Nonsteroidal Anti-inflammatory Drugs and the Esophageal Inflammation-Metaplasia-Adenocarcinoma Sequence

Research Article

Nonsteroidal Anti-inflammatory Drugs and the Esophageal Inflammation-Metaplasia-Adenocarcinoma Sequence 1

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Lesley A. Anderson, Brian T. Johnston, R.G. Peter Watson, Seamus J. Murphy, 1 4 2 5 Heather R. Ferguson, Harry Comber, Jim McGuigan, John V. Reynolds, 1 and Liam J. Murray

1 Centre for Clinical and Population Sciences, Queen’s University; 2Royal Group of Hospitals, Belfast, Northern Ireland; 3Ulster Hospital, Dundonald, Northern Ireland; 4National Cancer Registry, Cork, Ireland; and 5St. James’s Hospital, Dublin, Ireland

Abstract Observational studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of esophageal adenocarcinoma, but it is not known at what stage they may act in the esophageal inflammation-metaplasia-adenocarcinoma sequence. In an all-Ireland case-control study, we investigated the relationship between the use of NSAIDs and risk of reflux esophagitis, Barrett’s esophagus, and esophageal adenocarcinoma. Patients with esophageal adenocarcinoma, long-segment Barrett’s esophagus and population controls were recruited from throughout Ireland. Esophagitis patients were recruited from Northern Ireland only. Data were collected on known and potential risk factors for esophageal adenocarcinoma and on the use of NSAIDs, including aspirin, at least 1 year before interview. Associations between use of NSAIDs and the stages of the esophageal inflammationmetaplasia-adenocarcinoma sequence were estimated by multiple logistic regression. In total, 230 reflux esophagitis, 224 Barrett’s esophagus, and 227 esophageal adenocarcinoma and 260 population controls were recruited. Use of aspirin and NSAIDs was associated with a reduced risk of Barrett’s esophagus [odds ratio [OR; 95% confidence interval (95% CI)], 0.53 (0.31-0.90) and 0.40 (0.19-0.81), respectively] and esophageal adenocarcinoma [OR (95% CI), 0.57 (0.36-0.93) and 0.58 (0.31-1.08), respectively]. Barrett’s esophagus and esophageal adenocarcinoma patients were less likely than controls to have used NSAIDs. Selection or recall bias may explain these results and the results of previous observational studies indicating a protective effect of NSAIDs against esophageal adenocarcinoma. If NSAIDs have a true protective effect on the esophageal inflammation-metaplasia-adenocarcinoma sequence, they may act early in the sequence. (Cancer Res 2006; 66(9): 4975-82)

Introduction Gastroesophageal reflux disease is a commonly reported medical condition caused by reflux of acid and/or bile into the distal esophagus. In some people, chronic gastroesophageal reflux leads to Barrett’s esophagus, a condition in which the normal stratified squamous epithelium lining the distal esophagus is replaced by

Requests for reprints: Lesley A. Anderson, Centre for Clinical and Population Sciences, Queen’s University, Mulhouse Building, Grosvenor Road, Belfast, Northern Ireland BT12 6BJ. Phone: 44-28-9063-5046; Fax: 44-28-9024-8017; E-mail: l.anderson@ qub.ac.uk. I2006 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-05-4253

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columnar epithelium of intestinal type. Compared with the general population, Barrett’s esophagus patients are 17 to 125 times more likely to develop esophageal adenocarcinoma (1–5), a cancer that has been increasing rapidly in many western societies over recent decades (6–10). Evidence is emerging that nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, may prevent several cancers (11). NSAIDs inhibit cyclooxygenase (COX) enzymes COX-1 and COX-2. COX-1 is constitutively expressed in many human tissues, whereas COX-2 can be induced in response to cytokines, growth factors, and mitogens. Inhibition of COX-2 restores apoptosis (12, 13), decreases cell growth (13), and/or decreases proliferation (14) and inhibits angiogenesis (15). Most research to date has focused on colorectal cancer, with studies reporting that both aspirin and non-aspirin NSAIDs may be protective (16–19). Studies have also indicated that NSAIDs may prevent the development of premalignant colorectal adenomas (20, 21). Several studies have reported reduced risks of all esophageal carcinomas in NSAID users (11, 22–27) and NSAIDs, including aspirin, have been associated with a reduced risk of esophageal adenocarcinoma (23, 28, 29). One study has indicated that esophageal adenocarcinoma patients are less likely to use nonaspirin NSAIDs compared with Barrett’s esophagus patients (30), and a recent study reported that Barrett’s esophagus patients who used NSAIDs had a lower incidence of esophageal adenocarcinoma (27), but, as yet, no research has investigated whether NSAIDs protect against Barrett’s esophagus or specifically examined at what stage they may act in the esophageal inflammationmetaplasia-adenocarcinoma sequence. Using an all-Ireland case-control study, the Factors Influencing the Barrett’s Adenocarcinoma Relationship (FINBAR) study, we set out to investigate the relationship between the use of NSAIDs and reflux esophagitis, Barrett’s esophagus, and esophageal adenocarcinoma to shed light on the stage at which NSAIDs may exert a protective effect. In doing so, we hoped to determine at which stage chemoprevention with NSAIDs might be most effective.

