Prospective Endoscopic Follow-up of Patients With Submucosal and High Risk Mucosal Esophageal Adenocarcinoma

Official title

Endoscopic Management of Patients With High Risk T1a and T1b N0M0 Esophageal Adenocarcinoma: a Prospective Multicenter Registry.

Overview

Aim of this prospective multicenter study is to evaluate the safety of an endoscopic follow-up strategy in patients treated with endoscopic resection (ER) for submucosal or high-risk mucosal esophageal adenocarcinoma (T1bN0M0 or HR T1aN0M0 EAC).

Detailed description

Traditionally, the risk of lymph node metastasis associated with submucosal EAC was considered too high to offer patients endoscopic follow-up. Only in elderly patients with comorbidity, more often an endoscopic protocol is selected. However, the risk of lymph node metastasis associated with submucosal EAC is mainly based on surgical series. Recently a number of studies, which included patients treated endoscopically, were published indicating that the risk of lymph node metastasis may be much lower than generally assumed (1-5). Therefore, a less invasive and organ preserving approach may not only be an option in the frail and elderly, but for all patients with submucosal EAC's.

Yet, no data exists on the risk of lymph node metastasis in high risk T1a EAC. The risk is assumed to be lower than for EACs invading into the submucosal layer. However, a recent retrospective analysis from our own research group shows that this risk may be higher than previously assumed (6). In this nationwide retrospective study, we analyzed lymph node metastasis rates and EAC related mortality rates concerning patients with high risk T1a, low risk T1b or high risk T1b EAC who received endoscopic treatment. The study was performed in 9 Barrett Expert Centers in the Netherlands (2008-2019). 120 patients were included in the analysis, and results showed the highest lymph node metastasis risk in the high risk T1a patient group.

Aim of this multicenter study is to prospectively evaluate the safety of endoscopic follow-up in patients treated by endoscopic resection for submucosal (T1bN0M0) and high risk mucosal (T1aN0M0) EAC.

High-resolution upper endoscopy with white-light endoscopy and narrow-band imaging supplemented with an EUS are performed every three months during the first two years after ER. After 1 year, a CT-thorax/abdomen will be performed to check for distant metastasis. During the third and fourth year of follow-up, EUS and upper endoscopy are performed every six months. From the fifth year on, EUS and upper endoscopy are performed annually.

Interventions

• Procedure Endoscopic follow-up
  Endoscopic follow-up by means of regular upper endoscopies and endoscopic ultrasounds

Primary outcome measures

• 5-year disease-specific mortality/survival (descriptive statistics in SPSS, percentages, survival analysis) [Time frame: 5 years]
• Overall survival (descriptive statistics in SPSS, percentages, survival analysis) [Time frame: 5 years]

Secondary outcome measures (5)

• Lymph node metastasis, confirmed by cytology and/or histology (descriptive statistics in SPSS, number of patients (%)) [Time frame: 5 years]
• Local recurrence eligible for endoscopic therapy (descriptive statistics in SPSS, number of patients (%)) [Time frame: 5 years]
• Local recurrence requiring surgical therapy (descriptive statistics in SPSS, number of patients (%)) [Time frame: 5 years]
• Distant metastasis, histologically proven (descriptive statistics in SPSS, number of patients (%)) [Time frame: 5 years]
• Quality of life during follow-up endoscopies (questionnaires) [Time frame: 5 years]

Eligibility criteria

Inclusion criteria

• Patients with submucosal or high-risk mucosal EAC diagnosed in an ER specimen, by an expert gastrointestinal (GI) pathologists.
• Signed informed consent.

