The Effect of Chemoradiotherapy on Gastric Perfusion in Patients With Gastric Cancer.

Study Overview
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Brief Summary
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A study from our group (Osterkamp et al. in preparation) used ICG to evaluate intraoperative changes in gastric perfusion when reducing the circulating blood volume by blood withdrawal in pigs. We saw a significant reduction in gastric perfusion with decreased blood volume, and this reduction of gastric perfusion was detectable with ICG. As data from a previous trial (PRESET phase 2 Protocol nr: H-15014904) has shown that chemotherapy decreases the circulating red blood cell volume in patients with gastroesophageal cancer, we wish to evaluate if standard care neoadjuvant chemotherapy also influences gastric perfusion. Gastric perfusion will be assessed during a screening laparoscopy (before chemotherapy) and then compared with a second assessment during gastric resection (after chemotherapy). The gastric perfusion will be measured using fluorescence-guided surgery with Indocyanine Green. Participants will be offered the opportunity to have their blood volume measured during the trial. This is not required in order to take part in the fluorescence angiography part of the study.

Detailed Description
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Screening Laparoscopy: As part of the standard care for gastric cancer, all patients undergo a screening laparoscopy before entering neoadjuvant chemotherapy. The procedure is performed to detect overt metastases not detected on the CT/PET-CT scans. First, the patient is placed under a standardized general anesthesia, and the laparoscopic set-up is completed. After anesthesia a peripheral arterial catheter will be placed in order acquire reading of cardia output and stroke volume. The patient will then be fluid optimized using a standardized stroke volume (SV) optimization algorithm. The abdomen is inspected visually for signs of metastatic disease. The small bowel is then manipulated, allowing for visualization of the stomach. A bolus of ICG (0.2 mg/kg body weight) will be injected intravenously and flushed with 5 mL of saline. Gastric perfusion will subsequently be assessed along specific regions of interest (ROI) with q-ICG to obtain baseline perfusion values. As a substudy, 10 patients will have two measurements with ICG during the screening laparoscopy, one befor eand one after fluid optimization. These patients will receive an ICG dose of 0.1 mg/kg body weight per measurement, totalling 0.2 mg/kg after the two measurements. Resection of gastric cancer: The patient is placed under general anesthesia and after the stomach is visualized through surgical incision, a bolus of ICG (0.2 mg/kg body weight) will be injected intravenously and flushed with 5 mL of saline. The ROIs (the same ROIs as described in 3.7.1) will then be assessed with q-ICG. The anesthetic protocol will up to this point match that of the setting during the screening laparoscopy. Fluorescence angiography: During the screening laparoscopy, a laparoscope (telescope 30°, 5 mm, Arthrex Danmark A/S) will be connected to a camera system (Synergy, Arthrex Danmark A/S) and a light-source (Synergy Laser Light Source, Arthrex Danmark A/S) will supply the excitatory light and record the ICG angiography. The laparoscope will be fixed in a mechanical holding arm 10 cm from the tissue of interest, ensuring a stable position throughout the experiment. Measuring of blood volume: Hemoglobin mass (Hbmass) will be determined using a carbon monoxide (CO) rebreathing technique with a typical error of 1.0 %, as previously described (25). In brief, all individuals will rest for 20 min in the supine position before each measurement. During this time, a catheter will be inserted in an antecubital vein. Thereafter, 2 ml of blood will be sampled and analyzed immediately in triplicates for percentage carboxyhaemoglobin (% HbCO) and [Hb] (ABL800, Radiometer, Denmark). Subsequently, individuals will breathe 100 % O2 for 4 min to flush nitrogen from the airways. Then, a bolus of 1.5 ml kg-1 of 99.997 % chemically pure CO (CO N47, Air Liquide, France) will be administrated into the breathing circuit. Individuals will re-breath this gas mixture for 10 min. An additional 2 ml blood sample will be obtained and analyzed in triplicates. The change in % HbCO will be used to calculate Hbmass. Total RBCV, PV and BV will be derived from measures of Hbmass and hematocrit29. The collected blood samples will not be stored after the measurement. Statistics: A comparison of the gastric perfusion before and after chemotherapy will be performed using Friedman's test or a repeated measures ANOVA / linear mixed-effects depending on a non- or parametric nature of the data. A P-value < 0.05 will be considered significant. Statistic evaluation will be performed using IBM SPSS Statistics © (v 22.0 SPSS Inc. Chicago, IL, USA).

Official Title
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The Effect of Chemoradiotherapy on Gastric Perfusion in Patients With Gastric Cancer.

Conditions
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Gastric Cancer

Intervention / Treatment
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* Drug: Indocyanine green


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients (above 18 years) scheduled for planned open or robot-assisted resection of gastric cancer. Exclusion Criteria: Allergy towards; iodine, indocyanine green or shellfish Severe liver insufficiency Thyrotoxicosis Nephropathy requiring dialysis Pregnancy or lactation Legally incompetent for any reason Withdrawal of inclusion consent Disseminated disease or other that contraindicates curative surgery

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Interventional Model Description: Only patients with resectable gastric cancer are included in the study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ICG patient<br>All patients included in the study will be injected with ICG (0.2 mg/kg bodyweight) to assess gastric perfusion. | Drug: Indocyanine green<br>* A bolus of ICG (0.2 mg/kg body weight) will be injected intravenously and flushed with 5 mL of saline. Gastric perfusion will subsequently be assessed along specific regions of interest (ROI) with q-ICG (quantitative perfusion assessments with ICG) to obtain baseline perfusion values.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in gastric perfusion | The primary endpoint is the difference in gastric perfusion (obtained with q-ICG, using the slope of the fluorescence curve (as described by Nerup et al)) before and after neoadjuvant chemotherapy. A comparison of the gastric perfusion before and after chemotherapy will be performed using Friedman's test or a repeated measures ANOVA / linear mixed-effects depending on a non- or parametric nature of the data. A P-value < 0.05 will be considered significant. Statistic evaluation will be performed using IBM SPSS Statistics © (v 22.0 SPSS Inc. Chicago, IL, USA). | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Short term outcome | postoperative events and complications as graded by the Dindo-Clavien classification | 30 days after surgery | 
| Short term outcome | Postoperative events as graded by the Comprehensive Complication Index | 30 days after surgery | 
| Short term outcome | Length of hospital stay | 30 days after surgery |