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Assessment of Graft Perfusion and Oxygenation for Improved Outcome in Esophageal Cancer Surgery (EDOBS)

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ClinicalTrials.gov Identifier: NCT03587532
Recruitment Status : Recruiting
First Posted : July 16, 2018
Last Update Posted : December 28, 2023
Sponsor:
Collaborator:
Kom Op Tegen Kanker
Information provided by (Responsible Party):
University Hospital, Ghent

Tracking Information
First Submitted Date  ICMJE June 14, 2018
First Posted Date  ICMJE July 16, 2018
Last Update Posted Date December 28, 2023
Actual Study Start Date  ICMJE December 13, 2021
Estimated Primary Completion Date December 31, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 13, 2018)		 An ICGA based cutoff point to predict anastomotic leakage and graft necrosis after esophageal reconstructive surgery. [ Time Frame: within 3 months after intervention ]
quantitative analysis of the ICGA images. T inflow will be calculated based on time fluorescence curves, and correlated with anastomotic leakage and graft necrosis. This cutoff value will be an ICGA fluorescent intensity time measurement expressed in seconds.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 13, 2018)
  • The evaluation of ICGA as a quantitative perfusion imaging modality during gastric tube reconstruction. [ Time Frame: within 3 months after intervention ]
    First, intensity over time curves will be analysed in the regions of interest to generate quantitative values for maximal fluorescence intensity (I max), inflow time (T inflow), and outflow time (T outflow). For every patient a time intensity curve will be created and From that curve 3 quantitaive time measures will be extracted: for maximal fluorescence intensity (I max), inflow time (T inflow), and outflow time (T outflow). These 3 times will be expressed in seconds
  • Systemic lactate as a Biological Markers of hypoxia and ischemia [ Time Frame: within 24 hours after intervention ]
    Peroperative blood samples will be collected and analyzed
  • Capillary lactate as a Biological Markers of hypoxia and ischemia [ Time Frame: within 24 hours after intervention ]
    Peroperative blood samples will be collected and analyzed
  • Basal oxygen consumption (V0) as a Biological Markers of hypoxia and ischemia [ Time Frame: within 24 hours after intervention ]
    Peroperative biopsies will be collected and analyzed
  • Max respiratory oxygen consumption (Vmax) as a Biological Markers of hypoxia and ischemia [ Time Frame: within 24 hours after intervention ]
    Peroperative biopsies will be collected and analyzed
  • Severity of inflammation score as a pathological Markers of hypoxia and ischemia [ Time Frame: within 10 days after intervention ]
    Peroperative biopsies will be collected and analyzed. Four sections of the embedded material are examined using a Haematoxylin-eosin staining. A semiquantitive scoring based on presence of fibroblasts, polynuclear neutrophils, lymphocytes and macrophages will be used to evaluate the severity of the inflammation. Scoring system. Score 0 = normal mucosa Score 1: partial epithelial edema and necrosis Score 2: diffuse swelling and necrosis of the epithelium Score 3: necrosis with submucosal neutrophil infiltration Score 4: widespread necrosis and massive neutrophil infiltration and bleeding
  • HIF 1 alpha as a pathological Markers of hypoxia and ischemia [ Time Frame: within 10 days after intervention ]
    Peroperative biopsies will be collected and analyzed
  • Minor and major adverse events up to 30 days postoperative associated with esophagectomy [ Time Frame: within 1 year after intervention ]
    All adverse events will be classified by the Clavien Dindo score and based on the ECCG international consensus for complications associated with esophagectomy guidelines.The list is a predefined by the ECCG and can be found in reference 32.
  • Product related adverse endpoints [ Time Frame: within 24 hours after intervention ]
    • Anaphylactic adverse events (AE): discomfort, flushing, tachycardia, hypotension, dyspnoea, bronchial spasm, blushing, cardiac arrest, laryngeal spasm, and facial oedema.
    • Urticarial AE: pruritus, urticaria
    • Nausea.
    • hypereosinophilia
  • Intensive Care Unit (ICU) stay [ Time Frame: within 1 year after intervention ]
    duration of intensive care stay expressed in days
  • in hospital stay [ Time Frame: within 1 year after intervention ]