Materials and Methods The FINBAR study commenced in Ireland in March 2002 and continued until December 2004. The study included three groups of subjects: (a) patients with esophageal adenocarcinoma, (b) patients with long-segment Barrett’s esophagus, and (c) normal population controls, all recruited from both Northern Ireland and Republic of Ireland. From September 2004 to July 2005, a group of reflux esophagitis patients were recruited from Northern Ireland only. Esophageal adenocarcinoma cases (aged V85 years) were patients with a histologic confirmation of adenocarcinoma within the esophagus. In situ cancers were not included. Cases from Northern Ireland were identified from electronic pathology records from all pathology laboratories within

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Cancer Research the province. Republic of Ireland cases were identified from the main hospitals involved in the diagnosis and treatment of esophageal cancer, including St. James’s Hospital (Dublin, Ireland), which is a national referral center for esophageal cancer. All available relevant clinical and histologic records, including surgical and radiological reports, were reviewed by L.A.A., S.J.M., J.M., and a pathologist to confirm that the tumor was located in the esophagus and to assign tumors into two groups: (a) esophageal tumors (including tumors encroaching on the esophagogastric junction) and (b) junctional tumors (tumors involving the esophagus, esophagogastric junction, and gastric cardia). There was insufficient evidence available to classify the topography of four tumors; these were included in the overall analyses but excluded from the subgroup analyses. Barrett’s esophagus patients were eligible for inclusion if z3 cm of typical Barrett’s mucosa were seen at endoscopy, and the presence of specialized intestinal metaplasia was confirmed by histologic examination of biopsy specimens. Incident and prevalent cases were included. Patients with dysplasia on histologic examination were not included. In Northern Ireland, cases of Barrett’s esophagus were initially identified from pathology reports gathered from throughout Northern Ireland. Endoscopy note review was necessary in most patients to confirm the length of the segment of Barrett’s esophagus because length was infrequently recorded on the pathology report. In the Republic of Ireland, clinicians in the Dublin and Cork areas sent details of Barrett’s esophagus patients who met the inclusion criteria to the research personnel. Reflux esophagitis patients were patients diagnosed in Northern Ireland with macroscopically visible erosive esophagitis at upper gastrointestinal endoscopy. Erosive esophagitis was defined as evidence of mucosal breaks or erosions within the esophagus (grades 2-4 in the Savary Miller/HetzelDent classification or grades B, C, or D in the Los Angeles classification were included). Patients were excluded if they had Barrett’s esophagus visible endoscopically or at biopsy, if they had macroscopic or histologic evidence of infection, such as candidiasis, if they had documented dysmotility, or if there was gastric outlet obstruction. Eligible control subjects were adults without a history of esophageal or other gastrointestinal cancer or a known diagnosis of Barrett’s esophagus. Northern Ireland controls were frequency matched by sex and 5-year age band to the distribution of esophageal adenocarcinoma patients and selected at random from the General Practice Master Index (a provincewide database of all persons registered with a general practitioner). Republic of Ireland controls were frequency matched (within 5-year age and sex strata) to the distribution of esophageal adenocarcinoma patients. They were selected at random from four general practices (two urban and two rural) in the Dublin and Cork areas chosen by the researchers to reflect the urban/rural distribution of esophageal adenocarcinoma patients in the Republic of Ireland. All subjects underwent a structured computerized interview with trained interviewers. Information was collected on NSAID, aspirin, and paracetamol use, symptoms of gastroesophageal reflux, history of hiatus hernia, peptic ulcers, esophagitis, and Barrett’s esophagus, weight, height, smoking history, education, occupational type (manual/nonmanual), and alcohol consumption. Anthropometric measures (height, weight, waist, and hip circumference) were taken at the time of interview. Frequent gastroesophageal reflux was defined as symptoms of heartburn and/or acid reflux occurring at least once weekly (>50 times per year) >5 years before interview. Subjects were classified as having gastroesophageal reflux if they responded positively to either of the following questions: (a) Have you ever had frequent heartburn (i.e., a burning or ache behind the breastbone that is not due to heart problems) not including the last 5 years? or (b) Have you ever had frequent acid reflux (i.e., a bitter taste of stomach acid, which has come up to the back of your throat) not including the last 5 years? Body mass index (BMI) 5 years before the interview date was calculated by dividing self-reported weight in kilograms by current height in meters squared. Current smoking status was defined as smokers who had smoked at least one cigarette daily for z6 months 5 years before interview date. Previous smokers were those smokers who had quit smoking >5 years before interview date. People who had never smoked, who had smoked