Protective association of aspirin/NSAIDs and esophageal cancer: a systematic review and meta-analysis.

BACKGROUND & AIMS Esophageal carcinomas have high fatality rates, making chemoprevention agents desirable. We performed a systematic review with meta-analysis of observational studies evaluating the association of aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and esophageal cancer. METHODS We evaluated the MEDLINE, BIOSIS, and Web of Science electronic databases (1980-2001); manually reviewed the literature; and consulted with experts. Studies were included if they: (1) evaluated exposure to NSAIDs, aspirin, or both; (2) evaluated esophageal cancer; and (3) reported relative risks or odds ratios or provided data for their calculation. Data were independently abstracted by 2 investigators. The primary and sensitivity analyses used both fixed and random-effects models. RESULTS Nine studies (2 cohort, 7 case control) containing 1813 cancer cases were identified. All primary summary estimates were homogeneous. Statistical pooling showed a protective association between any use of aspirin/NSAID and esophageal cancer (odds ratio [OR] = 0.57; 95% confidence interval [CI], 0.47-0.71). Both intermittent (OR = 0.82; CI, 0.67-0.99) and frequent medication use were protective (OR = 0.54; CI, 0.43-0.67), with greater protection with more frequent use. Stratified by medication type, aspirin use was protective (OR = 0.5; CI, 0.38-0.66), and NSAIDs had a borderline protective association (OR = 0.75; CI, 0.54-1.0). Any use was protective against both esophageal adenocarcinoma (OR = 0.67; CI, 0.51-0.87) and squamous cell carcinoma (OR = 0.58; CI, 0.43-0.78). CONCLUSIONS Pooled results support a protective association between aspirin and NSAIDs and esophageal cancer (of both histological types) and provide evidence for a dose effect. These findings support evaluating these agents in clinical trials of high-risk patients.

[1]  E. Masini,et al.  Prognostic significance of cyclooxygenase-2 pathway and angiogenesis in head and neck squamous cell carcinoma. , 2002, Human pathology.

[2]  Pamela S. Sinicrope,et al.  Post-study aspirin intake and factors motivating participation in a colorectal cancer chemoprevention trial. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[3]  Michael J Thun,et al.  Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. , 2002, Journal of the National Cancer Institute.

[4]  R. Sandler,et al.  Chemoprevention of gastrointestinal malignancies with nonsteroidal antiinflammatory drugs , 2002, Cancer.

[5]  F. Sato,et al.  Expression of Cyclooxygenase-2 Is Associated with Carcinogenesis of the Lower Part of Thoracic Esophageal Squamous Cell Carcinoma and p53 Expression , 2002, Oncology.

[6]  M. Reilly,et al.  Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. , 2001, The New England journal of medicine.

[7]  R. Sperling,et al.  Cardiovascular Thrombotic Events in Controlled, Clinical Trials of Rofecoxib , 2001, Circulation.

[8]  N. Day,et al.  Risk factors for squamous cell carcinoma of the oesophagus in women: a case–control study , 2001, British Journal of Cancer.

[9]  Rajnish A. Gupta,et al.  Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2 , 2001, Nature Reviews Cancer.

[10]  Douglas G Altman,et al.  Systematic reviews in health care: Assessing the quality of controlled clinical trials. , 2001, BMJ.

[11]  S. Lippman,et al.  Nonsteroidal anti-inflammatory drugs induce apoptosis in esophageal cancer cells by restoring 15-lipoxygenase-1 expression. , 2001, Cancer research.

[12]  R. DuBois,et al.  Cyclooxygenase-2 Expression in Barrett's Esophagus , 2001, Digestive Diseases and Sciences.

[13]  P. Tsibouris,et al.  NSAIDs do not protect patients with barrett oesophagus from adenocarcinoma development , 2001 .

[14]  S. Attwood,et al.  Cyclooxygenase-2 expression in the Barrett’s metaplasia–dysplasia–adenocarcinoma sequence , 2001 .

[15]  R. Sandler,et al.  Is there publication bias in the reporting of cancer risk in Barrett's esophagus? , 2000, Gastroenterology.

[16]  C. Patrono,et al.  Differential effects of aspirin and non-aspirin nonsteroidal antiinflammatory drugs in the primary prevention of myocardial infarction in postmenopausal women. , 2000, Epidemiology.

[17]  S. Jick The Risk of Gastrointestinal Bleed, Myocardial Infarction, and Newly Diagnosed Hypertension in Users of Meloxicam, Diclofenac, Naproxen, and Piroxicam , 2000, Pharmacotherapy.

[18]  R. Lancashire,et al.  Effect of anti-inflammatory drugs on overall risk of common cancer: case-control study in general practice research database , 2000, BMJ : British Medical Journal.

