Management Of Low-grade Dysplasia Research Articles

Multicenter Randomized Controlled Trial of Surveillance Versus Endoscopic Therapy for Barrett’s Esophagus With Low-grade Dysplasia: The SURVENT Trial: Study Rationale, Methodology, Innovation, and Implications

The incidence of esophageal adenocarcinoma (EAC) has increased dramatically over the last 5 decades, making it one of the most rapidly increasing cancers in the Western world.1Kolb J.M. Han S. Scott F.I. et al.Early-onset esophageal adenocarcinoma presents with advanced-stage disease but has improved survival compared with older individuals.Gastroenterology. 2020; 159: 2238-2240Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Barrett’s esophagus (BE), the only identifiable premalignant condition for EAC, is remarkably common and progresses to EAC in a stepwise fashion from nondysplastic BE to low-grade dysplasia (LGD) to high-grade dysplasia (HGD) and then to EAC. Despite advances in the field of biomarkers and risk stratification, the degree of dysplasia is the most widely used biomarker to predict progression and to guide further management. Endoscopic eradication therapy (EET) for patients with BE-related dysplasia and intramucosal EAC is endorsed by multiple society guidelines,2Shaheen N.J. Falk G.W. Iyer P.G. et al.Diagnosis and management of Barrett's esophagus: an updated ACG guideline.Am J Gastroenterol. 2022; 117: 559-587Crossref PubMed Scopus (27) Google Scholar,3Standards of Practice Committee Wani S. Qumseya B. et al.Endoscopic eradication therapy for patients with Barrett's esophagus-associated dysplasia and intramucosal cancer.Gastrointest Endosc. 2018; 87: 907-931Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar a practice that has broadly and meaningfully impacted clinical care worldwide. Although substantial data support using EET in patients with BE and HGD or intramucosal EAC, a central unresolved issue in this field is whether BE patients with LGD also benefit from EET. Establishing the best therapy for these “middle ground” patients is highly clinically relevant, because approximately 40% of BE patients are diagnosed with LGD at some point during follow-up.4Wani S. Rubenstein J.H. 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: 822-835Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar,5Phoa K.N. van Vilsteren F.G. Weusten B.L. et al.Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial.JAMA. 2014; 311: 1209-1217Crossref PubMed Scopus (427) Google Scholar In BE with LGD, progression rates to EAC are lower (<1% per patient-year) as opposed to 6%–20% per patient-year in BE with HGD.3Standards of Practice Committee Wani S. Qumseya B. et al.Endoscopic eradication therapy for patients with Barrett's esophagus-associated dysplasia and intramucosal cancer.Gastrointest Endosc. 2018; 87: 907-931Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Several issues make management of LGD challenging: high interobserver variability among pathologists; lack of well-defined risk stratification tools to define individuals most likely to benefit from EET; the phenomenon of regression, in which those diagnosed with LGD using endoscopic biopsy do not demonstrate LGD on follow-up biopsies; and highly variable published rates of progression to HGD and EAC.4Wani S. Rubenstein J.H. 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: 822-835Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar Recent guidelines suggest that both EET and surveillance are acceptable approaches to the management of LGD patients.2Shaheen N.J. Falk G.W. Iyer P.G. et al.Diagnosis and management of Barrett's esophagus: an updated ACG guideline.Am J Gastroenterol. 2022; 117: 559-587Crossref PubMed Scopus (27) Google Scholar,3Standards of Practice Committee Wani S. Qumseya B. et al.Endoscopic eradication therapy for patients with Barrett's esophagus-associated dysplasia and intramucosal cancer.Gastrointest Endosc. 2018; 87: 907-931Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar The lack of strongly directive statements for 1 strategy over another is due to the limited comparative data between the 2 strategies. Despite the common nature of BE with LGD, studies focusing on treatment options in BE with LGD are limited. Critical limitations of existing trials are lack of adequate power to assess differences in outcomes6Shaheen N.J. Sharma P. Overholt B.F. et al.Radiofrequency ablation in Barrett's esophagus with dysplasia.N Engl J Med. 2009; 360: 2277-2288Crossref PubMed Scopus (1092) Google Scholar and limited generalizability.5Phoa K.N. van Vilsteren F.G. Weusten B.L. et al.Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial.JAMA. 2014; 311: 1209-1217Crossref PubMed Scopus (427) Google Scholar,7Barret M. Pioche M. Terris B. et al.Endoscopic radiofrequency ablation or surveillance in patients with Barrett's oesophagus with confirmed low-grade dysplasia: a multicentre randomised trial.Gut. 2021; 70: 1014-1022Crossref PubMed Scopus (10) Google Scholar The argument for EET in BE with LGD is largely based on a single European randomized controlled trial (RCT) comparing EET with endoscopic surveillance.5Phoa K.N. van Vilsteren F.G. Weusten B.L. et al.Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial.JAMA. 2014; 311: 1209-1217Crossref PubMed Scopus (427) Google Scholar,8Pouw R.E. Klaver E. Phoa K.N. et al.Radiofrequency ablation for low-grade dysplasia in Barrett's esophagus: long-term outcome of a randomized trial.Gastrointest Endosc. 2020; 92: 569-574Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar This trial reported that EET markedly reduced the risk of progression to a combined endpoint of HGD/EAC. However, several aspects of this study call into question its generalizability to the United States. First, there was a remarkably high rate of neoplastic progression in the surveillance arm (25%–34%), far higher than that reported in any American cohort. Second, despite this rather high rate of progression, patients in the surveillance arm overall fared well. Only 1 patient required esophagectomy, which was curative. Therefore, 211 radiofrequency ablation sessions were required in the treatment arm to prevent 1 esophagectomy. Third, this study found no difference in mortality between the arms. Fourth, EET was associated with an adverse event rate of 19%, with 3% being serious adverse events. Fifth, health-related quality of life, patient preference data, and other patient-centered outcomes (PCOs) were not assessed systematically. Additionally, this study was performed in highly specialized, tertiary care centers, and we have limited data on the effectiveness and safety of EET in other settings. For these reasons, although this was a well-designed and executed trial, its generalizability to a US population is unclear. A second RCT of EET in LGD from France is of limited utility because of a small sample size, use of a nontraditional primary endpoint, and remarkably low rates of complete eradication of intestinal metaplasia, far lower than that reported in any American cohort (including expert centers and community practices).7Barret M. Pioche M. Terris B. et al.Endoscopic radiofrequency ablation or surveillance in patients with Barrett's oesophagus with confirmed low-grade dysplasia: a multicentre randomised trial.Gut. 2021; 70: 1014-1022Crossref PubMed Scopus (10) Google Scholar Additionally, it should be noted that endoscopic surveillance is still required after successful completion of EET, given the concerns regarding durability of EET.9Wani S. Han S. Kushnir V. et al.Recurrence is rare following complete eradication of intestinal metaplasia in patients with Barrett's esophagus and peaks at 18 months.Clin Gastroenterol Hepatol. 2020; 18: 2609-2617Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 10van Munster S. Nieuwenhuis E. Weusten B. et al.Long-term outcomes after endoscopic treatment for Barrett's neoplasia with radiofrequency ablation ± endoscopic resection: results from the national Dutch database in a 10-year period.Gut. 2022; 71: 265-276Crossref PubMed Scopus (34) Google Scholar, 11Sami S.S. Ravindran A. Kahn A. et al.Timeline and location of recurrence following successful ablation in Barrett's oesophagus: an international multicentre study.Gut. 2019; 68: 1379-1385Crossref PubMed Scopus (52) Google Scholar For these reasons, it remains unclear whether the costs and side effects associated with EET are worth the likely modest benefit in cancer prevention in LGD. The common nature of LGD and the wide availability of EET means that, on a daily basis, clinicians and patients are making the challenging treatment decision of EET vs surveillance with inadequate data to guide them. The degree of dysplasia, the most widely used current biomarker to risk-stratify patients with BE and to guide further management, is inadequately accurate, and reliance on dysplasia continues to be a critical barrier to risk-based management of these patients.4Wani S. Rubenstein J.H. 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: 822-835Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar It is well established that certain molecular and cellular alterations associated with carcinogenesis in BE can be detected years before the tissue exhibits morphologic changes of dysplasia, suggesting that an appropriate biomarker could identify BE patients who are destined for malignancy.12Redston M. Noffsinger A. Kim A. et al.Abnormal TP53 predicts risk of progression in patients with Barrett's esophagus regardless of a diagnosis of dysplasia.Gastroenterology. 