Advances in surgical techniques for gastric cancer: Indocyanine green and near-infrared fluorescence imaging.Is it ready for prime time?

Erica Sakamoto,Adriana Vaz Safatle-Ribeiro,Ulysses Ribeiro Jr

Department of Gastroenterology,Instituto do Cancer do Estado de S?o Paulo,Hospital das Clinicas,Faculdade de Medicina,Universidade de S?o Paulo,(ICESP-HCFMUSP) S?o Paulo,SP 01246-000,Brazil

Abstract Surgery is still the primary curative treatment for gastric cancer,which includes resection of the tumor with adequate margins and extended lymphadenectomy.In order to improve the operative results and the quality of life of patients,several endeavors have been made toward precision medicine through image-guided surgery,allowing access to real-time intraoperative anatomy and accurate tumor staging.The goal of the surgeon is to achieve a more precise,individualized,and less invasive surgery without compromising oncological efficiency and safety.In this perspective,we have demonstrated the role of indocyanine green (ICG) and near-infrared (NIR) fluorescence imaging method in gastric cancer surgery.This technique may be used to improve localization of the tumor,detection of sentinel lymph nodes (SLN),real-time lymphatic mapping,and blood flow assessment (anastomosis perfusion).

Keywords: Indocyanine green;near-infrared fluorescence imaging;gastric cancer;lymphatic mapping

Introduction

Despite all advances and new technologies in medical oncology and endoscopic therapy,surgery is still the main curative treatment for gastric cancer (GC),which includes resection of the tumor with adequate margins and lymphadenectomy (1).

Nevertheless,several challenges are still present and influence the performance and feasibility of oncologically adequate surgeries.The intraoperative analysis of tumor location,disease extent,and patient anatomy still depends on the visual and tactile analysis,which may underperform in more challenging cases or less experienced surgeons.

Furthermore,lymph node (LN) metastasis and adequate lymphadenectomy is a main prognostic factor and can significantly improve long-term survival (2).However,due to the complex vascular anatomy,the learning curve for an adequate lymphadenectomy is difficult and especially demanding in countries where obesity is becoming more frequent.On the other hand,since lymphadenectomy increases the morbidity of surgical treatment (3,4),it might be limited in cases with a low risk of LN metastasis (e.g.early tumors) (5).

Therefore,efforts have been made toward precision medicine through image-guided surgery,allowing access to real-time intraoperative anatomy and accurate tumor staging.The ultimate goal is to achieve a more precise,individualized,and less invasive surgery without compromising oncological efficiency and safety.

In the last years,a novel approach using indocyanine green (ICG) and near-infrared (NIR) fluorescence imaging has been studied in gastric cancer surgery as a promising method to improve localization of the tumor,detection of sentinel lymph nodes (SLN) and real-time lymphatic mapping.

Infrared light has a wavelength of 700-900 nm that can penetrate millimeters to centimeters through tissues.Its low absorption,low dispersion and low autofluorescence characteristics allow greater contrast between tissues,which can be maximized using fluorescent contrast agents (6,7)with easy visualization of specific structures such as lymphatic vessels,LN,and blood vessels.

To date,NIR fluorescent contrast agents specific to many different targets have been developed.ICG is a United States Federal Drugs Administration-approved,sterile and water-soluble compound that binds to plasma proteins (8) and emits maximum fluorescence at a wavelength of approximately ≥820 nm upon stimulation by infrared light (9).The emitted ICG fluorescence is detected using specific scopes and a filter is used to switch to fluorescence mode,excluding lights below 820 nm,allowing the tracer in the tissue to be visualized (10).

The advantages of ICG in comparison to other tracers are its longer deposition in the lymphatic vessels and lymph nodes (around 3 d),which allows evaluation both intraoperatively and preoperatively,the absence of ionizing radiation,low reports of allergic reactions,and the fact that the infrared light is invisible to the human eye,thus not altering the surgical field visualized without a filter(6,7,10,11).

The ICG NIR fluorescence imaging can be used in GC surgery: 1) detection of SLN (12,13);2) determination of the lymphadenectomy range (14,15);3) tumor location and determination of resection margins (9);4) blood flow assessment (anastomosis perfusion) (16,17).

Surgical technique

ICG solution is prepared by diluting 25 mg of ICG in 10 mL of distilled water,to a final concentration of 2.5 mg/mL.After inspection of the abdominal cavity and confirmation of the absence of metastasis or unresectability criteria,the ICG administration is performed.

