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RECURRENCE IS RARE FOLLOWING COMPLETE ERADICATION OF INTESTINAL METAPLASIA IN PATIENTS WITH BARRETT’S ESOPHAGUS AND PEAKS AT 18 MONTHS
Journal Pre-proof RECURRENCE IS RARE FOLLOWING COMPLETE ERADICATION OF INTESTINAL METAPLASIA IN PATIENTS WITH BARRETT’S ESOPHAGUS AND PEAKS AT 18 MONTHS Sachin Wani, MD, Samuel Han, MD, Vladimir Kushnir, MD, Dayna Early, MD, Daniel Mullady, MD, Hazem Hammad, MD, Brian Brauer, MD, Adarsh Thaker, MD, Violette Simon, MS, Eze Ezekwe, BS, Thomas Hollander, MS, Mariah Wood, BS, Amit Rastogi, MD, Steven Edmundowicz, MD, V. Raman Muthusamy, MD, Srinadh Komanduri, MD PII: DOI: Reference:
S1542-3565(20)30098-7 https://doi.org/10.1016/j.cgh.2020.01.019 YJCGH 56964
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 11 January 2020 Please cite this article as: Wani S, Han S, Kushnir V, Early D, Mullady D, Hammad H, Brauer B, Thaker A, Simon V, Ezekwe E, Hollander T, Wood M, Rastogi A, Edmundowicz S, Muthusamy VR, Komanduri S, RECURRENCE IS RARE FOLLOWING COMPLETE ERADICATION OF INTESTINAL METAPLASIA IN PATIENTS WITH BARRETT’S ESOPHAGUS AND PEAKS AT 18 MONTHS, Clinical Gastroenterology and Hepatology (2020), doi: https://doi.org/10.1016/j.cgh.2020.01.019. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 by the AGA Institute
RECURRENCE IS RARE FOLLOWING COMPLETE ERADICATION OF INTESTINAL METAPLASIA IN PATIENTS WITH BARRETT’S ESOPHAGUS AND PEAKS AT 18 MONTHS Sachin Wani, MD,1 Samuel Han, MD,1 Vladimir Kushnir, MD,2 Dayna Early, MD,2 Daniel Mullady, MD,2 Hazem Hammad, MD,1 Brian Brauer, MD,1 Adarsh Thaker, MD,3 Violette Simon, MS,1 Eze Ezekwe, BS,1 Thomas Hollander, MS,2 Mariah Wood, BS,4 Amit Rastogi, MD,5 Steven Edmundowicz MD,1 V. Raman Muthusamy, MD,3 Srinadh Komanduri, MD4 1. Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado 2. Division of Gastroenterology and Hepatology, Washington University School of Medicine, St. Louis, Missouri 3. Vatche and Tamar Maoukian Division of Digestive Diseases, University of California Los Angeles, Los Angeles, California 4. Division of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 5. Division of Gastroenterology and Hepatology, University of Kansas School of Medicine, Kansas City, Kansas
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Correspondence: Sachin Wani, MD Associate Professor of Medicine Division of Gastroenterology and Hepatology University of Colorado Anschutz Medical Center Mail Stop F735 1635 Aurora Court, Rm 2.031 Aurora, CO 80045 Fax: 720-848-2749 Email: [email protected]
Results of this study were presented in part as oral presentations at the Digestive Disease Week 2019, San Diego. Conflict of Interest Disclosures: SW, RM, SK – consultants for Boston Scientific and Medtronic; AR – consultant for Olympus, Cook; BB – consultant for Medtronic. No author has other financial, personal or professional conflicts to declare related to this study. Funding/Support: This study was funded by the American Gastroenterological Association Research Scholar Award in GERD and Barrett’s Esophagus, the University of Colorado Department of Medicine Outstanding Early Scholars Program (SW), and NIH T32DK007038 (SH) Role of the Funder/Sponsor: The AGA had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Author Contributions: Dr. Wani had full access to all of the data and in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. 2
Concept and Design: Wani, Kushnir, Rastogi, Muthusamy and Komanduri Acquisition, analysis, or interpretation of data: Wani, Han, Simon, Kushnir, Early, Mullady, Hammad, Brauer, Thaker, Ezekwe, Hollander, Rastogi, Edmundowicz, Muthusamy, Komanduri Drafting of the manuscript: Wani Critical revision of the manuscript for important intellectual content: Wani, Han, Simon, Kushnir, Early, Mullady, Hammad, Brauer, Thaker, Ezekwe, Hollander, Rastogi, Edmundowicz, Muthusamy, Komanduri Statistical analysis: Han, Wani Obtained funding: Wani. Administrative, technical, or material support: Simon, Ezekwe, Hollander Supervision: Wani, Kushnir, Early, Rastogi, Muthusamy, Komanduri
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ABBREVIATIONS: BE – Barrett’s esophagus EAC – esophageal adenocarcinoma IMC – intramucosal cancer CI – confidence interval LGD – low-grade dysplasia HGD – high-grade dysplasia NDBE – non-dysplastic Barrett’s esophagus GEJ – gastroesophageal junction GI – gastrointestinal EET – endoscopic eradication therapy EMR – endoscopic mucosal resection PPI – proton pump inhibitor CE-IM – complete eradication of intestinal metaplasia CE-D – complete eradication of dysplasia OR – odds ratio aOR – adjusted odds ratio SD – standard deviation
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Abstract Background & Aims: There have been few studies of the long-term durability of complete eradication of intestinal metaplasia (CE-IM) in patients with Barrett’s esophagus (BE)-related neoplasia who received endoscopic eradication therapy (EET). Data are needed to guide surveillance interval protocols and identify patients at risk for recurrence. We assessed the rate of recurrence of intestinal metaplasia and dysplasia, histologic features, and outcomes after recurrence of CE-IM, and identified factors associated with recurrence. Methods: We performed a prospective study of 807 patients with BE who underwent EET, which produced CE-IM, at 4 tertiary-care referral centers, from January 2013 to October 2018. Kaplan-Meier estimates of cumulative incidence rates (IR) of recurrence were calculated for up to 5 years following CE-IM and were stratified by baseline level of histology. Density estimates of recurrence were used to determine the change in the rate of recurrence over time. We conducted logistic regression analysis to identify factors associated with recurrence. Results: Intestinal metaplasia recurred in 121 patients (15%; IR, 5.2/100 person-years), and dysplasia recurred in 36 patients (4.5%; IR, 1.6/100 person-years), after a median follow-up time of 2317 person-years. The rate of recurrence was not constant and the time to any recurrence converged to a normal distribution; recurrences peaked at 1.6 y after patients had CE-IM. Baseline high-grade dysplasia or intramucosal cancer (adjusted odds ratio [aOR], 4.19), presence of reflux symptoms (aOR, 12.1) or hiatal hernia (aOR, 13.8), and number of sessions required to achieve CE-IM (aOR, 1.8) were associated with recurrence. Conclusions: In a prospective study of a large cohort of patients with BE undergoing EET, we found a low rate of recurrence after CE-IM. The rate of recurrence peaked at 1–2 y after CE-IM. These findings indicate that aggressive surveillance might not be necessary more than 1 y after CE-IM and should be considered in surveillance guidelines. Clinicaltrials.gov no: NCT02634645 5
KEY WORDS: esophageal cancer, predictors, response to treatment, risk factor
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Introduction Barrett’s esophagus (BE) is characterized by the replacement of the normal stratified squamous epithelium of the distal esophagus with specialized columnar epithelium with intestinal metaplasia.1, 2 BE is associated with an increased risk of esophageal adenocarcinoma (EAC); a cancer that has increased dramatically in most Western populations over the last four decades and associated with a dismal 5-year survival rate of <20%.3 Malignant transformation of BE to EAC is thought to occur in a stepwise fashion through the histopathologic stages of low-grade dysplasia (LGD), then high-grade dysplasia (HGD) which in turn gives rise to intramucosal cancer (IMC) and eventually progresses to invasive EAC. This pathway provides an opportunity to halt the progression and decrease the incidence of Barrett’s-related EAC and ultimately impact the morbidity and mortality related to this lethal cancer.
Endoscopic eradication therapy (EET) in BE patients at highest risk for progression to invasive EAC (IMC, HGD and LGD) is a well-established and effective strategy that minimizes the risk of malignant progression; a practice that has been endorsed by gastrointestinal society guidelines and quality indicator documents.2, 4-6 Surveillance with serial endoscopy is recommended to assess for recurrence of BE and the frequency of surveillance is based on the grade of dysplasia at baseline prior to EET. 2, 5, 7, 8 Current guidelines recommend a higher frequency of surveillance endoscopies in the first two years of surveillance.1, 2, 5 Although an attenuated schedule of surveillance endoscopy in patients achieving CE-IM was recently proposed, results from this study also suggest a higher frequency of surveillance endoscopies in the first year after CE-IM.9 However, this study was based on registry data and therefore lacked granular information on timelines, predictors and outcomes of recurrence. Reports regarding the shape of the recurrence 7
curve remain conflicting: some published studies suggest a relatively constant rate of recurrence while others report a front-loaded risk of recurrence in year 1 after achieving CE-.10-12 A reliable estimate of the risk of recurrence after achieving CE-IM is critical to establish and validate surveillance guidelines (duration and frequency of surveillance endoscopy), assess costeffectiveness and educate physicians and patients before embarking on EET. In addition, current literature lacks studies that provide data with regards to long-term risk of recurrence and clinical outcomes of patients following recurrence and are generally under-powered to evaluate predictors of recurrence of intestinal metaplasia and dysplasia.
The aims of this study were: (i) to assess the rate of recurrence of intestinal metaplasia and dysplasia, (ii) to describe recurrence histology and outcomes after recurrence, and (iii) to determine the predictors of recurrence of IM and dysplasia in BE patients undergoing EET and achieving CE-IM.
Methods The Treatment with Resection and Endoscopic Ablation Techniques for Barrett’s esophagus (TREAT-BE) Consortium This is a multicenter study reporting outcomes after EET for BE patients at four tertiary care centers. The consortium was developed to establish quality indicators in EET and to assess clinical outcomes after EET.4 Approval from the Institutional Review Board or the Human
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Research Protection Office at each site was obtained (ClinicalTrials.gov: NCT02634645). All authors had access to the study data and reviewed and approved the final manuscript.