2022; 162: 468-481Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar However, most of studies of biomarkers in BE have been case-control or retrospective in nature. Little is known about the comparative efficacy of various commercially available biomarkers to predict either the risk of progression to EAC or the effectiveness of EET in BE with LGD patients. Thus, the appropriate use of molecular or imaging biomarkers for risk stratification and prediction of effectiveness of EET continues to be a gap in our current knowledge, one that is best addressed through a well-controlled prospective study. Despite the fact that none of the BE biomarkers has fulfilled the Early Detection Research Network criteria for validation,13Pepe M.S. Etzioni R. Feng Z. et al.Phases of biomarker development for early detection of cancer.J Natl Cancer Inst. 2001; 93: 1054-1061Crossref PubMed Scopus (1232) Google Scholar,14Timmer M.R. Sun G. Gorospe E.C. et al.Predictive biomarkers for Barrett's esophagus: so near and yet so far.Dis Esophagus. 2013; 26: 574-581Crossref PubMed Scopus (22) Google Scholar p53 immunohistochemistry (IHC), wide-area transepithelial sampling (WATS3D), and TissueCypher Barrett’s Esophagus Assay (Castle Biosciences, Pittsburgh, PA) are in clinical use, and 2 (p53 IHC and WATS3D) have been endorsed in guideline documents by the British Society of Gastroenterology15Fitzgerald R.C. di Pietro M. Ragunath K. et al.British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's oesophagus.Gut. 2014; 63: 7-42Crossref PubMed Scopus (837) Google Scholar and the American Society for Gastrointestinal Endoscopy.16Qumseya B. Sultan S. Bain P. et al.ASGE guideline on screening and surveillance of Barrett's esophagus.Gastrointest Endosc. 2019; 90: 335-359Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar The detection of p53 abnormalities has the largest body of evidence as a biomarker for risk stratification. p53 is an important tumor suppressor gene whose inactivation appears to be a key event, occurring early and often during Barrett’s carcinogenesis.17Stachler M.D. Camarda N.D. Deitrick C. et al.Detection of mutations in Barrett's esophagus before progression to high-grade dysplasia or adenocarcinoma.Gastroenterology. 2018; 155: 156-167Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar Immunostaining of esophageal biopsy specimens revealing aberrant (either overexpression or absence of expression) staining of p53 protein is evidence of p53 inactivation.12Redston M. Noffsinger A. Kim A. et al.Abnormal TP53 predicts risk of progression in patients with Barrett's esophagus regardless of a diagnosis of dysplasia.Gastroenterology. 2022; 162: 468-481Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar In LGD patients with aberrant p53 IHC in baseline biopsies, prospective cohort and case-control studies reported an elevated risk of progression to HGD/EAC.12Redston M. Noffsinger A. Kim A. et al.Abnormal TP53 predicts risk of progression in patients with Barrett's esophagus regardless of a diagnosis of dysplasia.Gastroenterology. 2022; 162: 468-481Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar,18Snyder P. Dunbar K.B. Cipher D.J. et al.Aberrant p53 immostaining in Barrett's esophagus predicts neoplastic progression: systematic review and meta-analyses.Dig Dis Sci. 2019; 64: 1089-1097Crossref PubMed Scopus (26) Google Scholar WATS3D is a recently developed test that can improve the identification of dysplasia. WATS3D uses a cytology brush to sample an extensive area of the BE segment, with analysis aided by a neural network–based, high-speed computer scan that generates a 3-dimensional image of the tissue and identifies abnormal cells based on cellular morphology and molecular diagnostics. Hence, WATS3D assists the pathologist in making a diagnosis of dysplasia. A retrospective cohort study recently reported that LGD diagnosed with WATS3D is a better predictor of progression to HGD/EAC than that diagnosed with forceps biopsy.19Shaheen N.J. Smith M.S. Odze R.D. Progression of Barrett's esophagus, crypt dysplasia, and low-grade dysplasia diagnosed by wide-area transepithelial sampling with 3-dimensional computer-assisted analysis: a retrospective analysis.Gastrointest Endosc. 2022; 95: 410-418Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar TissueCypher detects potentially carcinogenic molecular and cellular changes in BE biopsy specimens that can precede the appearance of dysplasia. It uses a computational pathology platform that rapidly extracts and integrates quantitative data on nuclear morphology and 9 protein-based biomarkers (p16, AMACR, p53, CD68, COX-2, CD45RO, HIF-1α, HER2/neu, and K20) to provide a risk score ranging from 0 to 10 that is used to classify patients as low, intermediate, and high risk for progression to HGD or EAC within 5 years.20Critchley-Thorne R.J. Duits L.C. Prichard J.W. et al.A tissue systems pathology assay for high-risk Barrett's esophagus.Cancer Epidemiol Biomarkers Prev. 2016; 25: 958-968Crossref PubMed Scopus (32) Google Scholar A recent pooled analysis of data on TissueCypher’s performance in predicting both prevalent and incident progression to HGD/EAC in 5 published studies involved 590 patients, including 68 patients with LGD. A high-risk TissueCypher score independently predicted a 7.81-fold increase in prevalent and incident HGD/EAC and significantly improved the predictive value of clinical features (age, sex, BE segment length, presence of hiatal hernia, and pathology diagnosis).21Iyer P.G. Codipilly D.C. Chandar A.K. et al.Prediction of progression in Barrett's esophagus using a tissue systems pathology test: a pooled analysis of international multicenter studies [published online ahead of print February 22, 2022]. Clin Gastroenterol Hepatol.https://doi.org/10.1016/j.cgh.2022.02.033Google Scholar In a blinded, retrospective cohort study of BE patients with community-diagnosed LGD enrolled in the surveillance arm of the SURF study,5Phoa K.N. van Vilsteren F.G. Weusten B.L. et al.Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial.JAMA. 2014; 311: 1209-1217Crossref PubMed Scopus (427) Google Scholar TissueCypher stratified these LGD patients with overall predictive accuracy comparable with that of 3 expert gastrointestinal pathologists.22Frei N.F. Khoshiwal A.M. Konte K. et al.Tissue systems pathology test objectively risk stratifies Barrett's esophagus patients with low-grade dysplasia.Am J Gastroenterol. 2021; 116: 675-682Crossref PubMed Scopus (9) Google Scholar Moreover, TissueCypher provided objective risk stratification, whereas the diagnosis of LGD had significant variability between the 3 expert pathologists.22Frei N.F. Khoshiwal A.M. Konte K. et al.Tissue systems pathology test objectively risk stratifies Barrett's esophagus patients with low-grade dysplasia.Am J Gastroenterol. 2021; 116: 675-682Crossref PubMed Scopus (9) Google Scholar These promising results from retrospective, case-control, and cohort studies suggest that p53 IHC, WATS3D, or TissueCypher may be useful for risk stratification of BE patients with LGD. However, they need to be validated in future RCTs. The presence of clinical equipoise indicates that a trial of endoscopic surveillance vs EET in patients with BE and LGD is an urgent, unmet need. The SURVENT (Surveillance vs Endoscopic Therapy for BE with LGD) trial is being conducted to address this significant gap in our knowledge by comparing the effectiveness of EET with surveillance endoscopy using established oncologic outcomes (specific aim 1), comparing PCOs and costs between the 2 groups (specific aim 2), and improving risk stratification of LGD patients by identifying patient characteristics and biomarkers (p53, TissueCypher, WATS3D) that predict progression and response to treatment (specific aim 3). The SURVENT trial is a multicenter comparative effectiveness Prospective, Randomized, Open with Blinded Endpoint trial of BE patients with LGD (Figure 1). The trial’s primary aim is to determine if patients undergoing EET will demonstrate less neoplastic progression and a lower incidence of EAC compared with patients undergoing surveillance. A maximum of 530 subjects will be enrolled over a 3.5-year period, with a total planned study duration of 5 years. The trial also includes an observational cohort that will follow the same data and biorepository protocols as the randomized trial (cohort 1, endoscopic surveillance [n = 100]; cohort 2, EET [n = 50]). The addition of an observational cohort to the RCT will inform us of potential selection bias, allowing us to make inferences as to the generalizability of the RCT results, and serve as a second, independent group in which to expand and validate the findings related to biomarkers assessed in this trial. The trial aims, outcomes, eligibility, and inclusion and exclusion criteria are highlighted in Table 1. PCOs were selected by key stakeholders (patients, caregivers, clinicians) during the U34 funding phase. The conceptual model of PCOs is highlighted in Supplementary Figure 1 and Supplementary Table 1. Further trial details are provided in Supplementary Methods. Biologic specimens will be obtained from all study subjects in the RCT and observational cohort (blood, saliva, endoscopic biopsies, cytology, and WATS3D brushings) at standardized intervals.Table 1Study SummaryProtocol titleA multicenter RCT of surveillance vs endoscopic therapy for BE with LGDAcronymSURVENT trialStudy sitesTwenty-one clinical centers in the United StatesStudy periodPlanned enrollment period: 3.5 yearsPlanned duration of the