 but never use any antacids. This limited the statistical power in our stratified analyses. In addition, we have few participants who reported use of PPI since the study was conducted before widespread use of these drugs. This limited our ability to evaluate these drugs. Further research is required to full assess the impact of H2-receptor antagonists and PPIs, which are now available as OTC drugs and to define the mechanisms by which the common OTC drugs used by our participants affect risk of esophageal adenocarcinoma. In summary, this study observed increases in risk of esophageal adenocarcinoma in persons who used non-prescription acid neutralizing agents regularly. This may be due to confounding by indication with the conditions for which these drugs are used etiologically related to disease risk, or the increase in risk associated with OTC drugs may be the result of alkaline reflux, resulting from the acid neutralization, entering the esophagus. 75 Table 3.1. Demographic characteristics of esophageal and gastric adenocarcinoma case patients and control subjects, Los Angeles County. Control Esophageal Gastric Cardia Gastric Distal (N=1356) (N=220) (N=277) (N=441) 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) UGI disease history * Yes 376 (27.33) 104 (47.27) 118 (42.60) 157 (35.60) No 976 (71.98) 111 (50.45) 154 (55.60) 267 (60.54) Self-report UGI symptoms * Yes 546 (40.27) 151 (68.64) 168 (60.65) 204 (46.26) No 316 (23.30) 35 (15.91) 77 (27.80) 147 (33.33) NSAID use Never use 160 (11.80) 36 (16.44) 50 (18.18) 145 (33.03) No regular use 767 (56.56) 119 (54.34) 126 (45.82) 208 (47.38) < 5 years 219 (16.15) 38 (17.35) 55 (20.00) 52 (11.85) > 5 years 210 (15.49) 26 (11.87) 44 (16.00) 34 (7.74) Note: * Percentage of missing data not shown. 75 76 Table 3.2. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) for duration of ANTACID USE in relation to esophageal, gastric cardia and distal gastric adenocarcinomas. Control Adenocarcinoma of esophagus Adenocarcinoma of gastric cardia Adenocarcinoma of distal stomach n n OR (95%CI) n OR (95%CI) n OR (95%CI) Never Use 130 12 1.0 - 39 1.0 - 82 1.0 - Non-prescription Use Irregular use 893 69 0.89 (0.47-1.71) 116 0.47 (0.30-0.72) 213 0.48 (0.34-0.68) < 1 year 80 11 1.48 (0.59-3.73) 21 0.82 (0.42-1.59) 32 0.62 (0.34-1.12) 1 - < 3 year 77 20 3.16 (1.39-7.2) 19 0.82 (0.41-1.61) 32 0.78 (0.45-1.37) >3 year 163 103 6.32 (3.14-12.69) 78 1.28 (0.76-2.18) 59 0.71 (0.43-1.18) p-trend < 0.01 0..07 0.61 Prescription Use Irregular use 54 14 1.24 (0.6-2.58) 12 0.74 (0.36-1.51) 14 0.89 (0.44-1.79) < 1 year 49 9 0.77 (0.34-1.75) 10 0.65 (0.31-1.37) 27 1.75 (1.00-3.08) 1 - < 3 year 44 20 1.72 (0.88-3.35) 11 0.70 (0.32-1.49) 28 1.76 (0.99-3.13) >3 year 45 21 1.27 (0.65-2.51) 23 1.29 (0.70-2.36) 16 1.15 (0.58-2.29) p-trend 0.17 0.18 0.17 Model includes both non-prescription and prescription antacid use and, additionally, is adjusted for age, gender, race, BMI, smoke and history of upper gastrointestinal disorders. 76 77 Table 3.3. ORs for OTC acid neutralizing agent use in relation to Esophageal, Gastric Cardia and Distal Gastric Adenocarcinomas, by upper gastrointestinal tract disorders. Esophageal UGI - UGI + Exposure case/ control OR (95%CI) case/ control OR (95%CI) Never used 11/127 1.0 - 2/12 1.0 - Irregular used 50/737 0.84 (0.41-1.74) 17/154 0.76 (0.14-4.06) < 1 year 3/34 1.11 (0.27-4.52) 8/46 1.19 (0.19-7.26) 1 - < 3 year 7/29 2.09 (0.64-6.83) 13/48 2.01 (0.35-11.4) >3 year 40/48 10.89 (4.73-25.05) 60/114 3.19 (0.62-16.48) p-trend < 0.01 < 0.01 P for heterogeneity 0.07 77 78 Table 3.3., continued. Cardia Distal UGI - UGI + UGI - UGI + case/ control OR (95%CI) case/ control OR (95%CI) case/ control OR (95%CI) case/ control OR (95%CI) 35/127 1.0 - 4/12 1.0 - 75/127 1.0 - 11/12 1.0 - 81/737 0.41 (0.26-0.66) 34/154 0.91 (0.22-3.82) 145/737 0.47 (0.33-0.69) 62/154 0.52 (0.18-1.53) 4/34 0.45 (0.14-1.40) 16/46 1.52 (0.33-6.92) 8/24 0.55 (0.22-1.37) 22/46 0.73 (0.22-2.38) 10/29 1.27 (0.54-2.99) 9/48 0.71 (0.14-3.55) 15/29 1.49 (0.70-3.18) 17/48 0.52 (0.16-1.71) 24/48 1.61(0.82-3.18) 54/114 1.60(0.38-6.71) 14/48 1.09 (0.51-2.36) 42/114 0.59 (0.20-1.79) 0.08 0.30 0.65 0.38 0.82 0.33 1.UGI=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 disease of stomach). 2. Model adjusted for age, gender, race, BMI, smoke, NSAID use, and prescription acid suppressive drug use. 78 79 Table 3.4. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) for number of different ANTACID USE in relation to Esophageal, Gastric Cardia and Distal Gastric Adenocarcinomas among irregular users. Control Adenocarcinoma of esophagus Adenocarcinoma of gastric cardia Adenocarcinoma of distal stomach # of different ANTACIDs n n OR (95%CI) n OR (95%CI) n OR (95%CI) Never user 130 12 1.0 - 39 1.0 - 82 1.0 - 1-2 334 25 0.79 (0.37-1.66) 44 0.43 (0.26-0.70) 88 0.47 (0.31-0.70) 3-4 235 20 0.89 (0.40-1.97) 27 0.31 (0.18-0.56) 52 0.48 (0.31-0.76) > 5 267 18 0.58 (0.25-1.33) 38 0.40 (0.23-0.68) 39 0.33 (0.20-0.54) p-trend 0.25 <0.01 <0.01 Model adjusted for age, gender, race, BMI, smoke, history of upper gastrointestinal disorders, and NSAID use. 79 80 Chapter 4: Passive Smoking and Risk of Esophageal and Gastric Adenocarcinomas Introduction Numerous epidemiologic studies have established that tobacco smoking is etiologically related to the development of esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (IARC 2002). In most studies, the risk for both types of esophageal cancer increases with increasing duration of smoking, and remains high for a number of years after smoking cessation (Gammon, Schoenberg et al. 1997). The literature on smoking and stomach cancer shows a less consistent association with cigarette smoking in both men and women (IARC 2002; Freedman, Abnet et al. 2007; Ladeiras-Lopes, Pereira et al. 2008). While much attention has focused on the association between active smoking and cancer risk, with the exception of lung cancer, less attention has been paid to the association between passive smoking and cancer risk (Sandler, Sandler et al. 1988; Sandler, Comstock et al. 1989; Nishino, Tsubono et al. 2001; Hanaoka, Yamamoto et al. 2005). A few studies have investigated the risk of gastric cancers in relation to passive smoking (Hirayama 1984; Jee, Ohrr et al. 1999; Nishino, Tsubono et al. 2001; Mao, Hu et al. 2002), but none have been published on the association with esophageal adenocarcinoma. In this population based case-control study, we investigated the relationship between passive smoking and the risk esophageal and gastric adenocarcinomas in Los Angeles County. This study is the first to address this issue in a US 81 population. Methods Study