Study population Patients with BE-related neoplasia referred for EET were recruited prospectively from January 2013 to October 2018. Selected patients with non-dysplastic BE (NDBE) were included if they were deemed high risk for progression (age <50 years with long-segment BE or family history of EAC in a first-degree relative). Patients were eligible for inclusion only if they had endoscopic evidence of columnar lined esophagus in the tubular esophagus, accompanying biopsies from the esophagus demonstrating intestinal metaplasia, and underwent EET. BE patients were categorized according to the revised Vienna classification for GI mucosal neoplasia into the following categories: NDBE, indefinite for dysplasia, LGD, HGD or EAC (sub-classified as IMC and invasive EAC).1, 13 The diagnosis at inception was confirmed by expert GI pathologists at their respective sites. Patients who had received one or more EET treatments prior to enrollment had collection of retrospective data with subsequent prospective data collection of ensuring treatments or surveillance endoscopies. Patients who had not yet undergone treatment were prospectively enrolled in this study.
Data collection and reporting system This consortium utilized standardized case report forms to collect the following information: a) demographics, medical comorbidities, smoking history, medication use [aspirin, non-steroid anti-
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inflammatory drugs, proton pump inhibitors (PPIs) and histamine-2 receptor blockers], past surgical history, family history of BE and EAC; b) endoscopic/histologic data from referring physicians; c) reflux symptoms and quality of life assessment data through self-administered, validated questionnaires d) endoscopic findings with landmarks, BE length, presence of visible lesions, details of EET including number of sessions and outcomes including adverse events, and histology data at inception and during treatment and e) endoscopic and histologic data in patients undergoing surveillance endoscopy. Study data were collected and managed using the REDCap electronic data capture tools, a secure online database system hosted at the University of Colorado. Real-time monitoring for logic checks and consistency were conducted to maintain data integrity.
Endoscopic eradication therapy and surveillance protocol While this consortium does not mandate protocols for care, a suggested protocol for EET and follow-up was discussed among participating endoscopists.14 Briefly, this protocol included medical therapy with twice-daily PPI prior to and throughout EET. EMR was performed for all visible lesions typically using band-ligation resection technique. Patients with invasive EAC were referred for consideration for esophagectomy. Ablation of the remaining BE segment or the entire BE in the absence of any visible lesions was predominantly performed using radiofrequency ablation (RFA). Ablation of the gastroesophageal junction and gastric cardia was routinely performed. Patients underwent EET every 2-3 months after the initial treatment with the goal of achieving CE-IM. Patients were enrolled in surveillance programs after achieving the endpoint of CE-IM. Endoscopic surveillance included systematic biopsies obtained in a four
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quadrant fashion every 1-2 cm through the entire pretreatment length of BE including the gastric cardia along with target biopsies of any visible lesion. Tissue acquisition at the gastroesophageal junction (GEJ) included sampling of the cardia, whether by sampling across the squamocolumnar junction (SCJ) or by separately sampling just below the top of gastric folds. Biopsies across the SCJ or distinctly from the gastric cardia were all considered together as biopsies at the GEJ.15 Surveillance intervals were determined based on pre-treatment histology: for HGD/IMC patients, every 3-6 months for years 1 and 2 then annually thereafter; for LGD patients, and every 6 months for year 1 then annually thereafter.
Study definitions CE-IM was defined as the absence of endoscopically visible BE and intestinal metaplasia on esophageal biopsies that included the entire pretreatment BE length and squamocolumnar junction after a single endoscopy.16 CE-D was defined as the absence of dysplasia on esophageal biopsies in the presence or absence of endoscopically visible BE after a single endoscopy. Recurrence of intestinal metaplasia or dysplasia was defined as histologic evidence of intestinal metaplasia or dysplasia on biopsies or EMR specimens taken from the esophagus or squamocolumnar junction after CE-IM was achieved in the presence or absence of endoscopically visible BE. Second or subsequent CE-IM was defined as CE-IM achieved after recurrence.
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Study outcomes and statistical analysis The primary study outcome was the overall rate of intestinal metaplasia and dysplasia recurrence in BE patients achieving CE-IM. The secondary outcomes were: (i) recurrence rates stratified by baseline histology, (ii) recurrence rate changes over time, (iii) post-recurrence histology and clinical outcomes, and (iv) intestinal metaplasia and dysplasia recurrence predictors in BE patients who underwent EET and achieved CE-IM. Given the lack of consensus in the literature regarding the definition of CE-IM with regards to the number of negative endoscopies, sensitivity analysis was performed with a definition of CE-IM requiring two such endoscopy visits.
Among patients who achieved CE-IM, the proportion of patients who had recurrence of intestinal metaplasia or dysplasia was calculated. Kaplan-Meier estimates of cumulative incidence were calculated for up to 5 years following CE-IM and were stratified by baseline level of histology (overall cohort, LGD only and HGD/EAC only cohorts). We constructed right-censored Kaplan Meier failure curves for any recurrence after CE-IM and calculated rate ratios, comparing the incidence rates of recurrence between patients with baseline LGD and HGD/EAC using the Mantel-Haenszel method. The incidence rates and 95% confidence intervals (CI) of any recurrence and dysplastic recurrence were calculated using a Poisson model. The EpanechikovKernel density estimate was used to determine the change in the rate of recurrence over time. Logistic regression was performed to identify factors associated with recurrence. All statistical analyses were performed using Stata (v.15.1, StataCorp, College Station, TX).
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Results Patient characteristics A total of 807 patients who achieved CE-IM were included in this analysis (Table 1, Figure 1). The mean age was 65.2 years [standard deviation (SD) 11.4] and the majority were Caucasian males with a mean BE length of 3.9 cm (SD 2.3). Of the included patients, 94% underwent EET for dysplasia or EAC [baseline histology: NDBE (7.6%), LGD (29.6%), HGD (32.6%), EAC 26.1%]. Overall 98% of patients in this cohort were treated with EMR and RFA (alone or in combination) for a mean of 2.6 (SD 1.3) sessions to achieve CE-IM. Patients were followed for 2317 person years [mean follow-up of 3.3 (SD 2.7) years per patient] after they achieved CE-IM.
Rates of recurrence of intestinal metaplasia and dysplasia in overall cohort and stratified by baseline histology Recurrence of intestinal metaplasia: Recurrence of intestinal metaplasia occurred in 121 (15%) of patients during a follow-up of 2317 person-years. The number of patients with recurrence of intestinal metaplasia with a baseline diagnosis of LGD and HGD/EAC was 27/239 (11.3%) and 55/507 (10.8%), respectively. The incidence rate of intestinal metaplasia was 5.2 (95% CI: 4.4-6.2) per 100 person-years in the overall cohort, 2.8 (95% CI: 1.9-4.0) per 100 person-years among patients with LGD and 6.7 (95% CI: 5.4-8.2) per 100 person-years among patients with HGD/EAC (Figure 2). Baseline HGD/EAC patients had higher recurrence rates (rate ratio 2.23, 95% CI 1.51-3.26) compared to patients with a baseline diagnosis of LGD (Figure 2).
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Recurrence of dysplasia: Recurrence of dysplasia was noted in 41 (5.1%) of patients included in this cohort. The number of patients with recurrence of dysplasia with a baseline diagnosis of LGD and HGD/EAC was 6/239 (2.5%) and 35/507 (6.9%), respectively. The incidence rate of dysplasia was 1.8 (95% CI: 1.3-2.4) per 100 person-years in the overall cohort, 0.6 (95% CI: 0.3-1.4) per 100 person-years among patients with LGD and 2.9 (95% CI: 2.1-3.9) per 100 person-years among patients with HGD/EAC.
Sensitivity analysis: A sensitivity analysis that included the entire cohort of 807 patients defining CE-IM as two negative endoscopies showed similar rates of recurrence. Recurrence of intestinal metaplasia occurred in 100 (12.4%) of patients. The number of patients with recurrence of intestinal metaplasia with a baseline diagnosis of LGD and HGD/EAC was 17/239 (7.1%) and 50/507 (9.9%), respectively. The incidence rate of recurrent intestinal metaplasia was 3.6 (95% CI: 3.65.2) per 100 person-years in the overall cohort, 2.5 (95% CI: 1.7-3.7) per 100 person-years among patients with LGD and 5.2 (95% CI: 4.1-6.6) per 100 person-years among patients with HGD/EAC. Recurrence of dysplasia was noted in 30 (3.7%) patients and the number of patients with recurrence of dysplasia with a baseline diagnosis of LGD and HGD/EAC was 6/239 (2.5%) and 24/507 (4.7%), respectively. The incidence rate of dysplasia was 1.3 (95% CI: 0.9-1.8) per 100 person-years in the overall cohort, 0.6 (95% CI: 0.3-1.4) per 100 person-years among patients with LGD and 1.9 (95% CI: 1.3-2.9) per 100 person-years among patients with HGD/EAC. 14
Change in the rate of recurrence over time Table 2 provides detailed Kaplan-Meier estimates of cumulative incidence with 95% CI of any recurrence, recurrence with any dysplasia, recurrence with HGD or higher histology and recurrence with EAC by year (up to year 5) following CE-IM in overall cohort and stratified based on baseline histology (LGD and HGD/EAC). Using the Epanechikov-Kernel density estimate, the time to any recurrence converges to a normal distribution with recurrences peaking at 1.6 years after achieving CE-IM (Figure 3). Weibull regression similarly demonstrated that the rate of recurrence did not conform to a constant rate (p<0.001, Supplementary Figure 1). A sensitivity analysis defining CE-IM as two negative endoscopies did not significantly impact these results. Supplementary Table 1 provides estimates of cumulative incidence with 95% CI of any recurrence, recurrence with any dysplasia, recurrence with HGD or higher histology and recurrence with EAC by year following CE-IM using this definition (sensitivity analysis) in overall cohort and stratified based on baseline histology. The time to any recurrence using this definition also followed a normal distribution.
Histologic and clinical outcomes associated with recurrence The histologic grade of recurrence stratified by baseline histology is provided in Supplementary Table 2. All recurrences were at the same baseline or lower histological grade. Second CE-IM was achieved in 118 (97.5%) of patients after which a second recurrence was noted in five (4.2%) patients at a mean surveillance period of 2.3 (SD 0.97) years. None of the patients included in this cohort progressed to invasive cancer or required esophagectomy.
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Predictors of recurrence of intestinal metaplasia and dysplasia Baseline HGD/EAC was a significant predictor of any recurrence [adjusted odds ratio (aOR) 4.2, 95% CI 1.9-9.4]. In addition, presence of ongoing GERD symptoms at inception (aOR 12.1, 95% CI 4.3-34.1) along with presence (aOR 13.8, 95% CI 3.4-56.3) and size of hiatal hernia (aOR 2.3, 95% CI 1.3-4.2) predicted a higher risk of any recurrence. The number of sessions required to achieve CE-IM also predicted a higher risk of any recurrence (aOR 1.78, 95% CI 1.4-2.2) (Table 3). There was no association of recurrence with other clinical variables such as age and BE length. Sensitivity analysis defining CE-IM as two negative endoscopies identified similar predictors of recurrence (Table 3).
