Neoplastic Barrett Esophagus: Endoscopic Piecemeal vs. En Bloc Resection

Study Overview
=================
Brief Summary
-----------------
The study will compare EMR versus ESD technique (both combined with subsequent ablative therapy) of mucosal resection in Barrett's esophagus with regard to efficacy and risk in a long term setting.

Detailed Description
-----------------
For Barrett's Esophagus neoplasia of at least LGIN up to early adenocarcinoma, the aim is to debulk or completely treat polypoid dysplastic or malignant lesions in Barrett's esophagus. The Endoscopic Mucosal Resection EMR has been established to be a less invasive, safe, and effective nonsurgical therapy. The most commonly employed modalities of EMR include snare resection with and without prior submucosal injection of fluid, and resection using a cap. Since resection of larger areas can only be done piece - by- piece this kind or resection is also called piecemeal resection or piecemeal EMR. Meanwhile, another endoscopic resection has been developed called Endoscopic Submucosal Dissection ESD.It enables complete resection of neoplasms that were impossible to resect en bloc by EMR. After circumferential cutting of the surrounding mucosa of the lesion, fluid is injected into the submucosa to elevate the lesion from the muscle layer, and subsequently the connective tissue beneath the lesion is dissected. As a basic principle on histopathological and oncological terms, the en bloc resection is to be preferred since resection integrity can be evaluated much more securely. However, complexity of this kind of resection technique as well as complication rates can be different and sometimes higher than with EMR. Current approach treating Barrett's esophagus is to eradicate both neoplastic as well as pre neoplastic or non neoplastic Barrett mucosa in order to lower the relapse risk. Current treatment standard is to combine resection of visible neoplastic areas with subsequent thermo-ablation such as RFA or APC, so this approach will also be the basis of the present study. Since RFA has the largest volume of data screened it shall be the preferred method of ablation in this study.In total, data situation ist inconsistent. Short- and Long term of EMR is excellent in centres(Pech et al, Gastroenterology 2014) whereas ESD achieved only suboptimal outcomes in tree minor western studies (Neuhaus et al. Endoscopy 2012, Höbel et al., Surg Endosc 2015, Chevaux et al. Endoscopy 2015). One randomised study published in 2016 (Terheggen et al. Gut 2016) had a higher rate of R0 resections with ESD on 40 patients but no difference in complete remissions in combination with RFA. Although, this study was not empowered sufficientliy, and also showed a higher complication rate on ESD . At present no randomised study data are availale to allow statements about long term developments, so we will set up this current randomised study. We will compare data with regard to efficacy (histological completeness and relapse rates), as well as risks, e.g. perforations and strictures or stenosis by scarring.

Official Title
-----------------
Prospektiv-randomisierter Vergleich Von En-bloc- Versus Piecemeal-Resektion Von Barrett Neoplasien Des Ösophagus Neoplastic Barrett Esophagus: Endoscopic Piecemeal vs. En Bloc Resection

Conditions
-----------------
Barrett Esophagus, Barrett Adenocarcinoma, Esophagus Neoplasm

Intervention / Treatment
-----------------
* Procedure: Endoscopic mucosal resection
* Procedure: Endoscopic submucosal dissection


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: patients to be treated for Barrett's esophagus by mucosal resection and following ablative therapy Barrett's mucosal extension up to 10 cm maximum. patient's ability for compliance to therapy signed Informed Consent Exclusion Criteria: any lesion questionable to be resectable by mucosectomy, e.g. bulky lesions ≥10 mm in endoscopy und endosonography, suspected deep submucosal infiltration, ulcers, suspected or by FNA confirmed lymph node infiltration Barrett's esophagus > 10 cm lesions that would afford resection of more than 2/3rd of esophagal circumference two or more single Barrett's lesions with bulky HGIN or early cancer histology, not to be resectable in one half of esophageal circumference planned circumferencial resections very serious general illness and metastatic carcinoma coagulation disorder or anticoagulants that make biopsies and resections impossible American Society of Anesthesiologists (ASA) status > III pregnancy and lactation remainders or recurrences after therapeutic history of Barrett's espohagus