[19]  N. Day,et al.  A case-control study of oesophageal adenocarcinoma in women: a preventable disease , 2000, British Journal of Cancer.

[20]  K. McPherson,et al.  H2-receptor antagonists may increase the risk of cardio-oesophageal adenocarcinoma: a case-control study. , 2000, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[21]  K. McPherson,et al.  An age, period and cohort analysis of pleural cancer mortality in Europe. , 2000 .

[22]  I. Olkin,et al.  Meta-analysis of observational studies in epidemiology - A proposal for reporting , 2000 .

[23]  P. Gøtzsche,et al.  Non-steroidal anti-inflammatory drugs , 2000, BMJ : British Medical Journal.

[24]  M. Omary,et al.  Cyclooxygenase 2 expression in Barrett's esophagus and adenocarcinoma: Ex vivo induction by bile salts and acid exposure. , 2000, Gastroenterology.

[25]  Blot Wj,et al.  The changing epidemiology of esophageal cancer. , 1999, Seminars in oncology.

[26]  M. Egger,et al.  The hazards of scoring the quality of clinical trials for meta-analysis. , 1999, JAMA.

[27]  S Greenland,et al.  Random-effects meta-analyses are not always conservative. , 1999, American journal of epidemiology.

[28]  T. Imperiale,et al.  Meta-analysis: when and how. , 1999, Hepatology.

[29]  A. Sajadieh,et al.  Nonsteroidal anti-inflammatory drugs after acute myocardial infarction. DAVIT Study Group. Danish Verapamil Infarction Trial. , 1999, The American journal of cardiology.

[30]  A. Lindgren,et al.  Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. , 1999, The New England journal of medicine.

[31]  J. Fraumeni,et al.  Changing patterns in the incidence of esophageal and gastric carcinoma in the United States , 1998, Cancer.

[32]  R. Sampliner,et al.  Practice guidelines on the diagnosis, surveillance, and therapy of Barrett's esophagus , 1998, American Journal of Gastroenterology.

[33]  V. Thursfield,et al.  Rising incidence of oesophageal adenocarcinoma in men in Australia , 1998, Journal of gastroenterology and hepatology.

[34]  M. Gammon,et al.  Use of aspirin and other nonsteroidal anti-inflammatory drugs and risk of esophageal and gastric cancer. , 1998, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[35]  M. Gammon,et al.  Body mass index and risk of adenocarcinomas of the esophagus and gastric cardia. , 1998, Journal of the National Cancer Institute.

[36]  T. Imperiale,et al.  Somatostatin or Octreotide Compared with H2 Antagonists and Placebo in the Management of Acute Nonvariceal Upper Gastrointestinal Hemorrhage , 1997, Annals of Internal Medicine.

[37]  M. Gammon,et al.  Tobacco, alcohol, and socioeconomic status and adenocarcinomas of the esophagus and gastric cardia. , 1997, Journal of the National Cancer Institute.

[38]  S. Tretli,et al.  Esophageal and gastric carcinoma in Norway 1958‐1992: Incidence time trend variability according to morphological subtypes and organ subsites , 1997, International journal of cancer.

[39]  H. Vainio,et al.  NSAIDs, Barrett's oesophagus and adenocarcinoma prevention. , 1997, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[40]  L. Signorello,et al.  Life‐style factors and medical conditions in relation to esophageal cancer by histologic type in a low‐risk population , 1996, International journal of cancer.

[41]  L. Karnell,et al.  National Cancer Data Base report on esophageal carcinoma , 1996, Cancer.

[42]  S. Lade,et al.  Incidence trends in oesophageal and proximal gastric carcinoma in Victoria. , 1996, The Australian and New Zealand journal of surgery.

[43]  A R Jadad,et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary? , 1996, Controlled clinical trials.

[44]  E. Funkhouser,et al.  Aspirin and reduced risk of esophageal carcinoma , 1995, Cancer.

[45]  P. Pasricha,et al.  The effects of sulindac on colorectal proliferation and apoptosis in familial adenomatous polyposis. , 1995, Gastroenterology.

[46]  L. Sharp,et al.  Oesophageal and gastric cancer in Scotland 1960-90. , 1995, British Journal of Cancer.

[47]  R. J. Hayes,et al.  Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. , 1995, JAMA.

[48]  M. Thun,et al.  Nonsteroidal antiinflammatory drugs and human cancer. Report of an interdisciplinary research workshop , 1994, Cancer.

[49]  E. Rimm,et al.  Aspirin Use and the Risk for Colorectal Cancer and Adenoma in Male Health Professionals , 1994, Annals of Internal Medicine.