    duration of the in hospital stay expressed in days
  • cardiac output [ Time Frame: within 24 hours after the intervention ]
    Advanced continuous hemodynamic monitoring during surgery will be performed using a PiCCO® (Pulse index Continuous Cardiac Output, Pulsion Medical Systems, Germany). This will provide specific perfusion measurements as cardiac output expressed in liters per minute from the Pulse contour analysis and Thermo dilution analysis.
  • Stroke Volume [ Time Frame: within 24 hours after the intervention ]
    Advanced continuous hemodynamic monitoring during surgery will be performed using a PiCCO® (Pulse index Continuous Cardiac Output, Pulsion Medical Systems, Germany). This will provide specific perfusion measurements as Stroke Volume (SV) expressed in milliliter and stroke volume variation (SVV) to predict Volume responsivity by Pulse contour analysis and Thermo dilution analysis.
  • pulse pressure [ Time Frame: within 24 hours after the intervention ]
    Advanced continuous hemodynamic monitoring during surgery will be performed using a PiCCO® (Pulse index Continuous Cardiac Output, Pulsion Medical Systems, Germany). This will provide specific perfusion measurements as pulse pressure (PP) expressed in millimeters of mercury (mmHg) and pulse pressure variation (PPV) to predict volume responsivity by Pulse contour analysis.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Assessment of Graft Perfusion and Oxygenation for Improved Outcome in Esophageal Cancer Surgery
Official Title  ICMJE Assessment of Graft Perfusion and Oxygenation for Improved Outcome in Esophageal Cancer Surgery
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
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Condition  ICMJE
  • Anastomotic Leak
  • Esophageal Cancer
Intervention  ICMJE
  • Diagnostic Test: Indocyanine green angiography
    ICGA will be performed twice during standard esophagectomy: 30 minutes after the stomach graft creation and immediately before the esophagogastric anastomosis. stock dose of 25 mg ICG (Pulsion Medical Systems, Germany) will be diluted to 5 mg/mL with sterile water. An IV bolus of 0.5 mg/kg of ICG will be injected via a central venous catheter. Video data will be obtained with a charge-coupled device (CCD) camera fitted with a light-emitting diode emitting at a wavelength of 760mm (Visera® elite II, Olympus medical system corp, Tokyo, Japan). Images will be recorded starting immediately prior to injection until 3 minutes afterwards.
    Other Name: near infrared fluorescent imaging
  • Diagnostic Test: Hemodynamic evaluation
    Advanced continuous hemodynamic monitoring during surgery will be performed using a PiCCO® (Pulse index Continuous Cardiac Output, Pulsion Medical Systems, Germany) catheter.
  • Diagnostic Test: Biological and pathological markers of ischemia
    • Systemic and local capillary lactate on blood samples
    • Mitochondrial Respiratory activity analyses on biopsies at 3 region of interest (ROI)
    • Pathological analyses of the biopsies at 3 ROI
Study Arms  ICMJE Experimental: Indocyanine Green Angiography
ICG based angiography 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.
Interventions:
  • Diagnostic Test: Indocyanine green angiography
  • Diagnostic Test: Hemodynamic evaluation
  • Diagnostic Test: Biological and pathological markers of ischemia
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 13, 2018)		 70
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2024
Estimated Primary Completion Date December 31, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Elke Van Daele, MD +323320829 elke.vandaele@uzgent.be
Contact: Yves Van Nieuwenhove, MD, PhD +3293324893 Yves.Vannieuwenhove@uzgent.be
Listed Location Countries  ICMJE Belgium
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03587532
Other Study ID Numbers  ICMJE EC/2018/0671
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
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party University Hospital, Ghent
Original Responsible Party Same as current
Current Study Sponsor  ICMJE University Hospital, Ghent
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Kom Op Tegen Kanker
Investigators  ICMJE
Study Director: Yves Yves.Vannieuwenhove@uzgent.be, MD, PhD University Hospital, Ghent
PRS Account University Hospital, Ghent
Verification Date December 2023

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP