Douglas A. Corley

Body Mass Index and Adenocarcinomas of the Esophagus or Gastric Cardia: A Systematic Review and Meta-analysis

Background: The incidence of esophageal adenocarcinoma has increased markedly in recent decades in many countries. Obesity is a potential risk factor, although the results of individual studies differ. We did a systematic review and statistical synthesis of studies that evaluated the association between body mass index (BMI) and the risk of esophageal adenocarcinoma or the adjacent gastric cardia adenocarcinoma. Methods: We identified potential studies using Medline, the Web of Science database, a manual review of the literature and expert bibliographies. Studies were included if they reported (a) a measure of body mass; (b) the occurrence of esophageal or cardia adenocarcinoma diagnosis; and (c) a relative risk or odds ratio (OR) with confidence intervals (CI) or provided sufficient data to permit their calculation. Results: We identified 14 studies (2 cohort, 12 case-control; 2,488 esophageal and 2,509 cardia adenocarcinomas). A high BMI (>25) was associated with an increased risk of esophageal adenocarcinoma (males, OR, 2.2; 95% CI, 1.7-2.7; females, OR, 2.0; 95% CI, 1.4-2.9). Higher levels of BMI were associated with increased risk (overweight males, OR, 1.8; 95% CI, 1.5-2.2; obese males, OR, 2.4; 95% CI, 1.9-3.2). The overall associations with cardia cancer were heterogeneous, although stratification by study location provided homogeneous results for populations from the United States or Europe. A high BMI was weakly associated with the risk of cardia adenocarcinoma (OR, 1.5; 95% CI, 1.3-1.8; Pheterogeneity = 0.38). Conclusions: Pooled results from observational studies support a positive association between high BMI and the risk for esophageal and possibly for cardia adenocarcinoma. (Cancer Epidemiol Biomarkers Prev 2006;15(5):872–8)

Consensus Statements for Management of Barrett's Dysplasia and Early-Stage Esophageal Adenocarcinoma, Based on a Delphi Process

BACKGROUND & AIMS Esophageal adenocarcinoma (EA) is increasingly common among patients with Barretts esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA. METHODS We performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. We used a Delphi process to develop consensus statements. The results of literature searches were screened using a unique, interactive, Web-based data-sifting platform; we used 11,904 papers to inform the choice of statements selected. An a priori threshold of 80% agreement was used to establish consensus for each statement. RESULTS Eighty-one of the 91 statements achieved consensus despite generally low quality of evidence, including 8 clinical statements: (1) specimens from endoscopic resection are better than biopsies for staging lesions, (2) it is important to carefully map the size of the dysplastic areas, (3) patients that receive ablative or surgical therapy require endoscopic follow-up, (4) high-resolution endoscopy is necessary for accurate diagnosis, (5) endoscopic therapy for HGD is preferred to surveillance, (6) endoscopic therapy for HGD is preferred to surgery, (7) the combination of endoscopic resection and radiofrequency ablation is the most effective therapy, and (8) after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. CONCLUSIONS We developed a data-sifting platform and used the Delphi process to create evidence-based consensus statements for the management of patients with BE and early-stage EA. This approach identified important clinical features of the diseases and areas for future studies.

Accuracy of Fecal Immunochemical Tests for Colorectal Cancer: Systematic Review and Meta-analysis

Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths in the United States (1). Randomized, controlled trials have shown that annual or biennial fecal occult blood tests (FOBTs) are associated with a 15% to 33% decrease in CRC mortality rates (24). However, FOBTs only detect approximately 13% to 50% of cancer with 1 round of screening in asymptomatic patients (5, 6). In addition, adherence to repeated rounds of FOBTs in real-world screening programs is low, raising concern about their effectiveness as screening tests (7, 8). Fecal immunochemical tests (FITs) are more sensitive at detecting both CRC and adenomas than FOBTs (9, 10). Many FITs require only 1 or 2 stool samples, and none require dietary or medication restrictions, increasing ease of use. In 2008, several U.S. professional societies endorsed the use of FITs to replace FOBTs because of the formers improved performance characteristics and potential for higher participation rates (10, 11). Countries in Europe and Asia have also adopted widespread CRC screening programs using FITs (12, 13). However, the diagnostic characteristics of these tests have been difficult to estimate, with reported sensitivities ranging from 25% to 100% for CRC and specificities usually exceeding 90% (9, 14, 15). The lack of a precise estimate of sensitivity has resulted in confusion among health care providers about the sources of this variation, how best to apply FITs for CRC screening, the optimal number of stool samples for testing, optimal cutoff value for a positive test result, and whether any brand of FIT is superior to others. Our analysis provides a quantitative meta-analysis of the diagnostic accuracy (sensitivity and specificity) of FITs for CRC. In addition, we explored potential sources of heterogeneity by analyzing subgroups classified by FIT sample number, cutoff value for a positive test result, FIT brand, and the reference standard. Methods We developed a protocol on the basis of standard guidelines for the systematic review of diagnostic studies (16, 17) and the strategy used for the U.S. Preventive Services Task Force review in 2008 (9). We followed the STARD (Standards for the Reporting of Diagnostic Accuracy Studies) (18) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (19) statements for reporting our systematic review. This study was conducted as part of the National Cancer Institutefunded consortium, Population-Based Research Optimizing Screening through Personalized Regimens. The overall aim of this consortium is to conduct multisite, coordinated, transdisciplinary research to evaluate and improve cancer screening processes. Data Sources and Searches We included all studies identified in the previous USPSTF report (9) plus other studies identified by a search of FIT for CRC between 1 January 2008 and 31 August 2013 using MEDLINE (via Ovid), EMBASE, Database of Abstracts of Reviews of Effects, Health Technology Assessment Database, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials. We also searched bibliographies and reference lists of eligible papers and related reviews, consulted experts in the field, and contacted several authors from the included studies to locate additional studies. The Appendix Table 1 provides further details of our search strategy. Appendix Table 1. Search Strategy Study Selection Two persons independently reviewed the pertinent studies to determine eligibility. We included studies if they met all of the following criteria: evaluated the diagnostic accuracy of FITs for CRC; reported absolute numbers of true-positive, false-negative, true-negative, and false-positive observations, or if these same variables could be obtained from personal communication; used a randomized trial or cohort study design; evaluated adult participants who were asymptomatic and older than 18 years with a mean age greater than 40 years; and reported an appropriate reference standard (colonoscopy or 2-year longitudinal follow-up of controls with medical records or cancer registry). Given that only a subset of studies reported data on adenomatous polyps and that there is variability in definitions of polyps, we limited the scope of this analysis to test performance characteristics for detecting CRC; we excluded studies reporting test performance estimates for detection of adenomas only. We did not include conference abstracts and casecontrol studies, which, by creating spectrum bias, can overestimate the accuracy of a test (20). To avoid duplicate reporting of the same population for studies reporting several cutoff values or numbers of samples, we used the cutoff value or sample number most commonly used in current practice in the United States, used in national recommendations, or recommended by expert opinion in the main analyses. In addition, we selected the sample number or cutoff value a priori that was most similar to those in other