study: 5 yearsSubject participation will be a minimum of 1 year (for subjects enrolled in month 42) and maximum of 4 years (for subject enrolled in month 6).Study populationPatients with BE and LGDPrimary study objectiveTo compare the effectiveness of 2 approaches for the management of BE and LGD, endoscopic surveillance and EET, with endpoints of neoplastic progression (HGD/mucosal EAC/invasive EAC) as determined by a blinded central adjudication committeeSecondary study objectiveTo compare PCOs in BE patients with LGD treated with EET with those undergoing surveillanceTo determine the utility of select biomarkers, including the biomarker panel TissueCypher, histologic assessment by WATS3D, and p53 IHC on forceps biopsies and on WATS3D samples, in risk stratificationTo conduct a safety and cost-effectiveness analysisExploratory clinical endpoints will include progression to mucosal or invasive EAC alone, complete eradication rates for intestinal metaplasia (CE-IM) and complete eradication rates for dysplasia, and recurrence of intestinal metaplasia and dysplasia.To establish a biorepository of specimens that include whole blood, serum, plasma, saliva, brushings, and biopsy specimens from the esophagus (squamous and BE), gastric cardia, and duodenum that will allow for future translational research, including time course studies on mechanisms of disease progression and therapeutic response; identification of novel diagnostic markers; and novel therapeutic targets in this patient population.Study designMulticenter comparative effectiveness Prospective, Randomized, Open with Blinded Endpoint trial of EET vs endoscopic surveillance in patients with BE and LGDObservational cohort study: This study will also include a prospective observational cohort study of BE and LGD patients who decline randomization in the RCT but undergo endoscopic surveillance (cohort 1) or EET (cohort 2) and are willing to provide longitudinal observational data,Sample sizeRCT: Using assumptions based on published literature and accounting for an attrition rate of 10%, we estimate that a total of 530 subjects (265 per study arm) would provide a statistical power of at least 80% to detect the hypothesized difference in the primary outcome of neoplastic progression rate between the 2 groups (15% progression rate in the surveillance arm, 6% in the EET arm). A blinded sample size re-estimation will be conducted before the interim analysis to confirm the assumptions of the event rate.Observational cohort study: The maximum enrollment for the observational cohort formed from the patients who decline randomization will be a maximum of 150 subjects total (cohort 1, n = 100; cohort 2, n = 50).Inclusion criteriaAny patient with BE and LGD who provides informed consent and meets all the following criteria will be eligible for enrollment:1. Male or female, age ≥18 years.2. Subject has endoscopic evidence of BE characterized by the presence of salmon-colored mucosa in the tubular esophagus of at least 1 cm in length as well as endoscopic biopsies from the involved areas demonstrating columnar metaplasia with goblet cells. This inclusion criterion will exclude patients with intestinal metaplasia with dysplasia of the gastric cardia.3. Biopsies within the previous 12 months demonstrating BE and LGD.4. Confirmation of LGD by expert central pathology panel from biopsies obtained within the previous 12 months (including those obtained from the referring physician).5. Demonstrated ability to tolerate proton pump inhibitor therapy based on patient self-report.6. Ability to discontinue antiplatelet and anticoagulant therapy based on standard guideline recommendations before and after endoscopic procedures.Exclusion criteria1. Pregnancy2. Prior EET for BE3. History of HGD or EAC4. History of esophageal resection/esophagectomy5. Active erosive esophagitis (Los Angeles grade B or higher): patients eligible on resolution of erosive esophagitis6. Esophageal strictures precluding passage of the endoscope or treatment catheters: patients eligible on resolution of esophageal stricture due to endoscopic dilation or resolution with medical therapy7. Esophageal varices or known portal hypertension8. Life expectancy < 2 years as judged by the site investigatorOf note, the presence of a visible lesion (nodularity) at the index endoscopy is not an exclusion criterion. Subjects with visible lesions will undergo endoscopic mucosal resection to determine pathology; those with HGD or EAC pathology will exit the study after a 30-day safety follow up.Study intervention and follow-upSubjects in the RCT and observational cohort study undergoing surveillance endoscopy will undergo surveillance biopsies in a 4-quadrant fashion every 1 cm throughout the extent of the BE using the Seattle biopsy protocol, along with targeted biopsies from any visible lesions. For incident LGD (newly diagnosed LGD, ie, within 12 months of enrollment), surveillance endoscopies will be performed every 6 months for the first year and then annually until the end of the study period. For prevalent LGD (diagnosed >1 year before enrollment), surveillance endoscopies will be performed annually until the end of the study period. The number of evaluations will depend on a subject’s enrollment time.Subjects undergoing EET will undergo radiofrequency ablation every 2–3 months until CE-IM is achieved or 5 treatments have been delivered, whichever is first. After achieving CE-IM, surveillance endoscopy will performed every 6 months for the first year and annually thereafter until the end of the study period. Surveillance biopsies will be obtained using a standardized protocol.Subjects will be contacted 48–72 hours and 30 days postprocedure. All subjects will also receive follow-up phone calls on a semiannual basis by a blinded central study coordinator.Primary outcome measureThe primary endpoint is neoplastic progression, defined as the occurrence of HGD/mucosal EAC/invasive EAC at any time during the study period after enrollment.Statistical analysisAll randomized subjects who are not identified at the index endoscopy with HGD or EAC are defined as the intention-to-treat population. The time to progression will be calculated from the time of randomization until the endoscopy date on which HGD/mucosal EAC/invasive EAC is detected. The hazard rates will be compared using a log-rank test. One interim analysis for overwhelming efficacy or futility will be conducted. Open table in a new tab Sample size was performed for the primary endpoint of neoplastic progression (the diagnosis of HGD/EAC at any time during the study period after enrollment) using a time-to-event analysis. We estimate that 15% of patients with confirmed LGD will progress to the composite primary endpoint in the surveillance arm compared with 6% in the EET arm.4Wani S. Rubenstein J.H. 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: 822-835Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 5Phoa K.N. van Vilsteren F.G. Weusten B.L. et al.Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial.JAMA. 2014; 311: 1209-1217Crossref PubMed Scopus (427) Google Scholar, 6Shaheen N.J. Sharma P. Overholt B.F. et al.Radiofrequency ablation in Barrett's esophagus with dysplasia.N Engl J Med. 2009; 360: 2277-2288Crossref PubMed Scopus (1092) Google Scholar,23Qumseya B.J. Wani S. Gendy S. et al.Disease progression in Barrett's low-grade dysplasia with radiofrequency ablation compared with surveillance: systematic review and meta-analysis.Am J Gastroenterol. 2017; 112: 849-865Crossref PubMed Scopus (43) Google Scholar We plan to accrue subjects for 3.5 years and follow them over time until progression to the primary endpoint or their censoring time if they do not progress. Follow-up will continue for approximately 1 year after the last subject is enrolled. Assuming an exponential survival curve and the above event rates, 215 subjects in each group are needed to obtain a total of 36 events for analysis to achieve 80% power using a 2-sided .05 alpha level. Using a 10% noncompliance rate, we inflate the sample size by a factor of 1.23 and plan to enroll 530 total subjects. The SURVENT trial is funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health. The organizational structure includes the Executive, Steering, Biorepository, Trial Operations, Protocol, Ancillary Studies, Publications, and Coordinator Committees with active participation from the principal investigators, NIDDK staff, and site investigators. The Clinical Coordinating Center and Central Biorepository is housed at the University of Colorado and the Statistical and Data Coordinating Center at the Medical University of South Carolina. An NIDDK-appointed Data and Safety Monitoring Board and a study-appointed independent medical safety monitor will oversee the safety in the SURVENT trial. The SURVENT trial will be completed at approximately 21 high-volume regional centers in the United States. All eligible subjects will be offered inclusion without any reference to sex or minority status. The SURVENT trial is the first US-based RCT exclusively for BE with LGD. The importance of PCOs has been recognized by major international health policy and regulatory authorities and patients and can provide valuable evidence to inform shared decision-making, clinical guidelines, and health policy.24Calvert M. Kyte D. Mercieca-Bebber R. et al.Guidelines for inclusion of patient-reported outcomes in clinical trial protocols: the SPIRIT-PRO extension.JAMA. 2018; 319: 483-494Crossref PubMed Scopus (351) Google Scholar This trial will

Post-endoscopy Esophageal Neoplasia in Barrett’s Esophagus: Consensus Statements From an International Expert Panel

Esophageal adenocarcinoma (EAC) is a lethal cancer with increasing incidence and mortality rates over the last several decades, with a rising incidence of 7-fold in the United States from 1975 to 2016.1Kolb J.M. Han S. Scott F.I. et al.Early-onset esophageal adenocarcinoma presents with advanced-stage disease but has improved survival compared with older individuals.Gastroenterology. 2020; 159: 2238-2240Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar As many as 40% of patients with Barrett’s esophagus (BE)-associated EACs present with advanced disease with a dismal 5-year survival rate. Several factors contribute to identification at an advanced stage, including the limited effectiveness of current screening and surveillance strategies.2Wani S. Gyawali C.P. Katzka D.A. AGA clinical practice update on reducing rates of post-endoscopy esophageal adenocarcinoma: commentary.Gastroenterology. 2020; 159: 1533-1537Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Similar to post-colonoscopy colorectal cancer,3Rutter M.D. Beintaris I. Valori R. et al.World Endoscopy Organization consensus statements on post-colonoscopy and post-imaging colorectal cancer.Gastroenterology. 2018; 155: 909-925Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar BE-associated high-grade dysplasia (HGD) and EAC can be diagnosed before the next recommended endoscopic evaluation after prior endoscopy that was negative for HGD or EAC.2Wani S. Gyawali C.P. Katzka D.A. AGA clinical practice update on reducing rates of post-endoscopy esophageal adenocarcinoma: commentary.Gastroenterology. 2020; 159: 1533-1537Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Meta-analyses and cohort studies suggest that a high proportion of HGD or EAC are missed within the first year after the index endoscopy that diagnosed BE.4Sawas T, Majzoub AM, Haddad J, et al. Magnitude and time-trend analysis of post-endoscopy esophageal adenocarcinoma: a systematic review and meta-analysis [published online ahead of print April 23, 2021]. Clin Gastroenterol Hepatol https://doi.org/10.1016/j.cgh.2021.04.032.Google Scholar Several factors may contribute to missed lesions, including lack of compliance with the Seattle biopsy protocol, missed dysplasia due to limited mucosal sampling with standard biopsies, inadequate BE segment inspection time (similar to colorectal cancer screening), inability to recognize subtle findings of early neoplasia, and reliance on observer-dependent histologic classification of dysplasia.5Qumseya B. Sultan S. et al.ASGE Standards of Practice CASGE guideline on screening and surveillance of Barrett's esophagus.Gastrointest Endosc. 2019; 90: 335-359Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar,6Wani S. Williams J.L. Komanduri S. et al.Endoscopists systematically undersample patients with long-segment Barrett's esophagus: an analysis of biopsy sampling practices from a quality improvement registry.Gastrointest Endosc. 2019; 90: 732-741Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar These shortcomings highlight the importance of optimizing endoscopy quality to reduce the incidence and mortality associated with EAC. An American Gastroenterological Association Clinical Practice Update on post-endoscopy EAC (PEEC) identified several knowledge gaps, including the need for consensus standardization of PEEC terminology and calculation.2Wani S. Gyawali C.P. Katzka D.A. AGA clinical practice update on reducing rates of post-endoscopy esophageal adenocarcinoma: commentary.Gastroenterology. 2020; 159: 1533-1537Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar To address these gaps, an international working group (28% women; mean years in clinical practice, 17.7 [SD, 17.1]) on post-endoscopy HGD and EAC was established to achieve the following aims using the RAND/University of California, Los Angeles Appropriateness Methodology: standardize terminology and definitions, identify and assess potential explanations, establish a conceptual framework for future research, introduce post-endoscopy HGD and EAC as performance measures to facilitate benchmarking and comparisons between healthcare settings, and provide best practice advice on reducing the rate of PEEC and HGD in clinical practice. Detailed methodology is reported in Figure 1, Supplementary Methods, and Appendices 1–4. The final statements that met the appropriateness criteria are listed in Table 1.Table 1Appropriate Statements Determined Using the RAND/University of California, Los Angeles Appropriateness Methodology With Median Score and Number of Experts in Each Category RangeConsensus statementsMedian scoreNo. of experts 1–3 range (inappropriate)No. of experts 4–6 range (uncertain)No. of experts 7–9 range (appropriate)MAD-M scoreTerminology and definitions1. PEEN is the preferred term for HGD or EAC detected before the next recommended surveillance endoscopy in a patient with nondysplastic BE81 (4)2 (8)22 (88)1.12. PEEC is the preferred term for EAC detected before the next recommended surveillance endoscopy in a patient with nondysplastic BE83 (12)2 (8)20 (80)1.33. The time interval for which the occurrence of PEEN/PEEC applies is between 6 months and 3 years after screening or surveillance endoscopy71 (4)7 (28)17 (68)1.2Potential explanations4. The potential explanations for PEEN/PEEC include missed HGD/EAC and rapidly progressive EAC81 (4)2 (8)22 (88)0.9Quality review of PEEN/PEEC cases5. Endoscopy practices can consider reviewing PEEN/PEEC cases to understand contributing factors and areas of improvement80 (0)2 (8)23 (92)16. To facilitate the use of a common language when categorizing PEEN/PEEC cases according to their most plausible explanations, we suggest the following categories be used: a. Possible missed visible lesion, prior examination adequateb. Possible missed visible lesion, prior examination inadequatec. Detected visible lesion, no or inadequate sampling with targeted biopsiesd. Detected visible lesion, incomplete resection of previously identified lesione. Prior examination adequate and clinically indicated follow-up not recommendedf. Prior examination inadequate and clinically indicated follow-up not recommendedg. Prior examination adequate and failure of patient to follow-up on a recommended surveillance endoscopy interval.71 (4)3 (12)21 (84)1Best practice advice to reduce PEEN/PEEC7. Endoscopists should define the extent of BE using a standardized grading system documenting the circumferential and maximal extent of the columnar lined esophagus (Prague classification) with a clear description of landmarks and characteristics of visible lesions, when present80 (0)1 (4)24 (96)0.68. Screening and surveillance endoscopy for BE should be performed using high-definition white-light endoscopy and chromoendoscopy (traditional or virtual)80 (0)2 (8)23 (92)0.79. Endoscopists should spend adequate time inspecting the BE segment90 (0)0 (0)25 (100)0.410. In patients undergoing screening or surveillance endoscopy for BE, endoscopists should obtain biopsies using the Seattle biopsy protocol (4-quadrant biopsies at least every 2 cm and additional targeted biopsies or resection or outlining a plan for resection for any visible lesions)80 (0)1 (4)24 (96)0.6Values are n (%). MAD-M, mean absolute deviation from the median. Open table in a new tab Values are n (%). MAD-M, mean absolute deviation from the median. The group agreed to define 2 terms for BE-related neoplasia after index endoscopy: include EAC only (PEEC) and include both HGD and EAC (post-endoscopy esophageal neoplasia [PEEN]). Inclusion of HGD in the PEEN definition was driven by the fact that the goal of endoscopic screening and surveillance programs, as recommended by professional societies, is detection of HGD and early EAC.5Qumseya B. Sultan S. et al.ASGE Standards of Practice CASGE guideline on screening and surveillance of Barrett's esophagus.Gastrointest Endosc. 