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

Overview

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.

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: November 27, 2020

Detailed Description

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.

Interventions

  • Drug: Subserosa injection of indocyanine green
    • 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.
  • Drug: submucosal injection of indocyanine green
    • 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.

Arms, Groups and Cohorts

  • Experimental: Subserosal injection of indocyanine green tracer group
    • 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.
  • Active Comparator: Submucosal injection of indocyanine green tracer group
    • Submucosal injection of indocyanine green, with a concentration of 1.25mg /ml, four points around the primary tumor, each point 0.5 ml.

Clinical Trial Outcome Measures

Primary Measures

  • Total Number of Retrieved Lymph Nodes
    • Time Frame: One month after surgery
    • Total Number of Retrieved Lymph Nodes

Secondary Measures

  • Total number of fluorescent lymph nodes in groups A and B
    • Time Frame: One month after surgery
    • Total number of fluorescent lymph nodes in groups A and B
  • Relationship between fluorescent lymph nodes and positive lymph nodes in groups A and B (true positive rate)
    • Time Frame: 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 negative lymph nodes in groups A and B (false positive rate)
    • Time Frame: One month after surgery
    • Relationship between fluorescent lymph nodes and negative lymph nodes in groups A and B (false positive rate)
  • Relationship between non-fluorescent and negative lymph nodes in groups A and B (true negative rate)
    • Time Frame: One month after surgery
    • Relationship between non-fluorescent and negative lymph nodes in groups A and B (true negative rate)
  • Relationship between non-fluorescent lymph nodes and positive lymph nodes in groups A and B (false negative rate)
    • Time Frame: One month after surgery
    • Relationship between non-fluorescent lymph nodes and positive lymph nodes in groups A and B (false negative rate)
  • Number of Metastasis Lymph Nodes
    • Time Frame: One month after surgery
    • Number of Metastasis Lymph Nodes
  • Metastasis rate of lymph node
    • Time Frame: One month after surgery
    • Metastasis rate of lymph node
  • Mortality rates
    • Time Frame: 30 days
    • This is for the early mortality, which defined as the event observed within 30 days after surgery.
  • Morbidity rates
    • Time Frame: 30 days
    • This is for the incidence of early postoperative complications, which defined as the event observed within 30 days after surgery.
  • 3-year disease free survival rate
    • Time Frame: 36 months
    • 3-year disease free survival rate
  • 3-year recurrence pattern
    • Time Frame: 36 months
    • Recurrence patterns are classified into five categories at the time of first diagnosis: locoregional, hematogenous, peritoneal, distant lymph node, and mixed type.
  • Time to first ambulation
    • Time Frame: 30 days
    • Time to first ambulation in hours is used to assess the postoperative recovery course.
  • Time to first flatus
    • Time Frame: 30 days
    • Time to first flatus in days is used to assess the postoperative recovery course.
  • Time to first liquid diet
    • Time Frame: 30 days
    • Time to first liquid diet in days is used to assess the postoperative recovery course.
  • Time to first soft diet
    • Time Frame: 30 days
    • Time to first soft diet in days is used to assess the postoperative recovery course.
  • Duration of postoperative hospital stay
    • Time Frame: 30 days
    • Duration of postoperative hospital stay in days is used to assess the postoperative recovery course.
  • The variation of weight
    • Time Frame: 3, 6, 9 and 12 months
    • The variation of weight on postoperative 3, 6, 9 and 12 months are used to access the postoperative nutritional status and quality of life.
  • The variation of BMI in kg/m^2
    • Time Frame: 3, 6, 9 and 12 months
    • 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.
  • Intraoperative morbidity rates
    • Time Frame: 1 day
    • The intraoperative postoperative morbidity rates are defined as the rates of event observed within operation.
  • The variation of white blood cell count
    • Time Frame: Preoperative 3 days and postoperative 1, 3, and 5 days
    • 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.
  • The variation of hemoglobin
    • Time Frame: Preoperative 3 days and postoperative 1, 3, and 5 days
    • 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.
  • The variation of C-reactive protein
    • Time Frame: Preoperative 3 days and postoperative 1, 3, and 5 days
    • 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.
  • Lymph node noncompliance rate
    • Time Frame: 1 day
    • 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.
  • Modified EORTC cancer in-patient satisfaction with care measure (EORTC IN-PATSAT14)
    • Time Frame: 30 days
    • Participants were asked to complete one modified European Organisation for Research and Treatment of Cancer (EORTC) IN-PATSAT14 questionnaire before their discharge from hospital.
  • The Surgery Task Load Index (SURG-TLX)
    • Time Frame: 1 day
    • Surgeons were required to complete one modified SURG-TLX questionnaire for each procedure.

