The evolving role of indocyanine green fluorescence in the treatment of low rectal cancer

Introduction

Indocyanine green fluorescense (ICG) has gained popularity in recent years in colorectal surgery in general with a special emphasis on low rectal resections. Moreover, in addition to perfusion assessment, other potential applications have been proposed.

The ICG compound was approved by the U.S Food and Drug Administration already in 1959 and has since that time has been used in various fields of surgery such as foregut and hepatobiliary. Its short half-life of less than 3 minutes and lack of hepatic metabolism has focused the interest of colorectal surgeons on its use in the assessment of bowel perfusion (1,2). The relevance of its application in modern colorectal surgery became pertinent after industry developed tools for the minimally invasive settings.

For decades, surgeons have acknowledged the paramount importance of adequate perfusion to the bowel as one of the basic surgical principles for a construction of healthy anastomosis.

The fear of the anastomotic leak (AL) is heightened in low rectal resections as reported leak rates are consistently above 10% (3,4). Thus, it is apparent that a method with a potential to discern acceptable perfusion, would carry a great promise to decrease the leak rate and improve outcomes.

Herein, we describe the technique of the ICG administration, the current available data on the potential benefits of ICG with regard to decreasing ALs. In addition, we also review other potential merits in Low rectal cancer surgery such as lymphatic mapping, peritoneal implants detection and avoiding ureteral injuries.

Avoiding anastomotic leakage

The much-dreaded complication of AL has a high prevalence in rectal resections, especially following low anterior resections (LAR) (4,5).

Several identified risk factors, such as the height of the anastomosis (<10 cm) and prior neoadjuvant radiation therapy enhance the patients’ susceptibility to AL (6,7).

The ensuing morbidity, mortality and economic burden (8) have led to a continuing quest to try and improve anastomotic healing. Maintaining sufficient blood supply to the newly created anastomosis has been recognized as a crucial factor (9,10). Various methods have been implemented with variable success rates. The most common of which is the subjective evaluation performed by the surgeon during operation. The experienced surgeon looks at bowel color, palpates for pulse within supplying mesentery, and looks for bleeding in the transected edges. However, studies have shown that this evaluation is not very accurate at predicting AL (11). Several, more objective modalities have been proposed, including: spectroscopy, Doppler flowmetry, pH measuring and even on-table angiography (12-14).

They are all limited for different reasons: difficulty to use in the operating room, time consuming or costly. The standardization and reproducibility of these various technologies is yet another obstacle

Fluorescence angiography (FA) utilizing ICG allows for real-time intraoperative evaluation of bowel perfusion (15). The method of its application is appealing due to its ease of repetition, short time of implementation, and excellent visualization.

Technique

The anesthesiologist administers a bolus of 3.5 mL of ICG intravenously followed by a 10-mL flush of sterile normal saline (NS). Colonic perfusion is visualized and assessed via fluoroscopic angiography (FA) with a laparoscopic system. The line of demarcation between perfused and non-perfused tissue is noted and the colon is then divided within an area of well-perfused tissue.

After completion of the anastomosis, the anastomosis is assessed with FA. A second bolus of 3.5 mL of ICG is injected and followed by a 10-mL flush of sterile NS. In the first step the FA is performed via laparoscopy to assess the serosal aspects of both ends of the anastomosis. Afterwards, the endoscope is inserted into a custom designed rigid proctoscope, advanced towards the anastomosis with injection of a third bolus of 3.5 mL of ICG, followed by a 10-mL flush of NS. Then, the perfusion of both proximal and distal anastomotic mucosal surface is appreciated.

Several studies have been published which demonstrate the lower leak rates with ICG.

In the PILLAR II trial (16) it was found that in the high-risk group (<10 cm anastomosis and/or irradiated pelvis) the use of FA caused a revision of anastomosis in 1.8% and changed the planned resection margin during surgery in 7.5%. Both the radiologic and clinical AL rate in this high-risk group was as low as 1.9%. Kim et al. (17) has published a large series of patients who underwent robotic assisted rectal resection with AL of 0.8% in the study group, compared to 5.4% in the control group.

Ris et al. (18) published a large series with implementing FA in 504 patients, 90 of whom underwent LAR. The leak rate was 3.3% vs. 10.7% in the control group with only 4 minutes added time to surgery. In our recent study (19), the surgical plan was changed in 13.3% with no AL in the ICG group, whereas the leak rate in the control group was 6.7%. Implementing the FA for our TaTME group of patients we found AL in 2 patients, 4.5% with a change of surgical resection margins in about 22% (20).

The consensus conference of experts, held in UK concluded that fluorescence imaging is the most promising technology to try to reduce the burden of ALs (21).

Ris and his colleagues (18) reported that in 5 patients a planned stoma was omitted formation due to the FA findings.

Lymphatic mapping and peritoneal implants

The property of the ICG uptake in the lymphatic system has appealed surgeons to improve surgical decision making and oncological outcomes. Cahill et al. (22) found that 4 out of 18 patients had involved lymph nodes outside the planned resection margins, in the pelvic side walls or periaortic region.