population. The details of the study population and study design have been described elsewhere (Wu, Wan et al. 2001; Wu, Crabtree et al. 2003; Wu, Tseng et al. 2003; Wu, Fu et al. 2005; Wu, Tseng et al. 2007; Duan, Ma et al. 2008). Incident cancer cases for this study were identified by the USC Cancer Surveillance Program (CSP). This cancer registry covers the ethnically diverse Los Angeles County population of more than 9.5 million people. Case patients who were newly diagnosed with first incident esophageal adenocarcinoma (International Classification of Disease for Oncology, ICDO, code C15.0-C15.9), gastric cardia adenocarcinoma (ICDO code C16.0) or distal gastric adenocarcinoma (ICDO codes C16.1-C16.6 and C16.8-C16.9) between 1992 and 1997 were identified and contacted for participation. Control subjects were matched individually to each case patient on sex, race, age ( + 5 years), and neighborhood of residence. To increase the statistical power, we sought two control subjects for each case patient whenever possible. An experienced interviewer conducted the in-person interview at the interviewees’ homes or other convenient locations. Next-of-kin were interviewed when case patients were unable to be interviewed due to death or illness. Although it was not feasible to blind the interviewers to case (or next-of-kin) or control status, interviewers and study participants were not aware of the study hypotheses. Written informed consent was obtained from each study participant before interview. 82 We identified 1716 eligible patients (429 esophageal adenocarcinomas (EA)/500 ardenocarcinomas of the gastric cardia (GCA) / 787 distal gastric adenocarcinomas (DGA); numbers for the three tumor sites are shown separated by slashes in the description below). However, we were unable to obtain interviews for 769 patients: 315 (92 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 EA/37 GCA /84 DGA) 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 passive smoking history was incomplete. A total of 938 (220 EA/277 GCA /441 DGA) cases patients and 1356 control subjects are included in the analyses presented. Age, sex, and race distributions did not differ between the case patients we interviewed and those we were unable to interview. Next-of-kin interviews accounted for 269 of the 938 interviews with case patients (65EA/85GCA/119DGA). Measure. Questions on active tobacco use have been described previously (Wu, Wan et al. 2001). We collected information on lifetime passive cigarette smoking, including duration of exposure in each residence (as child or adult), work place, or public place on a regular basis; and intensity of exposure (number 83 of smokers, including spouse, parents, siblings, relatives, coworkers, etc). With regard to passive smoking during childhood, the participants were asked whether anyone smoked in their presence for at least a year when they were growing up (including parents and other relatives). If the answer was “yes”, the participants were asked what tobacco product (cigarette, cigar, or pipe) the smoker smoked. We also obtained data on the number of years the subject was exposed to each smoker. Similar questions were asked for adulthood passive smoking exposures. In addition to smoking in the home, we queried regular exposures (at least 2 hours per week) at work or in restaurants, airports, or subways, etc. by decade of age at exposure from age 20 to age 70 years. Statistical Analysis. Active smoking (ex-smoker and current smoker) and passive smoking and their association with risk of esophageal and gastric adenocarcinomas were investigated together. Individuals who never actively smoked were categorized into 3 groups, never exposed to passive smoking, only exposed to passive smoking during childhood, exposed to passive smoking during adulthood (may have had exposure as a child). Non-smokers with no passive smoking exposure in childhood or adulthood were the reference group. We obtained the odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression by gender and cancer site, which allowed us to adjust for different confounders for the different cancer sites. Duration and intensity of household passive smoking exposure was examined among non-active smoking individuals only. Total years of exposure to 84 parents’ smoking in childhood were obtained by summing together the years of exposure to mother smoking and father smoking. Some participants lived with their parents through their adulthood ( > 20 years); we used 20 years as the maximum exposure years in childhood to a mother or a father who smoked. The remaining years of exposure to parents smoking were included in the duration of passive smoking exposure during adulthood. Similarly, total years of exposure to spouse smoking were obtained by summing the years of exposure across spouses. The duration of exposure to parents and spouse smoking were then categorized as < 15 years and > years, separately. For validity purposes, we repeated all statistical analyses excluding data collected from next of kin respondents. Risk estimates were not materially different from the results based on all subjects combined (i.e., self-respondents and next of kin respondents). Results The mean ages of study participants were 62.2 years (standard deviation (SD) =9.2) for patients with esophageal adenocarcinoma, 58.7 years (SD=12.9) for patients with adenocarcinoma of the gastric cardia, and 58.0 years (SD=12.5) for patients with distal gastric adenocarcinoma; control subjects were, on average, 57.0 years (SD=12.5) at their diagnosis. Among control subjects, 60.3% were male, compared with 81.4% of patients with esophageal adenocarcinoma, 63.4% of patients with gastric cardia adenocarcinoma, and 37.4% of the distal gastric cancer patients. Non-Latino Whites represented 72.1% of those with 85 esophageal adenocarcinoma, 63.4% of those with gastric cardia adenocarcinoma, and 24.1% of those with distal gastric adenocarcinoma. Patients with esophageal or gastric cardia adenocarcinomas tended to have greater BMI than controls. Among all of the 2294 participants, 769 never smoked any cigarette or other tobacco, 1050 were ex-smokers and 475 were current smokers. Tables 2 and 3 present the adjusted ORs and 95% CIs for active and passive smoking history in relation to the risk of esophageal, gastric cardia, and distal gastric adenocarcinomas, among males and females, separately. Among men, current smokers were at increased risk for esophageal adenocarcinoma relative to non smokers with no passive smoke exposure (adjusted OR, 4.40; 95% CI, 1.81-10.67) and at increased risk of gastric cardia adenocarcinoma (adjusted OR, 2.74; 95% CI 