Clinical trial NCT03587532: Assessment of Graft Perfusion and Oxygenation for Improved Outcome in Esophageal Cancer Surgery
Official title: Assessment of Graft Perfusion and Oxygenation for Improved Outcome in Esophageal Cancer Surgery
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Anastomotic Leak
Esophageal Cancer
Keywords: esophagectomy
indocyanine green
near infrared fluorescence
Lead sponsor: University Hospital, Ghent
Sponsor class: OTHER
Collaborators: name: Kom Op Tegen Kanker
First posted: 2018-07-16
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

Brief summary: After the esophagectomy, the stomach is most commonly used to restore continuity of the upper gastro-intestinal tract. The esophagogastric anastomosis is prone to serious complications such as anastomotic leakage (AL) The reported incidence of AL after esophagectomy ranges from 5%-20%. The AL associated mortality ranges from 18-40% compared with an overall in-hospital mortality of 4-6%. The main cause of AL is tissue hypoxia, which results from impaired perfusion of the pedicle stomach graft. Clinical judgment is unreliable in determining anastomotic perfusion. Therefore, an objective, validated, and reproducible method to evaluate tissue perfusion at the anastomotic site is urgently needed. Indocyanine green angiography (ICGA) is a near infrared fluorescent (NIRF) perfusion imaging using indocyanine green (ICG). ICGA is a safe, easy and reproducible method for graft perfusion analysis, but it is not yet calibrated. The purpose of this study is to evaluate the feasibility of quantification of ICGA to assess graft perfusion and its influence on AL in patients after minimally invasive Ivor Lewis esophagectomy (MIE) for cancer.

Detailed description: Background: The incidence of adenocarcinoma of the esophagus is rapidly increasing, resulting in 480 000 newly diagnosed patients annually in the world1. Surgery remains the cornerstone of therapy for curable esophageal cancer (EC) patients. After the esophagectomy, the stomach is most commonly used to restore continuity of the upper gastro-intestinal tract. The esophagogastric anastomosis is prone to serious complications such as anastomotic leakage (AL), fistula, bleeding, and stricture. The reported incidence of AL after esophagectomy ranges from 5%-20% 2-6. The AL associated mortality ranges from 18-40% compared with an overall in-hospital mortality of 4-6% 2, 7, 8. The main cause of AL is tissue hypoxia, which results from impaired perfusion of the pedicle stomach graft. Clinical judgment is unreliable in determining anastomotic perfusion. Therefore, an objective, validated, and reproducible method to evaluate tissue perfusion at the anastomotic site is urgently needed. Near infrared fluorescent (NIRF) perfusion imaging using indocyanine green (ICG) is an emerging modality based on excitation and resulting fluorescence in the near-infrared range (λ = 700-900 nm).

Aims:

* To perform intraoperative ICG based NIRF angiography of the stomach graft during minimally invasive esophagectomy in EC patients, and to calculate tissue blood flow and volume using curve analysis and advanced compartmental modeling;
* To validate imaging based perfusion parameters by comparison with hemodynamic parameters, blood and tissue expression of hypoxia induced markers, and tissue mitochondrial respiration rate
* To evaluate the ability of NIRF based perfusion measurement to predict anastomotic leakage.

Methods: Patients (N=70) with resectable EC will be recruited to undergo minimally invasive Ivor Lewis esophagectomy according to the current standard of care. ICG based angiography will be performed after creation of the stomach graft and after thoracic pull-up of the graft. Dynamic digital images will be obtained starting immediately after intravenous bolus administration of 0.5 mg/kg of ICG. The resulting images will be subjected to curve analysis (time to peak, washout time) and to compartmental analysis based on the AATH kinetic model (adiabatic approximation to tissue homogeneity, which allows to calculate blood flow, blood volume, vascular heterogeneity, and vascular leakage). The calculated perfusion parameters will be compared to intraoperative hemodynamic data (PiCCO catheter) to evaluate how patient hemodynamics affect graft perfusion. To verify whether graft perfusion truly represents tissue oxygenation, perfusion parameters will be compared with systemic lactate as well as serosal lactate from the stomach graft. In addition, perfusion parameters will be compared to tissue expression of hypoxia related markers and mitochondrial chain respiratory rate as measured in tissue samples from the stomach graft.

Finally, the ability of functional, histological, and cellular perfusion and oxygenation parameters to predict anastomotic leakage and postoperative morbidity in general will be evaluated using the appropriate univariate and multivariate statistical analyses.

Relevance: The results of this project may lead to a novel, reproducible, and minimally invasive method to objectively assess perioperative anastomotic perfusion during EC surgery. Such a tool may help to reduce the incidence of AL and its associated severe morbidity and mortality

Eligibility criteria: Inclusion Criteria:

Pre- and intraoperatively

* Subjects ≥ 18 years and ≤ 75 years who are willing to participate and provide written informed consent prior to any study-related procedures.
* Subjects scheduled for elective minimally invasive Ivor Lewis esophagectomy
* Intrathoracic circular stapled esophago-gastric anastomosis

Exclusion Criteria:

Preoperatively

* Known hypersensitivity to ICG
* Female patients who are pregnant or nursing
* Participation in other studies involving investigational drugs or devices.
* Use of Avastin™ (bevacizumab) or other anti vascular endothelial growth factor (VEGF) agents within 30 days prior to surgery

Intra-operatively

* Intra-operative findings that may preclude conduct of the study procedures
* Anastomosis performed differently than the standard of care
* Excessive bleeding (\>500 ml) prior to anastomosis

Primary outcomes:
measure: An ICGA based cutoff point to predict anastomotic leakage and graft necrosis after esophageal reconstructive surgery.
timeFrame: within 3 months after intervention
Secondary outcomes:
measure: The evaluation of ICGA as a quantitative perfusion imaging modality during gastric tube reconstruction.
timeFrame: within 3 months after intervention
measure: Systemic lactate as a Biological Markers of hypoxia and ischemia
timeFrame: within 24 hours after intervention
measure: Capillary lactate as a Biological Markers of hypoxia and ischemia
timeFrame: within 24 hours after intervention
measure: Basal oxygen consumption (V0) as a Biological Markers of hypoxia and ischemia
timeFrame: within 24 hours after intervention
measure: Max respiratory oxygen consumption (Vmax) as a Biological Markers of hypoxia and ischemia
timeFrame: within 24 hours after intervention
measure: Severity of inflammation score as a pathological Markers of hypoxia and ischemia
timeFrame: within 10 days after intervention
measure: HIF 1 alpha as a pathological Markers of hypoxia and ischemia
timeFrame: within 10 days after intervention
measure: Minor and major adverse events up to 30 days postoperative associated with esophagectomy
timeFrame: within 1 year after intervention
measure: Product related adverse endpoints
timeFrame: within 24 hours after intervention
measure: Intensive Care Unit (ICU) stay
timeFrame: within 1 year after intervention
measure: in hospital stay
timeFrame: within 1 year after intervention
measure: cardiac output
timeFrame: within 24 hours after the intervention
measure: Stroke Volume
timeFrame: within 24 hours after the intervention
measure: pulse pressure
timeFrame: within 24 hours after the intervention
Other outcomes:
Locations:
city: Ghent
country: Belgium
facility: University Hospital
Study officials:
affiliation: University Hospital, Ghent
name: Yves Yves.Vannieuwenhove@uzgent.be, MD, PhD
role: STUDY_DIRECTOR
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