A recent study by Chand and his colleagues from London demonstrated the feasibility of fluorescence for lymphatic mapping with 2 out of 10 patients having involved lymph nodes outside the planned resection margins, also confirmed in final pathology (23).

In a meta-analysis which included twelve studies looking at the detection of metastatic lymph nodes in colorectal cancer (24), the median sensitivity was found to be 73.7% and the specificity was as high as 100%.

The higher uptake of the ICG by colorectal peritoneal metastases was recently studied with an attempt to detect additional metastases during surgery that were otherwise overlooked. In cytoreductive surgery for peritoneal carcinomatosis from colorectal cancer with the use of ICG, 29% additional metastases were found (25). In their review, Liberale et al. found that though the data is scarce, the use of ICG might help in the detection of small hepatic, lymph nodes, and peritoneal metastatic deposits (26).

Ureter identification

Ureter identification is an integral part of any rectal resection surgery. The placement of ureteral stents to assist in the identification process during surgery is quite common, especially in pelvic reoperative surgery. However, the placement of stents is not without complications (27,28).

Thus, a non-invasive intra-operative method to recognize ureters during surgery is sought after. The novel technique to identify the ureters using FA was described in a rat model with sodium fluorescein (29) and then, in a latter study (30) with identification of ureters in 4 out of 11 patients, not otherwise identified. It was further described in a Yorkshire pig model with obtaining ureter visualization with near—infrared fluorescence, for over 2 hours in all of the pigs (31). This technique was also successfully utilized by gynecologic surgeons with an excellent safety profile, albeit in a small number of patients (32).

Conclusions

The use of ICG FA in the treatment of low rectal cancer is safe, cost-effective and carries a promise in reducing both intraoperative and post-operative complications. While there is already a pool of recent data for its role in lowering AL rates, studies are ongoing to establish its role as a cornerstone of modern colorectal surgery. The method’s additional potential added value in identifying circulating tumor cell and metastases, such as in lymphatic mapping and also for clarification of anatomic structures such as the ureters is still evolving with further research required for its better implementation in the future.

Acknowledgments

Funding: None.