1.37-5.48). Passive smoke exposure was associated with increased risk for esophageal adenocarcinoma among men, however, the increase in risk was not statistically significant (adjusted OR, 2.05; 95% CI, 0.77-5.49). Being exposed to passive smoking either during childhood or adulthood had no impact on risk of adenocarcinoma at gastric cardia or distal stomach among males (Table 2). No significant associations were observed among females (Table 3). We observed a statistically significant association between exposure to spousal smoking during adulthood and the risks of adenocarcinoma of the esophagus (adjusted OR, 2.56; 95% CI, 1.11-5.92) and gastric cardia (adjusted OR, 2.15; 95% CI, 1.03-4.49) among men who were non-smokers in analyses that adjusted for exposure to parents smoking during childhood (Table 4). Duration of 86 exposure to spousal smoking in adulthood that was no more than 15 years was statisticially significantly elevated for esophageal adenocarcinoma (adjusted OR, 3.31; 95% CI, 1.27-8.66). However, longer duration of exposure (> 15 years) was not associated with an increase in the risk of esophageal adenocarcinoma (adjusted OR, 1.56; 95% CI, 0.45-5.45). No other associations were observed. No statistically significant associations between duration of exposure and cancer risks were observed among non-smoking females (data not shown). Discussion We find no strong evidence that exposure of persons who have never actively smoked to passive smoke during their childhood years or during their adult years strongly influences their risk of adenocarcinomas of the esophagus, gastric cardia or distal stomach. We find an elevated risk for one duration (< 15 years) of adult exposure but no dose response effect. Substantial evidence in various parts of the world indicates that direct cigarette smoking plays an important role in the development of esophageal and gastric cancers (Mizoue, Tokui et al. 2000; IARC 2002; Nishino, Inoue et al. 2006). A recent cohort study in the US found that, relative to never smokers, current smokers were at increased risk of esophageal squamous cell carcinoma (SCC) with a hazard ratio of 9.27, which is almost 3-fold greater than the risk for esophageal adenocarcinoma (Freedman, Abnet et al. 2007). Laboratory studies provide some potential mechanisms for these associations. One possible link is 87 that the contents of cigarette smoke may form DNA adduct and induce mutations in tumor suppressor genes (Levitz, Bradley et al. 2004). Tobacco smoking may also increase the risk of esophageal adenocarcinoma by promoting reflux disease via reducing the pressure of lower esophageal sphincter and decreasing secretion of saliva (Dua, Bardan et al. 1998; Pandolfino and Kahrilas 2000; Dua, Bardan et al. 2002; Cockburn, Wu et al. 2005). In addition, among various carcinogens in tobacco smoke, N-nitroso compounds can damage the esophagus and gastric mucosa (Bernstein; Preston-Martin). Using this study population, we previously published that current cigarette smokers were at increased risk for esophageal, gastric cardia and distal gastric adenocarcinomas, and that the deleterious effect on the esophagus remained even 20 years after smoking cessation (Wu, Wan et al. 2001). In these previous analyses, the reference group included never smokers with passive smoke exposure at some time in their lives. Only a few studies have examined the association between passive smoking and the risk of gastric adenocarcinoma (Hirayama 1984; Jee, Ohrr et al. 1999; Nishino, Tsubono et al. 2001; Mao, Hu et al. 2002). In a Japanese cohort study, cancer mortality rates in a group of non-smoking wives were compared according to whether their husbands were smokers (Hirayama 1984). After 16 years follow-up, the investigators observed elevated risks of lung cancer in women whose husbands smoked. Although similar risk escalations were also observed for nasal sinus cancer, brain tumors, and cancer overall, none of these associations were statistically significant. No associations were noted 88 specifically for esophageal or gastric cancer (Hirayama 1984). More recently, Nishino et al. investigated whether passive smoking at home affected the cancer incidence of nonsmoking Japanese women by linking the cohort data with cancer registry after 9 years follow-up. Their results indicated that nonsmoking women with a husband who smoked were not at higher risk of gastric cancer than those with a nonsmoking husband (Nishino, Tsubono et al. 2001). However, a limitation of this study is that household members’ smoking status was collected at only one time point (at baseline). A Canadian population-based case-control study of stomach cancer has evaluated the relationship between both active smoking and passive smoking with the risk of gastric cardia cancer and distal gastric cancer, separately (Mao, Hu et al. 2002). In addition to a complete personal smoking history, the researchers collected data on duration of exposure (exposure year), intensity of exposure (number of regular smokers living in the subject’s home) and source of exposure (household or workplace) of lifetime passive smoking among the participants. Their findings suggest a dose-response effect between gastric cardia cancer and exposure to smoke, both actively and passively (Mao, Hu et al. 2002). Our results for passive smoke exposure among never smokers are essentially negative. Our study is limited by the small number of never smokers particularly among female cases. Future research with a larger sample size and more precise exposure estimates is needed for further investigations on the relationship between passive smoking and esophageal and gastric adenocarcinomas. 89 Table 4.1. Demographic characteristics of nonsmoking esophageal and gastric adenocarcinoma case patients and control subjects, Los Angeles County. Control Adenocarcinoma of Esophagus Adenocarcinoma of Gastric Cardia Adenocarcinoma of Distal Gastric (N=1356) (N=220) (N=277) (N=411) Age <60 637 (47.0) 79 (35.9) 109 (39.4) 170 (38.6) >60 719 (53.0) 141 (64.1) 168 (60.6) 271 (61.4) Sex Male 999 (73.7) 200 (90.9) 231 (83.4) 181 (59.0) Female 357 (26.3) 20 (9.1) 46 (16.6) 357 (41.0) Race Non-hispanic White 841 (62.0) 171 (77.7) 210 (75.8) 133 (30.2) Other 515 (38.0) 49 (22.3) 67 (24.2) 308 (69.8) BMI at reference age Normal ( <25 kg/m 2 ) 558 (41.2) 66 (30.0) 88 (31.8) 189 (46.0) Overweight ( 25-29.9 kg/m 2 ) 555 (41.0) 91 (41.4) 110 (39.7) 126 (30.7) Obese ( >30 kg/m 2 ) 218 (16.1) 55 (25.0) 68 (24.5) 78 (19.0) Smoking status* Never smoker 481 (35.5) 43 (19.6) 71 (25.6) 174 (39.5) Ex-smoker 639 (47.1) 107 (48.6) 127 (45.9) 177 (40.1) Current smoker 236 (17.4) 70 (31.8) 79 (28.5) 90 (20.4) Note: * Includes cigarette, cigar and pipe smoking. 