For the detection of SLN,an intraoperative endoscopic injection of the ICG solution is infused into the submucosal layer at four points around the neoplastic lesion (0.8-1.0 mL).After this procedure,the tumor location and margins can be clearly visualized.Then,the fluorescein diffusion is observed in the imaging system for five minutes.Once the SLN is identified,it is removed with the corresponding LN basin and sent for analysis separately.

For the determination of the lymphadenectomy extent,the ICG solution can be injected on the day before the surgery.The lymphadenectomy is performed in the usual way (D1 or D2,according to the indication) and the fluorescence system is activated simultaneously or at the end of the procedure for lymphatic drainage route assessment and/or identification of residual lymph nodes in the dissected area.

Finally,for the assessment of the anastomosis perfusion,a dose of 3.75-7.50 mg bolus is injected intravenously and an area that reveals good perfusion in the stomach is chosen to be sectioned.

Main applications of ICG NIR in GC surgery and previous research — SLN biopsy

SLN is defined as the first LN that receives drainage from a primary tumor and its concept is based on the fact that the SL status could reflect the LN status in patients with early-stage cancer.

The incidence of LN metastasis reported in patients with GC restricted to the mucosa (T1a) and submucosa (T1b)was only 2% and 18%-20%,respectively.Therefore,a high number of unnecessary lymphadenectomy may be performed.However,the application of SLN mapping for early-stage GC has been controversial for years,mainly due to the possibility of skip metastasis (18).

Over the last decades,different types of tracers have been proposed for SLN biopsy,and SLN biopsy with ICG was first described by Hiratsukaet al.in 2001 (12).

In 2018,Skublenyet al.published a systematic review and meta-analysis evaluating the use of the ICG NIR for SLN biopsy in GC.They included ten prospective studies,with 643 patients and a predominance of T1 tumors(79.8%).The researchers observed 100% specificity and 98% accuracy with the ICG NIR method.Sensitivity was sub-optimal (87%),but later studies (published after 2010)had increased sensitivity (93%),suggesting technical improvement with experience and technology development (19).

More recently,a meta-analysis including 54 studies,favored the use of ICG and dual tracer method (a combination of radio colloid with blue dye or ICG) for the identification of the SLN.But,considering the high costs and potential side effects of radioactive substances,the ICG alone may be the best option (20).

At last,the SENORITA trial was a multicenter,phase III,clinical trial conducted in South Korea to evaluate postoperative complications,long-term survival,and quality of life after laparoscopic sentinel node navigation surgery (LSNNS)vs.laparoscopic standard gastrectomy(LSG),using a dual tracer method (ICG and Technetium-99m human serum).In relation to 3-year disease-free survival,LSNNS did not show non-inferiority compared to LSG,but presented better long-term quality of life and nutrition (21).

Lymphadenectomy guidance

In Brazil and many developing countries,patients with advanced GC represent the majority of cases (22).In this scenario,the use of ICG NIR may be more helpful for LN mapping than for SLN biopsy (23).

The ICG NIR has been extensively studied to achieve a more precise lymphadenectomy.Because of the high protein content in the lymph,the bound ICG accumulates in the lymphatic system and highlights node stations prior to being metabolized by the liver (10).

Many studies have shown a higher number of LN retrieved with ICG (10,14,24-30).A Chinese prospective randomized controlled trial published in 2020 studied the safety and efficacy of ICG NIR tracer-guided imaging during laparoscopic D2 lymphadenectomy for GC.A total of 133 patients underwent ICG NIR tracer-guided laparoscopic gastrectomy and 133 underwent conventional laparoscopic gastrectomy.ICG NIR improved the number of LN dissections and mitigated the number of LN noncompliance-ICG NIR (31.8%)vs.non-ICG NIR group (57.4%),without increasing complications (14).

A recent systematic review and meta-analysis included 12 studies with a total of 1,365 GC patients for evaluation of ICG NIR fluorescent imaging-guided LN dissection during radical gastrectomy.The study corroborated the benefit of ICG NIR with a significantly greater number of retrieved LNs in the ICG group,which was also associated with reduced intraoperative blood loss.Operative time and postoperative complications were comparable between the groups (30).

Conclusions

ICG is a promising tool in GC surgery.Optimal outcomes hinge on appropriate patient selection,especially in SL biopsy,operative technique,learning curve,and pathologic analysis.There are still some limitations including the lack of standardization of the procedure for routine practice and concerns about safety with restricted lymphadenectomy in early GC cases (due to the risk of false negatives and skip metastasis).A more precise technique for intraoperative pathological examinations is still needed.Furthermore,ICG is not a cancer-specific tracer;therefore,its use is limited in identifying metastatic LN (31). Future perspectives include the use of tracers with high affinity for cancer cells,increasing the specificity for LN metastasis identification.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.