Discussion Literature to date has consistently demonstrated the risk of recurrence in BE patients undergoing EET and achieving CE-IM.7, 8 Variable rates and shape of recurrence curves have been described with some suggesting a relatively constant rate of recurrence while others have reported a frontloaded risk of recurrence.10-12 It is vital to understand how and when recurrences occur to plan effective surveillance after CE-IM.
The results of this large multicenter study that included 807 BE patients (majority with a diagnosis of HGD/IMC – 59%) achieving CE-IM demonstrated a low rate of recurrence of intestinal metaplasia and dysplasia. During a follow-up period of 2317 person-years, recurrence of intestinal metaplasia was noted in 15% of patients for an incidence rate of 5.2 per 100 person-
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years. Recurrence of dysplasia was noted in 5.1% of patients for an incidence rate of 1.8 per 100 person-years. This study provides robust estimates of annual incidence rates of recurrence of intestinal metaplasia and dysplasia (overall and stratified by baseline histology). Our results demonstrate that the Kaplan-Meier estimates of overall recurrence and those stratified by baseline histology were consistent with a normal distribution peaking between years 1 and 2. Unlike prior studies, the risk of recurrence was not highest immediately after achieving CE-IM but instead between the first and second year of follow-up. Surveillance endoscopy schemes that have the shortest intervals between endoscopies in the first year may not be optimally timed. Results from this study suggest that evenly spaced surveillance intervals should yield the same rate of recurrence and question the need for aggressive surveillance during the first year after CE-IM. Placing our results in context with other published studies, the results from the Ablation in Intestinal Metaplasia Containing Dysplasia trial that included 119 patients reported a propensity for an acute phase of elevated recurrence risk during the first year that is followed by a longer term trend toward decreased rates of recurrence over time.11 On the other hand, in a cohort study of 594 patients, Sami and colleagues reported that recurrence of BE following CEIM remained constant over time.12 Results from this study also emphasize the importance of keeping patients in surveillance programs after achieving CE-IM. Consistent with recent reports,7, 8, 10 our study showed that all recurrences were of the same or lower histological grade and second CE-IM was achieved in nearly 98% patients. None of the patients with recurrent disease progressed to invasive EAC or required surgery.
There are limited data describing the predictors of recurrence of intestinal metaplasia and dysplasia. This is due to the relatively small numbers of patients with recurrence limiting the 17
ability to perform multivariable regression analysis or lack of comprehensive data collection.7, 12, 17
This knowledge gap was addressed in this study which reported on clinical, histological and
endoscopic predictors of recurrence. This study showed that presence of GERD symptoms at inception (aOR 12.13), presence (aOR 13.8) and size (aOR 2.33) of hiatal hernia were significant predictors of recurrence. These data add to the growing body of literature demonstrating the impact of uncontrolled GERD symptoms on long-term outcomes related to EET.14 Optimizing anti-reflux therapy (confirming compliance to BID PPI therapy, medication maximization or fundoplication in appropriate candidates) during EET for optimal outcomes is critical. Baseline histology of HGD or EAC (aOR 4.2) was a significant predictor of recurrence in this study. The number of EET sessions needed to achieve CE-IM was a significant predictor of recurrence with the odds of recurrence increasing by 78% with each added endoscopic procedure to achieve CEIM. This finding suggests that the time to achieve CE-IM is associated with improved long-term outcomes. It should be noted that our sensitivity analysis defining CE-IM as occurring after two consecutive normal EGDs did not significantly alter these results.
These results have significant clinical implications. Using the RAND/University of California, Los Angeles Appropriateness Methodology, the TREAT-BE consortium recently developed quality indicators for EET in the management of patients with BE-related neoplasia in an effort to ensure the delivery of high-quality care, reduce variability in health care and ultimately improve patient outcomes.4, 18 Consistent with the framework for high-quality measures established by the National Quality Forum, outcomes measures tied to critical endpoints such as complete eradication rates were established. Among other quality indicators, this document identified the rate of CE-IM at 18 months among BE patients undergoing EET and the 18
importance of reflux control as priority quality indicators. This document highlighted research gaps in outcomes data and the need for future prospective studies using standardized definitions that focus on recurrence as the primary outcome. The results of this study address this research gap and provide outcomes data validating the importance of these two priority quality indicators.
This study has several limitations. These data describe treatment results at tertiary care centers by experienced endoscopists, thus limiting the generalizability of our results. Treatment and surveillance practices were discussed but not standardized. However, this is likely a better reflection of clinical practice at high-volume centers and thus these ‘real life’ data increase the external validity of our results. Central pathology reading was not performed but involved confirmation of dysplasia by expert dedicated GI pathologists at participating centers. The results of this study provide estimates for recurrence up to 5 years after CE-IM and although these follow-up times were long, whether rates of recurrence plateau or continue to decrease after year 5 needs to be explored in future studies with longer follow-up duration. Since the vast majority of patients were treated with EMR and RFA, these results may not be applicable to other ablative techniques such as cryotherapy. Inclusion of high-risk NDBE patients in this cohort also limits the overall generalizability of these results. There are several important strengths to this study. This study provides a robust estimate of annual incidence of recurrence after EET in one of the largest cohorts of patients treated with EET for BE in the United States. Unlike most prior studies, assessment of recurrence rates was an a priori primary outcome of this study.
In summary, results from this large cohort of BE patients undergoing EET demonstrate a low rate of recurrence of intestinal metaplasia and dysplasia after CE-IM. Importantly, the rate of 19
recurrence followed a normal distribution peaking between years 1 and 2 questioning the need for aggressive surveillance in year 1 after achieving CE-IM. Recurrent BE was never of a more severe histology than the baseline histology prior to EET and retreatment to second CE-IM can be achieved in the vast majority of patients. Finally, this study identified key predictors of recurrence providing validity evidence for proposed quality indicators in EET.
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Wani S, Muthusamy VR, Shaheen NJ, et al. Development of quality indicators for endoscopic eradication therapies in Barrett's esophagus: the TREAT-BE (Treatment with Resection and Endoscopic Ablation Techniques for Barrett's Esophagus) Consortium. Gastrointest Endosc 2017;86:1-17 e3.
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FIGURE LEGEND Figure 1: Study flow chart Figure 2: Estimated proportion of subjects with any recurrence in the overall cohort (top half) and stratified by baseline histologic grade (bottom half) after complete eradication of intestinal metaplasia Figure 3: Epanechikov-Kernel density estimate of any recurrence