89 90 Table 4.2. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for active and passive smoking history by cancer site among males, Los Angeles County. Adenocarcinoma of Esophagus Adenocarcinoma of Gastric Cardia Adenocarcinoma of Distal Gastric Exposure Control N OR* (95% CI) n OR* (95% CI) n OR* (95% CI) Never smoked, no passive smoke exposure 83 9 -1- 11 -1- 21 -1- Never smoked, passive smoke exposure in childhood only 96 5 0.63 ( 0.18 - 2.16 ) 14 1.00 ( 0.43 - 2.36 ) 11 0.56 ( 0.24 - 1.32 ) Never smoked, any adult expose to passive smoke 98 17 2.05 ( 0.77 - 5.49 ) 18 1.05 ( 0.46 - 2.43 ) 22 0.99 ( 0.47 - 2.08 ) Ex-smoker 521 100 2.11 ( 0.89 – 5.00 ) 114 1.37 ( 0.70 - 2.67 ) 131 1.13 ( 0.64 - 1.99 ) Current-smoker 188 65 4.4 ( 1.81 - 10.67 ) 72 2.74 ( 1.37 - 5.48 ) 64 1.57 ( 0.85 - 2.89 ) Notes: ORs from logistic regression model, adjusted for age, BMI at reference age, and ethnicity (others vs. non-Hispanic white). Table 4.3. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for active and passive smoking history by cancer site among females, Los Angeles County. Adenocarcinoma of Esophagus Adenocarcinoma of Gastric Cardia Adenocarcinoma of Distal Gastric Exposure Control n OR* (95% CI) n OR* (95% CI) n OR** (95% CI) Never smoked, no passive smoke exposure 39 3 -1- 6 -1- 18 -1- Never smoked, passive smoke exposure in childhood only 35 0 - 4 0.76 ( 0.20 - 2.92 ) 19 1.31 ( 0.55 - 3.15 ) Never smoked, any adult expose to passive smoke 109 5 0.55 ( 0.12 - 2.44 ) 14 0.79 ( 0.28 - 2.21 ) 63 1.38 ( 0.68 - 2.81 ) Ex-smoker 118 7 0.70 ( 0.17 - 2.89 ) 13 0.66 ( 0.23 - 1.87 ) 46 1.05 ( 0.51 - 2.19 ) Current-smoker 48 5 1.47 ( 0.32 - 6.69 ) 7 0.97 ( 0.3 - 3.13 ) 26 1.73 ( 0.76 - 3.90 ) Notes: ORs from logistic regression models. * Adjusted for age. **Adjusted for age, BMI at reference age, and ethnicity (others vs. non-Hispanic white). 90 91 Table 4.4. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for passive smoking history by cancer site among non-smoking males, Los Angeles County. Adenocarcinoma of Esophagus Adenocarcinoma of Gastric Cardia Adenocarcinoma of Distal Gastric Exposure Control n OR (95% CI) n OR (95% CI) n OR (95%CI ) Never regularly exposed to parents smoking during childhood 121 17 - 1.0 - 19 - 1.0 - 33 - 1.0 - Ever exposed (all duration) 167 16 0.55 ( 0.23 - 1.29 ) 23 0.79 ( 0.39 - 1.61 ) 22 0.62 ( 0.33 - 1.18 ) < 15 years 58 7 0.89 ( 0.30 - 2.63 ) 9 0.97 ( 0.39 - 2.42 ) 10 0.60 ( 0.26 - 1.39 ) > 15 years 109 9 0.42 ( 0.15 - 1.18 ) 13 0.62 ( 0.27 - 1.42 ) 12 0.56 ( 0.25 - 1.23 ) Never regularly exposed to spouse smoking during adulthood 231 20 - 1.0 - 30 - 1.0 - 55 - 1.0 - Ever exposed (all duration) 59 13 2.56 ( 1.11 - 5.92 ) 15 2.15 ( 1.03 - 4.49 ) 10 1.01 ( 0.45 - 2.27 ) < 15 years 34 9 3.31 ( 1.27 - 8.66 ) 9 1.85 ( 0.73 - 4.70 ) 5 0.87 ( 0.31 - 2.46 ) > 15 years 25 4 1.56 ( 0.45 - 5.45 ) 6 2.16 ( 0.77 - 6.10 ) 5 1.33 ( 0.41 - 4.32 ) Notes: ORs from logistic regression models, adjusted for age, BMI at reference age, and ethnicity (others vs. non-Hispanic white). 91 92 Chapter 5: Conclusions Esophageal adenocarcinoma is a highly deadly cancer. Although some of the known risk factors might contribute to the increasing incidence of esophageal adenocarcinoma, the explanation that can entirely explain the striking trend remains to be identified (Lagergren 2006). These three studies discussed the etiology clues for esophageal and gastric adenocarcinomas among residences of Los Angeles County from different angles. The first study, in consistent with literatures, found that 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. Moreover, rather than using no regular NSAID users as the reference group as in most previous studies, we further investigated the association using never users as the reference group. With this approach, we observed strengthened relationships, and also uncovered lower risks among individuals who were in the irregular user category. In addition, risk of gastric cardia adenocarcinomas was significantly reduced in the analysis using non users as the reference group. A history of UGI disorders did not modify these effects as none of the tests for homogeneity of trends was statistically significant. In the second study, we found that risk of esophageal adenocarcinoma increased with increasing duration of regular use of OTC acid neutralizing agents, but not 93 with increasing duration of regular use of prescription acid suppressive drugs. Our findings of increased esophageal adenocarcinoma risk among regular users of non-prescription acid neutralizing agents and reduced risk of adenocarcinomas of the gastric cardia and distal stomach among irregular users of OTC acid neutralizing agents were restricted to persons who did not report any physician diagnosed UGI disorders. None of the tests for homogeneity of trends in duration of regular use comparing those with and without UGI disorders were statistically significant. The association of adenocarcinomas of the esophagus with non-prescription acid neutralizing drugs, but not with prescription acid suppression drugs suggests that confounding by indication may account for the observed relationship. That the impact is greater among long-term users without physician diagnosed UGI conditions than among those with these conditions may represent self medication for undiagnosed precursor conditions; alternatively, it may be that non-prescription acid neutralizing drugs, taken without limitation on amount used when symptoms are the most intense, may impact the acid profile more than prescription acid suppression drugs or may permit alkaline bile acid to reflux into the lower esophagus, thereby increasing the risk of esophageal adenocarcinomas. Besides using never users as the reference group, another advantage of this study is that, it evaluated OTC acid neutralizing agent and acid suppressive drugs separately. The OTC acid neutralizing agent and acid suppressive drug work differently in changing the gastric pH level. Examining OTC acid neutralizing agent and acid suppressive drugs separately shed light on the possibility that reflux occurs at certain pH range may cause the carcinogenesis of the esophagus. 