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Laparoscopic Ischemic Conditioning Prior to Esophagectomy (ISCON)

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ClinicalTrials.gov Identifier: NCT03896399

Recruitment Status : Recruiting

First Posted : April 1, 2019

Last Update Posted : January 12, 2022

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Sponsor:

Collaborator:

University Hospital of Cologne

Information provided by (Responsible Party):

Richard van Hillegersberg, UMC Utrecht

Study Description

Brief Summary:

This is a two center phase II prospective single-arm safety and feasibility trial for 20 patients with resectable esophageal carcinoma with an increased risk for anastomotic leakage, as based upon UCS and NASCET calcification scores on pre-op CT-scan. In these patients, laparoscopic ischemic conditioning is performed 12-18 days before an Ivor-Lewis esophagectomy. The primary outcome is all complications grade 2 and higher (Clavien-Dindo classification) occurring during or after the laparoscopic ischemic conditioning. Secondary outcomes are complications after the esophagectomy, and the induction of angiogenesis by biomarkers of microcirculation and redistribution of blood flow by measurement of indocyanine green (ICG) fluorescence angiography.

Condition or disease	Intervention/treatment	Phase
Esophageal Cancer	Procedure: Laparoscopic ischemic conditioning followed by esophagectomy	Not Applicable

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Detailed Description:

Rationale:

Anastomotic leakage is the most important surgical complication following esophagectomy for esophageal cancer, leading to increased morbidity and mortality. A major cause of leakage is impaired healing due to ischemia of the gastric tube that is used for reconstruction of the gastrointestinal tract. Calcifications of the aorta or stenosis of the celiac trunk on pre-operative CT scan have been shown to be associated with an increased risk of anastomotic leakage. So far, no individualized treatment has been initiated for this selected group of patients. Laparoscopic ischemic conditioning (ISCON) of the gastric tube aims to increase perfusion at the anastomotic site by redistribution of the gastric blood flow and/or induction of angiogenesis. This is achieved by occlusion of the supplying gastric arteries except for the right gastroepiploic artery during a separate intervention prior to esophagectomy. Of note, these arteries would also be occluded during conventional esophagectomy, but with laparoscopic ISCON they are occluded at an earlier moment in time during a separate intervention. Retrospective studies have demonstrated the safety of this technique. Prospective studies have not yet been performed.

Primary objective:

Assess the safety and feasibility of laparoscopic ISCON 12-18 days prior to esophagectomy for esophageal cancer in patients with arterial calcifications.

Study design:

Two center phase II prospective single-arm safety and feasibility trial.

Study population:

Patients with resectable esophageal carcinoma (cT1-4a, N0-3, M0) with "major calcifications" of the thoracic aorta (UCS) and any additional calcification or stenosis of the celiac axis (modified NASCET score) on preoperative CT scan, who are planned to undergo esophagectomy.

Intervention:

Laparoscopic ISCON followed by esophagectomy after an interval of 12-18 days.

Primary outcome:

all complications grade 2 and higher (Clavien-Dindo classification) occurring during or after operation 1 (laparoscopic ISCON) and before operation 2 (esophagectomy).

Secondary outcomes:

secondary outcomes with regard to operation 1 (laparoscopic ISCON) are the duration of the procedure, blood loss, day of discharge postoperatively and grade 1 complications. Secondary outcomes with regard to operation 2 (esophagectomy) are anastomotic leakage rate, all other grade 3b or higher complications and 30 day mortality. Further secondary endpoints are the induction of angiogenesis by biomarkers of microcirculation and redistribution of blood flow by measurement of indocyanine green (ICG) fluorescence angiography.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

the additional burden for the patient consists of an extra operation of approximately 40 minutes during which laparoscopic ISCON will be performed, prior to the planned esophagectomy. We would classify the current study as medium risk. Potential benefits in comparison to current standard treatment are a reduced risk of anastomotic leakage and severity of anastomotic leakage. Potential risks are complications following operation 1 (laparoscopic ISCON). Mainly, based upon prior experience, we expect gastroparesis to occur in 25% of patients. Patients with gastroparesis have an increased risk of aspiration and will require a stomach emptying by nasogastric tube and nasojejunal tube feeding till the performance of operating 2 (esophagectomy).

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	20 participants
Allocation:	N/A
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Laparoscopic Ischemic Conditioning Prior to Esophagectomy in Patients With Esophageal Cancer and Arterial Calcifications
Actual Study Start Date :	April 9, 2019
Estimated Primary Completion Date :	June 2022
Estimated Study Completion Date :	December 2022

Resource links provided by the National Library of Medicine

Genetic and Rare Diseases Information Center resources: Esophageal Cancer

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Laparoscopic ischemic conditioning followed by esophagectomy All included patients will receive a laparoscopic ischemic conditioning followed by an esophagectomy after an interval of 12-18 days.	Procedure: Laparoscopic ischemic conditioning followed by esophagectomy All included patients will receive a laparoscopic ischemic conditioning followed by an esophagectomy after an interval of 12-18 days.