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Table 1: Baseline characteristics among patients in the overall cohort and among patients with and without recurrence after endoscopic eradication therapy and achieving complete eradication of intestinal metaplasia Age
Mean age, years (SD) Gender, males (n, %) Race (n, %) Caucasian Hispanic African-American Asian Other BMI Baseline Histology (n, %) NDBE LGD HGD IMC Length of BE (cm) mean (SD) Duration of BE (years) mean (SD) Presence of GERD Symptoms (n, %) Aspirin use (n, %) Hiatal Hernia (n, %) Size of Hiatal Hernia (cm) mean (SD) Nissen fundoplication (n, %) Treatment (n, %) RFA RFA + EMR Cryotherapy EMR alone
Patients Recurrence of achieving CE- Barrett’s IM (n= 807) Esophagus (n=121) 65.2 (11.4) 66.9 (10.6)
No Recurrence of Barrett’s Esophagus (n=686) 63.8 (12.6)
636 (78.9%)
94 (77.7%)
542 (79%)
702 (87%) 29 (3.6%) 8 (1%) 7 (0.9%) 61 (7.6%) 29.1 (6.3)
108 (89.3%) 5 (4.1%) 1 (0.8%) 3 (2.5%) 4 (3.3%) 28.5 (6.3)
594 (86.6%) 24 (3.5%) 7 (1%) 4 (0.6%) 57 (8.3%) 29.7 (7.1)
61 (7.6%) 239 (29.6%) 332 (32.6%) 175 (26.1%) 3.9 (2.3)
12 (9.9%) 27 (22.3%) 55 (45.5%) 27 (22.3%) 4.9 (3.3)
49 (7.1%) 212 (30.9%) 277 (40.4%) 148 (21.6%) 3.6 (1.9)
5.2 (6.2)
5.8 (5.6)
5 (6.4)
50 (6.2%)
24 (19.8%)
26 (3.8%)
158 (19.6%) 591 (73.2%)
33 (33.7%) 100 (82.6%)
125 (18.2%) 491 (71.6%)
2.2 (0.7)
2.4 (0.8)
2.1 (0.7)
39 (4.8%)
7 (5.8%)
32 (4.7%)
387 (47.9%) 394 (48.8%) 7 (0.9%) 7 (0.9%)
50 (41.3%) 45 (37.2%) 7 (5.8%) 7 (5.8%)
337 (49.14%) 349 (50.9%) 0 (0%) 0 (0%)
Sessions needed for CE-IM (mean, SD) Follow-up (months), mean (SD)
2.6 (1.3)
3.1 (1.9)
2.4 (1)
40.3 (32.4)
54.2 (31.4)
32.1 (31.8)
NDBE, non-dysplastic Barrett’s esophagus; LGD, low-grade dysplasia; HGD, high-grade dysplasia; IMC, intramucosal cancer; RFA, radiofrequency ablation; EMR, endoscopic mucosal resection; CE-IM, complete eradication of intestinal metaplasia; SD, standard deviation
Table 2: Kaplan-Meier estimates of the cumulative incidence of recurrence of Barrett’s esophagus and Barrett’s esophagus-related neoplasia by year following CE-IM in the overall cohort and stratified based on baseline histology HGD/EAC at baseline (508) Events Cumulative Incidence (95% CI)
LGD at baseline (239)
Overall cohort (n=807)
Events
Cumulative Incidence (95% CI)
Events
Cumulative Incidence (95% CI)
Any recurrence First
35
6.9 (5-9.4)
6
42
5.2 (3.8-7)
Second
22
6
29
8.8 (6.9-11)
Third
6
11 (9-13.4)
6
10
Fifth
2
7.9 (4.912.1) 8.8 (5.513.1) 10 (6.514.6)
18
Fourth
11.2 (8.814.3) 12.4 (9.815.6) 13.6 (10.916.8) 14 (11.217.3)
2.5 (0.95.4) 5 (2.6-8.6)
12.3 (10.114.7) 13.1 (10.915.7)
Recurrence with LGD or higher First
14
1
0.4 (0, 2.3)
15
1.9 (1-3)
Second
7
2
3 (1.9-4.4)
3
4
3.5 (2.3-5)
Fourth
2
2
Fifth
1
1.3 (0.3, 3.6) 1.7 (0.5, 4.2) 1.7 (0.5, 4.2) 2.1 (0.7, 4.8)
9
Third
2.8 (1.54.6) 4.1 (2.66.3) 4.7 (3.26.9) 5.1 (3.47.4) 5.3 (3.57.6)
3.7 (2.55.3) 4 (2.7-5.6)
Recurrence with HGD or higher First
11
0
0
11
Second
6
2.2 (1.13.8) 3.3 (2-5.3)
0
0
6
Third
3
3.9 (2.4-6)
0
0
3
Fourth
2
0
0
2
Fifth
1
4.3 (2.76.5) 4.5 (2.96.7)
0
0
1
Recurrence with IMC First
4
0.8 (0.2-2)
0
0
4
Year
7 2 3
1 0 1
7
2
1.4 (0.72.4) 2.1 (1.23.4) 2.5 (1.53.8) 2.7 (1.74.1) 2.9 (1.84.2)
0.5 (0.11.3)
Second
2
Third
2
Fourth
0
Fifth
0
1.2 (0.42.6) 1.6 (0.73.1) 1.6 (0.73.1) 1.6 (0.73.1)
0
0
2
0
0
2
0.7 (0.31.6) 1 (0.4-1.9)
0
0
0
1 (0.4-1.9)
0
0
0
1 (0.4-1.9)
LGD, low-grade dysplasia; HGD, high-grade dysplasia; IMC, intramucosal cancer
Table 3: Unadjusted and adjusted odds ratios for any recurrence following complete eradication of intestinal metaplasia [Primary Analysis (at least 1 surveillance endoscopy before recurrence) and Sensitivity Analysis (at least 2 surveillance endoscopies before recurrence)] Variables Unadjusted OR (95% CI)
Primary Analysis P value Adjusted OR (95% CI)
P value
Unadjusted OR (95% CI) 1.01 (0.991.04) 0.47 (0.092.48) 0.99 (0.961.03)
Age
1.02 (0.99-1.04)
0.07
1.01 (0.98-1.03)
0.53
Caucasian Race
7.7 (1.03-56.83)
0.05
4.35 (0.58-32.6)
0.15
BMI
0.98 (0.95-1.02)
0.36
Baseline Histology LGD HGD/EAC
Reference 3.23 (2.29-6.48)
<0.001
Reference 4.19 (1.87-9.39)
<0.001
Reference 3.72 (1.624.59)
Sensitivity Analysis P value Adjusted OR (95% CI) 0.1
P value
1.03 (0.99-1.07)
0.14
Reference 3.67 (1.16-11.59)
0.03
0.38 0.73
<0.001
Presence of GERD Symptoms Hiatal Hernia
4.35 (2.39-7.9)
<0.001
12.13 (4.3-34.1)
<0.001
1.88 (1.15-3.06)
0.01
13.8 (3.37-56.37)
<0.001
Size of Hiatal Hernia
0.61 (0.45-0.84)
0.002
2.33 (1.28-4.24)
0.005
Length of BE
1.23 (1.13-1.35)
<0.001
1 (0.87-1.16)
0.99
Duration of BE
1.02 (0.98-1.06)
0.4
3.25 (1.756.04) 2.38 (1.314.33) 0.66 (0.470.92) 1.22 (1.111.33) 1 (0.96-1.05)
Fundoplication
0.88 (0.38-2.04)
0.77
0.78 (0.3-2.07)
0.63
Family History of Esophageal Cancer
1.22 (0.51-2.95)
0.65
1.06 (0.392.87)
0.12
<0.001 0.005
32.69 (6.96153.72) 2.53 (1.45-4.56)
<0.001 <0.001
0.02
1.25 (0.55-2.82)
0.59
<0.001
0.94 (0.77-1.15)
0.54
0.16
0.94 (0.86-1.01)
0.1
2.07 (0.49-8.77)
0.32
Treatment modalities RFA
0.51 (0.06-4.28)
0.53
RFA + EMR
0.72 (0.09-6.15)
0.77
Cryotherapy
1.7 (0.16-17.3)
0.59
EMR alone
1 (0.1-9.6)
0.99
No. of EET Sessions needed for CE-IM
1.52 (1.3-1.79)
<0.001
1.29 (0.792.09) 0.78 (0.491.26) 23.05 (2.51211.3) 1 (0.2-8.6) 1.78 (1.44-2.21)
<0.001
1.43 (1.221.67)
0.31 0.3 0.006 0.95 <0.001
1.36 (1.02-1.81)
BMI: body mass index; LGD: low-grade dysplasia; HGD: high-grade dysplasia; EAC: esophageal adenocarcinoma; GERD: gastroesophageal reflux disease; BE: Barrett’s esophagus; RFA: radiofrequency ablation; EMR: endoscopic mucosal resection; CE-IM: complete eradication of intestinal metaplasia
0.04
Supplementary Table 1: Kaplan-Meier estimates of the cumulative incidence of recurrence of Barrett’s esophagus and Barrett’s esophagus-related neoplasia by year following CE-IM (under sensitivity analysis requiring 2 negative surveillance endoscopies) in the overall cohort and stratified based on baseline histology HGD/EAC at baseline (508)
LGD at baseline (239)
Overall cohort (n=807)
Events
Cumulative Incidence (95% CI)
Events
Cumulative Incidence (95% CI)
Events
Cumulative Incidence (95% CI)
First
23
4.5 (3-6.7)
5
2.1 (0.94.8)
29
3.6 (2.55.1)
Second
20
8.5 (6.311.2)
7
5 (2.9-8.6)
30
7.3 (5.79.3)
Third
7
9.8 (7.612.7)
7
8 (5.2-12.1)
18
9.5 (7.711.8)
Fourth
6
11 (8.614.1)
2
8.8 (5.813.1)
10
10.8 (8.813.1)
Fifth
2
11.4 (8.914.5)
2
9.6 (6.5-14)
6
11.5 (9.513.9)
First
8
1.6 (0.83.1)
1
0.4 (0.072.3)
9
1.1 (0.62.1)
Second
6
2.8 (1.74.6)
3
1.7 (0.74.2)
9
2.2 (1.43.5)
Third
3
3.4 (2.15.3)
1
2.1 (0.94.8)
4
2.7 (1.84.1)
Fourth
1
3.5 (2.35.5)
1
2.5 (1.25.4)
2
3 (2-4.4)
Fifth
1
3.7 (2.45.8)
1
2.9 (1.45.9)
2
3.2 (2.24.7)
Year
Any recurrence
Recurrence with LGD or higher
Recurrence with HGD or higher
First
5
1 (0.4-2.3)
0
0 (0-1.6)
5
0.6 (0.31.4)
Second
5
2 (1.1-3.6)
0
0 (0-1.6)
5
1.2 (0.72.3)
Third
3
2.6 (1.54.3)
0
0 (0-1.6)
3
1.6 (0.92.7)
Fourth
1
2.8 (1.74.6)
0
0 (0-1.6)
1
1.7 (1-2.9)
Fifth
1
3 (1.8-4.8)
0
0 (0-1.6)
1
1.9 (1.1-3)
0 (0-1.6)
Recurrence with IMC First
1
0.2 (0.031.1)
0
0 (0-1.6)
1
0.1 (0.020.7)
Second
2
0.6 (0.21.7)
0
0 (0-1.6)
2
0.4 (0.11.1)
Third
2
1 (0.4-2.3)
0
0 (0-1.6)
2
0.6 (0.31.4)
Fourth
0
1 (0.4-2.3)
0
0 (0-1.6)
0
0.6 (0.31.4)
Fifth
0
1 (0.4-2.3)
0
0 (0-1.6)
0
0.6 (0.31.4)
Supplementary Table 2: Histologic grade of recurrence based on baseline histology Baseline Histology
Recurrence of NDBE
Recurrence of LGD
Recurrence of HGD
Recurrence of EAC
NDBE (n=61)
12 (100%)
0 (0%)
0 (0%)
0 (0%)
LGD (n=239)
21 (77.8%)
6 (22.2%)
0 (0%)
0 (0%)
HGD (n=332)
35 (63.6%)
6 (10.9%)
14 (25.5%)
0 (0%)
EAC (n=175)
13 (48.1%)
4 (14.8%)
1 (3.7%)
9 (33.3%)
WHAT YOU NEED TO KNOW Background: There have been few studies of the long-term durability of complete eradication of intestinal metaplasia (CE-IM) in patients with Barrett’s esophagus (BE)-related neoplasia who received endoscopic eradication therapy (EET).
Findings: In a prospective study of a large cohort of patients with BE undergoing EET, we found a low rate of recurrence after CE-IM. The rate of recurrence peaked at 1–2 y after CE-IM.
Implications for patient care: Aggressive surveillance might not be necessary more than 1 y after CE-IM and should be considered in development of surveillance guidelines.
