Randomized Controlled Trial on Effect of Lymph Node Mapping by Indocyanine Green Via Submucosal or Subserosal Injection

Study Overview
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Brief Summary
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The purpose of this study was to evaluate whether submucosal or subserous injection of indocyanine green during laparoscopic lymphadenectomy for patients with gastric cancer was different. The patients with gastric adenocarcinoma (cT1-4a, N0/+, M0) were studied.

Detailed Description
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In recent years, with the successful application of ICG (indocyanine green) fluorescence imaging technology in laparoscopic equipment, scholars have found that ICG near-infrared imaging has better tissue penetration and can better identify lymph nodes in hypertrophic adipose tissue than other dyes under visible light, which makes ICG fluorescence imaging guide laparoscopic radical resection of gastric cancer lymph node dissection has become a new exploration direction. ICG near-infrared imaging technology has important research value, good application prospects, and broad development space in laparoscopic radical resection of gastric cancer. However, at present, the application of ICG near-infrared imaging technology in laparoscopic radical resection of gastric cancer is still in the exploratory stage, and there is no unified standard. Therefore, in the world, there is still a lack of high-level evidence-based evidence of large-sample prospective randomized controlled trials to evaluate the effectiveness, safety, and feasibility of submucosal or subserous injection of ICG in guiding laparoscopic D2 resection of gastric cancer. The investigator first carried out this study in the world to evaluate the lymph node dissection and perioperative safety of gastric cancer patients who received a submucosal injection of ICG and subserous injection of ICG during laparoscopic radical gastrectomy in the same period, to promote the standardized development of ICG near-infrared imaging in laparoscopic radical gastrectomy.

Official Title
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Comparison of Submucosal and Subserosal Approaches Toward Optimized Indocyanine Green Tracer-Guided Laparoscopic Lymphadenectomy for Patients With Gastric Cancer: The FUGES-019 Randomized Clinical Trial

Conditions
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Indocyanine Green, Gastric Cancer, Injection Site

Intervention / Treatment
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* Drug: Subserosa injection of indocyanine green
* Drug: submucosal injection of indocyanine green


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Age from 18 to 75 years Primary gastric adenocarcinoma (papillary, tubular, mucinous, signet ring cell, or poorly differentiated) confirmed pathologically by endoscopic biopsy Clinical stage tumor T1-4a (cT1-4a), N0/+, M0 at preoperative evaluation according to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual Eighth Edition. Preoperative staging was made by conducting mandatory computed tomography (CT) scans and an optional endoscopic ultrasound No distant metastasis, no direct invasion of pancreas, spleen or other organs nearby in the preoperative examinations Performance status of 0 or 1 on Eastern Cooperative Oncology Group scale (ECOG) American Society of Anesthesiology score (ASA) class I, II, or III Written informed consent Exclusion criteria: Women during pregnancy or breast-feeding Severe mental disorder History of previous upper abdominal surgery (except laparoscopic cholecystectomy) History of previous gastrectomy, endoscopic mucosal resection or endoscopic submucosal dissection Rejection of laparoscopic resection History of allergy to iodine agents Enlarged or bulky regional lymph node diameter over 3cm by preoperative imaging History of other malignant disease within past five years History of previous neoadjuvant chemotherapy or radiotherapy History of unstable angina or myocardial infarction within past six months History of cerebrovascular accident within past six months History of continuous systematic administration of corticosteroids within one month Requirement of simultaneous surgery for other disease Emergency surgery due to complication (bleeding, obstruction or perforation) caused by gastric cancer Forced expiratory volume in 1 second (FEV1)<50% of predicted values Linitis plastica, Widespread