94 The third study investigated the possible impact of passive smoking on those cancers from a behavioral perspective. This study is the first to address this issue in a US population. Our results for passive smoke exposure among never smokers are essentially negative. This study is limited by the small number of never smokers particularly among female cases. Future research with a larger sample size and more precise exposure estimates is needed for further investigations on the relationship between passive smoking and esophageal and gastric adenocarcinomas. A similarity with study 1 and study 2 is that, though we did not observe the effect among those who we considered regular users, we found irregular users of NSAIDs or acid neutralizing agents were at reduced risk of esophageal or gastric adenocarcinomas, which is a phenomenon we are unable to explain. This similarity may suggest some underlying common characters among those irregular users may play a role in the development of these UGI cancers. Several limitations to these studies must be noted. First, our overall response rate in this case-control study 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). Second, next-of-kin interviews accounted for 29% of the patient reports in this study. One would expect less complete reporting of medication use or other exposures by NOK. Although results based on self or NOK reports are not significantly different in the other studies 95 published to date(Wu, Wan et al. 2001; Wu, Tseng et al. 2003; Wu, Tseng et al. 2007), we conducted all analyses for these three studies with and without cases represented by NOK. Third, for measures of medication use, we have to rely on the self-report data, it is difficult to validate the use of over-the-counter medications and prescription medications as well. We did, however, ask extensive questions regarding each medication used regularly by asking about the starting and stopping dates, frequency of use and the name of the physician who prescribed the drug (for prescription medications). We did not ask about specific doses of the medications used but we recorded the frequency of use in pills per day, week, or month over each exposure time period whenever possible. For passive smoking histories, measurement recall bias is an unavoidable problem in personal interviews. Literatures on the reliability of measures for passive smoking histories suggested that respondents were more reliably reported residential exposure to spouse's passive smoke than to the passive smoke of others at home. Quantitative measures of exposure to passive smoke, i.e., number and duration of exposure, were even less reliably reported (Pron, Burch et al. 1988). Last, the number of regular users of NSAID or antacid drug or individuals that had exposure to passive smoking in this study was not substantial, which reduced the statistical power in our more detailed analyses that stratified by history of UGI symptoms or gender. The primary aim of this project was to understand how non-steroidal anti-inflammatory drugs, antacid drugs and passive smoking influence the risk of esophageal and gastric adenocarcinomas. The hope is that these three studies, 96 each with their own focus, provides valuable information to researchers interested in the etiology of these cancers. 97 References Abdalla, S. I., I. R. Sanderson, et al. (2005). "Effect of inflammation on cyclooxygenase (COX)-2 expression in benign and malignant oesophageal cells." Carcinogenesis 26(9): 1627-33. 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. Attwood, S. E., T. C. Smyrk, et al. (1992). "Duodenoesophageal reflux and the development of esophageal adenocarcinoma in rats." Surgery 111(5): 503-10. 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. Beresford, J., D. G. Colin-Jones, et al. (1998). "Postmarketing surveillance of the safety of cimetidine: 15-year mortality report." Pharmacoepidemiol Drug Saf 7(5): 319-22. Bernstein, L. "What are the epidemiologic similarities and differences between carcinomas arising in Barrett's mucosa and in the gastric cardia? In: R. Guili GJ, Jamieson GG, Scarpignato C, editor. Barrett's Esophagus. Amsterdam: Elsevier." Bernstein, L. (1999). Barrett's esophagus and adenocarcinoma: epidemiology. American Socienty of Clinical Oncology Education Book. M. Perry. Alexandria, ASCO: 99-105. Bernstein, L. (2003). What are the epidemiologic similarities and differences between carcinomas arising in Barrett's mucosa and in the gastric cardia? Barrett's Esophagus; Columnar Lined Esophagus. G. J. R. Guili, Jamieson GG, Scarpignato C. Montrouge, France, JohnLibbey Eurotext Ltd. 2: 702-710. Bosetti, C., S. Gallus, et al. (2002). "Aspirin and cancer risk: an update to 2001." Eur J Cancer Prev 11(6): 535-42. Buttar, N. S., K. K. Wang, et al. (2002). "The effect of selective cyclooxygenase-2 inhibition in Barrett's esophagus epithelium: an in vitro study." J Natl Cancer Inst 94(6): 422-9. Chandrasoma, P. T. and T. R. Demeester (2006). GERD Reflux to esophageal adenocarcinoma, Academic Press. 98 Chen, J. H., T. Y . Liu, et al. (2001). "Nonsteroidal anti-inflammatory drugs for treatment of advanced gastric cancer: cyclooxygenase-2 is involved in hepatocyte growth factor mediated tumor development and progression." Medical Hypotheses 57(4): 503-5. Cheng, K. K., L. Sharp, et al. (2000). "A case-control study of oesophageal adenocarcinoma in women: a preventable disease." Br J Cancer 83(1): 127-32. Chong, E. and M. H. H. Ensom (2003). "Pharmacogenetics of the Proton Pump Inhibitors: A Systematic Review." Pharmacotherapy 23(4): 460-471. Chow, W. H., W. D. Finkle, et al. (1995). "The relation of gastroesophageal reflux disease and its treatment to adenocarcinomas of the esophagus and gastric cardia." Jama 274(6): 474-7. Cockburn, M. G., A. H. Wu, et al. (2005). "Etiologic clues from the similarity of histology-specific trends in esophageal and lung cancers." Cancer Causes Control 16(9): 1065-74. Cohen, S. and H. P. Parkman (1999). "Heartburn--a serious symptom." N Engl J Med 340(11): 878-9. Colin-Jones, D. G., M. J. Langman, et al. (1991). "Post-cimetidine surveillance for up to ten years: incidence of carcinoma of the stomach and oesophagus." Q J Med 78(285): 13-9. 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. Corley, D. A., K. Kerlikowske, et al. (2003). "Protective association of aspirin/NSAIDs and esophageal cancer: a systematic review and meta-analysis." Gastroenterology 124(1): 47-56. Correa, P. (1992). "Human gastric carcinogenesis: a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention." Cancer Res 52(24): 6735-40. Dai, Y . and W. H. Wang (2006). "Non-steroidal anti-inflammatory drugs in prevention of gastric cancer." World J Gastroenterol 12(18): 2884-9. Dua, K., E. Bardan, et al. (1998). "Effect of chronic and acute cigarette smoking on the pharyngo-upper oesophageal sphincter contractile reflex and reflexive pharyngeal swallow." Gut 43(4): 537-41. Dua, K., E. Bardan, et al. (2002). "Effect of chronic and acute cigarette smoking on the pharyngoglottal closure reflex." Gut 51(6): 771-5. 