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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 : Not yet recruiting
First Posted : July 16, 2018
Last Update Posted : March 25, 2019
Sponsor:
Collaborator:
Kom Op Tegen Kanker
Information provided by (Responsible Party):
University Hospital, Ghent

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.

Condition or disease Intervention/treatment Phase
Anastomotic Leak Esophageal Cancer Diagnostic Test: Indocyanine green angiography Diagnostic Test: Hemodynamic evaluation Diagnostic Test: Biological and pathological markers of ischemia Not Applicable

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Assessment of Graft Perfusion and Oxygenation for Improved Outcome in Esophageal Cancer Surgery
Estimated Study Start Date : June 2019
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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


  7. 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

  8. 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.

  9. 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

  10. Intensive Care Unit (ICU) stay [ Time Frame: within 1 year after intervention ]
    duration of intensive care stay expressed in days

  11. in hospital stay [ Time Frame: within 1 year after intervention ]
    duration of the in hospital stay expressed in days

  12. 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.

  13. 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.

  14. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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): NCT03587532


Contacts
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Contact: Elke Van Daele, MD +323320829 elke.vandaele@uzgent.be
Contact: Yves Van Nieuwenhove, MD, PhD +3293324893 Yves.Vannieuwenhove@uzgent.be

Sponsors and Collaborators
University Hospital, Ghent
Kom Op Tegen Kanker
Investigators
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Study Director: Yves Yves.Vannieuwenhove@uzgent.be, MD, PhD University Hospital, Ghent
Additional Information:
Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University Hospital, Ghent
ClinicalTrials.gov Identifier: NCT03587532    
Other Study ID Numbers: EC/2018/0671
First Posted: July 16, 2018    Key Record Dates
Last Update Posted: March 25, 2019
Last Verified: March 2019

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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
Keywords provided by University Hospital, Ghent:
esophagectomy
indocyanine green
near infrared fluorescence
Additional relevant MeSH terms:
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Esophageal Neoplasms
Anastomotic Leak
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Postoperative Complications
Pathologic Processes