2019; 90: 335-359Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar,7Shaheen N.J. Falk G.W. Iyer P.G. et al.ACG clinical guideline: diagnosis and management of Barrett's esophagus.Am J Gastroenterol. 2016; 111 (; quiz 51): 30-50Crossref PubMed Scopus (816) Google Scholar,8Spechler S.J. Sharma P. et al.American Gastroenterological AssociationAmerican Gastroenterological Association medical position statement on the management of Barrett's esophagus.Gastroenterology. 2011; 140: 1084-1091Abstract Full Text Full Text PDF PubMed Scopus (708) Google Scholar Further, up to 40% of patients with HGD have prevalent EAC (most diagnosed with stage I or stage IIa), many of whom have an actionable recommendation for endoscopic eradication therapy, underscoring the importance of capturing this population.7Shaheen N.J. Falk G.W. Iyer P.G. et al.ACG clinical guideline: diagnosis and management of Barrett's esophagus.Am J Gastroenterol. 2016; 111 (; quiz 51): 30-50Crossref PubMed Scopus (816) Google Scholar,9Konda V.J. Ross A.S. Ferguson M.K. et al.Is the risk of concomitant invasive esophageal cancer in high-grade dysplasia in Barrett's esophagus overestimated?.Clin Gastroenterol Hepatol. 2008; 6: 159-164Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar,10Standards of Practice Committee Wani S. Qumseya B. et al.Endoscopic eradication therapy for patients with Barrett's esophagus-associated dysplasia and intramucosal cancer.Gastrointest Endosc. 2018; 87: 907-931Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar On the other hand, using EAC is a more clinically meaningful singular endpoint (similar to post-colonoscopy colorectal cancer), is the most impactful, and is the most serious missed lesion. In addition, the potential for different phenotypes of EAC11Sawas T. Killcoyne S. Iyer P.G. et al.Identification of prognostic phenotypes of esophageal adenocarcinoma in 2 independent cohorts.Gastroenterology. 2018; 155: 1720-1728Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar raises the possibility that some subset of interval HGD may represent truly incident, rapidly growing neoplasia, especially when these lesions are detected near the end of a 3–5-year surveillance interval. Inclusion of low-grade dysplasia was considered inappropriate because of interobserver variability among pathologists, variable natural history outcomes, and the need for risk stratification to determine ideal candidates likely to benefit from endoscopic eradication therapy compared with surveillance.12Wani S. Rubenstein J.H. 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: 822-835Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar The time interval of 6 months to 3 years after screening or surveillance endoscopy was rated as an appropriate window for occurrence of PEEN/PEEC. A minimum of 6 months was recommended to document healing and exclude BE in patients with erosive esophagitis. An upper limit of 3 years was selected because data from a national benchmarking quality registry suggest that endoscopists recommend a 3-year interval more commonly than a 5-year interval for endoscopic surveillance of nondysplastic BE patients.13Wani S. Williams J.L. Komanduri S. et al.Over-utilization of repeat upper endoscopy in patients with non-dysplastic Barrett's esophagus: a quality registry study.Am J Gastroenterol. 2019; 114: 1256-1264Crossref PubMed Scopus (16) Google Scholar Lesions detected beyond this window are likely incident rather than missed at the index endoscopy. Two analyses were conducted to provide contemporary estimates of PEEN/PEEC. In a retrospective US cohort study performed among 50,817 individuals diagnosed with incident BE and 366 with EAC, EAC was classified as prevalent, PEEC, and incident EAC in 67.2%, 13.7%, and 19.1% of cases, respectively.14Vajravelu RK, Kolb JM, Thanawala SU, et al. Characterization of prevalent, post-endoscopy, and incident esophageal cancer in the United States: a large retrospective cohort study [published online ahead of print February 5, 2021]. Clin Gastroenterol Hepatol https://doi.org/10.1016/j.cgh.2021.02.005.Google Scholar In other words, the magnitude of PEEC approached that of incident cancer. An updated systematic review and meta-analysis of 145,726 patients revealed a PEEC and PEEN rate of 21% (95% confidence interval, 13–31) and 26% (95% confidence interval, 19–34), respectively. Interestingly, meta-regression analysis demonstrated a strong inverse association between PEEC and incident EAC, suggesting that measures augmenting neoplasia detection will reduce the subsequent incidence of EAC detected in surveillance.4Sawas T, Majzoub AM, Haddad J, et al. Magnitude and time-trend analysis of post-endoscopy esophageal adenocarcinoma: a systematic review and meta-analysis [published online ahead of print April 23, 2021]. Clin Gastroenterol Hepatol https://doi.org/10.1016/j.cgh.2021.04.032.Google Scholar Although most cases of PEEN/PEEC may be attributed to missed HGD/EAC, rapidly progressive cancer due to accelerated pathways of neoplasia may also exist.11Sawas T. Killcoyne S. Iyer P.G. et al.Identification of prognostic phenotypes of esophageal adenocarcinoma in 2 independent cohorts.Gastroenterology. 2018; 155: 1720-1728Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar,15Jammula S. Katz-Summercorn A.C. Li X. et al.Identification of subtypes of Barrett's esophagus and esophageal adenocarcinoma based on DNA methylation profiles and integration of transcriptome and genome data.Gastroenterology. 2020; 158: 1682-1697Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Inadequate data on the natural history of progression of nondysplastic BE to HGD limit our ability to estimate these proportions. Intuitively, the shorter the interval between the endoscopic finding of HGD or EAC and the endoscopy finding of nondysplastic BE, the greater the likelihood the neoplasia was missed on the screening or surveillance endoscopy. As with post-colonoscopy colorectal cancer, investigators need to operationalize definitions and attempt to identify time intervals that distinguish missed from incident PEEN/PEEC. Further, BE-associated neoplasia may be diagnosed after successful endoscopic eradication therapy. The panelists acknowledged several factors that contribute to the finding of neoplasia after complete eradication of intestinal metaplasia including missed resectable lesions, incomplete resection or ablation, failure to complete recommended follow-up treatments, and failure to achieve complete eradication of intestinal metaplasia, among others.2Wani S. Gyawali C.P. Katzka D.A. AGA clinical practice update on reducing rates of post-endoscopy esophageal adenocarcinoma: commentary.Gastroenterology. 2020; 159: 1533-1537Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,16Sawas T. Alsawas M. Bazerbachi F. et al.Persistent intestinal metaplasia after endoscopic eradication therapy of neoplastic Barrett's esophagus increases the risk of dysplasia recurrence: meta-analysis.Gastrointest Endosc. 2019; 89: 913-925Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Given the increasing use of endoscopic eradication therapy in patients with BE-associated neoplasia, quality indicators for endoscopic eradication therapy have been developed using an evidence-based approach endorsed by gastroenterology societies.17Wani S. Muthusamy V.R. Shaheen N.J. 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: 1032-1048Crossref PubMed Scopus (21) Google Scholar Classification practices are surrogates for performing a high-quality endoscopy exam. The Prague classification system (see www.iwgco.net) is a validated grading system associated with high interobserver agreement among expert and nonexpert endoscopists to document the circumferential and maximal extent of the BE segment.18Sharma P. Dent J. Armstrong D. et al.The development and validation of an endoscopic grading system for Barrett's esophagus: the Prague C & M criteria.Gastroenterology. 2006; 131: 1392-1399Abstract Full Text Full Text PDF PubMed Scopus (754) Google Scholar The Paris classification is a standardized morphology categorization, recommended by the US Multi-Society Task Force on colorectal cancer, and can provide relevant information regarding the risk of a lesion harboring submucosal invasion. Endoscopists are encouraged to use the Prague and Paris classifications in descriptive terms for BE-associated lesions.3Rutter M.D. Beintaris I. Valori R. et al.World Endoscopy Organization consensus statements on post-colonoscopy and post-imaging colorectal cancer.Gastroenterology. 2018; 155: 909-925Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar Nevertheless, future studies are needed to assess whether use of these classifications leads to reduced rates of PEEN/PEEC. Consistent with recent guidelines,5Qumseya B. Sultan S. et al.ASGE Standards of Practice CASGE guideline on screening and surveillance of Barrett's esophagus.Gastrointest Endosc. 2019; 90: 335-359Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar the panelists rated the statement on the use of chromoendoscopy (virtual or traditional) in addition to high-definition white-light endoscopy during screening and surveillance endoscopy for BE patients as appropriate. In an updated meta-analysis that included 504 patients, chromoendoscopy with high-definition white-light endoscopy was associated with a higher detection rate of HGD/EAC compared with high-definition white-light endoscopy alone (14.7% vs 10.1%; relative risk, 1.44) (Supplementary Table 1, Appendix 5). There was low certainty of evidence because of risk of bias and imprecision associated with a low event rate. Available data suggest comparable rates of dysplasia detection between virtual and traditional chromoendoscopy techniques. Virtual chromoendoscopy (narrow-band imaging) is available in most endoscopes and thus requires no additional costs. Problems associated with dye-based chromoendoscopy include the need for dye-spraying equipment, additional time required, cumbersome nature of the procedure, difficulty in achieving uniform coating of the mucosal surface with the dye, and inability to detect superficial vascular patterns.5Qumseya B. Sultan S. et al.ASGE Standards of Practice CASGE guideline on screening and surveillance of Barrett's esophagus.Gastrointest Endosc. 2019; 90: 335-359Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar Incorporation of training in virtual and traditional chromoendoscopy during fellowship and training programs for the practicing endoscopists is important for widespread routine implementation in clinical practice. Although data are limited, there was agreement that adequate inspection time would potentially increase detection of BE-associated neoplasia.19Gupta N. Gaddam S. Wani S.B. et al.Longer inspection time is associated with increased detection of high-grade dysplasia and esophageal adenocarcinoma in Barrett's esophagus.Gastrointest Endosc. 2012; 76: 531-538Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Future studies need to define the optimal inspection time per centimeter of the BE segment. Although the panel purposefully did not provide a time period comprising an adequate exam because of lack of data on this issue, European societies recommend a procedure time of ≥7 minutes for upper endoscopy and inspection time of ≥1 min/cm of the circumferential extent of the Barrett’s mucosa.20Bisschops R. Areia M. Coron E. et al.Performance measures for upper gastrointestinal endoscopy: a European Society of Gastrointestinal Endoscopy (ESGE) quality improvement initiative.Endoscopy. 2016; 48: 843-864Crossref PubMed Scopus (110) Google Scholar With regards to evidence supporting the routine use of the Seattle biopsy protocol in patients undergoing screening or surveillance for BE, data from 2 observational studies that included 506 patients demonstrated that the use of the Seattle biopsy protocol was associated with a higher dysplasia detection rate (19.1% vs 2.6%; relative risk, 2.75) (Supplementary Table 2). Selection bias and imprecision and indirectness of evidence (because detection of dysplasia was used as a surrogate for PEEN/PEEC) limited interpretation. Endoscopists may avoid biopsy of a visible lesion with referral for endoscopic resection. Several studies have consistently demonstrated suboptimal compliance rates to the Seattle biopsy protocol.6Wani S. Williams J.L. Komanduri S. et al.Endoscopists systematically undersample patients with long-segment Barrett's esophagus: an analysis of biopsy sampling practices from a quality improvement registry.Gastrointest Endosc. 2019; 90: 732-741Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar Using a community-based pathology database, Abrams et al21Abrams J.A. Kapel R.C. Lindberg G.M. et al.Adherence to biopsy guidelines for Barrett's esophagus surveillance in the community setting in the United States.Clin Gastroenterol Hepatol. 2009; 7 (quiz 710): 736-742Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar reported that the odds of detecting dysplasia significantly decreased with noncompliance with the Seattle biopsy protocol (odds ratio, 0.53; 95% confidence interval, 0.35–0.82).21Abrams J.A. Kapel R.C. Lindberg G.M. et al.Adherence to biopsy guidelines for Barrett's esophagus surveillance in the community setting in the United States.Clin Gastroenterol Hepatol. 2009; 7 (quiz 710): 736-742Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar A recent analysis using a national quality benchmarking registry that included 58,709 endoscopies showed that nearly 20% of endoscopies were not compliant with the Seattle biopsy protocol and that endoscopists were less compliant with increasing BE length; the odds of noncompliance increased by 31% with every 1-cm increase in length.6Wani S. Williams J.L. Komanduri S. et al.Endoscopists systematically undersample patients with long-segment Barrett's esophagus: an analysis of biopsy sampling practices from a quality improvement registry.Gastrointest Endosc. 2019; 90: 732-741Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar The panelists also acknowledged the significant interobserver variability in the interpretation of dysplasia among pathologists and the importance of high-quality expert pathology review in the diagnosis of dysplasia.5Qumseya B. Sultan S. et al.ASGE Standards of Practice CASGE guideline on screening and surveillance of Barrett's esophagus.Gastrointest Endosc. 2019; 90: 335-359Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar,10Standards of Practice Committee Wani S. Qumseya B. et al.Endoscopic eradication therapy for patients with Barrett's esophagus-associated dysplasia and intramucosal cancer.Gastrointest Endosc. 2018; 87: 907-931Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar An accurate diagnosis of dysplasia is critical for clinical decision-making and risk stratification, including the selection of endoscopic eradication therapy vs intensive surveillance. Guidelines recommend that dysplasia of any grade should be confirmed by a second pathologist with expertise in gastroenterology pathology.7Shaheen N.J. Falk G.W. Iyer P.G. et al.ACG clinical guideline: diagnosis and management of Barrett's esophagus.Am J Gastroenterol. 