Outcomes of Endoscopically Resected High-risk Mucosal and Low- and High-risk Submucosal Adenocarcinoma Arising in Barrett's Esophagus

Outcomes of Endoscopically Resected High-risk Mucosal Adenocarcinoma and Low- and High-risk Submucosal Adenocarcinoma Arising in Barrett's Esophagus: an International Multicenter Retrospective Cohort Study

The purpose of this study is to assess lymph node metastasis rate, distant metastasis rate, disease-specific mortality, and overall mortality in patients with Barrett's related T1b and high risk T1a esophageal adenocarcinoma (EAC) who underwent a diagnostic endoscopic resection.

Study Overview

• Status: Unknown
• Conditions: Barrett Esophagus; Adenocarcinoma Esophagus; Submucosal Esophageal Adenocarcinoma; High-risk Mucosal Esophageal Adenocarcinoma
• Intervention / Treatment: Procedure: diagnostic endoscopic resection

Detailed Description

The incidence of esophageal adenocarcinoma (EAC) has increased six-fold over the last three decades, making it the most rapidly rising cancer in the Western world. The main histologic risk factor for development of EAC is the presence of Barrett's esophagus (BE). BE can develop from non-dysplastic BE, to low (LGD) and high grade dysplasia (HGD) and, eventually, EAC.

The past two decades minimally invasive endoscopic resection (ER) has replaced surgical esophagectomy as first-choice therapy for the treatment of early neoplastic lesions in Barrett's esophagus. ER provides adequate tissue specimens, allowing for accurate histopathological staging of a lesion, by assessment of invasion depth, differentiation grade, presence of lympho-vascular invasion (LVI), and radicality of the resection. Endoscopic resection thus similarly fulfils a diagnostic and therapeutic role in the management of Barrett's neoplasia.

However, ER offers local treatment and does not include lymph node dissection as is still standard of care during esophagectomy. Therefore, the choice to perform endoscopic follow-up after a radical ER of an early EAC, or to refer a patient for additional surgery, is guided by the assumed risk of lymph node metastasis (LNM).

Data from previous studies show that the risk of LNM is only 1% in patients with low risk mucosal EAC after endoscopic treatment (i.e., infiltration depth limited to the mucosa, G1-G2, without LVI), and <2% in low risk submucosal EAC (i.e., infiltration depth <500μm, good to moderate differentiation grade (G1-G2), without LVI). In high risk submucosal EAC (i.e., infiltration depth ≥500 μm, and/or G3-G4, and/or LVI), the LNM risk is estimated to be much higher (16-44%). Nevertheless, these numbers are mainly based on old surgical series.

Current data is limited in terms of small and heterogeneous patient cohorts, and data for patients with high risk T1a EAC is not available at all. Therefore, we would like to conduct an international multicenter retrospective cohort study in >10 centers to evaluate the safety and efficacy of endoscopic treatment and follow-up of patients with high risk mucosal and submucosal EAC. Our main focus will be the presence of lymph node metastasis and EAC related death.

Aim of this registration study is to collect data of the above-mentioned group of patients and thereby assess lymph node metastasis rate, disease-specific mortality, and overall mortality.

This study will be conducted according to the principles of the Declaration of Helsinki and in accordance with the Medical Research Involving Human Subjects Act (WMO), the Medical Treatment Contracts Act (WGBO) and the Dutch Personal Data Protection Act (WBP). The investigators will perform the study in accordance with this protocol and will make sure that participants do not object to using their data. Collection, recording, and reporting of data will be accurate and will ensure the privacy, health, and welfare of research subjects during and after the study.