S1542-3565(20)30098-7 https://doi.org/10.1016/j.cgh.2020.01.019 YJCGH 56964
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 11 January 2020 Please cite this article as: Wani S, Han S, Kushnir V, Early D, Mullady D, Hammad H, Brauer B, Thaker A, Simon V, Ezekwe E, Hollander T, Wood M, Rastogi A, Edmundowicz S, Muthusamy VR, Komanduri S, RECURRENCE IS RARE FOLLOWING COMPLETE ERADICATION OF INTESTINAL METAPLASIA IN PATIENTS WITH BARRETT’S ESOPHAGUS AND PEAKS AT 18 MONTHS, Clinical Gastroenterology and Hepatology (2020), doi: https://doi.org/10.1016/j.cgh.2020.01.019. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 by the AGA Institute
RECURRENCE IS RARE FOLLOWING COMPLETE ERADICATION OF INTESTINAL METAPLASIA IN PATIENTS WITH BARRETT’S ESOPHAGUS AND PEAKS AT 18 MONTHS Sachin Wani, MD,1 Samuel Han, MD,1 Vladimir Kushnir, MD,2 Dayna Early, MD,2 Daniel Mullady, MD,2 Hazem Hammad, MD,1 Brian Brauer, MD,1 Adarsh Thaker, MD,3 Violette Simon, MS,1 Eze Ezekwe, BS,1 Thomas Hollander, MS,2 Mariah Wood, BS,4 Amit Rastogi, MD,5 Steven Edmundowicz MD,1 V. Raman Muthusamy, MD,3 Srinadh Komanduri, MD4 1. Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado 2. Division of Gastroenterology and Hepatology, Washington University School of Medicine, St. Louis, Missouri 3. Vatche and Tamar Maoukian Division of Digestive Diseases, University of California Los Angeles, Los Angeles, California 4. Division of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 5. Division of Gastroenterology and Hepatology, University of Kansas School of Medicine, Kansas City, Kansas
1
Correspondence: Sachin Wani, MD Associate Professor of Medicine Division of Gastroenterology and Hepatology University of Colorado Anschutz Medical Center Mail Stop F735 1635 Aurora Court, Rm 2.031 Aurora, CO 80045 Fax: 720-848-2749 Email: [email protected]
Results of this study were presented in part as oral presentations at the Digestive Disease Week 2019, San Diego. Conflict of Interest Disclosures: SW, RM, SK – consultants for Boston Scientific and Medtronic; AR – consultant for Olympus, Cook; BB – consultant for Medtronic. No author has other financial, personal or professional conflicts to declare related to this study. Funding/Support: This study was funded by the American Gastroenterological Association Research Scholar Award in GERD and Barrett’s Esophagus, the University of Colorado Department of Medicine Outstanding Early Scholars Program (SW), and NIH T32DK007038 (SH) Role of the Funder/Sponsor: The AGA had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Author Contributions: Dr. Wani had full access to all of the data and in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. 2
Concept and Design: Wani, Kushnir, Rastogi, Muthusamy and Komanduri Acquisition, analysis, or interpretation of data: Wani, Han, Simon, Kushnir, Early, Mullady, Hammad, Brauer, Thaker, Ezekwe, Hollander, Rastogi, Edmundowicz, Muthusamy, Komanduri Drafting of the manuscript: Wani Critical revision of the manuscript for important intellectual content: Wani, Han, Simon, Kushnir, Early, Mullady, Hammad, Brauer, Thaker, Ezekwe, Hollander, Rastogi, Edmundowicz, Muthusamy, Komanduri Statistical analysis: Han, Wani Obtained funding: Wani. Administrative, technical, or material support: Simon, Ezekwe, Hollander Supervision: Wani, Kushnir, Early, Rastogi, Muthusamy, Komanduri
3
ABBREVIATIONS: BE – Barrett’s esophagus EAC – esophageal adenocarcinoma IMC – intramucosal cancer CI – confidence interval LGD – low-grade dysplasia HGD – high-grade dysplasia NDBE – non-dysplastic Barrett’s esophagus GEJ – gastroesophageal junction GI – gastrointestinal EET – endoscopic eradication therapy EMR – endoscopic mucosal resection PPI – proton pump inhibitor CE-IM – complete eradication of intestinal metaplasia CE-D – complete eradication of dysplasia OR – odds ratio aOR – adjusted odds ratio SD – standard deviation
4
Abstract Background & Aims: There have been few studies of the long-term durability of complete eradication of intestinal metaplasia (CE-IM) in patients with Barrett’s esophagus (BE)-related neoplasia who received endoscopic eradication therapy (EET). Data are needed to guide surveillance interval protocols and identify patients at risk for recurrence. We assessed the rate of recurrence of intestinal metaplasia and dysplasia, histologic features, and outcomes after recurrence of CE-IM, and identified factors associated with recurrence. Methods: We performed a prospective study of 807 patients with BE who underwent EET, which produced CE-IM, at 4 tertiary-care referral centers, from January 2013 to October 2018. Kaplan-Meier estimates of cumulative incidence rates (IR) of recurrence were calculated for up to 5 years following CE-IM and were stratified by baseline level of histology. Density estimates of recurrence were used to determine the change in the rate of recurrence over time. We conducted logistic regression analysis to identify factors associated with recurrence. Results: Intestinal metaplasia recurred in 121 patients (15%; IR, 5.2/100 person-years), and dysplasia recurred in 36 patients (4.5%; IR, 1.6/100 person-years), after a median follow-up time of 2317 person-years. The rate of recurrence was not constant and the time to any recurrence converged to a normal distribution; recurrences peaked at 1.6 y after patients had CE-IM. Baseline high-grade dysplasia or intramucosal cancer (adjusted odds ratio [aOR], 4.19), presence of reflux symptoms (aOR, 12.1) or hiatal hernia (aOR, 13.8), and number of sessions required to achieve CE-IM (aOR, 1.8) were associated with recurrence. Conclusions: In a prospective study of a large cohort of patients with BE undergoing EET, we found a low rate of recurrence after CE-IM. The rate of recurrence peaked at 1–2 y after CE-IM. These findings indicate that aggressive surveillance might not be necessary more than 1 y after CE-IM and should be considered in surveillance guidelines. Clinicaltrials.gov no: NCT02634645 5
KEY WORDS: esophageal cancer, predictors, response to treatment, risk factor
6
Introduction Barrett’s esophagus (BE) is characterized by the replacement of the normal stratified squamous epithelium of the distal esophagus with specialized columnar epithelium with intestinal metaplasia.1, 2 BE is associated with an increased risk of esophageal adenocarcinoma (EAC); a cancer that has increased dramatically in most Western populations over the last four decades and associated with a dismal 5-year survival rate of <20%.3 Malignant transformation of BE to EAC is thought to occur in a stepwise fashion through the histopathologic stages of low-grade dysplasia (LGD), then high-grade dysplasia (HGD) which in turn gives rise to intramucosal cancer (IMC) and eventually progresses to invasive EAC. This pathway provides an opportunity to halt the progression and decrease the incidence of Barrett’s-related EAC and ultimately impact the morbidity and mortality related to this lethal cancer.
Endoscopic eradication therapy (EET) in BE patients at highest risk for progression to invasive EAC (IMC, HGD and LGD) is a well-established and effective strategy that minimizes the risk of malignant progression; a practice that has been endorsed by gastrointestinal society guidelines and quality indicator documents.2, 4-6 Surveillance with serial endoscopy is recommended to assess for recurrence of BE and the frequency of surveillance is based on the grade of dysplasia at baseline prior to EET. 2, 5, 7, 8 Current guidelines recommend a higher frequency of surveillance endoscopies in the first two years of surveillance.1, 2, 5 Although an attenuated schedule of surveillance endoscopy in patients achieving CE-IM was recently proposed, results from this study also suggest a higher frequency of surveillance endoscopies in the first year after CE-IM.9 However, this study was based on registry data and therefore lacked granular information on timelines, predictors and outcomes of recurrence. Reports regarding the shape of the recurrence 7
curve remain conflicting: some published studies suggest a relatively constant rate of recurrence while others report a front-loaded risk of recurrence in year 1 after achieving CE-.10-12 A reliable estimate of the risk of recurrence after achieving CE-IM is critical to establish and validate surveillance guidelines (duration and frequency of surveillance endoscopy), assess costeffectiveness and educate physicians and patients before embarking on EET. In addition, current literature lacks studies that provide data with regards to long-term risk of recurrence and clinical outcomes of patients following recurrence and are generally under-powered to evaluate predictors of recurrence of intestinal metaplasia and dysplasia.
The aims of this study were: (i) to assess the rate of recurrence of intestinal metaplasia and dysplasia, (ii) to describe recurrence histology and outcomes after recurrence, and (iii) to determine the predictors of recurrence of IM and dysplasia in BE patients undergoing EET and achieving CE-IM.
Methods The Treatment with Resection and Endoscopic Ablation Techniques for Barrett’s esophagus (TREAT-BE) Consortium This is a multicenter study reporting outcomes after EET for BE patients at four tertiary care centers. The consortium was developed to establish quality indicators in EET and to assess clinical outcomes after EET.4 Approval from the Institutional Review Board or the Human
8
Research Protection Office at each site was obtained (ClinicalTrials.gov: NCT02634645). All authors had access to the study data and reviewed and approved the final manuscript.
Study population Patients with BE-related neoplasia referred for EET were recruited prospectively from January 2013 to October 2018. Selected patients with non-dysplastic BE (NDBE) were included if they were deemed high risk for progression (age <50 years with long-segment BE or family history of EAC in a first-degree relative). Patients were eligible for inclusion only if they had endoscopic evidence of columnar lined esophagus in the tubular esophagus, accompanying biopsies from the esophagus demonstrating intestinal metaplasia, and underwent EET. BE patients were categorized according to the revised Vienna classification for GI mucosal neoplasia into the following categories: NDBE, indefinite for dysplasia, LGD, HGD or EAC (sub-classified as IMC and invasive EAC).1, 13 The diagnosis at inception was confirmed by expert GI pathologists at their respective sites. Patients who had received one or more EET treatments prior to enrollment had collection of retrospective data with subsequent prospective data collection of ensuring treatments or surveillance endoscopies. Patients who had not yet undergone treatment were prospectively enrolled in this study.
Data collection and reporting system This consortium utilized standardized case report forms to collect the following information: a) demographics, medical comorbidities, smoking history, medication use [aspirin, non-steroid anti-
9
inflammatory drugs, proton pump inhibitors (PPIs) and histamine-2 receptor blockers], past surgical history, family history of BE and EAC; b) endoscopic/histologic data from referring physicians; c) reflux symptoms and quality of life assessment data through self-administered, validated questionnaires d) endoscopic findings with landmarks, BE length, presence of visible lesions, details of EET including number of sessions and outcomes including adverse events, and histology data at inception and during treatment and e) endoscopic and histologic data in patients undergoing surveillance endoscopy. Study data were collected and managed using the REDCap electronic data capture tools, a secure online database system hosted at the University of Colorado. Real-time monitoring for logic checks and consistency were conducted to maintain data integrity.
Endoscopic eradication therapy and surveillance protocol While this consortium does not mandate protocols for care, a suggested protocol for EET and follow-up was discussed among participating endoscopists.14 Briefly, this protocol included medical therapy with twice-daily PPI prior to and throughout EET. EMR was performed for all visible lesions typically using band-ligation resection technique. Patients with invasive EAC were referred for consideration for esophagectomy. Ablation of the remaining BE segment or the entire BE in the absence of any visible lesions was predominantly performed using radiofrequency ablation (RFA). Ablation of the gastroesophageal junction and gastric cardia was routinely performed. Patients underwent EET every 2-3 months after the initial treatment with the goal of achieving CE-IM. Patients were enrolled in surveillance programs after achieving the endpoint of CE-IM. Endoscopic surveillance included systematic biopsies obtained in a four
10
quadrant fashion every 1-2 cm through the entire pretreatment length of BE including the gastric cardia along with target biopsies of any visible lesion. Tissue acquisition at the gastroesophageal junction (GEJ) included sampling of the cardia, whether by sampling across the squamocolumnar junction (SCJ) or by separately sampling just below the top of gastric folds. Biopsies across the SCJ or distinctly from the gastric cardia were all considered together as biopsies at the GEJ.15 Surveillance intervals were determined based on pre-treatment histology: for HGD/IMC patients, every 3-6 months for years 1 and 2 then annually thereafter; for LGD patients, and every 6 months for year 1 then annually thereafter.