Exclusion criteria

• Prior history of high-risk mucosal or ≥T1sm.
• Synchronous esophageal squamous cell carcinoma.
• Suspicion on lymph node metastasis or distant metastasis on EUS, ultrasound of the neck or CT-thorax-abdomen performed six weeks after ER during baseline measurement.
• Tumor-positive deep resection margin (R1) in ER specimen.
• Patients unable to give signed informed consent.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Netherlands · 8 centers

• Amsterdam UMC — Amsterdam
• Catharina Hospital — Eindhoven
• University Medical Center Groningen — Groningen
• St. Antonius Hospital — Nieuwegein
• Radboudumc — Nijmegen
• Erasmus MC - University Medical Center — Rotterdam
• Haga Medical Center — The Hague
• Isala Clinics — Zwolle

Belgium · 4 centers

• CUB Hôpital Erasme — Brussels
• AZ Maria Middelares Ghent — Ghent
• UZ Leuven — Leuven
• AZ Delta Roeselare — Roeselare

Germany · 4 centers

• Universitätsklinikum Augsburg — Augsburg
• EVK Duesseldorf — Düsseldorf
• MRI TUM — Münich
• Barmherzige Brüder Regensburg — Regensburg

United Kingdom · 2 centers

• University College London Hospital — London
• Nottingham University Hospitals NHS Trust — Nottingham

Australia · 1 center

• Westmead hospital — Sydney

Switzerland · 1 center

• Hirslanden private hospital group — Zurich

Publications

• Alvarez Herrero L, Pouw RE, van Vilsteren FG, ten Kate FJ, Visser M, van Berge Henegouwen MI, Weusten BL, Bergman JJ. Risk of lymph node metastasis associated with deeper invasion by early adenocarcinoma of the esophagus and cardia: study based on endoscopic resection specimens. Endoscopy. 2010 Dec;42(12):1030-6. doi: 10.1055/s-0030-1255858. Epub 2010 Oct 19. PMID 20960392
• Scholvinck D, Kunzli H, Meijer S, Seldenrijk K, van Berge Henegouwen M, Bergman J, Weusten B. Management of patients with T1b esophageal adenocarcinoma: a retrospective cohort study on patient management and risk of metastatic disease. Surg Endosc. 2016 Sep;30(9):4102-13. doi: 10.1007/s00464-016-5071-y. Epub 2016 Jun 29. PMID 27357927
• Manner H, May A, Pech O, Gossner L, Rabenstein T, Gunter E, Vieth M, Stolte M, Ell C. Early Barrett's carcinoma with "low-risk" submucosal invasion: long-term results of endoscopic resection with a curative intent. Am J Gastroenterol. 2008 Oct;103(10):2589-97. doi: 10.1111/j.1572-0241.2008.02083.x. Epub 2008 Sep 10. PMID 18785950
• Manner H, Pech O, Heldmann Y, May A, Pohl J, Behrens A, Gossner L, Stolte M, Vieth M, Ell C. Efficacy, safety, and long-term results of endoscopic treatment for early stage adenocarcinoma of the esophagus with low-risk sm1 invasion. Clin Gastroenterol Hepatol. 2013 Jun;11(6):630-5; quiz e45. doi: 10.1016/j.cgh.2012.12.040. Epub 2013 Jan 26. PMID 23357492
• Manner H, Pech O, Heldmann Y, May A, Pauthner M, Lorenz D, Fisseler-Eckhoff A, Stolte M, Vieth M, Ell C. The frequency of lymph node metastasis in early-stage adenocarcinoma of the esophagus with incipient submucosal invasion (pT1b sm1) depending on histological risk patterns. Surg Endosc. 2015 Jul;29(7):1888-96. doi: 10.1007/s00464-014-3881-3. Epub 2014 Oct 8. PMID 25294553
• Nieuwenhuis EA, van Munster SN, Meijer SL, Brosens LAA, Jansen M, Weusten BLAM, Alvarez Herrero L, Alkhalaf A, Schenk E, Schoon EJ, Curvers WL, Koch AD, van de Ven SEM, Verheij EPD, Nagengast WB, Westerhof J, Houben MHMG, Tang T, Bergman JJGHM, Pouw RE; Dutch Barrett Expert Centers. Analysis of metastases rates during follow-up after endoscopic resection of early "high-risk" esophageal adenocarcin PMID 35288149

Identifiers

NCT: NCT03222635 · NL6116501817

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