Promising Novel Technique for Tumor Localization in Laparoscopic Colorectal Surgery Using Indocyanine Green-Coated Endoscopic Clips

BACKGROUND Minimally invasive surgery has become the standard for management of colorectal cancer. The accurate localization of a tumor before surgery is important, especially in the early stages of cancer, to clarify the extent of surgical resection.(1,2) Several methods are currently being proposed and used to identify the location of tumors. These include preoperative endoscopic tattooing using India ink, indocyanine green (ICG), or autologous blood, preoperative endoscopic clipping with detection using an x-ray or palpation during surgery, double-contrast barium enema, CT colonography, and intraoperative colonoscopy.(3-9) Recently, lesion site labeling using near-infrared fluorescent materials that penetrate the colonic wall has been proposed to overcome the shortcomings of the methods listed above.(10,11) This method involves placing endoscopic clips coated or mounted with near-infrared fluorescent material, such as ICG, at the lesion site and determining the location of the tumor by detecting the fluorescent signal through the intestinal wall by using a near-infrared laparoscope.(11) The purpose of this study is to assess the feasibility and efficacy of the ICG-coated endoscopic clips for tumor localization in laparoscopic colorectal surgery. IMPACT OF INNOVATION In this study, we propose the ICG-coated endoscopic clipping method as a safe and feasible technique for tumor localization in laparoscopic colorectal surgery. The accurate localization of colorectal lesions ensures adequate margins for resection and prevents resection of healthy segments of the colon. Furthermore, it can reduce the duration of surgery and prevent unnecessary colon traction and tumor handling, which could result in dissemination of tumor cells.(8,9) Recently, the injection of a dye into the colonic wall has been used increasingly for preoperative marking of colorectal lesions. Among the various dyes, India ink tattoos that are properly placed on the colon wall have been reported to be long lasting and permanent. However, India ink, commonly used in the United States, has not been approved by the Ministry of Food and Drug Safety in Korea and some European countries because of safety concerns. Indocyanine green is considered as a safe and useful alternative marking agent without adverse histological reactions, despite an approximately 2% to 3% risk of spreading into the peritoneal space.(12,13) Moreover, previous studies indicate that when tattoos using ICG are placed more than 2 days before surgery, the tattoo site is identified in only 40% of cases.(13) Furthermore, the identification rate of the tattoo site differs significantly between colon sites. As the tattooed solution spreads, the precise location is often difficult to identify, especially in rectal lesions. Preoperative endoscopic clipping is not widely used in minimally invasive colorectal surgery, because it requires confirmation by intraoperative x-ray or palpation. In laparoscopic surgery, it is difficult to identify the clip by palpation because of the risk that the clip will detach or be dropped while palpating the bowel. The various localization methods are compared in Table 1. The fluorescent clipping method proposed in this study is an innovative technique that can overcome the disadvantages of current tumor localization methods. Indocyanine green is the most widely used fluorophore in many medical procedures, and fluorescence imaging with ICG is a novel enhancement to techniques used for identifying the surgical anatomy or vascular perfusion.(14) In colorectal surgery, ICG fluorescence is used to assess anastomotic perfusion and to identify lymph nodes.(14) TECHNOLOGY MATERIALS AND METHODS Study Population We designed a prospective single-center clinical study and enrolled 30 consecutive patients who met the inclusion criteria at our hospital between July and October 2019 (Fig. 1). Written informed consent was obtained from all participants. The institutional review board of the National Cancer Center and the Ministry of Food and Drug Safety in Korea approved the study (approval number: NCC2019-0046), and the study was registered with ClinicalTrials.gov (NCT03924349). Patients between 20 and 80 years of age and in whom preoperative localization of the colonic lesion was deemed necessary were included. Patients with incomplete preoperative colonoscopy due to intestinal obstruction and rectal lesions palpable by digital rectal examination were excluded. Materials Indocyanine green-coated endoscopic clips, manufactured by KOSCO Medical (Siheung, Gyeonggi) in Korea, were provided by KOSCO Medical for this clinical trial. The Ministry of Food and Drug Safety in Korea approved the clinical hemostatic use of endoscopic clips for tumor localization in this early-phase clinical trial. Laparoscopic systems (1588 AIM camera system by Striker) for identification of ICG fluorescence were provided by SurgiTech Korea (Seongnam, Gyeonggi). Procedures A schematic diagram with instructions on how to attach an endoscopic fluorescent clip in the colon and confirm its presence during laparoscopic surgery is shown in Figure 2. The endoscopic ICG-coated clips were placed 2 days before surgery to prevent bowel distension due to intraluminal air insufflation, and patients underwent bowel preparation according to our standard protocol before colorectal surgery, including mechanical bowel preparation and oral antibiotics. During endoscopic procedures, we placed the ICG-coated clips just distal to the primary lesion at 3 different points located at 120 degrees to each other (Fig. 3). All procedures were performed by expert endoscopists with more than 5 years of experience. We recorded the tumor location, procedure time, number of clips used, procedure-related complications, and endoscopic images showing the attached clips. After clip placement, patients were only allowed to consume a liquid diet including protein supplements according to our modified enhanced recovery program protocol. During minimally invasive colorectal procedures, the colon and rectum were first visualized using white light. Next, the fluorescence of ICG was observed using a laparoscopic imaging instrument. If we were able to observe the ICG-coated clip well by using fluorescence imaging, we considered tumor localization successful (Fig. 3). A laparoscopic clip was then attached to the serosal side of the bowel at the location where fluorescence of the clip was identified. If we were unable to observe the ICG-coated clips, we performed intraoperative colonoscopy to localize the lesions. with thick fat tissues or adhesions, enhancing detection rates should be considered. Finally, to achieve improved visibility of fluorescent clips, the appropriate adjustment of a laparoscopic imaging instrument used for fluorescence detection will be necessary. Our study had several limitations. First, it was a single-center early-phase study with a small study population. Second, laparoscopic or robotic systems that can identify ICG fluorescence are commercially available, but their use is not widespread yet. The experimental results in this study were obtained using limited equipment, and the results should be validated using other laparoscopic equipment. Third, the method proposed has not yet been approved by the US Food and Drug Administration because of insufficient evidence of its feasibility and efficacy. Finally, the duration of visibility of the ICG-coated fluorescence clip has not been clinically verified, even though laboratory studies have suggested that the fluorescence persists for more than 6 months. In the future, efforts should be made to demonstrate the effectiveness of ICG-coated fluorescence clip through comparative studies with more participants. In conclusion, ICG-coated clips were safe and feasible in this study. Thus, this technique is a promising method for tumor localization in laparoscopic colorectal surgery.

Automated summary

ICG-coated endoscopic clipping method is proposed as a safe and feasible technique for tumor localization in laparoscopic colorectal surgery. It ensures adequate margins for resection, reduces surgery duration, and prevents unnecessary colon traction and tumor handling, thus minimizing dissemination of tumor cells. Additionally, the method overcomes the limitations of current tumor localization methods.