Complete Resection of Barrett's Esophagus Harboring Neoplasia With Endoscopic Submucosal Dissection.

Research plan Title Complete resection of Barrett's esophagus harboring neoplasia with endoscopic submucosal dissection. Background Barrett esophagus (BE) is a stablished risk factor for the development of esophageal adenocarcinoma. Current guidelines recommend complete eradication of Barrett's mucosa when neoplasia is detected, due to the risk of synchronous or metachronous neoplasia in 20-47% of cases [1, 2]. Advocated treatment demands resection of visible lesions and ablation of remaining Barrett's mucosa. This strategy is hampered by some factors: 1) it demands several treatment sessions (1 for resection of lesions and 2 or more for ablation); 2) is associated with complications in 11% of patients, such as severe pain, bleeding, stricture and perforation in up to 1-2%, 1%, 7 % and 0.6 % of cases, respectively [3-5]; 3) buried glands can grow beneath the neosquamous epithelium after treatment; 4) there is no histological assessment of what is ablated; 5) there is the need of continuous follow-up; 6) there are high costs associated with this strategy; 7) this approach may cause physical and physiological burden to the patients due to continuous follow-up and lack of full histological assessment. Endoscopic submucosal dissection (ESD) enables en bloc resection of neoplastic lesions and has been widely used along the GI tract. Initial reports of ESD on BE were discouraging due to high rate of positive lateral margins and significant rate ofcomplications . The lack of lateral free margins in those studies can be attributed to suboptimal diagnostic and endoscopic techniques.. More recent studies have shown good efficacy of ESD for neoplastic BE, with lateral R0 rates of 75-90% [6]. In our early series, of neoplastic BE treated with ESD, the rates of en bloc, R0 and curative resection were 99%, 86% and 72%, respectively. ESD of Barrett's esophagus might be associated with complications such as bleeding and perforation in 2-3% in most published studies, and in less than 1% each in our series. Another complication that might occur is stricture formation in the esophagus during the healing process after the ESD. That risk was historically high, increasing with increase in size of the resected specimen and with increase in the percentage lumen circumference resected. Historically, the rates of strictures after esophageal ESD were of > 30% in small resections, > 50% when more than 75% of the lumen circumference was resected and virtually 100% in cases of circumferential resection.

That high rate of strictures was the major factor hampering the development of ESD in the esophagus. With the introduction of steroids treatment for the prevention of stricture formation, there was a paradigm shift, and the corresponded stricture rates turn to be 2-10% in small resections [6], 10-14% in resections as big as > 75% of lumen circumference and 27-33% in cases of circumferencial ESD. Most of these studies evaluated the role of subepithelial injection of triamcinolone and the use of oral steroids [7-9]. In our series of 132 ESDs on Barrett's esophagus, 103 cases corresponded to resections up to 75% of luminal circumference, in those, only 4/103 (3.9%) had strictures and all were successfully treated with endoscopic balloon dilation. In the remaining 29 ESD, resection engaged more than 75% of luminal circumference. In these there was formation of stricture in 10/29 cases, all patients were successfully treated with balloon dilation and one with a temporary esophageal stent. Considering the 9 patients with Barrett's neoplasia that were treated by our team with circumferential ESD, 3/9 did not have stricture and the remaining 6/9 were successfully treated with endoscopic treatment (balloon dilation or temporary stent). So, preventive measures and close follow-up are associated with good outcome and safety profile, even in large ESDs on BE. Full resection of BE mucosa enables complete resection of all mucosa at risk, with full histological assessment and virtually no risk for presence of lesion in the margins or development of buried glands. Aims To evaluate the role of full resection of neoplastic Barrett's esophagus in one endoscopic session as an alternative to conventional treatment with partial endoscopic resection in one session, followed by several sessions of ablation of Barrett's mucosa and further follow-up endoscopies. We want to test the efficacy and safety of this approach of complete resection of Barrett's esophagus in patients with Barrett's neoplasia. We aim to do so, through the evaluation of resected specimens and the rates of complications such as bleeding, perforation and stricture. Furthermore, we aim to evaluate the histological results after full endoscopically resection comparing it with the previous histological assessment with conventional endoscopy and biopsies (prior to treatment).We also want to study this strategy in terms of early recurrence of Barrett's metaplasia and dysplasia, patient quality of life and in costs reduction. The main endpoints are the rates of complications such as bleeding, perforation and stricture. Secondary endpoints include: 1) length of the procedures; 2) recurrence of intestinal metaplasia or and dysplasia; 3) HRQL status; 4) costs 5) rates of en bloc, R0 and curative resections. Material and methods Study design This is a pilot study that will be run by Karolinska University Hospital. Study population Patients with neoplastic long-segment Barrett's esophagus will be invited to participate in this study. The study will include 40 patients (interim analysis will be performed after inclusion of the first 10 and 20 patients). Inclusion criteria

• Long segment Barrett's esophagus with circular component >= 3cm and maximum extent of 9cm.
• Presence of neoplastic Barrett's esophagus on previous biopsies confirmed by expert pathologist. Exclusion criteria
• Refractory esophagitis
• Presence of signs of deep submucosal invasion (>sm1)
• Anticoagulation therapy that cannot be discontinued (ASA allowed)
• Barrett's esophagus length > 9 cm (C and/or M)
• Immunosuppression that would contraindicate use of steroids.
• Diabetes Mellitus All patients will receive a detailed explanation regarding the procedure, its risks, benefits, and alternatives, and will provid written informed consent before inclusion (Appendix 1). Participants clinical, demographic, and procedural information will be obtained and recorded at enrollment (Appendix 2). Patients under antiplatelet drugs or anticoagulants will be handled according to published guidelines. OUTCOME PARAMETERS PRIMARY OUTCOME PARAMETERS Adverse events are defined as any complication in which ESD or ESD related procedures (such as anesthesia) are a contributing factor and include bleeding, perforation, stricture and aspiration pneumonitis. Perforation is defined as a full thickness breach in the GI wall with or without symptoms.

Intraprocedural bleeding is considered significant and a complication when:

• blood transfusion is needed
• premature termination of endoscopic occurs
• there is a drop in hemoglobin >= 2g/dL Delayed bleeding is defined as clinical evidence of bleeding manifested by melena or hematochezia from up to 14 days after the procedure that demanded presentation to the emergency department, hospital admission or medical intervention. Aspiration pneumonitis is defined as acute lung injury after the inhalation of regurgitated gastric contents, diagnosed by the development of new radiographic infiltrate and the presence of symptoms or signs suggestive of lower respiratory tract infection. Stricture: esophageal stricture is defined as