studies for our subgroup analyses. Data Extraction and Quality Assessment Two reviewers independently evaluated and extracted relevant information from each included study and assessed study quality via the Quality Assessment of Diagnostic Accuracy Studies 2 instrument (21). For studies with incomplete or unavailable information, we contacted the corresponding authors or coauthors to complete missing information. Of the 15 contacted authors, 12 provided additional data. We converted units for cutoff thresholds for a positive test result in each study to micrograms of hemoglobin per gram of stool, as recommended by leading experts (22). Data Synthesis and Analysis We calculated the sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio (LR), and negative LR with 95% CI of each study. A positive LR greater than 5 and a negative LR less than 0.2 provide strong diagnostic evidence to rule in or rule out diagnoses, respectively (23). The overall pooled sensitivity and specificity of FIT for CRC were estimated using a bivariate random-effects model (24). We calculated the pooled positive LR and negative LR along with the respective CI using the bivariate model (24) according to the method used by Zwinderman and colleagues (25). We also generated a hierarchical summary receiver-operating characteristic curve that plots the individual and summary estimates of sensitivities and specificities along with a 95% confidence and prediction region (26). Last, we calculated the area under the hierarchical summary receiver-operating characteristic curve. An area under the curve between 0.9 and 1.0 indicates that the test in question is highly accurate (27). The Q value and the inconsistency index (I 2) test were used to estimate the heterogeneity between each study (28). We regarded values of 25%, 50%, and 75% for the I 2 as indicative of low, moderate, and high statistical heterogeneity, respectively (28). In addition, we calculated the between-study variance of logit sensitivity and logit specificity (24, 29). In diagnostic accuracy studies, 1 of the primary causes of heterogeneity is the threshold effect, which occurs when different cutoff values are used between studies to define a positive (or negative) test result. We searched for evidence of a threshold effect by calculating the squared correlation coefficient estimated from the between-study covariance variable in the bivariate model (30). We stratified studies into 4 subgroups on the basis of the number of FIT samples (1, 2, or 3 samples), prespecified cutoff values of fecal hemoglobin concentration for a positive test result (<20 g/g, 20 to 50 g/g, and >50 g/g), brand, and reference standard used to follow up on patients with negative FIT results. Cutoff values were grouped to ensure an adequate number of data sets for each analysis. To determine whether studies using older (discontinued) FITs were causing heterogeneity in our summary estimates, we did sensitivity analyses by removing these studies and recalculating the I 2 test for the remaining group. In addition to threshold effect and subgroup analyses, we did a bivariate random-effects meta-regression analysis to identify additional sources of heterogeneity that may have influenced our overall summary estimates (30). We used the following prespecified variables for our meta-regression: type of FIT (qualitative, point-of-care tests or quantitative, automated tests), geographic region (Asian or non-Asian countries), and enrollment of patients younger than 40 years. We used Stata, version 12.0 (StataCorp, College Station, Texas), for all statistical analyses. All tests were 2-sided, and we considered P values less than 0.05 to be statistically significant. Role of the Funding Source The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute. The funding source had no role in the conception, design, analysis, or conduct of the review. Results Study Selection The 2008 USPSTF report (9) included 9 studies in its systematic review (3139); our literature search identified 1771 additional new potential sources (Figure 1). After abstract review, we identified 53 articles for full-text review; of these, 18 unique articles satisfied all inclusion criteria and were included in our analysis (14, 15, 3146). Because 1 article (46) evaluated more than 1 FIT brand in a head-to-head comparison, the final analysis included 19 studies or data sets. Figure 1. Summary of evidence search and selection. USPSTF = U.S. Preventive Services Task Force. Characteristics of Included Studies Table 1 and the Supplement show the main characteristics of the included studies. Eighteen articles described 19 cohort studies of FIT sensitivity and specificity for CRC in average-risk asymptomatic patients; sample sizes ranged from 80 to 27860. Twelve studies (14, 3336, 4042, 4446) used colonoscopy in all patients, regardless of FIT results, as the re

