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The Role of Gastroesophageal Reflux and Other Factors during Progression to Esophageal Adenocarcinoma.

ABSTRACT: U.S. esophageal adenocarcinoma (EAC) incidence increased over 5-fold between 1975 and 2009. Symptomatic gastroesophageal reflux disease (sGERD) elevates the risk for EAC. However, a simple calculation suggests that changes in sGERD prevalence can explain at most approximately 16% of this trend. Importantly, a mechanistic understanding of the influence of sGERD and other factors (OF) on EAC is lacking.A multiscale model was developed to estimate temporal trends for sGERD and OF, and their mechanistic role during carcinogenesis. Model calibration was to Surveillance, Epidemiology, and End Results (SEER) incidence and age-dependent sGERD data using maximum likelihood and Markov chain Monte Carlo (MCMC) methods.Among men, 77.8% [95% credibility interval (CI), 64.9%-85.6%] of the incidence trend is attributable to OF, 13.4% (95% CI, 11.4%-17.3%) to sGERD, and 8.8% (95% CI, 4.2%-13.7%) to sGERD-OF interactions. Among women, 32.6% (95% CI, 27.0%-39.9%) of the trend is attributable to OF, 13.6% (95% CI, 12.5%-15.9%) to sGERD, and 47.4% (95% CI, 30.7%-64.6%) to interactions. The predicted trends were compared with historical trends for obesity, smoking, and proton pump inhibitor use. Interestingly, predicted OF cohort trends correlated most highly with median body mass index (BMI) at age 50 (r = 0.988 for men; r = 0.998 for women).sGERD and OF mechanistically increase premalignant cell promotion, which increases EAC risk exponentially with exposure duration.Surveillance should target individuals with long-duration sGERD and OF exposures.

SUBMITTER: Hazelton WD

PROVIDER: S-EPMC4491004 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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The Role of Gastroesophageal Reflux and Other Factors during Progression to Esophageal Adenocarcinoma.

Hazelton William D WD Curtius Kit K Inadomi John M JM Vaughan Thomas L TL Meza Rafael R Rubenstein Joel H JH Hur Chin C Luebeck E Georg EG

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20150430 7

<h4>Background</h4>U.S. esophageal adenocarcinoma (EAC) incidence increased over 5-fold between 1975 and 2009. Symptomatic gastroesophageal reflux disease (sGERD) elevates the risk for EAC. However, a simple calculation suggests that changes in sGERD prevalence can explain at most approximately 16% of this trend. Importantly, a mechanistic understanding of the influence of sGERD and other factors (OF) on EAC is lacking.<h4>Methods</h4>A multiscale model was developed to estimate temporal trends ...[more]

PMID: 25931440

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Project description:ImportanceGastroesophageal reflux disease (GERD) is associated with a strong and severity-dependent increased risk of esophageal adenocarcinoma. Whether antireflux surgery prevents esophageal adenocarcinoma is a matter of uncertainty.ObjectivesTo examine whether antireflux surgery is associated with reduced risk of esophageal adenocarcinoma and whether the risk is different between surgically and medically treated patients.Design, setting, and participantsIn this multinational, population-based retrospective cohort study from Denmark, Finland, Iceland, Norway, and Sweden, patients undergoing surgery were followed up for a median of 12.7 years, and a comparison group of patients receiving medication only were followed up for a median of 4.8 years. All patients with a registered diagnosis of GERD (or an associated disorder), including 48 414 individuals undergoing surgery and 894 492 receiving medication only, were included in the study. The study periods varied in the different countries depending on the year of initiation of registration and the date of data retrieval, from January 1, 1964, to December 21, 2014.ExposuresAntireflux surgery for GERD.Main outcomes and measuresThe risk of esophageal adenocarcinoma over time after surgery was compared with that in a corresponding background population using standardized incidence ratios (SIRs) with 95% CIs and with patients with GERD who received medication using multivariable Cox proportional hazards regression, providing hazard ratios (HRs) with 95% CIs adjusted for confounders.ResultsIn this study of 942 906 patients with GERD, 48 414 underwent antireflux surgery (median [interquartile range] age, 66.0 [58.0-73.0] years; 27 161 male [56.1%]) and 894 492 received medication only (median [interquartile range] age, 71.0 [62.0-78.0] years; 434 035 male [48.6%]). Among patients undergoing surgery, 177 developed esophageal adenocarcinoma. Esophageal adenocarcinoma risk decreased in a time-dependent manner after surgery compared with the background population (5 to <10 years after surgery: SIR, 7.63; 95% CI, 5.42-10.43; ≥15 years after surgery: SIR, 1.34; 95% CI, 0.98-1.80). Among patients with more severe and objectively determined GERD, the SIRs were 10.08 (95% CI, 6.98-14.09) at 5 to less than 10 years after surgery and 1.67 (95% CI, 1.15-2.35) at 15 years or more after surgery. The risk of esophageal adenocarcinoma did not change over time in surgical patients compared with patients who received medication only (5 to <10 years after surgery: HR, 2.02; 95% CI, 1.44-2.84; ≥15 years: HR, 1.80; 95% CI, 1.28-2.54). The risk remained stable over time in analyses restricted to severe reflux disease (5 to <10 years after surgery: HR, 1.81; 95% CI, 1.24-2.63; ≥15 years after surgery: HR, 1.69; 95% CI, 1.14-2.51).Conclusions and relevanceMedical and surgical treatment of GERD were associated with a similar reduced esophageal adenocarcinoma risk, with the risk decreasing to the same level as that in the background population over time, supporting the hypothesis that effective treatment of GERD might prevent esophageal adenocarcinoma.