Participating in This Clinical Trial

Inclusion Criteria

1. Age from 18 to 75 years 2. Primary gastric adenocarcinoma (papillary, tubular, mucinous, signet ring cell, or poorly differentiated) confirmed pathologically by endoscopic biopsy 3. 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 4. No distant metastasis, no direct invasion of pancreas, spleen or other organs nearby in the preoperative examinations 5. Performance status of 0 or 1 on Eastern Cooperative Oncology Group scale (ECOG) 6. American Society of Anesthesiology score (ASA) class I, II, or III 7. Written informed consent Exclusion criteria:

1. Women during pregnancy or breast-feeding 2. Severe mental disorder 3. History of previous upper abdominal surgery (except laparoscopic cholecystectomy) 4. History of previous gastrectomy, endoscopic mucosal resection or endoscopic submucosal dissection 5. Rejection of laparoscopic resection 6. History of allergy to iodine agents 7. Enlarged or bulky regional lymph node diameter over 3cm by preoperative imaging 8. History of other malignant disease within past five years 9. History of previous neoadjuvant chemotherapy or radiotherapy 10. History of unstable angina or myocardial infarction within past six months 11. History of cerebrovascular accident within past six months 12. History of continuous systematic administration of corticosteroids within one month 13. Requirement of simultaneous surgery for other disease 14. Emergency surgery due to complication (bleeding, obstruction or perforation) caused by gastric cancer 15. Forced expiratory volume in 1 second (FEV1)<50% of predicted values 16. Linitis plastica, Widespread

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 75 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Fujian Medical University
  • Provider of Information About this Clinical Study
    • Principal Investigator: Chang-Ming Huang, Prof., Director, Head of Department of Gastric Surgery, Principal Investigator, Clinical Professor – Fujian Medical University
  • Overall Official(s)
    • Chang-Ming Huang, MD, Study Chair, Fujian Medical University Union Hospital
  • Overall Contact(s)
    • Chang-Ming Huang, MD, 86 13805069676, hcmlr2002@163.com

References

Lee JH, Ryu KW, Kim CG, Kim SK, Choi IJ, Kim YW, Chang HJ, Bae JM, Hong EK. Comparative study of the subserosal versus submucosal dye injection method for sentinel node biopsy in gastric cancer. Eur J Surg Oncol. 2005 Nov;31(9):965-8.

Kwon IG, Son T, Kim HI, Hyung WJ. Fluorescent Lymphography-Guided Lymphadenectomy During Robotic Radical Gastrectomy for Gastric Cancer. JAMA Surg. 2019 Feb 1;154(2):150-158. doi: 10.1001/jamasurg.2018.4267.

Cianchi F, Indennitate G, Paoli B, Ortolani M, Lami G, Manetti N, Tarantino O, Messeri S, Foppa C, Badii B, Novelli L, Skalamera I, Nelli T, Coratti F, Perigli G, Staderini F. The Clinical Value of Fluorescent Lymphography with Indocyanine Green During Robotic Surgery for Gastric Cancer: a Matched Cohort Study. J Gastrointest Surg. 2020 Oct;24(10):2197-2203. doi: 10.1007/s11605-019-04382-y. Epub 2019 Sep 4.

Herrera-Almario G, Patane M, Sarkaria I, Strong VE. Initial report of near-infrared fluorescence imaging as an intraoperative adjunct for lymph node harvesting during robot-assisted laparoscopic gastrectomy. J Surg Oncol. 2016 Jun;113(7):768-70. doi: 10.1002/jso.24226. Epub 2016 Mar 29.

Chen QY, Zhong Q, Liu ZY, Xie JW, Wang JB, Lin JX, Lu J, Cao LL, Lin M, Tu RH, Huang ZN, Lin JL, Li P, Zheng CH, Huang CM. Does Noncompliance in Lymph Node Dissection Affect Oncological Efficacy in Gastric Cancer Patients Undergoing Radical Gastrectomy? Ann Surg Oncol. 2019 Jun;26(6):1759-1771. doi: 10.1245/s10434-019-07217-x. Epub 2019 Feb 12.

Brédart A, Bottomley A, Blazeby JM, Conroy T, Coens C, D'Haese S, Chie WC, Hammerlid E, Arraras JI, Efficace F, Rodary C, Schraub S, Costantini M, Costantini A, Joly F, Sezer O, Razavi D, Mehlitz M, Bielska-Lasota M, Aaronson NK; European Organisation for Research and Treatment of Cancer Quality of Life Group and Quality of Life Unit. An international prospective study of the EORTC cancer in-patient satisfaction with care measure (EORTC IN-PATSAT32). Eur J Cancer. 2005 Sep;41(14):2120-31.

Wilson MR, Poolton JM, Malhotra N, Ngo K, Bright E, Masters RS. Development and validation of a surgical workload measure: the surgery task load index (SURG-TLX). World J Surg. 2011 Sep;35(9):1961-9. doi: 10.1007/s00268-011-1141-4.

Tajima Y, Yamazaki K, Masuda Y, Kato M, Yasuda D, Aoki T, Kato T, Murakami M, Miwa M, Kusano M. Sentinel node mapping guided by indocyanine green fluorescence imaging in gastric cancer. Ann Surg. 2009 Jan;249(1):58-62. doi: 10.1097/SLA.0b013e3181927267.

Chen QY, Xie JW, Zhong Q, Wang JB, Lin JX, Lu J, Cao LL, Lin M, Tu RH, Huang ZN, Lin JL, Zheng HL, Li P, Zheng CH, Huang CM. Safety and Efficacy of Indocyanine Green Tracer-Guided Lymph Node Dissection During Laparoscopic Radical Gastrectomy in Patients With Gastric Cancer: A Randomized Clinical Trial. JAMA Surg. 2020 Apr 1;155(4):300-311. doi: 10.1001/jamasurg.2019.6033.

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