99 Duan, L., H. Ma, et al. (2008). Histamine2-receptor Antagonists and Risk of Esophageal and Gastric Adenocarcinomas: A Meta-Analysis of Epidemiological Studies. Elder, J. B., P. C. Ganguli, et al. (1979). "Cimetidine and gastric cancer." Lancet 1(8124): 1005-6. Engelhardt, D., R. Karl, et al. (1985). "[Comparison between cimetidine-pirenzepine and antacids for the prevention of stress hemorrhage in intensive care patients. A controlled clinical study on 125 patients]." Dtsch Med Wochenschr 110(23): 908-14. 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. Farrow, D. C., T. L. Vaughan, et al. (2000). "Gastroesophageal reflux disease, use of H2 receptor antagonists, and risk of esophageal and gastric cancer." Cancer Causes & Control 11(3): 231-8. Fein, M., J. H. Peters, et al. (1998). "Duodenoesophageal reflux induces esophageal adenocarcinoma without exogenous carcinogen." J Gastrointest Surg 2(3): 260-8. Fordtran, J. S. and J. A. Collyns (1966). "Antacid pharmacology in duodenal ulcer. Effect of antacids on postcibal gastric acidity and peptic activity." N Engl J Med 274(17): 921-7. Fordtran, J. S., S. G. Morawski, et al. (1973). "In vivo and in vitro evaluation of liquid antacids." N Engl J Med 288(18): 923-8. Foster, A. B., M. Jarman, et al. (1980). "Structure and reactivity of nitrosocimetidine." Cancer Lett 9(1): 47-52. Freedman, N. D., C. C. Abnet, et al. (2007). "A prospective study of tobacco, alcohol, and the risk of esophageal and gastric cancer subtypes." Am J Epidemiol 165(12): 1424-33. Funkhouser, E. M. and G. B. Sharp (1995). "Aspirin and reduced risk of esophageal carcinoma." Cancer 76(7): 1116-9. Gammon, M. D., J. B. Schoenberg, et al. (1997). "Tobacco, alcohol, and socioeconomic status and adenocarcinomas of the esophagus and gastric cardia." J Natl Cancer Inst 89(17): 1277-84. 100 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. Gonzalez-Perez, A., L. A. Garcia Rodriguez, et al. (2003). "Effects of non-steroidal anti-inflammatory drugs on cancer sites other than the colon and rectum: a meta-analysis." BMC Cancer 3: 28. Graham, D. Y . (1989). "Campylobacter pylori and peptic ulcer disease." Gastroenterology 96(2 Pt 2 Suppl): 615-25. Hamoui, N., J. H. Peters, et al. (2004). "Increased acid exposure in patients with gastroesophageal reflux disease influences cyclooxygenase-2 gene expression in the squamous epithelium of the lower esophagus." Arch Surg 139(7): 712-6; discussion 716-7. Hanaoka, T., S. Yamamoto, et al. (2005). "Active and passive smoking and breast cancer risk in middle-aged Japanese women." Int J Cancer 114(2): 317-22. 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. Hetzel, D. J., J. Dent, et al. (1988). "Healing and relapse of severe peptic esophagitis after treatment with omeprazole." Gastroenterology 95(4): 903-12. Hirayama, T. (1984). "Cancer mortality in nonsmoking women with smoking husbands based on a large-scale cohort study in Japan." Prev Med 13(6): 680-90. 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. IARC (1994). World Health Organization, International Agency for Research on Cancer. IARC mongraphs on the evaluation of carcinogenic risks to humans: schistosomes, liver lukes, and Helicobacter pylori. Lyon. IARC (2002). "IARC Monographs on the evaluation of the carcinogenic risk of chemicals to human:Tobacco Smoke and Involuntary Smoking.V ol 83. Lyon; 2002." Ireland, A. P., J. H. Peters, et al. (1996). "Gastric juice protects against the development of esophageal adenocarcinoma in the rat." Ann Surg 224(3): 358-70; discussion 370-1. 101 Jee, S. H., H. Ohrr, et al. (1999). "Effects of husbands' smoking on the incidence of lung cancer in Korean women." Int J Epidemiol 28(5): 824-8. Johnson, A. G., S. S. Jick, et al. (1996). "Histamine-2 receptor antagonists and gastric cancer." Epidemiology 7(4): 434-6. Kandil, H. M., G. Tanner, et al. (2001). "Cyclooxygenase-2 expression in Barrett's esophagus." Dig Dis Sci 46(4): 785-9. Kim, R., J. L. Weissfeld, et al. (1997). "Etiology of Barrett's metaplasia and esophageal adenocarcinoma." Cancer Epidemiol Biomarkers Prev 6(5): 369-77. La Vecchia, C., E. Negri, et al. (1990). "Histamine-2-Receptor Antagonists and Gastric Cancer Risk." The Lancet 336: 355-357. Ladeiras-Lopes, R., A. K. Pereira, et al. (2008). "Smoking and gastric cancer: systematic review and meta-analysis of cohort studies." Cancer Causes Control. Lagergren, J. (2006). "Etiology and risk factors for oesophageal adenocarcinoma: possibilities for chemoprophylaxis?" Best Pract Res Clin Gastroenterol 20(5): 803-12. Lagergren, J., R. Bergstrom, et al. (1999). "Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma." N Engl J Med 340(11): 825-31. Lagergren, J., R. Bergstrom, et al. (2000). "The role of tobacco, snuff and alcohol use in the aetiology of cancer of the oesophagus and gastric cardia." Int J Cancer 85(3): 340-6. 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. Levitz, J. S., T. P. Bradley, et al. (2004). "Overview of smoking and all cancers." Med Clin North Am 88(6): 1655-75, xiii. 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. Mahue-Giangreco, M. and L. Berstein (2001). "Epidemiology of Barrett's Esophagus." Problems in General Surgery 18: 4-11. Mao, Y ., J. Hu, et al. (2002). "Active and passive smoking and the risk of stomach cancer, by subsite, in Canada." Eur J Cancer Prev 11(1): 27-38. 102 Marshall, R. E., A. Anggiansah, et al. (1998). "The temporal relationship between oesophageal bile reflux and pH in gastro-oesophageal reflux disease." Eur J Gastroenterol Hepatol 10(5): 385-92. Mendes de Almeida, J. C., P. Chaves, et al. (1997). "Is Barrett's esophagus the precursor of most adenocarcinomas of the esophagus and cardia? A biochemical study." Ann Surg 226(6): 725-33; discussion 733-5. Mizoue, T., N. Tokui, et al. (2000). "Prospective study on the relation of cigarette smoking with cancer of the liver and stomach in an endemic region." Int J Epidemiol 29(2): 232-7. Moller, H., K. Lindvig, et al. (1989). "Cancer occurrence in a cohort of patients treated with cimetidine." Gut 30(11): 1558-62. Moller, H., A. Nissen, et al. (1992). "Use of cimetidine and other peptic ulcer drugs in Denmark 1977-1990 with analysis of the risk of gastric cancer among cimetidine users." Gut 33(9): 1166-9. Morales, T. G. and R. E. Sampliner (1999). "Barrett's esophagus: update on screening, surveillance, and treatment." Arch Intern Med 159(13): 1411-6. Nebel, O. T., M. F. Fornes, et al. (1976). "Symptomatic gastroesophageal reflux: incidence and precipitating factors." Am J Dig Dis 21(11): 953-6. Neumann, C. S. and B. T. Cooper (1994). "24 hour ambulatory oesophageal pH monitoring in uncomplicated Barrett's oesophagus." Gut 35(10): 1352-5. Nishino, Y ., M. Inoue, et al. (2006). "Tobacco smoking and gastric cancer risk: an evaluation based on a systematic review of epidemiologic evidence among the Japanese population." Jpn J Clin Oncol 36(12): 800-7. Nishino, Y ., Y . Tsubono, et al. (2001). "Passive smoking at home and cancer risk: a population-based prospective study in Japanese nonsmoking women." Cancer Causes Control 12(9): 797-802. Pandolfino, J. E. and P. J. Kahrilas (2000). "Smoking and gastro-oesophageal reflux disease." Eur J Gastroenterol Hepatol 12(8): 837-42. Pera, M., A. J. Cameron, et al. (1993). "Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction." Gastroenterology 104(2): 510-3. Peterson, W. L. (1991). "Helicobacter pylori and peptic ulcer disease." N Engl J Med 324(15): 1043-8. Preston-Martin, S. "N-nitroso compounds as a cause of human cancer. IARC Sci Publ 1987;84:477-84." 