Clinical trial NCT03222635: 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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Submucosal Esophageal Adenocarcinoma
Barrett Esophagus
High-risk Mucosal Esophageal Adenocarcinoma
Keywords: Barrett's esophagus
Submucosal esophageal adenocarcinoma
Endoscopic treatment
Endoscopic follow-up
High-risk mucosal esophageal adenocarcinoma
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
First posted: 2017-07-19
Enrollment: 225
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Upon achieving the designated sample size of 141 patients of the original PREFER-trial, the enrolment of further patients diagnosed with T1b N0M0 EAC and treated endoscopically will be continued as a registration cohort (no sample size) within the same study database.

The high-risk T1a group will also continue as a registration cohort, since there is no available data yet to calculate a reliable sample size with. The high-risk T1a patient group will be analysed separately from the T1b patient group.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Primary outcomes:
measure: 5-year disease-specific mortality/survival (descriptive statistics in SPSS, percentages, survival analysis)
timeFrame: 5 years
measure: Overall survival (descriptive statistics in SPSS, percentages, survival analysis)
timeFrame: 5 years
Secondary outcomes:
measure: Lymph node metastasis, confirmed by cytology and/or histology (descriptive statistics in SPSS, number of patients (%))
timeFrame: 5 years
measure: Local recurrence eligible for endoscopic therapy (descriptive statistics in SPSS, number of patients (%))
timeFrame: 5 years
measure: Local recurrence requiring surgical therapy (descriptive statistics in SPSS, number of patients (%))
timeFrame: 5 years
measure: Distant metastasis, histologically proven (descriptive statistics in SPSS, number of patients (%))
timeFrame: 5 years
measure: Quality of life during follow-up endoscopies (questionnaires)
timeFrame: 5 years
Other outcomes:
Locations:
city: Sydney
country: Australia
facility: Westmead hospital
city: Brussels
country: Belgium
facility: CUB Hôpital Erasme
city: Gent
country: Belgium
facility: AZ Maria Middelares Ghent
city: Leuven
country: Belgium
facility: UZ Leuven
city: Roeselare
country: Belgium
facility: AZ Delta Roeselare
city: Augsburg
country: Germany
facility: Universitätsklinikum Augsburg
city: Duesseldorf
country: Germany
facility: EVK Duesseldorf
city: Münich
country: Germany
facility: MRI TUM
city: Regensburg
country: Germany
facility: Barmherzige Brüder Regensburg
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC
city: Eindhoven
country: Netherlands
facility: Catharina Hospital
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Nieuwegein
country: Netherlands
facility: St. Antonius Hospital
city: Nijmegen
country: Netherlands
facility: Radboudumc
city: Rotterdam
country: Netherlands
facility: Erasmus MC - University Medical Center
city: The Hague
country: Netherlands
facility: Haga Medical Center
city: Zwolle
country: Netherlands
facility: Isala Clinics
city: Zürich
country: Switzerland
facility: Hirslanden private hospital group
city: London
country: United Kingdom
facility: University College London Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
Study officials:
affiliation: Amsterdam UMC
name: J. J. Bergman, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Amsterdam UMC
name: R. E. Pouw, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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 adenocarcinoma. Gastrointest Endosc. 2022 Aug;96(2):237-247.e3. doi: 10.1016/j.gie.2022.03.005. Epub 2022 Mar 12.