Study definitions CE-IM was defined as the absence of endoscopically visible BE and intestinal metaplasia on esophageal biopsies that included the entire pretreatment BE length and squamocolumnar junction after a single endoscopy.16 CE-D was defined as the absence of dysplasia on esophageal biopsies in the presence or absence of endoscopically visible BE after a single endoscopy. Recurrence of intestinal metaplasia or dysplasia was defined as histologic evidence of intestinal metaplasia or dysplasia on biopsies or EMR specimens taken from the esophagus or squamocolumnar junction after CE-IM was achieved in the presence or absence of endoscopically visible BE. Second or subsequent CE-IM was defined as CE-IM achieved after recurrence.
11
Study outcomes and statistical analysis The primary study outcome was the overall rate of intestinal metaplasia and dysplasia recurrence in BE patients achieving CE-IM. The secondary outcomes were: (i) recurrence rates stratified by baseline histology, (ii) recurrence rate changes over time, (iii) post-recurrence histology and clinical outcomes, and (iv) intestinal metaplasia and dysplasia recurrence predictors in BE patients who underwent EET and achieved CE-IM. Given the lack of consensus in the literature regarding the definition of CE-IM with regards to the number of negative endoscopies, sensitivity analysis was performed with a definition of CE-IM requiring two such endoscopy visits.
Among patients who achieved CE-IM, the proportion of patients who had recurrence of intestinal metaplasia or dysplasia was calculated. Kaplan-Meier estimates of cumulative incidence were calculated for up to 5 years following CE-IM and were stratified by baseline level of histology (overall cohort, LGD only and HGD/EAC only cohorts). We constructed right-censored Kaplan Meier failure curves for any recurrence after CE-IM and calculated rate ratios, comparing the incidence rates of recurrence between patients with baseline LGD and HGD/EAC using the Mantel-Haenszel method. The incidence rates and 95% confidence intervals (CI) of any recurrence and dysplastic recurrence were calculated using a Poisson model. The EpanechikovKernel density estimate was used to determine the change in the rate of recurrence over time. Logistic regression was performed to identify factors associated with recurrence. All statistical analyses were performed using Stata (v.15.1, StataCorp, College Station, TX).
12
Results Patient characteristics A total of 807 patients who achieved CE-IM were included in this analysis (Table 1, Figure 1). The mean age was 65.2 years [standard deviation (SD) 11.4] and the majority were Caucasian males with a mean BE length of 3.9 cm (SD 2.3). Of the included patients, 94% underwent EET for dysplasia or EAC [baseline histology: NDBE (7.6%), LGD (29.6%), HGD (32.6%), EAC 26.1%]. Overall 98% of patients in this cohort were treated with EMR and RFA (alone or in combination) for a mean of 2.6 (SD 1.3) sessions to achieve CE-IM. Patients were followed for 2317 person years [mean follow-up of 3.3 (SD 2.7) years per patient] after they achieved CE-IM.
Rates of recurrence of intestinal metaplasia and dysplasia in overall cohort and stratified by baseline histology Recurrence of intestinal metaplasia: Recurrence of intestinal metaplasia occurred in 121 (15%) of patients during a follow-up of 2317 person-years. The number of patients with recurrence of intestinal metaplasia with a baseline diagnosis of LGD and HGD/EAC was 27/239 (11.3%) and 55/507 (10.8%), respectively. The incidence rate of intestinal metaplasia was 5.2 (95% CI: 4.4-6.2) per 100 person-years in the overall cohort, 2.8 (95% CI: 1.9-4.0) per 100 person-years among patients with LGD and 6.7 (95% CI: 5.4-8.2) per 100 person-years among patients with HGD/EAC (Figure 2). Baseline HGD/EAC patients had higher recurrence rates (rate ratio 2.23, 95% CI 1.51-3.26) compared to patients with a baseline diagnosis of LGD (Figure 2).
13
Recurrence of dysplasia: Recurrence of dysplasia was noted in 41 (5.1%) of patients included in this cohort. The number of patients with recurrence of dysplasia with a baseline diagnosis of LGD and HGD/EAC was 6/239 (2.5%) and 35/507 (6.9%), respectively. The incidence rate of dysplasia was 1.8 (95% CI: 1.3-2.4) per 100 person-years in the overall cohort, 0.6 (95% CI: 0.3-1.4) per 100 person-years among patients with LGD and 2.9 (95% CI: 2.1-3.9) per 100 person-years among patients with HGD/EAC.
Sensitivity analysis: A sensitivity analysis that included the entire cohort of 807 patients defining CE-IM as two negative endoscopies showed similar rates of recurrence. Recurrence of intestinal metaplasia occurred in 100 (12.4%) of patients. The number of patients with recurrence of intestinal metaplasia with a baseline diagnosis of LGD and HGD/EAC was 17/239 (7.1%) and 50/507 (9.9%), respectively. The incidence rate of recurrent intestinal metaplasia was 3.6 (95% CI: 3.65.2) per 100 person-years in the overall cohort, 2.5 (95% CI: 1.7-3.7) per 100 person-years among patients with LGD and 5.2 (95% CI: 4.1-6.6) per 100 person-years among patients with HGD/EAC. Recurrence of dysplasia was noted in 30 (3.7%) patients and the number of patients with recurrence of dysplasia with a baseline diagnosis of LGD and HGD/EAC was 6/239 (2.5%) and 24/507 (4.7%), respectively. The incidence rate of dysplasia was 1.3 (95% CI: 0.9-1.8) per 100 person-years in the overall cohort, 0.6 (95% CI: 0.3-1.4) per 100 person-years among patients with LGD and 1.9 (95% CI: 1.3-2.9) per 100 person-years among patients with HGD/EAC. 14
Change in the rate of recurrence over time Table 2 provides detailed Kaplan-Meier estimates of cumulative incidence with 95% CI of any recurrence, recurrence with any dysplasia, recurrence with HGD or higher histology and recurrence with EAC by year (up to year 5) following CE-IM in overall cohort and stratified based on baseline histology (LGD and HGD/EAC). Using the Epanechikov-Kernel density estimate, the time to any recurrence converges to a normal distribution with recurrences peaking at 1.6 years after achieving CE-IM (Figure 3). Weibull regression similarly demonstrated that the rate of recurrence did not conform to a constant rate (p<0.001, Supplementary Figure 1). A sensitivity analysis defining CE-IM as two negative endoscopies did not significantly impact these results. Supplementary Table 1 provides estimates of cumulative incidence with 95% CI of any recurrence, recurrence with any dysplasia, recurrence with HGD or higher histology and recurrence with EAC by year following CE-IM using this definition (sensitivity analysis) in overall cohort and stratified based on baseline histology. The time to any recurrence using this definition also followed a normal distribution.
Histologic and clinical outcomes associated with recurrence The histologic grade of recurrence stratified by baseline histology is provided in Supplementary Table 2. All recurrences were at the same baseline or lower histological grade. Second CE-IM was achieved in 118 (97.5%) of patients after which a second recurrence was noted in five (4.2%) patients at a mean surveillance period of 2.3 (SD 0.97) years. None of the patients included in this cohort progressed to invasive cancer or required esophagectomy.
15
Predictors of recurrence of intestinal metaplasia and dysplasia Baseline HGD/EAC was a significant predictor of any recurrence [adjusted odds ratio (aOR) 4.2, 95% CI 1.9-9.4]. In addition, presence of ongoing GERD symptoms at inception (aOR 12.1, 95% CI 4.3-34.1) along with presence (aOR 13.8, 95% CI 3.4-56.3) and size of hiatal hernia (aOR 2.3, 95% CI 1.3-4.2) predicted a higher risk of any recurrence. The number of sessions required to achieve CE-IM also predicted a higher risk of any recurrence (aOR 1.78, 95% CI 1.4-2.2) (Table 3). There was no association of recurrence with other clinical variables such as age and BE length. Sensitivity analysis defining CE-IM as two negative endoscopies identified similar predictors of recurrence (Table 3).
Discussion Literature to date has consistently demonstrated the risk of recurrence in BE patients undergoing EET and achieving CE-IM.7, 8 Variable rates and shape of recurrence curves have been described with some suggesting a relatively constant rate of recurrence while others have reported a frontloaded risk of recurrence.10-12 It is vital to understand how and when recurrences occur to plan effective surveillance after CE-IM.
The results of this large multicenter study that included 807 BE patients (majority with a diagnosis of HGD/IMC – 59%) achieving CE-IM demonstrated a low rate of recurrence of intestinal metaplasia and dysplasia. During a follow-up period of 2317 person-years, recurrence of intestinal metaplasia was noted in 15% of patients for an incidence rate of 5.2 per 100 person-
16
years. Recurrence of dysplasia was noted in 5.1% of patients for an incidence rate of 1.8 per 100 person-years. This study provides robust estimates of annual incidence rates of recurrence of intestinal metaplasia and dysplasia (overall and stratified by baseline histology). Our results demonstrate that the Kaplan-Meier estimates of overall recurrence and those stratified by baseline histology were consistent with a normal distribution peaking between years 1 and 2. Unlike prior studies, the risk of recurrence was not highest immediately after achieving CE-IM but instead between the first and second year of follow-up. Surveillance endoscopy schemes that have the shortest intervals between endoscopies in the first year may not be optimally timed. Results from this study suggest that evenly spaced surveillance intervals should yield the same rate of recurrence and question the need for aggressive surveillance during the first year after CE-IM. Placing our results in context with other published studies, the results from the Ablation in Intestinal Metaplasia Containing Dysplasia trial that included 119 patients reported a propensity for an acute phase of elevated recurrence risk during the first year that is followed by a longer term trend toward decreased rates of recurrence over time.11 On the other hand, in a cohort study of 594 patients, Sami and colleagues reported that recurrence of BE following CEIM remained constant over time.12 Results from this study also emphasize the importance of keeping patients in surveillance programs after achieving CE-IM. Consistent with recent reports,7, 8, 10 our study showed that all recurrences were of the same or lower histological grade and second CE-IM was achieved in nearly 98% patients. None of the patients with recurrent disease progressed to invasive EAC or required surgery.