103 Pron, G. E., J. D. Burch, et al. (1988). "The reliability of passive smoking histories reported in a case-control study of lung cancer." Am J Epidemiol 127(2): 267-73. Reed, P. I., P. L. Smith, et al. (1981). "Effect of cimetidine on gastric juice N-nitrosamine concentration." Lancet 2(8246): 553-6. Robertson, D., M. Aldersley, et al. (1987). "Patterns of acid reflux in complicated oesophagitis." Gut 28(11): 1484-8. Rodriguez, G., L. A., J. Lagergren, et al. (2006). "Gastric acid suppression and risk of oesophageal and gastric adenocarcinoma: a nested case control study in the UK." Gut 55(11): 1538-44. Romero, Y ., A. J. Cameron, et al. (1997). "Familial aggregation of gastroesophageal reflux in patients with Barrett's esophagus and esophageal adenocarcinoma." Gastroenterology 113(5): 1449-56. Sandler, D. P., G. W. Comstock, et al. (1989). "Deaths from all causes in non-smokers who lived with smokers." Am J Public Health 79(2): 163-7. Sandler, R. S., D. P. Sandler, et al. (1988). "Cigarette smoking and the risk of colorectal cancer in women." J Natl Cancer Inst 80(16): 1329-33. Sawaoka, H., S. Kawano, et al. (1998). "Effects of NSAIDs on proliferation of gastric cancer cells in vitro: possible implication of cyclooxygenase-2 in cancer development." J Clin Gastroenterol 27 Suppl 1: S47-52. Schreinemachers, D. M. and R. B. Everson (1994). "Aspirin use and lung, colon, and breast cancer incidence in a prospective study." Epidemiology 5(2): 138-46. Shirvani, V . N., R. Ouatu-Lascar, et al. (2000). "Cyclooxygenase 2 expression in Barrett's esophagus and adenocarcinoma: Ex vivo induction by bile salts and acid exposure." Gastroenterology 118(3): 487-96. 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. Souza, R. F., K. Shewmake, et al. (2000). "Selective inhibition of cyclooxygenase-2 suppresses growth and induces apoptosis in human esophageal adenocarcinoma cells." Cancer Res 60(20): 5767-72. Spechler, S. J. and R. K. Goyal (1986). "Barrett's esophagus." N Engl J Med 315(6): 362-71. 104 Stamp, D. H. (2006). "Bile acids aided by acid suppression therapy may be associated with the development of esophageal cancers in westernized societies." Med Hypotheses 66(1): 154-7. Stein, H. J., W. K. Kauer, et al. (1998). "Bile reflux in benign and malignant Barrett's esophagus: effect of medical acid suppression and nissen fundoplication." J Gastrointest Surg 2(4): 333-41. Sugawa, C., Y . Takekuma, et al. (1997). "Bleeding esophageal ulcers caused by NSAIDs." Surg Endosc 11(2): 143-6. Suleiman, U. L., M. Harrison, et al. (2000). "H2-receptor antagonists may increase the risk of cardio-oesophageal adenocarcinoma: a case-control study." Eur J Cancer Prev 9(3): 185-91. Tarnawski, A. S. and T. C. Caves (2004). "Aspirin in the XXI century: its major clinical impact, novel mechanisms of action, and new safer formulations." Gastroenterology 127(1): 341-343 Thun, M. J., M. M. Namboodiri, et al. (1993). "Aspirin use and risk of fatal cancer." Cancer Res 53(6): 1322-7. Todd, J. A., J. de Caestecker, et al. (2003). "Gastro-esophageal reflux disease and bile acids." J Pediatr Gastroenterol Nutr 36(2): 172-4. Tsibouris, P., M. T. Hendrickse, et al. (2004). "Daily use of non-steroidal anti-inflammatory drugs is less frequent in patients with Barrett's oesophagus who develop an oesophageal adenocarcinoma." Aliment Pharmacol Ther 20(6): 645-55. Tsuji, S., S. Kawano, et al. (1996). "Evidences for involvement of cyclooxygenase-2 in proliferation of two gastrointestinal cancer cell lines." Prostaglandins Leukot Essent Fatty Acids 55(3): 179-83. 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., S. Davis, et al. (1995). "Obesity, alcohol, and tobacco as risk factors for cancers of the esophagus and gastric cardia: adenocarcinoma versus squamous cell carcinoma." Cancer Epidemiol Biomarkers Prev 4(2): 85-92. 105 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. Vigen, C., L. Bernstein, et al. (2006). "Occupational physical activity and risk of adenocarcinomas of the esophagus and stomach." Int J Cancer 118(4): 1004-9. 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. Winters, C., Jr., T. J. Spurling, et al. (1987). "Barrett's esophagus. A prevalent, occult complication of gastroesophageal reflux disease." Gastroenterology 92(1): 118-24. 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., C. C. Tseng, et al. (2007). "Fiber intake and risk of adenocarcinomas of the esophagus and stomach." Cancer Causes Control 18(7): 713-22. 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. Wu, Y . L., S. L. Fu, et al. (2005). "Cyclooxygenase-2 inhibitors suppress angiogenesis and growth of gastric cancer xenografts." Biomedicine & Pharmacotherapy 59 Suppl 2: S289-92. 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. 106 Appendix A: Aspirin or non-aspirin NSAID 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 Relafen Salsalate Tolectin Voltaren 107 Appendix B: Antacid drug list. Oral non-prescription antacid drugs Oral prescription antacid Alka -mints chewable antacid Axid Pulvules Alka Seltzer-all types Bentyl Alka -mints chewable antacid Bentyl W/PB Alka Seltzer-all types Bicitra AlternaGEL Liquid Bismorex Aludrox Oral suspension Cytotec Aluminum hyroxide gel Donnatal Amitone Espaven Amphojel Librax Antacid Mint by Riker lab Mylicon/Mylacon Antacid Peru Pepcid Antacid Prevacid Bromo seltzer Prilosec or losec Camalox Robinul, robinul forte Citrocarbonate Tagmet Dicarbosil Zantac Di-Gel Antacid/Anti-Gas Eno fruit salts Gaviscon Gelusil Glygel powder Maalox Magonate Mi-Acid Mylanta Mylicon/Mylacon Pepto-Bismol Philip's milk of Magnesia Polycrol Pure Baking Soda Riopan Antacid Rolaids Sal de uvas Tempo Titralac antacid Titralac Extra Strength Tums Antacid WinGel liquid & tablets