Outcome Measures

Primary Outcome Measures :

Number of participants with a grade 2 or higher complication after laparoscopic ischemic conditioning [ Time Frame: Occuring after operation 1(laparosocpic ISCON), but before operation 2 (esophagectomy). This time-frame is usually 13-15 days. ]
Complications grade 2 and higher (Clavien-Dindo classification)

Secondary Outcome Measures :

Number of participants with a grade 1 complication after operation 1 (laparoscopic ISCON) [ Time Frame: Occuring after operation 1(laparosocpic ISCON), but before operation 2 (esophagectomy). This time-frame is usually 13-15 days. ]
Grade 1 complications after operation 1 (laparoscopic ISCON)
Duration of operation 1 (laparoscopic ISCON) [ Time Frame: During operation 1 ]
Duration of operation 1 (laparoscopic ISCON)
Bloodloss during operation 1 (laparoscopic ISCON) [ Time Frame: During operation 1 ]
Bloodloss during operation 1 (laparoscopic ISCON)
Day of discharge after operation 1 (laparoscopic ISCON) [ Time Frame: After operation 1, usually on the third post-operative day ]
Day of discharge after operation 1 (laparoscopic ISCON)
Number of participants with anastomotic leakage after operation 2 (esophagectomy) [ Time Frame: Within 30 days after operation 2 ]
Anastomotic leakage after operation 2 (esophagectomy)
Number of participants with grade 3b or higher complications after operation 2 (esophagectomy) [ Time Frame: Within 30 days after operation 2 ]
Grade 3b (Clavien-Dindo classification) or higher complications after operation 2 (esophagectomy)
Number of participants with 30 day mortality after operation 2 (esophagectomy) [ Time Frame: Within 30 days after operation 2 ]
30 day mortality after operation 2 (esophagectomy)
Induction of angiogenesis in tissue [ Time Frame: Biopsies are taken at the start, or within 24 hours of operation 1 and operation 2. In addition, the anastomoc donut or tip of gastric tube is collected during operation 2 (esophagectomy) after formation of the anastomosis. ]
Paraffin embedded sections (10µm) will be stained by immunohistochemistry against CD31 (vessel density) or smooth-muscle-actin positive pericytes to characterize vascularity
Induction of angiogenesis by biomarkers of microcirculation [ Time Frame: Peripheral blood is taken at the start, or within 24 hours of operation 1 ]
A cytokine profile will be measured in the peripheral blood, consisting of VEGF, IL-8, IL-6, TNF-alpha and Ang-2
Redistribution of blood flow by measurement of indocyanine green (ICG) fluorescence angiography [ Time Frame: During operation 1 and during operation 2 (esophagectomy) ]
Redistribution of blood flow by measurement of indocyanine green (ICG)

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion criteria:

Histologically proven adenocarcinoma (AC) or squamous cell carcinoma (SCC) of the esophagus or gastroesophageal junction (GEJ)
Planned to undergo transthoracic esophagectomy or transhiatal esophagectomy
Preoperative computed tomography (CT)
Vascular arterial changes: "major calcifications" of the thoracic aorta according to the "Uniform calcification score" (UCS) and or a stenosis of the celiac axis according to the "modified NASCET score". (Appendix 1 and 2) (7,17)
ASA I-III
European Clinical Oncology Group (ECOG) performance status of 0,1 or 2
Age > 17
Written informed consent

Exclusion criteria:

Not able to undergo study treatment.
Metastatic disease (M1)

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03896399

Contacts

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Contact: Eline De Groot, MD	+316 49391569	e.m.degroot-26@umcutrecht.nl
Contact: Isabel Bartella, MD, PhD	+492214784803	isabel.bartella@uk-koeln.de

Locations

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Germany
University Hospital of Cologne	Recruiting
Cologne, North Rhine-Westphalia, Germany, 50937
Contact: Isabel Bartella, MD, PhD +49 (0)221-478 4803 isabel.bartella@uk-koeln.de
Contact: Wolfgang Schröder, MD, PhD +49 (0)221-478 4803 wolfgang.schroeder@uni-koeln.de
Netherlands
University Medical Center Utrecht	Recruiting
Utrecht, Netherlands, 3584 CX
Contact: Arjen van der Veen, MD +31 (0)88-755 8507 a.vanderveen-12@umcutrecht.nl
Contact: Richard van Hillegersberg, MD, PhD +31 (0)88-755 8074 r.vanhillegersberg@umcutrecht.nl
Sub-Investigator: Eline De Groot, MD
Sub-Investigator: Lars Schiffman, MD, PhD

Sponsors and Collaborators

UMC Utrecht

University Hospital of Cologne

Investigators

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Principal Investigator:	Richard van Hillegersberg, MD, PhD	University Medical Center Utrecht, dept. of Surgery
Principal Investigator:	Wolfgang Schröder, MD, PhD	University Hospital of Cologne, department of Surgery

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Veen AV, Schiffmann LM, de Groot EM, Bartella I, de Jong PA, Borggreve AS, Brosens LAA, Santos DPD, Fuchs H, Ruurda JP, Bruns CJ, van Hillegersberg R, Schroder W. The ISCON-trial protocol: laparoscopic ischemic conditioning prior to esophagectomy in patients with esophageal cancer and arterial calcifications. BMC Cancer. 2022 Feb 5;22(1):144. doi: 10.1186/s12885-022-09231-x.

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Responsible Party:	Richard van Hillegersberg, Professor, surgeon, UMC Utrecht
ClinicalTrials.gov Identifier:	NCT03896399
Other Study ID Numbers:	NL67819.041.18
First Posted:	April 1, 2019 Key Record Dates
Last Update Posted:	January 12, 2022
Last Verified:	January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
Plan Description:	This will be published
Supporting Materials:	Study Protocol Statistical Analysis Plan (SAP)
Time Frame:	The protocol will be published in an international journal after the start of the study
Access Criteria:	The protocol will be accessibel from the journal in which it will be published

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

Keywords provided by Richard van Hillegersberg, UMC Utrecht:


Esophageal Cancer Esophagectomy Ischemic conditioning

Additional relevant MeSH terms:

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Esophageal Neoplasms Gastrointestinal Neoplasms Digestive System Neoplasms Neoplasms by Site Neoplasms	Head and Neck Neoplasms Digestive System Diseases Esophageal Diseases Gastrointestinal Diseases

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