Cigarette Smoking and Adenocarcinomas of the Esophagus and Esophagogastric Junction: A Pooled Analysis From the International BEACON Consortium

BACKGROUND Previous studies that showed an association between smoking and adenocarcinomas of the esophagus and esophagogastric junction were limited in their ability to assess differences by tumor site, sex, dose-response, and duration of cigarette smoking cessation. METHODS We used primary data from 10 population-based case-control studies and two cohort studies from the Barretts Esophagus and Esophageal Adenocarcinoma Consortium. Analyses were restricted to white non-Hispanic men and women. Patients were classified as having esophageal adenocarcinoma (n = 1540), esophagogastric junctional adenocarcinoma (n = 1450), or a combination of both (all adenocarcinoma; n = 2990). Control subjects (n = 9453) were population based. Associations between pack-years of cigarette smoking and risks of adenocarcinomas were assessed, as well as their potential modification by sex and duration of smoking cessation. Study-specific odds ratios (ORs) estimated using multivariable logistic regression models, adjusted for age, sex, body mass index, education, and gastroesophageal reflux, were pooled using a meta-analytic methodology to generate summary odds ratios. All statistical tests were two-sided. RESULTS The summary odds ratios demonstrated strong associations between cigarette smoking and esophageal adenocarcinoma (OR = 1.96, 95% confidence interval [CI] = 1.64 to 2.34), esophagogastric junctional adenocarcinoma (OR = 2.18, 95% CI = 1.84 to 2.58), and all adenocarcinoma (OR = 2.08, 95% CI = 1.83 to 2.37). In addition, there was a strong dose-response association between pack-years of cigarette smoking and each outcome (P < .001). Compared with current smokers, longer smoking cessation was associated with a decreased risk of all adenocarcinoma after adjusting for pack-years (<10 years of smoking cessation: OR = 0.82, 95% CI = 0.60 to 1.13; and > or =10 years of smoking cessation: OR = 0.71, 95% CI = 0.56 to 0.89). Sex-specific summary odds ratios were similar. CONCLUSIONS Cigarette smoking is associated with increased risks of adenocarcinomas of the esophagus and esophagogastric junction in white men and women; compared with current smoking, smoking cessation was associated with reduced risks.

Abdominal obesity, ethnicity and gastro-oesophageal reflux symptoms

Objective: To evaluate the associations between abdominal obesity and gastro-oesophageal reflux disease (GORD), and their interactions with ethnicity and gender. Design: A cross-sectional study. Participants completed detailed symptom questionnaires and underwent a standardised examination, including anthropometric measurements. Setting: A large integrated healthcare system. Patients: 80 110 members of the Kaiser Permanente multiphasic health check-up cohort. Main outcome measures: Gastro-oesophageal reflux-type symptoms. Results: Recent reflux-type symptoms were present in 11% of the population. The multivariate OR for symptoms with an abdominal diameter (adjusted for body mass index (BMI)) of ⩾26 vs <16.3 cm was 1.85 (95% CI 1.55 to 2.21) for the white population, 0.95 (95% CI 0.61 to 1.48) for the black population and 0.64 (95% CI 0.18 to 2.30) for Asians. The mean abdominal diameter was greater in men (22.0 cm, 95% CI 21.9 to 22.0) than in women (20.1 cm, 95% CI 20.0 to 20.1, p<0.01), but the risk of symptoms for any given diameter did not differ markedly by gender. The association between increasing BMI and symptoms was also much stronger among the white population than among the black population. The association between BMI and reflux-type symptoms was partially mediated through abdominal diameter. Conclusions: There was a consistent association between abdominal diameter (independent of BMI) and reflux-type symptoms in the white population, but no consistent associations in the black population or Asians. The BMI association was also strongest among the white population. These findings, combined with the increased prevalence of abdominal obesity in male subjects, suggest that an increased obesity may disproportionately increase GORD-type symptoms in the white population and in male subjects.

Is Diabetes Mellitus an Independent Risk Factor for Colon Cancer and Rectal Cancer

OBJECTIVES:Diabetes mellitus (DM) has been associated with an increased risk of colorectal cancer (CRC). The American College of Gastroenterology Guidelines for Colorectal Cancer Screening 2008 recommend that clinicians be aware of an increased CRC risk in patients with smoking and obesity, but do not highlight the increase in CRC risk in patients with DM. To provide an updated quantitative assessment of the association of DM with colon cancer (CC) and rectal cancer (RC), we conducted a meta-analysis of case–control and cohort studies. We also evaluated whether the association varied by sex, and assessed potential confounders including obesity, smoking, and exercise.METHODS:We identified studies by searching the EMBASE and MEDLINE databases (from inception through 31 December 2009) and by searching bibliographies of relevant articles. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated with fixed- and random-effects models. Several subgroup analyses were performed to explore potential study heterogeneity and bias.RESULTS:DM was associated with an increased risk of CC (summary RR 1.38, 95% CI 1.26–1.51; n=14 studies) and RC (summary RR 1.20, 95% CI 1.09–1.31; n=12 studies). The association remained when we limited the meta-analysis to studies that either controlled for smoking and obesity, or for smoking, obesity, and physical exercise. DM was associated with an increased risk of CC for both men (summary RR 1.43, 95% CI 1.30–1.57; n=11 studies) and women (summary RR 1.35, 95% CI 1.14–1.53; n=10 studies). For RC, there was a significant association between DM and cancer risk for men (summary RR 1.22, 95% CI 1.07–1.40; n=8 studies), but not for women (summary RR 1.09, 95% CI=0.99–1.19; n=8 studies).CONCLUSIONS:These data suggest that DM is an independent risk factor for colon and rectal cancer. Although these findings are based on observational epidemiological studies that have inherent limitations due to diagnostic bias and confounding, subgroup analyses confirmed the consistency of our findings across study type and population. This information can inform risk models and specialty society CRC screening guidelines.

Abdominal Obesity and the Risk of Esophageal and Gastric Cardia Carcinomas

Background: Esophageal adenocarcinoma is rapidly increasing in incidence. Body mass index (BMI) is a risk factor, but its distribution does not reflect the demographic distribution of the cancer (which is highest among White men). Abdominal obesity patterns may explain this discordance, but no studies exist to date. Methods: Nested case-control study within 206,974 members of the Kaiser Permanente multiphasic health checkup cohort; subjects received detailed questionnaires, a standardized examination including BMI and anthropometric measurements, and follow-up of esophageal and cardia cancers using registry data. Results: 101 incident esophageal adenocarcinomas, 105 cardia adenocarcinomas, and 144 esophageal squamous cell carcinomas were detected (BMI data available for all cases; abdominal measurements for a subset). Increasing abdominal diameter was strongly associated with an increased risk of esophageal adenocarcinoma [odds ratio (OR), 3.47; 95% confidence interval (95% CI), 1.29-9.33; abdominal diameter, ≥25 versus <20 cm]. Adjustment for BMI did not diminish this association (BMI-adjusted OR, 4.78; 95% CI, 1.14-20.11). The association was also not diminished by adjustment for gastroesophageal reflux-type symptoms, although reflux-type symptoms were separately associated with both abdominal diameter and cancer risk. Abdominal diameter was not associated with the risk of cardia adenocarcinomas (OR, 1.28; 95% CI, 0.38-4.25; diameter, ≥25 versus <20 cm) or esophageal squamous cell carcinomas (OR, 0.78; 95% CI, 0.32-1.92). Conclusions: Increasing abdominal diameter was associated with an increased risk of esophageal adenocarcinoma, independent of BMI. Cancer risk was not substantially mediated through gastroesophageal reflux-type symptoms, although symptoms may imperfectly measure reflux severity. Given abdominal obesity is more common among males, these findings suggest that increases in obesity may disproportionately increase the risk of esophageal adenocarcinoma in males. (Cancer Epidemiol Biomarkers Prev 2008;17(2):352–8)

Impact of Endoscopic Surveillance on Mortality From Barrett's Esophagus–Associated Esophageal Adenocarcinomas

