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

• ClinicalTrials.gov Identifier: NCT03222635
• Recruitment Status: Recruiting
• First Posted: July 19, 2017
• Last Update Posted: April 29, 2024
• Sponsor: Amsterdam UMC
• Information provided by (Responsible Party): Jacques J.G.H.M. Bergman, Amsterdam UMC, location VUmc

Tracking Information

• First Submitted Date: July 17, 2017
• First Posted Date: July 19, 2017
• Last Update Posted Date: April 29, 2024
• Actual Study Start Date: July 25, 2017
• Estimated Primary Completion Date: July 25, 2028 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 6, 2020)

• 5-year disease-specific mortality/survival (descriptive statistics in SPSS, percentages, survival analysis) [ Time Frame: 5 years ]
  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.
• Overall survival (descriptive statistics in SPSS, percentages, survival analysis) [ Time Frame: 5 years ]
  Overall survival of study population (tumor-related + non-tumor-related deaths). Measured in numbers and percentages, survival analysis (KM).

Original Primary Outcome Measures (submitted: July 18, 2017)

• 5-year disease-specific mortality/survival [ Time Frame: 5 years ]
• Overall survival [ Time Frame: 5 years ]

Current Secondary Outcome Measures (submitted: January 6, 2020)

• Lymph node metastasis, confirmed by cytology and/or histology (descriptive statistics in SPSS, number of patients (%)) [ Time Frame: 5 years ]
  Confirmed by cytology and/or histology by performing FNA during EUS or biopsies.
• Local recurrence eligible for endoscopic therapy (descriptive statistics in SPSS, number of patients (%)) [ Time Frame: 5 years ]
  In case a local recurrence is found during FU endoscopy, histopathology have to show if it is recurrent cancer.
• Local recurrence requiring surgical therapy (descriptive statistics in SPSS, number of patients (%)) [ Time Frame: 5 years ]
  In case a local cancer recurrence is not amendable for endoscopic re-treatment, for example due to extensive disease or fibrosis, a patient will be referred for surgery if possible.
• Distant metastasis, histologically proven (descriptive statistics in SPSS, number of patients (%)) [ Time Frame: 5 years ]
  Primary tumor of distant metastasis should be histopathologically evalueted by taking biopsies.
• Quality of life during follow-up endoscopies (questionnaires) [ Time Frame: 5 years ]
  Quality of life is assessed by using questionnaires on set time points during the whole study.

Original Secondary Outcome Measures (submitted: July 18, 2017)

• Lymph node metastasis, confirmed by cytology and/or histology [ Time Frame: 5 years ]
• Local recurrence eligible for endoscopic therapy [ Time Frame: 5 years ]
• Local recurrence requiring surgical therapy [ Time Frame: 5 years ]
• Distant metastasis, histologically proven [ Time Frame: 5 years ]
• Quality of life [ Time Frame: 5 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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.
• 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.

• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
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.

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Submucosal Esophageal Adenocarcinoma
• Barrett Esophagus
• High-risk Mucosal Esophageal Adenocarcinoma

Intervention

Procedure: Endoscopic follow-up

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

Study Arms

Experimental: Endoscopic follow-up

Patients treated with endoscopic resection (ER) for a submucosal or high-risk mucosal esophageal adenocarcinoma without lymphnode- or distant metastases (N0M0) will undergo endoscopic follow-up.

Intervention: Procedure: Endoscopic follow-up

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.
• 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. Erratum In: Surg Endosc. 2016 Sep;30(9):4114.
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 26, 2024): 225
• Original Estimated Enrollment (submitted: July 18, 2017): 141
• Estimated Study Completion Date: July 25, 2028
• Estimated Primary Completion Date: July 25, 2028 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Vincent Bos, MD; +31204445500; v.bos@amsterdamumc.nl

• Listed Location Countries: Australia, Belgium, Germany, Netherlands, Switzerland, United Kingdom
• Removed Location Countries: France

Administrative Information

• NCT Number: NCT03222635
• Other Study ID Numbers: NL6116501817
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Jacques J.G.H.M. Bergman, Amsterdam UMC, location VUmc
• Original Responsible Party: prof. dr. J.J.G.H.M. Bergman, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), Professor of Gastrointestinal Endoscopy
• Current Study Sponsor: Amsterdam UMC
• Original Study Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: Not Provided

Investigators

• Principal Investigator: J. J. Bergman, MD, PhD; Amsterdam UMC
• Principal Investigator: R. E. Pouw, MD, PhD; Amsterdam UMC

• PRS Account: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Verification Date: April 2024