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Subserosal injection of indocyanine green tracer group<br>Subserosal injection of indocyanine green, with a concentration of 0.5 mg /ml, 6 points along the lesser and greater curvature of the stomach, 1.5 ml for each point. | Drug: Subserosa injection of indocyanine green<br>* After preoperative exploration, the indocyanine green powder (Dandong Yichuang Pharmaceutical Co) is dissolved in 0.5 mg/ml of sterile water and the prepared solution (1.5 ml for each point) is injected along the subserosal of the stomach at 6 specific points along the lesser and greater curvature of the stomach.<br>* Other names: No other intervention;|
| Active Comparator: Submucosal injection of indocyanine green tracer group<br>Submucosal injection of indocyanine green, with a concentration of 1.25mg /ml, four points around the primary tumor, each point 0.5 ml. | Drug: submucosal injection of indocyanine green<br>* One day before surgery, 1.25 mg/ml indocyanine green (Dandong Yichuang Pharmaceutical Co) was prepared in sterile water and 0.5 ml of the solution was injected into the submucosal layer at 4 quadrants around the primary tumor, amounting to 2.5 mg of indocyanine green.<br>* Other names: No other intervention;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Number of Retrieved Lymph Nodes | Total Number of Retrieved Lymph Nodes | One month after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total number of fluorescent lymph nodes in groups A and B | Total number of fluorescent lymph nodes in groups A and B | One month after surgery | 
| Relationship between fluorescent lymph nodes and positive lymph nodes in groups A and B (true positive rate) | Relationship between fluorescent lymph nodes and positive lymph nodes in groups A and B (true positive rate) | One month after surgery | 
| Relationship between fluorescent lymph nodes and negative lymph nodes in groups A and B (false positive rate) | Relationship between fluorescent lymph nodes and negative lymph nodes in groups A and B (false positive rate) | One month after surgery | 
| Relationship between non-fluorescent and negative lymph nodes in groups A and B (true negative rate) | Relationship between non-fluorescent and negative lymph nodes in groups A and B (true negative rate) | One month after surgery | 
| Relationship between non-fluorescent lymph nodes and positive lymph nodes in groups A and B (false negative rate) | Relationship between non-fluorescent lymph nodes and positive lymph nodes in groups A and B (false negative rate) | One month after surgery | 
| Number of Metastasis Lymph Nodes | Number of Metastasis Lymph Nodes | One month after surgery | 
| Metastasis rate of lymph node | Metastasis rate of lymph node | One month after surgery | 
| Mortality rates | This is for the early mortality, which defined as the event observed within 30 days after surgery. | 30 days | 
| Morbidity rates | This is for the incidence of early postoperative complications, which defined as the event observed within 30 days after surgery. | 30 days | 
| 3-year disease free survival rate | Disease-free survival is calculated from the day of surgery to the day of recurrence or death (When the specific date of recurrence of the tumor is unknown, the endpoint is the date of death due to tumor causes). If neither death nor recurrence of the tumor is observed, the endpoint is the final date that a patient is confirmed as relapse-free. (The final date of DFS: The last date of the outpatient visit day or the date of acceptance of the examination). | 36 months | 
| 3-year recurrence pattern | Recurrence patterns are classified into five categories at the time of first diagnosis: locoregional, hematogenous, peritoneal, distant lymph node, and mixed type. | 36 months | 
| Time to first ambulation | Time to first ambulation in hours is used to assess the postoperative recovery course. | 30 days | 
| Time to first flatus | Time to first flatus in days is used to assess the postoperative recovery course. | 30 days | 
| Time to first liquid diet | Time to first liquid diet in days is used to assess the postoperative recovery course. | 30 days | 
| Time to first soft diet | Time to first soft diet in days is used to assess the postoperative recovery course. | 30 days | 
| Duration of postoperative hospital stay | Duration of postoperative hospital stay in days is used to assess the postoperative recovery course. | 30 days | 
| The variation of weight | The variation of weight on postoperative 3, 6, 9 and 12 months are used to access the postoperative nutritional status and quality of life. | 3, 6, 9 and 12 months | 
| The variation of BMI in kg/m^2 | The variation of BMI in kg/m^2 on postoperative 3, 6, 9 and 12 months are used to access the postoperative nutritional status and quality of life. | 3, 6, 9 and 12 months | 
| Intraoperative morbidity rates | The intraoperative postoperative morbidity rates are defined as the rates of event observed within operation. | 1 day | 
| The variation of white blood cell count | The values of white blood cell count from peripheral blood before operation and on postoperative day 1, 3, 5 are recorded to access the inflammatory and immune response. | Preoperative 3 days and postoperative 1, 3, and 5 days | 
| The variation of hemoglobin | The values of hemoglobin in gram/liter from peripheral blood before operation and on postoperative day 1, 3, 5 are recorded to access the inflammatory and immune response. | Preoperative 3 days and postoperative 1, 3, and 5 days | 
| The variation of C-reactive protein | The values of C-reactive protein IN milligram/liter from peripheral blood before operation and on postoperative day 1, 3, 5 are recorded to access the inflammatory and immune response. | Preoperative 3 days and postoperative 1, 3, and 5 days | 
| Lymph node noncompliance rate | Lymph node noncompliance was defined as the absence of lymph nodes that should have been excised from more than 1 lymph node station. Major lymph node noncompliance was defined as more than 2 intended lymph node stations that were not removed. | 1 day | 
| Modified EORTC cancer in-patient satisfaction with care measure (EORTC IN-PATSAT14) | Participants were asked to complete one modified European Organisation for Research and Treatment of Cancer (EORTC) IN-PATSAT14 questionnaire before their discharge from hospital. | 30 days | 
| The Surgery Task Load Index (SURG-TLX) | Surgeons were required to complete one modified SURG-TLX questionnaire for each procedure. | 1 day | 
| 3-year overall survival rate | The overall survival is calculated from the day of surgery until death or until the final follow-up date, whichever occurs first. For survival cases, the endpoint is the last date that survival was confirmed. If the loss to follow-up occurred, the endpoint is the final date that survival could be confirmed. | 36 months |