BACKGROUND & AIMS Although patients with Barretts esophagus commonly undergo endoscopic surveillance, its effectiveness in reducing mortality from esophageal/gastroesophageal junction adenocarcinomas has not been evaluated rigorously. METHODS We performed a case-control study in a community-based setting. Among 8272 members with Barretts esophagus, we identified 351 esophageal adenocarcinoma: 70 in persons who had a prior diagnosis of Barretts esophagus (who were eligible for surveillance); 51 of these patients died, 38 as a result of the cancers (cases). Surveillance histories were contrasted with a sample of 101 living persons with Barretts esophagus (controls), matched for age, sex, and duration of follow-up evaluation. RESULTS Surveillance within 3 years was not associated with a decreased risk of death from esophageal adenocarcinoma (adjusted odds ratio, 0.99; 95% confidence interval, 0.36-2.75). Fatal cases were nearly as likely to have received surveillance (55.3%) as were controls (60.4%). A Barretts esophagus length longer than 3 cm and prior dysplasia each were associated with subsequent mortality, but adjustment for these did not change the main findings. Although all patients should be included in evaluations of effectiveness, excluding deaths related to cancer treatment and patients who failed to complete treatment, changed the magnitude, but not the significance, of the association (odds ratio, 0.46; 95% confidence interval, 0.13-1.64). CONCLUSIONS Endoscopic surveillance of patients with Barretts esophagus was not associated with a substantially decreased risk of death from esophageal adenocarcinoma. The results do not exclude a small to moderate benefit. However, if such a benefit exists, our findings indicate that it is substantially smaller than currently estimated. The effectiveness of surveillance was influenced partially by the acceptability of existing treatments and the occurrence of treatment-associated mortality.

A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus.

Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barretts esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precancerous Barretts esophagus (n = 3,175) with 10,120 controls in 2 phases. For the combined case group, we identified three new associations. The first is at 19p13 (rs10419226: P = 3.6 × 10−10) in CRTC1 (encoding CREB-regulated transcription coactivator), whose aberrant activation has been associated with oncogenic activity. A second is at 9q22 (rs11789015: P = 1.0 × 10−9) in BARX1, which encodes a transcription factor important in esophageal specification. A third is at 3p14 (rs2687201: P = 5.5 × 10−9) near the transcription factor FOXP1, which regulates esophageal development. We also refine a previously reported association with Barretts esophagus near the putative tumor suppressor gene FOXF1 at 16q24 and extend our findings to now include esophageal adenocarcinoma.

Body mass index in relation to oesophageal and oesophagogastric junction adenocarcinomas: a pooled analysis from the International BEACON Consortium

Background Previous studies suggest an association between obesity and oesophageal (OA) and oesophagogastric junction adenocarcinomas (OGJA). However, these studies have been limited in their ability to assess whether the effects of obesity vary by gender or by the presence of gastro-oesophageal reflux (GERD) symptoms. Methods Individual participant data from 12 epidemiological studies (8 North American, 3 European and 1 Australian) comprising 1997 OA cases, 1900 OGJA cases and 11 159 control subjects were pooled. Logistic regression was used to estimate study-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between body mass index (BMI, kg/m2) and the risk of OA and OGJA. Random-effects meta-analysis was used to combine these ORs. We also investigated effect modification and synergistic interaction of BMI with GERD symptoms and gender. Results The association of OA and OGJA increased directly with increasing BMI (P for trend <0.001). Compared with individuals with a BMI <25, BMI ≥40 was associated with both OA (OR 4.76, 95% CI 2.96–7.66) and OGJA (OR 3.07, 95% CI 1.89–4.99). These associations were similar when stratified by gender and GERD symptoms. There was evidence for synergistic interaction between BMI and GERD symptoms in relation to OA/OGJA risk. Conclusions These data indicate that BMI is directly associated with OA and OGJA risk in both men and women and in those with and without GERD symptoms. Disentangling the relationship between BMI and GERD will be important for understanding preventive efforts for OA and OGJA.