Project description:The histologic changes associated with acute gastroesophageal reflux disease (GERD) have not been studied prospectively in humans. Recent studies in animals have challenged the traditional notion that reflux esophagitis develops when esophageal surface epithelial cells are exposed to lethal chemical injury from refluxed acid.To evaluate histologic features of esophageal inflammation in acute GERD to study its pathogenesis.Patients from the Dallas Veterans Affairs Medical Center who had reflux esophagitis successfully treated with proton pump inhibitors (PPIs) began 24-hour esophageal pH and impedance monitoring and esophagoscopy (including confocal laser endomicroscopy [CLE]) with biopsies from noneroded areas of distal esophagus at baseline (taking PPIs) and at 1 week and 2 weeks after stopping the PPI medication. Enrollment began May 2013 and follow-up ended July 2015.PPIs stopped for 2 weeks.Twelve patients (men, 11; mean age, 57.6 year [SD, 13.1]) completed the study. Primary outcome was change in esophageal inflammation 2 weeks after stopping the PPI medication, determined by comparing lymphocyte, eosinophil, and neutrophil infiltrates (each scored on a 0-3 scale) in esophageal biopsies. Also evaluated were changes in epithelial basal cell and papillary hyperplasia, surface erosions, intercellular space width, endoscopic grade of esophagitis, esophageal acid exposure, and mucosal impedance (an index of mucosal integrity).At 1 week and 2 weeks after discontinuation of PPIs, biopsies showed significant increases in intraepithelial lymphocytes, which were predominantly T cells (median [range]: 0 (0-2) at baseline vs 1 (1-2) at both 1 week [P?=?.005] and 2 weeks [P?=?.002]); neutrophils and eosinophils were few or absent. Biopsies also showed widening of intercellular spaces (confirmed by CLE), and basal cell and papillary hyperplasia developed without surface erosions. Two weeks after stopping the PPI medication, esophageal acid exposure increased (median: 1.2% at baseline to 17.8% at 2 weeks; ?, 16.2% [95% CI, 4.4%-26.5%], P?=?.005), mucosal impedance decreased (mean: 2671.3 ? at baseline to 1508.4 ? at 2 weeks; ?, 1162.9 ? [95% CI, 629.9-1695.9], P?=?.001), and all patients had evidence of esophagitis.In this preliminary study of 12 patients with severe reflux esophagitis successfully treated with PPI therapy, stopping PPI medication was associated with T lymphocyte-predominant esophageal inflammation and basal cell and papillary hyperplasia without loss of surface cells. If replicated, these findings suggest that the pathogenesis of reflux esophagitis may be cytokine-mediated rather than the result of chemical injury.clinicaltrials.gov Identifier: NCT01733810.

Dataset Information

The Role of Gastroesophageal Reflux and Other Factors during Progression to Esophageal Adenocarcinoma.

Publications

The Role of Gastroesophageal Reflux and Other Factors during Progression to Esophageal Adenocarcinoma.

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