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/ales.2018.10.05). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Mizrahi I, Wexner SD. Clinical role of fluorescence imaging in colorectal surgery—a review. Expert Rev Med Devices 2017;14:75-82. [Crossref] [PubMed]
2. Kubota K, Kita J, Shimoda M, et al. Intraoperative assessment of reconstructed vessels in living-donor liver transplantation, using a novel fluorescence imaging technique. J Hepatobiliary Pancreat Surg 2006;13:100-4. [Crossref] [PubMed]
3. Alberts JC, Parvaiz A, Moran BJ. Predicting risk and diminishing the consequences of anastomotic dehiscence following rectal resection. Colorectal Dis 2003;5:478-82. [Crossref] [PubMed]
4. Caulfield H, Hyman NH. Anastomotic leak after low anterior resection: a spectrum of clinical entities. JAMA Surg 2013;148:177-82. [Crossref] [PubMed]
5. Kagawa H, Kinugasa Y, Shiomi A, et al. Effects of a diverting stoma on symptomatic anastomotic leakage after low anterior resection for rectal cancer: a propensity score matching analysis of 1,014 consecutive patients. Surg Endosc 2015;29:995-1000. [Crossref] [PubMed]
6. Rullier E, Laurent C, Garrelon JL, et al. Risk factors for anastomotic leakage after resection of rectal cancer. Br J Surg 1998;85:355-8. [Crossref] [PubMed]
7. Kawada K, Hasegawa S, Hida K, et al. Risk factors for anastomotic leakage after laparoscopic low anterior resection with DST anastomosis. Surg Endosc 2014;28:2988-95. [Crossref] [PubMed]
8. Hammond J, Lim S, Wan Y, Gao X, Patkar A. The burden of gastrointestinal anastomotic leaks: an evaluation of clinical and economic outcomes. J Gastrointest Surg 2014;18:1176-85. [Crossref] [PubMed]
9. Karanjia ND, Corder AP, Bearn P, Heald RJ. Leakage from stapled low anastomosis after total mesorectal excision for carcinoma of the rectum. Br J Surg 1994;81:1224-6. [Crossref] [PubMed]
10. Shogan BD, Carlisle EM, Alverdy JC, Umanskiy K. Do we really know why colorectal anastomoses leak? J Gastrointest Surg 2013;17:1698-707. [Crossref] [PubMed]
11. Karliczek A, Harlaar NJ, Zeebregts CJ, et al. Surgeons lack predictive accuracy for anastomotic leakage in gastrointestinal surgery. Int J Colorectal Dis 2009;24:569-76. [Crossref] [PubMed]
12. Boyle NH, Manifold D, Jordan MH, Mason RC. Intraoperative assessment of colonic perfusion using scanning laser Doppler flowmetry during colonic resection. J Am Coll Surg 2000;191:504-10. [Crossref] [PubMed]
13. Karliczek A, Benaron DA, Baas PC, et al. Intraoperative assessment of microperfusion with visible light spectroscopy in esophageal and colorectal anastomoses. Eur Surg Res 2008;41:303-11. [Crossref] [PubMed]
14. Swift AJ, Parker P, Chiu K, et al. Intraoperative contrast-enhanced sonography of bowel blood flow: preliminary experience. J Ultrasound Med 2012;31:1-5. [Crossref] [PubMed]
15. Foppa C, Denoya PI, Tarta C, et al. Indocyanine green fluorescent dye during bowel surgery: are the blood supply “guessing days” over? Tech Coloproctol 2014;18:753-8. [Crossref] [PubMed]
16. Jafari MD, Wexner SD, Martz JE, et al. Perfusion assessment in laparoscopic left-sided/anterior resection (PILLAR II): a multi-institutional study. J Am Coll Surg 2015;220:82-92.e1. [Crossref] [PubMed]
17. Kim JC, Lee JL, Yoon YS, et al. Utility of indocyanine-green fluorescent imaging during robot-assisted sphincter-saving surgery on rectal cancer patients. Int J Med Robot 2016;12:710-7. [Crossref] [PubMed]
18. Ris F, Liot E, Buchs NC, et al. Multicentre phase II trial of near-infrared imaging in elective colorectal surgery. Br J Surg 2018;105:1359-67. [Crossref] [PubMed]
19. Mizrahi I, Abu-Gazala M, Rickles AS, et al. Indocyanine green fluorescence angiography during low anterior resection for low rectal cancer: results of a comparative cohort study. Tech Coloproctol 2018;22:535-40. [Crossref] [PubMed]
20. Mizrahi I. Transanal Total Mesorectal Excision (TaTME) for rectal cancer: High rates of change is surgical margins using Indocyanine green fluorescence angiography. Tech Coloproctol 2018; [Epub ahead of print].
21. Vallance A, Wexner S, Berho M, et al. A collaborative review of the current concepts and challenges of anastomotic leaks in colorectal surgery. Colorectal Dis 2017;19:O1-O12. [Crossref] [PubMed]
22. Cahill RA, Anderson M, Wang LM, et al. Near-infrared (NIR) laparoscopy for intraoperative lymphatic road-mapping and sentinel node identification during definitive surgical resection of early-stage colorectal neoplasia. Surg Endosc 2012;26:197-204. [Crossref] [PubMed]
23. Chand M, Keller DS, Joshi HM, et al. Feasibility of fluorescence lymph node imaging in colon cancer: FLICC. Tech Coloproctol 2018;22:271-7. [Crossref] [PubMed]
24. Emile SH, Elfeki H, Shalaby M, et al. Sensitivity and specificity of indocyanine green near-infrared fluorescence imaging in detection of metastatic lymph nodes in colorectal cancer: Systematic review and meta-analysis. J Surg Oncol 2017;116:730-40. [Crossref] [PubMed]
25. Liberale G, Vankerckhove S, Caldon MG, et al. Fluorescence Imaging After Indocyanine Green Injection for Detection of Peritoneal Metastases in Patients Undergoing Cytoreductive Surgery for Peritoneal Carcinomatosis From Colorectal Cancer: A Pilot Study. Ann Surg 2016;264:1110-5. [Crossref] [PubMed]
26. Liberale G, Bourgeois P, Larsimont D, et al. Indocyanine green fluorescence-guided surgery after IV injection in metastatic colorectal cancer: A systematic review. Eur J Surg Oncol 2017;43:1656-67. [Crossref] [PubMed]
27. Pathak RA, Taylor AS, Alford S, et al. Urologic-Induced Complications of Prophylactic Ureteral Localization Stent Placement for Colorectal Surgery Cases. J Laparoendosc Adv Surg Tech A 2015;25:966-70. [Crossref] [PubMed]
28. Hassinger TE, Mehaffey JH, Mullen MG, et al. Ureteral stents increase risk of postoperative acute kidney injury following colorectal surgery. Surg Endosc 2018;32:3342-8. [Crossref] [PubMed]
29. Dip FD, Nahmod M, Anzorena FS, et al. Novel technique for identification of ureters using sodium fluorescein. Surg Endosc 2014;28:2730-3. [Crossref] [PubMed]
30. Yeung TM, Volpi D, Tullis ID, et al. Identifying Ureters In Situ Under Fluorescence During Laparoscopic and Open Colorectal Surgery. Ann Surg 2016;263:e1-2. [Crossref] [PubMed]
31. Mahalingam SM, Dip F, Castillo M, et al. Intraoperative Ureter Visualization Using a Novel Near-Infrared Fluorescent Dye. Mol Pharm 2018;15:3442-7. [Crossref] [PubMed]
32. Siddighi S, Yune JJ, Hardesty J. Indocyanine green for intraoperative localization of ureter. Am J Obstet Gynecol 2014;211:436.e1-2. [Crossref] [PubMed]