[50]  S Greenland,et al.  Invited commentary: a critical look at some popular meta-analytic methods. , 1994, American journal of epidemiology.

[51]  Blot Wj,et al.  Esophageal cancer trends and risk factors. , 1994 .

[52]  D G Altman,et al.  Assessing the quality of randomization from reports of controlled trials published in obstetrics and gynecology journals. , 1994, JAMA.

[53]  R. Hayes,et al.  Adenocarcinoma of the esophagus and esophagogastric junction in White men in the United States: alcohol, tobacco, and socioeconomic factors , 1994, Cancer Causes & Control.

[54]  P R Taylor,et al.  Prevention of esophageal cancer: the nutrition intervention trials in Linxian, China. Linxian Nutrition Intervention Trials Study Group. , 1994, Cancer research.

[55]  Diana B. Petitti,et al.  Meta-Analysis, Decision Analysis, and Cost-Effectiveness Analysis: Methods for Quantitative Synthesis in Medicine , 1994 .

[56]  J. Williams,et al.  Inflammatory mediators in the oesophagus. , 1994, Gut.

[57]  C. Williams,et al.  Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis , 1993, The British journal of surgery.

[58]  J. Fraumeni,et al.  Continuing climb in rates of esophageal adenocarcinoma: an update. , 1993, JAMA.

[59]  P. Sparén,et al.  Increasing incidence of both major histological types of esophageal carcinomas among men in Sweden , 1993, International journal of cancer.

[60]  M. Thun,et al.  Aspirin use and risk of fatal cancer. , 1993, Cancer research.

[61]  P. Sparén,et al.  Increasing incidence of carcinoma of the gastric cardia in Sweden from 1970 to 1985 , 1993, The British journal of surgery.

[62]  A R Zinsmeister,et al.  Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction. , 1993, Gastroenterology.

[63]  M. Thun,et al.  Aspirin use and reduced risk of fatal colon cancer. , 1991, The New England journal of medicine.

[64]  P. Vielh,et al.  Sulindac causes regression of rectal polyps in familial adenomatous polyposis. , 1991, Gastroenterology.

[65]  C. Vecchia,et al.  Adenocarcinoma of the Esophagus in Switzerland , 1991 .

[66]  J. Fraumeni,et al.  Rising incidence of adenocarcinoma of the esophagus and gastric cardia. , 1991, JAMA.

[67]  C. McConkey,et al.  Increasing incidence of adenocarcinoma of the gastric cardia and adjacent sites. , 1990, British Journal of Cancer.

[68]  J. Chang-Claude,et al.  An epidemiological study of precursor lesions of esophageal cancer among young persons in a high-risk population in Huixian, China. , 1990, Cancer research.

[69]  C. Rubio,et al.  Effect of indomethacin in autotransplanted colonic tumors , 1989, Diseases of the colon and rectum.

[70]  S. Davis,et al.  Incidence of cancer of the esophagus in the US by histologic type , 1988, Cancer.

[71]  H. Lin,et al.  Prostaglandin synthesis by squamous carcinoma cells of head and neck, and its inhibition by non-steroidal anti-inflammatory drugs. , 1987, Journal of oral pathology.

[72]  C. Rubio Further studies on the therapeutic effect of indomethacin on esophageal tumors , 1986, Cancer.

[73]  N. Laird,et al.  Meta-analysis in clinical trials. , 1986, Controlled clinical trials.

[74]  C. Rubio Antitumoral activity of indomethacin on experimental esophageal tumors. , 1984, Journal of the National Cancer Institute.

[75]  T C Chalmers,et al.  Bias in treatment assignment in controlled clinical trials. , 1983, The New England journal of medicine.

[76]  H. Morgenstern,et al.  Epidemiologic Research: Principles and Quantitative Methods. , 1983 .

[77]  Maurice G. Kendall,et al.  Rank Correlation Methods , 1949 .

[78]  E. Fosslien Molecular pathology of cyclooxygenase-2 in neoplasia. , 2000, Annals of clinical and laboratory science.

[79]  S. Shapiro,et al.  Nonsteroidal anti-inflammatory drugs and risk of digestive cancers at sites other than the large bowel. , 2000, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[80]  Quan-hong Wang,et al.  Expression of cyclooxygenase-2 in human squamous cell carcinoma of the esophagus; an immunohistochemical survey. , 1999, Anticancer research.

[81]  A. Kristal,et al.  Cancer-related behavior of vitamin supplement users. , 1998, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[82]  R. Horwitz,et al.  Resolving conflicting clinical trials: guidelines for meta-analysis. , 1988, Journal of clinical epidemiology.