Abstract (if available)

Abstract A dramatic increase in the incidence of esophageal adenocarcinoma has been observed in the United States and Western Europe during the past 3 decades. Likewise, a similar pattern of incidence although of smaller magnitude has also been observed for adenocarcinomas of the gastric cardia over the same period. Compared to 30 years ago, the rates of esophageal adenocarcinoma have increased more than 350%. In contrast, the incidence rates of the squamous cell carcinoma of the esophagus and adenocarcinoma of the distal stomach have remained static or even decreased. The underlying reasons for the increase in the incidence of adenocarcinoma of the esophagus and gastric cardia remain mostly unknown. Evidence suggests environmental exposures and host factors may play a very important role in this change. Studies have evaluated behavioral factors like tobacco and alcohol consumption, diet, obesity and physical activity as risk factors for many types of cancers as well as for adenocarcinomas of the esophagus and gastric cardia. While the existence of some medical conditions, such as Helicobacter pylori infection, Barrett's esophagus and gastro-esophageal reflux disease, and medications that were used to treat these diseases may be uniquely related with the risk of adenocarcinomas of the esophagus and gastric cardia.

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Asset Metadata

Creator Duan, Lei (author)

Core Title Non-steroidal anti-inflammatory drugs, anti-acid drugs and passive smoking as impact factors for esophageal and gastric adenocarcinomas

School Keck School of Medicine

Degree Doctor of Philosophy

Degree Program Preventive Medicine (Health Behavior)

Publication Date 07/25/2010

Defense Date 06/09/2008

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

Tag ardenocarcinomas,esophageal,gastric,OAI-PMH Harvest

Place Name Los Angeles County (counties)

Language English

Advisor Bernstein, Leslie (committee chair), Chandrasoma, Parakrama (committee member), Chou, Chih-Ping (committee member), Reynolds, Kim D. (committee member), Wu, Anna (committee member)

Creator Email lduan@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-m1414

Unique identifier UC1212845

Identifier etd-Duan-20080725 (filename),usctheses-m40 (legacy collection record id),usctheses-c127-196882 (legacy record id),usctheses-m1414 (legacy record id)

Legacy Identifier etd-Duan-20080725.pdf

Dmrecord 196882

Document Type Dissertation

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