There are limited data describing the predictors of recurrence of intestinal metaplasia and dysplasia. This is due to the relatively small numbers of patients with recurrence limiting the 17
ability to perform multivariable regression analysis or lack of comprehensive data collection.7, 12, 17
This knowledge gap was addressed in this study which reported on clinical, histological and
endoscopic predictors of recurrence. This study showed that presence of GERD symptoms at inception (aOR 12.13), presence (aOR 13.8) and size (aOR 2.33) of hiatal hernia were significant predictors of recurrence. These data add to the growing body of literature demonstrating the impact of uncontrolled GERD symptoms on long-term outcomes related to EET.14 Optimizing anti-reflux therapy (confirming compliance to BID PPI therapy, medication maximization or fundoplication in appropriate candidates) during EET for optimal outcomes is critical. Baseline histology of HGD or EAC (aOR 4.2) was a significant predictor of recurrence in this study. The number of EET sessions needed to achieve CE-IM was a significant predictor of recurrence with the odds of recurrence increasing by 78% with each added endoscopic procedure to achieve CEIM. This finding suggests that the time to achieve CE-IM is associated with improved long-term outcomes. It should be noted that our sensitivity analysis defining CE-IM as occurring after two consecutive normal EGDs did not significantly alter these results.
These results have significant clinical implications. Using the RAND/University of California, Los Angeles Appropriateness Methodology, the TREAT-BE consortium recently developed quality indicators for EET in the management of patients with BE-related neoplasia in an effort to ensure the delivery of high-quality care, reduce variability in health care and ultimately improve patient outcomes.4, 18 Consistent with the framework for high-quality measures established by the National Quality Forum, outcomes measures tied to critical endpoints such as complete eradication rates were established. Among other quality indicators, this document identified the rate of CE-IM at 18 months among BE patients undergoing EET and the 18
importance of reflux control as priority quality indicators. This document highlighted research gaps in outcomes data and the need for future prospective studies using standardized definitions that focus on recurrence as the primary outcome. The results of this study address this research gap and provide outcomes data validating the importance of these two priority quality indicators.
This study has several limitations. These data describe treatment results at tertiary care centers by experienced endoscopists, thus limiting the generalizability of our results. Treatment and surveillance practices were discussed but not standardized. However, this is likely a better reflection of clinical practice at high-volume centers and thus these ‘real life’ data increase the external validity of our results. Central pathology reading was not performed but involved confirmation of dysplasia by expert dedicated GI pathologists at participating centers. The results of this study provide estimates for recurrence up to 5 years after CE-IM and although these follow-up times were long, whether rates of recurrence plateau or continue to decrease after year 5 needs to be explored in future studies with longer follow-up duration. Since the vast majority of patients were treated with EMR and RFA, these results may not be applicable to other ablative techniques such as cryotherapy. Inclusion of high-risk NDBE patients in this cohort also limits the overall generalizability of these results. There are several important strengths to this study. This study provides a robust estimate of annual incidence of recurrence after EET in one of the largest cohorts of patients treated with EET for BE in the United States. Unlike most prior studies, assessment of recurrence rates was an a priori primary outcome of this study.
In summary, results from this large cohort of BE patients undergoing EET demonstrate a low rate of recurrence of intestinal metaplasia and dysplasia after CE-IM. Importantly, the rate of 19
recurrence followed a normal distribution peaking between years 1 and 2 questioning the need for aggressive surveillance in year 1 after achieving CE-IM. Recurrent BE was never of a more severe histology than the baseline histology prior to EET and retreatment to second CE-IM can be achieved in the vast majority of patients. Finally, this study identified key predictors of recurrence providing validity evidence for proposed quality indicators in EET.
20
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Wani S, Rubenstein JH, Vieth M, et al. Diagnosis and Management of Low-Grade Dysplasia in Barrett's Esophagus: Expert Review From the Clinical Practice Updates Committee of the American Gastroenterological Association. Gastroenterology 2016;151:822-835. Shaheen NJ, Falk GW, Iyer PG, et al. ACG Clinical Guideline: Diagnosis and Management of Barrett's Esophagus. Am J Gastroenterol 2016;111:30-50; quiz 51. Rubenstein JH, Shaheen NJ. Epidemiology, Diagnosis, and Management of Esophageal Adenocarcinoma. Gastroenterology 2015;149:302-17 e1. Wani S, Muthusamy VR, Shaheen NJ, et al. Development of Quality Indicators for Endoscopic Eradication Therapies in Barrett's Esophagus: The TREAT-BE (Treatment With Resection and Endoscopic Ablation Techniques for Barrett's Esophagus) Consortium. Am J Gastroenterol 2017;112:1032-1048. Standards of Practice C, Wani S, Qumseya B, et al. Endoscopic eradication therapy for patients with Barrett's esophagus-associated dysplasia and intramucosal cancer. Gastrointest Endosc 2018;87:907-931 e9. Fitzgerald RC, di Pietro M, Ragunath K, et al. British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's oesophagus. Gut 2014;63:7-42. Fujii-Lau LL, Cinnor B, Shaheen N, et al. Recurrence of intestinal metaplasia and early neoplasia after endoscopic eradication therapy for Barrett's esophagus: a systematic review and metaanalysis. Endosc Int Open 2017;5:E430-E449. Krishnamoorthi R, Singh S, Ragunathan K, et al. Risk of recurrence of Barrett's esophagus after successful endoscopic therapy. Gastrointest Endosc 2016;83:1090-1106 e3. Cotton CC, Haidry R, Thrift AP, et al. Development of Evidence-Based Surveillance Intervals After Radiofrequency Ablation of Barrett's Esophagus. Gastroenterology 2018;155:316-326 e6. Guthikonda A, Cotton CC, Madanick RD, et al. Clinical Outcomes Following Recurrence of Intestinal Metaplasia After Successful Treatment of Barrett's Esophagus With Radiofrequency Ablation. Am J Gastroenterol 2017;112:87-94. Cotton CC, Wolf WA, Overholt BF, et al. Late Recurrence of Barrett's Esophagus After Complete Eradication of Intestinal Metaplasia is Rare: Final Report From Ablation in Intestinal Metaplasia Containing Dysplasia Trial. Gastroenterology 2017;153:681-688 e2. Sami SS, Ravindran A, Kahn A, et al. Timeline and location of recurrence following successful ablation in Barrett's oesophagus: an international multicentre study. Gut 2019. Schlemper RJ, Riddell RH, Kato Y, et al. The Vienna classification of gastrointestinal epithelial neoplasia. Gut 2000;47:251-5. Komanduri S, Kahrilas PJ, Krishnan K, et al. Recurrence of Barrett's Esophagus is Rare Following Endoscopic Eradication Therapy Coupled With Effective Reflux Control. Am J Gastroenterol 2017;112:556-566. Omar M, Thaker AM, Wani S, et al. The anatomic location of Barrett's esophagus recurrence after endoscopic eradication therapy: development of a simplified surveillance biopsy strategy. Gastrointest Endosc 2019. Wani S, Komanduri S, Muthusamy VR. Endoscopic Eradication Therapy in Barrett's EsophagusRelated Neoplasia: Setting the Bar Right to Optimize Patient Outcomes. Gastroenterology 2016;150:772-4. Tan MC, Kanthasamy KA, Yeh AG, et al. Factors Associated With Recurrence of Barrett's Esophagus After Radiofrequency Ablation. Clin Gastroenterol Hepatol 2019;17:65-72 e5.
21
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Wani S, Muthusamy VR, Shaheen NJ, et al. Development of quality indicators for endoscopic eradication therapies in Barrett's esophagus: the TREAT-BE (Treatment with Resection and Endoscopic Ablation Techniques for Barrett's Esophagus) Consortium. Gastrointest Endosc 2017;86:1-17 e3.