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: EMR<br>Endoscopic mucosal resection | Procedure: Endoscopic mucosal resection<br>* Endoscopic resection is carried out using a double-channel scope. The lesion borders are marked with a coagulator. Saline liquid and sometimes epinephrine are injected into the submucosal layer to swell the area containing the lesion and elucidate the markings. The resected mucosa is lifted, then trapped and strangulated with a snare, and subsequently resected by electrocautery. Another method of EMR employs the use of a clear cap and prelooped snare inside the cap. After insertion, the cap is placed on the lesion and the mucosa containing the lesion is drawn up inside the cap by aspiration. The mucosa is caught by the snare and strangulated, and finally resected by electrocautery.<br>* Other names: Piecemeal EMR;|
| Active Comparator: ESD<br>Endoscopic submucosal dissection | Procedure: Endoscopic submucosal dissection<br>* After circumferential cutting of the surrounding mucosa of the lesion, fluid is injected into the submucosa to elevate the lesion from the muscle layer, and the connective tissue of the submucosa beneath the lesion is dissected subsequently.<br>* Other names: ESD;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Eradication rate of neoplastic Barrett's Esophagus, initial therapy success | Rate of complete and curative eradication, free of recurrence of neoplastic Barrett's Esophagus. Endoscopical diagnostic and negative histologies for any kind of neoplasia, measured in follow up control EGD 3 months after end of treatment | 3 months after end of therapy (resection and ablation) | 
| Eradication rate of neoplastic Barrett's Esophagus, initial therapy success | Rate of complete and curative eradication, free of recurrence of neoplastic Barrett's Esophagus. Endoscopical diagnostic and negative histologies for any kind of neoplasia, measured in follow up control EGD 9 months after end of treatment | 9 months after end of therapy (resection and ablation) | 
| Eradication rate of neoplastic Barrett's Esophagus | Rate of complete and curative eradication, free of recurrence of neoplastic Barrett's Esophagus. Endoscopical diagnostic and negative histologies for any kind of neoplasia, measured in follow up control 24 months after end of treatment | 24 months after end of therapy (resection and ablation) | 
| Eradication rate of neoplastic Barrett's Esophagus | Rate of complete and curative eradication, free of recurrence of neoplastic Barrett's Esophagus. Endoscopical diagnostic and negative histologies for any kind of neoplasia, measured in follow up control EGD 33 months after end of treatment | 33 months after end of therapy (resection and ablation) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Eradication rate of complete Barrett's Esophagus, initial therapy success | Rate of complete and curative eradication, free of recurrence of neoplastic and non-neoplastic Barrett's Esophagus. Endoscopical diagnostics and negative histologies for any kind of neoplasia and Barrett's metaplasia measured in follow up control EGD 3 months after end of treatment | 3 months after end of treatment (resection and ablation) | 
| Eradication rate of complete Barrett's Esophagus, initial therapy success | Rate of complete and curative eradication, free of recurrence of neoplastic and non-neoplastic Barrett's Esophagus. Endoscopical diagnostics and negative histologies for any kind of neoplasia and Barrett's metaplasia measured in follow up control EGD 9 months after end of treatment | 9 months after end of treatment (resection and ablation) | 
| Eradication rate of complete Barrett's Esophagus, freedom of recurrence | Rate of complete and curative eradication, free of recurrence of neoplastic and non-neoplastic Barrett's Esophagus. Endoscopical diagnostics and negative histologies for any kind of neoplasia and Barrett's metaplasia measured in follow up control EGD 24 months after end of treatment | 24 months after end of treatment (resection and ablation) | 
| Eradication rate of complete Barrett's Esophagus, freedom of recurrence | Rate of complete and curative eradication, free of recurrence of neoplastic and non-neoplastic Barrett's Esophagus. Endoscopical diagnostics and negative histologies for any kind of neoplasia and Barrett's metaplasia measured in follow up control EGD 33 months after end of treatment | 33 months after end of treatment (resection and ablation) | 
| Recurrence rate of neoplastic Barrett's Esophagus, initial therapy success | rate of complete and curative eradication of neoplastic Barrett's Esophagus measured in follow up control EGD 3 months, Endoscopical diagnostic and negative histologies for any kind of neoplasia. | 3 months after end of therapy (resection and ablation) | 
| Recurrence rate of neoplastic Barrett's Esophagus, initial therapy success | rate of complete and curative eradication of neoplastic Barrett's Esophagus measured in follow up control EGD 9 months , Endoscopical diagnostic and negative histologies for any kind of neoplasia. | 9 months after end of therapy (resection and ablation) | 
| freedom of recurrence rate of complete Barrett's Esophagus, initial therapy success | Freedom of recurrence rate of neoplastic and non-neoplastic Barrett's Esophagus. Endoscopical diagnostics and negative histologies for any kind of neoplasia and Barrett's metaplasia measured in follow up control EGD 9 months (initial therapy success) after end of treatment | 9 months after end of treatment (resection and ablation) | 
| ESD success of resection | rate of en bloc and R0 resections among the initially by ESD resected tissues | 2 days | 
| EMR success of resection | Since with EMR resection success can only be measured for the depth of base initially, the second control EGD with negative histology has been chosen for Gold standard indication for resection success. After 2 negative bioptic controls a piecemeal resection of early carcinoma is classified as complete. | 9 months after end of treatment (resection and ablation) | 
| Surveillance of Barrett's mucosa after incomplete resections and recurrences | follow up of all cases with initially incomplete EMR or ESD resections as well as recurrences after resection and ablation | 51 months | 
| conclusions of Tumor Board in case of re resection and outcome if postitive cancer histology | any Treatment and follow up in case of positive cancer histology | 51 months | 
| Determination of differences in Barrett's esophagus subtypes: size | size of Barrett's mucosa, e.g. Prague Classification | 3 months | 
| Determination of differences in Barrett's esophagus subtypes: form | form of Barrett's mucosa | 3 months | 
| Determination of differences in Barrett's esophagus subtypes: patterns | patterns of Barrett's mucosa, e,g, Kudo Classification | 3 months | 
| Determination of differences in Barrett's esophagus subtypes: histologies | histological assessment of Barrett's mucosa | 3 months | 
| Intervention time | time requested for each resection and ablative sessions | 18 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Barrett Esophagus, ESD, EMR, Esophagus Neoplasm, endoscopic resection technique, ablation of esophageal mucosa