2016; 111 (; quiz 51): 30-50Crossref PubMed Scopus (816) Google Scholar,10Standards of Practice Committee Wani S. Qumseya B. et al.Endoscopic eradication therapy for patients with Barrett's esophagus-associated dysplasia and intramucosal cancer.Gastrointest Endosc. 2018; 87: 907-931Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Services and individual endoscopists are encouraged to review PEEN/PEEC cases periodically and identify areas for improvement. We provide a consensus-based categorization construct and acknowledge that this construct will need to be validated in future studies. An adequate examination was defined as one that met the prerequisites of documentation of landmarks, use of high-definition white-light endoscopy and chromoendoscopy, and complete sampling using the Seattle biopsy protocol. Similar to the disclaimer provided by the World Endoscopy Organization for post-colonoscopy colorectal cancer, the panelists recommended using the above construct of explanations to facilitate quality assurance but not to be used to support medicolegal decision-making or to define accountability at an individual level.3Rutter M.D. Beintaris I. Valori R. et al.World Endoscopy Organization consensus statements on post-colonoscopy and post-imaging colorectal cancer.Gastroenterology. 2018; 155: 909-925Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar An essential theme of this project was the development of consistent strategies to optimize detection of PEEN and PEEC, not to develop metrics for punitive use. In addition to the research directives outlined above, the panelists also discussed and voted on statements for which there was not sufficient agreement (Supplementary Table 3) but consensus that some of these statements were important for future discussion and resolution (Appendix 6). Panelists discussed that operationalizing PEEN/PEEC as a quality indicator for providers may be challenging given the low number of endoscopies performed for BE screening and surveillance and low annual number of incident EAC cases. Future efforts will need to focus on standardizing how PEEN/PEEC rates should be calculated in an automated fashion and establishing a minimum performance standard. The panelists acknowledged that the field would benefit from the BE equivalent of the adenoma detection rate, used to measure quality in colorectal cancer screening. Neoplasia detection rate, defined as the prevalence of HGD or EAC among BE patients at index upper endoscopy, has also been proposed as a quality indicator in the management of BE.22Parasa S. Desai M. Vittal A. et al.Estimating neoplasia detection rate (NDR) in patients with Barrett's oesophagus based on index endoscopy: a systematic review and meta-analysis.Gut. 2019; 68: 2122-2128Crossref PubMed Scopus (19) Google Scholar Nevertheless, significant work is needed to establish if the neoplasia detection rate can be adopted as a quality indicator to reliably differentiate between endoscopists (or endoscopy centers) with discordant detection rates of PEEN and PEEC, enable accountability between providers, and demonstrably improve the quality of care provided to patients. To be considered a high-value quality indicator, the neoplasia detection rate must be shown to correlate with important clinical outcomes such as interval development of EAC and/or mortality. In addition, although benchmarking thresholds need to be defined, it is imperative that these thresholds account for the different rates of neoplasia in the underlying population undergoing an upper endoscopy. This will most likely require risk adjustment based on well-established risk factors for the development and progression in BE. The routine use of wide-area transepithelial sampling in reducing rates of PEEN/PEEC in clinical practice was voted as uncertain. An updated systematic review and meta-analysis of the use of wide-area transepithelial sampling in BE screening and surveillance in 13,950 patients demonstrated an increase in detection of dysplasia among patients undergoing sampling using wide-area transepithelial sampling and forceps biopsies compared with forceps biopsies alone (3.2% vs 1.2%; relative risk, 2.13) (Supplementary Table 4). The certainty of evidence was reduced because of risk of bias (evidence largely driven by observational data), inconsistency (high heterogeneity, variability in detection rates of dysplasia), indirectness (detection of dysplasia was deemed as a surrogate for PEEN/PEEC), and uncertainty interpreting dysplasia diagnosed alone with wide-area transepithelial sampling. No study yet has evaluated the addition of wide-area transepithelial sampling to forceps biopsies for detection of dysplasia during BE surveillance when forceps biopsies are guided by both white-light and chromoendoscopy. There are also limited data on longitudinal follow-up of patients with nondysplastic biopsies but positive wide-area transepithelial sampling analyses to fully understand the prognostic significance of these discrepant findings. Inherent in this need is the evaluation of other proposed sampling or diagnostic techniques to predict development of neoplasia, such as TissueCypher, or more generic approaches including identification of additional methylation or other biomarkers.23Davison J.M. Goldblum J. Grewal U.S. et al.Independent blinded validation of a tissue systems pathology test to predict progression in patients with Barrett's esophagus.Am J Gastroenterol. 2020; 115: 843-852Crossref PubMed Scopus (10) Google Scholar Efforts are also needed to determine if implementation of further BE training leads to increased detection of PEEN/PEEC and a reduction in cancer mortality. It is critical that BE training courses designed to enhance detection of PEEN/PEEC undergo internal and external validation to achieve this goal. The “Barrett’s Oesophagus-Related Neoplasia” web-based training course is an available validated training course that primarily focuses on improving early neoplasia detection.24Bergman J. de Groof A.J. Pech O. et al.An interactive web-based educational tool improves detection and delineation of Barrett's esophagus-related neoplasia.Gastroenterology. 2019; 156: 1299-1308Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar This tool can be accessed at www.iwgco.net, www.ueg.eu, or www.best-academia.eu. No comprehensive training course is currently available that covers all facets of best practices in BE, and this deficit is the focus of ongoing research. Similarly, pathologist training may be needed to improve interobserver agreement when assessing Barrett’s dysplasia. One study from the Netherlands demonstrated that benchmarks defined previously by a group of core expert BE pathologists was validated by demonstrating consistency and training potential when enlisting other core pathologists to the group of BE experts.25van der Wel M.J. Klaver E. Duits L.C. et al.Adherence to pre-set benchmark quality criteria to qualify as expert assessor of dysplasia in Barrett's esophagus biopsies—towards digital review of Barrett's esophagus.United Eur Gastroenterol J. 2019; 7: 889-896Crossref PubMed Scopus (5) Google Scholar Finally, a checklist for future articles on this topic is proposed in Appendix 7. Using an evidence-based consensus process, an international multidisciplinary panel provided comprehensive guidance on standardizing the definition and etiology for PEEN/PEEC, potential explanations, and a template for the performance and improvement of high-quality endoscopy to reduce rates of PEEN/PEEC in clinical practice.