22
FIGURE LEGEND Figure 1: Study flow chart Figure 2: Estimated proportion of subjects with any recurrence in the overall cohort (top half) and stratified by baseline histologic grade (bottom half) after complete eradication of intestinal metaplasia Figure 3: Epanechikov-Kernel density estimate of any recurrence
23
Table 1: Baseline characteristics among patients in the overall cohort and among patients with and without recurrence after endoscopic eradication therapy and achieving complete eradication of intestinal metaplasia Age
Mean age, years (SD) Gender, males (n, %) Race (n, %) Caucasian Hispanic African-American Asian Other BMI Baseline Histology (n, %) NDBE LGD HGD IMC Length of BE (cm) mean (SD) Duration of BE (years) mean (SD) Presence of GERD Symptoms (n, %) Aspirin use (n, %) Hiatal Hernia (n, %) Size of Hiatal Hernia (cm) mean (SD) Nissen fundoplication (n, %) Treatment (n, %) RFA RFA + EMR Cryotherapy EMR alone
Patients Recurrence of achieving CE- Barrett’s IM (n= 807) Esophagus (n=121) 65.2 (11.4) 66.9 (10.6)
No Recurrence of Barrett’s Esophagus (n=686) 63.8 (12.6)
636 (78.9%)
94 (77.7%)
542 (79%)
702 (87%) 29 (3.6%) 8 (1%) 7 (0.9%) 61 (7.6%) 29.1 (6.3)
108 (89.3%) 5 (4.1%) 1 (0.8%) 3 (2.5%) 4 (3.3%) 28.5 (6.3)
594 (86.6%) 24 (3.5%) 7 (1%) 4 (0.6%) 57 (8.3%) 29.7 (7.1)
61 (7.6%) 239 (29.6%) 332 (32.6%) 175 (26.1%) 3.9 (2.3)
12 (9.9%) 27 (22.3%) 55 (45.5%) 27 (22.3%) 4.9 (3.3)
49 (7.1%) 212 (30.9%) 277 (40.4%) 148 (21.6%) 3.6 (1.9)
5.2 (6.2)
5.8 (5.6)
5 (6.4)
50 (6.2%)
24 (19.8%)
26 (3.8%)
158 (19.6%) 591 (73.2%)
33 (33.7%) 100 (82.6%)
125 (18.2%) 491 (71.6%)
2.2 (0.7)
2.4 (0.8)
2.1 (0.7)
39 (4.8%)
7 (5.8%)
32 (4.7%)
387 (47.9%) 394 (48.8%) 7 (0.9%) 7 (0.9%)
50 (41.3%) 45 (37.2%) 7 (5.8%) 7 (5.8%)
337 (49.14%) 349 (50.9%) 0 (0%) 0 (0%)
Sessions needed for CE-IM (mean, SD) Follow-up (months), mean (SD)
2.6 (1.3)
3.1 (1.9)
2.4 (1)
40.3 (32.4)
54.2 (31.4)
32.1 (31.8)
NDBE, non-dysplastic Barrett’s esophagus; LGD, low-grade dysplasia; HGD, high-grade dysplasia; IMC, intramucosal cancer; RFA, radiofrequency ablation; EMR, endoscopic mucosal resection; CE-IM, complete eradication of intestinal metaplasia; SD, standard deviation
Table 2: Kaplan-Meier estimates of the cumulative incidence of recurrence of Barrett’s esophagus and Barrett’s esophagus-related neoplasia by year following CE-IM in the overall cohort and stratified based on baseline histology HGD/EAC at baseline (508) Events Cumulative Incidence (95% CI)
LGD at baseline (239)
Overall cohort (n=807)
Events
Cumulative Incidence (95% CI)
Events
Cumulative Incidence (95% CI)
Any recurrence First
35
6.9 (5-9.4)
6
42
5.2 (3.8-7)
Second
22
6
29
8.8 (6.9-11)
Third
6
11 (9-13.4)
6
10
Fifth
2
7.9 (4.912.1) 8.8 (5.513.1) 10 (6.514.6)
18
Fourth
11.2 (8.814.3) 12.4 (9.815.6) 13.6 (10.916.8) 14 (11.217.3)
2.5 (0.95.4) 5 (2.6-8.6)
12.3 (10.114.7) 13.1 (10.915.7)
Recurrence with LGD or higher First
14
1
0.4 (0, 2.3)
15
1.9 (1-3)
Second
7
2
3 (1.9-4.4)
3
4
3.5 (2.3-5)
Fourth
2
2
Fifth
1
1.3 (0.3, 3.6) 1.7 (0.5, 4.2) 1.7 (0.5, 4.2) 2.1 (0.7, 4.8)
9
Third
2.8 (1.54.6) 4.1 (2.66.3) 4.7 (3.26.9) 5.1 (3.47.4) 5.3 (3.57.6)
3.7 (2.55.3) 4 (2.7-5.6)
Recurrence with HGD or higher First
11
0
0
11
Second
6
2.2 (1.13.8) 3.3 (2-5.3)
0
0
6
Third
3
3.9 (2.4-6)
0
0
3
Fourth
2
0
0
2
Fifth
1
4.3 (2.76.5) 4.5 (2.96.7)
0
0
1
Recurrence with IMC First
4
0.8 (0.2-2)
0
0
4
Year
7 2 3
1 0 1
7
2
1.4 (0.72.4) 2.1 (1.23.4) 2.5 (1.53.8) 2.7 (1.74.1) 2.9 (1.84.2)
0.5 (0.11.3)
Second
2
Third
2
Fourth
0
Fifth
0
1.2 (0.42.6) 1.6 (0.73.1) 1.6 (0.73.1) 1.6 (0.73.1)
0
0
2
0
0
2
0.7 (0.31.6) 1 (0.4-1.9)
0
0
0
1 (0.4-1.9)
0
0
0
1 (0.4-1.9)
LGD, low-grade dysplasia; HGD, high-grade dysplasia; IMC, intramucosal cancer
Table 3: Unadjusted and adjusted odds ratios for any recurrence following complete eradication of intestinal metaplasia [Primary Analysis (at least 1 surveillance endoscopy before recurrence) and Sensitivity Analysis (at least 2 surveillance endoscopies before recurrence)] Variables Unadjusted OR (95% CI)
Primary Analysis P value Adjusted OR (95% CI)
P value
Unadjusted OR (95% CI) 1.01 (0.991.04) 0.47 (0.092.48) 0.99 (0.961.03)
Age
1.02 (0.99-1.04)
0.07
1.01 (0.98-1.03)
0.53
Caucasian Race
7.7 (1.03-56.83)
0.05
4.35 (0.58-32.6)
0.15
BMI
0.98 (0.95-1.02)
0.36
Baseline Histology LGD HGD/EAC
Reference 3.23 (2.29-6.48)
<0.001
Reference 4.19 (1.87-9.39)
<0.001
Reference 3.72 (1.624.59)
Sensitivity Analysis P value Adjusted OR (95% CI) 0.1
P value
1.03 (0.99-1.07)
0.14
Reference 3.67 (1.16-11.59)
0.03
0.38 0.73
<0.001
Presence of GERD Symptoms Hiatal Hernia
4.35 (2.39-7.9)
<0.001
12.13 (4.3-34.1)
<0.001
1.88 (1.15-3.06)
0.01
13.8 (3.37-56.37)
<0.001
Size of Hiatal Hernia
0.61 (0.45-0.84)
0.002
2.33 (1.28-4.24)
0.005
Length of BE
1.23 (1.13-1.35)
<0.001
1 (0.87-1.16)
0.99
Duration of BE
1.02 (0.98-1.06)
0.4
3.25 (1.756.04) 2.38 (1.314.33) 0.66 (0.470.92) 1.22 (1.111.33) 1 (0.96-1.05)
Fundoplication
0.88 (0.38-2.04)
0.77
0.78 (0.3-2.07)
0.63
Family History of Esophageal Cancer
1.22 (0.51-2.95)
0.65
1.06 (0.392.87)
0.12
<0.001 0.005
32.69 (6.96153.72) 2.53 (1.45-4.56)
<0.001 <0.001
0.02
1.25 (0.55-2.82)
0.59
<0.001
0.94 (0.77-1.15)
0.54
0.16
0.94 (0.86-1.01)
0.1
2.07 (0.49-8.77)
0.32
Treatment modalities RFA
0.51 (0.06-4.28)
0.53
RFA + EMR
0.72 (0.09-6.15)
0.77
Cryotherapy
1.7 (0.16-17.3)
0.59
EMR alone
1 (0.1-9.6)
0.99
No. of EET Sessions needed for CE-IM
1.52 (1.3-1.79)
<0.001
1.29 (0.792.09) 0.78 (0.491.26) 23.05 (2.51211.3) 1 (0.2-8.6) 1.78 (1.44-2.21)
<0.001
1.43 (1.221.67)
0.31 0.3 0.006 0.95 <0.001
1.36 (1.02-1.81)
BMI: body mass index; LGD: low-grade dysplasia; HGD: high-grade dysplasia; EAC: esophageal adenocarcinoma; GERD: gastroesophageal reflux disease; BE: Barrett’s esophagus; RFA: radiofrequency ablation; EMR: endoscopic mucosal resection; CE-IM: complete eradication of intestinal metaplasia
0.04
Supplementary Table 1: Kaplan-Meier estimates of the cumulative incidence of recurrence of Barrett’s esophagus and Barrett’s esophagus-related neoplasia by year following CE-IM (under sensitivity analysis requiring 2 negative surveillance endoscopies) in the overall cohort and stratified based on baseline histology HGD/EAC at baseline (508)
LGD at baseline (239)
Overall cohort (n=807)
Events
Cumulative Incidence (95% CI)
Events
Cumulative Incidence (95% CI)
Events
Cumulative Incidence (95% CI)
First
23
4.5 (3-6.7)
5
2.1 (0.94.8)
29
3.6 (2.55.1)
Second
20
8.5 (6.311.2)
7
5 (2.9-8.6)
30
7.3 (5.79.3)
Third
7
9.8 (7.612.7)
7
8 (5.2-12.1)
18
9.5 (7.711.8)
Fourth
6
11 (8.614.1)
2
8.8 (5.813.1)
10
10.8 (8.813.1)
Fifth
2
11.4 (8.914.5)
2
9.6 (6.5-14)
6
11.5 (9.513.9)
First
8
1.6 (0.83.1)
1
0.4 (0.072.3)
9
1.1 (0.62.1)
Second
6
2.8 (1.74.6)
3
1.7 (0.74.2)
9
2.2 (1.43.5)
Third
3
3.4 (2.15.3)
1
2.1 (0.94.8)
4
2.7 (1.84.1)
Fourth
1
3.5 (2.35.5)
1
2.5 (1.25.4)
2
3 (2-4.4)
Fifth
1
3.7 (2.45.8)
1
2.9 (1.45.9)
2
3.2 (2.24.7)
Year
Any recurrence
Recurrence with LGD or higher
Recurrence with HGD or higher
First
5
1 (0.4-2.3)
0
0 (0-1.6)
5
0.6 (0.31.4)
Second
5
2 (1.1-3.6)
0
0 (0-1.6)
5
1.2 (0.72.3)
Third
3
2.6 (1.54.3)
0
0 (0-1.6)
3
1.6 (0.92.7)
Fourth
1
2.8 (1.74.6)
0
0 (0-1.6)
1
1.7 (1-2.9)
Fifth
1
3 (1.8-4.8)
0
0 (0-1.6)
1
1.9 (1.1-3)
0 (0-1.6)
Recurrence with IMC First
1
0.2 (0.031.1)
0
0 (0-1.6)
1
0.1 (0.020.7)
Second
2
0.6 (0.21.7)
0
0 (0-1.6)
2
0.4 (0.11.1)
Third
2
1 (0.4-2.3)
0
0 (0-1.6)
2
0.6 (0.31.4)
Fourth
0
1 (0.4-2.3)
0
0 (0-1.6)
0
0.6 (0.31.4)
Fifth
0
1 (0.4-2.3)
0
0 (0-1.6)
0
0.6 (0.31.4)
Supplementary Table 2: Histologic grade of recurrence based on baseline histology Baseline Histology
Recurrence of NDBE
Recurrence of LGD
Recurrence of HGD
Recurrence of EAC
NDBE (n=61)
12 (100%)
0 (0%)
0 (0%)
0 (0%)
LGD (n=239)
21 (77.8%)
6 (22.2%)
0 (0%)
0 (0%)
HGD (n=332)
35 (63.6%)
6 (10.9%)
14 (25.5%)
0 (0%)
EAC (n=175)
13 (48.1%)
4 (14.8%)
1 (3.7%)
9 (33.3%)
WHAT YOU NEED TO KNOW Background: There have been few studies of the long-term durability of complete eradication of intestinal metaplasia (CE-IM) in patients with Barrett’s esophagus (BE)-related neoplasia who received endoscopic eradication therapy (EET).
Findings: In a prospective study of a large cohort of patients with BE undergoing EET, we found a low rate of recurrence after CE-IM. The rate of recurrence peaked at 1–2 y after CE-IM.
Implications for patient care: Aggressive surveillance might not be necessary more than 1 y after CE-IM and should be considered in development of surveillance guidelines.