• Study Type: Observational
• Enrollment (Anticipated): 1000

Contacts and Locations

Study Locations

• Australia
  • Sydney, Australia
    • Not yet recruiting
    • Westmead Hospital
    • Contact: M. Bourke, MD, PhD
• Belgium
  • Leuven, Belgium
    • Recruiting
    • Uz Gasthuisberg
    • Contact: R. Bisschops, MD, PhD
• France
  • Nantes, France
    • Not yet recruiting
    • CHU Nantes
    • Contact: Emmanuel Coron
• Germany
  • Augsburg, Germany
    • Not yet recruiting
    • Universitätsklinikum Augsburg
    • Contact: H. Messmann; Email: Helmut.Messmann@uk-augsburg.de
  • Duesseldorf, Germany
    • Not yet recruiting
    • EVK Duesseldorf
    • Contact: Horst Neuhaus
  • Münich, Germany
    • Not yet recruiting
    • MRI TUM
    • Contact: Christoph Schlag
  • Regensburg, Germany
    • Not yet recruiting
    • Barmherzige Brüder Regensburg
    • Contact: Oliver Pech
• Netherlands
  • Amsterdam, Netherlands
    • Completed
    • Amsterdam UMC, location VUmc
  • Eindhoven, Netherlands
    • Completed
    • Catharina Hospital
  • Groningen, Netherlands
    • Completed
    • University Medical Center Groningen
  • Nieuwegein, Netherlands
    • Completed
    • St. Antonius Hospital
  • Rotterdam, Netherlands
    • Completed
    • Erasmus MC - University Medical Center
  • The Hague, Netherlands
    • Completed
    • Haga Medical Center
  • Zwolle, Netherlands
    • Completed
    • Isala Clinics
• Switzerland
  • Zürich, Switzerland
    • Recruiting
    • Hirslanden private hospital group
    • Contact: S. Seewald
• United Kingdom
  • London, United Kingdom
    • Not yet recruiting
    • University College London Hospital
    • Contact: R. Haidry, MD, PhD
    • Principal Investigator: R. Haidry, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients who underwent a diagnostic ER for Barrett's related HR T1a or T1b EAC in one of the participating centers, from 1/1/2008 up to the moment of data collection.

Description

Inclusion Criteria:

1. Males or females, all ages
2. Endoscopic resection of a histologically proven high risk T1a, low risk T1b EAC, or high risk T1b EAC
3. Between 1/1/2008 and 1/1/2019
4. Endoscopic resection and endoscopic FU (or other treatment after ER) have taken place in the participating center
5. No written or oral refusal to use subject's data

Exclusion Criterium:

Objection against participation in this study

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
HR-T1a; Patients who weretreated by radical endoscopic resection for a high-risk mucosal EAC (HR-T1a N0M0)	Procedure: diagnostic endoscopic resection; diagnostic endoscopic resection
LR-T1b; Patients who were treated by radical endoscopic resection for a low-risk submucosal EAC (LR-T1b N0M0)	Procedure: diagnostic endoscopic resection; diagnostic endoscopic resection
HR-T1b; Patients who were treated by radical endoscopic resection for a high-risk submucosal EAC (HR-T1b N0M0)	Procedure: diagnostic endoscopic resection; diagnostic endoscopic resection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
lymph node metastasis rate	Confirmed by cytology and/or histology by performing FNA during EUS or biopsies	10 years
distant metastasis rate	Primary tumor of distant metastasis should be histopathologically evalueted by taking biopsies.	10 years
disease-specific mortality	Disease specific mortality is decribed as mortality directly linked to the esophageal adenocarcinoma (i.e., metastasized EAC, metastasized disease with a simultaneously primary cancer present and it cannot be ruled out (based on histology) that the metastases are related to the other primary cancer, death due to complications of the endoscopic procedure, death due to complications after surgery or CRT, no clear cause of death in patients who have metastases or untreated local recurrence). If patients are diagnosed with distant metastases, and subsequently die of a non-tumor related cause, patients will still be documented as tumor-related death. Will be measured in number of patients and percentages. Survival analysis using Kaplan Meier will be performed.	10 years
overall mortality	Overall mortality of study population (tumor-related + non-tumor-related deaths). Measured in numbers and percentages, survival analysis (KM).	10 years

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Investigators: Principal Investigator: R.E. Pouw, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study record dates

Study Major Dates

• Study Start (Actual): February 10, 2020
• Primary Completion (Anticipated): December 31, 2022
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: March 24, 2021
• First Submitted That Met QC Criteria: March 24, 2021
• First Posted (Actual): March 26, 2021

Study Record Updates

• Last Update Posted (Actual): March 26, 2021
• Last Update Submitted That Met QC Criteria: March 24, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Endoscopic treatment; Barrett Esophagus; Submucosal esophageal adenocarcinoma; Endoscopic follow-up; High-risk mucosal esophageal adenocarcinoma
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Precancerous Conditions; Adenocarcinoma; Esophageal Neoplasms; Barrett Esophagus
• Other Study ID Numbers: X (Mirum Pharmaceuticals, Inc.)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No