Management of Barrett's esophagus with low-grade dysplasia

Barrett's esophagus progresses to esophageal adenocarcinoma in a stepwise histological fashion of no dysplasia, low grade dysplasia, high grade dysplasia and cancer. Hence the progression to cancer from various histological stages is different. Progression to cancer from low grade dysplasia is highly variable in the literature due to high inter-observer variability between pathologists in diagnosing it. Studies have shown the utility of having confirmation of low grade dysplasia by expert pathologists or documenting its persistence on two subsequent endoscopies in order to unify the diagnosis. The treatment of low grade dysplasia is variable. In this article we summarize the diagnosis, evaluation and management of low grade dysplasia in Barrett's Esophagus.

Radiofrequency ablation for low-grade dysplasia in Barrett's esophagus.

The diagnosis and management of low-grade dysplasia (LGD) in Barrett's esophagus continue to evolve and vary in practice. Radiofrequency ablation (RFA) is now an acceptable option for the treatment of LGD. Therefore, the purpose of this review article is to present current literature on the diagnosis and management of LGD, and to explore when to optimally pursue RFA for the treatment of LGD. The challenge of the management of LGD begins with its diagnosis. Because of high interobserver variability among pathologists in the diagnosis of dysplasia, it is recommended that an expert gastrointestinal pathologist confirms the diagnosis of LGD. Endoscopic mucosal resection is indicated to remove visible lesions in the setting of dysplasia to obtain an accurate diagnosis, especially regarding T staging. Management options include intense surveillance and endoscopic eradication therapy. RFA provides a reasonable method to eradicate flat Barrett's mucosa. Endoscopic eradication of confirmed LGD has been demonstrated to reduce the risk of progression to esophageal cancer. Additional data about the risk factors associated with progression, and the benefits and risks of treatment are discussed, and can be incorporated in patient counseling and decision making. Endoscopic eradication therapy with RFA may be an appropriate treatment option for LGD in Barrett's esophagus after the benefits and risks have been discussed in detail with the patient.

Low grade dysplasia in Barrett's esophagus: Should we worry?

The optimal management for low-grade dysplasia (LGD) in Barrett's esophagus is unclear. In this article the importance of LGD is discussed, including the significant risk of progression to esophageal adenocarcinoma. Endoscopic surveillance is a management option but is plagued by sampling error and issues of suboptimal endoscopy. Furthermore endoscopic surveillance has not been demonstrated to be cost-effective or to reduce cancer mortality. The emergence of endoluminal therapy over the past decade has resulted in a paradigm shift in the management of LGD. Ablative therapy, including radiofrequency ablation, has demonstrated promising results in the management of LGD with regards to safety, cost-effectiveness, durability and reduction in cancer risk. It is, however, vital that a shared-decision making process occurs between the physician and the patient as to the preferred management of LGD. As such the management of LGD should be "individualised."

Updated BSG guidelines for cancer surveillance in IBD – improving consensus and changing practice?

IntroductionBSG guidelines for screening and surveillance in IBD have been recently updated to account for changes in consensus opinion and evidence since their initial publication in 2002.1 2 Changes include...

Management of low and high-grade dysplasia in inflammatory bowel disease: the gastroenterologists?? perspective and current practice in the United Kingdom

Colonic dysplasia is a precursor to colorectal cancer (CRC) in inflammatory bowel disease (IBD). There is a risk of progression of both low-grade dysplasia (LGD) and high-grade dysplasia (HGD) to CRC over 5 years. The current British Society of Gastroenterology guidelines advocate colectomy when possible or at least colonoscopic surveillance every 6 months. To obtain an overview of the gastroenterologists' perspective on various aspects of colonic dysplasia in IBD and to understand current management practice in the UK. A national postal survey of 551 gastroenterologists listed in the British Society of Gastroenterology Handbook 2003. Some 56% of questionnaires were returned; 255 out of 551 completed questionnaires were included in the final analysis. A total of 70% considered LGD to be premalignant, whereas all considered HGD to be premalignant. Only 13% offered routine colectomy for LGD compared with 84% for HGD. More than a third felt that flat LGD might not have concurrent CRC, of which 95% performed surveillance colonoscopies in this group. A small proportion of the remaining gastroenterologists treated flat LGD surgically (13%), whereas 85% considered that LGD with dysplasia-associated lesion or mass (DALM) constituted a high risk of concurrent CRC, but only 52.5% offered total colectomy to this group. There was a wide variation in the frequency of surveillance for LGD in flat mucosa and DALM. A majority agreed that LGD progressed to HGD (82%) and CRC (75%). However, their perception of the risk of progression to either HGD or CRC over 5 years varied widely. All agreed that HGD may have coexistent CRC, and 98% thought it progressed to CRC. Patients were more likely to be treated with colectomy for flat HGD (77%) and HGD in the presence DALM (86%); 38% of gastroenterologists felt that over 30% of patients have coexistent CRC in HGD, and 10% continued to manage them conservatively. There are wide variations in the perceptions and management of LGD in IBD in the UK compared with HGD, in which there seems to be more uniform agreement. The need for more research in this area and a national agreement on management is paramount. Until this is reached gastroenterologists will remain open to criticism and litigation.

Inflammatory Bowel Disease

This review summarizes important publications that have appeared during the last year dealing with imaging techniques and endoscopy, as well as the management of low-grade dysplasia and stenosis in inflammatory bowel disease. Magnetic resonance enteroclysis and capsule endoscopy are currently emerging as new imaging techniques for the small bowel in Crohn's disease. While magnetic resonance enteroclysis is, at least in Europe, increasingly being used as a reference method, the value of capsule endoscopy for the management of inflammatory bowel disease is still being evaluated. Chromoendoscopy is being studied in patients with long-lasting ulcerative colitis and may be a promising and sensitive technique for the diagnosis of dysplasia. However, there are conflicting data regarding the appropriate management when low-grade dysplasia is diagnosed in patients with ulcerative colitis. Endoscopic dilation can often be successfully carried out in cases of intestinal stenosis. The results of long-term follow-up studies indicate that several dilation procedures are often necessary and that a relatively high percentage of patients still have to undergo surgery.

Surveillance colonoscopy for colitic cancer in inflammatory bowel disease

Patients with inflammatory bowel disease are known to be at increased risk for the development of colorectal cancer, especially those with long-standing extensive ulcerative colitis. Although some recommend prophylactic total proctocolectomy for these high-risk patients, surveillance colonoscopy to detect ulcerative colitis-associated colorectal cancer is, instead, generally performed. Dysplasia has been considered to be a useful marker to detect colorectal cancer at surveillance colonoscopy. High-grade dysplasia is a definite indication for total proctocolectomy, while management of low-grade dysplasia is still controversial. Patients with Crohn's disease are also considered to be at higher risk for the development of colorectal cancer, although the risk may be lower than in extensive ulcerative colitis. Molecular biology-based surveillance and chemoprevention for ulcerative colitis-associated colorectal cancer are also reviewed.